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This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Introduction Osteopenia, osteoporosis, hip fractures and their complications have significant morbidity and mortality in women and men of advanced age (>70) [1,2] . Osteoporosis is often viewed by medical professionals and laymen alike as a disease of the elderly, and not considered in the differential of clinical problems of middle-aged or young men. Furthermore, growing epidemiological evidence suggests that low bone mineral density may be more common in younger men (20 - 40’s) than previously believed [3]. Experience with these patients demonstrated clearly that lowering serum testosterone levels accelerates age-related annual decreases in bone density and significantly increases the risk of osteoporosis [7]. Screening for preexisting osteoporosis in men with advanced prostate cancer allows for early detection of men at risk of vertebral and hip fractures and early institution of preventative measures [8]. Lessons learned from this subset of patients should also be applied to young, hypogonadal men.
In current urological practice, these men often present for care dealing with infertility or sexual dysfunction, and as such urologists are presented with an opportunity to address this often overlooked aspect of their care. Management of sexual dysfunction, infertility, and low testosterone is an integral part of urological training and practice. Urologists are in a unique position to identify men with hypogonadism early in life and assess their risk of hypogonadism and low bone mineral density—potentially monitoring and intervening before costly and morbid late life complications occur.
As the population ages, the prevalence of osteoporosis-related fractures is expected to increase dramatically [10]. Once a hip fracture occurs in men, the morbidity and mortality related to low bone mass are much higher than expected for women. Short term (in-hospital) and long term (one year) hip fracture related mortality are twice as high in men as is in women when correcting for socioeconomic status and age.
Thus the prevention of hip fractures and osteoporosis has a direct impact on reducing morbidity and mortality among men, and a magnified economic impact as well when compared to female counterparts [13]. This becomes a significant issue for medical economics and quality of life, as more than half of men with hip fractures suffer from chronic pain and require assistance walking six months after surgery. One third of these men have to be placed in long-term care facilities, which is known to negatively affect men’s self esteem, independence and overall quality of life [14]. Bone undergoes constant remodelling by two types of cells: osteoblasts and osteoclasts. Osteoblasts form new bone matrix and osteoclasts are responsible for resorption of the bone (Figure 1).
Bone has three different components: cellular, extracellular, and mineral.
Osteoblasts, osteoclasts, osteocytes, blood vessels and lymphatics constitute the cellular components of bone.
The extracellular compartment consists mainly of type I collagen and organic matrix. Type I collagen is suspended in matrix which has multiple different proteins such as albumin, osteopontin, fibronectin and collagen binding proteins. Those proteins are responsible for cell to cell interaction and signaling. Crystalline hydroxyapatite is deposited in the holes created between collagen fibrils and hydroxyapatite and is responsible for bone strength [15].
The adequate balance between cellular and mineral components in the bone is a prerequisite for functional mechanical integrity of and Figure 1. Bone structure, cellular elements, and major pathways of hormonal control in men. Osteoclasts start resorption of bone through signaling initiated by osteocytes (microfractures), or low calcium levels. With initiation of bone resorption, the opposite process of bone formation is carried out by osteoblasts.
Androgens stimulate chondrocytes proliferation and periostal bone formation stimulating long bone growth. Androgens produced in testis and adrenals are converted to estradiol through peripheral and local action of aromatase CYP19 and other enzymes.
Please see text for full explanation of interactions. Normal bone undergoes constant remodeling necessary for growth and repair of daily impact microfractures (daily wear and tear) [16].
Full bone mineralization can take up to 3 - 5 months and it is regulated by inhibitors of mineralization which undergo hydrolysis by alkaline phosphatase.
Since alkaline phosphatase is released by osteoblasts and released into ECS, it can be used to assess function of osteoblasts [17]. Mineralization of the bone changes the environment around osteoblasts and stimulates their transformation into osteocytes. Osteocytes serve as sensors of any damage or changes to normal bone structure.
Any damage to the bone or decreased mineralization is then signaled to osteoclasts and then to osteoblasts to initiate bone remodeling [18] . Osteoblasts control normal development of osteoclasts via macrophage colony stimulating factor and an array of cytokines. Both parathyroid hormone (PTH) and vitamin D (1.25 (OH)2D) increase osteoclast number and activity.
