Management of Osteoporosis in Men: A Narrative Review

Male osteoporosis is a still largely underdiagnosed pathological condition. As a consequence, bone fragility in men remains undertreated mainly due to the low screening frequency and to controversies in the bone mineral density (BMD) testing standards. Up to the 40% of overall osteoporotic fractures affect men, in spite of the fact that women have a significant higher prevalence of osteoporosis. In addition, in males, hip fractures are associated with increased morbidity and mortality as compared to women. Importantly, male fractures occur about 10 years later in life than women, and, therefore, due to the advanced age, men may have more comorbidities and, consequently, their mortality is about twice the rate in women. Gender differences, which begin during puberty, lead to wider bones in males as compared with females. In men, follicle-stimulating hormones, testosterone, estrogens, and sex hormone-binding levels, together with genetic factors, interact in determining the peak of bone mass, BMD maintenance, and lifetime decrease. As compared with women, men are more frequently affected by secondary osteoporosis. Therefore, in all osteoporotic men, a complete clinical history should be collected and a careful physical examination should be done, in order to find clues of a possible underlying diseases and, ultimately, to guide laboratory testing. Currently, the pharmacological therapy of male osteoporosis includes aminobisphosphonates, denosumab, and teriparatide. Hypogonadal patients may be treated with testosterone replacement therapy. Given that the fractures related to mortality are higher in men than in women, treating male subjects with osteoporosis is of the utmost importance in clinical practice, as it may impact on mortality even more than in women

Clinical and molecular description of the first Italian cohort of 33 subjects with hypophosphatasia

IntroductionHypophosphatasia (HPP) is a rare genetic disease caused by inactivating variants of the ALPL gene. Few data are available on the clinical presentation in Italy and/or on Italian HPP surveys.MethodsThere were 30 suspected HPP patients recruited from different Italian tertiary cares. Biological samples and related clinical, biochemical, and anamnestic data were collected and the ALPL gene sequenced. Search for large genomic deletions at the ALPL locus (1p36) was done. Phylogenetic conservation and modeling were applied to infer the effect of the variants on the protein structure.ResultsThere were 21 ALPL variants and one large genomic deletion found in 20 out of 30 patients. Unexpectedly, NGS-driven differential diagnosis allowed uncovering three hidden additional HPP cases, for a total of 33 HPP subjects. Eight out of 24 coding variants were novel and classified as “pathogenic”, “likely pathogenic”, and “variants of uncertain significance”. Bioinformatic analysis confirmed that all the variants strongly destabilize the homodimer structure. There were 10 cases with low ALP and high VitB6 that resulted negative to genetic testing, whereas two positive cases have an unexpected normal ALP value. No association was evident with other biochemical/clinical parameters.DiscussionWe present the survey of HPP Italian patients with the highest ALPL mutation rate so far reported and confirm the complexity of a prompt recognition of the syndrome, mostly for HPP in adults. Low ALP and high VitB6 values are mandatory for the genetic screening, this latter remaining the gold standard not only to confirm the clinical diagnosis but also to make differential diagnosis, to identify carriers, to avoid likely dangerous therapy in unrecognized cases

Multiple Endocrine Neoplasia Type 1 Regulates TGFβ-Mediated Suppression of Tumor Formation and Metastasis in Melanoma

Over the past few decades, the worldwide incidence of cutaneous melanoma, a malignant neoplasm arising from melanocytes, has been increasing markedly, leading to the highest rate of skin cancer-related deaths. While localized tumors are easily removed by excision surgery, late-stage metastatic melanomas are refractory to treatment and exhibit a poor prognosis. Consequently, unraveling the molecular mechanisms underlying melanoma tumorigenesis and metastasis is crucial for developing novel targeted therapies. We found that the multiple endocrine neoplasia type 1 (MEN1) gene product Menin is required for the transforming growth factor beta (TGFβ) signaling pathway to induce cell growth arrest and apoptosis in vitro and prevent tumorigenesis in vivo in preclinical xenograft models of melanoma. We further identified point mutations in two MEN1 family members affected by melanoma that led to proteasomal degradation of the MEN1 gene product and to a loss of TGFβ signaling. Interestingly, blocking the proteasome degradation pathway using an FDA-approved drug and RNAi targeting could efficiently restore MEN1 expression and TGFβ transcriptional responses. Together, these results provide new potential therapeutic strategies and patient stratification for the treatment of cutaneous melanoma

Consequences of the COVID-19 pandemic on admissions to general hospital psychiatric wards in Italy: Reduced psychiatric hospitalizations and increased suicidality

