Vascular Dysfunction of COVID-19 Is Partially Reverted in the Long-Term.

BACKGROUND: COVID-19 is characterized by severe inflammation during the acute phase and increased aortic stiffness in the early postacute phase. In other models, aortic stiffness is improved after the reduction of inflammation. We aimed to evaluate the mid- and long-term effects of COVID-19 on vascular and cardiac autonomic function. The primary outcome was aortic pulse wave velocity (aPWV). METHODS: The cross-sectional Study-1 included 90 individuals with a history of COVID-19 and 180 matched controls. The longitudinal Study-2 included 41 patients with COVID-19 randomly selected from Study-1 who were followed-up for 27 weeks. RESULTS: Study-1: Compared with controls, patients with COVID-19 had higher aPWV and brachial PWV 12 to 24 (but not 25-48) weeks after COVID-19 onset, and they had higher carotid Young's elastic modulus and lower distensibility 12 to 48 weeks after COVID-19 onset. In partial least squares structural equation modeling, the higher the hs-CRP (high-sensitivity C-reactive protein) at hospitalization was, the higher the aPWV 12 to 48 weeks from COVID-19 onset (path coefficient: 0.184; P=0.04). Moreover, aPWV (path coefficient: -0.186; P=0.003) decreased with time. Study-2: mean blood pressure and carotid intima-media thickness were comparable at the end of follow-up, whereas aPWV (-9%; P=0.01), incremental Young's elastic modulus (-17%; P=0.03), baroreflex sensitivity (+28%; P=0.049), heart rate variability triangular index (+15%; P=0.01), and subendocardial viability ratio (+12%; P=0.01×10-4) were significantly improved. There was a trend toward improvement in brachial PWV (-6%; P=0.14) and carotid distensibility (+18%; P=0.05). Finally, at the end of follow-up (48 weeks after the onset of COVID-19) aPWV (+6%; P=0.04) remained significantly higher in patients with COVID-19 than in control subjects. CONCLUSIONS: COVID-19-related arterial stiffening involves several arterial tree portions and is partially resolved in the long-term.

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.

Special Issue: Metabolic Bone Diseases: Molecular Biology, Pathophysiology and Therapy.

Bone is a vital tissue as it carries out various metabolic functions: support of the body, protection of the internal organs, mineral deposit and hematopoietic functions [...].

Bone health in Duchenne muscular dystrophy: clinical and biochemical correlates.

PURPOSE: An increased fracture risk is commonly reported in Duchenne muscular dystrophy (DMD). Our aim was to investigate bone mineral density (BMD) and bone turnover, including sclerostin, and their association with markers of cardiac and respiratory performance in a cohort of DMD subjects. METHODS: In this single center, cross sectional observational study, lumbar spine (LS) BMD Z-scores, C-terminal telopeptide of procollagen type I (CTX) and osteocalcin (BGP), as bone resorption and formation markers, respectively, and sclerostin were assessed. Left ventricular ejection fraction (LVEF) and forced vital capacity (FVC) were evaluated. Clinical prevalent fractures were also recorded. RESULTS: Thirty-one patients [median age = 14 (12-21.5) years] were studied. Ambulant subjects had higher LS BMD Z-scores compared with non-ambulant ones and subjects with prevalent clinical fractures [n = 9 (29%)] showed lower LS BMD Z-scores compared with subjects without fractures. LS BMD Z-scores were positively correlated with FVC (r = 0.50; p = 0.01), but not with glucocorticoid use, and FVC was positively associated with BGP (r = 0.55; p = 0.02). In non-ambulant subjects, LS BMD Z-scores were associated with BMI (r = 0.54; p = 0.02) and sclerostin was associated with age (r = 0.44; p = 0.05). Age, BMI, FVC and sclerostin were independently associated with LS BMD Z-score in a stepwise multiple regression analysis. Older age, lower BMI, FVC and sclerostin were associated with lower LS BMD Z-scores. CONCLUSION: In a cohort of DMD patients, our data confirm low LS BMD Z-scores, mainly in non-ambulant subjects and irrespective of the glucocorticoid use, and suggest that FVC and sclerostin are independently associated with LS BMD Z-scores.