Osteoclasts lack the PTH receptor and require osteoblasts to release RANKL, which binds to RANK receptor in osteoclasts and stimulates their proliferation [19]. Estrogen decreases osteoclast number and activity through an indirect mechanism and thus prevents bone loss [20] . Resorption of mineralized bone is initiated by osteoclasts, which release the proton’s chloride into the extracellular space.
The proton pump ATPase lowers the pH and bone matrix loses its calcium; subsequently the organic matrix is digested through proteinases such as cathepsin K. At the same time 8 to 10 g of calcium are released from bone and pass through the kidneys [21]. The kidneys have a very tight mechanism of controlling of calcium secretion since the kidneys serve as a major regulator of calcium levels.
Most of the calcium is absorbed through the passive mechanism in the proximal tubules and re-absorption in the distal tubules is regulated through the PTH and vitamin D.
Despite this regulation, the intestines and skin have an inexorable daily calcium loss estimated to be approximately 200 mg per day.
Thus patients with low calcium intake cannot provide enough calcium to overcome obligatory losses despite normally functioning control of the calcium metabolism. The peak BMD depends on genetic background (family history), caloric and calcium intake, normal hormonal levels during childhood and adolescence [23] .
Therefore, problems affecting general health and nutrition during childhood will result in lower peak BMD (Figure 2). For example, a 20-year-old man with severe hypogonadism as a result of Kallmann syndrome will achieve lower peak BMD than his peers. Assuming similar rates of annual decline Figure 2. Normal bone density depends on close interactions between genetic, environmental, hormonal, and dietary factors. Although physiological loss of BMD begins around age of 50, any men with lower testosterone will suffer from accelerated annual BMD loss, since normal hormonal status is necessary to sustain normal mineralization. However, the molecular mechanism that conveys the action of testosterone and estradiol necessary for normal BMD in men and women as well as in different age groups is still debated and an area of intensive clinical and basic science research [27-29] .
In humans and most of animals regardless of sex, estrogens are derived from androgens through the action of aromatase CYP19 (Figure 1) [30,31] .
Thus, defects in steroidogenesis, inadequate aromatization or inactivation mutations in theEndoplasmic Reticulum will result in decrease in estradiol dependent gene expression [32]. This principal action of estradiol on bone metabolism is evident in men and mice with an inactivating mutation in the estrogen receptor or aromatase CYP19, who develop early onset osteoporosis [33].
Those observations strongly support the need for normal testosterone levels and adequate conversion of testosterone to estradiol to sustain normal BMD. It is important to note however that men with CYP19 deficiency show no effect on the axial growth of long bones, indicating that androgens specifically play a role in long bone growth [34] . In men, the periosteal deposition predominates, whereas in females the endocortical apposition predominates (Figure 1) [35]. Differences in length are directly related to timing of epiphyseal closure—an estradiol dependent event. In men the bones are longer because peak estradiol levels occur later than in women. After puberty, the sex-related bone dimorphism depends on the larger mass of the bone (especially in the bone cortex) in men as compared to women. Men have the greater total bone volume but volumetric density in men and bone mineral density (expressed per units of volume) are similar in men and women. The adrenals produce large amounts of DHEA, DHEAS, and androstenedione; these androgens can be converted to testosterone through activity of 17-?- hydroxysteroid dehydrogenase (17-?-HSD), 3-?-HSD, and steroids sulfatase [36] . It has been shown that the enzymes (aromatase CYP19, and 17-?–HSD) necessary for conversion of androgens to estrogens are localized in the bone, indicating that local conversion is necessary for normal bone structure [37] .


The importance of local conversion of androgens to estradiol may explain difficulties in linking the serum levels of sex steroids to the risk of osteoporosis in men [38,39] . Estrogens (through ER?) stimulate osteoblast proliferation and expression of cytokines, bone protein matrix, and transcription factors. Although ER? is expressed in osteoclasts of some species, ER? is expressed in osteoclasts of most studied animals and humans. Androgen receptor (AR) is expressed at higher levels in periosteal space in men, the area of most significant male bone growth [44]. Significant crosstalk between osteoblasts, osteoclasts, and macrophages exist, and this signaling is critical to sustaining normal bone metabolism. Testosterone treatment increases TGF-? levels in bone and orchiectomy decreases its expression [45]. Insulin-like growth factors are under modulatory effects of PTH and androgens.
