Osteoporosis: Diagnosis Treatment Diagnosis and Treatment

Gary W. Williams, M.D., Ph.D.Scripps Clinic/Scripps Green Hospital Grand Rounds

Wednesday, April 1, 2009

Osteoporosis:Diagnosis and Treatment

Gary W. Williams, M.D., Ph.D.GRAND ROUNDS APRIL 1, 2009

Osteoporosis:Diagnosis and Treatment

• Why are we losing bone mass?

• How can we find out how much we have lost?

• What can we do about it?

Definition of Osteoporosis

• A skeletal disorder characterized by

compromised bone strength

predisposing to an increased risk of

fracture.

• Bone strength reflects the

integration

of two main features:

A. Bone density and

B. Bone quality.

Normal Bone

Osteoporotic Bone

Images courtesy of Ralph Müller

Peak Bone Mass

• Peak Bone Mass occurs between ages 20 to 39

• During adolescent growth spurt, up to 60% of total bone mass is achieved

• Maximum increases in bone mass occurs between ages 11 and 14 for girls and 13 and 16 for boys

• By age 18, skeletal growth is complete with minor accumulations in bone density occurring until around age 30 (97% by age 20)

•



Common sources of calcium.Natural and fortified food sources

of vitamin D.

Fracture Incidence Projections, 2005-2025

2,0512,276

2,5102,754

3,036

-

500

1,000

1,500

2,000

2,500

3,000

3,500

2005 2010 2015 2020 2025

Fra

ctu

res

(000

s)

US fracture growth through 2025: 48% Burge,R. JBMR 2007 in press.

Bone Remodeling Units (BRUs)

• Bone remodeling facilitates repair of microdamage and provides calcium from bone stores for cellular functions .

• The metabolic component of bone is made up of bone remodeling units (BRUs), over 1 million of which are active at any given time in a healthy adult woman.

• It is estimated that complete turnover of the skeleton occurs every 10 years.

• Bone remodeling is, however, accelerated in postmenopausal women, in whom estrogen deficiency results in increased bone turnover with an excess of resorption over formation.

• Osteoclasts reabsorb bone over a period of about 3 weeks to create resorption cavities, which are collectively termed the remodeling space.

• Resorption is followed by osteoblast activation and formation of osteoid, which fills the resorption cavities over a period of about 3 months.

• When this active matrix synthesis is finished, osteoblasts become embedded in the matrix and function as osteocytes.

Bone Remodeling Unit (BRU)



Bone Remodeling in Healthy Individuals

Indications for Bone Mineral Density (BMD) Testing ISCD 2007

• Women aged 65 and older– Postmenopausal women under age 65 with risk factors for fracture.

• Women during the menopausal transition with clinical risk factors for fracture, such as low body weight, prior fracture, or high‐risk medication use.

• Men aged 70 and older.– Men under age 70 with clinical risk factors for fracture.

• Adults with a fragility fracture.• Adults with a disease or condition associated with low bone mass

or bone loss.• Adults taking medications associated with low bone mass or bone

loss.• Anyone being considered for pharmacologic therapy.• Anyone being treated, to monitor treatment effect.• Anyone not receiving therapy in whom evidence of bone loss

would lead to treatment.• Women discontinuing estrogen should be considered for bone

density testing

Image

Graph

Demographics

Graph

Results T‐ &Z‐scores

Major NOF Recommendations to Physicians

• BMD testing

• Women ≥ 65

• Younger post-menopausal women with risk factor(s)

• Fracture patients

• Pharmacologic therapy

– Postmenopausal women with T-score below -2.0 or

– T score below -1.5 with 1 or more risk factors

– Fracture patients,

NOF Physician’s Guide to Prevention and Treatment of Osteoporosis, 2003



Osteoporosis Treatment Guidelines

NOF AACE NAMS

Prior fragility

fracture

Vertebral or hip Any fracture

With low BMD

Vertebral only

T‐scoreWithout risk

factor< ‐2.0 < ‐2.5 < ‐2.5

With risk

factor< ‐1.5 < ‐1.5 < ‐2.0

Risk factors 5 Major,

8 Additional

Several, including

risk of falling

Thin, family

history, prior

fracture

National Osteoporosis Foundation Indications for Pharmacologic Treatment

National Osteoporosis Foundation Indications for Pharmacologic Treatment

• Postmenopausal women and men age 50 or older and– Hip or vertebral fracture

– T‐score < ‐2.5

– Low bone mass (T‐score ‐1.0 to ‐2.5) and prior fracture

– Low bone mass (T‐score ‐1.0 to ‐2.5) and secondary cause associated with high fracture risk

– Low bone mass (T‐score ‐1.0 to ‐2.5) and 10‐year probability of hip fracture > 3% or a 10‐year probability of any osteoporosis related fracture > 20% based on the US‐adopted WHO algorithm

WHO 10‐year fracture risk assessment model

• Current age

• Gender

• Personal history of a fracture

• Femoral neck BMD

• Low body mass index

• Alcohol intake: 3 or more drinks/day

• Use of oral glucocorticoid therapy

• Secondary osteoporosis

• Parental history of hip fracture

• Current smoking

http://http://www.shef.ac.ukwww.shef.ac.uk/FRAX/tool/FRAX/tool

Fig. 2 Relation between the 10‐year probability of a major osteoporotic fracture and the 10‐year probability of a hip fracture in women aged 50 years from the UK. Each point represents a particular combination of BMD and clinical risk factors

