成骨不全症小鼠模型中生长激素与唑来膦酸联合治疗。
Combination treatment with growth hormone and zoledronic acid in a mouse model of Osteogenesis imperfecta.
机构信息
Bioengineering and Molecular Medicine Laboratory, The Children's Hospital at Westmead, Westmead, NSW, Australia; The University of Sydney, Faculty of Medicine and Health, The University of Sydney Children's Hospital Westmead Clinical School, Sydney, NSW, Australia.
Bioengineering and Molecular Medicine Laboratory, The Children's Hospital at Westmead, Westmead, NSW, Australia.
出版信息
Bone. 2022 Jun;159:116378. doi: 10.1016/j.bone.2022.116378. Epub 2022 Mar 5.
INTRODUCTION
Osteogenesis imperfecta (OI) or brittle bone disease is a genetic disorder that results in bone fragility. Bisphosphonates such as zoledronic acid (ZA) are used clinically to increase bone mass and reduce fracture risk. Human growth hormone (hGH) has been used to promote long bone growth and forestall short stature in children with OI. The potential for hGH to improve bone quality, particularly in combination with ZA has not been robustly studied.
METHODS
A preclinical study was performed using n = 80 mice split evenly by genotype (WT, Col1a2). Groups of n = 10 were treated with +/-ZA and +/-hGH in a factorial design for each genotype. Outcome measures included bone length, isolated muscle mass, bone parameters assessed by microCT analysis, dynamic histomorphometry, and biomechanical testing.
RESULTS
Treatment with hGH alone led to an increase in femur length in WT but not OI mice, however bone length was increased in both genotypes with the combination of hGH/ZA. MicroCT showed that hGH/ZA treatment increased cortical BV in both WT (+15%) and OI mice (+14.3%); hGH/ZA were also found to be synergistic in promoting cortical thickness in OI bone. ZA was found to have a considerably greater positive impact on trabecular bone than hGH. ZA was found to suppress bone turnover, and this was rescued by hGH treatment in terms of cortical periosteal perimeter, but not by dynamic bone remodeling. Statistically significant improvements in long bone by microCT did not translate into improvements in mechanical strength in a 4-point bending test, nor did vertebral strength improve in L4 compression testing in WT/OI bone.
DISCUSSION/CONCLUSION: These data support hGH/ZA combination as a treatment for short stature, however the improvements granted by hGH alone and in combination with ZA on bone quality are modest. Increased periosteal perimeter does show promise in improving bone strength in OI, however a longer treatment time may be required to see effects on bone strength through mechanical testing.
简介
成骨不全症（OI）或脆骨病是一种遗传性疾病，导致骨骼脆弱。唑来膦酸（ZA）等双膦酸盐类药物临床上被用于增加骨量和降低骨折风险。人生长激素（hGH）已被用于促进长骨生长并预防 OI 儿童的身材矮小。hGH 改善骨质量的潜力，特别是与 ZA 联合使用的潜力尚未得到充分研究。
方法
使用 n = 80 只小鼠进行了一项临床前研究，按基因型（WT、Col1a2）平均分配。每组 n = 10 只，以 WT 和 OI 两种基因型为对象，采用因子设计分别接受 +/-ZA 和 +/-hGH 治疗。观察指标包括骨长度、分离肌肉质量、微 CT 分析评估的骨参数、动态组织形态计量学和生物力学测试。
结果
hGH 单独治疗可使 WT 小鼠的股骨长度增加，但 OI 小鼠无此效果；然而，hGH/ZA 联合治疗可使两种基因型的骨长度均增加。微 CT 显示，hGH/ZA 治疗可使 WT（增加 15%）和 OI 小鼠（增加 14.3%）的皮质骨体积增加；hGH/ZA 还可协同促进 OI 骨的皮质厚度增加。ZA 对骨小梁的积极影响明显大于 hGH。ZA 被发现可抑制骨转换，而 hGH 治疗可在皮质骨周径方面挽救这一作用，但不能通过动态骨重塑来挽救。微 CT 检测到长骨的显著改善并未转化为四点弯曲测试中的机械强度改善，也未改善 WT/OI 骨的 L4 压缩测试中的椎体强度。
讨论/结论：这些数据支持 hGH/ZA 联合治疗身材矮小，但 hGH 单独和联合 ZA 治疗对骨质量的改善效果有限。增加骨周径确实有希望改善 OI 骨的强度，但可能需要更长的治疗时间才能通过机械测试观察到对骨强度的影响。
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