OSTEOPOROSIS IN MEN. Nelson B. Watts, MD OSTEOPOROSIS AND BONE HEALTH SERVICES CINCINNATI, OHIO

OSTEOPOROSIS IN MEN Nelson B. Watts, MD OSTEOPOROSIS AND BONE HEALTH SERVICES CINCINNATI, OHIO DISCLOSURES Speakers Bureau: Amgen, Radius Consultant: Abbvie, Amgen, Janssen, Radius, Sanofi

Watts NB et al J Clin Endocrinol Metab 2012;97:1802-1822

OSTEOPOROSIS IN MEN Discuss the skeletal differences between men and women Describe criteria for diagnosing osteoporosis in men Explain the recommended evaluation Construct a plan for nonpharmacologic management Identify available treatments for men with osteoporosis State appropriate monitoring strategies

HOW ARE MEN DIFFERENT FROM WOMEN? Men have Higher peak bone mass Larger bones Different geometry Greater muscle mass Less likely to fall No equivalent to menopause Shorter life span

WHAT IS THE ECONOMIC BURDEN? The lifetime risk for any clinical fracture at age 60 is 29% in men and 56% in women. 1 U.S. expenditure for osteoporotic fractures in men (2005) was $4.1 billion, 24% of the total cost. 2 1. Jones G Osteoporosis Int 1994; 4:277-282 2. Burge R et al J Bone Miner Res 2007;22:465-475

FRACTURES IN MEN AND WOMEN Data from the UK Curtis EM et al Bone 2016;87:19-26

FRACTURES IN MEN AND WOMEN Incidence/1,000,000 Person-years 4,000 3,000 2,000 1,000 0 Forearm Spine Hip Women Men 40 60 80 40 60 80 40 60 80 Cooper C et al Trends Endocrinol Metab1992;3:224

DISTAL FOREARM FRACTURES IN WOMEN AND MEN Women Men Over time Forearm fractures Fewer in women More in men Amin S et al J Bone Miner Res 2014;29:581-590

PROXIMAL FEMUR FRACTURES IN WOMEN AND MEN Women Men Over time Hip fractures Fewer in women No change in men Amin S et al J Bone Miner Res 2014;29:581-590

VERTEBRAL FRACTURES IN WOMEN AND MEN Women Men Over time Vertebral fractures More in women More in men Amin S et al J Bone Miner Res 2014;29:581-590

MORTALITY AFTER FRACTURES IS GREATER IN MEN Bliuc D et al JAMA 2009;301:513-521

WHICH MEN SHOULD HAVE A BMD TEST? Men 70 years or older without additional risk factors Younger men (50-69) with low-trauma fractures Men with diseases/conditions/drugs known to cause bone loss Men considering therapy for osteoporosis Men receiving treatment for osteoporosis ISCD. Binkley NC et al J Clin Densitom 2002;5 (suppl):s19-s28 Endo. Watts NB et al J Clin Endocrinol Metab 2012;97:1802-1822 NOF. Cosman F et al Osteoporos Int 2014:25:2359-2381

DXA TESTING IS LOWER FOR MEN THAN FOR WOMEN Ever-enrolled 65+ Part B FFS recipients as reported in the 5% sample of LDS SAF claims Direct Research LLC, Medicare PSPS Master Files and Medicare 5 Percent Sample LDS SAF, analysis by Peter M. Steven, PhD

REIMBURSEMENT FOR DXA INTERIM FINAL RULE Effective July 1, 1998, Medicare covers bone densitometry for five indications: estrogen deficient women at clinical risk for osteoporosis patients with vertebral abnormalities patients receiving long-term glucocorticoids (prednisone 5 mg/d or more for 3+ months) patients with primary hyperparathyroidism patients being monitored to assess the response to an approved drug Federal Register June 24, 1998;63:34320-34328 Watts NB J Clin Densitom 1999;2:211-217

WHEN YOU ORDER A BMD TEST FOR A 70-YEAR- OLD MAN, HOW WOULD YOU GET IT COVERED? If patient has back pain or height loss, consider spine radiographs before DXA; radiographic osteopenia or vertebral fracture would be covered indications If you have a screening tests, such as heel ultrasound or finger DXA, provide that for free; T-score -1.0 or below is osteopenia Have the patient sign a waiver (ABN) so you can bill the patient if Medicare doesn t pay

