Musculoskeletal Therapies, Wyeth Discovery Research, Cambridge, MA 02140, USA.
J Bone Joint Surg Am. 2010 Feb;92(2):411-26. doi: 10.2106/JBJS.H.01732.
Bone resorption preceding bone formation has been reported following the administration of recombinant human bone morphogenetic protein-2 (rhBMP-2) delivered in an absorbable collagen sponge (ACS) in metaphyseal bone. This study characterizes treatment with rhBMP-2/ACS in metaphyseal bone with use of a nonhuman primate core-defect model.
Unilateral proximal femoral core defects were treated with 360 microg of rhBMP-2/ACS or ACS alone or were left untreated in seven, five, and five adult male cynomolgus monkeys, respectively. Distal femoral core defects in seven of the above animals were treated with 360 microg of rhBMP-2/ACS in one limb and ACS alone in the contralateral limb. Retention of rhBMP-2 in the proximal part of the femora was determined with use of tracer amounts of (125)I-rhBMP-2 imaged with a gamma camera. The distal part of the femora was evaluated with in vivo computed tomography. Computed tomography and histological evaluation were performed on harvested segments in all animals at twenty-four weeks. The histological response in the proximal and distal parts of the femora containing core defects treated with 360 microg of rhBMP-2/ACS in one limb and ACS alone in the contralateral limb was evaluated at one, two, and four weeks in three animals per time point.
Approximately 39.9%, 24.2%, 3.4%, and 0.5% of the rhBMP-2 was retained in the proximal part of the femora at one, seven, fourteen, and twenty-one days, respectively. The mineral density and trabecular volume fraction of the core defects treated with rhBMP-2/ACS, those treated with ACS alone, and untreated core defects in the proximal part of the femora were 81%, 54%, and 20%, respectively, and 94%, 36%, and 31%, respectively, of the corresponding region in the contralateral limbs at twenty-four weeks. The mineral density and trabecular volume fraction of the region surrounding the core defects treated with rhBMP-2/ACS, those treated with ACS alone, and untreated core defects were 112%, 105%, and 104%, respectively, and 117%, 108%, and 107%, respectively, of the corresponding region in the contralateral limbs. Treatment with rhBMP-2/ACS increased the size of the proximal and distal core defects compared with treatment with ACS alone. Histological evaluation of the rhBMP-2/ACS-treated limbs demonstrated that bone resorption was initiated at one week in association with osteoclasts and receptor activator of nuclear factor-kappaB ligand-positive stained spindle-shaped cells and peaked at two weeks. Bone formation was observed at two weeks and was ongoing at twenty-four weeks.
Treatment of metaphyseal core defects with rhBMP-2/ACS resulted in bone resorption followed by bone formation in nonhuman primates.
在吸收性胶原海绵（ACS）中给予重组人骨形态发生蛋白-2（rhBMP-2）后，在干骺端骨中已经报道了骨吸收先于骨形成。本研究采用非人类灵长类动物核心缺损模型对 rhBMP-2/ACS 在干骺端骨中的治疗作用进行了描述。
分别在 7 只、5 只和 5 只成年雄性食蟹猴的单侧股骨近端核心缺损处用 360μg rhBMP-2/ACS 或 ACS 单独治疗，或不治疗。在上述动物中的 7 只动物的远端股骨核心缺损处，用 360μg rhBMP-2/ACS 在一侧肢体治疗，而在对侧肢体用 ACS 单独治疗。用放射性示踪剂（125）I-rhBMP-2 用伽马相机成像来确定 rhBMP-2 在股骨近端的保留情况。用体内计算机断层扫描评估股骨远端。所有动物在 24 周时均对采集的标本进行计算机断层扫描和组织学评估。在三个时间点的每只动物中，评估了单侧肢体用 360μg rhBMP-2/ACS 治疗和对侧肢体用 ACS 单独治疗的股骨近端和远端核心缺损部位的组织学反应。
在第 1、7、14 和 21 天，rhBMP-2 在股骨近端的保留率分别约为 39.9%、24.2%、3.4%和 0.5%。rhBMP-2/ACS 治疗的核心缺损部位、单独用 ACS 治疗的核心缺损部位以及股骨近端未治疗的核心缺损部位的骨密度和骨小梁体积分数分别为 81%、54%和 20%，相应的对侧肢体的骨密度和骨小梁体积分数分别为 94%、36%和 31%，在 24 周时。rhBMP-2/ACS 治疗的核心缺损部位、单独用 ACS 治疗的核心缺损部位以及未治疗的核心缺损部位周围区域的骨密度和骨小梁体积分数分别为 112%、105%和 104%，相应的对侧肢体的骨密度和骨小梁体积分数分别为 117%、108%和 107%。rhBMP-2/ACS 治疗与 ACS 单独治疗相比，增加了股骨近端和远端核心缺损的大小。rhBMP-2/ACS 治疗肢体的组织学评估表明，破骨细胞和核因子κB 受体激活剂配体阳性的梭形细胞在第 1 周开始引起骨吸收，在第 2 周达到高峰。第 2 周观察到骨形成，并持续到第 24 周。
rhBMP-2/ACS 治疗干骺端核心缺损可导致非人类灵长类动物骨吸收后骨形成。
