Osteoporosis: Update 2011 Mini-Med School Marc C. Hochberg, MD, MPH Professor, Departments of Medicine and Epidemiology & Public Health

Objectives ► ► Identify common types of fractures ► ► Review current recommendations for diagnosis and treatment of postmenopausal women with osteoporosis ► ►Who should be tested ► ►Who should be treated ► ►How should they be treated ► ► Discuss the rare adverse events of bisphosphonate therapy

Definitions of Osteoporosis ► ► A skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. – –NIH Consensus Conference (2000) ► ► Bone mineral density that is >=2.5 standard deviations below the young gender-specific mean – –World Health Organization (1994)

Fracture prevention Stabilize or increase bone mass Provide tolerability and long-term safety Optimize adherence Goals for Therapy

Vertebral Fractures ► ► Involve both the thoracic and lumbar spine ► ► Only ~1/3 are associated with acute back pain ► ► Presence of vertebral deformities is associated with chronic back pain and disability, increased risk of hospitalization and excess mortality

► ► Can involve the entire appendicular and axial skeleton – –Upper extremity Humerus Forearm/ Wrist – –Lower extremity Femur Lower leg Ankle – –Pelvis – –Ribs ► ► Associated with substantial morbidity and excess mortality Non-Vertebral Fractures

Most serious clinical fracture Mortality is high 20% of patients die within 1 year Men have higher mortality than women Morbidity is high 50% do not regain independence 50% do not regain previous level of function Patients who survive – –are often not treated for osteoporosis – –are at increased risk of additional fractures Hip Fracture

Rationale for Measuring BMD ► ► Bone mineral density (BMD) – –Strongly related to bone strength – –Independent predictor of fracture risk For each SD decrease in BMD, fracture risk increases 1.5 – 2.5 times – –Gold standard for diagnosis of osteoporosis – –Can be used to monitor efficacy of therapy

How to Measure BMD ► ► Dual Xray Absorptiometry (DXA) is the gold standard for measuring BMD – –Hip (femoral neck and total hip) – –Lumbar spine – –Distal 1/3 rd radius Primary hyperparathyroidism When hips and lumbar spine can’t be measured or are not valid

Who Should be Tested ► ► Women aged 65 and above ► ► Younger postmenopausal women with clinical risk factors – –Prior low trauma fracture – –Current smokers – –Low body weight – –Family history of hip fracture ► ► Women with medical conditions or taking medications that are associated with low bone mass or an increased rate of bone loss

Diseases That Can Cause Secondary Osteoporosis ► ► Endocrine diseases – –Hyperthyroidism – –Hyperparathyroidism – –Hypogonadism ► ► GI diseases – –Malabsorption syndromes – –Chronic liver disease – –Gastric operations ► ► Organ transplant ► ► Other chronic diseases – –Rheumatoid arthritis – –Chronic lung disease – –Malignancy ► ► Dietary disorders – –Vitamin D deficiency/ insufficiency – –Excess alcohol intake – –Anorexia nervosa

Medications That Can Cause Secondary Osteoporosis Oral glucocorticoids Excess thyroid hormone replacement Chemotherapy Anticonvulsants Gonadal hormone suppression Immunosuppressive agents

Who Should Be Treated ► ► Women with a hip or vertebral fracture ► ► Women with BMD T-score < -2.5 at femoral neck or lumbar spine ► ► Women with low BMD and a 10-year probability of hip fracture > 3.0% or major osteoporotic fracture > 20% based on US-adapted FRAX model

US Race-Specific FRAX Model ► ► Calculates 10-year absolute risk of major osteoporotic and hip fracture ► ► Includes age, sex, height, weight, h/o prior fracture, family h/o hip fracture, current smoking, current alcohol consumption, current glucocorticoid use, medical conditions associated with 2 ary osteoporosis, and BMD

Calcium intake Diet and/or supplementation with an RDA of at least 1200 mg (upper limit [UL] 2000 mg) in conjunction with vitamin D Nonpharmacologic Approaches