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).

Venous thromboembolism in hospital emergency room. A retrospective study on climatic effect.

Several cardiovascular conditions exhibit seasonality in frequency and mortality, but little is known about the seasonality of Venous ThromboEmbolism (VTE), a very relevant medical condition, and seasonal influences are still conflicting. Patients having co-morbidities, individual suffered from dyspnea, swelling, edema of lower limb, pain (chest, lower limbs) are admitted frequently to the hospital emergency room (HER), particularly. Both mark a potential risk for VTE, that can be increased also by seasonality. A four years retrospective analysis (2016-2019) was carried out in individuals and patients admitted to the HER of the Hospital of Catania (a Mediterranean city of Sicily, Italy) to evaluate the VTE frequency and its seasonal differences, common symptoms, potential usage of some common laboratory tests. Dyspnea, swelling, edema of lower limb and pain (chest, lower limbs) were considered to suspect pulmonary embolism (PE) or for deep vein thrombosis of lower limb (DVT). Platelet count, platelet volume, fibrinogen, C-reactive protein, and D-dimer were considered. VTE frequency per year was 2.9/10,000 (2016), 4.9/10,000 (2017) 3.6/10,000 (2018), and 5.1/10,000 (2019) respectively. Dyspnea was highly frequent for PE, edema and lower limb pain were frequent in DVT patients. Fibrinogen, C reactive protein, and D-dimer values were found raised in all the VTE patients. Platelet volume was found higher in DVT than PE VTE events that occurred in warm periods were modestly greater (57 VTE: 38 DVT, 19 PE) compared to cold months (52 VTE: 34 DVT, 18 PE). Our results could be explained by the increased sweating due to the high temperatures, which in turn, can affect both on plasma concentration and on hematocrit value coupled to the reduction in atmospheric pressure determining both a hyper-coagulative condition. Climate seasonal characteristics, and environmental conditions in Catania city (Sicily) may be as reasonable items in expecting on different VTE rates in warm period compared to cold. This study highlights no specific symptoms, and confirms the common lab tests for individuals and patients admitted to HER as simple and helpful tools in initiating none or mini-invasive diagnostic strategy for the VTE. Finally, the climate/seasonality coupled with latitude can have a direct influence on the incidence of DVT.

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.

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.

Hematological Diseases and Osteoporosis.

Secondary osteoporosis is a common clinical problem faced by bone specialists, with a higher frequency in men than in women. One of several causes of secondary osteoporosis is hematological disease. There are numerous hematological diseases that can have a deleterious impact on bone health. In the literature, there is an abundance of evidence of bone involvement in patients affected by multiple myeloma, systemic mastocytosis, thalassemia, and hemophilia; some skeletal disorders are also reported in sickle cell disease. Recently, monoclonal gammopathy of undetermined significance appears to increase fracture risk, predominantly in male subjects. The pathogenetic mechanisms responsible for these bone loss effects have not yet been completely clarified. Many soluble factors, in particular cytokines that regulate bone metabolism, appear to play an important role. An integrated approach to these hematological diseases, with the help of a bone specialist, could reduce the bone fracture rate and improve the quality of life of these patients.

Melorheostosis and Osteopoikilosis Clinical and Molecular Description of an Italian Case Series.

Melorheostosis (MEL) is an uncommon, sclerosing disease, characterised by hyperostosis of long bones, resembling the flowing of candle wax. The disease is sporadic and the pathogenesis is still poorly understood. Occasionally, the same family can include individuals with MEL and Osteopoikilosis (OPK), a disease characterised by multiple round foci of increased bone density. LEMD3 gene mutations are related to OPK and Buschke-Ollendorff Syndrome, a genetic condition in which an association between MEL, OPK and skin lesions is observed. In rare cases, LEMD3 mutations and recently mosaic MAP2K1 gene mutations have been correlated to MEL suggesting that somatic mosaicism could be causative of the disease. In this study, we described the clinical, radiological and molecular findings of 19 individuals with MEL and 8 with OPK and compared the results to the medical literature. The molecular analyses of this case series corroborate the available data in the medical literature, indicating that LEMD3 germline mutations are not a major cause of isolated MEL and reporting five further cases of OPK caused by LEMD3 germline mutations.

