Medicographia86

Vol 28, No.1, 2006

A journal ofmedical informationand internationalcommunicationfrom Servier

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86I S S U E

ISSN 0243-3397

Medicographia

EDITORIAL

OSTEOPOROSIS: TAKING ACCOUNT OF RISK FACTORS

AND QUALITY OF LIFE

OSTÉOPOROSE : PRISE EN COMPTE DES FACTEURS

DE RISQUE ET DE LA QUALITÉ DE VIE

RISK FACTORS FOR OSTEOPOROSIS: AN EPIDEMIOLOGICAL OVERVIEW

IDENTIFICATION OF PATIENTS IN NEED OF

ANTIOSTEOPOROTIC TREATMENT: WHO TO TREAT TODAY?

WHO WILL MANAGE THE DIAGNOSIS AND

TREATMENT OF OSTEOPOROSIS?

RISK FACTORS FOR OSTEOPOROSIS: USE OF BONE

MINERAL DENSITY IN GUIDING TREATMENT DECISION

HEALTH-RELATED QUALITY OF LIFE

IN OSTEOPOROSIS

RISK FACTORS AND PHARMACOECONOMIC

CONSEQUENCES

J. A. KANIS, UNITED KINGDOM

O. JOHNELL, SWEDEN

C. COOPER, UNITED

KINGDOM, AND

S. GELBACH, USA

S. ADAMI, ITALY

R. G. JOSSE AND

S. A. JAMAL, CANADA

E. MCCLOSKEY, UNITED KINGDOM

B. JÖNSSON, SWEDEN

Emerging Trends in the Diagnosisand Treatment of Osteoporosis

Vol 28, No.1, 2006 Medicographia

86I S S U E

G. JONES, AUSTRALIA / Y. GOKCE-KUTSAL, TUR-KEY / J. F. CHEN, TAIWAN /H. M. ZHU, CHINA / W. PLUSKIEWICZ, POLAND /H. P. DIMAI, AUSTRIA / A. DÍEZ-PEREZ, SPAIN /J. A. MELO-GOMES, PORTUGAL

V. LEBLANC, FRANCE

B. CORTET, FRANCE

S. BOONEN, BELGIUM

G. BOIVIN AND

P. J. MEUNIER, FRANCE

C. RÉGNIER, FRANCE

I. SPAAK, FRANCE

CONTROVERSIAL QUESTION

IS ULTRASOUND A USEFUL METHOD FOR THE

DIAGNOSIS OF OSTEOPOROSIS?

PROTELOS

PROTELOS, THE FIRST DUAL-ACTION BONE AGENT

FOR THE TREATMENT OF POSTMENOPAUSAL

OSTEOPOROSIS

INTERVIEW

DO RISK FACTOR PROFILES FOR OSTEOPOROTIC

FRACTURES DIFFER IN WOMEN AND MEN?

FOCUS

MUSCULOSKELETAL REHABILITATION IN

POSTMENOPAUSAL OSTEOPOROSIS

UPDATE

DETERMINANTS OF BONE QUALITY

A TOUCH OF FRANCE

FRENCH MEDICINE IN RUSSIA. A TALE OF PASSION

A TOUCH OF FRANCE

WHEN RUSSIA SPOKE FRENCH

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Medicographiaa Servier publication

Editor in Chief: Jean-Philippe Seta, MD

Editorial Board: Laurence Alliot, PharmD;Christophe Charpentier, MD; WilliamGaussens, PharmD; Yves Langourieux, PhD; Didier Mochon, PharmD; AntoineMoukheiber, BSc Ph; Pascal Poullalié, MA;Frédéric Sesini, PharmD

Publisher: Laurence Alliot, PharmDProduction Manager: Noelle GuénotMedical Publications Editor:David Mason, MDProduction Editor: Iain Matheson, MB ChB Editorial Assistant: Judit SiklosiDesign & Layout: Myriam Bucquoit andBernard Crespin

Medicographia is published 4 times a yearand circulated throughout the world, inAfrica, the Americas, Asia, Australasia, andEurope, by Les Laboratoires Servier –22, rue Garnier – 92578 Neuilly sur SeineCedex – France, and printed by ImprimerieKapp Lahure Jombart, rue de l’Industrie Z.I.N°1 27025 Evreux Cedex

Printed in FranceDirecteur de la Publication:

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© 2006 by Les Laboratoires Servier

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Emerging Trends in the Diagnosisand Treatment of Osteoporosis

MedicographiaA S e r v i e r p u b l i c a t i o n

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I n t e r n a t i o n a l A d v i s o r y C o m m i t t e e

3Editorial – Kanis MEDICOGRAPHIA, VOL 28, No. 1, 2006

THERE IS NOW AN INCREASING ARRAY OF PHARMACOLOGICALinterventions that have been shown to decrease the risk of fracturesin patients with osteoporosis. These developments, together with theincreasing prevalence and awareness of osteoporosis, pose many chal-

lenges in the management of osteoporosis. Not least is the question of whom to treat. In otherwords, how do we identify patients in whom the risk of fracture is sufficiently high that treatmentis warranted, and conversely, patients in whom treatment is best avoided. These difficult issuesare addressed in this issue of Medicographia.

The clinical significance of osteoporosis resides in the fractures that arise, with their atten-dant morbidity and mortality. The common osteoporotic fractures include those at the spine,forearm, hip, and proximal humerus, and are a major cause of morbidity, particularly in theWestern world. At the age of 50 years, the remaining lifetime risk of an osteoporotic fractureexceeds 50% (see Cooper and Gehlbach; this volume), and fractures particularly at the spine andhip are a very significant cause of morbidity with long-term consequences on quality of life (seeMcCloskey; this volume). Unfortunately, the disorder crosses many disciplines of medicine withthe result that neither the treatment nor prevention of fracture is optimally managed (see Adami;this volume).

From an operational point of view, osteoporosis has been defined in terms of low bone min-eral density (BMD). Attention has focused, therefore, on the estimation of BMD to determine frac-ture risk and to direct interventions on this basis. Many population-based studies indicate thatthe risk of fracture increases by a factor of 1.5 to 3.0 for each standard deviation decrease in BMD(Josse and Jamal; this volume). The ability of BMD to predict fracture is comparable to the useof blood pressure to predict stroke, and significantly better than serum cholesterol to predictmyocardial infarction. The highest gradient of risk is found at the hip to predict hip fracturewhere the gradient of risk is 2.6 (see Josse and Jamal; this volume). Thus, an individual with aT-score of --3 standard deviations (SD) at the hip would have a 2.63 (ie, greater than 15-fold) high-er risk than an individual with a T-score of 0 SD. By contrast, the same T-score at the spine wouldyield a much lower risk estimate—approximately 4-fold increase (1.63). This emphasizes the im-portance of accuracy or gradient of risk in the categorization of fracture risk.

Although bone mass is an important component of the risk of fracture, other abnormalitiesoccur in the skeleton that contribute to fragility. These include the shape of bone, its micro-architecture, the ability to repair microdamage, and the material properties of bone such asthe degree of mineralization (see Boivin and Meunier; this volume). In addition, a variety of non-skeletal factors such as the liability to fall and the force of impact contribute to fracture risk. Itis evident, therefore, that the measurement of BMD is not a perfect strategy for identifying thosewho will fracture, since BMD represents but one component of a multifactorial causation. It isfor this reason that there has been a great deal of interest in the identification of risk factorsfor fracture in addition to that provided by BMD.

E D I T O R I A L

Osteoporosis: taking account of risk factors and quality of life

b y J . A . K a n i s , U n i t e d K i n g d o m

John A. KANIS, MDWHO Collaborating CenterUniversity of SheffieldMedical School, Sheffield UNITED KINGDOM

Address for correspondence:Prof John A. Kanis, MD, WHOCollaborating Center, University of Sheffield Medical School, BeechHill Road, Sheffield S10 2RX, UK(e-mail: [email protected])

Medicographia. 2006;28:3-8.

There are broadly two ways in which the identification of risk factors can be applied to clin-ical management. The first is to identify causally related risk factors that might be modified byintervention (see Boonen; Cooper and Gehlbach; this volume). A good example is the preventionof falls, since the majority of forearm and hip fractures arise from a fall. Although effective fallprevention strategies have been established in the elderly, as noted by Boonen in this volume,studies have so far failed to show an advantage of fall prevention programs for fracture risk. Ef-forts to reduce the impact of falls such as the use of hip protectors have also been met with lim-ited success. Other potential modifiable risk factors include the level of physical activity, atten-tion to nutritional factors, particularly calcium, vitamin D, and protein intake in the elderly, andthe avoidance of tobacco and excess amounts of alcohol. Modification of lifestyle in this way as-sumes that the association between the risk factor and fracture is both causal and reversible bylifestyle advice. Such global policies could have a major impact on the burden of disease, buthave not been formally tested.

A second use of risk factors is in case-finding to identify individuals at particularly high riskfor future fractures (see Johnell; this volume). The risk factors themselves do not necessarily needto be causally related to the fracture nor necessarily reversible, but they should identify a risk thatis amenable to intervention. An example is provided by a history of prior fragility fractures, whichis a strong risk factor for further fractures. Clinical trials have shown that patients recruited onthe basis of a prior vertebral fracture can benefit from a pharmacological intervention.

The risk factors used in case-finding vary according to different practice guidelines, but in-clude a family history of fragility fracture, a previous fragility fracture, low body mass index, andthe long-term use of corticosteroids (Josse and Jamal, this volume). Patients so identified are re-ferred for BMD measurements and intervention offered if BMD falls below a given threshold. Cur-rent guidelines in Europe suggest that intervention should be considered in those individualssubsequently shown to have osteoporosis (ie, a T-score of --2.5 SD or less). In North America, aless stringent threshold (--2.0 SD) is recommended in the absence of significant risk factors and--1.5 SD in the presence of risk factors. Despite these differences, both strategies direct inter-vention on the basis of BMD. A major problem with this approach is that the majority of frac-tures will occur in that segment of the population considered to be at low risk. In other words,the sensitivity or detection rate of the test (BMD) is low, even at relatively high specificities.

Because of the limitations of BMD tests alone there has been a great deal of interest in theidentification of risk factors that might give prognostic information on their own or in conjunc-tion with BMD. Several algorithms have been devised to predict osteoporosis, for example the,osteoporosis self-assessment tool. The algorithm is derived simply from weight and age and canbe used to predict the likelihood of a diagnosis of osteoporosis. This algorithm, and others likeit, have a high sensitivity (detection rate) for the prediction of osteoporosis, but poor specifici-ty (Josse and Jamal; this volume). The high sensitivity provides opportunities for cost savings byexcluding patients who do not need a BMD test. The use of such tests does not, however, help inthe more accurate identification of individuals at high risk, since it ultimately depends on theuse of BMD.

The performance characteristics of assessment algorithms can, however, be improved by theconcurrent consideration of risk factors that operate independently of BMD. Perhaps the bestexample is age. The same T-score with the same technique at any one site has a different signif-icance at different ages. At the threshold for osteoporosis (T-score =--2.5 SD) the probability ofhip fracture varies more than 5-fold between the ages of 50 and 80 years. Thus, the considera-tion of age and BMD together increases the range of risk that can be identified. In addition, thereare a large number of other risk factors that provide information on fracture risk independentlyof both age and BMD. The risk factors that have been best characterized on an international ba-sis include: prior fragility fracture; family history of hip fracture; smoking; chronic use of gluco-corticoids; high intakes of alcohol; and rheumatoid arthritis.

The integration of the information provided by these risk factors improves the performanceof the test. In other words, the gradient of risk is improved, which increases the detection ratewithout trading off specificity. Thus, more individuals above a threshold risk can be identified.

The ability to integrate risk factors with BMD poses some problems in the units of risk to beused. The T-score becomes of little value and, although the use of relative risks is feasible, theycan be misleading for patients and physicians alike. The metric best suited is absolute risk orprobability of fracture (see Cooper and Gehlbach; this volume). The fracture probability dependson age and life expectancy as well as the current relative risk. Estimates of lifetime risk are of val-ue in considering the burden of osteoporosis in the community, but are less relevant for assess-

E D I T O R I A L

4 Editorial – Kanis MEDICOGRAPHIA, VOL 28, No. 1, 2006

ing risk of individuals in whom treatment might be envisaged, so that the International Osteo-porosis Foundation (IOF) and the World Health Organization (WHO) recommend that risk offracture should be expressed as the probability over a 10-year interval. The major advantage ofusing absolute probability is that it standardizes the output from the multiple techniques avail-able for assessing risk.

The more accurate identification of fracture probability demands the question as to when isthe probability unacceptably high so that intervention should be offered. This is a complex ques-tion that depends upon local circumstances including the risk of fracture and death and will-ingness to pay for treatment. In many countries, treatment of osteoporosis has to compete withother health care priorities, which are usually based on health economic arguments, as out-lined by Jönsson, in this volume. Assessments that can be used include the cost per life-yearsaved, the cost per fracture averted, or the cost per quality of life year gained (quality-adjustedlife-year, QALY). The cost per life-year gained is problematic in those disorders that are not fatal,but cause a high degree of morbidity. Assessment of the cost per fracture averted is also prob-lematic because of the multiple outcomes in osteoporosis. Thus, the significance of averting aforearm fracture is quite different from that of preventing a hip fracture. For this reason, thefavored approach has been to integrate life-years lost with quality of life. Quality of life is gradedon the scale of 0 (death) to 1 (perfect health). The strength of this approach is that it allows com-parisons across disease states so that priorities can be made. In the UK, for example, a treatmentthat costs £30 000/QALY is considered to be cost-effective. Using this criterion, a 10-year hipfracture probability of 10% or more provides a cost-effective threshold for women in Sweden.When account is taken of other fractures, the threshold for hip fracture probability at which in-terventions become cost-effective decreases, particularly in younger individuals.

The contributions in this volume highlight the multifactorial nature of osteoporosis, andour inability to perfectly discriminate who will and who will not fracture. There is a growing ap-preciation that risk factors other than BMD can contribute independently to fracture risk andthat their use with BMD can more optimally direct interventions to those most at need and, asimportantly, avoid unnecessary treatment in those at low risk. The formalization of algorithmsto predict osteoporosis poses a challenge for the development of future practice guidelines. ❒

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5Editorial – Kanis MEDICOGRAPHIA, VOL 28, No. 1, 2006

Keywords: osteoporosis; quality of life; risk factor; bone mineral density; treatment; guideline

L ES TRAITEMENTS PHARMACOLOGIQUES CAPABLES DE RÉDUIREle risque fracturaire chez les patientes ostéoporotiques sont main-tenant de plus en plus nombreux. Cette évolution, tout comme laprévalence grandissante de l’ostéoporose et la prise de conscience

accrue de cette maladie, soulèvent de nombreux défis dans la prise en charge de l’ostéoporo-se, dont la question du « qui traiter » n’est pas le moindre. Autrement dit, comment pouvons-nous identifier les patientes pour lesquelles le risque de fracture est suffisamment importantpour justifier le traitement, et inversement, les patientes pour lesquelles il est préférable ne pastraiter. Ces questions difficiles sont abordées dans le numéro présent de Medicographia.

C’est la survenue de fractures et leurs conséquences en termes de morbidité et de mortalitéqui font toute la gravité de l’ostéoporose sur le plan clinique. Les fractures ostéoporotiques com-munes comprennent celles du rachis, de l’avant-bras, de la hanche et de l’humérus proximal etconstituent une des causes principales de morbidité, en particulier dans le monde occidental.À l’âge de 50 ans, le risque de fracture ostéoporotique au cours de la vie restante est supérieurà 50 % (voir l’article de Cooper et Gehlbach) et les fractures, en particulier du rachis et de lahanche, sont une cause très significative de morbidité avec des conséquences à long terme surla qualité de vie (voir l’article de McCloskey). Malheureusement, cette pathologie se situe au car-refour de nombreuses spécialités médicales, avec comme conséquence que ni le traitement nila prévention des fractures ne sont pris en charge de façon optimale (voir l’article d’Adami).

D’un point de vue opérationnel, l’ostéoporose a été définie en termes de densité minéraleosseuse basse (DMO). L’attention s’est donc portée sur l’estimation de la DMO pour déterminerle risque de fracture et prescrire un traitement en fonction des valeurs relevées. De nombreusesétudes de populations montrent que le risque de fracture est multiplié par 1,5 à 3,0 pour chaquediminution d’une déviation standard de la DMO (voir l’article de Josse et Jamal). La fiabilitéde la DMO pour prévoir une fracture est comparable à celle de la pression artérielle pour pré-voir un accident vasculaire cérébral et significativement meilleure que celle de la cholestéro-lémie pour prévoir un infarctus du myocarde. Le gradient de risque le plus élevé pour prévoirune fracture – soit 2,6 – est retrouvé à la hanche (voir l’article de Josse et Jamal). Ainsi, un in-dividu avec un T-score de --3 déviations standard (DS) à la hanche devrait avoir un risque supé-rieur ou égal à 2,6 3 soit 15 fois plus important qu’un individu avec un T-score de 0 DS. À l’op-posé, le même T-score au niveau du rachis devrait donner une estimation du risque beaucoupplus basse – augmentation d’environ 4 fois (1,63). Ceci renforce l’importance de l’exactitude oudu gradient de risque dans la classification du risque de fracture.

Bien que la masse osseuse soit un élément important du risque fracturaire, il existe d’autresanomalies du squelette qui contribuent à sa fragilité. Celles-ci comprennent la forme de l’os, samicroarchitecture, la possibilité de réparer les microlésions et les propriétés matérielles de l’oscomme le degré de minéralisation (voir l’article de Boivin et Meunier). De plus, plusieurs fac-

É D I T O R I A L

6 Éditorial – Kanis MEDICOGRAPHIA, VOL 28, No. 1, 2006

Ostéoporose : prise en compte des facteurs de risque et de la qualité de vie

p a r J . A . K a n i s , R o y a u m e - U n i

É D I T O R I A L

7Éditorial – Kanis MEDICOGRAPHIA, VOL 28, No. 1, 2006

teurs indépendants de ceux du squelette, tels que la prédisposition à la chute et la force du choc,contribuent au risque de fracture. La mesure de la DMO n’est donc pas la stratégie idéale pouridentifier les sujets qui auront une fracture, puisqu’elle ne représente qu’un seul des aspectsd’une causalité multifactorielle. C’est pourquoi l’identification des facteurs de risque de fractureautres que ceux fournis par la DMO a suscité un grand intérêt.

Il y a grossièrement deux façons d’appliquer l’identification des facteurs de risque à la priseen charge clinique. La première est d’identifier les facteurs de risque qui peuvent être modifiéspar un traitement (voir l’article de Boonen et celui de Cooper et Gehlbach). La prévention deschutes en est un bon exemple, puisque la majorité des fractures de l’avant-bras et de la hancheest due à des chutes. Cependant, malgré l’efficacité des techniques de prévention des chutesmises en place chez les personnes âgées, comme l’indique Boonen dans ce numéro, les étudesn’ont jamais réussi à montrer un bénéfice des programmes de prévention de ces chutes dans lerisque de fracture. Les efforts pour réduire l’impact des chutes, tels que l’utilisation de protec-teurs de hanche, ont également rencontré un succès limité. Le niveau d’activité physique, l’at-tention portée aux facteurs nutritionnels, en particulier la prise de calcium, de vitamine D et deprotéines chez les personnes âgées, l’abstention de tabac et d’excès d’alcool sont d’autres facteursde risque potentiellement modifiables. La modification du mode de vie dans ce sens implique quel’association entre un facteur de risque donné et la fracture est à la fois causale et réversiblegrâce aux conseils sur le mode de vie. Une telle politique pourrait avoir un impact majeur sur lefardeau de la maladie, mais n’a pas été testée officiellement.

L’identification des sujets à risque particulièrement élevé de futures fractures est une se-conde façon d’utiliser les facteurs de risque (voir l’article de Johnell). En eux-mêmes, les facteursde risque ne nécessitent pas obligatoirement d’être liés à la fracture ni d’être obligatoirementréversibles, mais ils devraient identifier un risque qui relève d’un traitement. Un antécédent defracture de fragilité constitue un bon exemple de puissant facteur de risque pour des fracturesultérieures. Les études cliniques ont montré que les sujets recrutés sur la base de fractures ver-tébrales antérieures peuvent tirer bénéfice d’un traitement pharmacologique.

Les facteurs de risque utilisés varient selon les différents critères définis, mais en tout étatde cause doivent inclure les antécédents familiaux de fracture de fragilité, les fractures de fra-gilité antérieures, un indice de masse corporelle bas, et une corticothérapie prolongée (voirl’article de Josse et Jamal). Les sujets ainsi identifiés sont alors orientés pour des mesures de DMOet un traitement leur est proposé si la DMO est en dessous d’un certain seuil. Les recomman-dations européennes actuelles suggèrent qu’il faut envisager un traitement chez les personnespour lesquelles une ostéoporose a été retrouvée (p. ex. T-score de --2,5 DS ou moins). En Amé-rique du Nord, les seuils recommandés sont moins sévères, de --2,0 DS en absence de facteursde risque significatifs et de --1,5 DS en présence de facteurs de risque. Malgré ces différences,c’est bien sur la base de la DMO que sont orientées ces deux stratégies de traitement. Le pro-blème majeur de cette approche réside dans le fait que la majorité des fractures survient dansla tranche de la population considérée à faible risque. Autrement dit, la sensibilité ou le tauxde prédiction du risque fracturaire par la DMO est faible, même pour des niveaux de spécificitérelativement élevés.

Étant donné les limites des mesures de la DMO, l’identification des facteurs de risque quipeuvent donner une information pronostique, seule ou en association à la DMO, a suscité unintérêt marqué. Plusieurs algorithmes ont été conçus pour prédire l’ostéoporose, tels le ques-tionnaire d’autoévaluation de l’ostéoporose. L’algorithme est simplement dérivé de la masse cor-porelle et de l’âge et peut être utilisé pour calculer la probabilité d’un diagnostic d’ostéoporose.Cet outil, et d’autres comme lui, ont une haute sensibilité (taux de détection) pour prédire l’os-téoporose, mais une faible spécificité (voir l’article de Josse et Jamal). Cette sensibilité élevéepermet des économies en excluant les sujets qui n’ont pas besoin de mesure de la DMO. Cepen-dant, l’utilisation de tels tests ne permet pas l’identification plus précise des individus à hautrisque, puisque qu’elle dépend en en définitive de l’utilisation de la DMO.

La performance des algorithmes d’évaluation peut cependant être améliorée par la priseen compte simultanée des facteurs de risque indépendants de la DMO. Le meilleur exempleen est peut-être l’âge. Le même T-score mesuré avec le même appareil et quel que soit le site,présente une signification différente selon l’âge. À la valeur seuil pour l’ostéoporose (T-score =--2,5 DS), la probabilité de fracture de hanche est multipliée par 5 entre 50 et 80 ans. La prise encompte simultanée de l’âge et de la DMO accroît l’intervalle de risque qui peut être identifié.De nombreux autres facteurs de risque fournissent également des renseignements sur lesrisques de fracture indépendants de l’âge et de la DMO. Les facteurs de risque les mieux défi-

nis sur des bases internationales sont les suivants : antécédents de fracture de fragilité ; anté-cédents familiaux de fracture de hanche ; tabagisme ; corticothérapie prolongée ; consomma-tion élevée d’alcool ; et polyarthrite rhumatoïde.

L’intégration des données fournies par ces facteurs de risque améliore la performance dutest. Autrement dit, le gradient de risque est amélioré, ce qui augmente le taux de détection sansque cela soit au détriment de la spécificité. Nous pouvons ainsi identifier un plus grand nombrede personnes situées au-delà d’un risque seuil.

L’intégration des facteurs de risque à la DMO pose quelques problèmes en ce qui concerneles unités de risque à utiliser. Le T-score perd alors beaucoup de sa valeur et, bien que l’utilisa-tion du risque relatif soit possible, elle peut prêter à confusion pour les patientes comme pour lesmédecins. Le risque absolu ou la probabilité de fracture (voir article de Cooper et Gehlbach)sont les mesures les mieux adaptées. La probabilité de fracture dépend de l’âge et de l’espérancede vie comme du risque relatif du moment. Les estimations de risque sur la vie entière sont va-lables en ce qui concerne le poids de l’ostéoporose pour la collectivité, mais moins pertinentespour évaluer le risque des individus chez lesquels il faut envisager un traitement. C’est pourquoil’International Osteoporosis Foundation (IOF) et l’Organisation Mondiale de la Santé (OMS)recommandent que le risque de fracture soit exprimé sous forme de probabilité à 10 ans. L’ar-gument majeur pour utiliser une probabilité absolue est qu’elle standardise le données issuesde multiples moyens pour évaluer les risques.

L’identification la plus exacte possible d’une probabilité de fracture amène à se poser laquestion suivante : à partir de quand cette probabilité atteint-elle un seuil à partir duquel ondoit proposer un traitement ? Cette question complexe dépend des circonstances locales commele risque de fracture et de décès et l’acceptation de payer pour un traitement. Dans de nombreuxpays, le traitement de l’ostéoporose entre en compétition avec d’autres priorités de soins, ce quifait généralement intervenir des arguments économiques de santé (cf. l’article de Jönsson). Lescritères d’évaluation qui peuvent être utilisés sont : le coût par année de vie gagnée, le coût parfracture évitée, ou le coût par année de vie ajustée sur la qualité (quality-adjusted life-year, QALY).Le coût par année de vie gagnée est problématique dans les pathologies qui ne sont pas fatalesmais dont le degré de morbidité est élevé. L’évaluation du coût par fracture évitée est égalementproblématique à cause des multiples évolutions de l’ostéoporose. Ainsi, la prévention d’une frac-ture de l’avant-bras n’a pas la même signification que la prévention d’une fracture de hanche.C’est pourquoi on a privilégié l’intégration des années de vie perdues avec la qualité de vie. Laqualité de vie est cotée sur une échelle qui va de 0 (décès) à 1 (santé parfaite). La force de cetteapproche, c’est qu’elle permet des comparaisons entre des états pathologiques, dégageant ainsides priorités. Par exemple, en Angleterre un traitement s’élevant à 30 000 £ par QALY est consi-déré comme rentable. Sur la base de ce critère, le seuil de rentabilité pour les femmes suédoisesse situe à un niveau de probabilité de 10 % ou plus pour une fracture de hanche à 10 ans. Si l’onprend en compte d’autres fractures, le seuil de probabilité de fracture de hanche à partir duquelles traitements deviennent rentables diminue, en particulier chez les sujets plus jeunes.

Les auteurs ayant contribué à ce numéro de Medicographia soulignent la nature multifac-torielle de l’ostéoporose, et notre incapacité à distinguer parfaitement qui fera ou ne fera pas defracture. L’opinion se dégage de plus en plus que des facteurs de risque autres que la DMO peu-vent contribuer de façon indépendante au risque de fracture et que leur utilisation avec la DMOpeut orienter de façon plus optimale les traitements vers les malades qui en ont le plus besoinet, de façon tout aussi importante, éviter un traitement non justifié chez les sujets à faible risque.La mise au point d’algorithmes de prédiction de l’ostéoporose constitue un défi pour l’élabora-tion de futures recommandations pratiques. ❒

É D I T O R I A L

8 Éditorial – Kanis MEDICOGRAPHIA, VOL 28, No. 1, 2006

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evidence of osteopenia and/or vertebral deformity,previous fragility fractures (particularly hip, spine,or wrist), loss of height, and thoracic kyphosis. TheNational Osteoporosis Foundation (NOF) present-ed their Physician’s Guide to Prevention and Treat-ment of Osteoporosis.3 In the United States, BMDmeasurement should be offered to all women >65years of age and for those <65 years of age depend-ing on whether they have a major risk factor suchas a personal history of fracture as an adult, a his-tory of fragility fracture in a first-degree relative,low body weight (<127 lbs [58 kg]), current smok-ing, or use of oral corticoid therapy for more than3 months. The NOF had additional risk factors inits algorithm. Moreover, based on age, BMD, andrisk factors such as previous fractures, the inter-vention was decided according to the BMD values.Thus, clinical risk factors were used to identify in-dividuals for BMD measurement.

However, the clinical significance of osteoporosisis the fracture that occurs because of it. BMD is animportant component of the risk of fracture, butother abnormalities that occur in the skeleton con-tribute to fragility. In addition, a variety of nonskele-tal factors such as a liability to fall and the force ofimpact contribute to fracture risk.4 Assessment offracture risk should take into account other readi-ly measurable indices of fracture risk that add fur-ther information to that provided by BMD. Thus,new algorithms for interventions should be basedon clinical risk factors and absolute risk. Followingan initial assessment of clinical risk factors, if theabsolute risk is high then the individual should betreated; if it is low, no action should be taken. In thecase of intermediate absolute risk based on clinicalrisk factors, a BMD measurement should be made

R isk factors for osteoporosis—low bonemass—have been investigated in severalstudies.1 The practical usefulness of current

case-finding strategies has been to identify menand women with clinical risk factors and, based onthese risk factors, select them for bone mineral den-sity (BMD) measurement. If the BMD measurementshowed a low value, usually a T-score <–2.5, an in-tervention was indicated. Guidelines for the diag-nosis and management of osteoporosis were drawnup by the European Foundation For Osteoporosis.2

Using this approach, clinical risk factors were iden-tified that could provide an indication for the diag-nostic use of bone densitometry, such as the pres-ence of strong risk factors: estrogen deficiency,corticosteroid therapy, maternal family history ofhip fracture, low body mass index (<19), other dis-orders associated with osteoporosis, radiographic

9Risk factors for osteoporosis: an epidemiological review – Johnell MEDICOGRAPHIA, VOL 28, No. 1, 2006

E M E R G I N G T R E N D S I N T H E D I A G N O S I S A N D T R E A T M E N T O F O S T E O P O R O S I S

P revious case-finding strategies for osteoporosis were based on identi-fying risk factors to justify bone mineral density (BMD) measurement.However, the clinical significance of osteoporosis is due to the fractures

that occur. Therefore, identifying risk factors for fractures is important for case-finding strategies. Algorithms for identifying high-risk patients should be basedon clinical risk factors, BMD, gender, and age. The risk factors for fracturesshould be validated in an international setting and in multiple populations, beadjusted for type of fractures, be readily assessable by primary care physicians,and contribute to a risk that is amenable to the therapeutic manipulation in-tended. Besides age, BMD, and gender, these risk factors are previous fractures,use of oral glucocorticoids, low body mass index, family history of fractures,smoking, high alcohol intake, and secondary osteoporosis. The interventionthreshold should be based on absolute risk.Medicographia. 2006;28:9-12. (see French abstract on page 12)

Keywords: osteoporosis; risk factor; bone mineral density; absolute risk

Olof JOHNELL, MD, PhDProfessor, Lund University Department of Clinical SciencesMalmö, SWEDEN

Address for correspondence: Professor Olof Johnell, Department of Orthopedics, Malmö University Hospital, SE-205 02 Malmö, Sweden(e-mail: [email protected])

Risk factors for osteoporosis: an epidemiological overview

b y O . J o h n e l l , S w e d e n

SELECTED ABBREVIATIONS AND ACRONYMS

BMD bone mineral densityNOF National Osteoporosis FoundationDXA dual energy x-ray absorptiometryEFFO European Foundation For Osteoporosis

in men and women with no significant sex differ-ence in the predictive ability. The effect was depen-dent on age with a significantly higher gradient ofrisk at age 50 years than at age 80 years. For osteo-porotic fracture, it was the opposite. The gradient ofrisk with the BMD measured at the femoral neckwas lower for any osteoporotic fracture comparedwith hip fractures where the relative risk (RR) foreach SD decrease was 2.9 (95% confidence interval[CI], 2.0-4.3). For prediction of osteoporotic frac-tures, the gradient was higher the lower the BMD.Data from ultrasound and peripheral measurementswere available only from 3 cohorts. The predictiveability of these techniques was somewhat less thanthat of DXA at the femoral neck.12

Thus, BMD is a risk factor for fractures of sub-stantial importance and is similar in both sexes. Itsvalidation on an international basis permits its usein case-finding strategies. The variation in predic-tive value with age and BMD should, however, betaken into account. The reason for the decreasinggradient of risk for hip fractures with age is notknown. It is possible that extraskeletal risk factors,such as liability to falls, have an effect on the gra-dient, but this does not seem likely, since most fallsdo not cause hip fracture. Another hypothesis is thatage adversely affects the structure or material, andthus properties, of the femur not captured by BMDmeasurement.

Additional risk factors

Apart from these important risk factors (age, gen-der, and BMD), there are now several risk factorsthat have been validated in an international setting,such as previous fracture, use of corticosteroids, afamily history of fracture, low body mass index, cer-tain diseases associated with osteoporosis (secondaryosteoporosis), smoking, and alcohol. Other potentialrisk factors are biochemical markers of bone resorp-tion and ultrasound findings. There are, however,several considerations concerning the selection ofthese risk factors for use in fracture prediction, anddifferent risk factors might have a different relevanceat different ages.Different risk factors also havea dif-ferent relevance for different fracture sites.4 Thus,clinical risk factors to be used in fracture predictionneed to be chosen with care and they should be:◆ Validated in multiple populations◆ Adjusted for age, sex, and type of fracture◆ Readily assessable by primary care practitioners◆ Proven to contribute to a risk that is amenable tothe therapeutic manipulation intended◆ Intuitive rather than contraintuitive to medicalcare.

In the large international cohorts where we haveaccess to individual data, validations have been car-ried out for risk factors and the following have beenfound to work in case-finding in an internationalsetting3,4:

◆ Previous fractureA previous fracture is a well-documented risk factorfor future fracture. In the meta-analysis, 11 cohortsworldwide were used for the follow-up of 250000

and thereafter the new absolute 10-year risk shouldbe calculated based on both BMD and clinical riskfactors. Thus, the intervention threshold is the frac-ture risk expressed as absolute 10-year risk.5

Identification of risk factors for fracture is impor-tant. In the previous guidelines2,3 based on BMDmeasurement, the majority of fractures will occurin those individuals who will never be assessed. Oth-er disadvantages with only using the BMD T-score asthe indication for intervention are that the T-scoreis only defined for dual energy x-ray absorptiome-try (DXA), the absolute risk is different for differentages with exactly the same T-score,4 the T-score isdifferent for different techniques, many high-riskindividuals go undetected, and DXA is not univer-sally available.

Risk factors for assessmentof fracture risk

◆ AgeAge is the most important risk factor. A woman atthe age of 50 with a T-score of <–2.5 has an absolute10-year risk of 1.7%, while a woman with exactlythe same T-score at the age of 80 has a 10-year riskof 11.5%, a more than 6-fold difference in fracturerisk with exactly the same BMD value.6

◆ GenderWomen have a higher incidence of osteoporoticfractures than men.7 The lifetime risk of an osteo-porotic fracture at the age of 50 is 53.2% for wom-en and 20.7% for men in the United Kingdom,8

46.4% for women and 22.4% for men in Sweden,9

and 39.7% for women and 13.1% for men in theUnited States.10 This is only partly dependent on theshorter life expectancy in men.

◆ BMDBMD is one of the most important risk factors forosteoporotic fractures, and the ability of BMD topredict fracture is comparable to the use of bloodpressure to predict stroke and substantially betterthan serum cholesterol to predict myocardial in-farction.11 In a meta-analysis, it was shown that theage-adjusted relative increase in risk of fracture isbest for hip fracture when BMD is measured at thefemoral neck with a risk increase of 2.6 and less formeasurement at the distal radius and lumbar spine.In the same meta-analysis, BMD measurement atthe lumbar spine was is slightly better at predictingvertebral fractures (relative risk [RR] 2.3) than mea-surement at the femoral neck and distal radius.11

A recent meta-analysis based on data for individu-als in 12 large cohorts in a total follow-up of 168 366person-years was undertaken in Europe, NorthAmerica, Australia, and Asia, and thus was an inter-national study. The study quantified the relation-ship between BMD and fracture risk and examinedthe effect of age, sex, and time since measurementand initial BMD value, as well as the predictive abil-ity of ultrasound and peripheral measurements inrelation to fracture risk.12 In this study, BMD wasmeasured at the femoral neck using DXA and wasfound to be a strong predictor of hip fracture both

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reduction in hip fracture risk of 17%. Body massindex also qualifies as an internationally validatedrisk factor, which is partly dependent on BMD. Thesignificance of body mass index as a risk factorvaries according to the level of body mass index.

◆ Family history of fractureThis is a well-established risk factor, based on epi-demiological studies and genetic studies. Seven in-ternational cohorts were studied to determine theeffect of a family history of osteoporotic or hip frac-tures in first-degree relatives.18 In the meta-analy-sis, a family history of fracture in first-degree rela-tives was associated with a significantly increasedrisk of any fracture, osteoporotic fracture, and hipfracture. The estimate of risk was slightly higher atyounger ages, but not significant. No difference wasseen between men and women. A family history ofhip fracture in parents was associated with a highrisk of osteoporotic fractures, and was 1.6 (95% CI,1.3-2.0) in women and 2.5 (95% CI, 1.5-3.9) for hipfractures but not significant in men. The risk wasnot significantly changed when BMD was added inthe model. Thus, we can conclude that a parentalhistory of hip fractures confers an increased risk offracture that is mainly independent of BMD, andthis can be used on an international basis in case-finding strategies.

◆ Secondary osteoporosisSecondary osteoporosis is also a well-recognizedrisk factor for osteoporosis.16,19 Several studies haveexamined this issue and there are various lists ofdiseases that affect osteoporosis and fractures.

◆ SmokingSmoking is also widely considered to be a risk fac-tor for future fractures. In a meta-analysis of inter-national cohorts, current smoking was associatedwith a significantly increased risk of any fracturecompared with nonsmokers (RR 1.3; 95% CI, 1.2-1.4).20 For an osteoporotic fracture, the risk wasmarginally higher (RR 1.3; 95% CI, 1.1-1.3). Thehighest risk was observed for hip fractures (RR 1.8;95% CI, 1.5-2.2), but was also somewhat lower afteradjustment for BMD (RR 1.6; 95% CI, 1.3-2.2) (therisk ratio was significantly higher in men than inwomen for all fractures and osteoporotic fractures,but not for hip fractures). Low BMD accounted foronly 23% of the smoking-related risk of fractures.Adjustment for body mass index gave a small down-ward effect on the all-fracture outcome. Thus, smok-ing is an interesting risk factor in a case-findingstrategy, but also has implications for a public healthapproach.

◆ Alcohol intakeExcessive alcohol intake is also a well-recognizedrisk factor for osteoporosis. The question is whethermoderate intake has an adverse effect. However, ahigher level of intake appears to be associated withan increased risk of fractures. In the internationalcohorts, a meta-analysis was undertaken with regardto alcohol intake, and alcohol in the linear modelwas associated with a 7% increase for each unit of

person-years.13 A history of previous fracture wasassociated with a significantly increased risk of anyfracture (RR=1.9; 95% CI, 1.8-2.0). The risk ratiooutcome was similar for osteoporotic fracture andfor hip fracture. There was no significant differ-ence in risk ratio between men and women. It wasmarginally adjusted downward when BMD was tak-en into account. Low BMD explained only a minor-ity of the risk for any fracture (8%) and for hip frac-tures (22%). The risk ratio was stable with age forosteoporotic and any fracture, but in the case of hipfracture outcome the risk ratio decreased signifi-cantly with age. Thus, previous fracture can be usedfor case-finding in an international setting, alsowhen taking into account that the risk is highest inthe lower ages.

Previous fracture was also the major risk factor inall guidelines presented and is easy to pick up as theinformation is already available in the health caresystem and no screening is needed. In anotherstudy,14 it was shown that when almost 2000 con-secutive patients were followed for 5 years, the riskof having a new fracture was highest immediatelyfollowing the initial fracture.

◆ Use of glucocorticoidsSeveral studies have shown that the use of gluco-corticoids is associated with increased fracturerisk.15 This risk factor is also included in most guide-lines, such as the EFFO and NOF guidelines. In anew meta-analysis based on 7 prospective interna-tional cohorts worldwide, the simple question—previous corticosteroid use?—was associated witha significantly increased risk of any fracture, osteo-porotic fracture, and hip fracture, including whenadjusted for BMD.16 The RR for hip fractures rangedfrom 4.4 at age 50 to 2.5 at age 85, thus the estimateof RR was higher in younger ages, but was not sig-nificant, with no difference between men and wom-en. The risk was only marginally changed whenBMD was included in the model and was indepen-dent of previous fracture. Again, a risk factor hasbeen identified that can be used in an internation-al setting.

◆ Low body mass indexLow body mass index has also been well document-ed in several studies, mainly because of its associa-tion with BMD. This parameter was studied in 12prospective worldwide cohorts. The age-adjustedrisk of fractures increased significantly with lowerbody mass index.17 Overall, the risk ratio per unitof higher BMD was 0.93 for hip fractures (95% CI,0.91-0.94). The RR per unit change in body mass in-dex was similar in men and women. After adjustingfor BMD, the RR was only significant for hip frac-tures, being 0.98 in women for one unit higher bodymass index. The contribution to fracture risk wasmuch more marked at low values of body mass in-dex than at values above the median. Comparedwith the body mass index of 25 kg/m2, a body massindex of 20 was associated with an almost 2-fold in-crease in RR for hip fracture; in contrast, a bodymass index of 30 when compared with a body massindex of 25 was only associated with a RR of 0.83, a

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signed, they will interact and alter the RR that wasfound in the univariate analyses; the risks will thusbe a little different in the final model with all riskfactors together. Such a model has to be created,and once this has been done, treatment can be basedon the absolute fracture risk. In this way, we canidentify and treat those at highest risk who needtreatment the most.5

Conclusion

The diagnosis of osteoporosis is based on a BMDmeasurement using the DEXA technique. The inter-vention thresholds should be based on absolutefracture risk as well as on several clinical risk fac-tors that contribute to fracture risk in an interna-tional setting and should be partly independent ofBMD in order to be able to contribute to the frac-ture risk. BMD is still one of the most important riskfactors together with age and gender. Other risk fac-tors that can be clinically used are a history of pre-vious fracture, the use of oral corticosteroids, a fam-ily history of fracture, secondary osteoporosis, highalcohol intake, and smoking. ❒

alcohol above 1 unit daily.21 The RR when compar-ing individuals consuming more than 2 units perday versus the rest was 1.7 for hip fracture (95%CI, 1.2-2.4) and after adjustment for BMD the RRwas unaffected. Nor did it change by adding thebody mass index. It fell slightly to 1.5 (95% CI, 1.1-2.2) when adjusted for smoking. Thus, high alcoholintake is an important risk factor and can be used inthe case-finding strategy and also in a public healthapproach.

There are several other risk factors, but these areones that have been validated in an internationalsetting and found to be significant in cohorts allover the world. There are several risk factors thatalso have an implication for public health, such asa tendency to falls22 and physical exercise23 (a topicthat is beyond the scope of this article).

Risk factors that have now been tested in inter-national settings are biochemical markers of boneturnover and ultrasound measurement.

The interactions between risk factors are also im-portant, such as BMD and age. BMD has a higherpredictive value at younger ages.12 If an algorithmwith all these validated clinical risk factors is de-

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REFERENCES1. Khan AA, Syed Z. Bone densitometry in premenopausal wom-en: synthesis and review. J Clin Densitom. 2004;7:85-92.2. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D.Guidelines for diagnosis and management of osteoporosis. Osteo-poros Int.1997;7:390-406.3. National Osteoporosis Foundation. Physician’s guide to pre-vention and treatment of osteoporosis. http://www.nof.org. Ac-cessed October 30, 2005.4. Kanis JA, Black D, Cooper C, et al. A new approach to the de-velopment of assessment guidelines for osteoporosis. OsteoporosInt. 2002;13:527-536.5. Kanis JA, Borgström F, De Laet C, et al. Assessment of fracturerisk. Osteoporos Int. 2005;16:581-589.6. Kanis JA, Johnell O, Odén A, Dawson A, De Laet C, Jönsson B.Ten year probabilities of osteoporotic fractures according to BMDand diagnostic thresholds. Osteoporos Int. 2001;12:989-995.7. Johnell O, Kanis J. Epidemiology of osteoporotic fractures.Osteoporos Int. 2005;16(suppl 2):S3-S7.8. van Staa TP, Dennison EM, Leufkens HG, Cooper C. Epidemiol-ogy of fractures in England and Wales. Bone. 2001;29:517-522.9. Kanis JA, Johnell O, Odén A, et al. Long-term risk of osteo-porotic fracture in Malmö. Osteoporos Int. 2000;11:669-674.10. Melton LJ III, Chriscilles EA, Cooper C, Lane AW, Riggs BL.Perspective: how many women have osteoporosis? J Bone MinerRes. 1992;7:1005-1010.11. Marshall D, Johnell O, Wedel H. Meta-analysis of how wellmeasures of bone mineral density predict occurrence of osteo-porotic fractures. BMJ. 1996;312:1254-1259.12. Johnell O, Kanis JA, Odén A, et al. Predictive value of BMDfor hip and other fractures. J Bone Miner Res. 2005;20:1185-1194.13. Kanis JA, Johnell O, De Laet C, et al. A meta-analysis of pre-vious fracture and subsequent fracture risk. Bone.2004;35:375-382.14. Johnell O, Kanis JA, Odén A, et al. Fracture risk followingan osteoporotic fracture. Osteoporos Int. 2004;15:175-179.15. van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C.Use of oral corticosteroids and risk of fractures. J Bone Miner Res.2000;15:993-1000.16. Kanis JA, Johansson H, Odén A, et al. A meta-analysis of priorcorticosteroid use and fracture risk. Osteoporos Int.2004;19:893-896.

17. De Laet C, Kanis JA, Odén A, et al. Body mass index as a pre-dictor of fracture risk: a meta-analysis. Osteoporos Int. 2005;16:Jun 1 [Epub ahead of print].18. Kanis JA, Johansson H, Odén A, et al. A family history of frac-ture and fracture risk: a meta-analysis. Bone.2004;35:1029-1037.19. Seeman E. Invited Review: Pathogenesis of osteoporosis.J Appl Physiol. 2003;95:2142-2151.20. Kanis JA, Johnell O, Odén A et al. Smoking and fracture risk:a meta-analysis. Osteoporos Int. 2005;16:155-162.21. Kanis JA, Johansson H, Johnell O, et al. Alcohol intake as arisk factor for fracture. Osteoporos Int. 2004;15:734-742.22. Pfeifer M, Sinaki M, Geusens P, Boonen S, Preisinger E, MinneWH. Musculoskeletal rehabilitation in osteoporosis: a review.J Bone Miner Res. 2004;19:1208-1214.23. Lock CA, Lecouturier J, Mason JM, Dickinson HO. Lifestyleinterventions to prevent osteoporotic fractures: a systematic re-view. Osteoporos Int. 2005;16:Jun 1 [Epub ahead of print].

FACTEURS DE RISQUE DE L’OSTÉOPOROSE : UNE REVUE ÉPIDÉMIOLOGIQUE

L es stratégies de recherche de cas étaient autrefois basées sur la mise enévidence de facteurs de risque cliniques justifiant de recourir à la me-sure de la densité minérale osseuse (DMO). Cependant, c’est la survenue

de fractures qui est l’événement significatif dans l’ostéoporose sur le plan cli-nique. C’est donc la mise en évidence des facteurs de risque de fractures qui estimportante dans les stratégies de recherche de cas. Les algorithmes d’identifi-cation des patients à haut risque doivent être fondés sur les facteurs de risquecliniques, la DMO, le sexe et l’âge. Les facteurs de risque pour les fractures, quantà eux, doivent être validés dans un cadre international et sur des populationsmultiples, être ajustés selon le type de fracture, être facilement évaluables parles médecins généralistes et faire partie d’un risque relevant des traitementsproposés. Outre l’âge, la DMO et le sexe, ces facteurs de risque comprennentles antécédents de fractures, la corticothérapie par voie orale, un indice demasse corporelle bas, des antécédents familiaux de fractures, le tabagisme, uneconsommation d’alcool élevée et l’ostéoporose secondaire. Enfin, le seuil d’in-tervention thérapeutique doit être basé sur le risque absolu.

✦

Fracture impact

A t the age of 50 years, the remaining lifetimerisk of at least one fracture of the hip, ver-tebral body, or distal forearm, approaches

50% among white women and 20% among whitemen.1 The most frequent site of fracture is the tho-racolumbar spine, with prevalence rates of mor-phometric vertebral deformities being around 25%among white women in the USA aged 50 years andover.2,3 Around two thirds of these morphometricvertebral deformities are subclinical. Other skeletalsites linked with osteoporosis include the hand,rib, foot, and toe.

While fragility fractures of the proximal femuroccur less frequently (lifetime risk=18% amongwomen aged 50 years), the mortality and morbid-ity associated with fractures at this site is consid-erably greater than that associated with vertebraldeformity. Hip fractures invariably require hospi-talization; 1 year following fracture, 27% of patientsenter a nursing home for the first time, 40% are un-able to walk independently, 60% have difficulty withat least one essential activity of daily living (ADL),and 80% are restricted in other activities such as

13Identification of patients in need of antiosteoporotic treatment – Cooper and Gehlbach MEDICOGRAPHIA, VOL 28, No. 1, 2006


I ncreased likelihood of fracture has often been expressed as relative risk, orrisk ratio, defined as the ratio of fracture occurrence among individualswith, versus without, a given risk factor. Thus, an osteoporotic bone miner-

al density (BMD) carries a risk ratio of 9.6 for hip fracture versus a ratio of 1.7for cigarette smoking, suggesting that low BMD confers markedly greater risk.However, relative risk alone is inadequate in informing clinical decisions: itdoes not express actual outcome frequency. Ten-year relative risks of fractureare similar in osteoporotic women aged 50 years and 70 years—3.7 and 4.2,respectively, versus their normal counterparts—but absolute rates are twiceas high in the older group. This difference has important implications for pre-ventive “who-to-treat” strategy. More informative than relative risk is an ap-proach that estimates the absolute risk of an individual with a given constel-lation of factors (age, sex, BMD, prior fracture, parental hip fracture, lifetimesystemic glucocorticoid use, body mass index, alcohol intake >2 units/day) sus-taining a fracture over a relative, but practical, time interval, eg, 10 years. Therecent multivariate World Health Organization algorithm was derived fromseveral large epidemiological surveys. The greatest benefit of absolute risk is itstransparent role in economic analyses and its ability to dovetail with healtheconomic modeling. Comparison of the impact of alternative interventions onabsolute risk can be used to set intervention thresholds for specific agents andtarget treatments against osteoporotic fracture to those clinical scenarios inwhich these agents are most cost-effective.Medicographia. 2006;28:13-20. (see French abstract on page 20)

Keywords: osteoporosis; fracture; bone mineral density; risk factor; epidemiology; prevention; treatment; cost-effectiveness

Cyrus COOPER, Ma, DM, FRCP, FFPH, FMedSci Professor of Rheumatology & Director, MRC EpidemiologyResource Center, University of Southampton, SouthamptonGeneral Hospital, Southampton, UNITED KINGDOM

Stephen GEHLBACH, MD, MPHProfessor of Epidemiology, School of Public Health and Health Sciences, University of Massachusetts at Amherst Amherst, USA

▲

Address for correspondence: Professor Cyrus Cooper, MRC Epidemiology Resource Center, University of Southampton, Southampton General Hospital, Southampton SO16 6YD, UK(e-mail: [email protected])

Identification of patients in need of antiosteoporotic

treatment: who to treat today? b y C . C o o p e r , U n i t e d K i n g d o m

a n d S . G e h l b a c h , U S A


ADL activity of daily livingBMD bone mineral densityBMI body mass indexDXA dual energy x-ray absorptiometry ERT estrogen-replacement therapyPTH parathyroid hormoneQUS quantitative ultrasonographySOF Study of Osteoporotic Fracture

eral density (BMD) is a major determinant of bonestrength; dual-energy x-ray absorptiometric (DXA)measurements of BMD account for 75% to 90% ofthe variance in bone strength observed during invitro and in vivo studies.5 However, bone strengthis determined by other aspects of bone structureincluding size, geometry, microarchitecture, andturnover.

Bone density in adult life is a function of the peakbone mass attained during early adulthood and thesubsequent rate of bone loss. The two major causesof involutional bone loss are secondary hyperpara-thyroidism (consequent upon reduced calcium in-take and hypovitaminosis D) and reduced physicalactivity. In addition, estrogen deficiency predisposesto bone loss among women. Other important caus-es of bone loss include thinness, cigarette smoking,heavy alcohol consumption, and drugs/diseases thatsecondarily predispose to osteoporosis (most im-portantly glucocorticoids). The multifactorial etiol-ogy of fracture is illustrated in Figure 2.

Preventive strategies

For regulatory purposes, specific definitions of pre-vention and treatment are used in the context ofosteoporosis. The term “prevention” is used to de-note the prevention of bone loss in postmenopausalwomen with osteopenia, whereas “treatment” isdefined as a reduction in fracture risk in post-menopausal women with osteoporosis. In clinicalpractice, this distinction between prevention andtreatment is less appropriate, since many agentscurrently in use act fundamentally in the samemanner, ie, by inhibition of bone resorption. Fur-thermore, with the increasing evidence for a rela-tively rapid rate of treatment onset and offset forthese interventions, there has been a move awayfrom long-term preventive strategies toward theuse of shorter-term therapy in high-risk individu-als. The latter approach is supported by the demon-stration of a significant reduction in vertebral andnonvertebral fracture rate among postmenopausalwomen with established osteoporosis after only 1year of treatment with antiresorptive agents.

A variety of bone mass measurement techniquesare predictive of fracture, including DXA and quan-

driving and shopping. Mortality rates are increasedamong subjects with both hip and vertebral frac-tures; reductions in survival of around 15% are re-ported during the 5 years following fracture at bothof these sites. The excess mortality in the case ofvertebral deformities is apparent among patientswith clinically diagnosed vertebral fracture, as wellas those with asymptomatic, morphometric defor-mities. Figure 11 shows the age- and sex-specific in-cidence rates for fractures of the hip, distal fore-arm, and vertebral body.

The economic burden of fragility fractures is con-siderable. In the USA, the care of these fracturescosts around US $20 billion each year. In the UK,this figure totals UK £1.5 billion. The most expen-sive fracture is hip fracture, and around half of hipfracture costs arise from care required after depar-ture from hospital. In the UK, 20% of all orthope-dic beds are occupied by patients with a hip frac-ture, and 19% of patients require long-term nursingcare (Table I).1

Pathophysiology of fracture

Fracture incidence depends on two factors: bonestrength and trauma. During the first three decadesof life, fractures typically arise from high-energytrauma, such as road traffic accidents. Above the ageof 65 years, around 90% of fractures result from afall from standing height or less.4 Reduced bonestrength is therefore an important, modifiable, de-terminant of fracture risk in the elderly. Bone min-

14 Identification of patients in need of antiosteoporotic treatment – Cooper and Gehlbach MEDICOGRAPHIA, VOL 28, No. 1, 2006


Hip Spine Wrist

Lifetime risk (%)Women 143 29 13Men 3 14 2

Cases/year 400 000 810 000 330 000

Hospitalization (%) 100 2-10 5

Relative survival 0.83 0.82 1.00

Costs: All sites combined ~ 25 billion Euros

Table I. Impact of osteoporosis-related fractures in Europe. Based on data from reference 1 (Harvey et al, 2005).

Figure 1. Incidence of osteoporotic fractures. Adapted from reference 1:Harvey NC, Dennison EM,

Cooper C. The epidemiology of osteoporotic fractures.

Osteoporos Rev. 2005;13:1-6.Copyright © 2005, Springer

Verlag, USA.

