DUAL-ENERGY X-RAY ABSORPTIOMETRY OF RALOXIFENE EFFECTS ON THE LUMBAR VERTEBRAE AND FEMORA OF OVARIECTOMIZED RATS

A new potential therapeutic agent for postmenopausal osteoporosis, ral oxifene, previously known as keoxifene, was evaluated by x-ray densito metry and more traditional techniques in quantitating the short-term ( 4-5 weeks) effects of ovariectomy on bones from 6-month-old rats. A Ho logic QDR 1000/W and, to a limited extent, a Lunar DPXL, was used to q uantitate ovariectomy, estrogen replacement, and raloxifene effects on vertebrae, femora, and tibiae. Both instruments performed well with p recisions of 1.6% (Hologic) and 0.9% (Lunar) for anesthetized rats, wh ich improved to 0.4% (Hologic) and 0.5% (Lunar) when the same rats wer e frozen. The lumbar vertebrae L1-4 showed a 12% decrease in bone mine ral density 4 weeks after ovariectomy, compared with a 9% decrease for femora. Tibiae were also examined, but edge-detection problems preven ted reproducible analysis of this site in vivo. The decrease in bone m ineral density postovariectomy, especially for femora, was found to in clude both an increase in the projected area and a slight but not sign ificant decrease in the bone mineral content of L1-4 and femora. These changes in density parameters of femora were supported by a decrease in dry weight and volume and a marginal increase in the second moment of inertia I for the identical femora examined ex vivo. Examination of individual lumbar vertbrae L1-5 suggested that the bone mineral densi ty of L3 changes most dramatically in response to ovariectomy, but pre sent techniques lack the spatial resolution and precision to quantitat e bone changes reliably in individual vertebrae. 17 beta-Estradiol adm inistered at 100 mu g/kg/day subcutaneously inhibited ovariectomy effe cts on L1-4 bone mineral density, femoral moment of inertia, dry weigh t, and volume and to a lesser extent, femoral bone mineral density. A nonsteroidal compound, raloxifene HCl, at 1 mg/kg/day per os, had bone effects and effects on body weight that were largely indistinguishabl e from those of 17 beta-estradiol; however, raloxifene did not produce the uterotrophic effects observed with estrogen. The half-maximal eff icacious dose of raloxifene on L1-4 bone mineral density was between 0 .1 and 1.0 mg/kg/day per os. These data show that dual-energy x-ray ab sorptiometry compares favorably with traditional methods in quantitati ng bone changes caused by ovariectomy in small rodents, that L1-4 is a more sensitive region than whole femora in evaluating the effect of e strogen deficiency on bone loss, and the raloxifene may have promise a s a treatment for conditions characterized by excessive bone loss afte r ovariectomy.