title: The new selective estrogen receptor modulator MDL 103,323 increases bone mineral density and bone strength in adult ovariectomized rats.
abstract: Selective estrogen receptor modulators (SERMs) can prevent the bone loss induced by ovariectomy (OVX), but it is not established whether they can increase bone mass and strength in a curative protocol in ovariectomized osteopenic animals. We investigated the influence of a SERM of the new generation, MDL 103,323, on areal bone mineral density (BMD), as measured by dual-energy X-ray absorptiometry, bone strength and remodeling in OVX osteopenic rats. Nine weeks after OVX, 8-month-old rats were divided into six groups of 10 animals. MDL 103,323 was given by gavage at doses of 0.01, 0.1 or 0.6 mg/kg body weight, 5 days a week. The effect of MDL 103,323 was compared with that of the bisphosphonate pamidronate (APD), which was injected subcutaneously at a dose of 1.6 mmol/kg body weight for 5 days every 4 weeks. Lumbar spine (LS), femoral neck (FN), proximal tibia (PT) and midshaft tibia (MT) BMD, bone strength, and proximal tibia histomorphometry, serum osteocalcin, urinary total deoxypyridinoline and serum insulin-like growth factor I (IGF-I) were measured. After 16 weeks of treatment, BMD changes (means +/- SEM) were -11.4 +/- 2. 2, +4.0 +/- 2.1 and +6.4 +/- 1.0% respectively in OVX controls, in rats treated with 0.1 mg/kg MDL 103,323 (p<0.05) and in APD-treated rats (p<0.02) at the level of LS; -0.4 +/- 1.1, +6.7 +/- 1.4, +7.2 +/- 1.8% (p<0.01 and NS) at the level of FN; and -2.6 +/- 1.2%, +5.8 +/- 1.2, +6.9 +/- 1.4% (p<0.03 and 0.01) at the level of PT. MDL 103, 323-treated animals had a higher trabecular bone volume, a higher number of trabeculae and smaller intertrabecular spaces compared with OVX controls. Vertebral body ultimate strength was 186 +/- 13, 292 +/- 16, 249 +/- 23 N (p<0.05) in OVX controls, MDL 103, 323-treated rats and APD-treated rats, respectively. The administration of 0.6 mg/kg of MDL 103,323 did not further increase BMD or bone strength, indicating a bell-shaped dose-response curve. MDL 103,323 lowered plasma osteocalcin concentration and urinary deoxypyridinoline excretion. In rats treated with 0.1 mg/kg MDL 103, 323, plasma IGF-I was increased as compared with OVX controls (664 +/- 36 ng/ml vs 527 +/- 39 ng/ml, p<0.05). In conclusion, these results indicate that this new SERM positively influences BMD and lumbar spine bone strength in estrogen-deficient rats.
authors.affiliation: Division of Bone Diseases, WHO Collaborating Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital, Geneva, Switzerland.
authors.forename: P
authors.initials: P
authors.lastname: Ammann
authors.forename: S
authors.initials: S
authors.lastname: Bourrin
authors.forename: J P
authors.initials: JP
authors.lastname: Bonjour
authors.forename: F
authors.initials: F
authors.lastname: Brunner
authors.forename: J M
authors.initials: JM
authors.lastname: Meyer
authors.forename: R
authors.initials: R
authors.lastname: Rizzoli
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001696:Biomechanical Phenomena; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016723:Bone Remodeling / Q000187:drug effects; D002996:Clomiphene / Q000031:analogs & derivatives* / Q000627:therapeutic use; D004164:Diphosphonates / Q000494:pharmacology; D005260:Female; D007334:Insulin-Like Growth Factor I / Q000032:analysis; D009929:Organ Size / Q000187:drug effects; D010052:Ovariectomy; D000077268:Pamidronate; D011897:Random Allocation; D051381:Rats; D017207:Rats, Sprague-Dawley; D020845:Selective Estrogen Receptor Modulators / Q000627:therapeutic use*; D013977:Tibia / Q000187:drug effects* / Q000473:pathology / Q000503:physiopathology; D014599:Uterus / Q000187:drug effects
chemical_list: D004164:Diphosphonates; D020845:Selective Estrogen Receptor Modulators; D002996:Clomiphene; C112138:MDL 103323; D007334:Insulin-Like Growth Factor I; D000077268:Pamidronate