Update on the Diagnosis and Treatment of Osteoporosis: 2008 Michael Maricic, MD Catalina Pointe Rheumatology Clinical Associate Professor of Medicine University of Arizona

Disclosures Speakers Bureau, Consultant or Clinical Research Grant Support Merck Proctor and Gamble Aventis Lilly Novartis Amgen Roche Glaxo-Smith-Kline

Pre-Test Questions

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Juliana, a 66-year-old woman comes in to follow up on her hypertension She does not drink alcohol or smoke. She exercises 3 times weekly, and rates her overall health as excellent. She has never had a fracture or used corticosteroids. Her family history is unremarkable. Does she need screening for osteoporosis? 1. Yes, age 65 is the appropriate time to begin screening. 2. No, she is extremely healthy with a great lifestyle and doesn't need it. 3. No, it is too late. She should have been screened at menopause.

With further questioning, Juliana says she was told she had osteoporosis after a screening at a local health fair. She said they checked her bone density at the wrist. Are you ready to prescribe treatment? 1.Yes. The test she had is reliable and she should begin treatment. 2.No. The test she had is called a pDXA and it may be helpful in predicting decreased bone density. She should have a confirmatory test with a DEXA of the central skeleton before treatment is considered. 3.No. The test she had is called a pDXA and is not at all accurate for predicting fracture.

Should Julianas 71 year old husband be screened? 1.No, because men rarely get osteoporosis. 2.Yes, starting at age 70, because men develop osteoporosis approximately 5 years later than women. 3.No, because studies addressing this have not been done in men.

Maxine, a 52-year-old African-American woman comes to your office requesting testing for osteoporosis. She stopped menstruating one year ago. She does not have any chronic medical problems, but she doesnt get any exercise and smokes about a pack of cigarettes a day. Two years ago, she broke her ankle stepping off a curb. Do you order a DEXA screening test? 1. No, it would be better to wait until she is Yes, she has important risk factors and needs screening now. 3. No, she does not need screening, but she does need to start weight bearing exercise.

According to the WHO algorithm for 2008, which of the following can be used to calculate 10-year fracture risk? 1. Femoral neck BMD and clinical risk factors 2. Total hip BMD 3. BMD from non-hip sites 4. All of the above 5. 1 & 2 only

Update Objectives WHO Fracture Assessment Tool 2008 NOF Guidelines for Treatment Calcium and Vitamin D New Treatment Data Osteonecrosis of the jaw

1999 NOF Treatment Guidelines Treat women with a fragility fracture Treat if T-score >-2.0 Treat if T-score > -1.5 with risk factors Problem- Which risk factors are more important in deciding to treat osteopenic women

National Osteoporosis Foundation Risk Factors for Low Bone Mass and Fractures (1999) Personal history of a fracture as an adult History of a fracture in a first-degree relative Caucasian race advanced age female sex dementia poor health/frailty Current cigarette smoking Low body weight (< 127 lbs) estrogen deficiency low calcium intake (lifelong) alcoholism impaired eyesight recurrent falls inadequate physical activity Non-modifiable Modifiable

Use of WHO Fracture Risk Algorithm The WHO Fracture Risk Assessment Tool (FRAX®) was developed to calculate the 10-yr probability of a hip fracture and any major osteoporotic fracture vertebral hip forearm humerus The algorithm takes into account femoral neck BMD and clinical risk factors for fracture

Non-density Related Risk Factors Age Previous low trauma fracture Parental history of hip fracture Current cigarette smoking High alcohol intake (> 3 units/day) Rheumatoid arthritis Prior or current glucocorticoid use Adapted from Kanis JA et al. Osteoporos Int. 2005;16:

Quantifying Fracture Risk

WHO Absolute Risk Prediction Model 10-Year probability of experiencing an osteoporosis-related fracture Model mimics the Framingham Heart Study 10- year coronary heart disease (CHD) risk predictor Treatment intervention thresholds will vary by country Recommendations for treatment based on absolute fracture risknot simply on T-scores

National Osteoporosis Foundation Clinicians Guide to Prevention and Treatment of Osteoporosis 2008 Dawson-Hughes B, Lindsay R, Khosla S, Melton J, Tosteson A, Favus M, Baim S

Synopsis of Major Recommendations General Recommendations A.Counsel on the risk of osteoporosis and related fractures. B. Check for secondary causes. C. Advise on adequate amounts of calcium (at least 1200 mg/d, and vitamin D (800 to 1000 IU per day of vitamin D3). D. Recommend regular weight-bearing and muscle- strengthening exercise to reduce the risk of falls and fractures. E. Advise avoidance of tobacco smoking and excessive alcohol intake.

