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Department of Medicine and Bioregulatory Sciences (T.Ma.), University of Tokushima Graduate School of Health Biosciences, Tokushima 770-8503, Japan; Osaka City University (T.Mi.), Osaka 545-0051, Japan; Tottori University (H.H.), Tottori 683-0826, Japan; Kobe University (T.S.), Kobe 650-0017, Japan; Sanyo Osteoporosis Research Foundation (S.O.) Oita 870-0924, Japan; Tsuji Academy of Nutrition (T.H.), Osaka 530-0021, Japan; Keio University Hospital (Y.T.), Tokyo 160-8582, Japan; Tokyo Metropolitan Geriatric Hospital (Y.H.), Tokyo 173-0015, Japan; Kawasaki Medical School (M.F.), Kurashiki 701-0192, Japan; Research Institute and Practice for Involutional Diseases (M.S.), Nagano 399-8101, Japan; and University of Occupational and Environmental Health (T.N.), Fukuoka 807-8582, Japan
Address all correspondence and requests for reprints to: Toshio Matsumoto, M.D., Department of Medicine and Bioregulatory Sciences, University of Tokushima Graduate School of Health Biosciences, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. E-mail: toshimat{at}clin.med.tokushima-u.ac.jp.
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Abstract |
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Objective: Our objective was to examine whether ED-71 can increase BMD in osteoporotic patients under vitamin D supplementation.
Design, Setting, and Patients: We conducted a randomized, double-blind, placebo-controlled clinical trial of 219 osteoporotic patients (49–87 yr of age).
Interventions: Subjects were randomly assigned to receive placebo or 0.5, 0.75, or 1.0 µg/d ED-71 for 12 months. All the subjects received 200 or 400 IU/d vitamin D3.
Main outcome measures: We assessed changes in lumbar and hip BMD and bone turnover markers from baseline.
Results: Lumbar BMD increased with ED-71 treatment for 12 months (2.2, 2.6, and 3.1% from baseline and 2.9, 3.4, and 3.8% vs. placebo group in subjects receiving 0.5, 0.75, and 1.0 µg ED-71, respectively). Total hip BMD also increased with 0.75 and 1.0 µg ED-71 (–0.8, 0.6, and 0.9% from baseline and 0.1, 1.5, and 1.8% vs. placebo group in the 0.5, 0.75, and 1.0 µg ED-71 groups, respectively). Bone formation and resorption markers were suppressed by approximately 20% after 12 months of 0.75 and 1.0 µg ED-71 treatment. Transient hypercalcemia over 2.6 mmol/liter occurred in 7, 5, and 23% of subjects in the 0.5, 0.75, and 1.0 µg ED-71 groups, respectively, but none of them developed sustained hypercalcemia.
Conclusions: These results demonstrate that ED-71 treatment at around 0.75 µg/d can effectively and safely increase lumbar and hip BMD in osteoporotic patients with vitamin D supplementation.
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Introduction |
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,25-DIHYDROXY-2ß-(3-hydroxypropoxy)vitamin D3] is an analog of 1,25-dihydroxyvitamin D3 [1,25(OH)2D3], bearing a hydroxypropoxy residue at the 2ß position. ED-71 has been demonstrated to show a pronounced effect in increasing bone mass and was able to enhance bone strength in rodents (1, 2). ED-71 binds to the vitamin D receptor (VDR) with less affinity but binds to vitamin D-binding protein with higher affinity than 1,25(OH)2D, showing a long half-life in plasma (3). An earlier open-labeled clinical trial in osteoporotic patients demonstrated that treatment with 0.25–1.0 µg/d ED-71 for 6 months increased lumbar bone mineral density (BMD) in a dose-dependent manner without causing sustained hypercalcemia or hypercalciuria (4, 5). However, because many patients had serum 25-hydroxyvitamin D [25(OH)D] levels less than 50 nmol/liter, there was a possibility that the effect of ED-71 on bone mass might have been influenced by nutritional vitamin D insufficiency of these patients and might merely reflect a correction of the vitamin D insufficiency.