Anticoagulants and Osteoporosis.

Anticoagulant agents are widely used in the treatment of thromboembolic events and in stroke prevention. Data about their effects on bone tissue are in some cases limited or inconsistent (oral anti-vitamin K agents), and in others are sufficiently strong (heparins) to suggest caution in their use in subjects at risk of osteoporosis. This review analyses the effects of this group of drugs on bone metabolism, on bone mineral density, and on fragility fractures. A literature search strategy was developed by an experienced team of specialists by consulting the MEDLINE platform, including published papers and reviews updated to March 2019. Literature supports a detrimental effect of heparin on bone, with an increase in fracture rate. Low molecular weight heparins (LMWHs) seem to be safer than heparin. Although anti-vitamin K agents (VKAs) have a significant impact on bone metabolism, and in particular, on osteocalcin, data on bone mineral density (BMD) and fractures are contrasting. To date, the new direct oral anticoagulants (DOACs) are found to safe for bone health.

Denosumab Inhibition of RANKL and Insulin Resistance in Postmenopausal Women with Osteoporosis.

The tumor necrosis factor-related cytokine receptor activator of nuclear factor kappa B ligand (RANKL) has been proposed as predictor of incident type 2 diabetes mellitus, and experimental blockade of RANKL resulted in a marked improvement of glucose tolerance. Denosumab is a fully human monoclonal antibody that binds to RANKL and prevents osteoclast formation, function and survival, leading to fracture risk reduction. The aim of our study was to investigate glucometabolic parameters, insulin resistance, and lipid profile in non-diabetic women receiving denosumab. Forty-eight women with postmenopausal osteoporosis were enrolled and treated with a subcutaneous dose (60 mg) of denosumab. At baseline and after 4, 12, ad 24 weeks, insulin resistance was computed by homeostasis model assessment of insulin resistance (HOMA-IR) and total cholesterol, triglycerides and HDL cholesterol were also measured. At baseline and after 24 weeks, bone turn-over markers were also evaluated. After denosumab administration, with the exception of a slight reduction of insulin and HOMA-IR values after 4 weeks (p < 0.05), neither fasting plasma glucose nor insulin and insulin resistance were significantly changed. Lipid parameters remained unchanged at each time-points of this study. A reduction of C-telopeptide of type 1 collagen (-63%, p < 0.0001) and osteocalcin (-45%, p < 0.0001), as bone resorption and formation markers, respectively, were observed after 24 weeks. Baseline levels of bone biomarkers were not predictive of HOMA-IR, and changes of osteocalcin were not associated to markers of glucose control. In osteoporotic otherwise healthy postmenopausal women, denosumab was not associated with relevant modification of insulin resistance and lipid profile.

Effects of strontium ranelate on bone mass and bone turnover in women with thalassemia major-related osteoporosis.

