Osteoporosis in Men Eric Orwoll Oregon Health & Science University

Osteoporosis in Men Eric Orwoll Oregon Health & Science University Ris k Factor Risk factors for hip fracture in men Multivariate HR + 95% CI Age 2.3 (1.6, 2.4) FN BMD 3.0 (2.5, 3.7) 5994 men age >65 yrs Follow-up 8.6 yrs 178 hip fractures Why do men fracture? Diagnostic work-up Testosterone Osteoporosis therapies Sleep Current smoker 2.0 (1.0, 4.0) Protein intake 0.8 (0.7, 0.96) Any frac ture after 50 yr 1.5 (1.1, 2.0) Height 1.2 (1.05, 1.5) Height loss 1.3 (1.2, 1.6) Tricyclic use 2.9 (1.4, 6.3) Hyperthyroidism 2.8 (1.3, 6.2) Parkinson s 3.3 (1.2, 9.1) MI 1.6 (1.1, 2.2) Cognition (executive fx) 1.3 (1.15, 1.5) Cauley et al JBMR 2016 Hip fracture as a function of BMD Study of Osteoporotic Fractures N= 8065, hip fracture/5yrs N= 245 46% of hip fracture BMD T score =/< -2.5 Wainwright et al. JCEM 2005 Men with major osteoporotic fractures usually do not have osteoporotic BMD 70 60 SOF MrOS 50 Osteoporotic Fractures in Men (MrOS) N= 5993, hip fracture/5 yrsn= 77 10% of hip fracture BMD T score =/< -2.5 Percent 40 30 20 10 Normal Low BMD Osteoporosis 0 All Women Women MOF All Men Men MOF Ensrud et al JBMR 2015 - BMD from DXA predicts fracture risk in men - The association between BMD is Before MrOS, it was not clear how well DXA similar BMD predicted in men fractures and women in community dwelling men Bone strength Trabecular density Cortical density Cortical thickness Risk of falls Muscle mass and function Balance and coordination Fracture Fraktur Cummings et al JBMR 2006 Ohlsson ASBMR 2016

Physical performance and risk of hip fractures in older men Hazzard ratio (95% CI) of hip fracture Test of physical performance Repeated chair stands Age adjusted Multiply adjusted* Unable 12.6 (4.1-38.9) 8.2 (2.7-25.0) Quartile 4 (worst) 4.7 (1.8-12.3) 3.6 (1.4-9.4) Quartile 3 3.0 (1.1-8.2) 2.7 (1.0-7.3) Quartile 2 1.9 (0.6-5.4) 1.6 (0.6-4.7) Quartile 1 1.0 (referent) 1.0 (referent) Walking speed Quartile 4 (worst) 3.0 (1.4-6.7) 2.4 (1.1-3.4) Quartile 3 1.4 (0.6-3.3) 1.3 (0.6-3.1) Quartile 2 0.9 (0.3-2.5) 0.9 (0.3-2.3) Quartile 1 1.0 (referent) 1.0 (referent) The contribution of activity and physical performance to the frequency of falls in older men 2741 men (78.8+5 years; range 71-98) Activity monitoring 5-7 days Multiple physical performance measures * Age, clinical center, FN BMD, BMI, hxof MI, hxstroke Cawthon et al. JBMR 2009 Men more often fracture because of high trauma SOF MrOS Tissue thickness and hip fracture risk in older men 70 men with incident hip fracture and 222 non-fractured controls, all with DXA and QCT finite element analysis Tissue thickness was minimally lower in hip fx vs controls (29 vs 31 mm, p= 0.2)(lower in trochanteric fx 26 mm) Tissue thickness was not associated with hip fracture risk (RR 1.01, 0.8-1.3) Tissue thickness was considerably lower in men than previously reported in women (49 vs 31 mm; Bouxsein et al JBMR 2007). Attenuation of fall force greater in women (61% vs 27%) Ensrud et al JBMR 2015 Nielson et al JCEM 2009 Femoral neck BMD (g/cm 2) 0.80 0.78 0.76 0.74 0.72 0.70 The rate of BMD loss accelerates with age in most, but not all, men Change: 0. 008 g/cm 2 Change: 0. 014 g/cm 2 65 70 75 80 85 90 95 Age at Enrollment (years) Implications of accelerated loss 65 year old 75 year old 85 year old Change: 0. 021 g/cm 2 Heterogeneity of loss 65 yr - BMD loss during follow-up (0.008 mg) = 9% increase in hip fx rate 85 yr - BMD loss during follow-up (0.021 mg) = 25% increase in hip fx rate 24% no loss/gain 63% expected loss 13% accelerated loss (at least 1 SD greater than mean loss) Fracture risk is higher in men with greater BMD loss Adjusted rate of non-spine and hip fracture per 100 person years, by category of BMD change and tertile of baseline BMD No n -spine fractures (per 100 person years) Category of femoral neck BMD change Tertile of femoral be treated neck earlier? baseline BMD Hip fractures (per 100 person years) Should men with low normal BMD (not yet in the range requiring treatment) routinely have a repeat measure in ~2-3 yrs? Should men with the greatest rate of bone loss Cawthon et al JBMR 2012 Cawthon et al JBMR 2012

