Top

Published in:

Open Access 01-03-2015 | Original Article

Efficacy of combined treatment with alendronate (ALN) and eldecalcitol, a new active vitamin D analog, compared to that of concomitant ALN, vitamin D plus calcium treatment in Japanese patients with primary osteoporosis

Authors: A. Sakai, M. Ito, T. Tomomitsu, H. Tsurukami, S. Ikeda, F. Fukuda, H. Mizunuma, T. Inoue, H. Saito, T. Nakamura, e-ADVANCED Study Group

Published in: Osteoporosis International | Issue 3/2015

Abstract

Summary

Combined treatment with alendronate and eldecalcitol was found to be more effective in reducing the bone turnover markers and increasing bone mineral density than alendronate treatment with vitamin D3 and calcium supplementation in the osteoporotic patients.

Introduction

We compared the clinical efficacy and safety of combined treatment with alendronate plus eldecalcitol (ALN + ELD) with those of treatment with ALN plus vitamin D and calcium (ALN + VitD).

Methods

Osteoporotic 219 patients were randomly assigned to the ALN + ELD, or the ALN + VitD group. Primary endpoint was the inter-group differences in lumbar spine BMD (L-BMD) at patient’s last visit. Secondary endpoints included the differences in BMD at other sites and the bone turnover marker (BTM) levels.

Results

L-BMD, total hip BMD and femoral neck (FN-BMD) increased from baseline by 7.30, 2.41, and 2.70 % in the ALN + ELD group, and by 6.52, 2.27, and 1.18 % in the ALN + VitD group, respectively. Inter-group differences of the L-BMD and total hip BMD values were not significant. The increase of the FN-BMD was larger in the ALN + ELD group than the ALN + VitD group. Reductions of the BTMs were greater in the ALN + ELD group than the ALN + VitD group. Interaction of the percent increase of the L-BMD with the baseline values of the BTMs was observed in the ALN + VitD group only. The increases of the FN-BMD in patients with lower baseline values of type-I-collagen C-telopeptide (sCTX) and serum 25(OH) D levels <20 ng/mL were significantly larger in the ALN + ELD group than the other group.

Conclusion

Combination treatment of ALN plus ELD was more effective in reducing the BTMs and increasing the FN-BMD than ALN treatment with vitamin D3 and calcium.

Miyamoto K, Murayama E, Ochi K, Watanabe H, Kubodera N (1993) Synthetic studies of vitamin D analogues. XIV. Synthesis and calcium regulating activity of vitamin D3 analogues bearing a hydroxyalkoxy group at the 2 beta-position. Chem Pharm Bull (Tokyo) 41:1111–1113CrossRef

Matsumoto T, Miki T, Hagino H, Sugimoto T, Okamoto S, Hirota T, Tanigawara Y, Hayashi Y, Fukunaga M, Shiraki M, Nakamura T (2005) A new active vitamin D, ED-71, increases bone mass in osteoporotic patients under vitamin D supplementation: a randomized, double-blind, placebo-controlled clinical trial. J Clin Endocrinol Metab 90:5031–5036CrossRefPubMed

Matsumoto T, Ito M, Hayashi Y, Hirota T, Tanigawara Y, Sone T, Fukunaga M, Shiraki M, Nakamura T (2011) A new active vitamin D3 analog, eldecalcitol, prevents the risk of osteoporotic fractures–a randomized, active comparator, double-blind study. Bone 49:605–612. doi:10.1016/j.bone.2011.07.011 CrossRefPubMed

NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795CrossRef

Russell RG, Xia Z, Dunford JE, Oppermann U, Kwaasi A, Hulley PA, Kavanagh KL, Triffitt JT, Lundy MW, Phipps RJ, Barnett BL, Coxon FP, Rogers MJ, Watts NB, Ebetino FH (2007) Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 1117:209–257CrossRefPubMed

Orimo H, Hayashi Y, Fukunaga M, Sone T, Fujiwara S, Shiraki M, Kushida K, Miyamoto S, Soen S, Nishimura J, Oh-Hashi Y, Hosoi T, Gorai I, Tanaka H, Igai T, Kishimoto H, Osteoporosis Diagnostic Criteria Review Committee: Japanese Society for Bone and Mineral Research (2001) Diagnostic criteria for primary osteoporosis: year 2000 revision. J Bone Miner Metab 19:331–337CrossRefPubMed

Mori S, Soen S, Hagino H, Nakano T, Ito M, Fujiwara S, Kato Y, Tokuhashi Y, Togawa D, Endo N, Sawaguchi T, Committee for Vertebral Fracture Evaluation (2013) Justification criteria for vertebral fractures: year 2012 revision. J Bone Miner Metab 31:258–261. doi:10.1007/s00774-013-0441-1 CrossRefPubMed

Genant HK, Jergas M, Palermo L, Nevitt M, Valentin RS, Black D, Cummings SR (1996) Comparison of semiquantitative visual and quantitative morphometric assessment of prevalent and incident vertebral fractures in osteoporosis. J Bone Miner Res 11:984–996CrossRefPubMed

