PHARMACOLOGIC MANAGEMENT OF OSTEOPENIA AND OSTEOPOROSIS Micol S.Rothman, MD Clinical Director, Metabolic Bone Program Assistant Professor of Medicine Diabetes, Endocrinology and Metabolism University of Colorado Hospital LEARNING OBJECTIVES Assess who is at high risk for fracture and should be treated for low bone density, and conversely, who may not need treatment based on low risk. Understand the different mechanisms of available therapy and how therapy can be tailored. Utilize the recent literature on drug holidays and incorporate this data into practice. 1
CASE #1 A 67 year old woman comes to see you for concerns about her bone health. She has no personal history of fracture, but her mother died after complications of a hip fracture. She went through menopause at age 51, and did not take hormone therapy. She does not currently smoke, but did smoke 1 PPD from age 18-33. She takes calcium and Vitamin D, does regular weight bearing exercise and has not had exposure to prednisone. Physical Exam and basic laboratory findings, including D level are all normal. DXA reveals her lowest site is a T-score of -2.2 in her femoral neck. WHAT DO YOU ADVISE? A) Daily estrogen therapy with cyclic progesterone 12 days a month B) Continue weight bearing exercise, calcium and Vitamin D. C) Begin therapy with alendronate. D) Wear hip protectors when walking. 2
CASE #1 WHO SHOULD BE TREATED WITH PHARMACOLOGICAL THERAPY? NOF guidelines Postmenopausal women or men>50 with: Hip or vertebral fracture T-score of <-2.5 with no other risk factors T-score of -1.0 to -2.5 with any of the following: a) other prior fractures, or (b) secondary cause associated with high risk of fracture, or (c) 10-year fracture risk as assessed by FRAX of 3% or more at the hip, 20% or more for major osteoporosis-related fracture (humerus, forearm, hip or clinical vertebral fracture) www.nof.org 3
REMEMBER THE GOOD STUFF Vertebral Fractures Reduction vs placebo Non Vertebral Fractures Alendronate Risedronate Ibandronate 45% 39% 48% 23% 20% 25% Hip Fractures 53% 26% None published? Decrease breast cancer risk (observational) Skeletal metastases Silverman Osteoporosis International 2012 CASE #2 A 57 year old woman comes to see you for concerns about her bone health. Her mother had rheumatoid arthritis and multiple compression fractures and the patient began alendronate at age 50. We have no prior DXA data, but current DXA shows her lowest site at the lumbar spine is -1.6 and femoral neck is -1.4. She takes calcium and Vitamin D and runs about 10 miles a week and skis all winter. She has heard about drug holidays but is worried about stopping her medication. What do you advise? 4
CASE #2 A) Stop alendronate-continue Ca/D and weight bearing exercise B) Stop alendronate and start teriparatide or denosumab C) Stop alendronate, but tell her to stop skiing and running. D) Continue alendronate How long should we treat with bisphosphonates? Black, D. M. et al. JAMA 2006;296:2927-2938. Copyright restrictions may apply. 5
Risk of Clinical Vertebral Fracture and Number Needed to Treat for 5 Years to Prevent One Clinical Vertebral Fracture in the Fracture Intervention Trial Long-Term Extension (FLEX) Study. Black DM et al. N Engl J Med 2012. DOI: 10.1056/NEJMp1202623 HOW LONG TO CONTINUE TREATMENT? Thus, for clinicians, we believe that the current evidence base supports the following conclusions. Patients with low bone mineral density at the femoral neck (T score below 2.5) after 3 to 5 years of treatment are at the highest risk for vertebral fractures and therefore appear to benefit most from continuation of bisphosphonates. Patients with an existing vertebral fracture who have a somewhat higher (although not higher than 2.0) T score for bone mineral density may also benefit from continued therapy. Patients with a femoral neck T score above 2.0 have a low risk of vertebral fracture and are unlikely to benefit from continued treatment. We recognize that these conclusions, which are based on reductions in vertebral fractures, might change as additional data about long-term risks of bisphosphonate therapy become available. Black et al NEJM May 9, 2012 6
