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Implications for Fracture Healing of Current and New Osteoporosis Treatments: An ESCEO Consensus Paper

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Abstract

Osteoporotic fracture healing is critical to clinical outcome in terms of functional recovery, morbidity, and quality of life. Osteoporosis treatments may affect bone repair, so insights into their impact on fracture healing are important. We reviewed the current evidence for an impact of osteoporosis treatments on bone repair. Treatment with bisphosphonate in experimental models is associated with increased callus size and mineralization, reduced callus remodeling, and improved mechanical strength. Local and systemic bisphosphonate treatment may improve implant fixation. No negative impact on fracture healing has been observed, even after major surgery or when administered immediately after fracture. Experimental data for denosumab and raloxifene suggest no negative implications for bone repair. The extensive experimental results for teriparatide indicate increased callus formation, improved biomechanical strength, and greater external callus volume and total bone mineral content and density. Case reports and a randomized trial have produced mixed results but are consistent with a positive impact of teriparatide on clinical fracture healing. Studies with strontium ranelate in models of fracture healing indicate that it is associated with improved bone microstructure, callus volume, and biomechanical properties. Finally, there is experimental evidence for a beneficial effect of some of the agents currently being developed for osteoporosis, notably sclerostin antibody and DKK1 antibody. There is currently no evidence that osteoporosis treatments are detrimental for bone repair and some promising experimental evidence for positive effects on healing, notably for agents with a bone-forming mode of action, which may translate into therapeutic applications.

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References

  1. Goldhahn J, Blauth M (2007) Osteoporotic fracture management: closing the gap of knowledge. Arch Orthop Trauma Surg 127:1–2

    Article  PubMed  CAS  Google Scholar 

  2. Goldhahn J, Suhm N, Goldhahn S et al (2008) Influence of osteoporosis on fracture fixation—a systematic literature review. Osteoporos Int 19:761–772

    Article  PubMed  CAS  Google Scholar 

  3. Cornell CN (2003) Internal fracture fixation in patients with osteoporosis. J Am Acad Orthop Surg 11:109–119

    PubMed  Google Scholar 

  4. Aspenberg P (2005) Drugs and fracture repair. Acta Orthop 76:741–748

    Article  PubMed  Google Scholar 

  5. Yates JE, Hadi Shah S, Blackwell JC (2011) Clinical inquiries: do NSAIDs impede fracture healing? J Fam Pract 60:41–42

    PubMed  Google Scholar 

  6. Goldhahn J, Mitlak B, Aspenberg P et al (2008) Critical issues in translational and clinical research for the study of new technologies to enhance bone repair. J Bone Joint Surg Am 90(Suppl 1):43–47

    Article  PubMed  Google Scholar 

  7. Goldhahn J, Scheele WH, Mitlak BH et al (2008) Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis. Bone 43:343–347

    Article  PubMed  Google Scholar 

  8. Goldhahn S, Sawaguchi T, Audige L et al (2009) Complication reporting in orthopaedic trials: a systematic review of randomized controlled trials. J Bone Joint Surg Am 91:1847–1853

    Article  PubMed  CAS  Google Scholar 

  9. Goldhahn S, Kralinger F, Rikli D et al (2010) Does osteoporosis increase complication risk in surgical fracture treatment? A protocol combining new endpoints for two prospective multicentre open cohort studies. BMC Musculoskelet Disord 11:256

    Article  PubMed  Google Scholar 

  10. Morshed S, Bhandari M (2008) Clinical trial design in fracture-healing research: meeting the challenge. J Bone Joint Surg Am 90(Suppl 1):55–61

    Article  PubMed  Google Scholar 

  11. Goldhahn J, Little D, Mitchell P et al (2010) Evidence for anti-osteoporosis therapy in acute fracture situations—recommendations of a multidisciplinary workshop of the International Society for Fracture Repair. Bone 46:267–271

    Article  PubMed  CAS  Google Scholar 

  12. Fleisch H (2001) Can bisphosphonates be given to patients with fractures? J Bone Miner Res 16:437–440

    Article  PubMed  CAS  Google Scholar 

  13. Aspenberg P (2009) Bisphosphonates and implants: an overview. Acta Orthop 80:119–123

    Article  PubMed  Google Scholar 

  14. Cao Y, Mori S, Mashiba T et al (2002) Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 17:2237–2246

    Article  PubMed  CAS  Google Scholar 

  15. Amanat N, McDonald M, Godfrey C et al (2007) Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res 22:867–876

    Article  PubMed  CAS  Google Scholar 

  16. Lenart BA, Lorich DG, Lane JM (2008) Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med 358:1304–1306

    Article  PubMed  CAS  Google Scholar 

  17. Odvina CV, Zerwekh JE, Rao DS et al (2005) Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 90:1294–1301

    Article  PubMed  CAS  Google Scholar 

  18. Rizzoli R, Akesson K, Bouxsein M et al (2011) Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report. Osteoporos Int 22:373–390

