Osteoporosis in men has been associated with diseases and drugs that threaten bone mass, such as hypogonadism, hyperthyroidism, excessive alcohol intake, smoking, and exposure to high-dose glucocorticoids [14-23]. In some instances, however, the cause of the osteoporosis is not apparent. Primary or idiopathic osteoporosis in adults does occur in men [16, 20, 22, 24-31]. Susceptibility to vertebral fractures has been recognized, and the hypercalciuria noted in previous studies has varied [16, 20, 24-31]. Both high and low skeletal turnover rates have been reported [16].

Our metabolic bone disease unit is a regional referral service for patients with osteoporosis and other metabolic bone diseases. We consecutively evaluated men with osteopenia over 7 years, and our clinical, biochemical, densitometric, and histomorphometric observations indicate that secondary osteoporosis is common in men with severe osteoporosis. We also reviewed 14 clinical reports of primary osteoporosis in men (377 cases) and compared the reported features with our findings from 17 patients for whom a cause of osteoporosis could not be determined.

Methods

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Patients

Forty-seven white men were referred to the Metabolic Bone Disease clinic at the Hospital of the University of Pennsylvania between 1980 and 1987. All referrals were prompted by fractures with no or minimal trauma or with severe osteopenia. All patients gave informed consent and were evaluated at our general clinical research center. At the center, the patients were provided a diet that matched their usual calcium intake, as determined from a diet history obtained by our nutritionist. Relevant roentgenograms were provided by referring physicians or were obtained during the evaluation. Previous medical records were reviewed to determine the patients' earlier medical disorders and treatments. Each patient completed a questionnaire designed to identify risk factors associated with skeletal compromise. Family members were interviewed to corroborate medical and social histories. At the time of evaluation, the patients with primary osteoporosis had no history of familial osteoporosis, delayed puberty [19], insulin-dependent diabetes mellitus, severe arthritis, malabsorption, gastrointestinal surgery, or malignant disease. None of these patients deviated more than 15% from their ideal body weight, and none had a history of serious concurrent medical illnesses or use of any drugs recognized to unfavorably affect bone metabolism [13, 16, 22]. Investigations were done to exclude secondary osteoporosis.

Biochemical Analyses

After an overnight fast, the following blood tests were done in our hospital's clinical laboratories: hematology profile; serum protein electrophoresis; and measurement of serum calcium, inorganic phosphorus, albumin, creatinine, alkaline phosphatase, electrolyte, hepatic enzyme, immunoreactive parathyroid hormone (carboxy-terminal assay), thyroxine, triiodothyronine resin uptake, thyroid-stimulating hormone, and testosterone levels. Tests to measure 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D levels were done by Nichols Laboratories (San Juan Capistrano, California). Twenty-four-hour urine specimens were analyzed for calcium, phosphorus, creatinine, and free cortisol levels. Fasting, second-void urine specimens were analyzed for calcium and creatinine levels.

Bone Mineral Densitometry

Bone mineral density of the lumbar spine was measured by quantitative computed tomography or dual-photon absorptiometry, or both. The latter technique was not available before 1984. Dual-photon absorptiometry of L1 to L4 (Lunar Radiation Corporation, Madison, Wisconsin) was done with a gadolinium source in a DP-3 scanner [32]. Quantitative computed tomography of T12 to L4 was done with a GE9800 computed tomographic scanner (General Electric, Milwaukee, Wisconsin) using previously described methods [33]. In follow-up studies, bone mineral density of the lateral spine was analyzed with a Lunar dual-energy x-ray absorptiometer, and reference values were obtained for age-matched normal men [34]. We did not do paired analyses with the dual-photon and dual-energy x-ray instruments. Bone density was expressed as the T score (number of standard deviations from the average value for healthy young men). We used the method of Eastell and colleagues [35] to assess nonovert vertebral fractures.

