5 Osteoporosis Prevention and Management

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OsteoporosisPrevention andManagementAn Evidence-based

ReviewMICHAEL KLEEREKOPER, MD, MACE,*and DEBORAH T. GOLD, PhDw

*Department of Internal Medicine, St. Joseph Mercy Hospital,Ann Arbor, and Department of Obstetrics and Gynecology,Wayne State University School of Medicine, Detroit, Michigan;wDepartments of Psychiatry & Behavioral Sciences, Sociology, andPsychology & Neuroscience, Duke University Medical Center,Durham, North Carolina

Abstract: Evidence-based guidelines that have been

prepared by many professional organizations aimed at

assisting the clinician in the initial evaluation of post-

menopausal women who should be considered for

bone mineral density evaluation by dual-energy

x-ray absorptiometry; history, physical examination,

and laboratory testing in those women being consid-ered for pharmacologic intervention; and monitoring

and management of women for whom therapy is

prescribed are discussed.

Key words: osteoporosis, peak adult bone mass,

menopause

Osteoporosis is defined as a systemic ske-letal disorder characterized by compro-mised bone strength predisposing to an

increased risk of fracture.1 Before frac-ture, osteoporosis can only be diagnosedon the basis of a bone mineral density(BMD) t score


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been approved for the prevention of os-teoporosis. The evidence supporting drugtherapy for the prevention and treatment

of postmenopausal osteoporosis (PMOP)is uniformly level 1.

Teriparatide (recombinant human para-thyroid hormone 1 to 34) is prescribed as aself-injected daily subcutaneous injection;calcitonin is administered as a daily nasalspray. Ibandronate can be administeredas an intravenous injection once every 3months and zoledronic acid is adminis-tered as an annual intravenous infusion.

All other therapies are available as oralpreparations that can be taken daily,weekly, 2 days a month, or monthly, 1tablet per dose. Side effects are few, andthere is little need to monitor for silentbiochemical abnormalities. Despite theoverwhelming evidence of safety, efficacy,and ease of use of osteoporosis therapies,compliance and persistence with therapyis suboptimal.25 Additionally many

perhaps mostpatients who have sus-tained an osteoporosis-related fractureor are at increased risk of sustaining sucha fracture have not been diagnosed withosteoporosis and are not prescribed ther-apy.

This article will focus on the evidence-based guidelines that have been preparedby many professional organizationsaimed at assisting the clinician in the:

Initial evaluation of postmenopausal wo-men who should be considered for BMDevaluation by DXA

History, physical examination, and labora-tory testing in those women being consid-ered for pharmacologic intervention

Monitoring and management of women forwhom therapy is prescribed.

The most up-to-date guidelines were

released by the National OsteoporosisFoundation in the United States in Feb-ruary 2008 (www.nof.org/professionals/Clinicians_Guide.htm). These guidelinesfollowed quickly on the heels of the an-nouncement by the World Health Orga-

nization of a new paradigmFRAXforestimating the 10-year fracture riskof an individual patient based on history,

anthropometry, and BMD. Direct accessto the FRAX program by healthcare pro-fessional is available at www.shef.ac.uk/FRAX, and full details of this paradigmand the implications for future osteoporo-sis care have been published.611

Bone mass, BMD, and bone strengthall reach their maximum during the thirddecade of life and, in health, remain stableuntil the sixth decade at which time

the universal phenomenon of age-relatedbone loss begins and continues at a slowrate for the remainder of life. In women,bone loss accelerates at menopause withthis accelerated rate lasting 5 to 7 years.Not surprisingly, PMOP is the most com-mon form of the disease. In this review,several options for the prevention andmanagement of osteoporosis, both beforeand after fracture, will be presented. At the

outset it must be emphasized that the onlyway to determine whether osteoporosisis present before fracture is by DXA mea-sured at the abovementioned skeletal sites.It must also be emphasized that many,perhaps most, PMOP-related fractures oc-cur in women in whom the t score is not yet 2.5 or lower and that BMD-independentrisk factors for fracture are a crucial part ofthe clinical evaluation for every postmeno-

pausal woman.