Low androgen levels are associated with decreased levels of IGF and decreased growth velocity [46,47] . Interleukin-6 mediates osteoclastogenic activity and bone resorption in hypogonadism and testosterone replacement therapy suppresses IL-6 expression.
This supports the clinical observation that androgens are most responsible for periosteal bone growth— thus estrogens and androgens stimulate formation of new bone in different areas.
Through indirect effect on the osteoclast, estradiol decreases the osteoclast-driven resorption [49] .
In humans and rodents, it is known that estrogens have negative effect on osteoclasts related bone resorption, however it is not clear if estrogens have direct or indirect effect on osteoclast differentiation and mobilization.
Androgen receptor is specifically expressed in the growth plates and cartilages of males and females and its expression is especially high during puberty [44]. In experimental settings, the injection of testosterone into the bone growth plate results in significant proliferation and increase in size of the growth plate; this indicates that androgens together with growth hormone are responsible for linear bone growth acceleration seen during puberty. Through AR, androgens increase bone length and thickness during puberty; subsequent closure of epiphyses and cessation of growth is under the control of estrogen.
Treatment with aromatase inhibitor has decreased trabecular bone mass but has minimal effect on cortical bone area in intact male rats [30,51] . Selective estradiol receptor modulators (SERMs) increase cortical and trabecular bone mass in orchiectomized rats and increases trabecular bone mass in intact males [52,53] .
DHEA and androstenedione increase trabecular bone formation in ovariectomized rats.
Five ?-reductase inhibitors or androgen receptor antagonists have no or minimal effect on cortical bone area. This is important to remember when choosing medications to modulate hypothalamic-pituitary-testicular axis in men. Serum levels of testosterone using a standardized sample in proficiency testing may vary by 30% between different clinical laboratories [56,57] . This significant lack of accuracy may drastically affect the statistical analysis.
Estradiol is even more difficult to measure in men because its molar concentration is 5000 times lower than concentrations of testosterone and often estradiol levels measured in men reach the limits of reliable detection [58]. Hypogonadal men are therefore at significant risks for complications related to low bone mineral density.
Aging and genetic background have been considered main risk factors for low BMD in older men, however based on our experience and growing epidemiological data, it seems that low testosterone may be a leading cause of low BMD in younger men who present with infertility and erectile dysfunction [60]. Prolonged use of glucocorticosteroid (GCS), equivalent of 5 mg of prednisone daily for minimum of 6 months, is clearly associated with low testosterone and decrease in bone mineral density [61]. Preventative measures include normalization of testosterone level, vitamin D3 supplementation and bisphosphonates. These should be instituted early on in men who are on chronic GCS therapy. Common anticonvulsant therapy like phenytoin and phenobarbital increase hepatic metabolism of vitamin D, with subsequent decreased intestinal absorption of calcium. Calcium supplementation with vitamin D3 should be started early; if osteopenia is confirmed one can consider bisphosphonate or teriparatide therapy. Hypogonadism in men is strongly associated with increased risk of decreased bone mineral density.
Excessive alcohol use and tobacco smoking is associated with low BMD in both men and women.
Tobacco-related bone loss is most likely secondary to overall lower body mass; however direct effect on bone mineralization is possible. Alcohol consumption has a bell-response curve with low and high consumption associated with decreased BMD; moderate consumption may actually have a protective effect.
Effects of excessive alcohol use are often most related to poor nutrition status and decreased physical activity, although direct detrimental effect on osteoblasts has been shown as well [62,63]. Peak BMD is achieved during puberty and early adulthood; with aging, progressive changes in calcium intake, vitamin D levels, declining sex steroid production and exercise level causes loss in both trabecular and cortical bone. Presence of osteoporosis indicates increased risk of complications like hip, radius and spine fractures [64].
