Background: Male hypogonadism can be defined as a disorder caused by decreased testosterone levels leading to low sperm count, multiorgan dysfunction and inadequate quality of life. Osteoporosis is defined as a debilitating condition which causes loss of bone mass and structure leading to considerable risk of fragility fracture and increased mortality. About 6% of men and 21% women between ages 50 to 84 years suffer from osteoporosis, changing the lives of 27.6 million males and females in the European Union (EU) in 2010. Osteoporosis is responsible for>8.9 million fractures yearly around the world, about 1000 cases an hour. The prevalence of osteoporosis increases as the population advances in age. Fracture risk increases in those with reduced bone mineral density(BMD) than those with osteoporosis.Although the risk of osteoporotic fracture is less in men than women however men are twice at risk of dying from the consequences of such fractures than women. World Health Organization (WHO) defined osteoporosis as a BMD of 2.5 standard deviation (SD) or more below the mean in young healthy female, with a T score of-2.5 or lower. The American college of physicians recommend early evaluation of men<65 years old who are at high risk of osteoporosis using Dual energy x-ray absorptiometry (DXA) scan.

Objective: The aim of this review is to conduct a systematic review of available literature to evaluate epidemiology and risk factors for osteoporosis in men. The focus of this work was to critically review evidence related to impact of hypogonadism on bone health in men.

Methods: A thorough search of different electronic databases was done including PubMed, google scholar, Cochrane database and FINDIT in the university of South Wales library and data collected.

Results: Some studies reported that only 4.5% men were treated for osteoporosis compared to 27% women. The annual death rate was 32% in men and 17% in women. In 1-5 years follow up, only 27% men were on any form of therapy while 71% women were on treatment. A study of 241 men who received 10mg of alendronate daily for 2 years compared to placebo showed a notable rise in BMD, and a notable decrease in fracture of the vertebra was documented with OR of 0.10, CI; 95%; 0.00-0.88. A study of 284 men treated with risedronate showed successful increase in BMD in contrast to placebo. Obesity is one of the most common causes of male hypogonadism, usually associated with normal or reduced follicle stimulating hormone (FSH), luteinizing hormone (LH) and low testosterone levels.

Conclusion: The burden of osteoporosis is severe and is shown in the increased level of disability and death in the affected patients and yet only a small number of men are given adequate treatment. Recognition and treatment of male hypogonadism and osteoporosis has received some attention lately, however, it remains under detected and under treated, much needs to be done in investigating for hypogonadism in men with fragility fractures.

Male hypogonadism; Testosterone; Osteoporosis; Aging men; Bone mineral density; Fragility fracture; Obesity

Male hypogonadism is a disorder caused by decreased testosterone levels leading to low sperm count, multiorgan dysfunction and inadequate quality of life [1]. Osteoporosis is a debilitating condition which causes loss of bone mass and structure leading to considerable risk of fragility fracture and increased mortality[2]. Historically, osteoporosis has been regarded as primarily a disease of post-menopausal women, as bone mass loss is relatively rapid after menopause due to reduced estrogen levels.

In contrast, the presence of osteoporosis in men is still under-recognized and inadequately treated. However, in recent years the high incidence of fragility fracture in men has highlighted the importance of prompt recognition of osteoporosis in men to reduce associated morbidity. A predicted 30% of all hip fractures occur in men. Approximately 1 in 5 men>50 years old will suffer fragility fracture in their lifetime [3].

The guidelines of the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA,2020) statement was used in conducting this systematic review. This is summarized in Figure 1 [4].

Data collection was done through a thorough search of various electronic databases; Cochrane database, PubMed, Google scholar and FINDIT in the university of South Wales library for relevant articles. The population, Intervention, Comparison and Outcome (PICO), question was used.

Is the risk of osteoporosis increased in aging men>50 years old with hypogonadism?

Does exposure to risk factors like glucocorticoid use, excess alcohol consumption, obesity and hypogonadism increase the incidence of osteoporosis.

How prevalent is male osteoporosis and what percentage is caused by hypogonadism?What is the effect of obesity on development of hypogonadism?

What is the effect of hypogonadism on bone mineral density and the development of osteoporosis in men?

Can early detection, diagnosis, and treatment of hypogonadism, including testosterone replacement therapy (TRT) prevent bone loss or improve bone mineral density (BMD), prevent osteoporosis, fragility fracture, associated disability, and death[5].

PRISMA flow diagram of Database search for male hypogonadism and osteoporosis Figure 1 [4].

Figure 1: PRISMA flow diagram of Database search for male hypogonadism and osteoporosis[4].

Search

The search terms were different combinations of male hypogonadism, osteoporosis in men, fragility fractures, BMD, obesity, body mass index (BMI), age, above 50 years, aging men, DXA, testosterone, oestrogen, TRT, and bisphosphonate.

Study selection

Articles involving male patients over 50 years old with hypogonadism, osteoporosis, and fragility fracture and written in English language only were selected.After reading titles and abstracts, the full texts of the relevant articles which met the inclusion criteria were retrieved Table 1.

Table 1: More details on inclusion and exclusion criteria are shown in the table. ADT: Androgen Deprivation Therapy, BMD: Bone Mineral Density, RCT: Randomized controlled trials, TRTs: Testosterone replacement therapy

Risk of bias

The included articles were evaluated for the risk of bias, quality of evidence was assessed using Grading of Recommendations, Assessment, Development and Evaluations, (GRADE).The articles were assessed for selection bias, flawed study design, confounding bias, observer, and publication bias.

Flawed study design

Some of the articles did not state the study design and objective, this can be avoided by clearly defining the study design and objective.The non RCTs lacked random allocation of subjects.Small sample size in some.The duration of follow was short in some but did not seem to affect the outcome much.

Selection bias

Most participants were selected from the same group with similar conditions. The risk of bias was rated low in most.

About 6% men and 21% women between 50 to 84 years of age suffer from osteoporosis, altering the lives of 27.6 million men and women in the European Union (EU) in 2010. Osteoporosis is responsible for>8.9 million fractures yearly around the world. About 1000 cases/hour. There are increased rates of fracture in the western world compared to the rest of the world. Although the population of Europe is lower, but about 1/3rd of all cases of osteoporosis are seen there [6].

About 1-2 million men in the United States of America (USA) have osteoporosis and an extra 8-13 million have decreased BMD. The risk of fractures rises with age in both men and women. Men tend to suffer osteoporotic fracture 10 years later than women.

Approximately 13% of white American men>50 years of age will suffer fragility fracture in their lifetime. Hip fracture is the most severe adverse outcome of osteoporosis with increased risk of death in men than in women. Men are twice at risk of dying from complications of hip fracture while in hospital than women [7].

According to some studies about 50% of osteoporosis was due to secondary causes and 16-30% of secondary causes were because of hypogonadism. Men tend to have greater peak bone mass compared to women; therefore, this gives men the advantage and decrease their risk of having fracture[5].The prevalence of osteoporosis increases as the population advances in age. Fracture risk increases in those with reduced BMD and most fractures happen in patients with reduced bone mass than those with osteoporosis [8,9].

Men>55 years old are at risk of bone loss due to advancing age, just as seen in females, and this progresses for the rest of their lives. The persistent bone density loss affects mostly the bones of the hip, and vertebrae leading to high rate of osteoporotic fractures[10].

Male hypogonadism is associated with loss of bone mass but not strictly related to the levels of testosterone. Estrogens levels is not usually considered in men on bone quality; however, bioactive estrogen level is said to be strongly related to sustaining bone mass. Bone loss is said to increase in the state of hypogonadism, this is noted especially in postmenopausal women [5]. Obesity is regarded as the most common cause of hypogonadism in men. The pathophysiology of hypogonadism related to obesity is linked to high aromatase action in the fat tissue [1].