WHO CRITERIA FOR POSTMENOPAUSAL OSTEOPOROSIS The T-score compares an individual s BMD with the mean value for young normal individuals and expresses the difference as a standard deviation score. T-Score NORMAL -1.0 and above OSTEOPENIA -1.0 to -2.5 OSTEOPOROSIS -2.5 and below Kanis JA et al J Bone Miner Res 1994;9:1137-1141

WHY THE WHO CHOSE A T-SCORE CUTOFF OF -2.5 FOR POSTMENOPAUSAL WOMEN "Such a cutoff value identifies approximately 30% of postmenopausal women as having osteoporosis using measurements made at the spine, hip, or forearm. This is approximately equivalent to the lifetime risk of fracture at these sites." "Criteria different from those just mentioned should be applied to men and to younger individuals before skeletal maturity, but there are insufficient data to establish them The use of a female referent for men is inappropriate." Kanis JA et al J Bone Miner Res 1994; 9:1137

WHO INTERIM REPORT-1999 The same absolute BMD value (after adjustment for larger body size) can, provisionally, be utilized for men. Genant HK et al Osteoporos Int 1999;10:259-264

DXA UNDERESTIMATES BMD OF SMALL BONES AND OVERESTIMATES BMD IN LARGE BONES 3 cm 3.5 cm 3 cm 4 cm Bone mineral content 2.12 g 3.85 g Volume 21.2 cm 3 38.5 cm 3 Volumetric density 0.1 g/cm 3 0.1 g/cm 3 Projected area 9.0 cm 2 14.0 cm 2 Areal density 0.236 g/cm 2 0.275 g/cm 2

USE A MALE OR FEMALE DATABASE TO CALCULATE T-SCORES FOR MEN? T-scores for men are lower with a male database than with a female database (~0.3 hip, ~1 SD spine). Some studies suggest that men fracture at the same BMD as women. If so, a female database should be used. Other studies suggest that men fracture at a higher BMD than women. If so, a male data base should be used.

USE A MALE OR FEMALE DATABASE TO CALCULATE T-SCORES FOR MEN? Prior to 2013, all DXA manufacturers used a male database for men and a female database for women (and some still do) FRAX uses femoral neck BMD and calculates T-scores using a female database for both men and women (though T-scores in FRAX don t matter FRAX uses BMD to determine fracture risk)

4. A uniform Caucasian (non-race adjusted) female reference database should be used to calculate T-scores for men of all ethnic groups. Watts NB et al J Clin Densitom 2013;16:472-481

NEWER HIP DATA FROM NHANES NHANES III (1988-1994) NHANES 2005-2008 Looker AC et al Osteoporos Int 2012;23:771-780

SPINE DATA FROM NHANES Looker AC et al Osteoporosis Int 2012:23:1351-1360

MOST MEN WITH FRACTURES DO NOT HAVE OSTEOPOROSIS Rotterdam Study Women Non-vertebral fractures 44% Osteoporosis 13% Normal BMD 21% 18% Men Non-vertebral fractures 43% Low BMD 61% Hip fractures 64% Osteoporosis 5% Normal BMD 31% Low BMD 39% 3% 58% Hip fractures Schuit SCE et al Bone 2004;34:195-202

OSTEOPOROSIS PREVALENCE AND FRACTURE RISK IN MEN Prevalence (FN -2.5 and below) Lifetime fracture risk 4% (NHANES female database) 6% (NHANES male database) 6-11% (hip fracture, age 50) 25-30% (any clin fx, age 60) Regardless of whether a male or female database is used, femoral neck T-score cut point of -2.5 identifies only a small proportion of men who will fracture

HOW MANY MEN WOULD BE TREATED? 3887 men from MrOs, age 65 5.0% Femoral neck -2.5 or below* 3.2% Spine -2.5 or below* 7.0% Femoral neck OR spine -2.5 or below* 29.0% FRAX 10-year hip fracture risk 3%** 8.3% FRAX 10-year major fracture risk 20%** Meeting any NOF criterion 34% *T-scores calculated using a male database **FRAX risk calculated February 2009 Donaldson MG et al J Bone Miner Res 2010;25:1506-1511

