Over the years male osteoporosis has received little attention. One in eight men older than 50 years will have a fragility fracture during their lifetime, which will contribute to dependency, morbidity and a higher mortality in the first year.1 Although the rate of bone loss in men is slower,2 the mortality risk is twice after a hip fracture when compared to women.3

Osteoporosis is not limited to post-menopausal women, but is also a significant cause of morbidity and mortality in older men that is usually underestimated, unrecognised and untreated. As men live longer, age-related osteopenia and osteoporosis are more prevalent and osteoporosis-related hip and spine fracture along with fragility fractures secondary to chronic intake of glucocorticoids and androgen deprivation therapy for prostate cancer are significantly on the rise and are often not carefully evaluated.

There are still immense controversies concerning routine evaluation of elderly men who are at risk or already have developed osteoporosis, but there is increasing concern amongst the medical fraternity in identifying the risk it poses for fractures and the financial burden it is likely to impose on the public purse. Male osteoporosis has to be recognised as a major public health issue and more research and resources should be deployed in understanding the pattern of the disease, the diagnostic criteria that should be used, the tools for fracture risk assessment and treatment and also those that should be employed for improving bone density and reducing fracture risk.

Epidemiology

Osteoporosis affects more than two million men in the US and 5.5 million adult males across 27 countries of the European Union.4 Amongst all osteoporosis related fractures, 30-40% occurs in men and the life-time risk for men aged 50 and older is between 13-30%.5 Conventionally, incidence of fracture in men shows a bimodal distribution: a peak between 15 and 45 years of age as a result of high-energy trauma at work, in traffic and in sports, followed by an exponential increase in osteoporosis-related fracture with advancing age.6 The risk of suffering a hip fracture among men is usually linked to advancing age, although 50% of these fractures are observed in patients below 80 years of age.7 By 2050, the worldwide incidence of hip fracture is projected to increase and the increase will be greater in men (310%) compared to women (240%).8 Osteopenia in men is more prevalent than osteoporosis4 and is a major risk factor for vertebral fractures (61%) when compared to osteoporosis (21%).9

Aetiology and pathogenesis

Osteoporosis in men is usually categorised as: a) involutional or senile osteoporosis (in older men) b) idiopathic osteoporosis (in men of 30-70 years of age) and c) secondary osteoporosis.10

The bone mineral density (BMD) in males starts to increase progressively during childhood and accelerates exponentially during puberty. They achieve greater peak bone mass11 and bigger sized bones with higher cortical density making them less prone to suffer fragility fractures, but decline in bone quality happens with advancing age with trabecular bone loss, beginning in the third decade followed with cortical bone loss at around 65-70 years of age.6 Oestrogens and androgens both contribute to bone forming mechanisms, but 70% of bone turnover and resorption is modulated by oestrogens alone.10 The oestrogen levels in females drop dramatically at menopause; in contrast hormonal changes in men are much more gradual. Sex hormone binding globulin (SHBG) increases with age lowering bioavailable free testosterone, but this alone is not the proximate cause of bone loss in ageing men.

The European Male Ageing Study demonstrated that higher free and total oestradiol, but not testosterone were independently associated with bone health.12 This was further confirmed in a report where oestrogen replacement improved BMD in men who had absent oestrogen receptor and aromatase enzyme suggesting that oestrogen is essential and may be even more important than androgens in maintaining skeletal integrity.6 In addition, androgen deficiency may also lead to sarcopenia (loss of appendicular muscle mass) that results in greater risk of osteoporosis thereby increasing propensity of falling and more fractures.13

Secondary osteoporosis is common and the frequent causes are summarised in Table 1. Excess of glucocorticoids (both exogenous and endogenous) are detrimental for bones and in systemic glucocorticoid therapy, increased risk of fracture can be demonstrated within three months of therapy.14 Androgen deprivation therapy used for treatment of prostate cancer also causes loss of BMD in up to 33% of patients and may have a fracture risk of 20% in five years and 17% of these patients may need treatment when their fracture risks is ascertained by the fracture prediction algorithm (FRAX).15

 

Table 1

Evaluation and diagnosis of male osteoporosis

A complete history and physical examination should be undertaken for men being evaluated for osteoporosis. Information should be obtained about medications, chronic diseases, alcohol or tobacco abuse, falls and/or fractures as an adult, and family history of osteoporosis. It is crucial to enquire about previous fractures; after one osteoporotic fracture, men and women have about the same, highly increased risk of another fracture and distal forearm fractures are an early and sensitive marker of male skeletal fragility.16 Physical assessment should evaluate patient’s height, kyphosis, balance, mobility, overall frailty, and evidence of causes of secondary osteoporosis, including testicular atrophy, signs of hyperthyroidism, and evidence of chronic obstructive pulmonary disease.17

Biochemical tests for serum calcium, phosphate, creatinine, alkaline phosphatase, liver function, vitamin D, testosterone, complete blood count, and 24-h urinary calcium excretion should be done. Additional testing for serum protein electrophoresis, tissue transglutaminase antibodies, thyroid function tests, and parathormone levels may be required. In men with osteopenia or osteoporosis who might have undiagnosed vertebral fractures, lateral spine radiographs or vertebral fracture assessment (VFA) is recommended.17

As in women the “gold standard” for defining osteoporosis in males is by using BMD measured by dual energy X-ray absorptiometry (DXA) scanning as BMD correlates strongly with fracture risk.18 The National Osteoporosis Foundation (NOF), International Society for Clinical Densitometry (ISCD), and the Endocrine Society (ES) recommend BMD testing for all men older than 70 years, and in men 50 to 70 years when risk factors are present. The World Health Organization (WHO) classification for osteoporosis, intended for Caucasian post-menopausal women is also used for males:19

  • Normal: “T” score of -1.0 or higher
  • Low bone mass (osteopenia): “T” score between -1.0 and -2.5
  • Osteoporosis: “T” score of -2.5 or lower
  • Severe osteoporosis: “T” score of -2.5 or lower and personal history of fragility fracture.

