Fracture healing: a consensus report from the International Osteoporosis Foundation Fracture Working Group

Abstract

Summary

We used the RAND UCLA appropriateness method to decide appropriateness of use of osteoporosis medication after incident fracture and potential for fracture healing and make suggestions for trial design for clinical and preclinical research.

Purpose

To develop appropriateness criteria to assist in the use and study of osteoporosis medications in patients with recent fracture and in the potential use of osteoporosis medications to enhance delayed fracture healing. To promote further research by suggesting preclinical and clinical trial design for studies where fracture healing is the endpoint.

Methods

Design: RAND/UCLA appropriateness method (RUAM). Participants: A panel of experts, both members and non-members of the International Osteoporosis Foundation Fracture Working Group, were identified consisting of geriatricians, rheumatologists, orthopedists, endocrinologists, and internists. This resulted in a round 1 panel of 15 panelists, round 2 panel of 15 members, and a round 3 panel of 14 members. Main outcome measure: Agreement on statements and scenarios using RUAM. Three rounds of voting by panelists took place. Agreement in a third round was reached for 111 statements and scenarios, measured by median panel ratings and the amount of dispersion of panel ratings, based on the interpercentile range.

Results

An expert panel validated a set of statements and scenarios about the use of osteoporosis medications after incident fracture and use of these medications to enhance delayed fracture healing and made recommendations for study designs to investigate the effect of osteoporosis medications on fracture healing.

Conclusions

The result of this exercise is intended to assist in improving patient care by identifying the appropriateness of use of osteoporosis medications after fracture and in fracture healing and to make suggestions for further preclinical and clinical research.

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Conflicts of interest

Stuart Silverman is a consultant for Amgen, Alexion, Eli Lilly, and Pfizer. He is a member of the Speakers Bureau for Lilly and Pfizer. He has received research grants from Pfizer, Lilly, and Amgen. Susan V. Bukata is a consultant for Amgen and Eli Lilly and a member of the Speakers Bureau for Eli Lilly, Amgen, and Novartis. Eli Kupperman has no disclosures.

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Corresponding author

Correspondence to S. L. Silverman.

Additional information

IOF Fracture Working Group Members include K Akesson, S Boonen, ML Brandi, M Chandran, T Chevalley, C Cooper, S Goemaere, J Goldhahn, N Harvey, S Hough, MK Javaid, EM Lewiecki, GP Lyritis, N Napoli, DD Pierroz, S Silverman, and M Sosa.

Appendices

Appendix 1

Statements voted as appropriate

In the Results section, we only show statements and scenarios that were voted by our panels as “appropriate” (median categories 7–9).

Introduction

  1. 1.

    An important goal in fracture healing is to reduce the number of individuals with delayed fracture healing (median rating of 9).

  2. 2.

    It is valuable to identify patients at high risk of delayed fracture healing after a fracture so that intervention can be considered (median rating of 7).

Risk factors

  1. 1.

    Smoking is a marker for increased risk of delayed fracture healing (median rating of 7).

  2. 2.

    Diabetes is a marker for increased risk of delayed fracture healing (median rating of 8).

Clinical judgment

  1. 1.

    The occurrence of fragility fracture while on osteoporosis treatment does not mean that the treatment was ineffective. Our current medications for osteoporosis reduce but do not eliminate fracture (median rating of 9).

  2. 2.

    In a patient on an osteoporosis medication who fractures, one should not stop therapy but rather reassess and look for causes of secondary osteoporosis (median rating of 9).

  3. 3.

    Patients who fracture on therapy may have had more fractures if they had not taken the medication (median rating of 9).

  4. 4.

    Patients who fracture on therapy may be poorly adherent, and poor adherence should be considered (median rating of 9).

Impact

  1. 1.

    In the absence of a systematic approach to delivery of secondary fracture prevention, the majority of patients will fail to receive treatment designed to reduce future fracture risk (median rating of 9).

  2. 2.

    Pharmacologic intervention following fragility fracture has the potential to halve fracture incidence within 3 years, assuming good persistence and compliance (median rating of 9).

