Manipulation of the anabolic and catabolic responses with OP-1 and zoledronic acid in a rat critical defect model.
Bone repair involves both anabolic and catabolic responses. We hypothesized that anabolic treatment with OP-1 (BMP-7) and anti-catabolic treatment with zoledronic acid could be synergistic. In a rat critical defect, this combination therapy produced significant increases in new bone volume and strength.


BACKGROUND
When used to augment bone healing, osteogenic protein 1 (OP-1/BMP-7) and other BMPs stimulate the anabolic response, inducing osteoblast recruitment, differentiation, and bone production. However, BMPs can also upregulate catabolism by direct stimulation of osteoclasts and indirectly by osteoblasts through RANKL/RANK. We hypothesized that if such osteoclastic upregulation were modulated by zoledronic acid (ZA), the combination of OP-1 and ZA should produce increased new bone over OP-1 alone.


METHODS
Rats with a surgically induced 6-mm femoral critical size defect were separated into five dosing groups: Carrier, Carrier + ZA, OP-1, OP-1 + ZA, and OP-1 + ZA administered 2 weeks after surgery (2W). Carrier +/- 50 microg OP-1 was placed in the defect, and 0.1 mg/kg ZA or saline was administered subcutaneously. Bone repair was analyzed by radiographs, QCT, mechanical testing, histology, and histomorphometry.


RESULTS
Carrier alone and Carrier ZA groups did not unite by 8 weeks. Radiological union occurred in all OP-1 groups but was tenuous in some animals treated with OP-1 alone. BMC was increased by 45% in the OP-1 ZA group and 96% in the OP-1 ZA 2W group over OP-1 alone (p < 0.01). Callus volume increased over OP-1 alone by 45% and 86% in the OP-1 ZA and OP-1 ZA 2W groups, respectively (p < 0.01). The increased callus volume in the OP-1 ZA 2W group translated to increases in strength of 107% and stiffness of 148% (p < 0.05). BFR was not significantly different between OP-1 groups regardless of ZA treatment.


CONCLUSIONS
ZA treatment significantly increased the BMC, volume, and strength of OP-1-mediated callus in a critical size defect in rats at 8 weeks. Thus, modulation of both anabolic and catabolic responses may optimize the amount and mineral content of callus produced, which could be of clinical benefit in obtaining bone union.
Little
David G
DG
Orthopaedic Research and Biotechnology, University of Sydney, Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Westmead, Australia. DavidL3@chw.edu.au
McDonald
Michelle
M
Bransford
Rick
R
Godfrey
Craig B
CB
Amanat
Negin
N
D000818:Animals; D001696:Biomechanical Phenomena; D015519:Bone Density; D050071:Bone Density Conservation Agents / Q000494:pharmacology; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000494:pharmacology* / Q000627:therapeutic use; D001861:Bone Regeneration / Q000187:drug effects*; D002146:Bony Callus / Q000378:metabolism; D002452:Cell Count; D004164:Diphosphonates / Q000494:pharmacology*; D004548:Elasticity; D005264:Femoral Fractures / Q000188:drug therapy / Q000473:pathology / Q000503:physiopathology; D005269:Femur / Q000187:drug effects / Q000293:injuries / Q000378:metabolism; D017102:Fracture Healing / Q000187:drug effects*; D006651:Histocytochemistry; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D010010:Osteoclasts / Q000166:cytology; D051381:Rats; D017208:Rats, Wistar; D013314:Stress, Mechanical; D016212:Transforming Growth Factor beta / Q000494:pharmacology* / Q000627:therapeutic use; D000077211:Zoledronic Acid
C525821:Bmp7 protein, rat; D050071:Bone Density Conservation Agents; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D004164:Diphosphonates; D007093:Imidazoles; D016212:Transforming Growth Factor beta; D000077211:Zoledronic Acid