Time to develop osteoporosis in older men MrOS. 5,415 community-dwelling men aged >65 years without hip or clinical vertebral fracture or antifracture treatment. Follow-up between 2000 and 2009. Osteoporosis in Men Estimated time for 10% to develop osteoporosis 8.5 years (95% CI=6.7, 10.9) for those with lowest T-score, 1.50 to 1.99 2.7 years (95% CI=2.1, 3.4) years for those with lowest T- score 2.00 to 2.49 Diagnostic work up Etiologies Genetic Secondary Idiopathic Gourlay et al Am J Prev Med 2016 Genetic Disorders Osteogenesis imperfecta (multiple genes): 80/10,000 Many cases may be unrecognized because of mild disease Type I (collagen 1A1, 1A2) most likely to present as osteoporosis - usually includes a history of fractures in childhood other phenotypic features (e.g. blue sclera, scoliosis, hearing loss) Marfan Syndrome (fibrillin): 5/10,000 people higher rate of fracture, lower BMD (Moura et al Joint Bone Spine 2006) characteristic physical findings Ehlers Danlos (multiple genes): 0.5/10,000 Genotyping is appropriate when the Joint/skin laxityclinical presentation is suggestive Lower BMD, increased fracture? (Carbone et al Osteoporos Int 2000) Estrogen receptor or aromatase mutations: rare Normal virilization Open epiphyses Forme fruste presentation as osteoporosis? Secondary Osteoporosis in Men Virtually all estimates of prevalence are in case series of patients referred for care 52% of 220 men with symptomatic vertebral fractures Evans and Davie Ann Rheum Dis 2000 47% of 154 men with vertebral fractures Pye et al. Rheumatology 2003 54% of 70 men with vertebral fractures Baille et al. Age Aging 1992 It is important to identify these conditions so they can be treated Secondary Osteoporosis in Men Alcoholism Endocrine disorders Hypogonadism Cushing s syndrome Diabetes (type 1 and 2) Hyperthyroidism Hyperparathyroidism (primary or secondary) Gastrointestinal disorders Malabsorption Syndromes Primary biliary cirrhosis Post gastrectomy syndromes Chronic obstructive pulmonary disease Organ transplantation osteoporosis Immobilization Neuromuscular disorders Hypercalciuria Systemic illnesses Mastocytosis Rheumatoid arthritis Multiple myeloma HIV disease Various other malignancies Medication/drug-related Glucocorticoids Androgen deprivation therapy Selective serotonin reuptake inhibitors Anticonvulsants Chemotherapeutics Thiazolidinediones Thyroid hormone (when used in excess) Gennariand Bilezikian Curr Osteopor Rep 2013 Secondary Osteoporosis in Men History and Physical Exam Targe te d laboratory testing Screening laboratory testing