Basic Care (suitable for all) Assess Risk Factors and BMD (if risk factors) T-score between -1.0 and year probability of hip fractures > 3% or probability of all major fractures > 20% (FN or total T- score only) Hip or vertebral fractures or T-score -2.5 (spine, FN, or total hip) 2008 NOF Guide: Treatment Initiation Postmenopausal Women and Men 50 years Other fractures > age 50 (excluding fingers, toes and face) Secondary causes with high fracture risk* *Such as glucocorticoid use or total immobilization

Nutrition: Calcium supplementation Vitamin D Other lifestyle modifications Avoiding alcohol and tobacco abuse Exercise: Fall prevention Treatment of Osteoporosis Non-Pharmacological Options

National Osteoporosis Foundation: March 2007 Recommendations Recommended Intake for Adults 50 Years and Older Calcium (mg/day) Vitamin D 3 (IU/day) Previous (2003) –800 March 2007 revision – – National Osteoporosis Foundation. Physicians Guide to Prevention and Treatment of Osteoporosis. Available at: Accessed April 26, National Osteoporosis Foundation. National Osteoporosis Foundations Updated Recommendations for Calcium and Vitamin D 3 Intake. Available at: Accessed April 26, 2007.

What type of Calcium should we use ? Long-term Proton Pump Inhibitor Therapy and Risk of Hip Fracture Case-control study conducted using the GPRD in the UK Users of PPI therapy, H2 receptor antagonists and nonusers of acid suppression drugs older than 50 years There were 13,556 hip fracture cases and 135,386 controls The adjusted odds ratio (AOR) for hip fracture associated with more than 1 year of PPI therapy was 1.44 (95% confidence interval [CI], ) The strength of the association increased with increasing dose and duration of PPI therapy Yang Y, Lewis J, Epstein S. JAMA. 2006;296:

Vitamin D Insufficiency (<30 ng/mL): Prevalence by Latitude 42 N 35 N n=198/362 (54.7%) n=259/532 (48.7%) n=342/642 (53.3%) P = NS for Test of Trend. Holick MF et al. JCEM 2005

Vitamin D Inadequacy and Effects on Osteoporosis and Muscle Strength Insufficiency (< 30 ng / ml) Suboptimal calcium aborption 2 nd hyperparathyroidism Decreased BMD, decreased response to pharmacological therapy, increased fracture risk Frank Deficiency (< 10 ng / ml) Osteomalacia Proximal myopathy, Increased postural instability, sway, falls

Effect of Vitamin D and Calcium Supplementation on Risk of Falling 122 women living in long-term care units Age: 63–99 Randomized, double- blind, controlled trial Calcium 1200 mg/day Calcium 1200 mg/day + vitamin D 800 IU/day 12-week duration Mean serum 25(OH)D 12 ng/ml at baseline Adapted from Bischoff HA et al J Bone Miner Res 2003;18:343–351. Calcium only (n=44) Calcium + vitamin D (n=45) Fall risk –49% Reduction in falls p=0.01

*With appropriate calcium and vitamin D. PREVENTION Estrogen Raloxifene Alendronate Risedronate Ibandronate TREATMENT Salmon Calcitonin Raloxifene Alendronate Risedronate Ibandronate Zoledronic acid Teriparatide (rhPTH) FDA-Approved Therapies for Postmenopausal Osteoporosis

Low BMD on DXA Does Not Equal Postmenopausal Osteoporosis

WHI Estrogen+Progestin Trial Study Results - Fractures 34% Reduced Risk* 34% Reduced Risk** *Hip Fractures: HR 0.66; Nominal 95% CI ( ), Adjusted 95% CI ( ) **Vertebral Fractures: HR 0.66; Nominal 95% CI ( ), Adjusted 95% CI ( ) Writing Group for the Womens Health Initiative. JAMA. 2002;288:

FDA Recommendations on ET/HT When prescribing medication to prevent osteoporosis, physicians should consider all non-estrogen preparations first When prescribing ET/HT, physicians should prescribe the smallest dose for the shortest amount of time to achieve treatment goals Physicians should prescribe ET/HT products only when the benefits are believed to outweigh the risks for a specific patient US Food and Drug Administration. FDA News, January 8, Although other doses and combinations of estrogens and progestins were not studied, the FDA believes the risks attributable to the combination in the WHI Study are applicable to all HT products.