Age group (y)

Men

Inci

denc

e pe

r 10

000/

year

400

300

200

100

050-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Age group (y)

Women400

300

200

100

050-54 55-59 60-64 65-69 70-74 75-79 80-84 85+

Vertebral fractureHip fracture

Forearm fracture

classes showed a significant reduction in back painand a nonsignificant trend in reduced further ver-tebral fractures.15 A small study has assessed a sim-ple home exercise program after hip fracture andfound an increase in quadriceps strength, walkingspeed, and subjective measures.16 However, therewas no effect on postural stability nor any commentpossible on fall prevention. Another study has ex-amined the role of early mobilization followingColles’ fracture and confirmed previous evidencethat there is quicker regain of wrist movement andthat this is not at the expense of increased analgesicuse nor worsening bony deformity.17

Although most nonvertebral fractures occur fol-lowing a fall, no study has shown an interventionthat has reduced fracture.18 Protecting the hip withhip protectors has been shown to reduce hip frac-ture.19 However, in view of their cumbersome de-sign, compliance is poor.

Both calcium and vitamin D act to reduce para-thyroid hormone (PTH) levels and so may preservebone mass. Some epidemiological studies of calci-um intake comparing different populations haveshown a protective effect against fracture in men,20

while others have not.21 After the menopause, cal-cium has been shown to reduce bone loss by reduc-ing bone turnover and increasing bone density.22

Calcium alone in pharmacological doses (1.2 g) hasbeen shown to reduce the risk of further vertebralfracture in patients who have a prevalent vertebralfracture.23 The evidence for hip fracture reductionhas only been shown by epidemiological studies(Figure 3, next page).24,25

VitaminD is biologically inert from dietary sourcesor from the skin. It is metabolized by the liver andthen the kidney to the active moiety 1,25(OH)2 vi-

titative ultrasound (QUS). Site-specific measure-ments are more predictive (relative risk (RR) =2.0-2.8 for 1 standard deviation (SD) reduction in BMD)than assessments at more distant sites (RR=1.5-2.2 for 1 SD reduction in BMD). The definition ofosteoporosis, according to World Health Organiza-tion (WHO) guidelines6,7, is a T-score of <--2.5 forwhite postmenopausal women. Diagnostic thresh-olds for other subpopulations such as men and pa-tients using glucocorticoids, are less clear. Sincedifferent approaches to bone mineral measurementresult in a variable classification of individuals ashaving osteoporosis, it has recently been proposedthat the gold standard for diagnostic purposes betotal hip BMD measured by DXA. However, the mostrational utility of these measurements is in fracturerisk prediction, and measures are already under wayin order that bone mineral measurements be ex-pressed as absolute fracture risk related to a relativetime interval, for example 10 years.

The aim of preventive strategies is to reduce thenumber of subsequent fractures in someone whohas been diagnosed with a low bone mass or whomay already have fragility fractures. The first line insuch preventive approaches is to correct the under-lying cause of osteoporosis (hypogonadism in men,hyperthyroidism, hyperparathyroidism, or gluco-corticoid exposure).

Lifestyle measures directed at the population

The main lifestyle changes that may impact on theoccurrence of fracture in patients with osteoporo-sis are smoking, exercise, and diet. Smoking affectsthe skeleton in many ways; there is a direct toxic ef-fect on new bone growth. Smoking may also reducecalcium absorption as well as increasing the risk offalling in elderly patients. The smoking-related in-crease in the risk of hip fracture is age-related, withgreater deleterious effects in the postmenopausalage group.8 The effect of smoking cessation onbone mass and fracture rate has been studied in a5-year Norwegian cohort. Despite adjustment forconfounding variables such as body mass index(BMI), physical inactivity, and self-reported poorhealth, ex-smokers still had an increased risk of hipfracture compared with nonsmokers, but a lowerrisk than current smokers.9,10 This would suggestthat the effect of smoking is partially reversible, butperhaps a portion of the damage to the skeleton isirreversible. However, these findings have not beensupported by a study of younger women wherethere was no effect of smoking status on wrist frac-ture11 or by the Framingham Study, which found areduction in the benefit from estrogen replacementtherapy (ERT) in smokers, but no independent ef-fect of smoking on BMD.12

The level of physical activity has been shown tobe associated with increased bone mass13 and alsoreduced fracture rate14 in observational studies. Ex-ercise therapy can be used to prevent fracture inthose at risk or form part of a rehabilitation pro-gram after a fracture. A study of patients with ver-tebral osteoporosis having twice-weekly exercise



◆ Genetic factors◆ Intrauterine programming◆ Childhood nutrition and exercise◆ Endocrine dysfunction

◆ Thinness ◆ Smoking◆ Estrogen deficiency◆ Secondary hyperparathyroidism◆ Drugs/disease (eg, cortico-

steroids)

◆ Vision◆ Muscle strength◆ Gait ◆ Medication◆ Balance◆ Cognitive impairment

◆ Domestic hazards (eg, loose rugs)

◆ Outdoor hazards (eg, icy pavements)

Bone mass

Risk of falling

Other skeletalfactors

Fracture

Bone strength

Trauma

Type of fall

Peak bone mass

Bone loss

Intrinsic

Extrinsic

Direction of fallPoint of impact

Size ArchitectureGeometry Turnover

➤

➤➤

➤

➤

➤

➤

➤

➤➤

Figure 2.Pathophysiology

of fracture.

interval [CI] 0.51±0.91) including the hip (OR 0.70;95% CI 0.51±0.91).29 Another study has shown thatan annual intramuscular injection of 150 000±200 000 units of vitamin D to those over 75 yearsresulted in a significant reduction in all fractures.30

Although participants in these studies were not di-agnosed as osteoporotic before entry, the benefitwould seem to be greatest in those at greatest risk.31

Individual risk assessment

Several individual characteristics have been linkedto fracture risk in case-control and cohort studies.These factors are interrelated to a variable extent,and in many instances the independence of theircontribution to fracture risk from BMD, and fromeach other, may not be clear. Moreover, risks coex-ist in differing combinations among different pa-tients. These issues constitute a major challenge tothe development of preventive strategies, an issuehighlighted by current guidelines. A number of in-vestigators have employed multivariable statisticaltechniques to build scoring systems that assess theinfluence of each risk factor while controlling or ad-justing for the presence of the others. Factors thatare found to contribute independently to risk areweighted by importance (as determined in the mod-eling) and allocated points. Each patient is thenevaluated and receives a score, based on accumu-lated points, that predicts the risk of fracture.

Some scoring systems have been designed to pre-dict low BMD (osteoporosis, as defined by the WHO)in the expectation that these scores will assist clin-icians in identifying patients who will benefit frombone density referrals to confirm suspected diag-noses.32,33 Other researchers have targeted fracturesas the outcome of importance.34,35 In these schemes,BMD becomes one of the predictor variables. Thelatter approach has the dual virtues of utilizing eas-ily obtained “clinical variables,” such as age, sex, andweight, and personal history to estimate risk beforeresorting to the added expense of a bone densitydetermination, as well as predicting the outcome(fracture) of clinical importance.

Two large population-based studies, one in Eu-rope and one in North America, provide useful il-lustrations of how variables can be combined to es-timate fracture risk. A cohort of over 5000 womenand men aged 55 years and above from a Nether-lands community was extensively evaluated from1990 through 1993, then followed over a 4-year pe-riod for the occurrence of hip fracture.35 Ten factorassessed at entry were associated with the outcome.After these were modeled in multivariable equations,the factors seen in Table II 35 emerged as indepen-dent contributors to fracture risk. Age, sex, height,use of an aid for walking, and current cigarettesmoking are included as are nine categories of bonedensity. As seen in Table II, the rounded estimatesof the β coefficients (weights of the factors) whenmultiplied by 10 become “points” given to each fac-tor. Points in turn are multiplied by the categoryvalue and summed to make acomposite score.With-in the Dutch population in which the scoring sys-tem was devised, subjects’ scores range from 6 to

tamin D. Its main action is to increase the absorp-tion of calcium and to a lesser extent phosphorusfrom the small bowel. In the calcium-deficient state,it also acts on bone via osteoblasts to increase os-teoclast numbers and mobilize calcium from theskeleton. Importantly, active vitamin D inhibits thesynthesis and secretion of PTH. In this way vita-min D may act to inhibit PTH-mediated age-relat-ed bone loss.

The effects of calcitriol on bone mass have beeninconsistent, reflecting the different calcium intakesin each of the studies.26,27 Calcitriol, compared withcalcium, has been shown to reduce vertebral frac-ture rates in postmenopausal women with prevalentvertebral deformity,27 but other studies have foundno benefit. A side effect of calcitriol therapy includeshypercalcemia, causing nephrocalcinosis and renalfailure.

One of the main mechanisms of age-related boneloss involves increased resorptive activity of PTH onthe bone, secondary to hypovitaminosis D. In am-bulatory elderly women resident in nursing homes,the combination of 1.2 g of calcium and 800 IU ofvitamin D3 (cholecalciferol) daily was given for 3years. After 18 months, the treatment group hadsignificant increases of 2.7% in total femur BMDcompared with a decline in the placebo group of4.6%.28 By the end of the 3-year period, there wasa significant reduction in fracture rates at nonver-tebral sites (odds ratio [OR] 0.70; 95% confidence



Figure 3. Calcium treatment and risk of hip fracture based on findings from epidemio-logical studies. The odds ratios and 95% confidence intervals are shown for an increaseof 300 mg/day of calcium and the risk of hip fracture in postmenopausal women. Adapted from reference 25 (Cumming et al, 1997).

Lau et al, 1988

Holbrook et al, 1988

Meyer et al, 1996

Johnell et al, 1995

Looker et al, 1993

Cooper et al, 1988

Cummings et al, 1995

Jaglal et al, 1993

Nieves et al, 1992

Tavani et al, 1996

Meyer et al, 1995

Paganini-Hill et al, 1991

Michaelsson et al, 1995

Wickham et al, 1989

Cumming et al, 1994

Krieger et al, 1992

POOLED ODDS RATIO

0.5 0.75 1.0 1.5 2.0

* *Not to scale

103 with a median value of 43. The scheme per-forms well in discriminating patients who are athigh and low risk of fracture. Those with a score ofless than 50, for example, have a chance of only 1 in1000 of sustaining a hip fracture over a 4-year in-terval. This risk increases 100-fold for those withscores of 75 or higher; their risk of hip fracture is10%.

Data from the US-based Study of OsteoporoticFracture (SOF) subjects with hip DEXA measure-ments available were also used to produce multi-variable derived prediction models.34,36 Twenty po-tential risk factors were included in the modeling.Their results compiled into the “FRACTURE Index”are shown in Table III.34 Like the Dutch models, age,weight and cigarette smoking appeared as indepen-dent risks, as did an indicator of physical condition,in this instance “using arms to stand from a chair”instead of “using a walking aid.” Significant addi-tions to the SOF models are the history of maternalhip fracture after the age of 50 years and the per-sonal history of a fracture in adult life. As in theDutch study, the American group built models thatincluded and excluded BMD determinations. Scoresfrom both FRACTURE Index models showed gooddiscrimination for fracture risk. Subjects with scoresin the lowest quintile have a 5-year risk of hip frac-ture of about 0.5% compared with a 14-fold in-creased risk of 8.5% for scores in the highest quin-tile. Good separation for those at high and low riskof vertebral fracture was also demonstrated. As withthe Dutch models, adding BMD values to the mod-els derived from clinical variables alone improvesperformance, although not dramatically. A particu-lar strength of the SOF study is the validation of theinstrument in a different population. The scoringsystem was applied to 6600 women aged 75 yearsand older from five regions in France who were par-ticipants in a hip fracture follow-up study.34 Al-though this group was on average 10 years olderthan SOF participants, the models, both with andwithout BMD, showed good discrimination with 23-fold and 6-fold increases in estimated risk respec-tively between lowest and highest quintiles.

Other efforts to combine risk factors have foundmore than 20 characteristics that predict increasedfracture risk in multivariate models.37-40 In additionto those observed by Black et al34 and Burger et al,35

ADLs, cognition, propensity to fall, poor overallhealth status, history of stroke, seizure disorder,and several different medications have been iden-tified. In four of five of these investigations, simplecounts of increasing number of risk factors havebeen shown to demonstrate increasing risk. In datafrom the Duke Established Population for Epidemi-ologic Studies of the Elderly in the USA the pres-ence of 1 of 9 factors carries a fracture risk of 1.8,while 4 factors increase risk to almost 10.37 Findingsfrom the General Practice Research Database in theUK indicate that the presence of 3 or more of 11medical risk factors (made up of diagnoses and med-ications) raises the risk of vertebral fracture 8-foldand of hip fracture by a factor of 4.6 when com-pared with patients with none of the attributes.38

Neither included measurements of BMD.



Point value

1. What is your current age?Less than 65 065-69 170-74 275-79 380-84 485 or older 5

2. Have you broken any bones after age 50?Yes 1No/Don’t know 0

3. Has your mother had a hip fracture after age 50?Yes 1No/Don’t know 0

4. Do you weigh 125 pounds or less?Yes 1No/Don’t know 0

5. Are you currently a smoker?Yes 1No 0

6. Do you usually need to use your arms to assist yourself in standing up from a chair?

Yes 1No 0

If you have a current bone mineral density (BMD) assessment, then answer next question

7. BMD results: Total Hip T-scoreT-score ≥ --1 0T-score between --1 and --2 2T-score between --2 and --2.5 3T-score <22.5 4

Table III. Fracture risk prediction using multiple clinical risk factors and bone densityin the Study of Osteoporotic Fractures (SOF). Based on data from reference 34 (Black et al 2001).

Odds ratio Predictor ß (95% confidence Points

interval)

Model including bone mineral densityIntercept - - -Age (5 years)* 10.2 1.8 (1.5-2.3) 6Gender (female) 0.61 2.6 (1.0-6.4) 9Height (5-cm class)† 0.94 1.5 (1.1-1.9) 4Use of a walking aid (yes/no) 0.39 2.7 (1.4-5.2) 10Current cigarette smoking (yes/no) 0.98 2.2 (1.1-4.4) 8Bone mineral density (0.05 g/cm2)‡ 0.80 1.5 (1.3-1.7) 4

0.39

Model excluding bone mineral densityIntercept --9.6 - 5Age (5 years)* 0.70 2.0 (1.6-2.5) 7Sex (female) 1.20 3.3 (1.3-8.3) 12Height (5 cm)† 0.40 1.5 (1.1-2.0) 4Weight (5 kg)§ 0.17 1.2 (1.0-1.4) 2Use of a walking aid (yes/no) 1.08 2.9 (1.5-5.8) 11Current cigarette smoking (yes/no) 0.87 2.4 (1.2-4.6) 9

*Age classes 0 to 6 are <60-64 etc, to ≥85 years. †Height classes 0 to 5 are <1.60-1.64 etc, to ≥1.80 m.‡ Bone mineral density classes 0 to 9 are ≥1.00, 0.95-0.99 etc to <0.60 g/cm2.§ Weight classes 0 to 9 are ≥95, 90-94 etc, to <55 kg.

Table II. Risk factors predicting hip fracture in the Rotterdam study. Based on data from reference 35 (Burger et al, 1999).

tion were able to reduce the “osteoporotic” risk tothe “normal” level, more fractures would be avert-ed in the older women (22.7 per 100 compared with10.1 per 100). This risk difference can be expressedin the useful notation “number needed to treat”(NNT) to avoid 1 fracture (the reciprocal of the riskdifference). Ten younger women would requiretreatment to avert 1 fracture compared with 4 inthe older age group.

Recent thinking has moved away from describ-ing fracture risk in relative terms.43 A more infor-mative approach is to estimate the likelihood thatan individual with a given constellation of factors(age, BMD, prior fracture) will sustain a fractureover a particular period of time. This means con-structing an estimate of absolute risk and utilizingrisk differences as a basis for evaluating interventionstrategies. The principal value to employing abso-lute risk is its transparent role in economic anal-yses. The cost-effectiveness and cost-utility calcu-lations that are assuming essential roles in bothclinical and policy decision-making depend uponthe values obtained from comparisons of the riskdifferences of alternative interventions. The inter-val over which risk is determined is arbitrary, but10 years has been proposed as a practical length oftime in which to observe maximum benefits of atreatment program.43 Couching estimates in longerframes, such as lifetime risk, presumes extendedbenefits that are not yet demonstrated and ignoresthe improvements in treatment approaches thatseem likely in coming years.

Integrating risk factors

The WHO has recently undertaken an initiative thatentailed amalgamation of several large epidemio-logical studies worldwide.44 From these, estimatesof the association between a number of risk factorsand osteoporotic fracture have been derived, bothbefore and after adjustment for BMD. These includeBMI; prior fracture after 50 years; parental historyof hip fracture; current smoking; ever use of sys-temic glucocorticoids; alcohol intake greater than2 units daily; and secondary osteoporosis. The com-bined use of these risk factors together with age andBMD have been entered into a multivariate modelpermitting the prediction of 10-year probability ofhip and other fractures. Thus, a woman at the ageof 60 years has on average a 10-year probability ofhip fracture of 2.4%. In the presence of a prior frag-ility fracture, this risk is increased approximately2-fold and a probability increases to 4.8%. Interven-tion thresholds for various agents to combat osteo-porosis can also be derived using health economicmodeling. Although the diagnosis of osteoporosiscenters on the assessment of BMD at the hip usingDEXA, other risk factors can be used to assist in en-hancement of fracture prediction. Since these riskfactors are partly independent of BMD, their use inconjunction with BMD improves sensitivity of frac-ture prediction without adverse effects on specifici-ty. In the absence of validated population screeningstrategies, a case-finding approach can be developedbased on the assessment of fracture probability uti-

Models that avoid reliance on BMD appear promis-ing. However, the prospect that preventive treat-ment decisions might be made without obtainingBMD determinations is mitigated by concern thatantiresorptive agents may not be equally effectiveacross a range of BMD. Data from randomized tri-als of alendronate41 and risedronate42 suggested thatthe bisphosphonates may have little effect on frac-ture reduction among subjects with BMD levelsabove the osteoporotic range. However, recent ob-servations made in randomized controlled trials ofselective estrogen receptor modulators, hormonereplacement therapy, and strontium ranelate, sug-gest that fracture risk may be effectively reducedamong postmenopausal women with bone densitylevels in the osteopenic (and even perhaps normal)range.

Relative risk, absolute risk, and risk difference

Identifying patients at increased likelihood of frac-ture is commonly expressed in terms of relative risk:the ratio of occurrence of fracture among thosewith the factor or characteristic over the occur-rence in those without the characteristic. Relativerisk (also referred to as risk ratio) estimates the po-tency or strength of an association between a factorand an outcome. A BMD in the osteoporotic rangecarries a risk ratio of 9.6 for hip fracture comparedwith a relative risk of 1.7 for cigarette smoking, forexample, suggesting that low BMD has the greaterimpact on producing fracture risk.

However, relative risk alone does not provide suf-ficient information for informed clinical decisions.It fails to convey an important dimension of risk,the absolute value. What is the actual magnitude ofrisk, the frequency with which the outcome or dis-ease occurs? Table IV ref shows data on the 10-yearfracture rates for women who are 50 years old andwomen aged 70 years by two levels of BMD, “osteo-porotic” and “normal.” The relative risks for the twogroups are similar (3.7 and 4.2, respectively), butthe absolute rates of fracture appear quite different.The 10-year risk of fracture is 2-fold higher for old-er osteoporotic women. This has important impli-cations for any preventive strategy. If an interven-



50 years old 70 years old

Absolute risk (per 100)Osteoporosis (BMD,* T<- 2.5 SD) 13.9 29.8Normal (BMD, T = mean†) 3.8 7.1

Relative risk 3.7 4.2

Risk difference (per 100) 10.1 22.7

NNT‡ 9.9 4.4

*BMD: bone mineral density. †mean BMD for young adult.‡ NNT: number needed to prevent one fracture (1/risk difference).

Table IV. Ten-year risk of fracture associated with osteoporosis for50-year-old and 70-year-old women. Based on data from reference 4 (Kanis et al, 2001).



and women where hip fracture probability over 10years ranges from 1% to 10%, depending on age.The widespread use of such algorithms of risk pre-diction will enhance our ability to target effectivetreatments against osteoporotic fracture to clini-cal scenarios in which these agents are most cost-effective. ❒

lizing clinical risk factors, and where appropriateadditional testing such as BMD. Because there aremany techniques for assessing fracture risk, andmultiple fracture outcomes, the most suitable mea-sure to determine intervention thresholds appearsto the be 10-year probability of fracture. Many treat-ments can now be given cost-effectively to men

REFERENCES1. Harvey NC, Dennison EM, Cooper C. The epidemiology of os-teoporotic fractures. Osteoporos Rev. 2005;13:1-6. 2. Melton LJ, Lane AW, Cooper C, et al. Prevalence and incidenceof vertebral deformities. Osteoporos Int. 1993;3:113-119.3. Matthis C, Weber U, O’Neill TW, Raspe H. Health impact as-sociated with vertebral deformities: results from the EuropeanVertebral Osteoporosis Study (EVOS). Osteoporos Int.1998;8:364-372.4. Parkkari J, Kannus P, Palvanen M, et al. Majority of hip frac-tures occur as a result of a fall and impact on the greater tro-chanter of the femur: a prospective controlled hip fracture studywith 206 consecutive patients. Calcif Tissue Int.1999;65:183-187.5. Lauritzen JB. Hip fractures: incidence, risk factors, energy ab-sorption, and prevention. Bone.1996;18:65S-75S.6. Meunier PJ. Evidence-based medicine and osteoporosis: a com-parison of fracture risk reduction data from osteoporosis ran-domised clinical trials. Int J Clin Pract.1999;53:122-129.7. World Health Organization Study Group. Assessment of Frac-ture Risk and its Application to Screening for PostmenopausalOsteoporosis. Geneva, Switzerland: WHO; 1994.8. Law MR, Hackshaw AK. A meta-analysis of cigarette smoking,bone mineral density and risk of hip fracture: recognition of amajor effect. BMJ.1997;315:841-846.9. Forsen L, Bjartveit K, Bjorndal A, et al. Ex-smokers and risk ofhip fracture. Am J Public Health.1998;88:1481-1483.10. Cornuz J, Feskanich D, Willett WC, Colditz GA. Smoking,smoking cessation, and risk of hip fracture in women. Am JMed.1999;106:311-314.11. Hemenway D, Colditz GA, Willett WC, et al. Fractures andlifestyle: effect of cigarette smoking, alcohol intake, and relativeweight on the risk of hip and forearm fractures in middle-agedwomen. Am J Public Health.1988;78:1554-1558.12. Kiel DP, Baron JA, Anderson JJ, et al. Smoking eliminatesthe protective effect of oral estrogens on the risk for hip fractureamong women. Ann Intern Med.1992;116:716-721.13. Chow R, Harrison JE, Notarius C. Effect of two randomisedexercise programmes on bone mass of healthy postmenopausalwomen. BMJ (Clin Res Ed).1987;295:1441-1444.14. Joakimsen RM, Magnus JH, Fonnebo V. Physical activity andpredisposition for hip fractures: a review. Osteoporos Int.1997;7:503-513.15. Harrison JE, Chow R, Dornan J, et al. Evaluation of a programfor rehabilitation of osteoporotic patients (PRO): 4-year follow-up.The Bone and Mineral Group of the University of Toronto. Os-teoporos Int. 1993;3:13-17.16. Sherrington C, Lord SR. Home exercise to improve strengthand walking velocity after hip fracture: a randomized controlledtrial. Arch Phys Med Rehabil. 1997;78:208-212.17. Dias JJ, Wray CC, Jones JM & Gregg PJ. The value of early mo-bilisation in the treatment of Colles’ fractures. J Bone Joint Surg(British Volume).1987;69:463-467.18. Tinetti ME, Baker DI, McAvay G, et al. A multifactorial inter-vention to reduce the risk of falling among elderly people livingin the community. N Engl J Med. 1994;331:821-827.19. Lauritzen JB, Petersen MM, Lund B. Effect of external hipprotectors on hip fractures. Lancet.1993;341:11-13.20. Cooper C, Barker DJ, Wickham C. Physical activity, musclestrength, and calcium intake in fracture of the proximal femurin Britain. BMJ.1988;297:1443-1446.21. Smith RW, Frame B. Concurrent axial and appendicular os-teoporosis: its relation to calcium consumption. N Engl J Med.1965;273:72-78.22. Kanis JA. Calcium nutrition and its implications for osteo-porosis. Part II. After menopause. Eur J Clin Nutr.1994;48:833-841.23. Recker RR, Hinders S, Davies KM, et al. Correcting calciumnutritional deficiency prevents spine fractures in elderly women.

J Bone Min Res. 1996;11:1961-1996.24. Kanis JA, Johnell O, Gullberg B, et al. Evidence for efficacyof drugs affecting bone metabolism in preventing hip fracture.BMJ.1992;305:1124-1128.25. Cumming RG, Nevitt MC. Calcium for the prevention of os-teoporotic fractures in post-menopausal women. J Bone MinerRes.1997;12:1321-1329.26. Aloia JF, Vaswani A, Yeh JK, et al. Calcitriol in the treatmentof postmenopausal osteoporosis. Am J Med. 1988;84:401-408.27. Falch JA, Odegaard OR, Finnanger AM, Matheson I. Post-menopausal osteoporosis: no effect of three years treatment with1,25-dihydroxycholecalciferol. Acta Med Scand.1987;221:199-204.28. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3 and cal-cium to prevent hip fractures in the elderly women. N Engl JMed.1992;327:1637-1642.29. Chapuy MC, Arlot ME, Delmas PD, Meunier PJ. Effect of cal-cium and cholecalciferol treatment for three years on hip frac-tures in elderly women. BMJ.1994;308:1081-1082.30. Heikinheimo RJ, Inkovaara JA, Harju EJ, et al. Annual injec-tion of vitamin D and fractures of aged bones. Calcif Tissue Int.1992;51:105-110.31. Ranstam J, Kanis JA. Influence of age and body mass on theeffects of vitamin D on hip fracture risk. Osteoporos Int.1995;5:450-454.32. Cadarette SM, Jaglal SB, Murray TM, McIsaac WJ, Joseph L,Brown JP. Evaluation of decision rules for referring women forbone densitometry by dual-energy x-ray absorptiometry. JAMA.2001;286:57-63.33. Geusens P, Hochberg MC, van der Voort DJ, et al. Performanceof risk indices for identifying low bone density in postmenopausalwomen. Mayo Clin Proc. 2002;77:629-637.34. Black DM, Steinbuch M, Palermo L, et al. An assessment toolfor predicting fracture risk in postmenopausal women. Osteo-poros Int. 2001;12:519-528.35. Burger H, de Laet CE, Weel AE, Hofman A, Pols HA. Addedvalue of bone mineral density in hip fracture risk scores. Bone.1999;25:369-374.36. Seeley DG, Browner WS, Nevitt MC, et al. Which fractures areassociated with low appendicular bone mass in elderly women?The Study of Osteoporotic Fractures Research Group. Ann InternMed.1991;115:837-842.37. Colon-Emeric CS, Pieper CF, Artz MB. Can historical andfunctional risk factors be used to predict fractures in communi-ty-dwelling older adults? Development and validation of a clini-cal tool. Osteoporos Int. 2002;13:955-961.38. van Staa TP, Leufkens HG, Cooper C. Utility of medical anddrug history in fracture risk prediction among men and women.Bone. 2002;31:508-514.39. McGrother CW, Donaldson MM, Clayton D, Abrams KR,Clarke M. Evaluation of a hip fracture risk score for assessingelderly women: the Melton Osteoporotic Fracture (MOF) study.Osteoporos Int. 2002;13: 89-96.40. Walterui LY, Eng C, Covinsky KE. Risk of hip fracture in dis-abled community-living older adults. J Am Geriatr Soc.2003;51:50-55. 41. Cummings SR, Black DM, Thompson DE, et al. Effect of al-endronate on risk of fracture in women with low bone density butwithout vertebral fractures: results from the Fracture Interven-tion Trial. JAMA.1998;280:2077-2082.42. McClung MR, Geusens P, Miller PD, et al. Effect of risedronateon the risk of hip fracture in elderly women. Hip InterventionProgram Study Group. N Engl J Med. 2001;344:333-340.43. Kanis JA, Black D, Cooper C, et al. A new approach to the de-velopment of assessment guidelines for osteoporosis. Osteoporo-sis Int. 2002;13:527-536.44. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracturerisk. Osteoporosis Int. 2005;16:581-589.



IDENTIFICATION DES PATIENTS NÉCESSITANT UN TRAITEMENTANTIOSTÉOPOROTIQUE : QUI TRAITER AUJOURD’HUI ?

L’ augmentation de la probabilité de fracture s’exprime souvent en risquerelatif, en d’autres termes en rapport de risque, défini comme le taux desurvenue d’une fracture pour des individus avec un facteur de risque

donné sur celui sans ce facteur de risque. Ainsi une densité minérale osseuse(DMO) de catégorie ostéoporotique est associée à un rapport de risque de 9,6pour une fracture de hanche contre 1,7 pour le tabagisme, ce qui suggère qu’uneDMO basse confère un risque nettement plus important. Cependant, le risquerelatif seul ne permet pas de prendre de décisions cliniques : il n’exprime pasle véritable taux de survenue de fracture. Ainsi, le risque relatif de fracture à10 ans est identique chez les femmes ostéoporotiques âgées de 50 et de 70 ans(étant respectivement de 3,7 et 4,2, en comparaison avec leurs homologuesnormales) mais les taux absolus sont deux fois plus élevés dans le groupe plusâgé. Cette différence a des implications importantes pour la stratégie préven-tive du « qui traiter ». Plus instructif que le risque relatif est l’estimation durisque absolu pour un individu présentant un cortège de facteurs (âge, sexe, an-técédent de fracture, fracture de hanche parentale, corticothérapie prolongéepar voie générale, indice de masse corporelle, prise d’alcool >2 verres par jour)et qui subit une fracture dans les limites d’un intervalle relatif mais réel de 10ans environ. À ce titre, l’Organisation Mondiale de la Santé a récemment définiun algorithme multivarié à partir de plusieurs grandes études épidémiologiques.Le risque absolu présente un avantage très important : il est transparent dansles analyses économiques et s’adapte parfaitement avec la modélisation éco-nomique de la santé. La comparaison de l’impact des diverses interventionsthérapeutiques contre les fractures ostéoporotiques sur le risque absolu peutêtre utilisée pour fixer des seuils d’intervention pour chaque type de traitement,et ainsi cibler ces traitements sur les scénarios cliniques dans lesquels ils s’avè-rent les plus rentables.

✦

Osteoporosis is, by definition, a systemic skele-tal disease characterized by low bone massand microarchitectural deterioration of bone

tissue, resulting in an increase in bone fragility andsusceptibility to fracture. Osteoporosis may derivefrom a number of factors. Traditionally, we refer toprimary osteoporosis as a condition of reduced bonemass appearing in postmenopausal women (post-menopausal osteoporosis) and in elderly individu-als (senile osteoporosis). Consequently, primary os-teoporosis is in a way a normal phase of aging andis considered a disease when the risk of fracture isunacceptably high for the individual life expectan-cy. It is for this reason, as with cardiovascular dis-eases, that the intervention strategy is now evaluat-ed in terms of “lifetime risk” rather than absoluterisk.1

The high prevalence of primary osteoporosisplaces general practitioners (GPs) on the front line.However, several specialists, such as gynecologists,geriatricians, physiatrists, rheumatologists, endo-crinologists, and orthopedic surgeons, may be in-volved. All these physicians are dealing with themanagement of osteoporosis as part of their prac-tice, but occasionally they may operate as “bonespecialists,” or be a bone specialist in a referralcenter.

21Who will manage the diagnosis and treatment of osteoporosis? – Adami MEDICOGRAPHIA, VOL 28, No. 1, 2006


T he diagnostic term “osteoporosis” refers to a skeletal condition that pre-disposes to fragility fractures. Osteoporosis may be secondary to a num-ber of conditions and the specialists dealing with the primary disease are

also expected to manage the bone complications. This is the case for the largemajority of patients with rheumatic or endocrine diseases. In other conditions,the risk of osteoporosis is either ignored or the patients are referred (usually toolate) to “bone specialists.” Primary osteoporosis is traditionally defined as acondition of low bone mass appearing with advancing age especially in post-menopausal women. Even though several specialists may be involved in oneway or another, the prevalence of primary osteoporosis is so high that generalpractitioners (GPs) are inevitably the physicians who will see the largest num-ber of osteoporotic patients. Their level of knowledge of the disease is relativelygood, but they tend to grossly underestimate both the prevalence and the clini-cal consequences of the disease. Inadequate access to densitometric centers fur-ther limits the possibility of intervention by GPs, but the implementation of spe-cific screening programs was shown to be a good strategy for increasing boththe frequency and efficacy of interventions managed by GPs. Patients who havehad fractures are at very high risk of new fractures and an early interventionin these cases is highly warranted. Almost all fragility fractures require the in-tervention of orthopedic surgeons. Although their level of knowledge is good,orthopedic surgeons are scarcely keen to intervene, also because of their busysurgical practice. In such a context, the most successful strategy that has so farbeen explored is the appointment a trained nurse in the orthopedic departmentto ensure that the patient with a fragility fracture receives appropriate osteo-porosis management. The ineffective management of osteoporosis by orthope-dic surgeons and GPs contributes to osteoporosis being severely underdiag-nosed and undertreated. Medicographia. 2006;28:21-26. (see French abstract on page 26)

Keywords: osteoporosis management; osteoporosis awareness; orthopedicsurgeon; general practitioner; fracture intervention program

Silvano ADAMI, MDFull Professor of Rheumatology University of Verona, VeronaITALY

Address for correspondence: Professor Silvano Adami, Department of Rheumatology, Ospedale Valeggio, University of Verona, 37067 Valeggio, Verona, Italy(e-mail: [email protected])

Who will manage the diagnosis and treatment

of osteoporosis? b y S . A d a m i , I t a l y


BMD bone mineral densityDXA dual energy x-ray absorptiometry EMEA European Agency for the Evaluation of

Medicinal ProductsGP general practitionerIOF International Osteoporosis FoundationNOF National Osteoporosis Foundation

ed to effectively deal with the bone involvement ofosteoporosis secondary to rheumatic and endocrinediseases, respectively, but information on how ef-fectively this is done is lacking. The general impres-sion is that, for example, only a few endocrinologistsassess the risk of osteoporosis in their patients start-ing suppressive doses of T4, which is associated withsevere bone loss, and that not all rheumatologistsare aware that rheumatoid arthritis is a major riskfactor for osteoporosis.

The risk of osteoporotic fracture in patients onchronic treatment with corticosteroids is extreme-ly high. Although remedies for reducing this riskare available, the proportion of patients who receivepreventive therapy is still low.2 It is also likely thatthis proportion is particularly low for specialists,like lung specialists, whose practice is far removedfrom the problem of osteoporosis, but who are fre-quent prescribers of corticosteroids.

The manager of primary osteoporosis

A number of specialists are potentially involved inprevention strategies for osteoporosis. Since peakbone mass is an important contributor to bone massin the elderly, pediatricians should be aware of therisk factors associated with inadequate acquire-ment of peak bone mass. Most of the patients seenby geriatricians are at high risk of primary osteo-porosis and the disease is considered of direct in-terest for the endocrinologist and even more so forthe rheumatologist. The latter is frequently involvedfor the differential diagnosis of back pain. However,the three health care providers dealing with thelargest number of patients at risk of osteoporosisare gynecologists, orthopedic surgeons, and gener-al practitioners (GPs).

◆ GynecologistsGynecologists, by dealing with menopausal symp-toms, have been heavily involved in the manage-ment of osteoporosis for a long time and osteo-porosis has been rated as one of the main factors toconsider when recommending hormonal therapy,testifying to a good level of awareness for osteo-porosis.

Gynecologists are, in principle, involved in theearly diagnosis and early treatment of the disease.Both these areas of intervention have been debatedand challenged in the most recent guidelines.

Because bone loss in women occurs at menopause,a readily diagnosable event, it has been intuitivelyreasoned that screening should be considered inwomen at the time of menopause. The most obvi-ous intervention is testing by bone mineral density(BMD) by dual energy x-ray absorptiometry (DXA).

There have been several analyses of the potentialutility of screening at the time of the menopause.3,4

These analyses acknowledge that the cost of screen-ing is not the dominant factor, since most treat-ments are relatively expensive. Opinions vary overthe use of BMD as a screening tool, but most do notrecommend widespread screening at the time of themenopause on the basis of BMD alone. The reasonsrelate to sensitivity and specificity. It has been esti-

Osteoporosis may be secondary to a large varietyof other conditions. The primary condition iden-tifies the reference specialist whose interests andknowledge may vary considerably.

In this review, I will analyze the type of interven-tion carried out by the individual specialists.

The manager of secondary osteoporosis

Secondary osteoporosis is defined a condition of re-duced bone mass resulting from a large variety ofspecific and well-defined disorders (Table I).

In some cases, osteoporosis may be so severe (eg,corticosteroid-induced osteoporosis and rheuma-toid arthritis) as to represent a major source of mor-bidity in addition to the underlying disease. In oth-ercases,osteoporosis may also be severe, butbecauseof the short life expectancy may not be considereda major cause of concern (eg, multiple myeloma).In some conditions, osteoporosis is part of the dis-ease, such that by treating the disease, osteoporosisis also cured (eg, primary hyperparathyroidism).Rheumatologists and endocrinologists are expect-

22 Who will manage the diagnosis and treatment of osteoporosis? – AdamiMEDICOGRAPHIA, VOL 28, No. 1, 2006


◆ Endocrine/metabolic diseases– Hyperparathyroidism– Thyrotoxicosis– Cushing syndrome– Hypogonadism– Diabetes mellitus– Pregnancy– Anorexia nervosa

◆ Inflammatory diseases– Rheumatoid arthritis– Ankylosing spondylitis

◆ Functional– Immobilization/weightlessness– Chronic obstructive lung diseases– Postgastrectomy– Hepatic disease (particularly primary biliary

cirrhosis)– Alcohol abuse– Following organ transplantation

◆ Hematopoietic– Multiple myeloma– Lymphoma/leukemia– Mastocytosis

◆ Congenital– Osteogenesis imperfecta– Menkes syndrome– Ehlers-Danlos syndrome– Homocysteinuria– Marfan syndrome

◆ Drugs– Corticosteroids– Thyroxine– Anticonvulsants (barbiturates, phenytoin)– Anticoagulants (heparin, coumarin)– Antimetabolites (methotrexate, cyclosporine) Table I. Etiology of

secondary osteoporosis.

awareness of osteoporosis in women by the timeof the menopause and to carry out an initial assess-ment of osteoporosis risk.

◆ General practitionersThe World Health Organization (WHO) has definedosteoporosis in terms of bone mass that is morethan 2.5 SD below the mean peak bone mass inhealthy young adults.3 Based on these criteria, ap-proximately 15% of women aged 50 and over haveosteoporosis and for those over the age of 80, theproportion rises to 70%.12 Fifty-one out of 1000women aged 65 and over or 6 per 1000 men andwomen of all ages have sustained a hip fracture.The prevalence of vertebral deformities has been es-timated in several epidemiological studies, by adopt-ing different diagnostic criteria: the prevalence ofvertebral deformities among postmenopausal wom-en ranges from 18% to 25%.13

Based on these epidemiological findings, a GPtaking care of 2000 adult subjects is expected tohave among his patients approximately 300 personswith osteoporosis and/or with a vertebral or hipfracture. Given these figures, osteoporosis shouldbe regarded as one of the main areas of interventionfor GPs and makes them the most obvious healthprovider for the management of the disease.

In a recent survey in 10 000 patients attending adensitometry center for osteoporosis screening, weobserved that 16% of all patients were referred byGPs (manuscript in preparation). The overall num-ber is very large, but the relative proportion is ratherlow. The general impression is that GPs are keenerto refer their patients to specialists even for evalu-ating whether DXA screening is appropriate.

A few studies have examined the knowledge ofGPs, including their knowledge regarding the di-agnosis and treatment of osteoporosis. Many fami-ly doctors in the United Kingdom report that theyhave never seen a case of osteoporosis.14 In specificstudies, GPs showed a reasonable level of knowledgeabout the definition of osteoporosis and its risk fac-tors, but they tended to underestimate the preva-lence of the disease.15,16 In data from a large sampleof postmenopausal women attending 925 primarycare physicians in Australia, 29% of women report-ed one or more fractures after the menopause.17

However, the great majority (72%) were not on anyspecific therapy.

In my experience, the level of knowledge amongGPs is distributed in a patchy manner. In our HealthDistricts (Azienda Sanitaria Locale 22, RegioneVeneto, Italy) our center is the only one providinga bone densitometry service. We have found thatonly 18% of local GPs directly refer their patientsfor osteoporosis screening following the regulatoryrestriction of the RegioneVeneto.For patients underthe care of other GPs, the referral is made throughother specialists (in order of frequency: gynecolo-gists, physiatrists, and orthopedic surgeons) andthen inevitably to a much lower extent.

In Spain, a survey of 850 GPs revealed a reason-able level of knowledge with a mean correct re-sponse rate of 63% in a questionnaire on the mostimportant risk factors.18 Younger practitioners were

mated that 1000 patients would need to be screenedto detect 100 for treatment, and the maximal im-pact on the community after menopause (% of hipfractures saved) would be approximately 8%.2

Current guidelines consistently recommend5 thatall women have a measurement of BMD at the ageof 65 years, while earlier screening is justified onlyin the presence of specific risk factors. In otherwords, guidelines negate the appropriateness ofgeneralized screening by the time of menopause.

Hormone therapy is also an issue in the contextof screening at the menopause. Estrogen/hormonetherapy is an effective antiresorptive agent for pre-venting postmenopausal bone loss and, at mediumestrogen doses, is equivalent to bisphosphonates inits effect on bone density. Hormone therapy reducesfractures even in women without osteoporosis andmay be the most effective antiresorptive agent inpreventing fractures.6 For these reasons, for a num-ber of years, hormone therapy has been the mostwidely accepted intervention for the prevention ofpostmenopausal osteoporosis. However, hormonetherapy must be taken continuously for bone pro-tection, since, after discontinuation, rapid boneloss ensues and fracture rates increase. It was alsorecognized that only treatment prolonged for atleast 10 years by the time of menopause providesoptimal benefits in terms of future fracture risk.However, even this effect tends to wane 15 to 25years later.7,8

The need for long-term treatments in order toachieve clinically meaningful benefits 2 decades lat-er, when the risk of fracture becomes high, con-trasts with two recent observations. The durationof hormone therapy in clinical practice is muchshorter: it has been estimated that only about 10%of American women continue treatment for morethan 1 year.9 In addition, the results of the Women’sHealth Initiative (WHI) study10 indicate a benefit-side effect ratio that is particularly negative thelonger the duration and the older the age of the pa-tients! As a consequence of these obvious contra-dictions, the European Agency for the Evaluationof Medicinal Products (EMEA) decided to modifythe label of hormone replacement therapy, deletingthe indication of prevention and treatment of os-teoporosis. These various considerations have sug-gested that interventions might be more optimallytargeted in later life, perhaps with the use of non-hormonal treatment modalities.11 The risk of osteo-porosis might still be considered when deciding onthe appropriateness of initiating hormonal therapyat the menopause, but only as an additional reasonto the main aim of relieving menopausal symptoms.

Gynecologists should become aware of this newphilosophy and redesign their approach to osteo-porosis prevention. A DXA scan can be recommend-ed at the time of menopause not only in women atrisk, but also in women generally concerned aboutosteoporosis. However, what should be realized isthat a normal value at the age of 50 years should notexclude another assessment at 65 years, as recom-mended in all guidelines.

In any case, the role of the gynecologists remainscrucial. It should be their responsibility to generate



scan34 and only a minority (0%-24%) of the patientsunderwent a DXA evaluation while in hospital.31,35

Only 2.8% of patients who sustained a fracture ofthe distal radius were evaluated for the presence ofosteoporosis in an American survey.28

According to National Osteoporosis Foundation(NOF) guidelines,5 individuals older than 70 yearswho have a fragility fracture can be treated for os-teoporosis without undergoing a DXA scan. Mostof the patients with fragility fractures seen by or-thopedic surgeons fall into this category. Yet only 6of 56 Danish orthopedic surgery departments treatpatients with low-energy fractures for osteoporosis.34

It has been reported that both in United States andin the United Kingdom only a small proportion ofpatients with a hip fracture are discharged with anykind of treatment.33,35,36

This disappointing attitude of orthopedic sur-geons to detecting and treating osteoporosis hasbeen recently investigated in a multinational surveysupported by the International Osteoporosis Foun-dation (IOF) and carried out among 3422 orthope-dic surgeons in France, Germany, Italy, Spain, theUK, and New Zealand.37 The survey revealed sub-stantial differences between countries in the percep-tion of the osteoporosis problem. German orthope-dic surgeons are apparently very keen to order aDXA evaluation in patients with fragility fracturesand to prescribe medication, while orthopedic sur-geons in the United Kingdom, France, and New Zea-land prefer to refer patients to other specialists forboth diagnosis and treatment. Overall, more thanhalf of the orthopedic surgeons surveyed said thatthey received no or insufficient training in osteo-porosis. While only approximately 40% of orthope-dic surgeons refer patients with a fragility fracturefor a bone density test, 60% to 70% admit that theorthopedic surgeon should assume the responsibil-ity for identifying and initiating the assessment ofosteoporosis in such patients!

The results of the IOF survey37 among Europeanorthopedic surgeons provide a somewhat confus-ing picture with a self-declared interest for osteo-porosis management that contradicts the extremelypoor data from patients discharged from orthope-dic surgery departments after any type of fracture.However, it should be mentioned that only 1 in 4European orthopedic surgeons responded to thesurvey. The surgeons who responded had probablyalready positively selected themselves! The generalimpression is that interest in osteoporosis is greateramong orthopedic surgeons working predominant-ly in outpatient clinics rather than in hospitals witha large surgical practice. Indeed, during the IOFsurvey, German orthopedic surgeons who showedthe greatest interest in osteoporosis were largelymade up of physicians working in private practiceonly. It therefore appears that in a busy orthopedicsurgery department orthopedic surgeons find it eas-ier to ignore the underlying cause and simply “treatthe fracture.”38 In such a setting, the concept of afracture liaison nurse has been tried with muchsuccess in several countries. The Glasgow centerhas pioneered this procedure, which consists in del-egating a trained nurse of the orthopedic depart-

those with the most up-to-date information on thedisease. The GPs interviewed also reported that aspecific program for osteoporosis was implementedin only 4% of their primary care centers and thatbone densitometry was readily available to 27.8% ofthem. Among GPs in the United Kingdom, a caseselection strategy for osteoporosis combined withopen access to DXA scans as opposed to no case-finding strategy and no DXA scan access is not as-sociated with an increased prescription rate of boneactive agents, but rather with more accurate treat-ment targeting.19 The implementation of specificprograms for osteoporosis management aimed atGPs appears to be cost-effective. The outcomes ofsuch a program set up in Geisenger (Pa, USA)20 arequite striking. The age-adjusted incidence of hipfracture fell significantly and this was associatedwith substantial reduction in health care costs!

The inadequate access to densitometric centersis obviously a factor limiting prevention and treat-ment of osteoporosis by GPs. However, the imple-mentation of specific screening programs, associ-ated with direct access to DXA evaluation, appearsto be effective and even more economically efficientthan referral to specialists.21

◆ Orthopedic surgeonsOrthopedic surgeons are the specialists most close-ly involved with fragility fractures. All peripheralfractures require intervention by the orthopedicsurgeon and he/she is usually the first and oftenonly physician seen by the fracture patients. Theproportion of patients requiring hospitalization af-ter a symptomatic vertebral fracture varies consid-erably among different European countries,22 and isof the order of 2% to 10%.23 In the United States,symptomatic vertebral fractures account for 111 999hospitalizations, a rate of 17.1 per 10 000 women.The annual rate in men was 3.7 per 10 000.24 Thehospital unit where patients with symptomatic ver-tebral fractures are referred has never been specif-ically investigated, but is likely to be in most casesan orthopedic ward. In the last decade, interest onthe part of orthopedic surgeons in recent painfulvertebral fractures has increased due to the possi-bility of successful treatment of symptoms by ver-tebroplasty.25

In the general strategy for preventing fragilityfractures, orthopedic surgeons should play a cru-cial role, because they are the specialists contactingthe patients at highest risk. Patients with low-en-ergy fracture of the wrist, hip, proximal humerus,or ankle have a nearly 4 times greater risk of futurefractures than individuals who have never experi-enced a low-energy fracture.26,27 Despite the fact thatorthopedic surgeons see most of the fragility frac-tures, a number of reports suggest that they do notmanage the risk of new fractures. Up to 95% of frac-ture patients are discharged without adequate de-termination of the cause of the fracture and severalrecent reports indicate that the majority of the pa-tients with recent fractures have not been assessedfor low BMD.28-33 It has been reported that only 13%of orthopedic surgery departments in Denmark re-fer their patients with low-energy fracture for DXA



el of knowledge about the disease is inconsistentamong specialists and within the same specialty.Generally, the highest level of expertise in osteo-porosis is found among rheumatologists and en-docrinologists, who make up the largest proportionof “bone specialists.” Even when the average levelof knowledge is acceptable, the intervention is ham-pered among GPs by the underestimation of theprevalence of the disease and among orthopedicsurgeons by their reluctance to intervene. Ortho-pedic surgeons and GPs are the physicians likely tosee the vast majority of osteoporotic patients. Thelack of involvement of the former and the underes-timation of the prevalence by the latter contributesto making osteoporosis severely underdiagnosedand undertreated. ❒

ment to ensure that fragility fracture patients re-ceive appropriate osteoporosis evaluation in additionto the fracture management.39 Using this approach,three quarters of patients were considered for BMDtesting and 20% of patients were recommendedtreatment without the need for BMD testing.39 Thesefigures are impressively different from those ob-served in orthopedic department in all Westerncountries.

Conclusions

Two characteristics make osteoporosis a peculiarcondition: it is very common and it is of multifac-torial origin. For these reasons, a large variety ofphysicians are involved in its management. The lev-



REFERENCES1. Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A.Ten-year risk of osteoporotic fracture and the effects of risk fac-tors on screening strategies. Bone. 2002;30:251-258.2. Ramsey-Goldman R. Missed opportunities in physician man-agement of glucocorticoid-induced osteoporosis? Arthritis Rheum.2002;46:3115-3120. 3. World Health Organisation. Assessment of fracture risk inscreening for osteoporosis. Geneva, Switzerland: WHO Techni-cal Report Series, No 843; 1994.4. Marshall DA, Sheldon TA, Jonsson E. Recommendations forthe application of bone density measurement. Int J Technol AssessHealth Care.1997;13:411-19.5. National Osteoporosis Foundation (NOF). Physician’s Guide toPrevention and Treatment of Osteoporosis.Washington, DC: Na-tional Osteoporosis Foundation; 2003.6. Cauley JA, Robbins J, Chen Z, et al; Women’s Health InitiativeInvestigators. Effects of estrogen plus progestin on risk of frac-ture and bone mineral density: the Women’s Health Initiative ran-domized trial. JAMA. 2003;290:1729-1738. 7. Cauley JA, Seely DG, Ensud K, Ettinger B, Black D, CummingsSR for the Study of Osteoporotic Fracture Research Group. Es-trogen replacement therapy and fracture in older women. AnnIntern Med.1994;122:9-16.8. Felson DT, Yuquin Z, Hannan MT, Keil DP, Wilson PWF, An-derson JJ. The effect of postmenopausal estrogen on bone densityin elderly women. N Engl J Med. 1993;329:1141-1146. 9. Barrett-Connor E, Gore R, Browner WS; Cummings SR. Pre-vention of osteoporotic hip fracture: global versus high-risk strate-gies. Osteoporos Int.1998;8(suppl 1):S2-S7.10. Rossouw JE, Anderson GL, Prentice RL, et al; Writing Groupfor the Women’s Health Initiative Investigators. Risks and bene-fits of estrogen plus progestin in healthy postmenopausal wom-en: principal results from the Women’s Health Initiative ran-domized controlled trial. JAMA. 2002;288:321-333. 11. Kanis JA. Treatment of osteoporosis in elderly women. Am JMed.1995;98(suppl 2A):60-66.12. Schuit SCE, van der Klift M, Weel AEAM, et al. Fracture in-cidence and association with bone mineral density in elderly menand women: the Rotterdam study. Bone.2004;34:195-202. 13. Cummings SR, Melton LJ. Epidemiology and outcomes ofosteoporotic fractures. Lancet.2002;359:1761-1767.14. Edwards L, Fraser M. How do we increase awareness of osteo-porosis? Bull Clin Rheumatol.1997;11:631-644.15. Werner P, Vered I. Attitudes, knowledge and practice regard-ing diagnosis of osteoporosis: a survey of Israeli physicians. Ag-ing: Clin Exp Res. 2002;14:52-59.16. Fleming R, Patrick K. Osteoporosis prevention: pediatricians’knowledge, attitudes, and counseling practices. Prev Med.2002;34:411-421.17. Eisman J, Clapham S, Kehoe L. Osteoporosis Prevalence andLevels of Treatment in Primary Care: The Australian BoneCareStudy. J Bone Miner Res. 2004;19:1969-1975.18. Perez-Edo L, Ciria Recasens M, Castelo-Branco C, et al. Man-agement of osteoporosis in general practice: a cross-sectional sur-vey of primary care practitioners in Spain. Osteoporos Int. 2004;15:252-257.19. Morison LS, Tobias JH. Effect of a case-finding strategy forosteoporosis on bisphosphonate prescribing in primary care. Os-teoporos Int. 2005;16:71-77.20. Newman ED, Ayoub WT, Starkey RH, Diehl JM, Wood GC. Os-teoporosis disease management in a rural health care population:hip fracture reduction and reduced costs in postmenopausal wom-

en after 5 years. Osteoporos Int. 2003;14:146-151.21. Dhillon V, Creiger J, Hannan J, Hurst N, Nuki G. The effect ofa DEXA scanning on a clinical decision making by general practi-tioners: a randomized, prospective trial of direct access versus re-ferral to a hospital consultant. Osteoporos Int.2003;14:326-333.22. Johnell O, Gullberg B, Kanis JA. The hospital burden of ver-tebral fracture in Europe: a study of national register sources. Os-teoporos Int.1997;7:138-44. 23. Kanis JA, McCloskey EV. Epidemiology of vertebral osteo-porosis. Bone.1992;13:S1-S10. 24. Jacobson SJ, Cooper C, Gottlied MS, et al. Hospitalization withvertebral fracture among aged: A national population-based study,1986-89. Epidemiology.1992;3:515-518. 25. Hide IG, Gangi A. Percutaneous vertebroplasty: history, tech-nique and current perspectives. Clin Radiol. 2004;59:461-467.26. Klotzbuecher C, Ross P, Landsman P, Abbott T, Berger M. Pa-tients with prior fractures have an increased risk of future frac-tures: a summary of the literature and statistical synthesis. J BoneMiner Res.2000;15:721-73927. Robinson CM, Royds M, Abraham A, McQueen MM, Court-Brown CM, Christie J. Refractures in patients at least forty-fiveyears old. A prospective analysis of twenty-two thousand and six-ty patients. J Bone Joint Surg Am. 2002;84:1528-1533.28. Freedman KB, Kaplan FS, Bilker WB, Strom BL, Lowe RA.Treatment of osteoporosis: are physicians missing an opportunity?J Bone Joint Surg Am. 2000;82:1063-1070.29. Bellantonio S, Fortinsky R, Prestwood K. How well are com-munity-living women treated for osteoporosis after hip fracture?J Am Geriatr Soc. 2001;49:1197-1204.30. Castel H, Bonneh DY, Sherf M, Liel Y. Awareness of osteo-porosis and compliance with management guidelines in patientswith newly diagnosed low-impact fractures. Osteoporos Int.2001;12:559-564.31. Harrington JT, Broy SB, Derosa AM, Licata AA, Shewmon DA.Hip fracture patients are not treated for osteoporosis: a call toaction. Arthritis Rheum. 2002;47:651-654.32. Khan SA, de Geus C, Holroyd B, Russell AS. Osteoporosis fol-low-up after wrist fractures following minor trauma. Arch InternMed. 2001;161:1309-1312.33. Kiebzak GM, Beinart GA, Perser K, Ambrose CG, Siff SJ,Heggeness MH. Undertreatment of osteoporosis in men with hipfracture. Arch Intern Med. 2002;162:2217–2222.34. Eiken PA. Osteoporosis: assessment, prevention and treat-ment in Danish departments of orthopedic surgery [in Danish].Ugeskr Laeger. 1996;158:5790-5793.35. Gardner MJ, Flik KR, Mooar P, Lane JM. Improvement in theundertreatment of osteoporosis following hip fracture. J BoneJoint Surg Am. 2002;84:1342-1348. 35. Marshall D, Johnell O, Wedel H. Meta-analysis of how wellmeasures of bone mineral density predict occurrence of osteo-porotic fractures. BMJ.1996;312:1254-1259.36. Torgerson DJ, Dolan P. Prescribing by general practitionersafter an osteoporotic fracture. Ann Rheum Dis.1998;57:378-379.37. Dreinhofer KO, Anderson M, Feron JM, et al. Multinationalsurvey of osteoporotic fracture management. Osteoporos Int.2005;16:S44-S53.38. Stephen AB, Wallace WA. The management of osteoporosis.J Bone Joint Surg Br. 2001;83:316-323.39. McLellan AR, Gallacher SJ, Fraser M, McQuillian C. The frac-ture liaison service: success of a program for the evaluation andmanagement of patients with osteoporotic fracture. OsteoporosInt. 2003;14:1028-1034.



