Original Article · Open access
The effect of pharmacological treatment in combination with vitamin K on healing in an experimental rat model of osteoporosis
- Keywords
- Osteoporosis, teriparatide, vitamin K, zoledronic acid.
Abstract
Objectives: This study aims to compare the effects of teriparatide, zoledronic acid, and their combination therapy with vitamin K on osteoporotic rats.
Materials and methods: We divided a total of 50 female Sprague-Dawley rats into five groups: A (the control group), B and D (the teriparatide group), and C and E (the zoledronic acid group). Following ovariectomy and subcutaneous heparin administration at a dose of 2 IU/kg for four weeks, osteoporosis was created. Groups A, B, and C were fed with standard feed, while Groups D and E were fed with vitamin K-rich feed. After four weeks of treatment, sacrification was performed. The right and left femurs were separated for histopathological and biomechanical evaluation, respectively. For histopathological evaluation, the femurs were decalcified, and the sections were stained with hematoxylin-eosin and evaluated under a light microscope. Fracture healing was evaluated using the classification system as described previously. For biomechanical evaluation, the 3-point stress test and torsion stress test were applied to 10 femurs from each group.
Results: Groups B-E were histopathologically and biomechanically superior to Group A in fracture healing of osteoporotic rats; however, it was not statistically significant (p>0.05). The group that received additional vitamin K was histopathologically and biomechanically superior to the group which was fed with standard feed, although it was not statistically significant (p>0.05).
Conclusion: Our study results indicated that both teriparatide and zoledronic acid had beneficial effects on osteoporotic fractures with comparable histological and biochemical results. Vitamin K promoted teriparatide and zoledronic acid treatment on osteoporotic fracture healing. Based on these findings, combination therapies may yield the most optimal results in biomechanical and histological examinations.
Declarations
Ethics Committee Approval
This study was approved by the Local Ethics Committee of Animal Experiments (date: 08/01/2020; no: 08) and conducted at Experimental Medicine Research and Application Centre laboratories.
Author Contributions
Writer of the manuscript: İ.Ö.; Designer of the study: A.K.; Co-writer: Y.L.A.; Data collection: D.K.; Reviewer of the manuscript: B.M.Ç.; Data collection: H.Ç.; Manuscript editing: H.P.
Conflict of Interest
The authors declared no conflicts of interest with respect to the authorship and/or publication of this article.
Financial Disclosure
The authors received no financial support for the research and/or authorship of this article.
Data Sharing Statement
The data that support the findings of this study are available from the corresponding author upon reasonable request.
References
- Sezgin EA, Tor AT, Markevičiūtė V, Širka A, Tarasevičius Š, Raina DB, et al. A combined fracture and mortality risk index useful for treatment stratification in hip fragility fractures. Jt Dis Relat Surg 2021;32:583-9. DOI: 10.52312/jdrs.2021.382.
- Wang Q, Dong JF, Fang X, Chen Y. Application and modification of bone cement in vertebroplasty: A literature review. Jt Dis Relat Surg 2022;33:467-78. DOI: 10.52312/jdrs.2022.628.
- Lee J, Shin KY, Nam HW, Oh M, Shim GS. Mortality rates of hip fracture patients with non-operative treatment. Jt Dis Relat Surg 2022;33:17-23. DOI: 10.52312/jdrs.2022.495.
- Tu KN, Lie JD, Wan CKV, Cameron M, Austel AG, Nguyen JK, et al. Osteoporosis: A review of treatment options. P T 2018;43:92-104.
- Sargin S, Konya MN, Gulcu A, Aslan A. Effects of zoledronic acid treatment on fracture healing, morbidity and mortality in elderly patients with osteoporotic hip fractures. Strategies Trauma Limb Reconstr 2019;14:126-31. DOI: 10.5005/jp-journals-10080-1439.
- Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-41. DOI: 10.1056/NEJM200105103441904.
- Kobayashi M, Hara K, Akiyama Y. Effects of vitamin K2 (menatetrenone) on calcium balance in ovariectomized rats. Jpn J Pharmacol 2002;88:55-61. DOI: 10.1254/jjp.88.55.
- Kalu DN. The ovariectomized rat model of postmenopausal bone loss. Bone Miner 1991;15:175-91. DOI: 10.1016/0169-6009(91)90124-i.
- He YX, Zhang G, Pan XH, Liu Z, Zheng LZ, Chan CW, et al. Impaired bone healing pattern in mice with ovariectomyinduced osteoporosis: A drill-hole defect model. Bone 2011;48:1388-400. DOI: 10.1016/j.bone.2011.03.720.
- Allen HL, Wase A, Bear WT. Indomethacin and aspirin: Effect of nonsteroidal anti-inflammatory agents on the rate of fracture repair in the rat. Acta Orthop Scand 1980;51:595-600. DOI: 10.3109/17453678008990848.
- Miller MM, Billiar RB. Relationship of putative nicotinic cholinergic receptors in the suprachiasmatic nucleus to levels of pineal serotonin N-acetyltransferase activity in the normally cycling female, the male, and the ovariectomized rat. J Pineal Res 1986;3:159-68. DOI: 10.1111/j.1600-079x.1986.tb00738.x.
