SpringerLink
Log in

Parathyroid hormone (1–34) promotes fracture healing in ovariectomized rats with type 2 diabetes mellitus

  • Original Article
  • Published:
Osteoporosis International Aims and scope Submit manuscript

Abstract

Summary

Ovariectomized (OVX) rats with type 2 diabetes mellitus (T2DM) with femur fracture received vehicle, insulin, or insulin plus parathyroid hormone (PTH) treatment for 2 and 3 weeks. Radiography, histomorphometry, histology, and immunohistochemistry in callus were evaluated.

Introduction

Reports about effects of PTH plus insulin on callus formation of osteoporotic fracture with T2DM were limited. This study was designed to investigate the effects of the combination of PTH and insulin on fracture healing in OVX rats with T2DM.

Methods

Two-month-old female rats were randomly divided into five groups: normal fracture (F), OVX fracture (OF), T2DM + OVX fracture (DOF), insulin-treated (2–4 u/daylight, 4–6 u/night, DOFI), and treated with insulin and PTH (50 μg/kg/day, 5 days/week, DOFIP). A closed mid-shaft fracture was established in the right femurs of all rats after 6 weeks of OVX. Rats were euthanized at 2 and 3 weeks post-fracture according to the time schedule, respectively.

Results

The administration of insulin alone or insulin combined with PTH significantly increased mineralized bone volume fraction (BV/TV) and connectivity density (Conn.D) compared with those of the DOF group at 3 weeks post-fracture and also increased cartilaginous callus area ratio in the DOFI and DOFIP groups at 2 weeks and bony callus area ratio in the DOFIP groups at both the 2 and 3 weeks post-fracture.

Conclusions

OVX rats with T2DM exhibited a marked delay in the fracture healing process; insulin treatment ameliorated these effects, and the healing process was enhanced following treatment with a combination of insulin and PTH.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
EUR 32.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or Ebook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price includes VAT (Germany)

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Loder RT (1988) The influence of diabetes mellitus on the healing of closed fractures. Clin Orthop Relat Res 232:210–216

    Google Scholar 

  2. Norris R, Parker M (2011) Diabetes mellitus and hip fracture: a study of 5966 cases. Injury 42:1313–1316

    Article  PubMed  Google Scholar 

  3. 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 28:80–86

    Article  CAS  PubMed  Google Scholar 

  4. de Paula FJ, Horowitz MC, Rosen CJ (2010) Novel insights into the relationship between diabetes and osteoporosis. Diabetes Metab Res Rev 26:622–630

    Article  PubMed  PubMed Central  Google Scholar 

  5. Kurra S, Siris E (2011) Diabetes and bone health: the relationship between diabetes and osteoporosis-associated fractures. Diabetes Metab Res Rev 27:430–435

    Article  PubMed  Google Scholar 

  6. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, Hodsman AB, Eriksen EF, Ish-Shalom S, Genant HK, Wang O, Mitlak BH (2001) Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 344:1434–1441

    Article  CAS  PubMed  Google Scholar 

  7. Hamann C, Picke AK, Campbell GM, Balyura M, Rauner M, Bernhardt R, Huber G, Morlock MM, Günther KP, Bornstein SR, Glüer CC, Ludwig B, Hofbauer LC (2014) Effects of parathyroid hormone on bone mass, bone strength, and bone regeneration in male rats with type 2 diabetes mellitus. Endocrinology 155:1197–1206

    Article  PubMed  Google Scholar 

  8. Yamamoto M, Yamaguchi T, Nawata K, Yamauchi M, Sugimoto T (2012) Decreased PTH levels accompanied by low bone formation are associated with vertebral fractures in postmenopausal women with type 2 diabetes. J Clin Endocrinol Metab 97:1277–1284

    Article  CAS  PubMed  Google Scholar 

  9. Cao YK, Zhang SF, Zou SE, **a X (2013) Daidzein improves insulin resistance in ovariectomized rats. Climacteric 16:111–116