Potential Harms of Calcium Supplementation ► ► Increased risk of renal stones when given in conjuction with vitamin D – –RR = 1.17 (95% CI: 1.02, 1.34) – –5.7 events per 10,000 women-years ► ► Increased risk of nonfatal MI – –RR = 1.31 (95% CI: 1.02, 1.67) for IPD – –RR = 1.27 (95% CI: 1.01, 1.59) for studies Bolland MJ et al: BMJ 2010;341:c3691

Cumulative incidence of myocardial infarction, stroke, composite of myocardial infarction, stroke, or sudden death, and death by treatment allocation in five studies that contributed patient level data. Bolland M J et al. BMJ 2010;341:bmj.c3691 ©2010 by British Medical Journal Publishing Group

Random effects models of effect of calcium supplementation on cardiovascular events and death. Bolland M J et al. BMJ 2010;341:bmj.c3691 ©2010 by British Medical Journal Publishing Group

Calcium intake Diet and/or supplementation with an RDA of at least 1200 mg (upper limit [UL] 2000 mg) in conjunction with vitamin D Vitamin D supplementation Diagnose and treat deficiency or insufficiency (< 20 ng/ml) Supplement with at least IU D 3 /day (UL 4000 IU/day) Nonpharmacologic Approaches

Vitamin D and Fractures: Bischoff-Ferrari Meta-analysis ► ► Systematic review of double-blind RCTs of at least 1 year duration with more than 1 fracture ► ► 7 studies with informative data for non-vertebral fractures: RR = 0.83 (0.70, 0.98) ► ► 5 studies with informative data for hip fractures: RR = 0.88 (0.69, 1.13) ► ► Heterogeneity based on vitamin D dosage – –Vitamin D at a dose of IU/d, but not 400 IU/d, reduced risk of both hip and nonvertebral fractures Bischoff-Ferrari H et al: JAMA 2005;293:

Fracture Risk Reduction with Vitamin D: Meta-analysis

Fracture Risk Reduction by Achieved Level of 25(OH)D

Vitamin D and Fractures: AHRQ-Ottawa Meta-analysis ► ► Systematic review of double-blind RCTs of at least 1 year duration with more than 1 fracture ► ► 13 studies with informative data for total fractures: RR = 0.90 (0.81, 1.02) ► ► 7 studies with data for non-vertebral fractures: RR = 0.87 (0.75, 1.00) ► ► 7 studies with informative data for hip fractures: RR = 0.83 (0.68, 1.00) ► ► Heterogeneity based on residence of participants – –Significant fracture reduction among institutionalized subjects but not among community-dwelling elders Cranney A et al: IOM 2011 report

Vitamin D and the Risk of Falling Bischoff-Ferrari HA. JAMA. 2004;291:1999–2006 Pfeifer et al (2000)0.47 (0.20–1.10) Bischoff et al (2003)0.68 (0.30–1.54) Gallagher et al (2001)0.53 (0.32–0.88) Dukas et al (2004)0.69 (0.41–1.16) Graafmans et al (1996)0.91 (0.59–1.40) Pooled (uncorrected)0.69 (0.53–0.88) Pooled (corrected)0.78 (0.64–0.92) Primary Analysis Odds Ratio (95% CI) Favors Vitamin D Favors Control Odds Ratio

Potential Harms of Vitamin D Supplementation ► ► Increased risk of renal stones when given in conjunction with calcium – –RR = 1.17 (95% CI: 1.02, 1.34) – –5.7 events per 10,000 women-years ► ► No clinically important adverse effects of vitamin D supplementation Rosen CJ: NEJM 2011;364:248-54

Calcium intake Diet and/or supplementation with an RDA of at least 1200 mg (upper limit [UL] 2000 mg) in conjunction with vitamin D Vitamin D supplementation Diagnose and treat deficiency or insufficiency (< 20 ng/ml) Supplement with at least IU D 3 /day (UL 4000 IU/day) Regular load-bearing and muscle-strengthening exercise (no weight lifting if BMD in spine is low) Fall prevention advice Smoking cessation Avoid excess alcohol intake Home safety evaluation Nonpharmacologic Approaches

