Effects of 1?-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis

Orimo, Hajime; Shiraki, Masataka; Hayashi, Yoshihiko; Hoshino, Tazue; Onaya, Toshimasa; Miyazaki, Satsuki; Kurosawa, Hisashi; Nakamura, Toshio; Ogawa, Norio

doi:10.1007/bf00305521

Cited by 216 publications

(104 citation statements)

References 23 publications

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“…This apparent difference may be partly due to the variability in BMD values resulting from the small sample size in our study, or because about one third of our patients were treated with combined use of RLX and ALF, suggesting that RLX in combination with ALF may be potentially more beneficial for bone health than RLX alone. Actually, several clinical studies [9,10] previously showed that ALF reduced bone turnover and prevented vertebral fractures although its effectiveness may be relatively low, and animal-model studies also showed that ALF inhibited bone resorption [11,12] and stimulated formation [11] to increase BMD. Moreover, although native vitamin D plus calcium, but not activated vitamin D, was supplemented in both patients and controls of the previous clinical studies for RLX [1-6], Nuti et al [13] recently reported superiority of ALF compared to native vitamin D plus calcium in increasing lumbar BMD.…”

Section: Discussionmentioning

confidence: 99%

Clinical Significance of 1-year Treatment with Raloxifene on Bone and Lipid Metabolism in Japanese Postmenopausal Women with Osteoporosis

et al. 2007

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Abstract. It has been well established that raloxifene (RLX) has beneficial effects on bone primarily in Caucasian women. However, to date, there is a dearth of data for Japanese postmenopausal women. In this study, we prospectively evaluated the effects of RLX on bone and lipid metabolism in fifty Japanese postmenopausal patients with untreated osteoporosis. We measured bone mineral density (BMD) by dual-energy X-ray absorptiometry at 7 sites including the lumbar spine, femoral neck, and distal radius. BMD was significantly increased at the lumbar spine both at 6 months and at 12 months compared with at baseline (p<0.01 for both), although the possibility could not be completely excluded that this increase may be partly explained by an apparent increase induced by degenerative changes in lumbar vertebrae since we had no control subjects to compare and be more certain of the findings in this study. Both bone-specific alkaline phosphatase (BAP) and serum N-terminal telopeptide of type I collagen (NTx) significantly decreased both at 6 months (p<0.01 for both) and at 12 months (p<0.01 for both) compared with at baseline, but not below the lower limit of the reference value. Total cholesterol and low-density lipoprotein cholesterol were significantly improved while triglycerides and high-density lipoprotein cholesterol were unaltered. Although longer and larger studies with fracture endpoints are needed to draw definite conclusions, our findings suggest the favorable effects of RLX on bone and lipid metabolism in Japanese postmenopausal women with osteoporosis as in Caucasian women.

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Section: Discussionmentioning

confidence: 99%

Clinical Significance of 1-year Treatment with Raloxifene on Bone and Lipid Metabolism in Japanese Postmenopausal Women with Osteoporosis

et al. 2007

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“…[12][13][14][15][16] Paradoxically, such beneficial effects are caused by inhibiting osteoclastogenesis. The present review describes the regulation of osteoclast differentiation and possible mechanisms by which active vitamin D compounds suppress bone resorption in vivo.…”

Section: Introductionmentioning

confidence: 99%

Vitamin D endocrine system and osteoclasts

Takahashi¹,

Udagawa²,

Suda³

2014

BoneKEy Reports

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Vitamin D was discovered as an anti-rachitic agent preventing a failure in bone mineralization, but it is now established that the active form of vitamin D 3 (1a,25(OH) 2 D 3 ) induces bone resorption. Discovery of the receptor activator of nuclear factor -kB ligand (RANKL) uncovered the molecular mechanism by which 1a,25(OH) 2 D 3 stimulates bone resorption. Treating osteoblastic cells with 1a,25(OH) 2 D 3 stimulates RANKL expression, which in turn induces osteoclastogenesis. Nevertheless, active vitamin D compounds such as calcitriol (1a,25(OH) 2 D 3 ), alfacalcidol (1a(OH)D 3 ) and eldecalcitol (1a,25-dihydroxy-2b-(3-hydroxypropoxy) vitamin D 3 ) have been used as therapeutic drugs for osteoporosis, as they increase bone mineral density (BMD) in osteoporotic patients. Paradoxically, the increase in BMD is caused by the suppression of bone resorption. Several studies have been performed to elucidate the mechanism by which active vitamin D compounds suppress bone resorption in vivo. Our study showed that daily administration of eldecalcitol to mice suppressed neither the number of osteoclast precursors in the bone marrow nor the number of osteoclasts formed in ex vivo cultures. Eldecalcitol administration suppressed RANKL expression in osteoblasts. This review discusses how the difference between in vitro and in vivo effects of active vitamin D compounds on bone resorption is induced.