The present study was undertaken to clarify whether ED-71 could increase bone mass in osteoporotic patients taking sufficient vitamin D supplementation to normalize serum 25(OH)D. The results demonstrate that ED-71 administration can effectively increase not only lumbar spine but also total hip bone mass in a dose-dependent manner under vitamin D supplementation and suggest that ED-71 can become a promising candidate for the treatment of osteoporosis.
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Subjects and Methods |
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We studied 219 subjects (215 females and four males, all Japanese) aged from 49–87 yr (mean, 67.3 yr) who had osteoporosis defined as low BMD (<70% of the young adult mean, 0.708 g/cm2 by a Hologic QDR) or osteopenia (<80% of the young adult mean, 0.809 g/cm2 by a Hologic QDR) with at least one vertebral fracture, according to the criteria of the Japanese Society for Bone and Mineral Research (6, 7). Vertebral fractures were assessed by x-ray examination of the vertebrae, and were diagnosed according to the criteria of the Japanese Society for Bone and Mineral Research (6). Female subjects were at least 3 yr after menopause or more than 60 yr of age. Subjects were excluded if they had fractures in any of lumbar spines L2–L4 or if they had disorders such as primary hyperparathyroidism, Cushing’s syndrome, gonadal insufficiency, poorly controlled diabetes mellitus (glycosylated hemoglobin over 9%), or other causes of secondary osteoporosis or a history or suspicion of active urolithiasis at any time. Subjects were also excluded if they had taken bisphosphonates until less than 12 months before entry, taken glucocorticoids, calcitonin, vitamin K, active vitamin D compounds, or hormone replacement therapy within the previous 2 months, had serum calcium levels above 10.4 mg/dl (2.6 mmol/liter) or urinary Ca excretion over 0.1 mmol/liter glomerular filtrate (GF), had serum creatinine levels above 115 µmol/liter, or had clinically significant hepatic or cardiac disorders. The subjects were enrolled at 13 centers in Japan. The protocol was approved by the internal human studies review board at each center, and informed consent was obtained from each subject.
Treatment
Subjects were randomly assigned to receive either placebo or 0.5, 0.75, or 1.0 µg ED-71 once a day for 12 months. Randomization was performed by a computerized system. The subjects were stratified into groups on the basis of serum 25(OH)D levels (<50 nmol/liter or 
50 nmol/liter) and prevalent vertebral fractures. Upon entry, subjects were supplemented with 400 IU/d vitamin D3 when serum 25(OH)D was less than 50 nmol/liter or with 200 IU/d vitamin D3 when serum 25(OH)D was 50 nmol/liter or higher.
If hypercalcemia over 2.6 mmol/liter in two consecutive measurements or over 2.75 mmol/liter developed, or if hypercalciuria over 0.1 mmol/liter GF developed in two consecutive measurements, ED-71 therapy was discontinued. Compliance with the study treatment was assessed with the use of medication diaries and counts of residual medication supplies.
Assessment of BMD
The BMD of the lumbar spine in the posteroanterior projections and the total hip was measured by dual-energy x-ray absorptiometry (DXA). The 13 study centers involved in this trial were all equipped with either Hologic QDR 4500 or 2000 for BMD measurements. A central facility (Department of Nuclear Medicine, Kawasaki Medical School) performed quality assurance of the longitudinal adjustment. Adjustment for DXA machine differences was made to calibrate each machine with standardized phantoms. All the DXA measurements were analyzed at a central site by a radiologist blinded to treatment group assignment.