Current FDA-Approved Treatments for Postmenopausal Osteoporosis: 2011 ► ► Bisphosphonates – –Alendronate – –Risedronate – –Ibandronate – –Zoledronic acid ► ► Calcitonin ► ► Denosumab ► ► Hormone therapy ► ► Raloxifene ► ► Teriparatide

Pharmacologic Approaches: Summary All FDA-approved treatments reduce the incidence of vertebral fractures Some, but not all, reduce the incidence of non-vertebral fractures Some, but not all, of the drugs that reduce the incidence of non-vertebral fractures also reduce the incidence of hip fractures

Hormone Therapy: Fracture Risk Reduction ► ► Identified a total of 57 trials – –47 prevention and 10 treatment ► ► Allowed pooling across 5 and 6 trials for vertebral and nonvertebral fractures, respectively ► ► Vertebral fractures – –RR = 0.66 (0.41, 1.07) ► ► Non-vertebral fractures – –RR = 0.87 (0.71, 1.08) Wells G, et al. Endocrin Rev 2002;23:

HT = hormone therapy; CEE = conjugated equine estrogens; MPA = medroxyprogesterone acetate. The Women's Health Initiative Study Group. Control Clin Trials. 1998;19: WHI Clinical Trials of HT – –Two large, parallel group, randomized, placebo- controlled trials sponsored by NIH Unopposed CEE vs placebo (E-alone study) CEE plus MPA vs placebo (E+P study) – –Objective: To evaluate the balance of chronic disease risks and benefits of postmenopausal HT – –Primary outcomes CHD (nonfatal MI, CHD death) Invasive breast cancer – –Approximately 8 years of follow up were planned for each trial

What Happened to the WHI Clinical Trials of HT? – –E+P trial stopped by the Data Safety Monitoring Board in July 2002 after a mean follow-up of 5.2 years 1 Breast cancer risk crossed pre-specified monitoring boundary Global index indicated trend towards greater risk than benefit – –E-alone trial stopped by NIH in March 2004 after a mean follow-up of 6.8 years 2 Trend toward increased risk of stroke without overall benefit 1 Writing Group for the Women's Health Initiative Investigators. JAMA. 2002;288:321-33; 2 Women's Health Initiative Steering Committee. JAMA. 2004;291:

WHI Fracture Results – –E+P used an average of 5.6 years 1 ↓ hip fractures 33% ↓ clinical vertebral fractures 35% ↓ forearm/wrist fractures 29% ↓ total fractures 24% – –Unopposed E used an average of 6.8 years 2 ↓ hip fractures 39% ↓ clinical vertebral fractures 38% ↓ total fractures 30% 1 Cauley JA, et al. JAMA. 2003;290: Women’s Health Initiative Steering Committee. JAMA. 2004;291:

WHI Fracture Results: Clinical Implications Women treated with E alone or E+P for menopausal symptoms do not need another anti-resorptive agent to reduce either the decline in BMD or risk of fracture HT is the only therapy that has been demonstrated to prevent fractures in a population of postmenopausal women at relatively low risk of fracture

Selective Estrogen Receptor Modulators (SERMs) ► ► Raloxifene, others in clinical trials ► ► Binds to ERs ► ► Effects on many tissues ► ► Bone effects mainly anti-catabolic  – –increases BMD – –reduces risk of vertebral fractures – –Does not reduce risk of nonvertebral fractures Approved for prevention and treatment of post- menopausal osteoporosis Reduces risk of ER+ breast cancer Can be used with other nonhormonal therapies Adverse effects include hot flashes, risk of VTE

Bisphosphonates ► ► Drug class of choice for treatment – –Oral: alendronate or risedronate – –IV: zoledronic acid ► ► Contraindications – –Impaired swallowing (oral only) – –eGFR < 35 ml/min – –Hypocalcemia – –Vitamin D deficiency Favus MJ: NEJM 2010;363:

Wells G et al: Cochrane Database Syst Rev 2008;(1):CD Search Results for Alendronate Review

