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Osteoporosis International

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Open Access 01-03-2014 | Original Article

Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing

Authors: S. Kuroshima, P. Entezami, L. K. McCauley, J. Yamashita

Published in: Osteoporosis International | Issue 3/2014

Abstract

Summary

Administration of intermittent parathyroid hormone (PTH) promoted healing of tibial osseous defects and tooth extraction wounds and prevented the development of necrotic lesions in rats on a combined bisphosphonate and steroid regimen.

Introduction

Osteonecrosis of the jaw (ONJ) has emerged in association with antiresorptive therapies. The pathophysiology of ONJ is unknown and no established cure currently exists. Our objective was to determine the effect of intermittent PTH administration on early osseous healing in the jaw and long bones of rats receiving bisphosphonate and steroid treatment.

Methods

Ovariectomized rats received the combination therapy of alendronate and dexamethasone (ALN/DEX) for 12 weeks. Osseous wounds were created in the jaw and tibia. PTH was administered intermittently and healing at 2 weeks post-op was compared between the jaw and tibia by microcomputed tomography and histomorphometric analyses.

Results

ALN/DEX treatment was associated with necrotic open wounds in the jaw but had no negative effects on healing and promoted bone fill in tibial defects. PTH therapy prevented the development of necrotic lesions in the jaw and promoted healing of the tibial defects. PTH therapy was associated with the promotion of osteocyte survival in osseous wounds both in the jaw and tibia.

Conclusions

Wound healing was impaired in the jaw in rats on a combined bisphosphonate and steroid regimen, and PTH therapy rescued necrotic lesions. These findings suggest that PTH therapy could be utilized to prevent ONJ from occurring in patients on combination antiresorptive and steroid therapy.

Verborgt O, Gibson GJ, Schaffler MB (2000) Loss of osteocyte integrity in association with microdamage and bone remodeling after fatigue in vivo. J Bone Miner Res 15:60–67PubMedCrossRef

Schell H, Lienau J, Epari DR, Seebeck P, Exner C, Muchow S, Bragulla H, Haas NP, Duda GN (2006) Osteoclastic activity begins early and increases over the course of bone healing. Bone 38:547–554PubMedCrossRef

Clark WD, Smith EL, Linn KA, Paul-Murphy JR, Muir P, Cook ME (2005) Osteocyte apoptosis and osteoclast presence in chicken radii 0–4 days following osteotomy. Calcif Tissue Int 77:327–336PubMedCrossRef

Pietrokovski J, Massler M (1971) Residual ridge remodeling after tooth extraction in monkeys. J Prosthet Dent 26:119–129PubMedCrossRef

Smith N (1974) A comparative histological and radiographic study of extraction socket healing in the rat. Aust Dent J 19:250–254PubMedCrossRef

Ruggiero SL, Mehrotra B, Rosenberg TJ, Engroff SL (2004) Osteonecrosis of the jaws associated with the use of bisphosphonates: a review of 63 cases. J Oral Maxillofac Surg 62:527–534PubMedCrossRef

Saad F, Brown JE, Van Poznak C, Ibrahim T, Stemmer SM, Stopeck AT, Diel IJ, Takahashi S, Shore N, Henry DH, Barrios CH, Facon T, Senecal F, Fizazi K, Zhou L, Daniels A, Carriere P, Dansey R (2011) Incidence, risk factors, and outcomes of osteonecrosis of the jaw: integrated analysis from three blinded active-controlled phase III trials in cancer patients with bone metastases. Ann Oncol 23:1341–1347PubMedCrossRef

Hoff AO, Toth BB, Altundag K, Johnson MM, Warneke CL, Hu M, Nooka A, Sayegh G, Guarneri V, Desrouleaux K, Cui J, Adamus A, Gagel RF, Hortobagyi GN (2008) Frequency and risk factors associated with osteonecrosis of the jaw in cancer patients treated with intravenous bisphosphonates. J Bone Miner Res 23:826–836PubMedCrossRef

Solomon DH, Mercer E, Woo SB, Avorn J, Schneeweiss S, Treister N (2013) Defining the epidemiology of bisphosphonate-associated osteonecrosis of the jaw: prior work and current challenges. Osteoporos Int 24:237–244PubMedCrossRef

10.