    Article  PubMed  CAS  Google Scholar 

  19. Gerstenfeld LC, Sacks DJ, Pelis M et al (2009) Comparison of effects of the bisphosphonate alendronate vs. the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 24:196–208

    Article  PubMed  CAS  Google Scholar 

  20. Boyce RW, Paddock CL, Gleason JR et al (1995) The effects of risedronate on canine cancellous bone remodeling: three-dimensional kinetic reconstruction of the remodeling site. J Bone Miner Res 10:211–221

    Article  PubMed  CAS  Google Scholar 

  21. Amanat N, Brown R, Bilston LE et al (2005) A single systemic dose of pamidronate improves bone mineral content and accelerates restoration of strength in a rat model of fracture repair. J Orthop Res 23:1029–1034

    Article  PubMed  CAS  Google Scholar 

  22. Li J, Mori S, Kaji Y et al (2000) Concentration of bisphosphonate (incadronate) in callus area and its effects on fracture healing in rats. J Bone Miner Res 15:2042–2051

    Article  PubMed  CAS  Google Scholar 

  23. Li J, Mori S, Kaji Y et al (1999) Effect of bisphosphonate (incadronate) on fracture healing of long bones in rats. J Bone Miner Res 14:969–979

    Article  PubMed  CAS  Google Scholar 

  24. Tengvall P, Skoglund B, Askendal A et al (2004) Surface immobilized bisphosphonate improves stainless-steel screw fixation in rats. Biomaterials 25:2133–2138

    Article  PubMed  CAS  Google Scholar 

  25. Skoglund B, Holmertz J, Aspenberg P (2004) Systemic and local ibandronate enhance screw fixation. J Orthop Res 22:1108–1113

    Article  PubMed  CAS  Google Scholar 

  26. Lyles KW, Colon-Emeric CS, Magaziner JS et al (2007) Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 357:1799–1809

    Article  PubMed  CAS  Google Scholar 

  27. Colon-Emeric C, Nordsletten L, Olson S et al (2011) Association between timing of zoledronic acid infusion and hip fracture healing. Osteoporos Int 22:2329–2336

    Article  PubMed  CAS  Google Scholar 

  28. van der Poest CE, van EM, Ader H, et al. (2002) Alendronate in the prevention of bone loss after a fracture of the lower leg. J Bone Miner Res 17:2247–2255

  29. van der Poest CE, Patka P, Vandormael K et al (2000) The effect of alendronate on bone mass after distal forearm fracture. J Bone Miner Res 15:586–593

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  31. Pulkkinen P, Eckstein F, Lochmuller EM et al (2006) Association of geometric factors and failure load level with the distribution of cervical vs. trochanteric hip fractures. J Bone Miner Res 21:895–901

    Article  PubMed  Google Scholar 

  32. Solomon DH, Hochberg MC, Mogun H et al (2009) The relation between bisphosphonate use and non-union of fractures of the humerus in older adults. Osteoporos Int 20:895–901

    Article  PubMed  CAS  Google Scholar 

  33. Moroni A, Faldini C, Hoang-Kim A et al (2007) Alendronate improves screw fixation in osteoporotic bone. J Bone Joint Surg Am 89:96–101

    Article  PubMed  Google Scholar 

  34. Hilding M, Aspenberg P (2007) Local peroperative treatment with a bisphosphonate improves the fixation of total knee prostheses: a randomized, double-blind radiostereometric study of 50 patients. Acta Orthop 78:795–799

    Article  PubMed  Google Scholar 

  35. Hilding M, Aspenberg P (2006) Postoperative clodronate decreases prosthetic migration: 4-year follow-up of a randomized radiostereometric study of 50 total knee patients. Acta Orthop 77:912–916

    Article  PubMed  Google Scholar 

  36. Adami S, Adachi J, Boonen S, et al. (2010) Denosumab administration is not associated with fracture healing complications in postmenopausal women with osteoporosis: results from the FREEDOM trial. J Bone Miner Res 25 Suppl 1:MO0405

