Osteoporosis in Men Professor Peter R Ebeling

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1 Osteoporosis in Men MD FRACP Head, Department of Medicine, School for Clinical Sciences Monash Health Translation Precinct Monash University, Clayton, Victoria 1 MonashHealth Potential Conflicts Departmental research funding from Merck, Novartis, Amgen and Eli-Lilly Honoraria from Amgen and Merck 2 Objectives Epidemiology and mechanisms of bone loss in men Review of the endocrine society guidelines on osteoporosis in men Assessing risk factors for osteoporosis in men Review of osteoporosis treatments Gaps in evidence base 3 1

2 Twenty Years of Studying Osteoporosis in Men: What Have We Learned? 4 Cooper C et al., JBMR 1992 Osteoporosis in Men Importance of Hip Fractures One third of hip fractures occur in men The increase in men with hip fractures is due to both an increase in longevity and a later-born (secular) increase Age-related hip fracture incidence rates in many Western countries are decreasing in women, but not in men Mortality after hip fracture in men is 50% higher than in women at 37.5% in 12 months 5 Annual and Projected Rates of Hip Fractures USA Year Men Women Total Overall % change 51.8% -3.5% 11.9% Actual and projected numbers are in thousands Hip fractures: NCHS, ICD-9 820, first listed diagnosis Over the next 20 years, rising numbers of hip fractures in men will counterbalance decreasing numbers of hip fractures in women 6 Stevens JA and Rudd RA Osteoporos Int

3 24 year old male Mechanisms of Bone Loss In Men Trabecular Thinning is Important Trabecular thinning is secondary BV/TV TbN TbTh TbSp /mm mm mm 48 year old male to reduced bone formation Women lose trabeculae due to increase bone resorption Bone loss accelerates after age 70 yrs BV/TV TbN TbTh TbSp /mm mm mm and is more common with low T or E 2 73 year old male 7 BV/TV TbN TbTh TbSp /mm mm mm Khosla S et al., J Bone Miner Res 2006 Aaron J et al., Clin Ortho Rel Res 1985 Seeman E, Lancet Natural History of Bone Loss in Men Role of IGF I and Sex Hormones Trabecular bone loss begins early in life associated with decreases in IGF-I Serum IGF-I associated inversely with fracture risk for all fractures and hip fractures HR 1.45 [ ] Population-attributable risk was 7.5% for all fractures and 22.9% for hip fractures 85% of cortical bone loss occurs after age 50 yrs in association with decreases in bioavailable T and E2 and increased bone remodeling Ohlsson C et al., JBMR 2011 ; Ebeling PR, New Engl J Med 2008 Cortical Porosity, not Thickness, is Related to Vertebral Fractures in Men with Idiopathic Osteoporosis Both trabecular marrow star volume and cortical porosity independently increase vertebral fracture risk with HRs of 3.9 and 4.1, both p=0.02, respectively BV/TV (%) 9 Without VFX Ostertag A et al., Bone 2009 With VFX Cortical porosity (%) 3

4 Age Related Changes in Bone Turnover Markers in Men STRAMBO Cohort BTM levels were high in young men and decreased until age 50 yrs Ur DPD increased after age 70 years, but other BTMs remained stable Incr BTMs after 70 yrs were associated with reduced cortical thickness and vbmd; and reduced Tb.Th and Tb.N 10 Chaitou A et al., JBMR 2010 Dissecting Relative Contributions of E vs. T to Bone Turnover in Men Visit Weeks Entry Baseline Final Leuprolide Leuprolide Letrozole 11 T + E Patch Falahati-Nini et al., JCI 106: , 2000 A: No Patch B: E Patch C: T Patch D: T + E Patch T Patch In Vivo Effects of Sex Steroids on Bone Resorption Markers % Change ** *** * * ** *** P < ** P < * P < 0.05 Dpd ANOVA E effect: P = T effect: P = NTx ANOVA E effect: P = Group A (-T, -E) Group B (-T, +E) Group C (+T, -E) Group D (+T, +E) T effect: P =

