Randomised trial of genetic testing and targeted intervention to prevent the development and progression of Paget's disease of bone.

INTRODUCTION: Paget's disease of bone (PDB) frequently presents at an advanced stage with irreversible skeletal damage. Clinical outcomes might be improved by earlier diagnosis and prophylactic treatment. METHODS: We randomised 222 individuals at increased risk of PDB because of pathogenic SQSTM1 variants to receive 5 mg zoledronic acid (ZA) or placebo. The primary outcome was new bone lesions assessed by radionuclide bone scan. Secondary outcomes included change in existing lesions, biochemical markers of bone turnover and skeletal events related to PDB. RESULTS: The median duration of follow-up was 84 months (range 0-127) and 180 participants (81%) completed the study. At baseline, 9 (8.1%) of the ZA group had PDB lesions vs 12 (10.8%) of the placebo group. Two of the placebo group developed new lesions versus none in the ZA group (OR 0.41, 95% CI 0.00 to 3.43, p=0.25). Eight of the placebo group had a poor outcome (lesions which were new, unchanged or progressing) compared with none of the ZA group (OR 0.08, 95% CI 0.00 to 0.42, p=0.003). At the study end, 1 participant in the ZA group had lesions compared with 11 in the placebo group. Biochemical markers of bone turnover were significantly reduced in the ZA group. One participant allocated to placebo required rescue therapy with ZA because of symptomatic disease. The number and severity of adverse events did not differ between groups. CONCLUSIONS: Genetic testing for pathogenic SQSTM1 variants coupled with intervention with ZA is well tolerated and has favourable effects on the progression of early PDB. TRIAL REGISTRATION NUMBER: ISRCTN11616770.

Glucagon-like Peptide-1 Receptor Agonists and Diabetic Osteopathy: Another Positive Effect of Incretines? A 12 Months Longitudinal Study.

Diabetic osteopathy is a frequent complication in patients with type 2 diabetes mellitus (T2DM). The association between T2DM and increased fracture risk has led to study the impact of new antidiabetic drugs on bone metabolism. Glucagon-like peptide-1 receptor agonists (GLP-1RAs) are incretin mimetic drugs which have many pleiotropic properties. The relationship between GLP-1RAs and bone is very complex: while in vitro and animal studies have demonstrated a protective effect on bone, human studies are scarce. We led a 12 months longitudinal study evaluating bone changes in 65 patients withT2DM for whom a therapy with GLP-1RAs had been planned. Fifty-four T2DM patients completed the 12-month study period; of them, 30 had been treated with weekly dulaglutide and 24 with weekly semaglutide. One-year therapy with GLP-1RAs resulted in a significant reduction in weight and BMI. Bone mineral density (BMD), bone metabolism, trabecular bone score (TBS), adiponectin, and myostatin were evaluated before and after 12 months of GLP-1RAs therapy. After 12 months of therapy bone turnover markers and adiponectin showed a significant increase, while myostatin values showed a modest but significant reduction. BMD-LS by DXA presented a significant reduction while the reduction in BMD-LS by REMS was not significant and TBS values showed a marginal increase. Both DXA and REMS techniques showed a modest but significant reduction in femoral BMD. In conclusion, the use of GLP-1RAs for 12 months preserves bone quality and reactivates bone turnover. Further studies are needed to confirm whether GLP-1RAs could represent a useful therapeutic option for patients with T2DM and osteoporosis.

Validation of the clinical consensus recommendations on the management of fracture risk in postmenopausal women with type 2 diabetes.

BACKGROUND AND AIMS: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.

Pathophysiology of Mild Hypercortisolism: From the Bench to the Bedside.