About 1 to 2% of serum testosterone is free in the circulation as bioavailable testosterone, while 98 to 99% is bound to albumin and SHBG. Approximately 40 to 50% is bound to albumin and about 50 to 60% to SHBG. The enzyme, 5 alpha reductase converts testosterone to dihydrotestosterone (DHT) which binds forcefully to androgen receptor or gets aromatized to estrogen. About 20% of DHT in the blood is secreted by the testes, while 80% is produced by testosterone conversion in the peripheral tissues [11]. Men who are at greater risk for osteoporotic fractures are those undergoing treatment for prostate cancer using androgen deprivation treatment, those who suffered osteoporotic fracture in the past, and those taking glucocorticoids orally [12]. Testosterone and estrogen levels tend to decrease gradually in men of advancing age but in women estrogen level decreases rapidly during menopause resulting to increase loss of bone mass. Men tend to lose trabecular bone from 40 years of age but not as rapid as seen in women, it is gradual therefore, bone loss in men is noted as thinning of trabecular unlike in women where there is trabecular loss [7,3]. Primary osteoporosis is usually caused by advancing age or idiopathic, while secondary osteoporosis is caused by alcohol abuse, oral glucocorticoid treatment, and hypogonadism. The part played by sex hormones in development of osteoporosis are particularly important.About 85% of estrogen in the blood is from aromatization of testosterone in the peripheral tissue. Sex hormone binding globulin (SHBG) level rises with advancing age resulting in the need to assess testosterone and estrogen levels.It is well known that the rate of BMD loss depends more on estrogen levels rather than testosterone. Also rise in bone turnover is said to be inhibited by estrogen in aging men rather than testosterone. Parathyroid hormone (PTH) is another cause of bone loss in men of advancing age, partly due to deficiency of vitamin D, growth hormone and insulin like growth factor (IGF-1) [3].

Osteoporosis according to WHO, is a BMD of 2.5 standard deviation (SD) or more below the mean in young healthy female, with a T-score of less than-2.5 SD Table 2 [13].

Table 2: Definition of osteoporosis using BMD according to WHO [8].

BMD at 1 SD of the reference value for a young healthy female adult with a T score of-1.0 is considered normal.A BMD of more than 1.0 but less than 2.5 SD lower than the mean for a healthy young adult female with a T score of less than-1.0 but more than-2.5 is considered osteopenia. Osteoporosis is regarded as a BMD of 2.5 SD or more lower than the mean value for healthy young adult female with a T score of equal to or less than-2.5. Severe or confirmed osteoporosis is a BMD of 2.5 SD or more, lower than the mean for a healthyyoung female adult with 1 or more fractures present Table 2 [8,13].

Risks factors for evaluation of osteoporotic fracture

The etiology of male osteoporosis is like those of females. Endocrinological etiologies such as hypogonadism remain important and often preventable contributory factor for secondary osteoporosis in men.Some of the risk factors include age, gender, smoking, alcohol abuse, family history of fracture or osteoporosis, BMD at the neck of femur, sedentary lifestyle, decreased body mass index (BMI), secondary osteoporosis, previous osteoporotic fracture, rheumatoid arthritis, prolonged use of glucocorticoid leading to decreased bone density, gastrointestinal disorders, deficiency of vitamin D, and use of anticonvulsant treatment. Also, ADT for prostate cancer, diabetes, lifestyle alterations and lack of physical activity Table 3 [7,10,12-14,].

Clinical manifestations of hypogonadism include low libido, loss of muscle mass and low energy, erectile dysfunction, reduced bone density, osteoporosis, elevated level of fat tissue, fatigue, and depression. Hypogonadism is often connected with other medical diseases like osteoporosis, type 2 diabetes, obesity, high blood pressure, and metabolic syndrome[11].

Table 3: Summarizes the risk factors as well as the signs and symptoms of both male hypogonadism and osteoporosis. COPD: Chronic obstructive pulmonary disease, IBD: Inflammatory bowel disease, HIV: Human immune deficiency virus, AIDS: Acquired immunodeficiency syndrome, PPIs: Proton pump inhibitors [7,9,11-14].

Effect of Exposure to risk factors including lifestyle on incidence of osteoporosis

Exposure to risk factors like glucocorticoids can cause osteoporosis. Osteoporosis caused by glucocorticoids is one of the major osteoporosis caused by medical treatment. It is significant because the elevated fracture risk due to glucocorticoid taken orally can be observed within three months of starting treatment with prednisolone 2.5mg or 5mg according to study conducted in a primary care setting in United Kingdom (UK). Another study even reported of elevated risk of fracture after 1 month of taking glucocorticoids orally. Glucocorticoids are used by many physicians in the treatment of chronic obstructive pulmonary disease (COPD), and rheumatoid arthritis [15].

The most common causes of secondary osteoporosis include hypogonadism, as study has shown that about 66% of elderly men with hip fractures, had hormone levels less than normal. Tobacco smoking is one of the most common causes of osteoporosis. Smoking is said to cause decreased BMD thereby increasing the risk of low trauma fracture. Smoking is said to be prevalent in the Spanish community among individual above 65 years old. Alcohol consumption is among toxic substances which affects BMD. It is said to be endemic in Spanish community among the males. Study conducted in the Spanish community on individuals>55 years old reported a high percentage of 16.7% men who drink heavily compared to just 0.7% of women [16].

The consumption of about 29g of alcohol daily was associated with BMD loss in the trochanter region. Moderate alcohol consumption is always advised while smoking cessation is recommended, to prevent bone loss [9]. Adult hypogonadism is recognized as a major cause of bone mineral density loss resulting to secondary osteoporosis in men [5]. The impact of exposure to risk factors on development of osteoporosis cannot be over emphasized, patient education and counselling regarding this is of paramount importance.

Age, and prevalence of male hypogonadism & osteoporosis

Male osteoporosis prevalence rises steadily and is stringently associated with advancing age and is linked to different diseases. Many of the patients attending routine clinic for other conditions like diabetes mellitus type 2, obesity, metabolic syndrome, osteoporosis, and hypertension, may have hypogonadism, so it is important that primary care physicians become aware of the prevalence of hypogonadism and be better equipped to recognize the symptoms which include, loss of bone mass, decreased libido, BMI, fatigue, erectile dysfunction, and depression and treat them appropriately. Study showed that as men advance in age their risk of osteoporosis increases due to loss of bone mass and due to decreased testosterone levels leading to hypogonadism [11].

BMD distribution is normal in the healthy younger community, while bone density loss is seen in the aging population. Prolonged life expectancy makes men prone to varying degrees of hypogonadism with consequent bone density loss which may eventually result to osteoporosis. Osteoporosis prevalence in males of the EU above 50 years was reported as 6.6% while females of the same age group was 22.1%[9]. It is expected that hypogonadism will impact about 2.1 to 12.8% of men in the society and the prevalence will rise to about 6.5 million by the year 2025 among those advanced in age [1].1 in 5 men and 1 in 3 women above 50 years old around the world will experience osteoporotic fracture in their lifetime. Hip fracture incidence rises after 75 years of age. The one-year mortality and requirement for hospitalization is usually increased following a hip fracture in males compared to females, however, men are most unlikely to undergo further assessment or management for any fundamental osteoporotic condition [6,3]. About 6% of males and 21% females between ages 50 to 84 years suffer from osteoporosis changing the lives of 27.6 million males and females in the EU in 2010 [6]. The risk of osteoporotic fracture in men>50 years of age associated with advancing age is 13-24% according to the Canadian Multicenter Osteoporosis Study (CaMos) [17]. Certain studies conducted in Sweden which assessed bone mineral density in the neck of the femur in males and females using DXA scan, found increased occurrence of osteoporosis in men between 70-85 years old [16]. A study conducted in Italy, showed that in men above age 50 years, the prevalence of osteopenia was 37% and osteoporosis was 6%, between the year 1995 to 2005 [2].