There is no commonly accepted guideline for screening for osteoporosis in younger men and it is likely that the screening of entire population of men is not cost-effective [66]. However, the literature regarding osteopenia and osteoporosis in men focuses exclusively on older men and not men of different ages.
One cannot generalize findings and recommendations from studies in older men to the population of younger men.
For example, the prevalence of osteoporosis in young men with low testosterone is quite high. The association between low levels of sex steroids and increased risk of osteoporosis is well established and thus screening in men should focus on at risk groups: men with history of minimal impact fractures of hip, vertebral bodies, or distal radius, men with hypogonadism, chronic steroid treatment and disorders listed as high and moderate risk in Table 1.
The most commonly used methods of screening for osteoporosis are dual-energy X-ray absorptiometry (DEXA scan), and quantitative ultrasound of the heel. The DEXA scan is approved for both men and women for screening for low BMD, as well as for monitoring therapy.
Ultrasound of the heel is not approved as a means of monitoring therapy in the United States. Although ultrasound-based equipment is easy to use and has no radiation exposure, the norms for younger men have not been established. Three measurements are commonly used and reported: absolute BMD, T score and Z score. The WHO defines osteopenia as a BMD expressed as Z or T score which is 1 SD below the mean BMD. Decrease in BMD by one standard deviation from mean increases risk of hip fracture by close to 3 times. The WHO definition and Z and T cutoffs have been adopted for diagnosis of osteoporosis among older men, but no large epidemiological data exist in men younger than 50, however based on increased risk of fractures in men with T scores below −2, it is commonly accepted that men with T score 5) Laboratory evaluation In our practice, men with low testosterone undergo DEXA scan and men who are found to have low bone mineral density undergo further laboratory evaluation to exclude other causes for low BMD. In general medical practice, screening for low BMD is usually offered to men older than 65 or may be offered to younger men if they have any risks factors.
The latter group should have sex steroids measured in addition to standard panel of laboratory tests.
The initial laboratory evaluation of men who have low BMD may include CBC, complete metabolic panel to assess renal and liver function, calcium, phosphorus, vitamin D, bone alkaline phosphatase, thyroid panel, parathyroid hormone level (PTH), estradiol level, 24-h urine calcium collection.
Low vitamin D is associated with elevated PTH; adequate supplementation over 3 months will usually correct elevated PTH. Cholecalciferol [D3) is an endogenous form of vitamin D, whereas ergocalciferol vitamin D2 is provided in commonly available preparations. Vitamins D3 and D2 can be reliably measured in serum and used to monitor adherence to therapy—especially in younger men who often forget about taking their medications. Formation of the bone may be measured using tartrate resistant acid phosphatase (TRAP), and products of collagen and protein matrix degradation: cross-linked N-telopeptide (NTx), C-telopeptide (CTx), deoxypyridinoline, pyridinoline, and hydroxyproline. Bone-specific alkaline phosphatase is elevated in osteoporosis, osteomalacia, Paget’s disease, and primary hyperparathyroidism. Testosterone replacement therapy doesn’t increase BMD in eugonadal men, which is often a reason of confusion about the role of testosterone replacement therapy in men with low BMD. In older hypogonadal men one needs to balance the risks and benefits of each form of therapy and limit testosterone treatment to men who are clearly hypogonadal. Considering that the estradiol level in both men and women has high predictive value for the bone mineral density, it is important to choose forms of therapy which do not lower available estradiol level. Vitamin D levels depend on normal synthesis in skin, oral intake, and normal gastrointestinal absorption. Weight bearing exercise and increase in lean body mass have a positive effect on circulating testosterone levels, and reduces risk of fractures by 25%. Moderate alcohol consumption and smoking cessation are important factors in preventing further BMD decline. Androgens Hypogonadism results in net negative trabecular bone mass loss which starts within days after orchiectomy. On average, men lose up to 10% of BMD in lumbar spine within 1 year after orchiectomy [72]. In vitro and in vivo animal studies have strongly supported the role of testosterone replacement in preventing post orchiectomy bone loss; adequate length of treatment may restore normal BMD.