Effect of Raloxifene on New Clinical Vertebral Fractures at 1 Year Maricic M, et al. Arch Intern Med. 2002;162: *P=.01 vs placebo RR 0.32* (95% CI = ) 68% Placebo (N=2576) Raloxifene 60 mg/d (N=2557) % of Women With Incident Vertebral Fractures

Raloxifene: Effect on Nonvertebral and Hip Fracture (MORE) Pooled Data (60 mg and 120 mg*) Placebo Raloxifene pooled Months Percent of Patients With Incident Nonvertebral Fractures Non-Vertebral FracturesHip Fractures Months Placebo Raloxifene pooled *Not FDA-approved dose. Ettinger B, et al. JAMA. 1999;282(7):

Effect of Raloxifene on Breast Cancer Incidence MORE Trial - 4 Years Years since Randomization Total Cases = 77 Arrow denotes annual mammogram Cauley J, et al. Breast Cancer Res Treatment. 2001;65: % of Randomized Patients Raloxifene Placebo RR = 0.38 (95% CI = )* *P <.001

Which Bisphosphonate is Best? We dont know

Real-World Persistence to Daily and Weekly Bisphosphonate Therapies Data from Downey TW, et al. South Med J. 2006;99: Months of Continuous Persistence Daily Weekly % of Patients P = NS

Oral Bisphosphonates Alendronate- Weekly Risedronate- Weekly, monthly Ibandronate- Monthly

I.V. Bisphosphonates: Potential Clinical Usage Oral bisphosphonate intolerance Contraindications to oral bisphosphonates Dysphagia, severe GERD, Bed-ridden patients Assure compliance where there is evidence for non-compliance

I.V. Bisphosphonates Ibandronate- 3 mg Q 3 months Zoledronic acid- 5 mg once yearly I.V. Route of administration - bypasses GI tract -assures compliance

Continued Increases in BMD in Women With Postmenopausal Osteoporosis Following 2 Years of IV Ibandronate: Dosing Intravenous Administration Study (DIVA) Lane N, Genant HK, Barr CE, Lewiecki EM, Maricic M Presented at the American College of Rheumatology. 11/06

Objectives Assess the efficacy of IV ibandronate 3 mg quarterly versus 2.5 mg PO daily in terms of relative (%) change from baseline in Bone Mineral Density at 1 and 2 years Assess the change from baseline in serum CTX (marker of bone resorption) Assess safety DIVA Study Lane N, et al. ACR 11/06

DIVA: Year 2 BMD Percent Change from Baseline 3.1 * * 6.3 * 4.8 Total HipFemoral NeckTrochanterLumbar Spine Mean % Change mg Daily PO (n=330)3 mg Quarterly IV (n=333) Quarterly IV dosing regimen had a significantly greater effect on mean BMD at Year 2 than the PO dosing regimen, PP population *P< Lane N, et al. ACR 11/06

Safety Parameters: DIVA study Acute Phase Reaction (APR) Occurred in 10% of patients receiving 3 mg IV quarterly Generally transient and mild to moderate in intensity Most cases occurred in the first year only Others Changes in serum creatinine were not significant Osteonecrosis of the jaw was not reported Lane N, et al. ACR 11/06

Zoledronic Acid HORIZON Pivotal Fracture Trial Randomized, double-blind, placebo-controlled, multinational study of the efficacy and safety of Zoledronic acid for the treatment of postmenopausal osteoporosis 7736 osteoporotic women aged years Zoledronic acid administered once a year for 3 consecutive years, as a single 5 mg dose, for a total of 3 doses

Two primary efficacy variables Incidence of hip fractures over a median duration of 3 years Incidence of morphometric vertebral fractures at 3 years Key secondary efficacy variables Incidence of clinical fractures over 3 years Incidence of non-vertebral fractures over 3 years Percentage change in BMD at lumbar spine, femoral neck, and total hip at 3 years HORIZON Pivotal Fracture Trial Black DM, et al. N Engl J Med. 2007;356:

HORIZON Pivotal Fracture Trial: Effect on Vertebral Fractures 0–1 years0–2 years0–3 years 3.7% 1.5% 7.7% 2.2% 10.9% 3.3% % Patients With New Vertebral Fracture *P <.001 RRR = Relative risk reduction ZA 5 mg Placebo RRR 60%* RRR 71%* RRR 70%* Proportion of Patients With New Morphometric Vertebral Fractures Black DM, et al. N Engl J Med. 2007;356:

Placebo (n = 3861) ZA (n = 3875) Time to First Hip Fracture (months) Cumulative Incidence (%) HORIZON Pivotal Fracture Trial: Effect on Hip Fractures Over 3 Years RRR 41% Stratified log-rank test P-value =.0024 Cumulative Incidence of Hip Fractures Over 3 Years Black DM, et al. N Engl J Med. 2007;356:

*Excluding finger, toe and facial fractures Includes clinical thoracic and clinical lumbar vertebral fractures Excluding finger, toe, facial, and clinical thoracic and lumbar vertebral fractures HORIZON Pivotal Fracture Trial: Effects on All Clinical Fractures Over 3 Years 8.4% 12.8% 2.6% 0.5% 10.7% 8.0% RRR 33% RRR 77% RRR 25% Event Rate (%) Any Clinical Fracture* Clinical Vertebral Fracture Non-Vertebral Fracture ZA 5 mg (n = 3875) Placebo (n = 3861) Black DM, et al. N Engl J Med. 2007;356:

Adverse Reactions Total SAEs were similar between groups (29.2% zoledronic acid vs 30.1% placebo) The most common adverse events were post dose symptoms Majority occur within 3 days after dosing Usually resolves within 3 days Incidence rate (%)

Zoledronic Acid: Hypocalcemia All women received 1,000 to 1,500 mg calcium plus 400 to 1,200 IU vitamin D per day Following zoledronic acid administration, ~0.2% of patients had notable declines in serum calcium levels (less than 7.5 mg/dL) No symptomatic cases of hypocalcemia Black DM, et al. N Engl J Med. 2007;356:

Zoledronic Acid: Atrial Fibrillation Overall incidence of atrial fibrillation AEs was 2.5% of zoledronic acid patients vs 1.9% in placebo patients Adjudicated Serious Adverse Events of atrial fibrillation (requiring hospitalization) occurred in 1.3% of patients compared to 0.4% in the placebo group Over 90% of these events in both groups occurred more than a month after the infusion Black DM, et al. N Engl J Med. 2007;356:

Zoledronic Acid: Renal Safety Not recommended for use in patients with severe renal impairment (creatinine clearance <35 mL/min) Monitor serum creatinine before each dose. Transient increase in serum creatinine may be greater in patients with impaired renal function; consider interim monitoring of serum creatinine in at-risk patients 1. Black DM, et al. N Engl J Med. 2007;356: Miller P, et al. Poster presented at: 7th European Congress on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis; March 28-31, 2007; Porto, Portugal. Poster P308. Mean (±SE) Change From Baseline in Calculated Creatinine Clearance (mL/min) Reclast (n = 3862) Placebo (n = 3852) –15 –10 –5–5 0 Months Changes in Calculated Creatinine Clearance* From Baseline Over Time 3 *Cockcroft-Gault equation

Zoledronic Acid: Osteonecrosis of the Jaw In the HORIZON Pivotal Fracture Trial, out of 7736 patients, symptoms consistent with ONJ occurred in 1 patient treated with placebo and 1 patient treated with zoledronic acid over 3 years Both cases resolved after appropriate treatment Black DM, et al. N Engl J Med. 2007;356:

Osteonecrosis of the Jaw (ONJ): Definition A confirmed case of bisphosphonate-associated ONJ was defined as an area of exposed bone in the maxillofacial region that did not heal within 8 weeks after identification by a health care provider in a patient who was receiving or had been exposed to a bisphosphonate J Bone Miner Res Oct;22(10):

Challenges of Studying ONJ ONJ rare event Difficult to get background rates in general population Difficulty in identifying cases with ONJ in databases- no unified definition The incidence of ONJ in the general population not exposed to bisphosphonates is unknown Although this association is consistent with a role for bisphosphonates, bisphosphonates have not been proven to be causal. J Bone Miner Res Oct;22(10):

Case Reports: ONJ in Osteoporosis Most cases have been described in cancer patients receiving monthly IV bisphosphonates As of Oct. 2007, 57 cases have been associated with oral bisphosphonate treatment for osteoporosis after duplicated case reports had been excluded. J Bone Miner Res Oct;22(10):

Recommendations Patients taking bisphosphonates should be encouraged to maintain good oral hygiene, and to have regular dental visits They should be urged to report any oral problems to their dentist and physician It is not necessary to recommend a dental examination before beginning oral bisphosphonate therapy or to otherwise alter routine dental management. J Bone Miner Res Oct;22(10):

Recommendations Patients should be informed that the risk of developing bisphosphonate-associated ONJ with routine oral therapy for osteoporosis appears to be low, ranging between 1/100,000 and 1/250,000 This risk should be balanced with the risk of osteoporotic fractures in that patient J Bone Miner Res Oct;22(10):

Teriparatide PTH (1-34): Indications Postmenopausal women or men with osteoporosis at high risk of fracture High-risk includes: Men and women with previous osteoporotic fracture(s) Men and women with multiple risk factors for fracture Those who have failed or are intolerant to other osteoporosis therapies US food and drug administration. FDA talk paper. November 26, 2002