Evidence-Based Review ALN Trials: Non-vertebral Fractures Data on incidence of NVFx in 9 trials Only 5 trials could be pooled for effects of 10 mg daily dose Pooled estimate for RR = 0.84 (0.74–0.94) for all non-vertebral fractures at doses of 10 mg or higher RR reduction greater in the 4 treatment trials (RR=0.77 [0.64, 0.92]) No difference using T-score of <-2.5 or <-2.0 as cut-point Pooled estimate for hip fracture derived from 6 trials RR = 0.61 (95% CI 0.40, 0.92) Wells G et al: Cochrane Database Syst Rev 2008;(1):CD

Copyright ©2002 The Endocrine Society Wells G et al: Cochrane Database Syst Rev 2008;(1)CD Search Results for Risedronate Review

Evidence-Based Review of RIS Trials: Nonvertebral Fractures Pooled estimate from 4 treatment trials for all nonvertebral fractures of RR=0.80 (0.72–0.90) Results consistent across trials Pooled estimate from 3 treatment trials for hip fractures RR = 0.74 (95% CI: 0.59, 0.94) Wells G et al: Cochrane Database Syst Rev 2008;(1)CD

Effect of Ibandronate on Fracture Risk in Women with PMO ► ► Post-hoc individual patient data meta-analysis of data from 4 phase III RCTs of at least 2 years duration ► ► Subjects categorized by estimated annual cumulative exposure: low, medium, high ► ► Patients in the high ACE group (either 150 mg orally once monthly, 2 mg IV bimonthly or 3 mg IV quarterly) had a lower adjusted incidence of non- vertebral fractures than women in pooled placebo groups – –RR = 0.70 ( ) for all non-vertebral fractures – –RR = 0.66 (0.45, 0.96) for “Big 6” fracture sites Harris S, et al: Curr Med Res Opin 2008:24;

Effect of Ibandronate on Fracture Risk in Women with PMO ► ► Post-hoc individual patient data meta-analysis of data from 8 phase II and III RCTs of at least 1 year duration ► ► Subjects categorized by estimated annual cumulative exposure: low, medium, high ► ► Based on data from the 2 non-inferiority studies, patients in the high ACE group (either 150 mg orally once monthly, 2 mg IV bimonthly or 3 mg IV quarterly) had a lower adjusted incidence of non- vertebral fractures than women in low ACE group – –RR = 0.63 (0.43, 0.94) for “Big 6” fracture sites Cranney A, et al: Osteoporos Int 2008;DOI /s00198=

Once- Yearly Zoledronic Acid: The Horizon Trial ► ► 7765 postmenopausal women aged 65 to 89 years randomized to IV zoledronic acid 5 mg or PBO annually for 3 years ► ► Inclusion criteria – –Femoral neck BMD T score < -2.5 – –T-score < -1.5 and morphometric VFx (2 mild or 1 mod) ► ► Stratified randomization – –1: No concomitant OP medication at baseline – –2: OP meds, other than BPs, at baseline Black DM et al: NEJM 2007;356:

Once-Yearly Zoledronic Acid: The Horizon Trial ► ► Primary endpoints – –Stratum 1: New vertebral fractures – –Stratum 1+2 combined: Hip fractures ► ► Secondary endpoints – –Any non-vertebral fracture – –Any clinical fracture – –Clinical vertebral fracture – –Change in bone mineral density – –Change in bone turnover markers Black DM et al: NEJM 2007;356:

Once-Yearly Zoledronic Acid: The Horizon Trial Relative risk Spine0.30 (0.24,0.38) Hip0.59 (0.42,0.83) Nonvert0.75 (0.64,0.87) Clinical0.67 (0.58,0.77) Black DM et al: NEJM 2007;356:

Comparative Efficacy of N- containing Bisphosphontes ComparisonNVFxHipFx ALN v RIS 0.96 (0.78, 1.19)0.63 (0.34, 1.20) ALN v ZA 1.04 (0.82, 1.31)0.80 (0.40, 1.58) RIS v ZA 1.08 (0.90, 1.30)1.25 (0.83, 1.89) ALN v IBAN 1.17 (0.77, 1.77)N/A RIS v IBAN 1.21 (0.82, 1.80)N/A IBAN v ZA 0.89 (0.59, 1.34)N/A Hochberg M: Curr Osteoporos Rep 2008;6:89-94.

