Osteoporosis in Men CME Away India & Sri Lanka March 23 - April 7, 2018 Richard A. Bebb MD, ABIM, FRCPC Consultant Endocrinologist Medical Subspecialty Institute Cleveland Clinic Abu Dhabi
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Barriers To Change
Disclosure of Commercial Support This program has not received financial support, or in-kind support, from any Pharmaceutical Company. Potential for conflict(s) of interest: None to declare
Faculty/Presenter Disclosure Faculty: Richard Bebb Relationships with commercial interests: None to report
What is Boys and Men s Health?
THESORRYSTATISTICS 84% more likely to die from arterial diseases 39% more likely to die from diabetes 29% more likely to be diagnosed with cancer and 40% more likely to die as a result 70% more likely to die from heart disease
THESORRYSTATISTICS 97% of workplace deaths (2005: 1,064 of 1,097) 35% of suicide attempts are male, but 80% of successful suicides 80% of spinal cord injuries, substance abuse, violence and crime
Learning Objectives: Appreciate the prevalence of male osteoporosis To review the available treatments for osteoporosis in men
Definitions: Osteoporosis 1913 Webster An absorption of bone so that the bone tissue becomes unusually porous. It occurs especially in elderly men and postmenopausal women, and predisposes the elderly to fractures of the bones. 1993 consensus conference A systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a resultant increase in bone fragility and risk of fracture. 1 2000 NIH (US) modifications A skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength reflects the integration of two main features; bone density and bone quality. 2 1. Consensus development conference. Am J Med 1993;94:646-650. 2. NIH Consensus Development Panel. JAMA 2001;285:785-795.
Definitions: BMD Results Status 1, 2 Normal T-score +2.5 to 1.0, inclusive Osteopenia Between 1.0 and 2.5 Osteoporosis Severe osteoporosis 2.5 2.5 + fragility fracture 1. Kanis JA, et al. J Bone Miner Res 1994;9:1137-1141. 2. WHO, Geneva 1994.
Questions: 1) 1 in 8 men over age 50 will suffer an osteoporotic fracture (T/F) 2) Mortality related to osteoporosis in men is less than women (T/F) 3) Women are 6 times more likely to be treated after an osteoporotic fracture than men (T/F)
Fracture incidence rate per 10,000 population in Leicester, UK, by age and gender. From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7 th Edition. www.asbmrprimer.org
Osteoporosis in Men 1 in 8 men over age 50 will suffer an osteoporotic fracture (1 in 4 for women) 30% of hip fractures occur in men More data needed to clarify BMD vs fracture risk in men BMD may reflect larger bone size Fracture risk also depends on likelihood of falls, bone size, geometry, as well as other health factors Josse RG. J Sex Reprod Med 2001 Melton LJI. J Bone Miner Res 1998 Gilsanz V, et al. Radiology 1994
Osteoporosis is often not treated in men Gender differences in bisphosphonate prescription: 1 in 4 women affected, 1 in 5 treated (20.4%) 1 in 8 men affected, 1 in 30 treated (3.3%) Treatment rates following atraumatic fracture requiring hospitalization: 4.5% of men treated at discharge (vs. 27% women) 27% of men treated at 5-year follow-up (vs. 71% women) CIHI 2009; Kiebzak Arch Intern Med 2002; Pajnu BJUI 2008
Mortality of hip fractures 30 % 25 20 15 10 Men Women 5 0 Overall <75 years >75 years Poór et al., Osteoporosis Int 1995;5:419-26
Osteoporosis in Men: Summary Lower risk of osteoporotic fractures, BUT Less likely to be treated than women More likely to die after a fracture
Causes of Osteoporosis in Men From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7 th Edition. www.asbmrprimer.org
Causes of Osteoporosis in Men From the Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism, 7 th Edition. www.asbmrprimer.org
Risk ratio for hip fracture in men Risk Factor Risk Ratio for Hip Fracture (95% CI) Parental history of hip fracture 2.28 (1.48-3.51) Corticosteroids (>3 months) 2.25 (1.60-3.15) Low testosterone 1.88 (1.24-2.82) Rheumatoid arthritis 1.73 (0.93-3.20) Excessive alcohol use 1.70 (1.20-2.42) Prior fracture (> 50 yrs of age) 1.62 (1.30-2.01) Current smoking 1.60 (1.27-2.02) Low BMI (20 vs. 25) 1.42 (1.23-1.65) High BMI (30 vs. 25) 1.00 (0.82-1.21) Kanis Osteoporosis Int 2005; Meier Arch Intern Med 2008.
