Update in Osteoporosis

Slide 1:Update in Osteoporosis

Teresa Bryan, M.D. General Medicine Noon Conference February 24, 2009

Slide 2:Objectives

WHO Task Force Fracture Risk Assessment Tool (FRAX) NOF Guidelines for pharmacologic intervention in postmenopausal women and men = age 50 ACP Practice Guidelines for Screening in Men ACP Practice Guidelines for Pharmacologic Therapy Association of Atrial fibrillation with bisphosphonates Bisphosphonate associated osteonecrosis of the jaw

Slide 3:Background

Estimated 44 million Americans 55% people 50 years of age or older 1 out of every 2 Caucasian women will experience osteoporotic fracture and 1 out of every 5 men. Hip fractures result in 10-20% excess mortality in 1 year. 20% hip fracture patients require long-term nursing home care.

Slide 4:US Preventive Services Task Force RecommendationsAnn Int Med. 2002;137:526-528

Routinely screen women 65 years of age and older. Screen women at increased risk beginning at 60 years of age. No recommendation for or against routine screening in women younger than 60 years of age.

Slide 5:Definitions

Osteoporosis: a skeletal disorder characterized by compromised bone strength predisposing to an increased risk for fracture. Diagnosed by: Occurrence of fragility fracture Osteoporosis by DXA criteria Osteoporotic fracture: (fragility fracture) those occurring from a fall from a standing height or less without major trauma such as a MVA.

Slide 6:Dexa Interpretation

T score: Difference in SDs compared to value of young adults same sex. Z score: Difference in SDs compared to value of individuals same age and sex. Osteoporosis: T score =-2.5 Osteopenia: T score between -1 and -2.5 SD=Standard Deviation

Slide 7:Osteoporotic Risk Assessment

Majority of fracture occur in those with low bone mass rather than osteoporosis WHO Fracture Risk Assessment Tool (FRAX) Considers 9 clinical risk factors for osteoporosis

Slide 8:FRAX Risk Factors

Age Previous Fracture Parent with h/o hip fracture Current smoking Glucocorticoids > 3 months Rheumatoid arthritis Secondary osteoporosis Alcohol 3 or more units daily Bone Mineral Density

Slide 9:WHO Fracture Risk Assessment Tool (FRAX)

http://www.shef.ac.uk/FRAX/ Country specificCountry specific

Slide 10:WHO Fracture Assessment Tool

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

Slide 11:Applications of FRAX in US

Not intended for young adults or children Only applies to previously untreated patients Total hip density may be substituted for femoral neck BMD Convert T score based on reference standard used in FRAX

Slide 12:Cost-effectiveness

Intervention threshold: 10 year fracture probability 2.5 to 4.9% Assumes annual treatment cost of $600 “Willingness to pay” threshold of $60,000 per QALY gained Osteoporosis International Dec 2007 http://www.nof.org/professionals/Cost-effective_osteoporosis_%20treatment_US.pdf

http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf

Slide 13:NOF clinicians guide: Endorsed by: AA clinical endocrinologists ACOG AC radiology AC rheumatology American Geriatric Society American orthopedic assn NOF clinicians guide: Endorsed by: AA clinical endocrinologists ACOG AC radiology AC rheumatology American Geriatric Society American orthopedic assn

Slide 14:National Osteoporosis FoundationScreening Recommendations

Women 65 and older Men 70 and older Postmenopausal and perimenopausal women with increased risk factor profile (low body wt, prior fx, meds) Men 50-70 with increased risk factor profile Fracture after age 50 Consider in postmenopausal women discontinuing estrogen. . .

Slide 15:Risk Factors

NEJM 2008;358:1474-82. RISK Factors: weighted. RISK Factors: weighted.