Approximately 13% of white males in the USA>50 years old will sustain a minimum of one fragility fracture during their life. The most severe complication of osteoporosis is hip fracture and leads to increased death rate in men than women. Men are said to be twice more likely to die at hospital after fracture of the hip than women [7].

WHO put together some facts from various epidemiological research on osteoporosis prevalence among men and women worldwide. They obtained data from European Vertebral Osteoporosis Study, (EVOS) (European), CaMos, Dubbo (Australia), Rochester (USA), Rotterdam study (Netherlands), and Hiroshima (Japan). The combined estimate of male osteoporosis prevalence was decreased in those<70 years but increased notably to 22.6% in the elderly above 90 years old. A comparable evaluation of osteoporosis prevalence in women showed a higher incidence for all ages and involving those<70. This is summarized in Table 4 [5]. The rising trend of osteoporosis and hypogonadism in aging men cannot be denied. Early detection of men at risk is necessary to reduce complications.

Table 4: Osteoporosis prevalence in males and females by age [5].

The possibility of a man of about 50 years old, sustaining a fragility fracture is predicted to be 13% while in females it is approximately 40%, and 25% in a male of about 80 years of age. The chances of a male experiencing osteoporotic fracture of his vertebrae is half of that seen in females. A cross sectional radiological discovery indicated that about 1/3rd of men>65 years old had experienced osteoporotic fracture [14].

Hypogonadism prevalence

Hypogonadism is prevalent in men of advancing age. As men are living longer these days, there is a prediction of rise in prevalence of hypogonadism in the elderly men. The Baltimore Longitudinal Study on Ageing discovered that 19% of men>60years of age had decreased testosterone levels. In this study there was an increase in the percentage of men with decreased testosterone from 12% in those around 50 years old to 49% in those>80 years old.

The hypogonadism in males (HIM) study evaluated the total hypogonadism prevalence at about 39% in men of 45 years and above. The HIM study estimated the prevalence of testosterone deficiency at 34% in men of ages between 45 and 54%, and at 50% in men>85 years old.It was assessed that only about 5 to 35% of men with hypogonadism are given treatment for the disease. There has been a notable difference between the measurement of testosterone levels and the measurement of symptoms of hypogonadism since a patient can have decreased testosterone levels but not necessarily have symptoms. Also measuring the symptoms of hypogonadism alone is unreliable since the symptoms are not specific. The Massachusetts Male Ageing Study (MMAS) assessed both the level of testosterone and the symptoms of hypogonadism and discovered that 6 to 12% of men with decreased androgen levels had symptoms. It was noted that about half of the men who had symptoms of low androgen levels at one time, had normal androgen levels when the test was repeated later, this was attributed to the existence of possible individual differences in the level of testosterone produced and at what point symptoms appear [11].

The different sites of osteoporotic fracture and the number in males and females>50 years old in the year 2000 according to WHO region Table 5 [6].

Primary hypogonadism

Primary hypogonadismis a gonadal dysfunction affecting the testicles in men leading to reduced testosterone production. It is also called hypergonadotropic hypogonadism because the LH and FSH levels are usually elevated.

Secondary hypogonadism

Secondary hypogonadism is attributed to dysfunction of the hypothalamic pituitary gonadal axis (HPGA), caused by inadequate Leydig cell stimulation. The LH and FSH may be decreased or normal therefore it is also called hypogonadotropic hypogonadism. The gradual decrease in the androgen levels affecting the total and bioavailable testosterone in the blood in men leads to bone loss and consequent osteoporosis [11].

Burden of male osteoporosis on health and economy

The impact of osteoporosis on the general population is quite severe due to occurrence of osteoporotic fractures resulting to major health and economic hazard on the patient as well as the society. Osteoporotic fractures tend to occur at the hip, vertebrae, and the wrist, but can occur also in the ribs, humerus, and pelvis.

Table 5: The western pacific region includes Australia, New Zealand, Japan, China, Republic of Korea[6].

They all cause tremendous health challenge; however, hip fracture tends to produce worst complications. Fracture of the hip most often lead to hospital admission and prolonged hospital stay or frequent hospital visits and may eventually lead to death in about 20% of patients, and prolonged disability in about 50% of patients. Just about 30% recover completely. It is necessary to recognize that Male osteoporosis is more common than we think [18-20]. Osteoporosis is a major cause of fractures and disability inpeople. Osteoporotic fracture is responsible for 2.8 million disability adjusted life years (DALYs) in Europe and America yearly, surpassing HTN and rheumatoid arthritis but less than DM and COPD. Osteoporotic fractures account for~1% of Daly’s related to non-communicable diseases. It was predicted that osteoporotic fracture occurrence will rise above 3-fold in the next 50 years among men and women because of advancing age, mostly in Latin America and Asia [13]. Approximately 740,000 deaths each year are connected to fracture of the hip. Osteoporotic fractures are responsible for 0.83% of non-communicable disease burden around the world, in Europe they account for 1.75% and are connected to DALYs than several chronic non-communicable diseases. A study conducted by the General Practice research Database (GPRD), which comprised of 6% of the population of the UK in 1993, showed that hip fracture risk among people of 50 years of age in the UK was 11.4% for women and 3.1% for men in their lifetime. Majority of the high fracture risk occurred in advancing age, for instance, a 10year hip fracture risk in a 50-year-old woman is estimated at 0.3% but increases to 8.7% by age 80 years. In men the 10year hip fracture risk is 0.2% at age 50 years but increases to 2.9% at age 80 years. The burden of osteoporosis in the USA was evaluated at ten million among those above 50 years old with a yearly incidence of osteoporotic fracture estimated at 1.5 million among the affected people. An extra 34 million Americans are said to be at risk of osteoporosis. [18].The burden of osteoporosis is shown in the increased level of disability and death in women and men and yet only a small number of men are given antiresorptive

therapy [10]. Rochester cohort studies demonstrated that 5 years survival rate following fractures of the hip and spine was about 80% of that predicted for men and women of the same age who did not suffer fracture. Death rate related to fracture of the hip rises with age and is more in men compared to women and worse in those with comorbidities.

In USA about 31,000 extra deaths happen in six months of almost 300,000 cases of hip fractures annually. In the UK, the survival rate 2 months following fracture of the hip is 63.3% in men compared to 90% predicted, while in women it is 74.9% compared to 91.1% predicted. The reported survival rate 12 months following fracture of the spine was 86.5% compared to predicted 93.6%, the survival rate reduced to 56.5% at 5 years in contrast to 69.9% predicted according to the UK GPRD study. The Dubbo study showed the standardized age adjusted mortality ratio to be 1.82 in women and 2.12 in men after fracture of the vertebra. The mortality rate related to radius/ulna fractures were not high apart from older men in which a mild increase in deaths was noted.

Table 6: The effect of osteoporosis associated fractures in the UK. Reproduced with permission from Cooper, C. Epidemiology of osteoporosis. Approximately UK£1.7 billion, combined cost for all sites [18].

Some of those who survive after osteoporotic fracture will have notable disability. About7% of those who survive will have some sort of permanent disability in the USA, about 8%will need prolonged care in an institution. [18].

