Orally administered simvastatin partially preserves lumbar vertebral bone mass but not integrity of intervertebral discs in ovariectomized rats

Tian,Fa‑Ming; Li,Shu‑Yang; Yang,Kai; Luo,Yang; Dai,Mu‑Wei; Liu,Guang‑Yuan; Song,Hui‑Ping; Zhang,Liu

doi:10.3892/etm.2017.4043

Orally administered simvastatin partially preserves lumbar vertebral bone mass but not integrity of intervertebral discs in ovariectomized rats

Authors:
- Fa‑Ming Tian
- Shu‑Yang Li
- Kai Yang
- Yang Luo
- Mu‑Wei Dai
- Guang‑Yuan Liu
- Hui‑Ping Song
- Liu Zhang
View Affiliations

Affiliations: Medical Research Center, North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China, Department of Orthopedic Surgery, Affiliated Hospital of North China University of Science and Technology, Tangshan, Hebei 063000, P.R. China
Published online on: January 13, 2017 https://doi.org/10.3892/etm.2017.4043
Pages: 877-884
Copyright: © Tian et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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 present study aimed to investigate the effect of orally administered simvastatin on lumbar vertebral bone mass and intervertebral disc (IVD) degeneration in ovariectomized (OVX) rats. A total of 30 female Sprague‑Dawley (SD) rats were subjected to either bilateral ovariectomy (n=20) or sham surgery (n=10). After 12 weeks, the OVX rats were orally administered either saline vehicle (OVX + V group; n=10), or 5 mg/kg/day simvastatin (OVX + SIM group; n=10). Following 12 weeks of treatment, necropsy was conducted and bone mineral density (BMD) was determined in the L5‑6 vertebrae. Furthermore, the microstructure and biomechanical properties of the L3 vertebrae were detected by micro‑computed tomography and compression testing, respectively. The L5‑6 vertebrae were analyzed by measurement of IVD height, observation of histological changes by van Gieson staining, and evaluation of collagen‑II (col‑II), aggrecan (AGG) and collagen I (col‑I) expression by immunohistochemical analysis. Rats in the OVX+V group had lower BMD, bone volume/trabecular volume ratio, maximum load and elastic modulus than the sham group. Rats in the OVX + SIM group had higher BMD and biomechanical strength values than the rats in the OVX+V group. Histological analysis showed that the OVX + V and OVX + SIM groups exhibited significantly higher disc degeneration scores and significantly lower IVD height than the sham group. Immunohistochemical analysis revealed lower expression levels of col‑II and AGG, but higher levels of col‑I in the annulus fibrosis and endplate in OVX+V rats compared with the sham group. The OVX + SIM group exhibited levels of col‑II, AGG and col‑I expression comparable with those of OVX+V rats, with the exception of an upregulation of col‑II expression in the annulus fibrosis. These data demonstrate that simvastatin treatment partially prevented bone loss and the deterioration of biomechanical properties of lumbar vertebrae, but not the progression of IVD degeneration in OVX rats.

