Hypocalcemia is a common manifestation frequently encountered secondary to hypomagnesemia. Both calcium and magnesium are essential for maintaining normal cellular physiology, and magnesium plays a pivotal role in modulating neuronal excitation, intracardiac conduction, and myocardial contraction by regulating several ion transporters. Associated disorders may include cardiac arrhythmia, heart failure due to insufficient contractility, and neuromuscular and central nervous system conditions with seizures. One of the most important factors underlying hypocalcemia in hypomagnesemia conditions is the impaired secretion of parathyroid hormone (PTH), referred to as paradoxical hypoparathyroidism. Because there is a positive functional correlation and association between serum magnesium and calcium concentrations, clinical hypocalcemia in cases of magnesium deficiency cannot be sufficiently corrected by supplementation with calcium, vitamin D, or both. In contrast to the clinical relevance of a rapid, consequent and effective detection, differential diagnosis, and subsequent initiation of an appropriate therapy, this phenomenon and underlying pathophysiology are not well understood. In this review we summarize on calcium and magnesium homeostasis through modulation of PTH and vitamin D and elaborate on the mechanism underlying the rare condition of paradoxical inadequate PTH secretion. Based on the relevant literature, our review includes interdisciplinary diagnostic and therapeutic recommendations.

Hypoparathyroidism denotes parathyroid hormone (PTH) deficiency and impaired mineral metabolism. MBX 2109, a novel prodrug yielding a biologically active PTH peptide agonist (PTH[1-32], extended by a fatty acylated Lys33), is being developed as a long-acting, once-weekly PTH replacement therapy. Here, we report the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of MBX 2109 in healthy volunteers. This phase 1, randomized, double-blind, placebo-controlled, multiple ascending-dose study (NCT05158335) enrolled healthy adults, who were randomly assigned 4:1 to receive MBX 2109 (200, 400, 600, and 900 μg; n = 8) or placebo (n = 2) by subcutaneous administration once weekly for 4 doses (days 1, 8, 15, and 22). The primary end point was safety and tolerability. Key secondary end points were PK and PD. Overall, 40 participants (MBX 2109 n = 32, placebo n = 8) were randomly assigned (mean age, 43.3 years; 22.5% female). Treatment-emergent adverse events (TEAEs) occurred in 50% to 88% of MBX 2109 groups and in 25% of placebo participants. In the MBX 2109 groups, no severe or serious TEAEs were observed. Injection-site reaction was the most common treatment-related TEAE. The half-lives were 79 to 95 hours for MBX 2109 and 184 to 213 hours for the fatty-acylated biologically active PTH peptide, which showed dose- and time-dependent exposure increases. The sustained-action PTH prodrug MBX 2109 was well tolerated with no unexpected, off-target safety issues. The long half-life and flat exposure profile of MBX 2109's biologically active PTH agonist supports once-weekly administration. MBX 2109 doses were identified for future studies.

Hypocalcemia and low parathyroid hormone levels have been commonly suggested as factors able to induce central nervous system disturbances. However, evidences on the occurrence of cognitive impairment are limited or underestimated. The aim of this review is, therefore, to systematically summarize the available evidence concerning the occurrence of cognitive impairment among subjects suffering from idiopathic or secondary hypoparathyroidism. A systematic selection of the available literature was performed by searching the online databases PubMed, Scopus and Web of Knowledge. The present systematic review included sixteen case report articles and one cross-sectional controlled study. Case reports were the most representative literature sources and involved ten women and seven men. The presence of cognitive impairment was mostly discussed in association with idiopathic hypoparathyroidism (HPT); five articles described the occurrence of cognitive impairment following postsurgical HPT. The case-controlled study reported a significant presence of peculiar cognitive deficits (e.g. reduced inhibitory control, impairment in visuo-spatial functioning among, and psychomotor retardation) among HPT subjects compared to healthy controls, with serum total calcium and its product with phosphorus as independent predictors of neuropsychological dysfunctions. Even though mostly based on single case reports, the presence of neuropsychological dysfunctions in the context of HPT appears to be a consistent core finding.

Low vitamin D (VD) is not always followed by the development of secondary hyperparathyroidism (SHPT). The study aimed to assess the prevalence of SHPT and functional hypoparathyroidism (FHPT) in relation to VD deficiency/insufficiency and factors predisposing to parathyroid hormone (PTH) response in old and very-old Caucasians. A sub-study of the cross-sectional PolSenior project analyzed serum 25(OH)D, intact PTH (iPTH) and C-terminal fibroblast growth factor 23 (cFGF23) concentrations in 3472 (1658 women) individuals aged ≥65 years. SHPT was defined as iPTH concentration > 65 pg/mL, while FHPT as iPTH within the reference range in the presence of 25(OH)D < 30 ng/mL. SHPT was diagnosed in 426 participants (14%) and was more frequent in very-old (≥ 80 years) than in the old (65-79 years) subgroup (18.8 vs 9.8%; OR = 2.12; 95% CI: 1.72-2.62). While, FHPT was found in 2269 subjects (85.2%) with 25(OH)D < 30 ng/mL, and was more prevalent in the old than very-old subgroup (89.3 vs 80.1%; OR = 2.03; 95% CI: 1.63-2.52). Multiple regression analysis showed that age ≥ 80 years, use of loop diuretics, decreased glomerular filtration rate, higher cFGF23 level but lower calcium and phosphate concentrations, predispose for the occurrence of SHPT. The interrelation between 25(OH)D deficiency and PTH response is complex. In older adults, PTH response is related to VD deficiency, age, impaired kidney function, the use of loop diuretics and the levels of calcium, phosphate, and cFGF23.

Parathyroid glands are the main regulator of body mineral metabolism through parathormone (PTH) actions on bone and kidney. Experimental evidence suggests that PTH may have non-classical target organs such as adipose tissue, arterial vascular wall, cardiac muscle cells, and adrenal cortex cells, where it may play a role in controlling body energy, blood pressure, and metabolism. Cardiometabolic features have been investigated in the wide spectrum of clinical parathyroid disorders, from hyperparathyroidism to pseudohypoparathyroidism and hypoparathyroidism. Indeed, in parathyroid disorders, besides altered PTH secretion, impaired serum calcium levels and vitamin D status occur. Both calcium and vitamin D have been shown to regulate metabolism and to be associated with cardiovascular diseases. However, despite the complexity of parathyroid disorders, features of metabolic syndrome, such as obesity, insulin resistance, and glucose intolerance, arterial blood hypertension, and dyslipidemia, are frequently diagnosed in primary and secondary hyperparathyroidism as well as in pseudohyperparathyroidism. Here, we reviewed the most consistent data highlighting challenges and providing clinical remarks.