Purpose X-linked hypophosphatemia (XLH) is a rare hereditary skeletal disorder that may be very disabling and significantly impacting the quality of life throughout the lifespan. The aim of this document was to inform stakeholders about the lifelong impact, management, and treatment of individuals with XLH, especially focusing on the new therapeutic approach with burosumab. Methods From October 2023 to April 2024, a multidisciplinary working group of Italian experts on bone and mineral metabolism convened periodic online meetings. Statements were formulated identifying the most relevant studies, including randomized controlled trials, international guidelines based on GRADE criteria, and systematic reviews, and the experts’ opinions. Results The panel of experts provided "consensus statements" on the clinical management of individuals with XLH across lifespan. Five main issues were identified: (1) clinical and biochemical diagnosis of individuals with XLH and monitoring of the progression of the disease; (2) effects of conventional treatment with phosphate supplements and active vitamin D metabolites; (3) effects of the treatment with burosumab; (4) multidisciplinary approach and management of individuals with XLH; (5) consensus statement for transition from pediatric to adult care in individuals with XLH. Conclusion Individuals with XLH often experience unmet needs throughout life; a multidisciplinary approach involving different specialists, is recommended. The new treatment with burosumab can provide an effective and safety therapeutic option in reducing the burden of the disease in both children and adults. Therefore, awareness about the XLH disease should be increased among stakeholders. The criteria and reimbursement policies of burosumab should be revised.

The expression of several key molecules is altered in parathyroid tumors due to gene mutations, the loss of heterozygosity, and aberrant gene promoter methylation. A set of genes involved in parathyroid tumorigenesis has been investigated in sporadic parathyroid adenomas (PAds). Thirty-two fresh PAd tissue samples surgically removed from patients with primary hyperparathyroidism (PHPT) were collected and profiled for gene, microRNA, and lncRNA expression (n = 27). Based on a gene set including MEN1, CDC73, GCM2, CASR, VDR, CCND1, and CDKN1B, the transcriptomic profiles were analyzed using a cluster analysis. The expression levels of CDC73 and CDKN1B were the main drivers for clusterization. The samples were separated into two main clusters, C1 and C2, with the latter including two subgroups of five PAds (C2A) and nineteen PAds (C2B), both differing from C1 in terms of their lower expression of CDC73 and CDKN1B. The C2A PAd profile was also associated with the loss of TP73, an increased expression of HAR1B, HOXA-AS2, and HOXA-AS3 lncRNAs, and a trend towards more severe PHPT compared to C1 and C2B PAds. C2B PAds were characterized by a general downregulated gene expression. Moreover, CCND1 levels were also reduced as well as the expression of the lncRNAs NEAT1 and VLDLR-AS1. Of note, the deregulated lncRNAs are predicted to interact with the histones H3K4 and H3K27. Patients harboring C2B PAds had lower ionized and total serum calcium levels, lower PTH levels, and smaller tumor sizes than patients harboring C2A PAds. In conclusion, PAds display heterogeneous transcriptomic profiles which may contribute to the modulation of clinical and biochemical features. The general downregulated gene expression, characterizing a subgroup of PAds, suggests the tumor cells behave as quiescent resting cells, while the severity of PHPT may be associated with the loss of p73 and the lncRNA-mediated deregulation of histones.

Background: Estrogens are fundamental to bone health, exerting life-long effects onbone metabolism. They regulate skeletal growth and maturation during adolescence andmaintain bone remodeling in adulthood. The decline in estrogen levels during perimenopauseand postmenopause leads to bone mass loss. Emerging evidence also supports a role forprogestins in bone metabolism. Several estrogen-progestins formulations are available andwidely used for contraception in fertile women and as hormone replacement therapy (HRT) incases of primary or secondary ovarian insufficiency as well as in physiologic menopause.Advances in both synthetic and natural preparations allowed for more personalized treatmentapproaches. When selecting estrogen-progestin therapies, it is essential to consider their impacton bone health and remodelling. Objective: This narrative review examines the effects of variousestrogen-progestin regimens on bone metabolism across the female lifespan, focusing on mechanisms of action, safety profiles, and clinical applications. Here we show that combined oralcontraceptives (COCs) are generally safe for bone mineral density (BMD) in adult women;however, caution is advised in adolescence, especially with very low-dose estrogen formulations.In hypogonadal women, postmenopausal hormone replacement therapy (HRT) is key forosteoporosis prevention. Physiological regimens, preferably transdermal estrogen at doseshigher than those used in typical postmenopausal therapy, may offer better bone protection.Additionally, oral gonadotropin-releasing hormone receptor (GnRH-R) antagonists combinedwith add-back therapy represent a novel long-term option for managing uterine fibroids andendometriosis without compromising BMD. In postmenopausal women, both HRT and selectiveestrogen receptor modulators (SERMs) effectively reduce fracture risk and support bone health. Main results & implications: Optimizing therapeutic strategies to balance efficacy and safety, iscritical to ensuring personalized care that preserves bone health and enhances quality of lifeacross a woman’s lifespan.

Diagnosis of primary hyperparathyroidism (PHPT) relies on the detection of hypercalcemia and increased circulating parathormone (PTH) levels. However, the disease induces a deep deregulation of phosphate metabolism. A total of 960 PHPT patients (848 females, 112 males) were retrospectively enrolled; biochemical and clinical data were collected at PHPT diagnosis. At variance with previous studies, hypophosphatemia was diagnosed using sex- and age-specific serum phosphate reference range. Reduced serum phosphate levels were detectable in 49% of PHPT males and 55% of PHPT females. Moderate hypophosphatemia (≤2.0 mg/dL) was more frequent in men than in women, and serum phosphate levels were lower in postmenopausal than premenopausal PHPT women. Vitamin D status did not alter the prevalence of hypophosphatemia. Serum phosphate levels negatively correlated with ionized calcium and PTH levels across PHPT premenopausal women, postmenopausal women, and men. Cluster analysis integrating the three interrelated parameters identified three distinct PHPT phenotypes: bone and kidney complications were more frequent in patients with more severe hypercalcemia and hypophosphatemia, though fractures were more abundant in the less severe phenotypes. Finally, considering the whole cohort, ionized calcium and PTH levels displayed a negative non-linear correlation with phosphate levels. In conclusion, hypophosphatemia in PHPT patients is common, and moderate hypophosphatemia is more frequent in males compared to females. Menopausal status is associated with less severe hypophosphatemia and PHPT disease. Hypophosphatemia is mainly determined by parathyroid tumor cells’ dysfunction. The non-linear negative relationships between phosphate, PTH and ionized calcium may suggest heterogeneous insensitivity of tumor parathyroid cells to extracellular phosphate.