When to order Densitometry in Men: 1) Age 50 or older with 1 major or 2 minor risk factors 2) Age 65 or older 3) Younger patients with low-trauma fractures 4) In the presence of diseases or medications that predispose to bone loss or fracture
Major risk factors Age 65 or older Vertebral compression fracture Fragility fracture after age 40 Family history of osteoporotic fracture (especially maternal hip fracture) Systemic glucocorticoid therapy of at least 3 months duration Malabsorption syndrome Primary hyperparathyroidism Propensity to fall Appearance of osteopenia on radiograph Hypogonadism
Minor risk factors Rheumatoid arthritis History of hyperthyroidism / hyperparathyroidism Long-term anticonvulsant therapy Weight loss greater than 10% of weight at age 25 Weight less than 57 kg Smoking Excess alcohol intake Excess caffeine consumption Low dietary calcium intake Long-term heparin therapy
BMD vs Age and Fracture Prediction Fracture Risk vs. BMD At Different Ages Hui et al. J Clin Invest 1988; 81:1804-9
CATEGORIZATION BASED ON 10-YEAR FRACTURE RISK Absolute fracture risk in 10 years: low: <10% moderate: 10-20% high: >20%
USING LOWEST T-SCORE TO FIND 10- YEAR FRACTURE RISK - WOMEN LOWEST T-Score 0.0-0.5-1.0-1.5-2.0-2.5-3.0-3.5-4.0-4.5 WOMEN Low Risk Moderate Risk High Risk 50 55 60 65 70 75 80 85 AGE (years)
LOWEST T-Score USING LOWEST T-SCORE TO FIND 10- YEAR FRACTURE RISK - MEN 0.0-0.5-1.0-1.5-2.0-2.5-3.0-3.5-4.0-4.5 Low Risk MEN Moderate Risk High Risk 50 55 60 65 70 75 80 85 AGE (years)
Comparison of FRAX vs Garvan Fracture Risk assessment Tools Risk factor FRAX Garvan Age Yes Yes Gender Yes Yes Height Yes No Weight Yes No Previous fracture Yes Since age 50 Parental hip fracture Yes No Current smoking Yes No Glucocorticoid use Yes No Rheumatoid arthritis Secondary osteoporosis Yes Yes No No EtOH> 3 units daily Yes No Femoral neck BMD Yes Yes Falls in last 12 months URL No http://shef.ac.uk/f RAX/ Yes http://fractureriskc alculator.com Bone Research (2014) 2, 14001
FRAX results Consider treatment if: 10-yr probability of hip fracture > 3% 10-yr probability of major osteoporosis-related fracture > 20%
Laboratory Tests to exclude secondary causes of osteoporosis: Complete blood count (CBC) Serum calcium Total alkaline phosphatase Serum creatinine Serum protein electrophoresis Total (& bioavailable) testosterone, (Prolactin, LH, FSH if testosterone low) TSH 1. Modified from Osteoporosis Society of Canada. Can Med Assoc J 1996;155:1113-1133.
Case 65 y.o. man with osteopenia 2 years postbariatric surgery Is he at greater risk for fracture due to bariatric surgery?
Fracture Risk Fracture Incidence post-bariatric Surgery Healthcare databases, Québec, Canada (2001-14) (N= 12,676) (N= 38,028) (N= 126,760) Time (years) Rousseau, BMJ, 2016
Fracture-free survival rate Fracture Incidence post-bariatric Surgery Gastric sleeve Non-Obese Gastric band Obese All Bariatric RYGB BP Diversion Time (years) Rousseau, BMJ, 2016
Restrictive vs. Malabsorptive Operations NIDDK
Approach to Treatment of Osteoporosis Pharmacotherapy (Antiresorptives and anabolics Address Secondary Factors (Drugs and Diseases) Lifestyle Changes (Nutrition, Physical Activity and Fall Prevention) Bone health and osteoporosis: A report of the Surgeon General. Rockville, MD: U.S. Department of Health and Human Services; 2004.
