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Osteoporosis is characterized by low bone mass associated with bone fragility and high fracture risk resulting in reduced quality of life and a higher mortality rate. Osteoporosis is a result of unbalanced bone remodeling with increased catabolic actions of osteoclasts. To date, mechanisms of coupling bone resorption to bone formation are not well understood limiting treatment for osteoporotic patients. Abaloaratide (ABL), a synthetic analog of PTHrP, has been recently approved by the FDA for the treatment of postmenopausal women with osteoporosis at high risk for fracture. ABL exhibits anabolic functions on bone with only limited effects on bone resorption when compared to hPTH(1-34). Noteworthy, in vitro studies suggest that certain PTH or PTHrP ligand analogs can distinguish between two high-affinity PTHR1 conformations resulting in different signaling responses, one possibility to explain the distinct effects on bone resorption. To compare the effects of ABL and PTH(1-34) on calvarial bone resorption in vitro and in vivo mouse models were used. Mice were subcutaneously injected once daily with 10µg/kg of either peptide for 5 and 12 consecutive days. Our data demonstrate that in peptide-treated mice numbers of TRAP+ cells and bone marrow filled cavities within the calvariae are significantly increased compared to controls. Intriguingly, ABL-treated mice exhibit ~50% less TRAP+ cells compared to PTH(1-34). The markedly reduced ratio of marrow cavity/region of interest in response to ABL correlates with lower serum Rankl levels. Besides, in vitro formation of pits and trails, a general hallmark of osteoclastic activity, was increased when bone-marrow derived osteoclasts were treated with conditioned media from peptide-treated osteoblasts. Similarly to in vivo data, the total resorbing area was 3-fold less in ABL- than in PTH(1-34) treated osteoclasts, and the numbers of long trenches representing continuous resorption were reduced when using conditioned medium from ABL treated cells. Moreover, osteoclastogenesis assays with Ocy454 cells co-cultured for seven days with primary bone marrow-derived macrophages and treated intermittently for 6hr/day with ABL, or PTH(1-34) resulted in more osteoclast numbers compared to vehicle controls. Consistent with our in vivo results, in PTH-treated cells, the increase in osteoclast number and size was 1.6-fold and 2-fold greater, respectively, than in ABL- treated cells. These data imply differences in the extent of induction of osteoclastogenesis by ABL and PTH(1-34)-dependent signaling, which might manifest in different amounts of bone resorption. Our studies comparing the effects of ABL and PTH (1-34) on bone resorption provide mechanistic explanation for the net bone gain observed in the ACTIVE trial indicating that increased bone mass is, at least partly, the consequence of reduced osteoclastogenesis in ABL-treated patients.