Temporal relationship between bone loss and increased bone turnover in ovariectomized rats

Abstract

To characterize osteopenic changes in ovariectomized (OVX) rats as a function of time, female Sprague Dawley rats (240 g body weight, 90 days old) were subjected to bilateral ovariectomy or sham surgery and killed at various times from 14-180 days postovariectomy. The proximal tibial metaphysis was processed undecalcified for quantitative bone histomorphometry. Osteopenia and increased indices of bone resorption and formation were detected in OVX rats as early as 14 days. Longitudinal bone growth was also significantly increased by ovariectomy at 14 days, but returned to control levels at all later times. In OVX rats, osteopenia became progressively more pronounced with time up to 100 days postovariectomy, after which trabecular bone volume appeared to stabilize at the markedly reduced level of 5%. Changes in osteoclast surface, osteoblast surface, and fluoro-chrome-based indices of bone formation in OVX rats followed a similar time course. The maximal increase in these parameters occurred during the first several months postovariectomy followed by a gradual decline toward control levels. Our results indicate that the initial rapid phase of bone loss in OVX rats is coincident with the maximal increase in bone turnover. At later times postovariectomy, bone loss and bone turnover both subside. These findings emphasize the close temporal association between the development of osteopenia and increased bone turnover in OVX rats.

The degree of bone mineralization is maintained with single intravenous bisphosphonates in aged estrogen-deficient rats and is a strong predictor of bone strength

“…In accordance with previous findings [25], substantial trabecular bone loss occurred predominantly by a reduction of the number of trabeculae, and loss of trabecular connectivity density. Estrogen-deficient animals treated for 180 days with either an intravenous dose of risedronate or zoledronic acid had significantly higher trabecular bone volumes as compared with age-matched controls.…”

The rational use of animal models in the evaluation of novel bone regenerative therapies

“…The first determinant depends on the availability of an animal model that mimics a human disease involving bone repair so that the data generated can be used to predict the drug efficacy and safety in patients. Examples of animal models with good predictability of clinical outcomes include models of postmenopausal osteoporosis [87][88][89][90][91][92], models of glucocorticoid induced bone loss [93][94][95][96], models of cancer metastasis to bone [97], disuse models [98,99], fracture healing models [100][101][102][103] and several others. The second determinant of successful experimentation relates to translational biomarkers of novel therapy efficacy and safety that can be accurately predicted and monitored in patients.…”

Changes in bone Pb accumulation: Cause and effect of altered bone turnover

“…Later, the same group has reported that, at different times from 14 to 180 days post-OVX performed on 90-day old rats, some, but not all, indices of bone formation rate already considered in the previous work differed between OVX and normal rats [39]. However, these conclusions are clouded with issues of correctness affecting the analysis of the data.…”

“…The current view for the response of rats to OVXinduced osteopenia relies largely on a few studies using histomorphometry analysis of static and dynamic parameters of bone turnover [37]. Since static parameters are not indicative of cellular activity and corresponding bone formation and resorption rates, the contrast with the accepted view will focus on the dynamic parameters which are more meaningful as indices of bone formation rate [39].…”

“…First, the high standard deviations in the dynamic parameters of bone formation, as noted by the authors themselves [40], jeopardize the conclusion of post-OVX increases in bone formation rates. Second, it is not immediately clear how a truly two-factorial design and a clear interaction between time and animal status, which is obvious from the depicted data, was tackled by using a two-tailed Student´s t-test for group comparisons at different time points [39]. Actually, recent research using more appropriate statistical analysis of the data has concluded that none of the histomorphometric indices of bone formation rate was different between OVX and normal rats, at any time point from 6 weeks to 9 months post-OVX performed at 10 months of age [41].…”