Bone Histomorphometry

In 35 men (74%), a full-thickness, transiliac bone biopsy specimen was obtained after tetracycline dual labeling. The cylindric biopsy specimens were processed undecalcified according to a standard protocol [36]. The following variables were quantitated using 200 microscopic fields: trabecular bone volume (percentage of total), trabecular wall thickness (microns), total osteoid surface (mm²/mm³), osteoclasts (cells per mm² of medullary space), eroded surface (percentage of total), and bone formation rate (µ m³/mu m² per year). The findings were compared with normal, age-matched male values reported in the literature.

Statistical Analysis

We calculated summary values and variances for patient characteristics and intergroup comparisons. Because our study did not include a paired, normal group, we interpreted our biochemical data in comparison with the laboratories' normal ranges. Because histomorphometric data for normal men were available, we used reference values that reflected a normal population and that matched the ages of our study group. Several patients in the idiopathic osteoporosis group were available for follow-up visits and repeated densitometric measurements. These data included unequal spacing and different lengths of follow-up and were therefore subjected to a random-effects regression analysis [37]. This approach permits an estimate of the effect of time within each patient, which is then averaged over patients; this gives more precision to the analysis of the trend over time.

Results

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Clinical Presentation

Clinical characteristics are shown in Table 1. Forty-three patients (91%) were referred because of fractures. Twenty-seven men (57%) had vertebral fractures, and 16 (34%) had appendicular fractures. Four patients (9%) were referred because of the incidental recognition of radiographic osteopenia, and all patients were found to have primary osteoporosis.

We grouped our patients according to the presence or absence of factors associated with osteoporosis (Table 1). Disorders that are known to be associated with bone loss were found in 30 men (64%). Group 1 (secondary osteoporosis) was composed of men with disorders that commonly cause osteoporosis and was subdivided according to the patients' underlying disorders. Group 1A consisted of seven men who had previously taken glucocorticoids (> 25 g of prednisone [or equivalent] total lifetime dose) but were not taking it at the time of the metabolic bone disease work-up and of one man with surgically documented Cushing disease. Group 1B consisted of seven men with excessive alcohol intake (> 100 g/d for many years), and group 1C consisted of seven men with primary or secondary hypogonadism.

We chose not to tabulate a miscellaneous group of men with the following diagnoses: osteomalacia related to renal phosphate wasting, aluminum antacid use, or anticonvulsant therapy (four patients); hyperthyroidism (two patients); osteoporosis related to anticonvulsant use (one patient); and multiple myeloma (one patient).

Group 2 (primary or idiopathic osteoporosis) consisted of 17 men (36%) who had no recognized condition or collection of risk factors associated with osteoporosis (Table 1).

Bone Densitometry

Densitometry showed strikingly low values in all groups studied, as would be expected from our referral pattern. For all groups, lower density was found with quantitative computed tomography (trabecular bone only) compared with the integral (cortical and trabecular bone) vertebral density measured by the dual-photon absorptiometry technique. Of 43 men measured, 94% had bone density values greater than 2 standard deviations below the mean value for healthy 30-year-old men. Thirty-six of 43 men (79%) were found to have bone density values greater than 2.5 standard deviations below the normal mean for young men.

Biochemical Analyses

Serum calcium, albumin, and creatinine levels and hemograms were usually in the normal range. Low serum phosphorus values were observed in the patients with renal phosphate-wasting. Total serum alkaline phosphatase levels were normal except in men with recent fracture, osteomalacia, and anticonvulsant use. Elevated hepatic aminotransferase levels were seen in three men in group 1B and one man in group 2; this latter patient was known to have hepatitis without cirrhosis. Serum vitamin D metabolite and C-terminal parathyroid hormone levels were within the normal range except for levels in two patients with osteomalacia. Mean serum testosterone levels were strikingly lower in the patients in group 1C (6.1 mmol/L) than levels in group 2 patients (22.3 mmol/L) and values in the normal reference range (12.5 to 31 mmol/L).

