Are osteoclasts needed for the bone anabolic response to parathyroid hormone? A study of intermittent parathyroid hormone with denosumab or alendronate in knock-in mice expressing humanized RANKL.
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.
Pierroz
Dominique D
DD
Service of Bone Diseases, Department of Rehabilitation and Geriatrics, Geneva University Hospital and Faculty of Medicine, 1211 Geneva 14, Switzerland.
Bonnet
Nicolas
N
Baldock
Paul A
PA
Ominsky
Michael S
MS
Stolina
Marina
M
Kostenuik
Paul J
PJ
Ferrari
Serge L
SL
D019386:Alendronate / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers / Q000378:metabolism; D015519:Bone Density / Q000187:drug effects; D001862:Bone Resorption / Q000188:drug therapy; D001842:Bone and Bones / Q000166:cytology / Q000187:drug effects / Q000378:metabolism* / Q000502:physiology; D000069448:Denosumab; D004305:Dose-Response Relationship, Drug; D005260:Female; D015870:Gene Expression; D055879:Gene Knock-In Techniques; D006801:Humans; D008297:Male; D051379:Mice; D010010:Osteoclasts / Q000187:drug effects* / Q000378:metabolism; D010012:Osteogenesis / Q000187:drug effects; D010052:Ovariectomy; D010281:Parathyroid Hormone / Q000008:administration & dosage / Q000494:pharmacology*; D053245:RANK Ligand / Q000008:administration & dosage / Q000494:pharmacology*; D053246:Receptor Activator of Nuclear Factor-kappa B / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D015415:Biomarkers; D010281:Parathyroid Hormone; D053245:RANK Ligand; D053246:Receptor Activator of Nuclear Factor-kappa B; D000069448:Denosumab; D019386:Alendronate