QUI PRENDRA EN CHARGE LE DIAGNOSTIC ETLE TRAITEMENT DE L’OSTÉOPOROSE ?

L e terme diagnostique d’« ostéoporose » se réfère à un état pathologiquedu squelette qui prédispose à des fractures de fragilité. L’ostéoporose peutêtre secondaire à un certain nombre de troubles et les spécialistes qui

s’occupent de la maladie primitive doivent aussi en traiter les complicationsosseuses. C’est le cas pour la grande majorité des patientes qui présentent desmaladies rhumatologiques ou endocriniennes. Dans d’autres contextes patho-logiques, soit le risque d’ostéoporose est ignoré, soit les patientes sont adressées(habituellement trop tard) à des « spécialistes des os ». L’ostéoporose primaireest traditionnellement définie comme un état pathologique où la masse osseuseest basse, apparaissant à un âge avancé et en particulier chez les femmes post-ménopausées. Même si plusieurs spécialistes sont impliqués à divers titres dansle suivi de ces patientes, la prévalence de l’ostéoporose primaire est telle que lesmédecins généralistes (MG) sont inévitablement ceux qui verront le plus grandnombre de patientes ostéoporotiques. Ceux-ci connaissent relativement bien lamaladie, mais ont tendance à beaucoup en sous-estimer la prévalence et lesconséquences cliniques. Si l’accès insuffisant aux centres de densitométrie li-mite d’autant la possibilité d’intervention des MG, la mise en œuvre de pro-grammes spécifiques de dépistage semble une bonne stratégie pour augmen-ter la fréquence et l’efficacité des traitements pris en charge par les MG. Lespatientes ayant des antécédents de fractures ont un risque très élevé de nou-velles fractures et dans ce cas, un traitement précoce est hautement justifié.Presque toutes les fractures de fragilité nécessitent l’intervention des chirur-giens orthopédiques. Cependant, bien que le niveau de connaissance de ces der-niers soit bon, ils ne sont guère enthousiastes pour intervenir, surtout à causede leur surcharge de travail. Ainsi, la stratégie qui s’est avérée la plus fruc-tueuse jusqu’à maintenant est le recrutement d’infirmières expérimentées dansun service d’orthopédie pour veiller à ce que les patientes présentant des frac-tures de fragilité soient prises en charge correctement pour l’ostéoporose. Laprise en charge inefficace de l’ostéoporose par les chirurgiens orthopédistes etles MG contribue à faire de cette pathologie une maladie sous-diagnostiquéeet sous-traitée.

✦

A skeletal disorder characterized by compro-mised bone strength predisposing a person toan increased risk of fracture (…) bone strengthreflects the integration of two main features:bone density and bone quality.2

the definition of osteoporosis is still largely basedon BMD values. This chapter will review the stan-dard method for assessing BMD, DEXA, the clinicaluse of BMD testing, and potential pitfalls of usingBMD alone to guide treatment decisions.

DXA measurements and fracture risk

Until recently little distinction was made betweendefinitions of osteoporosis (typically defined by BMDvalues) and fracture risk. Yet, this distinction is crit-ical, particularly as the goal of treatment is to re-duce fracture risk and BMD, while important, is onlyone component of fracture risk. Indeed, additionalrisk factors such as age, prior fragility fracture, bodymass index, use of corticosteroids, family history ofosteoporosis, and current smoking, among others,have been shown in prospective studies to be con-sistently and strongly associated with fracture riskand are somewhat independent of BMD.3-10 The fol-lowing section reviews the influence that four ofthese factors—low BMD, age, prior fragility frac-

Osteoporosis is traditionally defined as “a sys-temic skeletal disease characterized by lowbone mass and microarchitectural deterio-

ration of bone tissue with a resultant increase infragility and risk of fracture.1 Reflecting on this def-inition, it is clear that bone mineral density (BMD),typically assessed by dual-energy x-ray absorptiom-etry (DXA) and operationally based on T-scores, iskey to defining the condition. Indeed, even if weconsider the recently updated definition of osteo-porosis:

27Risk factors for osteoporosis and use of BMD in guiding treatment – Josse and Jamal MEDICOGRAPHIA, VOL 28, No. 1, 2006


W hile bone mineral density (BMD) assessed by dual-energy x-ray ab-sorptiometry (DXA) is a key component of fracture risk, it has becomeincreasingly clear that other factors such as age, prior fragility frac-

ture, and family history of osteoporosis also influence risk. Indeed, the use ofBMD alone as a screening strategy to identify men and women at high risk forfracture has a poor sensitivity; most individuals who fracture have “normal”BMD. One way to improve the clinical utility of BMD testing is to consider theresult together with other clinical risk factors to determine a fracture proba-bility. Clinicians can use these fracture probabilities to guide treatment deci-sions. In addition, clinicians can apply clinical risk factors to help guide whoshould have BMD testing—there are some patients in whom the combinationof risk factors yields a fracture risk so high or so low that a BMD test will notchange treatment decisions. Incorporating clinical risk factors and BMD resultsis similar to the current approach of combining laboratory data and risk factorsto guide treatment decisions in patients with cardiovascular disease. Ultimate-ly, this approach will improve the clinical utility of BMD testing and enhancethe care of patients at risk for fracture. Medicographia. 2006;28:27-32. (see French abstract on page 32)

Keywords: osteoporosis; fracture; risk factor; bone mineral density; dual-energy x-ray absorptiometry; treatment

Address for correspondence: Robert G. Josse, St Michael’s Hospital, 61 Queen Street East, 6th Floor, Suite 6122, Toronto, Ontario M5C 2T2, Canada(e-mail: [email protected])

Robert G. JOSSE, MB, BS, FRCP, FRCPC, FACPAssociate Physician-in-Chief, St Michael’s Hospital and Professor of Medicine, University of TorontoToronto, Ontario, CANADA

Sophie A. JAMAL, MD, PhD, FRCPCEndocrinologist, St Michael’s Hospital and AssistantProfessor of Medicine, University of TorontoToronto, Ontario, CANADA

▲ ▲▲


BMD bone mineral densityDXA dual energy x-ray absorptiometry LSC least significant changeSOF Study of Osteoporotic Fractures

Risk factors for osteoporosis:use of bone mineral density in

guiding treatment decision b y R . G . J o s s e a n d S . A . J a m a l , C a n a d a

Low BMD by DXA is a risk factor for fracture

◆ T-scores, Z-scores, and defining osteoporosisDXA measurements correlate well with fracturerisk, so although more fractures occur in peoplewith nonosteoporotic BMD scores (Figure 1), thefracture rate is higher the lower the BMD.11,12 Notethat there is no “fracture threshold” or cut pointbelow which fracture risk abruptly increases. In-deed the predictive ability of BMD for hip fracture issimilar to the relationship between blood pressureand stroke, and better than the relationship betweencholesterol and cardiovascular disease.13

BMD results from DXA are reported using twoterms: the T-score and the Z-score. Both of theseterms rely on a standard deviation (SD) for the mea-surement. The SD represents the normal variabilityin a measurement in a population: the distance be-tween the 5th and 95th percentile of a group coversabout 4 SDs. For hip and spine BMD, 1 SD corre-sponds to about 10% to 15% of the mean value.14

A Z-score is the number of SDs below (minus) orabove (plus) the mean value for people of the sameage. A T-score is the number of SDs below the meanvalue of BMD for young (20- to 29-year-old) adults.Osteoporosis is defined as a T-score of ≤-2.5 at any ofthe lumbar spine, femoral neck, or total hip sites.15

◆ DXA: which site to useDXA can measure BMD at the spine, hip, forearm,heel, and total body. The diagnosis of osteoporosisvaries greatly depending on the measurement site,and the number of sites measured. That said, hipDXA is considered by many to be the “gold stan-dard” for diagnosing osteoporosis and assessingfracture risk.16-18 Hip DXA is a stronger predictor ofhip fracture than BMD at other sites and predictsthe risk of all fractures as well as or better than oth-er measurements (Table I).19

Spine BMD measures the lumbar vertebrae, typ-ically L1 to L4. Note that spine BMD can be arti-factually increased by degenerative arthritis andaortic calcification, both of which become increas-ingly common and severe after age 65. As a result,spine BMD may increase after age 65, rather thandecrease, which might be seen with BMD measure-ments at other sites.20

The relationship between BMD and fracture riskis customarily quantified by the “relative risk (RR)per standard deviation decrease in BMD.” For ex-ample, a relative risk to standard deviation ratio(RR/SD) of 1.5 means that a woman with a BMDthat is 1 SD below the mean for her age has a 50%higher fracture risk than a woman with a BMD thatis average for her age. Among postmenopausal whitewomen, the relationship between hip BMD and hipfracture is about 2.6 RR/SD.17

There are fewer data on the relationship betweenBMD and fracture risk in men, premenopausalwomen, and nonwhite populations. However, mostexperts agree that for men the same threshold asutilized for women is reasonable since for any abso-lute BMD measurement the aged-adjusted fracturerisk is more or less the same.21-24

ture, and family history of osteoporosis—has onfracture risk. Note, that while we will discuss theeffect of each separately, patients often have morethan one of these risk factors, which may interactto increase fracture risk.

28 Risk factors for osteoporosis and use of BMD in guiding treatment – Josse and JamalMEDICOGRAPHIA, VOL 28, No. 1, 2006


Figure 1. Population bone mineral density (BMD) distribution, fracture rates, andnumber of women with fractures. Adapted from reference 12: Siris ES, Chen YT, Abbott TA, et al. Bone mineral density thresholds forpharmacological intervention to prevent fractures. Arch Intern Med. 2004;164:1108-1112. Copyright ©2004, American Medical Association.

BMD T-scores (peripheral)

BMD distribution

Fracture rate

No. of women with fractures

Frac

ture

per

100

0 pe

rson

-yea

rs No. of w

omen w

ith fractures

60

50

40

30

20

10

0

450

400

350

300

250

200

150

100

50

0>1.0 0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –1.5 to –2.0 <–2.0

1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5

Fracture BMD measurement sitesite Forearm Lumbar spine Calcaneus Femoral neck

Wrist 1.8 1.6 1.8 1.6Vertebrae 1.6 2.0 n/a 1.9Hip 1.6 1.3 1.8 2.6

Major risk factors

Age >65 years

Vertebral compression fracture

Fragility fracture after age 40

Family history of osteoporotic fracture(especially maternal hip fracture)

Systemic glucocorticoid therapy of >3 months’ duration

Malabsorption syndrome

Primary hyperparathyroidism

Propensity to fall

Osteopenia apparent on x-ray film

Hypogonadism

Early menopause (before age 45)

Minor risk factors

Rheumatoid arthritis

Past history of clinical hyperthyroidism

Chronic anticonvulsant therapy

Low dietary calcium intake

Smoker

Excessive alcohol intake

Excessive caffeine intake

Weight of <57 kg

Weight loss >10% of weight at age 25

Chronic heparin therapy

Table II. Risk Factors for fragility fracture that identify people who should be assessedfor osteoporosis. Adapted from reference 28: Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Societyof Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.CMAJ. 2002;167:S1-S34. By permission of the publisher. Copyright © 2002, CMA Media Inc.

Table I. Comparison of ability of various bone mass measurements topredict fracture risk. n/a, not available.Adapted from reference 19: No authors listed. Osteoporosis: review of the evidencefor prevention, diagnosis, and treatment, and cost-effective analysis. Status report.Osteoporos Int. 1998(suppl 4):1-88. Copyright © 1998, Springer Verlag USA.

fracture risks; the 80-year-old woman will have aseveral-fold greater risk of hip fracture than the50-year-old woman.37 The relationship between ageand fracture is illustrated in Table III and Figure 4(next page).

◆ Risk factors for fracture—putting DXA incontextThere have been several recently published guide-lines concerning the diagnosis and treatment of os-teoporosis.25-28 In general, in all of these guidelines,individuals are identified as being at risk for fractureon the basis of clinical risk factors (Table II),28 thenreferred for BMD testing and subsequently offeredintervention if the BMD falls below a given thresh-old. Guidelines from Europe suggest interventionshould be offered to patients who have osteoporo-sis (T-score of ≤--2.5). In North America, treatmentis recommended at T-scores of between --1.5 and--2.0.29 The clinical risk factors noted in all theguidelines are similar and include personal historyof fracture, long-term use of glucocorticoids, and agegreater than 65 years. Figures 2 and 3 illustrate therecommendations from the recently published Ca-nadianevidence-based guidelines for the assessmentand management of osteoporosis.28 A limitation ofall these guidelines is the fact that they use BMDas a case-targeting strategy (screening test) and be-cause most fractures occur in patients without anosteoporotic BMD T-score, this test has a poor sen-sitivity. In addition to guidelines, researchers havedeveloped decision aids designed to help cliniciansin selecting patients for BMD testing.27,30,31 Thesedecision aids have used a variety of risk factors,such as age, prior fractures, smoking, and low bodyweight, to identify patients at high risk for fracturein whom BMD testing would be useful. These toolshave a high sensitivity (identifying 95% to 99% ofwomen who have osteoporosis, defined as a T-scoreof ≤--2.5 at the hip), but a poor specificity (only 10%to 25% of postmenopausal women without osteo-porosis would avoid testing).32

◆ AgeThe incidence of both vertebral and nonvertebralfractures rises steadily after about age 50 in menand women.33-35 While part of this increased fracturerisk is related to bone loss there are also age-relat-ed changes, such as alterations in microarchitectureand an increased propensity for falling.36 Such anincrease in fracture risk is independent of BMD.As a result, two women with exactly the same BMD,one at age 50 and one at age 80 have very different



Figure 2. Who should be tested for osteoporosis? Abbreviations: BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry.Adapted from reference 28: Brown JP, Josse RG; Scientific Advisory Council of the Osteoporosis Societyof Canada. 2002 clinical practice guidelines for the diagnosis and management of osteoporosis in Canada.CMAJ. 2002;167:S1-S34. By permission of the publisher. Copyright © 2002, CMA Media Inc.

Figure 3. Who should undergo fracture risk assessment and be treatedfor osteoporosis? Abbreviations: BMD, bone min-eral density; DXA, dual-energy x-ray absorptiometry.Adapted from reference 28:Brown JP, Josse RG; ScientificAdvisory Council of the Osteo-porosis Society of Canada. 2002clinical practice guidelines forthe diagnosis and management of osteoporosis in Canada. CMAJ.2002;167:S1-S34. By permissionof the publisher. Copyright ©2002, CMA Media Inc.

➤

➤

➤

➤

Long-termglucocorticoid

therapy*

➤

Startbisphosphonate

therapy

➤

Personnal historyof fragility fracture

after age 40

➤➤

➤

Nontraumaticvertebral compression

deformities

➤

Clinical risk factor†

(1 major or 2 minor)Low BMD by DXA

(T-score below --1.5)

ANDLow BMD by DXA (T-score below --1.5)‡

Obtain BMDby DXA forfollow-up

Consider therapy

Repeat BMD by DXAafter 1 or 2 years

➤

➤➤ ➤➤ ➤➤

➤➤

History of low traumafracture confirmedby radiography

AgeLong-term

moderate- to high-doseglucocorticoids†

➤

➤

➤

Spine radiography

Stop Reassess at age 65

➤

Height loss* kyphosis

Yes Yes

➤➤

1 major or 2 minorrisk factors

➤

➤

➤

➤➤

➤

Osteoporosis§ Osteopenia§

Clinical and risk factorevaluation

➤➤

➤

Repeat BMD to evaluateresponse to treatment

(at 1-2 years)

Measure BMDif available

Yes No

<65 y ≥65 y

Measure BMD by central DXA‡

Normal§

Consider repeatBMD testing at

2-3 years to monitorchanging risk

Evaluate for treatment

No No

➤

* >4-cm historical height loss; >2-cm prospective height loss. † Low-to-moderate: 2.5-7.5 mg prednisone/day;

moderate-to-high: >7.5 mg prednisone/day. ‡ Central DEXA = spine and hip. § As defined by the World Health Organization.

* ≥ 7.5 mg prednisone for more than 3 months. † Defined in reference 28. ‡ Arbitrary choice of T-score below –1.5; nontraumatic

vertebral compression deformities; personal history of fragility fracture after age 40; clinical risk factors.

with the same BMD, one who had a fractured clav-icle at age 55 and one who has no history of frac-tures. The woman with the history of fracture hasabout a 1.5- to 2.0-fold greater risk of hip and othertypes of fractures than does the woman without anyfracture history.39,40 The risk of subsequent fracturesis influenced by other factors including age, the siteof the incident fracture, and the number of priorfractures.10,41-46

◆ Family historyData from observational studies suggest that a fam-ily history of fractures indicates an increased riskfor future fractures, and this appears to be type-spe-cific, so that an individual is at increased risk forhip fracture if there is a family history of hip frac-tures. This effect is independent of hip BMD, andsuggests that determinants of fracture risk, besidesBMD, presumably must also be inherited.6,39 Whilemost studies have focused on the fractures in femalerelatives, it is likely that fractures in male relativesalso contribute to fracture risk.

DXA—whom should we test?

From this discussion, it is clear that BMD is not theonly factor that influences fracture risk and thatthere are some patients in whom a combination ofother risk factors would yield a fracture risk so highthat a BMD test may not be required, for example,an 80-year-old female with a prior fragility fracture.Furthermore, while the majority of therapeutic tri-als report fracture reduction in those with low BMD,there are studies in which patients selected only onthe basis of fracture respond to bisphosphonates,which lends support to the concept of possibly lim-iting BMD testing to those patients in whom frac-ture risk is not clear.

Thus, it is reasonable to first assess fracture riskbased on clinical risk factors, which will lead to 3categories of individuals: (i) patients at very highrisk for fracture who should receive treatment re-gardless of BMD by DXA; (ii) patients at very lowrisk for fracture (for example, no major or less than2 minor risk factors listed in Table II), who regard-less of BMD, should not need or receive specifictreatment; and (iii) patients with moderate risk inwhom a BMD test would shift them to either a high-risk or low-risk category. Preliminary data suggestthat a smaller number of individuals would requirea BMD test if this type of system was used.47

Use of BMD to monitor responseto treatment

◆ How to interpret changes in BMDWhile initial BMD measurements are used to diag-nose osteoporosis, assess fracture risk, and guidetreatment decisions, repeat measurements are usedto monitor response to treatment. There are sever-al limitations in using BMD for this purpose. First,a response to treatment is not necessarily the sameas a gain in BMD. For example, a patient who loses3% of bone mass at the lumbar spine on treatmentmay still be showing some response (albeit not a

◆ Prior fragility fractureClearly, women with low bone mass are more likelyto suffer a fragility fracture, and the same low bonemass that increased the likelihood of the first frac-ture also predisposes them to further fractures.However, even beyond this observation, a history offracture indicates an increased risk of future frac-tures regardless of bone mass, which highlightsthe point that fracture risk is influenced by factorsthat we cannot yet measure, such as weaker bonestrength or an increased predisposition to falls.3,10,13,38

This is well-illustrated using data from the Study ofOsteoporotic Fractures (SOF): consider two women



Figure 4. Age and bone mineral density (BMD) are independent riskfactors for hip fracture. Adapted from reference 34: Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B,Dawson A. Ten-year risk of osteoporotic fracture and the effect of risk factors onscreening strategies. Bone. 2002;30:251-258. Copyright © 2002, Elsevier Science Ltd.

T-score (SD)

Age (y)

80

70

60

5010-Y

ear

fract

ure

prob

abili

ty (%

)

20

10

0

–3 –2 –1 0 1

Age Overall averageT-score

(y) probability 1 0 -1 -2 <-2.5

Men50 3.3 1.8 2.7 4.2 6.3 9.255 3.9 1.9 3.0 4.6 7.0 10.460 4.9 2.5 3.6 5.4 7.9 11.665 5.9 3.0 4.3 6.2 8.8 13.070 7.6 3.4 5.1 7.4 10.9 16.275 10.4 4.1 6.3 9.6 14.4 21.580 13.1 5.3 7.7 11.1 15.8 23.285 13.1 5.3 7.5 10.4 14.3 21.4

Women50 6.0 2.4 3.8 5.9 9.2 13.955 7.8 2.6 4.1 6.7 10.7 16.860 10.6 3.2 5.1 8.2 13.0 20.565 14.3 4.0 6.3 10.0 15.6 24.970 18.9 4.3 7.1 11.5 18.3 29.875 22.9 4.2 7.0 11.8 19.4 32.680 26.5 4.6 7.7 12.7 20.5 34.585 27.0 4.5 7.4 12.0 19.1 33.1

Table III. Average 10-year probability (%) of an osteoporotic fractureby sex, age, and BMD expressed as T-score.Adapted from reference 37: Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jon-sson B. Ten year probabilities of osteoporotic fractures according to BMD and diag-nostic thresholds. Osteoporos Int. 2001;12:989-995. Copyright © 2001, SpringerVerlag USA.

and the presence of fractures should dictate treat-ment decisions, not simply changes in BMD. Inaddition, using BMD to reinforce adherence withtherapy has limited value as most problems withadherence occur in the first 3 months of startingtreatment, long before BMD is useful enough to as-sess changes in BMD.

Summary

BMD assessed by DXA is a powerful tool for iden-tifying patients at risk for osteoporotic fractures,and selective use of densitometry is a valuable tech-nique for identifying and caring for patients withosteoporosis. However, there are some limitationsto DXA, the most important of which is that DXAonly captures one component of fracture risk. Ad-ditional factors that contribute to fracture risk, asdescribed earlier (Table II),28 must be taken into con-sideration. These risk factors are somewhat inde-pendent of BMD and as such can be used togetherwith BMD to improve the clinical utility (sensitiv-ity and specificity) of fracture prediction.

It follows from this discussion that the best ap-proach to identify and treat patients at high risk forfracture is the approach suggested by Kanis et al, inwhich clinicians concentrate on a combination ofeasily identifiable and/or modifiable risk factors(such as age, prior fracture, body mass index, cur-rent smoking, etc) in addition to DXA to provide a5- to 10-year fracture probability.47 Clinicians canuse these fracture probabilities to guide treatmentdecisions. This approach is similar to the currentuse of clinical risk factors in combination with lab-oratory data to predict risk and guide treatment de-cisions in patients with cardiovascular disease. In-corporation of such fracture prediction data intoBMD reports would make them more clinically use-ful. ❒

robust response) because without treatment shecould have lost more (5% to 6%). Second, most pa-tients who lose bone mass over the first year of treat-ment regain much of that bone mass over the nextyear, even without changing therapy.48 Third, whiletherapeutic agents result in differing gains in BMD,the reduction in fracture risk with all these agentsis similar.49 Fourth, from regression analyses, thegain in BMD with the usual therapeutic agents ac-counts for only a small part of the observed reduc-tion in fracture (some 5% to 35%). Indeed, a meta-analysis of 12 trials to describe the relationshipbetween improvement in spine BMD and reductionin vertebral fracture risk demonstrates that a 1%improvement in spine BMD was associated with a0.03 decrease in the relative risk of vertebral frac-ture. The reductions in risk were greater than pre-dicted from the improvement in BMD; for example,based on improvements in BMD we would expecta reduction in fracture risk of about 20%, but theseagents decrease fracture by about 45%.49 Fifth, smallchanges in BMD are often related to random vari-ations in testing. In order to interpret changes inBMD it is important to keep this in mind and to cal-culate the least significant change (LSC). The LSCis calculated as 2.8-fold precision error of the teston a specific machine and measurement site. Forexample, femoral neck BMD in expert centers has a2% precision error; therefore, changes of less than5.6% may be due to random variation and wouldnot be of clinical significance.50

◆ How often should we perform BMD testing?The optimum frequency with which to performBMD testing is not known. In order to decide theoptimum frequency, one must consider that mostpatients gain BMD over the first year of treatmentwith therapeutic agents. Also, an increase or de-crease in BMD may be due to measurement error



REFERENCES1. Consensus development conference: diagnosis, prophylaxis,and treatment of osteoporosis. Am J Med.1993;94:646-650.2. Osteoporosis prevention, diagnosis, and therapy. NIH consen-sus statements 2000. 2000;17:1-45.3. Kanis JA, De Laet C, Delmas P, et al. A meta-analysis of previ-ous fracture and fracture risk. Bone. 2004; 35:375-382.4. Kanis JA, Johansson H, Oden A, et al. A meta-analysis of priorcorticosteroid use and fracture risk. J Bone Miner Res. 2004;19:893-899.5. Kanis JA, Johnell O, Oden A, et al. Smoking and fracture risk:a meta-analysis. Osteoporos Int. 2005;16:155-162.6. Kanis JA, Johansson H, Oden A, et al. A family history of frac-ture and fracture risk: a meta-analysis. Bone.2004;35:1029-1037.7. Kanis JA, Johansson H, Johnell O, et al. Alcohol intake as arisk factor for fracture. Osteoporos Int. 2005;16:581-589; Epubahead of print. 2004, Sept 29. 8. Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C.Use of oral corticosteroids and risk of fractures. J Bone Miner Res.2001;15:993-1000.9. Van Staa TP, Leufkens HGM, Cooper C. The epidemiology ofcorticosteroid-induced osteoporosis: a meta-analysis. Osteoporo-sis Int. 2002;13:777-787.10. Klotzbuecher CM, Ross PD, Landsman PB, Abbott TA 3rd,Berger M. Patients with prior fractures have an increased risk offuture fractures: a summary of the literature and statistical syn-thesis. J Bone Miner Res. 2000;15:721-739.11. Seeley DG, Browner WS, Nevitt MC, Genant HK, Scott JC,Cummings SR. Which fractures are associated with low appen-dicular bone mass in elderly women? The Study of OsteoporoticFractures Research Group. Ann Intern Med.1991;115:837-842.12. Siris ES, Chen YT, Abbott TA, et al. Bone mineral density

thresholds for pharmacological intervention to prevent fractures.Arch Intern Med. 2004;164:1108-1112.13. Cummings SR, Cosman F, Jamal SA, eds.Osteoporosis. An ev-idenced-Based Guide to Prevention and Management. Philadel-phia: Pa: American College of Physicians; 2002.14. Grampp S, Genant HK, Mathur A, et al. Comparisons of non-invasive bone mineral measurements in assessing age-relatedloss, fracture discrimination, and diagnostic classification. J BoneMiner Res.1997;12:1954-1955.15. Kanis JA, Melton LJ, Christiansen C, Johnston CC, KhaltaevN. The diagnosis of osteoporosis. J Bone Miner Res.1994;9:1137-1141.16. Cummings SR, Black DM, Nevitt MC, et al. Bone density atvarious sites for prediction of hip fractures. The Study of Osteo-porotic Fractures Research Group. Lancet.1993;341:962-963.17. Marshall D, Johnell O, Wedel H. Meta-analysis of how wellmeasures of bone mineral density predict occurrence of osteo-porotic fractures. BMJ.1996;312:1254-1259.18. Kanis JA, Gluer CC. An update on the diagnosis and assess-ment of osteoporosis with densitometry. Osteoporos Int. 2000;11:192-202.19. No authors listed. Osteoporosis: review of the evidence forprevention, diagnosis, and treatment, and cost-effective analysis.Status report. Osteoporos Int. 1998(suppl 4):1-88.20. Steiger P, Cummings SR, Black DM, Spencer NE, Genant HK.Age-related decrements in bone mineral density in women over65. J Bone Miner Res. 1992;7:625-632.21. Kanis JA, Johnell O, Oden A, De Laet C, Mellstrom D. Diag-nosis of osteoporosis and fracture threshold in men. Calcif TissueInt. 2001;69:218-221.22. Ross P, Huang C, Davis J, et al. Predicting vertebral deformity

40. Melton LJ, Wahner HW, Riggs BL. Bone density measure-ment. J Bone Miner Res. 1988;3:ix-x.41. Wasnich RD, Davis JW, Ross PD. Spine fracture risk is pre-dicted by non-spine fractures. Osteoporos Int. 1994;4:1-5.42. Davis JW, Grove JS, Wasnich RD, Ross PD. Spatial relation-ships between prevalent and incident spine fractures. Bone.1999;24:261-264.43. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pre-existingfractures and bone mass predict vertebral fracture incidence inwomen. Ann Intern Med.1991;114:919-923.44. Tromp AM, Smit JH, Deeg DJH, Bouter LM, Lips P. Predictorsfor falls and fractures in the longitudinal aging study Amsterdam.J Bone Miner Res. 1998;13:1932-1939.45. Black DM, Palermo L, Nevitt MC, Genant HK, Christensen L,Cummings SR. Defining incident vertebral deformity: a prospec-tive comparison of several approaches. The Study of Osteoporot-ic Fractures Research Group. J Bone Miner Res.1999;14:90-101.46. Fox KM, Cummings SR, Williams E, Stone K. Study of Osteo-porotic Fractures. Femoral neck and intertrochanteric fractureshave different risk factors, a prospective study. Osteoporos Int.2000;11:1018-1023.47. Kanis J, Borgstrom F, De Laet C, et al. Assessment of fracturerisk. Osteoporos Int. 2005;16:581-589.48. Cummings SR, Palermo L, Browner W, et al. Monitoring os-teoporosis therapy with bone densitometry: misleading changesand regression to the mean. Fracture Intervention Trial ResearchGroup. JAMA. 2000;8:1318-1321.49. Cummings SR, Karpf DB, Harris F, et al. Improvement inspine bone density and reduction in risk of vertebral fracturesduring treatment with antiresorptive drugs. Am J Med. 2002;112:281-289.50. Gluer CC. Monitoring skeletal changes by radiological tech-niques. J Bone Miner Res. 1999;14:1952-1962.

using bone densitometry at various skeletal sites and calcaneousultrasound. Bone.1995;16:325-332.23. de Laet CE, Van Hout BA, Burger H, Weel AE, Hofman A, PolsHAP. Hip fracture prediction in elderly men and women: valida-tion in the Rotterdam study. J Bone Miner Res.1998;13:1587-1593.24. Lunt M, Felsenberg D, Reeve J, Benevolenskaya L, Cannata J,Dequeker J. Bone density variation and its effect on risk of ver-tebral deformity in men and women studied in thirteen EuropeanCentres: the EVOS Study. J Bone Miner Res.1997;12:1883-1894.25. Kanis JA, Delmas P, Burckhardt P, Cooper C, Torgerson D.Guidelines for diagnosis and management of osteoporosis. Osteo-poros Int. 1997;7:390-406.26. No authors listed. Clinical guidelines for the prevention andtreatment of osteoporosis. London, UK: Royal College of Physi-cians. 1999.27. Physicians’ guide to prevention and treatment of osteoporo-sis. Washington, DC: National Osteoporosis Foundation; 1998.28. Brown JP, Josse RG; Scientific Advisory Council of the Os-teoporosis Society of Canada. 2002 clinical practice guidelinesfor the diagnosis and management of osteoporosis in Canada.CMAJ. 2002;167:S1-S34.29. Kanis JA, Torgerson D, Cooper C. Comparison of the Euro-pean and USA practice guidelines for stoeoporosis. Trends En-docrinol Metab. 2000;11:28-32.30. Ungar WJ, Josse R, Lee S, et al. The Canadian SCORE ques-tionnaire: optimizing the use of technology for low bone densityassessment. Simple Calculated Osteoporosis Risk Estimate. J ClinDensitom. 2000;3:269-280.31. Cadarette SM, Jaglal SB, Kreiger N, McIsaac WJ, DarlingtonGA, Tu JV. Development and validation of the osteoporosis riskassessment instrument to facilitate selection of women for bonedensitometry. CMAJ. 2000;162:1289-1294.32. Cummings SR, Bates D, Black DM. Clinical use of bone den-sitometry: scientific review. JAMA. 2002;288:1889-1897.33. Melton LJ. Epidemiology of fractures. In: Riggs BL, MeltonLJ, eds. Osteoporosis Etiology, Diagnosis, and Management.Philadelphia, Pa: Lippincott-Raven; 1995:225-248.34. Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A.Ten-year risk of osteoporotic fracture and the effect of risk factorson screening strategies. Bone. 2002;30:251-258.35. Hui SL, Slemenda CW, Johnston CC. Age and bone mass aspredictors of fracture in prospective study. J Clin Invest.1988;81:1804-1809.36. Nguyen T, Sambrook SP, Kelly P, Jones G, Freund J, Eisman J.Prediction of osteoporotic fractures by postural instability andbone density. BMJ.1993;307:1111-1115.37. Kanis JA, Johnell O, Oden A, Dawson A, De Laet C, Jonsson B.Ten year probabilities of osteoporotic fractures according to BMDand diagnostic thresholds. Osteoporos Int. 2001;12:989-995.38. Ross PD, Genant HK, Davis JW, Miller PD, Wasnich RD. Pre-dicting vertebral fracture incidence from prevalent fractures andbone density among non black, osteoporotic women. OsteoporosInt.1993;3:120-126.39. Cummings SR, Nevitt MC, Browner WS, et al. Risk factors forhip fracture in white women. Study of Osteoporotic FracturesResearch Group. N Engl J Med. 1995;332:767-773.



FACTEURS DE RISQUE DE L’OSTÉOPOROSE : UTILISATION DE LA DENSITÉ MINÉRALE OSSEUSE

POUR GUIDER LA DÉCISION THÉRAPEUTIQUE

B ien que la densité minérale osseuse (DMO) évaluée par absorptiométriebi-énergétique aux rayons X (DXA, dual-energy x-ray absorptiometry)soit un élément clé du risque de fracture, il devient de plus en plus évi-

dent que d’autres facteurs tels que l’âge, un antécédent de fracture de fragilité,et des antécédents familiaux d’ostéoporose influent aussi sur ce risque. L’utili-sation de la DMO seule comme stratégie de dépistage pour identifier les hommeset les femmes ayant un risque élevé de fracture présente une faible sensibilité,car la plupart des personnes qui présentent une fracture ont une DMO « nor-male ». L’utilité clinique de cet examen peut être améliorée en associant à laDMO à d’autres facteurs de risque clinique pour en déduire une probabilitéd’une fracture, sur laquelle le clinicien pourra fonder sa décision thérapeutique.Les facteurs de risque clinique peuvent également être utilisés pour déterminerquels patients doivent être soumis à une mesure de la DMO, tout en sachantque chez certains patients l’association de facteurs de risque implique un risquede fracture tellement élevé ou tellement faible que la valeur de la DMO ne chan-gera pas la décision thérapeutique. Cette association de la DMO et des facteursde risque clinique suit la même logique que l’association désormais courantedes résultats des dosages biologiques et des facteurs de risque pour guider lesdécisions thérapeutiques chez les patients présentant une pathologie cardiovas-culaire. Une telle approche est garante d’une meilleure utilité clinique de laDMO et d’un meilleur suivi des patients présentant un risque de fracture.

✦

The immense impact of osteoporosis and its re-lated fractures on worldwide health resourcesis widely recognized. Osteoporosis in women

is associated with more days in hospital per yearthan several other major conditions, including my-ocardial infarction, breast cancer, and chronic ob-structive pulmonary disease,1 while hip fracturesaccount for more than 20% of orthopedic bed oc-cupancy in the UK.2 The combined social care andacute costs for treating the current level of osteo-porotic fractures in the UK have been estimated atmore than £1.7 billion annually.3 The majority ofosteoporotic fractures give rise to significant mor-bidity and, at least in the case of hip and vertebralfractures, are associated with significant mortality,particularly in the elderly.4-8 Of those patients sur-viving for at least 1 year after a hip fracture, 40%still cannot walk independently, 60% have difficul-ty with at least one activity of daily living (ADL) and20% are institutionalized.9,10 Vertebral fractures areassociated with acute and chronic back pain, theconsequences of kyphosis (loss of height, abdomi-nal protuberance, breathing difficulties, early satietywith reflux and other gastrointestinal symptoms,stress incontinence) and depression.11 While the im-pact on quality of life appears rather obvious, it isonly relatively recently that data have been report-ed for the impact of fractures on health-relatedquality of life (HR-QOL) using well-defined and val-idated tools. This impact is important to document,not just because of the consequences for an individ-ual, but also to allow estimates of the impact for so-ciety and the derivation of utility values to informcost-effectiveness analysis.12,13 The latter can facili-tate the development of intervention strategies aswell as permitting comparisons of the effects oftherapies both within and across diseases withinthe setting of finite health care resources. This ar-ticle will give some background to HR-QOL, theimpact of osteoporosis, and will describe some of theemerging data about the effects of osteoporosis ther-apies on HR-QOL.

Health-related quality of life

Over the past 30 years, quality of life (QOL) hasemerged as an important attribute of clinical in-vestigation and patient care, and is now a key com-ponent of what has recently come to be known as“patient-reported outcomes.”14 But what do we meanby “health-related quality of life?” It is clear thatHR-QOL is a reflection of the way that patients per-ceive and react to their health status, not simply adescription of a patient’s health or functional sta-tus.13 It incorporates their physical, functional, emo-tional, and mental well-being, but does not capture

33Health-related quality of life in osteoporosis – McCloskey MEDICOGRAPHIA, VOL 28, No. 1, 2006


H ealth-related quality of life (HR-QOL) has emerged as an important at-tribute of clinical investigation and patient care. It is a reflection of theway that patients perceive and react to their health status, and incor-

porates their physical, functional, emotional, and mental well-being. HR-QOLis usually captured by questionnaires that are either generic health-status in-struments or disease-specific instruments. Generic HR-QOL instruments (eg,the SF-36 [36-Item Short-Form]) are designed to be applicable across a widerange of populations and diseases. A number of osteoporosis-specific instru-ments have also been developed over the last 10 to 15 years (eg, OPAQ [Osteo-porosis Assessment Questionnaire], QUALEFFO [Quality of Life Questionnaireof the European Foundation for Osteoporosis], QUALIOST [QUAlity of LIfequestionnaire in OSTeoporosis]), but few comparative studies have been un-dertaken to assess the relative performances of these instruments. The morbid-ity associated with osteoporosis is almost exclusively related to the occurrenceof fragility fractures, and differs between genders and across skeletal sites offracture. Hip and clinical vertebral fractures appear to cause the greatest andcomparable decreases in QOL. Limited data suggest that some osteoporosistherapies can improve HR-QOL by decreasing the incidence of fractures. Con-tinuing use of HR-QOL instruments will lead to a better understanding of theburden of osteoporosis and will allow the development of therapeutic strategiesto minimize this burden for patients and society.Medicographia. 2006;28:33-39. (see French abstract on page 39)

Keywords: osteoporosis; quality of life; fracture; disability; therapy

Eugene McCLOSKEY, MDAcademic Unit of Bone Metabolism Metabolic Bone Center Northern General Hospital Sheffield, UNITED KINGDOM

Address for correspondence: Dr Eugene McCloskey, Academic Unit of Bone Metabolism, Metabolic Bone Center, Sorby Wing, Northern General Hospital, Herries Road, Sheffield S5 7AU, UK(e-mail: [email protected])

Health-related qualityof life in osteoporosis b y E . M c C l o s k e y , U n i t e d K i n g d o m


ADL activity of daily livingBMD bone mineral densityHR-QOL health-related quality of lifeQALY quality-adjusted life years QOL quality of life

directly the impact of nonmedical factors, such asfamily issues, friends, jobs, and other life events, un-less these have a direct effect on health.

HR-QOL is usually measured through the admin-istration, by the individual or an interviewer, of aninstrument (usually a questionnaire), which triesto achieve a balance between being too simple ortoo sophisticated. Commonly, such instruments aremade up of a number of items or questions that aredivided between a number of domains or dimen-sions that refer to specific areas of health. Exampleswould include physical function (usually encom-passing mobility and self-care) or emotional func-tion (encompassing depression, anxiety, and men-tal well-being). Such instruments can be devised tomeasure cross-sectional differences in HR-QOL ata point in time (eg, between patients with and with-out osteoporotic fractures) or longitudinal changesin HR-QOL within patients during a period of time(eg, in clinical trials or recovery post fracture). Re-gardless of their use, the instruments need to un-dergo a process of validation to demonstrate thatthey actually measure what they are supposed tomeasure and to optimize their signal-to-noise ratioso that they are reliable and/or responsive.13

Broadly speaking, two categories ofquestionnaireshave now been developed, namely generic health-status instruments and disease-specific instruments(Table I). Generic HR-QOL instruments are de-signed to be applicable across a wide range of pop-ulations and interventions.15 To date, the 36-ItemShort-Form (SF-36) health survey has been themost commonly used generic HR-QOL measure,but a recent review of 7 generic instruments report-ed that none of these performed uniformly betteror worse than the others.15 A number of osteoporo-sis-specific instruments have also been developedover the last 10 to 15 years (Table I) and have re-cently been the subject of reviews.12,16 Few compar-ative studies have been undertaken to assess the rel-ative performances of these instruments, the mostwidely used of which are the Osteoporosis Assess-ment Questionnaire (OPAQ) and Quality of LifeQuestionnaire of the European Foundation for Os-teoporosis (QUALEFFO). Clearly, the chosen instru-ment should be the most relevant for the partic-

ular HR-QOL measurement needs within a study.It has also been recommended that in most studiesof HR-QOL consideration should be given to usinga combination of disease-specific and generic in-struments.12,13 The advantage of using generic in-struments is that several of these, particularly theQuality of Well-Being (QWB) Scale, Health UtilitiesIndex (HUI), EuroQol (EQ-5D) Instrument, andmore recently the SF-36 derived SF-6D, are prefer-ence-based measures designed to summarize HR-QOL in a single number or utility ranging from 0(worst imaginable health state) to 1 (best imagin-able health state). The mechanisms by which thesepreference-based measures are derived, includingvisual analog scales, time trade-off, or standard gam-ble techniques, are beyond the scope of this reviewand are described in more detail elsewhere.12,17,18

They are, however, critical to economic evaluationsof the cost-effectiveness of therapeutic interventionsacross the full range of health, including osteoporo-sis, as they encompass the effect of the interventionon morbidity as well as mortality. A range of indiceshas been developed to combine quality and quanti-ty of life, the best known of which is quality-adjust-ed life-years (QALY). These are calculated by aggre-gating the number of days/years gained from a drugor health care intervention, weighted by a propor-tion that represents the relative value attached tothe health state (ie, length of life�QOL).19 Econom-ic results can be presented as the cost per QALYgained or, more correctly, the incremental cost perQALY gained (ie, taking into account the costs andbenefits of any competing intervention) and is in-creasingly used in informing decisions about theallocation of resources within finite health care bud-gets.20,21 Recently, attention has been brought tobear, however, on discrepancies between utilitiesderived by different instruments within the samepopulations,22,23 suggesting that there may be po-tential implications for the interpretation and com-parability of health outcome studies and economicanalyses.23

Fractures and HR-QOL in osteoporosis

The morbidity associated with osteoporosis is al-most exclusively related to the occurrence of fragili-ty fractures. Low bone mineral density (BMD), acentral component of the definition of osteoporosisas a disease,24 does not appear to have direct effectson quality of life once adjustments are made for ageor other comorbidities.25 It is clear that the effect onHR-QOL differs between genders and across skele-tal sites of fracture. For example, in the CanadianMulticenter Osteoporosis Study, HR-QOL measuredby the Health Utilities Index (HUI) was significant-ly lower in both women and men who had experi-enced a hip fracture as compared with those with-out fractures.26 In women, a past history of pelvicfracture had a similar impact as a hip fracture anda history of clinical vertebral deformity was nega-tively associated with pain, self-care, and emotion.No comment could be made for pelvic or clinicalvertebral fractures in men due to a low number of

34 Health-related quality of life in osteoporosis – McCloskeyMEDICOGRAPHIA, VOL 28, No. 1, 2006


Table I. Quality of life instruments used in studies of osteoporosis.

Generic

SF-36: Medical Outcomes Study 36-Item Short Form

NHP: Nottingham Health Profile

SIP: Sickness Impact Profile

QWB: Quality of Well-Being Scale*

HUI: Health Utilities Index*

EQ-5D: EuroQol Instrument*

Osteoporosis-specific

OQLQ and mini OQLQ: Osteoporosis Quality of Life Questionnaire

OPAQ: Osteoporosis Assessment Questionnaire

QUALEFFO: Quality of Life Question-naire of the European Foundation forOsteoporosis

OPTQoL: Osteoporosis Targeted Qualityof Life Questionnaire

OFDQ: Osteoporosis Functional Disabil-ity Questionnaire

QUALIOST: Quality of life Question-naire in Osteoporosis

*Most widely used systems for the derivation of health state values or utilities. Recently, the SF-6D has been developed to derive utilities from SF-36.

Over 6 years, 120 individuals sustained an incidenthip fracture, of whom 18% died within the first 6months afterwards. Among survivors, there was asustained decline in all of the physical functions at6 weeks after the fracture with little improvementby 6 months (Figure 1). Prefracture physical func-tion, mental status, and depression were the factorssignificantly associated with physical function at6 months after the fracture.31

Several studies have also undertaken formal QOLassessments in patients with hip fracture.29,32-34 In aprospective case-control study, the revised Osteo-porosis Assessment Questionnaire (OPAQ2) and theSF-36 were completed on two separate occasions,

within 1 week of fracture and 12 to 15 weeks afterfracture; the controls completed both question-naires on two occasions 12 weeks apart. The scoreson both instruments were stable in the control sub-jects, but the scores across all domains were lowerat baseline in the hip-fracture group and deteriorat-ed further over the next 3 months after the fracture(Figure 2, next page).32 In a further study, 90 patientswith recent femoral neck fractures completed theEQ-5D instrument at 1 week, 4 months and a meanof 17 months post-fracture.33 Patients with severecognitive dysfunction, not living independently orunable to walk unhindered prefracture, were exclud-ed from the study. The EQ-5D scores decreased from0.78 before the fracture (based on recall) to 0.59 at4 months and 0.51 at 17 months after surgery. Sim-ilar values for hip fracture have been reported byTosteson and colleagues.35 The decrease was signif-icantly larger among patients with displaced frac-tures at baseline, partly but not completely relatedto healing complications.35 Interestingly, the ratedprefracture EQ-5D scores showed good correspon-dence with the scores of an age-matched referencepopulation. This contrasts with prospective datausing the EQ-5D before and after hip fracture in apopulation of community-dwelling elderly womenrecruited into a clinical trial that may offer a morevalid estimate of the loss in health status associat-ed with a hip fracture.36 The mean scores at 6 and12 months after hip fracture were 0.49 and 0.48,

events. In women, a lower-body fracture was nega-tively associated with self-care, pain, and emotion,whereas it was associated with decreased dexterityin men. In both sexes, upper-body and wrist andhand fractures appeared to have a minimal impacton HR-QOL apart from a negative association withmanual dexterity in men.26 This is not surprising,perhaps, given that most forearm fractures usuallydemonstrate good fracture healing with regain offunction. QOL data obtained in 40 patients with dis-tal forearm fracture using the EuroQol (EQ-5D)instrument have demonstrated that while there wasconsiderable loss of HR-QOL in the first 3 months,recovery was fast, and the total QOL loss was 0.05for 1 year, ie, 0.05 QALY.27 In contrast, it is now be-coming clear that clinical vertebral fractures alsohave a severe impact on QOL, similar to or greaterthan that of hip fractures.28 The impacts of differentfractures on health and QOL are reviewed in moredetail below.

◆ Hip fracturesVirtually all patients with hip fracture are admittedto hospital, have surgery, and undergo relativelylengthy periods of rehabilitation. Cognitive impair-ment and other disabilities including deafness andpoor vision may hamper the collection of robust in-formation on HR-QOL in this population. Neverthe-less, there is overwhelming evidence that hip frac-ture results in significant impairment of functionalcapacity that may be irretrievable in the long term,even in those returning to the community. For ex-ample, in a cross-sectional study of 92 cases of hipfracture recruited 6 to 12 months after the fracture,and age-matched controls, the fracture group wasslower on the Timed “Up & Go” assessment (19 vs10.5 seconds), had more difficulties with balance,was less active, and was more dependent than thecontrol group for activities of daily living. Further-more, the fracture cases had significantly lower val-ues across all eight domains of the SF-36 question-naire.29 In a further case-control study undertakenan average of 7 years after a trochanteric hip frac-ture, only half of the surviving fracture cases wereresiding in their own homes or service apartmentscompared with over 90% of the controls.30 Only35% of the patients compared with 79% of the con-trols were able to move about independently andthe patients were significantly worse at ADLs, re-quired more home help, and had fewer social con-tacts and outdoor hobbies than the controls. Thepotential drawback of such studies is that the cross-sectional nature may not detect or completely ac-count for a lower functional status or QOL that ex-isted prior to the fracture. Prospective data on theimpact of hip fracture are available from a study inwhich functional status was assessed before and af-ter the fracture event as part of a longitudinal studyof health and aging (Figure 1).31 In this prospectivecohort study of over 2800 men and women aged 65years and older living in the community, self-re-ported performance of dressing, transferring, walk-ing across a room, climbing stairs, and walkingone-half mile were obtained before the fracture oc-curred and 6 weeks and 6 months post-fracture.



Figure 1. Impact of hip fracture on independence and mobility. Adapted from reference 31: Marottoli RA, Berkman LF, Leo-Summers L, Cooney LM Jr.Predictors of mortality and institutionalization after hip fracture: the New Haven EPESEcohort. Established Populations for Epidemiologic Studies of the Elderly. Am J PublicHealth. 1994;84:1807-1812. Copyright © 1994, American Public Health Association.

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were significantly lower in the women with frac-ture (36±11 vs 48±9, P<0.001) as were the mentalhealth component (50±11 vs 54±8, P<0.05) and theutility scores (0.64±0.08 vs 0.72±0.07, P<0.001). Incontrast to other studies, they observed no corre-lation between QOL and either the number of ver-tebral fractures or the time since last vertebral frac-ture. The impact of the first vertebral fracture onHR-QOL has been demonstrated in many of the val-idation studies for the disease-specific instruments.For example, the performance of the QUALEFFOwas studied in 159 patients aged 55 to 80 years withclinical osteoporosis compared with age- and sex-matched controls without chronic back pain or ver-tebral fractures.40 The median scores of QUALEFFOwere significantly higher in patients with verte-bral fractures than in controls in all five domains(P<0.001), consistent with decreased QOL in pa-tients with osteoporosis. Across patients and con-trols, the QUALEFFO showed a significant trend forincreasing scores with increasing numbers of frac-tures, but the significance was largely determinedby the step from no fracture to 1 fracture.40 Largerstudies have, however, shown a dose response be-tween the number of fractures and HR-QOL. In asubgroup of women enrolled to the phase 3 verte-bral fracture study of raloxifene (the Multiple Out-comes of Raloxifene Evaluation [MORE] study), 449women with vertebral fractures were compared with302 women with low BMD, but no evidence of ver-tebral fracture.41 The instruments used included theQUALEFFO, the Nottingham Health Profile (NHP),and the EQ-5D. The women with vertebral frac-tures were slightly, but significantly, older (mean 69vs 66 years, P<0.001) and had a higher prevalenceof reported nonvertebral fractures (25% vs 36%;P=0.002). The QUALEFFO scores were higher, indi-

respectively, but prior to the fracture patients hada significantly lower health state value comparedwith the average for their age (0.60 vs 0.73).36

◆ Vertebral fracturesSeveral studies have now reported the impact of ver-tebral fractures on symptoms, functional status,and/or QOL. In one of the earliest studies of backpain and vertebral fractures in Japanese-Americanand white postmenopausal women, back pain wasassociated with recent vertebral fractures (detectedwithin the previous 4 years).37 Back pain increasedprogressively with the number and severity of frac-tured vertebrae: a history of a single recent fracturewas associated with a 2.8-fold increase in the oddsof back pain, two recent fractures with a 7.8-fold in-crease, and three recent fractures with a 21.7-foldincrease. The same research group reported that ina prospective study, vertebral fractures occurringafter the initial radiograph were strong predictorsof back pain and disability at the end of follow-up.38

In this longitudinal analysis, new fractures wereassociated (odds ratio [OR]=6.4; 95% confidence in-terval [CI]=2.6, 15.6) with increases in back painfrequency (relative to prefracture levels).

Hall and colleagues reported a study in which thenumber, position, and severity of vertebral fractureson lateral spine radiographs were recorded in 100female clinic patients with vertebral fractures.39 QOLwas measured using the SF-36 and a utility scorederived. The fracture subjects had a mean of 3 ver-tebral fractures and the mean time since last frac-ture was approximately 5 years. A total of 100 age-matched controls without vertebral fractures wererecruited. Both cases and controls were judged tobe free of radiological evidence of degenerative discor spine disease. The SF-36 physical function scores



Figure 2. Mean absoluteSF-36 and OPAQ2 scores atbaseline and 3 months after

hip fracture, reported by fracture patients (A) and

controls (B). *P<0.05between baseline and theassessment at 3 months.

Adapted from reference 32:Randell AG, Nguyen TV, Bhalerao N,

Silverman SL, Sambrook PN,Eisman JA. Deterioration in quality

of life following hip fracture:a prospective study. Osteoporos Int.

2000;11:460-466. Copyright ©2000, Springer Verlag, USA.

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disability at the end of follow-up, and resulted ingreater back pain and disability than for prevalentfractures.38 These observations suggest that studiesof incident vertebral fractures are required to bettercharacterize the effects on HR-QOL.