Assessment of chemical parameters and bone turnover
Serum and postprandial urine samples were collected at baseline and at 1, 2, 3, 4, 5, 6, 8, 10, and 12 months for routine chemical analyses, including serum and urinary Ca corrected by dLGF, hematological, hepatic, and renal functions. At baseline and at 3, 6, and 12 months, markers of bone turnover, including serum bone-specific alkaline phosphatase (BALP) (Metra-BAP; Quidel Co., San Diego, CA), osteocalcin (Bone Gla protein-radioimmunoassay Mitsubishi, Mitsubishi Kagaku Bio-Chemical, Tokyo, Japan), and urinary type I collagen N-telopeptide (NTX) (Osteomark; Ostex International, Seattle, WA), along with serum calcium-regulating hormones including intact PTH (Allegro PTH; Nichols Institute, San Juan, CA), 25(OH)D (RIA, Immunodiagnostics Systems Ltd., Tyne and Wear, UK), 1,25(OH)2D (HPLC-radioreceptor assay) and 24,25(OH)2D (HPLC-competitive protein binding assay) were determined. Serum steady-state levels of ED-71 were also measured (liquid chromatography-tandem mass spectrometry, Hitachi Science Systems Ltd., Ibaraki, Japan) at 3, 6, and 12 months in all ED-71-treated patients.
Assessment of adverse events
All subjects were questioned about adverse events of treatment at each visit, and all adverse events reported during one month of follow-up were analyzed regardless of the investigators’ assessments of causality. The Medical Dictionary for Regulatory Activities (MedDRA, version 6) was used to categorize reported adverse events. We report all categories of adverse events for which the frequency was at least 2% in placebo or combined ED-71-treated groups and showed a higher incidence in the combined ED-71-treated group with an odds ratio higher than 3.
Statistical analysis
The predetermined primary end point was change in the posteroanterior lumbar BMD. Our prespecified analysis was to use data on the BMD measured from baseline to month 12. Analyses were performed according to the intention-to-treat principle, in which all randomized patients were included who had taken at least one dose of study drug and had both a baseline and at least one postrandomization measurement of BMD, bone markers, or other parameters.
Group means and 95% confidence intervals are given for the percent changes from baseline in lumbar and total hip BMD and are used to assess the significance of changes within each group. Medians and interquartile ranges are reported for changes in the levels of bone turnover markers. William’s tests were used to determine which ED-71-treated groups in a series are significantly different from the placebo group. The comparability among the treatment groups for demographic and background information and the incidence rates of adverse events was assessed with the use of one-way ANOVA for continuous variables and 
2 tests for dichotomous variables. The power calculation was based on the predictive percent change from baseline in lumbar BMD. A sample size of 50 patients per group was to provide more than 90% power for determining which ED-71-treated groups in a series are significantly different from the placebo group at a significance level of = 0.025 (one-sided), assuming a mean percent change of 0.5 in the placebo group, 1.5 in the 0.5-µg ED-71 group, 3.0 in the 0.75-µg ED-71 group, 3.0 in the 1.0-µg ED-71 group, and a pooled SD of 4.0.
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Results |
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There were no statistically significant differences in baseline characteristics. As shown in Table 1
, there was no significant difference in daily Ca intake among placebo and any treatment groups, and mean Ca intakes ranged from 761–840 mg/d. Mean serum 25(OH)D levels at the baseline were less than 50 nmol/liter, and 74% of the subjects showed serum 25(OH)D less than 50 nmol/liter (39 in placebo and 42, 41, and 41 nmol/liter in the 0.5-, 0.75-, and 1.0-µg ED-71-treated group, respectively). The subjects with serum 25(OH)D less than 50 nmol/liter were given 400 IU/d vitamin D3, and those with serum 25(OH)D over 50 nmol/liter were supplemented with 200 IU/d vitamin D3 throughout the study period. Vitamin D supplementation brought serum 25(OH)D to over 50 nmol/liter in 197 of 213 subjects (92%) at 3 months (Fig. 1).
