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Purpose: Hypercalcemic primary hyperparathyroidism (PHPT) is a common endocrine disorder that has been very well characterized. In contrast, many aspects of normocalcemic primary hyperparathyroidism (NPHPT) such as natural history, organ damage, and management are still matter of debate. In addition, both the pathophysiology and molecular basis of NPHPT are unclear. We investigated whether PHPT and NPHPT patient cohorts share the same pattern of genetic variation in genes known to be involved in calcium and/or bone metabolism., Research Design and Methods: Genotyping for 9 single nucleotide polymorphisms (SNPs) was performed by Real-Time PCR (TaqMan assays) on 27 NPHPT and 31 PHPT patients evaluated in a tertiary referral Center. The data of both groups were compared with 54 in house-controls and 503 subjects from the 1000 Genomes Project. All groups were compared for allele/haplotype frequencies, on a single locus, two loci and multi-locus basis., Results: The NPHPT group differed significantly at SNPs in OPG and ESR1. Also, the NPHPT cohort was peculiar for pairwise associations of genotypes and for the overrepresentation of unusual multilocus genotypes., Conclusions: Our NPHPT patient set harbored a definitely larger quota of genetic diversity than the other samples. Specific genotypes may help in defining subgroups of NPHPT patients which deserve ad hoc clinical and follow-up studies., (© 2023. The Author(s).)

Hypoparathyroidism (HypoPT) is a rare endocrine disorder characterized by the absence or insufficient parathyroid hormone production resulting in chronic hypocalcemia. Complications of HypoPT include perturbation of several target organs. The conventional treatment consists of the administration of active vitamin D, namely calcitriol. Regarding vitamin D status, few data are available, mostly in HypoPT subjects supplemented with parent vitamin D. In addition, perturbation of vitamin D metabolism has been poorly investigated, as well as the contribution of altered vitamin D status on the clinical expression of the disease. The most recent consensus on the management of chronic HypoPT suggests the baseline evaluation of serum 25-hydroxy-vitamin D [25(OH)D] and supplementation with parent vitamin D with the aim to achieve and maintain serum 25(OH)D levels in the range of 30-50 ng/mL. The rationale for using supplementation with parent vitamin D (either ergocalciferol or cholecalciferol) in HypoPT would be to provide sufficient 25(OH)D substrate to the residual 1-α-hydroxylase activity, thus ensuring its conversion to active vitamin D in renal and extra-renal tissues. More data from experimental and clinical studies are needed for better assessing how these mechanisms may significantly influence metabolic control in HypoPT and eventually skeletal and extra-skeletal manifestation of the disease. Finally, future data will clarify how the currently available parent vitamin D compounds (ergocalciferol, cholecalciferol, calcifediol) would perform in addressing these specific issues., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Purpose: To evaluate clinical features, treatments, and outcomes of osteoporotic patients admitted to internal medicine and geriatric wards compared with non-osteoporotic patients (REPOSI registry)., Methods: We studied 4714 patients hospitalized between 2010 and 2016. We reported age, sex, educational level, living status, comorbidities and drugs taken, Cumulative Illness Rating Scale (CIRS), Barthel Index, Short-Blessed Test, 4-item Geriatric Depression Scale, serum hemoglobin, creatinine, and clinical outcomes. Osteoporosis was defined based on the diagnoses recorded at admission, according to the following ICD9: 733, 805-813, 820-823., Results: Twelve percent of the patients had a preadmission diagnosis of osteoporosis. Only 20% of these had been prescribed oral bisphosphonates; 34% were taking vitamin D supplements. Osteoporotic patients were significantly older, with lower BMI, higher CIRS, and taking more drugs. They were significantly more depressed, less independent, with a higher severity of cognitive impairment compared with non-osteoporotic patients. At discharge, the number of patients receiving treatment for osteoporosis did not change. Length of stay and inhospital mortality did not differ between groups. Osteoporotic patients were more frequently nonhome discharged compared with those without osteoporosis (14.8 vs. 7.9%, p = 0.0007), mostly discharged to physical therapy or rehabilitation (8.8 vs. 2.5% of patients, p < 0.0001). Among osteoporotic patients deceased 3 months after discharge, the number of those treated with vitamin D, with or without calcium supplements, was significantly lower compared with survivors (12 vs. 32%, p = 0.0168)., Conclusions: The diagnosis of osteoporosis is poorly considered both during hospital stay and at discharge; osteoporotic patients are frailer compared to non-osteoporotic patients.