Mild hypercortisolism is defined as biochemical evidence of abnormal cortisol secretion without the classical detectable manifestations of overt Cushing's syndrome and, above all, lacking catabolic characteristics such as central muscle weakness, adipose tissue redistribution, skin fragility and unusual infections. Mild hypercortisolism is frequently discovered in patients with adrenal incidentalomas, with a prevalence ranging between 5 and 50%. This high variability is mainly due to the different criteria used for defining this condition. This subtle cortisol excess has also been described in patients with incidentally discovered pituitary tumors with an estimated prevalence of 5%. To date, the mechanisms responsible for the pathogenesis of mild hypercortisolism of pituitary origin are still not well clarified. At variance, recent advances have been made in understanding the genetic background of bilateral and unilateral adrenal adenomas causing mild hypercortisolism. Some recent data suggest that the clinical effects of glucocorticoid (GC) exposure on peripheral tissues are determined not only by the amount of the adrenal GC production but also by the peripheral GC metabolism and by the GC sensitivity. Indeed, in subjects with normal cortisol secretion, the combined estimate of cortisol secretion, cortisone-to-cortisol peripheral activation by the 11 beta-hydroxysteroid dehydrogenase enzyme and GC receptor sensitizing variants have been suggested to be associated with the presence of hypertension, diabetes and bone fragility, which are three well-known consequences of hypercortisolism. This review focuses on the pathophysiologic mechanism underlying both the different sources of mild hypercortisolism and their clinical consequences (bone fragility, arterial hypertension, subclinical atherosclerosis, cardiovascular remodeling, dyslipidemia, glucose metabolism impairment, visceral adiposity, infections, muscle damage, mood disorders and coagulation).

Bone Fragility in Gastrointestinal Disorders.

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.

Effects of Bisphosphonate Treatment on Circulating Lipid and Glucose Levels in Patients with Metabolic Bone Disorders.

Bisphosphonates are the first-choice treatment of osteoporosis and Paget's disease of bone. Among the bisphosphonates, the non-amino-bisphosphonates, such as clodronic acid, are intracellular converted into toxic analogues of ATP and induce cellular apoptosis whereas the amino-bisphosphonates, such as zoledronic acid, inhibit the farnesyl-diphosphate-synthase, an enzyme of the mevalonate pathway. This pathway regulates cholesterol and glucose homeostasis and is a target for statins. In this retrospective cohort study, we evaluated the effects of an intravenous infusion of zoledronic acid (5 mg) or clodronic acid (1500 mg) on blood lipid (i.e. total cholesterol, low-density lipoprotein-cholesterol, high-density lipoprotein-cholesterol and triglycerides) and glucose levels in patients with osteoporosis and Paget's disease of bone. All patients were evaluated before, 1 and 6 months after bisphosphonate treatment. Pagetic and osteoporotic patients treated with zoledronic acid showed a significant reduction in glucose and atherogenic lipids during follow-up whereas these phenomena were not observed after clodronic treatment. The effect on circulating lipid levels was similar in naïve and re-treated Pagetic patients. Zoledronic acid treatment was associated with a reduction in blood glucose and atherogenic lipids in patients with metabolic bone disorders. The extent of change was similar to that obtained with the regular assumption of a low-intensity statin. Further studies are warranted to better evaluate the clinical implications of these observations.

Vitamin D and COVID-19 severity and related mortality: a prospective study in Italy.

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.

Management of bone fragility in type 2 diabetes: Perspective from an interdisciplinary expert panel.

AIM: Bone fragility is increasingly recognized as a relevant complication of type 2 diabetes (T2D) and diabetic patients with fragility fractures have higher mortality rates than non diabetic individuals or diabetic patients without fractures. However, current diagnostic approaches for fracture risk stratification, such as bone mineral density measurement or the use of risk assessment algorithms, largely underestimate fracture risk in T2D patients. A multidisciplinary expert panel was established in order to in order to formulate clinical consensus recommendations on bone health assessment and management of fracture risk in patients with T2D. DATA SYNTHESIS: The following key questions were addressed: a) which are the risk factors for bone fragility in T2D?, b) which diagnostic procedures can be currently used to stratify fracture risk in T2D patients?, c) which are the effects of antidiabetic treatments on bone?, and d) how to prevent and treat bone fragility in T2D patients? Based on the available data members of this panel suggest that the stratification of fracture risk in patients with diabetes should firstly rely on the presence of a previous fragility fracture and on the individual risk profile, with the inclusion of T2D-specific risk factors (namely T2D duration above 10 yrs, presence of chronic T2D complications, use of insulin or thiazolidinediones and persistent HbA1c levels above 8% for at least 1 year). Two independent diagnostic approaches were then suggested in the presence or the absence of a prevalent fragility fracture, respectively. CONCLUSIONS: Clinical trials in T2D patients at risk for fragility fractures are needed to determine the efficacy and safety of available antiresorptive and anabolic agents in this specific setting.