Case finding for the management of osteoporosis with FRAX®—assessment and intervention thresholds for

the UK

Case finding for the management of osteoporosis with FRAX®—assessment and

intervention thresholds for the UK

Fig. 4 Management chart for osteoporosis. The brown area in the left hand panel shows the limits of fracture probabilities for the assessment of BMD. The right hand panel gives the intervention threshold



Table 7 Management decisions (N, no action; B, BMD testing at the femoral neck; T, treatment without BMD) in women according to risk factors and age (BMI=23.9)

Case finding for the management of osteoporosis with FRAX®—assessment and

intervention thresholds for the UK

Table 8 Management decisions (N, no action; B, BMD testing at the femoral neck; T, treatment without BMD) in

women according to risk factors and age (BMI=23.9)

The algorithm additionally takes account of hip fracture probability

Cells give the average 10-year probability of a major osteoporotic fracture according to body

mass index (BMI) and age

Reassure

Consider BMD

Consider Treatment

Assessment chart for men and women with clinical risk factors (CRFs) for fracture

Reassure

Consider BMD

Consider Treatment

Osteoporosis in MenOsteoporosis in Men

International Society for Clinical Densitometry International Society for Clinical Densitometry recommends that we use the male database recommends that we use the male database and the Tand the T--score of less than score of less than --2.5 to diagnose 2.5 to diagnose osteoporosisosteoporosis in men. in men.

the World Health Organization (WHO), it is the World Health Organization (WHO), it is estimated that 1 to 2 million men in the United estimated that 1 to 2 million men in the United States have States have osteoporosisosteoporosis (T(T--score < score < --2.5) and 2.5) and another 8 to 13 million have osteopenia (Tanother 8 to 13 million have osteopenia (T--score score between between --1.0 and 1.0 and --2.5). 2.5).

Luigi Gennari, John P. Bilezikian, Endocrinology and Metabolism Clinics - Volume 36, Issue 2 (June 2007)


About one in every four to five hip fractures in About one in every four to five hip fractures in people older than 50 occurs in men people older than 50 occurs in men 11

one in five men over the age of 50 will have an one in five men over the age of 50 will have an osteoporosisosteoporosis--related fracture in their remaining related fracture in their remaining lifetime lifetime 22

Causes of secondary Causes of secondary osteoporosisosteoporosis in menin men–– alcohol abuse, alcohol abuse, –– glucocorticoid excess (either endogenous Cushing's glucocorticoid excess (either endogenous Cushing's

syndrome or, more commonly, chronic glucocorticoid syndrome or, more commonly, chronic glucocorticoid therapy), and therapy), and

–– Hypogonadism Hypogonadism 33

1. 1. Cooper C., Campion G., Melton L.J.: Hip fractures in the elderly: a worldwide projection. Osteoporos Int 2. 285-289.19922. Melton L.J., Atkinson E.J., O'Conner M.K., et al: Bone density and fracture risk in men. J Bone Miner Res 13. (12): 1915-1923.19983. Orwoll E.S.: Osteoporosis in men. Endocr Rev 16. 87-116.1995




Largest populationLargest population--based study of BMD in older based study of BMD in older US menUS men–– the strongest factor determining BMD was the strongest factor determining BMD was

race/ethnicity. race/ethnicity. African American men African American men

–– 12% higher hip and 12% higher hip and –– 6% higher spine BMD than Caucasian men 6% higher spine BMD than Caucasian men

(consistent with previous findings in both men and women)1 (consistent with previous findings in both men and women)1 The higher bone mass was not explained by weight or other The higher bone mass was not explained by weight or other historical or lifestyle factors and historical or lifestyle factors and

–– was sufficiently large to account for their lower risk of fractuwas sufficiently large to account for their lower risk of fracture. re. Asian men had lower BMD than Caucasian men in ageAsian men had lower BMD than Caucasian men in age--adjusted analysis, but this difference was entirely explained byadjusted analysis, but this difference was entirely explained bybody weight. body weight.

1. Looker A.C., Orwoll E.S., Johnston C.C., et al: Prevalence of low femoral bone density in older US adults from NHANES III. J Bone Miner Res 12. 1761-1768.1997


In men, both estrogen and androgen levels, and In men, both estrogen and androgen levels, and particularly their bioavailable fractions, decline particularly their bioavailable fractions, decline slowly but progressively after 50 to 60 years of slowly but progressively after 50 to 60 years of age age Androgens, the dominant male sex steroid class, Androgens, the dominant male sex steroid class, have long been assumed to be critical for the have long been assumed to be critical for the growth and the maintenance of the male growth and the maintenance of the male skeleton; however, both observational and skeleton; however, both observational and interventional studies recently have confirmed interventional studies recently have confirmed that estrogens are even more important in the that estrogens are even more important in the growth and the maintenance of bone mass in growth and the maintenance of bone mass in men. men.



In a crossIn a cross--sectional analysis from the MINOS sectional analysis from the MINOS Study, men in the lowest quartile for bioavailable Study, men in the lowest quartile for bioavailable estradiol level showed significantly lower BMD at estradiol level showed significantly lower BMD at multiple sites as compared with men in the multiple sites as compared with men in the upper three estradiol quartiles upper three estradiol quartiles [55][55]. .

