Skeletal effects of withdrawal of estrogen and diphosphonate treatment in ovariectomized rats

The study was designed to determine the skeletal effects of withdrawal of estrogen and diphosphonate treatment in the estrogen-deplete state. Groups of ovariectomized (OVX) rats were treated with vehicle alone, estrogen, or the diphosphonates etidronate or risedronate for a 180-day period. A group of sham-operated control rats was treated for 180 days with vehicle alone. All treatments were then terminated, followed by sequential sacrifice of rats at 0, 35, 90, 180, and 360 days after withdrawal of treatment. The proximal tibia from each animal was processed undecalcified for quantitative bone histomorphometry. At the end of the treatment period, vehicle-treated OVX rats were characterized by cancellous osteopenia and increased bone turnover relative to vehicle-treated control rats. Treatment of OVX rats with estrogen or diphosphonates depressed bone turnover and protected against cancellous osteopenia. During the withdrawal period, OVX rats previously treated with estrogen exhibited rapid bone loss associated with increased bone turnover. The bone protective effect of the hormone in OVX rats was nearly completely lost by 90 days of withdrawal. In contrast, OVX rats maintained low levels of bone turnover and normal cancellous bone mass at 180 days of withdrawal from diphosphonate treatment. The results suggest that estrogen-deplete women who are withdrawn from estrogen replacement are at high risk for subsequent bone loss. They further suggest that widely spaced periods of intermittent diphosphonate treatment may be sufficient to prevent the development of osteopenia in postmenopausal and oophorectomized women.