When to Suspect Hidden Hypercortisolism in Type 2 Diabetes: A Meta-Analysis.

OBJECTIVE: To investigate whether the available literature helps to identify the characteristics of patients with type 2 diabetes (T2D) more frequently associated with hidden hypercortisolism (HidHyCo). METHODS: A meta-analysis was performed using studies that assessed both the prevalence of HidHyCo in patients with T2D and the characteristics of these patients with and without HidHyCo. The DerSimonian and Laird (DSL) and Hartung-Knapp-Sidik-Jonkman (HKSJ) methods were utilized. RESULTS: Among the 18 available studies, 6 provided the necessary data. The association between HidHyCo and advanced T2D (based on the patients' description given in each study in the presence of microvascular/macrovascular complications or insulin treatment plus hypertension or hypertension treated with 2 or more drugs), hypertension, insulin treatment, and dyslipidemia was reported in 5 (2184 patients), 6 (2283 patients), 3 (1440 patients), and 3 (987 patients) studies, respectively. HidHyCo was associated with advanced T2D as assessed by both the DSL (odds ratio [OR], 3.4; 95% confidence interval [95% CI], 2.12-5.67) and HKSJ (OR, 3.60; 95% CI, 2.03-6.41) methods and with the prevalence of hypertension or insulin treatment as assessed by the DSL method (OR, 1.92; 95% CI, 1.05-3.50 and OR, 2.29; 95% CI, 1.07-4.91, respectively) but not as assessed by the HKSJ method. CONCLUSION: Patients with advanced T2D have a higher prevalence of HidHyCo. These data inform about the selection of patients with T2D for HidHyCo screening.

Energy Metabolism and Ketogenic Diets: What about the Skeletal Health? A Narrative Review and a Prospective Vision for Planning Clinical Trials on this Issue.

The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a "poor" quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included.

Management and Medical Therapy of Mild Hypercortisolism.

Mild hypercortisolism (mHC) is defined as an excessive cortisol secretion, without the classical manifestations of clinically overt Cushing's syndrome. This condition increases the risk of bone fragility, neuropsychological alterations, hypertension, diabetes, cardiovascular events and mortality. At variance with Cushing's syndrome, mHC is not rare, with it estimated to be present in up to 2% of individuals older than 60 years, with higher prevalence (up to 10%) in individuals with uncontrolled hypertension and/or diabetes or with unexplainable bone fragility. Measuring cortisol after a 1 mg overnight dexamethasone suppression test is the first-line test for searching for mHC, and the degree of cortisol suppression is associated with the presence of cortisol-related consequences and mortality. Among the additional tests used for diagnosing mHC in doubtful cases, the basal morning plasma adrenocorticotroph hormone, 24-h urinary free cortisol and/or late-night salivary cortisol could be measured, particularly in patients with possible cortisol-related complications, such as hypertension and diabetes. Surgery is considered as a possible therapeutic option in patients with munilateral adrenal incidentalomas and mHC since it improves diabetes and hypertension and reduces the fracture risk. In patients with mHC and bilateral adrenal adenomas, in whom surgery would lead to persistent hypocortisolism, and in patients refusing surgery or in whom surgery is not feasible, medical therapy is needed. Currently, promising though scarce data have been provided on the possible use of pituitary-directed agents, such as the multi-ligand somatostatin analog pasireotide or the dopamine agonist cabergoline for the-nowadays-rare patients with pituitary mHC. In the more frequently adrenal mHC, encouraging data are available for metyrapone, a steroidogenesis inhibitor acting mainly against the adrenal 11-ßhydroxylase, while data on osilodrostat and levoketoconazole, other new steroidogenesis inhibitors, are still needed in patients with mHC. Finally, on the basis of promising data with mifepristone, a non-selective glucocorticoid receptor antagonist, in patients with mild cortisol hypersecretion, a randomized placebo-controlled study is ongoing for assessing the efficacy and safety of relacorilant, a selective glucocorticoid receptor antagonist, for patients with mild adrenal hypercortisolism and diabetes mellitus/impaired glucose tolerance and/or uncontrolled systolic hypertension.

