The role of antiosteoporotic drugs in fracture healing
Keywords:
bisphosphonates, denosumab, fracture healing, osteoporotic fractures, teriparatide
Abstract
This narrative review was carried out to investigate the effect of antiosteoporotic drugs (selective estrogen receptor modulators [SERMs], bisphosphonates, denosumab, teriparatide, romosozumab) in fracture healing process of vertebral, hip and distal radius fractures. The administration of bisphosphonates (BPs) didn’t affect the fracture healing process and clinical results after distal radius and hip fractures. However, there no evidence for vertebral fractures. Denosumab doesn’t seem to delay the process of fracture healing in patients with non-vertebral fractures in a study that was well documented and designed. There no human studies that appreciated the influence of SERMs and romosozumab in fracture healing process. In one study was reported that patients with distal radius fractures who were treated with teriparatide had shorter time of fracture healing, however this was not clinically significant. On one hand, in hip fractures, some recent studies suggested that in patients treated with teriparatide there was better improvement of pain and clinical outcomes of functionality. On the other hand, in vertebral fractures, there was no statistically significantly difference regarding the stability of fractures between teriparatide and control groups. Considering the fact that there is no evidence that antiosteoprotic drugs influence negatively the fracture healing, there is no reason to delay the initiation of antiosteoporotic treatment after the fracture.
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References
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2. Nakayama A, Major G, Holliday E, et al. Evidence of effectiveness of a fracture liaison service to reduce the re-fracture rate. Osteoporosis Int 2016; 27:873-9.
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5. Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. Journal of cellular biochemistry. 2003; 88(5):873-84.
6. Wang CJ. Extracorporeal shockwave therapy in musculoskeletal disorders. Journal of orthopaedic surgery and research. 2012; 7:11
7. Sahiner T, Aktan E, Kaleli B, et al. The effects of postmenopausal hormone replacement therapy on sympathetic skin response. Maturitas 1998; 30:85-8.
8.Taranta A, Brama M, Teti A, et al. The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro. Bone 2002; 30:368-76.
9. Cao Y, Mori S, Mashiba T, et al. Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 2002;17: 2237-46.
10. Beil FT, Barvencik F, Gebauer M, et al. Effects of estrogen on fracture healing in mice. J Trauma 2010; 69:1259-65.
11. Spiro AS, Khadem S, Jeschke A, et al. The SERM raloxifene improves diaphyseal fracture healing in mice. J Bone Miner Metab 2013; 31:629-36.
12. Qaseem A, Snow V, Shekelle P, et al. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008; 149:404-15.
13. Russell RG. Bisphosphonates: the first 40 years. Bone 2011; 49:2-19.
14. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90:1294-301.
15. Hedge V, Jo JE, Andreopoulou P, et al. Effect of osteoporosis medications on fracture healing. Osteoporos Int 2016; 861-71.
16. Amanat N, McDonald M, Godfrey C, et al. Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res 2007; 22:867-76.
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18. Shin YH, Shin WC, Kim JW. Effect of osteoporosis medication on fracture healing: An evidence-based review. J Bone Metab 2020; 27(1): 15-26.
19. Van der Poest Clement E, Patka P, Vandormael K, et al. The effect of alendronate on bone mass after distal forearm fracture. J Bone Miner Res 2000; 15:586-93.
20. Rozental TD, Vazquez MA, Chacko AT, et al. Comparison of radiographic fracture healing in the distal radius for patients on and off bisphosphonate therapy. J Hand Surg Am 2009; 34:595-602.
21. Shoji KE, Earp BE, Rozental TD. The effect of bisphosphonates on the clinical and radiographic outcomes of distal radius fractures in women. J Hand Surg Am 2018; 43:115-22.
22. Gong HS, Song CH, Lee YH, et al. Early initiation of bisphosphonate does not affect healing and outcomes of volar plate fixation of osteoporotic distal radial fractures. J Bone Joint Surg Am 2012; 94:1729-36.
23. Uchiyama S, Itsubo T, Nakamura K, et al. Effect of early administration of alendronate after surgery for distal radial fragility fracture on radiological fracture healing time. Bone Joint J 2013;95B:1544-50.
