Effects of the combination of vitamin K and teriparatide on the bone metabolism in ovariectomized rats

Nagura,Nana; Komatsu,Jun; Iwase,Hideaki; Hosoda,Hiroshi; Ohbayashi,Osamu; Nagaoka,Isao; Kaneko,Kazuo

doi:10.3892/br.2015.431

Effects of the combination of vitamin K and teriparatide on the bone metabolism in ovariectomized rats

Authors:
- Nana Nagura
- Jun Komatsu
- Hideaki Iwase
- Hiroshi Hosoda
- Osamu Ohbayashi
- Isao Nagaoka
- Kazuo Kaneko
View Affiliations

Affiliations: Department of Medicine for Motor Organs, Juntendo University Graduate School of Medicine, Tokyo 113‑8421, Japan, Department of Bio‑Engineering, Juntendo University Institute of Casualty Center, Izunokuni, Shizuoka 410‑2295, Japan, Department of Host Defense and Biochemical Research, Juntendo University Graduate School of Medicine, Tokyo 113‑8421, Japan
Published online on: February 18, 2015 https://doi.org/10.3892/br.2015.431
Pages: 295-300

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The purpose of the present study was to evaluate the combined effects of vitamin K (VK) and teriparatide (TPTD) on bone mineral density (BMD), mechanical strength and other parameters for bone metabolism using a rat ovariectomized osteoporosis model. Ovariectomized female Sprague‑Dawley rats were administered with VK (an oral dose of 30 mg/kg/day), TPTD (a subcutaneous dose of 30 µg/kg, three times a week) or a combination for 8 weeks. Thereafter, serum levels of γ‑carboxylated osteocalcin (Gla‑OC) were quantitated by ELISA; BMD and mechanical strength were measured by computed tomography and biomechanical testing, respectively at the femoral metaphysis. Additionally, histomorphometry was performed using the toluidine blue‑stained coronal sections of distal femur. The combination of VK and TPTD clearly increased the serum levels of Gla‑OC (a specific marker for bone formation) and osteoblast surface (the number of osteoblasts attaching with the surface of cancellous bone), compared to VK or TPTD alone. In addition, the combination of the two agents improved the BMD and bone strength of the femur in the ovariectomized rats, compared to VK or TPTD alone. Taken together, these findings suggest that the treatment with VK and TPTD may have a therapeutic advantage over VK or TPTD monotherapy for postmenopausal osteoporosis, possibly by enhancing the bone formation through the actions on OC and osteoblasts.

