PTH stimulates osteoblastic cells to form new bone and to produce osteoblast-osteoclast coupling factors such as RANKL. Whether osteoclasts or their activity are needed for PTH anabolism remains uncertain. We treated ovariectomized huRANKL knock-in mice with a human RANKL inhibitor denosumab (DMAb), alendronate (Aln), or vehicle for 4 weeks, followed by co-treatment with intermittent PTH for 4 weeks. Loss of bone mass and microarchitecture was prevented by Aln and further significantly improved by DMAb. PTH improved bone mass, microstructure, and strength, and was additive to Aln but not to DMAb. Aln inhibited biochemical and histomorphometrical indices of bone turnover, -i.e. osteocalcin and bone formation rate (BFR) on cancellous bone surfaces-, and Dmab inhibited them further. However Aln increased whereas Dmab suppressed osteoclast number and surfaces. PTH significantly increased osteocalcin and bone formation indices, in the absence or presence of either antiresorptive, although BFR remained lower in presence of Dmab. To further evaluate PTH effects in the complete absence of osteoclasts, high dose PTH was administered to RANK ؊/؊ mice. PTH increased osteocalcin similarly in RANK ؊/؊ and WT mice. It also increased BMD in RANK ؊/؊ mice, although less than in WT. These results further indicate that osteoclasts are not strictly required for PTH anabolism, which presumably still occurs via stimulation of modeling-based bone formation. However the magnitude of PTH anabolic effects on the skeleton, in particular its additive effects with antiresorptives, depends on the extent of the remodeling space, as determined by the number and activity of osteoclasts on bone surfaces.Parathyroid hormone (PTH), 2 when administered intermittently, increases bone mineral density (BMD) and improves bone microarchitecture and strength (1). PTH induces a rapid increase in markers of bone formation before it also increases bone resorption, which has been described as an "anabolic window" (2). In this window, PTH has been suggested to directly activate bone formation via bone lining cells on quiescent bone surfaces (i.e. modeling surfaces), as indicated by an increase in double tetracycline-labeled surfaces and a smooth cement line (3). PTH subsequently stimulates bone remodeling, first through activation of osteoclastic bone resorption in the basic multicellullar units (BMU), followed by new bone formation by osteoblasts. These remodeling-based BMUs are associated with scalloped cement lines by microscopy. Data from untreated adult rodents indicate that the ratio of bone modeling:remodeling surfaces is less than 1:5 and further decreases with age (4). Although PTH has been shown to increase bone modeling in rodents, the vast majority of bone formation in humans appears to be remodeling-based (5). Data from humans treated with PTH indicate that bone formation on modeling surfaces accounts for only 5-30% of PTH anabolic effects (6). While intermittent PTH can partially restore bone microarchitecture by increasing bone formation in mo...