Serum estradiol levels were more robust Serum estradiol levels were more robust predictors of BMD than serum testosterone predictors of BMD than serum testosterone levels, even in a sample of androgenlevels, even in a sample of androgen--deficient deficient men from the Framingham Study men from the Framingham Study [59][59]. .



Since the discovery of Since the discovery of osteoporosisosteoporosis and longitudinal and longitudinal bone growth in a young man with an inactivating bone growth in a young man with an inactivating mutation in the mutation in the ERERɑɑ gene, several clinical and gene, several clinical and experimental lines clearly indicate a dominant role of experimental lines clearly indicate a dominant role of estrogen over androgen for the initiation of the pubertal estrogen over androgen for the initiation of the pubertal growth spurt and growth plate fusion at the end of growth spurt and growth plate fusion at the end of puberty, as well as for longitudinal bone growth, puberty, as well as for longitudinal bone growth, attainment of peak bone mass, and normal bone attainment of peak bone mass, and normal bone remodeling in young males. remodeling in young males. Androgens are also important for bone growth in males, Androgens are also important for bone growth in males, –– periosteal bone expansion periosteal bone expansion –– The acquisition of increased bone sizeThe acquisition of increased bone size–– Androgens also important for muscle mass, and consequently, Androgens also important for muscle mass, and consequently,

for increasing bone mass. for increasing bone mass.


Copyright restrictions may apply.

Siris, E. S. et al. Arch Intern Med 2004;164:1108-1112.

Bone Mineral Density Thresholds for Pharmacological Intervention to Prevent Fractures






• 82% of women who sustained osteoporotic fractures of the wrist or forearm, hip, rib, or spine within 1 year after peripheral BMD testing had T scores greater than –2.5.

• Only 18% of the NORA* women who had fractures would have been treatment candidates if the intervention threshold had been set at –2.5 or less.

• This would result in no intervention in 82% of the women who actually experienced a new fractureduring the first year after BMD was measured.




*NORA ‐ National Osteoporosis Risk Assessment

• Therefore, treatment of only women with T scores of –2.5 or less would have a limited effect on reducing the number of women who sustain osteoporotic fractures, including hip fractures.

• Recent results from the Study of Osteoporotic Fractures showed a similar observation in older women (lowest age, 65 years), in which 54% of the womenwith hip fractures and 74% of the women with any nonvertebral fracture had a total hip T score greater than –2.5**.




**Wainwright SA, Phipps KR, Stone JV, et al. [abstract]. J Bone Miner Res. 2001;16:S155.

Cutaneous production of vitamin D and its metabolism and regulation for calcium homeostasis and cellular growth. 7-Dehydrocholesterol or provitamin

D3 (proD3) in the skin absorbs solar UV-B radiation and is converted to previtamin D3 (preD3)

Holick M. F. Mayo Clin Proc. 2006;81:353-373© 2006 Mayo Foundation for Medical Education and Research

■ Hypovitaminosis D, encompassing both vitamin D insufficiency and deficiency, is common in the general population

■ The optimal serum 25(OH)D level required for calcium homeostasis and skeletal health is debated

■ Evidence indicates that vitamin D must be administered with calcium to increase bone mineral density in adults

■ Three recent meta‐analyses concluded that vitamin D must be administered with calcium to reduce the risk of fracture in adults over age 50 years

■ Hypovitaminosis D causes sarcopenia, muscle weakness, and contributes to an increased risk of falls

■ Recent research suggests that vitamin D has a role in cancer risk and innate immunity

Anne E Wolff, Andrea N Jones and Karen E Hansen Nature Clinical Practice RHEUMATOLOGY November 2008 vol 4 no 11

Vitamin D and Musculoskeletal Health

Vitamin D and Musculoskeletal Health

Anne E Wolff, Andrea N Jones and Karen E Hansen Nature Clinical Practice RHEUMATOLOGY November 2008 vol 4 no 11

NORMAL



OSTEOMALACIA SEVERE OSTEOMALACIA

VIT D POST‐Rx

• CONTRAINDICATIONS:

• Undiagnosed and Abnormal Genital Bleeding

• Known, Suspected or History of Breast CA (Exception: Selected Patients Treated for Metastatic Disease)

• Active or Previous DVT or PE

• Active or Recent Arterial Thromboembolic Disease

• Liver Dysfunction

• Suspected Pregnancy

•DISADVANTAGES:

• [Hormone Rx]

•Increased Risk MI

• [Estrogen‐Progestin] •Invasive Breast Cancer

• Increased Risk of Venous Thromboembolism

• Increased Risk of Stroke

• Cognitive Dysfunction and Increased Risk of Dementia

ADVANTAGES (ESTROGEN +/‐Progestin)• Inexpensive

• Short Skeletal Half‐Life

• Rx Vasomotor Sx and Mild to Moderate Vaginal and Vulvar atrophy

• Decrease Fracture (Hip, Vertebral, Non‐vertebral)

• Estrogen‐Progestin Decreased Risk of Colorectal Cancer

• Approved in Early Menopausal women

ADVANTAGES (Raloxifene)Short Skeletal Half‐Life ‐ Reduced Risk of Breast Cancer ‐ Rx Vasomotor Sx – Rx Mild to Mod. Vaginal and Vulvar atriphy ‐Decrease Fracture (Vertebral)


• H/O Venous thromboembolism (DVT, PE and Retinal Vein Thrombosis)

• History of Stroke

• History of TIA

• Known Breast Cancer

•DISADVANTAGES:

• No Evidence of Reduction in Non‐Vertebral or Hip Fracture

•Increased Risk of Venous Thromboembolism

•Occurrence of Hot Flashes

•Leg Cramps

Actions of Estrogen, Tamoxifen and Raloxifene

Estrogen Tamoxifen Raloxifene

Hot flashes - 0 or + 0 or +

Breast CA ++ - -

Uterus ++ ++ -

U-G Epithelium ++ ? ?

