Review

. 2024 Aug;35(8):1337-1358.

doi: 10.1007/s00198-024-07059-8. Epub 2024 Apr 8.

Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review

M Chandran¹, K E Akesson², M K Javaid³, N Harvey⁴, R D Blank^{5

6}, M L Brandi⁷, T Chevalley⁸, P Cinelli⁹, C Cooper^{10

11}, W Lems¹², G P Lyritis¹³, P Makras¹⁴, J Paccou¹⁵, D D Pierroz¹⁶, M Sosa¹⁷, T Thomas¹⁸, S Silverman¹⁹; Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation, on behalf of the International Osteoporosis Foundation, Société Internationale de Chirurgie Orthopédique et de Traumatologie

Collaborators, Affiliations

Collaborators

Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation, on behalf of the International Osteoporosis Foundation, Société Internationale de Chirurgie Orthopédique et de Traumatologie:
Kristina E Åkesson, Robert D Blank, Maria Louisa Brandi, Derrick Chan, Manju Chandran, Thierry Chevalley, Cyrus Cooper, Patrice Fardellone, Julio C Fernandes, Stefan Goemaere, Nicholas Harvey, G Holzer, Kassim Javaid, Willem F Lems, Michael E Lewiecki, George P Lyritis, Polyzois Makras, Nicola Napoli, Julien Paccou, Stuart Silverman, Manuel Sosa Henriquez, Thierry Thomas

Affiliations

¹ Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, DUKE NUS Medical School, Singapore, Singapore. mchandran7@gmail.com.
² Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Department of Orthopedics, Skåne University Hospital, Malmö, Sweden.
³ NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.
⁴ MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁵ Garvan Institute of Medical Research, Medical College of Wisconsin, Darlinghurst, NSW, Australia.
⁶ Medical College of Wisconsin, Milwaukee, WI, USA.
⁷ Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Largo Palagi 1, Florence, Italy.
⁸ Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
⁹ Department of Trauma Surgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
¹⁰ MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
¹¹ NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
¹² Department of Rheumatology, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands.
¹³ Hellenic Osteoporosis Foundation, Athens, Greece.
¹⁴ Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece.
¹⁵ Department of Rheumatology, MABlab ULR 4490, CHU Lille, Univ. Lille, 59000, Lille, France.
¹⁶ International Osteoporosis Foundation, Nyon, Switzerland.
¹⁷ University of Las Palmas de Gran Canaria, Investigation Group on Osteoporosis and Mineral Metabolism, Canary Islands, Spain.
¹⁸ Department of Rheumatology, North Hospital, CHU Saint-Etienne and INSERM U1059, University of Lyon-University Jean Monnet, Saint‑Etienne, France.
¹⁹ Cedars-Sinai Medical Center and Geffen School of Medicine UCLA, Los Angeles, CA, USA.

PMID: 38587674
PMCID: PMC11282157
DOI: 10.1007/s00198-024-07059-8

Review

Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review

M Chandran et al. Osteoporos Int. 2024 Aug.

. 2024 Aug;35(8):1337-1358.

doi: 10.1007/s00198-024-07059-8. Epub 2024 Apr 8.

Authors

Collaborators

Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation, on behalf of the International Osteoporosis Foundation, Société Internationale de Chirurgie Orthopédique et de Traumatologie:
Kristina E Åkesson, Robert D Blank, Maria Louisa Brandi, Derrick Chan, Manju Chandran, Thierry Chevalley, Cyrus Cooper, Patrice Fardellone, Julio C Fernandes, Stefan Goemaere, Nicholas Harvey, G Holzer, Kassim Javaid, Willem F Lems, Michael E Lewiecki, George P Lyritis, Polyzois Makras, Nicola Napoli, Julien Paccou, Stuart Silverman, Manuel Sosa Henriquez, Thierry Thomas