Universal PreventionStrategiesDuring infancy, childhood, and adoles-cence, every effort should be made tooptimize peak adult bone mass (PABM),recognizing that as much as 75% of

PABM is genetically determined.12,13Nongenetic factors that could haveadverse effects on PABM that must beconsidered include nutrition, exercise, dis-ease, and medication. Pregnancy and lac-tation place an added strain on maternal

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bone mass, and nutritional support of theskeleton must be adjusted accordingly.Exactly when during the menopause tran-

sition bone loss begins to accelerate is notyet certain, but all would agree that by 12months after the last menstrual period,some increased bone loss is apparent. Aswith other clinical and laboratory mani-festations of the menopause, there is con-siderable person-to-person variability inthe rate and duration of accelerated post-menopausal bone loss. There seems to belittle relationship between gonadal ster-

oids and gonadotrophins and the extentof bone loss, but there is some evidencethat biochemical markers of bone resorp-tion may provide some information in thisregard.14 Estrogen provided for meno-pausal management offers protectionagainst this bone loss but only for as longas the estrogen is taken. Here too, there isconsiderable individual variability in theamount of estrogen required to prevent

bone loss.15All guidelines recommend a daily in-

take of calcium (1200 to 1500 mg dailyfrom food and/or supplements) and vita-min D (800 to 1000 units, generally fromsupplements) for all postmenopausal wo-men. These guidelines also recommendregular weight bearing and strength train-ing exercise, but the amount recom-mended varies substantially and the

evidence supporting any specific amountor type is minimal. Importantly it mustbe remembered that for most womenrigorous attention to these universalguidelines alone is not sufficient to reducethe likelihood of developing PMOP laterin life.

The final item in this list of universalprevention strategies is fall prevention.This too must be tailored to the individual

persons overall health, medication,physical fitness, gait, vision, hearing,living environment, etc. While most fallsdo not result in hip fracture, even in theelderly, most hip fractures are the resultof a fall.

When Should PreventionStrategies Be Initiated inRelation to the MenopauseTransition?While some practitioners recommend thatall women should have BMD measuredduring this menopausal transition, suchmeasurement has not been acceptedby any of the published evidence-basedguidelines (http://www.iscd.org/Visitors/positions/OfficialPositionsText.cfm,http://www.nof.org/professionals/Clinicians_Guide.

htmon a single bone density measurement.The United States Preventive ServicesTask Force recommended that BMDshould be measured in all women of age65 or older (if not already done).20

Clinical practice guidelines published bymany professional societies concur withthis recommendation but add further thatBMD testing should be performed earlierif there are one or more BMD-indepen-

dent clinical risk factors present (Table 1).This underscores the importance ofobtaining the appropriate skeletally or-iented history at each annual physicalexamination.

Pharmacologic Interventionat the MenopauseAs has been noted, estrogen ( proges-terone in women with an intact uterus)will prevent early postmenopausal boneloss, apparently for as long as such ther-apy is continued. Whether or not to pre-scribe hormone therapy at menopause isan individual decision to be made by thepatient and her doctor, but most currentrecommendations, based on the datafrom the Womens Health Initiative

study, state that such therapy should pre-ferably not be started solely for the pre-vention of bone loss. If a decision is madeto begin hormone therapy for nonskeletalreasons, there is little indication to mea-sure BMD before therapy.

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In women not prescribed hormonetherapy for management of the meno-pause, if BMD is measured and the t scoreis 1.0 or better, no pharmacologic inter-vention is indicated. If the t score is 2.5or lower, it is essential that a thoroughsearch for secondary causes of bone lossbe undertaken (Table 2). If no secondarycause is found, therapy should be initiated

with one of the approved therapies for thetreatment of osteoporosis (Table 3). If thet score is between 1.0 and 2.5, con-sideration should be given to prescribingone of the several approved therapies forthe prevention of osteoporosis (Table 3).For many of these women, particularlythose in whom thet score is not below 2.0, this initial BMD measurement maysimply reflect PABM, and intervention

may not be appropriate. As previouslynoted, in this group of women, there isevidence that measurement of the bio-chemical markers of bone remodeling(Table 4) can help identify those womenin whom rapid bone loss is more likely tooccur over the next 4 years, and, by in-ference, are most likely to benefit frompharmacologic intervention. Garneroand colleagues14 dichotomized over 4000

postmenopausal women into 2 groupsthose in whom the level of the marker wasstill within the reference interval(mean 2 SD) for premenopausal wo-men were considered to have low boneturnover; those in whom the value was

