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Endocrine Care |
Departments of Diabetes and Endocrinology (P.R.E., J.D.W., S.Y., C.P.) and Nuclear Medicine (N.S.), and Medicine, University of Melbourne Hospital, and Department of Medicine, Royal Melbourne Hospital (P.R.E., J.D.W.), Melbourne, Parkville 3050, Australia; and Department of Medicine, Geelong Hospital (G.C.N., M.A.K.), Geelong, Victoria 3220, Australia
Address all correspondence and requests for reprints to: Dr. Peter R. Ebeling, Department of Diabetes and Endocrinology, The Royal Melbourne Hospital, Melbourne, Victoria 3050, Australia.
Abstract
Osteoporosis in men is an emerging public health problem. As calcitriol reduces the rate of vertebral fractures in osteoporotic postmenopausal women, we conducted a prospective study of this treatment in men with primary osteoporosis. Our study was a 2-yr, randomized, double masked, double placebo-controlled trial of calcitriol (0.25 µg twice daily) or calcium (500 mg twice daily) in 41 men with primary osteoporosis and at least 1 baseline fragility fracture. Thirty-three men (85%) completed the study.
There were no differences in baseline characteristics. Spinal and femoral neck bone mineral densities at 2 yr were unchanged in both groups. Serum osteocalcin decreased in both groups by 30% (P < 0.05), whereas urine N-telopeptide cross-links decreased only in the calcium group by 30% (P < 0.05). After 2 yr, fractional calcium absorption increased by 34% (P < 0.01) in the calcitriol group. Nineteen incident fragility fractures occurred (14 vertebral and 5 nonvertebral) in 7 men. Over 2 yr, the number of men with vertebral fractures (6 vs. 1; P = 0.097) was similar in both groups.
In conclusion, the efficacy of calcitriol remains unproven as a single agent for the treatment of osteoporosis in men.
OSTEOPOROSIS IN men is already a public health concern (1, 2, 3). Over the next 15 yr, about 30% of all hip fractures will occur in men (4). Several recent population-based studies report that the prevalence of spinal fractures is similar or only slightly less in men compared with women (5, 6, 7, 8). Vertebral fractures occur earlier in men, and in middle-aged men the prevalence of vertebral fractures is higher than in women (9). Mortality after hip and spine fractures is also higher in men than in women (10).
Longevity is increasing the absolute number of elderly men and women in the community. In addition, there is evidence that the age-specific incidence of fractures is increasing in men. Despite this, there have only been two studies examining the antifracture efficacy of any drug in men with osteoporosis (11, 12). A recent, large prospective study showed that alendronate increases bone density and reduces vertebral fractures in hypo- or eugonadal men with osteoporosis (12). Until now, the choice of antiosteoporotic therapy in men had been based on small observational studies of the effects of drugs on bone mineral density (BMD) in men and on inferences from studies in women with osteoporosis. Further studies in men are needed to provide additional drug therapy that has proven antifracture efficacy in men.
Dietary calcium and vitamin D supplementation with 700 IU/d prevented age-related bone loss in men in one study (13), but not in another study of younger men with adequate dietary calcium intake (14). Dietary calcium and vitamin D supplementation results in small increases in spinal BMD in elderly men (13). Neither study had adequate power to detect changes in fracture rate adequately. Active intestinal fractional calcium absorption (FCA) declines with age in men, particularly after 80 yr, and may contribute to age-related secondary hyperparathyroidism and bone loss in both genders (15). Higher FCA values are associated with slower rates of femoral bone loss, but this may not be independent of 1,25-dihydroxyvitamin D [1,25-(OH)2D] concentrations. Men with spinal fractures also have lower FCA (16). In these men, low serum 1,25-(OH)2D concentrations only explain half of the deficit in FCA. In postmenopausal women with osteoporosis, calcitriol increases intestinal calcium absorption and prevents bone loss (17, 18, 19). In two studies, calcitriol has been reported to reduce the incidence of spine fractures (20, 21) in women with postmenopausal osteoporosis.
To test the hypothesis that calcitriol might reverse the deficit in FCA in men with osteoporosis and increase BMD, we compared the effects of calcitriol alone with those of calcium in men with primary osteoporosis. We used changes in BMDs and total body bone mineral content (BMC) as primary end points, whereas biochemical bone turnover markers, active calcium absorption, and the numbers of new fractures were secondary end points.
