Background: Several studies suggest an association between serum 25-hydroxyvitamin D (25OHD) and the outcomes of Severe Acute Respiratory Syndrome Corona-Virus-2 (SARS-CoV-2) infection, in particular Coronavirus Disease-2019 (COVID-19) related severity and mortality. The aim of the present meta-analysis was to investigate whether vitamin D status is associated with the COVID-19 severity, defined as ARDS requiring admission to intensive care unit (ICU) or mortality (primary endpoints) and with the susceptibility to SARS-CoV-2 and COVID-19-related hospitalization (secondary endpoints).Methods: A search in PubMed, ScienceDirect, Web of Science, Google Scholar, Scopus, and preprints repositories was performed until March 31th 2021 to identify all original observational studies reporting association measures, or enough data to calculate them, between Vitamin D status (insufficiency <75, deficiency <50, or severe deficiency <25 nmol/L) and risk of SARS-CoV-2 infection, COVID-19 hospitalization, ICU admission, or death during COVID-19 hospitalization.Findings: Fifty-four studies (49 as fully-printed and 5 as pre-print publications) were included for a total of 1,403,715 individuals. The association between vitamin D status and SARS-CoV2 infection, COVID-19 related hospitalization, COVID-19 related ICU admission, and COVID-19 related mortality was reported in 17, 9, 27, and 35 studies, respectively. Severe deficiency, deficiency and insufficiency of vitamin D were all associated with ICU admission (odds ratio [OR], 95% confidence intervals [95%CIs]: 2.63, 1.45–4.77; 2.16, 1.43–3.26; 2.83, 1.74–4.61, respectively), mortality (OR, 95%CIs: 2.60, 1.93–3.49; 1.84, 1.26–2.69; 4.15, 1.76–9.77, respectively), SARS-CoV-2 infection (OR, 95%CIs: 1.68, 1.32–2.13; 1.83, 1.43–2.33; 1.49, 1.16–1.91, respectively) and COVID-19 hospitalization (OR, 95%CIs 2.51, 1.63–3.85; 2.38, 1.56–3.63; 1.82, 1.43–2.33). Considering specific subgroups (i.e., Caucasian patients, high quality studies, and studies reporting adjusted association estimates) the results of primary endpoints did not change.Interpretations: Patients with low vitamin D levels present an increased risk of ARDS requiring admission to intensive care unit (ICU) or mortality due to SARS-CoV-2 infection and a higher susceptibility to SARS-CoV-2 infection and related hospitalization.

Background Vitamin D deficiency has been suggested to favor a poorer outcome of Coronavirus disease-19 (COVID-19). We aimed to assess if 25-hydroxyvitamin-D (25OHD) levels are associated with interleukin 6 (IL-6) levels and with disease severity and mortality in COVID-19. Methods We prospectively studied 103 in-patients admitted to a Northern-Italian hospital (age 66.1 ± 14.1 years, 70 males) for severely-symptomatic COVID-19. Fifty-two subjects with SARS-CoV-2 infection but mild COVID-19 symptoms (mildly-symptomatic COVID-19 patients) and 206 subjects without SARS-CoV-2 infection were controls. We measured 25OHD and IL-6 levels at admission and focused on respiratory outcome during hospitalization. Results Severely-symptomatic COVID-19 patients had lower 25OHD levels (18.2 ± 11.4 ng/mL) than mildly-symptomatic COVID-19 patients and non-SARS-CoV-2-infected controls (30.3 ± 8.5 ng/mL and 25.4 ± 9.4 ng/mL, respectively, p < 0.0001 for both comparisons). 25OHD and IL-6 levels were respectively lower and higher in severely-symptomatic COVID-19 patients admitted to intensive care Unit [(ICU), 14.4 ± 8.6 ng/mL and 43.0 (19.0–56.0) pg/mL, respectively], than in those not requiring ICU admission [22.4 ± 1.4 ng/mL, p = 0.0001 and 16.0 (8.0–32.0) pg/mL, p = 0.0002, respectively]. Similar differences were found when comparing COVID-19 patients who died in hospital [13.2 ± 6.4 ng/mL and 45.0 (28.0–99.0) pg/mL] with survivors [19.3 ± 12.0 ng/mL, p = 0.035 and 21.0 (10.5–45.9) pg/mL, p = 0.018, respectively). 25OHD levels inversely correlated with: i) IL-6 levels (ρ − 0.284, p = 0.004); ii) the subsequent need of the ICU admission [relative risk, RR 0.99, 95% confidence interval (95%CI) 0.98–1.00, p = 0.011] regardless of age, gender, presence of at least 1 comorbidity among obesity, diabetes, arterial hypertension, creatinine, IL-6 and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count; iii) mortality (RR 0.97, 95%CI, 0.95–0.99, p = 0.011) regardless of age, gender, presence of diabetes, IL-6 and C-reactive protein and lactate dehydrogenase levels, neutrophil cells, lymphocytes and platelets count. Conclusion In our COVID-19 patients, low 25OHD levels were inversely correlated with high IL-6 levels and were independent predictors of COVID-19 severity and mortality.

