Osteoporosis and Low Bone Mineral Density in Men with Testosterone Deficiency Syndrome

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Osteoporosis and Low Bone Mineral Density in Men with Testosterone Deficiency Syndrome Christopher D. Gaffney, BA,* Matthew J. Pagano, MD,† Adriana P. Kuker, MD,‡ Doron S. Stember, MD,§ and Peter J. Stahl, MD† *College of Physicians and Surgeons, Columbia University Medical Center, New York, NY, USA; †Department of Urology, Columbia University Medical Center, New York, NY, USA; ‡Division of Endocrinology, Department of Medicine, Columbia University Medical Center, New York, NY, USA; §Department of Urology, Icahn School of Medicine at Mount Sinai, New York, NY, USA DOI: 10.1002/smrj.63

ABSTRACT

Introduction. Testosterone deficiency syndrome (TDS) is a risk factor for low bone mineral density (BMD) and osteoporosis. Knowledge of the relationship between TDS and bone health, as well as the practical aspects of how to diagnose and treat low BMD, is therefore of practical importance to sexual medicine practitioners. Aim. The aim of this study was to review the physiologic basis and clinical evidence of the relationship between TDS and bone health; and to provide a practical, evidence-based algorithm for the diagnosis and management of low BMD in men with TDS. Methods. Method used was a review of relevant publications in PubMed. Main Outcome Measures. Pathophysiology of low BMD in TDS, morbidity, and mortality of osteoporosis in men, association between TDS and osteoporosis, indications for dual X-ray absorptiometry (DXA) scanning in TDS, evidence for testosterone replacement therapy (TRT) in men with osteoporosis, treatment for osteoporosis in the setting of TDS. Results. Sex hormones play a pleomorphic role in maintenance of BMD. TDS is associated with increased risk of osteoporosis and osteopenia, both of which contribute to morbidity and mortality in men. DXA scanning is indicated in men older than 50 years with TDS, and in younger men with longstanding TDS. Men with TDS and osteoporosis should be treated with anti-osteoporotic agents and TRT should be highly considered. Men with osteopenia should be stratified by fracture risk. Those at high risk should be treated with anti-osteoporotic agents with strong consideration of TRT; while those at low risk should be strongly considered for TRT, which has a beneficial effect on BMD. Conclusion. Low BMD is a prevalent and treatable cause of morbidity and mortality in men with TDS. Utilization of a practical, evidence-based approach to diagnosis and treatment of low BMD in men with TDS enables sexual medicine practitioners to make a meaningful impact on patient quality of life and longevity. Gaffney CD, Pagano MJ, Kuker AP, Stember DS, and Stahl PJ. Osteoporosis and low bone mineral density in men with testosterone deficiency syndrome. Sex Med Rev 2015;3:298–315. Key Words. Osteoporosis; Bone Mineral Density; Testosterone Deficiency; Hypogonadism; Men

Introduction

R

ising awareness of the associations between sexual dysfunction and health-relevant disease processes has enabled healthcare providers who specialize in male sexual dysfunction to play

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increasingly broad roles in men’s overall health. This paradigm has been most pronounced in men with erectile dysfunction (ED), a condition that independently predicts cardiovascular events, cerebrovascular events, and all-cause mortality [1]. However, the association of male sexual © 2015 International Society for Sexual Medicine

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Osteoporosis and Low Bone Mineral Density in Men with TDS dysfunction with other men’s health issues has received somewhat less attention. In particular, ED, low sexual desire, and decreased spontaneous and/or nocturnal erections each effectively double the risk of testosterone deficiency syndrome (TDS) [2]; and TDS is associated with osteoporosis. Osteoporosis is a progressive disorder of bone remodeling in which bone loss exceeds bone formation, resulting in micro-architectural defects and skeletal fragility. It is associated with fractures and increased mortality [3–6]. The overall risk of fracture in men with osteoporosis is correlated with loss of bone mineral density (BMD) [7], although other factors related to testosterone such as fragility and fall risk may also contribute to fracture risk in men [8,9]. In this review, we focus on the relationship between TDS and osteoporosis, which represents a critical opportunity for sexual medicine practitioners to diagnose and treat a medically important disorder in its early stages when intervention can make an important clinical difference. Sex Hormones and Bone Pathophysiology

In healthy adults, there is a balance between osteoblasts that create new bone and osteoclasts that resorb bone. This balance exists primarily to continuously repair and replace existing bone mass, and plays a prominent role in calcium and phosphate homeostasis. Cytokines (interleukin [IL]-6 and transforming growth factor-beta), hormones (parathyroid hormone, vitamin D3, calcitonin, sex hormones, glucocorticoids, and thyroid hormone), and lifestyle factors (alcohol and cigarette use) affect the dynamic balance between osteoblasts and osteoclasts. Dysregulation in any of these domains can adversely affect bone health [3]. Sex hormones have a pleomorphic effect on bone physiology. Androgens and estrogen both block IL-6, a cytokine important in activating bone resorption. Androgens increase periosteal bone formation and promote osteoblast proliferation, differentiation, and lifespan [10]. Estrogen decreases cytokines that activate bone resorption (IL-1, IL-7, tumor necrosis factor [TNF] α, and macrophage colony-stimulating factor), favor osteoclast apoptosis (TNF-β), and inhibit the receptor activator of nuclear factor kappa-B ligand (RANKL), an osteoclast activator produced by osteoblasts in response to parathyroid hormone [10].