Subjects and Methods
Subjects
The study comprised 41 Caucasian men with primary osteoporosis,
aged 27–77 yr, recruited consecutively from hospital clinics and the
participating physicians’ private practices. Each patient had at least
1 fragility fracture; 39 had low trauma vertebral fractures, and 2
young men had low trauma proximal femoral fractures. One of the men
with a prior hip fracture sustained a vertebral fracture during the
study. In 4 men (3 in the calcium group and 1 in the calcitriol group),
all evaluable lumbar vertebrae were fractured, and their LS-BMD data
were excluded from the spinal BMD analysis (Table 1
). The presence of a low trauma fracture
was the main criterion for entry. Although low BMD was not required,
the majority of men had a baseline spinal or hip t score of
less than -2.5. No men had disease known to affect bone or mineral
metabolism, and all had normal baseline 25-hydroxyvitamin D (25OHD) and
T concentrations.
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Bone densitometry and biochemical markers of bone turnover
BMDs of the spine (second to fourth lumbar vertebrae) and the femoral neck, and total body BMC were measured by dual x-ray absorptiometry using QDR-2000 (Hologic, Inc., San Francisco, CA; Royal Melbourne Hospital; n = 35) and DPX-L (Lunar Corp., Madison, WI; Geelong Hospital; n = 6) densitometers. The in vitro and in vivo coefficients of variation were 0.38% and 1% at the lumbar spine and 0.38% and 1.7% at the femoral neck, respectively (22). Standardized BMD was determined by comparison of the individual BMD with the appropriate North American reference data and was expressed as number of SD (z-score) different from the age- and sex-specific mean BMD.
For measurement of biochemical bone turnover markers, blood samples were taken, and 2-h urine specimens were collected between 0700–0900 h after an overnight fast. All samples were stored at -70 C until analysis. The urine total pyridinium cross-links, pyridinoline and deoxypyridinoline were measured by monitoring fluorescence of eluates from HPLC (23). All pyridinium cross-link values were corrected for the individual measured recovery of the internal standard, isodesmosine, and urinary creatinine concentrations. Intra- and interassay coefficients of variation were each 8% and 10% for pyridinoline and deoxypyridinoline, respectively. Urinary N-telopeptide (NTx) cross-links were measured by duplicate ELISAs (Osteomark, Seattle, WA). The intra- and interassay coefficients of variation were 8% and 9%, respectively.
Serum bone alkaline phosphatase was measured by duplicate immunoradiometric assays (24) using two monoclonal antibodies directed toward the bone isoenzyme of alkaline phosphatase (MetraBiosystems, Mountain View, CA). The intraassay coefficient of variation was 8%, and cross-reaction with other alkaline phosphatases was 6%. Serum osteocalcin (OC) was measured by duplicate immunoradiometric assays using antibodies raised against human OC (Immutopics, Palo Alto, CA). The intra- and interassay coefficients of variation were 7% and 9%, respectively.
Assessment of FCA
Active, or vitamin D-dependent, intestinal calcium absorption was assessed by a modification of the method described by Need et al. (16). Radiocalcium (45Ca) was purchased from the Australian Atomic Energy Commission (Lucas Heights, Australia) and was administered orally with 20 mg calcium carrier (as CaCl2) in 200 ml demonized water. Heparinized blood samples were obtained at baseline, 30 and 60 min after treatment, instead of at 60 min alone, and FCA was calculated as the fraction absorbed per h. FCA was not corrected for age or dietary calcium intake. Dietary calcium intakes were calculated from 4-d diet diaries at baseline and 2 yr.
Thoracicolumbar spine radiographs
Roentgenograms of the thoracic and lumbar spine were obtained using two x-ray machines. The heights of the anterior, mid, and posterior margins of each vertebral body were measured to the nearest 0.1 mm; all spinal measurements were made with a pair of calipers by two observers, masked to the treatment assignment (P.R.E. and M.A.K.). One of the observers (P.R.E.) remeasured vertebral heights measured at the second site. A vertebral fracture was defined as a decrease of 20% in the anterior, mid, or posterior height of the body of any vertebra from T4 to L4. The changes in vertebral heights at yr 1 and 2 were compared with baseline to detect new vertebral. All incident vertebral fractures represented changes from a normal vertebra, and the majority of fractures were also clinically apparent. Clinical nonvertebral fractures were ascertained by questioning the patient, and incident worsening of prevalent baseline vertebral fractures was also noted.
