EAA clinical guideline on management of bone health in the andrological outpatient clinic

Male osteoporosis is now a well‐recognized medical disorder with established clinical guidelines for both diagnosis and management. Prevention as well as management of osteoporosis in men consulting the andrological outpatient clinic because of low testosterone, however, is not well established. This gap of knowledge is—at least partly—explained by the controversy with respect to the threshold of testosterone needed for skeletal maintenance. However, testosterone deficiency may be clearly associated with bone loss as well as frailty in men. If anything, andrologists should therefore be aware of the potential silent presence of osteoporosis in men with confirmed hypogonadism. Therefore, the management of patients with potential hypogonadism should include a complete bone health assessment, besides clinical and biochemical evaluation of gonadal status. Such bone health assessment should include specific items in medical history and physical examination related to fracture risk. Furthermore, dual‐energy absorptiometry is indicated to evaluate fracture risk in men with confirmed clinical hypogonadism. Regarding treatment, besides general measures to prevent or manage male osteoporosis testosterone replacement can be initiated (as described in guidelines for hypogonadism), but data on its efficacy in preventing fractures are lacking. Thus, additional anti‐osteoporotic may be needed, especially in men with very low testosterone who are at high risk of bone loss and/or in men not able to receive testosterone replacement.


INTRODUCTION
Osteoporosis is an important health problem not only in women but also in men. Hypogonadism is a well-established cause of secondary osteoporosis in men. Both primary hypogonadism and secondary hypogonadism are associated with low bone density (Khosla et al., 1998;Fink et al., 2006;Rochira et al., 2006Rochira et al., , 2015. Increase in fracture risk is, however, only well documented in patients following androgen deprivation therapy (ADT: surgical or chemical castration in prostate cancer patients or hypersexuality) (Shahinian et al., 2005). Indeed, ADT is associated with rapid bone loss (Stepan et al., 1989) as well as subsequent bone fragility (Shahinian et al., 2005;Wang et al., 2015;Wu et al., 2015).
Moreover, testosterone prevents bone loss in hypogonadal men (Amory et al., 2004), especially in men with low testosterone concentrations (<200 ng/dL) (Snyder et al., 1999(Snyder et al., , 2017. In men with borderline low or low normal testosterone levels however, such as in some patients with Klinefelter syndrome, bone density may be preserved also without testosterone replacement (Bonomi et al., 2016).
Although male osteoporosis is now a well-recognized clinical entity, it remains an underdiagnosed and undermanaged condition (Madeo et al., 2007;Willson et al., 2015). Although several general guidelines for the management of osteoporosis contain advice concerning male osteoporosis (Appendix 1), only a few guidelines specific for male osteoporosis have been released. No specific guidelines on hypogonadal osteoporosis are however available.
For this reason, this manuscript presents a more practical approach for the assessment and management of bone health in patients consulting an andrological outpatient clinic, including both prevention and management of osteoporosis in hypogonadal men.
To enhance the value of the clinical advice here provided, we used the GRADE (Grading of Recommendations, Assessment, Development, and Evaluation) system for grading the quality of evidence and the strength of recommendations (Swiglo et al., 2008). The GRADE system is a method of developing evidence-based guidelines involving key recommendations and the use of a consistent language and graphical descriptions for standardizing the grading of both the strength of recommendation and the quality of evidence (Swiglo et al., 2008) (17, 20). The number 1 indicates a strong recommendation and is associated with the terminology 'we recommend'; the number 2 denotes a weak recommendation and is associated with the wording 'we suggest'. The grading of the quality of evidence employs the following graphical descriptions: ⊕○○○ denotes very low-quality evidence; ⊕⊕○○, low quality; ⊕⊕⊕○, moderate quality; and ⊕⊕⊕⊕, high quality (Swiglo et al., 2008). In addition, we provide three clinical vignettes that summarize different scenarios common in andrological patient practice (Boxes 1-3).

