Osteoporosis in Men1

John P. Bilezikian

Departments of Medicine and Pharmacology, Columbia University College of Physicians and Surgeons, New York, New York 10032

Address all correspondence and requests for reprints to: John P. Bilezikian, M.D., Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, New York 10032. E-mail: bilezik{at}medicine1.cpmc.columbia.edu

Osteoporosis has received increasing attention as one of the major disorders of our time. With over 20 million women at risk for fracture, and over 1 million fractures occurring annually, the importance of this disease cannot be overstated. The health care bill attributed to osteoporosis is well over 20 billion dollars. Moreover, fractures associated with osteoporosis, especially hip fracture, can lead to devastating effects on the quality of life, with many individuals unable to resume their former life style and requiring ongoing assistance thereafter. Thus, the table is set for a major thrust on this disease. Pharmaceutical companies are investing untold resources in the search for therapies, foundations are spreading the word among the public, and funding agencies such as the NIH are committed to an investigative agenda to gain key insights into bone biology and mechanisms associated with bone loss. This good news augurs well for the future.

Typical of our gender-oriented focus upon many diseases, however, the spotlight on osteoporosis has been on women, simply because women are much more likely to develop osteoporosis than men. This relative exclusivity has delayed progress in understanding the counterpart syndrome, osteoporosis in men. However, osteoporosis in men is not rare, nor are its consequences (1). This state of affairs is reminiscent of a decade ago when heart disease was considered to be primarily a disorder of males. With very little attention given to heart disease in women, it was also mistakenly assumed that what would be learned about male heart disease would automatically apply to female heart disease. Such erroneous assumptions have also been made in the field of osteoporosis; what we know about the female skeleton is often uncritically applied to the male skeleton. Alternatively, and also incorrect, what we know about the female skeleton has been regarded by some as nonoperative in men, simply because men with osteoporosis present differently.

Nevertheless, despite the pace, we are slowly learning about osteoporosis in men. It clearly is a pervasive disorder and in a number of respects is different from the disease in women. The purpose of this commentary is to place the available information about male osteoporosis into a practical and informative perspective.

Epidemiology

The number of men afflicted with osteoporosis is unknown. If one uses fracture as a clear end point, estimates of lifetime risk range from 13–25% (1). This is lower than estimates for Caucasian women, in whom lifetime fracture risk approaches 50%. The diagnosis of osteoporosis, however, no longer depends upon the end result of the disease process. The advent of quantitative imaging technology has allowed us to discover the population at risk before fractures occur. For men and women, fracture risk is directly related to bone mass. Using the WHO guidelines, osteoporosis is present if bone mineral density (BMD) is more than 2.5 SD below the peak bone mass reference standard for young women. When this criterion is applied to women in the United States, 4–6 million women have osteoporosis, and an additional 13–17 million women have osteopenia (BMD between 1–2.5 SD below peak bone mass). The respective age-adjusted prevalence figures are 18% and 50%. If one uses the same criterion for men, namely 2.5 SD below the peak bone mass reference standard for young men, 1–2 million men have osteoporosis, and another 8–13 million have osteopenia. The respective age-adjusted prevalence figures are 6% and 47%. It is not clear, however, whether the same cut-off values should be used, because men achieve more peak bone mass than women and have larger bones, two points that could argue that for the same percent reduction from the gender-based reference standard there would be fewer fractures in men. On the other hand, if one applies the female reference standard to men (2.5 SD below peak bone mass for women), the numbers become much smaller, namely 0.3–1 million men with osteoporosis (age-adjusted prevalence, 4%) and 4–9 million with osteopenia (age-adjusted prevalence, 33%). In either event, the proportion of men with osteoporosis or reduced bone mass relative to the entire population is substantial. Another key factor that tends to keep incidence figures below those for women is that men tend to develop osteoporosis later in life, by about a decade. As the male life span is shorter than the female life span, it has been quipped that men do not live long enough to sustain the complications of osteoporosis. For the same reason, however, namely that complications occur later in life, when men do sustain a hip fracture, associated mortality figures tend to be much higher than those in women.

