Osteoporosis Evaluation and Treatment

Osteoporosis Evaluation and Treatment Anne Schafer, MD Assistant Professor of Medicine Division of Endocrinology & Metabolism October 28, 2011 No conflicts of interest

Objectives Explain when to initiate screening Describe nonpharmacologic strategies for better bone health Identify candidates for pharmacologic therapy Answer patients questions about potential risks of osteoporosis medications Osteoporosis Has Tremendous Medical and Economic Impact Mortality after hip fracture ~25% at 1 yr Of survivors, only 50% recover prefracture functional status 1.5 million fractures per year in US Direct cost $18 billion (Lu-Yao, Am J Pub Health, 1994; Magaziner, J Gerontol, 1990; Burge, JBMR, 2007)

Osteoporosis Definition A chronic, progressive disease characterized by low bone mass, microarchitectural deterioration of bone, bone fragility and a consequent increase in fracture risk Decreased bone quality as well as quantity (National Osteoporosis Foundation, 2008) Osteopenia Definition Preferred term is low bone mass Bone mineral density (BMD) lower than that considered normal but not low enough to be classified as osteoporosis May be useful for epidemiologic studies, but not a disease

Risk Factors for Osteoporosis Non Modifiable Increasing age Female gender White or Asian race Family history Previous osteoporotic fracture Modifiable Low BMI Current smoking Alcohol ( 3/day) Immobilization Glucocorticoids Sex hormone deficiency Amenorrhea Menopause Risk Factors for Falls Cognitive impairment Frailty Impaired vision Residential facility History of falls

Screening for Osteoporosis National Osteoporosis Foundation: Women age 65 and men age 70 Younger postmenopausal women, and men age 50-69, with additional risk factors Adults with a condition or taking a medication associated with bone loss Adults who fracture after age 50 (National Osteoporosis Foundation, 2008) Screening for Osteoporosis US Preventive Services Task Force: Women age 65 Younger women whose risk is equal to that of a 65 y.o. white woman who has no additional risk factors 9.3% ten-year risk for any osteoporotic fracture, by the US FRAX algorithm Current evidence insufficient to assess benefits vs. harms in men (United States Preventive Services Task Force, 2011)

DXA Scanning Dual-energy X-ray absorptiometry (DXA) assesses areal (2-dimensional) BMD at key regions of interest Lumbar spine, total hip, femoral neck Same machine, by same operator, for optimal longitudinal assessment Reports BMD (g/cm 2 ), T-scores, Z-scores T-scores: compared to sex-matched reference population of young adults Z-scores: age- and sex-matched WHO Definitions - 1994 Normal = BMD within one SD of a young normal adult (T-score +1.0 to -1.0) Low bone mass ( osteopenia ) = BMD between 1 and 2.5 SDs below young normal adult (T-score -1.0 to -2.5) Osteoporosis = BMD 2.5 or more SDs below young normal adult (T-score -2.5) For use in postmenopausal women and men age 50 (WHO, 1994)

What about premenopausal women and men <50? Diagnose with care! ISCD: Use race-adjusted Z-scores, with low BMD for chronological age defined as Z-score -2.0 Diagnosis of osteoporosis not made on densitometric criteria alone Example of diagnostic challenge: Adolescent girl who has not attained peak bone mass (Simonelli et al., J Clin Densitom, 2008) Other Limitation of WHO Definition Does not recognize that a presumptive diagnosis of osteoporosis can be made by a low-trauma (fragility) fracture regardless of the patient s BMD

Approach to Osteoporosis Treatment 1) Evaluation for secondary causes of osteoporosis and/or fracture 2) Institution of nonpharmacologic strategies 3) Selection of pharmacologic therapy Secondary Causes of Osteoporosis and/or Fracture Vitamin D deficiency Rheumatoid arthritis Calcium deficiency Medications Malabsorption (e.g., celiac Glucocorticoids disease, gastric bypass Aromatase inhibitors surgery) Depo-Provera Hypogonadism Thyroid hormone Thyrotoxicosis excess Thiazolidinediones Primary hyperparathyroidism Phenytoin Anorexia nervosa Androgen deprivation Multiple myeloma therapy