APPROACHING BONE HEALTH IN THE PATIENT WITH HYPOGONADISM
Low circulating sex steroids (both androgens and estrogens) are associated with reduced bone mineral density (BMD) in men of any age (Khosla et al., 1998;Fink et al., 2006;Rochira et al., 2006Rochira et al., , 2015, and this association is supported by clear pathophysiological evidence (Almeida et al., 2017). Bone health assessment is therefore needed in men with confirmed hypogonadism.
Clinical evaluation: the role of patient's medical history and physical examination Both medical history and appearance at physical examination (Table 1) might prompt further investigation in hypogonadal patients. Further clinical workup should be addressed to (i) diagnose osteopenia/osteoporosis, (ii) assess fracture risk and/or concomitant presence of fractures, and finally (iii) establish therapeutic strategies Vescini et al., 2016).
A detailed patient's interview should be considered prior to proceed to a complete bone workup . Further examinations are needed if one or more of the aspects listed in Table 1 are present. Furthermore, risk factors for osteoporosis and fractures related to lifestyle, other treatments, and related diseases (Table 2) should be addressed (Kanis et al., 2005a,b;de Kam et al., 2009;Drake et al., 2012;. In particular, alcohol intake should be evaluated as alcohol abuse is an important cause of male osteoporosis. Smoking and excessive alcohol consumption (daily intake or ≥10 units per week or ≥3 units/day) are major risk factors for osteoporotic fractures in men (Kanis et al., 2005a,b;Drake et al., 2012).
Information on current or past glucocorticoid treatment should be obtained as glucocorticoid treatment is a strong risk factor for both osteoporosis and osteoporotic fractures .

Statements
• We recommend considering bone health in all andrological patients with documented hypogonadism at first visit. 1| ⊕⊕○○ • We suggest assessing clinical aspects of bone health as reported in Table 1. 2|⊕⊕○○ • We suggest including spine observation and follow-up of patient's height in the clinical workup. 2|⊕⊕○○

Evidence
Silent spine fractures may also occur in men similar to women and are an important first sign of osteoporosis . Decrease in height, the presence of dorsal kyphosis, a wall-toocciput distance >0 cm, and a rib-to-pelvis distance <2 fingers might suggest the presence of occult vertebral fractures in men (Table 1) (Green et al., 2004). Wall-to-occiput distance is easily obtained by placing the patient against the wall and measuring the distance between the wall and the occiput (Green et al., 2004).
Biochemical evaluation: the role of sex steroid measurements Statements • We recommend having serum total testosterone measured twice on a morning blood sample. 1|⊕⊕⊕○ • We recommend measuring again total testosterone and SHBG if only a single measurement documenting low testosterone is available. LH and prolactin are useful to better characterize hypogonadism. 1|⊕⊕⊕○ • We do not recommend routine measurement of serum estradiol. 1|⊕⊕○○ • We suggest measuring estradiol only when a validated mass spectrometry-based method is available and in rare cases in which severe estrogen deficiency is suspected. 2|⊕⊕○○

Evidence
It is well established that circulating sex steroids should be in the male normal range to ensure bone health (Rochira et al., 2006;Almeida et al., 2017). For this reason, all patients with documented low serum testosterone consulting with hypogonadal symptoms should receive a biochemical evaluation of their gonadal status, with measurement of serum total testosterone, SHBG, luteinizing hormone (LH), follicle-stimulating hormone (FSH), and prolactin (Wang et al., 2009;Bhasin et al., 2010;Buvat et al., 2013;Huhtaniemi, 2014;Lunenfeld et al., 2015). Gonadotropins are needed to differentiate primary hypogonadism from secondary hypogonadism, whereas normal prolactin levels allow excluding hyperprolactinemia as the cause of hypogonadism (Basaria, 2014).
When serum total testosterone is between 200 and 300 ng/dL, the presence of hypogonadal symptoms may help in confirming the diagnosis and other aspects (e.g., patients' age, obesity) are determinant for clinical relevance of low serum testosterone (e.g., vignette 3; Box 3).
Severe hypogonadism and mild hypogonadism have a different impact on bone mass than slightly low serum testosterone (in-between 200 and 300 ng/dL). Severe hypogonadism (serum total testosterone <100 ng/dL) may lead to bone loss and often osteoporosis, independently from the patient's age as illustrated in the clinical vignette 1 (Box 1). In case of severe hypogonadism, concomitant osteoporotic fractures (commonly of the spine) might be present at the diagnosis both in young and older men as in clinical vignette 1 (Box 1) and 2 (Box 2), respectively. Conversely, a clear cause-effect relationship between bone and gonadal status remains weak in case of mild to slight hypogonadism depicted by clinical vignette 3 (Box 3). These different phenotypes of male hypogonadism may therefore have different impact with respect to diagnosis and management of bone health.

Serum estradiol
Serum estradiol is an important determinant of bone mass in men (Rochira et al., 2015;Almeida et al., 2017), and bone loss in hypogonadal men may also be related to estrogen deficiency (Rochira et al., 2006;Finkelstein et al., 2016). Accordingly, hypogonadal men without relative estrogen deficiency have higher BMD than those with both low testosterone and estradiol (Aguirre et al., 2015). Theoretically, serum estradiol may be a good marker to identify hypogonadal men with a worse bone status, but the role of estradiol measurement for the diagnosis and management of hypogonadal osteoporosis is currently not well established, in part due to pitfalls related to the measurement of estradiol in the low male normal range (Rochira et al., 2015. Estradiol becomes important in hypogonadal osteoporosis only when severe estrogen deficiency is suspected (Rochira & Carani, 2009).

