Calcified Tissue International

, Volume 99, Issue 4, pp 408–422 | Cite as

The Effect of Vibration Treatments Combined with Teriparatide or Strontium Ranelate on Bone Healing and Muscle in Ovariectomized Rats

  • M. KomrakovaEmail author
  • D. B. Hoffmann
  • V. Nuehnen
  • H. Stueber
  • M. Wassmann
  • M. Wicke
  • M. Tezval
  • K. M. Stuermer
  • S. Sehmisch
Original Research


The aim of the present study was to study the effect of combined therapy of teriparatide (PTH) or strontium ranelate (SR) with whole-body vibration (WBV) on bone healing and muscle properties in an osteopenic rat model. Seventy-two rats (3 months old) were bilaterally ovariectomized (Ovx), and 12 rats were left intact (Non-Ovx). After 8 weeks, bilateral transverse osteotomy was performed at the tibia metaphysis in all rats. Thereafter, Ovx rats were divided into six groups (n = 12): (1) Ovx—no treatment, (2) Ovx + vibration (Vib), (3) SR, (4) SR + Vib, (5) PTH, and (6) PTH + Vib. PTH (40 μg/kg BW sc. 5×/week) and SR (613 mg/kg BW in food daily) were applied on the day of ovariectomy, vibration treatments 5 days later (vertical, 70 Hz, 0.5 mm, 2×/day for 15 min) for up to 6 weeks. In the WBV + SR group, the callus density, trabecular number, and Alp and Oc gene expression were decreased compared to SR alone. In the WBV + PTH group, the cortical and callus widths, biomechanical properties, Opg gene expression, and Opg/Rankl ratio were increased; the cortical and callus densities were decreased compared to PTH alone. A case of non-bridging was found in both vibrated groups. Vibration alone did not change the bone parameters; PTH possessed a stronger effect than SR therapy. In muscles, combined therapies improved the fiber size of Ovx rats. WBV could be applied alone or in combination with anti-osteoporosis drug therapy to improve muscle tissue. However, in patients with fractures, anti-osteoporosis treatments and the application of vibration could have an adverse effect on bone healing.


Whole-body vibration Teriparatide Strontium ranelate Combined therapy Bone healing Muscle structure 



This study was supported by the German Research Foundation (DFG, SE 1966/5-1). The authors are grateful to their colleagues R. Castro-Machguth, A. Witt, and R. Wigger for their technical support.

Compliance with Ethical Standards

Conflict of interest

M. Komrakova, D. B. Hoffmann, V. Nuehnen, H. Stueber, M. Wassmann, M. Wicke, M. Tezval, K. M. Stuermer, and S. Sehmisch declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

The animal study protocol was approved by the local regional government (33.9-42502-04-12/0854, Oldendurg, Germany) in accordance with German animal protection laws prior to performing the study.


