Journal of Bone and Mineral Metabolism

, Volume 35, Issue 2, pp 161–170 | Cite as

Effects of losartan treatment on the physicochemical properties of diabetic rat bone

  • Baris Ozgur Donmez
  • Mustafa Unal
  • Semir Ozdemir
  • Nihal Ozturk
  • Nurettin Oguz
  • Ozan Akkus
Original Article


Inhibitors of the renin−angiotensin system used to treat several diseases have also been shown to be effective on bone tissue, suggesting that angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may reduce fracture risk. The present study investigated the effects of losartan on the physicochemical and biomechanical properties of diabetic rat bone. Losartan (5 mg/kg/day) was administered via oral gavage for 12 weeks. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Whole femurs were tested under tension to evaluate the biomechanical properties of bone. The physicochemical properties of bone were analyzed by Fourier transform infrared spectroscopy. Although losartan did not recover decreases in the BMD of diabetic bone, it recovered the physicochemical (mineral and collagen matrix) properties of diabetic rat bone. Furthermore, losartan also recovered ultimate tensile strength of diabetic rat femurs. Losartan, an angiotensin II type 1 receptor blocker, has a therapeutic effect on the physicochemical properties of diabetic bone resulting in improvement of bone strength at the material level. Therefore, specific inhibition of this pathway at the receptor level shows potential as a therapeutic target for diabetic patients suffering from bone diseases such as osteopenia.