Remarks
Serum total testosterone can be assayed by commercially available kits or using the gold standard represented by liquid chromatography-tandem mass spectrometry (LC-MS/MS), which is becoming more and more available in the clinical setting (Simoni et al., 2012).
We suggest using calculated free testosterone when needed, based on the measurement of total serum testosterone, SHBG, and albumin (Vermeulen et al., 1999). It can easily be obtained using online available calculators (see Appendix 2 for Web links). Commercially available kits for direct measurement of free testosterone should not be used due to their poor accuracy and reliability (Rosner et al., 2007;Bhasin et al., 2010).
Commercially available kits for the measurement of serum estradiol have poor accuracy and are not reliable for the measurement of estradiol within the low male normal range (Rosner et al., 2013;Demers et al., 2015), the finding of elevated or normal to high serum estradiol being useful only to rule out relative estrogen deficiency in men with low testosterone (Finkelstein et al., 2016;Rochira & Carani, 2017). However, even when performed with accurate and precise techniques such as LC-MS/MS, the clinical use of serum estradiol remains not validated (Demers et al., 2015). Thus, at present, the measurement of serum estradiol is not useful in routine clinical practice (Demers et al., 2015).

Statements
• We suggest measuring serum 25(OH) vitamin D at baseline in all hypogonadal men, independently from their BMD. 2|⊕⊕○○ • We suggest measuring serum calcium (or calcium corrected for albumin when it is applied-see Appendix 2 for Web links), phosphorous, and PTH in all hypogonadal patients with documented low BMD. 2|⊕⊕○○ • We do not recommend the routine use of bone turnover markers in the management of male or hypogonadal osteoporosis. 1|⊕⊕⊕○

Vitamin D, calcium, PTH
Vitamin D deficiency may be more prevalent in hypogonadal men . Although low testosterone may also contribute to lowering circulating active forms of vitamin D (Ferlin et al., 2013), serum 25(OH) vitamin D should be used as the marker of vitamin D deficiency (Swanson et al., 2014). However, measuring 25(OH) vitamin D levels can be technically challenging and a properly validated assay should be used (Bouillon et al., 2013). For vitamin D, a 25(OH) vitamin D serum level of Box 1 Clinical vignette 1 depicting a standard case of an adult male patient with severe hypogonadism and severe osteoporosis characterized by multiple vertebral fractures at the time of the diagnosis.

Clinical Vignette 1
Patient: 40 year old man Past history: delayed puberty, one-year treatment with gonadotropins for hypogonadotropic hypogonadism at the age of 18 years, subsequent longterm period without androgen replacement treatment, heavy smoker Reasons for andrological consultation: signs (eunuchoid habitus, incomplete pubertal development, reduced body hair) and symptoms (anosmia) of hypogonadism (other: low libido, low volume of ejaculate, and erectile dysfunction) Physical examination: dorsal kyphosis, eunuchoid skeletal proportions Hormones: Low to suppressed LH and FSH, serum T: 73 ng/dL (normal range: 300-900 ng/dL), normal serum prolactin, and vitamin D DXA: lumbar T-score: À2.2; femoral T-score: À2.4 (lumbar and femoral osteopenia). FRAX: 18% risk of major osteoporotic fractures: 13% risk of hip fracture X-ray of the spine: showed wedge (grade 1) vertebral fractures of T9, T10, and T11 vertebrae. Diagnosis: severe hypogonadotropic hypogonadism due to Kallmann syndrome associated with severe osteoporosis Proposed treatment: should receive TRT or gonadotropin treatment if fertility is requested

Summary of relevant aspects
This clinical vignette highlights that: ○ BMD measurement alone may not be sufficient for a complete diagnosis ○ Osteoporotic, atraumatic fractures may appear early in life in case of severe male hypogonadism, especially if untreated ○ Physical examination is useful in suggesting further radiological examination that might change the diagnosis of osteoporosis Practical tools: ○ Check occult fractures in male patients with hypogonadism, especially in severe hypogonadism ○ Obtain FRAX score for assessing fracture risk ○ Young adults with osteoporosis and severe hypogonadism are good candidates for TRT ○ Occult osteoporotic fractures need also specific antiresorptive treatment TRT, testosterone replacement treatment.

