Purpose: The current cut-offs for the diagnosis of adrenal insufficiency (AI) have been established using outdated immunoassays. We compared the cortisol concentrations measured with Roche Cortisol I (R1), the newly available Roche Cortisol II (R2), and liquid chromatography tandem mass spectrometry (LC-MS/MS), the gold standard procedure to measure steroids in patients undergoing the corticotropin (ACTH) test. Methods: We enrolled 30 patients (age 47 ± 21 years) referred to undergo the ACTH test (1 or 250 μg). Cortisol was measured at 0, 30, and 60 min after stimulation with R1, R2, and LC-MS/MS. AI was diagnosed for R1-stimulated peak cortisol concentrations < 500 nmol/L. Results: Mean cortisol concentrations measured with R2 and LC-MS/MS were comparable, while mean cortisol concentrations measured by R1 were higher than those of both R2 and LC-MS/MS (respectively, basal 411 ± 177, 287 ± 119, and 295 ± 119 nmol/L; at 30 min, 704 ± 204, 480 ± 132, and 500 ± 132 nmol/L; at 60 min, 737 ± 301, 502 ± 196, and 519 ± 201 nmol/L, p ≤ 0.01 for R1 vs. both R2 and LC-MS/MS at each point). Considering the 500 nmol/L cortisol peak cut-off, AI was diagnosed in 5/30 patients using R1 and in 12/30 using R2 (+ 140%). Based on the correlation between R1 and R2, the threshold of 500 nmol/L became 351 nmol/L (12.7 μg/dL) when cortisol was measured with R2, and 368 nmol/L (13.3 μg/dL) with LC-MS/MS. Conclusions: The use of more specific cortisol assays results in lower cortisol concentrations. This could lead to misdiagnosis and overtreatment when assessing AI with the ACTH test if a different cut-off for cortisol peak is not adopted.

Background After denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impacts on women's health. A sequential therapy with bisphosphonates is recommended, and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study, we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. Methods We measured CTX levels and administered ZOL after 1 month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. Results Seventy-five percent of patients repeated ZOL infusion. In this group, spine BMD declined significantly (−5.5 ± 5.6%), while it remained stable in the group with CTX levels 5 Dmab injections and 2 ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 [odds ratio (OR) 2.9, interquartile range (IQR) 1.3-6.6, P = .009] and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, P = .014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss. Conclusion In patients with uncontrolled CTX levels after Dmab withdrawal, 2 ZOL infusions 6 months apart do not prevent BMD loss and FX.

The identification of hyperandrogenism in polycystic ovary syndrome (PCOS) is concerning because of the poor accuracy of the androgen immunoassays (IA) and controversies regarding which androgens should be measured. The aim of our study was to evaluate the impact of the assessment of testosterone (T) and androstenedione (A) by liquid chromatography in tandem with mass spectrometry (LC/MS-MS), in the diagnosis of PCOS. We evaluated 131 patients referred for suspected PCOS. Fourteen patients in total were excluded, some because of other diagnosis (n = 7) or incomplete diagnostic workup (n = 7). We measured T and A both by IA and LC-MS/MS in the 117 subjects included. We calculated free T (fT) by the Vermeulen formula and recorded clinical and metabolic data. 73 healthy females served as controls to derive immunoassays (IA) and LC-MS/MS reference intervals for T, fT and A. PCOS was confirmed in 90 subjects by IA and in 93 (+3.3%) by LC-MS/MS. The prevalence of biochemical hyperandrogenism in PCOS by LC-MS/MS increased from 81.7% to 89.2% if A was also considered. The most frequently elevated androgens were fT (73.1%) and A (64.5%) and they had similar levels of accuracy in differentiating PCOS and controls (0.34 ng/dL, Sn 91% Sp 89%; 1.16 ng/mL, Sn 91% Sp 88%, respectively). Free testosterone correlated with body mass index (BMI), homeostatic model assessment (HOMA)-index, glycated hemoglobin (HbA1c), and sex-binding globulin (SHBG). The results confirm that LC-MS/MS is slightly more sensitive than IA in the diagnosis of PCOS with LC-MS/MS detecting higher levels of fT and A. Moreover, assessment of fT and A by LC-MS/MS had a similar level of accuracy in discriminating between PCOs and control subjects. Lastly, fT by LC-MS/MS correlates with adverse metabolic parameters.