Migliorati CA, Saunders D, Conlon MS, Ingstad HK, Vaagen P, Palazzolo MJ, Herlofson BB (2013) Assessing the association between bisphosphonate exposure and delayed mucosal healing after tooth extraction. J Am Dent Assoc 144:406–414PubMedCrossRef

11.

Gerstenfeld LC, Sacks DJ, Pelis M, Mason ZD, Graves DT, Barrero M, Ominsky MS, Kostenuik PJ, Morgan EF, Einhorn TA (2009) Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 24:196–208PubMedCrossRef

12.

Cao Y, Mori S, Mashiba T, Westmore MS, Ma L, Sato M, Akiyama T, Shi L, Komatsubara S, Miyamoto K, Norimatsu H (2002) Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 17:2237–2246PubMedCrossRef

13.

Li J, Mori S, Kaji Y, Mashiba T, Kawanishi J, Norimatsu H (1999) Effect of bisphosphonate (incadronate) on fracture healing of long bones in rats. J Bone Miner Res 14:969–979PubMedCrossRef

14.

Lindsay R, Zhou H, Cosman F, Nieves J, Dempster DW, Hodsman AB (2007) Effects of a one-month treatment with PTH(1–34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium. J Bone Miner Res 22:495–502PubMedCrossRef

15.

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 344:1434–1441PubMedCrossRef

16.

Kwon YD, Lee DW, Choi BJ, Lee JW, Kim DY (2012) Short-term teriparatide therapy as an adjunctive modality for bisphosphonate-related osteonecrosis of the jaws. Osteoporos Int 23:2721–2725PubMedCrossRef

17.

Bashutski JD, Eber RM, Kinney JS, Benavides E, Maitra S, Braun TM, Giannobile WV, McCauley LK (2010) Teriparatide and osseous regeneration in the oral cavity. N Engl J Med 363:2396–2405PubMedCrossRef

18.

Abtahi J, Agholme F, Sandberg O, Aspenberg P (2012) Bisphosphonate-induced osteonecrosis of the jaw in a rat model arises first after the bone has become exposed. No primary necrosis in unexposed bone. J Oral Pathol Med 41:494–499PubMedCrossRef

19.

Sonis ST, Watkins BA, Lyng GD, Lerman MA, Anderson KC (2009) Bony changes in the jaws of rats treated with zoledronic acid and dexamethasone before dental extractions mimic bisphosphonate-related osteonecrosis in cancer patients. Oral Oncol 45:164–172PubMedCrossRef

20.

Reagan-Shaw S, Nihal M, Ahmad N (2008) Dose translation from animal to human studies revisited. FASEB J 22:659–661PubMedCrossRef

21.

Kuroshima S, Al-Salihi Z, Yamashita J (2013) Parathyroid hormone related to bone regeneration in grafted and nongrafted tooth extraction sockets in rats. Implant Dent 22:71–76PubMedCrossRef

22.

Kuroshima S, Go VA, Yamashita J (2012) Increased numbers of nonattached osteoclasts after long-term zoledronic acid therapy in mice. Endocrinology 153:17–28PubMedCrossRef

23.

Yamashita J, Koi K, Yang DY, McCauley LK (2011) Effect of zoledronate on oral wound healing in rats. Clin Cancer Res 17:1405–1414PubMedCentralPubMedCrossRef

24.

Enlow DH (1966) Osteocyte necrosis in normal bone. J Dent Res 45:213PubMedCrossRef

25.

Bonnet N, Lesclous P, Saffar JL, Ferrari S (2013) Zoledronate effects on systemic and jaw osteopenias in ovariectomized periostin-deficient mice. PLoS One 8:e58726

26.

McDonald MM, Dulai S, Godfrey C, Amanat N, Sztynda T, Little DG (2008) Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling. Bone 43:653–662PubMedCrossRef

27.

Peter CP, Cook WO, Nunamaker DM, Provost MT, Seedor JG, Rodan GA (1996) Effect of alendronate on fracture healing and bone remodeling in dogs. J Orthop Res 14:74–79PubMedCrossRef

28.

Allen MR, Chu TM, Ruggiero SL (2013) Absence of exposed bone following dental extraction in beagle dogs treated with 9 months of high-dose zoledronic acid combined with dexamethasone. J Oral Maxillofac Surg 71:1017–1026PubMedCrossRef

29.