TABLE 1. Risk Factors for Minimal Trau-ma Fractures That Should BeConsidered in the Decision About

Intervention to Prevent Fracturesin Women With BMD t Score inthe Low Bone Mass (Osteope-nia) Range

Personal history of fracture after age 45Family history of osteoporosis with fractureCurrent smokerHistory of frequent falls

BMD indicates bone mineral density.

TABLE 2. Conditions That Should Be Con-sidered When Evaluating thePossibility of a Secondary Cause

for Bone LossNutritional

Malnutrition from any causeLow calcium intakeLow vitamin D intakeExcess sodium intake (promotes hypercalciuria)Excess vitamin A intake (>20,000 units/d

many multivitamins contain 10,000 units/dose)Alcoholism

Endocrine disordersPrimary hyperparathyroidismHyperthyroidism (mainly a concern with chronic

excess exogenous thyroxine)Cushing syndrome/diseaseHyperprolactinemiaType 1 diabetes (type 2 diabetes is associated

with increased fracture risk at a higher BMDthan nondiabetics)

Gastrointestinal diseasesChirons diseaseInflammatory bowel diseasesAny surgical procedure resulting in short-

bowel syndromes, particularly bariatricsurgery

Chronic liver diseaseMedication

Glucocorticosteroids (a safe dose has not beenestablished but 5 mg/d or more of prednisoneshould be cause for concern. The data oninhaled or nasal steroids is unclear)

Antiepileptic medicationsProton pump inhibitorsThyroxineFurosemideThiazolidinediones (appear to increase fracture

risk in type 2 diabetes even when BMD is not

particularly low)Aromatase inhibitorsDepomedroxyprogesterone acetate (BMD is low

in women taking DMPA but appears torecover after therapy is discontinued. There isno good evidence that prior DMPA use affectspostmenopausal BMD)

Many DXA reports include a t score (BMD relative to themean value in the young normal reference population) and Zscore (BMD relative to the mean value in patients matchedfor age, sex, and ethnicity). A Z score lower than 2.0suggests that the BMD is lower than expected but themajority of patients with a secondary cause of bone loss donot have aZscore 2.0 or lower. This list is targeted towardpostmenopausal osteoporosis and is not an exhaustive list ofall secondary causes of bone loss.

BMD indicates bone mineral density; DMPA, depotmedroxyprogesterone acetate; DXA, dual-energy x-rayabsorptiometry.



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thromboembolic disease) that may not betolerated by some women. Against that,raloxifene has recently been approved by

the FDA for prevention of breast cancer,which would clearly appeal to many wo-men. There are also clinical trials report-ing prevention against cardiovasculardisease, but this is not an FDA-approvedindication.

The most potent antifracture therapiesare the bisphosphonates that can be takenorally daily, weekly, 2 days each month,or monthly, or intravenously by injection

quarterly (ibandronate) or by infusionannually (zoledronic acid). The short-term side effects (gastrointestinal) troublea number of women and, in an individualpatient, switching to a different bispho-sphonate does not always overcome this.The intravenous route would seem idealfrom a compliance point of view and sideeffects (acute phase reaction) are uncom-mon and short lived. The downside is that

many physician practices are not set upfor either an intravenous injection or in-fusion. Cancer centers throughout thecountry are set up for this purpose andhave extensive experience with intrave-nous bisphosphonates for treatment ofskeletal metastases. Whether or not wo-men with a benign disease, osteoporosis,feel comfortable receiving therapy in acancer treatment center has not yet been

formally studied.Patients often inquire about which bi-

sphosphonate is best. Until recently, thishas not been formally addressed but, inDecember 2007, the Agency for Health-care Research and Quality issued a state-ment indicating that there is no evidenceto support the use of one over the other(http://www.ahrq.gov/news/press/pr2007/osteomedpr.htm).

