Raloxifene and teriparatide (hPTH 1-34) have complementary effects on the osteopenic skeleton of ovariectomized rats

Abstract

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.

Teriparatide [rhPTH (1-34)], But Not Strontium Ranelate, Demonstrated Bone Anabolic Efficacy in Mature, Osteopenic, Ovariectomized Rats

“…Collectively these data show that teriparatide not only prevented loss of bone strength during treatment but also strengthened functional integrity of the axial and appendicular skeleton over the pretreatment condition. These results are consistent with previous studies demonstrating bone anabolic effects of teriparatide in OVX rodents with established osteopenia (20,41,42).…”

Prolonged Treatments With Antiresorptive Agents and PTH Have Different Effects on Bone Strength and the Degree of Mineralization in Old Estrogen-Deficient Osteoporotic Rats

“…The other remaining animals were treated with either vehicle (normal saline, SC, three times per week), risedronate (Ris, 500 μg/kg, single IV injection at day 0), zoledronic acid (Zol, 100 μg/kg, single IV injection at day 0), raloxifene (Ral, 2 mg/kg, oral gauge, three times per week, days 0–180), or hPTH(1–34) (25 μg/kg, SC, three times per week, day 180; Table 1). The medication dosages used in this experiment were derived from publications by the manufacturers that have been shown in osteopenic animals models to be effective and similar in concentration to clinical doses. Twenty‐four‐hour urine samples were collected every 60 days and were stored at –80°C until they were used to assessment of biochemical markers of bone turnover. Xylenol orange (90 mg/kg) was given to all rats except animals killed at baseline (day −60).…”

Sequential Treatment of Severe Postmenopausal Osteoporosis After Teriparatide: Final Results of the Randomized, Controlled European Study of Forsteo (EUROFORS)

“…Without follow-up treatment, BMD gradually decreases after teriparatide discontinuation, although vertebral antifracture efficacy may persist for at least 18 mo. (9) Results from preclinical (10,11) and clinical studies support the strategy of giving an antiresorptive agent after stopping teriparatide or PTH , but most of the available data are from nonrandomized studies. (9,(12)(13)(14)(15) In an extension of the controlled Parathyroid Hormone and Alendronate (PaTH) study, there was a much greater improvement in lumbar spine BMD (12.1%) among patients who received PTH(1-84) for 12 mo followed by alendronate for an additional 12 mo compared with the cumulative 4.1% gain in lumbar spine BMD when PTH(1-84) was followed by placebo.…”