Slide 16:Secondary Osteoporosis

Type 1 DM Osteogenesis imperfecta Untreated, longstanding hyperthyroidism Hypogonadism Premature menopause <45 year. Chronic malnutrition Malabsorption Chronic liver disease Meds: anticonvulsants, heparin, glucocorticoids

Slide 17:Clinical Assessment of Osteoporosis in Postmenopausal Women and Men >50

History and physical exam Consider laboratory tests: (esp if Z<2.0) Ca, phos, Cr, LFTs, TSH, CBC, VIt D level Testosterone level in men If clinically indicated: SPEP, Urine cortisol, Urine calcium, anti-tissue transglutaminase antibodies (Celiac sprue)

Slide 18:Pharmacologic Therapy(NOF Recommendations for Postmenopausal Women and Men >50)

Hip or vertebral fracture T score = -2.5 femoral neck, total hip or spine T score -1 to -2.5 hip or spine: 10 year hip fx probability = 3%* 10 year all major osteoporosis related fx probability = 20% * *WHO absolute fracture risk model

Slide 19:Case

57 year old woman. Healthy. FH: 80 year old mother with mult vertebral fx and “hump” in her back Prior fx: cervical spine when fell off bed playing with grandson No smoking, no ETOH, no prior prednisone, no RA or secondary causes Weight: 155 lb Height 5ft 6 in

Slide 20:Case (cont)

T score -2.4 Frax assessment tool: 10 year probability of fx Major osteoporotic: 21% Hip: 4.9

Slide 21:Universal Recommendations

Adequate intake of calcium and vitamin D: Adults > 50: 1200 mg elemental calcium /day All adults > 50: 800-1000 IU/day Regular Weight Bearing Exercise: At least 30 min 3x weekly Fall prevention strategies: Correct vision and hearing problems Evaluate neuro problems Review meds for Side effects Avoid tobacco and alcohol

Slide 22:Treatment OptionsFDA Approved

Bisphosphonates Estrogen SERMS (Selective Estrogen Receptor Modulators) Calcitonin Forteo (parathyroid hormone)

Slide 23:Bisphosphonates

Alendronate (fosamax): 10 mg qd or 70 q week Risedronate (actonel): 5 mg qd or 35mg q week Ibandronate (Boniva): 2.5mg qd, 150 mg q month, 3mg IV q3 months Zolendronic acid (Reclast): 5mg IV yearly Treatment efficacy: Bisphosphonates decrease risk vertebral fracture by approx 50% Risk of hip fracture decreased by 37%

Slide 24:Estrogen Agonists/Antagonists(Formerly SERMS)

Raloxifene (Evista) Decreased vertebral fx 30%-55% 60 mg qd Increase risk DVT No effect on endometrium Decreases risk of breast cancer Causes hot flashes (6%)

Slide 25:Calcitonin

Miacalcin: nasal, SQ or IM 200 IU intranasally qd 25-39% reduction vertebral Possible analgesic action for acute osteoporotic fracture

Slide 26:PTH (Teriparatide)

Forteo 20 ug SQ daily Previous failed therapy Decrease vertebral fx 65% Osteosarcoma in rats Expensive

Slide 27:Estrogen

FDA approved Osteoporosis prevention Vasomotor symptoms Vulvovaginal atrophy Progesterone combination if no hysterectomy Risk MI/Stroke/Breast CA Consider non-estrogen treatment first

Slide 28:Monitoring Effectiveness

Monitor and encourage compliance Review risk factor modification Calcium and vitamin D intake Repeat BMD q 2 years (medicare guidelines)

Slide 29:Osteoporosis in Men

1.5 million men over age 65 in US have osteoporosis Mortality with hip fractures higher in men up to 37.5% Absolute BMD in men who fracture hip is higher than in women. Prevalence: 7% white men 5% black men 3% Hispanic men

Slide 30:Case

68 year old WM COPD Stopped smoking 9 years ago 2 prior pred tapers x 2 weeks Wt 180 lb, Ht 5 ft 8in No alcohol, RA FH negative Frequent yard work

Slide 31:ACP Guidelines for Screening in Men Risk Factors

Age >70 years Low body weight (BMI<20-25 kg/m2) Weight loss > 10% Physical inactivity Use of oral corticosteroids Previous fragility fracture Ann Intern Med 2008;148:680-684.