FUNDAMENTAL MEASURES FOR BONE HEALTH Calcium and vitamin D intake Needs in men are similar to women; adequate intake must be ensured Appropriate physical activity Avoid smoking Avoid heavy alcohol use 3 or more units per day (FRAX )

SECONDARY OSTEOPOROSIS EVALUATION IN MEN History and physical exam CBC; chemistry profile incl. electrolytes and phosphorus; 25-hydroxyvitamin D; serum testosterone; 24-h urine calcium, sodium and creatinine In selected patients: PTH, SPEP/UPEP,TSH, serum free testosterone, urine free cortisol, skin fibroblast culture, tissue transglutaminase antibodies, IGF-1, histamine metabolites Bone turnover markers Bone biopsy

WHICH MEN TO TREAT WITH PHARMACOLOGIC AGENTS? Men with a clinical diagnosis of osteoporosis (spine or hip fracture) 1 Men with a DXA diagnosis of osteoporosis (T-score -2.5 or below) 1 Men at high risk of fracture based on FRAX 1 Where effectiveness of treatment has been shown in clinical trials 2 T-score -2.0 or below Non-spine, non-hip fragility fracture with T-score -1.0 or below 1. Cosman F et al Osteoporos Int 2014:25:2359-2381 2. Watts NB et al J Clin Endocrinol Metab 2012;97:1802-1822

FDA-APPROVED MEDICATIONS INDICATIONS Postmenopausal Osteoporosis Glucocorticoid-induced Osteoporosis Men Drug Prevention Treatment Prevention Treatment Estrogen Calcitonin (Miacalcin, Fortical ) Raloxifene (Evista ) Ibandronate (Boniva ) Alendronate (Fosamax ) Risedronate (Actonel ) Risedronate (Atelvia ) Zoledronate (Reclast ) Denosumab (Prolia ) Teriparatide (Forteo ) Abaloparatide (Tymlos )

ALENDRONATE INCREASES BMD IN MEN WITH OSTEOPOROSIS 241 men with femoral neck BMD 2.0 or below Men with secondary osteoporosis other than hypogonadism were excluded Lumbar Spine Total Hip Mean BMD (% change from baseline + SE) 8 7 6 5 4 3 2 1 0 Alendronate 10 mg/d Placebo 0 6 12 18 24 Months Mean BMD (% change from baseline + SE) 4 3 2 1 0 0 6 12 18 24 Months Orwoll ES et al N Engl J Med 2000;343:604-610

ALENDRONATE INCREASES BMD IN MEN REGARDLESS OF SEX HORMONE LEVELS Change in Lumbar Spine BMD Mean BMD Change (% Over 24 Months) 8 7 6 5 4 3 2 1 0 Alendronate < 69 69 87 88 102 103 126 > 126 Quintiles of Free Testosterone (pg/ml) 8 7 6 5 4 3 2 1 0 Placebo < 14 14 17 17 21 21 27 > 27 Quintiles of Estradiol (pg/ml) Orwoll ES et al N Engl J Med 2000;343:604-610

ALENDRONATE MAY REDUCE VERTEBRAL FRACTURES IN MEN WITH OSTEOPOROSIS 10 241 men with osteoporosis, age 31-87 Post hoc analysis Percent with new vertebral fractures over 2 Years 8 6 4 2 *P=0.02 Placebo ALN 10 mg 0-2 Semiquant. Quantitative After data of Orwoll E et al N Engl J Med 2000;343:604-610

REDUCTION IN NEW VERTEBRAL FRACTURES ZOLEDRONIC ACID IN MEN 1199 men Median age 66 T-scores -2.2 fem. neck -1.7 total hip ~1/3 had prior VFX Boonen S et al N Engl J Med 2012;367:1714-1723

