Bone remodeling balance: osteoclasts (resorption) + osteoblasts (formation). RANKL (from osteoblasts/osteocytes) → RANK on osteoclast precursors → osteoclast differentiation + activation; OPG (osteoprotegerin) is a soluble decoy that buffers RANKL. PTH increases bone turnover (continuous = catabolic; intermittent pulsatile = anabolic — the basis of teriparatide therapy). Sclerostin (from osteocytes) inhibits Wnt signaling → suppresses osteoblast activity; sclerostin-i (romosozumab) is anabolic. Bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) are pyrophosphate analogs that bind hydroxyapatite + are taken up by resorbing osteoclasts → inhibit farnesyl-PP synthase (N-containing BPs) → apoptosis. Denosumab is an anti-RANKL mAb that blocks osteoclast differentiation. Calcitonin (older, weaker antiresorptive) acts at osteoclast calcitonin-R. Cross-link: calcium_phosphate_pth_axis.
Organ Systems
musculoskeletal
endocrine
Pathway Steps
rankl → osteoclast-activation — via RANK on osteoclast precursors → NF-κB + NFATc1 → resorption. RANKL, expressed by osteoblasts/osteocytes, binds RANK on osteoclast precursors to drive their differentiation and activation — the master signal for bone resorption. Its decoy receptor osteoprotegerin (OPG) opposes it, so the RANKL:OPG ratio sets resorption; the antibody denosumab blocks RANKL to treat osteoporosis.
osteocyte-sclerostin → osteoblast-suppression — via sclerostin inhibits Wnt/β-catenin in osteoblasts → reduced bone formation. Osteocytes (the mechanosensing cells embedded in bone) secrete sclerostin, which inhibits Wnt signaling in osteoblasts to suppress bone formation. Blocking sclerostin (romosozumab) unleashes osteoblast activity — a bone-anabolic therapy — making this a key formation-side drug target.
intermittent-pth → osteoblast-activation — via pulsatile PTH-R1 activation → anabolic bone formation (teriparatide mimics this). Intermittent PTH (as opposed to continuous) preferentially activates osteoblasts, favoring bone formation over resorption. This anabolic window is the basis of teriparatide therapy — the same hormone that, when chronically elevated, is catabolic to bone, showing how dosing pattern determines the effect.
Known Modulators
denosumab (inhibitor) — RANKL (mAb). osteoporosis + bone metastases; q6month SC; rebound vertebral fractures on discontinuation if not bridged to bisphosphonate
teriparatide (activator) — PTH-R1 (recombinant PTH 1-34). anabolic osteoporosis therapy; daily SC; 2-year lifetime cap (osteosarcoma signal in rats, not seen in humans)