Harada S, Mizoguchi T, Kobayashi Y, Nakamichi Y, Takeda S, Sakai S, Takahashi F, Saito H, Yasuda H, Udagawa N, Suda T, Takahashi N (2012) Daily administration of eldecalcitol (ED-71), an active vitamin D analog, increases bone mineral density by suppressing RANKL expression in mouse trabecular bone. J Bone Miner Res 27:461–473. doi:10.1002/jbmr.555 CrossRefPubMed

10.

de Freitas PH, Hasegawa T, Takeda S, Sasaki M, Tabata C, Oda K, Li M, Saito H, Amizuka N (2011) Eldecalcitol, a second-generation vitamin D analog, drives bone minimodeling and reduces osteoclastic number in trabecular bone of ovariectomized rats. Bone 49:335–342. doi:10.1016/j.bone.2011.05.022 CrossRefPubMed

11.

Kikuta J, Kawamura S, Okiji F, Shirazaki M, Sakai S, Saito H, Ishii M (2013) Sphingosine-1-phosphate-mediated osteoclast precursor monocyte migration is a critical point of control in antibone-resorptive action of active vitamin D. Proc Natl Acad Sci U S A 110:7009–7013. doi:10.1073/pnas.1218799110 CrossRefPubMedCentralPubMed

12.

Krzeszinski JY, Wei W, Huynh H, Jin Z, Wang X, Chang TC, Xie XJ, He L, Mangala LS, Lopez-Berestein G, Sood AK, Mendell JT, Wan Y (2014) miR-34a blocks osteoporosis and bone metastasis by inhibiting osteoclastogenesis and Tgif2. Nature 512:431–435. doi:10.1038/nature13375 CrossRefPubMed

13.

Li H, Xie H, Liu W, Hu R, Huang B, Tan YF, Xu K, Sheng ZF, Zhou HD, Wu XP, Luo XH (2009) A novel microRNA targeting HDAC5 regulates osteoblast differentiation in mice and contributes to primary osteoporosis in humans. J Clin Invest 119:3666–3677. doi:10.1172/JCI39832 CrossRefPubMedCentralPubMed

14.

Lisse TS, Adams JS, Hewison M (2013) Vitamin D and microRNAs in bone. Crit Rev Eukaryot Gene Expr 23:195–214CrossRefPubMedCentralPubMed

15.

Campbell MJ (2014) Vitamin D and the RNA transcriptome: more than mRNA regulation. 5:1-13. doi: 10.3389/fphys.2014.00181

16.

Scott LJ (2014) Denosumab: a review of its use in postmenopausal women with osteoporosis. Drugs Aging 31:555–576. doi:10.1007/s40266-014-0191-3 CrossRefPubMed

17.

Shiraki M, Kushida K, Fukunaga M, Kishimoto H, Taga M, Nakamura T, Kaneda K, Minaguchi H, Inoue T, Morii H, Tomita A, Yamamoto K, Nagata Y, Nakashima M, Orimo H (1999) A double-masked multicenter comparative study between alendronate and alfacalcidol in Japanese patients with osteoporosis. The Alendronate Phase III Osteoporosis Treatment Research Group. Osteoporos Int 10:183–192CrossRefPubMed

18.

Kendler DL, Roux C, Benhamou CL, Brown JP, Lillestol M, Siddhanti S, Man HS, San Martin J, Bone HG (2010) Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res 25:72–81. doi:10.1359/jbmr.090716 CrossRefPubMed

19.

Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, Hadji P, Hofbauer LC, Alvaro-Gracia JM, Wang H, Austin M, Wagman RB, Newmark R, Libanati C, San Martin J, Bone HG (2009) Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 24:153–161. doi:10.1359/jbmr.080901 CrossRefPubMed

20.

Recknor C, Czerwinski E, Bone HG, Bonnick SL, Binkley N, Palacios S, Moffett A, Siddhanti S, Ferreira I, Ghelani P, Wagman RB, Hall JW, Bolognese MA, Benhamou CL (2013) Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol 121:1291–1299. doi:10.1097/AOG.0b013e318291718c CrossRefPubMed

21.

Roux C, Hofbauer LC, Ho PR, Wark JD, Zillikens MC, Fahrleitner-Pammer A, Hawkins F, Micaelo M, Minisola S, Papaioannou N, Stone M, Ferreira I, Siddhanti S, Wagman RB, Brown JP (2014) Denosumab compared with risedronate in postmenopausal women suboptimally adherent to alendronate therapy: efficacy and safety results from a randomized open-label study. Bone 58:48–54. doi:10.1016/j.bone.2013.10.006 CrossRefPubMed

22.

Nakamura T, Matsumoto T, Sugimoto T, Hosoi T, Miki T, Gorai I, Yoshikawa H, Tanaka Y, Tanaka S, Sone T, Nakano T, Ito M, Matsui S, Yoneda T, Takami H, Watanabe K, Osakabe T, Shiraki M, Fukunaga M (2014) Clinical trials express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab 99:2599–2607. doi:10.1210/jc.2013-4175 CrossRefPubMedCentralPubMed

23.