However the incidence figures and diagnostic criteria are viewed, it is true that men in western countries are less likely to develop osteoporosis than women. Men achieve greater peak bone mass than women, by about 8–10%, when areal density is measured. A larger areal density (grams per cm2) probably confers a mechanical advantage even though volumetric density (grams per cm3) at peak bone age is not too much different among the sexes. In addition, aging in the male is associated with an enlargement of tubular and axial bones because periosteal bone apposition in the aging male skeleton is greater than that in the aging female skeleton. This point also confers a mechanical advantage to the male skeleton. Curiously, this protective mechanism does not pertain as much to the hip region, where periosteal sites of bone apposition are much less active. Another observation of importance is that men do not lose as much bone mass as women during the middle years, because they do not experience a menopause equivalent. Age-related bone loss, which occurs in both women and men, is accentuated by the superimposition of estrogen deficiency in women. In contrast, androgen levels are well maintained late into life. Other points that distinguish the male from the female insofar as fracture risk is concerned relate to the fact that men are not as likely to fall as are women.

Causes of osteoporosis in men

Peak bone mass is a major determinant of osteoporosis risk, because it is the reservoir that will ultimately be drawn upon as aging and other forces erode the skeleton. It has been estimated that genetics accounts for upward of 50–60% of peak bone mass, but the specific genes involved have not yet been well delineated. Most of the work implicating certain genes in osteoporosis have focused upon women and include the vitamin D receptor, the estrogen receptor, and the collagen type I {alpha}1 gene. We and others have conducted studies on the insulin-like growth factor I (IGF-I) gene in men whose osteoporosis is otherwise not well explained. This work, to be summarized (see below), is based on the studies of Rosen and colleagues in several inbred strains of mice (2).

Two rare experiments of nature have implicated estrogens as key factors in the establishment of peak bone mass in men. Smith et al. described a 28-yr-old man with a disruptive mutation of the estrogen receptor gene associated with estrogen resistance (3). Testosterone and dihydrotestosterone levels were normal, but estradiol and estrone levels were 2–2.5 times higher than the normal range for men. The young man had osteoporosis with bone mineral density that was more than 2 SD below the mean for 15-yr-old boys (the patient’s bone age). Administration of estrogen to this patient did not result in any improvement because of end organ resistance to estrogen.

Another rare genetic disorder also underscores the importance of estrogens in achieving peak bone mass in the male. Morishima et al. described a 24-yr-old man with a mutation in the aromatase gene (4). Aromatase enzyme activity is required for the conversion of androgens to estrogens. The genetic defect, a point mutation in the aromatase gene, was associated with no aromatase enzyme activity. The three major androgens, androstenedione, testosterone, and dihydrotestosterone, were all markedly elevated, whereas estradiol and estrone levels were undetectable. The patient was osteoporotic. In contrast to the patient reported by Smith et al., this patient responded to therapy with conjugated estrogens (5). Sex steroid measurements showed an increase in estrone and estradiol levels to normal and a reduction in androgen levels to normal. After 3 yr of conjugated estrogen therapy, bone mass increased markedly at the lumbar spine, femoral neck, and forearm. A second osteoporotic male with aromatase deficiency has been reported. He, too, was improved by estrogen therapy (6). These cases illustrate the importance of estrogen in establishing peak bone mass in the male.

Obviously, cases of estrogen resistance or estrogen deficiency in men are going to be discovered rarely, but these cases do illustrate the possibility that more subtle deficiencies in estrogen action or presence could predispose some men to suboptimal achievement of peak bone mass. Genetic studies in men with unexplained osteoporosis are needed to test the hypothesis that certain polymorphisms of the genes involved in the genetic diseases described could be a major etiological determinant.

Establishment of peak bone mass in the male is also dependent upon adequate androgen levels, normal timing of puberty, and other factors that have been well established in women, such as adequate nutrition, sufficient dietary calcium, and exercise.

Maintenance of bone mass in men

Bone mass is generally well maintained in men, with slow, but perceptible, changes over time. In the unusual setting of acute hypogonadism in the male, however, bone loss can be rapid, similar to menopausal bone loss in the female (7). In part, slow, age-related declines are related to the slow decline in androgen levels. Recent observations have suggested, additionally, that declining estrogen levels may also be important. A reduction in estrogen levels has been shown in several studies to be more closely related to the reduction in bone mass than are declining androgen levels. Certainly, other factors are important in the maintenance of bone mass in the male. As in women, smoking, excessive alcohol intake, deficient dietary calcium, and sedentary life style are all additional factors that influence maintenance of bone mass (8).

