Osteoporosis: An Overview. Carolyn J. Crandall, MD, MS

Osteoporosis: An Overview Carolyn J. Crandall, MD, MS

Osteoporosis: An Overview Carolyn J. Crandall, MD, MS Professor of Medicine David Geffen School of Medicine at UCLA

Objectives Review osteoporosis guidelines: Screening Treatment Current controversies

The Situation 1 in 2 postmenopausal women and 1 in 5 older men will have an osteoporosis-related fracture in their lifetimes!! Because of the aging of the U.S. population, the number of hip fractures in the U.S. is expected to double or triple by 2040. (USPSTF, Ann Intern Med 3/1/2011, Schneider and Guralnik 1990, Wright et al JBMR 2014)

Direct medical care costs of osteoporotic fractures = $17 billion/yr U.S. (USPSTF 2011, Blume & Curtis OI 2011)

Definition Disorder characterized by low bone mass and microarchitectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk. (Consensus development conference: diagnosis, prophylaxis and treatment of osteoporosis, Am J Med 1993 & WHO Technical Report Series 843, Geneva, 1994)

Whom to screen

Screening Women Women 65 years or older (USPSTF 2011, NOF 2014) (USPSTF, Ann Intern Med 3/1/2011, National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org)

Screening guidelines: men Current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men. (USPSTF Ann Intern Med 3/1/2011)

Screening guidelines: men Considerations: Potential preventable burden is increasing due to aging U.S. population Potential harms are likely to be small Men most likely to benefit from screening have a 10- year risk for osteoporotic fracture equal to or greater than that of a 65-year-old white women without risk factors (which is 9.3%). (USPSTF, Ann Intern Med 3/1/2011)

U.S. FRAX in 2016 (version 3.10) Racespecific BMD info optional http://www.sheffield.ac.uk/frax/ Outputs: 10-year prob. of hip fracture & 10-year prob. of major osteoporotic fracture (clinical spine, forearm, hip or shoulder fracture)

FRAX practical considerations Not validated for spine bone mass If normal hip bone mass with low spine bone mass, FRAX underestimates fracture risk Not validated for: Patients treated with osteoporosis pharmacotherapy past 1-2 years Underestimates fracture risk in patients with: Recent or multiple fractures Those at increased risk for falling (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org)

Whom to screen How to diagnose

Clinical diagnosis is by either. Adulthood hip or vertebral fracture in the absence of major trauma (such as motor vehicle accident of multiple story fall)---regardless of BMD value!! or BMD T-score -2.5 at lumbar spine or hip by dualenergy x-ray absorptiometry (DXA) (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org)

World Health Organization Diagnostic class. Classification BMD T-score Normal Low Bone Mass (Osteopenia) Osteoporosis Severe or Established Osteoporosis Within 1 SD of a young adult reference population Between 1.0 and 2.5 SD below that of a young-adult reference population 2.5 SD or more below that of a young-adult reference population 2.5 SD or more below that of a young- adult reference population T-score at -1.0 and above T-score between -1.0 and -2.5 T-score at or below -2.5 T-score at or below -2.5 with one or more fractures (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org & ISCD.org)(ref 20-29 y/o NHANES Looker et al 1998)

Which test? Current diagnostic and treatment criteria rely on dualenergy x-ray absorptiometry (DXA) measurements of lumbar spine and hip ONLY. T-scores from other technologies cannot be used according to the WHO diagnostic classification because they are not equivalent to T-scores derived from DXA. (USPSTF Ann Intern Med 3/1/2011, National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org)

Whom to screen How to diagnose Whom to treat

Whom to treat Treat men and women with a history of: fragility fracture * ( * fracture from trauma that from a fall from a standing height) or osteoporosis (American College of Physicians 2008) Low bone mass (T-score between -1.0 and -2.5 at femoral neck, total hip, or spine) if: 10-yr probability of hip fracture 3% or 10-yr probability of major osteoporosis-related fracture 20% based on U.S. WHO FRAX. (AACE 2010, National Osteoporosis Foundation 2014 )