Hypogonadism is metabolically similar to highturnover osteoporosis since the induction of osteoclasts and resorptive activity is followed by increase in bone formation; however in prolonged hypogonadal states the net result is progressive loss of bone mass. The lumbar spine, which is predominantly trabecular in structure, is affected first by hypogonadism [73]. Thus optimal androgen replacement should be potent, and aromatizable, and at the same time not converted to DHT to avoid prostate enlargement and side effects related to BPH. Therapy with testosterone is indicated in symptomatic men with hypogonadism [74].
Androgens have also non-direct skeletal effects which affect BMD.
The growth hormone (GH) axis, especially amplitude of GH release, is regulated by androgens. Decreases in IGF-1, and loss of muscle strength, decreases mechanical strain and contribute to decreased BMD. The increase in muscle mass seen during puberty enhances mechanical loading and stimulates skeletal modeling, which underscores the importance of exercise and normal testosterone levels during puberty.
Therapy with testosterone is only indicated in men with hypogonadism since improvement in BMD is inversely related to pretreatment testosterone levels [75,76] .
AndroGel pump allows for easy dosing in broad range of patients. AndroGel has optimal pharmacological properties and restores normal physiological levels of testosterone [77,78] .
AndroGel is also well tolerated by patients and devoid of the musk-like smell which is characteristic of Testim. Injectable testosterone (cypionate, enanthate) has been used successfully in men with hypogonadism and osteoporosis, but the surge in testosterone level for first couple days after injection has been linked to polycythemia, mood swings, and sodium retention and increase in blood pressure, thus side effects of injectable form of testosterone replacement need to be balanced against the benefits [77]. However, side effects of injectable testosterone are not found in every patient, and some patients may prefer an intermittent visit to their provider for an injection rather than daily dosage at home. Concerns about gel transfer to partners or children and the lower cost of IM (intra-muscular) testosterone may also influence a patient’s decision to use the injectable preparation. Androderm can also be considered for testosterone replacement but more than 1:10 men will develop skin irritation from the patch. In a study of 72 hypogonadal men treated up to 16 years with testosterone, all men achieved long term and sustainable increase in BMD, with most evident increase in men who had low initial BMD [75].
Lumbar spine and other trabecular bones respond better to TRT (testosterone replacement therapy) than cortical bones like hip [79]. The increase in lean body mass during TRT may have additional positive effect on bone mass in men.
This observation together with reports that delayed testosterone therapy in men with Klinefelter syndrome diminishes the gain in BMD may indicate that the adolescents with delayed puberty, IHH, Kallmann syndrome and Klinefelter syndrome may benefit from early assessment of BMD and early treatment of hypogonadism to achieve expected peak bone mineral density [81,82] . It is prudent for now to aim at achieving testosterone serum levels in high normal quartile [83] . The CBC, CMP, PSA, and lipids are checked before the initiation of therapy and during semiannual follow-up visits. The BMD is rechecked after 12 months of therapy and increase in BMD by 3% is considered a significant response. DHEA decreases IL-6 and thus may have mild positive effect in men after orchiectomy, but it is unknown if DHEA supplementation in younger men and identified low DHEA will have any positive effect on BMD.
Androstenedione supplementation has not been studied in clinical trials and thus can’t be recommended at this time. Selective Estrogen Receptors Modulators (SERMs) For men who are currently trying to conceive, testosterone is a poor option since it lowers FSH and LH. SERMs like clomiphene citrate may be a better option in younger group.
SERMs have positive antiresorptive properties by acting on ER receptors and increase in testosterone level stimulates bone formation. SERMs are being actively investigated as a promising method of treatment of osteoporosis in men with history of prostate cancer [87].
Clomiphene citrate increases FSH and LH, thus having positive effect on spermatogenesis, testosterone level and at the same time has a known positive effect on bone mass. Unfortunately, available studies were not long enough to measure changes in BMD using DEXA and biochemical markers of bone metabolism were used instead. A Basic understanding of the roles of ER and AR signaling in the bone physiology in men, make SERMs and AR modulators an exciting target for new therapeutic modalities in men with osteoporosis, although further studies must be done to evaluate their optimal roles in patients with low BMD [88]. Bisphosphonates In men who do not respond to androgen replacement therapy, or have recent history of prostate cancer and osteoporosis with T score Differences in the R2 functional group result in disruption of different pathways and R2 substitutions are responsible for differences in BSNs activity in vitro and in vivo. The structural properties of BSNs allow them to bind to the surface of calcium phosphate and inhibit growth and dissolution of mineral bone structure [93].