Statistical analysis
Preliminary power calculations showed that we had 88% power
(
= 0.05) to detect a difference of 3% in spinal BMD between
groups at 2 yr, assuming an SD of 3% in the percent change
in BMD. Two-sample t tests or their nonparametric
equivalent, e.g. the Wilcoxon rank sum test if data were
found not to be normally distributed, were performed to test for
baseline differences and to compare differences between treatment
groups in responses of bone density, biochemical bone turnover markers,
and FCA. Changes from baseline were defined as the study time point
value minus the baseline value, expressed as a percentage. To assess
these changes, a one-sample t test and or its nonparametric
equivalent, e.g. Wilcoxon sign test, was performed for each
treatment group. The differences between groups were compared using
two-sample t tests or their nonparametric equivalent.
Repeated measures ANOVA was also used to test for differences between
treatment groups and changes over time within treatment groups for the
BMD parameters and the biochemical bone marker data. The differences in
incident vertebral fractures were tested by Fisher’s exact test. The
analysis was by intention to treat (ITT), and where there were missing
data, the last value entered was carried forward to each visit up to
month 24 for analysis of BMD data and repeated measures analyses. All
analyses were performed with the SAS software program
(25).
Results
Of the 41 men enrolled, 39 men were evaluable for ITT analysis.
Thirty-seven men (17 in the calcium group and 20 in the calcitriol
group) completed 12 months, and 33 men (16 in the calcium group and 17
in the calcitriol group) completed 24 months. The overall study
retention rate was 85%. Baseline variables for the 39 men evaluable
for ITT analysis are shown in Table 1
. There were no differences in
baseline characteristics. The men had an overall mean of 3.8 prevalent
baseline vertebral fractures (range, 0–12). Regarding baseline bone
turnover, mean serum OC and urinary bone resorption markers were in the
upper part of the normal range for men. The mean baseline FCA was
decreased by more than 1 SD in 18% compared with controls
(16). Baseline serum T, 25OHD, and
1,25-(OH)2D concentrations were all within the
normal range in both groups.
Changes in BMD, biochemical bone turnover markers, and FCA
The changes in regional BMDs and total body BMC are shown in Table 2 and Fig. 1. Although there was a transient
increase in femoral neck BMD in the calcium-treated group, by 2 yr
there were no significant changes in BMD in either group relative to
baseline or relative to each other. If spinal BMD data of the men with
four lumbar vertebral fractures were included, BMD appeared to increase
by 8.8% and 7.8% at 1 and 2 yr, respectively, in the calcium group.
There were also nonsignificant increases of 1.4% and 1.6%,
respectively, in the calcitriol group.
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and Fig. 2). Mean serum
bone alkaline phosphatase concentrations decreased during the first 6
months of treatment in both groups and then increased above baseline at
24 months; however, the percent increases in each group were not
significant. Urinary NTx/creatinine decreased significantly at 6 months
in both groups; however, at 24 months it had decreased by 30%
(P < 0.05) in the calcium group and by 6%
(P = 0.75) in the calcitriol group. The decrease in
NTx/creatinine after calcium treatment is greater than the decrease
seen with calcium (500 mg) and vitamin D (400–450 IU) in men with
osteoporosis, where NTx decreased by 9% (12). However, it
is less than the 59% decrease seen in men treated with alendronate in
addition to calcium and vitamin D in the same study. Serum osteocalcin
decreased by 35% in the calcium group and by 25% in the calcitriol
group (P < 0.01 and P < 0.05,
respectively) at 12 months, remained below baseline in both groups, and
was significant in the calcium group (P < 0.05) at 24
months.
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).
At 2 yr, the total daily calcium intake in the calcium group was 1729
mg. FCA increased by 34% (P < 0.01) at 2 yr in the
calcitriol group, but did not change significantly in the calcium group
(14%). Sixteen men (10 in the calcium group and 6 in the calcitriol
group) had low baseline fractional calcium absorption (<0.55/h). They
did not have greater increases in spinal, femoral neck, or total hip
BMDs with either calcitriol or calcium therapy than men with normal
baseline FCA. Fractures
A total of 19 new fragility fractures (14 vertebral and 5 nonvertebral) occurred in 7 men over 2 yr. Three incident vertebral fractures occurred in 3 men, and 10 incident vertebral fractures occurred in 5 men in the calcitriol group during the first and second years of the study, respectively. Two men in the calcitriol group had incident vertebral fractures in both years of the study. Only 1 incident vertebral fracture occurred in the calcium group in the first year of the study. Thus, over 2 yr, 1 of 16 patients (6%) in the calcium group and 6 of 19 patients (32%) in the calcitriol group had at least 1 new fracture. There was a nonsignificant trend for more men in the calcitriol group to sustain vertebral fractures (6 vs. 1; P = 0.097) over 2 yr. All 5 nonvertebral fractures (2 ribs, distal radius, and superior and inferior pubic rami) occurred in the calcitriol group. The fractured pubic rami were sustained after a fall down steps, whereas all other fractures were low trauma fractures. Incident worsening of a prevalent vertebral fracture occurred only in 1 patient in the calcium group, who also sustained an incident new vertebral fracture.