How extensive a laboratory workup does a patient need? Depends on degree of suspicion Pre-menopausal women, men deserve more Severe (e.g., multiple fractures, very low Z-scores) Basic: Serum Ca, alb, Cr, 25(OH)D, TSH, CBC, LFTs Next level: 24-hour urinary Ca, PTH, SPEP/UPEP, testosterone in men As clinically indicated: Celiac disease antibodies, 24-hour urinary free cortisol or dexamethasone suppression test Nonpharmacologic Strategies Calcium Vitamin D Weight-bearing & resistance exercise Smoking cessation Alcohol moderation Fall prevention measures Home safety evaluation Medication review Hip protectors

New IOM Dietary Reference Intakes AGE CALCIUM (mg) (RDA) CALCIUM (mg) (UL) VITAMIN D (IU) (RDA) VITAMIN D (IU) (UL) 19-50 1000 2500 600 4000 51-70 1000 (men) 1200 (women) 2000 600 4000 >70 1200 2000 800 4000 19-50, pregnant/ lactating 1200 2000 800 4000 (Institute of Medicine, 2010) Vitamin D: The Controversy IOM: 25-hydroxyvitamin D level of 20 ng/ml adequate for bone health Based on rigorous RCT evidence Population-based recommendation Others insist 30 ng/ml optimizes Ca absorption, suppresses PTH, protects against fractures/falls More than 600-800 IU daily may be needed to achieve 20 (or 30) ng/ml Malabsorption, obesity (Institute of Medicine, 2010; Endocrine Society, 2011)

Do calcium supplements cause heart attacks? 2008, 2010: Secondary analysis of calcium supplementation RCT, and subsequent metaanalysis, both suggested increase in CV events with calcium supplementation Limitations CV outcomes not primary outcomes Event frequency low Non-uniform adjudication of outcomes Other studies show no increased risk Calcium + vitamin D does reduce fracture risk in older adults (Bolland, BMJ, 2008; Bolland, BMJ, 2010; Chapuy, NEJM, 1992; Boonen, JCEM, 2007) Pharmacologic Therapy NOF recommends osteoporosis medication for postmenopausal women and men 50 with An osteoporotic hip or vertebral fracture T-score at the femoral neck or spine -2.5 after secondary causes excluded Low bone mass (T-score < -1.0 but > -2.5) and FRAX 10-year risk of - major osteoporotic fracture 20%, or - hip fracture 3% (Tosteson, Osteoporos Int, 2008)

FRAX Estimates 10-year absolute fracture risk Especially for those in low bone mass ( osteopenia ) range Example: 80 y.o. w/ prior fracture and taking prednisone, 52 y.o. with no risk factors, both with femoral neck T-score -2.0 Applies to postmenopausal women and men 50 y.o., who are treatment naïve (Kanis, Osteoporos Int, 2008) FRAX (www.sheffield.ac.uk/frax/)

Pharmacologic Therapy Antiresorptive agents Bisphosphonates (oral or IV) Raloxifene Hormone therapy Calcitonin Denosumab Anabolic agents Parathyroid hormone (PTH) Oral Bisphosphonates Alendronate, risedronate, ibandronate Alendronate and risedronate: Decreased risk of spine, nonvertebral, hip fractures Ibandronate: Decreased risk spine fracture Side effect: esophagitis Full glass of water, do not lie down Inefficiently absorbed Take on empty stomach (Black, 1996; Cummings, 1998; Harris, 1999; McClung, 2001; Chesnut, 2004)

IV Bisphosphonates Zoledronic acid Once yearly infusion Decreased risk spine, nonvertebral, hip fxs Given within 90 days after hip fracture: Decreased risk of new spine and nonvertebral fxs, and decreased mortality Side effect: transient flu-like symptoms Potential complication: osteonecrosis of the jaw Risk 1-10/100 with IV therapy at cancer doses; ~1/100,000 with oral therapy for osteoporosis (Black, N Engl J Med, 2007; Lyles, N Engl J Med, 2007; Khosla, JBMR, 2007) Raloxifene, Estrogen, Calcitonin Raloxifene Decreased risk spine fractures (not NVF) Decreased risk breast cancer Increased risk venous thromboembolism Estrogen or estrogen/progestin therapy Decreased risk spine, nonvertebral, hip fxs Other concerns Calcitonin Decreased risk spine fracture (not NVF) Analgesic benefit in pts with vertebral fxs? (Ettinger, JAMA, 1999; Rossouw, JAMA, 2002; Anderson, JAMA, 2004; Chesnut, Am J Med, 2000)