Bone turnover markers
The role of serum bone turnover markers such as bone-specific alkaline phosphatase, osteocalcin, urinary collagen type 1 cross-linked N-telopeptide (NTX), and collagen type 1 crosslinked C-telopeptide (CTX) in the workup of hypogonadal osteoporosis is not well established. High bone turnover markers in hypogonadal men may however reflect high bone turnover and therefore ongoing bone loss. At present, there is also no evidence about the value of bone turnover markers for either determination of fracture risk or selection of patients who need to be treated (Vasikaran & Chubb, 2016). Antiresorptive treatment may however reduce bone turnover markers in hypogonadal osteoporosis (Vasikaran & Chubb, 2016), but their use in followup of treatment is not well validated.

Diagnosis: the role of bone imaging
As male hypogonadism may cause osteoporosis, all andrological patients with confirmed hypogonadism should undergo further evaluation of bone density. Bone imaging, by the use of DXA and plain x-ray, aims to (i) ascertain whether osteopenia or osteoporosis is present; (ii) diagnose previous or concomitant osteoporotic fractures (often overlooked or underestimated in men); and (iii) prevent future fractures.
The role of DXA in the evaluation of bone status Statements • We recommend BMD measurement by DXA in all hypogonadal patients with documented hypogonadism and/or serum testosterone <200 ng/dL. 1|⊕⊕⊕○ • We suggest BMD measurement by DXA in all hypogonadal patients with slightly decreased serum total testosterone (between 200 and 300 ng/dL), especially in young patients or in patients with hypogonadal symptoms. 2|⊕⊕○○ • We recommend that all patients who need ADT (for prostate cancer or hypersexuality) should also be evaluated by DXA. 1|⊕⊕⊕⊕ • We suggest BMD measurement by DXA in men with a welldocumented history of hypogonadism. 2|⊕⊕⊕○ Box 2 Clinical vignette 2 depicting a standard case of an older man with severe hypogonadism and concomitant severe osteoporosis with multiple vertebral fractures.

Clinical Vignette 2
Patient: 70 year old man Past history: diagnosis of isolated hypogonadotropic hypogonadism treated since the age of 30 years. No TRT treatment during the last 40 years Reasons for andrological consultation: hospitalization for fatigue, slight degree of sarcopenia, and diffuse bone pain (particularly back pain) Physical examination: undervirilization, dorsal kyphosis, eunuchoid skeletal proportions, bilateral valgism, and bilateral gynecomastia, 2.5 cm reduction in height during the last 3 years Hormones: Low to suppressed LH and FSH, serum T: 130 ng/dL (normal range: 300-900 ng/dL), normal serum prolactin, 25(OH) vitamin D: 17.1 ng/mL (normal range: 30-100 ng/mL) DXA: lumbar T-score: À4.0 (z-score: À3.1); femoral T-score: À3.4 FRAX: 22% risk of major osteoporotic fractures: 11% risk of hip fracture X-ray of the spine: reduction in height of the vertebral body of D6, D7, D9, D10, D11, and L4 vertebrae together with a fracture of the sixth right rib Diagnosis: severe hypogonadotropic hypogonadism associated with severe osteoporosis Proposed treatment: should restart TRT treatment and receive also antiosteoporotic treatment with proven antifracture efficacy

Summary of relevant aspects
This clinical vignette highlights that: ○ Even when indicated, TRT treatment in older patients might be discontinued due to several reasons: lack of compliance, frailty and poor health conditions, and contraindications that are frequent in the elderly (e.g., increased hematocrit, suspected or diagnosed prostate cancer, severe chronic coronary disease) ○ The best option is to add antiresorptive or anabolic bone treatment to TRT (combined therapy) as TRT alone is not sufficient to guarantee bone health. ○ In case of contraindications to TRT administration, antiresorptive or anabolic bone treatment alone should be administered to treat osteoporosis. ○ Vitamin D deficiency should be corrected Practical tools: ○ Focus mainly on prevention of further fracture (specific treatment for osteoporosis) rather than on hypogonadism and prevention of bone loss with TRT ○ Severe osteoporosis in older patients needs prevention of falls, especially in case of sarcopenia TRT, testosterone replacement treatment.