Changes in calciotropic hormone and T concentrations
Neither serum 25OHD nor total T concentrations differed
significantly from baseline (Table 2). Serum
1,25-(OH)2D3 decreased by
9% in the calcium group (P < 0.01), but increased
slightly (P = 0.89) in the calcitriol group, with a
significant difference between treatment groups (P =
0.03). Venous sampling was performed at inconstant times after the
calcitriol treatment and may have been too late to detect increases in
serum 1,25-(OH)2D3
concentrations related to calcitriol therapy. Serum PTH concentrations
in the calcitriol group decreased by 23% and 26% at 1 and 2 yr
(P = 0.01 and P = 0.12, respectively),
but did not change significantly in the calcium group.
Safety
Two patients, one in each treatment group, were included in the safety population, although they were excluded from the ITT population, one because a repeat serum T concentration was below the normal range, and the second because prostatic carcinoma was diagnosed after the baseline visit. The withdrawal rate was similar in both groups, with another three patients withdrawing in each group. The reasons for withdrawal in the three patients who withdrew from the calcitriol group were multiple vertebral fractures, myalgia, and nausea. In the three patients who withdrew from the calcium group, the reasons for withdrawal were fatigue, diagnosis of a malignant fibrous histiocytoma, and an interstate move.
Serum calcium levels rose within the normal range, and urinary calcium excretion increased by 140% from baseline during calcitriol therapy. Although urinary calcium excretion was increased above 10 mmol/d in 2 of the patients taking calcitriol, it was asymptomatic. However, there were 22 of 35 patients (63%) with urinary calcium that increased by more than 0.1 mmol/d above baseline. No man complained of passing urinary gravel or of renal colic. In 1 of these patients, a decreased creatinine clearance did not return to normal. Serum calcium (corrected for the serum albumin concentration) increased above normal to 2.67 mmol/liter in only 1 man in the calcium group. No hypercalcemia occurred in the calcitriol group.
Discussion
We found that men with primary osteoporosis treated with calcitriol and calcium therapy had transient increases in spinal and femoral neck BMDs; however, in both groups BMD returned to baseline at both sites by 2 yr. No lasting increases were seen in the total body calcium with calcitriol or calcium treatment. FCA was increased by calcitriol, whereas serum PTH concentrations were decreased.
There are no previous data on the use of calcitriol therapy in men with osteoporosis. In a 3-yr study of postmenopausal women with osteoporosis, calcitriol therapy resulted in stabilization of the vertebral fracture rate compared with a 3-fold increase in the vertebral fracture rate over the last 2 yr of the study in women receiving calcium (20). In the first year of another 3-yr study, vertebral fracture rates were also reduced by calcitriol therapy; the latter 2 yr of this study were uncontrolled (21).
Differences between studies in the effects of calcitriol on BMD may be related to either differing doses of calcitriol used or differing habitual dietary calcium intakes. Aloia et al. (17) showed significant increases in spinal and distal radius BMDs and total body calcium with calcitriol at an average dose of 0.8 µg/d. Vertebral fracture rates tended to be higher in the placebo group, and there was a high incidence of hypercalciuria and hypercalcemia in the calcitriol group. Gallagher and Goldgar (18), using an average calcitriol dose of 0.62 µg/d, showed an increase in spinal BMD and stable total body calcium compared with decreases in subjects taking placebo, without an adverse effect on serum calcium concentrations. However, there were no differences in fracture rates.
Ott and Chestnut (26) used the lowest final average calcitriol dose (0.43 µg/d), and the dietary calcium intake of their placebo group was 400 mg/d higher. Changes in BMD at most sites were similar in each group. The incidence of vertebral fractures was 10% higher in the calcitriol group, but this difference was not significant. When subjects in this study were subdivided according to average daily calcitriol doses, those receiving more than 0.6 µg/d had the greatest increases in BMD (27). Only one study using low average daily calcitriol doses (0.42 µg/d) has shown vertebral height loss (28), which was not seen in women receiving hormone replacement therapy alone or placebo.