Slide 32:Common Secondary Causes in Men

Cushing’s or steroid therapy Excessive alcohol use Hypogonadism Low calcium intake of Vit D insufficiency Smoking Family history of minimal trauma fracture Ann Intern Med 2008;148:680-684

Slide 33:ACP Guidelines in MenRecommendations

1- Perform individualized assessment of risk factors for osteoporosis in older men (Strong recommendation; high-quality evidence) 2- Obtain DXA for men who are at increased risk for osteoporosis and are candidates for drug therapy (Strong recommendation; moderate-quality evidence) 3- Further research to evaluate osteoporosis screening tests in men Ann Intern Med 2008;148:680-684

Slide 34:Treatment in Men

Treat secondary causes Bisphosphonates reasonable first line Teriparatide Calcitonin Raloxifene not well studied in men

Slide 35:Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: A Clinical Practice Guideline from the ACP (Ann Intern Med 2008;149:404-415.)

What are the comparative benefits in fracture reduction among treatments for low bone density? How does fracture reduction resulting from treatments vary among individuals with different fracture risks? What are the short and long-term adverse effects and do these vary by specific subpopulations?

Slide 36:Effect of Bisphosphonates on Fracture Risk Reduction

Annals 2008;149:404-415

Slide 37:    

Slide 39:Effect on Fracture Risk Reduction

Annals 2008;149:404-415

Slide 42:ACP Recommendations

1- Offer pharmacologic treatment to men and women who have known osteoporosis and to those with h/o fragility fractures. (Strong recommendation; high-quality evidence) 2- Consider treatment for men and women at risk for developing osteoporosis. (weak recommendation; moderate-quality evidence) 3- Choose treatment options based on assessment of risk and benefit to individual patients. (Strong recommendation; moderate-quality evidence) 4- ACP recommends further research to evaluate treatment of osteoporosis in men and women. Ann Intern Med 2008;149:404-415

Slide 43:Risk of Afib with Bisphosphonates

Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly -Pivotal Fracture Trial (HORIZON)* RCCT: 7765 postmenopausal women with osteoporosis yearly zoledronic acid vs placebo x 3 yrs. Significant reduction in hip and vertebral fractures Increased incidence of Afib classified as serious adverse event (1.3% vs 0.4%) P<0.001 Overall freq of AF no different in 2 groups (2.4 vs 1.9%) Subsequent HORIZON-Recurrent Fracture Trial failed to find increased AF in treatment group.

Slide 44:Rate of AF serious adverse eventsHorizon-Pivotal Fracture Trial

Slide 45:Association of other Bisphosphonates with AF Risk

Fracture Intervention Trial (FIT): RCCT of alendronate in 6459 postmenopausal women. Serious adverse AF events alendronate (1.5%) vs placebo (1.0%) P=.07 NEJM 2007;356:1895-1896. Case control study: More AF patients (719) than controls(966) had ever used alendronate (6.5% vs 4.2%, P=.03) Arch Int Med. 2008;168(8):826-31. Larger case control study in Denmark: No assn of bisphosphonate use with AF in 13,586 patients w/AF and 68,054 controls. (3.2% vs 2.9%) BMJ 2008;336:813-16.

Slide 46:Summary

Some suggestion of increased AF serious adverse events with bisphosphonate therapy Not a consistent finding Prior RCCT were not designed to examine the occurrence of Afib. Unlikely that there is causal relation between AF and bisphosphonates.