5 E vs. T Effects on Bone Turnover in Men: Summary In men, E is the dominant sex steroid regulating bone resorption, although T (in the absence of aromatization to E) may make a smaller contribution (< 30%) Both E and T contribute to the maintenance of bone formation 13 Hypogonadism with Estrogen Removal Study Healthy men (age yrs) given GnRH and aromatase blocker for 16 weeks Treated with 5 doses of T (0, 1.25 g, 2.5 g, 5 g, 10 g) 14 Yu et al., ASBMR, 2012 (#1199) Cortical Porosity and Trabecular Microarchitecture % Change 10% increase in cortical porosity Cortical Porosity * p-value <0.005 * * Radius Tibia No significant change in trabecular microarchitecture Trabecular number Trabecular thickness Trabecular separation 15 5

6 Conclusions Hypogonadal bone loss in men is primarily due to estrogen deficiency Changes in bone microarchitecture due to estrogen deficiency are predominantly within the cortical compartment Therapies using non-aromatizable androgens may be inadequate to protect the skeleton in male hypogonadism 16 High Bone Turnover Predicts Increased Subsequent Fracture Risk in Elderly Men 17 Meier C et al., JBMR, 2005 Origins of the Fractures in Overweight/Obese Men High prevalence of overweight/obesity Increased risk due to obesity Fracture incidence 1000 person yrs Non-spine fx Hip fx Fractures 0 Normal Overweight Obese 1 Obese 2 18 High prevalence of obesity: In this large group, How can we identify men who are at increased risk? Good data are not available and recommendations not established 6

7 Is It Helpful to Measure BMD in Overweight/Obese Men? BMI and BMD are only modestly correlated Age adjusted association Pearson s r = Nielson et al., JBMR 2011 Obese/overweight men can have osteoporotic BMD Why Do Obese Men Fracture? Adiposity and bone mass Body composition and fracture risk 20 Stem cell differentiation (osteoblasts vs. adipocytes) Increased marrow fat = lower BMD Lower muscle density, fat infiltration = increased fracture risk Bone and energy metabolism : induction of increased adiposity associated with lower BMD Vitamin D deficiency Relative sex BMI hormone associated deficiency with greater BMD, but Body Composition Change and BMD Loss Total hip BMD Δ (g/cm 2 ) Weight Δ quartile 1 (most loss) Weight Δ quartile 2 (some loss) Weight Δ quartile 3 (stable) 4 (stable/gain) 3 (some loss) 2 (more loss) 1 (most loss) Weight Δ quartile 4 (most gain) 21 Nielson et al., JBMR 2011 ASM Δ quartile 7

8 22 The Endocrine Society Guidelines June 2012 GRADE system strength of recommendations and evidence quality Strong recommendations we recommend/1 (n = 10) Weak recommendations we suggest/2 (n = 13) Quality of evidence: Very low quality (3) Low quality (14) Moderate quality (6) High quality (0) Five step Evaluation and Treatment Plan for Men Aged 50 Years at High Risk of Fracture and Osteoporosis, Based on 2012 Endocrine Society Clinical Practice Guideline for Osteoporosis in Men 23 Geusens P & van den Bergh JP Nat. Rev. Rheumatol Evaluation BMD Testing Suggest testing men at increased risk of osteoporosis by measurement of BMD, using DXA Age 70 yrs Age yrs with risk factors: history of fracture after age 50 yrs; diseases/conditions associated with osteoporosis; drugs such as glucocorticoids or GnRH agonists; alcohol abuse, smoking; other causes of secondary osteoporosis FRAX, Garvan or other fracture risk calculators improve assessment of absolute fracture risk (2 ) 8

