ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis

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

doi:10.1016/s8756-3282(02)00682-8

Cited by 116 publications

(78 citation statements)

References 20 publications

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“…Using OVX rats, Uchiyama et al 8 compared the effects of eldecalcitol with those of alfacalcidol on BMD and bone remodeling processes as a function of their effects on Ca metabolism. Eldecalcitol increased lumbar BMD to a greater extent than did alfacalcidol but increased urinary Ca excretion to an extent similar to that of alfacalcidol.…”

Section: Preclinical Studiesmentioning

confidence: 99%

Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol

Matsumoto¹,

Takano²,

Saitô³

et al. 2014

BoneKEy Reports

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Eldecalcitol [1a,25-dihydroxy-2b-(3-hydroxypropyloxy)vitamin D 3 ] is an analog of 1a, 25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ], bearing a hydroxypropyloxy residue at the 2b position. In preclinical studies, eldecalcitol suppressed bone resorption to a greater extent than alfacalcidol but had a similar effect on bone formation and Ca metabolism, resulting in a greater increase in bone mineral density (BMD) in ovariectomized (OVX) rats. Histological analysis in OVX rats immediately after ovariectomy revealed that eldecalcitol reduced osteoclast number and bone resorption parameters with a decrease in bone formation parameters. Eldecalcitol also promoted focal bone formation independent of bone resorption, a process known as bone minimodeling. In clinical studies, eldecalcitol showed stronger effects than alfacalcidol in increasing BMD and reducing bone resorption markers in osteoporotic patients under vitamin D supplementation. A 3-year randomized, double-blind, active-comparator clinical trial demonstrated that once-daily 0.75 lg eldecalcitol reduced vertebral fracture incidence by 26% compared with 1.0 lg alfacalcidol. Eldecalcitol also reduced the incidence of wrist fractures by 71% compared with alfacalcidol. Although this may be due to the previously reported effect of vitamin D in reducing the incidence of falls, it is not known whether eldecalcitol has a stronger effect in preventing falls than alfacalcidol. Because eldecalcitol stimulates intestinal Ca absorption and improves Ca balance in addition to its skeletal effects, combination treatment with antiresorptive agents may be able to show better effects than native vitamin D and Ca supplementation in preventing fractures in osteoporotic patients. Further studies are warranted to clarify these issues.

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Section: Preclinical Studiesmentioning

confidence: 99%

Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol

Matsumoto¹,

Takano²,

Saitô³

et al. 2014

BoneKEy Reports

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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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“…The VDR has been identified on OC precursor cells, and Kogawa et al (4) reported that 1α,25-(OH) 2 D 3 induces OC precursor cells to differentiate into mature OCs that display bone absorption activity. In contrast to these findings, Uchiyama et al (5) have demonstrated that pharmacological doses of active vitamin D 3 suppress bone resorption. This discrepancy in the effects of vitamin D on bones requires further exploration.…”

Section: Introductionmentioning

confidence: 91%

1α,25-Dihydroxyvitamin D3 inhibits the differentiation and bone resorption by osteoclasts generated from Wistar rat bone marrow-derived macrophages

Wang

Yang

et al. 2015

Experimental and Therapeutic Medicine

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Abstract. The steroid hormone 1α, 2 D 3 ] plays an important role in maintaining a balance in calcium and bone metabolism. To study the effects of 1α,25-(OH) 2 D 3 on osteoclast (OC) formation and bone resorption, OC differentiation was induced in bone marrow-derived mononuclear cells from Wistar rats with the addition of macrophage colony stimulating factor and receptor activator for nuclear factor-κB ligand in vitro. Cells were then treated with 1α,25-(OH) 2 D 3 at 10 -9 , 10 -8 or 10 -7 mol/l. OCs were identified using tartrate-resistant acid phosphatase staining and activity was monitored in the absorption lacunae by scanning electron microscopy. Expression levels of functional proteins associated with bone absorption, namely carbonic anhydrase II, cathepsin K and matrix metalloproteinase-9 were evaluated by western blot analysis. The results showed that 1α,25-(OH) 2 D 3 inhibited the formation and activation of OCs in a dose-dependent manner and downregulated the expression levels of bone absorption-associated proteins.

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ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis

Cited by 116 publications

References 20 publications

Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol

Vitamin D analogs and bone: preclinical and clinical studies with eldecalcitol

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

1α,25-Dihydroxyvitamin D3 inhibits the differentiation and bone resorption by osteoclasts generated from Wistar rat bone marrow-derived macrophages

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