Parathyroid hormone (PTH) has a paradoxical dual effect on bone: chronic elevation (as in primary hyperparathyroidism) causes bone resorption, while intermittent exogenous PTH (teriparatide) promotes bone formation. This paradox is explained by:
- A Continuous PTH signaling activates RANKL on osteoblasts, promoting osteoclastogenesis and resorption; intermittent PTH activates osteoblast proliferation and survival pathways (Wnt/LRP5 activation, inhibition of osteoblast apoptosis via IGF-1 and sclerostin inhibition) before osteoclast coupling catches up ✓
- B Chronic PTH suppresses osteocalcin while intermittent PTH stimulates it
- C Intermittent PTH directly activates the RANK receptor on osteoclasts, causing their apoptosis
- D The dose of teriparatide is sub-threshold for RANKL activation but supra-threshold for osteoblast proliferation receptors
Explanation
PTH receptor (PTHR1) signaling in osteoblasts/osteocytes drives different downstream effects depending on the pattern of exposure. Continuous PTH: cAMP-PKA signaling persistently upregulates RANKL (receptor activator of NFκB ligand) on osteoblasts, driving osteoclast differentiation and bone resorption. It also stimulates FGF23 secretion. Intermittent PTH (1-34 fragment, teriparatide): the brief signaling pulse preferentially activates osteoblast proliferation, differentiation, and survival (via IGF-1, Wnt pathway through reduced sclerostin), and reduces osteoblast apoptosis. The net early anabolic effect precedes osteoclast activation, providing a 'bone formation window.' After prolonged intermittent PTH, osteoclast coupling does eventually increase, which is why teriparatide is limited to 2 years. This anabolic window effect is exploited in osteoporosis therapy.
Reference: Guyton & Hall, Textbook of Medical Physiology, 14th ed.
High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP
Written and medically reviewed by the StethoPrep medical team.