The goal of osteoporosis treatment is to prevent further fragility fractures. Although fractures were a secondary end point of our study, and we had limited power to detect differences between groups, we detected a trend for an increased number of new fractures in men receiving calcitriol. Only one man receiving calcium had a new vertebral fracture. Neither treatment group showed a decrease in BMD after 2 yr of treatment.
Although the men receiving calcitriol had an average dietary calcium intake below the recommended daily allowance, dietary calcium intakes were similar in men with and without fractures in the calcitriol group (857 ± 359 and 711 ± 402 mg/d; P = 0.45). An elevated bone resorption rate is an independent risk factor for fracture (29). However, there was no evidence of increased bone resorption in the calcitriol group in our study. It is also possible that there is a narrow therapeutic window for calcitriol, and the response to a fixed dose in a population is heterogeneous (30), or that there are gender differences in its effects on bone and mineral metabolism, including bone turnover. In women treated with calcitriol, bone turnover is decreased, and this may partially result from suppression of the activation of bone turnover by PTH. However, high doses of calcitriol (2 µg/d) given to normal men over 7 d increased bone formation markers without increasing bone resorption (31).
The incident fracture rate in our study is high, with a 32% 2-yr incidence of fractures in the calcitriol group. However, the main limitation of our study is its small sample size and limited power to detect differences in fracture rates. Although our study had only 38% probability to detect a difference in fracture rates, a 26% difference in fracture rates between treatment groups is of biological concern. Nevertheless, we cannot confidently distinguish fracture rates between groups. However, a larger study adequately powered to examine differences in fracture rates, would be unwise given that our study may indicate a safety problem with the use of calcitriol alone in men with severe osteoporosis. By comparison, our power to detect differences in BMD based on our current data were even more limited.
In conclusion, there were no differences between calcitriol and calcium with respect to their effects on BMD and bone turnover, but there was a trend for calcitriol therapy to be associated with an increased number of vertebral fractures. The latter raises concern, but our study had limited power to detect a difference in fracture rates. In conclusion, the efficacy of calcitriol remains unproven as a single agent for the treatment of osteoporosis in men.
Acknowledgments
We acknowledge the study participants for their time and enthusiasm in participating in the study. We also thank Bahtiyar Kaymakci for his technical expertise in bone densitometry. We are grateful to Profs. B. E. Christopher Nordin, Ego Seeman, and John Hopper for their critical comments regarding our study. The statistical analyses were performed by Datapharm Australia and were checked by Mr. Andrew Martin and Dr. Philip McCloud at Roche Products (Australia) Pty. Ltd.
Footnotes
This work was supported by the D. W. Keir Fellowship, The Royal Melbourne Hospital, and Roche Products (Australia) Pty. Ltd. Presented in part at the European Congress on Osteoporosis, Berlin, Germany, September 1998.
Abbreviations: BMC, Bone mineral content; BMD, bone mineral density; FCA, fractional calcium absorption; ITT, intention to treat; NTx, N-telopeptide cross-links; OC, osteocalcin; 25OHD, 25-hydroxyvitamin D; 1,25-(OH)2D3, 1,25-dihydroxyvitamin D3.
Received July 20, 2000.
Accepted May 16, 2001.
References
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  P. R. Ebeling Osteoporosis in Men N. Engl. J. Med., April 3, 2008; 358(14): 1474 - 1482. [Full Text] [PDF]
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 F. T. Murphy, A. J. Kivitz, and E. E. Sands Management of Postmenopausal Osteoporosis J Am Osteopath Assoc, October 1, 2003; 103(6_suppl): S6 - S11. [Abstract] [Full Text] [PDF]
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 B. A. L. Crawford, P. Y. Liu, M. T. Kean, J. F. Bleasel, and D. J. Handelsman Randomized Placebo-Controlled Trial of Androgen Effects on Muscle and Bone in Men Requiring Long-Term Systemic Glucocorticoid Treatment J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3167 - 3176. [Abstract] [Full Text] [PDF]
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 S P Tuck and R M Francis Osteoporosis Postgrad. Med. J., September 1, 2002; 78(923): 526 - 532. [Abstract] [Full Text] [PDF]
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