The burden of osteoporosis and associated fracture is tremendous on the sufferer Health wise, financially and socially, affecting the daily activity of living. This is summarized on Table 6. Early diagnosis and treatment remain the key to alleviating this burden.

In the UK it was predicted that the incidence of hip fracture would increase from 70,000 annually in 2006 to 91,500 in 2015 to 101,000 in2020. The cost of osteoporotic fractures in the healthcare services of the UK was predicted to be 1.8 billion pounds in the year 2000, with apossible rise to 2.2 billion pounds by the year 2025 and mostly associated with fracture of the hip[20]. It was documented that hip fracture caused 34.8 billion US dollars around the world in 1990 and the cost is estimated to rise in the next fifty years, due to increasing life expectancy.

More increase is expected in the developing countries due to the adoption of western lifestyle by these countries which increases their risk of fracture. The effect of hip fracture in Europe in previous years is summarized in [figure 2]. It is important to device some methods to prevent fracture occurrence in those at risk. [18].

Figure 2: Secular trends for hip fracture in Europe [18].

Obesity, metabolic syndrome, and hypogonadism in men

Obesity is regarded as the most common cause of hypogonadism in men. The rise in life expectancy and obesity prevalence in the western world, has led to increased cases of hypogonadism in men [1]. The effect of obesity on hypogonadism can be best explained because of its impact on the quality of sleep. It has been shown through study that obstructive sleep apnea (OSA) linked to obesity disturbs the gonadal axis and hinders LH secretion during the night thereby affecting the level of testosterone.

OSA is said to be separately connected to low levels of LH pulse range, low mean LH in the blood, the level of testosterone and the inhibition of the blood testosterone levels connected to the initial rapid eye movement (REM) sleep. There are increased levels of leptin in the circulation of men with OSA, despite their age or BMI. Also, the association between sleep and obesity appears to go both ways. Sleepless night has been lately associated with elevated risk for becoming overweight with its associated adverse outcome. Not with standing that the precise process is not clear but it seems to be caused by changes in the level of various neuroendocrine regulators comprising of leptin and cortisol. Some other studies however, noted that OSA does not cause hypogonadism in non-obese individuals.

Most testosterone in circulation is bound to albumin or SHBG while approximately 1 to 3% are free testosterone. Any alteration in the level of SHBG will severely influence testosterone interpretation. Obesity is associated with SHBG level in a negative way thereby affecting testosterone concentrations in the blood. In men who are moderately overweight there are often “falsely” reduced total testosterone (TT) levels with normal free testosterone (FT).SHBG is produced by the liver and attaches to testosterone with great affinity by so doing it controls its bioavailability.

It was commonly suggested that the connection between obesity and SHBG was regulated by insulin resistance and consequent compensation by excess insulin in the blood that inhibits secretion of SHBG by the liver. However, in recent times it has been demonstrated that it is liver fat and not total body fat or visceral fat that affects SHBG and liver fat is deemed responsible for decreased levels of SHBG. Decreased levels of SHBG levels permit increased levels of free testosterone for aromatization to estrogen in the fat tissue. The level of SHBG should be taken into consideration in the diagnosis of hypogonadism because of the influence of obesity in decreasing the level of SHBG in the circulation [1]. Adult male obesity was said to have a prevalence rate of 33.3% between 2005 and 2006 as reported by the review of National Health and Nutrition Examination Survey (NHANES). Obesity is related to decreased total testosterone and low sex hormone binding globulin (SHBG) levels. Total testosterone is said to be inversely related to BMI and free testosterone levels reduce as BMI rises.

Total testosterone in the blood is said to be inversely related to free testosterone and fat in the visceral tissue, therefore the level of hypogonadism positively associated with the level of obesity in the men.

Testosterone levels are said to be associated with components of metabolic syndrome; therefore, hypogonadism is said to be related to metabolic syndrome according to some studies in epidemiology. Metabolic syndrome means the existence of truncal obesity, together with any two out of four other conditions like high blood pressure of130/85mmHg, low HDL of less than 40mg/dl, high triglycerides of 150mg/dl or above, or high blood glucose of 100 mg/dl or above. Some epidemiological and interventional studies showed that decreased testosterone levels are associated with insulin resistance, which is said to be caused by testosterone action on adipose tissue. Reduced testosterone levels cause rise in adipose tissue and reduce lean muscle leading to rise in fat tissue [11].

A cross sectional study involving men with body mass index between the normal range to severely overweight, showed that leptin in the blood was intricately linked to decreased testosterone levels and negatively correlated to the response of the testicles to the activation by HCG.

Leptin functions to encourage feeling of fullness and raises the amount of energy consumed but men who are obese tend to be resistant to leptin. The amount of leptin in the circulation is positively associated with the entire weight of the body and amount of fat tissue. In physiological state, leptin stimulates GnRH release through its action on kisspeptin. Obesity is connected to leptin resistance and inhibits gene expression kisspeptin at the hypothalamic level.

A randomized controlled trial (RCT) documented that testosterone therapy decreased the concentration of leptin regardless of alterations in the mass of adipose tissue. In male obesity it is suggested that leptin resistance at the hypothalamic level in addition to the maintained sensitivity of the testicle to the inhibition of leptin could be responsible for the suppression of HPT axis. Also, it is stated that testosterone therapy reduces the level of leptin in the circulation, however, previous RCTs did not provide for alterations in body composition by testosterone therapy [21]. Obese men as well as diabetic men should be screened for hypogonadism which can lead to decreased BMD and osteoporosis in men.

Impact of testosterone and estrogen levels on BMD

Adult hypogonadism is recognized as a major cause of bone mineral density loss resulting to secondary osteoporosis in men [5]. The exact function of testosterone on sustenance of bone quality and the effect of reduced levels in the onset of osteoporosis is not well understood, but one of the major observational clinical trial, the osteoporotic fractures in men study (MrOS), carried out on thousands of men above 65 years of age, in different countries, namely Sweden, United States of America (USA) and Hong Kong over a mean period of 4½ years, showed that free testosterone was positively associated with BMD of the hip, arm, and femur, without involvement of the lumbar vertebrae. Decreased bioactive testosterone levels is associated with considerable risk of fractures. More information through multivariate assessment showed that estrogen levels are positively associated with BMD on all sites inclusive of the lumbar region. It was also noted that bioactive estrogen (BioE2) alone and sex hormone binding globulin (SHBG) not including testosterone were separately related to risk of fracture. The Sweden cohort of the MrOS in their first data analysis reported that bioactive testosterone (BioT) was associated with BMD in the femur, hip, and arm but not in the lumbar vertebrae. Decreased BioT levels were positively associated with elevated risk of fracture. Levels of estrogen were positively associated with BMD in all areas including the lumbar vertebrae.

Further evaluation of the Swedish cohort with multivariate assessment reported that BioE2 alone and sex hormone binding globular (SHBG) were related to fracture risk and not testosterone. The Hong Kong cohort of MrOS study, reported that BioE2 alone was notably related to BMD, while BioT and SHBG levels did not have significant association with BMD. None of testosterone or estrogen could predict the risk of fracture however, decreased levels of T and E2 resulted in elevated risk of fractures showing that both hormones were involved. The United States cohort of the MrOS study which involved men>65years had slightly different report compared to the Hong Kong and the Swedish cohorts. Estrogen levels produced notable associations with BMD and not testosterone levels.