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Of the 25 subjects who discontinued treatment, four subjects (1.8%) were assigned to the placebo group, seven (3.2%) to the 0.5-µg ED-71 group, five (2.3%) to the 0.75-µg ED-71 group, and nine (4.1%) to the 1.0-µg ED-71 group. Among them, one in the 0.5-µg ED-71 group and two in the 1.0-µg ED-71 group withdrew from the study because of repeated hypercalcemia over 2.6 mmol/liter or moderate hypercalcemia over 2.75 mmol/liter, and one in the 1.0-µg ED-71 group withdrew because of repeated hypercalciuria over 0.1 mmol/liter GF in two consecutive measurements. The incidence of hypercalcemia or hypercalciuria was significantly higher in the 1.0-µg ED-71 group (P < 0.01). Most of the other subjects who discontinued treatment did so because of reasons unrelated to adverse events.
We found no difference in adherence to treatment among the groups, and 97% of the subjects took more than 75% of the study medication.
Lumbar spine and total hip BMD
Lumbar spine BMD increased rapidly within 6 months of ED-71 treatment and gradually increased thereafter in a dose-dependent manner (Fig. 2). After 12 months of ED-71 treatment, lumbar spine BMD increased from baseline by 2.2, 2.6, and 3.1% in the 0.5-, 0.75-, and 1.0-µg ED-71 group, respectively, whereas lumbar spine BMD decreased by 0.7% in the placebo group. The change in lumbar spine BMD by the ED-71 treatment was significantly different from that in the placebo group (P < 0.01 in all comparisons).
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). The change in total hip BMD in the 0.75- and 1.0-µg ED-71-treated groups was significantly different from that in the placebo group (P < 0.05). There was a tendency that subjects with lower serum 25(OH)D levels at the baseline (<50 nmol/liter) showed a greater increase in lumbar BMD after 12 months of 0.75 µg ED-71 treatment (2.9 and 1.6% in low and normal 25(OH)D groups, respectively). In contrast, the effect of the same amount of ED-71 on hip BMD was opposite (0.5 and 0.9% in low and normal 25(OH)D groups, respectively). The patients were also stratified at the baseline by the presence or absence of prevalent fractures, and patients with prevalent fractures tended to show a greater increase in lumbar BMD but smaller increase in hip BMD compared with those without fractures after 0.75 µg ED-71 treatment (3.6 vs. 2.2% in lumbar and 0.0 vs. 0.9% in hip BMD in patients with prevalent fracture and without fracture, respectively). However, because the number of subjects in each group was small, it was difficult to draw any conclusions from these results.
Bone turnover markers
As shown in Fig. 3, median urinary NTX as a bone resorption marker decreased by 8, 20, and 24% within 3 months of treatment by 0.5, 0.75, and 1.0 µg ED-71, respectively, and remained suppressed throughout the study period. Serum BALP and osteocalcin as bone formation markers also decreased but with more gradual time courses to reach a nadir at around 6 months of ED-71 treatment.
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Figure 4 shows changes in the levels of calcium-regulating hormones at the baseline and during ED-71 treatment. Interestingly, serum intact PTH did not change significantly despite the increase in serum Ca levels in any of the ED-71-treated groups (Fig. 5). Serum 1,25(OH)2D levels were significantly suppressed by the treatment with ED-71 in a dose-dependent manner. In contrast, serum 24,25(OH)2D increased not only in ED-71-treated groups but also in the placebo group. In addition, 24,25(OH)2D levels were higher in ED-71-treated groups compared with those in the placebo group and increased in a dose-dependent manner with ED-71 treatment. The steady-state serum ED-71 concentration increased linearly with increasing doses of the compound.
