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Pretreatment with Pamidronate Decreases Bone Formation but Increases Callus Bone Volume in a Rat Closed Fracture Model

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Abstract

Clinical concerns have been raised over prior exposure to bisphosphonates impairing fracture healing. To model this, groups of male Wistar rats were assigned to saline control or treatment groups receiving 0.15 mg/kg (low dose), 0.5 mg/kg (medium dose), and 5 mg/kg (high dose) Pamidronate (PAM) twice weekly for 4 weeks. At this point, closed fractures were made using an Einhorn apparatus, and bisphosphonate dosing was continued until the experimental endpoint. Specimens were analyzed at 2 and 6 weeks (N = 8 per group per time point). Twice weekly PAM dosing was found to have no effect on early soft callus remodeling at 2 weeks post fracture. At this time point, the highest dose PAM group gave significant increases in bone volume (+ 10%, p < 0.05), bone mineral content (+ 30%, p < 0.01), and bone mineral density (+ 10%, p < 0.01). This PAM dosing regimen showed more substantive effects on hard callus at 6 weeks post fracture, with PAM treatment groups showing + 46–79% increased bone volume. Dynamic bone labeling showed reduced calcein signal in the PAM-treated calluses (38–63%, p < 0.01) and reduced MAR (32–49%, p < 0.01), suggesting a compensatory reduction in bone anabolism. These data support the concept that bisphosphonates lead to profound decreases in bone turnover in fracture repair, however, this does not affect soft callus remodeling.

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References

  1. Maraka S, Kennel KA (2015) Bisphosphonates for the prevention and treatment of osteoporosis. BMJ 351:h3783

    Article  Google Scholar 

  2. Baroncelli GI, Bertelloni S (2014) The use of bisphosphonates in pediatrics. Horm Res Paediatr 82(5):290–302

    Article  CAS  Google Scholar 

  3. Little DG, Ramachandran M, Schindeler A (2007) The anabolic and catabolic responses in bone repair. J Bone Joint Surg Br 89(4):425–433

    Article  CAS  Google Scholar 

  4. Schindeler A, McDonald MM, Bokko P, Little DG (2008) Bone remodeling during fracture repair: the cellular picture. Sem Cell Dev Biol 19(5):459–466

    Article  CAS  Google Scholar 

  5. Chambers TJ, Fuller K (2011) How are osteoclasts induced to resorb bone? Ann N Y Acad Sci 1240:1–6

    Article  CAS  Google Scholar 

  6. McDonald MM, Morse A, Mikulec K, Peacock L, Baldock PA, Kostenuik PJ, Little DG (2013) Matrix metalloproteinase-driven endochondral fracture union proceeds independently of osteoclast activity. J Bone Miner Res 28(7):1550–1560

    Article  CAS  Google Scholar 

  7. Hao Y, Wang X, Wang L, Lu Y, Mao Z, Ge S, Dai K (2015) Zoledronic acid suppresses callus remodeling but enhances callus strength in an osteoporotic rat model of fracture healing. Bone 81:702–711

    Article  CAS  Google Scholar 

  8. Menzdorf L, Weuster M, Klüter T, Brüggemann S, Behrendt P, Fitchen-Oestern S, Varoga D, Seekamp A, Purcz N, Glueer CC, Pufe T, Lippross S (2016) Local pamidronate influences fracture healing in a rodent femur fracture model: an experimental study. BMC Musculoskelet Disord 17:255

    Article  Google Scholar 

  9. Takuma S (1962) Electron microscopy of cartilage resorption by chondroclasts. J Dent Res 41:883–889

    Article  CAS  Google Scholar 

  10. Knowles HJ, Moskovsky L, Thompson MS, Grunhen J, Cheng X, Kashima TG, Athanasou NA (2012) Chondroclasts are mature osteoclasts which are capable of cartilage matrix resorption. Virchows Arch 461(2):205–210

    Article  CAS  Google Scholar 

  11. Colnot C, Thompson Z, Miclau T, Werb Z, Helms JA (2003) Altered fracture repair in the absence of MMP9. Development 130(17):4123–4133

    Article  CAS  Google Scholar 

  12. Behonick DJ, Xing Z, Lieu S et al (2007) Role of matrix metalloproteinase 13 in both endochondral and intramembranous ossification during skeletal regeneration. PLoS ONE 2(11):e1150

    Article  Google Scholar 

  13. Kidd LJ, Cowling NR, Wu AC, Kelly WL, Forwood MR (2011) Bisphosphonate treatment delays stress fracture remodeling in the rat ulna. J Orthop Res 29(12):1827–1833

    Article  CAS  Google Scholar 

  14. Shane E, Burr D, Ebeling PR, Abrahamsen B, Adler RA, Brown TD et al (2010) Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral research. J Bone Miner Res 25:2267–2294

    Article  Google Scholar 

  15. Shane E, Burr D, Abrahamsen B, Adler RA, Brown TD, Cheung AM et al (2014) Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral research. J Bone Miner Res 29:1–23

    Article  Google Scholar 

  16. Alharbi M, Pinto G, Finidori G, Souberbielle JC, Guillou F, Gaubicher S, Le Merrer M, Polak M (2009) Pamidronate treatment of children with moderate-to-severe osteogenesis imperfecta: a note of caution. Horm Res 71(1):38–44

