Alfacalcidol Inhibits Bone Resorption and Stimulates Formation in an Ovariectomized Rat Model of Osteoporosis: Distinct Actions from Estrogen

Shiraishi, Ayako; Takeda, Satoshi; Masaki, Tsuneo; Higuchi, Y.; Uchiyama, Yasushi; Kubodera, Noboru; Sato, Katsuhiko; Ikeda, Kyoji; Nakamura, Toshio; Matsumoto, Toshio; Ogata, Etsuro

doi:10.1359/jbmr.2000.15.4.770

Cited by 130 publications

(56 citation statements)

References 35 publications

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“…Alfacalcidol (Chugai Pharmaceutical, Tokyo, Japan) was dissolved in medium-chain triglyceride (MCT) and a dose of 0.1 μg/kg/day or vehicle (MCT) alone was administered orally every day for 4 weeks. The dose of alfacalcidol was determined based on a previous study showing that this dose did not elevate serum calcium levels (39).…”

Section: Methodsmentioning

confidence: 99%

Effects of a vitamin D analog, alfacalcidol, on bone and skeletal muscle in glucocorticoid-treated rats

et al. 2010

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Glucocorticoids cause secondary osteoporosis and myopathy. The efficacy of vitamin D on osteoporotic fractures is thought to be through direct effects on bone and indirect effects on muscles that help to prevent falls. However, effects of vitamin D on muscles under glucocorticoid treatment remain unclear. Six-month-old female Wistar rats were randomized to four groups: vehicletreated controls; a prednisolone (PSL)-administered group (PSL group); an alfacalcidol-administered group (D group); and a group administered both PSL and alfacalcidol (PSL+D group). After a 4-week treatment period, maximum contractile strength and strength decrement index (SDI), an indicator of muscle fatigue, were measured in the calf muscle by electrical stimulation of the sciatic nerve. Cross-sectional area (CSA) of muscle fibers in the tibialis anterior muscle and bone mineral density (BMD) of the femur were evaluated. The PSL group showed significantly lower muscle strength, BMD and CSA of muscle fibers, and significantly higher SDI compared to the other three groups (P < 0.05). No significant differences were observed in any of these parameters among control, D, and PSL+D groups. These results suggest that in glucocorticoid-treated rats, alfacalcidol preserved not only BMD, but also muscle strength and muscle volume, and prevented muscle fatigue.

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Section: Methodsmentioning

confidence: 99%

Effects of a vitamin D analog, alfacalcidol, on bone and skeletal muscle in glucocorticoid-treated rats

et al. 2010

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“…(30,31) In rodent models, vitamin D analogues have been shown to increase bone mass, improve spatial architecture, and strengthen bones. (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.…”

Section: Discussionmentioning

confidence: 99%

“…(5)(6)(7)(8) However, vitamin D analogues were shown to dose-dependently elevate calcium in sera and in urine, leading to concerns about hypercalcemia and hypercalciuria in humans (5,6,(9)(10)(11)(12)(13) and in animals. (14)(15)(16)(17)(18) ORIGINAL ARTICLE…”

Section: Introductionmentioning

confidence: 99%

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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“…Rats were orally administered vehicle or alfacalcidol (0.1 lg kg -1 ) (Chugai Pharmaceutical, Japan), 5 days a week during 6 weeks. This dose has been shown to inhibit bone resorption and enhance bone formation in ovariectomized rats treated for 5 weeks [25]. The 7-month-old rats did not receive any treatment.…”

Section: Animalsmentioning

confidence: 99%

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle

et al. 2011

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Supra-physiological levels of vitamin D induce skeletal muscle atrophy, which may be particularly detrimental in already sarcopaenic elderly. Neither the cause nor whether the atrophy is fibre type specific are known. To obtain supraphysiological levels of circulating vitamin D (1,25(OH) 2 D 3 ) 27.5-month-old female Fischer 344 9 Brown Norway F1 rats were orally treated for 6 weeks with vehicle or the vitamin D analogue alfacalcidol. Alfacalcidol treatment induced a 22% decrease in body mass and 17% muscle atrophy. Fibre atrophy was restricted to type IIb fibres in the low-oxidative part of the gastrocnemius medialis only (-22%; P \ 0.05). There was a concomitant 1.6-fold increase in mRNA expression of the ubiquitin ligase MuRF-1 (P \ 0.001), whereas those of insulin-like growth factor 1 and myostatin were not affected. Circulating IL-6 was unaltered, but leptin and adiponectin were decreased (-39%) and increased (64%), respectively. The treated rats also exhibited a reduced food intake. In conclusion, supraphysiological levels of circulating 1,25(OH) 2 D 3 cause preferential atrophy of type IIb fibres, which is associated with an increased expression of MuRF-1 without evidence of systemic inflammation. The atrophy and loss of body mass in the presence of supra-physiological levels of vitamin D are primarily due to a reduced food intake.

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Alfacalcidol Inhibits Bone Resorption and Stimulates Formation in an Ovariectomized Rat Model of Osteoporosis: Distinct Actions from Estrogen

Cited by 130 publications

References 35 publications

Effects of a vitamin D analog, alfacalcidol, on bone and skeletal muscle in glucocorticoid-treated rats

Effects of a vitamin D analog, alfacalcidol, on bone and skeletal muscle in glucocorticoid-treated rats

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

Effects of alfacalcidol on circulating cytokines and growth factors in rat skeletal muscle

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