The long term binding and incorporation of BSN into calcium phosphate may be less desired property in younger men who have long life span ahead of them, since the long terms effects of BSNs on reproduction are poorly understood.
Some of bisphosphonates negatively affect male and female fertility and FDA labeling for Fosamax and Boniva lists decreased female fertility, implementation rate, increased preimplantation loss and prolonged parturition with treatment related deaths (see FDA approved drug insert). The negative effects on female fertility are believed to be secondary to decreased calcium levels.
Fosamax does not have a negative effect on male fertility but doses used in reported preapproval studies were similar to doses normally used in humans. Male rats treated with Boniva (at much higher dose than normally recommended >40?) for 28 days experienced decreased sperm density and sperm morphology (package information). Although doses used in animal experiments were higher than recommended does in men, at this point it is prudent to avoid bisphosphonates in younger men who are treated for infertility. Normal calcium metabolism is necessary for normal sperm activity and lowering the available calcium levels can have a negative impact on sperm function.
There are no published studies evaluating the effects of bisphosphonates on human reproduction.
Bisphosphonates have been shown to reduce bone loss, increase BMD in postmenopausal women and in hypogonadal men, as well as in glucocorticosteroid induced osteoporosis [94,95] .
Alendronate (Fosamax) is approved in USA for use in men and has been shown to increase BMD with a trend toward reduction of non-vertebral and vertebral fracture risk [96] .
Risedronate (Actonel] is often used in men with chronic steroid use and it has been shown to increase BMD in men as well [97,98] . Its use should be restricted to men with metastatic prostate cancer, and multiple myeloma when pamidronate is preferable as per Mayo Clinic consensus statement [99] .
Because of very long half life after binding to bone, risk of osteonecrosis of jaw and reported impairment of renal function zoledronic acid should not be used in men in reproductive age since the risks outweigh the potential benefits [99,100] . Both pamidronate and alendronate given orally can cause esophagitis erosions and ulcerations. Growth Hormone Prepubertal and pubertal bone growth depends on GH-IGF-1 system, as evident by short stature in children and adolescent with growth hormone deficiency. Deficiency in GH results in loss of cortical bone mass but preservation of trabecular bone, which depends more on estradiol action [102]. Androgens stimulate GH release through their aromatization to estrogens in brain. Low doses of estradiol stimulate GH and high estrogens level suppresses the GH release.
GH therapy is indicated in men with low IGF-1 levels; however the experience in GH therapy in men with osteoporosis is limited [103]. In one study daily subcutaneous injections of 20 mcg of Forteo increased BMD in lumbar spine by 5.9%, but inadequate data exist about reduction of hip and vertebral fractures in men with osteoporosis.
Teriparatide can be used for short time since it has significant and fast anabolic action, but once therapy is stopped therapy with bisphosphonates are recommended since further gains in BMD can be achieved.
This form of therapy needs to be closely monitored and is contraindicated in primary hyperparathyroidism, Paget’s disease of bone, osteomalacia, renal failure, nephrolithiasis, elevated calcium or alkaline levels. Long term use of thiazide diuretics can lower risks of hip fractures.
Experience in Our Practice In search of better guidance for the screening and treatment of low BMD in younger men, we have conducted studies at our own practice. The aim of this study was to analyze risk factors for osteopenia or osteoporosis in younger, ( 5.3. Methods This study was prospective, observational, IRB approved study.
Patients (n = 199) referred because of infertility (50%), hypogonadism (20%), sexual dysfunction (27%), or chronic pelvic pain (3%) were seen by a single physician. Serum testosterone was measured using liquid chromatography-mass spectrometry; LH, FSH, PRL, and estradiol were evaluated using chemiluminescence assays.
Bone mineral density (BMD) was measured using new generation Prodigy GE DEXA scanner with race, sex, and age adjusted normograms.



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