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.

ZNF687 Mutations in Severe Paget Disease of Bone Associated with Giant Cell Tumor.

Paget disease of bone (PDB) is a skeletal disorder characterized by focal abnormalities of bone remodeling, which result in enlarged and deformed bones in one or more regions of the skeleton. In some cases, the pagetic tissue undergoes neoplastic transformation, resulting in osteosarcoma and, less frequently, in giant cell tumor of bone (GCT). We performed whole-exome sequencing in a large family with 14 PDB-affected members, four of whom developed GCT at multiple pagetic skeletal sites, and we identified the c.2810C>G (p.Pro937Arg) missense mutation in the zinc finger protein 687 gene (ZNF687). The mutation precisely co-segregated with the clinical phenotype in all affected family members. The sequencing of seven unrelated individuals with GCT associated with PDB (GCT/PDB) identified the same mutation in all individuals, unravelling a founder effect. ZNF687 is highly expressed during osteoclastogenesis and osteoblastogenesis and is dramatically upregulated in the tumor tissue of individuals with GCT/PDB. Interestingly, our preliminary findings showed that ZNF687, indicated as a target gene of the NFkB transcription factor by ChIP-seq analysis, is also upregulated in the peripheral blood of PDB-affected individuals with (n = 5) or without (n = 6) mutations in SQSTM1, encouraging additional studies to investigate its potential role as a biomarker of PDB risk.

Paget's Disease of Bone.

Paget's disease of bone (PDB) is a chronic and focal bone disorder, characterized by increased osteoclast-mediated bone resorption and a subsequent compensatory increase in bone formation, resulting in a disorganized mosaic of woven and lamellar bone at one or more affected skeletal sites. As a result, bone pain, noticeable deformities, arthritis at adjacent joints, and fractures can occur. In a small proportion of cases neoplastic degeneration in osteosarcoma, or, less frequently, giant cell tumor has been also described at PDB sites. While recent epidemiological evidences clearly indicate a decrease in the prevalence and the severity of PDB, over the past 2 decades there have been consistent advances on the genetic mechanisms of disease. It is now clear that PDB is a genetically heterogeneous disorder, with mutations in at least two different genes (SQSTM1, ZNF687) and more common predisposing variants. As a counterpart to the genetic hypothesis, the focal nature of lesions, the decline in prevalence rates, and the incomplete penetrance of the disease among family members suggest that one or more environmental triggers may play a role in the pathophysiology of PDB. The exact nature of these triggers and how they might interact with the genetic factors are less understood, but recent experimental data from mice models suggest the implication of paramixoviral infections. The clinical management of PDB has also evolved considerably, with the development of potent aminobisphosphonates such as zoledronic acid which, given as a single intravenous infusion, now allows a long-term disease remission in the majority of patients.

Vitamin D Status in Paget Disease of Bone and Efficacy-Safety Profile of Cholecalciferol Treatment in Pagetic Patients with Hypovitaminosis D.

