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LY353381·HCl: An Improved Benzothiophene Analog with Bone Efficacy Complementary to Parathyroid Hormone-(1–34)

Lilly Research Laboratories, Eli Lilly & Co., Lilly Corporate Center, Indianapolis, Indiana 46285; and the Biomechanics and Biomaterials Research Center and Department of Orthopedic Surgery, Indiana University Medical Center (C.H.T.), Indianapolis, Indiana 46202

Address all correspondence and requests for reprints to: Dr. Masahiko Sato, MC 797, Department of Endocrine Research, Lilly Corporate Center, Indianapolis, Indiana 46285. E-mail: sato_masahiko{at}lilly.com

LY353381·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·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·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, 17-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·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 17-ethynyl estradiol or equine estrogens. LY353381·HCl prevented further bone loss due to ovariectomy in tibia, femora, and lumbar vertebra, like 17-ethynyl estradiol but unlike equine estrogens. LY353381·HCl prevented the resorption of trabecular bone spicules, like 17-ethynyl estradiol, but inhibited bone formation activity to a lesser extent than 17-ethynyl estradiol. In this model, 17-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 17ß-estradiol in bone. PTH at 10 µg/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·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·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·HCl prevented the rapid loss of bone observed in controls. Therefore, LY353381·HCl appears to be useful by itself, in combination, or in sequence with PTH to replace lost bone in postmenopausal women.

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