    CAS  PubMed  Google Scholar 

  17. Dwan K, Phillipi CA, Steiner RD, Basel D (2016) Bisphosphonate therapy for osteogenesis imperfecta. Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD005088.pub4

    Article  PubMed  PubMed Central  Google Scholar 

  18. Bonnarens F, Einhorn TA (1984) Production of a standard closed fracture in laboratory animal bone. J Orthop Res 2(1):97–101

    Article  CAS  Google Scholar 

  19. Schindeler A, Ramachandran M, Godfrey C, Morse A, McDonald M, Mikulec K, Little DG (2008) Modeling bone morphogenetic protein and bisphosphonate combination therapy in wild-type and Nf1 haploinsufficient mice. J Orthop Res 26(1):65–74

    Article  CAS  Google Scholar 

  20. Amanat N, McDonald M, Godfrey C, Bilston L, Little D (2007) Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res 22(6):867–876

    Article  CAS  Google Scholar 

  21. Munns CF, Rauch F, Travers R, Glorieux FH (2005) Effects of intravenous pamidronate treatment in infants with osteogenesis imperfecta: clinical and histomorphometric outcome. J Bone Miner Res 20(7):1235–1243

    Article  CAS  Google Scholar 

  22. Biggin A, Munns CF (2014) Osteogenesis imperfecta: diagnosis and treatment. Curr Osteoporos Rep 12(3):279–288

    Article  CAS  Google Scholar 

  23. Trejo P, Fassier F, Glorieux FH, Rauch F (2017) diaphyseal femur fractures in osteogenesis imperfecta: characteristics and relationship with bisphosphonate treatment. J Bone Miner Res 32(5):1034–1039

    Article  CAS  Google Scholar 

  24. Munns CF, Rauch F, Zeitlin L, Fassier F, Glorieux FH (2004) Delayed osteotomy but not fracture healing in pediatric osteogenesis imperfecta patients receiving pamidronate. J Bone Miner Res 19(11):1779–1786

    Article  CAS  Google Scholar 

  25. Fu LJ, Tang TT, Hao YQ, Dai KR (2013) Long-term effects of alendronate on fracture healing and bone remodeling of femoral shaft in ovariectomized rats. Acta Pharmacol Sin 34(3):387–392

    Article  CAS  Google Scholar 

  26. Seo JB, Yoo JS, Ryu JW, Yu KW (2016) Influence of early bisphosphonate administration for fracture healing in patients with osteoporotic proximal humerus fractures. Clin Orthop Surg 8(4):437–443

    Article  Google Scholar 

  27. 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(2):196–208

    Article  CAS  Google Scholar 

  28. Sims NA, Martin TJ (2015) Coupling signals between the osteoclast and osteoblast: how are messages transmitted between these temporary visitors to the bone surface? Front Endocrinol (Lausanne) 6:41

    Article  Google Scholar 

  29. Bakr MM, Kelly WL, Brunt AR, Paterson BC, Massa HM, Morrison NA, Forwood MR (2019) Single injection of PTH improves osteoclastic parameters of remodeling at a stress fracture site in rats. J Orthop Res 37(5):1172–1182

    Article  CAS  Google Scholar 

  30. Ma YL, Zeng QQ, Chiang AY, Burr D, Li J, Dobnig H, Fahrleitner-Pammer A, Michalská D, Marin F, Pavo I, Stepan JJ (2014) Effects of teriparatide on cortical histomorphometric variables in postmenopausal women with or without prior alendronate treatment. Bone 59:139–147

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Orthopaedic Research & Biotechnology Unit, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead, NSW, 2145, Australia

    Alyson Morse, Michelle M. McDonald, Kathy Mikulec, Aaron Schindeler & David G. Little

  2. Discipline of Child and Adolescent Health, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia

    Alyson Morse, Aaron Schindeler, Craig F. Munns & David G. Little

  3. Bone Biology Division, The Garvan Institute for Medical Research, Sydney, Australia

    Michelle M. McDonald

  4. Department for Endocrinology and Diabetes, The Children’s Hospital at Westmead, Westmead, NSW, Australia

    Craig F. Munns

Authors
  1. Alyson Morse
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  2. Michelle M. McDonald
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  3. Kathy Mikulec
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  4. Aaron Schindeler
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  5. Craig F. Munns
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  6. David G. Little
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Correspondence to David G. Little.

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Conflict of interest

Dr. Little and Dr Schindeler report grants and non-financial support from Novartis Pharma, grants from N8 Medical, grants from Celgene, grants and nonfinancial support from Amgen Inc. outside the submitted work.

Human and Animal Rights and Informed Consent

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee (Westmead Hospital Animal Ethics Committee, #5024.06-07) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

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Morse, A., McDonald, M.M., Mikulec, K. et al. Pretreatment with Pamidronate Decreases Bone Formation but Increases Callus Bone Volume in a Rat Closed Fracture Model. Calcif Tissue Int 106, 172–179 (2020). https://doi.org/10.1007/s00223-019-00615-z

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  • DOI: https://doi.org/10.1007/s00223-019-00615-z

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