Studies over the past two decades have led to major advances in the pathogenesis of Paget’s disease of bone (PDB) and particularly on the role of genetic factors. Germline mutations of different genes have been identified, as a possible cause of this disorder, and most of the underlying pathways are implicated in the regulation of osteoclast differentiation and function, whereas other are involved in cell autophagy mechanisms. In particular, about 30 different germline mutations of the Sequestosome 1 gene (SQSTM1) have been described in a significant proportion of familial and sporadic PDB cases. The majority of SQSTM1 mutations affect the ubiquitin-binding domain of the protein and are associated to a more severe clinical expression of the disease. Also, germline mutations in the ZNF687 and PFN1 genes have been associated to severe, early onset, polyostotic PDB with increased susceptibly to neoplastic degeneration, particularly giant cell tumor. Mutations in the VCP (Valosin Containing Protein) gene cause the autosomal dominant syndrome “Inclusion Body Myopathy, PDB, Fronto-temporal Dementia,” characterized by pagetic manifestations, associated with myopathy, amyotrophic lateral sclerosis and fronto-temporal dementia. Moreover, germline mutations in the TNFRSF11A gene, which encodes for RANK, were associated with rare syndromes showing some histopathological, radiological, and clinical overlap with PDB and in two cases of early onset PDB-like disease. Likewise, genome wide association studies performed in unrelated PDB cases identified other potential predisposition genes and/or susceptibility loci. Thus, it is likely that polygenic factors are involved in the PDB pathogenesis in many individuals and that modifying genes may contribute in refining the clinical phenotype. Moreover, the contribution of somatic mutations of SQSTM1 gene and/or epigenetic mechanisms in the pathogenesis of skeletal pagetic abnormalities and eventually neoplastic degeneration, cannot be excluded. Indeed, clinical and experimental observations indicate that genetic susceptibility might not be a sufficient condition for the clinical development of PDB without the concomitant intervention of viral infection, in primis paramixoviruses, and/or other environmental factors (e.g., pesticides, heavy metals or tobacco exposure), at least in a subset of cases. This review summarizes the most important advances that have been made in the field of cellular and molecular biology PDB over the past decades.

Helicobacter pylori (HP) infection is a common and persistent disorder acting as a major cofactor for the development of upper gastrointestinal diseases and several extraintestinal disorders including osteoporosis. However, no prospective study assessed the effects of HP on bone health and fracture risk. We performed a HP screening in a population‐based cohort of 1149 adults followed prospectively for up to 11 years. The presence of HP infection was assessed by serologic testing for serum antibodies to HP and the cytotoxin associated gene‐A (CagA). The prevalence of HP infection did not differ among individuals with normal bone mineral density (BMD), osteoporosis, and osteopenia. However, HP infection by CagA‐positive strains was significantly increased in osteoporotic (30%) and osteopenic (26%) patients respect to subjects with normal BMD (21%). Moreover, anti‐CagA antibody levels were significantly and negatively associated with lumbar and femoral BMD. Consistent with these associations, patients affected by CagA‐positive strains had a more than fivefold increased risk to sustain a clinical vertebral fracture (HR 5.27; 95% CI, 2.23–12.63; p < .0001) and a double risk to sustain a nonvertebral incident fracture (HR 2.09; 95% CI, 1.27–2.46; p < .005). Reduced estrogen and ghrelin levels, together with an impaired bone turnover balance after the meal were also observed in carriers of CagA‐positive HP infection. HP infection by strains expressing CagA may be considered a risk factor for osteoporosis and fractures. Further studies are required to clarify in more detail the underlying pathogenetic mechanisms of this association. © 2020 American Society for Bone and Mineral Research (ASBMR).