Variation in the androgen receptors (AR), sex hormone-binding globulin (SHBG) levels, and androgen metabolites influences the role of sex hormones on bone physiology. The number of CAG repeats in the AR is an independent predictor of bone density in men [11,12], and men with shorter CAG repeats have a greater BMD response to testosterone [13]. SHBG, a protein that influences sex hormone levels in the serum, has been associated with decreased BMD in older men [14,15]. There may also be a role for androgen metabolites such as dihydrotestosterone (DHT) in bone health. Mice with a 5alpha-reductase deletion, normal androgen levels, and no DHT had reduced bone and muscle mass. However, this relationship has not been observed in humans [16]. Knowledge of the pathophysiological interplay between testosterone and bone is expanding through active research on the bone–testis axis. This research shows that osteocalcin, a protein produced by osteoblasts that requires osteoclast activation, increases serum testosterone independently of luteinizing hormone. Therefore, it appears that bone may actually directly regulate levels of serum testosterone in men [10,17,18]. Association between Sex Hormones, BMD, and Bone Health

Evidence from one large, multicenter prospective study, and several smaller retrospective and prospective studies supports an association between TDS and the diagnosis of osteoporosis and/or a history of fracture (Table 1). One large study that examined 2447 men over the age of 65 showed an increased odds ratio (OR) of osteoporosis in men with TDS (OR 2.6) when adjusted for weight, age, and estradiol levels [19]. In the only study that has specifically addressed men under 50 years of age, men with TDS (defined as total testosterone [TT] less than 350 ng/dL or free testosterone [FT] less than 1.5 ng/dL) seen at an andrology clinic had greater odds of osteopenia (OR 3.79) and osteoporosis (OR 7.64) as compared with age-matched reference data [20]. The associations between sex hormones and quantitative BMD have been very clearly delineated by large, well-designed studies (Table 2). It is important to note that these associations could be affected by the methodological variability in the assays that were utilized in each particular study to measure serum sex hormone levels. Immunoassays are generally less reliable than mass spectrometry (see table footnotes for assay methodologies used Sex Med Rev 2015;3:298–315

300 Table 1

Gaffney et al. Studies addressing hypogonadism and osteoporosis/fractures in men

Author

Sample

Design

Primary endpoint

Relevant results

Fink et al. 2006 [19]*

2447, >65 y/o community dwelling men

Prospective crosssectional and longitudinal multicenter study

Association of androgen deficiency and estrogen deficiency with osteoporosis and rapid hip bone loss

Kracker et al. 2014 [20]*

399, <50 y/o men presenting to an andrology clinic

Bours et al. 2011 [21]†

626 M + W > 50 y/o with clinical fractures

Retrospective analysis of men with both TDS and DXA scan results Prospective crosssectional study

Bogoch et al. 2012 [22]†

399, M + W > 50 y/o with clinical fracture

Retrospective crosssectional study

Comparison of the prevalence of osteoporosis in men with TDS to age matched reference values Prevalence of secondary osteoporosis in patients presenting with fracture Prevalence of secondary osteoporosis in patients presenting with fracture

TDS (TT < 200 ng/dL) ↑ osteoporosis (P = 0.003), rapid hip bone loss (P = 0.007) EDS (TE < 10 pg/mL) ↑ osteoporosis (P = 0.0001), rapid hip bone loss (P = 0.08) TDS (TT < 350 ng/dL or FT < 1.5 ng/dL) ↑ osteoporosis (OR 3.79) TDS (FT < 8 nmol/L) in 8.3% of men with clinical fracture TDS in 5.1% of men with fracture from secondary osteoporosis

*Serum measurement by immunoassay. †Serum measurement not reported. M = men; W = women; y/o = years old; TDS = androgen deficiency syndrome; EDS = estrogen deficiency syndrome; ↑ = associated with increase; TT = total testosterone; FT = free testosterone; BioT = bioavailable testosterone; BioE = bioavailable estrogen; DXA = dual X-ray absorptiometry; TE = total estrogen.

Table 2

Large studies addressing sex hormone levels and bone mineral density

“Name” Author

Sample

Design

Primary endpoint

Relevant results

“MrOS Sweden” Mellstrom 2006 [23]*

2908 Swedish M 69–80 y/o who could ambulate; w/o hx of b/l hip replacement

Cross-sectional, population survey based study

Association between BMD, fracture rate, and TT, FT, TE, FE, and SHBG

“MINOS” Szulc 2003 [24]*

792 M 19–85 y/o men with the same insurance from a single French town

Cross-sectional, population survey based study

Association between sex hormone levels, BMD, and clinical balance status.

“MrOS-Cohort” Cauley 2010 [25]†

Prospective crosssectional and longitudinal study

“Dubbo” Meyer 2008 [26]†

969 M in the MrOS study with full sex hormone panels and longitudinal analysis 609 M > 60 y/o from Dubbo, Australia; majority Caucasian

Association between sex hormone levels, BMD, and change in BMD over time Association between sex hormone levels, BMD, and fracture rate

“LASA” Kuchuk 2007 [27]*

623 M, 65–88 y/o randomly selected; 3 Dutch regions

Prospective crosssectional and longitudinal population based study

FT ↑ BMD (TB, H, Femoral Trochanter, R [MV] ) FT ≠ BMD at the LS (MV) FT (>median) ↓ nonvertebral fractures (OR 1.56) and vertebral fractures (OR 2.00) FE ↑ BMD (all sites, including LS (MV)) TT ≠ BMD (all sites) TDS (FT < 146 pmol/L) ↓ BMD at most sites (UV) FT ↓ fall risk (MV) E2 ↑ BMD at all sites (MV) EDS ↓ BMD at all sites (MV) BioE2, E2 ↑ BMD (MV) BioT ↑ Bone Hip Area (MV), but not BMD Subgroup of lowest BioE2, BioT, and highest SHBG exhibited the highest bone loss rate (MV) Low TT ↑ osteoporotic fracture [HR 1.28 (1.05–1.57)] (MV) Low TT ↑ Hip + other nonvertebral fracture Low TT ↑ fracture risk in quartile analysis [HR Q1 v. Q4 2.26 (1.22–4.20)] Low E2 ≠ osteoporotic fracture [HR 1.19 (0.97–1.47)] (MV) Q1 of E2 ↓ BMD, QUS Q1 of TT ↓ lower BMD, QUS E2 (
Prospective cross-sectional and longitudinal population survey based study

Associations between sex hormone levels and QUS, BMD, bone turnover markers, and fracture risk

*Serum measurement by immunoassay. †Serum measurement by mass spectrometry. M = men; W = women; y/o = years old; TDS = androgen deficiency syndrome; EDS = estrogen deficiency syndrome; ↑ = associated with increase; ↓ = associated with decrease; ≠ = no relationship; UV = univariate analysis; MV = multivariate analysis; TT = total testosterone; FT = free restosterone; BioT = bioavailable testosterone; BioE = bioavailable estrogen; H = hip; LS = lumbar spine; BMD = bone mineral density; OR = odds ratio; SHBG = sex hormone-binding globulin; QUS = quantitative ultrasound; HR = hazard ratio.