Bone fragility is recognized as a complication of type 2 diabetes (T2D). However, the fracture risk in T2D is underestimated using the classical assessment tools. An expert panel suggested the diagnostic approaches for the detection of T2D patients worthy of bone-active treatment. The aim of the study was to apply these algorithms to a cohort of T2D women to validate them in clinical practice. The presence of T2D-specific fracture risk factors (T2D ≥ 10 years, ≥1 T2D complications, insulin or thiazolidinedione use, poor glycaemic control) was assessed at baseline in 107 postmenopausal T2D women. In all patients at baseline and in 34 patients after a median follow-up of 60.2 months we retrospectively evaluated bone mineral density and clinical and morphometric vertebral fractures. No patient was treated with bone-active drug. Following the protocols, 34 (31.8%) and 73 (68.2%) patients would have been pharmacologically and conservatively treated, respectively. Among 49 patients without both clinical fractures and major T2D-related risk factors, who would have been, therefore, conservatively followed-up without vertebral fracture assessment, only one showed a prevalent vertebral fracture (sensitivity 90%, negative predictive value 98%). The two patients who experienced an incident fracture would have been pharmacologically treated at baseline. The clinical consensus recommendations showed a very good sensitivity in identifying T2D postmenopausal women at high fracture risk. Among those with treatment indication as many as 13% of patients experienced an incident fracture, and, conversely, among those without treatment indication no incident fractures were observed.

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.

Background/Objectives: The efficacy of zoledronic acid (ZOL) compared to denosumab (DMAB) after teriparatide (TPTD) is largely unknown. We compared the effect of ZOL or DMAB treatment after TPTD on BMD changes and fracture (FX) occurrence. Methods: We retrospectively revised data from 77 patients treated at Fondazione IRCCS Ca’Granda Milan, Italy, with TPTD (≥18 months), given at withdrawal (T0), single ZOL 5 mg (Group A, N = 56) or DMAB 60 mg/6 months (Group B, N = 21). BMD changes and incident FX were assessed after 24 months (T1) in all patients and after 48 months (T2) in 46 patients (Group A1, N = 15, treated with a single ZOL at T0; Group A2, N = 17, treated with ZOL at T0 and T1; Group B, N = 14, treated with DMAB since T0 to T2). Results: During the T0–T1 period, in all groups, both spine (LS) and total hip (TH) T-scores improved (mean ± SD, T0 vs. T1): Group A (LS −2.5 ± 1.2 vs. −2.3 ± 1.3, p = 0.006; TH −2.2 ± 1.0 vs. −2.0 ± 1.1, p = 0.002) and Group B (LS −2.4 ± 1.4 vs. −1.8 ± 1.4, p < 0.001; TH −2.4 ± 1.0 vs. −2.2 ± 1.0, p = 0.003). At T2 vs. T0, all groups showed an increase in TH-BMD (A1 −1.8 ± 0.9 vs. −1.4 ± 1.0, p = 0.008; A2: −1.8 ± 0.8 vs. −1.6 ± 0.9, p = 0.032; B: −2.6 ± 0.7 vs. −2.2 ± 0.7, p < 0.001), while LS-BMD increased only in Group B (−2.7 ± 1.4 vs. −2.0 ± 1.2, p = 0.002), with stability in A1 and A2. No significant differences in incident FX between groups were observed. Conclusions: At 24 months after TPTD withdrawal, both ZOL and DMAB improved BMD at all sites; after 48 months, both ZOL (1 or 2 infusions) and DMAB led to BMD improvement at TH, whereas only DMAB led to an increase in LS-BMD.