Recent studies have shown that genetic effects on bone mineral density (BMD) and bone turnover are related to allelic variation in the vitamin D receptor (VDR) gene. We examined allelic influences of the VDR gene on bone turnover and density in 202 normal healthy premenopausal Japanese women (age 30.1 +/- 1.2, mean +/- SEM). The VDR effect on BMD and turnover is similar to that observed in Caucasian women; however, there are major differences in allele frequency. The B allele by BsmI restriction fragment length polymorphisms (RFLPs), associated with low BMD and high bone turnover, is found in only 12% of Japanese women (1.4% homozygote BB), compared with 41% of Caucasians (16.7% homozygote BB). In comparing the two most frequent genotypes, Bb heterozygotes (21.5%) and bb homozygotes (77.1%), BMD is 5.3% lower in Bb heterozygotes, and levels of bone formation markers including osteocalcin and bone-specific alkaline phosphatase are 20-32% higher with lower serum calcium (2.30 +/- 0.02 vs 2.35 +/- 0.01 mmol/l) and higher 1,25-dihydroxyvitamin D (95 +/- 4.8 vs. 76 +/- 3.8 pmol/l). Further discrimination of the genotype was achieved using two additional RFLPs (ApaI, A and TaqI, T); the lumbar spine BMD of the common genotype BbAATt was 9.3% (0.94 SD) lower than in the bbaaTT genotype in premenopausal Japanese women. These data confirm that VDR RFLPs affect bone mineral metabolism regardless of racial differences. Moreover, the VDR genotypes based on haplotype analysis should yield useful insights into the potential prevention of osteoporosis.

Common vitamin D receptor (VDR) gene alleles have recently been shown to contribute to the genetic variability in bone mass and bone turnover, however, the physiological mechanisms involved are unknown. To examine this, the response to 7 days of 2 micrograms oral 1,25-dihydroxyvitamin D[1,25-(OH)2D] (calcitriol) stimulation was assessed in 21 premenopausal women, homozygous for one or other of the common VDR alleles (bb, n = 11; BB, n = 10). Indices of bone turnover and calcium homeostasis were measured during 2 weeks. Baseline osteocalcin, 1,25-(OH)2D, type I collagen carboxyterminal telopeptide, and inorganic phosphate levels were significantly higher and spinal bone mineral density was significantly lower in the BB allelic group. After calcitriol administration, similar levels of 1,25-(OH)2D were attained throughout the study in both genotypic groups. The increase in serum osteocalcin levels in the BB group was significantly less than that in the bb group (11% vs. 32%, P = 0.01). The genotype-related baseline difference in osteocalcin levels was not apparent at the similar serum 1,25-(OH)2D levels. By contrast, the baseline differences in phosphate and type I collagen carboxyterminal telopeptide persisted throughout the study. Serum ionized calcium levels did not differ between genotypes, nor did it move out of normal range values. However, parathyroid hormone was less suppressed in the low bone density group (38% vs. 11%, P = 0.01). These data indicate that the VDR alleles are associated with differences in the vitamin D endocrine system and may have important implications in relation to the pathophysiology of osteoporosis.

Abstract. The aim of this study was to investigate the effect of daily oral administration of calcitriol on calcium metabolism in Japanese postmenopausal women. For this purpose, we administered 0.5 mg of daily calcitriol to 18 Japanese postmenopausal women for up to 24 weeks. During the first 28 days, daily administration of 0.5 mg of oral calcitriol increased fasting serum 1,25(OH) 2 D levels significantly in 9 women (Group B) (p<0.005), while no significant change was seen in another 9 women without calcitriol administration (Group A). The first 28-day calcitriol supplement increased fasting urinary calcium excretion (urinary Ca/Cr) from 0.133 ± 0.072 to 0.171 ± 0.089 (p<0.05) and fractional excretion of calcium (FECa) without changing serum Ca 2+ . Urinary NTx/Cr excretion, an index of bone resorption, decreased significantly from 64.8 ± 24.5 to 50.3 ± 27.2 nMBCE/mMCr in Group B. Following the 28-day control period, 0.5 mg of oral calcitriol was also administered to women in Group A for another 20 weeks. At the end of the 24-week investigation period, the effects of oral calcitriol on urinary calcium excretion and bone resorption were still significant in both Group A and B. A positive correlation was found between urinary Ca/Cr and NTx/Cr excretion at the start (r = 0.657, p<0.05), but this correlation was lost by calcitriol treatment (r = 0.135). These results indicated that calcitriol supplement was effective in suppressing bone resorption in postmenopausal women, and that an increased fasting urinary calcium excretion due to calcitriol supplement was predominantly caused by increased intestinal calcium absorption in these women.

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