Bone in Parathyroid Diseases Revisited: Evidence From Epidemiological, Surgical and New Drug Outcomes

Abstract

PTH-related disorders have a major impact on bone metabolism and skeletal properties because of the pivotal role of PTH in calcium and phosphate homeostasis and bone remodeling. Hyperparathyroidism is characterized by continuous exposure to excessive endogenous PTH, causing increased bone turnover in favor of bone resorption. Depending on the background of PTH overproduction, hyperparathyroidism is divided into primary, secondary, and tertiary hyperparathyroidism. The clinical presentation varies from deterioration of bone microarchitecture and decreased bone mineral density to profound bone involvement, such as osteitis fibrosa cystica and fragility fractures. Although successful parathyroidectomy represents the definitive treatment and may promote regression of most of the skeletal defects, the medical approach of calcimimetics and antiresorptive agents is a promising alternative in cases where parathyroidectomy is not feasible or unsuccessful. Hypoparathyroidism is the pathophysiological counterpart of hyperparathyroidism and also leads to disorders of bone metabolism and structure. Chronic PTH deprivation is associated with low bone remodeling and increased bone mineral density. The defective microarchitecture might affect bone strength and raise the risk for adverse skeletal events. Recombinant human PTH acts as a replacement therapy and is safe and efficient in restoring calcium/phosphate homeostasis and bone turnover. However, it is approved only for refractory cases, as conventional management with calcium and active vitamin D remains the first-line treatment. This article reviews the skeletal involvement in the most frequent parathyroid disorders, hyperparathyroidism and hypoparathyroidism, and rare familial disorders of PTH metabolism, as assessed by clinical, laboratory, and imaging parameters, and the effect of the available treatment strategies.

Keywords: bone; fracture; hyperparathyroidism; hypoparathyroidism; parathyroid disorders; pseudohypoparathyroidism.

Graphical Abstract

Figure 1.

The calcium-sensing receptor (CaSR) signaling in the parathyroid cell. CaSR is a G-coupled protein receptor consisting of an extracellular domain, an intramembrane domain of seven hydrophobic helices, and an intracellular domain. The large extracellular domain interacts with the extracellular ionized calcium (Ca²⁺) leading to activation of the G-protein and in turn of the phospholipase C (PLC). PLC hydrolyses phosphatidylinositol-4,5-diphosphate (PIP2) to inositol-14,5-triphosphate (InsP3) and diacylglycerol (DAG). InsP3 mediates the release of intracellular calcium from the endoplasmic reticulum, resulting in inhibition of PTH secretion. DAG activates protein kinase C (PKC) resulting in gene transcription in the nucleus by activating mitogen-activated protein kinase (MAPK) and extracellular signal-regulated kinases (ERK).

Figure 2.

Parathyroid hormone (PTH) is a main regulator of calcium and phosphate metabolism. Calcium levels (Ca²⁺) are tightly controlled through the action of PTH and 1,25(OH)₂D₃ (calcitriol). Calcium-sensing receptors (CaSRs) are localized on the parathyroid cell membrane and detect changes in the serum Ca²⁺ concentrations. Hypocalcemia triggers the release of PTH by the parathyroid cells; conversely, hypercalcemia suppresses the release of PTH. PTH stimulates bone resorption, which increases serum calcium and phosphate (PO₄³⁻) levels. In the kidney, PTH stimulates the reabsorption of calcium and promotes phosphate excretion. PTH promotes the conversion of 25-hydroxyvitamin D (25(OH)D) to calcitriol in the kidney, the active form of vitamin D responsible for increased intestinal absorption of calcium and phosphate. All these well-orchestrated steps restore calcium levels to the normal range (8.5-10.5 mg/dL) and via actions of PTH and other hormones, such as fibroblast growth factor 23, in the kidney, restore the phosphate levels within the normal range (2.5-4.5 mg/dL).

Figure 3.

X-ray of the knee joint. Brown tumor of the fibula as a manifestation of primary hyperparathyroidism in a 52-year-old man.

Figure 4.

Cascade of events leading to CKD bone and 1,25(OH)₂D₃ mineral disorder. During the progression of kidney disease, the elevation of FGF23 and PTH fail to decompensate the decreased renal phosphate excretion; thus, serum phosphate rises. Inhibition of 1-a-hydroxylase synthesis of 1,25-(OH)₂ vitamin D by FGF23, which leads to a decrease in intestinal calcium absorption, along with the retention of uremic toxins that inhibits osteoclastogenesis and osteoblastogenesis, result in hypocalcemia. Hypocalcemia and hyperphosphatemia further stimulate PTH and FGF23 secretion, creating a vicious circle. Resistance of parathyroid cells to calcitriol- and calcium-mediated regulation of PTH secretion contributes to aggravation of the condition. With time, chronic stimulation of parathyroid cells leads to parathyroid cell proliferation, hyperplasia, or even nodular hyperplasia. PTH stimulates osteoblasts and osteoclasts and increases bone remodeling. However, in CKD, bone remodeling may be decreased due to other mechanisms, such is elevation of sclerostin, Dickkopf-1, activin A, and uremic toxins. BMD is decreased and, depending on the level of bone mineralization and bone turnover state, bone disease may vary from osteitis fibrosa cystica with high bone turnover to adynamic bone disease with low bone turnover. 1,25(OH)₂D₃, calcitriol; FGF23, fibroblast growth factor 23; GFR, glomerular filtration rate; Pi, inorganic phosphate; PTH, parathyroid hormone.