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Serum Ca increased by ED-71 treatment in a dose-dependent manner, and mean serum Ca levels at 12 months of treatment were 2.38, 2.38, 2.4, and 2.43 mmol/liter in the placebo and the 0.5-, 0.75-, and 1.0-µg ED-71 groups, respectively. As shown in Fig. 5, there was a rapid increase in serum Ca during the initial 1 month of ED-71 treatment, followed by a sustained slight elevation in serum Ca levels throughout the treatment period. Postprandial urinary Ca excretion also increased with ED-71 treatment in a dose-dependent manner, and mean urinary Ca levels at 12 months were 0.045, 0.048, 0.058, and 0.06 mmol/liter GF in placebo 0.5-, 0.75-, and 1.0-µg ED-71 groups, respectively. The incidence of at least one episode of hypercalcemia over 2.6 mmol/liter was 7, 5, and 23% and that of hypercalciuria over 0.1 mmol/liter GF was 7, 9, and 25% in 0.5-, 0.75-, and 1.0-µg ED-71 groups, respectively. The incidence of serum and urinary Ca-related adverse events was significantly higher in the 1.0-µg ED-71-treated group (P < 0.01). Serum and urinary Ca returned to baseline levels in most of the subjects within 1 month after the end of the study period (Fig. 5).
Other adverse events that showed at least 2% in frequency in placebo or combined ED-71-treated groups with an odds ratio higher than 3 in the combined ED-71-treated group are listed in Table 2. None of them was considered by the investigators to be related to treatment. There was no difference in the incidence of serious adverse events between the placebo and combined ED-71-treated groups (7.5 and 9.6%, respectively). There was no increase in the development of hematological, hepatic, or renal abnormalities in ED-71-treated groups. Clinical fractures were captured as adverse events, and there was no significant difference in the incidence of vertebral (two in the placebo and one each in the 0.5-, 0.75-, and 1.0-µg ED-71-treated groups) or nonvertebral fractures (one in the placebo and 0.5- and 1.0-µg ED-71-treated groups and two in the 0.75-µg ED-71-treated group).
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Discussion |
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In the present study, vitamin D3 was supplemented to maintain serum 25(OH)D over 50 nmol/liter in 92% of the enrolled subjects, and the results demonstrated that ED-71 can increase BMD in osteoporotic subjects even with sufficient vitamin D supplementation. These results suggest that ED-71 can exert its effect on bone independently of the nutritional supplementation with native vitamin D. Supplementation with a large amount of vitamin D3 (800 IU daily) and calcium (1200 mg daily) is associated with a reduction in the risk of nonvertebral fractures in elderly women (8). However, controversy remains whether the actions of vitamin D on the density and strength of bone is merely a result of nutritional supplementation of vitamin D. A large meta-analysis of the effects of native and hydroxylated active vitamin D compounds revealed that hydroxylated vitamin D exhibited a consistently larger impact on bone density than native vitamin D in postmenopausal women (9). Thus, there is a possibility that vitamin D has specific effects on bone and that some vitamin D analogs can exert stronger effects on bone. In fact, in a rat ovariectomy model of osteoporosis, ED-71 increased bone mass at the lumbar vertebra to a greater extent than alfacalcidol, while enhancing calcium absorption and suppressing serum PTH to a similar extent to alfacalcidol (2). In those animals, ED-71 lowered the biochemical and histological parameters of bone resorption more potently than alfacalcidol, with maintenance of bone formation. In addition to ED-71, some vitamin D analogs have been reported to have preferential effects on bone both in vitro and in vivo. Ro-26-9228 showed preferential gene regulation in osteoblasts over duodenum and had a bone-protective effect via induction of growth factors in osteopenic rats (10). A highly potent analog of 1,25(OH)2D3, 2-methylene-19-nor-(20S)-1,25(OH)2D3, was shown to have selective effects on osteoblasts and to induce bone formation in ovariectomized rats (11). A later in vitro study suggested that 2-methylene-19-nor-(20S)-1,25(OH)2D3 promoted VDR binding to specific DNA elements via a formation of unique VDR conformation (12).
