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Alendronate Treatment of Established Primary Osteoporosis in Men: Results of a 2-Year Prospective Study

Medizinische Klinik 4, Klinikum Leverkusen, Akademisches Lehrkrankenhaus der Universität zu Köln, 51375 Leverkusen Germany

Address all correspondence and requests for reprints to: Prof. Dr. Johann D. Ringe, Medizinische Klinik 4, Klinikum Leverkusen, Akademisches Lehrkrankenhaus der Universität zu Köln, 51375 Leverkusen Germany.

Abstract

Men with osteoporosis have been neglected in the past, and only a few therapeutic trials have been performed in men. The bisphosphonate, alendronate, has been widely used for the treatment of postmenopausal osteoporosis. This prospective, open label, active controlled, randomized clinical study compared the effects of oral alendronate (10 mg daily) and alfacalcidol (1 µg daily) on bone mineral density (BMD), safety, and tolerability in 134 males with primary established osteoporosis. All men received supplemental calcium (500 mg daily). After 2 yr, alfacalcidol-treated patients showed a mean 2.8% increase in lumbar spine BMD (P < 0.01) compared with a mean increase of 10.1% in men receiving alendronate (P < 0.001). The corresponding changes in femoral neck BMD were +2.2% and +5.2% for the alfacalcidol and alendronate groups, respectively (P = 0.009). The incidence rates of patients with new vertebral fractures were 18.2% and 7.4% for the alfacalcidol and alendronate groups, respectively (P = 0.071). Both therapies were well tolerated.

Thus, alendronate produced favorable effects on BMD consistent with the results from another study in male osteoporosis. The average increase rates were higher than with alfacalcidol. Alendronate may be superior to alfacalcidol in the treatment of men with established primary osteoporosis.

OSTEOPOROTIC FRACTURES ARE a common and important cause of morbidity and mortality among postmenopausal women (1). Osteoporosis occurs less frequently in men due to several factors, including greater accumulation of skeletal bone mass during youth, greater bone size, the absence of a distinct equivalent of menopause, and a shorter average life span (2). However, approximately 25–30% of all hip fractures occur in men (3), and the age-adjusted prevalence of vertebral deformities appears to be similar in men and women (4).

In the past no widely accepted or approved therapies existed for the treatment of osteoporosis in men. Androgen replacement therapy has been shown to have positive effects on bone mineral density (BMD) in hypogonadal men (5, 6), but not in men with normal gonadal function (7), who represent the majority of men with osteoporosis. Very little information is available on other therapeutic agents (8, 9).

Alendronate, a potent bisphosphonate that inhibits osteoclast-mediated bone resorption, has been shown to increase bone mineral density (BMD) and reduce the incidence of fractures, including those at the spine and hip, in postmenopausal women (10, 11, 12). Recently, alendronate has also been shown to increase BMD and decrease the incidence of vertebral fractures in osteoporotic men (13). In the current study we confirmed the positive effects of alendronate on BMD in men and showed a favorable trend to reduced vertebral fractures. As a consequence, alendronate was approved in 2000 for the treatment of osteoporosis in men in the United States.

Subjects and Methods

Study subjects

This single center, open label, randomized, prospective 2-yr study enrolled 134 men with established primary osteoporosis. Osteoporosis was defined as a baseline lumbar spine BMD t-score more than 2.5 SD below the normal young male mean.

Exclusion criteria included hypogonadism, other causes of secondary osteoporosis, major upper gastrointestinal disease (ulcer or esophagitis), renal insufficiency, hypo- or hypercalcemia, and prior treatment with fluoride during the previous 6 months. No patient had ever previously received bisphosphonates.

Patients were recruited consecutively from males referred to our department for care. Patients with reduced serum T and/or clinical symptoms of hypogonadism were excluded. Vitamin D was not measured at baseline, but normal values for serum calcium, alkaline phosphatase, and 24-h urinary calcium excretion excluded clinically relevant vitamin D deficiency in these middle-aged men.

Study design

One hundred and thirty-four patients, who all gave informed consent, were randomized to receive either alendronate (10 mg daily; n = 68) or 1-alfacalcidol (1 µg daily; n = 66). All patients received 500 mg/d elemental calcium. The alfacalcidol preparation was Doss (Byk-Gulden, Konstanz, Germany). No other vitamin D preparation was given to either group.