View Figures

View References

1	Manek NJ and MacGregor AJ: Epidemiology of back disorders: Prevalence, risk factors, and prognosis. Curr Opin Rheumatol. 17:134–140. 2005.PubMed/NCBI
2	Masuda K and An HS: Prevention of disc degeneration with growth factors. Eur Spine J. 15:(Suppl 3). S422–S432. 2006. View Article : Google Scholar : PubMed/NCBI
3	Andersson GB: Epidemiological features of chronic low-back pain. Lancet. 354:581–585. 1999. View Article : Google Scholar : PubMed/NCBI
4	Feng C, Liu H, Yang Y, Huang B and Zhou Y: Growth and differentiation factor-5 contributes to the structural and functional maintenance of the intervertebral disc. Cell Physiol Biochem. 35:1–16. 2015. View Article : Google Scholar : PubMed/NCBI
5	Hadjipavlou AG, Tzermiadianos MN, Bogduk N and Zindrick MR: The pathophysiology of disc degeneration: A critical review. J Bone Joint Surg Br. 90:1261–1270. 2008. View Article : Google Scholar : PubMed/NCBI
6	Fabreguet I, Fechtenbaum J, Briot K, Paternotte S and Roux C: Lumbar disc degeneration in osteoporotic men: Prevalence and assessment of the relation with presence of vertebral fracture. J Rheumatol. 40:1183–1190. 2013. View Article : Google Scholar : PubMed/NCBI
7	Wang YX and Griffith JF: Effect of menopause on lumbar disc degeneration: Potential etiology. Radiology. 257:318–320. 2010. View Article : Google Scholar : PubMed/NCBI
8	Wang T, Zhang L, Huang C, Cheng AG and Dang GT: Relationship between osteopenia and lumbar intervertebral disc degeneration in ovariectomized rats. Calcif Tissue Int. 75:205–213. 2004. View Article : Google Scholar : PubMed/NCBI
9	Luo Y, Zhang L, Wang WY, Hu QF, Song HP, Su YL and Zhang YZ: Alendronate retards the progression of lumbar intervertebral disc degeneration in ovariectomized rats. Bone. 55:439–448. 2013. View Article : Google Scholar : PubMed/NCBI
10	Tian FM, Yang K, Wang WY, Luo Y, Li SY, Song HP, Zhang YZ, Shen Y and Zhang L: Calcitonin suppresses intervertebral disk degeneration and preserves lumbar vertebral bone mineral density and bone strength in ovariectomized rats. Osteoporos Int. 26:2853–2861. 2015. View Article : Google Scholar : PubMed/NCBI
11	Chuengsamarn S, Rattanamongkoulgul S, Suwanwalaikorn S, Wattanasirichaigoon S and Kaufman L: Effects of statins vs. Non-statin lipid-lowering therapy on bone formation and bone mineral density biomarkers in patients with hyperlipidemia. Bone. 46:1011–1015. 2010. View Article : Google Scholar : PubMed/NCBI
12	Yang N, Cui Y, Tan J, Fu X, Han X, Leng H and Song C: Local injection of a single dose of simvastatin augments osteoporotic bone mass in ovariectomized rats. J Bone Miner Metab. 32:252–260. 2014. View Article : Google Scholar : PubMed/NCBI
13	Hernández JL, Olmos JM, Romaña G, Martinez J, Castillo J, Yezerska I, Pinedo G and González-Macías J: Bone mineral density in statin users: A population-based analysis from a Spanish cohort. J Bone Miner Metab. 32:184–191. 2014. View Article : Google Scholar : PubMed/NCBI
14	Tan J, Yang N, Fu X, Cui Y, Guo Q, Ma T, Yin X, Leng H and Song C: Single-dose local simvastatin injection improves implant fixation via increased angiogenesis and bone formation in an ovariectomized rat model. Med Sci Monit. 21:1428–1439. 2015. View Article : Google Scholar : PubMed/NCBI
15	Oxlund H and Andreassen TT: Simvastatin treatment partially prevents ovariectomy-induced bone loss while increasing cortical bone formation. Bone. 34:609–618. 2004. View Article : Google Scholar : PubMed/NCBI
16	Than KD, Rahman SU, Wang L, Khan A, Kyere KA, Than TT, Miyata Y, Park YS, La Marca F, Kim HM, et al: Intradiscal injection of simvastatin results in radiologic, histologic, and genetic evidence of disc regeneration in a rat model of degenerative disc disease. Spine J. 14:1017–1028. 2014. View Article : Google Scholar : PubMed/NCBI