ONJ AND AFF RISK DIFFERENT FOR MEN vs WOMEN? Swedish Medical Products Agency BP users 2 AFF 1 RR 3 for AFF Men 39,294 2 4.31 (1.02,18.25) ONJ 1 Women 185488 41 57 RR 3 for ONJ 6 1.84 (0.80, 4.33) 1. Spontaneous reports of AFF and ONJ, excluding non-confirmed cases 2. Bisphosphonate use estimated from Swedish Prescription Register Duration of use similar for men (5 yrs) and women (6 yrs) 3. RR calculated from age-stratified incidence proportions Kharazmi M et al ann Rheum Dis 2014;73:1594

EFFECT OF DENOSUMAB ON BMD IN MEN Lumbar Spine Femoral Neck 1/3 Radius 7 6 5 4 3 D mab 60 mg Q 6 mos Placebo * * 4 3 2 * * 1.5 1.0 0.5 * 2 1 0.0 1 0-1 *p<0.0001 vs placebo 0 6 12 0-1 *p<0.0001 vs placebo 0 6 12-0.5-1.0 *p<0.0144 vs placebo 0 6 12 Months Months Months Orwoll E et al J Clin Endocrinol Metab 2012;97:3161-3169

REDUCTION IN NEW VERTEBRAL FRACTURES D MAB IN MEN RECEVING ADT 1468 men Median age 75 T-scores -1.5 fem. neck -0.9 total hip ~22% had prior VFx 85% 69% 62% Smith M et al N Engl J Med 2009;361:745-744

OSTEOPOROSIS IN MEN: TREATMENT WITH TESTOSTERONE Pharmacologic therapy should be prescribed for men at high risk of fracture, whether testosterone is offered or not, and is effective even if testosterone level is low and not treated Testosterone alone might be considered for Men at high risk for fracture who are not candidates for other agents Candidates for testosterone therapy at borderline risk for fracture Not recommended unless Serum testosterone level is low (<200 ng/ml) Hypogonadism is organic (e.g., pituitary tumor) There are symptoms of hypogonadism (e.g., low libido, erectile dysfunction) Reduce dose or discontinue if there are side effects or no clinical improvement in symptoms

EFFECT OF IM TESTOSTERONE ON BMD 70 men age 65 or older Serum testosterone less than 350 ng/dl on two occasions (mean baseline T ~290 ng/dl) Assigned at random to IM testosterone + oral finasteride IM testosterone + oral placebo IM placebo + oral placebo Average serum T with Rx ~750±180 ng/dl Amory JK, Watts NB et al J Clin Endocrinol Metab 2004;89:508-510

EFFECT OF IM TESTOSTERONE ON BMD Amory JK, Watts NB et al J Clin Endocrinol Metab 2004;89:508-510

EFFECT OF IM TESTOSTERONE ON BTM Amory JK, Watts NB et al J Clin Endocrinol Metab 2004;89:508-510

EFFECT OF TESTOSTERONE PATCH ON BMD Conclusion: testosterone doesn t help if the blood level is normal but may increase spine BMD in men with low baseline serum testosterone levels Stratified effect on hip BMD not reported Snyder PJ et al J Clin Endocrinol Metab 1999;84:1966-1972

META-ANALYSIS OF THE EFFECTS OF TESTOSTERONE THERAPY ON BMD Tracz MJ et al J Clin Endocrinol Metab 2006; 91:2011-2016

META-ANALYSIS OF THE EFFECTS OF TESTOSTERONE THERAPY ON BMD Spine Femoral Neck Tracz MJ et al J Clin Endocrinol Metab 2006;91:2011-2016

Geusens PM and van den Bergh JP Nature Rev Rheum 2012;8:568-570

TREATMENT RATES FOR OSTEOPOROSIS ARE LOWER FOR MEN THAN FOR WOMEN van de Velde RY et al Bone 2017;94:50-55

OSTEOPOROSIS IN MEN Osteoporosis in men is a serious public health problem BMD testing is recommended for men age 70 and older, as well as younger men at increased risk A female database is recommended to calculate T-scores for men Fracture risk calculation should be done for men with osteopenia (enter femoral neck BMD, not T-score) All men at risk of fracture should be evaluated for cause of secondary osteoporosis Alendronate, risedronate, zoledronate, denosumab and teriparatide are FDA-approved to treat osteoporosis in men Testosterone may be used in limited circumstances

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