Interview: Bone health is also for men




Maurice AUDRAN, MD
Head, Department of
Bone and Joint Disorders
INSERM U922
CHU Angers and Faculty
of Medicine, UNAM
Angers, FRANCE

Bone health is also for men

 

Interview with M. Audran,France

Osteoporosis is a major health issue in men: 1 in 8 men older than 50 years has a risk of sustaining an osteoporotic fracture. Fractures of the hip and vertebrae are associated with the greatest morbidity and mortality. Sexual differences exist in skeletal bonemetabolism. Boys have larger bones, thicker cortices, whereas trabecular pattern appears similar at the end of adolescence. Aging in men is mainly characterized by trabecular thinning and a decrease in trabecular number. A decrease in cortical volumetric bone mineral density (BMD) due to an increase in midcortical and endocortical porosity has been described. Significant associations between bone loss and estrogen levels have been found in men. BMD measures are effective to define the risk of future fractures and should be performed in patients with risk factors. A careful assessment of secondary osteoporosis as well as of mineralization disorders due tomalignant diseases ismandatory inmen. The FRAX® tool is a significant advance in clinical care and should prove useful in appropriate targeting of osteoporosis therapy. US NOF (National Osteoporosis Foundation) Guidelines recommend treating men older than 50 years with a history of hip or vertebral fracture, or with a 10-year probability of hip fracture of 3%, or a 10-year probability of major fractures 20% as calculated by FRAX®. Yet, men rarely receive osteoporosis treatment, despite the availability of a variety of agents (bisphosphonates, teriparatide, and may-be in future strontium ranelate) with proven efficacy in women, and which are presumed to be as efficient in men with equivalent fracture risk.

Medicographia. 2010;32:417-421 (see French abstract on page 421)

Could you describe the epidemiological data of osteoporosis in men? Is it a common disease?

Osteoporosis-related fractures constitute a major health concern in men. Fracture incidence is even higher in men than in women below the age of 50, but they are very often related to high-energy trauma events. After the age of 50, women tend to have a higher incidence of fractures than men; differences in bone mass and strength, the type and frequency of trauma, the fact that elderly women appear to have an increased frequency of falls relative to men may explain this inversion of the curves. Nonetheless, in aging men, fractures may also occur after minimal trauma; fractures of the hip and vertebrae are associated with the greatest morbidity and mortality.

A recent review on the annual worldwide incidence of fractures showed that 39% occur in men and that 1 in 8 men older than 50 years has a risk of sustaining an osteoporotic fracture. In 42% of cases it will be a vertebral fracture, in 30% of cases a hip fracture, in 20% a wrist fracture, in 25% a fracture of the humerus. Fragility fractures in aging men may also occur at other sites, including the pelvis, ribs, and collarbone. With the increasing life expectancy of men, osteoporosis in men will become a greater burden to society. In 2000, in France, the medical cost of male osteoporosis was estimated at €197.5 million.

It is also important to take into account that the risk of a subsequent fracture is the same in male patients as in osteoporotic women after a low-energy fracture.

The mortality and morbidity associated with hip fractures are greater in men than in women. Men are twice as likely to die in hospital after a hip fracture. Comorbid conditions might contribute to this increased mortality risk. In men aged 60 to 69, the life expectancy after a hip fracture is 7.9 years, versus 19.4 in controls.1 Loss of physical function and autonomy results in up to 50% of men having to be institutionalized after a hip fracture.

What is the pathophysiology of osteoporosis in men? Are there differences with that in women?

Sexual differences exist in skeletal development and peak bone mass acquisition. Boys have larger bones and thicker cortices, whereas trabecular pattern appears similar at the end of adolescence. Age-related changes in bone mass have been studied by means of several independent techniques (histomorphometry, x-ray microtomography [micro- QCT], high resolution QCT [HR-QCT], micro-MRI, synchrotron, finite element analysis). Our group and others have shown that parameters of trabecular microarchitecture are a major and independent determinant of vertebral fractures in middle- aged men with osteopenia. Increased cortical porosity has been observed in patients with severe osteoporosis.2,3 Using a different approach, significant decreases in trabecular volumetric BMD at the vertebrae have been shown in crosssectional as well as in longitudinal studies. Aging in men is therefore mainly characterized by trabecular thinning and to a lesser extent by a decrease in trabecular number. In cortical bone, a decrease in cortical volumetric BMD due to an increase in the mid-cortical and endocortical porosity is observed. In contrast, cortical volumetric BMD shows little changes in men or in women.4 Changes in bone geometry in aging men are defined by an increase in cross-sectional area at different axial and peripheral sites of the skeleton, mainly due to continued periosteal apposition.