Comparative Efficacy of N- containing Bisphophonates ► ► Mixed treatment comparison (MTC) of reduction in vertebral fractures – –7 placebo-controlled trials – –ZA more likely to be associated with greater risk reduction than oral BPs ZA vs ALNOR = 0.54 (0.39, 0.75) ZA vs RISOR = 0.49 (0.34, 0.69) ZA vs IBANOR = 0.57 (0.36, 0.92) Jansen JP et al: CMRO 2009;25: and Semin Arthritis Rheum 2011;40:

Comparative Efficacy of N- containing Bisphosphontes ComparisonNVFxHipFx ALN v RIS 0.90 (0.66, 1.24)0.77 (0.37, 1.59) ZA v ALN 0.55 (0.41, 0.76)*0.95 (0.54, 1.68) ZA v RIS 0.50 (0.36, 0.70)*0.73 (0.37, 1.44) ALN v IBAN 1.05 (0.68, 1.63)0.40 (0.09, 1.55) RIS v IBAN 1.16 (0.74, 1.84)0.52 (0.12, 2.15) ZA v IBAN 0.58 (0.37, 0.92)*0.38 (0.09, 1.43) Jansen JP et al: Semin Arthritis Rheum 2011;40:

Bisphosphonates ► ► Adverse Events – –Upper GI complaints – –Acute phase reaction (IV >>> oral) – –Erosive esophagitis – –Esophageal cancer – –Osteonecrosis of the jaw – –Atypical femoral fractures Favus MJ: NEJM 2010;363:

Potential Harms of BPs: Esophageal Cancer ► ► Two studies that analyzed data from the GPRD ► ► Study 1 (cohort study) found no increase in risk (HR = 1.07 [95% CI: 0.77, 1.49]) with mean follow- up of 4.5 years ► ►Cardwell CR et al: JAMA 2010;304: ► ► Study 2 (case-control) found an increase in risk (OR = 1.30 [95% CI: 1.02, 1.66]) with mean follow- up of 7.5 years. Significant dose and duration response relationships with excess risk for >10 Rxs and duration of use >3 years ► ►Green J et al: BMJ 2010;341:c4444.

Potential Harms of BPs: Subtrochanteric Fractures ► ► Several studies have examined this relationship ► ► Most recent, a nested case-control study of older women who received Rx for oral bisphosphonate: 716 subtrochanteric and 9723 hip fractures ► ►Park-Wyllie LY et al: JAMA 2011;305: ► ► aOR = 2.74 (95% CI: 1.25, 6.02) for long-term use (>5 years) based on 121 cases ► ► Significant reduction in risk of hip fractures for both intermediate (3-5 years) and long-term use ► ►IntermediateaOR = 0.86 (0.73, 1.00) ► ►Long-termaOR = 0.76 (0.63, 0.93)

Intranasal Calcitonin ► ► Acts on specific receptors, decreases number and resorptive activity of osteoclasts, acts on kidneys to increase Ca and P i excretion ► ► Originally injected subcutaneously, now administered as a daily nasal spray ► ► Increases lumbar spine (not forearm or hip) BMD and registered for treatment of osteoporosis in women  5 years post- menopause ► ► Effects on fracture risk are not as well established as for other registered drugs ► ► Adverse events: hypersensitivity, local effects

Anabolic Therapy: Teriparatide ► ► Recombinant human PTH 1-34 – –PTH 1-84 and other analogs currently under investigation ► ► Indicated for treatment – –of women with PMO at high risk for fracture – –to increase bone mass in men with primary or hypogonadal osteoporosis who are at high risk for fracture ► ► Not for use in patients with Paget’s disease, hypercalcemia, renal disease or skeletal cancer

