{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nParathyroid hormone (PTH) is a master regulator of systemic mineral metabolism whose dysregulation is closely tied to chronic kidney disease (CKD), aging, and metabolic–cardiovascular disturbances. In patients with CKD, for example, studies demonstrate that elevations in fibroblast growth factor 23 (FGF23) occur early—even when serum phosphate and PTH levels remain within the normal range—suggesting that disturbances in mineral metabolism evolve in parallel with altered PTH dynamics. In addition, epidemiologic observations link rising PTH levels (especially in the context of low dietary calcium and vitamin D insufficiency) with adverse changes in bone mineral density and an increased cardiovascular risk. Such findings underscore the systemic impact of PTH dysregulation on bone turnover and cardiovascular health in at‐risk populations."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "15"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nWithin bone tissue, PTH orchestrates a delicate balance between resorption and formation. On one hand, PTH stimulates osteoclastogenesis by directly enhancing receptor activator of nuclear factor–κB ligand (RANKL) transcription while suppressing osteoprotegerin (OPG) production via a cyclic AMP/protein kinase A (PKA)–CREB–dependent pathway. Concurrently, PTH promotes osteoblast survival and differentiation by decreasing apoptosis, modulating sclerostin expression, and inducing the synthesis of factors like ephrinB2 that favor osteoblast function. Moreover, intermittent PTH administration has been shown to synergize with mechanical loading to boost bone formation, reinforcing its dual anabolic and catabolic roles in skeletal remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "16", "end_ref": "25"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular and cellular levels, PTH signals through complex intracellular cascades. Its receptor engagement triggers cyclic AMP–dependent pathways that interface with key regulators such as B‐Raf and various transcription factors, thus fine‐tuning gene expression programs critical for bone cell function. Genetic investigations have revealed that while common polymorphisms in the PTH gene itself may not always predict bone mineral density variations, alterations in PTH fragment processing and downstream signaling—as exemplified by its regulation of channels (e.g. TRPV5 via calmodulin) and the generation of non–(1–84) fragments—play important roles in modulating both classical and nonclassical responses in bone and mineral homeostasis."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "26", "end_ref": "36"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its endocrine and autocrine actions within bone, the action of PTH is markedly influenced by biomechanical and immunological factors. Mechanical loading and exercise modulate PTH secretion and its downstream effects on bone remodeling—evidenced by studies using controlled calcium “clamping” protocols and dynamic loading models—and emerging data highlight a role for T lymphocytes in mediating PTH’s anabolic actions. Together, these findings integrate hormonal, mechanical, and osteoimmune signals into a comprehensive paradigm of PTH‐dependent regulation of bone remodeling."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "37", "end_ref": "40"}]}, {"type": "t", "text": ""}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Allan G Need, Peter D O'Loughlin, Howard A Morris, et al. 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