  1. 1.
    Alegre DN, Ribeiro C, Sousa C, Correia J, Silva L, de Almeida L (2012) Possible benefits of strontium ranelate in complicated long bone fractures. Rheumatol Int 32:439–443CrossRefPubMedGoogle Scholar
  2. 2.
    Andreassen TT, Fledelius C, Ejersted C, Oxlund H (2001) Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 72:304–307CrossRefPubMedGoogle Scholar
  3. 3.
    Andersen P (1975) Capillary density in skeletal muscle of man. Acta Physiol Scand 95:203–205CrossRefPubMedGoogle Scholar
  4. 4.
    Baron R, Kneissel M (2013) WNT signaling in bone homeostasis and disease: from human mutations to treatments. Nat Med 19:179–192CrossRefPubMedGoogle Scholar
  5. 5.
    Baczynski R, Massry SG, Magott M, El-Belbessi S, Kohan R, Brautbar N (1985) Effect of parathyroid hormone on energy metabolism of skeletal muscle. Kidney Int 28:722–727CrossRefPubMedGoogle Scholar
  6. 6.
    Berchtold MW, Brinkmeier H, Müntener M (2000) Calcium ion in skeletal muscle: its crucial role for muscle function, plasticity, and disease. Physiol Rev 80:1215–1265PubMedGoogle Scholar
  7. 7.
    Boivin G, Deloffre P, Perrat B, Panczer G, Boudeulle M, Mauras Y, Allain P, Tsouderos Y, Meunier PJ (1996) Strontium distribution and interactions with bone mineral in monkey iliac bone after strontium salt (S 12911) administration. J Bone Miner Res 11:1302–1311CrossRefPubMedGoogle Scholar
  8. 8.
    Bosco C, Colli R, Introini E, Cardinale M, Tsarpela O, Madella A, Tihanyi J, Viru A (1999) Adaptive responses of human skeletal muscle to vibration exposure. Clin Physiol 19:183–187CrossRefPubMedGoogle Scholar
  9. 9.
    Bouxsein ML, Boyd SK, Christiansen BA, Guldberg RE, Jepsen KJ, Müller R (2010) Guidelines for assessment of bone microstructure in rodents using micro-computed tomography. JBMR 25:1468–1486CrossRefGoogle Scholar
  10. 10.
    CEN (2002) European committee for standardization. Determination of calcium and magnesium. EN ISO 7980Google Scholar
  11. 11.
    Chen GX, Zheng S, Qin S, Zhong ZM, Wu XH, Huang ZP, Li W, Ding RT, Yu H, Chen JT (2014) Effect of low-magnitude whole-body vibration combined with alendronate in ovariectomized rats: a random controlled osteoporosis prevention study. PLoS One 9:e96181. doi: 10.1371/journal.pone.0096181 CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Deeks ED, Dhillon S (2010) Strontium ranelate: a review of its use in the treatment of postmenopausal osteoporosis. Drugs 70:733–759CrossRefPubMedGoogle Scholar
  13. 13.
    Dempster DW, Compston JE, Drezner MK, Glorieux FH, Kanis JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM (2012) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR histomorphometry nomenclature committee. JBMR 28:1–16Google Scholar
  14. 14.
    Dobnig H, Turner RT (1997) The effects of programmed administration of human parathyroid hormone fragment (1–34) on bone histomorphometry and serum chemistry in rats. Endocrinology 138:4607–4612PubMedGoogle Scholar
  15. 15.
  16. 16.
    Faloona GR, Srere PA (1969) Escherichia coli citrate synthase. Purification and the effect of potassium on some properties. Biochemistry 8:4497–4503CrossRefPubMedGoogle Scholar
  17. 17.
    Folkman J, Klagsbrun M (1987) Angiogenic factors. Science 235:442–447CrossRefPubMedGoogle Scholar
  18. 18.
    Frolik CA, Black EC, Cain RL, Satterwhite JH, Brown-Augsburger PL, Sato M, Hock JM (2003) Anabolic and catabolic bone effects of human parathyroid hormone (1–34) are predicted by duration of hormone exposure. Bone 33:372–379CrossRefPubMedGoogle Scholar
  19. 19.
    Fink RH, Stephenson DG, Williams DA (1986) Calcium and strontium activation of single skinned muscle fibres of normal and dystrophic mice. J Physiol 373:513–525CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Habermann B, Kafchitsas K, Olender G, Augat P, Kurth A (2010) Strontium ranelate enhances callus strength more than PTH 1–34 in an osteoporotic rat model of fracture healing. Calcif Tissue Int 86:82–89CrossRefPubMedGoogle Scholar
