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Primary hyperparathyroidism (PHPT) is a common endocrinopathy, predominantly caused by a single parathyroid adenoma that is responsible for the excessive secretion of parathyroid hormone (PTH)—the hallmark of disease. Excess of this hormone causes remarkable changes in bone metabolism, including an increased level of bone remodeling with a predominance of bone resorption. Those changes lead to deterioration of bone structure and density, especially in cortical bone. The main treatment for PHPT is surgical removal of the adenoma, which normalizes PTH levels and terminates the progression of bone disease and leads to its regeneration. However, because not all the patients are suitable candidates for surgery, alternative therapies are needed. Current non-surgical treatments targeting bone disease secondary to PHPT include bisphosphonates and denosumab. Those antiresorptives prevent further bone loss, but they lack the ability to regenerate already degraded bone. There is ongoing research to find targeted drugs capable of halting resorption alongside stimulating bone formation. This review presents the advancements in understanding the molecular mechanisms responsible for bone disease in PHPT and assesses the efficacy of new potential therapeutic approaches (e.g., allosteric inhibitors of the PTH receptor, V-ATPase, or cathepsin inhibitors) aimed at mitigating bone loss and enhancing bone regeneration in affected patients. [ABSTRACT FROM AUTHOR]

Introduction: 24-Hydroxylase, encoded by the CYP24A1 gene, is a crucial enzyme involved in the catabolism of vitamin D. Loss-of-function mutations in CYP24A1 result in PTH-independent hypercalcaemia with high levels of 1,25(OH) 2D3. The variety of clinical manifestations depends on age, and underlying genetic predisposition mutations can lead to fatal infantile hypercalcaemia among neonates, whereas adult symptoms are usually mild. Aim of the study: We report a rare case of an adult with primary hyperparathyroidism and loss-of-function mutations in the CYP24A1 gene and a review of similar cases. Case presentation: We report the case of a 58-year-old woman diagnosed initially with primary hyperparathyroidism. Preoperatively, the suspected mass adjoining the upper pole of the left lobe of the thyroid gland was found via ultrasonography and confirmed by 99mTc scintigraphy and biopsy as the parathyroid gland. The patient underwent parathyroidectomy (a histopathology report revealed parathyroid adenoma), which led to normocalcaemia. After 10 months, vitamin D supplementation was introduced due to deficiency, and the calcium level remained within the reference range. Two years later, biochemical tests showed recurrence of hypercalcaemia with suppressed parathyroid hormone levels and elevated 1,25(OH)2D3 concentrations. Further investigation excluded the most common causes of PTH-independent hypercalcaemia, such as granulomatous disease, malignancy, and vitamin D intoxication. Subsequently, vitamin D metabolites were measured using LC-MS/MS, which revealed high levels of 25(OH)D3, low levels of 24,25(OH)2D3 and elevated 25(OH)2D3/24,25 (OH)2D3 ratios, suggesting a defect in vitamin D catabolism. Molecular analysis of the CYP24A1 gene using the NGS technique revealed two pathogenic variants: p.(Arg396Trp) and p.(Glu143del) (rs114368325 and rs777676129, respectively). Conclusions: The diagnostic process for hypercalcaemia becomes complicated when multiple causes of hypercalcaemia coexist. The measurement of vitamin D metabolites using LC-MS/MS may help to identify carriers of CYP24A1 mutations. Subsequent molecular testing may contribute to establishing the exact frequency of pathogenic variants of the CYP24A1 gene and introducing personalized treatment. [ABSTRACT FROM AUTHOR]

Primary hyperparathyroidism (PHPT) is a frequent endocrine disease which mainly affects the skeletal system and kidney. Some of its signs and symptoms are similar to those seen in rheumatic diseases such as rheumatoid arthritis, Sjögren's disease, fibromyalgia, polymyalgia rheumatica, gout or systemic lupus erythematosus. Coexistence of primary hyperparathyroidism with those pathologies potentiate their effects on muscles, bones and joints, increasing the risk of complications such as osteoporosis and fractures. Therefore, rheumatologists should be familiar with symptoms and diagnostic criteria of PHPT and consider it in the differential diagnosis of rheumatic diseases. In 2022 the Fifth International Workshop guidelines on the PHPT evaluation and management were published. They are based on a profound analysis of advances in research concerning multiple fields, that include genetics, outcomes and new imaging modalities of PHPT. They have led to revision of previous renal indications for parathyroidectomy in PHPT. There is also more evidence for the other recommendations regarding evaluation of the disease. This article summarizes the most relevant elements of these recommendations and refers them to Polish realities. I focus on the symptoms of primary hyperparathyroidism and its diagnosis as I consider these areas to be the most important for non-endocrinologists. [ABSTRACT FROM AUTHOR]