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.