Bone Losartan Diabetes mellitus Osteopenia Renin–angiotensin system 


  1. 1.
    Hamada Y, Kitazawa S, Kitazawa R, Fujii H, Kasuga M, Fukagawa M (2007) Histomorphometric analysis of diabetic osteopenia in streptozotocin-induced diabetic mice: a possible role of oxidative stress. Bone 40:1408–1414CrossRefPubMedGoogle Scholar
  2. 2.
    Inzerillo AM, Epstein S (2004) Osteoporosis and diabetes mellitus. Rev Endocr Metab Disord 5:261–268CrossRefPubMedGoogle Scholar
  3. 3.
    Lieberman D, Fried V, Castel H, Weitzmann S, Lowenthal MN, Galinsky D (1996) Factors related to successful rehabilitation after hip fracture: a case-control study. Disabil Rehabil 18:224–230CrossRefPubMedGoogle Scholar
  4. 4.
    Beam HA, Parsons JR, Lin SS (2002) The effects of blood glucose control upon fracture healing in the BB Wistar rat with diabetes mellitus. J Orthop Res 20:1210–1216CrossRefPubMedGoogle Scholar
  5. 5.
    Schwartz AV (2003) Diabetes mellitus: does it affect bone? Calcif Tissue Int 73:515–519CrossRefPubMedGoogle Scholar
  6. 6.
    Nicodemus KK, Folsom AR (2001) Type 1 and type 2 diabetes and incident hip fractures in postmenopausal women. Diabetes Care 24:1192–1197CrossRefPubMedGoogle Scholar
  7. 7.
    Schwartz AV, Sellmeyer DE, Ensrud KE, Cauley JA, Tabor HK, Schreiner PJ, Jamal SA, Black DM, Cummings SR (2001) Older women with diabetes have an increased risk of fracture: a prospective study. J Clin Endocrinol Metab 86:32–38CrossRefPubMedGoogle Scholar
  8. 8.
    Keegan TH, Kelsey JL, Sidney S, Quesenberry CP Jr (2002) Foot problems as risk factors of fractures. Am J Epidemiol 155:926–931CrossRefPubMedGoogle Scholar
  9. 9.
    Reddy GK, Stehno-Bittel L, Hamade S, Enwemeka CS (2001) The biomechanical integrity of bone in experimental diabetes. Diabetes Res Clin Pract 54:1–8CrossRefPubMedGoogle Scholar
  10. 10.
    Namazi S, Ardeshir-Rouhani-Fard S, Abedtash H (2011) The effect of renin angiotensin system on tamoxifen resistance. Med Hypotheses 77:152–155CrossRefPubMedGoogle Scholar
  11. 11.
    Lau T, Carlsson P-O, Leung P (2004) Evidence for a local angiotensin-generating system and dose-dependent inhibition of glucose-stimulated insulin release by angiotensin II in isolated pancreatic islets. Diabetologia 47:240–248CrossRefPubMedGoogle Scholar
  12. 12.
    Inaba S, Iwai M, Furuno M, Kanno H, Senba I, Okayama H, Mogi M, Higaki J, Horiuchi M (2011) Role of angiotensin-converting enzyme 2 in cardiac hypertrophy induced by nitric oxide synthase inhibition. J Hypertens 29:2236–2245CrossRefPubMedGoogle Scholar
  13. 13.
    Lavoie JL, Sigmund CD (2003) Minireview: overview of the renin–angiotensin system—an endocrine and paracrine system. Endocrinology 144:2179–2183CrossRefPubMedGoogle Scholar
  14. 14.
    Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, Sigmund CD (2007) Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest 117:1088–1095CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Izu Y, Mizoguchi F, Kawamata A, Hayata T, Nakamoto T, Nakashima K, Inagami T, Ezura Y, Noda M (2009) Angiotensin II type 2 receptor blockade increases bone mass. J Biol Chem 284:4857–4864CrossRefPubMedGoogle Scholar
  16. 16.
    Asaba Y, Ito M, Fumoto T, Watanabe K, Fukuhara R, Takeshita S, Nimura Y, Ishida J, Fukamizu A, Ikeda K (2009) Activation of renin–angiotensin system induces osteoporosis independently of hypertension. J Bone Miner Res 24:241–250CrossRefPubMedGoogle Scholar
  17. 17.
    S-s Gu, Zhang Y, Li X-l Wu, S-y Diao T-y, Hai R, H-w Deng (2012) Involvement of the skeletal renin–angiotensin system in age-related osteoporosis of ageing mice. Biosci Biotechnol Biochem 76:1367–1371CrossRefGoogle Scholar
  18. 18.
    Garcia P, Schwenzer S, Slotta J, Scheuer C, Tami A, Holstein J, Histing T, Burkhardt M, Pohlemann T, Menger M (2010) Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation—role of a local renin–angiotensin system. Br J Pharmacol 159:1672–1680CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Gebru Y, Diao T-Y, Pan H, Mukwaya E, Zhang Y (2013) Potential of RAS inhibition to improve metabolic bone disorders. Biomed Res Int 2013:932691CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    De Mello WC, Danser AH (2000) Angiotensin II and the heart: on the intracrine renin–angiotensin system. Hypertension 35:1183–1188CrossRefPubMedGoogle Scholar