9 Evaluation Role of DXA Recommend DXA of spine and hip in men at risk of osteoporosis (1 ) Suggest measuring forearm DXA (1/3 or 33% radius) when spine or hip BMD cannot be interpreted and for men with hyper-parathyroidism or receiving androgen deprivation therapy (ADT) for prostate cancer (2 ) 25 Evaluation Identification of Spinal Fractures In men with low bone mass (osteopenia) or osteoporosis who might have had previously undiagnosed vertebral fractures, vertebral facture assessment using DXA is recommended (1 ) If VFA is not available or is technically limited, lateral spinal radiographs should be considered (1 ) 26 Evaluation Clinical Risk Factors Suggest a complete history and physical examination for men being evaluated for osteoporosis or its pharmacological treatment (2 ) Suggest measuring serum Ca, phosphate, Cr and egfr, ALP, liver function, 25(OH)D, total testosterone, complete blood count and 24-h urine Ca (Cr and sodium) excretion in these men (2 ) 27 9

10 Evaluation Further Directed Testing Includes, but is not limited to: calculated free or bioavailable testosterone using SHBG; serum protein electrophoresis with free k or l light chains and/or urine protein electrophoresis; tissue transglutaminase antibodies, thyroid function tests, and PTH levels (2 ) 28 Lifestyle Calcium and Vitamin D Recommend that men with or at risk of osteoporosis consume mg Ca daily, ideally from dietary sources, with calcium supplements added if dietary Ca is insufficient (1 ) Suggest that men with low vitamin D levels [<30 ng/ml (75 nmol/l)] receive vitamin D supplementation to achieve blood 25(OH)D levels of at least 30 ng/ml (75 nmol/l) (2 ) Lifestyle Weight bearing Exercise, Alcohol and Tobacco Suggest that men at risk of osteoporosis participate in weight-bearing activities (type?) for min per session, 3-4 sessions per week (2 ) Suggest that men at risk of osteoporosis who consume three or more units ( 30g) of alcohol per day reduce their alcohol intake (2 ) Recommend that men at risk of osteoporosis who smoke cease smoking (1 ) 10

11 Studies of Anti Fracture Efficacy in Men Lack of data from published trials using fractures as a primary end-point Data exist for spine fractures, mainly as secondary end-points for alendronate, risedronate and teriparatide Bisphosphonates or teriparatide increase spine and hip BMD Combination therapy with PTH and bisphosphonates is not recommended Treatment Pharmacological therapy is recommended for men at a high risk for fracture: Men who have had a vertebral or hip fracture without major trauma (1 ) Men without fractures, but whose T-score is -2.5 at the spine, hip or femoral neck (1 ) Men who have a T-score between 1.0 and 2.5 in the spine, femoral neck, or total hip plus a 10-yr risk of experiencing any fracture 20% or 10-yr risk of hip fracture 3% using FRAX (1 ) Treatment Pharmacological therapy is recommended for men at a high risk for fracture: Men who are receiving long-term glucocorticoid therapy in pharmacological doses (e.g., prednisone or equivalent >7.5 mg/d) for 3 months or longer who have a T-score of 1.5 or less (1 ) 33 11

12 34 Selection of Therapeutic Agent We recommend that men at high risk of fracture be treated with medication approved by regulatory agencies such as the U.S. FDA or EU EMA (1 ) Alendronate, risedronate, zoledronic acid, and teriparatide; also denosumab for men receiving ADT for prostate cancer): And that selection of therapeutic agent be individualized In men with a recent hip fracture, we suggest treatment with zoledronic acid Teriparatide should not be given with concomitant antiresorptive therapy (true for risedronate or denosumab?) Calcitonin, ibandronate, strontium ranelate, should be used only if approved agents cannot be administered Effects of Alendronate on Spinal BMD and Fractures in Hypo and Eugonadal Men with Osteoporosis In a two-year double-blind trial, 10 mg of alendronate given daily showed a statistically significant increase in men s spinal BMD Semiquantitative vertebral fractures 8.1 vs. 3.1% (p = 0.12) Quantitative vertebral fractures 7.1 vs. 0.8% (p = 0.02) 35 Orwoll et al., NEJM 2000 Risedronate Treatment in Men One yr, open-label study Ringe JD et al., Rheumatol Int 2006 Increase in spinal and hip BMD Reduced the risk of radiologic vertebral fractures Not blinded Reduced hip fractures after CVA RR 0.19 ( ) Sato Y et al., Arch Int Med 2005 Increases in spine and hip BMD Boonen S et al., J Bone Miner Res