Evidence
In clinical practice, dual-energy X-ray absorptiometry (DXA) is the best diagnostic tool to assess BMD in hypogonadal men, whereas pQCT and bone ultrasound only have a role in research or screening (Lewiecki, 2013).
All patients with documented or previous history of hypogonadism should undergo DXA analysis at both lumbar and femoral site . Even patient's documented hypogonadism in the past might have caused bone loss, especially if occurred during puberty or early adult life (Finkelstein et al., 1987;Soyka et al., 2000). In the andrological setting, DXA provides information about baseline bone status as well as on the patient's risk of future osteoporotic fractures. BMD as assessed by DXA, in fact, correlates with fracture risk at all sites in men (Cummings et al., 2006;Lewis et al., 2007) when measured at lumbar and femoral sites . The association between low BMD and fracture is therefore also valid in hypogonadal patients (Gaffney et al., 2015) and especially patients undergoing androgen deprivation (Wadhwa et al., 2009). In particular, future bone loss is also strongly associated with osteoporotic fractures (Cawthon et al., 2012).
According to the WHO criteria, in men a T-score equal or <À2.5 is used for the clinical diagnosis of osteoporosis, and a T-score between À1.0 and À2.5 indicates low bone mass (osteopenia) (Kanis et al., 1994). The diagnosis of severe osteoporosis occurs also when a fragility fracture is documented (Kanis et al., 1994).

Remarks
The WHO criteria for the diagnosis of osteoporosis in men are still controversial (Binkley et al., 2014). The site of BMD measurement (lumbar vs. femoral), the use of different T-scores coming from different populations (male vs. female), and how to consider a given T-score in relation to a patient's age (young vs. older men) are the main controversial issues (Binkley et al., 2014).
A T-score equal or <À2.5 at the femoral neck is considered as the reference standard in men by the WHO Collaborating Centre, the International Osteoporosis Foundation (IOF) (Kanis et al., 2008, and the UK National Osteoporosis Guideline Group (NOGG) .
The recommended site of DXA measurement differs across various guidelines: hip and spine by the US National Osteoporosis Foundation and the Endocrine Society , and the lowest T-score value for the BMD measured at the lumbar spine, total hip, or femoral neck by the Osteoporosis Canada .
As far as the population used for the T-score is concerned, the Endocrine Society recommends using male reference data , the International Society of Clinical Densitometry recommends the female standards for calculating male T-scores (Watts et al., 2013), while the WHO, IOF, and Scientific Advisory Council of Osteoporosis Canada recommend the use of the reference database at the femoral neck of Third National Health and Nutrition Examination Survey (NHANES III) obtained from young women (20-29 years old) (Kanis et al., 2008;Papaioannou et al., 2010).
In guidelines of male osteoporosis, DXA is mostly indicated after age 50 . However, in young patients with confirmed hypogonadism, it may be important to have a DXA at start of TRT to be able to follow up evolution at later stages . For instance, if patients interrupt their TRT, Gastrointestinal malabsorption (e.g., celiac disease, bariatric surgery)/ rheumatoid arthritis/chronic kidney disease/HIV a /COPD/neoplastic diseases/iron overload (thalassemia, hemochromatosis)/idiopathic hypercalciuria/osteogenesis imperfecta/neuromuscular diseases/ multiple myeloma ADT, androgen deprivation therapy; HIV, human immunodeficiency virus infection; COPD, chronic obstructive pulmonary disease. a Osteoporosis is more prevalent in men than in women with HIV.
Box 3 Clinical vignette 3 depicting a standard case of an adult man with borderline serum total testosterone and osteopenia.

Summary of relevant aspects
This clinical vignette highlights that: ○ Slightly reduced borderline serum testosterone has little impact on bone loss ○ Overweight and obese men with hypogonadism have a reduced risk of osteoporosis thanks to increased aromatization and protective estrogen effect ○ Borderline serum testosterone usually does not require additional radiological examinations other than DXA ○ Check vitamin D and replace if deficient

Statements
• We recommend X-ray of the dorsolumbar spine when osteoporotic fractures are suspected on the basis of patient's medical history, physical examination, and/or the presence of localized bone pain. 1|⊕⊕⊕○ • We recommend using X-ray to confirm the diagnosis of severe osteoporosis. 1|⊕⊕○○ • We however do not recommend the use of X-ray for the diagnosis of osteoporosis or osteopenia. 1|⊕⊕⊕⊕ Evidence X-ray is the best diagnostic tool to identify vertebral fractures as first-line examination. Spine fractures in men as well as in women occur at the distal thoracic and upper lumbar spine. CT scan and MRI may confirm the diagnosis but are rarely needed (Lewiecki, 2013). X-rays are easy to perform, not expensive, available worldwide also in basic clinical setting, and are very sensitive for the detection of fractures (especially vertebral fractures) (see Appendix 2 for Web links to the Genant classification).