Osteoporosis in Men: the Value of Laboratory Testing Ryan, Petkov, Adler Osteoporosis Int2011 Retrospective chart review of 234 men referred to a metabolic bone clinic for osteoporosis as a result of DXA screening; mean age was 70.6 years. Screening chemistries, 25-hydroxyvitamin D, testosterone, luteinizing hormone, follicle-stimulating hormone, thyroid-stimulating hormone, and spot urinary calcium-to-creatinine ratio Secondary osteoporosis in 75%. Many known at the time of referral. New diagnoses by lab tests in ~50%, almost all due to hypogonadism or vit D deficiency Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the Osteoporotic Fractures in Men (MrOS) Study Fink et al Osteoporosis Int2016 1572 men with both BMD and laboratory measures available, 10.4 % (n=163) met criteria for osteoporosis (T-score 2.5 at total hip, femoral neck, or lumbar spine using a male reference database) Of the 163 men with osteoporosis, 58.3 % had at least one of several laboratory abnormalities postulated as potential secondary factors 30.7 % with 25(OH)D <20 ng/ml 17.1 % with kidney disease 10.5 % with TSH <0.55 miu/l Men with osteoporosis were not significantly more likely than men without osteoporosis to have any of these laboratory abnormalities, except for high alkaline phosphatase or 25(OH) vitamin D insufficiency (<30 ng/ml) In referral patients or groups with a higher burden of chronic disease, the number of conditions associated with bone/mineral disturbance is high In community based men identified by screening, the prevalence of potential risk factors is also high, but often not more prevalent than in unaffected men Are the conditions related to the causation of he osteoporosis? Does treatment of these conditions improve outcomes? Is testing cost-effective? Clinical utility of routine laboratory testing to identify possible secondary causes in older men with osteoporosis: the Osteoporotic Fractures in Men (MrOS) Study Fink et al Osteoporosis Int2016 For laboratory testing in osteoporotic men to be of benefit, identification of specific laboratory abnormalities should inform a clinical decision that leads to improved patient-important health outcomes Still to be defined: treatment costs and potential harms the prevalence of laboratory-defined medical conditions that may contribute to osteoporosis in older men the validity, reliability, and cost of tests for these medical conditions whether there are treatments for these conditions that improve outcomes whether the benefits and/or harms of osteoporosis-specific treatments differ between men with versus without specific laboratory-defined medical conditions Evaluation of Osteoporosis in Men 1.4.1. We suggest measuring serum calcium, phosphate, creatinine (with estimated glomerular filtration rate), alkaline phosphatase, liver function, 25(OH)D, total testosterone, complete blood count, and 24-h urinary calcium (creatinine and sodium) excretion in men being evaluated for osteoporosis or considered for pharmacological treatment with bone-active agents. (low quality evidence) 1.4.2. If history or physical examination suggest a specific cause of osteoporosis, further testing should be done. Depending on the findings of the history and physical examination, such testing may include (but is not limited to) calculated free or bioavailable testosterone (using measurements of SHBG), serum protein electrophoresis with free and light chains and/or urine protein electrophoresis, tissue transglutaminase antibodies (for celiac disease), thyroid function tests, and PTH levels. (low quality evidence) Osteoporosis in Men: An Endocrine Society Clinical Practice Guideline (Watts et al JCEM 2012) Idiopathic Osteoporosis in Men Incidence perhaps 0.4/100,000 (Khosla et al Bone 1994) Variable characteristics: Age (20-60 yrs) Clinical severity (# fractures, severity of BMD deficit) Levels of remodeling markers - usually normal Biochemical etiology unclear; probably heterogeneous. Poor peak bone mass development Osteoblast dysfunction, potentially because of disturbance in IGF-I, IGF-II, IGFBP-3 Sex steroid inadequacy (lower free E2 levels, lower free T levels, higher SHBG) Kurland et al JCEM 1997 There is no specific test for idiopathic osteoporosis. Definition: when no secondary cause is identified. It is a diagnosis of exclusion.

Osteoporosis in Men Low testosterone is associated with increased fall risk Testosterone Hypogonadism has adverse effects on bone development during adolescence, and bone density/strength in adulthood Effects on bone in adults - estradiol >> testosterone Androgens Bone strength Fracture Fraktur Risk of falls Aromatase Bone Estrogens Orwoll et al JAMA Internal Medicine 2006, Vandenput et al JBMR 2017 Eligibility criteria included an age of 65 years or older and serum testosterone levels that averaged less than 275 ng per deciliter. The T Trials Effect of Testosterone Treatment on Volumetric Bone Density and Strength in Older Men With Low Testosterone: A Controlled Clinical Trial No fracture trials with testosterone No controlled data on long term adverse effects Snyder et al. JAMA Intern Med. 2017 The limited clinical utility of testosterone, estradiol, and sex hormone binding globulin measurements in the prediction of fracture risk and bone loss in older men Total T Total E2 Age, BMI, FN BMD Age, BMI, FN BMD + T Results the same for hip fracture and shorter follow-up times Age, BMI, FN BMD + E2 MrOS US, Sweden, Hong Kong 5087 men Major osteoporotic fracture 10 yr follow-up Orwoll et al. JBMR. 2017 Sex steroids and bone in men Sex steroids, especially estradiol, are important for the maintenance of skeletal integrity in men In men with severe hypogonadism (androgen deprivation therapy) the risk of bone mass and factures is clearly higher Measure BMD and assess risk factors Preventive and therapeutic treatment is appropriate In men who present for osteoporosis evaluation Significantly low testosterone levels are unlikely Measure testosterone levels if there is a clinical suspicion that significant hypogonadism is present Therapy with testosterone is likely to increase BMD in men with low T Should T be used for osteoporosis in men? Fracture data are not available (reduce falls? Improve bone strength?) Testosterone therapy for osteoporosis in hypogonadal may be appropriate in men under certain circumstances When T therapy is indicated for other reasons When fracture risk is modest In hypogonadal men at high fracture risk who don t have indications for T, anti-osteoporosis drugs are appropriate