Effect of Teriparatide (rhPTH(1-34)) on the Risk of New 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)* 65%69% Neer RM, et al. N Engl J Med. 2001;344(19):

Effect of rhPTH(1-34) on the Risk of Nonvertebral Fragility Fractures * p = 0.02 vs. Placebo ** p = 0.01 vs. Placebo % 54% (n=544)(n=552)(n=541) No. of women who had > 1 fragility fracture RR 0.46 (95% CI, 0.25 to 0.86)** RR 0.47 (95% CI, 0.25 to 0.88)*

Teriparatide PTH (1-34): Adverse Effects Side effects are usually mild and may include nausea, leg cramps or dizziness Use currently limited to 2 years PTH trials were stopped early due to the finding of osteosarcoma in animal studies FDA assigned a black box warning because of osteosarcoma findings in animal studies. US Food and Drug Administration. FDA. Talk Paper. November 26, 2002.

Teriparatide PTH (1-34): Warnings Hypercalcemia Paget's disease of bone Growing children and young adults Pregnant or nursing women A history of bone cancer A history of cancer that has metastasized to the bones Radiation to the skeleton from any condition US food and drug administration. FDA talk papers. November 26, 2002

Other Issues with Teriparatide Cost How to combine/sequence it with bisphosphonates

*With appropriate calcium and vitamin D. PREVENTION Estrogen Raloxifene Alendronate Risedronate Ibandronate TREATMENT Salmon Calcitonin Raloxifene Alendronate Risedronate Ibandronate Zoledronic acid Teriparatide (rhPTH) FDA-Approved Therapies for Postmenopausal Osteoporosis

Post-Test Questions

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Juliana, a 66-year-old woman comes in to follow up on her hypertension She does not drink alcohol or smoke. She exercises 3 times weekly, and rates her overall health as excellent. She has never had a fracture or used corticosteroids. Her family history is unremarkable. Does she need screening for osteoporosis? 1. Yes, age 65 is the appropriate time to begin screening. 2. No, she is extremely healthy with a great lifestyle and doesn't need it. 3. No, it is too late. She should have been screened at menopause.

With further questioning, Juliana says she was told she had osteoporosis after a screening at a local health fair. She said they checked her bone density at the wrist. Are you ready to prescribe treatment? 1.Yes. The test she had is reliable and she should begin treatment. 2.No. The test she had is called a pDXA and it may be helpful in predicting decreased bone density. She should have a confirmatory test with a DEXA of the central skeleton before treatment is considered. 3.No. The test she had is called a pDXA and is not at all accurate for predicting fracture.

Should Julianas 71 year old husband be screened? 1.No, because men rarely get osteoporosis. 2.Yes, starting at age 70, because men develop osteoporosis approximately 5 years later than women. 3.No, because studies addressing this have not been done in men.

Maxine, a 52-year-old African-American woman comes to your office requesting testing for osteoporosis. She stopped menstruating one year ago. She does not have any chronic medical problems, but she doesnt get any exercise and smokes about a pack of cigarettes a day. Two years ago, she broke her ankle stepping off a curb. Do you order a DEXA screening test? 1. No, it would be better to wait until she is Yes, she has important risk factors and needs screening now. 3. No, she does not need screening, but she does need to start weight bearing exercise.

According to the WHO algorithm for 2008, which of the following can be used to calculate 10-year fracture risk? 1. Femoral neck BMD and clinical risk factors 2. Total hip BMD 3. BMD from non-hip sites 4. All of the above 5. 1 & 2 only

Clinical Practice Recommendation Practice Recommendation: All postmenopausal women should be evaluated for risk factors of osteoporosis which include increasing age, white race, low weight or weight loss, nonuse of estrogen replacement, history of previous fracture, family history of fracture, history of falls, and low scores on one or more measures of physical activity or function. Evidence-Based Source: AHRQ Web Site of Supporting Evidence: Strength of Evidence: A systematic review of 530 articles about risk factors, 123 about bone measurement tests, 23 about bone density monitoring, 277 about biochemical markers, and 53 about costs. An additional 242 studies were retrieved after reviewing reference lists of studies and by suggestion of the expert panel or leading researchers in the field

Clinical Practice Recommendation Practice Recommendation: Bisphosphonates (alendronate, etidronate, and risedronate) are recommended as treatment options for the secondary prevention of osteoporotic fragility fractures Evidence-Based Source: National Guideline Clearinghouse Web Site of Supporting Evidence: Strength of Evidence: The recommendations are based primarily on the available evidence from randomized controlled trials.