Abstract
Bisphosphonates increase bone mineral density (BMD) by suppressing remodeling space and elongating the duration of mineralization. Menatetrenone (vitamin K2) reduces the incidence of fractures by improving bone quality through enhanced γ-carboxylation of bone glutamic acid residues of osteocalcin in osteoporotic patients. This study investigated the effects of combination treatment with alendronate (ALN) and vitamin K2 on BMD and bone strength in ovariectomized (OVX) mice. Thirty-three female mice, 16 weeks of age, were assigned to four groups: (1) OVX-control group; (2) oral vitamin K2 group; (3) subcutaneous ALN group; and (4) ALN + vitamin K2 group. The treatment was started 4 weeks after OVX and continued for 4 weeks. BMD, geometric parameters measured by peripheral quantitative computed tomography, and mechanical strength at the femoral metaphysis and mid-diaphysis were evaluated after an 8-week treatment period. ALN alone significantly increased total BMD (20%, P < 0.05) and trabecular BMD (25%, P < 0.05), but not the mechanical parameters of the femur, compared with the OVX-control group. Combination treatment with ALN and vitamin K2 increased not only total BMD (15%, P < 0.05) and trabecular BMD (32%, P < 0.05) but also maximum load (33%, P < 0.05) and breaking energy (25%, P < 0.05) of compression test at the distal metaphysis, and maximum load (20%, P < 0.05) and breaking force (33%, P < 0.05) of three-point bending test at the mid-diaphysis compared with the OVX-control group. These results suggest that ALN, alone or in combination with vitamin K2, showed significant improvement in BMD, but that the combination treatment was more effective than ALN alone for improving bone strength in OVX mice.
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References
Colucci S, Minielli V, Zambonin G, Cirulli N, Mori G, Serra M, Patella V, Zambonin Zallone A, Grano M (1998) Alendronate reduces adhesion of human osteoclast-like cells to bone and bone protein-coated surfaces. Calcif Tissue Int 63:230–235
Azuma Y, Sato H, Oue Y, Okabe K, Ohta T, Tsuchimoto M, Kiyoki M (1995) Alendronate distributed on bone surfaces inhibits osteoclastic bone resorption in vitro and in experimental hypercalcemia models. Bone (NY) 16:235–245
Liberman UA, Weiss SR, Bröll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M (1995) Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med 333:1437–1443
Tonino RP, Meunier PJ, Emkey R, Rodriguez-Portales JA, Menkes CJ, Wasnich RD, Bone HG, Santora AC, Wu M, Desai R, Ross PD (2000) Skeletal benefits of alendronate: 7-year treatment of postmenopausal osteoporotic women. Phase III Osteoporosis Treatment Study Group. J Clin Endocrinol Metab 85:3109–3115
Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, Nevitt MC, Suryawanshi S, Cummings SR (2000) Fracture Intervention Trial. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. FIT Research Group. J Clin Endocrinol Metab 85:4118–4124
Orwoll E, Ettinger M, Weiss S, Miller P, Kendler D, Graham J, Adami S, Weber K, Lorenc R, Pietschmann P, Vandormael K, Lombardi A (2000) Alendronate for the treatment of osteoporosis in men. N Engl J Med 343:604–610
Li J, Mashiba T, Burr DB (2001) Bisphosphonate treatment suppresses not only stochastic remodeling but also the targeted repair of microdamage. Calcif Tissue Int 69:281–286
Mashiba T, Turner CH, Hirano T, Forwood MR, Johnston CC, Burr DB (2001) Effects of suppressed bone turnover by bisphosphonates on microdamage accumulation and biomechanical properties in clinically relevant skeletal sites in beagles. Bone (NY) 28:524–531
Mashiba T, Hirano T, Turner CH, Forwood MR, Johnston CC, Burr DB (2000) Suppressed bone turnover by bisphosphonates increases microdamage accumulation and reduces some biomechanical properties in dog rib. J Bone Miner Res 15:613–620
Odvina CV, Zerwekh JE, Rao DS, Maalouf N, Gottschalk FA, Pak CY (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301