Statements
• We do not recommend the use of other different techniques than DXA and X-ray for the diagnosis of osteoporosis or osteopenia and osteoporotic fractures. 1|⊕⊕⊕○

Evidence
Although QCT shows a disturbed microarchitecture and bone density assessed by ultrasound is also lower in hypogonadal men Finkelstein et al., 2016), these techniques are less well-established markers of fracture risk (Lewiecki, 2013).

Statements
• We suggest calculating the FRAX score in all men with confirmed hypogonadism. 2|⊕⊕⊕○

Evidence
BMD measurement represents a surrogate marker of fracture risk as low BMD is associated with an increased risk of fractures at all sites in men (Pasco et al., 2014).
The Fracture Risk Assessment Tool (FRAX) â (see Appendix 2 for Web links) is also of value in predicting fracture risk in men (Harvey et al., 2016) with or without BMD value (Ettinger et al., 2013). It is not time-consuming and therefore could be easily used in hypogonadal patients. The score obtained allows an estimation of future osteoporotic fractures and hereby might help to decide whether or not additional anti-osteoporotic treatment is needed (Cosman et al., 2014).

Remarks
It has been suggested that a 10-year risk of hip fracture greater than or equal to 3% (obtained by FRAX) in men older than 50 years with low bone mass (osteopenia or osteoporosis) at femoral neck, total hip, or lumbar spine by DXA should be considered as a possible threshold for starting a treatment for osteoporosis .
It has been suggested that a 10-year risk of major osteoporotic fractures greater than or equal to 20% (obtained by FRAX) in men older than 50 years with low bone mass (osteopenia or osteoporosis) at femoral neck, total hip, or lumbar spine by DXA should be considered as a possible threshold for starting a treatment for osteoporosis .
No evidence exists to propose treatment thresholds based on FRAX score in men younger than 50 years.

Treatment
The main goal of treating hypogonadal men with osteoporosis is to decrease the risk of osteoporotic fractures. However, most studies in men have addressed only surrogate endpoints such as BMD, but not fracture endpoints. Furthermore, the data available from the trials investigating the efficacy of anti-osteoporotic drugs for the treatment of osteoporosis represent an additional limitation as the number of men enrolled in those studies is much smaller compared to the female participants.

Statements
• In general, smoking cessation, a reduction in alcohol intake, and weight-bearing exercises are recommended. 1|⊕⊕○○ • We suggest introducing lifestyle interventions when hypogonadism is diagnosed or when ADT is started and should be continued throughout life. 2|⊕⊕○○

Evidence
Lifestyle interventions are recommended in all men at risk of osteoporosis and therefore also in all hypogonadal men (Pye et al., 2010). Smoking cessation and alcohol abstention are needed for heavy smokers or alcoholics, and in general, reduction in smoking and in alcohol intake is advisable . Furthermore, increasing physical activity can have a positive effect on BMD and may reduce the risk of falls and fall-related fractures (de Kam et al., 2009). In addition, weight loss in obese subjects might, in part, increase serum testosterone (Corona et al., 2013).

Statements
• We suggest increasing dietary intake of calcium if the dietary calcium intake is insufficient. 2|⊕⊕○○ • If dietary calcium intake remains inadequate and/or vitamin D serum levels are low, we suggest initiating pharmacological supplementation with both calcium and vitamin D. 2|⊕○○○ • We do not recommend monotherapy with either one of them.

1|⊕⊕○○
• We do not recommend the use of calcium/vitamin D supplementation as the only treatment for hypogonadal osteoporosis or androgen deprivation therapy-associated bone loss. 1|⊕⊕⊕○ • We recommend starting antiresorptive therapy only in combination with calcium and vitamin D supplementation. 1|⊕⊕○○

Evidence
Both calcium and vitamin D are important for bone health. An average daily intake of 1000-1200 mg of calcium and 800 units of vitamin D is generally recommended, ideally via dietary intake (Bouillon et al., 2013). Daily dietary calcium intake can be estimated via a dietary history (see Appendix 2 for Web links).

Remarks
Men with malabsorption (for instance, after bariatric surgery) or low sunlight exposure (institutionalized patients) are at increased risk of vitamin D deficiency.
Monotherapy with either calcium or vitamin D, however, has not proven to increase BMD or decrease fracture risk (Bouillon et al., 2013;Avenell et al., 2014;Reid et al., 2014).
Compliance and continuation of treatment with calcium/vitamin D are important. BMD increases are lost when supplementation is stopped.

