Previous studies have indicated that bisphosphonate pretreatment can inhibit the anabolic actions of parathyroid hormone (PTH). We examined the capacity of two anti-catabolic agents with different mechanisms of action, alendronate and osteoprotegerin (OPG), to influence the anabolic activity of PTH. Oophorectomized mice were pretreated for 30 days with, alendronate or osteoprotegerin (OPG) and then treated for 30 days with the respective anti-catabolic alone or the respective anti-catabolic plus PTH(1-34). Bones were analyzed by bone mineral density (BMD), microCT, histology and histomorphometry and biochemical bone markers. OPG pretreatment produced a greater inhibition of bone turnover and a greater increase in bone than alendronate. Increases in bone were sustained during subsequent treatment with vehicle or with continued administration of the anti-catabolic. Pretreatment with each anti-catabolic blunted the capacity of PTH to increase BMD and bone volume, and continued treatment with each anti-catabolic agent also reduced the effectiveness of PTH. Although both anti-catabolics decreased the maximal PTH effect, BMD and bone volume increased more when PTH was added than when only anti-catabolics were used. These results demonstrate that mechanistically distinct anti-catabolics may reduce PTH efficacy, that the characteristics of this inhibition may reflect the different modes of action of the anti-catabolics but that the addition of PTH still provides a skeletal benefit even if the anabolic effect is sub-maximal.