Case 67 year-old healthy woman (no fracture) baseline screening DXA: femoral neck T-score of -1.7 lumbar spine T-score of -1.9. The most appropriate next step is: 1. No further evaluation 2. FRAX assessment 3. prescribe bisphosphonate 4. prescribe raloxifene

Case 67 year-old healthy woman (no fracture) baseline screening DXA: femoral neck T-score of -1.7 lumbar spine T-score of -1.9. The most appropriate next step is: 1. No further evaluation 2. FRAX assessment 3. prescribe bisphosphonate 4. prescribe raloxifene

Whom to screen How to diagnose Whom to treat Benefits and risks of therapy

U.S. FDA-approved prescription osteoporosis therapies * Bisphosphonates Alendronate Risedronate Ibandronate (IV/PO) Zoledronic acid (IV) Monoclonal antibody: inhibitor of receptor activator of nuclear factor-kappa B Denosumab Recombinant parathyroid hormone Teriparatide Selective estrogen receptor modulator Raloxifene Calcitonin * All anti-resorptives except for teriparatide

Benefits of therapy: Systematic review High-strength evidence that the following drugs reduce fractures compared with placebo: Bisphosphonates Denosumab Teriparatide Risk reductions (vs. placebo) 40-60% for vertebral fractures, 20-40% for nonvertebral fractures Raloxifene reduces only vertebral fractures. Demonstrated hip fracture reduction: bisphosphonates, denosumab (Crandall et al Annals of Internal Medicine 2014)

Adverse effects of therapy: Systematic review Mild upper GI symptoms: Bisphosphonates Denosumab Teriparatide Influenza-like symptoms: Zoledronic acid Serious infections: Denosumab (cellulitis, infectious arthritis, endocarditis) (Crandall et al Annals of Internal Medicine 2014) VTE, fatal stroke: raloxifene Atypical subtrochanteric fracture: Bisphosphonates 2-100 per 100,000 women Osteonecrosis of the jaw: Bisphosphonates 0.03%-4.3% (pending new standardized case definitions)

June 1, 2016

Atypical Subtrochanteric and Diaphyseal Femoral Fractures: Second Report of a Task Force of the American Society for Bone and Mineral Research Reported in patients taking BPs, and in patients taking denosumab Also occur in patients with no exposure to these drugs. Absolute risk with BPs is low, 3.2 to 50 cases per 100,000 person-years. Long-term use may be associated with higher risk (~100 per 100,000 person-years) MRI: If unilateral or bilateral prodromal symptoms such as dull or aching pain in the groin or thigh (Shane et al JBMR 2014)

Osteonecrosis of the Jaw: A Systematic Review and International Consensus Vast majority of cases (>90%) have occurred in cancer patients receiving six-fold to 10-fold higher doses of BPs than those used to treat osteoporosis. In patients taking lower-dose BPs for osteoporosis, the risk of ONJ is extremely low (1 in 10,000 to 1 in 100,000 patients, compared with 1% to 2% per year for cancer patients receiving higher doses of BPs). Risk factors: Invasive oral surgery procedures, glucocorticoids, DM, poor oral hygiene. (Khan et al JBMR 2015)

Bisphosphonates and osteonecrosis of the jaw: American Association of Oral and Maxillofacial Surgeons 2014 Scenario 1: Oral bisphos. < 4 years, no risk factors: No alteration or delay in planned surgery. If implants placed, consider drug holiday Scenario 2. Oral bisphosphonate > 4 years: Or Scenario 3: Oral bisphosphonate for < 4 years and corticosteroids or antiangiogenic meds concomitantly: Consider d/c bisphosphonate for at least 2 months prior to oral surgery, if systemic conditions permit. Do not restart until osseous healing has occurred. http://www.aaoms.org/docs/position_papers/mronj_positi on_paper.pdf?pdf=mronj-position-paper

Upshot The harms of bisphosphonates, the most commonly prescribed therapies, are no greater than small. (USPSTF, Ann Intern Med 3/1/2011). Alendronate, risedronate, zoledronic acid, denosumab 1 st line (American Assoc. Clin. Endocrinologists 2010)