During the MORE study, 1058 women at non-Eu-ropean sites had follow-up radiographs and OPAQassessments, and 157 (14.8%) developed at least 1incident vertebral fracture during the 3-year studyperiod.42 Of these, 151 (96.2%) had at least 1 preva-lent vertebral fracture at baseline. The incident ver-tebral fractures significantly decreased OPAQ scoreson physical function, emotional status, clinicalsymptoms, and overall HR-QOL (all P<0.001) to asimilar or greater degree than prevalent fractures.42

Interestingly, in a further analysis of a subset of361 women with prevalent vertebral fractures fromthe MORE study, 67 patients sustained an incidentfracture in a vertebra that was not fractured at base-line (incident vertebral fractures).46 Twenty of these

were accompanied by signs and symptoms necessi-tating immediate doctor’s attention (clinical verte-bral fractures) and 47 vertebral fractures were onlydiagnosed on radiographs (subclinical vertebral frac-tures). Incident vertebral fractures (clinical and sub-clinical) were associated with an increase in backpain (mean score change 6.4; 95% CI 2.1-10.7), de-terioration of physical function (mean score change2.4; 95% CI 0.1-4.8), and worse general health per-ception (mean score change 3.8; 95% CI 0.1-7.5).The score changes for patients with subclinical ver-tebral fractures were intermediate between thosewith clinical vertebral fractures or no incident ver-tebral fracture, demonstrating that even subclini-cal incident vertebral fractures can have an adverseimpact on HR-QOL.46

Osteoporosis therapies and HR-QOL

Given the impact of incident vertebral and/or hipfractures on HR-QOL, it might be expected that atherapy that reduces the incidence of such fractureswould result in a relatively better quality of life. Arecent review of utility values for osteoporotic frac-tures to be used in economic analyses has high-lighted the remarkably few studies of the impact

cating worse HR-QOL in the fracture group (36±17vs26±14, P<0.001), and increased progressivelywithincreasing numbers of vertebral fractures, especial-ly lumbar fractures (P<0.001).41 Very similar resultswere reported from another subgroup analysis with-in the MORE study using the OPAQ.42 At baseline,women with a prevalent vertebral fracture had sig-nificantly lower OPAQ scores on physical function,emotional status, clinical symptoms, and overallHR-QOL compared with women without a preva-lent fracture (all P<0.01) and HR-QOL scores werelower with each additional fracture (Figure 3). Themore marked impact of vertebral fractures in thelumbar region was again noted. It has also beensuggested that the severity of vertebral fractures,as judged by the loss of vertebral height, may alsocontribute to impaired HR-QOL independently ofthe number of fractures.43 Patients with the mostsevere vertebral fractures (Grade 3) as classified bythe semiquantitative method of Genant (or the SQ

method) had a significantly lower overall HR-QOLscore with significantly lower physical function,symptoms, and emotional status dimension scoresthan nonfractured patients at entry to a trial of teri-paratide.43

Several studies have suggested an interaction be-tween the time since a vertebral fracture and thedegree of pain or impairment of function and QOL.For example, in a prospective cross-sectional case-control study, 51 women with osteoporosis with atleast one vertebral fracture were divided into twosubgroups, according to the delay since the last ver-tebral fracture had occurred (ie, more or less than3 months).44 NHP scores for physical mobility andenergy were significantly poorer (P<0.05) in wom-en with osteoporosis with a recently diagnosed ver-tebral fracture, compared with other women withosteoporosis.44 In a further study, 50 patients withvertebral fractures were split into two groups basedon the time since fracture being less than or greaterthan 2 years.45 Patients with the more recent frac-tures had greater pain, social extroversion, andpoorer well-being, but there was no difference inlimitations in everyday life.45 In one of the earlieststudies, new fractures that occurred after the initialradiograph were strong predictors of back pain and



Figure 3. Number of prevalentvertebral fractures and progressivedecreases in health-related qualityof life (HR-QOL; assessed by theOsteoporosis Assessment Question-naire [OPAQ]). All P<0.001 forlinear trend for each dimension/overall HR-QOL. For subjectswith 0 to 1 fracture, P<0.05 forphysical function and emotionalstatus. Adapted from reference 42:Silverman SL, Minshall ME, Shen W,Harper KD, Xie S. The relationship ofhealth-related quality of life to prevalentand incident vertebral fractures in post-menopausal women with osteoporosis:results from the Multiple Outcomes ofRaloxifene Evaluation Study. ArthritisRheum. 2001;44:2611-2619. Copyright ©2001, John Wiley & Sons.

1 Fractures (n=559)0 Fracture (n=371)

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bral fractures in established postmenopausal os-teoporosis on patients’ HR-QOL. It was developedas a specific module of the generic SF-36 question-naire and therefore avoids the redundancy of itemsthat often exists when both a generic and a specificquestionnaire are used.12 It comprises 23 items, 10of them addressing physical dimensions regardingpain, limitations, and difficulties while the 13 otherscorrespond to the emotional dimension, character-ized by negative feelings.

Of 1649 patients included in the multicenterstudy for 3 years, 1240 patients (75%) participatedin the HR-QOL evaluation, with both instrumentsbeing completed at baseline and 6-monthly there-after. Regardless of treatment group, the QUALIOSTglobal score showed a significant impact of incidentvertebral fractures on HR-QOL. Strontium ranelatewas associated with a significant 41% reduction inthe risk of experiencing a first new vertebral frac-ture over the 3 years of the study. Moreover, theQUALIOST global score showed a small, but signifi-cantly lower impairment of HR-QOL in the SR group(P=0.016) as compared with the placebo group. Sim-ilar effects were drawn from results of the psycho-logical or the physical scores of the QUALIOST(P=0.019 and 0.032, respectively) demonstratingfor the first time improvements in HR-QOL by anosteoporosis therapy, mediated at least in part bythe prevention of vertebral fractures. These positiveeffects of strontium ranelate on QOL have been en-shrined in the European Summary of Product Char-acteristics, and this agent is the only antiosteo-porotic treatment thus qualified.50

Summary

The impact of osteoporosis and its treatment onQOL has become a major interest in recent years.While the number of studies addressing HR-QOLhas recently increased, further information is re-quired, particularly with regard to fractures at sitesother than the spine and hip. The accuracy of util-ity estimates of these fracture types needs to be fur-ther enhanced and supported as they play a key rolein cost effectiveness analyses and policy decision-making. A better understanding of the burden ofosteoporosis will allow the development of currentand novel therapeutic strategies to minimize thisburden for patients and society. ❒

of osteoporotic fractures.36 The authors have recom-mended the administration of a preference-basedgeneric health status measure to a large prospec-tive population cohort with long-term follow-up toimprove the reference case values.

Until recently, few studies have shown a direct ef-fect on QOL in patients with osteoporosis, so thatthis has to be inferred.42,43,46 For example, in a studyof teriparatide, therapy was associated with an 86%reduction in new or worsened severe (grade 3 SQ)vertebral fractures, but, as conceded by the authors,this does not directly demonstrate a benefit of teri-paratide on HR-QOL.43 Such observations probablyrelate to inadequate statistical power in the majori-ty of studies, which are usually designed to show areduction in vertebral fracture risk, but not HR-QOL.

In the Fracture Intervention Trial (FIT) of alen-dronate, investigators examined the impact of newvertebral fractures on the number of days of limit-ed activity and bed rest caused by back pain.47 Bothindices were significantly increased in the periodafter a new clinical vertebral fracture, as comparedwith the period before a clinical vertebral fractureand the increase was similar in women receivingalendronate or placebo. Severe back pain, as indi-cated by 7 or more limited-activity days and 7 ormore bed-rest days, increased sharply immediatelyafter a clinical vertebral fracture so that by 3 monthsafter a new fracture, about 30% of women had ex-perienced 7 or more bed-rest days and about 80%had 7 or more limited-activity days. Women in thealendronate-treated group had 63% fewer bed-restdays and 16% fewer days of limited activity becauseof back pain compared with those in the placebogroup. The effect was even more pronounced forthe cumulative incidence of 7 or more days of bedrest: 4.2% of women receiving alendronate report-ed this more severe degree of functional limitation,compared with 8.7% of women receiving placebo.47

More recently, results have been presented forthe effect of strontium ranelate on QOL in womenwith established vertebral osteoporosis.48 In the so-called SOTI trial (Spinal Osteoporosis TherapeuticIntervention), QOL was assessed using a genericquestionnaire, the SF-36, and a disease-specificquestionnaire developed for use in the study, theQuality-of-Life Questionnaire in Osteoporosis(QUALIOST).49 The QUALIOST questionnaire wasspecifically designed to assess the impact of verte-



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2004;15:108-112.7. Kanis JA, Oden A, Johnell O, De Laet C, Jonsson B, Oglesby AK.The components of excess mortality after hip fracture. Bone.2003;32:468-473.8. Empana JP, Dargent-Molina P, Breart G. Effect of hip fractureon mortality in elderly women: the EPIDOS prospective study.J Am Geriatr Soc. 2004;52:685-690.9. Cooper C. The crippling consequences of fractures and theirimpact on quality of life. Am J Med.1997;103:12S-17S; discussion17S-19S.10. Norton R, Butler M, Robinson E, Lee-Joe T, Campbell AJ. De-clines in physical functioning attributable to hip fracture amongolder people: a follow-up study of case-control participants. Dis-abil Rehabil. 2000;22:345-351.11. Silverman SL. The clinical consequences of vertebral com-pression fracture. Bone.1992;13(suppl 2):S27-S31.12. Tosteson AN, Hammond CS. Quality-of-life assessment in os-teoporosis: health-status and preference-based measures. Phar-

40. Lips P, Cooper C, Agnusdei D, et al. Quality of life in patientswith vertebral fractures: validation of the Quality of Life Ques-tionnaire of the European Foundation for Osteoporosis (QUAL-EFFO). Working Party for Quality of Life of the European Foun-dation for Osteoporosis. Osteoporos Int. 1999;10:150-160.41. Oleksik A, Lips P, Dawson A, et al. Health-related quality of lifein postmenopausal women with low BMD with or without preva-lent vertebral fractures. J Bone Miner Res. 2000;15:1384-1392.42. Silverman SL, Minshall ME, Shen W, Harper KD, Xie S. Therelationship of health-related quality of life to prevalent and inci-dent vertebral fractures in postmenopausal women with osteo-porosis: results from the Multiple Outcomes of Raloxifene Eval-uation Study. Arthritis Rheum. 2001;44:2611-2619.43. Crans GG, Silverman SL, Genant HK, Glass EV, Krege JH.Association of severe vertebral fractures with reduced quality oflife: reduction in the incidence of severe vertebral fractures byteriparatide. Arthritis Rheum. 2004;50:4028-4034.44. Cortet B, Houvenagel E, Puisieux F, Roches E, Garnier P,Delcambre B. Spinal curvatures and quality of life in women withvertebral fractures secondary to osteoporosis. Spine.1999;24:1921-1925.45. Begerow B, Pfeifer M, Pospeschill M, et al. Time since verte-bral fracture: an important variable concerning quality of life inpatients with postmenopausal osteoporosis. Osteoporos Int.1999;10:26-33.46. Oleksik AM, Ewing S, Shen W, van Schoor NM, Lips P. Impactof incident vertebral fractures on health related quality of life(HRQOL) in postmenopausal women with prevalent vertebralfractures. Osteoporos Int. 2005;16:861-870.47. Nevitt MC, Thompson DE, Black DM, et al. Effect of alen-dronate on limited-activity days and bed-disability days causedby back pain in postmenopausal women with existing vertebralfractures. Fracture Intervention Trial Research Group. Arch In-tern Med. 2000;160:77-85.48. Marquis P, De la Loge C, Diaz-Curiel M, et al. Beneficial effectsof strontium ranelate on the quality of life in patients with verte-bral osteoporosis (SOTI study). Osteoporos Int.2005;16(suppl 3):S54(P223).49. Marquis P, Cialdella P, De la Loge C. Development and val-idation of a specific quality of life module in post-menopausalwomen with osteoporosis: the QUALIOST. Qual Life Res.2001;10:555-566.50. European Medicines Agency (EMEA). Summary of ProductCharacteristics – Protelos. http://www.emea.eu.int/humandocs/Humans/EPAR/protelos/protelos.htm. Accessed November 3,2005.

macoeconomics. 2002;20:289-303.13. Guyatt GH, Feeny DH, Patrick DL. Measuring health-relatedquality of life. Ann Intern Med.1993;118:622-629.14. Willke RJ, Burke LB, Erickson P. Measuring treatment im-pact: a review of patient-reported outcomes and other efficacyendpoints in approved product labels. Control Clin Trials. 2004;25:535-552.15. Coons SJ, Rao S, Keininger DL, Hays RD. A comparative re-view of generic quality-of-life instruments. Pharmacoeconomics.2000;17:13-35.16. Lips P, van Schoor NM. Quality of life in patients with osteo-porosis. Osteoporos Int. 2005; 16:447-455.17. Torrance GW. Measurement of health state utilities for eco-nomic appraisal. J Health Econ. 1986;5:1-30.18. Torrance GW. Utility approach to measuring health-relatedquality of life. J Chronic Dis. 1987;40:593-603. 19. Hughes D, Lara AM, Mujica-Mota R. Approaches to phar-macoeconomic analysis. In: Walley T, Haycox A, Boland A, eds.Pharmacoeconomics. Edinburgh, New York: Churchill Living-stone; 2004:101-126.20. NICE 2005 A guide to NICE. National Institute for Healthand Clinical Excellence. http://www.nice.org.uk/page.aspx?o=guidetonice. Accessed 29 September 2005.21. NICE Framework Document. National Institute for Healthand Clinical Excellence. http://www.nice.org.uk/pdf/appendixB_framework.pdf.22. Hatoum HT, Brazier JE, Akhras KS. Comparison of the HUI3with the SF-36 preference based SF-6D in a clinical trial setting.Value Health. 2004;7:602-609.23. Hawthorne G, Richardson J, Day NA. A comparison of the As-sessment of Quality of Life (AQoL) with four other generic utilityinstruments. Ann Med. 2001;33:358-370.24. Osteoporosis Prevention, Diagnosis, and Therapy. NIH Con-sens Statement Online. 2000;17:1-36. 25. Martin AR, Sornay-Rendu E, Chandler JM, Duboeuf F, GirmanCJ, Delmas PD. The impact of osteoporosis on quality-of-life: theOFELY cohort. Bone. 2002;31:32-36.26. Adachi JD, Loannidis G, Berger C, et al. The influence of os-teoporotic fractures on health-related quality of life in commu-nity-dwelling men and women across Canada. Osteoporos Int.2001;12:903-908.27. Dolan P, Torgerson D, Kakarlapudi TK. Health-related qualityof life of Colles’ fracture patients. Osteoporos Int.1999;9:196-199.28. Zethraeus N, Borgström F, Johnell O, Kanis J, Önnby K,Jönsson B. Costs and quality of life associated with osteoporosisrelated fractures. SSE/EFI Working Paper Series in Economicsand Finance. October 2002; No 512.29. Hall SE, Williams JA,Senior JA,Goldswain PR,Criddle RA.Hipfracture outcomes: quality of life and functional status in olderadults living in the community. Aust N Z J Med.2000;30:327-332.30. Willig R, Keinanen-Kiukaaniemi S, Jalovaara P. Mortalityand quality of life after trochanteric hip fracture. Public Health.2001;115:323-327.31. Marottoli RA, Berkman LF, Leo-Summers L, Cooney LM Jr.Predictors of mortality and institutionalization after hip frac-ture: the New Haven EPESE cohort. Established Populations forEpidemiologic Studies of the Elderly. Am J Public Health.1994;84:1807-1812.32. Randell AG, Nguyen TV, Bhalerao N, Silverman SL, SambrookPN, Eisman JA. Deterioration in quality of life following hip frac-ture: a prospective study. Osteoporos Int. 2000;11:460-466.33. Tidermark J, Zethraeus N, Svensson O, Tornkvist H, Ponzer S.Femoral neck fractures in the elderly: functional outcome and qual-ity of life according to EuroQol. Qual Life Res. 2002;11:473-481.34. Tidermark J, Zethraeus N, Svensson O, Tornkvist H, PonzerS. Quality of life related to fracture displacement among elderlypatients with femoral neck fractures treated with internal fixa-tion. J Orthop Trauma. 2002;16:34-38.35. Tosteson AN, Gabriel SE, Grove MR, Moncur MM, KneelandTS, Melton LJ 3rd. Impact of hip and vertebral fractures on qual-ity-adjusted life years. Osteoporos Int. 2001;12:1042-1049.36. Brazier JE, Green C, Kanis JA. A systematic review of healthstate utility values for osteoporosis-related conditions. OsteoporosInt. 2002;13:768-776.37. Huang C, Ross PD, Wasnich RD Vertebral fractures andother predictors of back pain among older women. J Bone MinerRes. 1996;11:1026-1032.38. Ross PD, Davis JW, Epstein RS, Wasnich RD. Pain and dis-ability associated with new vertebral fractures and other spinalconditions. J Clin Epidemiol. 1994;47:231-239.39. Hall SE, Criddle RA, Comito TL, Prince RL. A case-controlstudy of quality of life and functional impairment in women withlong-standing vertebral osteoporotic fracture. Osteoporos Int.1999;9:508-515.


QUALITÉ DE VIE LIÉE À LA SANTÉ DANS L’OSTÉOPOROSE

L a qualité de vie liée à la santé (QVLS) s’est imposée comme un paramètreimportant de la recherche clinique et du soin des patients. Elle reflète lafaçon dont les patients perçoivent et réagissent à leur état de santé, et in-

tègre leur bien-être physique, fonctionnel, émotionnel et mental. La QVLS esthabituellement évaluée grâce à des questionnaires dont il existe deux types,génériques ou spécifiques. C’est ainsi qu’outre les instruments de QVLS géné-riques (par exemple la SF-36 [36-Item Short-Form]), destinés à un large éven-tail de populations et de maladies, un certain nombre d’instruments d’évalua-tion spécifiques de l’ostéoporose ont été développés ces 10 à 15 dernières années(par exemple, le Questionnaire d’Évaluation de l’ostéoporose [OPAQ, Osteopo-rosis Assessment Questionnaire], le Questionnaire de Qualité de Vie de la Fon-dation Européenne pour l’Ostéoporose [QUALEFFO, Quality of Life Question-naire of the European Foundation for Osteoporosis], le Questionnaire de Qualitéde Vie dans l’Ostéoporose [QUALIOST, QUAlity of LIfe questionnaire in OSTeo-porosis]). Toutefois, peu d’études comparatives ont été entreprises pour évaluerles résultats respectifs de ces instruments. La morbidité associée à l’ostéoporoseest presque exclusivement liée à la survenue de fractures de fragilité, et diffèreselon le sexe et les sites de fracture du squelette. Les fractures vertébrales et lesfractures de hanche à expression clinique semblent induire de façon compa-rable les baisses les plus importantes de la QVLS. Des données encore limitéessuggèrent que certains traitements anti-ostéoporotiques peuvent améliorer laQVLS en diminuant l’incidence des fractures. La généralisation de l’utilisationdes instruments de QVLS devrait permettre une meilleure compréhension dufardeau représenté par l’ostéoporose ainsi que le développement de stratégiesthérapeutiques destinées à alléger ce fardeau pour les patients et la société.

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40 Risk factors and pharmacoeconomic consequences – JönssonMEDICOGRAPHIA, VOL 28, No. 1, 2006

The aim of the prevention and treatment of os-teoporosis is to reduce the risk of fractures.The risk of an osteoporotic fracture varies with

a number of factors, one of the most important be-ing age.1,2 The assessment of risk is thus the key tothe cost-effectiveness of interventions. Since mostinterventions involve the same costs, regardless ofthe risk level of the patient, and the relative risk re-duction is also similar, treating patients at high riskwill yield more benefits, and thus be more cost-ef-fective. Targeting high-risk populations has thusbeen one strategy in identifying efficient ways of us-ing scarce resources for reducing the burden of os-teoporosis.3

Finding the right population for intervention,through different strategies for screening and casefinding, can also be seen as an economic problem.The more resources that are spent on finding a pa-tient for treatment, the more costs will be added,which has to be balanced by the benefits of inter-vention. This is particularly important if compli-ance with treatment is low, and benefits thus ac-cordingly reduced. If the patient stays on therapyfor a long time, the initial costs of case finding willbe relatively less important.

Defining cost-effectiveness and intervention cri-teria is thus a complicated undertaking, involvingepidemiological, clinical, and economic factors. Athorough analysis requires these data to be com-bined in a logical, consistent, and transparent way.The following section describes the principles forsuch models, and the data required. A descriptionof available data for such models, and the resultsfrom simulations based on Swedish data, will follow.

Cost-effectiveness models

There is a long history of modeling cost-effective-ness in osteoporosis.4,5 Until the mid 1990s, mostmodels were aimed at evaluating the costs and ben-efits of hormone replacement therapy. The modelsthus included a number of “extraskeletal effects,”mainly coronary heart disease and cancer. The re-sults were thus strongly influenced by the assump-tion made about these positive and negative side ef-fects of treatment. Later models, aimed at studyingthe effects of bone-specific interventions, such asbisphosphonates, are simpler to compare and inter-pret, since the results only depend on the reductionin fractures. However, the result differs with respectto which fractures are included in the model, therisk factors considered, and the data used for thestudy. The need for a “reference model” is thus rec-ognized.6

Jönsson et al7 introduced a computer model in-cluding hip, wrist, vertebral, and other fractures(Figure 1). The model was the first osteoporosismodel of the Markov type, based on absolute risksof fracture and relative risk reduction from inter-vention, with outcome defined as quality-adjustedlife years (QALYs). This makes it possible to aggre-gate the benefits in terms of survival and quality oflife from a reduction in several different fractures.The health states that are included are: healthy, hipfracture first year, hip fracture second and follow-


T he prevention and treatment of osteoporosis involves costs for case find-ing, treatment, and follow-up. Drug costs are only one part of the inter-vention costs. But the risk of fractures and the side effects of treatment—

positive as well as negative—also have cost consequences, which have to beconsidered when assessing the cost-effectiveness of different measures to reducethe risk of fractures. Since the beginning of the 1990s, cost-effectiveness mod-eling in osteoporosis has been based on fracture reduction data from clinicaltrials. The advantage of this approach, compared with earlier models based onchanges in bone mineral density, is that the measured effectiveness variable inthe trial is directly related to the final objective of the intervention, a reductionin fractures. Since fractures are associated with mortality, reductions in qual-ity of life, and costs, a reduction in fracture rates can be translated into costsavings and quality-adjusted life years gained. The method and data used formodeling cost-effectiveness of the treatment of osteoporosis are described. Re-sults using this type of model for determining cost-effectiveness are presented.Cost-effectiveness is sensitive to the cost of the intervention, the relative risk re-duction, and the absolute risk of a fracture if not treated. Such models can alsobe used for assessing intervention thresholds. With the base case (US $500 peryear; 35% efficacy), treatment in women was cost-effective with a 10-year hipfracture probability that ranged from 1.2% at the age of 50 years to 7.4% at theage of 80 years. Similar results were observed in men except that the thresholdfor cost-effectiveness was higher at younger ages than in women (2.0% versus1.2%, respectively, at the age of 50 years). Intervention thresholds were sensi-tive to the assumed effectiveness and intervention cost. The exclusion of osteo-porotic fractures other than hip fracture significantly increased the cost-effec-tiveness ratio because of the substantial morbidity from these other fractures,particularly at younger ages.Medicographia. 2006;28:40-44. (see French abstract on page 44)

Keywords: osteoporosis; risk; cost; cost-effectiveness

Bengt JÖNSSON, PhDProfessor, Stockholm School of Economics, Stockholm SWEDEN

Address for correspondence: Professor Bengt Jönsson, Stockholm School of Economics,Klarabergsgaten 33, Box 6501, SE 113 83, Stockholm, Sweden (e-mail: [email protected])

Risk factors and pharmacoeconomic consequences b y B . J ö n s s o n , S w e d e n

been implemented is a health state for vertebralfracture the second and following years after thefracture event, which is in line with data that in-dicate that vertebral fractures are associated withboth cost and quality of life reductions that lastlonger than the first year.11-13

There are different versions of fracture modelsin the literature.14-16 All these models are similar intheir structure, but can differ somewhat in the cal-

culation method. Instead of using the Markov co-hort technique, individual state transition-basedcalculations have been used.16 However, the calcu-lation method used for the model evaluation shouldnot impact the results if the models are populatedwith the same data.

Data

An economic evaluation should ideally be based oncost and health data as reflected in the routine careof patients. To obtain such data, a naturalistic studydesign can be used where patients are randomizedto different treatment alternatives in a real-worldsetting (eg, a phase 4 study). Data for cost-effective-ness studies can also be obtained from randomizedcontrolled trials (RCTs) where the main purpose isto investigate whether the treatment is safe and hasan effect. The advantage of using a controlled trialas the basis for the economic evaluation is that theresults from the clinical study are of high internalvalidity showing whether a new therapy has an ef-fect or not. The drawback is that the clinical studymay not reflect the cost and health effects for pa-tients in routine care when the drug is on the mar-ket. Placebo-controlled studies pose a special prob-lem, since a placebo is not an alternative used inclinical practice. Compliance and costs observed ina placebo-controlled clinical trial may not thus re-flect the real world. However, since the only evi-dence-based effectiveness data that we have comefrom such trials, it is standard practice to perform atleast one set of economic evaluations linked close-ly to the trial data. But such studies cannot assessthe long-term costs and outcome in terms of sur-vival and quality of life in patients with and with-out fracture. The short-term clinical trial data mustbe complemented with data from registries of dif-ferent types.

ing years, vertebral fracture first year, forearm frac-ture first year, and other fracture first year, anddeath. A defined population is subject to risks ofhaving a fracture over its lifetime. The model canfollow the population (set at 1000 initially) and keeptrack of the patient distribution each year. Inter-vention decreases the risk of fracture, which meansthat the population will be distributed differentlyamong health states each year. Linked to each healthstate is a cost and quality-of-life weighting. By sum-mating costs and health effects for all patients forall years, the total costs and health effects are ob-tained for the natural course (without treatment).The intervention affects the transition probabilitiesand implies a different allocation of individualseach year. The cycle length is 1 year and all patientsare followed through the model from the age oftreatment initiation until they are 100 years old ordead. There is always the probability of remainingin the same state or dying. All the patients begin inthe well health state. Each year, a patient has theprobability of having a fracture, remaining healthy,or dying. If a patient dies, she will move to the deadhealth state and remain there for the rest of the sim-ulation (arrows to the dead health state were ex-cluded to simplify the figure). If the patient incursa fracture she will move, depending on fracturetype, to the hip fracture, spine fracture, wrist frac-ture, or other osteoporotic fracture health state. Af-ter 1 year in one of these states, the patient can havea new fracture, move to the post–hip fracture state,or die.

Wrist fracture, spine fracture, and other osteo-porotic fracture were assumed to have an impacton costs and morbidity only in the first year afterfracture, therefore after 1 year in these health statespatients move, if not fractured once more, back tothe well health state. From the post–hip fracturestate, it is only possible to stay in the post–hip frac-ture state, have another hip fracture, or die. Conse-quently, patients who have had a hip fracture can-not experience any future wrist, vertebral, or otherosteoporotic fractures. The probability of having avertebral or a wrist fracture after a hip fracture islow, and the consequences on mortality and qual-ity of life after having experienced multiple, differ-ent fractures has been poorly investigated. Also, thecosts and quality of life reductions from multiplefractures can be included in the state “post–hip frac-ture.” The slight underestimation of the number offractures in the model will not significantly effectthe cost-effectiveness estimates.

An application of the model is found in Jönssonet al3 where the cost-effectiveness of the treatmentof a 62-year-old woman is investigated. A 5-yeartreatment duration was assumed and a risk reduc-tion of 50% during treatment. The annual inter-vention cost was assumed to be SEK 6000. The re-sulting cost per QALY gained was estimated as SEK107 000, which was similar to the cost-effectivenessratio of treating the same women for mild hyper-tension.

The model introduced by Jönsson et al7 dates backto 1993 and since then the model has gone throughseveral developments.8-10 The main change that has

41Risk factors and pharmacoeconomic consequences – Jönsson MEDICOGRAPHIA, VOL 28, No. 1, 2006


Figure 1. Model structure for evaluating the cost-effectiveness of fractureprevention. Adapted from reference 7.

➤

➤

➤

Healthynext year Death

➤

➤

Healthy

WristHip Vertebrae Other

Fracture

ciated with osteoporosis-related fractures (the KO-FOR study). The KOFOR study prospectively followsfracture patients for 18 months after the fractureevent and collects information about all relevantresource use for the estimation of fracture-relatedcosts in a societal perspective.18 For some fractures,increased mortality is a reality that can be calculat-ed if the relevant epidemiological data are avail-able.19-22 However, it is important that the modeledexcess mortality after fracture is adjusted for co-morbidity.

Results

In the model presented in Zethraeus et al,23 the cost-effectiveness of a bone-specific treatment is com-pared with no treatment. The base case assesses thecost-effectiveness of the treatment of a 70-year-oldwoman with a twofold increase in the risk of hip,spine, and wrist fracture. A 5-year treatment dura-tion is assumed to reduce the risk of fracture by35%. After the cessation of the therapy, the riskgradually adjusts to the normal risk 5 years later.An annual treatment cost of SEK 5000 is assumed,and costs and health effects are discounted at a 3%discount rate. Two scenarios are shown, one wherecosts in added life years are included and one wherethey are excluded. In a sensitivity analysis, the cost-effectiveness is calculated changing some of thebase case assumptions.

The results presented in Table I show the cost-effectiveness ratios in the base case and for differentassumptions about the parameters in the model.If quality of life is assumed to improve slightly dur-ing treatment, the cost-effectiveness ratios decrease.On the other hand, if a small negative side effectis assumed, the “no intervention” alternative dom-inates the treatment alternative. The results arealso sensitive to changes in relative risk of fractureand set time after cessation of therapy. Higher riskand longer set time reduce the cost-effectivenessratios and thus improve cost-effectiveness. The cost-effectiveness results are not very sensitive to the in-clusion of costs in added life years, since the effecton mortality is small.

Models can be designed to take into account dif-ferential effects on different fractures. Data on frac-ture reduction rates from clinical trials can be usedfor translating the results for that specific popula-tion and specific end-point into cost-effectivenessratios. This has been done for alendronate in theFracture Intervention Trial (FIT) and for the rise-dronate clinical trials.8-10

Data from clinical trials have limitations, how-ever, since the trial is usually powered only for aspecific population, end point (fracture), and timeof follow-up. It would be an advantage to have amodel that took into account the effect on all osteo-porotic fractures, particularly if it could be shownthat the relative risk reduction from interventionis similar over fracture types. Since very few coun-tries have a detailed risk function for all possible, oreven the major, osteoporotic fractures, but manycountries have data on hip fractures, the concept of“hip fracture equivalents” has been used for assess-

Most studies are thus based on models that inte-grate clinical, epidemiological, and cost data. Mod-els are very flexible, but their validity and reliabilitydepend on the quality of the data used. Hip fracturerisk data are available for many countries, or can becalculated.17 For other fractures, data on risk arescarce and, for most countries, nonexistent.

Intervention costs and the cost of patient man-agement can be fairly easily calculated. However,costs related to different types of fractures need tobe collected through registries or observational stud-ies. Registries are the easiest, but limited to the in-formation previously collected. Registries capturehospitalization data very well, but less well ambula-tory care and costs in the community. To have dataon quality of life, informal care, and absence fromwork, there is generally a need for specific studies.An example of such a study is the Swedish-basedstudy estimating the costs and quality of life asso-



Cost in added life years (SEK)

Parameters included excluded

Base case 520 000 420 000

Starting age65-year treatment initiation 850 000 790 00075-year treatment initiation 330 000 200 000

Effect envelopeOffset time = 0 years 810 000 720 000Offset time = 10 years 350 000 240 000

Discount rateHealth effects = 0 400 000 320 000Costs and effects = 5 610 000 510 000Costs and effects = 0 410 000 300 000

Relative risk of fractureHip RR=3 330 000 240 000Hip RR=4 230 000 140 000

Intervention10-year treatment duration 520 000 410 000Risk reduction fracture = 50% 320 000 220 000Intervention costs = 3000 250 000 150 000Intervention costs = 7000 800 000 700 000

Quality of life during intervention+1% 250 000 200 000+0.5% 340 000 280 000--1% Dominated Dominated--0.5% 1 140 000 920 000

Quality of life after fracture+10% 800 000 650 000--10% 400 000 320 000

Table I. Cost-effectiveness ratios for a 5-year bone specific treatment basedon the model presented by Zethraeus et al.5,23 The base case indication isa 70-year-old woman with a twofold increase in fracture risk. The basecase assumes a risk reduction of 35% during therapy and a 5-year offsettime. The annual intervention cost is assumed to be SEK 5000. All ratiosare given in Swedish crowns (SEK). Adapted from reference 5: Zethraeus N, Ben Sedrine W, Caulin F, et al. Models for assess-ing the cost-effectiveness of the treatment and prevention of osteoporosis. OsteoporosInt. 2002;13:841-857. Copyright © 2002, International Osteoporosis Foundation andNational Osteoporosis Foundation.

life reduction, but other osteoporosis-related frac-tures contribute significantly to the burden, partic-ularly at younger ages.24

Models are useful tools for assessing the relationbetween risk, risk reduction, and cost-effectivenessof intervention. Clinical trials provide evidence ofhow different interventions can be used for reduc-ing the risk of fractures, and to some extent theirconsequences in terms of costs and quality of lifereductions. But there is also a need for additionalepidemiological and economic data to feed into themodels in order to provide a correct estimate of thecost-effectiveness of such interventions in differentpopulations and in different countries.

Such studies are also important for the access ofpatients to treatment, as is seen by the use of suchstudies for making decisions about reimbursementand funding for treatment. See, for example, thestudy of a range of osteoporosis drugs by the Na-tional Institute for Clinical Excellence (NICE).26

Thus, there is a responsibility to make sure thatsuch studies are undertaken with the best scien-tific methods and based on the most relevant data.With the introduction of additional new alterna-tives for treatment and intervention, such studieswill be even more important. ❒

ing intervention thresholds. When defining suchthresholds, it is important that all positive effects ofthe intervention be taken into account, not just theeffect on hip fracture.

Table II shows the threshold for intervention de-fined as absolute 10-year risk of hip fracture.24,25 Thethreshold is lower for younger ages, since they losemore from an event, but also since the relative im-portance of fractures other than hip fracture in-creases with reduced age. Table III shows the per-centage of the population treated at different agesusing two different assumptions on the gradient offracture risk.

Discussion

Economic evaluations have gained increasing im-portance for the design of cost-effective strategiesfor prevention and treatment. Such studies takeinto account both costs of the interventions, the ef-fect on the risk of fracture, and the consequencesof fractures. One important positive impact of suchstudies is that they have put the focus on the sig-nificant, and often underestimated, burden of os-teoporotic fractures. Hip fracture has major conse-quences in terms of costs, mortality, and quality of

43Risk factors and pharmacoeconomic consequences – Jönsson MEDICOGRAPHIA, VOL 28, No. 1, 2006


Hip fracture probability Hip fracture probability

Age (% at 10 years) (% at 10 years)*

(years) Men Women Men Women

50 1.98 1.17 0.41 0.55

55 2.36 1.80 0.68 1.16

60 2.96 2.73 1.17 2.35

65 3.72 3.98 2.02 4.54

70 4.74 5.11 3.22 7.67

75 5.42 6.08 4.46 12.24

80 6.46 7.40 6.23 18.38

85 6.31 7.23 7.25 21.90

90 6.16 6.62 8.03 22.00

* Average probability in the general population for age and sex.

Table II. Threshold 10-year hip fracture probability at which intervention became cost-effective. Adapted from reference 25: Kanis JA, Johnell O, Oden A, De Laet C, OglesbyA, Jönsson B. Intervention thresholds for osteoporosis. Bone. 2002;31:26-31.Copyright © 2002, Elsevier Inc.

Proportion of population identified (%)

Age Gradient of risk = 2.6/SD Gradient of risk =4.0/SD

(years) Men Women Men Women

50 1.4 9.7 3.1 10.4

55 3.4 16.9 5.2 15.3

60 6.8 26.0 8.2 21.0

65 12.5 37.0 12.4 27.7

70 18.0 49.6 16.0 35.5

75 24.4 62.9 20.0 44.6

80 30.2 72.6 23.5 52.0

85 37.5 80.7 28.0 59.2

90 43.0 84.3 31.4 62.9

Table III. The percentage of men and women at the ages shown whowould be identified as having a risk that exceeds the interventionthreshold according to the gradient of fracture risk/SD of the assess-ment algorithm specified. Adapted from reference 25: Kanis JA, Johnell O, Oden A, De Laet C, Oglesby A,Jönsson B. Intervention thresholds for osteoporosis. Bone. 2002;31:26-31. Copy-right © 2002, Elsevier Inc.

REFERENCES1. Kanis JA, Johnell O, Oden A, De Laet C, Jonsson B, Dawson A.Ten-year risk of osteoporotic fracture and the effect of risk fac-tors on screening strategies. Bone. 2002.30:251-258.2. Kanis JA, Johnell O, Oden A, et al. Long-term risk of osteo-porotic fracture in Malmö. Osteoporos Int. 2000;11:669-674.3. Jonsson B. Targeting high-risk populations. Osteoporos Int.1998;8(suppl 1):S13-S16.4. Johannesson M, Jonsson B. Economic evaluation of osteoporo-sis prevention. Health Policy.1993;24:103-124.5. Zethraeus N, Ben Sedrine W, Caulin F, et al. Models for assess-ing the cost-effectiveness of the treatment and prevention of os-teoporosis. Osteoporos Int. 2002;13:841-857.6. Kanis JA, Jonsson B. Economic evaluation of interventions forosteoporosis. Osteoporos Int. 2002;13:765-767.7. Jönsson B, Hedbrandt J, Johnell O. A computer simulationmodel to analyse the cost-effectiveness of fracture prevention ofosteoporosis. EFI research paper no. 6525. Stockholm, Sweden:Stockholm School of Economics; 1993.

8. Borgstrom F, Johnell O, Jönsson B, Zethraeus N, Sen SS. Costeffectiveness of alendronate for the treatment of male osteoporo-sis in Sweden. Bone. 2004;34:1064-1071.9. Kanis JA, Borgstrom F, Johnell O, Jönsson B. Cost-effectivenessof risedronate for the treatment of osteoporosis and preventionof fractures in postmenopausal women. Osteoporos Int.2004;15:862-871.10. Johnell O, Jönsson B, Jönsson L, Black D. Cost effectivenessof alendronate (fosamax) for the treatment of osteoporosis andprevention of fractures. Pharmacoeconomics. 2003;21:305-314.11. De Laet CE, van Hout BA, Burger H, Weel AE, Hofman A, PolsHA. Incremental cost of medical care after hip fracture and firstvertebral fracture: the Rotterdam study. Osteoporos Int. 1999;10:66-72.12. Oleksik A, Lips P, Dawson A, et al. Health-related quality oflife in postmenopausal women with low BMD with or withoutprevalent vertebral fractures. J Bone Miner Res. 2000;15:1384-1392.

J Am Geriatr Soc. 2000;48:338-339.20. Kanis J et al. Excess mortality after vertebral fracture.Sheffield, UK: WHO Collaborating Centre for Metabolic Bone Dis-eases; 2002.21. Cauley JA, Thomson De, Ensrud KC, Scott JC, Black D. Riskof mortality following clinical fractures. Osteoporos Int. 2000;11:556-561.22. Johnell O, Kanis JA, Oden A. Mortality after osteoporotic frac-tures. Osteoporos Int. 2004;15:38-42.23. Zethraeus N. A computer model to analyse the cost-effective-ness of hormone replacement therapy: a revised version. SSE/EFIWorking Paper Series in Economics and Finance, 368. Stockholm,Sweden: Stockholm School of Economics; 2000:57.24. Kanis JA, Oden A, Johnell O, Jönsson B, de Laet C, Dawson A.The burden of osteoporotic fractures: a method for setting in-tervention thresholds. Osteoporos Int. 2001;12:417-427.25. Kanis JA, Johnell O, Oden A, De Laet C, Oglesby A, Jönsson B.Intervention thresholds for osteoporosis. Bone. 2002;31:26-31. 26. Stevenson M, Lloyd-Jones M, De Nigris E, Brewer N, Davis S,Oakley J. A systematic review and economic evaluation of alen-dronate, etidronate, risedronate, raloxifene and teriparatide forthe prevention and treatment of postmenopausal osteoporosis.Health Technol Assess. 2005;9:1-160.

13. Zethraeus N, Borgström F, Johnell O, Kanis J, Önnby K, Jöns-son B. Costs and Quality of Life Associated with OsteoporosisRelated Fractures—Results from a Swedish Survey. WorkingPaper Series in Economics and Finance, 512. Stockholm, Swe-den: Stockholm School of Economics; 2002.14. Schousboe JT, Nyman JA, Kane RL, Ensrud KE. Cost-effec-tiveness of alendronate therapy for osteopenic postmenopausalwomen. Ann Intern Med.2005;142:734-741.15. Iglesias CP, Torgerson DJ, Bearne A, Bose U. The cost utilityof bisphosphonate treatment in established osteoporosis. Q J Med.2002;95:305-311.16. Stevenson MD, Oakley J, Chilcott JB. Gaussian process mod-eling in conjunction with individual patient simulation model-ing: a case study describing the calculation of cost-effectivenessratios for the treatment of established osteoporosis. Med DecisMaking. 2004;24:89-100.17. Kanis JA, Johnell O, Oden A, Jönsson B, De Laet C, Dawson A.Risk of hip fracture according to the World Health Organizationcriteria for osteopenia and osteoporosis. Bone. 2000;27:585-590.18. Borgström F, Zethraens N, Johnell O, et al. Cost and qualityof life related to osteoporotic fractures in Sweden. Accepted forpublication, 2005.19. Melton LJ 3rd. Excess mortality following vertebral fracture.



FACTEURS DE RISQUE ETCONSÉQUENCES PHARMACOÉCONOMIQUES

L a prévention et le traitement de l’ostéoporose comportent des coûts liésaux recherches de cas, aux traitements et au suivi. Les médicaments nereprésentent qu’une partie des coûts de la prise en charge thérapeutique.

Mais le risque de fractures et les effets secondaires du traitement, aussi bienpositifs que négatifs, ont aussi des conséquences financières qui doivent êtreprises en compte dans l’évaluation du rapport coût/efficacité des différentesmesures visant à réduire le risque de fractures. Depuis le début des années 90,la modélisation du rapport coût/efficacité dans l’ostéoporose a été basée surles données de réduction du nombre de fractures, issues des études cliniques.L’avantage de cette approche, comparée aux modèles précédents basés sur desmodifications de densité minérale osseuse, est que la variable “ efficacité ” me-surée dans l’étude est directement liée à l’objectif final du traitement, c’est-à-dire la réduction du nombre de fractures. Les fractures étant associées à la mor-talité, à la diminution de la qualité de vie et aux coûts, une réduction des tauxde fractures peut se traduire en économies et en années de vie gagnées ajustéessur la qualité. La méthode et les données utilisées pour cette modélisation sontdécrites et les résultats obtenus sont présentés. Le rapport coût/efficacité dé-pend du coût du traitement, de la réduction du risque relatif et du risque abso-lu de fracture en l’absence de traitement. De tels modèles peuvent être aussiutilisés pour évaluer les seuils d’intervention. Dans le cas de base (500 $ par an;35% d’efficacité), le traitement chez les femmes était rentable avec une pro-babilité de fracture de hanche à 10 ans allant de 1,2% à l’âge de 50 ans à 7,4%à l’âge de 80 ans. Des résultats similaires ont été observés chez les hommes àl’exception des âges plus jeunes pour lesquels le seuil de rentabilité est plus éle-vé que celui des femmes (2% versus 1,2% respectivement à l’âge de 50 ans). Lesseuils d’intervention étaient sensibles à l’efficacité présumée et au coût du trai-tement. Le rapport coût/efficacité était significativement amélioré par l’exclu-sion des fractures ostéoporotiques autres que les fractures de hanche en raisonde la morbidité importante liée à ces autres fractures, en particulier aux âgesplus jeunes.

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45Is ultrasound a useful method for the diagnosis of osteoporosis? MEDICOGRAPHIA, VOL 28, No. 1, 2006

C O N T R O V E R S I A L Q U E S T I O N

Is ultrasound a useful method for the diagnosis of osteoporosis?

generally the machines are considerably cheap-er than DXA, making it more likely to havewidespread uptake (even in the absence of healthsystem rebates in most countries). Ultrasoundcan measure multiple sites (heel, radius, tibia,and phalanges), although different machines areneeded for different sites. Ultrasound measuresare predictive of bone breaking strength ex vivoand there are a number of studies confirmingthat ultrasound measures are significant predic-tors of fracture in younger and older populationsof males and females. As the site measured isgenerally peripheral, the fracture prediction isnot quite as good as DXA at the hip for hip frac-tures or DXA at the spine for spine fractures,but is better than hip DXA and total fracturerisk. Many studies have shown a modest correla-tion between DXA and ultrasound, which hasled to dismissal of ultrasound as an alternative.However, this is erroneous as both look at differ-ent components of bone and it is fracture riskthat matters. Indeed, ultrasound adds to DXAfor fracture prediction. Thus, a patient with bothlow ultrasound and low DXA is at higher frac-ture risk than someone who is low in one mea-sure. Ultrasound also has potential as a screeningtool in locations where DXA is not available.Furthermore, ultrasound is responsive to antire-sorptive treatment, but it is uncertain whetherthis responsiveness leads to a reduction in frac-ture risk, as the trials have not been of sufficientsize. Therefore, ultrasound is a reasonable mea-sure of fracture risk, but can the WHO criteriabe applied? Unfortunately, the answer is no. Mostauthors are suggesting that ultrasound cutoffsbe more liberal, in the range of --1 to --1.5 (espe-cially for lower-limb measures). Certainly, some-one below this range, aged over 65 with a lowDXA score, is also at high fracture risk. Howev-er, a fracture intervention trial measuring bothultrasound and DXA at baseline is required toaccurately answer the question regarding cut-offs for intervention for ultrasound alone andcombinations of ultrasound and DXA, whichwill benefit most from treatment. Such data arenow necessary to move the ultrasound debateforward, particularly given the limitations ofDXA. ❒

F ractures are a very common and increas-ing public health problem. Fracture risk isdetermined by both bone strength and

risk of falls. All measures of bone strength cannever be “perfect” measures of fracture risk asthey cannot take the risk of falls into account. Itis only when markers of bone strength and riskof falls are combined that highly sensitive andspecific fracture prediction models can be devel-oped (as in the Dubbo study for both elderly menand women). There are numerous methods ofnoninvasively assessing bone strength in humans.These include plain x-ray, computed tomography,dual photon absorptiometry, dual energy x-rayabsorptiometry (DXA), and ultrasound. The cur-rent gold standard is DXA, although current evidence for all of these measures indicates thatthey have similar ability to predict fractures. Therelationship between each measure and fracturerisk is exponential, with fracture risk roughlydoubling for each standard deviation (or 10%)decrease in that measure. Thus, there is no cut-point above which fractures do not occur andsimilarly there is no lower level below which frac-tures are guaranteed. The World Health Organi-zation (WHO) derived cutoffs for osteoporosis(T<--2.5) and osteopenia (T --1.0 to --2.5) fromcomparison with a young reference range. Theseare based on DXA scans only and have obviouslimitations as the majority of fractures occurabove the osteoporosis cutpoint. Nevertheless,many of the trials that have been performed inosteoporosis in recent years have used these WHOcutoffs and have yielded much information onwho to treat, both with and without fracture. Despite DXA being widely used for monitoringosteoporosis therapy, there is only a modest re-lationship between change in bone mass in theindividual and reduction in fracture risk. The rea-sons for this are poorly understood and may in-clude the effect of measurement error (so calledregression dilution bias) or that change in DXAdoes not adequately reflect underlying bonequality. So why not use ultrasound? This is a to-tally noninvasive scan mode that can accuratelyand reproducibly measure bone status (even ininexperienced hands and diverse locations) with-out any radiation exposure. It is portable and

1◆ G. Jones, Australia

Graeme JONES, MD, FRACPProfessor and HeadMusculoskeletal UnitMenzies Research UnitPrivate Bag 23, HobartTasmania 7000AUSTRALIA(e-mail:[email protected])


46 Is ultrasound a useful method for the diagnosis of osteoporosis?MEDICOGRAPHIA, VOL 28, No. 1, 2006

titative sonography and DXA of the forearm, aswas true for most quantitative techniques in theassessment of skeletal status.13 QUS was alsofound to not correlate well with DXA in a high-risk population of transplant recipients.14 In con-trast, another study showed that QUS identifiedsevere bone abnormalities in children with celiacdisease (CD), and the authors suggest that inthis small cohort of children with CD, QUS pro-vided more information relevant to the diseasestatus than DXA.15 In a study comparing theability of QUS and DXA measurements to dis-criminate between rheumatoid arthritis patientswith or without vertebral deformities, BMD dis-criminated significantly between patients withand without vertebral deformities, and the re-sults were similar to those obtained in controls.16

Risk factors usually associated in other studieswith DXA-BMD in elderly women were found tobe associated with calcaneal bone stiffness, asmeasured by QUS in postmenopausal women.6 Insome studies, there is poor correlation betweenthe results obtained from the two methods Thiscould be due to the fact that while DXA is onlyaffected by bone mineral content, QUS is affectedby other variables, namely elasticity and bonemicroarchitecture.17 Most clinical ultrasounddevices use calcaneus measurements to deter-mine broadband ultrasound attenuation (BUA)and speed of sound (SOS). Studies showed that,although a normal BUA did not exclude an os-teoporotic BMD result at hip or lumbar spine, alow BUA appeared to be a highly specific predic-tor of low BMD at these sites. Hakulinen et alperformed a study to find the most sensitive fre-quency range for the QUS analyses. NormalizedBUA, SOS, broadband ultrasound backscatter(BUB), and integrated reflection coefficient (IRC)were determined for each sample and the resultsof the study suggested that frequencies up to 5MHz can be useful in QUS analyses for the predic-tion of bone mechanical properties and density.18

To demonstrate in vitro the feasibility of QUSimaging at the upper part of the femur, and to in-vestigate the relationships between BUA and BMD,Padilla et al carried out research that yieldedresults consistent with previous findings at thecalcaneus, and demonstrated the feasibility ofQUS measurements at the femur in vitro withreasonable reproductibility.19 Significant effortshave been devoted to the development of a non-invasive, easy, and relatively inexpensive methodfor the assessment of bone quality with a portabledevice. A large number of studies published inthe last decade have convincingly shown thatboth BUA and SOS measurements at the calca-neum can identify individuals at risk for osteo-porotic fracture as reliably as BMD. Because ofits low cost, QUS has become the preferred toolfor large-scale screening.6,20 ❒

I t is well known that bone strength and frac-ture risk depend not only on bone mass, buton bone microarchitecture and quality of

bone tissue as well. In spite of the importance ofthese parameters, it is not always possible to mea-sure them in daily clinical practice. Measurementof bone mineral density (BMD) by dual-energyx-ray densitometry (DXA) is the validated methodfor assessing bone mass, and is widely availablein most of the clinical centers in the world. Never-theless, it is very difficult to apply this procedurein community-based studies because of its lackof portability and costs. Furthermore, DXA mea-sures areal density and the procedure exposessubjects to low, but significant doses of ionizingradiation.1 Clinical assessment of bone in publichealth setting has been facilitated by the avail-ability of quantitative ultrasound (QUS) instru-ments designed to measure bone quality quicklyand relatively inexpensively. Because of its beingportable and involving less radiation, QUS wasthought to be an ideal tool to screen for osteo-porosis at the community level and has been pro-posed for measuring bone density in large popula-tions.1,2 The World Health Organization (WHO)approach to the definition of osteoporosis meansthat QUS results cannot currently be diagnosticof osteoporosis, and DXA is likely to remaincentral to diagnosis and follow-up. However, inrecent years, ultrasound measures have beenshown to be highly correlated to BMD measuresby DXA throughout life, and QUS measures havethus been used in research undertaken in college-aged adults, to identify postmenopausal womenwho are at risk for osteoporotic fractures, to ex-clude osteoporosis, and for follow-up studies.3-7 Inprimary health care, selective screening by QUScould be used to screen for low BMD in patientswith fragility fracture or stress fracture.8,9 Sincepatients with diseases causing secondary osteo-porosis may be prone to osteopenia, a low-costpreventive medicine screening strategy, with aconvenient detection method and minimal bio-hazard, such as that offered by ultrasound, isneeded.10 In patients in whom central DXA BMDassessment is not possible (for geographic, finan-cial, cognitive, or mobility reasons), peripheralQUS, despite its limitations, likewise providesvaluable additional information, on top of clinicaldata, thereby facilitating the diagnosis of osteo-porosis.11 The correlation between QUS and DXAhas long been debated by many researchers, andno strong consensus has yet emerged. Diagnosticperformance of QUS calcaneus measurementwas evaluated in a case-finding study for osteo-porosis in Thai postmenopausal women, usingDXA as a gold standard. The results showed thatBMD measurement for predicting osteoporosisusing QUS had very low sensitivity.12 Considerablediagnostic disagreement existed between quan-

2◆ Y. Gokce-Kutsal, Turkey

Yesim GOKCE-KUTSAL, MDProfessor of PhysicalMedicine and Rehabilitation-PMR, Hacettepe MedicalSchool, Dept of PMRReasearch Center ofGeriatrics Sciences–HUGEBAM ([email protected]) President of GeriatricSociety (www.geriatri.org),Ankara, TURKEY(e-mail:[email protected])



bone mineral density in cognitively impaired seniors. J AmMed Dir Assoc. 2004:377-381.12. Panichkul S, Sripramote M, Sriussawaamorn N. Diagnos-tic performance of quantitative ultrasound calcaneus measure-ment in case finding for osteoporosis in Thai postmenopausalwomen. J Obstet Gynaecol Res. 2004;30:418-426.13. Krestan CR, Grampp S, Henk C, Peloschek P, Imhof H.Limited diagnostic agreement of quantitative sonography ofthe radius and phalanges with dual energy x-ray absorptiom-etry of the spine, femur and radius for diagnosis of osteo-porosis. AJR Am J Roentgenol. 2004;183:639-644.14. Mack-Shipman L, O’Grady DM, Erickson JM, et al. Heelultrasonography is not a good screening tool for bone loss afterkidney and pancreas transplantation. Clin Transplant. 2004;18:613-618.15. Hartman C, Hino B, Lerner A, et al. Bone quantitativeultrasound and bone mineral density in children with Celiacdisease. J Pediatr Gastroenterol Nutr. 2004;39:504-510.16. Orstavik RE, Haugeberg G, Uhkig T, et al. Quantitativeultrasound and bone mineral density: discriminatory ability inpatients with rheumatoid arthritis and controls with and with-out vertebral deformities. Ann Rheum Dis. 2004;63:945-951.17. Camozzi V, Carraro V, Zangari M, Fallo F, Mantero F,Luisetto G. Use of quantitative ultrasound of the hand pha-langes in the diagnosis of two different osteoporotic syndromes:Cushing’s syndrome and postmenopausal osteoporosis. J ClinInvest. 2004;27:510-515.18. Hakulinen MA, Day JS, Töyras J, et al. Prediction of den-sity and mechanical properties of human trabecular bone invitro by using ultrasound transmission and backscatteringmeasurements at 0.2-6.7 MHz frequency range. Phys Med Biol.2005;50:1629-1642.19. Padilla F, Akrout L, Kolta S, Latremouille C, Roux C,Laugier P. In vitro ultrasound measurement at the humanfemur. Calcif Tissue Int. 2004;75:421-430.20. Boonen S, Nijs J, Borghs H, Peeters H, Vanderschueren D,Luyten F. Identifying postmenopausal women by calcanealultrasound, metacarpal digital x-ray radiogrammetry andphalangeal radiographic absorptiometry: a comperative study.Osteoporosis Int. 2005;16:93-100.