Bone ++ ++ ++

LDL Cholesterol ↓ ↓ ↓HDL Cholesterol ↑ 0 0

Clotting ↑ ↑ ↑Brain ? ? ?

Colon CA ↓ ? ?



•ADVANTAGES (Bisphosphonates)Reduction in Fracture Rates (Hip, Vertebral, Non‐vertebral ) Dosing options: Daily, Weekly, Monthly, q 3 Months, qYearRoute of Administration Oral Pill or solution, IV Infusion


• Abnormalities of the Esophagus with Delayed Emptying (Oral Forms)

• Inability to Sit or Stand for > 30 Minutes (Oral Forms)

• Patients with Risk of Aspiration (Oral Forms)

• Hypocalcemia

• Renal Insufficiency (<30‐35 mL/min Cr Cl)

Disadvantages

•Long‐term Skeletal Retention

•GI Side Effects

•Musculoskeletal Pain

•Low Risk ON of the Jaw

•Small Risk of Subtrochanteric Insufficiencey/Femoral Shaft Fracture

•Questionalble Association With Risk Of Atrial Fibrillation

Sales growth of the top five osteoporosis products in the us and the eu

FDA‐approved agents for osteoporosis.

AGENT DOSE FREQUENCY ROUTE FRACTURE PREVENTION

Alendronate 5,35,10,70, 70mg+D

Daily, Weekly Oral, (70 mg Liquid)

HIP, Vertebral, non‐vertebral

IbandronateBONIVA

2.5 mg PO150 mg PO3 mg IV

DailyQ MonthQ 3 Months

OralOralIV

Vertebral

Risedronate 535 +/‐ CA75150 mg

DailyWeeklyX2 q MonthMonthly

Oral HIP, Vertebral, non‐vertebral

Zolendronic Acid 5 mg Yearly IV Infusion HIP, Vertebral, non‐vertebral

Calcitonin 200 IU Daily Intranasal Vertebral

Estrogen/Hormone Therapy

Varies by Agent

DailyTwice Per Week

OralTransdermal Patch


Raloxifene 60 mg Daily Oral Vertebral

Teriparatide 20ug Daily Subcutaneous Vertebral, non‐vertebral

AGENT DOSE FREQUENCY ROUTE FDA APPROVAL FRACTURE PREVENTION

Alendronate

Fosamax ®5,35,10,70,70mg+D


PM OP in Womenop in MenGC Induced OP


Ibandronate

Boniva ®2.5 mg PO150 mg PO3 mg IV


OralOralIV

Oral Prevention OPOral & IV Rx of OP

Vertebral

RisedronateActonel ®

535 +/‐ CA75150 mg


Oral Prevent & Rx OPOP in MenGC Induced OP


Zolendronic AcidReclast ®

5 mg Yearly IV Infusion PM OP in WomenAfter OP Hip Fx Men and Women Prevention and Rx of GC Induced OP


CalcitoninMiacalcin Nasal ®

200 IU Daily Intranasal PM OP Women 5 Years PM Vertebral


Varies by Agent

DailyTwice Per Week


Prevention of OP HIP, Vertebral, non‐vertebral

RaloxifeneEvista ®

60 mg Daily Oral Prevention of OP and relief of Vasomotor Sx

Vertebral

Parathyroid Hormone (1‐34) TeriparatideForteo ®

20ug Daily Subcutaneous Treatment of OP in PM Women and men with Primary or Hypogonadal Osteoporosis at High Risk for Fracture

Vertebral, non‐vertebral

AGENT DOSE FREQUENCY ROUTE FDA APPROVAL % Fracture Reduction

AlendronateFosamax ®Fosamax Plus D ®

5,35,10,70,70mg+D


PM OP in Womenop in MenGC Induced OP

HIP, (50% Reduction)Vertebral, (47% Reduction)non‐vertebral

IbandronateBoniva ®

2.5 mg PO150 mg PO3 mg IV


OralOralIV

Oral Prevention OPOral & IV Rx of OP

Vertebral (62% Reduction)

RisedronateActonel ®

535 +/‐ CA75150 mg


Oral Prevent & Rx OPOP in MenGC Induced OP

HIP, Vertebral, (49% ReductionNon‐vertebral (33‐39%)

Zolendronic AcidReclast ®

5 mg Yearly IV Infusion PM OP in WomenAfter OP Hip Fx Men and Women Prevention and Rx of GC Induced OP

HIP (41% Reduction)Vertebral (70% Reduction)non‐vertebral (25% Reduction)

