Top

Osteoporosis International

Published in:

01-10-2017 | Original Article

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

Authors: G. Y. Liu, G. L. Cao, F. M. Tian, H. P. Song, L. L. Yuan, L. D. Geng, Z. Y. Zheng, L. Zhang

Published in: Osteoporosis International | Issue 10/2017

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.

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

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

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 28:80–86CrossRefPubMed

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

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

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 344:1434–1441CrossRefPubMed

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 155:1197–1206CrossRefPubMed

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 97:1277–1284CrossRefPubMed

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

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 23:1463–1474CrossRefPubMed

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 14:960–968CrossRefPubMed

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 52:313–320CrossRefPubMed

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 145:233–240CrossRefPubMed

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 31:828–838CrossRefPubMed

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 22:560–568CrossRefPubMedPubMedCentral

16.

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

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 44:357–363CrossRefPubMed

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 33:108–114CrossRefPubMed

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 46:852–859CrossRefPubMed

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 44:485–494CrossRefPubMed

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 44:335–344CrossRefPubMed

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 159:1672–1680CrossRefPubMedPubMedCentral

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 37:711–719CrossRefPubMed

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 43:136–146CrossRefPubMed

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 26:384–393CrossRefPubMed

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 41:631–618CrossRefPubMed

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 16:1042–1048CrossRefPubMed

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 41:373–379CrossRefPubMed

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 43:832–839CrossRefPubMed

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 28:2145–2155CrossRefPubMed

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 88:873–884CrossRefPubMed

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 111:12097–12102CrossRefPubMedPubMedCentral

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 13:22–31CrossRefPubMed

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):1185–1192CrossRefPubMed

35.

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

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 97:461–467CrossRefPubMed

37.

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

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:e0136390CrossRefPubMedPubMedCentral

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 39:837–844CrossRefPubMed

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 97:581–591CrossRefPubMed

41.

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

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 8:1669–1679CrossRefPubMed

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 62:34–38CrossRefPubMed

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 120:227–234CrossRefPubMed

Title: Parathyroid hormone (1–34) promotes fracture healing in ovariectomized rats with type 2 diabetes mellitus
Authors: G. Y. Liu
G. L. Cao
F. M. Tian
H. P. Song
L. L. Yuan
L. D. Geng
Z. Y. Zheng
L. Zhang
Publication date: 01-10-2017
Publisher: Springer London
Published in: Osteoporosis International / Issue 10/2017
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-017-4148-3

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

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

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

Please log in to get access to this content

Other articles of this Issue 10/2017

Skeletal complications of rheumatoid arthritis

Habitual levels of higher, but not medium or low, impact physical activity are positively related to lower limb bone strength in older women: findings from a population-based study using accelerometers to classify impact magnitude

Adverse bone effects of medications used to treat non-skeletal disorders

Abdominal obesity and risk of hip fracture: a meta-analysis of prospective studies

Gene mutation spectrum and genotype-phenotype correlation in a cohort of Chinese osteogenesis imperfecta patients revealed by targeted next generation sequencing

Effect of denosumab on trabecular bone score in postmenopausal women with osteoporosis