24.Duckworth AD, McQueen MM, Tuck CE, et al. Effect of alendronic acid on fracture healing: A multicenter randomized placebo-controlled trial. J Bone Miner Res 2019; 34:1025.
25.Altintaş F, Ozkut AT, Beyzadeoğlu T, et al. The effect of risedronate treatment on bone turnover markers in patients with hip fracture. Acta Orthop Traumatol Turc 2007;41: 132-5.
26. Cecilia D, Jódar E, Fernandez C, et al. Effect of alendronate in elderly patients after low trauma hip fracture repair. Osteoporosis Int 2009; 20:903-10.
27. Colón-Emeric C, Nordsletten L, Olson S, et al. Association between timing of zoledronic acid infusion and hip fracture healing. Osteoporos Int 2011; 22:2329-36.
28. Kim TY, Ha YC, Kang BJ, et al. Does early administration of bisphosphonate affect fracture healing in patients with intertrochanteric fractures? J Bone Joint Surg Br 2012;94: 956-60.
29. Lim EJ, Kim JT, Kim CH, et al. Effect of preoperative bisphosphonate treatment on fracture healing after internal fixation treatment of intertrochanteric femoral fractures. Hip Pelvis 2019; 31:75-81.
30. Ha KY, Park KS, Kim SI, et al. Does bisphosphonate-based anti-osteoporosis medication affect osteoporotic spinal fracture healing? Osteoporos Int 2016; 27:483-8.
31. Goldhahn J, Feron JM, Kanis J, et al. Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int 2012; 90:343-53.
32. Gerstenfeld LC, Sacks DJ, Pelis M, et al. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 2009; 24:196-208.
33. Adami S, Libanati C, Boonen S, et al. Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. J Bone Joint Surg Am 2012; 94:2113-9.
34. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21:115-37.
35. Friedl G, Turner RT, Evans GL, et al. Intermittent parathyroid hormone (PTH) treatment and age-dependent effects on rat cancellous bone and mineral metabolism. J Orthop Res 2007; 25:1454-64.
36. Kakar S, Einhorn TA, Vora S, et al. Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J Bone Miner Res 2007; 22:1903-12.
37. Nakazawa T, Nakajima A, Shiomi K, et al. Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone 2005; 37:711-9.
38. Manabe T, Mori S, Mashiba T, et al. Human parathyroid hormone (1-34) accelerates natural fracture healing process in the femoral osteotomy model of cynomolgus monkeys. Bone 2007; 40:1475-82.
39. Jorgensen NR, Schwarz P. Effects of anti-osteoporosis medications on fracture healing. Curr Osteoporos Rep 2011;9: 149-55.
40. Aspenberg P, Johansson T. Teriparatide improves early callus formation in distal radial fractures. Acta Orthop 2010; 81:234-6.
41. Shin YH, Gong HS. Recent update in the diagnosis and treatment of bone frailty in patients with a distal radius fracture. J Hand Surg Asian Pac Vol 2016; 21:307-12.
42. Aspenberg P, Genant HK, Johansson T, et al. 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 2010; 25:404-14.
43. Bhandari M, Jin L, See K, et al. Does teriparatide improve femoral neck fracture healing: Results from a randomized placebo-controlled trial. Clin Orthop Relat Res 2016;474: 1234-44.
44. Huang TW, Chuang PY, Lin SJ, et al. Teriparatide improves fracture healing and early functional recovery in treatment of osteoporotic intertrochanteric fractures. Medicine (Baltimore) 2016;95: e3626.
45. Kim SJ, Park HS, Lee DW, et al. Short-term daily teriparatide improve postoperative functional outcome and fracture healing in unstable intertrochanteric fractures. Injury 2019; 50:1364-70.
46. Tsuchie H, Miyakoshi N, Kasukawa Y, et al. The effect of teriparatide to alleviate pain and to prevent vertebral collapse after fresh osteoporotic vertebral fracture. J Bone Miner Metab 2016; 34:86-91.