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Osteoporosis and Low Bone Mineral Density in Men with TDS in the included studies). The data consistently suggest that free estrogen is a primary determinant of BMD. The independent association of testosterone with BMD and fracture risk is less clear. The Osteoporotic Fractures in Men Study (MrOS Sweden), which looked at 2908 men 69–80 years old, found that FT was independently associated with BMD at the total body, hip, and femoral trochanter when accounting for age and BMI. In MrOS Sweden, men with less than the median-FT had more nonvertebral (OR 1.56) and vertebral (OR 2.00) fractures [23]. Another study found an association between the lowest quartile of TT and BMD at the total hip that was independent of serum estrogen [27]. A third large crosssectional study found significant associations between TT and osteoporotic, hip, and nonvertebral fractures [26]. However, two other large studies did not find estrogen-independent associations of total or FT with BMD. One did find an association between FT and BMD on univariate analysis and demonstrated a threshold effect for TDS (defined as FT < 4.21 ng/dL) that was associated with falls and decreased functionality [24,25]. No studies were identified that primarily addressed this association in men under the age of 50 in the general population. Therefore, although we cannot conclude that TDS is directly responsible for decreased BMD, there is strong evidence that TDS is correlated with low BMD, fractures, falls, and poor bone health. From a practical standpoint, it does not matter if the association of TDS with BMD abnormalities is driven independently by androgen levels, or indirectly through androgens that have been aromatized to estrogens. Testing for TDS is far more common than testing for estrogen deficiency in men, and therefore patients with low serum testosterone represent a prime opportunity to identify patients at risk for osteoporosis because of sex-hormone abnormalities. Osteoporosis in Men

An estimated 1–4% of men over the age of 50 in the United States have osteoporosis and 15–33% have osteopenia [28]. Approximately 40–50% of osteoporosis is associated with identifiable, occasionally correctable, secondary causes including TDS, alcohol abuse, glucocorticoid excess, functional hyperthyroidism, chronic obstructive pulmonary disease, neuromuscular disorders, malignancy, celiac disease, HIV, chronic kidney disease, diabetes, and drug side effects [29]. Fra-

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gility fractures are an important cause of morbidity and mortality in men. Overall, the lifetime incidence of hip fracture in men is 6% and rising [30] with around 29% of hip fractures occurring in men [31] and 21 million men experiencing osteoporosis-related fractures annually around the world [32]. One meta-analysis of 28,516 patients from eight studies found that a standard deviation decrease in BMD (osteopenia) was associated with a significant increase in all-cause mortality (hazard ratio [HR] 1.16) [33]. In men progressing to fracture, all-cause mortality is high for hip (HR 7.95 at 3 months) [4] and for nonhip (HR 1.45–2.2 at 1 year) [5] fracture compared with the general population, with an overall inpatient case fatality rate of 5.4% for hip fracture [6]. This rate is similar to the overall inpatient case fatality rate of acute myocardial infarction [34]. While patients with osteoporosis are individually more likely to progress to fractures than patients with osteopenia, osteopenia contributes significantly to the burden of pathological fractures because of its larger prevalence. In one study of 144 men presenting with fracture who were referred to a bone metabolism clinic, 45.7% of patients had osteopenia, 39.3% had osteoporosis, and 15% had normal BMD [21].

Important Populations with Increased Prevalence of Both Androgen Deficiency and Osteoporosis

The following are populations prone to comorbid TDS and osteoporosis, which underscore the relationship between TDS and bone health.

Late Onset Hypogonadism (LOH) LOH is hypogonadism of older men. Studies with varying age and TT cut-offs estimate low TT in 7–49% of older men. When symptoms are included in the definition, one study found prevalence of TDS (defined by serum T < 7 nmol/L or FT < 308 pmol/L plus three clinical symptoms) between 5 and 12% based on age [35] and the European Menopause and Andropause Society, which defined LOH as three sexual symptoms (low libido, decreased morning erection, and ED), TT < 317 ng/dL, and FT < 6.48 ng/dL, found a prevalence of 2.1% in men 40–80 years old [35]. LOH is associated with poor bone health, increased fat composition, depression, and sexual side effects [36]. A joint European recommendation suggests radiographic bone monitoring every 2 years for men with LOH because of the risk of poor bone health [37]. Sex Med Rev 2015;3:298–315

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Hypogonadotropic Hypogonadism (HH) HH is a congenital (Kallman Syndrome or normosmic HH) or acquired (iatrogenic, ischemic, or hyperprolactinemic destruction of pituitary function) deficiency in gonadotropins that leads to low serum testosterone levels. Congenital HH interferes with the development of peak bone mass, a strong predictor of future osteoporosis [38]. Patients with congenital HH have significantly lower spinal trabecular and nondominant radial BMD than age-matched controls [39]. Furthermore, two case-control trials have shown that testosterone replacement increases BMD in these patients, though it does not restore BMD to within normal limits [40,41]. A third retrospective study on idiopathic HH, testosterone replacement therapy (TRT), and BMD found that lower BMD was associated with a history of TRT treatment pause for greater than 5 years or a history of lowdose TRT [42]. Androgen Deprivation Therapy (ADT) ADT is a common treatment modality for latestage prostate cancer that is associated with decreased BMD and fractures. A meta-analysis examining 32 studies with 116,911 total patients found that patients with nonmetastatic (M0) prostate cancer on ADT had a higher risk of osteoporosis and fractures compared with men who were not on ADT (RR 1.30 and 1.17, respectively) [43]. One retrospective study of 395 patients receiving ADT for M0 prostate cancer, that followed patients for a mean of 5.5 years, found that 23% of patients had developed osteoporosis and 7% had experienced a fracture. In multiple regression analysis, the independent variables that predicted development of osteoporosis included age greater than 70 during ADT initiation, continuous ADT, and treatment duration [44]. These results bolster those of early, smaller trials [45] and are in line with fracture rates for patients on ADT in placebo groups of other large randomized control trials [46]. The most significant change in BMD on ADT likely occurs within the first year of treatment [47,48]. Because of this risk, the American Urological Association recommends empiric vitamin D and calcium regardless of BMD for men with prostate cancer receiving ADT [49]. Klinefelter’s Syndrome (KS) KS, most commonly associated with the 47,XXY karyotype, is highly associated with poor bone health and hypoandrogenism. Of the patients with Sex Med Rev 2015;3:298–315