In men, as in women, sex steroids are important for skeletal development during growth as well for maintenance of peak bone mass. Their role in fracture risk in men has been recently extensively studied. Sex steroids, estrogens, and androgens circulate either free or bound to sex-hormone binding globulin (SHBG). Significant associations between BMD, bone resorption, and bone loss have now been found with estrogen levels in men. Our group showed that serum SHBG may predict the risk of future fractures. The respective roles of sex steroids and SHBG have been recently confirmed in the Osteoporotic Fractures in Men (MrOS) studies. In the Swedish arm of the cohort, elderly men with low serum E2 and high SHBG levels had an increased risk of fractures. In the US cohort, men with lowest bioavailable estradiol or highest levels of SHBG had greater risk of all nonvertebral fractures.5 Nonskeletal effects of testosterone, on muscle mass and reduced risk of falls, might also play a role on fracture risk in elderly men.

Vitamin D deficiency is common among older adults and may result in secondary hyperparathyroidism and increased bone resorption. In a US prospective cohort study of community- dwelling men aged 65 or older, the annualized average rate of loss in total hip BMD was twice higher among men with 25(OH)D levels below 15 ng/mL than among men with 25(OH)D levels of at least 30 ng/mL, suggesting that low 25(OH)D levels are detrimental to BMD in older men.

Declining levels of insulin-like growth factor–1 (IGF-1), possibly mediated by alterations of IGF binding proteins with age, may alter bone microarchitecture, with a thinning of bone trabeculae. The decrease in IGF-1 activity, which is an inhibitor of SHBG synthesis by the hepatocytes, might also indirectly influence bone metabolism through an increase in SHBG levels.4

Are risk factors for osteoporosis similar in men and women?


Low BMD is a major risk factor of osteoporotic fractures in men. BMD measures are therefore effective to define the risk of future fractures, regarding low-trauma fractures, but also high-trauma fractures.

Cessation of estrogen secretion is the main causal factor of osteoporosis in women. In men, in the absence of such a cause, osteoporosis is described as secondary in up to 40% of cases. The causes are heterogeneous and may be combined.

Table I
Table I. Main causes of secondary osteoporosis in men.

Three major causes have been identified: (i) prolonged glucocorticoid therapy; (ii) hypogonadism (sometimes induced by gonadotropin-releasing hormone [GnRH] treatment in patients suffering from prostate cancer); (iii) excessive alcohol intake.

Some others factors have also been consistently documented to be associated in men with a significant increase in fracture risk (Table I). Osteoporosis may be defined as primary or idiopathic when no cause or risk factor is identified; some cases might be due to genetic factors in the acquisition of peak bone mass. A careful assessment of secondary osteoporosis as well as of mineralization disorders due to malignant diseases (myeloma, lymphomas) is mandatory in men.

How and when are patients diagnosed? Is it only after fractures or before? What are the diagnostic criteria?

Prevention and treatment of bone loss and fractures are often underestimated priorities. In many clinical situations it might be useful to perform a careful evaluation because they represent a significant risk factor of osteoporosis (Table I). Risk factors may interfere with bone fragility in different ways: (i) by decreasing bone mass; (ii) by qualitative alterations of cortical or trabecular bone; (iii) by increasing the risk of falls. Both the National Osteoporosis Foundation (NOF) and the International Society for Clinical Densitometry (ISCD) recommend performing BMD measurement after 70 years of age (but a cost-effectiveness analysis showed this measure to be effective only over 80 years or in men aged 65 or more with a prevalent vertebral fracture), after a prior vertebral or nonvertebral low-trauma fracture, and when secondary causes (including medications) have been identified. Several different factors may be associated and should be considered in the future risk of osteoporosis.

