| Background Post-menopause osteoporosis (PMO) is considered as a common disorder due to the morbidity and mortality assosiciated with fracture in elder women. All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. They are effective in enhance bone mineral density (BMD) but could not improve the quality of the bone. Recently, people found that low dose and intermittent parathyroid hormone (PTH) increased bone formation and bone architecture. It represents a new class for the treatment of primary osteoporosis. PTH is reported to increase the production of osteoprogenitors and the differentiation of osteoblasts, make lining cells become osteoblasts, and reduced apoptosis of preexisting osteoblasts. But the underlying mechanism is still controversial and unclear. Accumulated evidence has shown that insulin-like growth factor (IGF)-l is an attractive candidate as a mediator for some or all of the anabolic actions of PTH on bone in that PTH stimulates IGF-1 production by osteoblastic cells and IGF-1 blocking antibodies inhibited the expression of markers of bone formation induced by PTH stimulation on osteoblasts. But in vivo study, the evidence is absent. The mechanism of IGF-1 is complicated. IGF-1 system is composed of IGF-1, IGFBPs and receptors. IGF-1 bound to six specific high-affinity IGF-1 binding proteins to modulate IGF action in a positive or negative manner. The influence of PTH on IGFBP is very important to the study of mechanism of PTH action. In addition, PTH act anabolic effect on bone by increase bone turnover, the effect of PTH in combined with antiresorptive agents become a hot topic.Objective1. To investigate the effects of PTH and estrogen on bone histomorphometry and biomechanics in ovarictomized rats.2. To investigate the influence of PTH and estrogen on IGF-1 system in ovarictomized rats.Methods:1. Forty five female Sprague-Dawley rets, four months old, were devided randomly into 5 groups: sham-operated (sham, 8), ovariectomized group (OVX, 9), ovariectomized and received with estrogen (OVX+E, 10), ovariectomized and received with parathyroid hormone (OVX+PTH, 9), ovariectomized and received with estrogen and parathyroid hormone (OVX+E+PTH, 9). After three and half months, all animals were sacrified. Static and dynamic parameters of right tibias, biomechanics parameters and some related bone metabolic markers are evaluated.2. when the rats sacrificed, the lumbar vertebra were collected instantly. The expression of IGF-1, IGFBP-4, 5 were assessed by immunohistochemistry. The expression of IGF- 1mRNA was assessed by in situ hybridization.Results:1. OVX rats demonstrated significantly lower wet weight of uterus and serum estradiol level compared to sham group. In addition, serum ALP, osteocalcin, Ca and P levels were significantly higher in OVX rats. E2 treatment reversed changes in wet weight of uterus and serum estradiol, ALP, osteocalcin, Ca and P levels. Compared to OVX group, wet weight of uterus and serum estradiol in PTH treatment shown no difference. ALP, osteocalcin levels in PTH and combination treatment significant increase in comparison to sham and E group.2. Compared to Sham group, OVX were associated with significant decrease in trabecular thickness and number of proximal tibial metaphyses as well as increase in trabecular spacing, labeled perimeter, mineral apposition rate, bone formation rate and osteoclast number. Both E2 and PTH treatment increase bone mass. The parameters of formation and resorption decreased in E group while the bone formation rate increased in OVX+PTH group in comparison to OVX. The osteoclast nuber of OVX+PTH group was higher than that of sham group, but lower than OVX group. Parameters of bone mass and formation in rats treated with PTH+E2 revealed a significant increase not only compared to the OVX+Egroup, but also compared to OVX+PTH group. The parameters of bone turnover in OVX+PTH+E group between the PTH and E2 individual treatment.3. OVX rats demonstrated significantly lower break load, stiffness of compression test and indentation test compared to sham group. The break load, stiffness in E2, PTH and E+PTH treated rats were slightly elevated compared to OVX rats, especially the OVX+E+PTH group. The bio-mechanical property in OVX+E group were not significantly different than OVX+PTH group. Changes in break load and stiffness of tri-bending test among five groups were not significantly different.4. Sample from PTH, E2 and the combination treated rats showed elevated protein and mRNA levels of IGF-1 by immunohistochemistry. The expression of IGFBP-5 increased in OVX+PTH and OVX+PTH+E groups while IGFBP-4 showed no altered expression in five groups.Conclusion:1. Bone formation and resorption increased significantly in OVX group, which indicates bone loss rapidly.2. Estrogen prevents bone loss effectively by inhibiting bone resorption and bone formation, leading to decrease of bone turnover in ovariectomized rats.3. PTH increases bone mass effectively by improve bone resorption and bone formation, leading to increase of bone turnover in ovariectomized rats.4. The combination treatment of PTH and Estrogen resulted in a marked overall increase of cancellous bone and exhibited synergistic effects.5. Estrogen increased the expression of IGF-1 and IGF-1 mRNA in the cancellous bone of ovariectomized rats.6. PTH increased the IGF-1, IGF-1 mRNA and IGFBP-5 in the cancellous bone of ovariectomized rats. |
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