title: Recombinant human bone morphogenetic protein-2 enhances osteotomy healing in glucocorticoid-treated rabbits.
abstract: The objectives of this study were to evaluate the effect of chronic prednisolone treatment on osteotomy healing in rabbits and to determine whether recombinant human bone morphogenetic protein-2 (rhBMP-2) would enhance healing in the presence of chronic glucocorticoid therapy. Forty-nine skeletally mature, male rabbits were injected with either prednisolone (n = 26; 0.35 mg/kg per day, three times a week) or saline (n = 23). After a 6-week pretreatment period, bilateral ulnar osteotomies were created surgically. One osteotomy was treated with rhBMP-2 (0.2 mg/ml of rhBMP-2, 40 microg of rhBMP-2 total) delivered on an absorbable collage sponge (ACS), whereas the contralateral osteotomy remained untreated. Prednisolone or saline treatment was continued until the rabbits were killed either 6 weeks or 8 weeks after creation of the osteotomy. Osteotomy healing was evaluated by radiography, peripheral quantitative computed tomography (pQCT), torsional biomechanics, and undecalcified histology. Because we observed similar responses to both prednisolone and rhBMP-2/ACS treatment in the 6-week and 8-week cohorts, the results from these time points were combined. Serum osteocalcin and vertebral trabecular bone density were lower in the prednisolone-treated rabbits. Prednisolone treatment dramatically inhibited osteotomy healing. In the untreated ulnas, callus area and torsional strength were 25% and 55% less, respectively, in the prednisolone-treated rabbits than in the saline group (p < 0.001 for both). rhBMP-2/ACS enhanced healing in both the prednisolone- and the saline-treated groups, although the effect was larger in the prednisolone-treated rabbits. In the prednisolone-treated rabbits, callus area and torsional strength were 40% and 165% greater (p < 0.001 for both), respectively, in osteotomies treated with rhBMP-2/ACS compared with the contralateral, untreated osteotomies. Histological evaluation confirmed that osteotomy healing was inhibited by prednisolone and accelerated by rhBMP-2/ACS. In summary, a single application of rhBMP-2/ACS counteracted the inhibition of osteotomy healing caused by prednisolone exposure. These results suggest that rhBMP-2/ACS may be a useful treatment for enhancing fracture healing in patients who are undergoing chronic glucocorticoid therapy.
authors.affiliation: Bone Biology and Applications, Genetics Institute-Wyeth Ayerst Research, Cambridge, Massachusetts, USA.
authors.forename: C A
authors.initials: CA
authors.lastname: Luppen
authors.forename: C A
authors.initials: CA
authors.lastname: Blake
authors.forename: K M
authors.initials: KM
authors.lastname: Ammirati
authors.forename: M L
authors.initials: ML
authors.lastname: Stevens
authors.forename: H J
authors.initials: HJ
authors.lastname: Seeherman
authors.forename: J M
authors.initials: JM
authors.lastname: Wozney
authors.forename: M L
authors.initials: ML
authors.lastname: Bouxsein
mesh_terms: D000818:Animals; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins / Q000235:genetics / Q000494:pharmacology*; D005938:Glucocorticoids / Q000494:pharmacology*; D008297:Male; D010027:Osteotomy; D011239:Prednisolone / Q000494:pharmacology; D011817:Rabbits; D011994:Recombinant Proteins / Q000235:genetics / Q000494:pharmacology; D016212:Transforming Growth Factor beta; D014458:Ulna Fractures / Q000601:surgery; D014945:Wound Healing / Q000187:drug effects*
chemical_list: C525718:BMP2 protein, human; D055396:Bone Morphogenetic Protein 2; D019485:Bone Morphogenetic Proteins; D005938:Glucocorticoids; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta; D011239:Prednisolone