The lowest bioavailable estrogen levels showed the most BMD loss.Men with decreased levels of free testosterone and estrogen in addition to increased levels of SHBG were found to have the greatest risk of osteoporotic fracture.SHBG was associated negatively with BMD depicting the amount of BioT available, since SHBG is the main link with testosterone [5]. Previously BMD was associated with androgens from the testes in males and with estrogen in females, but in recent years it has been noted that bone tissues can produce both androgens and estrogen has important part to play in men as well as in women BMD. The rapid decrease of bone mass and BMD seen in postmenopausal women does not happen in men, rather the blood testosterone level decreases gradually in men of advancing age leading to late onset hypogonadism (LOH).About 30 to 50 mcg of estradiol are made from aromatization of testosterone daily. Approximately 5 to 10 mcg (10 to 20%) are produced in the testes, while the remaining 40 to 45 mcg (80 to 90%) of estradiol are from testosterone conversion in the peripheral tissues.Male hypogonadism is often linked to reduced BMD and is the most common cause of secondary osteoporosis in young adult males.Partial decline in androgen levels in the elderly males is said to be responsible for age associated osteoporosis in men, therefore a slight to serious reduction in androgen levels in men of advancing age could result to bone loss [2].

The Framingham cohort

The Framingham cohort subgroup evaluated the risk of fractures in hypogonadal men with blood testosterone levels<3ng/mL and compared them with men who were eugonadal and found out that men with the most elevated estrogen levels also had the most elevated bone mineral density, while those men with the least level of estrogen were at the greatest risk of developing fracture of the hip.

The study did not find any variation between risk of hip fracture or BMD in men with hypogonadism in contrast to men who were eugonadal, which indicates that testosterone levels have no notable part in the quality of bone but rather estrogen. This finding of no role of testosterone in bone health is quite controversial as some other studies like the Dubbo study of Australian men above 60 years of age reported an association between reduced testosterone levels and the occurrence of osteoporosis in men [5].

Diagnostic investigations

Diagnosis is done through detailed history, physical examination, and dual energy x ray absorptiometry (DXA) of the hip and spine. Evaluating absolute fracture risk with tools like fracture risk assessment (FRAX) and Canadian association of radiologists and osteoporosis Canada (CAROC) are helpful to predict the impact of therapeutic decisions for osteoporosis [2,3]. There is no specific blood test for osteoporosis, however, some basic blood investigations can be done to assist with diagnosis and treatment plan, like blood levels of calcium, 25 hydroxyvitamin D, alkaline phosphatase as a marker of bone turnover, kidney function tests to assess safety of using some medication, albumin levels, hematocrit through complete blood count (CBC), thyroid function tests (TFTs), parathyroid hormone (PTH) and 24-hour urinary calcium [15].Early diagnosis and commencement of treatment is the key to preventing complications like fragility fractures and improving patients’ life quality. [19].

QFracture are the main tools recommended in the UK

National Institute for Health and Care Excellence (NICE) guidance recommends the evaluation of men 70 years and above for the risk of osteoporotic fracture and those<70 years with previous history of fragility fracture, smoking and other risk factors listed above, using FRAX, or QFracture according to age range, to assess 10year predicted fracture risk. There is a lack of consensus in the fracture risk measurement using bone mineral density (BMD), e.g., NICE guidance does not recommend routine use of BMD measurement without first using FRAX or Q Fracture. BMD screening in men should be done using dual X ray absorptiometry (DXA) [20].It is recommended by the American society of endocrinology that BMD should be assessed in men of 70 years old and above and in men of 50 to 69 years old who are at risk. FRAX tool is said to be effective in predicting 10-year fracture risk in the hip and other sites. FRAX is also beneficial in deciding treatment plan for each patient.

The recommendation of the national osteoporosis foundation (NOF) is to treat patients with fracture of the vertebrae who are>50 years old, those with BMD<2.5 SD, and those with BMD between-2.5 and-1 SD depending on the 10 years fracture risk evaluation [16].Men with hip fracture are said to require hospitalization more often than females but are unlikely to be treated or further investigated for underlying osteoporosis. Fractures of the vertebrae are usually asymptomatic and are often ignored on X ray. It is necessary to recognize vertebral fractures because their existence is indicative of possible fragility fractures elsewhere which can cause high mortality[3].

The most generally approved assessment tool for BMD measurement is DXA used at different sites of biological importance like the hip, vertebra, and forearm. DXA measures BMD at the appropriate sites which predicts high risk of fracture with 1.5/SD reduction in BMD called the “gradient of risk.” DXA shows the highest gradient of risk of~2.6/SD at the neck of femur for prediction of fracture of the hip.

The worldwide established guide for describing osteoporosis in men above 50 years of age and postmenopausal women is the BMD at the neck of femur of 2.5 SD or high below that of a young adult female [13]. Osteoporosis in men is still underestimated and underdiagnosed. A man of 50 years has a 13 to 25% risk of sustaining osteoporotic fracture in his lifetime. DXA is useful in assessing men at increased risk of osteoporotic fracture including men of 80 years of age, those on glucocorticoid treatment or ADT.Detecting and treating those at increased risk will reduce the incidence of fragility fracture and mortality rate [15,22]. Clinical assessment of hypogonadism in older men should be done using bioavailable estrogen and testosterone in combination with SHBG [9]. Evaluation of decreased blood testosterone levels plus symptoms are necessary to diagnose hypogonadism [11]. The goal of the Hippisley-Cox 2009 study was to show and internally confirm the risk assessment tool, QFracture. It evaluated the facts gathered in the QResearch record, being a large primary care electronic database for England and Wales. Approximately 2 million individuals were involved in the evaluation from ages 30 to 85 years, without prior documented fracture and were allocated to one or the other dataset, 67% to derivation cohort and 33% to validation cohort, respectively Figure 3 [23].

Figure 3: The figure shows the number of incident cases of main osteoporotic fractures in males by age[23].

It is obvious that the current diagnostic tools are effective the problem is putting them into use and on time. The ability to detect fragility fracture in men appearing at the clinic for some routine chronic disease appointment and investigating them is crucial.

Treatment of male hypogonadism

Management of hypogonadism include testosterone treatment which could be in the form of intramuscular injections, transdermal gels or patches, subcutaneous pellets, or buccal patches. These are effective in normalizing blood testosterone levels and symptom alleviation. Testosterone therapy is not recommended for patients undergoing treatment for prostate cancer or benign prostatic hyperplasia (BPH).

Testosterone treatment is considered by some healthcare practitioners as risky due to adverse effects, however, in some cases the benefit may outweigh the side effects. Treatment benefits and adverse effects of male hypogonadism are summarized on Table 7 [11].

Table 7: Treatment for male hypogonadism, benefits, adverse effects, and contraindications is summarized in the table [11,24].