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“…(14)(15)(16)(17)32) Histomorphometry showed that vitamin D analogues can stimulate bone-formation activity on cortical and trabecular bone surfaces; however, bone-formation activity was best demonstrated at hypercalcemic doses. (14,15) Similarly in clinical studies, skeletal efficacy was demonstrated for vitamin D analogues, including reduction of nonvertebral fractures, (5)(6)(7) but the realization of bone efficacy in the absence of hypercalcemia or hypercalciuria has been difficult to achieve. (6)(7)(8)(9)(10)33) We hypothesized that nonsecosteroidal vitamin D receptor ligands could be synthesized to preferentially modulate skeletal efficacy over hypercalcemic effects in vivo.…”

Section: Discussionmentioning

confidence: 99%

“…(14,15) Similarly in clinical studies, skeletal efficacy was demonstrated for vitamin D analogues, including reduction of nonvertebral fractures, (5)(6)(7) but the realization of bone efficacy in the absence of hypercalcemia or hypercalciuria has been difficult to achieve. (6)(7)(8)(9)(10)33) We hypothesized that nonsecosteroidal vitamin D receptor ligands could be synthesized to preferentially modulate skeletal efficacy over hypercalcemic effects in vivo. Additionally, we hypothesized that a synthetic compound could have other potential benefits to the elderly, such as improved neuromuscular function, anti-inflammatory/immunomodulation properties, inproved skin quality, and prevention of breast, colon, and prostate cancer.…”

Section: Discussionmentioning

confidence: 99%

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A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia

Sato

Iturria

et al. 2010

Journal of Bone and Mineral Research

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Vitamin D 3 analogues were shown to be beneficial for osteoporosis and other indications, but their narrow therapeutic window between efficacy and hypercalcemia has limited their clinical utility. A nonsecosteroidal, tissue-selective, orally bioavailable, vitamin D receptor (VDR) ligand was ascertained to be efficacious in bone while having modest calcemic effects in vivo. This compound (VDRM2) potently induced Retinoid X Receptor alpha (RXR)-VDR heterodimerization (EC 50 ¼ 7.1 AE 1.6 nM) and induced osteocalcin promoter activity (EC 50 ¼ 1.9 AE 1.6 nM). VDRM2 was less potent in inducing Ca 2þ channel transient receptor potential cation channel, subfamily V, member 6 (TRPV6) expression (EC 50 ¼ 37 AE 12 nM). VDRM2 then was evaluated in osteopenic ovariectomized (OVX) rats and shown to dose-dependently restore vertebral bone mineral density (BMD) from OVX to sham levels at 0.08 mg/kg per day. Hypercalcemia was observed at a dose of 4.6 mg/kg per day of VDRM2, suggesting a safety margin of 57 [90% confidence interval (CI) 35-91]. 1a,25-dihydroxyvitamin D 3 [1a,25(OH) 2 D], ED71, and alfacalcidol restored BMD at 0.030, 0.0055, and 0.046 mg/kg per day, respectively, whereas hypercalcemia was observed at 0.22, 0.027, and 0.23 mg/kg per day, indicating a safety margin of 7.3, 4.9, and 5.0, respectively (90% CIs 4.1-13, 3.2-7.7, and 3.5-6.7, respectively). Histomorphometry showed that VDRM2 increased cortical bone area and stimulated the periosteal bone-formation rate relative to OVX at doses below the hypercalcemic dose. By contrast, ED71 increased the periosteal boneformation rate only above the hypercalcemic dose. VDRM2 suppressed eroded surface on trabecular bone surfaces at normal serum calcium dosage levels, suggesting dual anabolic and antiresorptive activity. In summary, vitamin D analogues were more potent than VDRM2, but VDRM2 had a greater safety margin, suggesting possible therapeutic potential. ß

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Effects of 1?-hydroxyvitamin D3 on lumbar bone mineral density and vertebral fractures in patients with postmenopausal osteoporosis

Cited by 216 publications

References 23 publications

Clinical Significance of 1-year Treatment with Raloxifene on Bone and Lipid Metabolism in Japanese Postmenopausal Women with Osteoporosis

Clinical Significance of 1-year Treatment with Raloxifene on Bone and Lipid Metabolism in Japanese Postmenopausal Women with Osteoporosis

Vitamin D endocrine system and osteoclasts

A nonsecosteroidal vitamin D receptor ligand with improved therapeutic window of bone efficacy over hypercalcemia

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