CASE #3 A 32 year old woman is referred for low bone mass. She had a history of anorexia in her teens, but has maintained a normal BMI for about 10 years now. Her menstrual cycles are currently regular. She is physically active, taking calcium and D. She had a heel screening done at a Health Fair which was low so a central DXA was done and showed Z -scores of -1.8 in the spine and Z-scores of -1.2 in the hip. Age affects fracture risk independently of bone mineral density Copyright 2006 BMJ Publishing Group Ltd. Poole, K. E S et al. BMJ 2006;333:1251-1256 7
CASE #4 A 76 year old woman with a known history of osteoporosis is seen in the hospital after left hip fracture. She has been taking alendronate for 5 years, did note some GERD symptoms with it. PMH is also significant for HTN, DM2 and mildly elevated Cr with CrCl of 33. Recent DXA showed lowest site at the right hip with a T -score of -2.7. What would you suggest for future therapy? FDA-APPROVED THERAPIES: FRACTURE REDUCTION Vertebral Hip Nonvertebral Drug First New Estrogen Calcitonin + Raloxifene + + Not approved for treatment Alendronate + + + + Risedronate + + + + Ibandronate + Zoledronate + + + Teriparatide + + Denosumab + + + www.nof.org adapted from slide by N Watts (U Cincinnati) 8
WHY NOT ZOLEDRONIC ACID Not studied in CrCl<35 Reports of renal toxicity 9/2011 Package insert change that zoledronic acid is contra indicated in patient with CrCl<35 ml/mn Hydration and infusion rate appear to impact this as well. Booden et al JBMR 2012 Denosumab Copyright 2007 The Endocrine Society Shoback, D. J Clin Endocrinol Metab 2007;92:747-753 RANKL (expressed by osteoblasts) binds RANK receptor on osteoclast precursors to stimulate their differentiation. OPG (osteoprotegerin) is the endogenous receptor that acts as a decoy to inhibit this bone resorption. Denosumab is a human monoclonal antibody with specificity toward RANK. 9
Risk of vertebral fracture was reduced by 68% at 3 y 2.3% in the denosumab group, versus 7.2% in the placebo group. Hip fracture (secondary) was reduced by 40%, other non-vert fx reduced by 20%. www.nejm.org Cummings et al 2009 WHO IS DENOSUMAB APPROVED FOR? Post menopausal women with osteoporosis at high risk for fracture Men at high risk for fracture receiving androgen deprivation therapy for non metastatic prostate cancer. Women at high risk for fracture receiving aromatase inhibitor therapy. 10
CASE #5 A 68 year old man is seen after compression fracture at L2, followed by adjacent fracture at L1. He has a strong prior history of alcohol and tobacco use, now sober for several years. He is known to have COPD and has had several bursts of steroids during the last few winters. He is currently on 5mg of prednisone. Bone density reveals lowest site of -2.6 in the hip, the sine is difficult to interpret due to degenerative changes and fractures. What agents have been studied? At what dose of steroid should therapy be started even without a fracture? Treatment of Glucocorticoid-Induced Osteoporosis. Off label Weinstein RS. N Engl J Med 2011;365:62-70. 11
% Change Absolute Number 6/15/2012 Glucocorticoid Induced Osteoporosis Treatment Vertebral Fracture Reduction 428 women and men with GIOP, on > 5 mg/d prednisone for > 3 months RCT: Alendronate (n=214) vs Teriparatide (n=214) for 18 months 10 8 6 4 2 0 Bone Mineral Density P <.001 7.2% 3.4% Spine P <.005 Alendronate Teriparatide 3.8% 2.4% Hip 10 8 6 4 2 0 Vertebral Fractures 10 P <.004 1 Slide courtesy of M. McDermott Saag K, N Engl J Med 2007; 357:2028 Guidelines for Management of Glucocorticoid-Induced Osteoporosis. Weinstein RS. N Engl J Med 2011;365:62-70. 12