**1. Introduction**

Parathyroid hormone (PTH) is a 9400 D molecular weight peptide, containing 84 amino acids that are secreted after cleavage from preproparathyroid hormone (115 amino acids) to proparathyroid hormone (90 amino acids). The active biological form is the intact PTH (1–84), whose half-life in the circulation is less than three minutes, and which clearance occurs mainly in the liver (60%–70%) and kidney (20%–30%) [1].

The secretion of PTH is regulated by changes of extracellular calcium through a feedback mainly mediated by the calcium-sensing receptor (CaSR). This receptor, a G protein-coupled receptor on parathyroid cells, regulates calcium-influenced PTH secretion [2]. A reduction of ionized calcium stimulates the PTH secretion, whereas high levels suppress the PTH release and enhance calcitonin secretion.

The e ffects of PTH are summarized in Figure 1. In renal proximal tubular cells, PTH inhibits phosphate reabsorption and upregulates the 1 α-hydroxylase gene, responsible for conversion of 25-hydroxyvitamin D to the active metabolite 1,25-dihydroxyvitamin D (1,25[OH]2D3). It also increases calcium reabsorption by inserting calcium channels in the apical membrane of distal tubules and stimulating basolateral sodium-calcium transporters [3].

**Figure 1.** Physiological actions of parathyroid hormone (PTH). PTH plays a key role in the maintenance of calcium levels. It stimulates bone turnover and calcium release from the skeleton. In renal tubular cells, PTH increases calcium reabsorption, inhibits phosphate reabsorption, and upregulates the <sup>1</sup>α-hydroxylase gene, responsible for conversion of 25-hydroxyvitamin D to the active metabolite, 1,25[OH]2D3. It also enhances calcium and phosphate intestinal absorption by increasing the production of activated vitamin D. Down arrow = decrease, Up arrow = increase.

In bone tissue, PTH influences gene expression in osteoblasts, supporting the synthesis of proteins required for bone formation and osteoclast differentiation. Intermittent exposure to PTH is antiosteoporotic and osteoanabolic via stimulation of bone formation, which is mediated by Wnt signaling activation. Upon binding to the frizzled receptor and co-receptors, LRP5 and LRP6, Wnt activates a signaling pathway, leading to translocation of beta-catenin into the nucleus, specific gene expression, protein synthesis, and bone formation. Extracellular regulators of Wnt signaling include dickkopf 1 and sclerostin, a product of the *SOST* gene expressed by osteocytes that inhibits Wnt signaling [4,5]. PTH inhibits sclerostin and, therefore, stimulates bone formation.

Continuous exposure to PTH increases osteoclast activity, causing osteoporotic changes [6], mostly mediated by enhancing the production of RANKL (receptor activator of nuclear factor-κB ligand) and decreasing the production of osteoprotegerin (OPG), a natural decoy of RANKL, by osteoblasts and stromal cell. By binding to RANK (receptor activator of nuclear factor-κB), a member of the tumor necrosis factor family expressed by osteoclasts and their precursors, RANKL controls the differentiation, proliferation, and survival of osteoclasts [7]. As a result, continuous exposure to high levels of PTH causes bone loss, whereas intermittent exposure leads to bone mass gain.