View Figures

View References

1	Orimo H, Nakamura T, Fukunaga M, et al: Effects of alendronate plus alfacalcidol in osteoporosis patients with a high risk of fracture: The Japanese Osteoporosis Intervention Trial (JOINT)-02. Curr Med Res Opin. 27:1273–1284. 2011. View Article : Google Scholar : PubMed/NCBI
2	Ushiroyama T, Ikeda A, Sakai M, Higashiyama T and Ueki M: Effects of the combined use of calcitonin and 1 alpha-hydroxycholecalciferol on vertebral bone loss and bone turnover in women with postmenopausal osteopenia and osteoporosis: A prospective study of long-term and continuous administration with low dose calcitonin. Maturitas. 40:229–238. 2001. View Article : Google Scholar : PubMed/NCBI
3	Kobayashi M, Hara K and Akiyama Y: Effects of vitamin K2 (menatetrenone) and alendronate on bone mineral density and bone strength in rats fed a low-magnesium diet. Bone. 35:1136–1143. 2004. View Article : Google Scholar : PubMed/NCBI
4	Price PA: Vitamin K-dependent formation of bone Gla protein (osteocalcin) and its function. Vitam Horm. 42:65–108. 1985. View Article : Google Scholar : PubMed/NCBI
5	Tabb MM, Sun A, Zhou C, et al: Vitamin K2 regulation of bone homeostasis is mediated by the steroid and xenobiotic receptor SXR. J Biol Chem. 278:43919–43927. 2003. View Article : Google Scholar : PubMed/NCBI
6	Igarashi M, Yogiashi Y, Mihara M, Takada I, Kitagawa H and Kato S: Vitamin K induces osteoblast differentiation through pregnane X receptor-mediated transcriptional control of the Msx2 gene. Mol Cell Biol. 27:7947–7954. 2007. View Article : Google Scholar : PubMed/NCBI
7	Akiyama Y, Hara K, Kobayashi M, Tomiuga T and Nakamura T: Inhibitory effect of vitamin K2 (menatetrenone) on bone resorption in ovariectomized rats: A histomorphometric and dual energy X-ray absorptiometric study. Jpn J Pharmacol. 80:67–74. 1999. View Article : Google Scholar : PubMed/NCBI
8	Hara K, Akiyama Y, Nakamura T, Murota S and Morita I: The inhibitory effect of vitamin K2 (menatetrenone) on bone resorption may be related to its side chain. Bone. 16:179–184. 1995. View Article : Google Scholar : PubMed/NCBI
9	Shiraki M, Shiraki Y, Aoki C and Miura M: Vitamin K2 (menatetrenone) effectively prevents fractures and sustains lumbar bone mineral density in osteoporosis. J Bone Miner Res. 15:515–521. 2000. View Article : Google Scholar : PubMed/NCBI
10	Inoue T, Fujita T, Kishimoto H, Makino T, Nakamura T, Nakamura T, Sato T and Yamazaki K: Randomized controlled study on the prevention of osteoporotic fractures (OF study): A phase IV clinical study of 15-mg menatetrenone capsules. J Bone Miner Metab. 27:66–75. 2009. View Article : Google Scholar : PubMed/NCBI
11	Iwamoto J: Vitamin K₂ therapy for postmenopausal osteoporosis. Nutrients. 6:1971–1980. 2014. View Article : Google Scholar : PubMed/NCBI
12	Feskanich D, Weber P, Willett WC, Rockett H, Booth SL and Colditz GA: Vitamin K intake and hip fractures in women: A prospective study. Am J Clin Nutr. 69:74–79. 1999.PubMed/NCBI
13	Tam CS, Heersche JN, Murray TM and Parsons JA: Parathyroid hormone stimulates the bone apposition rate independently of its resorptive action: Differential effects of intermittent and continuous administration. Endocrinology. 110:506–512. 1982. View Article : Google Scholar : PubMed/NCBI
14	Rubin MR, Cosman F, Lindsay R and Bilezikian JP: The anabolic effects of parathyroid hormone. Osteoporos Int. 13:267–277. 2002. View Article : Google Scholar : PubMed/NCBI
15	Rosen CJ: The role of parathyroid hormone in the management of osteoporosis. Horm Res. 64 (Suppl 2):81–85. 2005. View Article : Google Scholar : PubMed/NCBI
16	Kishi T, Hagino H, Kishimoto H and Nagashima H: Bone responses at various skeletal sites to human parathyroid hormone in ovariectomized rats: Effects of long-term administration, withdrawal, and readministration. Bone. 22:515–522. 1998. View Article : Google Scholar : PubMed/NCBI
17	Okimoto N, Tsurukami H, Okazaki Y, Nishida S, Sakai A, Ohnishi H, Hori M, Yasukawa K and Nakamura T: Effects of a weekly injection of human parathyroid hormone (1–34) and withdrawal on bone mass, strength, and turnover in mature ovariectomized rats. Bone. 22:523–531. 1998. View Article : Google Scholar : PubMed/NCBI
18	Neer RM, Arnaud CD, Zanchetta JR, et al: Effect of parathyroid hormone (1–34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 344:1434–1441. 2001. View Article : Google Scholar : PubMed/NCBI