- Nayak S, Greenspan SL. How can we improve osteoporosis care? A systematic review and metaanalysis of the efficacy of quality improvement strategies for osteoporosis. J Bone Miner Res 2018;33:1585-94. DOI: 10.1002/jbmr.3437.
- Huang Y. Combined treatment of vitamin K and teriparatide on bone metabolism and biomechanics in rats with osteoporosis. Exp Ther Med 2018;15:315-9. DOI: 10.3892/etm.2017.5420.
- Nagura N, Komatsu J, Iwase H, Hosoda H, Ohbayashi O, Nagaoka I, et al. Effects of the combination of vitamin K and teriparatide on the bone metabolism in ovariectomized rats. Biomed Rep 2015;3:295-300. DOI: 10.3892/br.2015.431.
- Lou S, Lv H, Wang G, Zhang L, Li M, Li Z, et al. The effect of teriparatide on fracture healing of opsteoporotic patients: A meta-analysis of randomized controlled trials. Biomed Res Int 2016;2016:6040379. DOI: 10.1155/2016/6040379.
- Hornby SB, Evans GP, Hornby SL, Pataki A, Glatt M, Green JR. Long-term zoledronic acid treatment increases bone structure and mechanical strength of long bones of ovariectomized adult rats. Calcif Tissue Int 2003;72:519-27. DOI: 10.1007/s00223-002-2015-4.
- Gasser JA, Ingold P, Venturiere A, Shen V, Green JR. Longterm protective effects of zoledronic acid on cancellous and cortical bone in the ovariectomized rat. J Bone Miner Res 2008;23:544-51. DOI: 10.1359/jbmr.071207.
- Zhao B, Zhao W, Wang Y, Zhao Z, Zhao C, Wang S, et al. Prior administration of vitamin K2 improves the therapeutic effects of zoledronic acid in ovariectomized rats by antagonizing zoledronic acid-induced inhibition of osteoblasts proliferation and mineralization. PLoS One 2018;13:e0202269. DOI: 10.1371/journal.pone.0202269.
- Li YF, Zhou CC, Li JH, Luo E, Zhu SS, Feng G, et al. The effects of combined human parathyroid hormone (1-34) and zoledronic acid treatment on fracture healing in osteoporotic rats. Osteoporos Int 2012;23:1463-74. DOI: 10.1007/s00198-011-1751-6.
- Jansen JP, Bergman GJ, Huels J, Olson M. The efficacy of bisphosphonates in the prevention of vertebral, hip, and nonvertebral-nonhip fractures in osteoporosis: A network meta-analysis. Semin Arthritis Rheum 2011;40:275-84.e1-2. DOI: 10.1016/j.semarthrit.2010.06.001.
- Yishake M, Yasen M, Jiang L, Liu W, Xing R, Chen Q, et al. Effects of combined teriparatide and zoledronic acid on posterior lumbar vertebral fusion in an aged ovariectomized rat model of osteopenia. J Orthop Res 2018;36:937-44. DOI: 10.1002/jor.23682.
- Cosman F, Eriksen EF, Recknor C, Miller PD, Guañabens N, Kasperk C, et al. Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1-34)] in postmenopausal osteoporosis. J Bone Miner Res 2011;26:503-11. DOI: 10.1002/jbmr.238.
- Tsubouchi Y, Ikeda S, Kataoka M, Tsumura H. Combination therapy with low-dose teriparatide and zoledronate contributes to fracture healing on rat femoral fracture model. J Orthop Surg Res 2018;13:267. DOI: 10.1186/s13018-018-0917-8.
- Barrionuevo P, Kapoor E, Asi N, Alahdab F, Mohammed K, Benkhadra K, et al. Efficacy of pharmacological therapies for the prevention of fractures in postmenopausal women: A network meta-analysis. J Clin Endocrinol Metab 2019;104:1623-30. DOI: 10.1210/jc.2019-00192.
- Akiyama Y, Hara K, Ohkawa I, Tajima T. Effects of menatetrenone on bone loss induced by ovariectomy in rats. Jpn J Pharmacol 1993;62:145-53. DOI: 10.1254/jjp.62.145.
- Hara K, Kobayashi M, Akiyama Y. Vitamin K2 (menatetrenone) inhibits bone loss induced by prednisolone partly through enhancement of bone formation in rats. Bone 2002;31:575-81. DOI: 10.1016/s8756-3282(02)00874-8.
- Huang ZB, Wan SL, Lu YJ, Ning L, Liu C, Fan SW. Does vitamin K2 play a role in the prevention and treatment of osteoporosis for postmenopausal women: A metaanalysis of randomized controlled trials. Osteoporos Int 2015;26:1175-86. DOI: 10.1007/s00198-014-2989-6.
- Palermo A, Tuccinardi D, D'Onofrio L, Watanabe M, Maggi D, Maurizi AR, et al. Vitamin K and osteoporosis: Myth or reality? Metabolism 2017;70:57-71. DOI: 10.1016/j.metabol.2017.01.032.