Outcome measurements

The patients were seen at baseline and at 6, 12, 18, and 24 months. A medical history and physical examination, including single height measurements, were obtained at each visit. The BMDs of the lumbar spine and femoral neck were measured at baseline and at 6, 12, 18, and 24 months by dual energy x-ray absorptiometry using the DEXA-Expert technique (Lunar Corp., Madison, WI). Regular instrument and operator quality control measures were carried out and analyzed. The t-score values at baseline for both measuring sites were calculated from a young male database provided by the manufacturer.

Spine x-rays were obtained at baseline and yearly thereafter. All x-rays were reviewed by a radiologist who was blinded to treatment assignment. The radiologist determined, by visual inspection, the presence of a definitive fracture. For questionable vertebral fractures, vertebral heights were measured (anterior, median, posterior), and a new vertebral fracture was defined as a decrease in any vertebral height of at least 20%.

Statistical analysis

The primary end points of our study were the mean change in lumbar spine and femoral neck BMD. Secondary end points included vertebral and nonvertebral fractures and stature. All analyses were performed as intention to treat (i.e. participants were classified according to their treatment assignment regardless of compliance). All comparisons were two-sided and used P 0.05 or less to ascertain significance.

Results

Baseline characteristics

The baseline characteristics of the 134 patients are shown in Table 1 and were similar in both treatment groups. The mean lumbar spine and femoral neck BMD were approximately 3.4 and 2.5 SD, respectively, below the normal reference young adult mean. Approximately 54% of the subjects enrolled had at least one prevalent vertebral fracture at baseline. The median number of vertebral fractures for those who had fractures was 1.2 in the alfacalcidol group and 1.3 in the alendronate group.

One-hundred and eighteen patients (88%) completed 2 yr of treatment: 60 in the alfacalcidol group and 58 in the alendronate group.

BMD changes

Mean changes in BMD relative to baseline after 2 yr are shown in Table 2, and the time course is shown in Fig. 1 , A and B. At the end of yr 2, the BMD increases relative to baseline seen in the alendronate group at both the lumbar spine and the femoral neck were significantly greater than those in the alfacalcidol group (P = 0.001 and P = 0.009, respectively). Most of the increases in BMD took place during the first year of the study, but in the second year the tendency for increase persisted. About 87% of the patients taking alendronate had an increase in spine BMD of at least 3% compared with only 46% in the alfacalcidol group. The corresponding figures at the femoral neck were 63% and 33% for alendronate and alfacalcidol, respectively.

View larger version (20K): [in this window] [in a new window]   Figure 1. A, Mean (±SE) percent change in lumbar spine BMD. B, Mean (±SE) percent change in femoral neck BMD. ALN, Alendronate; AC, alfacalcidol.

Fractures

Vertebral fractures occurred in 5 of 68 alendronate patients (7.3%) and 12 of 66 patients (18.2%) in the alfacalcidol group (P = 0.071). The odds ratio of incident vertebral fractures in alendronate patients compared with patients treated with alfacalcidol was 0.36 (95% confidence interval = 0.09, 1.18). This 64% reduction in vertebral fracture risk seen in the alendronate group was not statistically significant (P = 0.071). The total number of vertebral fractures in the alendronate group (n = 5) was significantly reduced compared with the total number of vertebral fractures in the alfacalcidol group (n = 14; P = 0.046).

Nonvertebral fractures occurred in six patients (8.7%) in the alendronate group and eight patients (12.1%) in the alfacalcidol group (P = NS).

Stature

After 2 yr of treatment, the men in the alfacalcidol group lost 8.3 mm in stature compared with a loss of only 1.4 mm in the alendronate group (group difference, P = 0.030).

Safety and tolerability

Both treatment regimens were generally well tolerated. Clinical adverse experiences were reported by 31 patients taking alfacalcidol and 26 patients taking alendronate. The most frequent events were epigastric pain, hypercalciuria, soft stool, and obstipation. All adverse events were clinically moderate. There were no treatment-related drop-outs. Of note, hypercalciuria was reported in 12.1% of the alfacalcidol-treated patients compared with only 4.4% of the men receiving alendronate (P = 0.04). Nephrolithiasis was reported in 3 patients in the alfacalcidol group and 1 patient in the alendronate group. Two patients in each group had a history of previous kidney stones. There was no event of hypercalcemia in both groups.

