Eldecalcitol

Osteoporosis is characterized by a reduction in bone mass with age, contributing to a loss in bone strength. Vitamin D is a crucial factor for the intestinal absorption of calcium to maintain bone strength. 1α,25(OH)2D3 and its prodrugs alfacalcidol (ALF) and eldecalcitol are widely used in the treatment of Ca- and bone-related diseases including osteoporosis, hyperparathyroidism, osteomalacia, and renal osteodystrophy.

In vitro: Compared with 1α,25(OH)2D3, eldecalcitol has a higher affinity for serum DBP, binds more weakly to VDR, and shows lower potency in suppression of serum PTH. Moreover, the plasma half-life of eldecalcitol is longer than that of 1α,25(OH)2D3, probably due to the higher affinity for DBP [1].

In vivo: In ovariectomized rat model of osteoporosis, eldecalcitol was found to have a greater activity than alfacalcidol in suppressing bone resorption as well as increasing bone mineral density (BMD) [2].

Clinical trial: Eldecalcitol is approved in Japan for the treatment of osteoporosis. Compared to a placebo treatment, treatment with eldecalcitol for 1 year significantly increased lumbar spine and total hip bone mineral density (BMD) and reduced bone turnover markers in a dose-dependent manner [3].

Reference:
[1] Noguchi Y, Kawate H, Nomura M, Takayanagi R.  Eldecalcitol for the treatment of osteoporosis. Clin Interv Aging. 2013;8:1313-21.
[2] Sakai S, Endo K, Takeda S, Mihara M, Shiraishi A.  Combination therapy with eldecalcitol and alendronate has therapeutic advantages over monotherapy by improving bone strength. Bone. 2012 May;50(5):1054-63.
[3] Shiraki M, Saito H, Matsumoto T.  Eldecalcitol normalizes bone turnover markers regardless of their pre-treatment levels. Curr Med Res Opin. 2012 Sep;28(9):1547-52.

Combined use of ibandronate and eldecalcitol in postmenopausal Japanese women with osteoporosis.[Pubmed:28031507]

J Orthop Surg (Hong Kong). 2016 Dec;24(3):362-366.

PURPOSE: To evaluate the effect of combined use of ibandronate and Eldecalcitol for 6 to 12 months on bone mineral density (BMD) and bone strength of the proximal femur in postmenopausal Japanese women with osteoporosis. METHODS: BMD and bone strength of the proximal femur were evaluated in 78 postmenopausal women (mean age, 73.6 years) who underwent treatment for osteoporosis with combined use of ibandronate and Eldecalcitol for at least 6 months. BMD was measured at the lumbar spine, femoral neck, and total hip using dual-energy X-ray absorptiometry (DXA) at baseline and every 6 months thereafter. Hip structure analysis of the narrow neck and intertrochanter was performed by a radiologist using DXA images. RESULTS: Respectively for the lumbar spine, femoral neck, and total hip, BMD significantly increased (from baseline) by 4.54%, 2.31%, and 1.56% at 6 months and by 5.92%, 3.02%, and 2.70% at 12 months. In hip structure analysis, most parameters improved significantly. Respectively for the narrow neck and intertrochanter, BMD significantly increased (from baseline) by 2.37% and 2.71% at 6 months and by 3.46% and 3.52% at 12 months; cross-sectional area significantly increased by 1.83% and 3.39% at 6 months and by 2.91% and 3.46% at 12 months; section modulus significantly increased by 2.42% and 4.11% at 6 months and by 4.84% and 3.26% at 12 months; cortical thickness significantly increased by 2.49% and 3.33% at 6 months and by 3.73% and 3.37% at 12 months; and buckling ratio significantly decreased by 2.97% and 2.57% at 6 months and by 3.86% and 2.99% at 12 months. CONCLUSION: Combined use of ibandronate and Eldecalcitol for 6 months significantly improved bone strength of the proximal femur in postmenopausal Japanese women with osteoporosis.

Effect of osteoporosis medication on changes in bone mineral density and bone turnover markers after 24-month administration of daily teriparatide: comparison among minodronate, raloxifene, and eldecalcitol.[Pubmed:28293779]

J Bone Miner Metab. 2018 Mar;36(2):221-228.