Statements
• We recommend antiresorptive treatment in hypogonadal men at high fracture risk (see also our practical proposal in our clinical vignettes). 1|⊕⊕⊕○

Evidence
Antiresorptive therapy (bisphosphonates as well as denosumab) has not been evaluated in a selected population of hypogonadal patients as randomized controlled trials were performed in osteoporotic men, including both eugonadal and hypogonadal men. Most of the hypogonadal men in these trials had low or borderline serum testosterone levels without clear documentation of their gonadal status. An overview of the drugs available for treating osteoporosis in men is given in Table 3.
Antiresorptive treatment increases bone density in osteoporotic men, but data on fracture risk are limited . To date, evidence for fracture risk reduction in men with low bone density is only available for zoledronate IV. Importantly, in this study hypogonadal subgroup was included, new osteoporotic fractures were a primary endpoint, and X-ray assessment of spinal fractures was used .
In addition, there is also evidence that zoledronate reduces fracture risk as well as mortality in mixed male-female population irrespective of bone density (Lyles et al., 2007).
Calcium and vitamin D supplements should always be started when starting antiresorptive therapy as supplements were used in all clinical trials.
Hypocalcemia and/or vitamin D deficiency should be corrected before an antiresorptive drug is started.

Statements
• We recommend TRT in young adult hypogonadal patients in order to prevent bone loss and to help acquire peak bone mass. 1|⊕⊕○○ • For the indication of TRT in other patient groups, we suggest referring to guidelines on male hypogonadism. The potential benefit of TRT on BMD and fracture risk will probably depend on the etiology of hypogonadism, age of onset, duration, and severity of testosterone deficiency but is not well documented. 2|⊕⊕○○ • We do not recommend using TRT alone to treat osteoporosis in hypogonadal men with high fracture risk (in the absence of documented effect on fracture risks), and we recommend to add specific antiresorptive drugs to the therapy, even if these men are receiving adequate TRT. 1|⊕⊕○○

Evidence
In young hypogonadal men (<25 years old), testosterone replacement therapy may prevent bone loss, reduce markers of bone resorption, and help to acquire peak bone acquisition (Laitinen et al., 2012). Furthermore, in young hypogonadal patients with open epiphyses the effect of testosterone replacement on bone density may be more pronounced.
Besides, in elderly men, the effect of TRT on bone density seems to depend on the severity of testosterone deficiency. This was evaluated in a meta-analysis. The effect of TRT was considered significant at the lumbar spine and when using parenteral testosterone (Tracz et al., 2006). Furthermore, in a recent randomized controlled trial, testosterone treatment increased BMD in hypogonadal men. Also in this study, the effect was more pronounced in the spine than in the hip (Snyder et al., 2017). Importantly, there is no evidence that TRT reduces fracture risk in older men with normal or borderline low testosterone levels . Additionally, the role of testosterone replacement on top of antiresorptive treatment in hypogonadal patients at high risk of fractures is not established.

Statements
• We recommend starting antiresorptive treatment in ADTtreated prostate cancer patients with moderate to high fracture risk (see section on FRAX score). 1|⊕⊕⊕⊕ • We suggest close follow-up of ADT-treated patients with a low fracture risk. 2|⊕⊕○○

Evidence
Despite their high fracture risk, prostate cancer patients and hypersexuality patients on ADT remain undertreated for osteoporosis. A decrease in BMD is already observed following 6 months of ADT therapy. The longer the duration of ADT, the higher the fracture risk (Bienz & Saad, 2015).
Benefits of antiresorptive therapy on fracture risk are well established, and several antiresorptive drugs have been evaluated in these patients. Both bisphosphonates and denosumab have positive effects on BMD as well as on fracture risk. In most RCTs, antiresorptive therapy is initiated when ADT is started, to prevent ADT-related bone loss, also in men without osteoporosis. For some drugs, higher doses were used than in men with idiopathic osteoporosis. An overview is given in Table 4.

Remarks
Calcium/vitamin D supplementation alone, without an antiresorptive agent, is inadequate to prevent ADT-associated bone loss.
The risk of osteonecrosis of the jaw following antiresorptive treatment is overall considered very low but may be higher in the population of oncological patients. Therefore, dental evaluation before initiating therapy is recommended at the start of treatment.
In men with hormone-sensitive bone metastatic prostate cancer, bisphosphonates have not shown to decrease the rate of skeletal-related events (complications from bone metastases: pain, functional impairment, pathologic fractures). Denosumab has not been tested for this indication .
Monotherapy with the anti-androgen bicalutamide results in a stable or increased BMD (Smith, 2002;Wadhwa et al., 2009). These patients are not at risk of developing osteoporosis.