17	Mosekilde L, Danielsen CC and Knudsen UB: The effect of aging and ovariectomy on the vertebral bone mass and biomechanical properties of mature rats. Bone. 14:1–6. 1993. View Article : Google Scholar : PubMed/NCBI
18	Sehmisch S, Galal R, Kolios L, Tezval M, Dullin C, Zimmer S, Stuermer KM and Stuermer EK: Effects of low-magnitude, high-frequency mechanical stimulation in the rat osteopenia model. Osteoporos Int. 20:1999–2008. 2009. View Article : Google Scholar : PubMed/NCBI
19	Khan K, Sharan K, Swarnkar G, Chakravarti B, Mittal M, Barbhuyan TK, China SP, Khan MP, Nagar GK, Yadav D, et al: Positive skeletal effects of cladrin, a naturally occurring dimethoxydaidzein, in osteopenic rats that were maintained after treatment discontinuation. Osteoporos Int. 24:1455–1470. 2013. View Article : Google Scholar : PubMed/NCBI
20	Oliver RA, Yu Y, Yee G, Low AK, Diwan AD and Walsh WR: Poor histological healing of a femoral fracture following 12 months of oestrogen deficiency in rats. Osteoporos Int. 24:2581–2589. 2013. View Article : Google Scholar : PubMed/NCBI
21	Roberts S, Evans H, Trivedi J and Menage J: Histology and pathology of the human intervertebral disc. J Bone Joint Surg Am. 88:(Suppl 2). S10–S14. 2006. View Article : Google Scholar
22	Le Maitre CL, Pockert A, Buttle DJ, Freemont AJ and Hoyland JA: Matrix synthesis and degradation in human intervertebral disc degeneration. Biochem Soc Trans. 35:652–655. 2007. View Article : Google Scholar : PubMed/NCBI
23	Zhang H and Lin CY: Simvastatin stimulates chondrogenic phenotype of intervertebral disc cells partially through BMP-2 pathway. Spine (Phila Pa 1976). 33:E525–E531. 2008. View Article : Google Scholar : PubMed/NCBI
24	Shi S, Wang C, Yuan W, Wang X and Zhou X: Potential prevention: Orally administered statins may retard the pathologic process of disc degeneration. Med Hypotheses. 76:125–127. 2011. View Article : Google Scholar : PubMed/NCBI
25	Corsino A, Bellosta S, Baetta R, Fumagalli R, Paoletti R and Bernini F: New insights into the pharmacodynamic and pharmacokinetic properties of statins. Pharmacol Ther. 84:413–428. 1999. View Article : Google Scholar : PubMed/NCBI
26	Reinoso RF, SánchezNavarro A, García MJ and Prous JR: Preclinical pharmacokinetics of statins. Methods Find Exp Clin Pharmacol. 24:593–613. 2002.PubMed/NCBI
27	William D and Feely J: Pharmacokinetic-pharmacodynamic drug interaction with HMG-CoA reductase inhibitors. Clin Pharmacokinet. 41:343–370. 2002. View Article : Google Scholar : PubMed/NCBI
28	Soukane DM, Shirazi-Adl A and Urban JP: Computation of coupled diffusion of oxygen, glucose and lactic acid in an intervertebral disc. J Biomech. 40:2645–2654. 2007. View Article : Google Scholar : PubMed/NCBI
29	Kaleağasıoğlu F, Olcay E and Olgaç V: Statin-induced calcific Achilles tendinopathy in rats: Comparison of biomechanical and histopathological effects of simvastatin, atorvastatin and rosuvastatin. Knee Surg Sports Traumatol Arthrosc. 2015.(Epub ahead of print). View Article : Google Scholar
30	Miyazawa A, Matsuno T, Asano K, Tabata Y and Satoh T: Controlled release of simvastatin from biodegradable hydrogels promotes odontoblastic differentiation. Dent Mater J. 34:466–474. 2015. View Article : Google Scholar : PubMed/NCBI
31	Oryan A, Kamali A and Moshiri A: Potential mechanisms and applications of statins on osteogenesis: Current modalities, conflicts and future directions. J Control Release. 215:12–24. 2015. View Article : Google Scholar : PubMed/NCBI