  21. 21.
    Hatefi Y, Stiggall DL (1978) Preparation and properties of NADH: cytochrome c oxidoreductase (complex I–III). Methods Enzymol 53:5–10CrossRefPubMedGoogle Scholar
  22. 22.
    Hill F, Stewart AW, Verrier CS (1996) Age and sensitivity of rat skeletal muscle fibers to calcium and strontium. BAM 6:373–376Google Scholar
  23. 23.
    Hodsman AB, Bauer DC, Dempster DW, Dian L, Hanley DA, Harris ST, Kendler DL, McClung MR, Miller PD, Olszynski WP, Orwoll E, Yuen CK (2005) Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use. Endocr Rev 26:688–703CrossRefPubMedGoogle Scholar
  24. 24.
    Hoffmann DB, Sehmisch S, Hofmann AM, Eimer C, Komrakova M, Saul D, Wassmann M, Stürmer KM, Tezval M (2016) Comparison of parathyroid hormone and strontium ranelate in combination with wholebody vibration in a rat model of osteoporosis. J Bone Miner Metab. doi: 10.1007/s00774-016-0736-0
  25. 25.
    Hoppeler H (1986) Exercise-induced ultrastructural changes in skeletal muscle. Int J Sports Med 7:187–204CrossRefPubMedGoogle Scholar
  26. 26.
    Horak V (1983) A successive histochemical staining for succinate dehydrogenase and “reversed”—ATPase in a single section for the skeletal muscle fibre typing. Histochem Cell Biol 78:545–553Google Scholar
  27. 27.
    Ji LL, Stratman FW, Lardy HA (1988) Enzymatic down regulation with exercise in rat skeletal muscle. Arch Biochem Biophys 263:137–149CrossRefPubMedGoogle Scholar
  28. 28.
    Komrakova M, Werner C, Wicke M, Nguyen BT, Tezval M, Semisch S, Stuermer KM, Stuermer EK (2009) Effect of daidzein, 4-methylbenzylidene camphor or estrogen on gastrocnemius muscle of osteoporotic rats undergoing tibia healing period. J Endocrinol 201:253–262CrossRefPubMedGoogle Scholar
  29. 29.
    Komrakova M, Stuermer EK, Werner C, Wicke M, Kolios L, Sehmisch S, Tezval M, Daub F, Martens T, Witzenhausen P, Dullin C, Stuermer KM (2010) Effect of human parathyroid hormone hPTH (1–34) applied at different regimes on fracture healing and muscle in ovariectomized and healthy rats. Bone 47:480–492CrossRefPubMedGoogle Scholar
  30. 30.
    Komrakova M, Krischek C, Wicke M, Sehmisch S, Tezval M, Rohrberg M, Brandsch T, Stuermer KM, Stuermer EK (2011) Influence of intermittent administration of parathyroid hormone on muscle tissue and bone healing in orchidectomized rats or controls. J Endocrinol 209:9–19CrossRefPubMedGoogle Scholar
  31. 31.
    Komrakova M, Sehmisch S, Tezval M, Ammon J, Lieberwirth P, Sauerhoff C, Trautmann L, Wicke M, Dullin C, Stuermer KM, Stuermer EK (2013) Identification of a vibration regime favorable for bone healing and muscle in estrogen-deficient rats. Calcif Tissue Int 92:509–520CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Komrakova M, Stuermer EK, Tezval M, Stuermer KM, Dullin C, Schmelz U, Doell C, Durkaya-Burchhard N, Fuerst B, Genotte T, Sehmisch S (2014) Evaluation of twelve vibration regimes applied to improve spine properties in ovariectomized rats. Bone Rep. doi: 10.1016/j.bonr.2014.12.001 Google Scholar
  33. 33.
    Komrakova M, Weidemann A, Dullin C, Ebert J, Tezval M, Stuermer KM, Sehmisch S (2015) The impact of strontium ranelate on metaphyseal bone healing in ovariectomized rats. Calcif Tissue Int 97:391–401CrossRefPubMedGoogle Scholar
  34. 34.
    Kiel DP, Hannan MT, Barton BA, Bouxsein ML, Sisson E, Lang T, Allaire B, Dewkett D, Carroll D, Magaziner J, Shane E, Leary ET, Zimmerman S, Rubin CT (2015) Low-magnitude mechanical stimulation to improve bone density in persons of advanced age: a randomized. Placebo-controlled trial. J Bone Miner Res. 30:1319–1328CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    Larsson S, Fazzalari NL (2014) Anti-osteoporosis therapy and fracture healing. Arch Orthop Trauma Surg 134:291–297CrossRefPubMedGoogle Scholar