The 24-hour urinary excretion of free cortisol and serum thyroid function test results were normal in all groups. All men had normal creatinine clearances. The mean (±SD) 24-hour excretion of urinary calcium was in the high end of the normal range (3.7 ± 1.8 mg/kg body weight) for patients in group 2. In six patients (35%) in group 2, the 24-hour urinary excretion of calcium was 4 mg/kg or greater while they were receiving a moderate amount of daily calcium (12 to 25 mmol/d). The mean fasting calciuria level was normal in all groups, but the mean fasting calcium/creatinine ratio was at the high end of the normal range (0.136 ± 0.09) in the patients in group 2. Studies were not repeated during dietary calcium restriction.

Bone Biopsy Specimens

In the men with primary osteoporosis, histologic variables were compared with published data for healthy men aged 20 to 44 years and 46 to 75 years [27, 28, 38, 39]. As expected, cancellous bone volume was considerably lower in the younger men with primary osteoporosis and in all of the older men (Table 2). Osteoid surface and thickness of the trabecular wall did not differ from published normal values, indicating that osteoblastic activity had not markedly decreased. Bone formation rates varied widely and did not differ from the control values found in the literature. Percentages of eroded surface were modestly increased in both age groups within the primary osteoporotic group. The osteoclast numbers were slightly increased. Thus, clear increases in bone resorption variables were not seen in our patients.

Follow-up Studies

Of the 17 men with idiopathic osteoporosis, 5 elected to receive pharmacologic treatment (calcitonin, thiazides, sodium fluoride, or bisphosphonate), 2 were lost to follow-up, and 2 died of unrelated conditions. The remaining 8 men did not choose any management other than low-impact, moderate physical activity; avoidance of heavy lifting; and elemental calcium supplementation of their diets to a total intake of 1 g/d. These men reported no further fractures. Repeated bone mineral density testing was done over a period of 6 months to 9 years after diagnosis. Trend analysis, by random-effects regression [37], showed a slight (0.02 standard deviations per year) average increase in spinal bone mineral density during the conservative management of these men.

Follow-up spinal bone mineral density measurements were done in three of the five men receiving pharmacologic treatment. In two men intermittently receiving oral sodium fluoride, 40 mg/d, bone mineral density improved by 46% (as shown by quantitative computed tomography after 30 months of drug treatment) and 24% (as shown by dual energy x-ray absorptiometry after 22 months of treatment), respectively. In another patient intermittently receiving disodium etidronate, 10 mg/kg per day, spinal bone mineral density increased by 14% (as shown by dual-energy x-ray absorptiometry after 20 months of therapy). None of these three men developed any further skeletal morbid conditions. Two other patients began receiving thiazide or calcitonin but did not return for reevaluation.

Discussion

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We found that severe osteoporosis in nonelderly men was usually associated with conditions known to be major causes of bone loss. Approximately two thirds of our referred patients had diseases, medication use, or lifestyles that have been linked to substantial bone loss [16]. In published series (Table 3), secondary causes of osteoporosis are found in 26% to 72% of patients (some of the series included likely secondary causes among the patients with primary osteoporosis). The true incidence of idiopathic osteoporosis in men is difficult to determine because population characteristics and referral patterns differ so widely. However, Khosla and colleagues [27] have recently reported that osteoporosis in young persons occurs at an incidence rate of 4.1/10⁵ patient-years, with a female to male ratio of 1.2/1.0.

Among men with secondary osteoporosis, several conditions are repeatedly found in previous studies: glucocorticoid excess; hypogonadism; liver disease and excessive ethanol consumption; severe, miscellaneous medical conditions; gastrointestinal diseases and surgery; protracted immobilization; and heavy tobacco use [13-31]. In our series, we detected excessive glucocorticoids (17% of patients), hypogonadism (15%), and excessive alcohol consumption (15%) as major causal factors. Our findings resemble those of Seeman and colleagues [22], Jackson and colleagues [17], Francis and colleagues [26], and Resch and colleagues [31].