REFERENCES1. Hien VTT, Khan NC, Lam NT, et al. Determining the preva-lence of osteoporosis and related factors using quantitativeultrasound in Vietnamese adult women. Am J Epidemiol.2005;161:824-830.2. Inanıcı-Ersoz F, Gokce Kutsal Y, Oncel S, Eryavuz M,Peker O, Ok S. A multicenter, case control study of risk factorsfor low tibial speed of sound among residents of urban areasin Turkey. Rheumatol Int. 2002;22:20-26.3. Wetter AC, Economos CD. Relationship between quantita-tive ultrasound, anthropometry and sports participation incollege aged adults. Osteoporos Int. 2004;15:799-806.4. Saadi HF, Reed RL, Carter AO, Al-Suhaili AR. Correlationof quantitative ultrasound parameters of the calcaneus withbone density of the spine and hip in women with prevalenthypovitaminosis D. J Clin Densitom. 2004;7:313-318.5. Gudmundsdottir SL, Indridason OS, Franzson L, SigurdssonG. Age related decline in bone mass measured by dual energyx-ray absorptiometry and quantitative ultrasound in a popula-tion based sample of both sexes: identification of useful ultra-sound thresholds for osteoporosis screening. J Clin Densitom.2005;8:80-86.6. Adami S, Giannini S, Giorgino R, et al. Effect of age, weightand lifestyle factors on calcaneal quantitative ultrasound inpremenopausal women: The ESOPO study. Calcif Tissue Int.2004;74:317-321.7. Hans D, Schott AM, Duboeuf F, Durosier C, Meunier PJ.Does follow-up duration influence the ultrasound and DXAprediction of hip fracture? The EPIDOS study. Bone. 2004;35:357-363.8. Blivik J, Karlsson MK, Möller M. Screening for low bone min-eral density with quantitative ultrasound within the primaryhealth care system. Scand J Prim Health Care. 2004;22:78-82.9. Lappe J, Davies K, Recker R, Heaney R. Quantitative ultra-sound: use in screening for susceptibility to stress fractures infemale army recruits. J Bone Mineral Res. 2005;20:571-578.10. Zadik Z, Sinai T, Zung A, Reifen R. Longitudinal moni-toring of bone measured by quantitative multisite ultrasoundin patients with Crohn’s disease. J Clin Gastroenterol. 2005;39:120-123.11. Juby AG. The use of calcaneal ultrasound evaluation of

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to provide information beyond the mere calcu-lation of bone mass density (ultrasound tissuecharacterization), and numerous authors havecontributed to defining the clinical applications ofQUS, of which three have major implications4:◆ QUS can be used to diagnose patients with osteoporosis and associated fracture. In theFrench ÉPIDémiologie de l’OStéoporose (EPIDOS)study,5 QUS has shown equivalent ability to hipDXA for the in diagnosing osteoporosis and hip fracture.◆ QUS can independently predict the risk of os-teoporosis-related fractures. In two large-scaleprospective studies, (Study of Osteoporotic Frac-tures [SOF] 6 and EPIDOS 5), ultrasound parame-ters (SOS and BUA) predicted the risk of hip frac-ture as well or better than did measurements of BMD at the femoral neck, using DXA.◆ Serial QUS testing for monitoring. Longitudinaldata7 found a decline in QUS measurements overtime of a similar magnitude to DXA, suggestingQUS testing may be used for serial monitoringof osteoporotic individuals or those at high risk.Antiosteoporotic treatment studies (hormone

I n 2001, the National Institutes of Health(NIH) redefined osteoporosis as a skeletaldisorder characterized by compromised “bone

strength,” as determined through bone densityand bone quality, in spite of the fact that dual-energy x-ray absorptiometry (DXA)—the onlycurrently available method for measuring bonemineral density (BMD)—can only reveal 70% ofassociated fracture risk and that it is limited byits relatively high cost, exposure to a certain degree of ionizing radiation, and the fact that itcan only be carried out in hospital setting.1 In1984, diagnosis of osteoporosis and fracture pre-diction were aided by the development by Langtonet al2 of quantitative ultrasound (QUS). Subse-quently, speed of sound (SOS) and/or broadbandultrasound attenuation (BUA) were defined, andmathematically combined into a stiffness indexor quantitative ultrasound index (QUI).3 SeveralQUS devices have been approved by the FDA. Al-though the most common site of measurementis at the calcaneus, measurements can also becarried out at the radius, fingers, and tibia. Thephysics of ultrasound suggested it would be able

3◆ J. F. Chen, Taiwan

Jung Fu CHEN, MDDivision of MetabolismChang Gung MemorialHospital at KaohsiungTaiwanTAIWAN

for QUS, there is a great expectation that QUSwill in future play an important and cost-effectiverole in the screening, diagnosis, and monitoringof osteoporosis and its treatment, especially inthe developing world and when applied to com-munity surveys, but many challenges still remainto be met. ❒

therapy, nasal calcitonin, alendronate, etc) haveconsistently shown that serial QUS measurementssuccessfully monitored the extent of pharmaco-logical response, though parathyroid hormone(PTH) and strontium data are still lacking.8-10

Although the majority of countries across theworld currently have no reimbursement schemes



in older women: a prospective study. Arch Intern Med. 1997;157:629-634.7. Van Daele P, Burger H, De LC, et al. Longitudinal changesin ultrasound parameters of the calcaneus. Osteoporos Int.1997;7:207-212.8. de Aloysio D, Rovati LC, Cadossi R, et al. Bone effects oftransdermal hormone replacement therapy in postmenopausalwomen as evaluated by means of ultrasound: an open one-year prospective study. Maturitas. 1997:27:61-68.9. Gonnelli S, Cepollaro C, Pondrelli C, Martini S, Rossi S,Gennari C. Ultrasound parameters in osteoporotic patientstreated with salmon calcitonin: a longitudinal study. Osteo-poros Int. 1996;6:303-307.10. Giorgino R, Mancuso S. Oral alendronate and calcaneusultrasound densitometry: a three-year prospective study. TheSecond International Conference on Osteoporosis. OsteoporosInt. 1997;7(suppl 2):15.

REFERENCES1. NIH Consensus Development Panel on Osteoporosis Pre-vention, Diagnosis, and Therapy. JAMA. 2001;285:785-795.2. Langton CM, Palmer SB, Porter RW. The measurement ofbroadband ultrasound attenuation in cancellous bone. EngMed. 1984;13:89-91.3. Bonnick SL. Bone Densitometry in Clinical Practice. Totowa,NJ: Humana Press; 2004;13:301-343.4. Glüer CC, Wu CY, Jergas M, Goldstein SA, Genant HK. Threequantitative ultrasound parameters reflect bone structure.Calcif Tissue Int. 1994;55:46-52.5. Hans D, Dargent-Molina P, Schott AM, et al. Ultrasono-graphic heel measurements to predict hip fracture in elderlywomen: the EPIDOS prospectively study. Lancet. 1996;348:511-514.6. Bauer DC, Glüer CC, Cauley JA, et al; Study of OsteoporoticFractures Research Group. Broadband ultrasound attentionpredicts fractures strongly and independently of densitometry

from the combination of bone density and bonequality.9 Osteoporosis treatment aims to improvebone strength and increase the threshold of load-ing failure of bone. Mechanical testing has beenconsidered as a gold standard investigation, andrate of fracture as a good clinical marker to in-dicate bone strength. Clinical studies have shownthat QUS measurements are reproducible anduseful to quantity fracture risk.7,10 Between 2003and 2005, we performed a survey of the relation-ship between nonviolent (low-trauma) fracture(at any site) and G. E. Achilles QUS parametersin 15 772 citizens aged 20 to 85 years (unpub-lished data). The result showed that prevalenceof fracture was 9.9% (1371 cases) with a strong-ly significant difference among three groups: T-Score --1, --2, and --3 SD of speed of sound(SOS) and broadband ultrasound attenuation(BUA) parameters on the calcaneus, suggestingthat QUS may be used to assess fracture risk.The predictive power of fracture risk by QUS isgenerally lower than with dual-energy x-ray ab-sorptiometry (DXA) because osteoporotic frac-tures occur mainly at vertebral, proximal femur,and distal radius sites, which are characterizedby the presence of more abundant trabecularbone. QUS has not been used at these sites sofar. Some experimental studies have shown thatQUS parameters provide no significant improve-ment over DXA alone. Measurement of bone massby DXA or pQCT (peripheral quantitative com-puted tomography) appears to be sufficient as asurrogate of mechanical strength and fracturerisk of the distal radius.11

O ver the past decade, several quantitativeultrasound (QUS) devices have been devel-oped for the assessment of bone status.1,2

Although QUS measurements do reflect bonemass,3 some reports suggest that QUS also assess-es elements of bone quality, including trabecularthickness, separation, orientation, and connec-tivity.4,5 Many studies have shown that low QUSpredicts increased risk of hip and other nonspinalfractures in older women.6,7 The main advantagesof these systems consist in the use of nonioniz-ing radiation, their portability, user-friendliness,and low cost. QUS is an attractive choice for pop-ulation-based screening programs and a promis-ing tool in diagnosing osteoporosis and moni-toring treatment response. However, while thepractice of QUS appears to have undisputable val-ue, there are still some questions that remain tobe discussed.

QUS in evaluation of mechanical strength of boneCurrently, there are two definitions of osteoporo-sis that emphasize the role of decreased bonestrength. One is from the World Health Organi-zation (WHO), which characterizes the disease bylow bone mass and microarchitectural deterio-ration of bone tissue, leading to enhanced bonefragility and a consequent increase in fracturerisk.8 The other definition is from the NationalInstitute of Health (NIH) describing osteoporosisas a skeletal disorder characterized by compro-mised bone strength predisposing a person to anincreased risk of fracture. Bone strength results

4◆ H. M. Zhu, China

Hanmin ZHU, MDOsteoporosis Center Division of Geriatrics, HuaDong (East China) HospitalFu Dang University TeachingHospital, 221 Yen-An RoadWest, 200040 ShanghaiCHINA(e-mail:[email protected])

en.14,15 But using SOSR as a preselection tool, thepercentage of women with or without osteoporo-sis that could have avoided DXA examinationsof the axial skeleton was only 1%. QUS mea-surements at the phalanges and radius appearto have less value for the detection of healthywomen and those with low axial BMD.16 Anotherproblem is the different sensitivity to bone losschange revealed by different methods. Annualrates of bone loss measured by QUS were signif-icantly lower than with spine DXA, so that QUSwas not considered to be suitable for monitoringbone change in the context of response to aging,intervention, and treatment.17 QUS devices fromdifferent manufacturers vary significantly, mak-ing the clinical use of QUS even more complexthan that of DXA. The World Health Organizationbases the diagnostic criteria for osteoporosis(and low bone mass) on BMD measurement atspine and femur. However, the T-score definedas the threshold value for osteoporosis cannotbe used interchangeably between sites and acrosstechnologies. Although several threshold QUSdevices are used routinely in clinical practicearound the world, no criteria for diagnostic de-cision-making have yet been established. Despitethe widespread acceptance of the T-score, theWHO threshold is not suitable for use in multi-site QUS measurements.18 For these reasons, al-though the QUS method is an inexpensive andrelatively portable noninvasive technique, itsutilization in clinical practice is still limited. Itsmain current advantage resides in its use inscreening programs. ❒

QUS in women with low axial BMDThe most common osteoporotic fracture regionsare located at the spine and femur, which containmore cancellous bone than other sites. Imbalanceof bone turnover is a major pathophysiologicalmechanism, which results in bone loss and micro-architectural deterioration of bone tissue in os-teoporosis. The ratio of metabolic area to corticaland cancellous bone is about 2/8. Measurementof bone mass at the spine and femur is a key parameter in diagnosing osteoporosis and moni-toring its treatment. The degree of mineralizationis a determinant of bone strength As we know, thestrength of bone depends on bone matrix volume,bone microarchitecture, and also on the degreeof mineralization of bone. Clinical experienceshows that, in osteoporotic patients treated withalendronate, fracture risk decreased and bonemineral density (BMD) increased, with a parallelincrease in the mineralization of bone due toprolonged secondary mineralization, but withoutmodifications of bone matrix volume or bonemicroarchitecture. Bone strength will also in-crease when mineralization of bone is modified ina physiologic range, without there having to bea change of bone matrix volume or bone micro-architecture.12 BMD assessed by DXA explains upto 70% to 75% of the variance in bone strength.13

Can the widespread availability of QUS scannerspredict measurements of axial BMD? Recentstudies have shown that SOS at the proximalphalanx of the third finger (SOSP) is a bettermeasurement than SOS at radius (SOSR) in dis-criminating diseased subjects from healthy wom-



of interest location on ultrasound measurements of the cal-caneus. Calcif Tissue Int. 1998;63:300-305. 11. Hudelmaier M, Kuhn V, Lochmüller EM, et al: Can geom-etry-based parameters from pOST and material parametersfrom quantitative ultrasound (QUS) improve the prediction ofradial bone strength over that by bone mass (DXA)? Osteo-poros Int. 2004;15:375-381. 12. Follet H, Bovin G, Rumelhart C, et al. The degree of min-eralization is a determinant of bone strength: a study on hu-man calcanei. Bone. 2004;34:783-789. 13. Hans D, Hartl F, Krieg MA. Device-specific weighted T-scorefor two quantitative ultrasounds: operational propositions forthe management of osteoporosis for 65 years and older womenin Switzerland. Osteoporos Int. 2003;14:251-258. 14. Has D, Ish-Shaloms S, Wu CY, et al. Discrimination be-tween hip fractures and age matched controls using a commer-cialized multisite quantitative ultrasound device. Bone. 23:S638. 15. Knapp KM, Blake GM, Fogelman I, et al. Multisite quan-titative ultrasound: Colles’ fracture discrimination in post-menopausal women. Osteoporos Int. 2002;13:474-479. 16. Damliasis J, Papadokostakis G, Perisinakis K, et al: Canradial bone mineral density and quantitative ultrasoundmeasurements reduce the number of women who need axialdensity skeletal assessment? Osteoporos Int. 2003;14:688-693.17. Ito M, Nishida A, Kono J, et al. Which bone densitometryand which skeletal site are clinically useful for monitoringbone mass? Osteoporos Int. 2003;14:959-964. 18. Knapp KM, Blake GM, Spector TD, et al. Can the WHO def-inition of osteoporosis be applied to multi-site axial transmis-sion quantitative ultrasound? Osteoporos Int. 2004; 15:367-374.

REFERENCES1. Blake GM, Wahner HW, Fogelman I. The Evaluation of Osteoporosis. Dual Energy absorptiometry and ultrasound inclinical practice. London, UK: Martin Dunitz; 1999:127-146. 2. Njeh C, Hans D Fuerst T, Glüer CC, et al: Quantitative ul-trasound assessment of osteoporosis and bone status. London,UK: Martin Dunitz London; 1999:107-162. 3. Glüer CC. Quantitative ultrasound techniques for the as-sessment of osteoporosis: expert agreement on current status.The International Quantitative ultrasound Consensus Group. J Bone Miner Res. 1997;12:1280-1288.4. McCarthy RN, Jeffcott LB, McCartney RN. Ultrasound speedin equine cortical bone: effects of orientation, density, porosityand temperature. J Biomech. 1990;70:691-696. 5. Bouxsein ML, Radloff SE. Quantitative ultrasound of thecalcaneus reflects the mechanical properties of calcaneal tra-becular bone. J Bone Miner Res. 1997;12:839-846.6. Buauer DC, Glüer CC, Cauley JA, et al: Broadband ultra-sound attenuation predicts fractures strongly and independent-ly of densitometry in older women: a prospective study. TheOsteoporotic Fractures Research Group. Arch Intern Med.1997;157:629-634.7. Hans D, Dargent-Molina P, Schott AM, et al. Ultrasono-graphic heel measurements to predict hip fracture in elderlywomen: the EPIDOS prospective study. Lancet. 1996;348:511-514. 8. Report of a WHO Scientific Group. Prevention and Man-agement of osteoporosis, WHO Technical Report Series 921.Geneva, Switzerland: World Health Organization; 2003. 9. NIH consensus Development Panel on Osteoporosis Preven-tion, Diagnosis, and therapy. JAMA. 2001;285:785-795. 10. Damilakis J, Perisinakis K, Vagios E, et al. Effect of region



osteoporotic fractures.9-13 The only other skeletalsite used, besides the calcaneus, in fracture pre-diction has been the phalanges.14 Studies com-paring the value of DXA and QUS measurementshave found that fracture discrimination or pre-diction is comparable with QUS and DXA.10,11,13,15

The clinical utility of QUS was also evaluatedusing receiving operating characteristic (ROC)analysis, to determine how this method discrim-inates between subjects with and without frac-tures. ROC analysis plots a sensitivity versusspecificity curve and quantifies the accuracy ofQUS by estimating the area under the ROC curve(AUC). A perfect tool, which would correctly clas-sify individuals into a disease or no disease state100% of the time, would have an AUC estimateof 1.0. With QUS, AUC values ranged from 0.62 13

to 0.96.5 The majority of studies using QUS mea-surements have been performed in female popu-lations, and only a few studies have looked atthe method's ability to detect skeletal changes inmales as well. Some studies found adequate frac-ture discrimination in males, with OR valuesranging from 1.05 to 3.4.16,17 The sensitivity andspecificity of ultrasound measurements in maleswas also established, with AUC values rangingfrom 0.66 to 0.81.16,17 Prospective fracture studiesare not available. Despite these promising results,longitudinal observation of bone changes ishampered by relatively poor precision, and meth-ods with improved precision are eagerly awaited.To conclude, QUS has proven utility in fracturerisk assessment in osteoporotic female and malepopulations and is therefore helpful in guidingmanagement. There is a wide consensus that diagnosis of osteoporosis should be based on DXAmeasurement, but, from the clinical point of view,it is vital to be able to measure the enhancedfracture risk resulting from osteoporosis, whichis assessed by QUS. In my opinion, the term “di-agnosis” of osteoporosis should be replaced by“fracture risk assessment,” as from the clinicalpoint of view the consequences of the disease aremainly due to fractures. Thus, the answer to thetitle question is YES: QUS is currently useful asa screening method for fracture risk assessment.Future progress in methodology and further stud-ies will doubtless result in much improvement inthe diagnosis of osteoporosis. ❒

D ensitometry is the most commonly usedmethod in clinical practice to assessskeletal status in osteoporosis. Dual-en-

ergy x-ray absorptiometry (DXA) has becomethe “gold standard” of densitometry. It providesquantitative data on the content of hydroxyap-atite calcium in bones, but provides no informa-tion on qualitative features. Yet, is well knownthat the biomechanical competence of the skele-ton is dependent both on bone mineral density(BMD) measured by DXA and qualitative featuresof bone, like elasticity or microarchitecture. Therole of bone quality is currently widely recog-nized and there is an urgent need to developnew methods able to assess it. Other methods maygive additional data on bone tissue, like quanti-tative ultrasound (QUS). QUS has several impor-tant advantages: the ability to assess some qualitative features of bone tissue, the lack ofionizing radiation, relatively low costs, and thesmall size of equipment. QUS also has some dis-advantages, such as the difficulty in obtainingprecise measurement of bone tissue features, andthe fact that it can only be applied to peripheralskeletal sites. The calcaneus is the most popularmeasurement site as it is an easily accessibleweight-bearing bone that consists almost exclu-sively of metabolically active trabecular tissue.Osteoporosis is a common disease causing frac-tures in several skeletal sites, including spine andhip. Currently, bone densitometry serves as amethod for diagnosis of the disease, but it is im-portant to point out that the most importantproblem is the assessment of fracture risk. Frac-ture risk may be established in cross-sectional(fracture discrimination) and prospective studies(fracture prediction). QUS was used in severalretrospective studies (subjects with fractures ver-sus subjects without fractures), and showed thatpatients with past, low-energy fractures (due tominimal trauma caused by a fall from standingheight or less) had significantly lower QUS val-ues.1-8 The odds ratios (OR), calculated as increas-ing risk per 1 standard deviation (SD) decreasein measured QUS parameters, usually rangedfrom to 1.5 do 4.0. Longitudinal studies providethe most important data on the clinical utilityof QUS in osteoporosis, and show that calcanealQUS measurements are able to predict future

5◆ W. Pluskiewicz, Poland

Wojciech PLUSKIEWICZ, MDProfessor, Head of MetabolicBone Diseases UnitDepartment and Clinic ofInternal DiseasesDiabetology, and NephrologySilesian School of MedicineKatowice, POLAND(e-mail:[email protected])

sonogrammetry study: age-related changes, diagnostic sensi-tivity, and discrimination power. J Bone Miner Res. 2000;15:1603-1614.6. Drozdzowska B,. Pluskiewicz W. Quantitative ultrasoundat the calcaneus in premenopausal women and their post-menopausal mothers. Bone. 2001;29:79-83.7. Drozdzowska B, Pluskiewicz W. The ability of quantitativeultrasound at the calcaneus to identify postmenopausal wom-en with different types of non-traumatic fractures. UltrasoundMed Biol. 2002;28:1491-1497.8. Drozdzowska B, Pluskiewicz W. The usefulness of quanti-tative ultrasound at the hand phalanges in the detection ofdifferent types of non-traumatic fractures. Ultrasound MedBiol. 2003;29:1545-1550.

REFERENCES1. Bauer DC, Glüer CC, Genant HK, et al. Quantitative ultra-sound and vertebral fracture in postmenopausal women. J Bone Miner Res. 1995;10:353-358.2. Schott AM, Weill-Engerer S, Hans D, et al. Ultrasound discriminates patients with hip fracture equally well as dualenergy x-ray densitometry and independently of bone mineraldensity. J Bone Miner Res. 1995;10:243-249.3. Pluskiewicz W, Drozdzowska B. Ultrasonic measurement ofthe calcaneus in Polish normal and osteoporotic women andmen. Bone. 1999;24:611-617.4. Benitez CL, Schneider DL, Barrett-Connor E, Sartoris DJ.Hand ultrasound for osteoporosis screening in postmenopausalwomen. Osteoporos Int. 2000;11:203-210.5. Wuster C, Albanese C, de Aloysio D, et al. Phalangeal osteo-



fractures as well as axial BMD. A prospective study of 422women. Osteoporos Int. 2004;15:190-195. 14. Mele R, Masci G, Ventura V, et al. Three-year longitudinalstudy with quantitative ultrasound at the hand phalanx in afemale population. Osteoporos Int. 1997;7:550-557.15. Langton CM, Langton DK. Comparison of bone mineraldensity and quantitative ultrasound of the calcaneus: site-matched correlation and discrimination of axial BMD status.Br J Radiol. 2000;73:31-35.16. Pluskiewicz W, Drozdzowska B. Ultrasound measurementsat the calcaneus in men: differences between healthy and frac-tured persons and the influence of age and anthropometricfeatures on ultrasound parameters. Osteoporos Int. 1999;10:47-51. 17. Mullemann D, Legroux-Gerot I, Duquesnoy B, et al. Quan-titative ultrasound of bone in male osteoporosis. OsteoporosInt. 2002;13:388-393.

9. Porter RW, Miller CG, Grainger D, Palmer SB. Predictionof hip fracture in elderly women: a prospective study. BMJ.1990;29:638-641.10. Hans D, Dargent-Molina P, Schott AM, et al. Ultrasono-graphic heel measurements to predict hip fracture in elderlywomen: the EPIDOS prospective study. Lancet. 1996;348:511-514.11. Bauer DC, Gluer CC, Cauley JA, et al. Broadband ultra-sound attenuation predicts fractures strongly and indepen-dently of densitometry in older women: a prospective study.Study of Osteoporotic Fractures Research Group. Arch IntMed. 1997;157:629-634.12. Pluijm SMF, Graafmans WC, Bouter LM, et al. Ultrasoundmeasurements for the prediction of osteoporotic fractures inelderly people. Osteoporos Int. 1999;9:550-556.13. Huopio J, Kroger H, Honkanen R, Jurvelin J, Saarikoski S,Alhava E. Calcaneal ultrasound predicts early postmenopausal

for widespread application than DXA. Ultrasoundis a mechanical wave that can be measured bothin transmission and in reflection. Measurementoutcomes are typically expressed as SOS (speedof sound = the velocity of the wave travelingthrough skin and bone), and as BUA (broadbandultrasound attenuation = rate at which the en-ergy is attenuated with increasing frequency).While BUA is considered to be related more tobone structure, SOS appears to be more stronglyrelated to material properties.4 Thus, QUS param-eters reflect not only BMD, but also other boneproperties, some of which may be related to bonequality. It is therefore not surprising that QUSmeasurement, particularly at the heel, has beendemonstrated in several cross-sectional andprospective studies to discriminate prevalent, orpredict incident, osteoporotic fractures at the hip,wrist, or spine at least as well as DXA (eg, refer-ences 5, 6, 7, and 8). In addition, QUS parametershave been shown to better predict women withlow bone mass than do clinical risk factors.9

However, in view of the fact that diagnosis of os-teopenia or osteoporosis should be based on WHOT-score criteria, QUS results often are also rou-tinely expressed in terms of T-scores. Unfortunate-ly, this practice can potentially lead to misdiag-nosis, as it has been clearly demonstrated thatT-scores in a given population significantly differbetween DXA and QUS.10 In other words, QUSparameters have been found to correlate onlymoderately with BMD measurements by DXA,and identification of individuals with osteopeniaor osteoporosis would greatly disagree betweenQUS and DXA if WHO T-score criteria were equal-ly applied to QUS and DXA. For example, usinga T-score of --2.5, roughly 15% of white womenaged 60 years would be expected to be osteo-porotic based on DXA of the spine, whereas only3% of the same population would be diagnosedas osteoporotic based on measurement at theheel by QUS.10 These differences have been shown

O steoporosis is currently defined as “…askeletal disorder characterized by compro-mised bone strength predisposing to an

increased risk of fracture …” 1 Bone strength it-self is determined by both bone density and bonequality. Because no clinical tool is currently avail-able to measure specified determinants of bonequality, individuals with increased fracture riskare primarily identified by measurement of bonemineral density. The current “gold standard”method for measurement of bone mineral densi-ty (BMD) is dual-energy x-ray absorptiometry(DXA). BMD is defined as the measured bonemineral content in grams divided by the measuredtwo-dimensional projected area of the bone beingmeasured. Accordingly, BMD is always expressedas g/cm2. In clinical practice, however, the resultsof a DXA measurement are given as T-scores,which are calculated by comparing the patient’sBMD with the mean value for young normal in-dividuals. This standardized procedure is basedon the fact that in 1994, a World Health Organi-zation (WHO) working group on osteoporosisproposed diagnostic categories based on such T-scores. Accordingly, a T-score of --1.0 and aboveis considered normal; a T-score between --1.0 and--2.5 is considered as osteopenia (low bone mass),and a T-score of --2.5 and below is considered asosteoporosis.2 Furthermore, according to the re-cently published Position Guidelines of the Inter-national Society for Clinical Densitometry (ISCD),for diagnosis in postmenopausal women, thelowest T-score of posterior-anterior (PA) spine,femoral neck, total hip, trochanter, or the 33%radius, if measured, should be selected.3 As analternative to DXA, which is a radiation-basedbone densitometry technique, quantitative ultra-sound (QUS) for the noninvasive assessment offracture risk is attracting increasing attention.Compared with DXA, QUS is relatively inexpen-sive, simple to use, portable, and radiation-free.QUS would thus appear to have greater potential

6◆ H. P. Dimai, Austria

Hans P. DIMAI, MDProfessor of Medicine andEndocrinology, MedicalUniversity of GrazDepartment of InternalMedicine, Division ofEndocrinology and NuclearMedicine, Auenbruggerplatz15, A-8036 GrazAUSTRIA(e-mail: [email protected])

by an experienced clinician. Diagnosis of os-teopenia or osteoporosis in terms of WHO crite-ria, however, cannot be achieved using QUS parameters. To assign an individual to one ofthe WHO diagnostic categories, measurement of BMD by DXA continues to remain the “goldstandard.” ❒

to be primarily due to discordances in age-relat-ed BMD loss.10 Although numerous efforts havebeen undertaken, hitherto no algorithm has beendeveloped to overcome these inconsistencies.Thus, at present, QUS appears to suffice to iden-tify individuals at risk of fracture at differentskeletal sites if results are carefully interpreted



6. Hans D, Dargent-Molina P, Schott AM, Sebert JL, CormierC, Kotzki PO, Delmas PD, Pouilles JM, Breart G, Meunier PJ.Ultrasonographic heel measurements to predict hip fracturein elderly women: the EPIDOS prospective study. Lancet.1996;348:511-514.7. Thompson PW, Taylor J, Oliver R, Fisher A. Quantitativeultrasound (QUS) of the heel predicts wrist and osteoporosis-related fractures in women age 45-75 years. J Clin Densitom.1998;1:219-225.8. Gluer CC, Eastell R, Reid DM, Felsenberg D, Roux C, Bark-mann R, Timm W, Blenk T, Armbrecht G, Stewart A, Clowes J,Thomasius FE, Kolta S. Association of five quantitative ultra-sound devices and bone densitometry with osteoporotic ver-tebral fractures in a population-based sample: the OPUS Study.J Bone Miner Res. 2004;19:782-793. 9. Stewart A, Reid DM. Quantitative ultrasound or clinicalrisk factors – which identifies women at risk of osteoporosis?Br J Radiol. 2000;73:165-171.10. Faulkner KG, von Stetten E, Miller P. Discordance in patientclassification using T-scores. J Clin Densitom. 1999;2:343-350.

REFERENCES1. NIH Consensus Development Panel on Osteoporosis Pre-vention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795.2. Kanis JA, Melton LJ III, Christiansen C, Johnston CC,Khaltaev N. The diagnosis of osteoporosis. J Bone Miner Res.1994;9:1137-1141.3. Leib ES, Lewiecki EM, Binkley N, Hamdy RC; InternationalSociety for Clinical Densitometry. Official positions of the In-ternational Society for Clinical Densitometry. J Clin Densitom.2004;7:1-6.4. Glueer CC, Vahlensieck M, Faulkner KG, Engelke K, Black D,Genant HK. Site-matched calcaneal measurements of broad-band ultrasound attenuation and single x-ray absorptiometry:do they measure different skeletal properties? J Bone MinerRes. 1992;7:1071-1079.5. Bauer DC, Gluer CC, Cauley JA, Vogt TM, Ensrud KE, GenantHK, Black DM. Broadband ultrasound attenuation predictsfractures strongly and independently of densitometry in olderwomen. A prospective study. Study of Osteoporotic FracturesResearch Group. Arch Intern Med. 1997;157:629-634.

of whom 1042 (20.1%) had prevalent fracture,QUS parameters showed a significant odds ratiofor every standard deviation (SD) decrease, rang-ing from 1.47 to 1.55.14 In this same study, wedemonstrated that the area under the ROC curvewas as high as 0.656. All these values were com-parable to those obtained in similar studies withDXA. Another question is how well QUS resultscorrelate with DXA results, measured in thesame patient. Since DXA values taken in differ-ent regions show only modest correlation, thesame can be expected for QUS vs DXA. In a sub-group of 267 women from the ECOSAP cohort,both hip DXA and heel QUS measurementswere obtained.15 The overall correlation was 0.47(0.37-0.56) (r, 95% CI). For a QUS T-score of --1.5,the sensitivity and specificity of the diagnosis ofosteoporosis were 64% and 58%, respectively,when compared with DXA-based World HealthOrganization (WHO) criteria. The kappa index ofagreement between the two techniques was over0.2. These results enable a diagnostic thresholdto be established when QUS is the only availabletechnique to assess a patient with possible os-teoporosis. A QUS T-score below --1.5 roughlycompares with the classic --2.5 T-score measuredby DXA. Extreme values exclude or support thediagnosis of osteoporosis in more than 20% ofcases, even in the absence of a DXA measure-ment. From all these data we can draw someconclusions. First, the ability of QUS to predict

U ltrasounds are the basis for the noninva-sive investigation of bone tissue. Measure-ments can be obtained in several anatomi-

cal regions, mainly the phalanges, tibia, andheel. The main advantages of quantitative ultra-sound (QUS) devices are their portability, lackof ionizing radiation, and relative low cost whencompared with conventional dual-energy x-ray(DXA) densitometers. However, in clinical prac-tice, the precision and reproducibility of QUS arelimited by its coefficient of variability, even thoughit has demonstrated good ability to predict bonestiffness and failure load.1,2 The World HealthOrganization (WHO) definition of osteoporosis isbased on bone mineral density measured byDXA. However, in clinical practice, DXA equip-ment availability is limited, which poses a prob-lem. Therefore, in recent years, considerable attention has been given to the diagnostic capa-bility of ultrasound for the diagnosis of osteoporo-sis. A technique able to diagnose osteoporosisshould be efficient in differentiating patients withthe disease from normal individuals. Ultrasoundshave been found to be effective in detecting os-teoporotic fracture vs nonfracture. Results froma number of cross-sectional studies have demon-strated that QUS values are lower in women withfracture than in controls.3-8 Moreover, in prospec-tive studies, the predictive ability of QUS for frac-tures is comparable to that of DXA.9-13 In theECOSAP study of 5200 postmenopausal women,

7◆ A. Díez-Perez, Spain

Adolfo DÍEZ-PEREZ, MD, PhDProfessor of MedicineAutonomous University ofBarcelonaDepartment of InternalMedicineHospital del MarPasseig Maritim 25-2908002 BarcelonaSPAIN(e-mail: [email protected])

So what is the overall answer to the controver-sial question posed? In settings in which accessto DXA devices is difficult, ultrasounds permit a reliable diagnosis of osteoporosis and of theincreased risk of fracture. Even when DXA is accessible, a QUS-based screening policy can bebeneficial to better select candidates for DXA.Future developments of the QUS technique shouldimprove its intrinsic variability and make it asuitable method to monitor the evolution of osteoporosis. ❒

fractures is good and similar to the predictionmade by DXA. In this respect, the technique ac-ceptably stratifies individual risk in a popula-tion of postmenopausal women, thereby select-ing candidates for intervention. Second, for a T-score of --1.5 measured by QUS, the quantita-tive values are comparable to the values mea-sured by DXA that provide the widely accepteddiagnostic T-score threshold value of --2.5. How-ever, the agreement between both measurementsis only modest, though statistically significant.



erally nonfracture sites, like the heel, shin, patella,and phalanges) or in the modes of data acquisi-tion and analysis;◆ Different QUS devices give different values forthe same patient.2

The only good correlation of ultrasound deter-minations is with fracture, independently of themeasured bone mass of the patient,3,4 and eventhis correlation only holds for population groups,being poor on an individual basis. However, any-thing that would in some way correlate with theaging process would also be a good method of as-sessing the risk of fracture on a population basis.The most obvious parameter is the age of thepatient. Since age is a main determinant of therisk of fracture, we would also have a good corre-lation with fracture rates, on a population basis,but not on an individual basis—and this is muchcheaper. Could this, to some extent, be the casewith QUS? In some studies,5,6 QUS has shown a

F or more than a decade, quantitative ultra-sound (QUS) has been considered as hav-ing a good potential for the diagnosis of

osteoporosis due to its lack of ionizing radiation,low cost, fast and simple operation procedures,and lightness of the hardware, allowing easytransportation from one place to another.1 In theearly days of the technique, some authors evenpredicted that QUS would, in the near future, su-persede dual-energy x-ray absorptiometry (DXA).However, so far, this hasn’t happened, and themain reasons are:◆ We still don’t know what exactly is measuredby QUS devices; ◆ Whatever is measured, it does not correlatewell with bone mass or the response to treatmentwith the most efficacious drugs available for thetreatment of osteoporosis;◆ Diversity is the main feature of QUS technolo-gy, either in the sites chosen for evaluation (gen-

8◆ J. A. Melo-Gomes, PortugalJosé A. MELO-GOMES, MDSenior ConsultantRheumatologistInstituto Português deReumatologiaLisbonPORTUGAL(e-mail:[email protected])

tive ultrasound in the discrimination of prevalent osteoporoticfractures in a bone metabolic unit. Bone. 2003;32:571-578.9. Lee SH, Dargent-Molina P, Bréart G. Risk factors for fractures of the proximal humerus: results from the EPIDOSprospective study. J Bone Miner Res. 2002;17:817-825.10. Bauer DC. Clinical applications of quantitative ultra-sound. In: Njeh CF, Hans D, Fuerst T, Gluër CC, Genant HK,eds. Quantitative Ultrasound: Assessment of Osteoporosis andBone Status. London, UK: Martin Dunitz Ltd; 1999:284-297.11. Miller PD, Siris ES, Barrett-Connor E, et al. Prediction offracture risk in postmenopausal white women with peripheralbone densitometry: evidence from the National OsteoporosisRisk Assessment. J Bone Miner Res. 2002;17:2222-2230. 12. Pluijm SMF, Graafmans WC, Bouter LM, Lips P. Ultra-sound measurements for the prediction of osteoporotic frac-tures in elderlypeople. Osteoporos Int. 1999;9:550-556. 13. Thompson PW, Taylor J, Oliver R, Fisher A. Quantitativeultrasound (QUS) of the heel predicts wrist and osteoporosis-related fractures in women age 45-75 years. J Clin Densitom.1998;1:219-225.14. Hernández JL, Marin F, González-Macías J, et al. Discrim-inative capacity of calcaneal quantitative ultrasound and ofosteoporosis and fracture risk factors in postmenopausalwomen with osteoporotic fractures. Calcif Tissue Int. 2004;74:357-365.15. Diez-Pérez A, Marín F, Vila J, et al. Evaluation of calcanealquantitative ultrasound in a primary care setting as a screen-ing tool for osteoporosis in postmenopausal women. J ClinDensitom. 2003;6:237-245.

REFERENCES1. Glüer CC. Quantitative ultrasound techniques for the as-sessment of osteoporosis: expert agreement on current status.J Bone Miner Res. 1997;12:1280-1288.2. Bouxsein ML, Radloff SE. Quantitative ultrasound of thecalcaneus reflects the mechanical properties of calcanealTrabecular bone. J Bone Miner Res. 1997;12:839-846.3. Karlsson MK, Duan Y, Ahlborg H, et al. Age, gender, andfragility fractures are associated with differences in quantita-tive ultrasound independent of bone mineral density. Bone.2001;28:118-122.4. Frost ML, Blake GM, Fogelman I. Quantitative ultrasound andbone mineral density are equally strongly associated with riskfactors for osteoporosis. J Bone Miner Res. 2001;16: 406-416.5. Frost ML, Blake GM, Fogelman I. Does the combination ofquantitative ultrasound and dual-energy X-ray absorptiometryimprove fracture discrimination? Osteoporos Int. 2001;12:471-477.6. Hartl F, Tyndall A, Kraenzlin M, et al. Discriminatory abil-ity of quantitative ultrasound parameters and bone mineraldensity in a population-based sample of postmenopausalwomen with vertebral fractures: results of the Basel Osteo-porosis Study. J Bone Miner Res. 2002;17:321-330.7. Frost ML, Blake GM, Fogelman I. A comparison of fracturediscrimination using calcaneal quantitative ultrasound anddual x-ray absorptiometry in women with a history of fractureat sites other than the spine and hip. Calcif Tissue Int. 2002;71:207-211.8. López-Rodríguez F, Mezquita-Raya P, de Dios Luna J, Escobar-Jiménez F, Muñoz-Torres M. Performance of quantita-



the lack of ionizing radiation, QUS may also become a good method to study osteoporosis inchildren with chronic rheumatic diseases8 or oth-er forms of osteoporosis, provided that the doubtslaid out above are resolved. In conclusion, I wouldsay that the compact and nonradiation technol-ogy of QUS make it an appropriate choice forpopulation-based screening programs and couldbe used on an individual basis only if DXA is notavailable locally. However, provided that DXA is available, I wouldn’t feel comfortable usingQUS alone to make a decision on whether or nottreat an individual patient. ❒

good discriminatory ability in the diagnosis ofosteoporosis, similar to that of DXA in the iden-tification of risk for vertebral osteoporotic frac-ture. However, others7 have shown that QUS isnot substantially more cost-effective than DXAalone for the diagnosis of postmenopausal os-teoporosis. The fact that all drugs now availableto treat osteoporosis act by changing bone turn-over and/or increasing bone mass makes thesetwo parameters the best surrogate markers forthe decrease of osteoporotic fracture risk, leavingthus QUS with an, yet, uncertain role in the di-agnosis and evaluation of osteoporosis. Due to

women population with osteoporotic fracture. Calcif TissueInt. 2003;73:555-564. 6. Gluer CC, Eastell R, Raid DM, et al. Association of five quan-titative ultrasound devices and bone densitometry with os-teoporotic vertebral fractures in a population-based sample:the OPUS study. J Bone Miner Res. 2004;19:782-793. 7. Marin F, López-Bastida J, Diez-Pérez A, et al. Bone mineraldensity referral for dual-energy x-ray absorptiometry usingquantitative ultrasound as a pre-screening tool in postmeno-pausal women from the general population: a cost-effective-ness analysis. Calcif Tissue Int. 2004;74: 277-283. 8. Hartman C, Shamir R, Eshash-Adiv O, et al. Assessment ofosteoporosis by quantitative ultrasound versus dual energyx-ray absorptiometry in children with chronic rheumatic dis-eases. J Rheumatol. 2004;31:981-985.

REFERENCES1. Faulkner KG. Update on bone density measurement. RheumDis Clin N Am. 2001;27:81-99.2. Falgarone G, Porcher R, Duché A, et al. Discrimination ofosteoporotic patients with quantitative ultrasound usingimaging and non-imaging device. Joint Bone Spine. 2004;71:419-423. 3. Bauer D, Gluer C, Cauley J, et al. Bone ultrasound predictsfractures strongly and independently of densitometry in old-er women. A prospective study. Arch Intern Med. 1997;157:629-634.4. Marshall D, Johnell O, Wedel H. Meta-analysis of how wellmeasures of bone mineral density predict the occurrence ofosteoporotic fractures. BMJ. 1995;312:1254-1259. 5. Pinheiro MM, Castro CHM, Frisoli Jr A, Szenfeld VL. Dis-criminatory ability of quantitative ultrasound measurementsis similar to dual-energy x-ray absorptiometry in a Brazilian

✦

bral and hip fractures, are associated with importantmorbidity and often permanent loss of quality of life,and high mortality.1

Postmenopausal osteoporosis requires effectivetreatment, and because osteoporosis is a chronicdisease, persisting into old age, patients are often onmultiple therapies, so that antiosteoporotic treat-ment needs to be as free as possible of any unto-ward drug interactions, and have excellent toler-ability and safety. Most agents available today arelimited by the fact that they have a mode of actionthat is either antiresorptive or bone-forming. Dueto the coupling of bone formation and bone resorp-tion, antiresorptive agents are associated with a con-

Osteoporosis is characterized by a decrease inbone mass and a deterioration in skeletal mi-croarchitecture, leading to increased fragility

and susceptibility to fracture. Bone loss is a majordeterminant of skeletal weakness in osteoporosisand the single most important risk factor is themenopause.1 After the menopause sets in, there isan increase in bone turnover in which the markedincrease in bone resorption is partly balanced bythe increase in bone formation, thus leading to boneloss. The prevalence of osteoporosis peaks in mid-dle-aged to elderly postmenopausal women, eventhough it is observed in all age groups and popu-lations. Osteoporotic fractures, in particular verte-

55Protelos in the treatment of postmenopausal osteoporosis – Leblanc MEDICOGRAPHIA, VOL 28, No. 1, 2006

P R O T E L O S

P rotelos (strontium ranelate) is a new first-line therapyfor the treatment of postmenopausal osteoporosis, withdemonstrated efficacy in reducing the risk of the osteo-

porotic fractures and good tolerability. Postmenopausal osteo-porosis is a dramatically increasing, widespread, and urgentclinical problem. One out of two women will experience an osteo-porosis-related fracture in their lifetime, with major associatedmorbidity and mortality, which increases with age. Fragility frac-tures most commonly involve the vertebrae, hips, and wrists. Al-though vertebral fractures are the most frequent, hip fracturesare associated with the highest morbidity and mortality. Osteo-porosis results from an imbalance between bone resorption andformation. Most currently available therapies are either exclu-sively antiresorptive or exclusively bone-forming. Protelos, dis-covered and developed by Servier, is the first antiosteoporoticagent with a dual mode of action, resulting in a simultaneous in-crease in bone formation and decrease in bone resorption. Thisdual action rebalances bone turnover in favor of the formation ofnew, thus strong, bone. Two international, randomized, double-blind phase 3 placebo-controlled clinical trials have been con-ducted to establish the efficacy and safety of Protelos (strontiumranelate 2 g/day orally) in the treatment of postmenopausal os-teoporosis, SOTI (Spinal Osteoporosis Therapeutic Intervention)and TROPOS (TReatment Of Peripheral OSteoporosis). Thesetrials confirmed the effectiveness of Protelos whatever the sever-ity of the disease (with or without previous vertebral fractures),whatever the site (vertebra, hip), and whatever the age (includ-ing patients aged 80 and above). Protelos resulted in a significant49% reduction in relative risk of new vertebral fractures as early

as by the first year of treatment, with sustained efficacy over 3years, and in a significant 41% reduction in relative risk in pa-tients with prevalent vertebral fractures. In osteoporotic patientswithout prevalent vertebral fractures, Protelos decreased frac-ture risk by 48% over 3 years of treatment. New clinical vertebralfractures (ie, those associated with back pain and/or loss of bodyheight of at least 1 cm) were reduced by 52% as early as by the1st year of treatment. Protelos resulted in a significant 16% re-duction in relative risk of nonvertebral fractures, with a 19% de-crease in risk of major osteoporotic nonvertebral fractures, anda 36% decrease in risk of hip fractures in osteoporotic patientsaged 74 years or more, ie, the population mainly suffering fromhip fractures. Protelos significantly increased bone mineral den-sity (BMD). After 3 years, mean BMD difference between groupswas 14.4% at the lumbar spine and 8.3% at the femoral neck.Protelos not only provides fracture risk reduction, but also im-proves patient quality of life, with studies showing good tolera-bility, including in elderly patients. These findings confirm theindication of Protelos 2 g/day orally (one sachet at bedtime), inthe first-line treatment of postmenopausal osteoporosis in wom-en, to reduce the risk of vertebral and hip fractures. Medicographia. 2006;28:55-62. (see French abstract on page 62)

Keywords: osteoporosis; fracture; bone mineral density; Protelos(strontium ranelate); mode of action; antifracture efficacy;quality of life

✦

Véronique LEBLANC, MDInternational Scientific

Project LeaderNeuilly-sur-Seine

FRANCE

PROTELOS, THE FIRST DUAL-ACTIONBONE AGENT FOR THE TREATMENT OF

POSTMENOPAUSAL OSTEOPOROSIS

b y V . L e b l a n c , F r a n c e

Address for correspondence: Véronique Leblanc, MD, Servier International, 192 avenue Charles de Gaulle, 92578 Neuilly-sur-Seine Cedex, France(e-mail: [email protected])

Protelos: a unique dual mode of action

The majority of treatments available today are an-tiresorptive (bisphosphonates, selective estrogen re-ceptor modulators [SERMs], and calcitonins). Theydecrease or inhibit bone resorption. As a conse-quence of the coupling between bone formation

and bone resorption, they also decrease bone for-mation, so that the net result is a global decrease inbone turnover. In contrast, parathyroid hormoneand its analogs increase bone formation, while alsoincreasing bone resorption. Protelos has a uniquedual mode of action, and is the first and only treat-ment to dissociate the processes of bone resorptionand bone formation, thereby rebalancing bone turn-over in favor of formation and achieving early andsustained antifracture efficacy (Figure 2).2,4-10

The molecular basis for this dual mode of actionis still under investigation. Current knowledge sug-gests that Protelos influences the cellular mecha-nisms regulating bone cell differentiation and activ-ity. Protelos enhances preosteoblastic cell replication,leading to an increase in bone-forming activity byosteoblasts,4-7 and this is accompanied by a decreasein the differentiation of preosteoclasts, thus a de-crease in the resorbing activity of osteoclasts.7-10 Thedual mode of action of Protelos was tested in vitroand confirmed in the intact animal and in animalmodels of osteoporosis. Its unique mode of actionwas clinically confirmed by the resulting changesin bone metabolism markers. In postmenopausalpatients with osteoporosis, findings from the SpinalOsteoporosis Therapeutic Intervention (SOTI) tri-al showed that serum bone-specific alkaline phos-phatase (bALP) levels (a marker of bone formation)were significantly higher (+8.1%, P<0.001 at the

comitant decrease in bone formation, while bone-forming agents are associated with an increase inbone resorption. Ideally, an optimal drug treatmentfor osteoporosis should be able to both increasebone formation and decrease bone resorption: Pro-telos fulfills this requirement.

Protelos: a new antiosteoporotic agent

Protelos, or strontium ranelate (5-[bis(carboxy-methyl)amino]-2-carboxy-4-cyano-3-thiophena-cetic acid distrontium salt), discovered and devel-oped by Servier, is a new antiosteoporotic treatmentwith an innovative mode of action on bone turn-over. It is the first antiosteoporotic agent able to si-multaneously increase bone formation and decreasebone resorption,2 thereby rebalancing bone turnoverin favor of the formation of new and strong bone,resulting in an increase in bone mass. Protelos iscomposed of an organic moiety (ranelic acid) andtwo atoms of stable (nonradioactive) strontium.Ranelic acid was chosen among 26 strontium saltsfor its pharmacokinetic characteristics (eg, bioavail-ability), physicochemical characteristics (eg, solu-bility, stability, etc), high ratio between strontiumand organic moiety (two atoms of strontium linkedto the molecule), good tolerability (especially excel-lent gastric tolerance), and safety (Figure 1).

Protelos was granted a European marketing au-thorization by the European Agency for the Evalu-ation of Medicinal Products (EMEA) with the fol-lowing indication: “Treatment of postmenopausalosteoporosis to reduce the risk of vertebral and hipfractures.” Only alendronate and risedronate hadpreviously been given this indication. Recently reg-istered products in Europe like teriparatide andibandronate have not obtained a hip fracture indi-cation.3 Protelos is now registered and launchedin European Union (EU) countries as well as sev-eral non-EU countries, with many more to followshortly.

P R O T E L O S

56 Protelos in the treatment of postmenopausal osteoporosis – LeblancMEDICOGRAPHIA, VOL 28, No. 1, 2006


BMD bone mineral densityFIRST Fracture International Run-in

Strontium ranelate TrialQUALIOST QUAlity of LIfe questionnaire in

OSTeoporosisSERM selective estrogen receptor modulatorSF-36 36-Item Short-Form SurveySOTI Spinal Osteoporosis Therapeutic

InterventionTROPOS TReatment Of Peripheral OSteoporosis

Figure 1. Molecularstructure of Protelos (strontium ranelate).

Figure 2. The dual mode of action of Protelos: simultaneous increase in the replica-tion of preosteoblasts (Pre-OB) resulting in an increase in osteoblasts (OB), and decrease in the differentiation of preosteoclasts (Pre-OC) into osteoclasts (OC), and a decrease in the bone-resorbing activity of osteoclasts.Modified from reference 2: Marie PJ, Ammann P, Boivin G, Rey C. Mechanisms of action and therapeuticpotential of strontium in bone. Calcif Tissue Int. 2001;69:121-129. Copyright © 2001, Springer-VerlagNew York Inc.

PROTELOS +

PROTELOS –

PROTELOS –

BONE FORMATION➔

Bone-forming activity➔ Bone- resorbingactivity

➔

BONE RESORPTION➔

Pre-OB Pre-OC

OC

Replication

Differentiation

Bone matrix

OB OB OB

S N

CN

COO----

COO-------OOC

----OOC

Sr++

Sr++

Protelos proved similarly effective in immobiliza-tion-induced osteoporosis in rats.14 Evidence fromthese studies thus confirmed that Protelos consis-tently decreases bone resorption, while having astimulatory effect on bone formation, thereby re-balancing bone turnover in favor of bone formationand improving bone strength.

Experiments in monkeys show that strontium isdose-dependently incorporated into the mineralsubstance of cortical and trabecular bone. The great-est proportion of strontium is adsorbed on the sur-face of the hydroxyapatite crystals, and only a verysmall proportion is incorporated into the crystal.Less than 1 out of 10 calcium ions present per crys-tal unit are substituted by strontium ions at highdoses. Strontium is rapidly cleared from bone aftercessation of treatment with Protelos. Bone stron-tium content decreases by up to 50% within 10weeks after stopping treatment. Protelos preservesthe characteristics of bone crystal structure and ofthe mineralization process.15,16 Based on the resultsof a phase 2 study, 2 g/day orally was found to be theadequateeffectivedosage forosteoporosis treatment,ensuring the best combination of clinical benefits(eg, significant increase in bone mineral density)and tolerability.17

Clinical efficacy of Protelos on vertebraland nonvertebral/hip fracture risk

A large-scale phase 3 development program was car-ried out in women with postmenopausal osteoporo-sis to assess the antifracture efficacy of Protelos.18

This program consisted of an initial run-in trialcalled FIRST (Fracture International Run-in Stron-tium ranelate Trial) followed by two multicenter,randomized, double-blind, placebo-controlled clin-ical trials: the Spinal Osteoporosis Therapeutic In-tervention (SOTI) trial, to study the effect of Pro-telos on vertebral fracture risk, and the TReatmentOf Peripheral OSteoporosis (TROPOS) trial, whichdid the same on nonvertebral fracture risk. FIRST,which included more than 9000 patients, was in-tended to start normalizing the patients’ calcium/vitamin D status. Of these patients, 6740 could sub-sequently be included in SOTI or TROPOS. Bothtrials were planned for a duration of 5 years and themain statistical analysis was carried out after 3 yearsof treatment. Analyses were performed on the inten-tion-to-treat (ITT) population (Table I, next page).19

Clinical efficacy of Protelos on vertebral fracture risk

In osteoporotic patients with prevalent vertebralfracture, Protelos resulted in early and sustainedantifracture efficacy. In SOTI, Protelos, 2 g/dayorally, significantly reduced the risk of experienc-ing a new vertebral fracture by 49% (relative risk[RR], 0.51; 95% confidence interval [CI], 0.36-0.74;P<0.001) as early as by the first year of treatment,and by 41% (RR, 0.59; 95% CI, 0.48-0.73; P<0.001)over 3 years, compared with placebo, based on asemiquantitative visual assessment of vertebral frac-tures. From these data it can be calculated that treat-

3rd month of treatment), and that serum type Icollagen C-telopeptide crosslinks (sCTX) levels (amarker of bone resorption) were significantly low-er (--12.2%, P<0.001 at the 3rd month of treatment)in patients receiving Protelos than in the placebogroup. These changes were sustained throughoutthe 3 years of treatment (Figure 3).11

Preclinical evidence of efficacy of Protelos: increase in bone strength

with preserved mineralization

There is extensive in vitro and in vivo evidence of asignificant decrease in bone resorption and increasein bone formation with Protelos. Thus, Protelosshares the characteristic profile of antiresorptiveagents in exhibiting a direct and/or matrix-mediat-ed decrease in osteoclast activity9 and differentia-tion.8 In addition, Protelos stimulates bone forma-tion by increasing preosteoblast cell replication,leading to an increase in bone-forming activity.4 Theeffect of Protelos has also been extensively stud-ied in various models of estrogen deficiency, a con-dition that results in significant bone loss and highbone turnover. After 8 weeks, Protelos significantlyincreased femoral bone mineral content and bonevolume in ovariectomized rats,6 and partially inhib-ited trabecular bone loss. Histological indices ofbone resorption were reduced compared with thosein untreated models. Protelos significantly increasedcortical area without any change in cortical poros-ity. Periosteal perimeter was also significantly in-creased, while endocortical bone perimeter re-mained unchanged,12 resulting in an increase incortical thickness. No variation in osteoid thick-ness or in osteoid volume was observed, indicatingthat the mineralization process was preserved.13

P R O T E L O S


Figure 3. Between-group differences over time in biochemical markers of bone metab-olism with Protelos. bALP, serum bone-specific alkaline phosphatase (marker of boneformation); sCTX, serum type I collagen C-telopeptide crosslinks (marker of bone resorption).Modified from reference 11: Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate onthe risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468. Copyright © 2004, Massachusetts Medical Society.