Medications

Bisphosphonates

  1. 1.

    There is no evidence in preclinical studies that antiresorptive drugs impair the restoration of mechanical integrity following fracture, despite the fact that they may delay remodeling of the callus (median rating of 8).

  2. 2.

    Antiresorptive therapy may delay fracture healing in claims data and marketing surveillance data (although the risk is low) (median rating of 8).

  3. 3.

    There is no evidence for harm (median rating of 7) or delay in fracture healing (median rating of 8) when injectable bisphosphonates are given in the first 2 weeks after fracture4. Randomized clinical trials have shown no effect of antiresorptive therapy (both bisphosphonates and denosumab) on fracture healing (median rating of 8).

  4. 5.

    During the time that a fracture callus is forming, there is increased sequestration of bisphosphonates at the fracture site (median rating of 7).

  5. 6.

    When using an IV bisphosphonate after an acute fracture, one should wait 2 weeks before starting medication (median rating of 7).

  6. 7.

    Bisphosphonate therapy is sequestered to callus when bone is forming (median rating of 7).

Denosumab

  1. 1.

    There is some data to suggest that denosumab does not delay (median rating of 7) or interfere with fracture healing (median rating of 8).

Teriparatide

  1. 1.

    Teriparatide may enhance healing of vertebral fractures (median rating of 8).

  2. 2.

    Teriparatide may help the fracture healing in a non-vertebral fracture (median rating of 7).

  3. 3.

    It is expected that anabolic agents used to treat osteoporosis would have a beneficial effect on fracture healing (median rating of 8).

  4. 4.

    Currently known anabolic agents have not been shown to accelerate fracture healing in patients with normal fracture healing but may improve fracture healing in individuals at high risk of delayed fracture healing (median rating of 7).

Bone physiology

  1. 1.

    The timing to assess delayed healing after fracture varies across skeletal sites (median rating of 8).

  2. 2.

    Fracture repair involves different stages of tissue differentiation that resemble embryological skeletal development (median rating of 9).

  3. 3.

    Clinical observations suggest that fragility fractures heal despite the abnormality of bone remodeling in osteoporosis (median rating of 8).

  4. 4.

    Implant anchorage is impaired in bone based on biomechanical testing and clinical experience (median rating of 7).

Trial design

Research goals

  1. 1.

    An important research goal is the identification of clinical markers of delayed fracture healing. These markers should be simple and reliable (median rating of 9).

  2. 2.

    An important research goal is to develop simple, reliable clinical measures related to fracture healing (median rating 9).

Study design recommendations

  1. 1.

    The duration of a fracture healing study should be 12 months (median rating of 7).

  2. 2.

    Fracture healing trials should have co-primary endpoints of imaging, pain, function, and clinical endpoints such as need for revision (median rating of 8).

  3. 3.

    It is recommended that adjudicated fracture healing should be considered as a secondary endpoint in all future clinical trials (median rating of 8).

Imaging endpoints

  1. 1.

    The primary imaging endpoint for fracture healing should be bridging and consolidation of three out of four cortices, and the preferred imaging to technique is sequential X-rays (median ratings of 8 and 7).

  2. 2.

    The primary endpoint for fracture healing should be reached within the first year after fracture. No additional endpoints are needed except a single follow-up X-ray at the end of the second year (median rating of 7.5).

  3. 3.

    The preferred imaging endpoint for fracture healing depends on the fracture site (e.g., CT for sacrum and pelvis and plain X-rays for tibia) (median rating of 8).

  4. 4.

    The preferred imaging endpoint for spinal fusions is CT scanning (median rating of 8).

  5. 5.

    CT scanning may be used as an endpoint for studies of fracture healing but is expensive, has high radiation burden, and is not accessible everywhere in the world (median rating of 8).

  6. 6.

    Intermediate endpoints (e.g., month 18) should be obtained in the second year after a fracture is considered healing in the setting of a known fracture site infection (median rating of 7).

  7. 7.

    Secondary imaging endpoints should be bridging and consolidation of two out of four oppositional cortices (median rating of 7).