Bone density (BMD) predicts fracture risk in men as it does in women, but the prevalence of osteoporosis depends on the reference population. The World Health Organization (WHO) definition of osteopenia and osteoporosis (BMD measured by dual-energy x-ray absorptiometry (DXA) that is 2.5 or more standard deviations (SD) below that of a young normal adult, that is, a T-score of –2.5 or below) applies to white postmenopausal women and there is no consensus on the densitometric diagnosis of osteoporosis in men. Nonetheless, using the WHO criteria to define osteopenia and osteoporosis, two cutoffs have been proposed for men, based either on the young normal male or female reference groups.

Osteoporosis in men was defined as a BMD value 2.5 SD below the mean of either white men or women aged 20 to 29 years; low BMD or osteopenia was characterized as a BMD value between 1 and 2.5 SD below the respective young male and female reference means. Based on data from the Mayo Clinic, when bone density at any of the total hip, spine, or wrist sites was used, the prevalence of osteoporosis in men over age 50 was 19% using male reference ranges, and only 3% when using the female reference ranges.6 The prevalence of osteoporosis in men, using sex-specific normal values, is therefore more substantial and may provide a better estimate for the proportion of men at risk for an osteoporotic fracture. The current ISCD recommendation is to use a male database for T-score derivation in men.

Spinal degenerative changes are common after the age of 65 years and have to be taken into account because they may falsely elevate the measured spine BMD.

It should also be underlined that, in the Rotterdam study, only 21% of all nonvertebral fractures occurred in men with a T-score below –2.5.7

How is ostoporososis in men handled by health autorities? What are the main recommendations and guidelines? Are doctors aware enough of the risk of osteoporosis in their elderly male patients?

In 2008, the American College of Physicians, the US NOF, and the ISCD made recommendations relative to BMD measurement in men. French guidelines have been also released regarding the indications of the measure by DXA. The 2008 US NOF Guidelines warrant a recommendation for treatment in men: (i) older than 50 years with a history of hip or vertebral fracture; or (ii) with a T-score between –1 and –2.45; or (iii) a T-score between –1 and –2.5 and a 10-year probability of hip fracture of ≥3% or a 10-year probability of major fractures (spine, forearm, hip, humerus fracture) ≥20% as calculated by FRAX®. The French Health Authorities (“Haute Autorité de Santé”) recommended in 2007 to treat male patients suffering from osteoporosis characterized by a T-score less than –2.5 with other risk factors or with T-score less than –3.
Is FRAX®useful in the diagnosis of male patients?


Anormal BMD measurement is no guarantee that a fracture will not occur. The use of risk factors may in this way add useful information on fracture risk independently of BMD.

FRAX® is a computer-based algorithm derived from data obtained in 11 independent cohorts (http://www.shef.ac.uk/ FRAX) that provides models for the assessment of 10-year probability of fracture risk (hip, clinical spine, humerus, or wrist fracture) and the 10-year probability of hip fracture alone in men and women using clinical risk factors. The tool can be used alone or with femoral neck BMD to enhance fracture risk prediction. The presence of more than one risk factor increases fracture probability in an incremental manner.

FRAX® has limitations: (i) it has largely been validated in women and additional evaluation of FRAX® in men is needed; (ii) some risk factors are described as dichotomous variables (yes or no), despite data clearly showing a dose–response relationship; (iii) silent, radiological vertebral fractures are not taken into account. It appears nonetheless as a significant advance in clinical care and should prove useful in appropriate targeting of osteoporosis therapy.

What are the main bases of the management of osteoporosis in men (pharmacologic, nonpharmacologic treatments)?


In the Framingham osteoporosis study, the proportion of men meeting the 2008 NOF criterion increased with advancing age (1.7% of men aged 50 to 65 and 37.9% of men aged >75 years).8 In total, one sixth of men aged over 50 years would be recommended for osteoporosis treatment. Nonetheless, the loss of potential years of life in younger age-groups suggests that preventive strategies for fracture should not only focus on older patients at the expense of younger highrisk men.

Although hypogonadism in men leads to bone loss, deterioration of trabecular architecture, loss of muscle mass, and increased risk of fracture, androgen treatment remains controversial. Testosterone therapy has been shown to increase BMD in hypogonadal men, but clinical trials concerned a small number of patients, were of short duration, without any definitive evidence of fracture risk reduction. The issue of the long-term safety of testosterone treatment in older men, (increased risk of prostate cancer, adverse cardiovascular effects), must be taken into account.