Purpose: We evaluated the early effect of denosumab on circulating markers of atherosclerosis in women with postmenopausal osteoporosis., Methods: Denosumab (60 mg) was administered subcutaneously every 6 months (m) in 27 women (mean age 75 ± 5 years) with postmenopausal osteoporosis and high cardiovascular risk for a total of 24 m. Zoledronic acid was administered in 6 age-matched women as a single intravenous dose. Serum levels of vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E and P selectin, CD-40 ligand (CD40L), interleukin-6 (IL-6), matrix metalloproteinase (MMP) 1 and 9, monocyte chemoattractant protein-1 (MCP-1), fibrinogen (FBG), and high sensitivity C-reactive protein (hs-CRP) were measured at baseline, 15 days (d), 2, 6 and 12 m after dosing. In the denosumab group, observation was extended to 24 m as secondary endpoint., Results: Serum ICAM-1 levels showed significant increase in the zoledronic acid group (+18 ± 0.1%; p < 0.01) at 12 m. In the denosumab group, we observed a significant increase in serum CD40L (+2 ± 0.8%; p < 0.001), MMP-1 (+11 ± 0.4%, p < 0.02), and MMP-9 (+39.4 ± 0.8%, p < 0.01) at 24 m. There was a significant increase in serum FBG and hs-CRP in both groups at 12 m (denosumab:+2.2 ± 0.2% and +50.3 ± 1.6%; zoledronic acid: +9.4 ± 0.1 and +81.8 ± 0.8%; p < 0.01). No significant between-group differences were found., Conclusions: 24-m treatment with denosumab has no effect on the circulating markers of atherosclerosis in women with postmenopausal osteoporosis. Fluctuation of serum ICAM-1, CD40L, MMPs, FBG and hs-CRP can be ascribed to perturbation of immunological mechanisms stimulated by denosumab and zoledronic acid.

The aim of this clinical narrative review is to summarize and critically appraise the literature on the differential diagnosis of hypocalcemia and to provide its correct management. Calcium is essential for muscle contraction and neurotransmitter release, but clinical manifestations of hypocalcaemia (serum calcium level <8 mg/dl; 2.12 mmol/L) may involve almost any organ and system and may range from asymptomatic to life-threating conditions. Disorders causing hypocalcemia can be divided into parathyroid hormone (PTH) and non-PTH mediated. The most frequent cause of hypocalcemia is postsurgical hypoparathyroidism, while a more comprehensive search for other causes is needed for appropriate treatment in the non PTH-mediated forms. Intravenous calcium infusion is essential to raise calcium levels and resolve or minimize symptoms in the setting of acute hypocalcemia. Oral calcium and/or vitamin D supplementation is the most frequently used as treatment of chronic hypocalcemia. In hypoparathyroidism, providing the missing hormone with the use of the recombinant human (rh) PTH(1-84) has been recently approved both by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This new therapy has the advantage of being effective for correcting serum calcium levels and significantly reducing the daily requirements of calcium and active vitamin D supplements. However, due to the high cost, a strict selection of candidates to this therapy is necessary. More challenging is the long-term hypocalcemia treatment, due to its associated complications. The development of long-acting recombinant human PTH will probably modify the management of chronic hypoparathyroidism in the future.

Purpose: Prostate cancer is the most common tumor in men. To the best of our knowledge a systematic assessment of bone and mineral abnormalities has not been performed in prostatic cancer patients consecutively enrolled., Methods: This study was therefore carried out to investigate changes of skeletal and mineral metabolism in patients with prostate cancer (n  = 69). A population of patients with cancer of various origin was also investigated as a control group (n  = 53), since a comparison with non-prostate cancer patients has not been previously reported., Results: In the prostatic cancer group, one patient had extremely high values of C-terminal Fibroblast Growth Factor 23, low values of tubular reabsorption of phosphate and very high values of bone alkaline phosphatase, suggesting the diagnosis of oncogenic osteomalacia. We found nine patients with primary hyperparathyroidism in the group of prostate cancer vs. only one in cancer patients group (p  <  0.026). We stratified the population on the basis of Gleason score, prostate specific antigen and hormonal therapy. Using a generalized linear model with a logit link to predict the probability of developing primary hyperparathyroidism, only Gleason score, C-terminal fibroblast growth factor 23 and hormonal therapy had a significant effect (p  < 0.05). Controlling for other covariates, a rise in fibroblast growth factor 23 increases the odds of developing primary hyperparathyroidism by 2% (p  = 0.017), while patients with higher values of Gleason score have a much greater probability of developing primary hyperparathyroidism (log-odds  =  3.6, p  <  0.01). The probability decreases with higher values of Gleason score while on hormonal therapy; a further decrease was observed in patients on hormonal treatment and lower values of GS. Finally, lower grade of Gleason score without hormonal therapy have a significant protective factor (p  <  0.01) decreasing the odds of developing primary hyperparathyroidism by 8%., Conclusion: We showed a remarkable prevalence of primary hyperparathyroidism in men with prostate cancer; the multivariate analysis demonstrates that higher aggressiveness of prostate cancer, as determined by Gleason score, is a significant predictor of increased risk of developing primary hyperparathyroidism.