Affiliations

¹ Osteoporosis and Bone Metabolism Unit, Department of Endocrinology, Singapore General Hospital, DUKE NUS Medical School, Singapore, Singapore. mchandran7@gmail.com.
² Clinical and Molecular Osteoporosis Research Unit, Department of Clinical Sciences, Lund University, Department of Orthopedics, Skåne University Hospital, Malmö, Sweden.
³ NIHR Musculoskeletal Biomedical Research Unit, University of Oxford, Oxford, UK.
⁴ MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
⁵ Garvan Institute of Medical Research, Medical College of Wisconsin, Darlinghurst, NSW, Australia.
⁶ Medical College of Wisconsin, Milwaukee, WI, USA.
⁷ Department of Biomedical, Experimental and Clinical Sciences, University of Florence, Largo Palagi 1, Florence, Italy.
⁸ Division of Bone Diseases, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
⁹ Department of Trauma Surgery, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
¹⁰ MRC Lifecourse Epidemiology Centre, University of Southampton, NIHR Southampton Biomedical Research Centre, University of Southampton, University Hospitals Southampton NHS Foundation Trust, Southampton, UK.
¹¹ NIHR Oxford Biomedical Research Unit, University of Oxford, Oxford, UK.
¹² Department of Rheumatology, Amsterdam UMC, Location VUmc, Amsterdam, The Netherlands.
¹³ Hellenic Osteoporosis Foundation, Athens, Greece.
¹⁴ Department of Medical Research, 251 Hellenic Air Force & VA General Hospital, Athens, Greece.
¹⁵ Department of Rheumatology, MABlab ULR 4490, CHU Lille, Univ. Lille, 59000, Lille, France.
¹⁶ International Osteoporosis Foundation, Nyon, Switzerland.
¹⁷ University of Las Palmas de Gran Canaria, Investigation Group on Osteoporosis and Mineral Metabolism, Canary Islands, Spain.
¹⁸ Department of Rheumatology, North Hospital, CHU Saint-Etienne and INSERM U1059, University of Lyon-University Jean Monnet, Saint‑Etienne, France.
¹⁹ Cedars-Sinai Medical Center and Geffen School of Medicine UCLA, Los Angeles, CA, USA.

PMID: 38587674
PMCID: PMC11282157
DOI: 10.1007/s00198-024-07059-8

Abstract

Antiresorptive medications do not negatively affect fracture healing in humans. Teriparatide may decrease time to fracture healing. Romosozumab has not shown a beneficial effect on human fracture healing.

Background: Fracture healing is a complex process. Uncertainty exists over the influence of osteoporosis and the medications used to treat it on fracture healing.

Methods: Narrative review authored by the members of the Fracture Working Group of the Committee of Scientific Advisors of the International Osteoporosis Foundation (IOF), on behalf of the IOF and the Société Internationale de Chirurgie Orthopédique et de Traumatologie (SICOT).

Results: Fracture healing is a multistep process. Most fractures heal through a combination of intramembranous and endochondral ossification. Radiographic imaging is important for evaluating fracture healing and for detecting delayed or non-union. The presence of callus formation, bridging trabeculae, and a decrease in the size of the fracture line over time are indicative of healing. Imaging must be combined with clinical parameters and patient-reported outcomes. Animal data support a negative effect of osteoporosis on fracture healing; however, clinical data do not appear to corroborate with this. Evidence does not support a delay in the initiation of antiresorptive therapy following acute fragility fractures. There is no reason for suspension of osteoporosis medication at the time of fracture if the person is already on treatment. Teriparatide treatment may shorten fracture healing time at certain sites such as distal radius; however, it does not prevent non-union or influence union rate. The positive effect on fracture healing that romosozumab has demonstrated in animals has not been observed in humans.

Conclusion: Overall, there appears to be no deleterious effect of osteoporosis medications on fracture healing. The benefit of treating osteoporosis and the urgent necessity to mitigate imminent refracture risk after a fracture should be given prime consideration. It is imperative that new radiological and biological markers of fracture healing be identified. It is also important to synthesize clinical and basic science methodologies to assess fracture healing, so that a convergence of the two frameworks can be achieved.

Keywords: Fracture healing; Osteoporosis; Osteoporosis medication; Union.

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Conflict of interest statement

MC has received honoraria and travel grants from AMGEN and DKSH for speaking engagements outside the submitted work.

KEA has received speaker fees from Amgen, Astellas Pharma, Chugai, and UCB outside the submitted work.

MKJ has received honoraria, unrestricted research grants, and travel and/or subsistence expenses from Amgen, Lilly UK, Internis, Consilient Health, Zebra Medical Vision, Kyowa Kirin Hakin, and UCB outside the submitted work.

NCH reports personal fees, consultancy, lecture fees, and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Kyowa Kirin, Consilient Healthcare, Theramex, and Internis Pharma, outside the submitted work.

RDB serves on an advisory board for Amgen, has received royalties from Wolters-Kluwer, and has ownership/stock interests in Abbott Labs, Abbvie, Amgen, Doctorpedia, Glaxo, JangoBio, Johnson & Johnson, Procter & Gamble, and ROMTech outside the submitted work.

