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Abstract
ABSTRACTAge is a well‐known influential factor in bone healing, with younger patients generally healing bone fractures more rapidly and suffering fewer complications compared with older patients. Yet the impact age has on the response to current bone healing treatments, such as delivery of bone morphogenetic protein 2 (BMP‐2), remains poorly characterized. It remains unclear how or if therapeutic dosing of BMP‐2 should be modified to account for age‐related differences in order to minimize potential adverse effects and consequently improve patient bone‐healing outcomes. For this study, we sought to address this issue by using a preclinical critically sized segmental bone defect model in rats to investigate age‐related differences in bone repair after delivery of BMP‐2 in a collagen sponge, the current clinical standard. Femoral defects were created in young (7‐week‐old) and adult (8‐month‐old) rats, and healing was assessed using gene expression analyses, longitudinal radiography, ex vivo micro‐computed tomography (µCT), as well as torsional testing. We found that young rats demonstrated elevated expression of genes related to osteogenesis, chondrogenesis, and matrix remodeling at the early 1‐week time point compared with adult rats. These early gene expression differences may have impacted long‐term healing as the regenerated bones of young rats exhibited higher bone mineral densities compared with those of adult rats after 12 weeks. Furthermore, the young rats demonstrated significantly more bone formation and increased mechanical strength when BMP‐2 dose was increased from 1 µg to 10 µg, a finding not observed in adult rats. Overall, these results indicate there are age‐related differences in BMP‐2‐mediated bone regeneration, including relative dose sensitivity, suggesting that age is an important consideration when implementing a BMP‐2 treatment strategy. © 2018 The Authors JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
Highlights
The repair of large bone defects represents one of the most challenging problems faced by orthopedic and craniofacial surgeons today
It has been demonstrated in vitro that age influences the responsiveness of bone marrow stromal cells to bone morphogenetic protein 2 (BMP-2).(14) clinical studies have shown similar trends, as use of bone morphogenetic protein (BMP)-2 and allograft in spine fusion in elderly patients (>65 years) demonstrated lower fusion rate and longer fusion time compared with younger patients (
These observations were verified by hierarchical clustering analysis (Supplemental Fig. S2), which showed overall clustering of treated samples based on age rather than BMP-2 dose
Summary
The repair of large bone defects represents one of the most challenging problems faced by orthopedic and craniofacial surgeons today. Whereas the elderly animals showed an increase in thickness of new bone over a large range of increasing BMP-2 doses (0 to 16 mg), the younger animals exhibited a much smaller benefit window (0 to 4 mg), beyond which a significant reduction in new bone thickness was observed. Taken together, these results indicate that BMP-2 dose sensitivity is influenced by age, and the optimal dose requirement for young animals/patients is likely to be lower than that for older animals/patients. This is problematic because it has been well documented that delivery of supraphysiological doses of BMP-2 is fraught with risks, including heterotopic mineralization, osteolysis, infection, and potentially life-threatening inflammation/swelling.[17,18,19] use of higher BMP-2 doses has been shown to result in heterotopic ossification and formation of abnormal spongy bone with thin trabecular networks.[20,21] These complications could potentially be most devastating in the pediatric population, with reports of massive inflammatory reactions and acute pain in some pediatric patients.[22,23,24] As a result, the use of any BMPs in skeletally immature patients is currently not approved by the U.S Food and Drug Administration (FDA).(25) Despite these known risks, off-label use of BMP-2 still occurs due to a lack of better alternatives in many scenarios, as well as documented successful cases without any noticeable complications.[24,26,27] In the absence of controlled trials to optimize therapeutic dosing (which remain unfeasible because of ethical considerations and costs), the use of relevant preclinical animal models represent the best approach to gain insight into this important question of how age influences the response to BMP-2 treatment during bone healing
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