    Article  CAS  PubMed  Google Scholar 

  10. Li YF, Zhou CC, Li JH, Luo E, Zhu SS, Feng G, Hu J (2012) The effects of combined human parathyroid hormone (1-34) and zoledronic acid treatment on fracture healing in osteoporotic rats. Osteoporos Int 23:1463–1474

    Article  CAS  PubMed  Google Scholar 

  11. Andreassen TT, Ejersted C, Oxlund H (1999) Intermittent parathyroid hormone (1-34) treatment increases callus formation and mechanical strength of healing rat fractures. J Bone Miner Res 14:960–968

    Article  CAS  PubMed  Google Scholar 

  12. Srinivasan K, Viswanad B, Asrat L, Kaul CL, Ramarao P (2005) Combination of high-fat diet-fed and low-dose streptozotocin-treated rat: a model for type 2 diabetes and pharmacological screening. Pharmacol Res 52:313–320

    Article  CAS  PubMed  Google Scholar 

  13. Liu Z, Li W, Li X, Zhang M, Chen L, Zheng YN et al (2013) Antidiabetic effects of malonyl ginsenosides from Panax ginseng on type 2 diabetic rats induced by high-fat diet and streptozotocin. J Ethnopharmacol 145:233–240

    Article  CAS  PubMed  Google Scholar 

  14. Zhou Z, Tian FM, Gou Y, Wang P, Zhang H, Song HP, Shen Y, Zhang YZ, Zhang L (2016) Enhancement of lumbar fusion and alleviation of adjacent segment disc degeneration by intermittent PTH (1-34) in ovariectomized rats. J Bone Miner Res 31:828–838

    Article  PubMed  Google Scholar 

  15. Kayal RA, Tsatsas D, Bauer MA, Allen B, Al-Sebaei MO, Kakar S, Leone CW, Morgan EF, Gerstenfeld LC, Einhorn TA, Graves DT (2007) Diminished bone formation during diabetic fracture healing is related to the premature resorption of cartilage associated with increased osteoclast activity. J Bone Miner Res 22:560–568

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Holstein JH, Menger MD, Culemann U, Meier C, Pohlemann T (2007) Development of a locking femur nail for mice. J Biomech 40:215–219

    Article  CAS  PubMed  Google Scholar 

  17. Kayal RA, Alblowi J, McKenzie E, Krothapalli N, Silkman L, Gerstenfeld L, Einhorn TA, Graves DT (2009) Diabetes causes the accelerated loss of cartilage during fracture repair which is reversed by insulin treatment. Bone 44:357–363

    Article  CAS  PubMed  Google Scholar 

  18. Suzuki K, Miyakoshi N, Tsuchida T, Kasukawa Y, Sato K, Itoi E (2003) Effects of combined treatment of insulin and human parathyroid hormone(1-34) on cancellousbone mass and structure in streptozotocin-induced diabetic rats. Bone 33:108–114

    Article  CAS  PubMed  Google Scholar 

  19. Tägil M, McDonald MM, Morse A, Peacock L, Mikulec K, Amanat N, Godfrey C, Little DG (2010) Intermittent PTH (1-34) does not increase union rates in open rat femoral fractures and exhibits attenuated anabolic effects compared to closed fractures. Bone 46:852–859

    Article  PubMed  Google Scholar 

  20. Warden SJ, Komatsu DE, Rydberg J, Bond JL, Hassett SM (2009) Recombinant human parathyroid hormone (PTH 1-34) and low-intensity pulsed ultrasound have contrasting additive effects during fracture healing. Bone 44:485–494

    Article  CAS  PubMed  Google Scholar 

  21. Morgan EF, Mason ZD, Chien KB, Pfeiffer AJ, Barnes GL, Einhorn TA, Gerstenfeld LC (2009) Micro-computed tomography assessment of fracture healing: relationships among callus structure, composition, and mechanical function. Bone 44:335–344

    Article  PubMed  Google Scholar 

  22. Garcia P, Schwenzer S, Slotta JE, Scheuer C, Tami AE, Holstein JH, Histing T, Burkhardt M, Pohlemann T, Menger MD (2010) Inhibition of angiotensin-converting enzyme stimulates fracture healing and periosteal callus formation—role of a local renin-angiotensin system. Br J Pharmacol 159:1672–1680