13 Comparison of Once Yearly i.v. Zoledronic Acid 5 mg vs. Once Weekly 70 mg Oral Alendronate in Men with Osteoporosis BMD 37 Orwoll E et al., J Bone Miner Res 2010 Effect of Once Yearly i.v. Zoledronic Acid 5 mg vs. Placebo on 1 Vertebral Fractures in Men with Osteoporosis 38 Primary end point (24 months) 67% relative risk reduction, 3.3% absolute risk reduction Secondary end point (12 months) 68% relative risk reduction, 1.9% absolute risk reduction Boonen S et al., New Engl J Med 2012 Treatment with Zoledronic Acid after Hip Fracture Reduces Clinical Fractures and Mortality B. Mortality Treatment had reduced the incidence of clinical fractures Treatment had reduced mortality by 28% 39 Lyles KW et al., New Engl J Med

14 Effects of Denosumab vs. Placebo on BMD in Men with Osteopenia Denosumab increases lumbar spine/total hip/femoral neck/ trochanter BMD much more than placebo Denosumab increase cortical bone density after 12 months 40 Orwoll E et al., JCEM 2012; 97: Effects of Denosumab on New Vertebral Fractures in Men on ADT for Prostate Cancer 41 Denosumab reduced new vertebral fractures Absolute risk reductions of 2.4% at 36 months Bisphosphonates, SERMs (toremifene) also effective at reducing fractures Smith MR et al., New Engl J Med, 2009 Incidence of Vertebral Fractures in Men During 11 Mths Treatment and 18 Mths Follow Up 16 RR 0.52 (0.19, 1.41) % of men with 1 fracture RR 0.48 (0.18, 1.32) RR of moderate or severe vertebral fractures was 0.17, p= Placebo PTH20 PTH40 42 Kaufman J-M et al., Osteoporos Int,

15 Effects of Strontium Ranelate vs. Placebo on BMD in Men with Osteoporosis Strontium ranelate increases bone density at the lumbar spine, femoral neck and total hip over two years treatment Strontium ranelate should be used only when other treatments are not possible in patients with osteoporosis 43 Kaufman J et al., JCEM 2013; 98: Management of Hypogonadal Men at High Risk of Fracture Men at high risk of fracture who are receiving testosterone (T) therapy: Add an agent with proven antifracture efficacy (e.g., bisphosphonate or teriparatide) (1 ) T therapy alone for men at borderline high risk for fracture who have serum T levels below 200 ng/dl (6.9 nmol/ liter), with signs or symptoms of androgen deficiency (2 ) T therapy for men at high risk for fracture with T levels below 200 ng/dl (6.9 nmol/liter) who lack standard indications for T therapy, but who have contraindications to approved pharmacological agents for osteoporosis (2 ) Effect of Baseline Testosterone Levels on Changes in Spinal BMD Pre-treatment testosterone concentration is correlated to the % change in spinal bone density (those with initially low testosterone levels have greater increase in the spinal BMD) 45 Snyder P et al., JCEM

16 Clinical Implications Use of serum estradiol levels in the evaluation of male osteoporosis 46 Potential Clinical Approach Male with low T (< 300 ng/ml), osteoporosis/increased fracture risk E 2 normal (> 16 pg/ml by mass spec): standard pharmacological therapy (e.g., bisphosphonate) E 2 low (< 16 pg/ml): Consider trial of T therapy and monitor BMD 47 Changes in Serum E 2 Following Transdermal T Replacement After 12 months of treatment there is an increase of E 2, from around 20 pg/ml to 47 pg/ml 48 Wang et al., JCEM 89: 2085,