Calcium and Vit. D: Institute of Medicine Recommended Dietary Allowance Group Dose Sex Age Calcium Vitamin D Women 51-70 1,200 mg/d 600 IU/d Men 51-70 1,000 mg/d 600 IU/d Women and Men >70 y/o 1,200 mg/d 800 IU/d GENERAL POPULATION! http://www.iom.edu/reports/2010/dietary-reference-intakes-forcalcium-and-vitamin-d.aspx

Vitamin D levels For individuals with osteoporosis, recommend vitamin D supplements in amounts sufficient to bring the serum 25(OH)D level to approximately 30 ng/ml (75 nmol/l). Many patients with osteoporosis will need more than the general recommendation of 800-1,000 IU per day. (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis 2014 www.nof.org) I check 25-OH vit. D levels annually if osteoporosis.

Whom to screen How to diagnose Whom to treat Benefits and risks of therapy Monitoring/Treatment Duration

Monitoring: Measurement error Changes in BMD of < 3-6% at hip and 2-4% at spine from test to test may be due to the precision error of the test itself! (National Osteoporosis Foundation Clinician s Guide to Prevention and Treatment of Osteoporosis www.nof.org 2014)

Monitoring: Serial testing USPSTF Evidence is lacking about optimal intervals. Because of limitations in the precision of testing: minimum of 2 years to reliably measure a change in BMD longer intervals may be necessary to improve fracture prediction. (Ann Intern Med 3/1/2011)

Monitoring: Untreated older women Study of Osteoporotic Fractures postmenopausal women 65 y/o without prior fracture If baseline T-score is. -1.01 to -1.49 17 years -1.50 to -1.99 5 years -2.00 to -2.49 1 year then the time period required for 10% of women to progress to osteoporosis BMD (before having a fracture) was: (Gourlay et al NEJM 2012)

Monitoring during treatment: post hoc RCT data Examples: incidence of nonvertebral fx in risedronate-treated pts was not different between pts whose femoral neck BMD decreased and those whose femoral neck BMD increased (Watts et al JBMR 2005) Women assigned to teriparatide who lost femoral neck BMD still have 89% decrease in vertebral fracture risk vs. placebo (Watts et al JBMR 2009) So: Measured BMD changes during osteoporosis pharmacotherapy are poor predictors of fracture reduction with pharmacotherapy. Reductions in vertebral fracture risk were greater than predicted from improvement in BMD.

Treatment Duration: Systematic review RCTs were not specifically designed to compare shorter with longer duration of therapy post-hoc analyses only Optimal duration of therapy unknown. (Crandall et al Annals of Internal Medicine 2014) (see post-hoc data Black NEJM 2012 & Black JBMR 2012)

ASBMR Task Force 2016 70-75 y/o, other strong fracture risk factors, high FRAX score (Journal of Bone and Mineral Research 2016, 31(1): 16 35)

(A few ) Gaps in knowledge? optimal: Exercise type, intensity, duration, freq.? (NOF) Role of drug combinations/sequential meds? Screening/treatment in men? Role of turnover markers? (excess random within-person variation!! Bell 2012) How to assess: bone strength? fracture risk during rx?

What I do Women 65 y/o screen, re based on initial T-score: T-score -1.0 to -1.9: I wait 5 years T-score -2.0 to -2.4: I wait 1-2 years Men:? consider screening if 10-year risk for osteoporotic fracture 9.3%, secondary causes.

Summary Don t ignore incidentally-detected vertebral fx Treat women and men 50 y/o if : Hip or vertebral fracture or BMD T-score -2.5. Treat BMD T-score between -1 and -2.5 selectively based on presence of other fracture risk factors. To decrease hip fracture, use bisphosphonates or denosumab. (I consider bisphosphonate 1 st line). After 5 years oral bisphosphonate, recheck BMD, reassess rx duration.

Only 3 in 10 fractures in U.S. are followed up with testing or treatment! After hip fracture: Only 40% fully regain their pre-fracture level of independence. Only 1 in 3 are treated within 12 months of d/c (The State of Health Care Quality 2015 National Committee for Quality Assurance http://www.ncqa.org/, NOF 2014, Ota 1994; Magaziner et al 2003, Solomon et al JBMR 2014)