47. Kitaguchi K, Kashii M, Ebina K, et al. Effects of weekly teriparatide administration for vertebral stability and bony union in patients with acute osteoporotic vertebral fractures. Asian Spine J 2019; 13:763-71.
48. Min HK, Ahn JH, Ha KY, et al. Effects of anti-osteoporosis medications on radiological and clinical results after acute osteoporotic spinal fractures: a retrospective analysis of prospectively designed study. Osteoporos Int 2019; 30:2249-56.
49. Takase R, Tsubouchi Y, Otsu T, et al. The effects of romosozumab combined with vitamin D3 on fracture healing in ovariectomized rats. Journal of Orthopaedic Surgery and Research 2022; 17:384-393.
50. Aspenberg P, Malouf J, Tarantino U, et al. Effects of teriparatide compared with risedronate on recovery after per trochanteric hip fracture: Results of a randomized, active-controlled, double-blind clinical trial at 26 weeks. J Bone Joint Surg Am 2016; 98:1868-78.
51. Iwata A, Kanayama M, Oha F, et al. Effect of teriparatide (rh-PTH 1-34) versus bisphosphonate on the healing of osteoporotic vertebral compression fracture: A retrospective comparative study. BMC Musculoskeletal Disord 2017; 18:148.
52. Kang JH, Yang SM, Im SB, et al. Can three months of teriparatide be one of treatment options for osteoporotic vertebral compression fracture patients? Korean J Neurotrauma 2019; 15:19-27.
53. Hadji P, Zanchetta JR, Russo L, et al. The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures. Osteoporos Int 2012;23:2141-50
2. Nakayama A, Major G, Holliday E, et al. Evidence of effectiveness of a fracture liaison service to reduce the re-fracture rate. Osteoporosis Int 2016; 27:873-9.
3. Sietsema DL, Araujo AB, Wang L, et al. The effectiveness of a private orthopedic practice-based osteoporosis management service to reduce the risk of subsequent fractures. J Bone Joint Surg Am 2018; 100:1819-28.
4. Alkhawashki HM. Shock wave therapy of fracture nonunion. Injury. 2015; 46(11):2248-52.
5. Gerstenfeld LC, Cullinane DM, Barnes GL, Graves DT, Einhorn TA. Fracture healing as a post-natal developmental process: molecular, spatial, and temporal aspects of its regulation. Journal of cellular biochemistry. 2003; 88(5):873-84.
6. Wang CJ. Extracorporeal shockwave therapy in musculoskeletal disorders. Journal of orthopaedic surgery and research. 2012; 7:11
7. Sahiner T, Aktan E, Kaleli B, et al. The effects of postmenopausal hormone replacement therapy on sympathetic skin response. Maturitas 1998; 30:85-8.
8.Taranta A, Brama M, Teti A, et al. The selective estrogen receptor modulator raloxifene regulates osteoclast and osteoblast activity in vitro. Bone 2002; 30:368-76.
9. Cao Y, Mori S, Mashiba T, et al. Raloxifene, estrogen, and alendronate affect the processes of fracture repair differently in ovariectomized rats. J Bone Miner Res 2002;17: 2237-46.
10. Beil FT, Barvencik F, Gebauer M, et al. Effects of estrogen on fracture healing in mice. J Trauma 2010; 69:1259-65.
11. Spiro AS, Khadem S, Jeschke A, et al. The SERM raloxifene improves diaphyseal fracture healing in mice. J Bone Miner Metab 2013; 31:629-36.
12. Qaseem A, Snow V, Shekelle P, et al. Pharmacologic treatment of low bone density or osteoporosis to prevent fractures: a clinical practice guideline from the American College of Physicians. Ann Intern Med 2008; 149:404-15.
13. Russell RG. Bisphosphonates: the first 40 years. Bone 2011; 49:2-19.
14. Odvina CV, Zerwekh JE, Rao DS, et al. Severely suppressed bone turnover: a potential complication of alendronate therapy. J Clin Endocrinol Metab 2005; 90:1294-301.
