CASE 1 WHY IS IT IMPORTANT TO TREAT? FACTS CONCERNS

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1 4:30-5:15pm Ask the Expert: Osteoporosis SPEAKERS Silvina Levis, MD OSTEOPOROSIS - FACTS 1:3 older women and 1:5 older men will have a fragility fracture after age 50 After 3 years of treatment, depending on the drug and the individual, bisphosphonates can decrease: vertebral fractures by 40% -70% hip fractures by 20% - 50% Melton LJ et al J Bone Miner Res 13:1915 Melton LJ et al J Bone Miner Res 7:1005 Kanis JA et al Osteoporos Int 11:669 Black DM and Rosen CJ N Engl L Med 374:254 CASE 1 69 y/o woman with diabetes, hypertension, smoker, who has 3 drinks/day and no history of fracture Menopause at 53 DXA T-score L spine -1.9, total hip -2.1 and femoral neck -2.3 You recommend she stops smoking and decreases alcohol intake. What else would you do? FACTS High morbidity and mortality after a fracture Fracture rates increase after the first fracture Fracture risk decreases with treatment CONCERNS Increasingly lower rates of treatment High rates of discontinuation in first year of treatment

2 Observed and Expected Race- and Gender-Specific Survival After a Hip Fracture FACTS High morbidity and mortality after a fracture Fracture rates increase after the first fracture Fracture risk decreases with treatment CONCERNS Increasingly lower rates of treatment High rates of discontinuation in first year of treatment U.S. Medicare Population ,817 white & 24,210 black discharges 65 y/o Jacobsen S et al. J Public Health. 1992; 82: FACTS High morbidity and mortality after a fracture Fracture rates increase after the first fracture Fracture risk decreases with treatment CONCERNS Increasingly lower rates of treatment High rates of discontinuation in first year of treatment The relative risk of a hip fracture after a previous wrist or spine fracture among men and women 50 years old RR RR Haentjens P. et.al. J Bone Joint Surg 2003:85-A:

3 Zoledronate Reduces Hip Fracture FACTS High morbidity and mortality after a fracture Fracture rates increase after the first fracture Fracture risk decreases with treatment CONCERNS Increasingly lower rates of treatment High rates of discontinuation in first year of treatment Cumulative Incidence (%) Placebo (n = 3861) ZOL 5 mg (n = 3875) P =.0024 *Relative risk reduction (95% CI) vs placebo Time to First Hip Fracture (months) 41%* (17%, 58%) Black et al., NEJM 2007;356(18): Zoledronate Reduces Vertebral Fracture Cumulative Incidence (%) Placebo (n = 3861) ZOL 5 mg (n = 3875) P < Time to First Clinical Vertebral Fracture (months) *Relative risk reduction (95% CI) vs placebo 77%* (63%, 86%) FACTS High morbidity and mortality after a fracture Fracture rates increase after the first fracture Fracture risk decreases with treatment CONCERNS Increasingly lower rates of treatment High rates of discontinuation in first year of treatment Black et al., NEJM 2007;356(18):

4 Under recognition of Osteoporosis Following Fragility Fractures DXA and pharmacy claims Under recognition and under treatment of Osteoporosis Following Fragility Fractures 95% of men not screened or treated 51% of women not screened or treated y/o y/o n = 2804 persons with fractures Feldstein A et al., Arch Int Med 2003;163(18): Feldstein A et al., Arch Int Med 2003;163(18): FACTS High morbidity and mortality after a fracture Fracture rates increase after the first fracture Fracture risk decreases with treatment Persistence With Weekly Alendronate Therapy among Postmenopausal Women CONCERNS Increasingly lower rates of treatment High rates of discontinuation in first year of treatment AOW, alendronate once weekly BOM, Boniva once monthly FOW, Fosamax once weekly (n = 40, y/o) Fan T. et al. Clinicoecon Outcomes Res. 2013;19(5):589 95