Discussion

In this study of men with primary osteoporosis, alendronate (10 mg daily) treatment for 2 yr produced approximately a 10% gain in BMD at the lumbar spine and a 5% gain in BMD at the femoral neck. Alendronate therapy did not significantly reduce the number of patients with new vertebral fractures. Only the total number of new vertebral fractures was significantly decreased in the alendronate group. The latter is remarkable if one considers that the control group was receiving active therapy with alfacalcidol, which also produced a significant increase from baseline in lumbar spine BMD. Consistent with the vertebral fracture data, height loss was significantly reduced in patients taking alendronate compared with those receiving alfacalcidol. Alendronate was generally well tolerated in these men. Overall, these results are very consistent with those previously reported in studies of postmenopausal women with osteoporosis and in another clinical study of osteoporotic men (13). The alendronate-treated patients in the latter study experienced similar changes from baseline in lumbar spine and femoral neck BMD (7.1% and 2.5%, respectively) as the men in our study (10.1% and 5.2%, respectively). The greater increase in BMD relative to baseline observed in our study may be due in part to the lower BMD levels at baseline.

Consistent findings are not surprising in view of similarities between male and female osteoporosis. Although the etiology of osteoporosis may differ somewhat between men and women, the underlying pathophysiological mechanism is, nonetheless, the same, namely, an absolute or relative (to bone formation) increase in osteoclast-mediated bone resorption, leading to progressive bone loss. At menopause, bone loss accelerates in women, accounting for the high prevalence of osteoporosis in older women. However, bone loss also occurs in men as they age, and the rates of bone loss are very similar in elderly men and women (14). Despite the absence of a "menopause equivalent," men, on the average, undergo two thirds of the bone loss that occurs in women (15). Biochemical markers of bone turnover are increased in both elderly women and men relative to younger adults (16). In aging men, E is the dominant sex steroid regulating bone resorption, whereas both E and T are important in maintaining bone formation (17). Histomorphometric changes that occur during the process of bone loss are essentially similar in men and women (18). Additionally, new data suggest that E may play an important and previously unrecognized role in bone health in men as well as women (19, 20), making the etiology of osteoporosis potentially much more similar across genders than previously recognized.

It is also well established that low BMD is a risk factor for osteoporotic fractures and that patients with higher BMD (controlling for other variables) have a lower risk of fractures. This relationship has been well established in postmenopausal women (21, 22, 23, 24), and there is now a growing body of data showing an analogous relationship in men (25, 26, 27, 28, 29, 30). In a recent study Selby et al. (31) found that the BMD at which there was a 50% risk of fractures was somewhat higher in men than in women (0.908 vs. 0.844 g/cm²). However, the t-score-associated 50% prevalence of fractures was similar in the two sexes (women, -2.77; men, -2.60). The authors concluded that the current WHO threshold of osteoporosis in postmenopausal women can be appropriately applied to men.

This theoretical rationale is now supported by data obtained in our study, the study by Orwoll et al. (13), and a third study that enrolled both men and women with osteoporosis. This prospective, controlled, open label study compared the effects of alendronate (10 mg daily) in 23 men and 18 postmenopausal women with osteoporosis. Similar increases in lumbar spine BMD were seen in men (7%) and women (5.4%) after 12 months of treatment (32).

Our study has some limitations. It is an open label study and enrolled only men with primary osteoporosis, but this is thought to account for 40–50% of all cases of osteoporosis in men (19, 33). Vitamin D levels were not determined at baseline, but in men with normal parameters of calcium-phosphate metabolism and a mean age of 53 yr, there is a very low risk of vitamin D insufficiency. As a single center trial it was relatively small in size, although greater than in most other studies previously conducted in men. The study was only 2 yr in duration; thus, longer-term responses to alendronate therapy remain of interest. Only one dose of alendronate (10 mg daily) was used, but this dose has been found to be optimal in the treatment of postmenopausal osteoporosis.

In summary, in men with established primary osteoporosis, treatment with alendronate plus calcium was well tolerated, increased lumbar spine and femoral neck BMD, and may be superior to the alfacalcidol plus calcium regimen by producing higher average increase rates.

Acknowledgments

We thank Ms. S. M. Snodgrass for her assistance with preparing the manuscript, and Drs. A. Daifotis and A. Lombardi (Merck & Co., Inc., Rahway, NJ) for their valuable input.

Footnotes

Abbreviations: BMD, Bone mineral density.

Received December 15, 2001.

Accepted July 26, 2001.

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This Article Abstract Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Ringe, J. D. Articles by Dorst, A. Search for Related Content PubMed PubMed Citation Articles by Ringe, J. D. Articles by Dorst, A.