Raloxifene and teriparatide (hPTH 1-34) have complementary effects on the osteopenic skeleton of ovariectomized rats.
The skeletal efficacy of raloxifene (Ral) plus weekly teriparatide [recombinant human parathyroid hormone (1-34), TPTD] combinations relative to each treatment alone or sequentially were evaluated in osteopenic, ovariectomized rats. In the first study, 6-month-old Sprague-Dawley rats were ovariectomized (Ovx) and permitted to lose bone for 1 month before treatment for the following 3 months. Raloxifene (Ral, 1 mg/kg/day orally) was evaluated alone and in combination with TPTD (10 or 30 microg/kg/week) administered weekly by subcutaneous injection. QCT, biomechanical testing, and histomorphometry were used to quantitate skeletal effects. Weekly TPTD alone at either dose had no skeletal effect relative to Ovx. Daily Ral prevented further loss of vertebral bone mineral density (BMD), resulting in BMD that was significantly greater than Ovx, but significantly less than age-matched, sham-Ovx, vehicle controls (sham). The raloxifene plus 30 microg/kg/week TPTD group had vertebral BMD that was significantly greater than Ovx, Ral alone, and both TPTD dose-alone groups. Therefore, the Ral plus TPTD group completely restored bone mass to sham levels. Compression testing of lumbar vertebra L5 confirmed increased strength for both Ral plus TPTD combinations relative to Ovx, with strength not different from sham. Histomorphometry of the proximal tibial metaphysis showed that Ovx significantly increased eroded surface and bone formation compared to sham. Raloxifene treatment restored eroded surface and bone formation rate back to sham levels. Raloxifene plus TPTD at 30 microg/kg/week resulted in a significantly higher mineral appositional rate compared to Ral and sham, which was not different from Ovx and TPTD alone. Raloxifene plus TPTD at both doses had eroded surfaces that were significantly less than Ovx but not different from sham or Ral alone. In a sequential study, 6-month-old Ovx rats were permitted to develop osteopenia for 2 months before a daily TPTD 80 microg/kg/day subcutaneous injection was initiated. Following 2 months of TPTD treatment, animals were either (1) continued on TPTD, (2) discontinued from TPTD, (3) switched to Ral 3 mg/kg/day, oral, or 17 alpha-ethynyl estradiol (EE2) 0.1 mg/kg/day, oral, for another 2 months. Raloxifene and EE2 maintained most of TPTD-induced new bone in Ovx rats by preventing the increase in bone turnover rate after withdrawal of TPTD. Raloxifene also restored the elevated bone formation activity induced by TPTD to the level of sham. These data suggest that Ral and TPTD have complementary interactions in osteopenic, Ovx rats. Raloxifene inhibited bone resorption, and reduced high bone turnover without significantly retarding TPTD stimulation of bone formation activity.
Ma
Yanfei L
YL
Lilly Research Laboratories, Lilly Corporate Center, Bldg. 98C/B, DC 0403, Indianapolis, IN 46285, USA. ma_linda@lilly.com
Bryant
Henry U
HU
Zeng
Qingqiang
Q
Schmidt
Allen
A
Jee
Webster S S
WS
Sato
Masahiko
M
D000818:Animals; D001851:Bone Diseases, Metabolic / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016723:Bone Remodeling / Q000187:drug effects; D002113:Calcification, Physiologic / Q000187:drug effects; D004357:Drug Synergism; D004965:Estrogen Antagonists / Q000008:administration & dosage*; D005260:Female; D007279:Injections, Subcutaneous; D008159:Lumbar Vertebrae / Q000473:pathology / Q000503:physiopathology*; D010052:Ovariectomy; D020849:Raloxifene Hydrochloride / Q000008:administration & dosage*; D051381:Rats; D017207:Rats, Sprague-Dawley; D019379:Teriparatide / Q000008:administration & dosage*
D004965:Estrogen Antagonists; D019379:Teriparatide; D020849:Raloxifene Hydrochloride