Gaffney et al. KS, 25–48% have decreased bone mass and 6–15% have osteoporosis [50]. The effect of KS on bone health is likely multifactorial and is the subject of ongoing research. Possible etiologic factors for poor bone health in KS include hypogonadism during puberty, hypogonadism during adulthood, inadequate TRT, androgen resistance, other physiological actors such as INSL3, and/or failed inactivation of the SHOX protein on the X-chromosome leading to increased androgen resistance [51–53]. Guidelines from the American Journal of Medical Genetics suggest BMD monitoring every 2–3 years in patients with KS [54].

AIDS Uncontrolled HIV is associated with TDS and osteoporosis. Between 30% and 50% of men with symptomatic HIV have low testosterone [55,56]. Patients with HIV can have decreased BMD that is responsive to testosterone repletion. A crosssectional study of 232 patients with HIV showed that patients with HIV were more likely to have osteopenia (56.5% vs. 50.7%) and osteoporosis (10.7% and 4.0%) compared with controls [57]. TRT in eugonadal men with HIV and osteopenia has been shown to increase lumbar BMD [58]. Glucocorticoid Therapy Glucocorticoid therapy is a known risk factor for both osteoporosis and TDS. A study in men receiving corticosteroids compared 16 patients taking steroids with age-matched controls and found the treatment group to have significantly decreased TT levels (211 ± 93 ng/dL) inversely related to steroid dosing [59]. Two studies that compared testosterone treatment in men on glucocorticoids found that testosterone replacement was significantly associated with increased BMD at the lumbar spine and improved body composition [60,61]. Diagnosing Osteoporosis

The most widely used method for diagnosing osteoporosis in modern clinical practice is dual energy absorptiometry (DXA). Modern DXA scans take about 1–2 minutes and utilize fan beam x-rays for minimal radiation exposure (1–6 microSv per scan relative to an average 2,400 microSv exposure per person per year in the general population). Newer machines achieve resolutions of 0.35–0.50 mm. Figure 1 depicts an image of a modern DXA scanner. The data output

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Figure 1 Dual X-ray absorptiometry (DXA) scanner–typical size and appearance of a modern DXA scanner.

of DXA scanners includes areal BMD (aBMD), bone mineral content, and bone area. aBMD is a measure of mass divided by the area of a segment of bone rather than traditional density (mass divided by volume). Scans are most accurate at the lumbar spine and the proximal femur, but DXA can also be used to estimate aBMD at the trochanter, Ward’s area, and the distal third of the radius. aBMD can be overestimated in large bones and underestimated in small bones [62]. The Endocrine Society recommends evaluation at the hip and the lumbar spine because BMD at these sites is most associated with hip fracture, the most morbid common complication of osteoporosis. Radial BMD is useful in patients in whom accurate results at the hip or lumbar spine cannot be obtained and for men on ADT (as ADT preferentially decreases BMD at the radius) [63]. Overall, BMD measurement at a certain site is always a better predictor of fracture at that site than BMD at other sites. DXA provides clinically relevant results in the form of a T-score or a Z-score. The T-score, generally used for men over 50 years old, is a measurement of deviation from the mean that compares patients to reference data from a different population. When interpreting DXA results, this means that a patient over 50 will be compared with the mean BMD for a predefined population of young adults. This is distinct from a Z-score, which functions as a measurement of deviation from the mean that compares the patient with age-, sex-, and ethnicity-matched reference data,

and is generally used for men under 50 years old [63]. There remains controversy as to the ideal reference standard for BMD in men; in particular, whether to compare male BMD to the reference data from young men or young women. There are strong arguments in favor of each approach [8,9,64–67]. DXA scanners in the United States report BMD values for men as compared with the reference values for young men. In men age 50 and older, the National Osteoporosis Foundation (NOF) (based on the World Health Organization diagnostic classification) considers DXA T-score of <−2.5 at any site as compared with the mean reference values of young men diagnostic of osteoporosis and a score between −1.0 and −2.5 is classified as low bone mass or osteopenia. For men under 50, this diagnostic classification should not be used and the diagnosis of osteoporosis should not be made on BMD alone, but rather on the patient’s clinical picture, including history of low trauma fractures [68]. To assist in the diagnosis of osteoporosis in this population, the International Society of Clinical Densitometry (ISCD) recommends using Z-scores rather than T-scores, with Z-scores of −2.0 or lower defined as low BMD for chronological age and those above −2.0 considered within the expected range for age [63]. Additionally, a radiographically confirmed vertebral fracture is consistent with osteoporosis regardless of BMD because it is a sign of impaired bone quality and strength. Vertebral imaging can be performed using lateral thoracic and lumbar spine X-rays or lateral vertebral fracture Sex Med Rev 2015;3:298–315

304 assessment, which is available on many modern DXA machines and allows for an integrated evaluation [68]. A T-score at the spine, total hip, or femoral neck of less than −1 in men over 80, less than −1.5 in men 70–79, or specific risk factors in men over 50 (low-impact fracture, glucocorticoid treatment, loss of 1.5 cm from peak height or loss of 0.8 cm height since previous visit) warrants vertebral films [68]. Other technologies such as computed tomography-based absorptiometry, trabecular bone score, and quantitative ultrasound densitometry are also capable of predicting fracture risk because of osteoporosis, but are not readily available in clinical practice and have not been extensively validated in men [68–71]. Indications for DXA in Men with TDS