Follow-up
DXA is useful to follow up the efficacy as well as compliance of antiresorptive treatment. The frequency of DXA follow-up is however not well defined or established. In patients considered at low risk at baseline, a 5-year follow-up of bone status should probably be sufficient. In patients at higher risks, shorter intervals may be needed. In men treated with antiresorptive therapy, regular measurement of calcium, vitamin D, and kidney function is recommended.

CONCLUSIONS (SEE KEY MESSAGES)
Within the context of the andrological setting, bone health should receive full consideration in patients with hypogonadism and osteoporosis should be ruled out or treated based on specific partial or complete workup (Box 4 & Fig. 1). • We suggest measuring estradiol only when a validated mass spectrometry-based method is available and in rare cases in which severe estrogen deficiency is suspected. 2|⊕⊕○○

List of all recommendations
• We suggest measuring serum 25(OH) vitamin D at baseline in all hypogonadal men, independently from their BMD. 2|⊕⊕○○ • We suggest measuring serum calcium (or calcium corrected for albumin when it is applied-see Appendix 2 for Web links), phosphorous, and PTH in all hypogonadal patients with documented low BMD. 2|⊕⊕○○ • We do not recommend the routine use of bone turnover markers in the management of male or hypogonadal osteoporosis. 1|⊕⊕⊕○  • We recommend BMD measurement by DXA in all hypogonadal patients with documented hypogonadism and/or serum testosterone <200 ng/dL. 1|⊕⊕⊕○ • We suggest BMD measurement by DXA in all hypogonadal patients with slightly decreased serum total testosterone (between 200 and 300 ng/dL), especially in young patients or in patients with hypogonadal symptoms. 2|⊕⊕○○ • We recommend that all patients who need ADT (for prostate cancer or hypersexuality) should also be evaluated by DXA. 1|⊕⊕⊕⊕ • We suggest BMD measurement by DXA in men with a welldocumented history of hypogonadism. 2|⊕⊕⊕○ • We recommend X-ray of the dorsolumbar spine when osteoporotic fractures are suspected on the basis of patient's medical history, physical examination, and/or the presence of localized bone pain. 1|⊕⊕⊕○ • We recommend using X-ray to confirm the diagnosis of severe osteoporosis. 1|⊕⊕○○ • We however do not recommend the use of X-ray for the diagnosis of osteoporosis or osteopenia. 1|⊕⊕⊕⊕ • We do not recommend the use of other techniques different than DXA and X-ray for the diagnosis of osteoporosis or osteopenia and osteoporotic fractures. 1|⊕⊕⊕○ • We suggest calculating the FRAX score in all men with confirmed hypogonadism. 2|⊕⊕⊕○ • In general, smoking cessation, a reduction in alcohol intake, and weight-bearing exercises are recommended. 1|⊕⊕○○ • We suggest introducing lifestyle interventions when hypogonadism is diagnosed or when ADT is started and should be continued throughout life. 2|⊕⊕○○ • We suggest increasing dietary intake of calcium if the dietary calcium intake is insufficient. 2|⊕⊕○○ • If dietary calcium intake remains inadequate and/or vitamin D serum levels are low, we suggest to initiate pharmacological supplementation with both calcium and vitamin D. 2|⊕○○○ • We do not recommend monotherapy with either one of them.

1|⊕⊕○○
• We do not recommend the use of calcium/vitamin D supplementation as the only treatment for hypogonadal osteoporosis or androgen deprivation therapy-associated bone loss. 1|⊕⊕⊕○ • We recommend starting antiresorptive therapy only in combination with calcium and vitamin D supplementation. 1|⊕⊕○○ • We recommend antiresorptive treatment in hypogonadal men at high fracture risk (see also our practical proposal in our clinical vignettes). 1|⊕⊕⊕○ • We recommend TRT in young adult hypogonadal patients in order to prevent bone loss and to help acquire peak bone mass. 1|⊕⊕○○ • For the indication of TRT in other patient groups, we suggest to refer guidelines on male hypogonadism. The potential benefit of TRT on BMD and fracture risk will probably depend on the etiology of hypogonadism, age of onset, duration, and severity of testosterone deficiency but is not well documented. 2|⊕⊕○○ • We do not recommend using TRT alone to treat osteoporosis in hypogonadal men with high fracture risk (in the absence of documented effect on fracture risks), and we recommend to add specific antiresorptive drugs to the therapy, even if these men are receiving adequate TRT. 1|⊕⊕○○ • We recommend starting antiresorptive treatment in ADTtreated prostate cancer patients with moderate to high fracture risk (see section on FRAX score). 1|⊕⊕⊕⊕ • We suggest close follow-up of ADT-treated patients with a low fracture risk. 2|⊕⊕○○