{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,8]],"date-time":"2026-06-08T22:24:09Z","timestamp":1780957449835,"version":"3.54.1"},"reference-count":41,"publisher":"Oxford University Press (OUP)","issue":"1","license":[{"start":{"date-parts":[[2000,1,1]],"date-time":"2000-01-01T00:00:00Z","timestamp":946684800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/academic.oup.com\/journals\/pages\/open_access\/funder_policies\/chorus\/standard_publication_model"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2000,1,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Postmenopausal osteoporosis is caused mainly by a deficiency of oestrogen with rapid bone loss. To target oestrogen to the bone effectively, we have synthesized and evaluated the effects of a novel hybrid compound of oestrogen and bisphosphonate, SM-16896. The tissue distribution pattern and pharmacological potential are reported.<\/jats:p>\n               <jats:p>Although the affinity for calf uterine oestrogen receptor was very low (IC50: 73.3 \u03bcM; 1\/25000 of that of 17\u03b2-oestradiol (2.84 nM)), SM-16896 showed oestrogenic activity. SM-16896 (1 \u03bcM) induced a 4.5-fold transcriptional activity in rat osteosarcoma UMR-106 cells compared with vehicle-treated control, when we used the expression vector for human oestrogen receptor and a CAT reporter plasmid containing an oestrogen-responsive element. The distribution of SM-16896 after a subcutaneous administration to 7-week-old female rats was examined by radioluminography using 3H-labelled SM-16896. At 30 min after the administration, significant radioactivity was detected in the bone. At 24 h after administration, a high level of radioactivity was detected in the bone, but in the uterus it was only at a background level. Daily subcutaneous administration of 0.5 mg kg\u22121 SM-16896 for 12 weeks (five times per week) to 13-week-old ovariectomized rats suppressed the ovariectomized-induced reduction in bone mineral density. A bone mineral density ratio of 120% was maintained compared with sham-operated rats, whereas a relatively low suppression of uterine weight was observed (about 50% loss compared with sham-operated rats). In the same experiment, the implantation of a 17\u03b2-oestradiol time-release pellet (0.25 mg\/pellet\/90 days) almost completely suppressed the reduction of both the bone mineral density and uterine tissue weight. It is likely that the effect of SM-16896 on bone was due to its oestrogenic activity, since 1.0 mg kg\u22121 SM-18108, the bisphosphonate moiety of this compound, had no effect on bone in 7-week-old ovariectomized rats.<\/jats:p>\n               <jats:p>The results suggest that SM-16896, a bisphosphonate-conjugated oestrogen, showed a preference profile in the uterus and bone due to its characteristic distribution pattern compared with the natural oestrogen analogue 17\u03b2-oestradiol. Thus, bisphosphonate-conjugated oestrogens have the potential to improve patient compliance in oestrogen therapy by minimizing adverse effects and reducing the frequency of medication.<\/jats:p>","DOI":"10.1211\/0022357001773652","type":"journal-article","created":{"date-parts":[[2003,7,18]],"date-time":"2003-07-18T23:43:52Z","timestamp":1058571832000},"page":"27-37","source":"Crossref","is-referenced-by-count":16,"title":["Tissue Distribution and Pharmacological Potential of SM-16896, a Novel Oestrogen-bisphosphonate Hybrid Compound"],"prefix":"10.1093","volume":"52","author":[{"given":"Naomi","family":"Tsushima","sequence":"first","affiliation":[{"name":"Sumitomo Pharmaceuticals Research Center , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Yabuki","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hideyuki","family":"Harada","sequence":"additional","affiliation":[{"name":"Sumitomo Pharmaceuticals Research Center , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Katsumata","sequence":"additional","affiliation":[{"name":"Sumitomo Pharmaceuticals Research Center , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroshi","family":"Kanamaru","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Iwao","family":"Nakatsuka","sequence":"additional","affiliation":[{"name":"Environmental Health Science Laboratory, Sumitomo Chemical Co. Ltd , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Michihiro","family":"Yamamoto","sequence":"additional","affiliation":[{"name":"Sumitomo Pharmaceuticals Research Center , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Masashi","family":"Nakatsuka","sequence":"additional","affiliation":[{"name":"Sumitomo Pharmaceuticals Research Center , 1-98 Kasugade Naka 3-chome, Konohana-ku, Osaka 554,","place":["Japan"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2000,1,1]]},"reference":[{"key":"2024103110044645100_cit1","doi-asserted-by":"crossref","first-page":"168","DOI":"10.1007\/s002239900104","article-title":"Effect of 17beta-estradiol-bisphosphate conjugates, potential bone-seeking estrogen pro-drugs; on 17beta-estradiol serum kinetics and bone mass in rats","volume":"59","author":"Bauss","year":"1996","journal-title":"Cal. 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Biochem."},{"key":"2024103110044645100_cit6","doi-asserted-by":"crossref","first-page":"1589","DOI":"10.1056\/NEJM199506153322401","article-title":"The use of estrogens and progestins and the risk of breast cancer in postmenopausal women","volume":"332","author":"Colditz","year":"1995","journal-title":"New Eng. J. Med."},{"key":"2024103110044645100_cit7","doi-asserted-by":"crossref","first-page":"14S","DOI":"10.1016\/0002-9343(91)90241-O","article-title":"Evaluating the benefits and risks of postmenopausal hormone therapy","volume":"91","author":"Cummings","year":"1991","journal-title":"Am. J. 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Int."},{"key":"2024103110044645100_cit29","first-page":"174","article-title":"Metabolic fate of 4-amino-1-hydroxy-butylidene-1,1-bisphosphonate (alendronate) (II): plasma concentration, distribution and excretion after repeated intravenous administration to 7-week old rats and after single intravenous administration to 30-week old rats, and transfer into the fetus and milk in rats","volume":"10","author":"Mochizuki","year":"1995","journal-title":"Yakubutudotai"},{"key":"2024103110044645100_cit30","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1016\/0041-008X(87)90050-0","article-title":"Distribution of [14C]clodronate (dichloromethylene bisphosphonate) disodium in mice","volume":"89","author":"Monkkonen","year":"1987","journal-title":"Toxicol. Appl. 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