  37. Stuermer EK, Sehmisch S, Rack T et al (2010) Estrogen and raloxifene improve metaphyseal fracture healing in the early phase of osteoporosis. A new fracture-healing model at the tibia in rat. Langenbecks Arch Surg 395:163–172

    Article  PubMed  CAS  Google Scholar 

  38. Bukata SV, Puzas JE (2010) Orthopedic uses of teriparatide. Curr Osteoporos Rep 8:28–33

    Article  PubMed  Google Scholar 

  39. 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  PubMed  CAS  Google Scholar 

  40. Andreassen TT, Fledelius C, Ejersted C et al (2001) Increases in callus formation and mechanical strength of healing fractures in old rats treated with parathyroid hormone. Acta Orthop Scand 72:304–307

    Article  PubMed  CAS  Google Scholar 

  41. Holzer G, Majeska RJ, Lundy MW, et al. (1999) Parathyroid hormone enhances fracture healing: a preliminary report. Clin Orthop Relat Res 258–263

  42. Nakajima A, Shimoji N, Shiomi K et al (2002) Mechanisms for the enhancement of fracture healing in rats treated with intermittent low-dose human parathyroid hormone (1–34). J Bone Miner Res 17:2038–2047

    Article  PubMed  CAS  Google Scholar 

  43. Jahng JS, Kim HW (2000) Effect of intermittent administration of parathyroid hormone on fracture healing in ovariectomized rats. Orthopedics 23:1089–1094

    PubMed  CAS  Google Scholar 

  44. Warden SJ, Komatsu DE, Rydberg J et al (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  PubMed  CAS  Google Scholar 

  45. Bostrom MP, Gamradt SC, Asnis P et al (2000) Parathyroid hormone–related protein analog RS-66271 is an effective therapy for impaired bone healing in rabbits on corticosteroid therapy. Bone 26:437–442

    Article  PubMed  CAS  Google Scholar 

  46. Alkhiary YM, Gerstenfeld LC, Krall E et al (2005) Enhancement of experimental fracture-healing by systemic administration of recombinant human parathyroid hormone (PTH 1–34). J Bone Joint Surg Am 87:731–741

    Article  PubMed  Google Scholar 

  47. Kakar S, Einhorn TA, Vora S et al (2007) Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J Bone Miner Res 22:1903–1912

    Article  PubMed  CAS  Google Scholar 

  48. O’Loughlin PF, Cunningham ME, Bukata SV, et al. (2009) Parathyroid hormone (1–34) augments spinal fusion, fusion mass volume, and fusion mass quality in a rabbit spinal fusion model. Spine (Phila Pa 1976) 34:121–130

  49. Lehman RA Jr, Dmitriev AE, Cardoso MJ et al (2010) Effect of teriparatide [rhPTH(1,34)] and calcitonin on intertransverse process fusion in a rabbit model. Spine 35:146–152

    Article  PubMed  Google Scholar 

  50. Skripitz R, Aspenberg P (2001) Implant fixation enhanced by intermittent treatment with parathyroid hormone. J Bone Joint Surg Br 83:437–440

    Article  PubMed  CAS  Google Scholar 

  51. Reynolds DG, Takahata M, Lerner AL et al (2011) Teriparatide therapy enhances devitalized femoral allograft osseointegration and biomechanics in a murine model. Bone 48:562–570

    Article  PubMed  CAS  Google Scholar 

  52. Knecht TP (2004) Teriparatide and fracture healing in cortical bone. Endocr Pract 10:293

    PubMed  Google Scholar 

  53. Rubery PT, Bukata SV (2010) Teriparatide may accelerate healing in delayed unions of type III odontoid fractures: a report of 3 cases. J Spinal Disord Tech 23:151–155

    Article  PubMed  Google Scholar 

  54. Yu CT, Wu JK, Chang CC et al (2008) Early callus formation in human hip fracture treated with internal fixation and teriparatide. J Rheumatol 35:2082–2083

    PubMed  Google Scholar 

  55. Aspenberg P, Genant HK, Johansson T et al (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 25:404–414

    Article  PubMed  CAS  Google Scholar 

  56. Aspenberg P, Johansson T (2010) Teriparatide improves early callus formation in distal radial fractures. Acta Orthop 81:234–236