Treatment of male osteoporosis

Treatment of osteoporosis is focused on preventing loss of bone mass in those at risk of osteoporosis and this entails prior screening to detect at risk individuals. Thorough history should be obtained including time of puberty onset, or existence of other conditions like thyroid disorders, hypogonadism, deficiency of vitamin D, use of steroid medications, smoking habits, alcohol intake, dietary habits, level of exposure to the sun, and physical exercise. Treatment of male osteoporosis, benefits, adverse effects, and contraindications are summarized on Table 8. Bisphosphonate isthe first line of treatment for osteoporosis and are more effective than polypeptide hormone, Calcitonin. Bisphosphonates can decrease resorption of bone and hinder the activity of osteoclasts. Alendronate specifically is said to cause a notable rise in BMD of the total body, hip and vertebrae thereby inhibiting loss of height and fractures in men with osteoporosis [9]. Treatment of osteoporosis depends on clinical assessment, evaluation of fracture risk, BMD measurement and diagnosis. Men with decreased BMD, osteopenia with T score of-1 to-2.2 or osteoporosis will require drug treatment. Teriparatide which is a recombinant human parathyroid hormone, may be considered as treatment option in men with severe osteoporosis. Calcium and vitamin D supplementation are advised for maintaining healthy bone mass. Lifestyle changes should be advised comprising regular weight bearing exercise, reduced alcohol intake, stopping smoking.Advise about how to prevent falls especially in aging men. Treatment is recommended in men>50 years old with fracture of the hip or spine, t score of -2.5 or lower at the neck of the femur or spine after other secondary causes have been excluded and 10 year fracture risk has been assessed at about 3% at the hip or a 10year risk of major fracture of about 20% using FRAX [7]. Testosterone treatment is not routinely recommended for male osteoporosis treatment due to serious side effects like polycythemia, OSA, BPH and prostate cancer. However, it can be used in osteoporotic male patients with hypogonadism to improve BMD [16] .An RCT of 241 osteoporotic men who received alendronate compared to placebo showed a BMD improvement in the vertebra and neck of femur and a decrease in occurrence of fracture in the spine. The placebo group had 8.1% incidence of vertebral fracture compared to 3.1% in the alendronate group (P: 12, ARR: 5%, NNT: 20).A meta-analysis which compared the potency of alendronate against placebo, calcium or vitamin D reported a decrease in fracture of the vertebra in the treatment group, (OR: 0.44, CI: 95%, 0.23-0.83). Further study of 280 men of 65 years and over with stroke were randomized to risedronate or placebo, the risedronate group showed 2.5% rise in BMD in contrast to 3.5% reduction in the placebo group. Risedronate treatment resulted in decrease in hip fracture. (CI: 95%, 9-32, NNT: 16).Zoledronic acid or ibandronate are given intravenously to men who unable to tolerate bisphosphonate orally.An RCT showed that zoledronic acid infusion in ninety days after hip fracture repair caused a decrease in incidence of fracture and improved survival rate. (P; .001, NNT: 19, ARR: 5.3%).Osteonecrosis of the jaw (ONJ) was not reported among the zoledronic acid group.

Teriparatide is used in men with severe osteoporosis or several risk factors for fracture or in whom bisphosphonates treatment was unsuccessful. It activates formation of bone and improves BMD in the lumbar vertebra and neck of femur in osteoporotic men. The recommended maximum duration of treatment with teriparatide is 2 years. Combination of PTH and bisphosphonate is not approved.A placebo-controlled study randomized 437 men with severe osteoporosis to teriparatide treatment with doses of 20mcg or 40mcg daily or placebo. The teriparatide group showed a rise in BMD of 5.4% at the vertebra on dose of 20mcg and 9% on 40mcg dose, and 1.5% on neck of femur on a dose of 20 mcg, 2.9% on dose of 40mcg in contrast to placebo. Another RCT showed improved BMD in the hip and vertebra with teriparatide and a decrease in fractures of the spine. The men in the treatment group demonstrated a 51% decrease in new vertebral fracture incidence (P: 07, ARR: 6%, NNT: 17), compared to placebo.A meta-analysis of 8 trials comprising 365 men demonstrated testosterone given intramuscularly caused 8% increase BMD in the lumbar vertebra in contrast to placebo (CI: 95%, 4-13%). Vitamin D and calcium supplements are important in men with osteoporosis for bone mass sustenance [7]. The most dreaded adverse effect of effects, ONJ and atypical femoral fracture (AFF) seen in postmenopausal women on alendronate, is said to occur about 1 in 10,000 cases/patient year and should not deter patients from using bisphosphonate. Although AFF has been documented in men, but it is unclear whether men or women are more at risk.It was stated that AFF has been documented in subjects who were never on bisphosphonate [15].

Treatment with aromatase inhibitor

In hypogonadism induced by obesity, there is high activity of aromatase in the fat tissue. Testosterone is aromatized to estrogen which hinders the secretion of LH by the pituitary gland. Letrozole is aromatase inhibitor which can be used in obese men with hypogonadism, it was shown reduce estrogen levels and raise LH and TT levels significantly with the level of SHBG remaining unchanged in ten men with average age of 48.2, at a dose of 7.5 mg and 17 mg weekly over a period of six weeks. Another study conducted in 12 men showed results like the above, letrozole 2.5 mg/week was given to the patients and it resulted in a rise in the level of FT above physiological levels in about 50% of the subjects, showing that FT is the greatest indicator in assessing patients on letrozole during follow up management and in determining dose adjustment in prolonged treatment.It is worth noting that letrozole has been linked to high risk of osteoporosis, therefore care must be taken before giving it to individuals at increased risk for fractures [1].Sirtuin1 (SIR1) belongs to the family of nicotinamide adenine dinucleotide, NAD+ that regulates several activities of metabolism and apoptosis.SIRT1 production is said to decrease with advancing age while increased presence is said to slow down aging process.In their study Zainabadi, et al. demonstrated that deleting SIRT1 led to loss of bone mass and produced osteoporotic phenotype, while activation of SIRT1 with medication for a short duration resulted in a notable rise in bone mass. They reported treating an osteoporotic postmenopausal mice model with SIRT1 agonist 100mg per kg daily for a period of five months and found a notable rise in bone density, approximately 30% in the bone of the femur. There was also a reported rise in bone density in ovariectomized (OVX) model treated with SIRT1 agonist for only one month. In the same study they reported that stimulation of SIRT1 produced action similar to calorie restriction (CR). Models on calorie restricted diet showed enhanced SIRT1 presence in some tissues leading to increase in bone density. CR was also found to increase catabolism and result in weight loss. According to this same study, research in humans in which resveratrol, a SIRT1 activator was used, showed enhanced bone density in obese aged menZainabadi, et al.This is surely great research with positive prospects for future management of osteoporosis using sirtuin 1 agonists.

According to the Endocrine Society Osteoporosis in Men, 2012 clinical guidelines, osteoporosis treatment was shown to enhance BMD moderately. Using alendronate resulted in rise in BMD of the spine by 7% and that of the neck of the femur by 2.5% within two years. Also, treatment with risedronate caused a rise in BMD of the spine by 6% and that of the neck of femur by 1.5% within two years of treatment. Treatment with teriparatide 20 microgram/d was shown to increase the BMD in the neck of the femur by 1.5% and in the spine by 6% within nine months. In the case of men with hypogonadism, treatment with testosterone enanthate 200 mg 2weekly, was shown to raise BMD in the entire hip by 3.5 %, the spine by 8% and in the trochanter by 5%, within two years. Although there is no convincing evidence to support continual BMD monitoring as assessment of patients’ response to treatment, but it was estimated that a rise or steady BMD level suggests positive response [25].

Bisphosphonate- Alendronate decreased hip and vertebral fracture risk by 50% in those with previous history of vertebral fractures in a 3-year period, and 48% in patients without previous vertebral fracture. Ibandronate decreased the risk of vertebral fracture by 50% within 3 years, but no report on nonvertebral fracture risk reduction. Risedronate decreased the occurrence of vertebral fracture by 41-49% & non vertebral fracture by 36% in a 3-year period. Zoledronic acid decreased vertebral fracture occurrence by 70%, with notable decrease at 1-year, hip fracture decreased by 41% non-vertebral fractures by 25% in a 3-year period. It contraindicated in individuals with creatinine clearance<35mL/min or in patients with acute kidney disease.

Bisphosphonates are said to affect kidney function and are to be avoided in patients with eGFR<30 to 35 ml/min. They can also cause ONJ when used for long period over 5 years period as increased intravenous dose. Within a period of 3 years, Denosumab decreased the occurrence of vertebral fracture by 68, hip fractures by 40% & by 20% in non-vertebral fractures. Teriparatide decreased vertebral fracture occurrence by 65% & non vertebral fracture by 53% in patients with osteoporosis with a mean time of 18 months of treatment.