CalcitoninMiacalcin Nasal ®

200 IU Daily Intranasal PM OP Women 5 Years PM

Vertebral (33 to 36% Reduction)


Varies by Agent

DailyTwice Per Week


Prevention of OP HIP, (34% Reduction)Vertebral, (34% Reduction)

non‐vertebral(32% Reduction)

RaloxifeneEvista ®

60 mg Daily Oral Prevention of OP and relief of Vasomotor Sx

Vertebral (40‐50% Reduction)(30‐50% Prior Vertebral Fx)

Parathyroid Hormone (1‐34) TeriparatideForteo ®

20ug Daily Subcutaneous Treatment of OP in PM Women and men with Primary or Hypogonadal Osteoporosis at High

Vertebral (65% Reduction)Non‐vertebral (53% Reduction)Treatment Mean of 21 Months



• Evidence for significant vertebral fracture relative risk reduction(RR) at 1 year: – Risedronate (RR 81%; p<0.001),

– Teriparatide (RR 65%; p<0.05) and

– Strontium Ranelate (RR 59%; p=0.002) and

• Evidence for significant vertebral fracture relative risk reduction(RR) at 3 years:– Risedronate (RR 44%; p=0.003),

– Alendronate (RR 38%; p<0.05) and

– Strontium Ranelate (RR 32%; p=0.013).

Efficacy and safety of pharmacological agents in managing osteoporosis in the old old: Review of the evidence

Inderjeeth CA, Foo AC, Lai MM, Glendenning P. , Bone 2008 Dec 16

• Evidence for significant non‐vertebral fracture relative risk reduction at 1 year– Strontium Ranelate (RR 41%; p=0.027) but not Teriparatide (p=0.66)

and

• Evidence for significant non‐vertebral fracture relative risk reduction at 3 years– Strontium Ranelate (RR 31%; p=0.011) but not Risedronate (p=0.66).

• The only study to report a reduction in hip fracture at 3 years is the TRopOS study with Strontium Ranelate (RR 36%; p=0.046).


Inderjeeth CA, Foo AC, Lai MM, Glendenning P. Bone 2008 Dec 16


• DISCUSSION: This review reinforces the irony that the least evidence is available for fragility fracture reduction in the group at greatest risk; – the old old and – those with non vertebral and hip fracture.

• Although there is good evidence for the benefit of the bisphosphonates (Alendronate and Risedronate), Teriparatide and Strontium Ranelate in vertebral fracture reduction, there are very limited data for non vertebral and hip fracture reduction.

• Strontium Ranelate is the only agent to date that has demonstrated a reduction in non vertebral and hip fracture events in this high risk elderly female population.

Inderjeeth CA, Foo AC, Lai MM, Glendenning P. Bone 2008 Dec 16

Zoledronic Acid Injection: Reclast ®

• Zoledronic Acid is a bisphosphonate indicated for:

• Treatment of osteoporosis in postmenopausal women

• Treatment to increase bone mass in men with osteoporosis

• Treatment and prevention of glucocorticoid‐induced osteoporosis in patients expected to be on glucocorticoids for at least 12 months

• Treatment of Paget’s disease of bone in men and women


• Approved Indication United States:

• Zoledronic acid is indicated for treatment of osteoporosis in postmenopausal women. In postmenopausal women with osteoporosis,diagnosed by BMD or prevalent vertebral fracture, – zoledronic acid reduces the incidence of fractures (hip, vertebral and non‐

vertebral osteoporosis‐related fractures). – In patients at high risk of fracture, defined as a recent low‐trauma hip

fracture, zoledronic acid reduces the incidence of new clinical fractures.

• Zoledronic acid is indicated for treatment of Paget's disease of bone in men and women. – Treatment is indicated in patients with Paget’s disease of bone with elevations

in serum alkaline phosphatase of two times or higher than the upper limit of the age‐specific normal reference range,

– or those who are symptomatic, – or those at risk for complications from their disease.


DOSAGE AND ADMINISTRATION

• Treatment of osteoporosis in postmenopausal women• Treatment to increase bone mass in men with osteoporosis• Treatment and prevention of glucocorticoid‐induced

osteoporosis– 5 mg infusion once a year given intravenously over no less than 15

minutes

• Treatment of Paget’s disease of bone: – single 5 mg infusion given intravenously over no less than 15 minutes – Patients with Paget’s disease should receive 1500 mg elemental

calcium and 800 IU vitamin D daily, particularly during the 2 weeks after dosing

– Administer through a separate vented infusion line and do not allow to come in contact with any calcium or divalent cation‐containing solutions