Osteoporosis in Men Osteoporosis therapies Treatment of osteoporosis in men Anti-resorptives Bisphosphonates Denosumab Anabolics Teriparat ide Abaloparatide Pending Anti-sclerostins Alendronate therapy in osteoporotic men Percent change in lumbar spine BMD and vertebral fracture incidence after 2 years o alendronate 10 mg/day in 241 men with low BMD Incident fx (%) 8 7 6 5 4 3 2 1 0 Radiographic vertebral fracture rate Placebo Alendronate Odds ratio 0.10 (95% CI 0.00-0.88) Same BMD response in men with low T Effects on BMD with other bisphosphonates in the treatment of men with low BMD - very similar to those in women Residronate Ibandronate Zoledronate Results with denosumab in the treatment of men with low BMD - very similar to those in women Beneficial effects in men treated with teriparatide very similar to those in women Orwoll et al NEJM 2000 Zoledronate treatment in men reduced the rate of new radiographic vertebral fractures 1199 men with osteoporosis, aged 50-85 Treatment of osteoporosis in men Although most trials in men have been small and designed to evaluate BMD change rather than fracture rates, the effects of drug therapies in men have been very similar to those in women No a priori reason to believe osteoporosis drugs should be less effective than in women Similar results with moderate-severe morphometric fractures (RR reduction 81% and 63% at 12 and 24 months). Evaluate and treat men using methods the same as in women Exception broad BMD screening in men >70 years Boonen S et al. N Engl J Med 2012

US Preventive Services Task Force (2011) The USPSTF concludes that the current evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men. American College of Physicians (2017) ACP recommends that clinicians offer pharmacologic treatment with bisphosphonates to reduce the risk of vertebral fracture in men who have clinically recognized osteoporosis. Endocrine Society (2012) We recommend pharmacological therapy for men at high risk for fracture including, but not limited to: Men who have had a hip or vertebral fracture without major trauma. Men who have not experienced a spine or hip fracture but whose BMD of the spine, femoral neck, and/or total hip is 2.5 SD or more below the mean of normal young white males. In the United States, men who have a T-score between 1.0 and 2.5 in the spine, FN, or TH plus a 10-yr risk of experiencing any fracture 20% or 10-yr risk of hip fracture 3% using FRAX. Men who are receiving long-term glucocorticoid therapy in pharmacological doses (e.g. prednisone or equivalent 7.5 mg/d), according to the 2010 guidelines of the American Society of Rheumatology. Disordered sleep and bone Clock genes, which have been identified in virtually all cells (Per1, Per2, Cry1, Clock, and BMAL1), contribute to the rhythmicity of numerous physiological systems The intrinsic central, or master, circadian clock is located in the hypothalamic suprachiasmatic nucleus (SCN). The SCN receives light/dark cycle input to synchronize its own activity and thereby orchestrate behavioral, physiologic, and cellular rhythms The SCN communicates and synchronizes with clock genes located centrally and in the periphery via direct neural connections, the SNS, hormonal signals (such as melatonin and cortisol), and the regulation of body temperature Circadian control Swanson et al. JBMR 2015 Obstructive sleep apnea Obstructive sleep apnea (OSA) affects nearly one in seven adults, many of whom are undiagnosed OSA predominantly affects older, obese, males; some studies suggest that up to one in four older men are affected OSA has been associated with impaired motor function, cognitive function, and memory, which contribute to an increased risk of falls and accidents. Apneic events cause hypoxia and recurrent, apparently life-saving arousals that result in marked elevations in sympathetic nervous system (SNS) activity, which is often sustained beyond sleep throughout the waking hours. OSA is linked to increased inflammation. Hypoxia? In OSA, sleep restriction and disruption contribute to disorganized sleep architecture, disordered sleep-wake homeostasis, and subsequent disturbances in normal hormonal rhythms. Swanson et al. JBMR 2015 Bone Turnover Markers After Sleep Restriction and Circadian Disruption in Humans: A Mechanism for Sleep-Related Bone Loss Thus far, studies of sleep disturbance and BMD have been cross sectional and conflicting Some have shown increased bone turnover in those with sleep apnea Some have shown lower BMD Similarly, studies of sleep disturbance and fractures have been underpowered and conflicting Swanson et al. Endocrine Society 2017 Swanson et al. JBMR 2015