    Article  PubMed  Google Scholar 

  57. Bashutski JD, Eber RM, Kinney JS et al (2010) Teriparatide and osseous regeneration in the oral cavity. N Engl J Med 363:2396–2405

    Article  PubMed  CAS  Google Scholar 

  58. Peichl P, Holzer LA, Maier R, Holzer G (2011) Parathyroid hormone 1–84 accelerates fracture-healing in pubic bones of elderly osteoporotic women. J Bone Joint Surg Am 93:1583–1587

    Article  PubMed  Google Scholar 

  59. Li YF, Luo E, Feng G et al (2009) Systemic treatment with strontium ranelate promotes tibial fracture healing in ovariectomized rats. Osteoporos Int 21:1889–1897

    Article  PubMed  Google Scholar 

  60. Ozturan KE, Demir B, Yucel I et al (2011) Effect of strontium ranelate on fracture healing in the osteoporotic rats. J Orthop Res 29:138–142

    Article  PubMed  CAS  Google Scholar 

  61. Habermann B, Kafchitsas K, Olender G et al (2010) Strontium ranelate enhances callus strength more than PTH 1–34 in an osteoporotic rat model of fracture healing. Calcif Tissue Int 86:82–89

    Article  PubMed  CAS  Google Scholar 

  62. Cebesoy O, Tutar E, Kose KC et al (2007) Effect of strontium ranelate on fracture healing in rat tibia. Joint Bone Spine 74:590–593

    Article  PubMed  Google Scholar 

  63. Maimoun L, Brennan T, Badoud I et al (2010) Strontium ranelate improves implant osseointegration. Bone 46:1436–1441

    Article  PubMed  CAS  Google Scholar 

  64. Li Y, Feng G, Gao Y et al (2010) Strontium ranelate treatment enhances hydroxyapatite-coated titanium screws fixation in osteoporotic rats. J Orthoped Res 28:578–582

    CAS  Google Scholar 

  65. Alegre DN, Ribeiro C, Sousa C et al (2012) Possible benefits of strontium ranelate in complicated long bone fractures. Rheumatol Int 32:439–443

    Article  PubMed  Google Scholar 

  66. Tarantino U, Celi M, Saturnino L et al (2010) Strontium ranelate and bone healing: report of two cases. Clin Cases Miner Bone Metab 7:65–68

    PubMed  Google Scholar 

  67. Li X, Ominsky MS, Warmington KS et al (2009) Sclerostin antibody treatment increases bone formation, bone mass, and bone strength in a rat model of postmenopausal osteoporosis. J Bone Miner Res 24:578–588

    Article  PubMed  CAS  Google Scholar 

  68. Agholme F, Li X, Isaksson H et al (2010) Sclerostin antibody treatment enhances metaphyseal bone healing in rats. J Bone Miner Res 25:2412–2418

    Article  PubMed  CAS  Google Scholar 

  69. Secreto FJ, Hoeppner LH, Westendorf JJ (2009) Wnt signaling during fracture repair. Curr Osteoporos Rep 7:64–69

    Article  PubMed  Google Scholar 

  70. Chen Y, Whetstone HC, Lin AC et al (2007) Beta-catenin signaling plays a disparate role in different phases of fracture repair: implications for therapy to improve bone healing. PLoS Med 4:e249

    Article  PubMed  Google Scholar 

  71. Komatsu DE, Mary MN, Schroeder RJ et al (2010) Modulation of Wnt signaling influences fracture repair. J Orthop Res 28:928–936

    PubMed  CAS  Google Scholar 

  72. Garrison KR, Shemilt I, Donell S, et al. (2010) Bone morphogenetic protein (BMP) for fracture healing in adults. Cochrane Database Syst Rev CD006950

  73. Tzioupis C, Giannoudis PV (2007) Prevalence of long-bone non-unions. Injury 38(Suppl 2):S3–S9

    Article  PubMed  Google Scholar 

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Acknowledgements

This article was derived from a working group meeting on December 2, 2010, supported by the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO).