In our earlier clinical studies, ED-71 substantially suppressed bone resorption markers but reduced bone formation markers to a lesser extent (4, 5). In the present study, both bone formation and bone resorption markers decreased to almost a similar extent. These results are similar to those obtained by antiresorptive agents. For example, 60 mg/d raloxifene reduced osteocalcin and NTX by 27.0 and 20.9%, respectively, with a 1.5% increase in lumbar BMD after 6 months of treatment in postmenopausal Asian women (13). Nevertheless, the dose-dependent increase in BMD by ED-71 in the present study at 6 months is comparable to that observed in our earlier study in which a 2.5% increase in lumbar BMD was observed after 6 months of 0.75 µg ED-71 treatment (4). The only difference between the present study and our previous study is the supplementation of native vitamin D3 to normalize serum 25(OH)D levels. It is not known whether the difference in vitamin D status can influence responsiveness in bone turnover markers, and the reasons for the differences in the responsiveness of bone turnover markers remains unclear.
The incidence of hypercalcemia or hypercalciuria was much higher in the 1.0-µg ED-71 group compared with the 0.5- and 0.75-µg ED-71 groups. In contrast, the increase in both lumbar and total hip BMD was almost the same in the 0.75- and 1.0-µg ED-71-treated groups. When the effects of ED-71 on lumbar BMD vs. serum and urinary Ca were compared with those of alfacalcidol, 0.75 µg/d ED-71 increased lumbar BMD by 2.6%, serum Ca by 0.03 mmol/liter and urinary Ca by 0.023 mmol/liter GF, whereas 1.0 µg/d alfacalcidol increased BMD by 0.65%, serum Ca by 0.03 mmol/liter, and urinary Ca by 0.028 mmol/liter GF after 12 months of treatment (14). Thus, 0.75 µg ED-71 appears to be a safe, well tolerated, and effective dose in increasing both lumbar and femoral BMD and is superior to alfacalcidol in increasing BMD compared with its effects on serum and urinary Ca.
Finally, the present study has limitations. First, the effect of ED-71 was examined for only 12 months in about 50 patients in each group, which is too short a period and too small a number of patients to evaluate its effect on osteoporotic fractures. A prospective, randomized, double-blind, 3-yr study to compare the effect of ED-71 with that of alfacalcidol on fracture incidence in osteoporotic patients is currently under way. Second, the effect of ED-71 on the microstructure, mineralization, and other histological parameters is not examined. Because these parameters may influence the quality and strength of bone, additional studies are needed to clarify this issue.
In conclusion, the present observations demonstrate that ED-71 can effectively increase both lumbar and hip BMD in patients with vitamin D supplementation and suggest that ED-71 can become a promising candidate for the treatment of osteoporosis.
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Acknowledgments |
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Footnotes |
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Abbreviations: BALP, Bone-specific alkaline phosphatase; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; GF, glomerular filtrate; NTX, type I collagen N-telopeptide; 1,25(OH)2D3, 1,25-dihydroxy-2ß-(3-hydroxypropoxy)vitamin D3; 25(OH)D, 25-hydroxyvitamin D; VDR, vitamin D receptor.
Received December 27, 2004.
Accepted June 14, 2005.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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, 25-dihydroxyvitamin D3 (ED-71), increases bone mass by stimulating the bone formation in normal and ovariectomized rats. Calcif Tissue Int 54:142–149[Medline]
,25-Dihydroxy-2ß-(3-hydroxypropoxy) vitamin D3 (ED-71): a promising candidate for the treatment of osteoporosis. In: Norman A, Bouillon R, Thomasset M, eds. Vitamin D endocrine system: structural, biological, genetic and clinical aspects. Riverside, CA: Vitamin D Workshop, Inc., University of California, Riverside; 985–992
,25-dihydroxyvitamin D3 selectively induces bone formation. Proc Natl Acad Sci USA 99:13487–13491-hydroxyvitamin D3 on lumbar BMD and vertebral fractures in patients with postmenopausal osteoporosis. Calcif Tissue Int 54:370–376[CrossRef][Medline]
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, P < 0.01 for the comparison with placebo; 
, P < 0.05 for the comparison with placebo.
