Assessment of maintenance therapy with reduced doses of PTH(1-34) in combination with a raloxifene analogue (LY117018) following anabolic therapy in the ovariectomized rat

This experiment was designed to evaluate the ability of a raloxifene analog ue (RA), LY117018, with or without reduced dosing of human parathyroid horm one (hPTH)(1-34) to maintain gains in bone mass after a fully anabolic trea tment regimen given to aging osteopenic rats. Six-month-old rats were ovari ectomized (ovx) or sham-operated (sham), After 1 month, ovx rats were treat ed with an anabolic regimen consisting of subcutaneous hPTH(1-34) 80 mu g/k g/day and oral raloxifene 3 mg/kg/day, each given 5 days/week for 3 months. Thereafter, the treated ovx rats went on to an 8 week maintenance phase of treatment with either RA alone at the same dose, hPTH(1-34) at a reduced d osing interval (twice a week), or a combination of the two. Bone mineral de nsity (BMD) was measured ex vivo at four skeletal sites, lumbar spine (L2-4 ), proximal hemipelvis, whole femur, and tibia, by dual-energy X-ray densit ometry, All four sites showed a similar pattern of response. After the 3 mo nth anabolic phase, the sham group had significantly higher BMD values than ovx rats at all skeletal sites (p less than or equal to 0.002), The ovx ra ts treated with PTH + RA during the anabolic phase of the protocol had sign ificantly higher BMD than the sham group in the femur, tibia, and spine (p less than or equal to 0.02) and higher but not significantly different valu es in the pelvis. Following the 2 month maintenance phase, comparisons were made with the PTH-RA group at the end of the anabolic phase. Decrements in BMD were seen in all three maintenance therapy groups, but they were not s tatistically significant in the RA plus reduced PTH dose group. However, re duced hPTH(1-34) dosing and RA alone resulted in significant reductions of bone mass measurements at several skeletal sites during the maintenance pha se. We conclude that the raloxifene analogue LY117018 may be useful in main taining bone mass in aging ovx rats following anabolic therapy with hPTH(1- 34) and raloxifene analogue, but that this strategy only allows for dose re duction of hPTH(1-34) rather than its discontinuation, (C) 1999 by Elsevier Science Inc. All rights reserved.