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Authors and Affiliations

  1. AO Clinical Priority Program “Fracture Fixation in Osteoporotic Bone”, Institute for Biomechanics of ETH, Zurich, Switzerland

    J. Goldhahn

  2. Department of Orthopaedic and Trauma Surgery, Saint Antoine Hospital, AP-HP, UPMC-Sorbonne Universities, Paris, France

    J.-M. Féron

  3. WHO Collaborating Centre for Metabolic Bone Diseases, University of Sheffield Medical School, Sheffield, UK

    J. Kanis

  4. Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Leiden, The Netherlands

    S. Papapoulos

  5. Public Health and Health Economics, University of Liège, Liege, Belgium

    J.-Y. Reginster

  6. Division of Bone Disease, Department of Rehabilitation and Geriatrics, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland

    R. Rizzoli

  7. Amgen, Ltd, Uxbridge, UK

    W. Dere

  8. Lilly Corporate Center, Eli Lilly and Company, Indianapolis, IN, USA

    B. Mitlak

  9. Institute de Recherches Internationales Servier, Courbevoie, France

    Y. Tsouderos

  10. Division of Gerontology and Geriatrics, Department of Experimental Medicine, Centre for Metabolic Bone Disease, Leuven University, Leuven, Belgium

    S. Boonen

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  1. J. Goldhahn
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  2. J.-M. Féron
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  3. J. Kanis
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  4. S. Papapoulos
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  6. R. Rizzoli
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  7. W. Dere
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  10. S. Boonen
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Correspondence to J. Goldhahn.

Additional information

S. Boonen has received consulting fees, advisory board fees, lecture fees, and/or grant support from Amgen, Eli Lilly, GlaxoSmithKline, Merck, Novartis, Ono, Roche, Sanofi-Aventis, Servier, and Warner Chilcott. J-M. Feron has received advisory boards or lecture fees from Amgen, Lilly, Novartis, and Servier. W. Dere is an employee of Amgen. J. Goldhahn has received consulting fees or paid advisory board fees from Amgen, Eli Lilly, Novartis, Pfizer, and Servier. J. Kanis has received consulting and lecture fees, on paid advisory boards, and/or grant support from Abiogen, Italy; Amgen, USA, Switzerland and Belgium; Bayer, Germany; Besins-Iscovesco, France; Biosintetica, Brazil; Boehringer Ingelheim, UK; Celtrix, USA; D3A, France; European Federation of Pharmaceutical Industry and Associations, (EFPIA) Brussels; Gador, Argentina; General Electric, USA; GSK, UK, USA; Hologic, Belgium and USA; Kissei, Japan; Leiras, Finland; Leo Pharma, Denmark; Lilly, USA, Canada, Japan, Australia and UK; Merck Research Labs, USA; Merlin Ventures, UK; MRL, China; Novartis, Switzerland and USA; Novo Nordisk, Denmark; Nycomed, Norway; Ono, UK and Japan; Organon, Holland; Parke-Davis, USA; Pfizer USA; Pharmexa, Denmark; Procter and Gamble, UK, USA; ProStrakan, UK; Roche, Germany, Australia, Switzerland, USA; Rotta Research, Italy; Sanofi-Aventis, USA; Schering, Germany and Finland; Servier, France and UK; Shire, UK; Solvay, France and Germany; Strathmann, Germany; Tarsa Therapeutics, US; Tethys, USA; Teijin, Japan; Teva, Israel; UBS, Belgium; Unigene, USA; Warburg-Pincus, UK; Warner-Lambert, USA; Wyeth, USA. B. Mitlak is an employee of Eli Lilly and Company. S. Papapoulos has received consulting, advisory board and/or lecture fees from Amgen, Eli Lilly, GlaxoSmithKleine, Merck & Co, Novartis, Roche, Warner Chilcott and Wyeth. J-Y. Reginster has received consulting fees, advisory board fees, lecture fees, and/or grant support from Servier, Novartis, Negma, Lilly, Wyeth, Amgen, GlaxoSmithKline, Roche, Merckle, Nycomed, NPS, Theramex, UCB, Merck Sharp and Dohme, Rottapharm, IBSA, Genevrier, Teijin, Teva, Ebewee Pharma, Zodiac, Analis, Novo-Nordisk, and Bristol Myers Squibb. R. Rizzoli has received advisory board or lecture fees for Merck Sharp and Dohme, Eli Lilly, Amgen, Novartis, Servier, Nycomed, Nestlé, and Danone. Y. Tsouderos is an employee of Servier.

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Goldhahn, J., Féron, JM., Kanis, J. et al. Implications for Fracture Healing of Current and New Osteoporosis Treatments: An ESCEO Consensus Paper. Calcif Tissue Int 90, 343–353 (2012). https://doi.org/10.1007/s00223-012-9587-4

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