Osteoporosis in men

The three major causes of osteoporosis in men are alcohol abuse, glucocorticoid excess (either endogenous Cushing’s syndrome or, more commonly, chronic glucocorticoid therapy), and hypogonadism (1, 9). In many series, these etiologies account for 40–50% of all men with osteoporosis. Other causes are also important to rule out, such as primary hyperparathyroidism, excessive thyroid hormone exposure (hyperthyroidism or overtreatment with thyroid hormone), multiple myeloma and other malignancies, anticonvulsants, high dose chemotherapeutics, and gastrointestinal disorders (8, 10). Occult gastrointestinal tract disease is important to consider in a man whose osteoporosis is not readily explained. In my experience, these men are typically not symptomatic of gastrointestinal manifestations. Clues to a possible occult gastrointestinal disorder are low 25-hydroxyvitamin D levels, high PTH levels, and low urinary calcium excretion. In this setting, gluten enteropathy needs to be considered in particular.

Osteoporosis in men is sometimes associated with hypercalciuria and biochemical indexes suggesting high bone turnover (11). The hypercalciuria could be etiological or a marker for some other disorder of mineral metabolism. The mechanisms of bone loss in men with hypercalciuria are not clear.

The list of potential other causes of osteoporosis in men is long and should be reviewed in anyone in whom the diagnosis is unknown. When all known or likely causes are ruled out, approximately 40–50% of men in most series will not be shown to have a clear-cut etiology (8, 10). The term idiopathic osteoporosis has been applied to these individuals. Idiopathic osteoporosis can be defined simply as osteoporosis that occurs in men without any known cause. There is an age limit associated with this definition, because eventually, if men live long enough, bone loss due to aging will reach a point at which osteoporosis can be explained reasonably on the basis of age alone. It seems acceptable, therefore, to set an upper age limit of 70 yr to this diagnostic category. This is not to say that the ultimate cause(s) of idiopathic osteoporosis will not also be applicable sometimes to men over 70 yr. Similarly, it is possible that some men younger than 70 yr will become osteoporotic simply due to an aggregate of risk factors and that their osteoporosis can be explained without invoking other, as yet unknown, mechanisms. In general, however, the younger the patient the more likely it seems that other explanations are needed to account for the syndrome. In men under 70 yr with osteoporosis of unknown etiology, a rather typical clinical and histomorphometric phenotype is seen.

Characteristics of idiopathic osteoporosis in men

Men with idiopathic osteoporosis are usually symptomatic of fracture or back pain. This presentation is quite different from the typical postmenopausal woman with osteoporosis, in whom it is becoming more common for the diagnosis to be made by bone mass measurement in the absence of symptoms. Not so is the current situation in men. It is uncommon for bone mass measurements to be obtained in men, even in the presence of clear-cut risk factors for osteoporosis. In virtually all series that have been published on this subject (12, 13, 14, 15, 16), including our own, the initial presentation is a symptomatic one, with fracture or back pain. By definition, gonadal, hepatic, and adrenal function are normal, as are the serum calcium, phosphorus, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, PTH, and TSH concentrations. The average urinary calcium concentration is normal. Serum and urinary markers of bone turnover are all also normal. Typical bone mass measurement reveals markedly reduced bone mineral density. In our experience, the mean T score is less than -3.0. Histomorphometric analysis of the bone biopsy indicates a low turnover state.

Etiological considerations

In a syndrome defined by ignorance, as the word idiopathic implies, etiological considerations are clearly speculative, but among causal candidates, IGF-I has received much attention. Several reports have shown a significant reduction in IGF-I values and have correlated these reductions with reduced bone density of the spine and forearm (15, 16, 17). IGF-I levels decline as a function of age, but at any age, the reductions in these men are lower than expected. GH deficiency does not easily explain these reductions, because these men respond normally to GH stimulation tests (18). However, it remains possible that subtle abnormalities in GH dynamics exist in terms of either pulsatility or circadian rhythm. The reduction in IGF-I levels seem to be associated with a particular allelic configuration of the polymorphic microsatellite region of the IGF-I gene composed of variable cytosine-adenosine repeats 1 kb upstream from the transcription start site. The frequency of homozygosity for the allele in question, designated 192, in the men with idiopathic osteoporosis was 64%, twice as high as that in a number of control populations (19). The gene frequency for this allele was greater than 90%. The mean IGF-I level for those with the 192/192 genotype was significantly lower than that for subjects with any other genotype. Ongoing studies will hopefully clarify further a pathophysiological relationship between these genetic studies and clinical aspects of the disorder.