Slide 47:Case

68 year old WF calls you saying that her dentist wants to extract a tooth, but he is very concerned because she is on alendronate 70mg weekly. She wants to know your opinion regarding her risk for ONJ. PMH: 2 prior fragility fractures, T score <2.5 MEDS: alendronate 70 mg x 8 years

Slide 48:ONJ

Slide 49:Bisphosphonate Associated ONJ: Definition

Current or previous treatment with a bisphosphonate Exposed, necrotic bone in the maxillofacial region > 8 weeks No history of radiation therapy to the jaws American Academy of Oral and Maxillofacial Surgeons

Slide 50:Case Series 119 patients

. J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75

Slide 51:Case Series 119 patients

J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75

Slide 52:Epidemiology

Annals systematic review: 368 ONJ patients 84% with multiple myeloma or breast cancer 4% with osteoporosis 60% after dentoalveolar surgery Remaining 40% probably related to infection, denture trauma or other trauma Prevalence of ONJ in cancer patients 6-10% Prevalence in osteoporosis patients unknown Ann Intern Med 2006;144:753-761.

Slide 53:Epidemiology

ASBMR task force review of case reports estimated risk as 1 in 10,000 to 1 in 100,000 patient years of treatment. Post-marketing surveillance Merk: 170 cases/20 million patient years (0.7/100,000patient years) Proctor and Gamble: 1/10,000 patient years RCCTs: No cases of ONJ reported alendronate, risedronate, ibandronate HORIZON: 2 cases (control, and placebo equal) Population based prevalence studies : 3 cases in 780,000 patients receiving bisphosphonates for osteoporosis. <1 in 100,000 patient-years

Slide 54:Case

Patient later informed you that she underwent procedure without incident. The dentist had drawn “blood-work” which indicated that her risk for ONJ was very low.

Slide 55:Bone Turnover Markers as Predictors of Risk?

Serum levels of morning fasting C terminal telopeptide (CTX) Based on data from 17 ONJ patients receiving bisphosphonates <100 low risk 100-150 moderate risk >150 high risk Limitations: No controls Reduced markers of resorption expected in patients receiving bisphosphonates Low normal range in healthy women falls within range proposed as high risk. J Oral Maxillofac Surgery 2007;65:2397-2410

Slide 56:Clinical Application

Risk of ONJ <1 in 100,00 patient years in non-cancer patients using bisphosphonate treatment suggests a positive benefit-risk profile. All patients taking bisphosphonates should be informed of the benefits and risks of treatment. Patients taking bisphosphonates should be encouraged to maintain good oral hygeine.

Slide 57:Summary

Consider screening postmenopausal women and men over 50 at increased risk for osteoporosis Educate patients on universal recommendations Consider treating patients with: Prior fragility fracture T<-2.5 Osteopenic patients with elevated risk profile Review risk/benefit profile with all patients

Slide 58:Medicare Coverage for BMD Testing

Estrogen deficient women at clinical risk Individuals with vertebral abnormalities Individuals receiving or planning to receive long term glucocorticoid therapy Primary hyperparathyroidism To assess response to therapy Medicare coverage: Including but not limited to. = 5mg daily for 3 months. Medicare coverage: Including but not limited to. = 5mg daily for 3 months.

Slide 59:Screening: Pros and Cons

Pros: Common disease with significant morbidity Screening methods available Interventions available to reduce risk Knowledge of risk could improve compliance Cons: Little direct evidence that screening improves outcome. No cutoff value for BMD that delineates fracture risk. Other risk factors may be more important than BMD Cost efficiency issues Knowledge of normal value may hinder compliance

Slide 60:Non-FDA Approved Drugs

Calcitriol Other bisphosphonates: (etidronate, pamidronate, tiludronate) Parathyroid Hormone (PTH-84) Sodium Flouride Strontium renelate Tibolone

Slide 61:Adverse Effects of Drugs

Bisphosphonates: Gastrointestinal: Esophageal ulcerations Mild upper GI events (reflux, nausea) Osteonecrosis of the jaw: Atrial fibrillation: Alendronate and zolendronic acid

Slide 62:Adverse Effects

Estrogen Thromboembolic events Breast cancer (estrogen + progesterone) Teripartide RCCTS ? no evidence of serious adverse events SERMs Pulmonary embolism Thromboembolic Calcium and vitamin D RCCTs no clinically important serious adverse events.