Watts NB, Diab DL (2010) Long-term use of bisphosphonates in osteoporosis. J Clin Endocrinol Metab 95:1555–1565PubMedCrossRef

30.

McMillan MD (1975) An ultrastructural study of the relationship of oral bacteria to the epithelium of healing tooth extraction wounds. Arch Oral Biol 20:815–822PubMedCrossRef

31.

Ravanelli A, J, K (2006) Cranifofacial development. Lippincott Williams & Wikins, Philadelphia

32.

Eames BF, Helms JA (2004) Conserved molecular program regulating cranial and appendicular skeletogenesis. Dev Dyn 231:4–13PubMedCrossRef

33.

Aghaloo TL, Kang B, Sung EC, Shoff M, Ronconi M, Gotcher JE, Bezouglaia O, Dry SM, Tetradis S (2011) Periodontal disease and bisphosphonates induce osteonecrosis of the jaws in the rat. J Bone Miner Res 26:1871–1882PubMedCentralPubMedCrossRef

34.

Aguirre JI, Akhter MP, Kimmel DB, Pingel JE, Williams A, Jorgensen M, Kesavalu L, Wronski TJ (2012) Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis. J Bone Miner Res 27:2130–2143PubMedCentralPubMedCrossRef

35.

Lopez-Jornet P, Camacho-Alonso F, Martinez-Canovas A, Molina-Minano F, Gomez-Garcia F, Vicente-Ortega V (2011) Perioperative antibiotic regimen in rats treated with pamidronate plus dexamethasone and subjected to dental extraction: a study of the changes in the jaws. J Oral Maxillofac Surg 69:2488–2493PubMedCrossRef

36.

Li D, Gromov K, Proulx ST, Xie C, Li J, Crane DP, Soballe K, O’Keefe RJ, Awad HA, Xing L, Schwarz EM (2010) Effects of antiresorptive agents on osteomyelitis: novel insights into the pathogenesis of osteonecrosis of the jaw. Ann N Y Acad Sci 1192:84–94PubMedCentralPubMedCrossRef

37.

Aspenberg P, Genant HK, Johansson T, Nino AJ, See K, Krohn K, Garcia-Hernandez PA, Recknor CP, Einhorn TA, Dalsky GP, Mitlak BH, Fierlinger A, Lakshmanan MC (2010) Teriparatide for acceleration of fracture repair in humans: a prospective, randomized, double-blind study of 102 postmenopausal women with distal radial fractures. J Bone Miner Res 25:404–414PubMedCrossRef

38.

Yamashita J, Datta NS, Chun YH, Yang DY, Carey AA, Kreider JM, Goldstein SA, McCauley LK (2008) Role of Bcl2 in osteoclastogenesis and PTH anabolic actions in bone. J Bone Miner Res 23:621–632PubMedCrossRef

39.

Nakajima A, Shimoji N, Shiomi K, Shimizu S, Moriya H, Einhorn TA, Yamazaki M (2002) Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1–34). J Bone Miner Res 17:2038–2047PubMedCrossRef

40.

Ettinger B, San Martin J, Crans G, Pavo I (2004) Differential effects of teriparatide on BMD after treatment with raloxifene or alendronate. J Bone Miner Res 19:745–751PubMedCrossRef

41.

Jilka RL, Weinstein RS, Bellido T, Roberson P, Parfitt AM, Manolagas SC (1999) Increased bone formation by prevention of osteoblast apoptosis with parathyroid hormone. J Clin Invest 104:439–446PubMedCentralPubMedCrossRef

42.

Abtahi J, Agholme F, Aspenberg P (2013) Prevention of osteonecrosis of the jaw by mucoperiosteal coverage in a rat model. Int J Oral Maxillofac Surg 42:632–636PubMedCrossRef

Title: Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing
Authors: S. Kuroshima
P. Entezami
L. K. McCauley
J. Yamashita
Publication date: 01-03-2014
Publisher: Springer London
Published in: Osteoporosis International / Issue 3/2014
Print ISSN: 0937-941X
Electronic ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-013-2570-8

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing

Abstract

Summary

Introduction

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Summary

Introduction

Methods

Results

Conclusions

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