  21. 21.
    Ozdemir S, Tandogan B, Ulusu NN, Turan B (2009) Angiotensin II receptor blockage prevents diabetes-induced oxidative damage in rat heart. Folia Biol (Praha) 55:11–16Google Scholar
  22. 22.
    Dinh DT, Frauman AG, Johnston CI, Fabiani ME (2001) Angiotensin receptors: distribution, signalling and function. Clin Sci (Lond) 100:481–492CrossRefGoogle Scholar
  23. 23.
    Rejnmark L, Vestergaard P, Mosekilde L (2006) Treatment with beta-blockers, ACE inhibitors, and calcium-channel blockers is associated with a reduced fracture risk: a nationwide case-control study. J Hypertens 24:581–589CrossRefPubMedGoogle Scholar
  24. 24.
    Donmez BO, Ozdemir S, Sarikanat M, Yaras N, Koc P, Demir N, Karayalcin B, Oguz N (2012) Effect of angiotensin II type 1 receptor blocker on osteoporotic rat femurs. Pharmacol Rep 64:878–888CrossRefPubMedGoogle Scholar
  25. 25.
    Lynn H, Kwok T, Wong SY, Woo J, Leung PC (2006) Angiotensin converting enzyme inhibitor use is associated with higher bone mineral density in elderly Chinese. Bone 38:584–588CrossRefPubMedGoogle Scholar
  26. 26.
    Shimizu H, Nakagami H, Osako MK, Hanayama R, Kunugiza Y, Kizawa T, Tomita T, Yoshikawa H, Ogihara T, Morishita R (2008) Angiotensin II accelerates osteoporosis by activating osteoclasts. FASEB J 22:2465–2475CrossRefPubMedGoogle Scholar
  27. 27.
    Zhang Y, Diao T-Y, Gu S-S, Wu S-Y, Gebru YA, Chen X, Wang J-Y, Ran S, Wong M-S (2013) Effects of angiotensin II type 1 receptor blocker on bones in mice with type 1 diabetes induced by streptozotocin. J Renin Angiotensin Aldosterone Syst 15:218–227CrossRefPubMedGoogle Scholar
  28. 28.
    Diao T-Y, Pan H, Gu S-S, Chen X, Zhang F-Y, Wong M-S, Zhang Y (2014) Effects of angiotensin-converting enzyme inhibitor, captopril, on bone of mice with streptozotocin-induced type 1 diabetes. J Bone Miner Metab 32:261–270CrossRefPubMedGoogle Scholar
  29. 29.
    Nyman JS (2013) Effect of diabetes on the fracture resistance of bone. Clin Rev Bone Miner Metab 11:38–48CrossRefGoogle Scholar
  30. 30.
    Vashishth D (2007) The role of the collagen matrix in skeletal fragility. Curr Osteoporos Rep 5:62–66CrossRefPubMedGoogle Scholar
  31. 31.
    Wang X, Shen X, Li X, Mauli Agrawal C (2002) Age-related changes in the collagen network and toughness of bone. Bone 31:1–7CrossRefPubMedGoogle Scholar
  32. 32.
    Bailey A, Sims T, Ebbesen E, Mansell J, Thomsen JS, Mosekilde L (1999) Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength. Calcif Tissue Int 65:203–210CrossRefPubMedGoogle Scholar
  33. 33.
    Wachter N, Krischak G, Mentzel M, Sarkar M, Ebinger T, Kinzl L, Claes L, Augat P (2002) Correlation of bone mineral density with strength and microstructural parameters of cortical bone in vitro. Bone 31:90–95CrossRefPubMedGoogle Scholar
  34. 34.
    Bousson V, Bergot C, Meunier A, Barbot F, Parlier-Cuau C, Laval-Jeantet A-M, Laredo J-D (2000) CT of the middiaphyseal femur: cortical bone mineral density and relation to porosity 1. Radiology 217:179–187CrossRefPubMedGoogle Scholar
  35. 35.
    Paschalis E, Verdelis K, Doty S, Boskey A, Mendelsohn R, Yamauchi M (2001) Spectroscopic characterization of collagen cross-links in bone. J Bone Miner Res 16:1821–1828CrossRefPubMedGoogle Scholar
  36. 36.
    Paschalis E, Recker R, DiCarlo E, Doty S, Atti E, Boskey A (2003) Distribution of collagen cross-links in normal human trabecular bone. J Bone Miner Res 18:1942–1946CrossRefPubMedGoogle Scholar
  37. 37.
    Bouillon R (1991) Diabetic bone disease. Calcif Tissue Int 49:155–160CrossRefPubMedGoogle Scholar
  38. 38.
    Forsen L, Meyer HE, Midthjell K, Edna TH (1999) Diabetes mellitus and the incidence of hip fracture: results from the Nord-Trondelag Health Survey. Diabetologia 42:920–925CrossRefPubMedGoogle Scholar
  39. 39.