The utilization of DXA testing in clinical practice in men is endorsed by several clinical societies, but is not universally accepted. The Endocrine Society, the NOF, the ISCD, the ISSM, and guidelines published by the Canadian Medical Association generally agree on certain criteria for DXA screening based on age and risk factors for osteoporosis [35,63,68,72,73]. The American College of Physicians guidelines are less specific and advocate for screening in men with increased risk of osteoporosis who could tolerate therapy [74]. The United States Preventative Services Task Force (USPSTF) [75], however, did not find enough evidence to recommend DXA screening in men, regardless of age or risk factor profile, citing limited evidence that pharmaceutical therapies prevent fractures in men. The USPSTF notes that there are no data that support screening alone to reduce fracture risk or mortality in men. Nonetheless, there is clinical rationale for measuring BMD in men at risk for low BMD and fractures. Decreased BMD is clearly associated with fracture risk [7], and there is robust recent evidence that osteoporosis pharmacotherapy improves BMD and reduces fracture risk (Table 3) [105]. Risk stratification can assist in the clinical decision of whether or not to order a DXA scan in a hypogonadal man. The Endocrine Society, the NOF, the ISCD, and the Canadian guidelines use age to risk-stratify patients to improve the yield of DXA testing. These societies generally recommend that screening with DXA of the hip and lumbar spine should occur in all men aged 70 or older, all men between 50 and 69 years old with certain risk factors for osteoporosis, and all men over 50 with a history of fracture. While the Sex Med Rev 2015;3:298–315

Gaffney et al. ISCD does not elaborate on the risk factors that should trigger screening in men 50–69 years old, both the Endocrine Society guidelines and the Canadian guidelines specifically delineate TDS as one such risk factor and the NOF specifically mentions KS, androgen insensitivity, and hyperprolactinemia as risk factors warranting further investigation in men over in this age range. The ISSM guidelines for men with TDS endorse BMD monitoring every 2 years for men with long-standing hypogonadism regardless of age [35] and a joint recommendation sponsored by the International Society of Andrology (ISA), the International Society for the Study of the Aging Male (ISSAM), the European Association of Urology (EAU), the European Academy of Andrology (EAA), and the American Society of Andrology (ASA) that recommends DXA scanning every 2 years in men with late onset hypogonadism [37]. The Endocrine Society suggests BMD monitoring in men with established osteoporosis or fragility fracture 1–2 years following initiation of TRT [116]. The benefit of osteoporosis screening with DXA scanning in men younger than 50 years old is not known. The guideline from the Canadian Medical Association is the only consensus statement that addresses this population of patients globally; it recommends BMD testing in men under the age of 50 with certain risk factors including TDS [73]. The NOF recommends BMD testing in all adults with risk factors for low BMD [68]. In particular, certain patient populations at high risk for TDS-associated loss of BMD may benefit from testing at an early age. Male bone mass peaks near the third decade of life and then exhibits a slow, linear decline as men age. Peak bone mass is predictive of osteoporosis later in life [38] and earlier onset osteoporosis is associated with greater morbidity than late onset osteoporosis [5]. The literature shows strong associations between low BMD and KS/HH and low BMD is associated with both low FT and the diagnosis of TDS (Tables 1 and 2). In addition, low BMD on DXA may impact treatment decisions in young hypogonadal men with borderline symptoms, as TRT has been shown to increase BMD. On balance, the decision to order a DXA scan on a hypogonadal man under 50 years old is likely best left to clinical judgment regarding the duration of TDS. Treatment Indications

Consensus exists as to the general recommendations for pharmacological therapy in men at risk

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Osteoporosis and Low Bone Mineral Density in Men with TDS Table 3

Summary of trial based literature concerning osteoporosis treatment in men Administration

Exercise

Weight bearing 3–5× per week

Vitamin D and calcium

PO

TRT

IM preferred [84]

Clomiphene

PO

Bisphosphonates Alendronate

PO

Risedronate

PO

Zoledronic Acid

IV

Pamidronate

IV

Neridronate

IM

Denosumab

SubQ

Teriparatide

SubQ

Increases BMD at the following locations:

Association with decreased fracture risk

Notable adverse events/ complications

↑LS, PF (eugonadism) [76,77] ≠ADT for Prostate cancer [78,79]. ↑H, LS (eugonadism) [80]

No evidence

Limited by health and energy

↓Hip, nonvertebral fractures [81,82]

↑FN, H, LS, trabecular bone (hypogonadism; see Table 4) ↑FN, LS (symptomatic hypogonadism) [85]

No evidence

Daily Ca2+ supplementation > 1000 mg may increase CVD mortality in men [83] Increased hematocrit and prostate-related events [37] Hot flashes

↑FN, LS, TB (eugonadism and hypogonadism) [86–89] ↑FN, H, LS (ADT for prostate cancer) [87–90] ↑FN, FT, PF (eugonadism and hypogonadism) [91] ↑LS (ADT for prostate cancer) [92] ↑FN, FT, LS, TH (eugonadism and hypogonadism) [93] ↑FN, FT, H, LS (ADT for prostate cancer) [94–104] FN, LS (eugonadism) [107] H, LS, (ADT for prostate cancer) [108] LS (ADT for prostate cancer) [109,110] ↑FN, FT, LS, R, TH (eugonadism and hypogonadism) [111] ↑FN, TH, (ADT for prostate cancer [46] w/ most benefit with lowest testosterone) [112] ↑FN, LS, TB (eugonadism and hypogonadism) [114]

↓Fractures (eugonadism and hypogonadism) [86]

No evidence

No evidence

↓morphometric fractures (eugonadism and hypogonadism) [105,106] No evidence

Patients taking bisphosphonates are at increased risk of osteonecrosis of the jaw. Patients taking PO bisphosphonates may develop chemical esophagitis if they cannot sit up for thirty minutes following administration

No evidence ↓Fractures in ADT for prostate cancer

Small increased risk (RR 1.6) of osteonecrosis of the jaw [113]

No evidence

Transient post-administration hypercalcemia; possible association with rare osteosarcoma [115]