5 Persistent patients Secondary Prevention Strategies: Adherence to Therapy Weeks of follow up 23,146 patients with hip fracture, 6% prescribed bisphosphonates at 12 mo. Of those, 48% compliance 80% at 12 months Decreased mortality rate 37% vs. 11% (p< ) OSTEOPOROSIS FDA-APPROVED TREATMENTS Antiresorptives Bisphosphonates zoledronate alendronate ibandronate risedronate denosumab Anabolics teriparatide abaloparatide Rabenda V. et al. Osteoporos Int. 2008;19(6):811-8 RECOMMENDATIONS FOR TREATMENT Our Goal is to Prevent Fractures The National Osteoporosis Foundation (NOF) recommends osteoporosis medical treatment: 1. After a low trauma fracture 2. If the bone mineral density T score is 2.5 or lower 3. When the Fracture Risk Assessment Tool (FRAX) indicates a high fracture risk 1. WHAT IS A LOW TRAUMA FRACTURE? Fracture that occurs after falling when walking or from standing or sitting position Exception for fractures of the skull, finger or toes Most common osteoporotic fractures occur in the thoracic and lumbar spine, proximal femur and wrist Other common sites: ribs, humerus, pelvis NOF.org

6 2. Diagnostic Categories for Bone Mass Measurement Diagnosis Normal Osteopenia Osteoporosis T-score 1.0 SD or higher (from mean of young adult) < 1.0 to > 2.5 SD 2.5 SD or lower Visualizing a Patient s T Score SD Peak Bone Mass T-score = Age (years) T score = Number of standard deviations (SDs) by which the patient s bone mass falls above or below the mean peak bone mass for normal young adult women T score for this patient, a 60 year old woman, T = 3.0 WHO Technical Report Series. 1994;843:1-129 SOF -Study of Osteoporotic Fractures older no exercise falls vision imp preval vert fx FRACTURE RATES IN PERSONS WITH OSTEOPENIA Copyright 2005 The Endocrine Society Total hip BMD T-scores at the start of observation among incident hip fracture cases (n = 243) and all participants (n = 8065); women 65 y/o; f/u 5 years Wainwright, S. A. et al. J Clin Endocrinol Metab 2005 Copyright restrictions may apply. N = 150,000 WW 50 y/o f/u 1 yr 393 fx Siris, E. S. et al. Arch Intern Med 2004;164:

7 3. FRAX The Fracture Risk Assessment tool (FRAX) developed by the World Health Organization combines bone mineral density results of the femoral neck and clinical risk factors for fractures. Provides estimation of: 10 year risk of a major osteoporotic fracture 10 year risk of a hip fracture This tool does not include some important risk factors for fractures: frequent falls, recent fracture, bone turnover and skeletal geometry. FRAX In the US, the NOF recommends treatment if the 10 year risk of: 20% for a major osteoporotic fracture or 3% for a hip fracture FRAX FRAX

8 FRAX update Tool tailored for use in different continents and countries. Each country has established its own treatment thresholds. To estimate fracture risk in immigrants, it is best to use the FRAX tool for the country of origin. WHO IS AT RISK OF FRACTURE? Someone with a previous fracture. A previous osteoporotic fracture at least doubles the risk of developing another fracture, everything else being equal. Low bone mineral density remains the best predictor of future fractures, which is improved by adding clinical risk factors. Older age is the most significant clinical risk factor. Observed incidence of osteoporotic and hip fractures during follow up in the control arm of the SCOOP study, within quintiles of baseline FRAX hip probability Cumulative Incidence of Fractures and Change in Height in Older Women with Osteopenia McCloskey E et al. J Bone Miner Res 2018; 33(6): IR Reid et al. N Engl J Med DOI: /NEJMoa

