Do osteoporotic fractures constitute a greater recalcitrant challenge for skeletal regeneration? Investigating the efficacy of BMP-7 and zoledronate treatment of diaphyseal fractures in an open fracture osteoporotic rat model.
Osteoporotic fractures may pose a challenge for skeletal regeneration. This study investigates if pharmaceutical interventions such as bone morphogenetic protein 7 (BMP-7) alone or in combination with Zoledronate have equivalent efficacy in osteoporotic bone? Our findings suggest they do and that an osteoporotic bone environment may increase sensitivity to BMP-7.



Osteoporosis is thought to contribute to delayed or impaired bone healing. Bone morphogenetic protein 7 (BMP-7) alone or synergistically combined with zoledronate (ZA) has proven effective in augmenting the regenerative response in healthy young male rats. Yet their comparative efficacy in an osteoporotic bone environment is unknown. Our study aimed to answer the following questions using the ovariectomized (OVX) rat model of osteoporosis: Do osteoporotic fractures pose a greater challenge for skeletal regeneration? Are interventions with BMP-7-alone or combined with ZA of equivalent efficacy in osteoporotic bone?



Sham operations (n = 33) or ovariectomies (n = 34) were performed in 12-week-old female Sprague-Dawley rats. Mid-diaphyseal open femoral osteotomies were created at 24 weeks of age and the rats allocated to either (i) untreated, (ii) BMP-7-only or (iii) BMP-7 + ZA treatment groups. At 6 weeks post-osteotomy, fracture healing was evaluated by radiography, μCT and 3-point bending mechanical tests.



Cumulatively, radiological, micro-structural and mechanical measures were equivalent in both healthy and osteoporotic environments. A reduced response to BMP-7-alone was observed in healthy rats that may be age/gender- or protocol/fracture-model dependent. Conversely, the BMP-7-only treated OVX group attained 100 % union in addition to significantly increased measures of mineralized bone volume, total callus volume, peak force and absorbed energy relative to untreated OVX fractures.



Our findings refute the hypothesis that osteoporotic fractures constitute a greater recalcitrant challenge for skeletal regeneration. Furthermore, our results suggest that an oestrogen-deficient environment may in fact cause an increased sensitivity to BMP-7.
Department of Biomedical Engineering, Lund University, PO Box 118, 221 00, Lund, Sweden. neashan.mathavan@bme.lth.se.
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http://orcid.org/0000-0002-5900-1396
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Mathavan
Department of Orthopaedics, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.
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M
Tägil
Department of Biomedical Engineering, Lund University, PO Box 118, 221 00, Lund, Sweden.|Department of Orthopaedics, Clinical Sciences, Lund University and Skåne University Hospital, Lund, Sweden.|Department of Applied Physics, University of Eastern Finland, Kuopio, Finland.
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H
Isaksson
D000818:Animals; D050071:Bone Density Conservation Agents / Q000627:therapeutic use*; D055419:Bone Morphogenetic Protein 7 / Q000627:therapeutic use*; D018483:Diaphyses / Q000293:injuries; D004164:Diphosphonates / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004341:Drug Evaluation; D004359:Drug Therapy, Combination; D005260:Female; D005264:Femoral Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy; D017102:Fracture Healing / Q000187:drug effects; D005597:Fractures, Open / Q000000981:diagnostic imaging / Q000188:drug therapy; D007093:Imidazoles / Q000627:therapeutic use*; D058866:Osteoporotic Fractures / Q000000981:diagnostic imaging / Q000188:drug therapy*; D010052:Ovariectomy; D011859:Radiography; D017207:Rats, Sprague-Dawley; D013314:Stress, Mechanical; D055114:X-Ray Microtomography; D000077211:Zoledronic Acid
D050071:Bone Density Conservation Agents; D055419:Bone Morphogenetic Protein 7; D004164:Diphosphonates; D007093:Imidazoles; D000077211:Zoledronic Acid
Bmp-7; Fracture healing; Osteoporosis; Ovariectomy; Zoledronate