17 Clinical Implications Use of serum estradiol levels in the evaluation of male osteoporosis Use of selective estrogen receptor modulators in male osteoporosis 49 Raloxifene in Men with Prostate Cancer on GnRH 50 Study showed maintenance of bone density in the men treated with raloxifene, and bone loss in the lumbar spine, total hip and trochanter of untreated men Changes at the femoral neck were not different between the groups Smith et al., JCEM 89: 3841, 2004 Effects of the Serm, Toremifine, on Vertebral Fractures in Men with Prostate Cancer 1284 men with prostate cancer on ADT randomized to receive 80 mg toremifine or placebo for up to 24 months 50% reduction noted in vertebral fractures in the toremifene treated group (P = 0.05) 51 Smith et al., J Urol 184: 1316,

18 52 Monitoring Therapy BMD We suggest clinicians monitor BMD by DXA at the spine and hip every 1 to 2 yr to assess the response to treatment (2 ) If BMD appears to reach a plateau, the frequency of BMD measurements may be reduced Increase of 3% and 5% at spine and hip, respectively, in the short term are likely to be significant Increase in BMD may not be a suitable surrogate for fracture risk reduction in men Longer intervals between scans (2-3 yrs) may be indicated in untreated men BMD monitoring is associated with good compliance in men 53 Monitoring Therapy Bone Turnover Markers (BTM) We suggest clinicians consider measuring a BTM at 3 6 months after initiation of treatment using a bone resorption marker (serum CTX, or serum or urine NTX) for antiresorptive therapy, and a bone formation marker (such as serum PINP) for anabolic therapy (2 ) The concept of least significant change in a BTM can be used (~40% for urine NTX) after 3 mths of treatment A target could be below the median of the normal range in men for a BTM, but this has not been validated in men A lack of change in a BTM may mean considering non-compliance, secondary osteoporosis, a change in therapy, or the route of administration Comparison of Once Yearly i.v. Zoledronic Acid 5 mg vs. Once Weekly 70 mg Oral Alendronate in Men with Osteoporosis BTMs Serum β CTx Urine P1NP Zoledronic acid Alendronate Serum P1NP BSAP 54 Orwoll E et al., J Bone Miner Res

19 Predicting Anabolic Responses to Teriparatide with PINP and PICP Changes in PICP and PINP Changes in abmd, trabecular and cortical BMD Spine Bauer D et al., J Clin Endocrinol Metab 2006 Spinal BMD (DXA), spinal trabecular BMD (QCT) and cortical BMD (QCT) all showed greater increase in the highest tertile of 3-months change in PINP 55 Chen P et al., J Bone Miner Res 2005 No fracture outcome data Duration of Bisphosphonate Therapy Bisphosphonates for Osteoporosis - Where Do We Go from Here? Whitaker M et al., New Engl J Med : Waning effects after 3 or 5 years for zoledronic acid or oral bisphosphonates, respectively Continuing Bisphosphonate Treatment for Osteoporosis For Whom and for How Long? Black DM et al., New Engl J Med : Continuing reductions in vertebral fractures in those at highest risk T-score < -2.5 and no prevalent vertebral fractures T-score < -2.0 and a prevalent vertebral fracture 56 Duration of Bisphosphonate Therapy The group to benefit the most from treatment, and having lowest number of needed to treat are those women with no prevalent vertebral fractures at the start of the study who had a femoral neck T score -2.5 Similarly, the groups of women with prevalent vertebral fractures at the start of the study with a femoral neck T score of either -2.5, or -2.5 < T score -2, also had a low number of needed to treat 57 Black DM et al., New Engl J Med :

20 Continuing or Stopping Treatment After 3 Yrs of Intravenous Zoledronate, or 5 Yrs of Oral Bisphosphonates Continue treatment in those at high risk FN T-score -2.5 FN T-score -2 in the presence of a vertebral fracture The benefits of treatment will far outweigh the risks 58 Conclusions The Endocrine Society Guidelines provide a useful management framework for fracture prevention in men However, there is a lack of the highest quality evidence on which to base recommendations Further research in osteoporosis in men is required to increase the level of evidence to that in women Osteoporosis in men deserves more attention 59 Thank You! 60 20

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