Restoration of the euparathyroid state is associated with improvement of bone dynamics both in hypoparathyroidism and primary hyperparathyroidism. To date, no study has directly compared these two groups following correction of parathyroid hormone excess or deficiency. The study was designed to investigate changes in bone mineral density and trabecular bone score with restoration of the euparathyroid state by parathyroidectomy in primary hyperparathyroidism or recombinant parathyroid hormone [rhPTH(1-84)] replacement in hypoparathyroidism. This was a 2-year prospective intervention study in which we evaluated areal bone mineral density by DXA and trabecular bone score in 52 hypoparathyroid patients on rhPTH(1-84) replacement and 27 patients with primary hyperparathyroidism who underwent parathyroidectomy. We evaluated changes in areal bone mineral density by DXA and trabecular bone score at baseline, 6, 12, 18, and 24 months. After parathyroidectomy, areal bone mineral density increased from baseline at the lumbar spine and total hip at 6 months and at the femoral neck at 12 months, while there were no changes at the distal 1/3 radius. Treatment with rhPTH(1-84) was associated with significant increases in lumbar spine and decreases in distal 1/3 radius areal bone mineral density by 18 months in hypoparathyroid patients. At this time point, hypoparathyroid subjects demonstrated a significant increase in trabecular bone score from baseline, while there were no significant changes in trabecular bone score following parathyroidectomy. Bone mineral density increases both with administration of parathyroid hormone in a state of parathyroid hormone deficiency or removal of parathyroid hormone in a state of parathyroid hormone excess. However, only hypoparathyroid patients on rhPTH(1-84) appeared to have improvements in micro-architectural pattern as assessed by trabecular bone score.

The best repletion and maintenance dosing regimens with cholecalciferol in vitamin D-deficient HIV-1 patients remain unknown. Protease inhibitors (PIs) have been shown to inhibit vitamin D 1α- and 25α-hydroxylation in hepatocyte and monocyte cultures. We therefore evaluated the effect of a single high dose of cholecalciferol in vitamin D-deficient HIV-1 postmenopausal women undergoing treatment with highly active anti-retroviral therapy (cART), with and without PIs. Forty HIV-1 postmenopausal women treated with cART, with hypovitaminosis D (<20 ng/ml), were enrolled. We measured serum changes of 25-hydroxyvitamin D [25(OH)D]; 1,25-dihydroxyvitamin D [1,25(OH)2D], parathyroid hormone (PTH), serum calcium, and urinary calcium excretion following a loading dose of 600,000 IU of cholecalciferol after 3, 30, 60, 90, and 120 days. Patients were divided into two groups, whether or not they were taking PI. A significant increase in mean 25(OH)D and 1,25(OH)2D levels at day 3 and throughout the entire observation period was found in both groups (p < 0.001). PTH levels concomitantly decreased in both groups (p < 0.001). Mean albumin-adjusted serum calcium increases with respect to baseline were significant only at day 3 and day 30 for both groups (p < 0.01). Considering remaining parameters, there were no significant differences between the groups at any time, by two-way RM ANOVA. An oral dose of 600,000 IU of cholecalciferol in HIV-1 postmenopausal women rapidly increases 25(OH)D and 1,25(OH)2D levels reducing PTH levels, regardless of the presence of PIs in the cART scheme.

We investigated how the Hume's equation, using the antipyrine space, could perform in estimating fat mass (FM) and lean body mass (LBM). In 100 (40 male ad 60 female) subjects, we estimated FM and LBM by the equation and compared these values with those measured by a last generation DXA device. The correlation coefficients between measured and estimated FM were r = 0.940 (p < 0.0001) and between measured and estimated LBM were r = 0.913 (p < 0.0001). The Bland-Altman plots demonstrated a fair agreement between estimated and measured FM and LBM, though the equation underestimated FM and overestimated LBM in respect to DXA. The mean difference for FM was 1.40 kg (limits of agreement of -6.54 and 8.37 kg). For LBM, the mean difference in respect to DXA was 1.36 kg (limits of agreement -8.26 and 6.52 kg). The root mean square error was 3.61 kg for FM and 3.56 kg for LBM. Our results show that in clinically stable subjects the Hume's equation could reliably assess body composition, and the estimated FM and LBM approached those measured by a modern DXA device.