LY353381 x HCl is a
benzothiophene analog that is structurally related to
raloxifene with potent
selective estrogen receptor modulator activity in the ovariectomized rat model of
postmenopausal osteoporosis. The effects of
LY353381 x HCl on bones,
body weight, and uterine weight were evaluated in 7-month-old rats with
osteopenia that was induced by ovariectomizing animals for 1 month before initiation of treatment with several agents individually, in combination, or in sequence.
LY353381 x HCl was administered daily by itself for 90 days, in combination with the amino-terminal fragment of PTH-(1-34) (PTH) for 90 days, or sequentially after PTH when PTH was discontinued after 45 days of treatment. Additionally, comparisons were made of animals treated with PTH alone, 17alpha-ethynyl
estradiol alone, equine
estrogens (
Premarin) alone,
raloxifene alone, or combinations of PTH and equine
estrogens or
raloxifene.
Ovariectomy induced increases in the rate of bone turnover and
body weight while decreasing bone mineral density, bone mineral content, bone strength, trabecular bone volume, trabecular thickness, trabecular number, and uterine weight.
LY353381 x HCl at 0.01-1 mg/kg had marginal effects on
body weight and no effect on uterine weight compared with those in ovariectomized controls, in contrast to 17alpha-ethynyl
estradiol or equine
estrogens.
LY353381 x HCl prevented further bone loss due to
ovariectomy in tibia, femora, and lumbar vertebra, like 17alpha-ethynyl
estradiol but unlike equine
estrogens.
LY353381 x HCl prevented the resorption of trabecular bone spicules, like 17alpha-ethynyl
estradiol, but inhibited bone formation activity to a lesser extent than 17alpha-ethynyl
estradiol. In this model, 17alpha-ethynyl
estradiol appeared to be more efficacious after 3 months of treatment than equine
estrogens in the proximal tibia metaphysis, suggesting efficacy differences between metabolites of 17beta-estradiol in bone. PTH
at 10 microg/kg had no effect on
body weight or uterine weight, but significantly increased bone mass to beyond those in
sham-operated controls, baseline controls, and groups receiving other individual treatments at both axial and appendicular sites. The combination of
LY353381 x HCl and PTH increased bone mass at a faster rate and to a greater extent than PTH alone or the combinations of equine
estrogens/PTH and
raloxifene/PTH at trabecular bone sites. The
LY353381 x HCl/PTH combination improved bone mass and quality beyond any agent alone in regions enriched for cancellous bone, but was not significantly better than PTH alone on cortical bone. Additionally, when PTH was discontinued at 45 days,
LY353381 x HCl prevented the rapid loss of bone observed in controls. Therefore,
LY353381 x HCl appears to be useful by itself, in combination, or in sequence with PTH to replace lost bone in postmenopausal women.