↑ = associated with increase; ↓ = associated with decrease; ≠ = no relationship; ADT = androgen deprivation therapy; FN = femoral neck; FT = femoral trochanter; H = hip; PF = proximal femur; LS = lumbar spine; R = radius; TH = total hip; TB = total body; PO = by mouth; RR = risk ratio.

for fracture. Treatment decisions should primarily be based on history, BMD, and the Fracture Risk Assessment Tool (FRAX), which can be found at https://www.shef.ac.uk/FRAX/tool.aspx. The FRAX tool predicts the 10-year probability of hip or other major osteoporotic fractures [117]. It is validated to assess fracture risk in patients over 50 years of age with or without DXA data. For patients with TDS, physicians can choose “yes” for item 10, “secondary osteoporosis.” [118] An example of the online form used for FRAX risk calculator is seen in Figure 2. Patients in the following categories over the age of 50 should be treated with pharmacotherapy for osteoporosis: 1. History of hip or vertebral fracture without major trauma.

2. Spine, femoral neck, or total hip T-score ≤ −2.5 on DXA. 3. Spine, femoral neck, or total hip T-Score between −1 and −2.5 in addition to a 10-year risk of experiencing any fractures ≥ 20% or 10-year risk of hip fracture ≥ 3% using FRAX. 4. Glucocorticoid therapy [68,72]. Table 3 summarizes the pharmacotherapy for osteoporosis, which includes vitamin D, calcium, bisphosphonates, denosumab, and teriparatide in addition to lifestyle modification. Less guidance exists for patients with TDS who might benefit from TRT and for patients under the age of 50. Figure 3 proposes a streamlined and evidencebased management algorithm. Sex Med Rev 2015;3:298–315

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Gaffney et al.

Figure 2 FRAX tool. The FRAX tool can be found at https://www.shef.ac.uk/FRAX/tool.aspx.

Lifestyle Modification and Supplements as Treatment

Weight Management, Smoking Cessation, and Alcohol Restraint Alcohol abuse and smoking are causes of secondary osteoporosis and should be avoided in men at risk for poor bone health [72]. Weight management in men with TDS and osteoporosis is more complicated. Adiposity leads to aromatization and elevated estrogen levels in men. Therefore, weight is positively associated with BMD and is protective against osteoporotic fractures. However, weight loss has been shown to increase testosterone levels and decrease estrogen levels in bariatric patients with TDS [119]. Therefore, although weight loss may be beneficial to overall health, no recommendation can be offered for weight loss as a general intervention to promote bone health with the presently available evidence. Weight-Bearing Exercise Studies of lifestyle interventions in men with osteoporosis have found that weight-bearing exercise improves BMD [76,77,120]. No studies were identified that correlated exercise with fracture risk in men. The only study that specifically looked at lifestyle interventions in men with hypogonadism is found in the ADT literature [78] and examined 120 men on ADT for Sex Med Rev 2015;3:298–315

nonmetastatic prostate cancer randomized to zoledronic acid vs. placebo. Although underpowered to find an independent association between BMD and exercise, there was an association between days of exercise per week and BMD on univariate analysis [79]. Based largely on evidence from eugonadal men, we recommend weight-bearing exercise, proportional to the health and safety of the patient, as a supplementary method of increasing BMD in patients at risk for fracture.

Vitamin D and Calcium Vitamin D and calcium are important for maintaining bone health and likely reduce fracture risk. A case-cohort trial in older men showed increased hip fractures (HR 2.36) for patients in the lowest quartile of serum vitamin D compared with men in the highest quartile of serum vitamin D [81]. A large meta-analysis of over 30,000 patients from the general population, of which 2,730 were men, found that repletion of >800 IU of vitamin D daily reduced hip and nonvertebral fracture risk [82]. A meta-analysis which explored the effect of calcium and vitamin D supplementation on BMD found that treatment was associated with significantly less bone loss at the hip and the spine and that treatment was most effective when vitamin D and calcium intake exceeded 800 IU and 1,200 mg, respectively [80]. Although

Osteoporosis and Low Bone Mineral Density in Men with TDS

307

×

Figure 3 An evidence-based algorithm for diagnosis and treatment of osteoporosis in men with testosterone deficiency syndrome (TDS). See attachment entitled.

no trials have explored the relationship between testosterone level and response to vitamin D therapy, the fact that vitamin D has been associated with improved BMD at the lumbar spine in patients with prostate cancer on ADT suggests that the effect of vitamin D on bone health is independent of testosterone level [47]. Despite this evidence, treatment must account for the adverse effects of calcium and vitamin D. Because calcium may be associated with increased cardiovascular disease mortality in men [80] and hypervitaminosis D can cause hypercalcemia and hyperuricemia, the Endocrine Society recommends daily calcium intake of 1,000–1,200 mg with supplementation offered only for dietary insufficiency and vitamin D supplementation of 1,000–2,000 IU for men with serum vitamin D < 30 ng/mL [72].

Hormonal Treatment

TRT Testosterone therapy in men can increase lean muscle mass, improve mood, and help exercise tolerance, but it has also been associated with adverse effects such as increased hematocrit and gynecomastia. The relationship of TRT with cardiovascular events is currently the subject of vigorous debate [2,121–124]. TRT for hypogonadism has been associated with increased prostate-related events, including prostate enlargement, voiding symptoms, prostate biopsy, and prostate specific antigen (PSA) elevation, that might be concerning for older patients at high risk of prostate cancer. However, meta-analysis has not shown an association between TRT and prostate cancer [125]. Although TRT has not been shown to decrease Sex Med Rev 2015;3:298–315