36Time (mo)

0 3 6 12 24

Bone formation

**

*

**

**

***

***

***

***

***

1.2

0.8

0.4

0

*P<0.05 **P<0.01

***P<0.001

a = Estimate change of difference PROTELOS minus placebo, covariance analysis, baseline-adjusted

–200

–400

–600

b-A

LP n

g/m

Ls-

CTX

pm

ol/L

Absolute change from baseline between groupsa

➔

Bone resorption

➔

by the European Committee for Medicinal Prod-ucts for Human Use (CHMP), subsequent to thestart of the approved protocol of TROPOS, nonver-tebral fractures (hip and other major nonvertebralfractures) were documented separately. Moreover, aposthoc subgroup of particular medical interest wasanalyzed to complete the TROPOS efficacy data.21

TROPOS included 5091 osteoporotic postmeno-pausal women aged 74 years and over or 70 yearswith one additional osteoporotic fracture risk fac-tor (eg, personal history of osteoporotic fractureafter the menopause, or residence in a retirementhome, or maternal history of osteoporotic fracture.

Analysis of the findings in postmenopausal osteo-porotic patients over 3 years of treatment showedthat Protelos significantly reduced the total risk ofnonvertebral fracture by 16% vs placebo (RR, 0.84;95% CI, 0.702-0.995; P=0.04) and decreased therisk of major nonvertebral osteoporotic fractures(hip, wrist, pelvis and sacrum, ribs-sternum, clavi-

ing 9 patients for 3 years would prevent 1 patientfrom having a vertebral fracture (Figure 4).11

Clinical vertebral fracture is defined by back painand/or body height loss of at least 1 cm over 3 years.In SOTI, the number of patients experiencing a newclinical vertebral fracture was significantly reducedby 52% (RR, 0.48; 95% CI, 0.29-0.80; P=0.003) overthe first year and by 38% (RR, 0.62; 95% CI, 0.47-0.83; P<0.001) after 3 years of treatment with Pro-telos (Figure 5).11

Vertebral fracture risk reduction was a secondaryend point in TROPOS. The risk reduction of newvertebral fracture in the Protelos-treated group,compared with placebo, was 45% (RR, 55; 95% CI,0.39-0.77; P<0.001) over the first year of treatmentand 39% (RR, 0.61; 95% CI, 0.51-0.73; P<0.001)over 3 years.18 In addition, the efficacy of Protelos inpreventing vertebral fractures was assessed sepa-rately in patients without prevalent fracture. Pro-telos, 2 g/day orally, significantly reduced the risk ofexperiencing a first vertebral fracture by 45% (RR,0.55; 95% CI, 0.42-0.72; P<0.001) compared withplacebo over 3 years.18 These data are consistent withthe findings of SOTI, confirming the effectivenessof Protelos in decreasing the risk of vertebral frac-tures in postmenopausal women whether or notthey had a prevalent vertebral fracture. This resultwas confirmed in a pooled analysis of the SOTI andTROPOS studies, which showed that Protelos re-duced vertebral fracture risk in patients withoutprevalent vertebral fracture by 48% (RR, 0.52; 95%CI, 0.40-0.67; P<0.001).20

Thus, Protelos is effective in reducing the verte-bral fracture risk whatever the severity of the dis-ease, including women with severe osteoporosis(T score <--2.5 SD with at least one prevalent ver-tebral fracture). Protelos achieves an early and sus-tained reduction in vertebral fracture risk in wom-en with postmenopausal osteoporosis, whatever theseverity of the disease.

Clinical efficacy of Protelos on nonvertebral/hip fracture risk

Efficacy on nonvertebral fractures was evaluated inTROPOS, in which the primary end point was glob-al nonvertebral fracture risk reduction. As required

P R O T E L O S


Figure 4. Reduction in new vertebral fractures over 1 and 3 years with Protelos2 g/day in the Spinal Osteoporosis Therapeutic Intervention (SOTI) trial(Grading of H. K. Genant).Modified from reference 11: Meunier PJ, Roux C, Seeman E, et al. The effects of strontiumranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N EnglJ Med. 2004;350:459-468. Copyright © 2004, Massachusetts Medical Society.

35

30

25

20

15

10

5

00-3 years0-1 year

Patie

nts

(%)

New vertebral fractures

RR=0.5995% CI[0.48; 0.73]

RR=0.5195% CI

[0.36; 0.74]

Placebo

*P<0.001

Protelos 2 g/day N=1442

49%

41%

*

*

➔

➔

NNT=9

Figure 5. Reduction in new clinical vertebral fractures over 1 and 3 yearswith Protelos 2 g/day in the Spinal Osteoporosis Therapeutic Intervention(SOTI) trial. (Based on data from reference 11.)

20

15

10

5

0

New clinical vertebral fractures

0-3 years0-1 year

Patie

nts

(%)

RR=0.6295% CI [0.47; 0.83]

RR=0.4895% CI

[0.29; 0.80]

*P=0.003 **P<0.001

N=1442

PlaceboProtelos 2 g/day

52%

38%

*

**

➔

➔

Protelos (2 g per day) PlaceboSOTI (n=719) (n=723)

Age (y) 69.4±7.2 69.2±7.3Time since menopause (y) 22.1±8.8 21.6±8.7BMD T-score (lumbar spine) --3.5±1.3 --3.6±1.2

Protelos (2 g per day) PlaceboTROPOS (n=2479) (n=2453)

Age (y) --3.13±0.59 --3.13±0.60Time since menopause (y) --2.70±0.94 --2.70±0.96BMD T-score (lumbar spine) --2.83±1.63 --2.84±1.62

Table I. Baseline characteristics of the SOTI (Spinal Osteoporosis Thera-peutic Intervention) and TROPOS (TReatment Of Peripheral OSteoporo-sis) trials (mean±SD): the Protelos and placebo populations are compa-rable. BMD, bone mineral density. (Based on data from reference 19.)

global score on quality of life.25 By using QUALIOSTin the SOTI study, the effect of Protelos on qualityof life, assessed after 3 years of treatment, showeda significant benefit (P=0.016 for the total score;P=0.019 and 0.032 for emotional and physicalscores, respectively, in favor of Protelos).

In SOTI, Protelos increased the number of pa-tients free of back pain by 29% (P=0.006 after 3years), with a significant effect from the first year oftreatment.26 Protelos was also shown to decrease thenumber of patients experiencing a body height lossof at least 1 cm, by 20% (P=0.003) (Figure 8).11,26

cle, and humerus) by 19% (RR, 0.81; 95% CI, 0.66-0.98; P=0.031). In osteoporotic patients aged ≥74years Protelos significantly reduced the risk of hipfracture by 36% (RR, 0.64; 95% CI, 0.412-0.997;P=0.05) (Figure 6).18

Thus, based on the above phase 3 study results,Protelos can be summed up as a powerful antios-teoporotic agent providing protection against bothvertebral and hip fractures.

Clinical efficacy of Protelosin elderly patients

A preplanned pooled analysis of 1488 elderly SOTIand TROPOS patients was carried out in order toassess the antifractureefficacy of Protelos in patientsaged 80 years and above, a population in whom therisk of osteoporotic fracture is particularly high.22

Results of the analysis showed that Protelos signif-icantly reduced the relative risk of experiencingnew vertebral fractures by 32% (RR, 0.68; 95% CI,0.50-0.92; P=0.013) over 3 years. A similar signifi-cant decrease, by 31% (RR, 0.69; 95% CI, 0.52-0.92;P=0.011), was seen in nonvertebral fracture risk re-duction. Thus, Protelos is the only treatment able toachieve proven effective and safe reduction in riskof vertebral and nonvertebral fractures in osteo-porotic women aged 80 years and over (Figure 7).22

Clinical efficacy of Protelosin patients with osteopenia

Another pooled analysis of SOTI and TROPOS pa-tients was carried out in 176 patients with baselinelumbar spine and/or femoral neck bone mineraldensity (BMD) in the osteopenic range (at least onesite T-score between –1 and –2.5 SD, and both T-scores >–2.5 SD), and no prevalent fracture. Inthese patients, Protelos significantly reduced therisk of a first vertebral fracture by 72% (RR, 0.28;95% CI, 0.07-0.99; P=0.045) over 3 years.23

Overall, Protelos is effective in reducing osteo-porotic vertebral and hip fracture risk, regardless ofthe severity of the patients’ disease and whether ornot they have had previous vertebral fractures, andwhether they are osteopenic or osteoporotic.

Protelos improves quality of life

It is well known that osteoporosis is associated witha reduction in health-related quality of life in rela-tion with the frequent back pain and loss of heightassociated with vertebral fractures.24 These disor-ders can seriously affect patients’ quality of life. Pro-telos not only reduces the fracture risk, but alsodirectly improves patients’ quality of life. The effectof Protelos on quality of life was assessed using twoquestionnaires during the phase 3 program, the36-Item Short-Form Health Survey (SF-36) andthe QUAlity of LIfe questionnaire in OSTeoporosis(QUALIOST). As opposed to SF-36, which is a gener-ic questionnaire, QUALIOST is a specific question-naire for vertebral osteoporosis containing 23 itemsassessing various aspects of patients’ physical andemotional well-being and which gives an overall

P R O T E L O S


Figure 6. Reduction in hip fracture risk with Protelos 2 g/day in the TReatment OfPeripheral OSteoporosis (TROPOS) trial. (Based on data from reference 19.)

Hip fractures

*P<0.05

0 1 2 3

8

6

4

2

0 Time (y)N=1977

Patie

nts

(%)

36%*

➔

PlaceboProtelos 2 g/day

Figure 7. Effectiveness of Protelos 2 g/day in reducing the risk of ver-tebral and nonvertebralfractures in patients aged 80 years and above.(Based on data from reference 22.)

0-3 years

Placebo

*P=0.013

Protelos 2 g/day

N=895

RR=0.68; 95%CI [0.50; 0.92]

Elderly: vertebral and peripheral fractures

30

25

20

15

10

5

0

10

8

6

4

2

00-3 years

*P=0.011N=1488

RR=0.69; 95%CI [0.52; 0.92]

Patie

nts (

%)

Patie

nts (

%)RR: –32%

*

➔

RR: –31%*

➔

Figure 8. Increase in number of patients free of back pain at 1 year (left) and decreasein risk of height loss at 3 years (right) with Protelos 2 g/day in the Spinal OsteoporosisTherapeutic Intervention (SOTI) trial. (Based on data from reference 11).

20

15

10

5

0

Back pain

0-1 year

Patie

nts

with

out b

ack

pain

(%)

Placebo

*P=0.03

**P=0.003

Protelos 2 g/day

N=1088

40

30

20

10

0

Height loss

0-3 years

Patie

nts

with

hei

ght l

oss

≥1 c

m (%

)

29%20%

***

➔

➔

telos did not differ from that with placebo and thepercentage of withdrawals following adverse eventswas the same as in the placebo group. The mostcommon adverse events were nausea (6.6%vs 4.3%),diarrhea (6.5% vs 4.6%), headache (3.0% vs 2.4%),dermatitis (2.1% vs 1.6%), and eczema (1.5% vs1.2%). These were usually mild and transient.

The safety and tolerability of Protelos were thusstudied in a large population of elderly and very el-derly (80 years of age and over) women and was con-sidered as very good. No dosage adjustment is need-ed in the elderly, or in the very elderly, or in patientswith moderate or mild renal dysfunction. Analysisof bone biopsies, obtained from postmenopausal os-teoporotic patients during the clinical developmentprogram, confirmed that Protelos is safe at the bonetissue level: patients having taken Protelos for upto 5 years had normal lamellar bone with no min-eralization defects or delay and no sign of osteoma-lacia.11,27

Practical recommendations

Protelos is easy to use: it is administered once dai-ly orally, as one 2-g sachet diluted in water, to betaken at bedtime. As Protelos is very well toleratedat the upper gastrointestinal level, patients are notsubjected to complicated dosage instructions (as isthe case with the bisphosphonates): there is no needto remain in upright position for any length of timefollowing administration of Protelos). Due to thechronic nature of osteoporosis, Protelos is intendedfor long-term use.

Conclusion

Clinical development findings indicate that Pro-telos is an effective first-line treatment for post-menopausal women with osteoporosis. Protelosprovides early and sustained vertebral and hip an-tifracture efficacy and is effective regardless of theseverity of the patients’ disease and of their age. Thisefficacy results from Protelos’ unique dual action on

BMD, a good tool to monitor patients’ progress and compliance

In SOTI, Protelos progressively increased lumbarspine BMD by 12.7% vs baseline after 3 years oftreatment (P<0.001). This represents a difference of14.4% (P<0.001) between the active treatment andplacebo at 3 years. The increase in lumbar spineBMD was linear and significant from the 6th month

of treatment and sustained thereafter (P<0.001).11

In TROPOS, femoral neck and total hip BMD in-creased by 5.7% and 7.1%, respectively, at 3 years inthe Protelos group compared with baseline. Com-pared with placebo, the differences were 8.3% (95%CI, 7.7-8.7; P<0.001) and 9.8% (95% CI, 9.3-10.4;P<0.001), respectively.18 Treatment with Protelosinduced a sustained increase in BMD. Importantly,this increase did not wane over a period of 3 years,which is a strong asset in long-term therapy. Thisincrease in BMD provides a good tool to monitorthe improvement in the course of the disease andcompliance with treatment, and helps motivate pa-tients to continue their treatment (Figure 9).11

Tolerability and safety

The phase 3 studies showed that Protelos was welltolerated, especially at upper gastrointestinal lev-el.11,18 There was no difference between Protelos andplacebo groups concerning esophagitis, gastritis,and gastric ulcers. The safety of Protelos was as-sessed based on the pooled data from the SOTI andTROPOS trials involving a total of 6669 patients.Overall, the incidence of adverse events with Pro-

P R O T E L O S


Figure 10. Summary of the antifracture efficacy of Protelos on vertebral and periph-eral/hip fractures. (Based on data from reference 11.)

Over 3 years

Clinical VF

Vertebral F

Vertebral F, without prevalent VFVertebral F, with prevalent VF

Vertebral F, ≥80 years

RR

–52%

–49%

–48%–41%

–32%

Vertebral fractures Peripheral - Hip fractures

After 1 yearFavors PROTELOS

0 0.5 1 1.5

Over 3 years

Hip fractures

Peripheral fractures ≥80 years

0 0.5 1 1.5

VF=vertebral fracture

➔

RR

–36%

–31%

Favors PROTELOS

➔

Figure 9. Increase in lumbar (top) and femoral neck bone mineral density (below) with Protelos 2 g/day in the Spinal Osteoporosis Therapeutic Inter-vention (SOTI) trial.Modified from reference 11: Meunier PJ, Roux C, Seeman E, et al. The effects of strontiumranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468. Copyright © 2004, Massachusetts Medical Society.

16

12

8

4

0

-40 6 12 18 24 30 36

Months

Mea

n ch

ange

(%)

Lumbar spine BMD(SOTI)

Placebo

*P<0.001

At M36E (SE)=14.4 (0.58)95% CI [13.27; 15.53]

+14.4%*

**

**

*

Protelos 2 g/day

16

12

8

4

0

-40 6 12 18 24 30 36

Months

Mea

n ch

ange

(%)

Femoral neck BMD(TROPOS)

At M36E (SE)=8.3 (0.41)95% CI [7.60; 9.10]

+8.3%* * * *

*

*

resorption from bone formation, with a positivebone balance, results in creation of strong, newbone, thereby ensuring sustained antifracture ef-ficacy. These assets, together with its good tolera-bility, make Protelos a major new weapon in thetreatment of osteoporosis. ❒

bone metabolism, which rebalances bone turnoverin favor of formation and creates new strong bone.The efficacy of Protelos on vertebral and hip frac-ture prevention and the sustained increase in BMDwere demonstrated over the 3 years covered by theanalyses of the phase 3 studies. Protelos has alsobeen shown to improve patients’ quality of life andosteoporosis-related symptoms, and is very well tol-erated. All of these key properties of Protelos havebeen enshrined in the Summary of Product Char-acteristics accepted across the European Union, andhave also been registered in many other countries.Protelos is now available for the treatment of allpostmenopausal women with osteoporosis to re-duce the risk of vertebral and hip fractures (Fig-ure 10).11,18,20,22,23

The findings discussed in this article confirmProtelos (strontium ranelate) as an effective and safetreatment for vertebral and hip osteoporosis, char-acterized by a unique dual bone-forming and anti-resorptive mode of action. The dissociation of bone

P R O T E L O S


ESSENTIALS OF PROTELOS

◆ Protelos is a new antiosteoporotic treatmentwith a unique dual mode of action, increasingbone formation and decreasing bone resorption

◆ Protelos is effective in the treatment of post-menopausal osteoporosis whatever the severity ofthe disease (with or without previous fractures),whatever the site (vertebrae, hip), whatever theage (including patients 80 years of age and above)

◆ Protelos has very good tolerability

◆ Protelos is administered orally, as a 2-g sachet,once daily, at bedtime

REFERENCES1. Woolf A, Pfleger B. Burden of major musculoskele-tal conditions. Bull WHO. 2003;81:646-656.2. Marie PJ, Ammann P, Boivin G, Rey C. Mechanismsof action and therapeutic potential of strontium inbone. Calcif Tissue Int. 2001;69:121-129.3. SPC Protelos. European Medicines Agency.www.emea.eu.int. Accessed 25 Oct 2005.4. Canalis E, Hott M, Deloffre P, et al. The divalentstrontium salt S12911 enhances bone cell replicationand bone formation in vitro. Bone. 1996;18:517-523.5. Delannoy P, Bazot D, Marie PJ. Long-term treat-ment with strontium ranelate increases vertebralbone mass without deleterious effect in mice. Metab-olism. 2002;51:906-911.6. Arlot ME, Braillon P, Roux JP, Deloffre P, TsouderosY, Meunier PJ. A new agent containing strontium(S12911) has a protective effect on bone loss in ovari-ectomized rats. Bone.1992;13:A1. Abstract 4.7. Marie PJ, Hott M, Modrowski D, et al. An uncou-pling agent containing strontium prevents bone lossby depressing bone resorption and maintaining boneformation in estrogen-deficient rats. J Bone MinerRes.1993;8:607-615.8. Wattel A, Hurtel-Lemarie AS, Godin C, et al. Stron-tium ranelate decreases in vitro osteoclastic differen-tiation and bone resorption. Osteoporos Int.2005;16:S53-S54. Abstract P222. 9. Baron R, Tsouderos Y. In vitro effects of S12911-2on osteoclast function and bone marrow macrophagedifferentiation. Eur J Pharmacol. 2002;450:11-17.10. Takahashi N, Sasaki T, Tsouderos Y, Suda T.S12911-2 inhibits osteoclastic bone resorption in vit-ro. J Bone Miner Res. 2003;18:1082-1087.11. Meunier PJ, Roux C, Seeman E, et al. The effectsof strontium ranelate on the risk of vertebral fracture

postmenopausal osteoporosis. Osteoporos Int. 2003;14(suppl 3):S66-S76.20. Reginster JY, Rizzoli R, Balogh A, et al. Strontiumranelate reduces the risk of vertebral fractures in os-teoporotic postmenopausal women without prevalentvertebral fracture. Osteoporos Int. 2005;16:S53. Ab-stract P220.21. Wasnich RD. Epidemiology of osteoporosis. InFavus MJ, ed. Primer on the Metabolic Bone Diseasesand Disorders of Mineral Metabolism. Philadelphia,Pa: Lippincott Williams & Wilkins; 1999:257-259. 22. Seeman E, Vellas B, Meunier PJ, et al. Vertebraland nonvertebral antifracture efficacy of strontiumranelate in very elderly women with osteoporosis.Osteoporos Int. 2005;16:S6. Abstract OC21.23. Sawicki A, Reginster JY, Roux C, et al. Strontiumranelate reduces the risk of vertebral fractures in post-menopausal women with osteopenia. Calc Tissue Int.2004;74(suppl 1):S84. Abstract P153.24. Hallberg I, Rosenqvist AM, Kartous L, et al. Healthrelated quality of life after osteoporotic fractures. Os-teoporos Int. 2004;15:834-841.25. Marquis P, Cialdella P, De la Loge C, et al. Devel-opment and validation of a specific quality of life mod-ule in post-menopausal women with osteoporosis: TheQUALIOST. Qual Life Res. 2001;10:555-566.26. Marquis P, De La Loge C, Diaz-Curiel M, et al.Beneficial effects of strontium ranelate on the qualityof life in patients with vertebral osteoporosis. Osteo-poros Int. 2005;16:S54. Abstract P223.27. Arlot, ME, Delmas P, Burt-Pichat B, et al. Effectsof strontium ranelate on bone remodeling and bonesafety assessed by histomorphometry in patients withpostmenopausal osteoporosis. J Bone Miner Res.2005;20(suppl 1)S22. Abstract 1084.

in women with postmenopausal osteoporosis. N EnglJ Med. 2004;350:459-468.12. Ammann P, Shen V, Robin B, et al. Strontiumranelate improves bone resistance by increasing bonemass and improving architecture in intact female rats.J Bone Miner Res. 2004;19:2012-2020.13. Buehler J, Chappuis P, Saffar JL, et al. Strontiumranelate inhibits bone resorption while maintainingbone formation in alveolar bone in monkeys (Macacafascicularis) Bone. 2001;29:176-179.14. Hott M, Deloffre P, Tsouderos Y, et al. S12911-2 re-duces bone loss induced by short-term immobiliza-tion in rats. Bone. 2003;33:115-123.15. Farlay D, Boivin G, Panczer G, et al. Long-termstrontium ranelate administration in monkeys pre-serves characteristics of bone mineral crystals anddegree of mineralization of bone. J Bone Miner Res.2005;20:1569-1578.16. LeGeros R, Lin S, LeGeros J, et al. Strontiumranelate treatment preserves bone crystal character-istics and bone mineral reactivity. Osteoporos Int.2004;15(suppl 1):S116-S117. Abstract P420MO.17. Meunier PJ, Slosman DO, Delmas PD, et al. Stron-tium ranelate: dose-dependent effects in establishedpostmenopausal vertebral osteoporosis: a 2-year ran-domized placebo-controlled trial. J Clin EndocrinolMetab. 2002;87:2060-2066.18. Reginster JY, Seeman E, De Vernejoul MC, et al.Strontium ranelate reduces the risk of nonvertebralfractures in postmenopausal women with osteoporo-sis: treatment of peripheral osteoporosis (TROPOS)study. J Clin Endocrinol Metab. 2005;90:2816-2822.19. Meunier PJ, Reginster JY. Design and methodol-ogy of the phase 3 trials for the clinical developmentof strontium ranelate in the treatment of women with

(see French abstract on next page)

P R O T E L O S


✦

P rotelos (ranelate de strontium) est un nouveau traitementde première ligne pour le traitement de l’ostéoporose post-ménopausique, dont l’efficacité dans la réduction du risque

fracturaire ostéoporotique et la bonne tolérance ont été démon-trées. L’ostéoporose postménopausique représente un problèmeclinique important, en forte croissance et urgent. Une femme surdeux, au cours de sa vie, aura une fracture ostéoporotique, et cesfractures sont source d’une morbi-mortalité majeure. Les sitesles plus concernés par les fractures de fragilité sont les vertèbres,les hanches et les poignets. Alors que les fractures vertébrales sontles plus fréquentes, ce sont les fractures de hanche qui sont asso-ciées aux taux de morbidité et de mortalité les plus élevés. L’ostéo-porose résulte d’un déséquilibre entre la résorption et la forma-tion de l’os. La plupart des traitements actuellement disponiblessont soit antirésorptifs, soit ostéoformateurs. Protelos, découvertet développé par Servier, est le premier agent antiostéoporotiqueprésentant un mode d’action double : il augmente simultané-ment la formation osseuse et diminue la résorption osseuse. Cettedouble action permet de rééquilibrer le métabolisme osseux enfaveur de la formation osseuse, avec production d’un os nouveaurésistant. Deux études cliniques internationales de phase III, ran-domisées, en double aveugle, contrôlées contre placebo ont étémenées pour démontrer l’efficacité et la tolérance de Protelos(ranélate de strontium à la dose de 2 g/jour par voie orale) :SOTI (Spinal Osteoporosis Therapeutic Intervention) et TROPOS(TReatment Of Peripheral OSteoporosis) dans le traitement del’ostéoporose postménopausique. Ces études ont démontré l’effi-cacité de Protelos quelle que soit la sévérité de la maladie (qu’il

y ait ou non des antécédents de fractures vertébrales), quel quesoit le site (vertèbre ou hanche) et quel que soit l’âge (y comprischez les patientes âgées de 80 ans et plus). Protelos réduit de fa-çon significative le risque relatif de nouvelles fractures (49 %) dèsla première année de traitement, avec une efficacité qui persistesur 3 ans, et diminue de façon significative le risque relatif, de41 %, chez les patientes ayant une fracture vertébrale prévalente.Chez les patientes ostéoporotiques sans fracture vertébrale pré-valente, Protelos a diminué le risque de fracture de 48 % sur 3ans de traitement. Les nouvelles fractures vertébrales cliniques(fractures vertébrales associées à des douleurs dorsales et/ou àune perte de taille d’au moins 1 cm) étaient réduites de 52 % dèsla première année de traitement. Protelos a entraîné une réduc-tion significative du risque relatif de fractures non vertébrales(16 %), des fractures de hanche (36 %) chez les patientes ostéo-porotiques de 74 ans ou plus, c’est-à-dire la population à risquepour ce type de fractures. Protelos augmente de façon significa-tive la densité minérale osseuse (DMO). Après 3 ans, la différenceintergroupes de la DMO moyenne était de 14,4 % au niveau durachis lombaire et de 8,3 % au niveau du col fémoral. Protelosn’a pas seulement permis une réduction du risque fracturaire,mais également d’améliorer la qualité de vie des patientes. Dansces études, Protelos a été bien toléré même chez les personnesâgées. Ces données confirment l’intérêt de Protelos, à raison de2 g/jour par voie orale (un sachet au coucher) dans le traitementde première ligne de l’ostéoporose postménopausique chez lesfemmes pour réduire le risque de fractures vertébrales et dehanche.

PROTELOS : PREMIER TRAITEMENT DE L’OSTÉOPOROSE POSTMÉNOPAUSIQUEAVEC UN MODE D’ACTION DOUBLE

may be that a many men had vertebralfractures when young that had nothingto do with osteoporosis, but were trau-matic in origin (eg, an industrial orsports injury).

Proximal femur. The sex ratio is simi-lar to that for fractures as a whole, ie,two to three times less frequent in men.There are many reasons, in particularthe longer lifespan of women. The mostimportant and consistently observed dif-ference is that hip fracture mortality istwo to three times higher in men (10%to 14% versus 5% in women at 1 month),again for many reasons, not all fully elu-cidated, but in part related to the higherrates of smoking and alcoholism. Recentdata also suggest a higher prevalence ofpostoperative infection in men.

Could you explain the reasons why suchdifferences in prevalence are observedbetween genders?

The reasons are multiple. Peakbone mass, by which we mean

the maximum bone mass achieved at theend of growth, is much higher in men.This in itself is enough to account for

no sex difference in this regard. Whatmatters is that despite its relative rarity,wrist fracture in man should prompt anosteoporosis workup as it is predictiveof other potentially more serious osteo-porotic fractures. It increases the risk ofvertebral fracture 10-fold, as opposed to5-fold in women, and the risk of hip frac-ture 2- to 3-fold, as opposed to only 40%to 50% in women.

Spine. Earlier studies showed that ver-tebral fracture prevalence in men washalf that in women, at least in the under-80s. The most recent data, however, pointto a similar prevalence of vertebral “de-formities.” In the European VertebralOsteoporosis Study (EVOS), the preva-lence of vertebral fractures in men under65 was 18.7% versus 14.3% in women.A North American study reached similarconclusions, with a 29% prevalence ofvertebral “deformities” in men over 50versus 11% in women; sex differencesin prevalence only ceased over the ageof 80 (40% in men and 45% in women).Although these more recent studies areinteresting, they need to be interpretedwith caution. Not all “deformities” werefractures. In addition, one explanation

Could you comment on the prevalenceof osteoporosis in men in comparisonwith women?

Osteoporosis is overwhelminglya disease of women. The epi-

demiologic data show a 40% prevalenceof osteoporotic fracture in women over50, which is three times the figure inmen of the same age (13%). As in wom-en, the main sites of fracture in men arethe wrist, spine and, at a later stage, hip.Their specificities in men are as follows:

Wrist. Fracture of the wrist is alonein being relatively less common in men(sex ratio: one man to four women). Inaddition, unlike in women, the incidencedoes not increase with age. Wrist fracturecan produce a number of complications,in particular reflex sympathetic dystro-phy (30% of cases), as in women, with

63Risk factor profiles for osteoporotic fractures in women and men – Cortet MEDICOGRAPHIA, VOL 28, No. 1, 2006

I N T E R V I E W

A lthough overwhelmingly a disease of women, osteoporosisis still a significant problem in men, with a 13% preva-lence of osteoporotic fracture in those over 50, affecting

the same sites, namely wrist, spine, and hip. In men, wrist fractureshould always prompt an osteoporosis workup as it increases therisks of vertebral fracture 10-fold (versus 5-fold in women) and ofhip fracture 2- to 3-fold (versus only 40% to 50% in women). Hipfracture in men carries double to triple the mortality in women,partly because of higher rates of smoking and alcoholism. Other-wise, the main sex differences are based on peak bone mass andbone thickness, both of which are higher in men and directly re-lated to mechanical resistance. These two factors, combined withthe absence of a true male equivalent of the menopause, accountfor the comparative rarity of osteoporosis in men. For these rea-sons, it is particularly important in men to exclude secondary os-teoporosis, which can account for 6 in 10 cases. Metastasis and

multiple myeloma are the key primary suspects, but exogenousglucocorticoids are much more frequently involved, especially inmen, notably due to chronic obstructive airways disease, whichis far more frequent than in women. Densitometry is as useful inscreening men as it is in women. The same T-score threshold of≤--2.5 should probably apply, provided the reference populationconsists of young men, not young women, since this would low-er the prevalence of densitometric osteoporosis to an unrealisticfigure of only 3%.Medicographia. 2006;28:63-65. (see French abstract on page 65)

Keywords: osteoporosis; secondary osteoporosis; sex difference;epidemiology; fracture risk; densitometry; glucocorticoid

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DO RISK FACTOR PROFILESFOR OSTEOPOROTIC FRACTURESDIFFER IN WOMEN AND MEN?I n t e r v i e w w i t h B . C o r t e t , F r a n c e

Bernard CORTETMD, PhDRheumatologyDepartment, HôpitalRoger Salengro CHU Lille Lille, FRANCE

Address for correspondence: Prof Bernard Cortet, Service de Rhumatologie, Hôpital Roger Salengro, CHU Lille, 59037 Lille Cedex, France(e-mail: [email protected])

women, some risk factors relate solely tofractures and are independent of BMD.But data on this subject are much fewerthan in women. In addition, some riskfactors are more frequent in men forlifestyle reasons: the steroid therapy al-ready mentioned, and also alcoholism,which some investigators classify as adirect cause, and others as simply a riskfactor, as in women.

Are the significant risk factors forosteoporosis and osteoporotic fractures different in men from those in women ?

Not overall. However, some riskfactors are commoner in men:

alcoholism, smoking and, to a lesser extent, steroid therapy.

Is it easy to diagnose osteoporosis in men?

Evidence shows that broadlyspeaking—and somewhat para-

doxically, given its frequency—osteo-porosis often goes undiagnosed. In men,the diagnosis is not always easy (this canalso apply in women) in so far as physi-cians do not always suspect osteoporosiswhen faced with fracture. It is importantto remember that although trauma maybe responsible for the great majority ofosteoporotic fractures it tends to be dis-proportionately minor—the revelatoryevent rather than the true cause. It istherefore important to diagnose osteo-porosis before fracture occurs. From thispoint of view, bone densitometry is auseful investigation in women, in partic-ular because of the correlation shownbetween decreasing bone density and in-creasing fracture risk.

To what extent does this apply in men?Again, the data are far fewer than in wom-en. However, a number of longitudinalstudies are available, including one veryrecent meta-analysis pooling 12 cohortsinto a total of 9891 men and 29 082women. The authors showed that at age65, every standard deviation decrease infemoral bone density multiplied the gen-eral fracture risk by 2.88 in women and2.94 in men, confirming earlier longitu-dinal studies that it doubled vertebralfracture risk.

Having shown that densitometry is animportant tool in assessing fracture riskin men, the next question is to decidewhether the World Health Organizationdefinition of osteoporosis, which datesback over a decade, should apply to men.Strictly speaking, the answer is “No,” inthat the original definition was stated toapply only to women. However, there is

hyperthyroidism and minor tubulopathy(eg, moderate idiopathic proximal tubu-lopathy), which can cause low-grade hypercalciuria and/or phosphate diabetes.Overall, osteoporosis in men is secondaryin around 6 cases in 10. In addition tothese direct causes, there are also a num-ber of risk factors. Once you’ve excludedsecondary osteoporosis, the remaining40% of cases can be considered idiopathic.

Two factors need to be borne in mindhere in terms of pathophysiology. Thefirst is estrogen deficiency. As we’ve seen,what little impact testosterone has onbone is indirect, mediated by estrogen. Inunselected men, it has been shown thatcirculating estradiol levels (which arenaturally very low and can only be detect-ed using ultrasensitive kits) correlatewith BMD and thus help to explain age-related bone loss. No such correlation—or at least a much lower correlation—is found with circulating testosteronelevels. In osteoporotic men, on the oth-er hand, the data are less clear-cut, withsome investigators finding no differencein circulating estradiol levels betweenosteoporotic men and controls. One ex-planation is that most studies measuredtotal estradiol and not the active form,namely free estradiol. On the other hand,there is convincing evidence to showthat sex hormone binding globulin(SHBG) is higher in osteoporotic menthan in controls. Overall fracture riskdoubles with every standard deviation inSHBG level.

The second factor to bear in mind inthe pathophysiology of idiopathic osteo-porosis in men is osteoblast dysfunction.Preliminary histomorphometry data sug-gest that although osteoblasts are quanti-tatively normal in osteoporosis in men,their capacity for synthesis is impaired.These findings require confirmation.

Lastly, we now know that the microar-chitecture of bone, which is a major as-pect in female osteoporosis, is also a keyfactor in osteoporosis in men. This hasbeen clearly demonstrated by MauriceAudran and his group in Angers, France,with particular regard to both steroid-and hypogonadism-induced osteoporosisin men.

What are the significant risk factorsfor osteoporosis and osteoporotic frac-tures in men?

In addition to the causes alreadymentioned, there is an impor-

tant risk factor to be considered in men,namely, smoking. Overall risk factors forosteoporosis and osteoporotic fracturesare similar in men and women. As in

osteoporosis being so much rarer in men,given the close correlation between bonemass, whether trabecular bone volume orbone mineral density (BMD), and me-chanical resistance. However, this pointrequires qualification in so far as moststudies have determined peak bone massusing dual-energy x-ray absorptiometry(DXA), a technique that has been exten-sively validated (including in men), andthat measures area—not volume—bonedensity. The few data derived using vol-ume density measures acquired by quan-titative computed tomography (qCT)show that peak bone mass is largely sim-ilar in men and women.

A second important reason for the sexdifference in osteoporosis prevalence liesin the thickness of the bones studied.Bones are thicker in men, which is onereason why area bone density is higherthan in women. In addition, it is a basicbiomechanical fact that bone thickness isdirectly related to mechanical resistance.

A third reason is the absence—despitewhat is sometimes said—of a true maleequivalent to the menopause, with itsmajor impact on bone. Bone loss in menover 50 is relatively linear, in parallelwith the decline in circulating levels ofandrogens, in particular testosterone. In fact, however, what little bone activitytestosterone may have seems to be me-diated by estrogen.

Could you briefly comment on thepathophysiology of osteoporosis in menin comparison with women?

Osteoporosis in men is a mixedbag, much more so than in

women. The main culprit in women is themenopause. In the absence of a genuinemale equivalent, we have to look else-where. The main message to get acrossis the importance in men of excludingsecondary osteoporosis. Previously oneshould exclude malignancy, such asmetastasis or multiple myeloma, as wellas other causes of low bone mass not re-lated to osteoporosis, such as osteomala-cia and primary hyperparathyroidism.Otherwise, the main cause of osteoporosisin men is hypercortisolism, due to thenoxious effects of exogenous steroids onbone rather than to the comparativelyrare cases of Cushing disease. It is notthat glucocorticoids are especially toxicin men, but rather that they are moreoften prescribed in men, especially forchronic obstructive airways disease,which is much more frequent than inwomen. Other primary causes are alco-holism and hypogonadism. On a moreanecdotal level, we should also not forget

I N T E R V I E W

64 Risk factor profiles for osteoporotic fractures in women and men – CortetMEDICOGRAPHIA, VOL 28, No. 1, 2006

I N T E R V I E W

65Risk factor profiles for osteoporotic fractures in women and men – Cortet MEDICOGRAPHIA, VOL 28, No. 1, 2006

had T-scores <–2.5 (spine, hip, or wrist),a percentage approximating to that ofosteoporotic fractures in men over 50(13%). A final point is that while thisdefinition is probably applicable, it is essential to use young men, and notyoung women, as the reference popula-tion. If young women are used, the preva-lence of densitometric osteoporosis wouldonly be 3%, which is much lower thanthe figure derived from fracture epi-demiology. ❒

A more direct method for defining arelevant threshold is to attempt a matchbetween the epidemiological fractureand densitometry data. One reason forchoosing a T-score threshold of ≤–2.5 inwomen to define osteoporosis was thatit gave a prevalence of osteoporosis inwomen over 50 as 30%, which approxi-mated to the percentage of osteoporoticfractures observed in this population. AMayo Clinic study applying this approachin a vast male cohort showed that 19%

evidence to justify an identical thresh-old in men. A UK group used DXA tocompare BMD in men and women withvertebral fractures. As we’d expect, meanBMD was higher in men. However, byexpressing the results as mean T-scoresreferred to the young male populationrather than in absolute terms, the au-thors showed that they were similar inboth sexes, and very close to the ≤ –2.5threshold (–2.42 in men versus –2.40 in women).

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B ien qu’il s’agisse avant tout d’une maladie touchant lafemme, l’ostéoporose n’en pose pas moins un problèmeimportant chez l’homme, avec une prévalence à 13 % pour

les fractures ostéoporotiques dans la population masculine deplus de 50 ans, touchant les mêmes sites que chez la femme, à sa-voir le poignet, la vertèbre et la hanche. Chez l’homme, la frac-ture du poignet nécessite toujours une évaluation de l’ostéopo-rose, car si cette dernière est en cause, la fracture du poignet estprédictive d’un risque multiplié par 10 de fracture vertébrale(contre 5 chez la femme) et d’un risque multiplié par 2 ou 3 defracture de hanche (contre seulement 40 à 50 % chez la femme).Chez l’homme, la fracture de hanche est associée à une morta-lité double ou triple de celle chez la femme, en partie en raison dela fréquence plus élevée du tabagisme et de l’alcoolisme. Hormisces facteurs, les différences principales liée au sexe ont trait aupic de masse osseuse et l’épaisseur des pièces squelettiques, lavaleur de ces deux paramètres étant plus élevée chez l’homme etconditionnant directement la résistance mécanique osseuse. Ces

deux paramètres auxquels s’ajoute l’absence d’un équivalent réelmasculin de la ménopause, expliquent la relative rareté de l’os-téoporose chez l’homme. Dans ce contexte, il est particulièrementimportant d’éliminer une ostéoporose secondaire, présente dans6 cas sur 10. Les causes principales en sont malignes (métastasesosseuses ou myélome multiple), mais surtout l’hypercorticisme,en particulier d’origine exogène (glucocorticoïdes prescrits pourune bronchopathie chronique obstructive, plus fréquemment ob-servée dans la population masculine que féminine). La densito-métrie osseuse s’avère aussi utile dans les deux sexes pour le dé-pistage de l’ostéoporose. Il faut vraisemblablement appliquerla même valeur seuil (T-score ≤--2.5) chez l’homme que chez lafemme, à condition que la population de référence soit représen-tée par des hommes jeunes, et non des femmes jeunes, faute dequoi la prévalence de l’ostéoporose densitométrique se verraitabaissée à une valeur de seulement 3%, en opposition à ce quelaissent apparaître les données épidémiologiques fracturaires.

LES PROFILS DE FACTEUR DE RISQUE DANS LES FRACTURES OSTÉOPOROTIQUESDIFFÈRENT-ILS CHEZ LA FEMME ET CHEZ L’HOMME ?

66 Rehabilitation in osteoporosis – BoonenMEDICOGRAPHIA, VOL 28, No. 1, 2006

There is also a large overlap in BMD values be-tween patients with and without fractures.6 In addi-tion, increasing BMD with antiresorptive therapiesdoes not substantially reduce the risk of fracture.Clearly, additional factors are involved. Althoughbone remodeling and bone microarchitecture mustbe considered, the largest and most important con-tribution is the increased propensity for falling.7 Forpredicting hip fracture, risk factors for falls and lowBMD are independent and additive.8

Physicians, particularly bone specialists but alsogeneral practitioners, tend to treat these patientsonly with antiresorptive or anabolic drugs. Howev-er, osteoporosis is a musculoskeletal disease, so oth-er factors, such as muscle strength and falls, are alsoimportant and need to be understood. In fact, theseextraskeletal factors have been largely ignored byclinicians when considering how to prevent frac-tures and how to rehabilitate patients after fractureshave occurred. The aim of this chapter is to describeseveral nonpharmacological approaches to muscu-loskeletal rehabilitation for fractures in postmeno-pausal women with osteoporosis.

Preventing falls and fall-related fractures

Falls are the single largest cause of injury in olderpeople, and they are quite common: about a thirdof people over 65 years old fall each year.9 In thispopulation, about half of all falls cause minor trau-

Osteoporosis is a common and serious healthproblem, particularly among postmenopaus-al women. Of great concern is the increased

likelihood of fractures in these patients. In fact, theincidence of osteoporotic fractures is greater thanthat of myocardial infarction, stroke, or breast can-cer.1 Osteoporotic fractures tend to occur most fre-quently in the spine and hip, and less frequently inthe pelvis, wrist, and upper arm.

Fractures in these mostly elderly women cangreatly reduce quality of life and functional abili-ties and often result in institutionalization and evenmortality.2,3

Several musculoskeletal factors are implicated inosteoporotic fractures in the elderly. Among themare loss of bone mass (low bone mineral density[BMD]) and an increased propensity to falls.4

Historically, BMD has been regarded as the mainrisk factor for osteoporotic fracture. Low BMD, asmeasured by dual x-ray absorptiometry, is specificfor osteoporotic fractures: low BMD is associatedwith a high risk of fracture. Because it is so specif-ic, absorptiometry is a powerful diagnostic tool.However, it is not very sensitive: patients with nor-mal BMD may be osteoporotic, because the damageto the microarchitecture is not fully reflected in ab-sorptiometry measurements. In fact, only a modestproportion of fractures—between 10% and 44%—occur in women with absorptiometry-defined os-teoporosis (a BMD value 2.5 standard deviations be-low normal for young adults).5

F O C U S

M ost antifracture strategies have focused on increasingbone strength by reducing bone turnover. The efficacy ofthese interventions in reducing the risk of fracture has

been consistently documented in well-defined patients with con-firmed osteoporosis (low bone mineral density or prevalent ver-tebral fracture). However, fractures result from both a loss ofskeletal integrity and an increased risk of falls. Nevertheless, littleattention has been given to the targeting of extraskeletal factorsto prevent fractures in selected individuals. In the managementof patients with increased risk of fracture due to osteoporosis orextraskeletal risk factors, measures of musculoskeletal rehabil-itation should be considered (along with pharmacotherapy) tooptimize musculoskeletal health, improve quality of life, and re-

duce the risk of fracture and fracture recurrence. Given the im-portance of muscle function to bone quality and to the risk offalls and fall-related injuries, this article emphasizes the role ofelements of muscle function, such as strength and coordination,in the prevention of fracture and postfracture rehabilitation inpatients with osteoporosis.Medicographia. 2006;28:66-71. (see French abstract on page 71)

Keywords: rehabilitation; osteoporosis; fall; physical activity

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Steven BOONEN, MD, PhDLeuven University Center forMetabolic Bone Disease and

Division of Geriatric MedicineKatholieke Universiteit Leuven

Leuven, BELGIUM

MUSCULOSKELETAL REHABILITATION INPOSTMENOPAUSAL OSTEOPOROSIS

b y S . B o o n e n , B e l g i u m

Address for correspondence: Prof Steven Boonen, Leuven University Center for MetabolicBone Disease and Division of Geriatric Medicine, Katholieke Universiteit Leuven,Herestraat 49, B-3000 Leuven, Belgium (e-mail: [email protected])

F O C U S

67Rehabilitation in osteoporosis – Boonen MEDICOGRAPHIA, VOL 28, No. 1, 2006

ous activities, but no effect was observed on wristor vertebral fractures. A multidisciplinary programtested a comprehensive combination of general andresident-specific tailored strategies to reduce fallsin persons over the age of 65 living in residential-care facilities. The interventions included individ-ual exercise programs in conjunction with staff ed-ucation, environmental modification, mobility aids,medication review, hip protectors, and problem-solving conferences after falls.18 Both falls and fall-related injuries were reduced. Similar, positive find-ings were observed in a pooled analysis from studies

including a total of 566 community-dwelling wom-en at least 80 years old who participated in the sameprogram of progressive muscle strengthening, bal-ance retraining, and walking. This intervention re-duced the number of women who fell over a 1-yearperiod by some 20%.15 The number of injurious fallswas also reduced, by 33%.

Body sway is a well-documented risk factor forfalls and fall-related fractures.5 Proprioceptive dy-namic posture training minimizes body sway, aswell as decreases kyphosis by strengthening theback extensors, and thus reduces pain and increas-es mobility. In a controlled trial, proprioceptive dy-namic posture training improved balance in osteo-porotic patients with kyphosis and reduced the riskof falls.19

These findings contrast with those from a system-atic review of randomized trials testing whetherphysical exercise or physical therapy could preventfalls in elderly people.15 Pooled data showed no sig-nificant differences between intervention and con-trol groups in the number of persons who fell. Oneof the studies even reported that brisk walking sig-nificantly increased falls.

◆ Vitamin D to reduce falls and fracturesVitamin D supplementation can improve musclefunction in older persons with vitamin D deficiency.In women between 63 and 99 years old given cal-cium (1200 mg/day) plus vitamin D (800 IU/day) for

ma, up to 6% of falls result in fractures, and be-tween 1% and 2% are associated with hip fractures.9

However, more than 90% of all hip fractures are as-sociated with falls.10

Multiple factors predispose elderly patients to falls:muscular weakness, disability of the legs, reducedvisual acuity, balance and gait abnormalities, seda-tive use, cognitive impairment, and foot problems.11

The risk of falling rises directly as the number ofthese risk factors increases.11

The ÉPIDémiologie de l’OStéoporose (EPIDOS)study, a prospective cohort study of risk factors forhip fractures conducted in France, found a relation-ship between falls and risk factors for falls (low phys-ical activity or disturbed body balance) and the oc-currence of fractures of the humerus in patientswith osteoporosis. This relationship was not foundin participants with normal BMDs.12

In keeping with these findings, a retrospectivestudy of postmenopausal women reported an in-creased risk for fractures during the preceding yearin women who reported a fall during that periodand who had low BMDs, but not in women with ahistory of falling and normal BMDs or in womenwho reported no falls, irrespective of their BMD.4

These results suggest that the risk for fractures isincreased,particularly in women with low BMD whofall (Table I). These results could also explain whyeven women with osteopenia might have an in-creased risk of fracture, if they fall.

Although treatment for elderly people can reducethe risk of falls, no study has reported an effect onthe incidence of fall-related osteoporotic fractures.13

This issue will require clinical trials specifically de-signed to study fall-related osteoporotic fractures,and their findings may inform the design and im-plementation of strategies to prevent falls in pa-tients with hip fracture.

◆ Multifactorial intervention programs to reducefalls and fracturesReduced muscle strength, lack of coordination, hy-perkyphosis, increased postural sway, slow walkingvelocity, and poor functional performance are im-portant risk factors for falls.5,14 Addressing these riskfactors can reduce the incidence of falls. In partic-ular, falls may be prevented with multidisciplinaryintervention programs, including education, exer-cise, environmental modifications, mobility aids,and individually tailored exercise programs. How-ever, it remains to be clarified whether and to whatextent these strategies will reduce the risk of fall-related fractures.15

◆ Physical training programs to reduce falls andfracturesThe positive effects of physical activity on the rateof falls have been confirmed in a number of stud-ies.15-19 Increased physical activity can even poten-tially reduce the risk of fracture, but antifracture ef-ficacy has not been consistently documented. In aprospective cohort study of 9704 women 65 years ofage, high-level physical activity reduced the risk ofhip fracture.16 The risk of hip fracture was reducedamong women who performed moderate-to-vigor-

No. of Adjusted 95% confidenceBone mineral density women risk* interval

No recent fallNormal† 1145 1.0 –Osteopenia‡ 705 2.8 0.9-8.9Osteoporosis§ 289 2.8 0.6-12.8

Recent fall Normal† 208 1.1 0.1-9.6Osteopenia‡ 189 21.0 7.1-62.3Osteoporosis§ 113 24.8 6.9-88.6

* Adjusted for age and body mass index, both included in logistic model as contin-uous variable.

† T score >-1.0.‡ T score between -1.0 and -2.5.§ T score <-2.5.

Table I. Association between osteopenia, osteoporosis, history of falls,and fracture in the preceding year in postmenopausal women. Modified from reference 4: Geusens P, Autier P, Boonen S, Vanhoof J, Declerck K, Raus J.The relationship among history of falls, osteoporosis, and fractures in postmenopausalwomen. Arch Phys Med Rehabil. 2002;83:903-906. With permission from the AmericanCongress of Rehabilitation Medicine and the American Academy of Physical Medicineand Rehabilitation.

F O C U S


of vertebral fractures. In one study, progressive, re-sistive back strengthening reduced the risk for ver-tebral fractures in women 58 to 75 years old.27

Several studies have found that intensive phys-ical training does improve strength and functionalperformance in older people, even in frail nursinghome residents.28 In postmenopausal women, pro-gressive resistance training to strengthen the para-spinal muscles maintains or increases BMD.29 Back-strengthening exercises can also reduce thoracichyperkyphosis, vertebral fracture, loss of height, andpain of the anterior rib cage, which are the most dis-figuring consequences of osteoporosis.27

Increased back strength reduces the kyphoticposture that can occur with osteoporosis and ag-ing.30 A hyperkyphotic posture can also increase therisk of falls when hip motion, rather than anklemotion, is used to compensate for moments of off-balance.14 Stronger back muscles may decrease theangle of kyphosis and thus improve body height.30

This result may be associated with better postureand a correction of the center of gravity, which thenresults in less body sway.19

In severe kyphosis, the lower part of the rib cagecan press on the pelvic rim, causing considerablepain and tenderness and even compromised breath-ing. Therefore, decreasing the kyphosis throughrecruitment of back extensors provides better dy-namic-static posture and can reduce pain, increasemobility, reduce depression, and improve the pa-tient’s quality of life.31 Hyperkyphosis is also a com-mon disfiguration after vertebral fracture.

◆ Spinal orthoses in vertebral fracture patientsOrthoses increase back extensor strength and de-creases body sway, which are both risk factors forfalls and fall-related fractures. Kaplan et al foundthat rigid bracing is not necessary for managingpostural osteoporotic back pain and that a weight-ed kypho-orthosis was better tolerated by patientsand provided better pain relief.32 Moreover, the useof rigid thoracolumbar braces in osteoporosis islimited by factors such as short stature, atrophiedtrunk muscles, hiatus or inguinal hernia, moderateto severe obesity, scoliosis caused by osteoporosisand compression fractures, and restricted respira-tion, all of which can lead to low adherence in wear-ing the orthosis.

Most recently, Pfeifer et al33 reported the effective-ness of orthoses for stabilizing osteoporotic ver-tebral fractures. In that study, the use of one par-ticular orthosis was associated with a significantincrease in trunk muscle strength, most likely be-cause of increased muscular activity while wearingthe orthosis.

◆ Vertebro- or kyphoplastyIn percutaneous transpedicular polymethylmetha-crylate vertebroplasty (PTPV), acrylic cement (usu-ally polymethylmethacrylate) is injected into apartially collapsed vertebral body. The objective isto relieve the associated back pain and improve themechanical stability of the vertebra.34 In one studyof patients with osteoporotic fractures, PTPV re-duced the use of narcotics and analgesics in 63%

3 months, muscle strength improved by 5% to 11%over that of a control group receiving only calcium(1200 mg/day).20 However, in a 6-month study ofhigh-dose vitamin D therapy (a single 300 000 IUdose), frail elderly men and women showed no im-provement in quadriceps strength or leg function,suggesting that this regimen may not be effective,at least in frail patients.21

Several randomized controlled trials have report-ed that vitamin D supplementation, with or with-out calcium, reduced falls in at-risk patients. Calci-um (1200mg/day) plus vitamin D (800 IU/day) givenfor 3 months reduced the rate of falling by 49%compared with patients receiving only calcium.20

In another study of the same treatment applied over8 weeks, the risk of falling over the next year was re-duced from 45% to 24%.22 The incidence of fracturedropped from 9% to 4%, but the difference was notstatistically significant.

A meta-analysis combined the results from 5 ran-domized, double-blind clinical trials that evaluatedany form of vitamin D treatment in patients olderthan 60 years and in stable health (1237 patients;81%women; mean age70 years).23 Treatment rangedfrom 2 months to 3 years. The risk of falling was sig-nificantly reduced by 22% in patients receiving anyform of vitamin D compared with those receivingcalcium alone or placebo, and the number neededto treat to prevent 1 fall was 15.

The question remains whether, and to what ex-tent, vitamin D reduces the risk of fracture by pre-venting falls. The inconsistencies among studiesare probably caused by differences in the type of sup-plement, the concomitant use of a calcium sup-plement, and the degree of vitamin D deficiency atbaseline, in addition to differences in patient pop-ulations and study design.

◆ Hip protectors to reduce the impact of falls andto prevent fracturesAn external hip protector is a polypropylene or poly-ethylene shell that fits around the hip. It is designedto absorb the energy from a fall and especially toshunt the energy to the soft tissues around the hip.

Several studies have found that hip protectorslower the incidence of hip fractures in nursing-home residents.24 Other studies have found no suchprotective effect.25 In these negative studies, shunt-ing the impact away from the greater trochanter atleast did not increase the risk of nonhip fractures.However, most of the residents who experienced ahip fracture in these negative studies were not wear-ing the protector at the time of the fall. Thus, adher-ence is a factor that could potentially be improvedwith good results. The effect of wearing a hip pro-tector on activity levels and, hence, its effectivenessin preventing fractures, also needs to be studied.