9 CASE 1 69 y/o woman with diabetes, hypertension, smoker, who has 3 drinks/day and no history of fracture Menopause at 53 DXA T score L spine 1.9, total hip 2.1 and femoral neck 2.3 CASE 2 67 y/o white Hispanic woman with history of right wrist fracture in 2014 DXA 2019 shows T score Lumbar Spine 2.8, Total Hip 2.3 Standard approach Treatment based on BMD and/or FRAX score Start with 1st line drug, usually bisphosphonate F/u BMD in 1 2 years to see if pt. is responding If responding, continue If not responding, consider switching to another antiresorptive drug or PTH A drug holiday after 5 years of treatment Bisphosphonate Drug Holidays Bisphosphonates have been available > 20 years Most frequently prescribed drugs for osteoporosis Concerns about rare but serious adverse events: atypical femur fractures and osteonecrosis of the jaw American Society for Bone Mineral Research Task Force report provides guidance regarding the duration of treatment with bisphosphonates. Recommendations based on limited evidence for vertebral fracture reduction in white postmenopausal women. It may be applicable to men and persons with glucocorticoid induced osteoporosis. Use recommendations together with clinical judgment, assessing the riskbenefit in each individual patient.

10 Bisphosphonate Drug Holidays Bisphosphonate Drug Holidays Risk of atypical femoral fracture increases with the duration of the bisphosphonate treatment. (~ incid cases/100,000 person yrs) Risk of osteonecrosis of the jaw does not. (~ incid. 1/10,000 1/100,000 pt. treatm. yrs) Rare adverse effects outweighed by the decrease in vertebral fractures in patients at high risk. or IV BP up to 6 yrs older yrs anticipated bone loss (AI, glucocortic) frequent faller Adler R. Endocrine. 2016;51(2):222 4 TREAT TO TARGET The goal of osteoporosis medical treatment is to prevent fractures Applying goal directed therapy (or treat to target therapy) in the management of osteoporosis Comparable to targeting glycosylated hemoglobin in the management of diabetes or lipid levels in cases of cardiovascular disease In order to treat to target, it is necessary to have a clinical parameter that can be: measured easily, accurately and consistently can show a response to the medical intervention correlates with clinical outcomes FRAX scores are not responsive enough after treatment to be used as a target for goal directed treatment. Many strong clinical risk factors included in FRAX: remain unchanged (history of personal or parental fracture) worsen(age) DXA is still the best treatment goal target Good news: we have many effective treatments DRUG Vertebral Non Vertebral Hip Estrogen Alendronate Risendronate Zoledronate Ibandronate + Denosumab Teriparatide + + Raloxifene + Calcitonin +

11 New Drug Percentage Change from Baseline in Bone Mineral Density. January 19, FDA s Advisory Committee gave a positive vote on romosozumab for the treatment of osteoporosis in postmenopausal women at high risk for fracture. FDA is not bound by the Advisory Committee's recommendations. Romosozumab is an antisclerostin monoclonal antibody. Sclerostin, Which is Secreted by Osteocytes, Negatively Regulates Bone Formation Osteocyte Mature Osteoblasts New bone Ott SM. J Clin Endocrinol Metab. 2005;90: Semenov M, et al. J Biol Chem. 2005;280: Semenov MV, et al. J Biol Chem. 2006;281: Li X, et al. J Biol Chem. 2005;280: X Sclerostin Pre-osteoblast lining cells Bone X Mesenchymal stem cells McClung MR et al. N Engl J Med 2014;370: Incidence of New Vertebral, Clinical, and Non-vertebral Fracture Osteoporosis Treatment Options CATEGORY RESORPTION FORMATION Anti remodeling agents Bisphosphonates, RANKL inhibitor Osteoanabolics PTH and analogues Sclerostin inhibitors Saag KG et al. N Engl J Med 2017;377:

12 Osteoporosis Prevention and Treatment Weight bearing exercise Calcium and vitamin D Avoid smoking, excessive ETOH, glucocorticoids Fall prevention Medications to prevent fractures WHY IS IT IMPORTANT TO PREVENT FRACTURES? to decrease mortality reduce morbidity maintain independence ASK QUESTIONS USING OUR NEW SOCIAL Q&A FEATURE! Navigate to Ask a Question Click a Session Up-Vote a Question