    Wiens M, Etminan M, Gill SS, Takkouche B (2006) Effects of antihypertensive drug treatments on fracture outcomes: a meta-analysis of observational studies. J Intern Med 260:350–362CrossRefPubMedGoogle Scholar
  40. 40.
    Sealand R, Razavi C, Adler RA (2013) Diabetes mellitus and osteoporosis. Curr Diab Rep 13:411–418CrossRefPubMedGoogle Scholar
  41. 41.
    Pietschmann P, Patsch J, Schernthaner G (2010) Diabetes and bone. Horm Metab Res 42:763–768CrossRefPubMedGoogle Scholar
  42. 42.
    Kanis JA, Borgstrom F, De Laet C, Johansson H, Johnell O, Jonsson B, Oden A, Zethraeus N, Pfleger B, Khaltaev N (2005) Assessment of fracture risk. Osteoporos Int 16:581–589CrossRefPubMedGoogle Scholar
  43. 43.
    Faulkner KG (2000) Bone matters: are density increases necessary to reduce fracture risk? J Bone Miner Res 15:183–187CrossRefPubMedGoogle Scholar
  44. 44.
    Schuit S, Van der Klift M, Weel A, De Laet C, Burger H, Seeman E, Hofman A, Uitterlinden A, van Leeuwen J, Pols H (2004) Fracture incidence and association with bone mineral density in elderly men and women: the Rotterdam Study. Bone 34:195–202CrossRefPubMedGoogle Scholar
  45. 45.
    Gamsjaeger S, Mendelsohn R, Boskey A, Gourion-Arsiquaud S, Klaushofer K, Paschalis E (2014) Vibrational spectroscopic imaging for the evaluation of matrix and mineral chemistry. Curr Osteoporos Rep 12:454–464CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Boskey A, Pleshko Camacho N (2007) FT-IR imaging of native and tissue-engineered bone and cartilage. Biomaterials 28:2465–2478CrossRefPubMedGoogle Scholar
  47. 47.
    Boskey A, Mendelsohn R (2005) Infrared analysis of bone in health and disease. J Biomed Optics 10:031102–0311029CrossRefGoogle Scholar
  48. 48.
    Huang R, Miller L, Carlson C, Chance M (2002) Characterization of bone mineral composition in the proximal tibia of cynomolgus monkeys: effect of ovariectomy and nandrolone decanoate treatment. Bone 30:492–497CrossRefPubMedGoogle Scholar
  49. 49.
    Saito M, Marumo K (2010) Collagen cross-links as a determinant of bone quality: a possible explanation for bone fragility in aging, osteoporosis, and diabetes mellitus. Osteoporos Int 21:195–214CrossRefPubMedGoogle Scholar
  50. 50.
    Banse X, Sims T, Bailey A (2002) Mechanical properties of adult vertebral cancellous bone: correlation with collagen intermolecular cross-links. J Bone Miner Res 17:1621–1628CrossRefPubMedGoogle Scholar
  51. 51.
    Oxlund H, Barckman M, Ørtoft G, Andreassen T (1995) Reduced concentrations of collagen cross-links are associated with reduced strength of bone. Bone 17:S365–S371Google Scholar
  52. 52.
    Paschalis EP, Shane E, Lyritis G, Skarantavos G, Mendelsohn R, Boskey AL (2004) Bone fragility and collagen cross-links. J Bone Miner Res 19:2000–2004CrossRefPubMedPubMedCentralGoogle Scholar
  53. 53.
    Ruppel ME, Burr DB, Miller LM (2006) Chemical makeup of microdamaged bone differs from undamaged bone. Bone 39:318–324CrossRefPubMedGoogle Scholar
  54. 54.
    Lazarev YA, Grishkovsky B, Khromova T (1985) Amide I band of IR spectrum and structure of collagen and related polypeptides. Biopolymers 24:1449–1478CrossRefPubMedGoogle Scholar
  55. 55.
    Danser AJ (2009) The increase in renin during renin inhibition: does it result in harmful effects by the (pro) renin receptor and quest. Hypertens Res 33:4–10CrossRefPubMedGoogle Scholar

Copyright information

© The Japanese Society for Bone and Mineral Research and Springer Japan 2016

Authors and Affiliations

  • Baris Ozgur Donmez
    • 1
  • Mustafa Unal
    • 2
  • Semir Ozdemir
    • 3
  • Nihal Ozturk
    • 3
  • Nurettin Oguz
    • 4
  • Ozan Akkus
    • 2
  1. 1.Department of Nutrition and Dietetics, School of HealthAkdeniz UniversityAntalyaTurkey
  2. 2.Department of Mechanical and Aerospace Engineering, Orthopaedic Bioengineering LaboratoriesCase Western Reserve UniversityClevelandUSA
  3. 3.Department of Biophysics, Faculty of MedicineAkdeniz UniversityAntalyaTurkey
  4. 4.Department of Anatomy, Faculty of MedicineAkdeniz UniversityAntalyaTurkey

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