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Effects of Alfacalcidol on Mechanical Properties and Collagen Cross-Links of the Femoral Diaphysis in Glucocorticoid-Treated Rats

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Abstract

Bone fragility is increased in glucocorticoid (GC)-induced osteopenia even though GC-treated patients have higher bone mineral density (BMD), suggesting that the impaired bone quality may affect bone strength. This study was conducted to clarify the effects of GC on bone strength and collagen cross-links of adult rats and the effect of coadministration of alfacalcidol (ALF), a prodrug of active vitamin D3. Six-month-old male Wistar-Imamichi rats (n = 32) were divided into the following four groups with equal average body weight: (1) 4-week age-matched controls, (2) 4-week GC (prednisolone, 10 mg/kg daily, i.m.) with concomitant administration of vehicle, (3) 4-week GC with concomitant administration of ALF (0.05 μg/kg daily, p.o.), and (4) 4-week GC with concomitant administration of ALF (0.1 μg/kg daily, p.o.). At the end of treatment, BMD, collagen cross-links, mechanical properties of the femoral midshaft, bone metabolic markers, and biochemical parameters were analyzed. In the GC group, femoral bone strength decreased without any change of BMD. This was accompanied by a decrease in the content of enzymatic cross-links. ALF (0.1 μg/kg) inhibited the GC-induced reduction in bone strength. The content of mature cross-links in the 0.1-μg/kg ALF group was significantly higher than that in the GC group. GC treatment caused a decrease in bone metabolic markers and serum calcium levels, which was counteracted by ALF coadministration. Preventive treatment with ALF inhibited the deterioration of bone mechanical properties primarily in association with the restoration of enzymatic cross-link formation and amelioration of the adverse effects of GC treatment on calcium metabolism.

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References

  1. van Staa TP, Leufkens HG, Cooper C (2002) The epidemiology of corticosteroid-induced osteoporosis:a meta-analysis. Osteoporos Int 13:777–787

    Article  PubMed  Google Scholar 

  2. Ton FN, Gunawardene SC, Lee H, Neer RM (2005) Effects of low-dose prednisone on bone metabolism. J Bone Miner Res 20:464–470

    Article  PubMed  CAS  Google Scholar 

  3. Patschan D, Loddenkemper K, Buttgereit F (2001) Molecular mechanisms of glucocorticoid-induced osteoporosis. Bone 29:498–505

    Article  PubMed  CAS  Google Scholar 

  4. Canalis E (2005) Mechanisms of glucocorticoid action in bone. Curr Osteoporos Rep 3:98–102

    Article  PubMed  Google Scholar 

  5. Canalis E, Delany AM (2002) Mechanisms of glucocorticoid action in bone. Ann N Y Acad Sci 966:73–81

    Article  PubMed  CAS  Google Scholar 

  6. de Nijs RN, Jacobs JW, Lems WF, Laan RF, Algra A, Huisman AM, Buskens E, de Laet CE, Oostveen AC, Geusens PP, Bruyn GA, Dijkmans BA, Bijlsma JW, STOP Investigators (2006) Alendornate or alfacacidol in glucocorticoid-induced osteoporosis. N Engl J Med 355:675–684

    Article  PubMed  Google Scholar 

  7. de Nijs RN, Jacobs JW, Algra A, Lems WF, Bijlsma JW (2004) Prevention and treatment of glucocorticoid-induced osteoporosis with active vitamin D3 analoges: a review with meta-analysis of randomized controlled trials including organ transplantation studies. Osteoporos Int 15:589–602

    Article  PubMed  Google Scholar 

  8. Clowes JA, Peel N, Eastell R (2001) Glucocorticoid-induced osteoporosis. Curr Osteoporos Rep 13:326–332

    CAS  Google Scholar 

  9. NIH Consensus Development Panel (2001) Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785–795

    Article  Google Scholar 

  10. Paschalis EP, Shane E, Lyritis G, Skarantavos G, Mendelsohn R, Boskey AL (2004) Bone fragility and collagen cross-links. J Bone Miner Res 19:2000–2004