308 fracture risk, it has demonstrated efficacy in most studies for improving BMD in patients with various etiologies of TDS. A review and meta-analysis which looked at eight trials through 2006 found significant gains for intramuscular (IM) TRT on lumbar BMD, but did not find improvement with transdermal therapy [126]. In addition, meta-analysis has demonstrated that TRT decreases markers of bone resorption in TDS [127]. It has been less effective in eugonadal men, men with borderline TDS, or men with other secondary causes of osteoporosis (Table 4). The Endocrine Society Guidelines recommend TRT as primary therapy in men with symptomatic TDS (total testosterone < 200 ng/dL) who do not meet thresholds for treatment with general osteoporosis medications, and in men with high fracture risk and TDS who cannot tolerate any agents that have been proven to reduce fracture risk. TRT is recommended in combination with agents that have established fracture risk reductions, such as bisphosphonates, in men with TDS who meet the established criteria for general osteoporosis treatment (see Treatment Indications). The Italian Society of Endocrinology recommends TRT in men with TDS to improve or stabilize BMD at the lumbar spine and femoral neck [149]. In addition, there is some evidence that intramuscular TRT produces the greatest gains in BMD [84] and is the least likely form of administration to contribute to increased cardiovascular risk [123]. Therefore, it is the preferred form of TRT administration in this population. Because TRT has not been shown to reduce fracture risk, TRT should be used to supplement drugs with proven anti-fracture efficacy in men with TDS and high risk of fracture, rather than as monotherapy.

Clomiphene Citrate We only identified one trial, consisting of 46 patients with hypogonadism, that explored the relationship between clomiphene and BMD. This study found that clomiphene increased BMD at the lumbar spine and femoral neck in hypogonadal men [85]. No trials have been completed in eugondal men and there is no evidence of reduced fracture risk in hypogonadal men who take clomiphene citrate. However, as some men with hypogonadism and poor bone health may desire fertility preserving hormonal modulation, this trial suggests that substituting clomiphene for TRT may be a reasonable option in such patients. Sex Med Rev 2015;3:298–315

Gaffney et al. Pharmacotherapy for Osteoporosis

Bisphosphonates Bisphosphonates are pyrophosphate analogs that bind to the bone matrix and structurally inhibit bone resorption. They are currently the first-line treatment for men with primary osteoporosis because they have been shown to increase BMD in men and certain bisphosphonates have been shown to decrease the risk of fractures independent of testosterone level (Table 3) [86,87,105,106]. Bisphosphonates can be administered by mouth (PO), intravenously (IV), or IM and are generally well-tolerated with adverse event rates similar to placebo in the majority of clinical trials (Table 3). However, bisphosphonates may increase risk of osteonecrosis of the jaw (<1/10,000 patients) [150] and patients taking PO bisphosphonates must be able to sit up for 30–60 minutes following administration or they may develop chemical esophagitis [151]. Bisphosphonates should be avoided in patients with renal failure and low BMD secondary to renal osteodystrophy [152]. Denosumab Denosumab is a monoclonal antibody that inactivates RANKL to indirectly inhibit osteoclast activation and bone resorption. Denosumab increases BMD in osteoporotic men independent of testosterone levels (Table 3) [111]. Furthermore, denosumab is the only treatment proven to decrease fracture risk in men receiving ADT and delay time-to-skeletal-event in prostate cancer [46,153] Therefore, denosumab is an effective first-line option for men receiving ADT and is an appropriate medication for hypogonadal men with osteoporosis who cannot tolerate bisphosphonates. Denosumab is administered subcutaneously and does not need dose adjustments for renal impairment [152]. Patients taking denosumab have an increased, but uncommon, relative risk (RR) of osteonecrosis of the jaw (RR 1.6) [113]. Teriparatide Teriparatide is a parathyroid hormone (PTH) analog. PTH leads to bone resorption in high doses, but low doses of PTH are thought to induce bone formation. This is the only anabolic agent available for the treatment of osteoporosis. The literature on teriparatide in men is summarized in Table 3. Teriparatide has been found to increase BMD in men with low BMD independent of testosterone level. However, no trials have been powered to show fracture benefit for teriparatide

Transdermal Growth hormone + enanthate Esters

Hypogonadism on lifelong TRT

Hypogonadism Men over 65 y/o Hypogonadism Men over 65 y/o with low BioT LH > 8 IU, T < 20 nmol/L Age-related-TDS Glucocorticoid Tx Age-related-TDS T < 12.1 nmol/L

Age-related-TDS

Borderline hypogonadism Low/normal testosterone Age-related-TDS Age-related-TDS Age-related-TDS w/fracture history or T-score < −2.0 Hypogonadism + metabolic syndrome Age-related-TDS + osteoporosis

72T

32T (34 ± 1.7) 54T vs. 20P (73.1 ± 5.8 73 ± 5.9)

76T-patch, 73 5g T-gel, 78 10g T-gel

24T vs. 20P (76 ± 4 vs. 75 ± 5)

16T vs. 19P (40.9 vs. 40.9) 19T vs. 17P (70 ± 0.7 vs. 70 ± 1.1) 18T vs. 16P (58.7 ± 20.7 59.9 ± 16)

24T vs. 24P (71 ± 4 vs. 71 ± 5)

27T 66.2 (62–72) vs. 31P 67.1 (64–73)

20T vs. 19P (63 ± 9 vs. 59.7 ± 10.2) 113T vs. 110P (67.1 ± 5 67.4 ± 4.9) 17T vs. 18P (69 ± 5 vs. 69 ± 5)

25 T vs. 23P (63.2 ± 8.5 vs. 63.1 ± 7.7)

69T vs. 62P (77.9 ± 7.3 vs. 76.3 ± 8)

60(57 ± 10), 40T vs. 20P

62 40 mg/d (68.1 ± 5.4), 62 20 mg/d (68.4 ± 5.5), 62P (68.0 ± 4.8)