Rehabilitation strategies in fracture patients

◆ Strength training and vertebral fracturesBack strength is significantly lower in persons withosteoporosis than in healthy persons.26 Strength-ening the paraspinal muscles can reduce the risk

F O C U S


Prospective randomized trials to assess interven-tions targeted at this critical time period are war-ranted. The evidence that exercise programs canimprove strength and mobility in patients withhip fracture is strong.39 However, further researchis needed to determine whether the extent of im-provement in these risk factors is sufficient to pre-vent additional falls and any associated fracturesin this high-risk population.

In the year after a vertebral fracture, almost 20%of women will experience an additional vertebralfracture.40 The risk of subsequent hip fracture overthe next 3 to 4 years also increases, by two to fourtimes, compared with the risk in patients withoutvertebral fractures.41 In the years after a hip frac-ture, the risk of a second hip fracture is 10%, andthat of any additional fracture ranges from 2% to8%.42

Most studies of rehabilitation on functional re-covery after hip fracture have taken place in acuteor subacute rehabilitation facilities and have en-rolled patients on wards and in outpatient settings.The aims, interventions, and outcome measuresused in these studies differ considerably, and thestudies themselves have produced inconsistent andconflicting results. According to a recent meta-anal-ysis,43 there is no conclusive evidence that coordi-nated, multidisciplinary inpatient rehabilitation ismore effective than conventional hospital care (withno rehabilitation professionals involved) for olderpatients with hip fracture.

Most hip fractures result from a fall and, thus, allpatients who sustain a hip fracture should be as-sessed for the presence of risk factors for falls. Sub-sequently, different interventions that target mul-tiple intrinsic and extrinsic risk factors of individualpatients should be considered.

Because many community-living older personswho fracture a hip eventually return home, muchpostfracture rehabilitation occurs at home, so littleis known about effective ambulatory strategies forthe rehabilitation of geriatric patients after hip sur-

of patients, increased it in 7%, and had no apparenteffect in 30%. Ambulation and mobility improvedin 50% of the patients, worsened in 1%, and did notchange in 48%.7

Complications associated with PTPV may includepressure on the spinal cord or nerve roots, pain andweakness, pulmonary embolism (if cement entersthe blood and travels to the lungs), rib fracture (af-ter lying prone for a prolonged period during theprocedure), infection, and bleeding. The presenceof methylmethacrylate in fractured vertebrae mayalso cause adjacent vertebrae to fracture more eas-ily. Thus, PTPV can relieve pain in a high percent-age of patients with refractory pain caused by spinalcompression fractures.35 However, it is not a sub-stitute for other rehabilitative measures.

◆ Rehabilitation in hip fracture patientsBy any measure, hip fracture is the most devastat-ing complication of osteoporosis (Figure 1). Themortality rate in patients with hip fracture is be-tween 12% and 20% higher than in persons of sim-ilar age and sex who have not had a fracture.36 Ofthose who survive surgery for an osteoporotic hipfracture, less than one third return to their pre-fracture functional state, and both those with andthose without restored status require some form ofambulatory support or even institutionalized care.37

Clinicians may not consistently treat patients forosteoporosis, even after a hip fracture, because themost common drugs have been tested—and aremarketed—for the primary prevention of hip frac-tures. No studies have yet evaluated either phar-macological or nonpharmacological measures forthe secondary prevention of hip fractures. For ex-ample, it is unknown whether calcium supplemen-tation after a hip fracture can reduce the subsequentloss of bone mineral from the contralateral hip and,in turn, diminish the risk of another hip fracture.However, data from patients with hip fracture haveshown a significant relationship between calciumintake and bone loss from the proximal femur.38

Figure 1. Impact of hip fracture occurrence on different domains of quality of life: scores on the 36-item Short-Form HealthSurvey (SF-36) at hospital discharge (initial score) and 1 year after hospital discharge (1-year score). *P<0.05 betweenfracture patients and controls. Modified from reference 2: Boonen S, Autier P, Barette M, Vanderschueren D, Lips P, Haentjens P. Functional outcome and quality of life followinghip fracture in elderly women: a prospective controlled study. Osteoporos Int. 2004;15:87-94. Copyright © 2004, International Osteoporosis Foundationand National Osteoporosis Foundation.

Physical function

Initial score One-year score

Role physical

Bodily pain

General health

Vitality

Social functioning

Role emotional

Mental health

0 25 50SF-36 Score SF-36 Score

75 100

*

*

*

*

*

*

*

Physical function

Role physical

Bodily pain

General health

Vitality

Social functioning

Role emotional

Mental health

0 25 50 75 100

ControlHip fracture

*

*

*

*

*

*

*

*

*

F O C U S


eficial for preventing falls in elderly people. Reha-bilitation after vertebral fractures caused by osteo-porosis consists of improving muscle strength (par-ticularly of the legs) to decrease the risk of falls andfractures, back-strengthening exercises to improveposture and decrease hyperkyphosis, and sedativephysical therapy to decrease postural deficit-relat-ed pain.

Among other factors, a loss of musculoskeletalintegrity after hip fracture is likely to have a majorimpact on the outcome of rehabilitation and on therisk of fracture recurrence. However, it remains tobe clarified whether targeted interventions (phar-macological or nonpharmacological) might be ableto modify this process by enhancing bone and mus-cle mass and thus facilitate postsurgical rehabilita-tion and reduce the risk of recurrent fractures. ❒

gery. A recent randomized controlled trial found thata home-based systematic multicomponent rehabili-tation strategy was no more effective for promotingrecovery than usual home-based rehabilitation.44

Conclusions

Patients who have both low BMD and a propensityto fall will benefit most from specific exercise pro-grams, as well as from the use of hip protectors insome instances. Low BMD and the propensity to fallboth contribute to osteoporotic fractures, particu-larly in the elderly. Professionally prescribed, home-based balance retraining,muscle strengthening, andwalking, as well as tai chi group exercises, and amultidisciplinary, multifactorial risk factor screen-ing and intervention program, are likely to be ben-

REFERENCES1. Cummings SR, Black DM, Rubin SM. Lifetime risksof hip, Colles’, or vertebral fracture and coronary heartdisease among white postmenopausal women. ArchIntern Med.1989;149:2445-2448.2. Boonen S, Autier P, Barette M, Vanderschueren D,Lips P, Haentjens P. Functional outcome and quali-ty of life following hip fracture in elderly women: aprospective controlled study. Osteoporos Int.2004;15:87-94.3. Autier P, Haentjens P, Bentin J, et al. Costs inducedby hip fractures: a prospective controlled study inBelgium. Belgian Hip Fracture Study Group. Osteo-poros Int. 2000;11:373-380.4. Geusens P, Autier P, Boonen S, Vanhoof J, DeclerckK, Raus J. The relationship among history of falls, os-teoporosis, and fractures in postmenopausal women.Arch Phys Med Rehabil. 2002;83:903-906.5. Nguyen T, Sambrook P, Kelly P, et al. Prediction ofosteoporotic fractures by postural instability and bonedensity. BMJ.1993;307:1111-1115.6. Marshall D, Johnell O, Wedel H. Meta-analysis ofhow well measures of bone mineral density predict oc-currence of osteoporotic fractures. BMJ. 1996;312:1254-1259.7. Jensen ME, Evans AJ, Mathis JM, Kallmes DF, CloftHJ, Dion JE. Percutaneous polymethylmethacrylatevertebroplasty in the treatment of osteoporotic ver-tebral body compression fractures: technical aspects.AJNR Am J Neuroradiol. 1997;18:1897-1904.8. Cummings SR, Nevitt MC, Browner WS, et al., theStudy of Osteoporotic Fractures Research Group. Riskfactors for hip fracture in white women. N Engl J Med.1995;332:767-773.9. Tinetti ME, Williams CS. Falls, injuries due to falls,and the risk of admission to a nursing home. N EnglJ Med. 1997;337:1279-1284.10. Melton LJI, Chao EYS, Lane J. Biomechanical as-pects of fractures. In: Riggs BL, Melton LJ, eds. Os-teoporosis: Etiology, Diagnosis, and Management.New York, NY: Raven Press; 1998:111-131.11. Fiatarone MA, O’Neill EF, Ryan ND, et al. Exercisetraining and nutritional supplementation for physi-cal frailty in very elderly people. N Engl J Med.1994;330:1769-1775.12. Lee SH, Dargent-Molina P, Bre´art G, for the EPI-DOS Group. Risk factors for fractures of the proximalhumerus: Results from the EPIDOS prospective study.J Bone Miner Res. 2002;17:817-825.13. Tinetti ME. Clinical practice: preventing falls inelderly persons. N Engl J Med. 2003;348:42-49.14. Lynn SG, Sinaki M, Westerlind KC. Balance char-acteristics of persons with osteoporosis. Arch PhysMed Rehabil.1997 ;78:273-277.15. Gillespie LD, Gillespie WJ, Robertson MC, LambSE, Cumming RG, Rowe BH. Interventions for pre-venting falls in elderly people. Cochrane DatabaseSyst Rev. 2001;3:CD000340.

in calcium-replete postmenopausal women. J BoneMiner Res. 2001;16:175-181.30. Itoi E, Sinaki M. Effect of back-strengthening ex-ercise on posture in healthy women 49 to 65 years ofage. Mayo Clin Proc. 1994;69:1054-1059.31. Malmros B, Mortensen L, Jensen MB, Charles P.Positive effects of physiotherapy on chronic pain andperformance in osteoporosis. Osteoporos Int. 1998;8:215-221.32. Kaplan RS, Sinaki M, Hameister M. Effect of backsupports on back strength in patients with osteoporo-sis: a pilot study. Mayo Clin Proc. 1996;71:235-241.33. Pfeifer M, Begerow B, Minne HW. Effects of a newspinal orthosis on posture, trunk strength, and qual-ity of life in women. Med Rehabil. 2004;83:177-186.34. Amar AP, Larsen DW, Esnaashari N, AlbuquerqueFC, Lavine SD, Teitelbaum GP. Percutaneous trans-pedicular polymethylmethacrylate vertebroplasty forthe treatment of spinal compression fractures. Neu-rosurgery. 2001;49:1105-1114.35. Lieberman IH, Dudeney S, Reinhardt MK, Bell G.Initial outcome and efficacy of “kyphoplasty” in thetreatment of painful osteoporotic vertebral compres-sion fractures. Spine. 2001;26:1631-1638.36. Parker MJ, Palmer CR. Prediction of rehabilitationafter hip fracture. Age Ageing. 1995;24:96-98.37. Greendale GA, Barrett-Connor E, Ingles S, HaileR. Late physical and functional effects of osteoporot-ic fracture in women: The Rancho Bernardo Study.J Am Geriatr Soc. 1995 ;43:955-961.38. Dirschl DR, Henderson RC, Oakley WC. Acceler-ated bone mineral loss following a hip fracture: a pros-pective longitudinal study. Bone.1997;21:79-82.39. Sherrington C, Lord SR. Home exercise to im-prove strength and walking velocity after hip fracture:a randomized controlled trial. Arch Phys Med Rehabil.1997;78:208-212.40. Lindsay R, Silverman SL, Cooper C, et al. Risk ofnew vertebral fracture in the year following a fracture.JAMA. 2001;285:320-323.41. Ismail AA, Cockerill W, Cooper C, et al. Prevalentvertebral deformity predicts incident hip though notdistal forearm fracture: results from the EuropeanProspective Osteoporosis Study. Osteoporos Int. 2001;12:85-90.42. Colon-Emeric C, Kuchibhatla M, Pieper C, et al.The contribution of hip fracture to risk of subsequentfractures: data from two longitudinal studies. Osteo-poros Int. 2003;14:879-883.43. Cameron I, Crotty M, Currie C, et al. Geriatric re-habilitation following fractures in older people: Asystematic review. Health Technol Assess. 2000;4:1-111.44. Tinetti ME, Baker DI, Gottschalk M, et al. Home-based multicomponent rehabilitation program forolder persons after hip fracture: A randomized trial.Arch Phys Med Rehabil. 1999;80:916-922.

16. Gregg EW, Cauley JA, Seeley DG, Ensrud KE,Bauer DC, for the Study of Osteoporotic FracturesResearch Group. Physical activity and osteoporoticfracture risk in older women. Ann Intern Med.1998;129:81-88.17. Wolff SL, Barnhart HX, Kutner NG, McNeely E,Coogler C, Xu T, the Atlanta FICSIT Group. Reducingfrailty and falls in older persons: an investigation oftai chi and computerized balance training. J Am Geri-atr Soc. 1996;44:489-497.18. Jensen J, Lundin-Olsson L, Nyberg L, Gustafson Y.Fall and injury prevention in older people living inresidential care facilities: a cluster randomized trial.Ann Intern Med. 2002;136:733-741.19. Sinaki M, Lynn SG. Reducing the risk of fallsthrough proprioceptive dynamic posture training inosteoporotic women with kyphotic posturing: a ran-domized pilot study. Am J Phys Med Rehabil. 2002;81:241-246.20. Bischoff HA, Stahelin HB, Dick W, Akos R, KnechtM, Salis C, et al. Effects of vitamin D and calcium sup-plementation on falls: a randomized controlled trial.J Bone Miner Res. 2003;18:343-351.21. Latham NK, Anderson CS, Lee A, Bennett DA,Moseley A, Cameron ID. A randomized, controlled tri-al of quadriceps resistance exercise and vitamin D infrail older people: the Frailty Interventions Trial in El-derly Subjects (FITNESS). J Am Geriatr Soc. 2003;51:291-299.22. Pfeifer M, Begerow B, Minne HW, Abrams C,Nachtigall D, Hansen C. Effects of a short-term vita-min D and calcium supplementation on body swayand secondary hyperparathyroidism in elderly wom-en. J Bone Miner Res. 2000;15:1113-1118.23. Bischoff-Ferrari HA, Dawson-Hughes B, WillettWC, et al. Effect of Vitamin D on falls: a meta-analy-sis. JAMA. 2004;291:1999-2006.24. van Schoor NM, Deville WL, Bouter LM, Lips P.Acceptance and compliance with external hip protec-tors: a systematic review of the literature. OsteoporosInt. 2002;13:917-924.25. van Schoor NM, Smit JH, Twisk JW, Bouter LM,Lips P. Prevention of hip fractures by external hip pro-tectors: a randomized controlled trial. JAMA. 2003;289:1957-1962.26. Sinaki M, Khosla S, Limburg PJ, Rogers JW, Mur-taugh PA. Muscle strength in osteoporotic versus nor-mal women. Osteoporos Int. 1993;3:8-12.27. Sinaki M, Itoi E, Wahner HW, et al. Stronger backmuscles reduce the incidence of vertebral fractures:a prospective 10 year follow-up of postmenopausalwomen. Bone. 2002;30:836-841.28. Mulrow CD, Gerety MB, Kanten D, et al. A ran-domized trial of physical rehabilitation for very frailnursing home residents. JAMA.1994;271:519-524.29. Kerr D, Ackland T, Maslen B, Morton A, Prince R.Resistance training over 2 years increases bone mass

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✦

L a plupart des stratégies antifracturaires ont axé leurs ef-forts sur l’augmentation de la résistance osseuse par di-minution du renouvellement de l’os. L’efficacité de ces trai-

tements pour réduire le risque de fracture a été régulièrementprouvée chez des patientes bien définies présentant une ostéopo-rose confirmée (densité minérale osseuse basse ou fracture ver-tébrale prévalente). Cependant, les fractures sont provoquées àla fois par une perte de l’intégrité du squelette et par une aug-mentation du risque de chutes. Néanmoins, les facteurs extra-squelettiques dans la prévention des fractures chez des sujets sé-lectionnés ont peu retenu l’attention. On devrait envisager des

mesures de réadaptation musculosquelettique (et de pharma-cothérapie) pour optimiser la santé au niveau musculosquelet-tique, améliorer la qualité de vie, et réduire le risque de fractureset de récurrence de fractures dans la prise en charge des patientesqui présentent un risque accru de fractures à cause de l’ostéo-porose ou des facteurs de risque extrasquelettiques. Étant donnél’importance de la fonction musculaire vis-à-vis de la qualité os-seuse et du risque de chutes ou de lésions dues aux chutes, cet ar-ticle met l’accent sur le rôle des différents aspects de la fonctionmusculaire, tels que la force et la coordination, dans la préventiondes fractures et la réadaptation des patientes ostéoporotiques.

RÉADAPTATION MUSCULOSQUELETTIQUE DANS L’OSTÉOPOROSE POSTMÉNOPAUSIQUE

72 Determinants of bone quality – Boivin and MeunierMEDICOGRAPHIA, VOL 28, No. 1, 2006

gression of microcracks), and the apoptosis of osteo-cytes. Bone quality is deeply influenced by the rateof bone turnover.2 Changes in fracture risk and BMDwere recently evidenced in osteoporotic patientstreated with alendronate, without any modificationin bone matrix volume or bone microarchitecture.3

Thus, mineralization and mineral characteristicsshould not be neglected among the factors deter-mining the mechanical competence of bone.

Bone mineral density (BMD)

Currently, areal BMD is measured by dual-energyx-ray absorptiometry (DXA). BMD is a major de-terminant of bone strength, and BMD values ob-tained at the proximal femur and lumbar spine areused to diagnose osteoporosis by applying the cri-teria established by the World Health Organiza-tion (WHO). Most of the clinical studies carried outon bone resorption inhibitors, such as bisphos-phonates, selective estrogen receptor modulators(SERMs), or estrogen, have shown some association

Bone strength and fracture risk are generallyassessed by measuring bone mineral density(BMD). Fracture risk increases with age, part-

ly as a function of changes in BMD. However, therisk of fracture in a 75-year-old woman is 4 to 7times that in a 45-year-old woman with an identi-cal BMD.1 This demonstrates that there is a com-ponent of bone fragility that is independent ofbone mass, and is associated with bone quality.This has been recently emphasized by the obser-vation that major treatments for osteoporosis allhave about the same fracture efficacy, thoughthere is a 7-fold difference in their effect on BMD.The drugs used to treat bone fragility aim to im-prove bone strength, and thus decrease the risk offracture. In humans, the end point used to evaluatebone strength is the fracture rate, but large num-bers of patients are required to demonstrate signif-icant reductions as a result of therapeutic interven-tion. Furthermore, fracture is not only caused bydecreased bone mineral mass, or alteration of themicroarchitecture, but also by falls, which can oc-cur as a result of loss of balance, inappropriate pro-tective responses, or muscle weakness.

Bone strength corresponds to the maximal loadthat can be applied before a fracture occurs. It is in-fluenced by a variety of determinants, such as mass,size, geometry, microarchitecture, as well as by theintrinsic properties of bone tissue, such as the de-gree of mineralization of bone (DMB) and the or-ganic matrix characteristics (orientation and chem-ical structure of the collagen fibers), as well as theaccumulation of microdamage (initiation and pro-

U P D A T E

B one strength is defined as the maximal load that can beapplied before a fracture occurs. It is influenced by a num-ber of determinants, such as mass, size, geometry, micro-

architecture, as well as by intrinsic bone tissue properties. Thelatter include the degree of mineralization of bone, the charac-teristics of the organic matrix (collagen fiber orientation andchemical structure), bone microdamage accumulation (initiationand progression of microcracks), and osteocyte apoptosis. Bonequality in general as well as the degree of mineralization of boneare both deeply influenced by the rate of bone turnover. This mayexplain the changes in fracture incidence and the increase in bonemineral density and bone strength observed independently ofchanges in bone matrix volume and bone microarchitecture. Thegrowing interest in the evaluation of the determinants of bonequality reflects the importance of bone mineral substance in the

pathophysiology of osteoporosis and other bone conditions, andhas led to the rediscovery of the mineral dimension of bone, whichhad been all but forgotten for many years, and which is assessedby means of the following parameters: degree of mineralizationof bone; heterogeneity index of bone mineralization; mechanicalproperties of bone tissue (microhardness tester); size and matu-rity of crystals; and the degree of collagen maturation (Fouriertransform infrared microspectroscopy). Medicographia. 2006;28:72-77. (see French abstract on page 77)

Keywords: bone strength; bone quality; microarchitecture;mineralization; hardness; bone remodeling

✦

Georges BOIVIN, PhDDirector of Research

INSERM Unit 403

Pierre J. MEUNIER, MDProfessor of Medicine

René Laennec Faculty ofMedicine, Claude Bernard

University, Lyon FRANCE

DETERMINANTS OF BONE QUALITY

b y G . B o i v i n a n d P. J . M e u n i e r , F r a n c e

Address for correspondence: Georges Boivin, Director of Research, INSERM Unité403, Faculté de Médecine René Laennec, Université Claude Bernard Lyon1, 69372Lyon Cedex 08, France (e-mail: [email protected])


BMD bone mineral densityBMU basic multicellular unitBSU basic structural unitsDXA dual energy x-ray absorptiometry DMB degree of mineralization of bonePTH parathyroid hormoneSERM selective estrogen receptor modulator

U P D A T E

73Determinants of bone quality – Boivin and Meunier MEDICOGRAPHIA, VOL 28, No. 1, 2006

apy with only a 5% increase in BMD. Teriparatideincreases trabecular number and connectivity vialongitudinal tunneling, converting thickened tra-beculae to multiple struts of normal thickness.15 Al-though its increases cortical porosity, the porosityis located close to the marrow cavity where its me-chanical effect is small.16,17 Simultaneously, teripara-tide favors periosteal apposition, which maintainsor improves cortical bone strength.18

Among the invasive methods that preserve tissuestructure, bone histomorphometry allows the di-rect measurement of the amount of bone matrixin a given volume of biopsied bone, in particularthrough measurements of cancellous or total bonevolume, expressed as a percentage of either spongybone tissue or core volume.19 Bone histomorphom-etry is performed on undecalcified transiliac bonebiopsies embedded in methyl methacrylate. Thismethod is used to measure: (i) static parametersreflecting bone structure and microarchitecture incancellous and compact bone; (ii) bone remodel-ing (resorption and formation); and (iii) dynamicparameters such as the rate of osteoblast activity,after double tetracycline labeling. It is the onlymethod suited to evaluate tissue and cell changesat the level of the intermediaryorganization of bone,ie, the basic structural units (BSU), of which thereare two varieties, the osteon in cortical bone andthe cancellous bone packet in spongy bone. Bonehistomorphometry allows good discrimination ofcompletely nonmineralized matrix, but this methodis in no way capable of providing information onthe individual DMB of each BSU.

Sex hormone deficiency is associated with alter-ations in the connectivity of trabecular structures,ie, decrease in the number of trabeculae, increasein trabecular separation, changes in trabecularshape from plate-like to rod-like, and various alter-ations in parameters of connectivity evidenced byhistomorphometry.20,21 These alterations in trabec-ular structure may contribute to changes in bonestrength. Ovariectomy can reduce bone strengthand bone mass; however, significant modificationsof vertebral bone strength can be detected beforeany decrease in BMD. Dissociation between thesetwo variables may be due to early alteration of themicroarchitecture (perforation and/or disappear-ance of trabeculae) without major effects on BMD.Therefore, the mechanical properties of trabecularbone are dominated by bone volume fraction andthe extent of anisotropy. In fact, most morpholog-ic properties calculated from three-dimensional mi-crocomputed tomography images, such as trabec-ular thickness, trabecular spacing, connectivity, andstructural index, are to some extent correlated withbone volume fraction.

Intrinsic determinants of bone qualityother than bone mineralization

Microdamage accumulation reduces bone strength,stiffness, and toughness.22 Bone from older womenis more subject to microcracks and is inherentlymore fragile than bone from younger women. Thismay be why there is a significant accumulation of

between the increment in areal BMD and the de-crease in risk of fracture, but the relationship be-tween the two is not always straightforward.4 Thus,raloxifene and alendronate treatment are both as-sociated with a reduction in vertebral fracture, butthe effect on BMD is less pronounced with ralox-ifene (+3%) than with alendronate (+8%).5 In un-treated bone, ex vivo studies performed on humansamples have evidenced an excellent correlationbetween BMD of the proximal femur and bonestrength, as evaluated by the shear test applied tothe femoral neck6 or by compression of the verte-brae.7 According to these ex vivo studies, BMD pre-dicts approximately 60% to 70 % of the variance ofbone strength. BMD is not a volumetric (mass pervolume) density, but an areal density (mass per area).The high level of prediction of bone strength byareal BMD could be explained, at least in part, bythe fact that bone size is integrated in this mea-surement.

Bone geometry

Among the determinants of bone strength, dimen-sions such as external diameters and cortical thick-ness play a major role. Mechanical studies havedemonstrated that increasing the external diameterof a cylinder greatly increases its resistance to flex-ion. Increase in cortical thickness also improvesbone strength, but to a lesser extent. The outer di-ameter of the long bones predicts up to 55% of thevariance of bone strength.8-12

Stimulators of bone formation, such as insulin-like growth factor I, growth hormone,13 and parathy-roid hormone (PTH), stimulate periosteal apposi-tion14 and increase the external diameter of longbones. This expansion of the outer diameter of longbones is associated with a marked increment inbone strength. An increase in cortical thickness mayalso be observed with antiresorptive therapies, andresults from inhibition of endosteal bone resorp-tion, thereby contributing to the increase in bonestrength.

Expansion of bone diameter is also observed inhumans.12 During growth, bone diameter is influ-enced by nutritional factors such as calcium andphosphate salt supplements. In elderly men, an ex-pansion of bone outer diameter occurs, and withPTH treatment an increased bone area can be de-tected. An excess of growth hormone, as in acro-megaly, also increases bone size. Thus, an increasein bone size is possible in adults, but its specific roleas a determinant of fracture risk remains to be de-termined.

Bone microarchitecture

If cancellous bone is more plate-like, with thickerand more numerous trabeculae, there is an en-hancement of strength. Trabecular architecture,which is more isotropic, having similar mechani-cal properties in all directions, may further lowerfracture risk. This could provide a rationale for theclinical observation that fracture risk decreases by50% to 60% in the first year of bisphosphonate ther-

U P D A T E


graphic observations made in the 70s clearly showthat DMB is heterogeneously distributed in the BSU(both in the osteons in cortical bone and in thetrabecular packets in cancellous bone), the recent-ly deposited BSU being much less mineralized thanthe older ones. Young BSU appear in dark grey onmicroradiographs, whereas the old BSU are whiter(Figure 1). This heterogeneity in DMB is explainedby the fact that the bone formation that followsbone resorption in the remodeling sequence is amultistep process: the new matrix begins to min-eralize after about 5 to 10 days from the time of de-position and the linear rate of this primary miner-alization can be measured directly in vivo by meansof double tetracycline labeling. After full completionof the BSU, a phase of secondary mineralization setsin.31 This process consists of a slow and gradual mat-uration of the mineral component, including anincrease in the amount of crystals and/or an aug-mentation of crystal size toward their maximumdimensions. This secondary mineralization progres-sively augments the mineral content on bone ma-trix. At the end of the primary mineralization phase,the mineral content is only about 50% to 60% ofthe maximum degree of mineralization achieved atthe end of the secondary mineralization phase.

DMB is commonly measured by x-ray attenuationexperiments. Most studies have used contact micro-radiography, which yields a high linear resolution.Quantitative microradiography using a computer-ized microdensitometric method allows the mea-surement of the focal DMB of each BSU within thelimits imposed by the thickness of the section.31-33

Microscopic mineral variations and mineral densitydistributions have also been evaluated by quantita-tive backscattered electron imaging, as previouslyreviewed.34 DMB has also been measured usingsynchrotron radiation microtomography,35,36 whichmay also provide 3-D images with a spatial resolu-tion as high as 1 micrometer, which is very accuratefor quantifying human bone microarchitecture. TheDMB values measured by the two different tech-niques show an extensive overlap of distributionsand exhibit the same range of variation (0.5 to 1.6 g.mineral/cm3).

Quantitative microradiography has been used todetermine control values in 43 iliac bone samplestaken at necropsy from 30 women and 13 men whodied suddenly and in whom no apparent bone dis-order was found.32 In terms of mean values, distri-bution, and evolution with age, the DMB was notsignificantly different between both sexes and didnot change significantly with age. The mean (±SEM)DMB expressed in g mineral/cm3 was 1.09±0.02 intotal bone. The distributions of DMB revealed asmall shift towards the high values in cancellousbone compared with compact bone (maximum DMBwas 1.10 and 1.05 g/cm3, respectively, and the indexof heterogeneity was 0.28 and 0.34 g/cm3, respec-tively). This may reflect either the presence in can-cellous bone of a higher proportion of interstitialbone than in compact bone, or an “edge effect”(100-µm thick sections) with suppression of themeasurements in the least mineralized parts of thetrabeculae.

microdamage at several anatomical sites with age.23

The pharmacological suppression of remodelingalso increases microdamage accumulation,24 andthe extent of this increase is probably dependent onthe magnitude of the suppression.25

The collagen matrix exerts a profound influenceon bone mechanical properties.26 The risk of ver-tebral fracture is significantly increased in subjectswith the Sp1 polymorphism of the COL1A1 gene.Changes in collagen with aging are known to affectthe amount of energy required to cause fracture.27

This may be related either to the amount of colla-gen in the matrix or to the extent or nature of itscross-linking. Antiresorptive treatments probablyincrease the amount of cross-linking, but whetherthis is a positive or a negative change is unclear atthis time.

Both hypo- and hypermineralization of bone tis-sue reduce the amount of energy that can be ab-sorbed before fracture.28,29 As discussed later on inthis paper, suppression of remodeling favors tissuemineralization by increasing the period of timeover which secondary mineralization can occur. Thismay increase the tendency for microcracks to ini-tiate. Suppression of remodeling increases tissuehomogeneity, possibly making crack growth easi-er as well. However, the magnitude of the effect isprobably determined by the amount of suppression.

Degree of mineralization of bone (DMB)

Although there is widespread consensus on the factthat bone strength depends on the volume of bonematrix and the microarchitectural distribution ofthis volume, DMB is rarely mentioned as a deter-minant of bone strength. Yet, not only does DMBstrongly influence the mechanical resistance ofbones,30 but this is also true of BMD.3 Microradio-

Figure 1. Microradiograph of a section from an iliac bone sample (controlman 76-year-old, mean degree of mineralization of bone tissue (DMB) =1.33±0.16 g/cm3 and heterogeneity index of mineralization = 0.35 g/cm3).The heterogeneity of the mineralization is illustrated by the wide distribu-tion from dark grey young basic structural units (BSU) to clear grey old BSU.

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gesting that the mean DMB increase probably ac-counts for the major part of the increase in BMDseen with alendronate. After 2 and 3 years of alen-dronate, the index of heterogeneity was smallerthan after placebo. This illustrates the fact that withalendronate, which achieves a more complete sec-ondary mineralization, the homogeneity of min-eralization is better. Similar data have been re-ported after etidronate treatment for 1 and 2 years.36

Treatments with other bisphosphonates like rise-dronate40 and zoledronate41 also revealed decreasesin vertebral fractures and increases in BMD with-out any significant changes in bone mass and mi-croarchitecture, but marked reduction in activationfrequency. Another antiresorptive agent, the SERMraloxifene, whose action on the decrease of remod-eling rate is less potent than that of alendronate,has also been tested.42 Raloxifene induces a mildincrease in BMD, a moderate decrease in the bio-chemical markers of bone turnover, and decreasesthe risk of vertebral fractures in postmenopausalwomen. In the absence of significant changes inbone mass and microarchitecture, the changes inBMD reflect even mild modifications in DMB.43 Sim-ilar changes in DMB have been reported after ad-ministration of high doses of estrogen.44

Finally, strontium ranelate (Protelos®), a neworally effective and safe treatment of postmenopaus-al osteoporosis, has been shown to decrease verte-bral and hip fractures and increase BMD.45,46 Themechanismofactionof strontium ranelate is uniquein that it acts as a decoupling agent that decreasesbone resorption and increases bone formation. Itseffects at bone tissue level have recently been inves-tigated in animals47 and in women.37

Conclusions

The methods used for the evaluation of bonestrength depend on the part of the skeleton beinginvestigated48: compression for the vertebral bodyor of proximal tibia; 3- or 4-point bending test forthe long bones (tibia, femur); and shear test for thefemoral neck. Recently, racial and sex differenceshave been reported to explain differences in bonestrength, bone loss, and bone geometry.49,50 Biome-chanical tests are used to record a load-deflectioncurve, allowing the calculation of various compo-nents: stiffness by measuring the slope of the lin-ear part of the curve; ultimate strength by measur-ing the highest load obtained before fracture; andenergy absorbed (toughness) by measuring the areaunder the curve. Other parameters can be derived,for example, the yield point, which corresponds tothe transition from an elastic to a plastic, ie, irre-versible, deformation of the sample. All these testsare well described, and their reproducibility hasbeen evaluated (3% to 5 %). These measurementscan be used to evaluate the severity of bone fragilityas well as the integrate effect of treatment on thevarious determinants of bone strength. However, inclinical studies based on bone biopsies, the amountof bone available is too small to investigate the bio-mechanical properties. Recently, a nanoindentationtechnique has been applied to investigate tissue

In adult bone, the major biological determinantof mineralization is the rateof turnover.Thus, in ourmodel (Figure 2),37 any agent (PTH) or event (meno-pause, ovariectomy) that causes an increase in the“birthrate” or activation frequency of basic multi-cellular units (BMU), induces a decrease in the “life-

span” of BSU, in other words, in the time availablefor secondary mineralization. This leads to new BSUbeing resorbed before they have fully completedtheir secondary mineralization, as proven by thepresence of a large amount of incompletely miner-alized BSU and a low mean DMB. In primary hyper-parathyroidism, a shift of DMB toward the low val-ues was observed (mean 0.92±0.07 g/cm3; DMB max0.90), but the index of heterogeneity was unchanged(0.30 g/cm3). In patients treated with teriparatide,the DMB was decreased, but with an increased het-erogeneity of the values,38,39 as expected after a shortprolongation of bone formation activity.

Conversely, antiresorptive agents (bisphospho-nates, estrogen, SERMs), which cause a markedreduction in the “birthrate” of BMU, prolong the“lifespan” of the BSU, allowing a more complete sec-ondary mineralization. This should finally lead toan increase in DMB. Recently, mean DMB was mea-sured by quantitative microradiography3 on transil-iac bone biopsies taken from 53 postmenopausalosteoporotic women who had been treated with al-endronate (10 mg/day) for2or3 years, or with place-bo. In the same patients, BMD values were obtainedat lumbar spine level. After 2 years on alendronate,mean DMB in total bone was 7.5% higher than onplacebo (P=0.0026). After 3 years on alendronate,mean DMB in total bone was 10.7% higher thanon placebo (P=0.0001). After alendronate, the dis-tribution of the DMB in total bone showed a clearshift toward the highest mineralization values con-comitantly with a decrease in the number of BSUhaving low values of mineralization. The between-group differences in mean DMB were similar tothose in BMD at lumbar spine level (+8.7% after 2years and +9.6% after 3 years, respectively), sug-

Figure 2. Diagram summarizing the effects of the rate of bone remodel-ing activity on the secondary mineralization and consequently on thedegree of mineralization of bone. The black arrows relate to decreasedbone remodeling activity, and the green arrows to increased bone re-modeling activity.Abbreviations: BMU, basic multicellular unit, BSU, basic structural unit; DMB, degreeof mineralization of bone tissue; OVX, ovariectomy; PTH, parathyroid hormone.Adapted from reference 37: Boivin G, Meunier PJ. The mineralization of bone tissue: a forgotten dimension in osteoporosis research. Osteoporos Int. 2003;14(suppl 3)S19-S24. Copyright © 2003, Springer Verlag USA.

Birthrate of BMU

Lifespan of BSU

Duration of secondarymineralization

Degree of mineralization of bone tissue (DMB)

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➤➤ ➤

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Bone remodelingFormative effects:OVX, PTH…

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Bone remodelingAnti-resorptive effects:biphosphonates,estrogen, raloxifene…

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U P D A T E


may explain the observation of modifications infracture incidence and the increase in the BMD andin bone strength independently of changes in bonematrix volume and bone microarchitecture. Thisnew approach to the determinants of bone qualityemphasizes the importance of bone mineral sub-stance in the pathophysiology of osteoporosis andother bone conditions, and of taking a fresh look atthe long forgotten mineral dimension of bone. Inaddition to parameters of DMB such as the hetero-geneity index of the distribution of mineralization,we are now able to evaluate the mechanical prop-erties at tissue level, by means of microhardnesstesters, and the role of the size/maturity of crystalsand of the maturation of collagen, by means of Fou-rier transform infrared microspectroscopy. ❒

The expert technical assistance of Delphine Farlay, Cather-ine Simi and Yohann Bala (INSERM Unité 403, Facultéde Médecine R. Laennec, Lyon, France) is gratefully ac-knowledged.

quality by measuring both hardness and elasticityof dry and wet bone tissue with a high spatial res-olution.51,52 Nanoindentation involves compressinga pyramidal diamond tip into a material, and simul-taneously recording the resulting force and dis-placement. From the force-displacement curves ob-tained, hardness (the maximal force per unit area),and indentation modulus (a purely elastic property)can be calculated. The nanoindentation method al-lows the mechanical properties of bone lamellae tobe quantified. To study the mechanical properties ofbone tissue at the level of each BSU—the true in-termediate level of organization allowing a correctapproach to remodeling—we are developing inves-tigation techniques using microhardness testers(Vickers and Knoop). Finally, the correlation be-tween mineralization, hardness, and the classic me-chanical tests is being actively investigated.

Changes in bone remodeling activity directly in-fluence the degree of mineralization of bone. This

REFERENCES1. Hui S, Slemenda CW, Jonhston CC. Age and bonemass as predictors of fracture in a prospective study.J Clin Invest. 1988;81:1804-1809.2. Dempster DW. The impact of bone turnover andbone-active agents on bone quality: focus on the hip.Osteoporos Int. 2002;13:349-352.3. Boivin G, Chavassieux PM, Santora AC, et al. Alen-dronate increases bone strength by increasing themean degree of mineralization of bone tissue in osteo-porotic women. Bone. 2000;27:687-694.4. Hauselmann HJ, Rizzoli R. A comprehensive reviewof treatments for postmenopausal osteoporosis. Os-teoporos Int. 2003;14:2-12.5. Riggs BL, Melton LJ III. Bone turnover matters: theraloxifene treatment paradox of dramatic decreases invertebral fractures without commensurate increasesin bone density. J Bone Miner Res. 2002;17:11-14.6. Dalen N, Hellstrom LG, Jacobson B. Bone miner-al content and mechanical strength of the femoralneck. Acta Orthop Scand. 1976;47:503-508.7. Granhed H, Jonson R, Hansson T. Mineral contentand strength of lumbar vertebrae. A cadaver study.Acta Orthop Scand. 1989;60:105-109.8. Turner CH, Burr DB. Basic biomechanical mea-surements of bone: a tutorial. Bone.1993;14:595-608.9. Ammann P, Rizzoli R, Bonjour JP. Preclinicalevaluation of new therapeutic agents for osteoporosis.In: Meunier PJ, ed. Osteoporosis: Diagnosis and Man-agement. London, UK: Martin Dunitz; 1998:257-273.10. Bonjour JP, Ammann P, Rizzoli R. Importance ofpreclinical studies in the development of drugs fortreatment of osteoporosis: a review related to the 1998WHO guidelines. Osteoporos Int. 1999;9:379-393.11. Turner CH. Biomechanics of bone: determinantsof skeletal fragility and bone quality. Osteoporos Int.2002;13:97-104.12. Seeman E. Pathogenesis of bone fragility in wom-en and men. Lancet. 2002;359:1841-1850.13. Andreassen TT, Jorgensen PH, Flyvbjerg A, et al.Growth hormone stimulates bone formation andstrength of cortical bone in aged rats. J Bone MinerRes. 1995;10:1057-1067.14. Ejersted C, Andreassen TT, Oxlund H, et al. Hu-man parathyroid hormone (1-34) and (1-84) increasethe mechanical strength and thickness of corticalbone in rats. J Bone Miner Res. 1993;8:1097-1101.15. Jerome CP, Burr DB, van Bibber T, Hock JM,Brommage R. Treatment with human parathyroidhormone (1-34) for 18 months increases cancellousbone volume and improves trabecular architecturein ovariectomized cynomolgus monkeys (Macaca fas-cicularis). Bone. 2001;28:150-159.16. Hirano T, Burr DB, Turner CH, Sato M, Cain RL,Hock JM. Anabolic effects of human biosynthetic para-thyroid hormone fragment (1-34), LY333334, on re-modeling and mechanical properties of cortical bone

strength. A study on human calcaneus. Bone. 2004;34:783-789.31. Meunier PJ, Boivin G. Bone mineral density reflectsbone mass but also degree of mineralization of bone:therapeutical implications. Bone.1997;21:373-377.32. Boivin G, Meunier PJ. The degree of mineraliza-tion of bone tissue measured by computerized quan-titative contact microradiography. Calcif Tissue Int.2002;70:503-511.33. Boivin G, Meunier PJ. Effects of bisphosphonateson matrix mineralization. J Musculoskel Neuron In-teract. 2002;2:538-543.34. Boivin G, Meunier PJ. Methodological considera-tions in measurement of bone mineral content. Os-teoporos Int. 2003;14(suppl 5):22-28.35. Nuzzo S, Peyrin F, Cloetens P, Bachurel J, BoivinG. Quantification of the degree of mineralization ofbone in three dimension using synchrotron radiationmicrotomography. Medical Physics. 2002;29:2672-2681.36. Nuzzo S, Lafage-Proust MH, Martin-Badosa E, etal. Synchrotron radiation microtomography allowsthe analysis of three-dimensional microarchitectureand degree of mineralization of human iliac crestbiopsies: effects of etidronate treatment. J Bone MinerRes. 2002;17:1372-1382.37. Boivin G, Meunier PJ. The mineralization of bonetissue: a forgotten dimension in osteoporosis research.Osteoporos Int. 2003;14(suppl 3):S19-S24.38. Misof BM, Roschger P, Cosman F, et al. Effects ofintermittent parathyroid hormone administration onbone mineralization density in iliac crest biopsiesfrom patients with osteoporosis: a paired study beforeand after treatment. J Clin Endocrinol Metab. 2003;88:1150-1156.39. Arlot ME, Meunier PJ, Boivin G, et al. Differentialeffects of teriparatide and alendronate on bone remod-eling in postmenopausal women assessed by histo-morphometric parameters. J Bone Miner Res.2005;20:1244-1253.40. Borah B, Ritman EL, Dufresne TE, et al. The ef-fects of risedronate on bone mineralization as mea-sured by micro-computed tomography with synchro-tron radiation: correlation to histomorphometricindices of turnover. Bone. 2005;37:1-9.41. Boivin G, Arlot M, Trechsel U, Meunier PJ. Effectsof intravenous zoledronic acid on the degree of min-eralization of bone in post-menopausal osteoporosis:a quantitative microradiographic analysis of transiliacbiopsies after one year. J Bone Miner Res. 2003;18(suppl 2):S261.42. Ott SM, Oleksik A, Lu Y, Harper K, Lips P. Bonehistomorphometric and biochemical marker resultsof a 2-year placebo-controlled trial of raloxifene inpostmenopausal women. J Bone Miner Res. 2002;17:341-348.

in rabbits. J Bone Miner Res. 1999;14:536-545.17. Burr DB, Hirano T, Turner CH, Hotchkiss C,Brommage R, Hock JM. Intermittently administeredhuman parathyroid hormone (1-34) treatment in-creases intracortical bone turnover and porosity with-out reducing bone strength in the humerus of ovariec-tomized cynomolgus monkeys. J Bone Miner Res.2001;16:157-165.18. Zanchetta JR, Bogado CE, Ferretti JL, et al. Ef-fects of teriparatide (recombinant human parathyroidhormone (1-34) on cortical bone in postmenopausalwomen with osteoporosis. J Bone Miner Res.2003;18:539-543.19. Chavassieux P, Arlot M, Meunier PJ. Clinical useof bone biopsy. In: Marcus R, Feldman D, Kelsey J,eds. Osteoporosis. 2nd edition. San Diego, Ca: Aca-demic Press Inc; 2001;2:501-509.20. Compston JE. Sex steroids and bone. Physiol Rev.2001;81:419-447.21. Gallagher JC. Effect of estrogen on bone. In: FavusMJ, ed. Primer on the Metabolic Bone Diseases andDisorders of Mineral Metabolism. Fifth edition. Chap-ter 23. Washington, DC: ASBMR; 2003:327-330.22. Burr DB, Forwood MR, Fyhrie DP, Martin RB,Schaffer MB, Turner CH. Bone microdamage andskeletal fragility in osteoporotic and stress fractures.J Bone Miner Res. 1997;12:6-15.23. Burr DB. Bone quality: understanding whatmatters. J Musculoskel Neuron Interact.2004;4:184-186.24. Mashiba T, Turner CH, Hirano T, Forwood MR,Johnston CC, Burr DB. The effects of suppressed boneturnover by bisphosphonates on microdamage accu-mulation and biomechanical properties in clinicallyrelevant skeletal sites of beagles. Bone. 2001;28:524-531.25. Mashiba T, Hirano T, Turner CH, Forwood MR,Johnston CC, Burr DB. Suppressed bone turnover bybisphosphonates increases microdamage accumula-tion and reduces some biomechanical properties indog rib. J Bone Miner Res. 2000;15:613-620.26. Burr DB. The contribution of the organic matrixto bone’s mechanical properties. Bone. 2002;31:8-11.27. Burr DB, Turner CH. Biomechanical measure-ments in age-related bone loss. In: Rosen CJ, GlowackiJ, Bilezikian JP, eds. The Aging Skeleton. San Diego,Ca: Academic Press Inc; 1999:301-311.28. Currey JD. The effect of strain rate, reconstructionand mineral content on some mechanical propertiesof bovine bone. J Biomech.1975;8:81-86.29. Currey JD, Brear K, Zioupos P. The effects of ag-ing and changes in mineral content in degrading thetoughness of human femora. J Biomech. 1996;29:257-260.30. Follet H, Boivin G, Rumelhart C, Meunier PJ. Thedegree of mineralization is a determinant of bone

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L a résistance osseuse est définie comme la charge maximaleapplicable avant la survenue d’une fracture. Celle-ci varieen fonction d’un certain nombre de facteurs, tels que la

masse, la taille, la géométrie, la microarchitecture, mais égale-ment les propriétés matérielles intrinsèques du tissu osseux. Cesdernières comprennent le degré de minéralisation osseuse et lescaractéristiques de la matrice organique (orientation et struc-ture chimique des fibres de collagène), l’accumulation de micro-lésions osseuses (apparition et progression de microfissures) ain-si que l’apoptose des ostéocytes. La qualité osseuse en général etle degré de minéralisation osseuse sont tous deux profondémentinfluencés par le taux de remodelage osseux. Ceci peut expliquerles modifications de l’incidence des fractures et l’augmentationde la densité minérale osseuse et de la résistance osseuse appa-

raissant indépendamment de toute modification de la microar-chitecture osseuse et du volume de la matrice. L’intérêt croissantporté à l’évaluation des déterminants de la qualité osseuse reflètel’importance de la substance minérale osseuse dans la physio-pathologie de l’ostéoporose et d’autres pathologies osseuses et aconduit à la redécouverte de la dimension minérale de l’os quiavait été reléguée dans l’oubli pendant de nombreuses années.Cette dimension fait intervenir des paramètres tels que le degréde minéralisation osseuse ; l’indice d’hétérogénéité de distributionde la minéralisation ; les propriétés mécaniques du tissue osseux(testeur de microdureté) ; la taille et la maturité des cristaux ;ainsi que le degré de maturation du collagène (microspectrosco-pie infrarouge par transformée de Fourier).

DÉTERMINANTS DE LA QUALITÉ OSSEUSE

43. Boivin G, Lips P, Ott SM, Harper KD, Sarkar S,Pinette KV, Meunier PJ. Contribution of raloxifene andcalcium and vitamin D3 supplementation to the in-crease of the degree of mineralization of bone in post-menopausal women. J Clin Endocrinol Metab. 2003;88:4199-4205.44. Boivin G, Vedi S, Purdie DW, Compston JE, Meu-nier PJ. Influence of estrogen therapy at convention-al and high doses on the degree of mineralization ofiliac bone tissue: a quantitative microradiographicanalysis in postmenopausal women. Bone. 2005;36:562-567.45. Meunier PJ, Roux C, Seeman E, et al. The effectsof strontium ranelate on the risk of vertebral fracturein women with postmenopausal osteoporosis. N Engl

contributions of growth and ageing to racial and sexdifferences in femoral neck structure and strengthin old age. Bone. 2005;36:978-986.50. Duan Y, Wang XF, Evans A, Seeman E. Structuraland biomechanical basis of racial and sex differencesin vertebral fragility in Chinese and Caucasians. Bone.2005;36:987-998.51. Zysset PK, Guo XE, Hoffler CE, et al. Elastic mod-ulus and hardness of cortical and trabecular bonelamellae measured by nanoindentation in the humanfemur J Biomech.1999;32:1005-1012.52. Hengsberger S, Boivin G, Zysset PK. Morpholog-ical and mechanical properties of bone structuralunits: a two cases study. Int J Japan Soc MechanicalEngineers. 2002. Series C;45:936-943.

J Med. 2004;350:459-468.46. Reginster JY, Seeman E, De Vernejoul MC, et al.Strontium ranelate reduces the risk of nonvertebralfractures in postmenopausal women with osteo-porosis: Treatment of Peripheral Osteoporosis (TRO-POS) study. J Clin Endocrinol Metab. 2005;90:2816-2822.47. Farlay D, Boivin G, Panczer G, Lalande A, Meu-nier PJ. Long-Term strontium ranelate administrationin monkeys preserves characteristics of bone mineralcrystals and degree of mineralisation of bone. J BoneMiner Res. 2005;20:1569-1578.48. Ammann P, Rizzoli R. Bone strength and its de-terminants. Osteoporos Int. 2003;14(suppl 3):13-18.49. Wang XF, Duan Y, Beck TJ, Seeman E. Varying

he first Russian to obtain his degree of doctor of medicine was a certain Posnikov who receivedhis degree at Padua in 1692.1 This anecdotal and controversial event marks the beginning of the

history of Russian medicine. Up until the 18th century, there was no organized medical teaching inRussia. In the absence of “traditional Russian medicine,” foreign doctors practiced at the imperial court,

and also looked after the families of aristocrats and the wealthy bourgeois. At the beginning of the Ageof Enlightenment, and encouraged by the “enlightened” czars, Russia became a land of knowledge and

expertise. The first Russian doctors were now taught in their own country, but still had to go abroad toperfect their knowledge and defend their theses. These doctors had a good reputation and specialized incertain fields of which they became masters: neurology, physiology, ophthalmology, epidemiology, pedi-atrics, and hygiene.

Russian doctors in the face of German competitionAt the beginning of the 18th century, during the reign of Peter 1, a network of lazarets, apothecaries, hos-pitals, and medical schools began to spread across the Russian landscape. Organized, regulated, and fi-nanced by the state, medicine began to be taught in Moscow in 1706, to be followed by Saint Petersburg,Kronstadt, Barnaul, and Elizabethgrad. These institutions produced mainly military doctors, and taughtWestern medicine with the accent on practicality, but they did not award doctoral degrees. Everythingchanged in 1776 when the czarina Catherine II the Great transformed the Moscow medical school into afaculty. In order to launch this new project along western lines, the czarina consulted the French philoso-pher Denis Diderot who in 1775 sent her a Plan for a university [of medicine] in which he recommended

78 French medicine in Russia – Régnier MEDICOGRAPHIA, VOL 28, No. 1, 2006

A T O U C H O F F R A N C E

Christian RÉGNIER, MDPraticien Attaché des Hôpitaux de ParisSociété Internationale d’Histoire de la Médecine9, rue Bachaumont 75002 Paris, FRANCE (e-mail: [email protected])

French medicine in Russia

A tale of passionb y C . R é g n i e r , F r a n c e

or a long while medicine in Russia was the stamping ground of European doctors, then, at thebeginning of the 18th century, medical schools were established in Moscow and Saint Peters-

burg. The first Russian doctors could now practice their art in their own country, but they stillhad to go abroad to acquire their doctorates. The czars and czarinas in the Age of Enlightenment

were open to foreign influences, and wanting to modernize Russia they sought the assistance of Ger-man and French professors to teach in the newly created medical schools. The choice of either German

or French instructors was more or less haphazard, and could depend on family history, personal affinity,or the origins of the Russian sovereigns. Medico-scientific exchanges between France and Russia flourishedin the Age of Enlightenment, were almost nonexistent under Napoleon I, and took off in the middle of the19th century under the influence of the great French scientists like Claude Bernard, Jean-Martin Charcot,and Louis Pasteur—all of them strongly pro-Russian. However, Franco-Russian relations, including inthe field of medicine, always seem to have been subject to hazard. With the exception of the short-livedFranco-Russian alliance of 1891, nothing was organized or programmed officially. Everything was a ques-tion of intuition, enthusiasm, disappointment, or sudden impulse. Medicographia. 2004;26:78-87. (see French abstract on page 87)

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F

T

that there should be seven chairs of which two should be devoted to practicalmedicine. When the faculty opened, six chairs had been assigned to professorsfrom Holland, Germany, and England (the French professor declined to acceptthe honor). The Russian faculty decided to adopt Latin nomenclature for anato-my, thus forcing Western works to be adapted. Around 1780, the first Russianprofessors of medicine began to replace their European counterparts. Nonethe-less, a considerable number of foreign practitioners remained in Russia until thefirst half of the 19th century. In 1809, a census revealed that out of 2596 doctorsin the empire only 1187 (45%) were of Russian origin.2-8

In 1888, Doctor Georges Dujardin-Beaumetz, aided by his Russian studentWinocourov, drew up a register of medical schools in Russia. He listed nine activemedical faculties: Moscow, Karlov, Kiev, Odessa, Kazan, Dorpat, Warsaw, Tomsk,and Saint Petersburg. Students had to pay for tuition, and the curriculum lasted5 years for basic medicine (the lekars). Doctor Dujardin-Beaumetz estimated

the number of Russian doctors to be about 15 000, of which 750 were women.9 The foreign doctors wereusually German or Dutch. The fact that the czars did not speak Russian, the pro-German policy of Peter Ithe Great, and the reigns of the German-born czars like Peter III who was raised in Kiel, and that of hiswife Catherine the Great (born in Stettin, the daughter of the Prince of Anhalt-Zerbst), favored the estab-lishment and spread of German medicine in Russia.

Up until 1785, Russian medical students had to finish their studies and defend their theses at the OpenUniversity of Strasbourg (Straßburg in German), which accepted students from Alsace, Switzerland, andGermany. The Russian doctor Lepekhin who studied in Strasbourg from 1762 to 1767, wrote:

As far as medicine is concerned, I could not wish for better; here, in Straßburg, there are great advantages formedical students compared with other universities (…) There are two hospitals, one military and the othercivilian, where students are welcomed and can study diseases.