It is well recognized that excessive glucocorticoid exposure unfavorably uncouples bone remodeling and leads rapidly to skeletal morbid conditions. Patients exposed to steroids can develop hypercalciuria, secondary hypogonadism, and mildly elevated serum parathyroid hormone levels [13, 16, 21, 22, 38, 40, 41]. As in women, hypogonadism in men is a serious threat to skeletal integrity [14-17, 19]; the evolution of this disorder may be insidious because its nonskeletal features may not be clinically apparent in as many as 50% of cases [30]. Hypogonadism might play a role in aging-related bone loss in men [13, 42, 43], but the differentially regional bone loss in women that develops after menopause appears more convincing [1, 4]. The recent report of a 28-year-old man with osteoporosis and an estrogen receptor mutation suggests that androgen indirectly affects the skeleton [44]. Longitudinal studies of bone density in aging men have shown substantial appendicular and axial bone loss [45]. Seven of our patients reported long-term heavy ethanol consumption, and six of the seven had vertebral fractures as well as severe osteoporosis (Table 1). Alcohol excess has clearly been associated with markedly reduced rates of bone formation [17, 46] and decreased vertebral cancellous density [46]. Appendicular and rib fractures are also seen [13, 30, 47], and osteoporosis can develop in young alcoholic men before cirrhosis is seen [48].

Primary Osteoporosis

Fractures and Bone Mineral Density

Our patients with primary osteoporosis (Table 1, group 2) had severe axial osteoporosis, and 47% had spine fractures. This fracture incidence is similar to incidences reported for primary osteoporosis in men (Table 3) in studies in which selection was not determined by the presence of vertebral fractures [25, 27, 29, 39] associated with minimal to no trauma. Although we did not measure appendicular bone mineral density, five of six previous reports found low opacity in the hand, forearm, or hip, and 5 of our 17 patients with primary osteoporosis sustained appendicular fractures during minimal trauma. Together, our data and published reports suggest that primary osteoporosis in men is associated with both cancellous and cortical bone loss.

Biochemical Tests

Hypercalciuria is a frequent finding in the reported cases of primary osteoporosis in men (7 of 11 published series), apparently occurring more frequently than idiopathic hypercalciuria in normal men. In studies in which calciuria was measured while patients received full and restricted amounts of dietary calcium [25, 29, 39], calciuria was sharply reduced during dietary restriction. These findings suggest intestinal hyperabsorption of calcium. We observed fasting calciuria values at the high end of normal range and values higher than normal in 7 (41%) of our 17 patients with primary osteoporosis; this finding is similar to one by Resch and colleagues [31]. Hypercalciuria can also indicate bone resorptive or renal mechanisms, but most published information does not clearly indicate strongly increased bone resorption or renal leak of calcium as the reasons for hypercalciuria in primary osteoporosis. Furthermore, studies of calcium balance have shown a spectrum of results with no consistent imbalances [26, 29]. Francis and colleagues [26] described decreased intestinal absorption of calcium in 10 men with primary osteoporosis and reduced plasma 1,25-dihydroxyvitamin D concentrations within the normal range. Zerwekh and coworkers [25] found normal calcium absorption in 12 of 16 patients and increased absorption in 4 men with increased plasma 1,25-dihydroxyvitamin D concentrations. The published experience (Table 3) indicates that hypercalciuria frequently occurs in men with primary osteoporosis, but the mechanism of this condition has not been consistently defined.

Urine hydroxyproline excretion was measured in a few studies [24-2629, 31], but inconsistent results (normal or high excretion) were seen in men with primary osteoporosis. Because more specific biochemical markers of bone resorption and formation have recently been developed, their applications in this condition will be of interest.

Blood parathyroid hormone levels are uniformly reported to be normal or at the low end of the normal range, and, except for some subgroups, vitamin D metabolite levels are usually in the normal range. Decreased 25-hydroxyvitamin D levels were seen in persons with poor nutrition [20]. Our patients without a diagnosis of osteomalacia had normal parathyroid hormone and vitamin D metabolite levels.