Adequate vitamin D status is essential for skeletal health. Paget's disease of bone (PDB) is a common metabolic skeletal disorder, but data regarding the vitamin D status in PDB patients are lacking. We performed a case-control study to estimate vitamin D status in 708 PDB patients and in 1803 healthy controls from Italy and an observational prospective study to evaluate the efficacy-safety profile of oral cholecalciferol treatment [400.000 International Units (UI) of cholecalciferol administered in cycles of 8 weeks until 25OHD levels reaches 70 nmol/L as primary therapy and 50.000 UI of cholecalciferol administered every 2 weeks for 52 weeks for the maintenance therapy] in 82 PDB patients with hypovitaminosis D, i.e., 25OHD < 50 nmol/L. The main outcome measures for the prospective study were 25OHD levels, metabolic risk factors (RF) for nephrolithiasis, bone pain score (BPS), and pain medication score (PMS). Over half of PDB patients had hypovitaminosis D. Among PDB patients treated with cholecalciferol, 76 patients reached 25OHD levels ≥ 70 nmol/L after the first cycle of primary therapy and the remaining six patients after a second cycle. The maintenance therapy guaranteed 25OHD levels ≥ 70 nmol/L during the entire follow-up. The increase in 25OHD levels reduced PTH, BPS, and PMS levels, without changes in RF for nephrolithiasis. We can conclude that (i) hypovitaminosis D is frequent in PDB patients, (ii) cholecalciferol significantly increased 25OHD levels in PDB patients, and (iii) the correction of hypovitaminosis D improves the quality of life of PDB patients without inducing significant changes in RF for nephrolithiasis.

Paget disease of bone-associated UBA domain mutations of SQSTM1 exert distinct effects on protein structure and function.

SQSTM1 mutations are common in patients with Paget disease of bone (PDB), with most affecting the C-terminal ubiquitin-associated (UBA) domain of the SQSTM1 protein. We performed structural and functional analyses of two UBA domain mutations, an I424S mutation relatively common in UK PDB patients, and an A427D mutation associated with a severe phenotype in Southern Italian patients. Both impaired SQSTM1's ubiquitin-binding function in pull-down assays and resulted in activation of basal NF-κB signalling, compared to wild-type, in reporter assays. We found evidence for a relationship between the ability of different UBA domain mutants to activate NF-κB signalling in vitro and number of affected sites in vivo in 1152 PDB patients from the UK and Italy, with A427D-SQSTM1 producing the greatest level of activation (relative to wild-type) of all PDB mutants tested to date. NMR and isothermal titration calorimetry studies were able to demonstrate that I424S is associated with global structural changes in the UBA domain, resulting in 10-fold weaker UBA dimer stability than wild-type and reduced ubiquitin-binding affinity of the UBA monomer. Our observations provide insights into the role of SQSTM1-mediated NF-κB signalling in PDB aetiology, and demonstrate that different mutations in close proximity within loop 2/helix 3 of the SQSTM1 UBA domain exert distinct effects on protein structure and stability, including indirect effects at the UBA/ubiquitin-binding interface.

Undiagnosed vertebral fractures influence quality of life in postmenopausal women with reduced ultrasound parameters.

BACKGROUND: Osteoporosis, a multifactorial systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to increased bone fragility, is a worldwide public health problem. Vertebral fractures affect approximately 20% of postmenopausal women and are a hallmark of osteoporosis, but they may pass unnoticed, although they may lead to long-term immobility and disability. QUESTIONS/PURPOSES: The aims of the present study were (1) to determine the prevalence and the severity of vertebral fractures in a large cohort of Italian women aged 60 years or older with reduced values of quantitative ultrasound parameters; and (2) to assess whether vertebral fractures and other variables may be associated with health-related quality of life. METHODS: A total of 2450 women without back pain aged 60 years or older, after the completion of the Quality of Life Questionnaire of the European Foundation for Osteoporosis QUALEFFO, underwent quantitative ultrasound evaluation of the calcaneus; in those with a stiffness t-score of ≤ -2 (n = 1194), radiographic evaluation of the thoracic and lumbar spine was carried out and then quantitative morphometry was performed by dedicated software (MorphoXpress). The radiographic analysis was carried out on 885 women who presented films of adequate quality. Multivariate regression was used to adjust for confounding variables. RESULTS: Of those who underwent radiographic analysis, 681 had no vertebral fractures, and 204 women (23.1%) had one or more previously undiagnosed vertebral fractures. The prevalence of previously undiagnosed vertebral fractures increased with advancing age with more than 30% of women older than 75 years having at least one fracture. Older age, body mass index, and severe vertebral fractures were independently associated with a worse total QUALEFFO score. CONCLUSIONS: We found that approximately one in four women showed evidence of undiagnosed vertebral fractures, and there was a strong age effect trend. Moreover, the severity grade of vertebral fractures, more than the number of fractures, was associated with a worsening of health-related quality of life as assessed by QUALEFFO. These findings confirm the clinical relevance of an early diagnosis of vertebral fractures and seem to support the usefulness of quantitative ultrasound measurements in the stratification of postmenopausal women at increased fracture risk. LEVEL OF EVIDENCE: Level III, prognostic study. See the Guidelines for Authors for a complete description of levels of evidence.