Preclinical models

  1. 1.

    Animal models may be appropriate for exploring mechanisms of fracture healing pathophysiology (median rating of 7).

  2. 2.

    Whole animal models may not predict efficacy of fracture healing in humans (median rating of 8).

  3. 3.

    Results with different animal models of fracture healing may be conflicting (median rating of 8).

  4. 4.

    It is recommended for a new agent which may influence fracture healing that both a rodent and a non-rodent large animal model be done (median rating of 8).

  5. 5.

    In animal models, there is an effect of age on fracture healing. Fracture healing takes longer in older animals (median rating of 8).

Specialty statements

Atypical femur fractures

  1. 1.

    When a patient has an atypical femoral fracture, one should stop the bisphosphonate (median rating of 8).

  2. 2.

    When a patient has an atypical femoral fracture, after stopping the bisphosphonate, one should consider teriparatide (median rating of 8).

Osteogenesis imperfecta

  1. 1.

    In osteogenesis imperfecta, bisphosphonates may delay healing of osteotomies (median rating of 8).

  2. 2.

    In osteogenesis imperfecta, bisphosphonates do not delay healing of fractures (median rating of 8).

Scenarios

  1. 1.

    In scenarios of

    1. (a)

      Non-healing non-displaced metaphyseal non-vertebral fractures after 3 months.

    2. (b)

      First 2 weeks after a new non-vertebral fracture without significant displacement.

    3. (c)

      First 2 weeks after a new vertebral compression fracture.

      Our panel agreed that treatment with any of the antiosteoporosis medications (bisphosphonates, RANKL inhibitors, anabolic therapy or strontium) was safe to use (median ratings 7 to 8).

  2. 2.

    In the scenario of a non-healing non-displaced diaphyseal non-vertebral fracture after 3 months, the panel agreed that treatment with anabolic therapy or strontium were safe to use, but not bisphosphonates or RANKL inhibitors (median rating of 7).

  3. 3.

    In the scenario of a non-healing instrumented spinal fusion after 3 months, our panel agreed that treatment with anabolic therapy was safe to use but was unable to come to a consensus on the safety of treatment with other osteoporosis medications (median rating of 7).

  4. 4.

    Our panel was in agreement that treatment with an anabolic therapy such as teriparatide could return a patient with delayed healing of a non-displaced non-vertebral fracture or of an instrumented spinal fusion to a more normal rate of fracture healing (median rating of 7).

  5. 5.

    Our panel agreed that only treatment with an anabolic therapy such as teriparatide may enhance fracture healing in a patient with normal rate of fracture healing who is seen in the first 2–4 weeks after a new non-vertebral fracture or in the first 2 weeks after a compression fracture (median rating of 7).

  6. 6.

    Treatment with any of the listed osteoporosis medications (bisphosphonates, RANKL inhibitors, anabolics, or strontium) would not delay fracture healing in patients with non-healing non-vertebral fractures without significant displacement after 3 months (median ratings 7 to 8). An example would be a femur fracture that is healing but is not completely healed but is showing progression to healing radiographically at 3 months.

  7. 7.

    The panel agreed that teriparatide and strontium will not delay healing of an uninstrumented spinal fusion after 3 months (median rating of 8) but was unable to agree that the other medications would not cause a healing delay.

    Comment: These statements were approved by our panel prior to the recent actions of the European Medical Evaluation Agency (EMEA) with regards to strontium (3).

  8. 8.

    For patients with delayed healing of a non-displaced non-vertebral fracture after 3 months, only anabolic therapy will return them to a normal rate of healing (median rating of 8), a claim deemed untrue for bisphosphonate therapy and RANKL inhibitors (median rating of 3).

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Silverman, S.L., Kupperman, E.S., Bukata, S.V. et al. Fracture healing: a consensus report from the International Osteoporosis Foundation Fracture Working Group. Osteoporos Int 27, 2197–2206 (2016). https://doi.org/10.1007/s00198-016-3513-y

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Keywords

  • Fracture healing
  • Osteoporotic fracture
  • Trial design