15. Hedge V, Jo JE, Andreopoulou P, et al. Effect of osteoporosis medications on fracture healing. Osteoporos Int 2016; 861-71.
16. Amanat N, McDonald M, Godfrey C, et al. Optimal timing of a single dose of zoledronic acid to increase strength in rat fracture repair. J Bone Miner Res 2007; 22:867-76.
17. McDonald MM, Dulai S, Godfrey C, et al. Bolus or weekly zoledronic acid administration does not delay endochondral fracture repair but weekly dosing enhances delays in hard callus remodeling. Bone 2008; 43:653-62.
18. Shin YH, Shin WC, Kim JW. Effect of osteoporosis medication on fracture healing: An evidence-based review. J Bone Metab 2020; 27(1): 15-26.
19. Van der Poest Clement E, Patka P, Vandormael K, et al. The effect of alendronate on bone mass after distal forearm fracture. J Bone Miner Res 2000; 15:586-93.
20. Rozental TD, Vazquez MA, Chacko AT, et al. Comparison of radiographic fracture healing in the distal radius for patients on and off bisphosphonate therapy. J Hand Surg Am 2009; 34:595-602.
21. Shoji KE, Earp BE, Rozental TD. The effect of bisphosphonates on the clinical and radiographic outcomes of distal radius fractures in women. J Hand Surg Am 2018; 43:115-22.
22. Gong HS, Song CH, Lee YH, et al. Early initiation of bisphosphonate does not affect healing and outcomes of volar plate fixation of osteoporotic distal radial fractures. J Bone Joint Surg Am 2012; 94:1729-36.
23. Uchiyama S, Itsubo T, Nakamura K, et al. Effect of early administration of alendronate after surgery for distal radial fragility fracture on radiological fracture healing time. Bone Joint J 2013;95B:1544-50.
24.Duckworth AD, McQueen MM, Tuck CE, et al. Effect of alendronic acid on fracture healing: A multicenter randomized placebo-controlled trial. J Bone Miner Res 2019; 34:1025.
25.Altintaş F, Ozkut AT, Beyzadeoğlu T, et al. The effect of risedronate treatment on bone turnover markers in patients with hip fracture. Acta Orthop Traumatol Turc 2007;41: 132-5.
26. Cecilia D, Jódar E, Fernandez C, et al. Effect of alendronate in elderly patients after low trauma hip fracture repair. Osteoporosis Int 2009; 20:903-10.
27. Colón-Emeric C, Nordsletten L, Olson S, et al. Association between timing of zoledronic acid infusion and hip fracture healing. Osteoporos Int 2011; 22:2329-36.
28. Kim TY, Ha YC, Kang BJ, et al. Does early administration of bisphosphonate affect fracture healing in patients with intertrochanteric fractures? J Bone Joint Surg Br 2012;94: 956-60.
29. Lim EJ, Kim JT, Kim CH, et al. Effect of preoperative bisphosphonate treatment on fracture healing after internal fixation treatment of intertrochanteric femoral fractures. Hip Pelvis 2019; 31:75-81.
30. Ha KY, Park KS, Kim SI, et al. Does bisphosphonate-based anti-osteoporosis medication affect osteoporotic spinal fracture healing? Osteoporos Int 2016; 27:483-8.
31. Goldhahn J, Feron JM, Kanis J, et al. Implications for fracture healing of current and new osteoporosis treatments: an ESCEO consensus paper. Calcif Tissue Int 2012; 90:343-53.
32. Gerstenfeld LC, Sacks DJ, Pelis M, et al. Comparison of effects of the bisphosphonate alendronate versus the RANKL inhibitor denosumab on murine fracture healing. J Bone Miner Res 2009; 24:196-208.
33. Adami S, Libanati C, Boonen S, et al. Denosumab treatment in postmenopausal women with osteoporosis does not interfere with fracture-healing: results from the FREEDOM trial. J Bone Joint Surg Am 2012; 94:2113-9.
34. Manolagas SC. Birth and death of bone cells: basic regulatory mechanisms and implications for the pathogenesis and treatment of osteoporosis. Endocr Rev 2000; 21:115-37.