Maxillofacial Bone Involvement in Fibro-Osseous Lesions: Emphasizing the Significance of Differential Diagnosis.

The World Health Organization's (WHO) 2022 update on the classification of odontogenic and maxillofacial bone tumors has revolutionized diagnostic and treatment paradigms by integrating novel molecular insights. Fibro-osseous lesions of the maxillo-facial bones constitute a heterogeneous group encompassing fibrous dysplasia, Psammomatoid Ossifying Fibroma (PSOF), Juvenile Trabecular Ossifying Fibroma (JTOF), and other variants. Despite histological similarities, their distinct clinical manifestations and prognostic implications mandate precise differentiation. The intricacies of diagnosing fibro-osseous lesions pose challenges for pathologists, maxillofacial surgeons, dentists and oral surgeons, underscoring the importance of a systematic approach to ensure optimal patient management. Herein, we present two cases, fibrous dysplasia and Cemento-Ossifying Fibroma, detailing their clinical encounters and management strategies. Both patients provided informed consent for publishing their data and images, adhering to ethical guidelines.

A novel proteomic signature of osteoclast differentiation unveils the deubiquitinase UCHL1 as a necessary osteoclastogenic driver.

Bone destruction, a major source of morbidity, is mediated by heightened differentiation and activity of osteoclasts (OC), highly specialized multinucleated myeloid cells endowed with unique bone-resorptive capacity. The molecular mechanisms regulating OC differentiation in the bone marrow are still partly elusive. Here, we aimed to identify new regulatory circuits and actionable targets by comprehensive proteomic characterization of OCgenesis from mouse bone marrow monocytes, adopting two parallel unbiased comparative proteomic approaches. This work disclosed an unanticipated protein signature of OCgenesis, with most gene products currently unannotated in bone-related functions, revealing broad structural and functional cellular reorganization and divergence from macrophagic immune activity. Moreover, we identified the deubiquitinase UCHL1 as the most upregulated cytosolic protein in differentiating OCs. Functional studies proved it essential, as UCHL1 genetic and pharmacologic inhibition potently suppressed OCgenesis. Furthermore, proteomics and mechanistic dissection showed that UCHL1 supports OC differentiation by restricting the anti-OCgenic activity of NRF2, the transcriptional activator of the canonical antioxidant response, through redox-independent stabilization of the NRF2 inhibitor, KEAP1. Besides offering a valuable experimental framework to dissect OC differentiation, our study discloses the essential role of UCHL1, exerted through KEAP1-dependent containment of NRF2 anti-OCgenic activity, yielding a novel potential actionable pathway against bone loss.

Idiopathic osteoporosis in men.

Over the last decade, the increasingly significant problem of osteoporosis in men has begun to receive much more attention than in the past. In particular, recent observations from large scale population studies in males led to an advance in the understanding of morphologic basis of growth, maintenance and loss of bone in men, as well as new insights about the pathophysiology and treatment of this disorder. While fracture risk consistently increases after age 65 in men (with up to 50 % of cases due to secondary etiologies), osteoporosis and fractures may also occur in young or middle aged males in the absence of an identifiable etiology. For this category (so called idiopathic osteoporosis), there are still major gaps in knowledge, particularly concerning the etiology and the clinical management. This article provides a summary of recent developments in the acquisition and maintenance of bone strength in men, as well as new insights about the pathogenesis, diagnosis, and treatment of idiopathic osteoporosis.