Clinical approach and management

The diagnosis of osteoporosis in the male patient is typically made by bone densitometry in the context of symptoms or signs. As most men are symptomatic, with skeletal complaints or fractures, a bone mineral density T score of less than -2.5 would be consistent with the diagnosis of osteoporosis. If the patient is asymptomatic, however, a T score of less than -2.5, using a male standard database, would not carry with it the same risk of fracture as a T score of less than -2.5 using the female database. In the absence of symptoms or signs, therefore, there is need to reconsider what is the best T score definition of osteoporosis in the male. When a consensus is reached finally, it is likely that the definition by T score will be adjusted downward (i.e. less than -2.5) to match the risk that is present in the Caucasian female with a T score of -2.5.

All reasonable potential causes of bone loss should be considered. Routine measurements of calcium, phosphorus, alkaline phosphatase, and serum proteins as well as liver, renal, adrenal, pituitary, and thyroid function tests are indicated. Sex steroid measurements should include total testosterone, estrone, estradiol, and sex hormone-binding globulin. Tests of the calciotropic axis include PTH, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels. Specific markers of bone formation (serum bone-specific alkaline phosphatase activity or osteocalcin) and of bone resorption (urinary calcium and collagen cross-links N-telopeptide or deoxypyridinoline) are obtained. A percutaneous bone biopsy can be helpful to ascertain more definitively the histomorphometric and dynamic indexes of the disorder. The bone biopsy can also help to rule out potential causes not readily apparent, such as occult forms of osteomalacia, acquired osteogenesis imperfecta, mastocytosis, and malignancy.

If the diagnosis is known, one takes specific therapeutic measures to deal with the underlying disorder. In those patients as well as in those in whom the diagnosis is not known, initial therapeutic considerations are similar to the approach used for osteoporotic woman. Dietary calcium intake should be 1200–1500 mg, consistent with the NIH and Food and Nutrition Board recommendations for optimal calcium intake (20, 21). Vitamin D intake must also be adequate. Individuals should receive 400–600 IU/day. This is somewhat higher than the current RDA for vitamin D, but is consistent with the newer Food and Nutrition Board guidelines.

Adequate exercise is certainly to be strongly recommended. In individuals who have sustained compression vertebral fractures or other complications, exercise should be appropriate to the setting. The nature of the antigravity exercise and its extent are issues that sometimes may require the services of a physical therapist. Weight training that provides additional mechanical stimulus to selected sites may also have a role. Smoking should be banned, and excessive alcohol intake must be avoided. In general, androgen therapy is not used in individuals whose gonadal function is normal.

Information about specific therapies are limited. Data on the effectiveness of alendronate therapy in men will soon be available. It is reasonable to expect that antiresorptive therapy with alendronate and newer bisphosphonates will be shown to be effective. In view of the fact that bone dynamics appear to be suppressed in men with idiopathic osteoporosis, an attractive alternative therapeutic approach to this syndrome is the use of an anabolic agent. Low dose, intermittent administration of PTH can be associated with anabolic effects at cancellous sites (22, 23, 24). Such impressive gains are promising and encourage further development of PTH as a therapeutic agent in idiopathic osteoporosis in men. Other possible anabolic approaches for which there are even more limited data include fluoride and GH.

Patients are monitored with sequential bone mass measurements, as they are useful surrogate indexes of therapeutic efficacy. The use of bone markers that give information about changes in bone formation and resorption may also be helpful, as has been shown in a number of large scale studies in postmenopausal women (25, 26). It is possible that a reduction in bone markers after antirresorptive therapy in men will provide the same predictive information about therapeutic results as has been shown in postmenopausal women, but such studies are not yet available.

Footnotes

1 This work was supported by Grants FD-R001024 from the FDA, AR-39191 and RR-MO1–000645 from the NIH, and the Partnership for Women’s Health (Columbia University, New York, NY). Back

Received May 12, 1999.

Revised June 30, 1999.

Accepted July 17, 1999.

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