MLB has served as a consultant for Aboca, Alexion, Amolyt, Bruno Farmaceutici, Calcilytix, Echolight, Kyowa Kirin, Personal Genomics, and Smoke-Free World Foundation; has received honoraria from Amgen, Bruno Farmaceutici, Calcilytix, Kyowa Kirin, and UCB; and received grants from Abiogen, Alexion, Amgen, Amorphical, Bruno Farmaceutici, CGeDi, Echolight, Eli Lilly, Enterabio, Gedeon Richter, Italfarmaco, Kyowa Kirin, Menarini, Monter Rosa Therapeutics, SPA, Takeda, Thermax, and UCB outside the submitted work.

TC has no conflict of interest to disclose.

GPL has no conflict of interest to disclose.

PΜ reports fees for lectures/advisory boards and research grants from Amgen and Galenica and fees for lectures/advisory boards and conference travel from UCB, Elpen, Bianex, and Eli-Lilly outside the submitted work.

JP has no conflict of interest to disclose.

PC has no conflict of interest to disclose.

DP has no conflict of interest to disclose.

MS has no conflict of interest to disclose.

TT has received consultancy/speaker’s fees from AMGEN, Arrow, Biogen, Chugai, Expanscience, Grunenthal, Jansen, LCA, Lilly, MSD, Nordic, Novartis, Pfizer, Sanofi, Thuasne, Theramex, TEVA, and UCB and financial support or fees for research activities from Bone Therapeutics, Chugai, and UCB outside the submitted work.

SS reports consultancy fees from Radius, Amgen, Lilly, and Pfizer and grants from Amgen outside the submitted work.

Figures

**Fig. 1**
Indirect fracture healing. (1) Reaction phase: (a) Hematoma attracts inflammatory cells. (b) Neutrophils, platelets, erythrocytes, and lymphocytes form fibrin clot. (2) Repair phase: (a) Neutrophils are replaced by monocytes that transform to macrophages. Macrophages secrete tumor necrosis factor α (TNF-α), interleukin-1 (IL-1), interleukin-6 (IL-6), transforming growth factor β (TGF-β), and angiogenic factors. These recruit mesenchymal stem cells (MSC). (b) MSC differentiate to osteoblasts, prehypertrophic chondrocytes, and endothelial cells. (c) Prehypertrophic chondrocytes form collagen rich matrix. (d) Prehypertrophic chondrocytes enlarge to hypertrophic chondrocytes which release microvesicles coated with alkaline phosphatase and which has vascular endothelial growth factor (VEGF), bone morphogenic protein 2 (BMP2), and nanohydroxyapatite. (e) VEGF draws endothelial cells derived from MSC. Osteoblasts also accumulate. Osteoblasts promote deposition of microhydroxyapatite on cartilaginous matrix to form soft callus. (3) Remodelling phase: (a) Osteoclasts resorb soft callus. Osteoblasts deposit new bone and mineralization occurs to from Hard Woven Callus. (b) Further osteoclastic remodelling occurs to form lamellar bone

**Fig. 2**
Direct fracture healing occurs when the fracture fragments are in proximity to each other. Bone fragments are directly bridged by new bone formed by intramembranous ossification for which initially, osteoclasts are harnessed to form cutting cones. These cutting cones cross the fracture line, bringing in their wake, vascular endothelial cells that differentiate into blood vessels and perivascular mesenchymal cells that differentiate into osteoblasts which then fill the canals with bone

See this image and copyright information in PMC

References

1. Johansson H, Siggeirsdóttir K, Harvey NC, Odén A, Gudnason V, McCloskey E et al (2017) Imminent risk of fracture after fracture. Osteoporos Int 28(3):775–780 - PMC - PubMed
1. Mills LA, Aitken SA, Simpson AHRW (2017) The risk of non-union per fracture: current myths and revised figures from a population of over 4 million adults. Acta Orthop 88(4):434–439 - PMC - PubMed
1. Kanakaris NK, Giannoudis PV (2007) The health economics of the treatment of long-bone non-unions. Injury 38(Suppl 2):S77-84 - PubMed
1. Antonova E, Le TK, Burge R, Mershon J (2013) Tibia shaft fractures: costly burden of nonunions. BMC Musculoskelet Disord 14:42 - PMC - PubMed
1. Yeo JH, Kim JY (2018) Surgical strategy for scaphoid nonunion treatment. J Hand Surg Asian-Pac Vol 23(4):450–462 - PubMed

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Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review

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Impact of osteoporosis and osteoporosis medications on fracture healing: a narrative review

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