• INDICATIONS AND USAGE– Treatment of Osteoporosis in Postmenopausal Women

– Osteoporosis in Men

– Glucocorticoid‐Induced Osteoporosis

– Paget's Disease of Bone

• DOSAGE AND ADMINISTRATION– Treatment of Osteoporosis in Postmenopausal Women

– Osteoporosis in Men

– Treatment and Prevention of Glucocorticoid‐Induced Osteoporosis

– Treatment of Paget’s Disease of Bone


• CONTRAINDICATIONS– Hypocalcemia

– Hypersensitivity to zoledronic acid or any components of Reclast

• WARNINGS AND PRECAUTIONS– Drug Products with Same Active Ingredient

– Hypocalcemia

– Renal Impairment

– Osteonecrosis of the Jaw

– Pregnancy

– Musculoskeletal Pain

– Patients with Asthma

Randomized, multicenter, double‐blind, double‐dummy, parallel group study to determine the efficacy and safety of intravenous zoledronic acid 5 mg annually compared to oral alendronate 70

mg weekly for the treatment of osteoporosis in men

Norvartis Clinical Trial Results Databasewww.Novartis.com Accessed 3.30.2009

Primary Objective Result(s) Between-treatment comparison in percent change inlumbar spine BMD (g/cm2)

at Month 24 (LOCF) relative to baseline

Randomized, multicenter, double‐blind, double‐dummy, parallel group study to determine the efficacy and safety of intravenous zoledronic acid 5 mg annually compared to oral alendronate 70

mg weekly for the treatment of osteoporosis in menSecondary Objective Result(s)Between‐treatment comparison in percent change in lumbar spine BMD (g/cm2) at Months 6, 12 and 24 relative to baseline (ITT population)


Between‐treatment comparison in percent change in femoral neck BMD (g/cm2) at Months 6, 12 and 24 relative to baseline

(ITT population)


Serious Adverse Events and DeathsDeaths, other serious or clinically significant adverse events or related discontinuations – n (%) of patients (Safety population)




10 Most Frequently Reported AEs Overall by Preferred Term n (%) Adverse events overall and most frequent events – n (%) of patients

(>= 5% in any group) (Safety population)



Miller, P. D. et al. Arch Intern Med 2004;164:1113-1120.

An Approach to Identifying Osteopenic Women at Increased Short‐term Risk of Fracture


• Paget's Disease of Bone

• Unexplained Increased Alkaline Phosphatase

• Prior Radiation Therapy to the Skeleton

• H/O Bone Metastases or Bone Malignancies

• Non‐Osteoporotic Bone Disease

• Preexisting Hypercalcemia

• Hyperparathyroidism

Disadvantages•COST

•Daily Injectio

•Storage

•Osteosarcoma

ADVANTAGES (Teriparatide)

• Increased BMD at Spine, Femoral Neck, Total Body > Alendronate (in Postmenopausal Osteoporotic Women)

• Decrease Fracture (Vertebral, Non‐vertebral ) vs. Placebo

• Decreased Vertebral Fractures vs. Alendronate in Glucocorticoid‐op induced Osteoporosis

• Improved Cancelous and Cortical Bone Architecture

• Improved Measures of Bone Strength vs. Alendronate (KievneyData)

Monitoring Patients on Osteoporosis Therapy

Test Frequency •Where to Test

BMD Assessment •Every 1‐2 Years for Patients with Stabilized Osteoporosis•Testing More Frequently in Uncontrolled Osteoporosis, Long‐Term Glucocorticoid Osteoporosis•Children/Adolescents

•Hip and Spine•Radius (in Hyperparathyroidism or if other site(s) unavailable)

Bone Resorption Marker Analysis

•3‐6 Months after Initiation of Treatment•Every 6‐12 Months if Patient Taken off Treatment

•Serum: C‐Terminal Peptide•Urine: N‐Terminal Peptide


Kiebzak, G. M. et al. Arch Intern Med 2002;162:2217-2222.

Undertreatment of Osteoporosis in Men With Hip Fracture




Majumdar, S. R. et al. Arch Intern Med 2007;167:2110-2115.

Osteoporosis management within 6 months of hip fracture. aORindicates adjusted odds ratio comparing intervention to control; BMD,

bone mineral density

Copyright ©2008 Canadian Medical Association or its licensors

Majumdar, S. R. et al. CMAJ 2008;178:569-575

Likelihood of receiving osteoporosis testing and treatment within 6 months after a wrist fracture

137 patients randomly assigned to the intervention group (patient education, physician reminder about patient's risk of osteoporosis and physician receipt of evidence‐based treatment guidelines) and135 patients assigned to control group (usual care)


Cuddihy, M.-T. et al. Arch Intern Med 2002;162:421-426.

Osteoporosis Intervention Following Distal Forearm FracturesA Missed opportunity?

Electronic medical record reminder improves osteoporosis management after a fracture: a

randomized, controlled trial.• OBJECTIVES: Evaluated methods to increase guideline‐recommended

osteoporosis care post‐fracture. • DESIGN: Participants were randomly assigned to usual care or one of two

interventions. – Analysis of primary outcomes used electronic data and linear regression.

• PARTICIPANTS: Female patients aged 50 to 89 who suffered a fracture in 1999 and – had not received bone mineral density (BMD) measurement – or medication for osteoporosis (n=311) and their primary care providers

(n=159).

• INTERVENTION: – Patient‐specific clinical guideline advice to the primary care provider delivered

by electronic medical record (EMR) message or – electronic reminder to the provider plus an educational letter mailed to the

patient.

• MEASUREMENTS: BMD measurement and osteoporosis medication.

Feldstein A, Elmer PJ, Smith DH, Herson M, Orwoll E, Chen C, Aickin M, Swain MC.J Am Geriatr Soc. 2006 Mar;54(3):450‐7

Center for Health Research, Kaiser Permanente, Portland, Oregon 97227, USA. [email protected]

Electronic medical record reminder improves osteoporosis management after a fracture: a

randomized, controlled trial.