Denosumab Monoclonal antibody to RANK-ligand Decreased risk of spine, nonvertebral, hip fractures SubQ injection q 6 months Expensive Can be used in renal failure But be careful that you are treating osteoporosis, not CKD-MBD (Cummings, N Engl J Med, 2009) Teriparatide (PTH Therapy) Sole anabolic agent available Increases bone formation Decreased risk of spine and nonvertebral fractures Daily subq injection Approved for 2 years of use Consider in severe disease, especially spine > hip Follow course with a bisphosphonate (Neer, N Engl J Med, 2001; Black, N Engl J Med, 2005)

You start Ms. O, a 70 y.o. woman with osteoporosis, on alendronate. How long will I take this medication? Duration of Bisphosphonate Therapy FLEX trial: After 5 years of alendronate (ALN), randomized to continued ALN vs. placebo ALN group had continued reduction in clinical (but not radiographic) vertebral fx Those in ALN group with femoral neck T- scores -2.5 had continued nonvertebral fx risk reduction (Black, JAMA, 2006; Schwartz, J Bone Miner Res, 2010)

Duration of Bisphosphonate Therapy HORIZON-PFT extension trial: After 3 years of zoledronic acid (ZOL), randomized to continued ZOL vs. placebo Those with 3 years on, 3 years off had a small but significant decline in BMD Those with 6 years ZOL had fewer radiographic vertebral fractures (but no difference in other fracture types) (Black, ASBMR abstract, 2010) Duration of Bisphosphonate Therapy No formal guidelines One reasonable approach: Discuss with pt after ~5 yrs Repeat DXA If FN (or other?) T-score at that point is -2.5, or if very high risk of fracture (e.g., hx of hip or vertebral fracture), continuing therapy may be beneficial.

My friend told me this medication actually causes fractures of the femur. Atypical Femur Fractures Recent reports, some in setting of long-term bisphosphonate therapy Xray findings: Subtrochanteric Transverse Thick cortices Atraumatic Fx before fall +/- prodromal pain (Neviaser, J Orthop Trauma, 2008)

Atypical Femur Fractures Is the connection to bisphosphonate therapy real? Should it change practice? Danish registry study: Similar associations between ALN use and atypical femur fracture, typical hip fracture Post-hoc analysis of RCT data: 12 fractures in 10 (of 14,195) women 2.3 per 10,000 person-years Wide confidence intervals, not stat sig (Abrahamsen, J Bone Miner Res, 2009; Black, N Engl J Med, 2010) Atypical Femur Fractures If relationship is real, risk is very low: Treating 1000 women for 3 years would prevent 100 fxs, including 10 hip fxs, and could cause 1 atypical femur fx ASBMR Task Force: Causal association not established But, risk may with duration of med use Thoughtful decision-making about duration of therapy (Black, N Engl J Med, 2010; Shane, J Bone Miner Res, 2010)

How will we know whether the medication is working? Monitoring response to therapy The challenge: Not all patients BMD will increase on therapy. Treatment failure? Women adherent to ALN but with no change or a 4% decrease in BMD still had fracture reduction compared to those taking placebo. Bisphosphonates also appear to improve bone quality, geometry. (Chapurlat, Osteoporos Int, 2005)

Monitoring response to therapy One reasonable approach: Educate patient that while BMD helps decide whether to treat, it s less useful for assessing treatment response. If repeating DXA, look for meaningful loss in BMD, and be prepared to explain this to patient. Meaningful loss reassess adherence, secondary causes Objectives Explain when to initiate screening Describe nonpharmacologic strategies for better bone health Identify candidates for pharmacologic therapy Answer patients questions about potential risks of osteoporosis medications

Thank you! Thank you for your attention!

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