Nakamura T, Shiraki M, Fukunaga M, Tomomitsu T, Santora AC, Tsai R, Fujimoto G, Nakagomi M, Tsubouchi H, Rosenberg E, Uchida S (2014) Effect of the cathepsin K inhibitor odanacatib administered once weekly on bone mineral density in Japanese patients with osteoporosis—a double-blind, randomized, dose-finding study. Osteoporos Int 25:367–376. doi:10.1007/s00198-013-2398-2 CrossRefPubMed

24.

Greenspan SL, Parker RA, Ferguson L, Rosen HN, Maitland-Ramsey L, Karpf DB (1998) Early changes in biochemical markers of bone turnover predict the long-term response to alendronate therapy in representative elderly women: a randomized clinical trial. J Bone Miner Res 13:1431–1438CrossRefPubMed

25.

Ravn P, Clemmesen B, Christiansen C (1999) Biochemical markers can predict the response in bone mass during alendronate treatment in early postmenopausal women. Alendronate Osteoporosis Prevention Study Group. Bone 24:237–244CrossRefPubMed

26.

Nenonen A, Cheng S, Ivaska KK, Alatalo SL, Lehtimäki T, Schmidt-Gayk H, Uusi-Rasi K, Heinonen A, Kannus P, Sievänen H, Vuori I, Väänänen HK, Halleen JM (2005) Serum TRACP 5b is a useful marker for monitoring alendronate treatment: comparison with other markers of bone turnover. J Bone Miner Res 20:1804–1812CrossRefPubMed

27.

Iwamoto J, Takeda T, Sato Y, Uzawa M (2005) Early changes in urinary cross-linked N-terminal telopeptides of type I collagen level correlate with 1-year response of lumbar bone mineral density to alendronate in postmenopausal Japanese women with osteoporosis. J Bone Miner Metab 23:238–242CrossRefPubMed

28.

Okano T, Tsugawa N, Masuda S, Takeuchi A, Kobayashi T, Takita Y, Nishii Y (1989) Regulatory activities of 2 beta-(3-hydroxypropoxy)-1 alpha, 25-dihydroxyvitamin D3, a novel synthetic vitamin D3 derivative, on calcium metabolism. Biochem Biophys Res Commun 163:1444–1449CrossRefPubMed

29.

Saito H, Harada S (2014) Eldecalcitol replaces endogenous calcitriol but does not fully compensate for its action in vivo. J Steroid Biochem Mol Biol 144:189–196. doi:10.1016/j.jsbmb.2013.11.013 CrossRefPubMed

30.

Matsumoto T, Takano T, Yamakido S, Takahashi F, Tsuji N (2010) Comparison of the effects of eldecalcitol and alfacalcidol on bone and calcium metabolism. J Steroid Biochem Mol Biol 121:261–264. doi:10.1016/j.jsbmb.2010.03.035 CrossRefPubMed

31.

Chugai Pharmaceutical Co., Ltd. [Common Technical Document: Eldecalcitol 2.6.2.2.1.6]. http://www.info.pmda.go.jp/shinyaku/P201100025/index.html. Japanese

32.

Ochi H (1998) 2β-(3-Hydroxypropoxy)1α,25-Dihydroxyvitamin D (3) (ED-71), increases bone mass by stimulating bone formation in hypophosphatemic mice. J Okayama Med Assoc 110:31–37, Japanese

33.

Bauer DC, Garnero P, Hochberg MC, Santora A, Delmas P, Ewing SK, Black DM; Fracture Intervention Research Group (2006) Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial. J Bone Miner Res 21:292–299

Title: Efficacy of combined treatment with alendronate (ALN) and eldecalcitol, a new active vitamin D analog, compared to that of concomitant ALN, vitamin D plus calcium treatment in Japanese patients with primary osteoporosis
Authors: A. Sakai
M. Ito
T. Tomomitsu
H. Tsurukami
S. Ikeda
F. Fukuda
H. Mizunuma
T. Inoue
H. Saito
T. Nakamura
e-ADVANCED Study Group
Publication date: 01-03-2015
Publisher: Springer London
Published in: Osteoporosis International / Issue 3/2015
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-014-2991-z

At a glance: The STEP trials

Springer Medicine

Efficacy of combined treatment with alendronate (ALN) and eldecalcitol, a new active vitamin D analog, compared to that of concomitant ALN, vitamin D plus calcium treatment in Japanese patients with primary osteoporosis

Abstract

Summary

Introduction

Methods

Results

Conclusion

At a glance: The STEP trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 3/2015

Response to Hotta: High prevalence of vitamin D insufficiency and deficiency among patients with anorexia nervosa in Japan

Bone health management in men undergoing ADT: examining enablers and barriers to care

Is thoracolumbar fascia injury the cause of residual back pain after percutaneous vertebroplasty? A prospective cohort study

Local renin-angiotensin system is associated with bone mineral density of glucocorticoid-induced osteoporosis patients

Anthropometric models of bone mineral content and areal bone mineral density based on the bone mineral density in childhood study

The complex relationship between bone remodeling and the physical and material properties of bone