Koshihara Y, Hoshi K, Ishibashi H, Shiraki M (1996) Vitamin K2 promotes 1alpha, 25(OH)2 vitamin D3-induced mineralization in human periosteal osteoblasts. Calcif Tissue Int 59:466–473
Tabb MM, Sun A, Zhou C, Grün F, Errandi J, Romero K, Pham H, Inoue S, Mallick S, Lin M, Forman BM, Blumberg B (2003) Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J Biol Chem 278:43919–43927
Shiraki M, Shiraki Y, Aoki C, Miura M (2000) Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res 15:515–521
Ishida Y, Kawai S (2004) Comparative efficacy of hormone replacement therapy, etidronate, calcitonin, alfa-calcidol, and vitamin K in postmenopausal women with osteoporosis: the Yamaguchi osteoporosis prevention study. Am J Med 117:549–555
Cockayne S, Adamson J, Lanham-New S, Shearer MJ, Gilbody S, Torgerson DJ (2006) Vitamin K and the prevention of fractures: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med 166:1256–1261
Kobayashi M, Hara K, Akiyama Y (2004) Effects of vitamin K2 (menatetrenone) and alendronate on bone mineral density and bone strength in rats fed a low-magnesium diet. Bone (NY) 35:1136–1143
Kasukawa Y, Baylink DJ, Wergedal JE, Amaa Y, Srivastava AK, Guo R, Mohan S (2003) Lack of insulin-like growth factor I exaggerates the effect of calcium deficiency on bone accretion in mice. Endocrinology 144:4682–4689
Iwamoto J, Takeda T, Sato Y, Yeh JK (2007) Additive effect of vitamin K2 and risedronate on long bone mass in hypophysectomized young rats. Exp Anim 56:103–110
Iwamoto J, Takeda T, Sato Y (2006) Effects of vitamin K2 on the development of osteopenia in rats as the models of osteoporosis. Yonsei Med J 47:157–166
Kobayashi M, Hara K, Akiyama Y (2007) Infrared analysis of bones in magnesium-deficient rats treated with vitamin K2. J Bone Miner Metab 25:12–18
Andersson N, Surve VV, Lehto-Axtelius D, Ohlsson C, Håkanson R, Andersson K, Ryberg B (2002) Drug-induced prevention of gastrectomy- and ovariectomy-induced osteopaenia in the young female rat. J Endocrinol 175:695–703
Iwasaki Y, Yamato H, Murayama H, Sato M, Takahashi T, Ezawa I, Kurokawa K, Fukagawa M (2003) Combination use of vitamin K2 further increases bone volume and ameliorates extremely low turnover bone induced by bisphosphonate therapy in tail-suspension rats. J Bone Miner Metab 21:154–160
NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy (2001) Osteoporosis Prevention, Diagnosis, and Therapy. JAMA 285:785–795
Mawatari T, Miura H, Higaki H, Moro-Oka T, Kurata K, Murakami T, Iwamoto Y (2000) Effect of vitamin K2 on three-dimensional trabecular microarchitecture in ovariectomized rats. J Bone Miner Res 15:1810–1817
Knapen MH, Schurgers LJ, Vermeer C (2007) Vitamin K2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women. Osteoporosis Int 18:963–972
Borah B, Dufresne TE, Ritman EL, Jorgensen SM, Liu S, Chmielewski PA, Phipps RJ, Zhou X, Sibonga JD, Turner RT (2006) Long-term risedronate treatment normalizes mineralization and continues to preserve trabecular architecture: sequential triple biopsy studies with micro-computed tomography. Bone (NY) 39:345–352
Boivin GY, Chavassieux PM, Santora AC, Yates J, Meunier PJ (2000) Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone (NY) 27:687–694
Durchschlag E, Paschalis EP, Zoehrer R, Roschger P, Fratzl P, Recker R, Phipps R, Klaushofer K (2006) Bone material properties in trabecular bone from human iliac crest biopsies after 3- and 5-year treatment with risedronate. J Bone Miner Res 21:1581–1590
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We thank Kaoru Sakamoto for her technical assistance in this research.
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Sasaki, H., Miyakoshi, N., Kasukawa, Y. et al. Effects of combination treatment with alendronate and vitamin K2 on bone mineral density and strength in ovariectomized mice. J Bone Miner Metab 28, 403–409 (2010). https://doi.org/10.1007/s00774-009-0148-5
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DOI: https://doi.org/10.1007/s00774-009-0148-5