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Nakazawa T, Nakajima A, Shiomi K, Moriya H, Einhorn TA, Yamazaki M (2005) Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone 37:711–719

    Article  CAS  PubMed  Google Scholar 

  24. Li B, Wang Y, Liu Y, Ma J, Li Y (2013) Altered gene expression involved in insulin signaling pathway in type II diabetic osteoporosis rats model. Endocrine 43:136–146

    Article  CAS  PubMed  Google Scholar 

  25. McCann RM, Colleary G, Geddis C, Clarke SA, Jordan GR, Dickson GR, Marsh D (2008) Effect of osteoporosis on bone mineral density and fracture repair in a rat femoral fracture model. J Orthop Res 26:384–393

    Article  PubMed  Google Scholar 

  26. Hao YJ, Zhang G, Wang YS, Qin L, Hung WY, Leung K, Pei FX (2007) Changes of microstructure and mineralized tissue in the middle and late phase of osteoporotic fracture healing in rats. Bone 41:631–618

    Article  PubMed  Google Scholar 

  27. Ito M, Nishida A, Aoyagi K, Uetani M, Hayashi K, Kawase M (2005) Effects of risedronate on trabecular microstructure and biomechanical properties in ovariectomized rat tibia. Osteoporos Int 16:1042–1048

    Article  CAS  PubMed  Google Scholar 

  28. Diniz SF, Amorim FP, Cavalcante-Neto FF, Bocca AL, Batista AC, Simm GE, Silva TA (2008) Alloxan-induced diabetes delays repair in a rat model of closed tibial fracture. Braz J Med Biol Res 41:373–379

    Article  CAS  PubMed  Google Scholar 

  29. Ogasawara A, Nakajima A, Nakajima F, Goto K, Yamazaki M (2008) Molecular basis for affected cartilage formation and bone union in fracture healing of the streptozotocin-induced diabetic rat. Bone 43:832–839

    Article  CAS  PubMed  Google Scholar 

  30. Ellegaard M, Kringelbach T, Syberg S, Petersen S, Beck Jensen JE, Brüel A, Jørgensen NR, Schwarz P (2013) The effect of PTH(1-34) on fracture healing during different loading conditions. J Bone Miner Res 28:2145–2155

    Article  CAS  PubMed  Google Scholar 

  31. Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA (2003) Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. J Cell Biochem 88:873–884

    Article  CAS  PubMed  Google Scholar 

  32. Yang L, Tsang KY, Tang HC, Chan D, Cheah KS (2014) Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proc Natl Acad Sci U S A 111:12097–12102

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Koerner JD, Yalamanchili P, Munoz W, Uko L, Chaudhary SB, Lin SS, Vives MJ (2013) The effects of local insulin application to lumbar spinal fusions in a rat model. Spine J 13:22–31

    Article  PubMed  Google Scholar 

  34. Torres ES, Andrade CV, Fonseca EC, Mello MA, Duarte ME (2003) Insulin impairs the maturation of chondrocytes in vitro. Braz J Med Biol Res 36(9):1185–1192

    Article  CAS  PubMed  Google Scholar 

  35. Gandhi A, Beam HA, O’Connor JP, Parsons JR, Lin SS (2005) The effects of local insulin delivery on diabetic fracture healing. Bone 37:482–490

    Article  CAS  PubMed  Google Scholar 

  36. Erdal N, Gürgül S, Demirel C, Yildiz A (2012) The effect of insulin therapy on biomechanical deterioration of bone in streptozotocin (STZ)-induced type 1 diabetes mellitus in rats. Diabetes Res Clin Pract 97:461–467

    Article  CAS  PubMed  Google Scholar 

  37. Sandberg O, Macias BR, Aspenberg P (2014) Low dose PTH improves metaphyseal bone healing more when muscles are paralyzed. Bone 63:15–19