Fall Prevention 12 Modifiable Items
Therapeutic options Nonpharmacologic therapy / risk reduction Lifestyle Fall prevention Calcium & Vitamin D Pharmacologic therapy Bisphosphonates Teriparatide Testosterone Denosumab (Calcitonin removed from market due to cancer risk) (Strontium CV risk) Khan CMAJ 2007; Ebeling NEJM 2008; Qaseem Ann Intern Med 2008
Pharmacologic Therapy: Bisphosphonates Bisphosphonates first line treatment option Alendronate 10 mg/day or 70 mg/wk 7.1% increase in lumbar spine vs. 1.8% with placebo Reduce radiologic fractures at 2 years (0.8% vs. 7.1% with placebo) Risedronate 5 mg/day or 35 mg/wk, or 150 mg/month Reduced risk of hip fractures (RR = 0.25) Zoledronic acid 5 mg IV once yearly Reduced rate of clinical fracture and death in men with hip fracture Khan CMAJ 2007; Ebeling NEJM 2008
ONJ Comparative Risks (1) Women age 65-69 (from Swedish National Bureau of Statistics and database of Olmsted County, MN, USA.) M. Lewiecki 2007 Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf. 2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150. www.nssl.noaa.gov/papers/techmemos/nws-sr-193/techmemo-sr193-4.html
Rough long term harm benefit considerations (ASBMR Task Force) Vertebral fracture benefit Hip fracture benefit Adler, JBMR 2016
Other potential complications of bisphosphonate therapy 1) Esophageal Cancer? 2) Atrial Fibrillation? 3) Atypical femoral fractures (Subtrochanteric and mid femoral shaft)
Pharmacologic Therapy: Teriparatide 20 mcg/day sc x 24 months (maximum duration) Increase bone mass in men with primary or hypogonadal osteoporosis at high risk for fracture Reduced risk of moderate/severe vertebral fractures, no nonvertebral fracture data in men Contraindicated if prior radiotherapy Testosterone Hypogonadal men only 8.9% increase in spine vs. placebo No data re: fracture rates Khan CMAJ 2007; Ebeling NEJM 2008; Qaseem Ann Intern Med 2008, Girotra M, Rubin MR, Bilezikian JP 2006 Rev Endocr Metab Disord
Percent change in lumbar spine BMD Antiresorptive Therapy Prevents Bone Loss when PTH Discontinued 2D Graph 2 Percent change in BMD 18 16 14 12 10 8 6 4 2 Antiresorptive starting before 6 mos (n = 65) Antiresorptive starting after 6 mos (n = 34) No OP use (n=144) 0 EP Visit 1 Visit 2 Visit 3 (6 mos) (18 mos) (30 mos) Lindsay R et al. Arch Intern Med. 2004;164:2024-2030.
TRT effect on % change in BMD as a function of pre-treatment serum tt levels TRT effect (% change BMD) 10 5 * * * DB-PC,108 men, > 65 Y, 36 months tt 12.7± 2.7 nmol/l ft 0.2 ± 0.06 nmol/l * : p<0.01 effect of TRT on BMD change related to pretreatment serum tt 0-5 3.5 7 10.5 14 17.5 Pre-treatment serum tt (Nmol/l) Snyder PJ, J Clin Endocrinol Metab 1999;84:1966-72
Pharmacologic Therapy: Denosumab - most data is in men with metastatic prostate cancer - fracture data in men with osteoporosis extrapolated from female studies - warning re: rebound osteoporosis if discontinued without consolidation with bisphosphonate denosumab sandwich? M. R. Smith et al 2009 NEJM, 361, 8:745 55 Toth E et al 2005 Bone 36:47 5
Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer Mean Percent Changes from Baseline Bone Mineral Density (BMD) Values Smith MR et al. N Engl J Med 2009;361:745-755
Denosumab in Men Receiving Androgen-Deprivation Therapy for Prostate Cancer Cumulative Incidence of New Vertebral Fracture at 12, 24, and 36 Months Smith MR et al. N Engl J Med 2009;361:745-755
Long term effects on Bone Mineral Density Different studies superimposed Reid, I. R. (2015) Short-term and long-term effects of osteoporosis therapies Nat. Rev. Endocrinol. doi:10.1038/nrendo.2015.71
Percentage Change From Baseline New Anabolic Agents Abaloparatide Analog of PTHrP Romosozumab (not FDA approved) Humanized anti-sclerostin antibody Both increase lumbar spine and total hip BMD at 12 months more than teriparatide in head-to-head studies 12 10 8 6 4 2 0 2 Placebo ALN TPTD Romosozumab 210 mg QM Lumbar Spine *P < 0.0001 vs placebo P < 0.0001 vs ALN ʌ P 0.0025 vs TPTD * ʌ * ʌ * ʌ 11.3% 0 3 6 9 12 Month 5 4 3 2 1 0 1 2 *P < 0.0001 vs placebo P < 0.0001 vs ALN ʌ P < 0.0001 vs TPTD * Total Hip * ʌ * ʌ 4.1% 0 3 6 9 12 Month Miller PD et al. JAMA 2016;316:722-33 McClung et al. New Engl J Med 2014;370:412-20
Available Agents for the treatment of Osteoporosis in Men: Drug Potential advantages Potential disadvantages Oral bisphosphonates Intravenous bisphosphonates Denosumab Teriparatide Strontium ranelate Inexpensive Long experience Long intervals between infusions Potential improved adherence Convenient 6 month dosing Appears to increase BMD up to 6 years, ADT efficacy Anabolic No ONJ or AFF Improves BMD in men May have some anabolic effect Adherence and compliance Side effects: GERD, ONJ, AFF More expensive Side effects: ONJ, AFF More expensive Side effects: ONJ, AFF Expensive Daily subcutaneous injection Less long-term experience New concern about cardiovascular safety Abbreviations: ADT; Androgen Deprivation Therapy; AFF, atypical femoral fracture; BMD, bone mineral density; ONJ, osteonecrosis of the jaw. Bone Research (2014) 2, 14001