    Article  PubMed  Google Scholar 

  11. Viguet-Carrin S, Garnero P, Delmas PD (2006) The role of collagen in bone strength. Osteoporos Int 17:319–336

    Article  PubMed  CAS  Google Scholar 

  12. Knott L, Bailey AJ (1998) Collagen cross-links in mineralizing tissues: a review of their chemistry, function, and clinical relevance. Bone 22:181–287

    Article  PubMed  CAS  Google Scholar 

  13. Saito M, Marumo K (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214

    Article  PubMed  CAS  Google Scholar 

  14. Saito M, Fujii K, Mori Y, Marumo K (2006) Role of collagen enzymatic and glycation induced cross-links as a determinant of bone quality in spontaneously diabetic WBN/Kob rats. Osteoporos Int 17:1514–1523

    Article  PubMed  CAS  Google Scholar 

  15. Saito M, Marumo K, Soshi S, Kida Y, Ushiku C, Shinohara A (2010) Raloxifene ameliorates detrimental enzymatic and non-enzymatic collagen cross-links and bone strength in rabbits with hyperhomocysteinemia. Osteoporos Int 21:655–666

    Article  PubMed  CAS  Google Scholar 

  16. Saito M, Fujii K, Soshi S, Tanaka T (2006) Reductions in degree of mineralization and enzymatic collagen cross-links and increases in glycation induced pentosidine in the femoral neck cortex in cases of femoral neck fracture. Osteoporos Int 17:986–995

    Article  PubMed  CAS  Google Scholar 

  17. Saito M, Fujii K, Marumo K (2006) Degree of mineralization-related collagen crosslinking in the femoral neck cancellous bone in cases of hip fracture and controls. Calcif Tissue Int 79:160–168

    Article  PubMed  CAS  Google Scholar 

  18. Kuboki Y, Kudo A, Mizuno M, Kawamura M (1992) Time-dependent changes of collagen cross-links and their precursors in the culture of osteogenic cells. Calcif Tissue Int 50:473–480

    Article  PubMed  CAS  Google Scholar 

  19. Uzawa K, Grzesik WJ, Nishiura T, Kuznetsov SA, Robey PG, Brenner DA, Yamauchi M (1999) Differential expression of human lysyl hydroxylase genes, lysyl hydroxylation, and cross-linking of type I collagen during osteoblastic differentiation in vitro. J Bone Miner Res 14:1272–1280

    Article  PubMed  CAS  Google Scholar 

  20. Yamauchi M, Katz EP (1993) The post-translational chemistry and molecular packing of mineralizing tendon collagens. Connect Tissue Res 29:81–98

    Article  PubMed  CAS  Google Scholar 

  21. Saito M, Soshi S, Fujii K (2003) Effect of hyper- and microgravity on collagen post-translational controls of MC3T3-E1 osteoblasts. J Bone Miner Res 18:1695–1705

    Article  PubMed  CAS  Google Scholar 

  22. Saito M, Sohsi S, Tanaka T, Fujii K (2004) Intensity-related differences in collagen post-translational modification in MC3T3-E1 osteoblasts after exposure to low and high intensity pulsed ultrasound. Bone 35:644–655

    Article  PubMed  CAS  Google Scholar 

  23. Oxlund H, Barckman M, Ortoft G, Andreassen TT (1995) Reduced concentrations of collagen cross-links are associated with reduced strength of bone. Bone 17(4 Suppl):365S–371S

    PubMed  CAS  Google Scholar 

  24. Oxlund H, Mosekilde L, Ortoft G (1996) Reduced concentration of collagen reducible crosslinks in human trabecular bone with respect to age and osteoporosis. Bone 19:448–479

    Google Scholar 

  25. Banse X, Sims TJ, Bailey AJ (2002) Mechanical properties of adult vertebral cancellous bone: correlation with collagen intermolecular cross-links. J Bone Miner Res 17:1621–1628

    Article  PubMed  CAS  Google Scholar 

  26. Brommage R, DeLuca HF (1985) Evidence that 1,25-dihydroxyvitamin D3 in the physiologically active metabolite of vitamin D3. Endocr Rev 6:491–511

    Article  PubMed  CAS  Google Scholar 

  27. Hara K, Akiyama Y, Ohkawa I, Tajima T (1993) Effects of menatetrenone on prednisolone-induced bone loss in rats. Bone 14:813–818