Behre 1997 [133]*

Leifke 1998 [134]* Snyder 1999 [135]*

Wang 2001 [136]*

Kenny 2001 [137]*

Howell 2001 [138]* Christmas 2002 [139]* Crawford 2003 [61]*

Amory 2004 [140]*

Nair 2006 [141]*

Merza 2006 [142]* Emmelot-Vonk 2008 [143]* Svartberg 2008 [144]*

Basurto 2008 [145]†

Aversa 2012 [147]†

Wang 2013 [148]*

Undecanoate

Undecanoate

Transdermal

Enanthate

24 m

36 m

12 m

12 m

6m 6m 12 m

24 m

36 m

12 m 6m 12 m

12 m

6m

3.2 ± 1.7 y 36 m

→16 y

12 m

6m 9m

18 m

12 m 11.8 ± 4.9 m

Follow up

↑Radial ↑Neck, Ward’s, and lumbar for both KS and HH, P < 0.001 ↑Spinal: (+5 ± 1%, P < 0.001) + trabecular (+14 + /−3%, P < 0.001) ≠ radial ≠Total, hip, and spine ↑Lumbar, fem. ≠neck ↑Lumbar: +5% vs. −0.2% (P = 0.05) ≠Neck, Wards, trochanter, whole body ↑treatment naïve patients 100% TRT for 3 + years achieved age-dependent reference range ↑Spine TDS (<200 ng/dL) ↑ BMD (5.9%) ≠Neck, Ward’s, trochanter, lumbar ↑Hip (+1.1 ± 0.3%10g T-gel), ↑Spine: (2.2 ± 0.5% 10g T-gel) ↑Neck: +0.3% vs. −1.6, P = 0.015 ≠Ward’s, trochanter, lumbar, and whole body ≠Lumbar, neck, total hip, radius ≠Lumbar, neck, trochanter, radius, total ↑Lumbar (+4.7% vs. −0.7%, P < 0.05) ≠Neck, Ward’s, trochanter BMD ↑Lumbar (+10.2% vs. 1.3%, P < 0.001), ↑Total hip: (+2.7 vs. −0.2%, P < 0.05) ≠Fem. Neck: NS gain Neck: +0.03 g/cm2 (0.01–0.05), P = 0.002 total hip BMD: NS gain Radius: NS gain lumbar BMD: NS gain ≠Lumbar, neck, total hip ≠Lumbar, total hip ↑Total hip (1.5% vs. 0, P < 0.05) ≠Lumbar ↑Lumbar ≠Neck ↑Lumbar L1–L2: +3.25%, P = 0.03, L2–L4: +3.07%, P = 0.005 ↑Radius: +1.29% vs. 0.20, P = 0.008 ≠Neck, trochanter, total hip ↑Lumbar: +1.053 ± 0.145 g/cm2, P < 0.002 ↑Femoral: +0.989 ± 0.109 g/cm2, P < 0.003 ↑Lumbar, femoral neck

Results (BMD change)

*Serum measurement by immunoassay. †Serum measurement not reported. T = treatment group; P = placebo group. ↑ = associated with increase; ↓ = associated with decrease; ≠ = no relationship; HH = hypogonadotropic hypogonadism; BMD = bone mineral density; TRT = testosterone replacement therapy; TDS = testosterone deficiency syndrome; NS = non-significant; y/o = years old; m = months; y = years; KS = Klinefelter’s syndrome. Adapted and expanded from Hoppe et al. 2013.

Kenny, 2010

[146]†

Transdermal Undecanoate Undecanoate

Low-dose transdermal

Enanthate

Ca2+

Transdermal or gel

Multiple Transdermal

Multiple

Esters

Sublingual Enanthate

Enanthate

/VitD

Transdermal +

Glucocorticoid Tx

15T vs. 15P (61 ± 11 vs. 61 ± 11)

Reid 1996 [60]

Wang 1996 [131]* Hall 1996 [132]*

Acquired hypogonadism

Enanthate Cypionate

Hypogonadism Rheumatoid arthritis

Testosterone Treatment

Katznelson 1996 [130]*

Population

Arisaka 1995 [128] Choi 1995 [129]

Adolescents w/ HH 20 KS and 7 HH

Patients (age)

6T vs. 6P 27 T (26.5 ± 1.1 KS and 28.0 ± 3.3 HH) vs. controls 35 hypogonadal vs. 44 controls (53 ± 3 vs. 53 ± 2) 67T 15T (64.2 ± 10.3 ) vs. 15P (59.4 ± 7)

Author

Table 4 Clinical trials of TRT and BMD in patients with various forms of TDS

Osteoporosis and Low Bone Mineral Density in Men with TDS 309

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310 in men with osteoporosis. Teriparatide is administered subcutaneously for men with severe osteoporosis and history of fragility fracture as monotherapy or for men who cannot tolerate other agents. Adverse effects include transient hypercalcemia and a possible rare, but increased, risk of osteosarcoma [115]. Conclusion

TDS is a risk factor for bone density abnormalities including osteopenia and osteoporosis that are associated with significant morbidity and mortality for men. We suggest an algorithm to guide screening, assessment, and management of men with TDS and low BMD that is supported by society recommendations, the available literature, and clinical experience (Figure 3). Large, high-quality studies have described the incidence of TDS in osteoporosis and the effect of FT and TT on BMD in men over 50, while more data are needed on BMD in men with TDS under the age of 50. TRT increases BMD in men with TDS, but larger-scale studies are necessary to more clearly define the anti-fracture efficacy of TRT monotherapy in patients with comorbid TDS and osteoporosis. TRT monotherapy is appropriate for hypogonadal men with osteopenia at low risk of fracture. Patients at high risk of future fracture should be treated with a bisphosphonate with the option for supplemental TRT directed at treating symptoms of TDS. Corresponding Author: Peter J. Stahl, MD, Department of Urology, Columbia University Medical Center, New York, NY 10032, USA. Tel: 212-342-4574; Fax: 212-305-0106; E-mail: [email protected] Conflict of Interest: The author(s) report no conflicts of interest. Statement of Authorship

Category 1 (a) Conception and Design Christopher D. Gaffney; Matthew J. Pagano; Doron S. Stember; Peter J. Stahl (b) Acquisition of Data Christopher D. Gaffney (c) Analysis and Interpretation of Data Christopher D. Gaffney; Matthew J. Pagano; Adriana P. Kuker; Doron S. Stember; Peter J. Stahl

Category 2 (a) Drafting the Article Christopher D. Gaffney; Matthew J. Pagano; Peter J. Stahl Sex Med Rev 2015;3:298–315

Gaffney et al. (b) Revising It for Intellectual Content Christopher D. Gaffney; Matthew J. Pagano; Adriana P. Kuker; Doron S. Stember; Peter J. Stahl

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