Neer et al. N Engl J Med. 2001;344: Teriparatide for Osteoporosis ► ► RCT in 1637 PMW with 1 or more vertebral fractures and low BMD ► ► Median follow-up 19 months ► ► Dose-dependent increase in BMD ► ► Reduction in incidence of both vertebral and non-vertebral fractures

*P<0.001 vs placebo. Risk Reduction (RR) Placebo (n=448) rhPTH 20 (n=444) rhPTH 40 (n=434) % 75% 50% 0% 25% % of Women RR 0.31 (95% CI, 0.19 to 0.50)* RR 0.35 (95% CI, 0.22 to 0.55)* Number of women who had ≥1 fracture Effect of Teriparatide on Risk of New Vertebral Fractures

*P=0.01 vs placebo. † P=0.02 vs placebo (n=544)(n=552)(n=541) Number of women who had ≥1 nonvertebral fracture RR 0.46 (95% CI, 0.25 to 0.86)* RR 0.47 (95% CI, 0.25 to 0.88) † Effect of Teriparatide on Risk of Non-vertebral Fractures

Adverse Events With Teriparatide ≥1 elevated sCa Confirmed high sCa Nausea Headache Leg cramps Withdrawn for AE Placebo 8 (2) 1 (0) 41 (7) 45 (8) 6 (1) 32 (6) PTH (11) ‡ 16 (3 ) ‡ 51 (9) 44 (8) 17 (3)* 35 (6) PTH (28) ‡ 53 (10) ‡ 98 (18) ‡ 72 (13) † 13 (2) 59 (11) § *P=0.02 vs placebo. † P = 0.01 vs placebo. ‡P< vs placebo. § P=0.004 vs placebo. No. of Adverse Events (% of total) Reported

Denosumab: The Freedom Trial ► ► 7868 postmenopausal women aged 60 to 90 years randomized to denosumab 60 mg subq or PBO q6months for 3 years ► ► Inclusion criteria – –Femoral neck BMD T score < -2.5 ► ► Primary endpoints – –New vertebral fractures ► ► Secondary endpoints – –Time to 1 st non-vertebral fracture – –Time to 1 st hip fracture – –Change in bone mineral density – –Change in bone turnover markers Cummings SR et al: NEJM 2009;361:

Denosumab: The Freedom Trial Relative risk Spine0.32 (0.26,0.41) Hip0.60 (0.37,0.97) Nonvert0.80 (0.67,0.95) Cummings SR et al: NEJM 2009;361:

*Also reduce the risk of hip fracture Evidence-Based Review of Osteoporosis Trials ► ► Several drugs reduce the risk of vertebral fractures – –Calcitonin – –Raloxifene – –Hormone Rx – –Alendronate – –Risedronate – –Ibandronate – –Zoledronic acid – –Teriparatide – –Denosumab ► ► Some drugs reduce the risk of non-spine fractures – –Hormone Rx* – –Alendronate* – –Risedronate* – –Ibandonate (?) – –Zoldedronic acid* – –Teriparatide – –Denosumab*

Safety and Tolerability Issues ► ► Bisphosphonates – –GI tolerability, ONJ, Atypical femur fractures ► ► Hormone therapy – –CV thrombotic events, Breast Ca, others ► ► Raloxifene – –Venous thrombotic events ► ► Teriparatide – –Hypercalcemia ► ► Denosumab – –Increased risk of infections

Treatments Under Development   SERMs   Bazedoxifene, lasofoxifene   Oral calcitonin   Transdermal PTH   Cathepsin K inhibitors   Sclerostin monoclonal antibody   rhIGF-1 Kawai M et al: Nat Rev Drug Discov 2011;10:141-56

All pharmacologic agents should be added to a background of calcium and vitamin D supplementation and education in non- pharmacologic treatment strategies. Recommendations: 2011 ► ► For postmenopausal women with osteoporosis – –Oral bisphosphonate (alendronate or risedronate) – –Zoledronic acid (if contraindication to or intolerant of oral BP) – –Teriparatide (“severe OP” or contraindication to, failure of or unable to tolerate BPs) – –Denosumab (as above plus contraindication to or unable to tolerate TPTH)

Thank you for your attention!