    Article  PubMed  CAS  Google Scholar 

  28. Tanaka Y, Nakamura T, Nishida S, Suzuki K, Sato K, Takeda S, Nishii Y (1996) Effects of synthetic vitamin D analog, ED-71, on bone dynamics and strength in cancellous and cortical bone in prednisolone-treated rats. J Bone Miner Res 11:325–336

    Article  PubMed  CAS  Google Scholar 

  29. Shiraishi A, Takeda S, Masaki T, Higuchi Y, Uchiyama Y, Kubodera N, Sato K, Ikeda K, Nakamura T, Matsumoto T, Ogata E (2000) Alfacalcidol inhibits bone resorption and stimulates formation in an ovariectomized rat model of osteoporosis: distinct actions from estrogen. J Bone Miner Res 15:770–779

    Article  PubMed  CAS  Google Scholar 

  30. Shiraishi A, Ito M, Hayakawa N, Kubota N, Kubodera N, Ogata E (2006) Calcium supplementation does not reproduce the pharmacological efficacy of alfacalcidol for the treatment of osteoporosis in rats. Calcif Tissue Int 78:152–161

    Article  PubMed  CAS  Google Scholar 

  31. Katsumata T, Nakamura T, Ohnishi H, Sakurawa T (1995) Intermittent cyclical etidronate treatment maintains the mass, structure and the mechanical property of bone in ovariectomized rats. J Bone Miner Res 10:921–931

    Article  PubMed  CAS  Google Scholar 

  32. Saito M, Marumo K, Fujii K, Ishioka N (1997) Single column high-performance liquid chromatographic-fluorescence detection of immature, mature and senescent cross-links of collagen. Anal Biochem 253:26–32

    Article  PubMed  CAS  Google Scholar 

  33. van Staa TP, Laan RF, Barton IP, Cohen S, Reid DM, Cooper C (2003) Bone density threshold and other predictors of vertebral fracture in patients receiving oral glucocorticoid therapy. Arthritis Rheum 48:3224–3229

    Article  PubMed  Google Scholar 

  34. Hayashi K, Yamamoto M, Murakawa Y, Yamauchi M, Kaji H, Yamaguchi T, Sugimoto T (2009) Bone fragility in male glucocorticoid-induced osteoporosis is not defined by bone mineral density. Osteoporos Int 20:1889–1894

    Article  PubMed  CAS  Google Scholar 

  35. Lane NE, Yao W, Balooch M, Nalla RK, Balooch G, Habelitz S, Kinney JH, Bonewald LF (2006) Glucocorticoid-treated mice have localized changes in trabecular bone material properties and osteocyte lacunar size that are not observed in placebo-treated or estrogen-deficient mice. J Bone Miner Res 21:466–476

    Article  PubMed  CAS  Google Scholar 

  36. Oxlund H, Mosekilde L, Ortoft G (1996) Reduced concentration of collagen reducible crosslinks in human trabecular bone with respect to age and osteoporosis. Bone 19:479–484

    Article  PubMed  CAS  Google Scholar 

  37. Atsawasuwan P, Mochida Y, Parisuthiman D, Parisuthiman D, Yamauchi M (2005) Expression of lysyl oxidase isoforms in MC3T3-E1 osteoblastic cells. Biochem Biophys Res Commun 327:1042–1046

    Article  PubMed  CAS  Google Scholar 

  38. Benson SC, LuValle PA (1998) Inhibition of lysyl oxidase and prolyl hydroxylase activity in glucocorticoid treated rats. Biochem Biophys Res Commun 99:557–562

    Article  Google Scholar 

  39. Feres-Filho EJ, Choi YJ, Han X, Takala TE, Trackman PC (1995) Pre- and post-translational regulation of lysyl oxidase by transforming growth factor-beta 1 in osteoblastic MC3T3-E1 cells. J Biol Chem 270:30797–30803

    Article  PubMed  CAS  Google Scholar 

  40. Centrella M, McCarthy TL, Canalis E (1991) Glucocorticoid regulation of transforming growth factor beta 1 activity and binding in osteoblast-enriched cultures from fetal rat bone. Mol Cell Biol 11:4490–4496