RESULTS: Patients receiving BMD or osteoporosis medication at 6 months, – Provider reminder 51.5%

– Provider reminder plus patient education 43.1%

– Usual care 5.9% (P<.001).

– Patients aged 60 to 69 were 18% (95% confidence interval=3‐34) more likely to receive BMD measurement or an osteoporosis medication than those aged 80 to 89.

Feldstein A, Elmer PJ, Smith DH, Herson M, Orwoll E, Chen C, Aickin M, Swain MC. J Am Geriatr Soc. 2006 Mar;54(3):450‐7

OSTEopOROSISHIP FRACTURE PROTOCOL

GREEN HOSPITAL

OSTEopOROSISHIP FRACTURE PROTOCOL

GREEN HOSPITAL

Farahnaz Joarder, MD

Division of Endocrinology

SCRIPPS CLINIC/GREEN HOSPITAL



The Green Hospital ExperienceThe Green Hospital Experience

• Study Population: • patients age 55 and older admitted to Scripps Green

Hospital for hip fracture between July 1, 2004 and June 31, 2005

• Methods:• Retrospective review of IDX medical records:

• Admission H & P• Discharge Summary• Progress Notes up to 6 months post discharge• Review of BMD studies in the 5 years prior to admission and

up to 6 months post discharge

• Exclusion criteria:• Patients with traumatic fracture and pathologic fracture

Results:Study Population

Results:Study Population

• Total Admissions for Hip Fracture 65• Men: 19

• Median age: 80• Preexisting osteoporosis diagnosis: 15%• History of previous fracture: 20%

• Most frequent site: hip

• Women: 46• Median age: 81• Preexisting osteoporosis diagnosis: 32%• History of previous fracture: 26%

• Most frequent sites: hip, vertebral

Results:Screening for Osteoporosis in Hip Fracture Patients

Results:Screening for Osteoporosis in Hip Fracture Patients

• 18 (27%) patients had received a BMD study in the 5 years prior to admission• Among patients screened

• 11 (61%) had osteoporosis

• 7 (39%) had osteopenia

• 5 (8%) patients received BMD in the 6 months following discharge

Results:Pre-Admission Anti-Osteoporosis Therapy in Patients with

Hip Fracture

Results:Pre-Admission Anti-Osteoporosis Therapy in Patients with

Hip Fracture

Medication Prior to

Admisssion

After Discharge

Any anti-osteoporosis* 31% 50%

Calcium 25% 38%

Vitamin D 5% 16%

Bisphosphonate 16% 25%

HRT 7% 4%

Parathyroid Hormone < 5% < 5%

SERM < 5% < 5%

Calcitonin <5% <5%

* Includes CA++ and Vit D

RESULTS:Rate of Treatment After Discharge for Hip Fracture:

Green Hospital and Literature Comparison

RESULTS:Rate of Treatment After Discharge for Hip Fracture:

Green Hospital and Literature Comparison

GREEN HOSPITAL• 2004/2005 Scripps Clinic/Green Hospital:

• Any anti-osteoporosis therapy: 50%• Calcium: 38%• Bisphosphonate: 25%

LITERATURE COMPARISON• Hospital for Special Surgery, New York

• 1997: 11%• 1998: 13%• 1999: 24%• 2000: 29%

Gardner MJ, Flik KR, Mooar P, Lane JM, The American Journal of Bone and Joint Surgery 84: 2002.

Treatment rates of osteoporosis in the United States


• Retrospective study • Study sites: 7 HMOs across the U.S• Study population:

• 3492 women 60 years +• fracture of the hip, vertebra or wrist 1994-1996

• Frequency of treatment of osteoporosis during 1 year period following fracture• Overall treatment rate 24%

• Hip fracture patients 21%• Percent receiving bisphosphonate 5%

• Among women without prior treatment 14%

Andrade SE, Majumdar SR, Chan A, Buist DSM, Go AG, Smith DH, Platt R, Gurwitz JH Arch Int Med Vol 163, Sep 22 2003





• Percent of patients receiving prescription medication targeting osteopenia or osteoporosis after admission for hip fracture• 1997: 11%

• 1998: 13%

• 1999: 24%

• 2000: 29%

Gardner et al, The American Journal of Bone and Joint Surgery 84; 2002

Utilization of a Case ManagerUtilization of a Case Manager

• Majumdar et al Arch Intern Med Jan 2009• Effectiveness of hospital based case manager

• Randomized trial

• Increased treatment rates 51% vs 22%

• Cost of $56 Canadian /patient

• BenefitReduced rate of fracture

Gain in 4 quality adjusted life years

Savings of $260,000 by the health care system

Scripps ClinicOsteoporotic Hip Fracture

Clinical Pathway

Scripps ClinicOsteoporotic Hip Fracture

Clinical Pathway

ADMISSION FOR HIP FRACTURE• Inpatient consultation by hospitalist as needed

• Baseline labs (creatinine, 25-hydroxy vitamin D)

opERATE•Routine postoperative care

•Routine postoperative physical therapy

PREDISCHARGE•Physical Therapy: Inpatient counseling to reduce risk of falls

•Patient education

Scripps Clinic Osteoporotic Hip Fracture

Clinical Pathway

Scripps Clinic Osteoporotic Hip Fracture

Clinical Pathway

•At the time of discharge to SNF•Ancillary Scheduling for follow-up visits

•Provide LSR for follow-up labs ( 25-hydroxy vitamin D and CMP)•Provide Patient Letter (Recommendations for follow up)

•Provide Patient Safety Handout•Arrange Home Health/Home Physical Therapy

Follow-up•Division of Orthopedics (4 weeks)

•Scripps Clinic Osteoporosis Consultation (Endocrinology/Rheumatology) (8 weeks)•Primary Care Follow-up (as needed and after Osteoporosis Consultation)

•Treatment•Reclast infusion if indicated (12 weeks)

•Baseline bone mineral density study (12 weeks)

Thank YouQUESTIONS ?