Context Paget disease of bone (PDB) is a metabolic bone disease whose genetic cause remains unknown in up to 50% of familial patients. Objective Our aim was to investigate the underlying genetic defect in a large pedigree with a severe, early onset, autosomal dominant form of PDB across 3 generations. Methods Whole exome sequencing was performed in affected and unaffected family members, and then mutation screening was replicated in a sample of PDB patients with early-onset, polyostotic PDB. Results We identified a frameshift D107Rfs*3 mutation in PFN1 (encoding for profilin 1, a highly conserved regulator of actin-polymerization and cell motility) causing the truncation of the C-terminal part of the protein. The mutation was also detected in a 17-year-old asymptomatic family member who upon biochemical and radiological analyses was indeed found to be affected. Sequencing of the entire PFN1 coding region in unrelated PDB patients identified the same mutation in 1 patient. All mutation carriers had a reduced response to bisphosphonates, requiring multiple zoledronate infusions to control bone pain and achieve biochemical remission over a long term. In vitro osteoclastogenesis in peripheral blood mononuclear cells (PBMCs) from mutation carriers showed a higher number of osteoclasts with PDB-like features. A similar phenotype was observed upon PFN1 silencing in murine bone marrow-derived monocytes, suggesting that the frameshift PFN1 mutation confers a loss of function in profilin 1 activity that induces PDB-like features in the osteoclasts, likely due to enhanced cell motility and actin ring formation. Conclusions Our findings indicate that PFN1 mutation causes an early onset, polyostotic PDB-like disorder.

Context Nephrolithiasis (NL) and primary hyperparathyroidism (HPTH) are metabolic complications of Paget’s Disease of Bone (PDB), but recent data regarding their prevalence in PDB patients are lacking. Objectives Study 1: To compare the prevalence of primary HPTH and NL in 708 PDB patients and in 1803 controls. Study 2: To evaluate the prevalence of NL-metabolic risk factors in 97 PDB patients with NL, 219 PDB patients without NL, 364 NL patients without PDB and 219 controls, all of them without HPTH Design Cross-sectional multicentric study Setting Italian referral Centers for metabolic bone disorders Participants PDB patients from the AIP (Associazione Italiana malati di osteodistrofia di Paget) registry. Participants to the Olivetti Heart and the Siena Osteoporosis Studies Main Outcome Measures HPTH; NL; NL-metabolic risk factors Results PDB patients showed higher prevalence of primary HPTH and NL compared to controls (p&0.01). The NL recurrence occurs more frequently in patients with polyostotic PDB. About half of PDB patients without NL showed one or more NL-related metabolic risk factors. The hyperoxaluria (HyperOx) prevalence was higher in PDB patients with NL compared to NL patients without PDB and in PDB patients without NL compared to controls (p=0.01). PDB patients with HyperOx showed a longer lapse of time from the last aminobisphosphonate treatment. Conclusions NL and HPTH are frequent metabolic complication of PDB. The NL occurrence should be evaluated in PDB patients, particularly in those with polyostotic disease and/or after aminobisphosphonate treatment, in order to apply an adequate prevention strategy.

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Osteoporosis is a common systemic disease of the skeleton, characterized by compromised bone mass and strength, consequently leading to an increased risk of fragility fractures. In women, the disease mainly occurs due to the menopausal fall in estrogen levels, leading to an imbalance between bone resorption and bone formation and, consequently, to bone loss and bone fragility. Moreover, osteoporosis may affect men and may occur as a sequela to different diseases or even to their treatments. Despite their wide prevalence in the general population, the skeletal implications of many gastrointestinal diseases have been poorly investigated and their potential contribution to bone fragility is often underestimated in clinical practice. However, proper functioning of the gastrointestinal system appears essential for the skeleton, allowing correct absorption of calcium, vitamins, or other nutrients relevant to bone, preserving the gastrointestinal barrier function, and maintaining an optimal endocrine-metabolic balance, so that it is very likely that most chronic diseases of the gastrointestinal tract, and even gastrointestinal dysbiosis, may have profound implications for bone health. In this manuscript, we provide an updated and critical revision of the role of major gastrointestinal disorders in the pathogenesis of osteoporosis and fragility fractures.