Because of the presumed role of estrogens on bone in men, the effects of selective estrogen receptor modulators (SERMs) has been studied. Raloxifene reduced bone turnover in men with low estradiol concentrations and increased BMD in men treated with GnRH agonists for prostate cancer. Toremifene reduced the risk of vertebral fractures in patients on androgen deprivation therapy for prostate cancer.

Calcitonin has received limited evaluation in men and no conclusions may be drawn from the small short-term clinical trials.

Most studies with alendronate or risedronate in men have shown a beneficial effect on BMD at lumbar and femoral sites, when compared with placebo. Intravenous zoledronic acid increased BMD in men after hip fracture and in patients with androgen-deprivation treatment for prostate cancer. Few clinical trials clearly proved a significant reduction in fracture risk. Because vertebral and nonvertebral fracture risk reduction has been well documented in women at risk of fractures receiving bisphosphonate therapy, it has been suggested that such treatment interventions would have a similar efficacy in men with equivalent fracture risk, and therefore bisphosphonates are considered to be first-line therapy for men with osteoporosis.4

The effects of daily SC teriparatide appear similar in men and women. The induced lumbar and femoral increase in BMD was of the same magnitude as in women, with similar changes in bone remodeling. Teriparatide appears to reduce the risk of vertebral fracture, but not of nonvertebral fracture.4

Strontium ranelate induces an increase in bone formation and a decrease in bone resorption. It has been shown to decrease vertebral and nonvertebral fracture in women at different ages, for different levels of risk. This dual-effect bone agent may represent an interesting alternative to bisphosphonates in men.4 A large clinical trial (MALEO) is under way.

Long-term vitamin D daily supplementation (800 IU) is often required. A daily calcium intake of 1000 to 1200 mg has been recommended.

Men rarely receive osteoporosis treatment. Following a hip fracture, less than 10% of patients are treated and only one third of men receiving androgen deprivation therapy for prostate cancer receive osteoporosis evaluation or treatment.

In 2008, the recommendations of the American College of Physicians (ACP) were that pharmacologic treatment should be offered to men with known osteoporosis and those having sustained a fragility fracture, as well as to patients with BMD T-scores above –2.5, but at risk due to clinical factors. A cost-effectiveness analysis conducted by NOF found pharmacologic treatment to be cost-effective for both men and women provided the 10-year estimated fracture risk exceeded approximately 20% for major osteoporotic fracture or 3% for hip fracture, based on a US-adapted FRAX® model. In future, health and economic considerations, not simply fracture risk, will influence treatment recommendations, based on the resources dedicated to health care. Nonpharmacological measures are useful in the management of male osteoporosis. Increasing physical exercise may be considered, but the way to optimize its effects on skeleton is not well defined. Prevention of falls is mandatory in elderly patients, with different measures: correction of functional disability, treatment of comorbidity known to facilitate gait disorders; reduction of drug consumption or alcohol abuse; action on architectural or environmental factors. The interest of hip protectors is still controversial. _

References

1. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999;353(9156):878-882.
2. Legrand E, Chappard D, Pascaretti C, et al. Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis. J Bone Miner Res. 2000;15(1):13-19.
3. Ostertag A, Cohen-Solal M, Audran M, et al. Vertebral fractures are associated with increased cortical porosity in iliac crest bone biopsy of men with idiopathic osteoporosis. Bone. 2009;44(3):413-417.
4. Khosla S, Amin S, Orwoll E. Osteoporosis in men. Endocr Rev. 2008;29(4): 441-464.
5. LeBlanc ES, Nielson CM, Marshall LM, et al. Osteoporotic fractures in men study group. The effects of serum testosterone, estradiol, and sex hormone binding globulin levels on fracture risk in older men. J Clin Endocrinol Metab. 2009;94 (9):3337-3346.
6. Melton III LJ, Atkinson EJ, O’Connor MK, O’Fallon WM, Riggs BL. Bone density and fracture risk in men. J Bone Miner Res. 1998;13(12):1915-1923.
7. Schuit SCE, van der Klift M, Weel AEAM, et al. Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam study. Bone. 2004;34(1):195-202.
8. Berry SD, Kiel DP, Donaldson MG, et al. Application of the National Osteoporosis Foundation Guidelines to postmenopausal women and men: the Framingham Osteoporosis Study. Osteoporos Int. 2010;21(1):53-60.

Keywords: osteoporosis; fracture; men; FRAX®; morbidity; mortality