Samadfam Rana, Xia Qingwen, Goltzman David
Department of Medicine, McGill University Health Centre, Montreal, Quebec, Canada.
J Bone Miner Res. 2007 Jan;22(1):55-63. doi: 10.1359/jbmr.060915.
We examined the effects of 60 days of co-treatment of PTH with either OPG or alendronate in oophorectomized mice. Compared with PTH alone, co-treatment of PTH with either of these two mechanistically distinct anti-catabolics improved bone volume, mechanical strength, and appendicular and axial mineralization and prolonged the beneficial effect of PTH on BMD.
Conflicting evidence exists as to whether the anabolic effect of PTH is inhibited by the action of anti-catabolics. To examine this issue, we assessed the effects of alendronate and osteoprotegerin (OPG), two anti-catabolics with different modes of action, on the anabolic activity of PTH(1-34) in the skeleton of 4-month-old oophorectomized mice.
Mice treated with vehicle alone (PBS), alendronate alone (100 microg/kg/week), OPG alone (10 mg/kg twice a week), or PTH alone (80 microg/kg/day) were compared with each other and with animals administered PTH plus alendronate or PTH plus OPG. We assessed lumbar spine and femoral BMD at 0, 30, and 60 days. Contact radiography, histology, and histomorphometry, three-point bending assay of the femur, and serum osteocalcin and TRACP5b assays were performed at 2 months.
Although alendronate and OPG each suppressed bone turnover, at the doses used, this was more profound with OPG. Increases in lumbar spine and femoral BMD and in trabecular bone volume were at least as great with OPG as with alendronate, and mechanical indices of femoral bone strength improved only with OPG. Both produced a plateau in spine and femoral BMD increases by 30 days. Co-treatment of PTH with each anti-catabolic produced additive increases in BMD in the femur and supra-additive increases in the lumbar spine with no plateau effects. Neither anti-catabolic impeded the PTH-induced increase in bone volume or the increase in mechanical strength of the femur.
These studies show that the highly potent anti-catabolic OPG can produce dramatic increases in BMD and bone strength; that the temporal pattern of activity of bone formation and resorption modulators may have major influence on net skeletal accrual; and that, depending on timing, inhibition of osteoclastic activity may markedly augment the anabolic action of PTH.
我们研究了甲状旁腺激素（PTH）与骨保护素（OPG）或阿仑膦酸钠联合治疗60天对去卵巢小鼠的影响。与单独使用PTH相比，PTH与这两种作用机制不同的抗分解代谢药物联合治疗可改善骨体积、机械强度、四肢和轴向矿化，并延长PTH对骨密度（BMD）的有益作用。
关于抗分解代谢药物的作用是否会抑制PTH的合成代谢作用，存在相互矛盾的证据。为研究此问题，我们评估了阿仑膦酸钠和骨保护素（OPG）这两种作用方式不同的抗分解代谢药物对4月龄去卵巢小鼠骨骼中PTH（1-34）合成代谢活性的影响。
将单独用赋形剂（PBS）、单独用阿仑膦酸钠（100μg/kg/周）、单独用OPG（10mg/kg，每周两次）或单独用PTH（80μg/kg/天）处理的小鼠相互比较，并与给予PTH加阿仑膦酸钠或PTH加OPG的动物进行比较。我们在第0、30和60天评估腰椎和股骨的骨密度。在2个月时进行接触放射照相、组织学和组织形态计量学分析、股骨三点弯曲试验以及血清骨钙素和TRACP5b检测。
尽管阿仑膦酸钠和OPG均抑制骨转换，但在所使用的剂量下，OPG的抑制作用更强。腰椎和股骨骨密度以及小梁骨体积的增加，OPG至少与阿仑膦酸钠一样显著，并且仅OPG能改善股骨的机械指数。两者在30天时均使脊柱和股骨骨密度增加达到平台期。PTH与每种抗分解代谢药物联合治疗均使股骨骨密度呈累加性增加，腰椎骨密度呈超累加性增加，且无平台效应。两种抗分解代谢药物均未阻碍PTH诱导的骨体积增加或股骨机械强度增加。
这些研究表明，高效的抗分解代谢药物OPG可使骨密度和骨强度显著增加；骨形成和骨吸收调节剂的活性时间模式可能对骨骼净积累有重大影响；并且，根据时间不同，抑制破骨细胞活性可能会显著增强PTH的合成代谢作用。