Thank YouQUESTIONS ?

Gary W. Williams, M.D., Ph.D.GRAND ROUNDS APRIL 1, 2009



Effect of Soy Protein Containing Isoflavoneson Cognitive Function, Bone Mineral Density,and Plasma Lipids in Postmenopausal Women

A Randomized Controlled Trial

• Context : Postmenopausal estrogen therapy has been posited to have some beneficial effects on aging processes, but its use has risks. Isoflavones, estrogenlike compounds naturally occurring in plant foods, might confer positive effects with fewer adverse effects.

• Objective To investigate whether soy protein with isoflavones improves cognitive function, bone mineral density, and plasma lipids in postmenopausal women.

Sanne Kreijkamp‐Kaspers et al. JAMA, July 7, 2004—Vol 292, No. 1

Effect of Soy Protein Containing Isoflavoneson Cognitive Function, Bone Mineral Density,and Plasma Lipids in Postmenopausal Women

A Randomized Controlled Trial

• Design, Setting, and Participants Double‐blind, randomized, placebo controlled trial of 202 healthy postmenopausal women aged 60 to 75 years, recruited from a population‐based sample in the Netherlands, conducted between April 2000 and September 2001.

• Intervention Participants were randomly assigned to receive 25.6 g of soy protein containing 99 mg of isoflavones (52 mg genistein, 41 mg daidzein, and 6 mg glycetein or total milk protein as a powder on a daily basis for 12 months.


Effect of Soy Protein Containing IsoflavonesMain Outcome Measures

• Cognitive function was assessed using the following instruments: dementia, Mini‐Mental State Examination; memory, Rey Auditory Verbal Learning Test, immediate recall, delayed recall, and recognition, the Digit Span forward and reversed, and the Doors test; complex attention tasks, Digit Symbol Substitution and Trailmaking, A1, A2, and B; and verbal skills, Verbal Fluency A and N, animals and occupations, and the Boston Naming Task.

• Bone mineral density of the hip and lumbar spine was assessed using dual‐energy x‐ray absorptiometry scanning.

• Lipid assessment included lipoprotein(a), total cholesterol, low‐density lipoprotein, highdensity lipoprotein, and triglycerides.


Effect of Soy Protein Containing IsoflavonesResults

• A total of 175 women completed the baseline and at least 1 postintervention analysis and were included in the modified intent‐to‐treat analysis.

• Adherence was good (median plasma genistein levels, 17.2 and 615.1 nmol/L for placebo and soy group, respectively).

• Cognitive function, bone mineral density, or plasma lipids did not differ significantly between the groups after a year.


Effect of Soy Protein Containing IsoflavonesConclusions

• Conclusion :

• This double‐blind randomized trial does not support the hypothesis that the use of soy protein supplement containing isoflavones

– improves cognitive function,

– bone mineral density,

– or plasma lipids in healthy postmenopausal women when started at the age of 60


Denosumab Theory • Bone remodelling involves the RANK/RANK Ligand (RANKL)/

osteoprotegerin (OPG) pathway, with osteoclasts requiring RANKL for their differentiation, activation and survival.

• OPG works as a native inhibitor of RANKL, binding it, therefore preventing binding to its receptor RANK and blocking bone resorption.

• One hypothesis of the pathophysiology of osteoporosis suggests that elevated levels of RANKL relative to OPG may result in bone loss.

• Rectifying this imbalance by increasing OPG levels relative to RANKL or at least increasing the inhibition of RANKL, is a potential therapeutic pathway.

• Denosumab, an investigational fully human monoclonal antibody to human RANKL, mimics the effects of OPG on bone resorption but with the advantage of a longer half‐life.



Denosumab

• Denosumab, a humanized monoclonal antibody that inhibits RANK‐L (the ligand of receptor activator of nuclear factor‐kB), thereby preventing osteoclast precursors from differentiating into bone‐resorbing osteoclasts.

• Its convenience (once‐yearly or twice‐yearly subcutaneous injections), tolerability and potential as a treatment for patients who are refractory to bisphosphonates make denosumab particularly attractive.

• In a pivotal Phase III trial in post‐menopausal osteoporosis patients Amgen announced that denosumab has met its primary and secondary end points of reducing new vertebral fractures, as well as non‐vertebral and hip fractures6.

Amgen. Press Release 25 July: Amgen Announces Positive Top‐Line Results for Denosumab Pivotal Postmenopausal Osteoporosis Trial. Amgen web site[online], <http://www.amgen.com/media/media_pr detail.jsp?year=2008&releaseID=1179628> (2008).

Proposed mechanism of action for Denosumab

Documents

Osteoporosis: Diagnosis Treatment Diagnosis and Treatment