19	Miyauchi A, Matsumoto T, Sugimoto T, Tsujimoto M, Warner MR and Nakamura T: Effects of teriparatide on bone mineral density and bone turnover markers in Japanese subjects with osteoporosis at high risk of fracture in a 24-month clinical study: 12-month, randomized, placebo-controlled, double-blind and 12-month open-label phases. Bone. 47:493–502. 2010. View Article : Google Scholar : PubMed/NCBI
20	Dempster DW, Cosman F, Kurland ES, et al: Effects of daily treatment with parathyroid hormone on bone microarchitecture and turnover in patients with osteoporosis: A paired biopsy study. J Bone Miner Res. 16:1846–1853. 2001. View Article : Google Scholar : PubMed/NCBI
21	Shimizu T, Takahata M, Kameda Y, Hamano H, Ito T, Kimura-Suda H, Todoh M, Tadano S and Iwasaki N: Vitamin K-dependent carboxylation of osteocalcin affects the efficacy of teriparatide (PTH(1–34)) for skeletal repair. Bone. 64:95–101. 2014. View Article : Google Scholar : PubMed/NCBI
22	Turner RT, Vandersteenhoven JJ and Bell NH: The effects of ovariectomy and 17 beta-estradiol on cortical bone histomorphometry in growing rats. J Bone Miner Res. 2:115–122. 1987. View Article : Google Scholar : PubMed/NCBI
23	Kalu DN: The ovariectomized rat model of postmenopausal bone loss. Bone Miner. 15:175–191. 1991. View Article : Google Scholar : PubMed/NCBI
24	Koshihara Y and Hoshi K: Vitamin K2 enhances osteocalcin accumulation in the extracellular matrix of human osteoblasts in vitro. J Bone Miner Res. 12:431–438. 1997. View Article : Google Scholar : PubMed/NCBI
25	Iwasaki Y, Yamato H, Murayama H, Takahashi T, Ezawa I, Kurokawa K and Fukagawa M: Menatetrenone prevents osteoblast dysfunction in unilateral sciatic neurectomized rats. Jpn J Pharmacol. 90:88–93. 2002. View Article : Google Scholar : PubMed/NCBI
26	Hori M, Uzawa T, Morita K, Noda T, Takahashi H and Inoue J: Effect of human parathyroid hormone (PTH(1–34)) on experimental osteopenia of rats induced by ovariectomy. Bone Miner. 3:193–199. 1988.PubMed/NCBI
27	Fox J, Miller MA, Newman MK, Metcalfe AF, Turner CH, Recker RR and Smith SY: Daily treatment of aged ovariectomized rats with human parathyroid hormone (1–84) for 12 months reverses bone loss and enhances trabecular and cortical bone strength. Calcif Tissue Int. 79:262–272. 2006. View Article : Google Scholar : PubMed/NCBI
28	Iwaniec UT, Mosekilde L, Mitova-Caneva NG, Thomsen JS and Wronski TJ: Sequential treatment with basic fibroblast growth factor and PTH is more efficacious than treatment with PTH alone for increasing vertebral bone mass and strength in osteopenic ovariectomized rats. Endocrinology. 143:2515–2526. 2002. View Article : Google Scholar : PubMed/NCBI
29	Hock JM, Gera I, Fonseca J and Raisz LG: Human parathyroid hormone-(1–34) increases bone mass in ovariectomized and orchidectomized rats. Endocrinology. 122:2899–2904. 1988. View Article : Google Scholar : PubMed/NCBI
30	Alexander JM, Bab I, Fish S, et al: Human parathyroid hormone 1–34 reverses bone loss in ovariectomized mice. J Bone Miner Res. 16:1665–1673. 2001. View Article : Google Scholar : PubMed/NCBI
31	Li M, Liang H, Shen Y and Wronski TJ: Parathyroid hormone stimulates cancellous bone formation at skeletal sites regardless of marrow composition in ovariectomized rats. Bone. 24:95–100. 1999. View Article : Google Scholar : PubMed/NCBI
32	Wronski TJ, Yen CF, Qi H and Dann LM: Parathyroid hormone is more effective than estrogen or bisphosphonates for restoration of lost bone mass in ovariectomized rats. Endocrinology. 132:823–831. 1993. View Article : Google Scholar : PubMed/NCBI
33	Matsumoto T, Miyakawa T and Yamamoto D: Effects of vitamin K on the morphometric and material properties of bone in the tibiae of growing rats. Metabolism. 61:407–414. 2012. View Article : Google Scholar : PubMed/NCBI
34	Saito M and Marumo K: 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. 2010. View Article : Google Scholar : PubMed/NCBI
35	Iwamoto J, Sato Y, Takeda T and Matsumoto H: Bone quality and vitamin K2 in type 2 diabetes: Review of preclinical and clinical studies. Nutr Rev. 69:162–167. 2011. View Article : Google Scholar : PubMed/NCBI
36	Shiraishi A, Higashi S, Masaki T, Saito M, Ito M, Ikeda S and Nakamura T: A comparison of alfacalcidol and menatetrenone for the treatment of bone loss in an ovariectomized rat model of osteoporosis. Calcif Tissue Int. 71:69–79. 2002. View Article : Google Scholar : PubMed/NCBI