35. Friedl G, Turner RT, Evans GL, et al. Intermittent parathyroid hormone (PTH) treatment and age-dependent effects on rat cancellous bone and mineral metabolism. J Orthop Res 2007; 25:1454-64.
36. Kakar S, Einhorn TA, Vora S, et al. Enhanced chondrogenesis and Wnt signaling in PTH-treated fractures. J Bone Miner Res 2007; 22:1903-12.
37. Nakazawa T, Nakajima A, Shiomi K, et al. Effects of low-dose, intermittent treatment with recombinant human parathyroid hormone (1-34) on chondrogenesis in a model of experimental fracture healing. Bone 2005; 37:711-9.
38. Manabe T, Mori S, Mashiba T, et al. Human parathyroid hormone (1-34) accelerates natural fracture healing process in the femoral osteotomy model of cynomolgus monkeys. Bone 2007; 40:1475-82.
39. Jorgensen NR, Schwarz P. Effects of anti-osteoporosis medications on fracture healing. Curr Osteoporos Rep 2011;9: 149-55.
40. Aspenberg P, Johansson T. Teriparatide improves early callus formation in distal radial fractures. Acta Orthop 2010; 81:234-6.
41. Shin YH, Gong HS. Recent update in the diagnosis and treatment of bone frailty in patients with a distal radius fracture. J Hand Surg Asian Pac Vol 2016; 21:307-12.
42. Aspenberg P, Genant HK, Johansson T, et al. 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 2010; 25:404-14.
43. Bhandari M, Jin L, See K, et al. Does teriparatide improve femoral neck fracture healing: Results from a randomized placebo-controlled trial. Clin Orthop Relat Res 2016;474: 1234-44.
44. Huang TW, Chuang PY, Lin SJ, et al. Teriparatide improves fracture healing and early functional recovery in treatment of osteoporotic intertrochanteric fractures. Medicine (Baltimore) 2016;95: e3626.
45. Kim SJ, Park HS, Lee DW, et al. Short-term daily teriparatide improve postoperative functional outcome and fracture healing in unstable intertrochanteric fractures. Injury 2019; 50:1364-70.
46. Tsuchie H, Miyakoshi N, Kasukawa Y, et al. The effect of teriparatide to alleviate pain and to prevent vertebral collapse after fresh osteoporotic vertebral fracture. J Bone Miner Metab 2016; 34:86-91.
47. Kitaguchi K, Kashii M, Ebina K, et al. Effects of weekly teriparatide administration for vertebral stability and bony union in patients with acute osteoporotic vertebral fractures. Asian Spine J 2019; 13:763-71.
48. Min HK, Ahn JH, Ha KY, et al. Effects of anti-osteoporosis medications on radiological and clinical results after acute osteoporotic spinal fractures: a retrospective analysis of prospectively designed study. Osteoporos Int 2019; 30:2249-56.
49. Takase R, Tsubouchi Y, Otsu T, et al. The effects of romosozumab combined with vitamin D3 on fracture healing in ovariectomized rats. Journal of Orthopaedic Surgery and Research 2022; 17:384-393.
50. Aspenberg P, Malouf J, Tarantino U, et al. Effects of teriparatide compared with risedronate on recovery after per trochanteric hip fracture: Results of a randomized, active-controlled, double-blind clinical trial at 26 weeks. J Bone Joint Surg Am 2016; 98:1868-78.
51. Iwata A, Kanayama M, Oha F, et al. Effect of teriparatide (rh-PTH 1-34) versus bisphosphonate on the healing of osteoporotic vertebral compression fracture: A retrospective comparative study. BMC Musculoskeletal Disord 2017; 18:148.
52. Kang JH, Yang SM, Im SB, et al. Can three months of teriparatide be one of treatment options for osteoporotic vertebral compression fracture patients? Korean J Neurotrauma 2019; 15:19-27.
53. Hadji P, Zanchetta JR, Russo L, et al. The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures. Osteoporos Int 2012;23:2141-50
Published
2023-06-26
Section
Review
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