Table 8: A summary of the treatment of male osteoporosis, benefits, adverse effects, and contraindications [3, 6-8, 12-14, 25].

Raloxifene reduced vertebral fractures by 30% in those with previous vertebral fracture & 55% in those without previous vertebral fracture within a 3-year period. No reported decrease in non-vertebral fractures with this drug [8]. 3 years treatment with testosterone was shown to raise BMD of the lumbar spine by 7.5%, which validates the fact that 29 men with hypogonadism who were treated with testosterone enanthate 100mg once weekly for a period of a one and half years improved their BMD by 5% in the lumbar spine region.

Further treatment and checking of BMD for 3 years showed the most effect happened within 2 years of treatment.TRT raised the fat free body mass by about 5.8% or 3kg in the first six months, like documented reports from other research where men with hypogonadism were treated with testosterone. The reports reflect the period needed for treatment and observation of the efficacy of testosterone in men with hypogonadism [26]. It was found that testosterone treatment is efficacious in reversing hypogonadism caused by loss of bone mass in men, however, the first line of treatment for osteoporosis is bisphosphonates. Testosterone improves formation of trabecular bone by osteoblasts via androgen receptor and prohibits loss of trabecular bone via osteocytes [5]. There have not been many studies done on male osteoporosis treatment and in the few existing ones, there have been notable changes in BMD alone compared to studies done in women after menopause. A study on zoledronic acid was the only one planned from the onset to evaluate the effect of risk of fracture as the major outcome.

The studies did not anticipate long term follow up.In men with decreased testosterone, replacement of the hormone causes increase in BMD mostly in patients with testosterone levels<2.0 ng/ml (7.5nmol/l). The effect of testosterone treatment on fracture risk has not been reported. A study of 241 men who received 10mg of alendronate daily for 2 years compared to placebo showed a notable rise in BMD. Also, a notable decrease in fracture of the vertebra was documented with OR of 0.10, CI; 95%; 0.00-0.88, compared to placebo. A study of 284 men treated with risedronate showed successful increase in BMD in contrast to placebo, but no notable impact on fracture risk was seen.

A placebo controlled RCT of 1199 osteoporotic men treated with zoledronic acid showed a notable decrease in the risk of the fracture of the vertebra of 67% with RR of 0.33; CI of 95%: 0.16-0.70. Treatment with Strontium ranelate showed notable increase in BMD in osteoporotic men just like in women, however, there was not enough statistical significance to show decrease in risk of fracture. Teriparatide has been approved for treatment of men with severe osteoporosis, following multiple osteoporotic fractures associated with various risk factors or where previous treatment failed.

Denosumab treatment in osteoporotic men for 2 years, showed notable rise in BMD in the entire hip (3.4%), trochanter (3.4%), one-third radius (4.6%) and the lumbar spine (8.0%), with a p value of<0.01 overall. The patients who started with placebo during the 1st year of the trial, then changed to denosumab in the 2nd year showed increased BMD like the one seen in the men who were given denosumab from the onset. The total BMD achieved can be compared to the amount seen in women after menopause and men undergoing ADT for cancer of the prostate [14].

A study conducted in 160 males with obesity reported that>40% of them with body mass index of 40 kg/m2 and above, had bioavailable testosterone levels less than 225 pmol/L. Another study conducted with 1849 males to decide hypogonadism prevalence, showed low testosterone levels in 40% of obese men with BMI of 30 kg/m2 and above and in 50% of men with obesity and diabetes who were about 45 years old and above [27].

Bisphosphonates was beneficial with loss of bone mass due to secondary causes like glucocorticoid use, ADT, rheumatoid arthritis, and hypogonadism. Alendronate use in osteoporotic men resulted in improved BMD in the vertebrae and neck of femur and decrease in the occurrence of fracture of the vertebrae. Teriparatide caused rise in BMD at the lumbar region and neck of femur in osteoporotic men [7]. Calcitonin decreases the activity of osteoclasts.

Bisphosphonates can decrease resorption of bone and hinder the activity of osteoclasts. Alendronate specifically is said to cause a notable rise in BMD of the total body, hip and vertebrae thereby inhibiting loss of height and fractures in men with osteoporosis [9]. Evaluation of risk of fracture is suggested in men>75 years of age and women>65 years old [20].

Class 1 obese men with BMI between 30 to 35kg/mc and class 2 obese men with BMI 35 to<40kg/m2 basically showed reduced total testosterone level, decreased by up to 50% in contrast to nonobese men of similar ages used as controls. Class 3 obese men with BMI≥40kg/m2 showed decrease in both total and free testosterone levels.293 middle aged men with average age of 55 years with obesity and average BMI of 32 kg/m2, were randomized to strict lifestyle changes were reported to have weight loss of 7.9kg within twelve months. there was a mild rise in total T level by 1.15 nmol/L as well as SHBG but notable change in bioavailable T levels.

RCT with clomiphene or placebo in 17men erectile dysfunction & low T levels of less than 9.5nmol/L for 2 months showed increased T levels with clomiphene from 8.3 nmol/L-19.1 nmol/L, however, there were no reports of improved sexual function. Selective estrogen receptor modulators (SERMs) or aromatase inhibitors (AIs) may cause adverse effects. SERMs can cause decrease of insulin like growth factor1 through its estrogen like actions in the liver compared to T thereby decreasing anabolism, whereas the rise in SHBG levels can reduce the concentration of bioactive testosterone.

Studies have shown decreased LH and T production in those treated with SERMs or AIs in the elderly men in contrast to younger men, and this is worsened by the presence of obesity and any comorbidity like proinflammatory state. Lifestyle changes are indicated as the 1st line treatment for obesity associated hypogonadism. Mostly in men with severe obesity, productive weight loss was instrumental in reviving the HPT axis. Bariatric surgery led weight loss and the level of weight loss was mostly related to improved sexual function, rather than the rise testosterone level.

About 10% weight loss is needed to attain rise in testosterone levels [21]. Within three months of therapy, testosterone levels in the blood became normal and persisted till the end of treatment.BMD of the lumbar region was raised by 7.7 plus/minus 7.6% (P<0.001) and the trochanter region by 4.0 plus/minus 5.4% (P=0.02). Highest levels were reached in both areas within 2 years of treatment [27]. Testosterone therapy is not recommended for patients undergoing treatment for prostate cancer or benign prostatic hyperplasia (BPH).

Testosterone treatment is considered by some healthcare practitioners as risky due to adverse effects, however, in some cases the benefit may outweigh the side effects [11]. DXA scan is said to be the gold standard tool for evaluating osteoporosis in the hip and spine. Treatment with bisphosphonates in osteoporotic men was shown to improve BMD and its action on markers of bone turnover is said to be like in women.A study involving 1200 men in which zoledronic acid was compared with placebo infusion over a 2year period, showed that the zoledronic group had less fractures of the vertebra than the placebo group.

Another study showed that a group of>1400 men receiving ADT for prostate cancer were randomized to either denosumab SC injections 6 monthly or placebo injection 6 monthly for 2 years and the end of the study, the denosumab group showed a smaller number of fractures of the vertebra than the placebo groupRCT showed that teriparatide use as a once daily subcutaneous injection in reduced incidence of fracture of the vertebra. It can only be used for a maximum of 2 years. [12].