    PubMed  CAS  Google Scholar 

  41. Delany AM, Durant D, Canalis E (2001) Glucocorticoid suppression of IGF I transcription in osteoblasts. Mol Endocrinol 15:1781–1789

    Article  PubMed  CAS  Google Scholar 

  42. Reiser K, Summers P, Medrano JF, Rucker R, Last J, McDonald R (1996) Effects of elevated circulating IGF-1 on the extracellular matrix in high-growth C57BL/6 J mice. Am J Physiol Regul Integr Comp Physiol 271:R696–R703

    CAS  Google Scholar 

  43. Iwamoto J, Seki A, Takeda T, Sato Y, Yamada H, Shen CL, Yeh JK (2006) Comparative effects of risedronate and calcitriol on cancellous bone in rats with glucocorticoid-induced osteopenia. J Nutr Sci Vitaminol 52:21–27

    Article  PubMed  CAS  Google Scholar 

  44. Nagaoka H, Mochida Y, Atsawasuwan P, Kaku M, Kondoh T, Yamauchi M (2008) 1,25(OH)2D3 regulates collagen quality in an osteoblastic cell culture system. Biochem Biophys Res Commun 377:674–678

    Article  PubMed  CAS  Google Scholar 

  45. Pornprasertsuk S, Wagner R, Duarte WR, Mochida Y, Yamauchi M (2005) Overexpression of lysyl hydroxylase-2b leads to defective collagen fibrillogenesis and matrix mineralization. J Bone Miner Res 20:81–87

    Article  PubMed  CAS  Google Scholar 

  46. Jowell PS, Epstein S, Fallon MD, Reinhardt TA, Iamail F (1987) 1,25-Dihydroxyvitamin D3 modulates glucocorticoid-induced alteration in serum bone Gla protein and bone histomorphometry. Endocrinology 120:531–536

    Article  PubMed  CAS  Google Scholar 

  47. Reid IR, Katz JM, Ibbertson HK, Gray DH (1986) The effects of hydrocortisone, parathyroid hormone and the bisphosphonate, APD, on bone resorption in neonatal mouse calvaria. Calcif Tissue Int 38:38–43

    Article  PubMed  CAS  Google Scholar 

  48. Hodgson SF (1990) Corticosteroid-induced osteoporosis. Endocrinol Metab Clin North Am 19:95–111

    PubMed  CAS  Google Scholar 

  49. Lindgren JU, Merchant CR, DeLuca HF (1982) Effect of 1,25-dihydroxyvitamin D3 on osteopenia induced by prednisolone in adult rats. Calcif Tissue Int 34:253–257

    Article  PubMed  CAS  Google Scholar 

  50. Shiraishi A, Higashi S, Ohkawa H, Kubodera N, Hirasawa T, Ezawa I, Ikeda K, Ogata E (2006) The advantage of alfacalcidol over vitamin D in the treatment of osteoporosis. Calcif Tissue Int 65:311–316

    Article  Google Scholar 

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Acknowledgements

The authors are grateful to Ms. Mika Imamura and Ms. Kazumi Hirakawa (research assistants, Jikei University School of Medicine) for aiding specimen preparation and testing.

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Authors and Affiliations

  1. Department of Orthopedic Surgery, Jikei University School of Medicine, 3-25-8, Nishi-Skinbaski, Minato-ku, Tokyo, 105-8461, Japan

    Mitsuru Saito, Keishi Marumo, Chikara Ushiku & Soki Kato

  2. Product Research Department, Chugai Pharmaceutical Co., Ltd, 1-135 Komakado, Gotemba, Shizuoka, 412-8513, Japan

    Sadaoki Sakai, Naohiko Hayakawa, Masahiko Mihara & Ayako Shiraishi

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  1. Mitsuru Saito
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Correspondence to Mitsuru Saito.

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Saito, M., Marumo, K., Ushiku, C. et al. Effects of Alfacalcidol on Mechanical Properties and Collagen Cross-Links of the Femoral Diaphysis in Glucocorticoid-Treated Rats. Calcif Tissue Int 88, 314–324 (2011). https://doi.org/10.1007/s00223-011-9472-6

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