The reputation of Strasbourg was based on the quality of its practical teaching, particularly the dissec-tions and experiments in physiology. From 1785 to 1787, there were 44 Russian medical students outof a total of 125 undergraduates. A great many of the Russian medical pioneers studied and defended theirtheses in Strasbourg. However, during the Revolution, teaching of medicine in France collapsed and


79French medicine in Russia – Régnier MEDICOGRAPHIA, VOL 28, No. 1, 2006

Map of Saint Petersburg (1737, anonymous). Founded in 1713 by Peter I the Great, the “Venice ofthe North”—thus called because of its numerous canals and over 500 bridges—became the capitalof the Russian Empire in 1715, though the period of its greatest development took place underempresses Anna Ivanovna (1730-1740) and Elizabeth Petrovna (1741-1762). In 1725, the czarfounded the first Academy of Sciences, which was to be transferred to Moscow in 1934. Courtesy of Historic Cities Research Project http://historic-citiesKhuji.ac.il. © The Hebrew University of Jerusalem & The Jewish National and University Library.

Czar Peter I the Great (1672-1725), portrait in glass mosaic, by Mickhail Lomonosov. Lomonosov, the son of a fisherman who became a self-taught scientist, founded Moscow University in 1755.Hermitage Museum, St Petersburg. © Hermitage Museum.

Strasbourg did not escape the slaughter, especially since its statute of political autonomy vanished in theupheaval. For Russian medical students, the new pole of attraction was Berlin where an institute was spe-cially created for their needs. In 1802, Czar Alexander I decided to reopen the faculty of medicine in Dorpat(now Tartu in Estonia) where teaching was conducted in German, the scientific language of the 19th cen-tury. Dorpat was noted for medical and scientific exchanges between Russian- and German-speaking Slavs.In 1871, after the defeat of the French by Prussia, Russian students returned to Strasbourg to complete

their studies (Alsace was occupied by Germanyuntil 1918).2,3,5,7,9-11 In the 19th century, the om-nipresence of German doctors was often de-picted with irony by Russian writers. In TheDead Souls, Nicolas Gogol mocked ChristianIvanovitch, a German doctor in a provincialRussian hospital, who could not speak Russian:

Man is not very complicated: if he has to die, hewill die anyway; if he is going to get better, hewill get better anyway. In any case, ChristianIvanovitch would have had difficulty explain-ing anything to his patients, since he can onlygabble in German.12

Another Russian author, Alexandre Ghertsen,described in Who is Guilty? the sad fate of Doc-tor Cruciferski, a Russian doctor who neverhad sufficient clients:

Cruciferski dragged himself from one end of Russia to the other and finally settled in a country town. To beginwith he had enough clients. The dignitaries and landed gentry would have preferred to be treated by a Germandoctor. But, fortunately for Cruciferski, there was no German on hand (except for a clockmaker).13

In War and Peace (1869), Leo Tolstoy also alluded to German doctors who could not speak Russian. Afterbreaking off her engagement, Natacha became ill:

the doctors who came to treat her, sometimes alone, sometimes in a group, discussed furiously in French, Ger-man, and Latin, criticized each other, prescribed medicines of every sort against all the diseases they knew, butit never occurred to any of them that they hadn’t a clue abouch which disease Natacha was suffering from.14

Franco-Russian relations: between enthusiasm and deceptionAware of the archaic state of Russian society, still too feudal and under the thumb of a powerful bureau-cratic hierarchy, Czar Peter I the Great decided to breathe a touch of modernism into his vast empire.Wishing to give Russia a window on Europe, he built Saint Petersburg on the banks of the Baltic. Draw-ing inspiration from Amsterdam, where he had studied navigation, Peter I wanted his capital to be as sump-tuous as Versailles, and naturally chose French architects. In his History of Russia Under Peter the Great,Voltaire explained that the czar’s sobriquet was given to him “because he had the courage to take on theenormous tasks that had never even entered the minds of his predecessors.” Hoping to form an allianceagainst Sweden, and wanting to marry his daughter Elizabeth, aged 7, to little Louis XV, aged 6, the czarremained in Paris from 4 May to 20 June 1717. He visited hospitals, the Jardin des Plantes, the Academyof Science, and witnessed an operation for cataract. Not bothering much about protocol, he shocked thecourt with his unpolished manners. Despite initial hopes, the visit did not stimulate scientific exchangesbetween the two countries, nor did it foster political relations (there was no marriage), perhaps because theczar could not speak French, which became mandatory at the Russian court in the reign of his daughter,Czarina Elizabeth. The Saint Petersburg Academy of Science was established towards the end of the reignof Peter I the Great, and became a meeting place for European academics. In 1721, the king dispatchedSchumacher, the academy librarian, to Paris with instructions to acquire surgical instruments, medicalsamples, and anatomical models. Schumacher was also to recruit experienced doctors and surgeons, amongwhom Duvernoy, a celebrated Parisian anatomist. However, not knowing much about this large ratherrugged country and its customs, the doctors declined. During this period, the French Jesuits in Pekingmaintained close links with the Saint Petersburg Academy of Science (which inherited their library). TheJesuits, under Father Parennin, sent the academy samples of Chinese plants with antivenereal qualities.

The daughter of Peter the Great, Elizabeth Petrovna, ascended the throne in November 1741 after a coupd’état fomented by the Marquis de la Chétardie, the representative of the king of France in Saint Peters-burg. The marquis was backed up by Armand Lestocq, an adventurous doctor who bled the young czarina



Medical Faculty of Straßburg (German spelling), which attracted many as-piring Russian doctors. Engraving by Perrin (1840), showing the Universitypremises, formerly the Foundlings Hospice. © Coll. Inter-Activités.

(and taught her French). In 1759, the czarina acquired a “surgi-cal arsenal” in Paris, which included an obstetrical manikin andnumerous instruments covering all aspects of surgery. The inven-tory covered 44 pages and is conserved in the French NationalLibrary.3,8,15-17 Medical exchanges with France increased underCatherine II who enjoyed the services of a French doctor, PierreIsaac Poissonnier, whose political mission seems to have occupiedmore of his time than his medical activity. Indeed, it was to herfriend Voltaire—passionately interested in medicine—that theczarina turned for advice in 1768 on whether to be inoculatedagainst smallpox. Catherine the Great could speak and write inFrench with elegance.

One speaks a purer French at the Empress’s court than at Versailles, because there our beautiful ladies do notbother to learn the grammar

wrote Voltaire diplomatically. Aware of the modernizing influence of thought in the Age of Enlightenment,the czarina proposed unsuccessfully to d’Alembert and Diderot that they should choose Riga or any othertown in the empire for the printing of their Encyclopédie Raisonnée des Sciences et des Arts (RationalEncyclopedia of Sciences and Art). In 1773-4, Diderot resided in Saint Petersburg for six months delud-ing himself that he could influence Catherine the Great and make her change her politics in Poland. How-ever, the czarina contented herself with purchasing the philosopher’s library and in return he recruitedFrench artists and doctors for her.

Two historic events sapped the development of relations between France and Russia: the French Rev-olution and the invasion of Moscow by Napoleon’s Grande Armée in 1812. The beheading of Louis XVIappalled Catherine the Great, and the invasion of Russia by Napoleon was strongly resented by the Rus-sian intellectuals who had been rather favorable to the ideas of the Revolution. Moreover, 1812 markeda turning point in Russia when all hope of reforming the regime went up in smoke with the burning ofMoscow. In 1801, at the beginning of the reign of Alexander I, the czar had aroused considerable enthu-siasm among the liberals for his efforts to reform serfdom and autocracy; however, in 1812, after the warwith France, the Russian king adopted authoritarian politics before sinking into mysticism.1,4,6,17-19 In thefirst half of the 19th century, at a time when the anatomicoclinical method spread abroad by the Paris

School was dominating medicine, in Rus-sia the medical and scientific influence ofFrance had grown more or less non-exis-tent. Even the great military surgeon trainedin Dorpat, Nicolas Ivanovitch Pigorov, whovisited Paris in 1837, was not enthusiastic:“From a surgical point of view, Paris did notimpress me. The hospitals were gloomy andmortality was high.” 2

Claude Bernard and Jean-MartinCharcot: the Russomania periodIn the second half of the 19th century,Claude Bernard, Louis Pasteur, and Jean-Martin Charcot, three universally recog-nized representatives of French science andmedicine, attracted young Russian doctorsand scholars to Paris. As was usual in Franceat that time, the three men were profound-ly Russophile. This sympathy for Russia andRussians was nursed by the presence ofnumerous exiled Russian writers who had



Meeting between Napoleon I and Czar Alexander I and the sovereign vassals of Germany,at Erfurt (27 September to 14 October 1808). The Czar agreed to lend Napoleon his sup-port in the event Austria declared war to France. In exchange, Russia would annex Fin-land and the Romanian provinces of Moldavia and Walachia. Painting by Nicolas Gosse.Museum of French History, Versailles. © Musée de l’Histoire de France, Versailles.

French man of letters and philosopher Denis Diderot(1713-1784) by Louis Michel Van Loo. Oil on canvas 81�65 cm,

1767, Louvre Museum, Paris. Diderot was the Father of theEncyclopedia, the first volume of which appeared in 1751 and

the 31st and last in 1776. In his later years, he was rescuedfrom financial difficulties by Catherine II the Great. © RMN.

settled in Paris, among them Turgenev. Claude Bernard, the founder of experimental medicine, was themost famous of the French physiologists; however, his works were competing with those of the Germanexperimenters such as Karl Ludwig and Justus von Liebig, the founder of organic chemistry. In this climateof increasing rivalry, Claude Bernard enjoyed receiving in his laboratory at the Collège de France youngRussian savants. Among them was Ivan Mikhailovitch Setchenov, pioneer of Russian neurophysiology,who identified the inhibitory centers of spinal reflexes in 1865. His popular work, The Reflexes of the Brain(1863), was a great success in Russia and pointed the way for numerous researchers such as Pavlov. Otherresidents at Claude Bernard’s laboratory included the young Sergei Petrovitch Botkin who later taughtexperimental medicine at the Saint Petersburg Academy, and Élie de Cyon who studied experimental phys-iology, focusing on the regulation of heartbeat by the sympathetic nervous system. From 1869, ClaudeBernard had as assistant and confidante, Marie Sarah Raffalovitch, who was born into a family of Russianfinanciers in Odessa. She could speak eight languages and translated his scientific and medical articles.Bernard wrote nearly 480 letters to the young woman whom he met during one of his courses at the Col-lège de France. The letters are conserved in the Claude Bernard Museum in Saint Julien-en-Beaujolaisand portray the solitude of this great scientist who could always rely on the comprehension and disinter-ested friendship of Marie Raffalovitch.10,15,18,20

Famous for his lessons on hysteria and hypnosis, the neurologist Jean-Martin Charcot attracted Rus-sian doctors to the Salpêtrière Hospital who went on to found the highly respected Russian schools of neu-rology and psychiatry. One of them was Vladimir Bechterev, who held the position of professor and chairof mental and nervous diseases in Saint Petersburg, and described the cortical localization of motor func-tions in 1887. Another Russian student, Alexis Kojevnikov, frequented Charcot’s department, and later in1893 described focal epilepsy. Charcot, a connoisseur of Russia and friend of Grand Duke Nicholas, wassummoned to Russia to treat the royal family. He was regularly invited to dinner parties by the Daudetswhere Turgenev, inspired by champagne, enthusiastically declaimed Russian folk tales.18,21

Pasteur at the time of the Franco-Russian allianceLouis Pasteur played an important role in the strengthening of scientific relations between France andRussia. A fervent patriot, considering the 1870 defeat at the hands of Germany a profound humiliation,and now constantly having to compete with German bacteriologists, Pasteur was as passionately pro-Rus-sian as he was anti-German.

Already in 1881, Pasteur contemplated going to Russia to study an infection known as “Siberian plague”that he suspected to be quite simply anthrax. On July 1, in a letter to Count Orloff, Russian Ambassadorin Paris, he wrote: “I take the liberty to inform Your Excellency that I have discovered the vaccine againstanthrax.” In November, 1883, Pasteur wrote to the Saint Petersburg Academy of Science proposing thatthey join forces to study diseases of the silkworm.4

When Pasteur’s rabies vaccine had proved its efficacy after the first two successful tests in July and Oc-tober 1885, the news traveled the length and breadth of Russia where the disease was a permanent menace.On March 1, 1886, Pasteur published the first statistics based on 350 humans vaccinated against rabies. Thesame month, 19 Russians from the region of Smolensk were dispatched to Paris after having been bittenby a rabid wolf. On their arrival in the capital, five of them, in a very serious state, were hospitalized at the



Louis Pasteur(1822-1895). The iconic

French chemist, fatherof modern bacteriology.

Painting by Edelfeldt.© Institut Pasteur, Paris.

The rabid Russians from Smolensk, at Pasteur’s laboratoryat the École Normale, in the rue d’Ulm, in Paris, in 1886:

the early days of international humanitarian medicine.© Musée de l’Institut Pasteur, Paris.

Hôtel Dieu. Pasteur immediately applied his vaccination pro-tocol and saved sixteen of the patients. Their long voyage,their strange garments, and their successful treatment madethe Russians from Smolensk a sensation and everyone wantedto interview them.22-24

Since the efficacy of the rabies vaccine seemed proven, princeAlexander of Oldenburg decided to found an antirabies lab-oratory in Saint Petersburg and thus produce the vaccina-tions on site using Pasteur’s method. On July 14, 1886, AdrienLoir, Pasteur’s nephew, set sail for the imperial city with a cagecontaining two rabbits with rabies. The first two Russian an-tirabies centers were established in conjunction with the Pas-teur Institute at Saint Petersburg and Odessa in 1886. Stim-ulated by research on the antirabies vaccine, many medicaland scientific ideas were exchanged between the Russian and French biologists.22,23 On November 14, 1888,the Pasteur Institute was inaugurated in Paris in the presence of Prince Oldenburg and the Grand DukesVladimir and Alexis of Russia who had contributed generously to the public subscription for the founda-tion of the institute. During the ceremony, Pasteur wore the grand cross of Saint Anne of Russia awardedhim by the czar for saving the Smolensk Russians. Pasteur had written to Nikolai Federovitch Gamaleia,the future head of the Russian Institute:

You are going to direct Russian research, which I hope will prosper. You know my warm feelings for your coun-try which extend well beyond the walls of the laboratory.

Russian researchers were the first foreigners to be invited to work at the Pasteur Institute.4,25 This blos-soming of scientific relations between France and Russia was officially reinforced in 1891 with the sign-ing of the Franco-Russian treaty. This pact freed the two countries from a certain diplomatic isolation. Inaddition, France hoped that the treaty would put pressure on Germany. However, Czar Alexander III wasfar from being an enlightened sovereign. Having been traumatized by the assassination of his father



Born in Lipowice (Poland), Xavier Galezowski (1833-1907) studiedmedicine in Saint Petersburg where he defended his thesis on theuse of von Helmholtz’s ophthalmoscope, for which he received a goldmedal (and later perfected the instrument). In 1859, he accompaniedhis uncle, Séverin Galezowski, who was also a doctor, to Paris. For thenext five years, the young Xavier was assistant to the famous Parisianophthalmologist, Louis-Auguste Desmarres. In 1865, he presentedhis dissertation, An Ophthalmoscopic Study on the Alterations of theOptic Nerve and the Cerebral Alterations on Which They Depend.In 1867, he opened his own private ophthalmological clinic in the rueDauphine. In thirty years, nearly 260 000 patients were treated in thisclinic, which served as a model for French ophthalmology. Galezowskiwas decorated with the Légion d’honneur after the Franco-Prussian

war, and in 1872 founded the Journal of Ophthalmology, the first French journal devoted to thisspecialty, which later became the Ophthalmology Collection. In 1886, he invented plaques of gelatinmoistened with a mercury salt (the forerunner of contact lenses) to protect the cornea after opera-tions for cataract. He also gave his name to a round-ended catheter for exploring the lachrymal glands.In 1872, he published a Treatise on the Diseases of the Eye (464 figures), in 1876 an Illustrated Trea-tise on Ophthalmoscopy, and in 1902 Clinical Lessons in Ophthalmology. Finally, in 1883, he pro-posed the use of optometric and chromatic scales to measure visual acuity.28

XAVIER GALEZOWSKI, A MASTER OF OPHTHALMOLOGY

Galezowski’s ophthal-moscope: method of use.

Extracted from: Traitédes Maladies des Yeux

[Treatise on the Diseasesof the Eye], 1875, by

Xavier Galezowski.© BIUM.

Czar Nicholas II (1868-1918) and his wife, the Princess of Hesse(née Alexandra Feodorovna), and their children. Engraving

published in Le Petit Journal, a French newspaper, in July 1901.The oval framed–painting behind the Nicholas II shows

his father, Alexander III (one of Paris’ most beautiful bridgesis named after him). © Coll. Inter-Activités.

Alexander II, he adopted a harsh authoritarianism, kept Russian society un-der his thumb, and imposed a forced russianization on the country. Despitethat, “official” medical links between France and Russia kept flourishing.Thus, from 1896 to 1902, the Russian Archives for Pathology, Clinical Med-icine, and Bacteriology were published in Saint Petersburg in several lan-guages including French; France was instrumental in getting the TwelfthInternational Medical Congress held in Moscow in 1897; a Russian editionof the journal Paris Médical was published from 1910.

Though France had succeeded in imposing its superiority in scientific re-search on Russian savants, the medical field was still dominated by the Ger-mans. Very few French doctors settled in Russia; however, in 1903, DoctorMarcou, senior doctor at the French Hospital in Petrograd, was called to thebed of a young patient:

With rather startling frankness, she told me she was astonished to see a Frenchdoctor working in Russia. A dancer, a hairdresser, or a good cook, those were the

three trades exported to Russia and elsewhere (…) It was with these words, which were rather unflatteringfor my self-esteem, that my patient greeted me. (…) For them [the Russians], good medical care and doctorsexist only in Germany (…) The microscopes and all the laboratory paraphernalia impress them enormously.

It is true that medical works published in France were known to the Russians thanks only to German re-views, since French medical journals could not be found outside Saint Petersburg. Marcou deplored thelack of audacity of the French:

the German suppliers provide everything up front (medical material and books), and are happy to be paid later;whereas French suppliers demand down payment. (…) German interests are winning in all countries thanksto their admirable organization.10,11

Mechnikov, the most French of the Russian scientistsBorn in 1845 in Ivanoska, near Kharkov, the son of a policeman and a Jewish mother, Ilya Ilich Mechnikovstudied zoology in Saint Petersburg, then microbiology in Giessen, Göttingen, and Munich. As a resulthe had perfect mastery of the microscopic techniques at which the German bacteriologists excelled: cel-lular coloration, studies of artificial milieus, and optics. He had also carried out zoological experiments inNaples and Denmark. In 1882, fleeing the pogroms perpetrated by the police of Alexander III, Mechnikovand his family moved to Italy, France, and North Africa. In Messina, he discovered phagocytosis, the foun-dation of modern immunology.

One day when the whole family was at the circus, I was observing the life of mobile cells of a transparent starfishlarva when I was struck by a sudden thought. The idea came to me that similar cells could serve as a defensefor the organism against harmful intruders.

He then pierced the starfish larvae with rose thorns and observed cellular digestion. Transposing his find-ings to man, he realized that the phagocytosis served to combat infection. Mechnikov communicated theresults of his experiments to his former teachers at the German universities: the reception was lukewarmand even hostile.22,24,26 Later, when directing the Institute of Microbiology in Odessa, and again a victim toanti-Jewish persecution, Elie Mechnikov set off in 1887 on another voyage to Europe. His main stop wasParis where after a decisive meeting with Pasteur he planned to settle permanently. The two men had atleast two points in common: they both possessed an exceptional scientific intuition and both had sufferedfrom the hostile reactions of the medical profession. By nature austere and reserved, Pasteur—who knewthe work of Mechnikov on phagocytosis—was immediately won over by the strong personality of the Rus-sian scientist, whom he received at home with his wife Olga. Though it was not easy to make friends withPasteur, the two men esteemed each other very highly. Moreover, the French savant was not averse at re-ceiving an “enemy” of Robert Koch, his archrival on the bacteriological battlefield.22,23,25,26 In his newlyinaugurated institute, Pasteur proposed in 1888 that Mechnikov should direct the “morphological mi-crobial forms department” that occupied the whole of the 4th story. Louis Pasteur Vallery-Radot, Pasteur’sson-in-law, described the Russian scientist in action:



Cover of the Russian-language version of the monthly medical journal Paris-Médical, 1913, published in France and Russia.Paris-Médical, later merged with the Journal des Praticiens to becomethe Revue du Praticien. In the central box, the last line states that that “the entry of this journal into Russia is authorized by circular No. 235 of the Interior Ministry.” © Coll. Inter-Activités.



Between the two Great Wars, Doctor Serge Voronoff (1866-1951) hit the headlines. The expression going to see Voronoffmeant going to be rejuvenated or wanting to recover one’svirility.

Samuel Abrahamovitch (aka, Sergey, Serge) Voronoff wasborn into a rich Jewish family at Voronezh, some 600 milessouth of Moscow. Suspected of being a political agitator, theyoung Voronoff, who spoke excellent French, abandoned hisvillage in February 1885 to study medicine in Paris (he was nat-uralized French in 1895), with his brother George, who was todie at Auschwitz. He became assistant to the famous surgeonJules Péan and defended his medical thesis in 1893. After spend-ing seven years in Egypt, where he reorganized surgery, he em-barked in 1910 on a ship to New York. There he joined the fa-mous Rockefeller Institute where he made friends with theFrench surgeon Alexis Carrel, who taught him the techniqueof transplanting. On his return to France at the beginning ofthe Great War, Voronoff performed bone autografts on soldiersat the Russian Hospital that Nicholas II had put at France’sdisposal. To general skepticism, Voronoff succeeded in Novem-ber 1915 in grafting fetal membranes on badly burned soldiers.

Convinced that the role of the testicles was not confined toreproduction, but that they acted on skeletal, muscular, ner-vous, and psychological development as well, he started on a10-year course of experimentation on animals and, on Octo-ber 5, 1922, at the thirty-first Surgical Congress, Voronoff, pho-tos in hand, presented his surgical technique for “rejuvenatingpatients.” His “anthropoid-anthropic grafting technique” con-sisted in transplanting the testicle of a chimpanzee into the

“subject to be rejuvenated.” After administering a local anes-thetic (Novocain), Voronoff cut the chimpanzees testicle intosix parts, which remained attached to the spermatic cord. Eachof the 6 grafts was then inserted into the patient’s testicle. Thepatient remained recumbent for several days, then two or threemonths later the alleged miracle occurred. According to Voro-noff, glandular transplants would allow the production of sex-

ual hormones for an extended period of time, as opposed toopotherapy, which required repeated injections with unconvinc-ing results. The first (official) transplant took place on June 12,1920, to be followed by upwards of 50 operations, carried outat private clinics in Auteuil, Neuilly, and Paris. Louis Dartigues,President of the Paris Surgeons, and an admirer of Voronoff,reported in June 1924:

The renewal of vitality is marked by the reawakening of intelligence,a more vivid imagination, a sharper memory, an increased speedof action, and a feeling of euphoria.

By 1925, the “revitalizing grafts” were already a great success.Politicians, intellectuals, industrialists, scientists, doctors, andartists flocked to Voronoff to get themselves “rejuvenated.” Thedemand for chimpanzees to satisfy the laboratory of Experi-mental Surgery at the Collège de France—directed by Voro-noff—soon exceeded supply. Mr Carde, governor of French WestAfrica, was obliged to regulate the exportation of chimpanzeesin order to curb poaching. Voronoff was already planning thecreation of a farm in the south of France for the breeding ofchimpanzees, which he built in Menton.

In 1926, Voronoff was decorated with the Légion d’honneur(Legion of Honor). By the early 30s, more than 500 men hadbeen operated on in France, and thousands of others through-out the world. Despite this success, the proliferation of emula-tors abroad and the numerous journals praising the methodin France finally began to worry the medical community. Se-rious reservations were voiced concerning the scientific basis ofthe procedure, whose claims of success were based only on thepresentation of photographs taken before and after.

Turning his attention to women, Voronoff implanted mon-key ovaries to women. Standing on increasingly shaky ethicalground, he also transplanted a woman’s ovary in Nora, a femalemonkey, which he then proceded to inseminate with humansperm (his own?)—fortunately to no avail. The use of surgeryfor rejuvenation gradually went out of fashion, but Serge Voro-noff pursued his studies on the grafting of endocrine tissues.In 1928, he wanted to graft the kidney of a decapitated prison-er on a young girl suffering from renal failure due to tubercu-losis, but the state prosecutor did not allow it.27

SERGE VORONOFF: CRAZY SCIENTIST OR PRECURSOR OF GENIUS?

Monkey business? Inspite of the apparent incongruity, Voronoffcarried out what in effectwas the first xenograft.He made important con-tributions to such currenthot topics as gerontologyand the biology of aging,endocrinology, hormonereplacement therapy, and organ transplants.Learned articles on thisfascinating pioneer arebeing published to thisday. Engraving from Le Petit Journal in October 1922.

Voronoff’s “split n’splice” technique

of grafting monkeytesticle slices tohuman testicles

drew both interestfrom his peers, andridicule—as here in

a satirical medicaljournal called

Chanteclair dated1910 (No. 59), butit also made inter-national headlines.

Time magazinedevoted two arti-

cles to the “famedgland-grafter”

in 1923 andagain in 1926.

with his imagination working overtime, living, like Doctor Faust, in a laboratory swamped with books, notes,and drawings, in the middle of which guinea pigs and rabbits scamper around, while in the aquariums axolotlsdream of their tropical seas, and in a nearby research room giant crocodiles languish.

Charles Nicolle, Nobel prize in medicine (1928) for his work on the transmission of typhus, rubbed shoul-ders with the Russian scientist and noted: “I cannot say whether he was a poet or a scientist, since his ideaswere so extravagant.” The Belgian doctor Jules Bordet, Nobel Prize in 1919 for his discovery of humoralimmunity, also worked in Mechnikov’s laboratory.23,24,26

With great ease, Mechnikov switched from zoology to human pathology, and dubbed himself “the zo-ologist who got lost in medicine.” Returning to his studies on phagocytosis, he applied his theories on cel-lular immunity to the pathogenesis of cholera, leprosy, typhus, anthrax, tuberculosis, and syphilis.

As early as 1889, Mechnikov’s theory of cellular immunity wasaccepted by the Pasteur Institute, which made it its “official doc-trine” that a system of phagocytes kept permanent watch to pre-vent infection. Mechnikov distinguished “microphages” (white cor-puscles) and “macrophages” (cells located in certain organs). Theresults of his studies were published in two landmark works in thehistory of immunology: Lessons on the Comparative Physiology ofInflammation (1892) and Immunity in Infectious Diseases (1901).

In 1904, he became assistant director of the Pasteur Institute, incharge of scientific studies. In 1908, he shared the Nobel Prize inmedicine, for works on immunization, with the German biologistPaul Ehrlich who pioneered humoral immunity.24-26 Mechnikov en-couraged several of his Odessa students to join him, among themWaldemar Khavkine, a young zoologist (and active opponent of theczarist regime) who was given the post of Institute librarian. He

worked evenings in the laboratory of his mentor on vibrions, and in 1892 developed the first vaccine againstcholera. Just like Pasteur, Mechnikov had a paternalistic approach to his students.

In 1917, despite financial difficulties at the Institute due to the war, most of the Russian students re-mained in Paris and pursued the immunological work of their mentor. These included Alexandre Besredka,who became Mechnikov’s successor at the Institute, as well as Nicolas Gamaleia, Serge Metalnikov, andSerge Winogradsky.23-26

The strong links between scientists based in Russia and the Pasteurians was reflected in the large num-ber of articles published in Russia supporting the work of Pasteur and his students, and, more anecdotal-ly, in the spate of Russian towns that boasted a Pasteur street. A highly symbolic testimony to the strongmedical ties between Russia and France was, so to speak, carved in stone in the heavens, when the RussianAcademy of Science gave Pasteur’s name to site N 393 of their Cartographic Atlas of the Moon. ❒



REFERENCES1. Gantt HW. Russian Medicine. New York, NY: Paul B. Hoeber;1935.2. Debono L. La Médecine en Russie de 1801 à 1917. Medicalthesis. Besançon, France. 1997.3. Huard P, Wong M. Les Activités Médicales en Russie au XVIIIe

Siècle. Concours Med. 1967;89:9033-9038.4. Efremenko A. Histoire de la collaboration scientifique franco-russe. In: Histoire des Sciences Médicales.1972;6(chap 3):173-186.5. Efremenko A. Relations médicales franco-russes à l’universitéde Strasbourg. In: Comptes Rendus du 92e Congrès National desSociétés Savantes à Strasbourg et Colmar en 1967. Paris, France:Bibliothèque Nationale; 1969 ;1.6. Garrison FH. Russian medicine under the old regime. BullN Y Acad Med. 1931;7,9:693-734.7. Grmek MD. Les bases historiques de l'enseignement médicalen Russie. Episteme.1970;4:131-145; 334-356.8. Goldwin RM. Peter the Great and Russian medicine. Surg Gy-necol Obstet.1960;3:523-525.9. Dujardin-Beaumetz G. De l'enseignement médical et de la pra-tique médicale en Russie. Gazette Hebdomadaire Med Chir.1888;51:809-811 ; 52:821-623.10. Marcou. L’Allemagne médicale en Russie. Arch Gen Med.1903;80:1825-1828.11. Fuster. Organisation des études médicales en Russie. Mont-pellier Med.1904;19:455-463.12. Gogol N. Les Âmes Mortes [Dead Souls] Paris, France: Galli-mard; 1996 (1st ed 1842)13. Herzen A. À Qui la Faute ? Moscow, Russia: Progress Eds,1970 (première édition 1848).

14. Tolstoy L. Guerre et Paix [War and Peace]. Paris, France:Gallimard; 1993 (1st ed 1869).15. Régnier C. La médecine russe au XVIIIe siècle. PanoramaMed.1986;2375:41.16. Huard P, Wong M. Médecins étrangers et médecine russe auXVIIIe siècle. Ouest Med.1964;17:705-711.17. Féron B. La Galerie des Tsars: Dictionnaire des Chefs Su-prêmes de la Russie. Paris, France: Les Éditions Noir sur Blanc;2004.18. Taton R. Sur l’histoire des relations scientifiques franco-russes. Rev Hist Sci.1970;23:257-264.19. Fumaroli M. Quand L’Europe Parlait Français. Paris, France:Éditions de Fallois; 2001.20. Bernard C. Lettres à Madame R. Saint Julien-en-Beaujolais,France: Fondation Mérieux et Jacqueline Sonolet; 1974.21. Thuillier J. Monsieur Charcot de la Salpêtrère. Paris, France:Robert Laffont; 1993.22. Hutchinson JF. Tsarist Russia and the bacteriological revolu-tion. J Hist Med Allied Sci.1928;21:1406-1408. 23. Moulin AM. L’Aventure de la Vaccination. Paris, France:Fayard; 2003.24. Dubos R. La Leçon de Pasteur. Paris, France: Albin Michel;1987.25. Debré P. Louis Pasteur. Paris, France: Flammarion; 1994.26. Moulin AM. Le Dernier Langage de la Médecine. Histoire del’Immunologie de Pasteur au Sida. Paris, France: PUF; 1991.27. Real J. Voronoff. Paris, France: Stock; 2001.28. Amalric P. The Galezowski tradition in Paris. DocumentaOphtalmologica. 1999;98: 105-113.

Ilya Ilich Mechnikov(1845-1916), in

his laboratory inParis. © Musée del’Institut Pasteur.



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ongtemps la médecine fut exercée en Russie par des médecins européens. Au début du XVIIIe

siècle, des écoles de médecine furent fondées à Moscou et à Saint-Pétersbourg; les premiers mé-decins russes purent alors exercer leur art chez eux mais ils devaient encore soutenir leur docto-

rat à l’étranger. Ouverts aux échanges avec l’étranger, souhaitant moderniser la Russie, les tsa-rines et les tsars du siècle des Lumières s’assurèrent du concours de professeurs de médecine

allemands et français pour enseigner dans ces écoles nouvellement créées. Ce furent les aléas del’histoire, le jeu des alliances, les affinités personnelles ou les origines familiales des souverains russes quidéterminèrent souvent ces choix germanophiles ou francophiles. Intenses au siècle des Lumières, distantssous Napoléon Ier, les échanges médico-scientifiques entre la France et la Russie se développèrent aumilieu du XIXe siècle sous l’impulsion de grands savants français comme Claude Bernard, Jean-MartinCharcot ou Louis Pasteur animés de puissants sentiments russophiles. Les relations franco-russes – y com-pris dans le domaine médical – semblent avoir toujours été soumises à des aléas passionnels ; à l’excep-tion de l’éphémère traité d’alliance franco-russe de 1891, rien ne fut vraiment organisé ni programmé.Tout ne fut qu’intuitions, exaltations, déceptions et coups de cœur…

LLA MÉDECINE FRANÇAISE ET LA RUSSIE

UNE HISTOIRE PASSIONNELLE

uring a party on the banks of the Neva, the poet Pushkin was asked whether the woman he hadbeen talking to for some time was intelligent. “I’ve no idea,” replied the poet, “we were talkingFrench.” This was in no way intended to be ironic, nor to express scorn. But is due to the factthat at the beginning of the 19th century French served as a special language. At that period it

was used for conversation, but not to express one’s feelings. In Saint Petersburg in 1807, Czar Alexander I concluded a treaty with Napoleon I in which they

agreed to split Europe between them, while ignoring England entirely. The two powers signed the Treatyof Tilsit, with France taking the West and Russia the East. The treaty lasted for only a short period sinceNapoleon, blinded by his lust for conquest, set out a few years later on his ill-fated march to Moscow. How-

ever, at the time, France, its fashions, its art, and itslanguage carried away the hearts in the Russian cap-ital. The aristocracy ate, drank, dressed, flirted, andcultivated themselves in French, while the Russianlanguage was reserved for ordinary people and per-sonal matters. Though official correspondence and

88 When Russia spoke French – Spaak MEDICOGRAPHIA, VOL 28, No. 1, 2006


aint Petersburg was founded in 1703 by Czar Peter I who wanted to open up Russia to Westernprogress. By battling the Swedes and winning the swampy territory at the mouth of the Neva to

build a port that would bear his name, Peter the Great opened up a trade route to the Baltic thatgave him access to Europe and France. The French architect Jean-Baptiste Alexandre Leblond wasentrusted with the task of designing the city along the lines of Versailles, and it is to him that we

owe the lakeside scenery and the numerous canals. Peter’s daughter, Elizabeth, crowned empress in1741, was like her father, an unconditional admirer of France and its arts. Architects, philosophers, ac-tors, and musicians were invited to the burgeoning port or were consulted. The French Theater becamethe favorite rendezvous of the Petersburg aristocrats by the middle of the 18th century, and speakingFrench became a must for the nobility. From the beginning of her reign in 1762, Catherine II confirmedthis predilection for European ways and particularly for the philosophy of the Enlightenment. Voltaire,Diderot, and Montesquieu were reference personalities for this enlightened but ironhanded czarina. Hence-forth, in Saint Petersburg one spoke, thought, and amused oneself in French. This custom was continuedunder the reign of Alexander I (1801-1825) who, despite being a relentless opponent of Napoleon on thebattlefield, kept up a mutually admiring relationship with his rival that was based on the French way oflife. The vast majority of the aristocracy of the Russian capital chose to be Francophile long after the reignof Nicholas I who became emperor in 1825.Medicographia. 2004;26:88-94. (see French abstract on page 94)

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S

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Isabelle SPAAK, journalist37 rue des Plantes, 75014 Paris, FRANCE(e-mail: [email protected])

The fame of the new city on the edge of the Baltic spreadsin all directions, to Europe and Asia. View of St Petersburg:Japanese lacquered plaque copied from a painting by Mihail Ivanovich Mahaev (1717-1770). Chido museum.Courtesy of the National Museum of Japanese History(http://rekihaku.ac.jp). All rights reserved.

When Russia spoke French

b y I . S p a a k , F r a n c e

social conversations were carried out in the language of Voltaire and Diderot, so close to the heart ofCatherine II, a fervent believer in the philosophy of the Enlightenment, billets-doux and family letterswere written in Russian. This complicated duality was mocked irreverently by Astolphe de Custine in histravel-journal cum scathing attack on Russia. Without any regard for Czar Nicholas I whose hospitalityhe had enjoyed from May to September 1839, and egged on by Balzac and the perfidious Talleyrand, theeccentric marquis penned “Russia in 1839.” The book mocked the “Tatars” who used two languages, butneither of them perfectly: one for social relations, the other for informal situations. Ironically, the first edi-tion in 1843 was an immediate success in Russia as well as in France. In fact, this linguistic duality was

used as a façade that enabled the nobility to masktheir true feelings, which suited the Russian men-tality perfectly.

However, unaware of the future criticisms of thecaustic Custine, Pushkin and his friends indulgedthemselves with Bordeaux wines and Veuve Clic-quot champagne when they dined “chez Dumé,”a famous restaurant that had succeeded in subtlymarrying Russian and French dishes. In fact, thoughthe nobility swore only by Paris, it was also in orderto adapt the style to the Russian way of life. Theycopied and borrowed while at the same time in-sisting on the specificity of their own language. In-deed, there was no question of slavishly copyingFrench fashions. On the contrary. Those who didnot know how to strike the happy medium weremercilessly mocked and dubbed copycats.

Peter the Great’s flowery FrenchThough in the time of Catherine II the nobility hadbegun to take an interest in French ideas and art,it was nevertheless much earlier that Saint Peters-burg had begun to gaze in the direction of France.Created by Peter the Great, the imperial city openedup the Baltic and gave Russia access to Europe. Thecity was officially born on May 16, 1703 when thetwo fortresses, Peter and Paul, were founded. Butthe vast building site was surrounded by swamps,at the center of which Peter the Great establishedhis headquarters in a modest wooden house whilethe Peterhof Palace was being built. The czar hadgreat ambitions for his city and planned to model iton the great Western cities and make Saint Peters-burg a model of harmony. An enthusiastic traveler

interested in marine matters and the art of war, he had visited naval shipyards in Holland and at Deptfordin England (where he even did a stint, incognito, as a shipwright) and studied navigation in the KremlinNaval Museum. Meanwhile, under appalling conditions, Russian peasants, and Finnish, Estonian, andSwedish prisoners toiled to create Peter’s dream port. The czar enjoyed wandering in the streets talkingto strangers, whether noblemen or valets, and in this manner picked up some knowledge of various lan-guages including French. Up to a point. Dubois, the minister of foreign affairs under Philip of Orleans,who met the emperor when he came to Paris in 1717, noted: “When I speak to the emperor in French,I have to ask myself who on earth could have taught him our language. He does not know a single every-day word, but he uses expressions that would make a guardsman flinch. In Versailles, he swore so profuse-ly, with such profanities, that even the grooms gaped.”

During a disastrous famine that raged in Russia, Peter I did not hesitate to abandon his fellow country-men for the delights of Paris. And he enjoyed himself accosting strangers, investigating boutique back-rooms, visiting museums, and inspecting the Louvre’s marble stores and the Gobelins tapestry workshops.He also enjoyed immersing himself in classical architecture, as well as chasing the pretty ladies in the al-leys of the Versailles park. From Marly-le-Roi to the Invalides via Saint-Cyr, he visited all the centers ofculture and the art of living. He also tried without success to marry off his daughter, Elizabeth, to the


89When Russia spoke French – Spaak MEDICOGRAPHIA, VOL 28, No. 1, 2006

Gold snuff box with miniature portrait of Peter the Great (1727).Kremlin Museums, Moscow. © The Brigdeman Art Library.

Map of St Petersburg, 1738. © Rue des Archives/The Granger Coll.

young Louis XV. To sum up, Peter I wanted France bothfor its cultural distinction and as a political ally. On hisreturn to Saint Petersburg, he obliged men and wom-en of social standing to club together as in Paris andorganize pageants like those he had seen in Versailles.

A French architect for Saint PetersburgDespite the fact that Italian, German, and Dutch ar-chitects had been requested to draw up plans for con-struction, the czar decided in 1716 to entrust the plan-ning of his dream city to the Frenchman Jean-BaptisteAlexandre Leblond. The architect got to work imme-diately, set up workshops to provide planks, carvedstones, metal castings, and locks. Above all he designedan aquatic labyrinth in the muddy earth snatchedfrom the marshes over which blew a wind that nothingcould stop. It is freezing cold in this lakeside city onthe edge of the Baltic. Slowly the face of Saint Peters-burg emerged. It was on the scale of the absolute pow-er wielded by the sovereign who demanded pure lines,totally visible buildings, and rigorously majestic align-ments to contrast with the medieval chaos of Moscow.He wanted to attract as much scientific, artistic, andintellectual knowledge as possible into his city destinedfor a glittering future.

But much work remained to be done to establish thisorder, this vision of a perfect world that was being cre-ated ex nihilo. In winter the fog penetrated everywhere.

In 1725, the year Peter the Great died, one hundred and fifty thousand men were sacrificed in the con-struction of four neighborhoods that were won from the forests, fields, and swamps. The apotheosis ofSaint Petersburg and the peak of its diplomatic relations with France still lay in the future. After a suc-cession of four sovereigns who reigned briefly, in 1741, Elizabeth Petrovna followed in the footsteps of herfather and mounted the throne, thanks, it is said, to the French ambassador, who was not averse to sup-plement his diplomatic counseling with a little bit of courting of the future empress on the side.

Czarina Elizabeth imposes French on the Russian nobilityElizabeth undertook vast works in the insalubrious citythat had been the dream of her father. Its once sump-tuous facades were already nearly in ruins and seem tohave been built hastily simply to satisfy the insatiableappetite of a megalomaniac emperor. Elizabeth busiedherself perfecting the image of the imperial city, givingpriority to the construction of magnificent palaces—among them the Winter Palace—and several church-es, witnesses to her religious faith. Greatly influencedby French culture she built the French Theater and in-vited stars of the Comédie Française to perform. Eliz-abeth succeeded in imposing the language of Voltaireon Russian society, and even had Voltaire elected tothe Saint Petersburg Academy of Science—after hehad publicly expressed his admiration for her:

I have praised Elizabeth of England, but what can I sayof the empress who exceeds the queen in magnificenceand equals her in virtue?



Layout of the gardens and waterworks of the PeterhofPalace, by Jean-Baptiste Leblond. The center of the foun-tain features a “water pyramid.” Colored engraving by P. A.de St-Hilaire, 1774. © AKG-images.

The Hermitage Theater, as seen from the Vassily Island, 1822. Color litho-graph. Anonymous. Pushkin Museum, Moscow. © The Bridgeman Art Library.

View of the south façade of the Winter Palace, fromPalace Square, by Bartolomeo Francesco Rastrelli(1700-1771). St Petersburg. © The Bridgeman Art Library.

In his acception speech on the occasion of his entry into an-other academy, this time on home turf, the French Academy,and after having expressed his affection for the city of Peterthe Great, Voltaire praised in more than laudatory terms theinfluence of his fellow academicians on the court of Elizabeth.

Your writings, Gentlemen, have penetrated to the capital of themost remote empire in Europe and the largest in the world.In this city, that forty years ago was nothing but a wildernessinhabited by savage beasts, your dramas are now presented,and the same natural good taste that enables Italian musicto be enjoyed in the city of Peter the Great and his worthydaughter, also enables your eloquence to be appreciated.

The reign of Elizabeth and her love of France has given riseto a dubious story of purported romance between Elizabethand a mysterious emissary sent by Louis XV. It is said that theyoung and handsome knight succeeded in introducing him-self into the czarina’s court disguised as a woman and won herfavors. The anecdote was recounted by the knight himself inhis memoirs. Without any delicacy he elaborated on a wealthof details concerning the physical aging of a woman in searchof young flesh.

The czarina, he wrote, had turgid bluish lips, shiny cheekbones, swollen eyelids, and watery eyes… Her skin wassweaty and discharged wantonness from all its pores… I said to myself that this woman in front of me hadtaken into her arms innumerable men, picked up by chance in the streets, and that her mouth, her neck, andher breasts had been stained and withered by the kisses of soldiers…

Catherine II and the French EnlightenmentWhether or not the story is true, the fact remains that the secret agent contributed to the Franco-Russianreconciliation and that he returned to Versailles in 1755, bearing a letter from Elizabeth to “My brotherLouis XV,” to whom her father had dreamed of marrying her twenty-five years before.

In fact, the czarina who did the most for Franco-Russian relations was Catherine II. Married very youngto Peter III, the adopted son of Elizabeth, she came from the minor German aristocracy, had spoken Frenchsince her childhood, and was an adept of the philosophy of the Enlightenment. Armed with this knowl-edge she settled down rapidly. Her reign (1762-1796) was one long sequence of correspondence and ofquest for knowledge. Her mentor was Voltaire, biographer of Peter the Great, and she cherished a bust of

Rousseau in her apartments. She invited Diderot tospend several months in Saint Petersburg, and thephilosopher, alarmed by her firm-handed rulingand her political absolutism on the lines of Peter I,dubbed her the “Semiramis of the North” (a semi-legendry Assyrian Queen who convinced Ninus tomake her “Regent” for the day, and then promptlyhad him executed).

Nevertheless, he presented her with a bookcase,and on his return to Paris helped her put togethera collection of paintings by Watteau, Le Lorrain,and Poussin that formed the nucleus of the Her-mitage Museum inaugurated in 1764. To justify heracts, she explained to the author of The Nun: “YouMr Diderot, work on paper. But I work on the skinof man.” A lucid reflection that says much on thelack of liberty and the suffering of her people. Yet,Catherine II was considered a civilized sovereign inthe eyes of the European elite, and was largely in-spired by Montesquieu when drawing up her firstlegislative treatise. His comparative study of legaland political issues, De l’Esprit des Lois [The Spiritof Laws], made her dream of reforming Russia in-



Catherine II the Greatin full imperial regalia.

Oil on canvas, by StefanoTorrelli, towards 1780.

St Petersburg.© Rue des Archives/

The Granger Coll.

Voltaire (1694-1778), admirer of czarinaElizabeth Petrovna, the younger daughter ofPeter the Great. Pastel by Maurice Quentinde la Tour, 1736, Château de Ferney, Ferney-Voltaire. © Rue des Archives.

spired by the philosophy of the Enlightenment. Yet, notwithstanding such generous principles, she pub-lished in 1785 a Charter of Nobility, which codified even further the social differences and enclosed thearistocracy in a hermetic bubble with codes of value and an attachment to the French language that com-pletely isolated them from the rest of Russia. An error the empress would become aware of a few monthsbefore her death. Nevertheless, it is thanks to her that Russia was finally saved from obscurantism and be-came impregnated with Western practices that would eventually bring order and a better future.

A French statue “for Peter the First from Catherine the Second”Peter I had already sought to domesticate society symbolically by converting the swamps into well-orderedcanals that in 1774 occupied a fifth of the urban space, according to Leblond’s plans. Under Catherine II,the city was smartened up and the czarina marked her admiration for the founder of the city by commis-sioning a French sculptor, Etienne Falconnet, to create a statue of Peter the Great and gave it a rather re-vealing inscription: “To Peter the First, from Catherine the Second.”

Thanks to her, the nobility acquired an independent spirit and a taste for education based on the “Frenchmethod,” which was taught in a few expensive private institutes and by tutors who were more or less com-petent. Described by Diderot as riffraff, they were often jailbirds or charlatans come to try their luck in thecountries of the North. It was not until the end of the 18th century that genuine tutors began to arrivein the Russian capital. One of them, Boudry, the brother of Marat (French politician stabbed to death inhis bath by Charlotte Corday during the Revolution), became a friend of Pushkin who had been broughtup on French culture. Boudry was appointed Professor of French at Tsarskoe Selo (the sprawling archi-tectural ensemble that was the beloved summer residence of the Russian czars and an inspiration to manycelebrated Russian poets, painters, and musicians), and requested Catherine II to change his name by pre-fixing it with the aristocratic “de”—thus improving his social status. The nobility became an educatedminority who enjoyed all the privileges and it became more natural for them to express themselves in

French rather than in their mother tongue, evenif Paul I, who succeeded his mother Catherine II,rebelled against the pervading Francophilia andordered the collars of tail coats to be cut off becausehe thought they were “the uniform of the FrenchJacobins.” Nonetheless, Paul spoke perfect Frenchand recited verses of Racine. His reign was short(1796-1801), but he had time to conclude a treatywith Napoleon against all advice that led to the warwith England, a long-standing commercial partnerof Russia. This led to discontent, and hearsay hasit that when conspirators entered his bedroom tostrangle him, he harangued them unsuccessfullyin French.



Treaty of Tilsit (1807): Czar Alexander I and Emperor Napoleon I. © Rue des Archives.

The poet AlexanderSergevich Pushkin

(1799-1837), theRussian Shakespeare.© Rue des Archives.

Bronze equestrianstatue of Peter theGreat, by ÉtienneFalconet, offered byCatherine: “PetroPrimo, Catharina Secunda” “To Peterthe First, fromCatherine the Sec-ond” (dated 1782).© AKG-images.

Alexander I: staunch francophile despite the war with NapoleonPaul I’s son, Alexander I, his successor and probable murderer, continued to support the influence ofFrance. Even fashion was modeled on the latest Parisian creations, and elegant Russian ladies wore thesame simple and diaphanous dresses inspired by Greece that were “reborn on the Seine and copied on theNeva.” After having been officially forgotten under Paul I, French art was revived as a source of inspira-tion under Alexander I. From 1805 to 1807, the czar joined a coalition against France at the side of Austria,England, and Prussia. However, the victories of Napoleon at Austerlitz, Jena, Eylau, and Friedland soonencouraged him to seek a separate peace. The two men met at Tilsit to sign the treaty. It was the start ofthe “French Follies” that invaded the court, the streets, the interior of palaces, and architecture. Carryingmimicry to the ridiculous, Alexander I courted Mlle George, a buxom actress whom Napoleon had prob-ably seduced before him, and let slip: “I wanted to taste the water at the same well at which my rival hadsatisfied his thirst.” He ordered the French architects Percier and Fontaine to provide him with a sum-mary of all the works of art with which the French Emperor had embellished the capital of his empire.The French colony at the beginning of the 19th century numbered more than four thousand persons, andthe boutiques were named “Madame Louise,” “Fleur de Nice,” “Vrai savon de Marseille,” etcetera. In short,Francophilia was top of the pops up until Napoleon’s troops entered Moscow on September 14, 1812, thussounding the knell of this excessive infatuation. For the first time in their life, numerous women donnedtraditional dress and spurned the French language. But this rejection was only temporary. The victory ofRussia over the Napoleonic armies made Empire style fashionable again. On the orders of Alexander I,

who wanted the capital of his empirethat had defeated Napoleon to have animperial dimension, work started upagain. Just as if nothing had happened,French engineers (Bétancourt and Ba-sin), decorators, architects (AugusteRicard de Montferrand), and financiersonce again contributed to the bloom-ing of Saint Petersburg, symbol of a Eu-rope that refused to be subdued. ❒



1682 Ten-year-old Peter I is proclaimed czar 1703 Foundation of Saint Petersburg1712 Saint Petersburg becomes the capital

of Russia1717 Peter I travels to Paris1725 Death of Peter I1725-1727 Reign of Catherine I1727-1730 Reign of Peter II1730-1740 Reign of Anna Ivanovna1741-1761 Reign of Elizabeth Petrovna1747-1762 Russia participates in the Seven

Years’ War

1761-1762 Reign of Peter III1762-1796 Reign of Catherine II1796-1801 Reign of Paul I1801-1825 Reign of Alexander I1805 Victory of Napoleon I over the Austro-

Russian coalition at Austerlitz1807 Treaty of Tilsit between Napoleon and

Alexander I1812 Napoleon enters Moscow1814 Allied troops enter Paris1815 Waterloo1825-1855 Reign of Nicholas I 1837 Death of Pushkin

MILESTONES

Kazan Cathedral, St Petersburg. Color lithograph printed by Lemercier (1840s), Paris,after a painting by Louis Jules Arnout. Pushkin Museum, Moscow. © The BridgemanArt Library.

FURTHER READING– Vladimir Fédorovski: Le Roman de Saint-Pétersbourg. Paris, France: Editions du Rocher.– Catalog of the exhibition at the Musée del’Armée on May 21 to August 31, 2003: ParisSaint-Pétersbourg 1800-1830: Quand la RussieParlait Français. Paris, France: Editions RMN;2003.



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ondée en 1703 par Pierre 1er, Saint-Pétersbourg est née de la volonté du tsar d’inscrire la Rus-sie dans le progrès occidental. En arrachant de haute lutte aux Suédois ce morceau de terre

marécageux à l’embouchure de la Neva pour y installer un port baptisé en son honneur, Pierrele Grand s’offrait un balcon sur la Baltique et une fenêtre sur l’Europe, donc sur la France. C’est

à un architecte français, Jean-Baptiste Alexandre Leblond, que Pierre confia le soin de dessiner lesjardins de la ville à l’image de ceux de Versailles et c’est à lui que l’on doit le paysage lacustre façonné

par d’innombrables canaux. À son tour, sa fille Elisabeth, sacrée impératrice en 1741, fut une admira-trice inconditionnelle de la France et de ses arts. Architectes, philosophes, acteurs et musiciens sont in-vités ou consultés. Le théâtre français devient l’endroit le plus prisé des aristocrates pétersbourgeois aumilieu du XVIIIe siècle et la langue française s’impose dans la noblesse. Dès le début de son règne en 1762,Catherine II confirme cette disposition envers l’Europe et particulièrement la philosophie des Lumières.Voltaire, Diderot, Montesquieu font partie des personnalités de référence de cette souveraine à la poignede fer mais aux idées éclairées. A Saint-Pétersbourg on parle, on pense et on s’amuse dorénavant en fran-çais. Une habitude poursuivie sous le règne d’Alexandre 1er (1801-1825), qui malgré les combats achar-nés qui l’opposaient à Napoléon sur les champs de bataille, entretenait avec son rival des relations d’ad-miration réciproque inscrites dans un style de vie « à la française » revendiqué par la plus grande partiede l’aristocratie de la capitale russe bien au-delà du règne de Nicolas 1er sacré empereur en 1825.

QUAND LA RUSSIE PARLAIT FRANÇAIS

F

Named after a political organization and not in honor of a crowned head, Empire style appearedin France at the time of the 1789 revolution and ended with the fall of Napoleon. Arriving at the sametime in Russia, “Alexander” style survived until 1825. Though the two monarchs fought each othermercilessly on the battlefield, they nonetheless maintained close relations in time of peace, andRussia enthusiastically adopted the Parisian way of life, the city at that time being the capital of theworld. Whereas classicism embodied simplicity, soft colors, and pure lines, Empire style expressed thecool and virile, drawing from ancient Greece and Egypt to suggest power and force.

Silhouettes of Egyptians carrying vessels, sphinxes, crowned maidens bearing lyres, warriors, eagles,and griffins, the source of inspiration was the same in France and Russia. But it was the painter David,the architects Percier and Fontaine, and the cabinetmakers François-Honoré-Georges and Jacob-Desmelter who set the tone for this way of life that exalted victory and honor. Vases, plates, table set-tings, silverware, furniture, and ladies’ and men’s wear, everything was a pretext for Russians andFrench to correspond and discuss the tastes and styles decreed by the Empress Josephine with whomAlexander I had an excellent relationship and often visited in her Malmaison residence. The symbolicfigures that can be seen on the everyday objects of that time—cups, plates, cameos—illustrate theextent to which the language had imitated this unity of cultures.

“EMPIRE” STYLE

Symbol of Empire style:the Austerlitz Table, inlaidwith Sevres plaques, com-memorating Napoleon’svictory at Austerlitz(1808-1810). FrenchSchool. Musée Nationaldu Château de Malmaison,Rueil-Malmaison. © TheBridgeman Art Library.

Empire stylefurniture at the

Château deFontainebleau:

in the fore-front, NapoleonI’s desk. © Rue

des Archives/Talliandier.

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