In women in whom the diagnosis ofosteoporosis is established at the time ofthe first fragility fracture, the initial treat-ment of choice remains bisphosphonateas all controlled clinical trials includedwomen with 1 or more such fractures. In

women who sustain a fracture while onbisphosphonate therapy, considerationshould be given to switching to treatment

with teriparatide by daily self-adminis-tered subcutaneous injection. This ther-apy should also be considered for womenwho present with a history of multiplefragility fractures.

All randomized-controlled clinicaltrials of osteoporosis therapies were con-ducted with both the placebo and activetreatment arms receiving supplementaloral calcium and vitamin D. Accordingly

all patients treated for osteoporosismust be prescribed these supplements.Equally important is the need to restateand emphasize fall prevention, and tostress the importance of compliance withtherapy.

Monitoring the response to therapyremains a big problem and a barrier tomedication compliance and persistence.BMD measured by DXA is only covered

by Medicare once every 2 years, andsome carriers do not cover any follow-up densitometry studies. Patients needpositive feedback earlier than that andto faithfully take medication for 2 yearsonly to learn that BMD has not increasedis disheartening. The bisphosphonates actby inhibiting bone resorption, and mostclinical trails have included data indicat-ing that biochemical markers of bone

resorption (or formation) are significantlyreduced from baseline within 3 monthsof initiating therapy. While the patient iscompliant with therapy, these markersremain constant and the effect on boneremodeling may last for a year or longerafter therapy is discontinued. Thereare limited data to suggest that feedbackabout the biochemical response doesimprove compliance/persistence. This

has been addressed in some studies butthe level of evidence is not strong.

The effect of an anabolic agent (teri-paratide) is to increase bone formation;this too can be monitored using a bio-chemical marker of bone formation.



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The duration of therapy with teripara-tide has been set by the FDA at 2 years.For the antiresorptive class of therapies,

no such time constraints for the durationof therapy have been imposed by theFDA. However, this does not mean thatpatients need to continue therapy indefi-nitely. In fact, researchers have reportedthat discontinuation or interruption oftherapy may not be harmful.21,22 The levelof evidence for this is not strong, and thereare no data to indicate that such intermit-tent therapy is actually beneficial.

Summary and ConclusionsBMD measured by DXA is at least asstrong a predictor of an adverse healthoutcome (fragility fracture) as cholesterolor blood pressure is at predicting acutemyocardial infarction or cerebrovascularaccident. Therapies for patients withlow BMD or osteoporosis (diagnosed byBMD and/or fragility fracture) are safeand effective and have all been approvedonly after antifracture effectiveness hasbeen demonstrated in controlled clinicaltrials. Compliance and persistence tolong-term therapy is nonetheless subopti-mal. The long interval needed for BMDfollow-up and the limited change in BMDover time may be contributing factors, butearlier follow-up using biochemical mar-kers of bone remodeling does not substan-tially improve this. The evidences tosupport the use of BMD as a screeningand diagnostic tool, and the safety andefficacy of the available therapies are level1. Improving compliance and persistenceis suboptimal and remains perhaps thebiggest challenge still to be overcome inthe management of PMOP.

References1. NIH Consensus Development Panel on

Osteoporosis Prevention, Diagnosis, andTherapy.JAMA. 2001;285:785795.

2. Kimber CM, Grimmer-Somers KA. Eva-luation of current practice: compliancewith osteoporosis clinical guidelines in

an outpatient fracture clinic.Aust HealthRev.2008;32:3443.PMID: 18241147.3. Silverman SL, Gold DT, Cramer JA.

Reduced fracture rates observed onlyin patients with proper persistence andcompliance with bisphosphonate thera-pies. South Med J. 2007;100:12141218.PMID: 18090964.

4. Kothawala P, Badamgarav E, Ryu S,et al. Systematic review and meta-analysisof real-world adherence to drug therapy

for osteoporosis. Mayo Clin Proc. 2007;82:14931501. PMID: 18053457.5. Rabenda V, Mertens R, Fabri V, et al.

Adherence to bisphosphonates therapyand hip fracture risk in osteoporoticwomen. Osteoporos Int. 2007;19:811818.PMID: 17999022.