  36. 36.
    Li X, Ominsky MS, Warmington KS, Morony S, Gong J, Cao J, Gao Y, Shalhoub V, Tipton B, Haldankar R, Chen Q, Winters A, Boone T, Geng Z, Niu Q-T, Ke HZ, Kostenuik PJ, Simonet WS, Lacey DL, Paszty C (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588CrossRefPubMedGoogle Scholar
  37. 37.
    Li YF, Luo E, Feng G, Zhu SS, Li JH, Hu J (2010) Systemic treatment with strontium ranelate promotes tibial fracture healing in ovariectomized rats. Osteoporos Int 21:1889–1897CrossRefPubMedGoogle Scholar
  38. 38.
    Livak KJ, Schmittgen TD (2001) Analysis of relative gene expression data using real-time quantitative PCR and the 2-DDCT method. Methods 25:402–408CrossRefPubMedGoogle Scholar
  39. 39.
    Lynch MA, Brodt MD, Stephens AL, Civitelli R, Silva MJ (2011) Low-magnitude whole-body vibration does not enhance the anabolic skeletal effects of intermittent PTH in adult mice. J Orthop Res 29:465–472. doi: 10.1002/jor.21280 CrossRefPubMedGoogle Scholar
  40. 40.
    Marie PJ (2006) Strontium ranelate: a physiological approach for optimizing bone formation and resorption. Bone 38:S10–S14CrossRefPubMedGoogle Scholar
  41. 41.
    Meyer RA, Meyer MH, Tenholder M, Wondracek S, Wasserman R, Garges P (2003) Gene expression in older rats with delayed union of femoral fractures. J Bone Joint Surg Am 85:1243–1254PubMedGoogle Scholar
  42. 42.
    Murfee WL, Hammett LA, Evans C, Xie L, Squire M, Rubin C, Judex S, Skalak TC (2005) High-frequency, low-magnitude vibrations suppress the number of blood vessels per muscle fiber in mouse soleus muscle. J Appl Physiol 98:2376–2380CrossRefPubMedGoogle Scholar
  43. 43.
    Namkung-Matthai H, Appleyard R, Jansen J, Hao Lin J, Maastricht S, Swain M, Mason RS, Murrell GA, Diwan AD, Diamond T (2001) Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone 28:80–86CrossRefPubMedGoogle Scholar
  44. 44.
    Nozaka K, Miyakoshi N, Kasukawa Y, Maekawa S, Noguchi H, Shimada Y (2008) Intermittent administration of human parathyroid hormone enhances bone formation and union at the site of cancellous bone osteotomy in normal and ovariectomized rats. Bone 42:90–97CrossRefPubMedGoogle Scholar
  45. 45.
    Ozturan KE, Demir B, Yucel I, Cakıcı H, Yilmaz F, Haberal A (2011) Effect of strontium ranelate on fracture healing in the osteoporotic rats. J Orthop Res 29:138–142CrossRefPubMedGoogle Scholar
  46. 46.
    Peter JB, Barnard RJ, Edgerton VR, Gillespie CA, Stempel KE (1972) Metabolic profiles of the three fiber types of skeletal muscle in guinea pigs and rabbits. Biochemistry 11:2627–2633CrossRefPubMedGoogle Scholar
  47. 47.
    Prior BM, Lloyd PG, Yang HT, Terjung RL (2003) Exercise-induced vascular remodelling. Exerc Sport Sci Rev 31:26–33CrossRefPubMedGoogle Scholar
  48. 48.
    Roudsari JM, Mahjoub S (2012) Quantification and comparison of bone-specific alkaline phosphatase with two methods in normal and paget’s specimens. Caspian J Intern Med 3:478–483Google Scholar
  49. 49.
    Savard R, Smith LJ, Palmer JE, Greenwood MRS (1987) Site specific effects of acute exercise on muscle and adipose tissue metabolism in sedentary female rats. Physiol Behav 43:65–71CrossRefGoogle Scholar
  50. 50.
    Shorey CD, Everitt AV, Armstrong RA, Manning LA (1993) Morphometric analysis of the muscle fibres of the soleus muscle of the ageing rat: long-term effect of hypophysectomy and food restriction. Gerontology 39:80–92. doi: 10.1159/000213518 CrossRefPubMedGoogle Scholar
  51. 51.
    Slatkovska L, Alibhai SMH, Beyene J, Cheund AM (2010) Effect of whole-body vibration on BMD: a systematic review and meta-analysis. Osteoporos Int 21:1969–1980CrossRefPubMedGoogle Scholar