    Article  CAS  PubMed  Google Scholar 

  38. Qian C, Zhu C, Yu W, Jiang X, Zhang F (2015) High-fat diet/low-dose streptozotocin-induced type 2 diabetes in rats impacts osteogenesis and Wnt signaling in bone marrow stromal cells. PLoS One 10:e0136390

    Article  PubMed  PubMed Central  Google Scholar 

  39. Mastaglia SR, Pellegrini GG, Mandalunis PM, Gonzales Chaves MM, Friedman SM, Zeni SN (2006) Vitamin D insufficiency reduces the protective effect of bisphosphonate on ovariectomy-induced bone loss in rats. Bone 39:837–844

    Article  CAS  PubMed  Google Scholar 

  40. Liu A, Li Y, Wang Y, Liu L, Shi H, Qiu Y (2015) Exogenous parathyroid hormone-related peptide promotes fracture healing in Lepr (−/−) mice. Calcif Tissue Int 97:581–591

    Article  CAS  PubMed  Google Scholar 

  41. Wang B, ** H, Shu B, Mira RR, Chen D (2015) Chondrocytes-specific expression of osteoprotegerin modulates osteoclast formation in metaphyseal bone. Sci Rep 5:13667

    Article  PubMed  PubMed Central  Google Scholar 

  42. Feng ZY, He ZN, Zhang B, Chen Z (2013) Osteoprotegerin promotes the proliferation of chondrocytes and affects the expression of ADAMTS-5 and TIMP-4 through MEK/ERK signaling. Mol Med Rep 8:1669–1679

    Article  CAS  PubMed  Google Scholar 

  43. O’Sullivan EP, Ashley DT, Davenport C, Penugonda L, Kelleher G, Devlin N, Crowley R, O’Shea P, Agha A, Thompson CJ, O’Gorman DJ, Smith D (2013) A comparison of osteoprotegerin with adiponectin and high-sensitivity C-reactive protein (hsCRP) as a marker for insulin resistance. Metabolism 62:34–38

    Article  PubMed  Google Scholar 

  44. Bortolin RH, Freire Neto FP, Arcaro CA, Bezerra JF, da Silva FS, Ururahy MA, Souza KS, Lima VM, Luchessi AD, Lima FP, Lia Fook MV, da Silva BJ, Almeida MD, Abreu BJ, de Rezende LA, de Rezende AA (2016) Anabolic effect of insulin therapy on the bone: osteoprotegerin andosteocalcin up-regulation in streptozotocin-induced diabetic rats. Basic Clin Pharmacol Toxicol 120:227–234

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

The study was supported by the National Natural Science Foundation of China (NSFC 31671325), the Major Project of Nature Science Foundation of Hebei Province (H2016209176), and the Scientific Innovation Team Foundation of Tangshan City (No. 15130208C).

The authors would like to thank Hong Xu, Mu-wei Dai, and Yu Gou for providing technical and assessment support during histological and immunohistochemical analysis.

Author information

Authors and Affiliations

  1. Department of Orthopedic Surgery, Hebei Medical University, Shijiazhuang, China

    G. Y. Liu, G. L. Cao & L. Zhang

  2. Medical Research Center, North China University of Science and Technology, Tangshan, China

    F. M. Tian

  3. Department of Orthopedic Surgery, The Affiliated Hospital of North China University of Science and Technology, Tangshan, China

    H. P. Song, L. L. Yuan, L. D. Geng, Z. Y. Zheng & L. Zhang

Authors
  1. G. Y. Liu
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. G. L. Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. F. M. Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. H. P. Song
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. L. L. Yuan
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. L. D. Geng
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Z. Y. Zheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. L. Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to L. Zhang.

Ethics declarations

Conflicts of interest

None.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Liu, G.Y., Cao, G.L., Tian, F.M. et al. Parathyroid hormone (1–34) promotes fracture healing in ovariectomized rats with type 2 diabetes mellitus. Osteoporos Int 28, 3043–3053 (2017). https://doi.org/10.1007/s00198-017-4148-3

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00198-017-4148-3

Keywords

Search

Navigation