This study reveals the changes in bone mineral density (BMD), the turnover rate, and the balance [multiple of median formation/multiple of median resorption (MoMf/MoMr)] affected by the selection of different bone resorption inhibitors after 24-month daily teriparatide (20 microg/day) administration. The turnover rate was calculated as radical(MoMf(2) + MoMr(2)), where MoMf = bone-specific alkaline phosphatase (BAP) value/18.6 and MoMr = tartrate-resistant acid phosphatase 5b (TRACP-5b) value/463. One hundred and twenty-one osteoporotic women (mean age 82.4 years) were randomly administered minodronate (50 mg/28 days), raloxifene (60 mg/day), or Eldecalcitol (0.75 microg/day) after teriparatide discontinuation. BMD was measured at 0, 24, and 48 weeks; BAP values and TRACP-5b were measured at 0, 12, 24, 36, and 48 weeks after administration of bone resorption inhibitors. In the minodronate group, BMD increased significantly from week 0 to weeks 24 and 48. The turnover rate was significantly reduced at week 12, and remained so over the entire course in all three groups. The speed of change of turnover rate was greatest in the minodronate group. The balance in the minodronate group shifted significantly toward formation dominance at week 12 (to 0.97 from 0.87) and then again toward resorption dominance (to 0.84) at week 24. However, no further advancement in resorption dominance was observed until week 48. Conversely, the balance in the raloxifene and Eldecalcitol groups shifted toward resorption dominance gradually over the entire course. In conclusion, the BMD-increasing effect was greatest with minodronate administration and depends not only on the decrease in turnover rate but also on changes in balance after teriparatide discontinuation.

A vitamin D analogue, eldecalcitol, enhances expression of fast myosin heavy chain subtypes in differentiated C2C12 myoblasts.[Pubmed:28017710]

J Orthop Sci. 2017 Mar;22(2):345-350.

BACKGROUND: Several lines of evidence indicate that the active form of vitamin D has an anabolic effect on skeletal muscle. Eldecalcitol, an analogue of the active form of vitamin D, has the potential to increase bone density and decrease fracture risk. The objective of this study was to investigate the effect of Eldecalcitol in C2C12 myogenic cells. METHODS: C2C12 cells were grown to confluency and the culture medium was replaced with low-glucose DMEM containing 2% horse serum. Eldecalcitol was added at a concentration of 1, 10 or 100 nM. Gene expression profiles of vitamin D receptor (VDR), MyoD, IGF-1, neonatal myosin heavy chain (MHC), and the fast MHC subtypes Ia, IIa, IIb and IId/x were analyzed by quantitative RT-PCR. Protein expression of MHC subtypes was evaluated by western blotting and immunostaining. RESULTS: Eldecalcitol upregulated gene expression of VDR, MyoD and IGF-1. Incubation with Eldecalcitol in the absence of serum followed by the addition of serum after 1 h was associated with greater increases in the expression of these genes compared with co-incubation with Eldecalcitol and serum. Gene expression of MHC subtypes IIa, IIb and IId/x was significantly increased by Eldecalcitol. Protein expression of fast MHC subtypes was significantly increased by Eldecalcitol at 1 and 10 nM. CONCLUSION: Similar to the active form of vitamin D, Eldecalcitol had an anabolic effect on fast MHC subtypes. Taking into account its pharmacokinetic profile, Eldecalcitol is expected to be beneficial for the maintenance and improvement of muscle function in elderly individuals.

Selective estrogen receptor modulators and the vitamin D analogue eldecalcitol block bone loss in male osteoporosis.[Pubmed:27974229]

Biochem Biophys Res Commun. 2017 Jan 22;482(4):1430-1436.

Rapid increases in the number of elderly people have dramatically increased the number of female and male osteoporosis patients. Osteoporosis often causes bone fragility fractures, and males exhibit particularly poor prognosis after these fractures, indicating that control of osteoporosis is crucial to maintain quality of men's lives. However, osteoporosis therapies available for men have lagged behind advances available for women. Here, we show that three selective estrogen receptor modulators (SERMs), namely, raloxifene, bazedoxifene, and tamoxifen, plus the vitamin D analogue ED71, also called Eldecalcitol, completely block orchiectomy-induced, testosterone-depleted bone loss in male mice in vivo. Patients treated with hormone deprivation therapy for prostate cancer also exhibit male osteoporosis, and bone management is critical for these patients. Given that androgen replacement therapy is not an option for these patients, our results represent a novel approach potentially useful to control male osteoporosis.

Eldecalcitol (ED-71) is an orally active analogue of active vitamin D used in the treatment of osteoporosis. Eldecalcitol (ED-71) possesses a strong inhibitory effect on bone resorption and causes a significant increase in bone mineral density.

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