Skeletal Histologic Findings

The skeletal histologic findings reported in primary osteoporosis have been used to help sort out the nature of the bone loss mechanisms involved. Of 11 studies of biopsy specimens (excluding our paper), 9 have shown some decrease in osteoblastic activity [17, 20, 24-2839, 49, 50], especially in cancellous bone. In young men with primary osteoporosis, decreases in osteoid and osteoblast surfaces were frequently seen, along with decreased bone formation rates and decreased numbers of trabeculae without thinning. The amount of trabecular bone formed by osteoblasts during a remodeling cycle (mean wall thickness) was not reduced in our series Table 2, but a reduction has been seen in young (< 50 years) persons in two of five series [27, 40]. This latter finding may suggest a premature onset of the sluggish osteoblast activity seen in the elderly [51]. However, a wide spectrum of wall thickness values was seen in these studies, indicating a heterogeneous histologic picture compared with available normal data. In these studies, bone resorption measurements, which are generally less secure, varied and were not usually increased in absolute terms. In most studies of young patients, the bone loss in primary osteoporosis therefore appears to be due to an absolute decrease in bone-forming activity and a relative and modest increase in resorptive activity. In our patients Table 2, failure to clearly detect such changes was probably due to our center's lack of normal reference data, the small number of patients studied, and generally recognized interlaboratory variations.

Heterogeneous Features of Primary Osteoporosis in Men

A review of the series of primary osteoporosis in men leads us to conclude that most of the reported findings are not consistently seen. For example, calciuria, calcium balance alterations, and increased hydroxyprolinuria are not uniformly present. Bone histologic findings indicate some decreased osteoblastic activity in most cases, but increased bone resorption measures have also been reported. However, evidence (when examined) for both cortical and trabecular bone loss is convincing. A confounding factor in previous clinical reports has been the sparse characterization of patients and the inclusion of now-recognized patients with secondary osteoporosis along with the patients with primary osteoporosis [20, 30, 52, 53].

Patient Management

Little information is available on the course or treatment of primary osteoporosis in men [54-56]. Most of the related information has been derived from studies in women or from relatively short-term analyses of bone mineral density changes or biochemical changes in men [54-56]. All the antifracture efficacy studies evaluating therapy for osteoporosis have been done in osteoporotic women [56]. The only controlled trial to evaluate calcium supplementation in healthy, aging men did not show a beneficial effect on spinal or appendicular bone density [45]. We observed stable to slightly increased bone mineral density during conservative management of a subgroup of our patients with primary osteoporosis. However, we cannot fairly extrapolate our findings to all patients with primary osteoporosis because our follow-up involved only a few, severely affected men during a time when our densitometric technology changed. Substantial bone loss in men, as with women [2], may be followed by a slower rate of loss. It is also conceivable that some men have primary osteoporosis as a result of attaining a low peak bone mineral density earlier in life [56].

Conclusions

Osteoporosis in men is a relatively neglected disorder, but most thorough evaluations of severe cases should show secondary causes. Primary osteoporosis in men is not rare, appears to be heterogeneous in many of its features, and involves the axial and appendicular skeleton. Because we currently have sparse data on pathogenetic mechanisms and almost no information on the course or treatment of primary osteoporosis in men, more analyses and effort, possibly in multicenter studies and trials, are welcome.

Dr. Harper: Bone and Metabolic Diseases, Duke University, 702 Trent Drive, Durham, NC 27705.

Dr. Gannon: Department of Pathology and Laboratory Medicine, Hospital of the University of Pennsylvania, 6 Founders, 34th and Spruce Streets, Philadelphia, PA 19104.

Dr. Kaplan: Department of Orthopaedic Surgery, University of Pennsylvania, 2 Silverstein, 34th and Spruce Streets, Philadelphia, PA 19104.

Dr. Haddad: Division of Endocrinology, Diabetes, and Metabolism, University of Pennsylvania School of Medicine, 611 Clinical Research Building, 415 Curie Boulevard, Philadelphia, PA 19104-6149.