For men, if DXA is used alone, osteoporosis will be underestimated as bone size and peak bone density is higher, but if DXA is combined with FRAX, then the same standards will be used for both sexes and this will identify a larger proportion of older men suitable for osteoporosis treatment. In the case of men aged 50 and older reference ranges of young men should be used to diagnose osteoporosis whereas in men younger than age 50, Z-scores should be preferably used.6 The ES also recommends that men at increased risk for osteoporosis ie. men aged 70 or older and younger men (aged 50-69) with additional risk factors, should have measurement of BMD of hip and spine. Forearm measurements (1/3 or 33% radius) is advised when spine or hip BMD cannot be interpreted and for men with hyperparathyroidism or receiving androgen-deprivation therapy (ADT) for prostate cancer.17

Treatment

The primary objective of osteoporosis treatment, in men as in women, is to reduce fracture risk that is calculated by the FRAX score, which is country specific. Treatment is aimed to improve bone density and to treat the secondary causes of osteoporosis.6

The ES17 recommends that pharmacological treatment for osteoporosis in males should be offered when there is:

  • Hip or vertebral fracture without major trauma
  • BMD of spine, femoral neck, or total hip 2.5 SD or more below mean of normal young males
  • T-score between -1.0 and -2.5 in the spine, femoral neck, or total hip plus a 10-year risk of experiencing any fracture is 20% or 10-year risk of hip fracture is 3% using FRAX
  • Age ≥50 years and long-term glucocorticoid therapy in pharmacological doses (eg. equivalent to 7.5mg or greater of prednisolone for three months).

In most cases patients are advised to engage themselves into daily physical activities and also ensure adequate intake of calcium (1000-2000mg daily, dietary or supplements), with vitamin D supplementation if vitamin D levels are low (<75nmol/liter). They should also reduce alcohol intake and stop smoking.

Men at high risk of fracture should be treated with medication approved by regulatory agencies such as the US Food and Drug Administration (FDA) or European Medicines Agency (EMA). Choice of therapeutic agent should be individualised and based on factors including fracture history, severity of osteoporosis (T-scores), the risk for hip fracture, comorbid conditions, cost etc.17 Drugs approved for male osteoporosis include bisphosphonates (alendronate, risedronate, zoledronic acid), anabolic agents (teriparatide) and anti-resorptive antibody (denosumab). Most of the bisphosphonates increase BMD in men as in women, but there is little information on whether they result in reduced fracture risk. Intermittent administration of teriparatide activates osteoblasts and increases bone formation leading to fewer fractures in men20 and is also effective in glucocorticoid-induced osteoporosis.21 Denosumab, a monoclonal antibody acts on RANK-ligand and has demonstrated an increase in BMD and significant decrease in the incidence of vertebral fractures especially in patients who have received androgen deprivation treatment.22

Calcitonin, ibandronate and strontium ranelate are not recommended for use in male osteoporosis, but can be prescribed if the approved agents are not tolerated or contraindicated.17 Testosterone therapy is not routinely recommended in most guidelines, but may be used when serum testosterone levels are less than 6.9nmol/l on more than one occasion, and if accompanied with signs or symptoms of androgen deficiency. For men at high risk of fracture on testosterone therapy, bisphosphonate or teriparatide can be added.17

Newer treatments like anti-sclerostin monoclonal antibodies (romosozumab, blosozumab, and BPS804) that increase bone formation by inhibiting sclerostin are currently under development.23 Abaloparatide, a PTH- related peptide analogue which acts as an anabolic agent has been approved by the FDA, but did not receive a go-ahead in Europe; from a safety point of view, the EMA is concerned about the medicine’s effect on the heart, such as increases in the heart rate and palpitations.24

Monitoring and follow-up

Patients on treatment for osteoporosis should be carefully monitored at frequent intervals to reduce occurrence of fragility fractures. The ES recommends monitoring BMD by DXA every two years to assess the response to treatment although this may not actually reflect the full effect of certain treatments like anti-resorptive agents. If BMD reaches a plateau, the frequency of monitoring can be reduced. In cases where interpretation of BMD is difficult due to degenerative changes of spine and hip, bone turnover markers can be measured at 3-6 months after starting treatment using a bone resorption marker [eg. C-telopeptide of type I collagen (CTX)] for anti-resorptive therapy (50% suppression expected within three months of treatment) and a bone formation marker [eg. procollagen I N-propeptide (PINP)] for anabolic therapy.17

Conclusion

Male osteoporosis is a serious public health problem, which is increasing in parallel with other diseases in the elderly causing significant osteoporotic fracture-related morbidity and mortality. Although the incidence of the disease remains high, it is still an under diagnosed, undertreated and under researched condition. It is important to raise awareness amongst physicians and patients and new research should be directed to establish standards of diagnostic screening tests, assessment of fracture risks, and the effectiveness and long-term implications of different treatments for male osteoporosis.

 

Conflict of interest: none declared

 

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Uzma Khan

Clinical Fellow (Endocrinology) Sheffield Teaching Hospitals NHS Foundation Trust, Royal Hallamshire Hospital

uzmaanis@gmail.com

Gautam Das

Consultant Physician, Cwm Taf Local Health Board, Prince Charles Hospital, Gurnos Estate, Merthyr Tydfil