6. Kanis JA, Johnell O, Oden A, et al. Riskof hip fracture according to World HealthOrganization criteria for osteoporosisand osteopenia. Bone. 2000;27:585590.

PMID: 11062343.7. Kanis JA, Johnell O, Oden A, et al. Ten

year probabilities of osteoporotic frac-tures according to BMD and diagnosticthresholds. Osteoporos Int. 2001;12:989995.PMID: 11846333.

8. Kanis JA, Johnell O, De Laet C, et al.International variations in hip fractureprobabilities: implications for risk assess-ment. J Bone Miner Res. 2002;17:12371244. PMID: 12096837.

9. De Laet C, Oden A, Johnell O, et al. Theimpact of the use of multiple risk factorson case finding strategies: a mathematicalframework. Osteoporos Int. 2005;16:313318. PMID: 15241584.

10. Tosteson AN, Melton LJ III, Dawson-Hughes B, et al; National OsteoporosisFoundation Guide Committee. Cost-effective osteoporosis treatment thresh-olds: the United States perspective.Osteoporos Int.2008;19:437447. PMID:

18292976.11. Dawson-Hughes B, Tosteson AN, Mel-

ton LJ III, et al.; National OsteoporosisFoundation Guide Committee. Implica-tions of absolute fracture risk assessmentfor osteoporosis practice guidelines in the

562 Kleerekoper et al


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USA. Osteoporos Int. 2008;19:449458.PMID: 18292975.

12. Jones G, Nguyen TV. Associations be-

tween maternal peak bone mass and bonemass in prepubertal male and femalechildren. J Bone Miner Res. 2000;15:19982004. PMID: 11028453.

13. Ferrari S, Rizzoli R, Slosman D, et al.Familial resemblance for bone mineralmass is expressed before puberty. J ClinEndocrinol Metab. 1998;83:358361.PMID: 9467541.

14. Garnero P, Sornay-Rendu E, Duboeuf F,et al. Markers of bone turnover predict

postmenopausal forearm bone lossover 4 years: the OFELY study. J BoneMiner Res. 1999;14:16141621. PMID:10469291.

15. Do ren M, Nilsson JA, Johnell O. Effectsof specific post-menopausal hormonetherapies on bone mineral density inpost-menopausal women: a meta-analy-sis. Hum Reprod. 2003;18:17371746.PMID: 12871893.

16. Kanis JA, Burlet N, Cooper C, et al;

on behalf of the European Society forClinical and Economic Aspects of Osteo-porosis and Osteoarthritis (ESCEO).European guidance for the diagnosisand management of osteoporosis inpostmenopausal women. Osteoporos Int.2008;19:399428. PMID: 18266020.

17. Barlow DH. Osteoporosis guidelines. Cli-macteric. 2007;10(suppl 2):7982. PMID:17882679.

18. North American Menopause Society.Management of osteoporosis in post-menopausal women: 2006 position state-

ment of The North American MenopauseSociety. Menopause. 2006;13:340367;quiz 368369. PMID: 16735931.

19. AACE Osteoporosis Task Force. Amer-ican Association of Clinical Endocrinol-ogists medical guidelines for clinicalpractice for the prevention and treatmentof postmenopausal osteoporosis: 2001edition, with selected updates for 2003.Endocr Pract. 2003;9:544564. No ab-stract available. Erratum in: Endocr

Pract.2004;10:90. PMID: 14715483.20. U.S. Preventive Services Task Force.Postmenopausal hormone replacementtherapy for primary prevention ofchronic conditions: recommendationsand rationale.Ann Intern Med.2002;137:834839. Summary for patients in:Ann Intern Med. 2002;137:I48. PMID:12435221.

21. Brookhart MA, Avorn J, Katz JN, et al.Gaps in treatment among users of osteo-

porosis medications: the dynamicsof noncompliance. Am J Med. 2007;120:251256.

22. Black DM, Schwartz AV, Ensrud KE,et al; FLEX Research Group. Effectsof continuing or stopping alendronateafter 5 years of treatment: the FractureIntervention Trial Long-term Extension(FLEX): a randomized trial. JAMA.2006;296:29272938. PMID: 17190893.


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5 Osteoporosis Prevention and Management