Hypogonadism linked to obesity in men is common and is rising in parallel with rising obesity prevalence. Hypogonadism prolongs obesity mostly truncal obesity which is connected to cardiometabolic problems like cardiovascular disease (CVD) and type 2 diabetes mellitus (T2DM). It is important to evaluate obese patients for hypogonadism mostly obese men with T2DM. Although lifestyle changes and weight loss are the main management for these patients, however, testosterone treatment may be required in some cases especially in men with various symptoms of hypogonadism and low testosterone levels. Testosterone treatment has been reported to be useful in enhancing body structure and improving metabolic risks underlying etiology in men who are obese. The use has not been implicated in any rise in CVD.

It is important to consider hypogonadism caused by obesity when deciding for bariatric surger [1]. The overall results show the positive effect of early diagnosis and treatment to alleviate the risks of fracture and associated complications like prolonged disability. Bisphosphonates remains the first line of treatment. There may be side effects, but the benefits outweigh the adverse effect. Early dental check before starting treatment is encouraged to prevent ONJ.TRT is beneficial in men with hypogonadism and osteoporosis. Supplementation with vitamin D and calcium are also important.

Table 9: Summary of study authors, type, results, and comments.

Male osteoporosis remains under-recognized despite being a significant contributor to morbidity especially in older men. There has been a surge in reported prevalence of hypogonadism in men as a result of global epidemic of obesity and Type 2 Diabetes Mellitus (T2DM). Recognition and prompt treatment of male hypogonadism in men with obesity with or without T2DM can potentially improve long term outcomes for such individuals.

The key intervention includes lifestyle changes including increased level of physical activity, smoking cessation, decreased alcohol consumption, reduction in carbohydrate/caloric consumption. In addition, testosterone replacement therapy has a role in such men with established hypogonadism to improve bone mass. Last though not the least, physicians need to be mindful of impact of glucocorticoids on metabolic and bone health.

Early screening through thorough history, physical examination and measurement of BMI, BMD, using FRAX and DEXA scan will help in early detection and prompt management before complication sets in. Based on this systematic review, there is a clear need to improve awareness of male hypogonadism and osteoporosis. Further studies are needed in this field to help understand impact of lifestyle intervention and testosterone replacement therapy on bone health.

This work was completed as partial fulfillment of an MSc in Endocrinology from the University of South Wales.

Declaration of interests

The authors declare no conflicts of interest.

This research did not receive any grant or funding from any institution or individual.

1. Molina-Vega M, Muñoz-Garach A, Damas-Fuentes M, Fernández-García JC, Tinahones FJ. Secondary male hypogonadism: A prevalent but overlooked comorbidity of obesity. Asian J Androl. 2018;20(6):531. PubMed | CrossRef

2. Rochira V, Balestrieri A, Madeo B, Zirilli L, Granata AR, Carani C. Osteoporosis and male age-related hypogonadism: role of sex steroids on bone(patho) physiology. Eur J Endocrinol. 2006;154(2):175-85. PubMed | CrossRef

3. Sutton RA, Dian L, Guy P. Osteoporosis in men: an underrecognized and undertreated problem. BC Med J. 2011;53(10):535-40.PubMed | CrossRef

4. Page MJ, McKenzie JE, Bossuyt PM, Boutron I, Hoffmann TC, Mulrow CD, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;88:105906. PubMed | CrossRef

5. Golds G, Houdek D, Arnason T. Male hypogonadism and osteoporosis: the effects, clinical consequences, and treatment of testosterone deficiency in bone health. Int J Endocrinol. 2017. PubMed | CrossRef

6. Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. Arch Osteoporos. 2013;8(1):1-15. PubMed | CrossRefAdler RA. Osteoporosis in men: a review. Bone Res. 2014;2(1):1-8. PubMed | CrossRef

7. Rao SS, Budhwar N, Ashfaque A. Osteoporosis in men. Am Fam Physician 2010;82(5):503-8. PubMed

8. Cosman F, de Beur SJ, LeBoff MS, Lewiecki EM, Tanner B, Randall S, et al. Clinician’s guide to prevention and treatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-81.PubMed | CrossRef

9. Madeo B, Zirilli L, Caffagni G, Diazzi C, Sanguanini A, Pignatti E, et al. The osteoporotic male: overlooked and undermanaged. Clin Interv Aging. 2007;2(3):305. PubMed

10. Kiebzak GM, Beinart GA, Perser K, Ambrose CG, Siff SJ, Heggeness MH. Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med. 2002;162(19):2217-22. PubMed | CrossRef

11. Dandona P, Rosenberg MT. A practical guide to male hypogonadism in the primary care setting. Int J Clin Pract. 2010;64(6):682-96. PubMed | CrossRef

12. Adler RA. Update on osteoporosis in men. Best Pract Res Clin Endocrinol Metab. 2018;32(5):759-72. PubMed | CrossRef

13. World Health Organization. WHO scientific group on the assessment of osteoporosis at primary health care level. InSummary meeting report. 2004;5:5-7.

14. Misiorowski, W. ‘Osteoporosis in Men’. PrzMenopauzalny. 2017;16(2):70. PubMed | CrossRef

15. Adler, RA. ‘Update on Osteoporosis in Men.’ Best Pract Res Clin Endocrinol Metab, 2018;32(5):759-772. PubMed | Crossref

16. Herrera A, Lobo-Escolar A, Mateo J, Gil J, Ibarz E, Gracia L. Male osteoporosis: a review. World J Orthop. 2012;3(12):223.PubMed | CrossRef

17. Papaioannou A, Kennedy CC, Ioannidis G, Gao Y, Sawka AM, Goltzman D, et al. The osteoporosis care gap in men with fragility fractures: the Canadian Multicentre Osteoporosis Study. Osteoporos Int. 2008;19(4):581-7.PubMed | CrossRef

18. Harvey N, Dennison E, Cooper C. Osteoporosis: impact on health and economics. Nat Rev Rheumatol. 2010;6(2):99-105. PubMed | CrossRef

19. Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev. 2008;29(4):441-64. PubMed | CrossRef

20. Osteoporosis: assessing the risk of fragility fracture. National Institute for Health and Care Excellence (NICE). 2017. PubMed

21. Grossmann M. Hypogonadism and male obesity: focus on unresolved questions. Clin Endocrinol. 2018;89(1):11-21. PubMed | CrossRef

22. Kaufman JM, Reginster JY, Boonen S, Brandi ML, Cooper C, Dere W, et al. Treatment of osteoporosis in men. Bone. 2013;53(1):134-44. PubMed | CrossRef

23. UK NC. Osteoporosis: Fragility Fracture Risk: Osteoporosis: Assessing the Risk of Fragility Fracture.

24. Bhasin S, Brito JP, Cunningham GR, Hayes FJ, Hodis HN, Matsumoto AM, et al. Testosterone therapy in men with hypogonadism: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2018;103(5):1715-44.PubMed | CrossRef

25. Watts NB, Adler RA, Bilezikian JP, Drake MT, Eastell R, Orwoll ES, et al. Osteoporosis in men: An Endocrine Society clinical practice guideline. J Clin Endocrinol Metab. 2012;97(6):1802-22. PubMed | CrossRef

26. Snyder PJ, Peachey H, Berlin JA, Hannoush P, Haddad G, Dlewati A, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85(8):2670-7. PubMed | CrossRef

27. Saboor Aftab SA, Kumar S, Barber TM. The role of obesity and type 2 diabetes mellitus in the development of male obesity‐associated secondary hypogonadism. Clin Endocrinol. 2013;78(3):330-7. PubMed | CrossRef

28. Zainabadi K, Liu CJ, Caldwell AL, Guarente L. SIRT1 is a positive regulator of in vivo bone mass and a therapeutic target for osteoporosis. PLoS One. 2017;12(9):e0185236. PubMed | CrossRef