Aims: The present investigation aimed at evaluating differences in psychiatric hospitalizations in Italy during and after the lockdown due to the novel coronavirus disease 2019 (COVID-19), compared to the same periods in 2018 and 2019. Methods: We obtained and analyzed anonymized data on psychiatric admissions (n = 4550) from 12 general hospital psychiatric wards (GHPWs) in different Italian regions (catchment area = 3.71 millions of inhabitants). Using a mixed-effects Poisson regression model, we compared admission characteristics across three periods: (a) March 1-June 30, 2018 and 2019; (b) March 1-April 30, 2020 (i.e., lockdown); and (c) May 1-June 30, 2020 (i. e., post-lockdown). Results: During the COVID-19 lockdown, there was a 41% reduction (IRR = 0.59; p 0.001, CI: 0.45-0.79) in psychiatric admissions in the enrolled GHPWs with respect to the 2018 and 2019 control period. Conversely, admission rates in the post-lockdown period were similar to those observed in the control period. Notably, a consistent and significant reduction in psychiatric hospitalizations of older patients (aged 65 years) was observed in the lockdown (40%; IRR = 0.60; 95% CI: 0.44-0.82) and post-lockdown (28%; IRR = 0.72; 95% CI: 0.54-0.96) periods. Long-stay admissions (>14 days) increased (63%; IRR = 1.63; 95% CI: 1.32-2.02) during the lockdown and decreased by 39% thereafter (IRR = 0.61; 95% CI: 0.49-0.75). A significant 35% increase in patients reporting suicidal ideation was observed in the post-lockdown period, compared to the rate observed in the 2018 and 2019 control period (IRR = 1.35; 95% CI: 1.01-1.79). Conclusion: The COVID-19 lockdown was associated with changes in the number of psychiatric admissions, particularly for older patients and long-stay hospitalizations. Increased admission of patients reporting suicida

Primary aldosteronism as a cause of secondary osteoporosis

OBJECTIVE: Patients with primary aldosteronism (PA) have a high prevalence of osteoporosis (OP) and fractures (Fx). We evaluated the presence of PA in patients admitted to our metabolic bone disease outpatient clinic. DESIGN: Study conducted on an in- and outpatient basis in a referral Italian endocrinology unit. METHODS: A total of 2632 patients were evaluated. 2310 were excluded because they were taking drugs known to affect bone or mineralocorticoids metabolism or were diagnosed to have a secondary cause of osteoporosis. The remaining 322 subjects (304 females, 18 males) took part in the study. Bone mineral density (BMD) and thoracic and lumbar spine vertebral morphometry were performed by dual X-ray absorptiometry. All patients were screened for PA with aldosterone-to-renin ratio. In those who had positive results, confirmatory tests were performed. RESULTS: Among 322 subjects, 213 were osteoporotics and 109 were not. PA was diagnosed in eleven out of 213 osteoporotic patients (5.2%) and one out of 109 non-osteoporotic subjects (0.9%, P = 0.066). PA was observed in the 26.1% of patients with the concomitant presence of osteoporosis, hypertension and hypercalciuria. Compared with patients without PA, patients with PA had mean values of urinary calcium excretion, 4.8 ± 2.5 mmol/day vs 7.6 ± 3.2 mmol/day, P < 0.001 and serum PTH levels, 5.4 pmol/L vs 7.3 pmol/L, P < 0.01, significantly higher. CONCLUSIONS: PA should be considered among the causes of secondary OP

The degree of cortisol secretion is associated with diabetes mellitus and hypertension in patients with nonfunctioning adrenal tumors

Abstract Background Similarly to cortisol-secreting adrenal tumors, also non-functioning adrenal tumors (NFAT) may be associated with an increased cardiovascular risk. We assessed in NFAT patients: (i) the association between hypertension (HT), diabetes mellitus (DM), obesity (OB), dyslipidemia (DL) and cardiovascular events (CVE) and cortisol secretion; (ii) the cut-off of the cortisol secretion parameters for identifying NFAT patients with a worse cardiometabolic profile. Patients and methods In 615 NFAT patients (with cortisol levels after 1 mg overnight dexamethasone suppression test, F-1mgDST < 1.8 µg/dL [50 nmol/L]) F-1mgDST and adrenocorticotroph hormone (ACTH) levels and data on HT, DM, OB, DL and CVEs prevalence were retrospectively collected. Results HT, DM and HT plus DM were associated with F-1mgDST levels (area under the ROC curve: 0.588 ± 0.023, 0.610 ± 0.028, 0.611 ± 0.033, respectively, p < 0.001 for all comparisons) but not with ACTH. The cut-off for identifying patients with either HT or DM or HT plus DM was set at ≥ 1.2 µg/dL (33 nmol/L). As compared with patients with F-1mgDST < 1.2 µg/dL (n = 289), patients with F-1mgDST 1.2–1.79 µg/dL (33–49.4 nmol/L) (n = 326) had lower ACTH levels (17.7 ± 11.9 vs 15.3 ± 10.1 pg/mL, respectively, p = 0.008), older age (57.5 ± 12.3 vs 62.5 ± 10.9 years, respectively, p < 0.001), and higher prevalence of HT (38.1% vs 52.5% respectively p < 0.001), DM (13.1% vs 23.3%, respectively, p = 0.001), HT plus DM (8.3% vs 16.9%, respectively, p < 0.002) and CVE (3.2% vs 7.3%, respectively, p = 0.028). F-1mgDST 1.2–1.79 µg/dL was associated with either HT (odd ratio, OR, 1.55, 95% confidence interval, 95% CI 1.08–2.23, p = 0.018) or DM (OR 1.60, 95% CI 1.01–2.57, p = 0.045) after adjusting for age, gender, OB, DL, and DM (for HT) or HT (for DM), and with the presence of HT plus DM (OR 1.96, 95% CI 1.12–3.41, p = 0.018) after adjusting for age, gender, OB and DL. Conclusions In NFAT patients, F-1mgDST 1.2–1.79 µg/dL seems to be associated with a higher prevalence of HT and DM and a worse cardiometabolic profile, even if the poor accuracy of these associations suggests caution in interpreting these results