  52. 52.
    Stuermer KM, Rack TH, Kauer F (1980) Intravitale Bewegungsmessung bei der Frakturheilung. Hefte zur Unfallheilkunde 212:489–498Google Scholar
  53. 53.
    Stuermer EK, Komrakova M, Werner C, Wicke M, Kolios L, Sehmisch S, Tezval M, Utesch C, Mangal O, Zimmer S, Dullin C, Stuermer KM (2010) Musculoskeletal response to whole body vibration during fracture healing in healthy and ovariectomized rats. Calcif Tissue Int 87:168–180CrossRefPubMedPubMedCentralGoogle Scholar
  54. 54.
    Stuermer EK, Sehmisch S, Rack T, Wenda E, Seidlova-Wuttke D, Tezval M, Wuttke W, Frosch KH, Stuermer KM (2010) Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat. Langenbeck’s Arch Surg 395:163–172. doi: 10.1007/s00423-008-0436-x CrossRefGoogle Scholar
  55. 55.
    Stuermer EK, Komrakova M, Sehmisch S, Tezval M, Dullin C, Schaefer N, Hallecker J, Stuermer KM (2014) Whole body vibration during fracture healing intensifies the effects of estradiol and raloxifene in estrogen-deficient rats. Bone 64:187–194CrossRefPubMedGoogle Scholar
  56. 56.
    Tarantino U, Celi M, Saturnino L, Scialdoni A, Cerocchi I (2010) Strontium ranelate and bone healing: report of two cases. Clin Cases Miner Bone Metab 7:65–68PubMedPubMedCentralGoogle Scholar
  57. 57.
    Turner RT, Vandersteenhoven JJ, Bell NH (1987) The effects of ovariectomy and 17 beta-estradiol on cortical bone histomorphometry in growing rats. JBMR 2:115–122CrossRefGoogle Scholar
  58. 58.
    Visser M, Deeg DJH, Lips P (2003) Low vitamin D and high parathyroid hormone levels as determinants of loss of muscle strength and muscle mass (sarcopenia): the longitudinal aging study Amsterdam. J Clin Endocrinol Metab 88:5766–5772CrossRefPubMedGoogle Scholar
  59. 59.
    Vogel C, Marcotte EM (2012) Insights into the regulation of protein abundance from proteomic and transcriptomic analyses. Nat Rev/Genetics 13:227–232PubMedGoogle Scholar
  60. 60.
    Wehrle E, Liedert A, Heilmann A, Wehner T, Bindl R, Fischer L, Haffner-Luntzer M, Jakob F, Schinke T, Amling M, Ignatius A (2015) The impact of low-magnitude high-frequency vibration on fracture healing is profoundly influenced by the oestrogen status in mice. Dis Model Mech. 8:93–104. doi: 10.1242/dmm.018622 CrossRefPubMedGoogle Scholar
  61. 61.
    Wells SA, Stirman JA, Bolman RM (1977) Parathyroid transplantation. World J Surg 1:747–756CrossRefPubMedGoogle Scholar
  62. 62.
    Wohl GR, Chettle DR, Pejović-Milić A, Druchok C, Webber CE, Adachi JD, Beattie KA (2013) Accumulation of bone strontium measured by in vivo XRF in rats supplemented with strontium citrate and strontium ranelate. Bone 52:63–69. doi: 10.1016/j.bone.2012.09.002 CrossRefPubMedGoogle Scholar
  63. 63.
    Wolfe RR (2006) The underappreciated role of muscle in health and disease. Am J Clin Nutr 84:475–482PubMedGoogle Scholar
  64. 64.
    Yingjie H, Ge Z, Yisheng W, Ling Q, Hung WY, Kwoksui L, Fuxing P (2007) Changes of microstructure and mineralized tissue in the middle and late phase of osteoporotic fracture healing in rats. Bone 41:631–638CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2016

Authors and Affiliations

  • M. Komrakova
    • 1
    Email author
  • D. B. Hoffmann
    • 1
  • V. Nuehnen
    • 1
  • H. Stueber
    • 1
  • M. Wassmann
    • 3
  • M. Wicke
    • 2
  • M. Tezval
    • 1
  • K. M. Stuermer
    • 1
  • S. Sehmisch
    • 1
  1. 1.Department of Trauma Surgery and Reconstructive SurgeryUniversity Medicine of GoettingenGöttingenGermany
  2. 2.Department of Animal SciencesUniversity of GoettingenGöttingenGermany
  3. 3.Department of Medical Microbiology, Subdivision of General Hygiene and Environmental HealthUniversity of GoettingenGöttingenGermany

Personalised recommendations