Subjects affected by thalassemia major (TM) often have reduced bone mass and increased fracture risk. Strontium ranelate (SrR) is an effective treatment for postmenopausal and male osteoporosis. To date, no data exist on the use of SrR in the treatment of TM-related osteoporosis. Our aim was to evaluate the effects of SrR on bone mineral density (BMD), bone turnover markers and inhibitors of Wnt signaling (sclerostin and DKK-1). Twenty-four TM osteoporotic women were randomized to receive daily SrR 2 g or placebo in addition to calcium carbonate (1,000 mg) and vitamin D (800 IU). BMD at the lumbar spine and femoral neck, bone turnover markers (C-terminal telopeptide of procollagen type I [CTX], bone-specific alkaline phosphatase [BSAP]) and insulin-like growth factor-1 (IGF-1), sclerostin and DKK-1 were assessed at baseline and after 24 months. Back pain was measured by visual analog scale (VAS) every 6 months. After 24 months, TM women treated with SrR had increased their spine BMD values in comparison to baseline (p < 0.05). Moreover, they also exhibited a reduction of CTX and sclerostin levels (but not DKK-1) and exhibited an increase of BSAP and IGF-1 (p < 0.05); however, no significant changes were observed in the placebo group. In the SrR group, a reduction of back pain was observed after 18 months in comparison to baseline (p < 0.05) and after 24 months in comparison to placebo (p < 0.05). Our study reports for the first time the effects of SrR in the treatment of TM-related osteoporosis. SrR treatment improved BMD and normalized bone turnover markers, as well as lowering sclerostin serum levels.

Successful neridronate therapy in pregnancy-associated osteoporosis.

Pregnancy-associated osteoporosis is a rare condition. The pathogenesis is probably multifactorial but has not yet been completely clarified. In this case report, a 38-year-old woman was referred to hospital after suffering an acute, non-traumatic back pain one month after delivering her first child. The radiological examination revealed four vertebral fractures. Bone mineral density was reduced, particularly at spine level. Biochemical tests were within normal range, except for increased urinary deoxypyridinoline and a slight reduction of the serum 25-OH vitamin D level. The patient was treated with neridronate, calcium and cholecalciferol. After one month, the patient was free of pain and DXA measurement after six months showed a marked recovery of bone mineral density at the spine and hip level.

COVID-19-related retinal microvasculopathy and systemic implications in patients with severe disease: results from the Methuselah study.

Objectives: To assess the reversibility of retinal microvascular changes in the long term and to investigate the potential links with other vascular diseases of COVID-19. Methods: We designed a prospective multicenter observational study. Patients were enrolled from the Methuselah study cohort. Retinal vascular function was studied in these patients using optical coherence tomography angiography (OCTA); aortic stiffness was measured using aortic pulse wave velocity. These examinations were performed 1 (Visit 1) and 12 (Visit 2) months after the hospital discharge for severe COVID-19. A control subject group matched for age and sex was included to define normal values. Results: A total of 28 control subjects (56 eyes) and 25 patients (50 eyes) completed the scheduled OCTA assessment; 18 patients (36 eyes) also completed the macrovascular examination. Compared to controls, the vessel density of the superficial capillary plexus (SCP) was reduced, whereas the foveal avascular zone area was enlarged at Visit 1 (p = 0.016 and < 0.001, respectively) and was not modified after the 12-month follow-up in COVID-19 patients (p = 0.011 and 0.001, respectively). Higher inflammation and lower renal function during hospitalization were linked to higher aortic stiffness and reduced vessel density of the SCP 1 month after the acute phase of COVID-19. A slower recovery of aortic dysfunction was linked to worse retinal vascular outcomes at Visit 2. Conclusion: Retinal vascular alterations were not reversible 12 months after COVID-19 and were linked to inflammation and renal dysfunction during hospitalization as well as to aortic stiffness measured during follow-up.

Indirect Effects of the COVID-19 Pandemic on In-Hospital Outcomes among Internal Medicine Departments: A Double-Center Retrospective Study.

The coronavirus disease 19 (COVID-19) emergency led to rearrangements of healthcare systems with a significant impact on those internal medicine departments that had not been converted to COVID-19 wards. A reduced number of departments, indeed, had to cope with the same number of patients along with a lack of management of patients' chronic diseases. We conducted a retrospective study aimed at examiningthe consequences of the COVID-19 pandemic on internal medicine departments that were not directly managing COVID-19 patients. Data from 619 patients were collected: 247 subjects hospitalized in 2019 (pre-COVID-19 era), 178 in 2020 (COVID-19 outbreak era) and 194 in 2021 (COVID-19 ongoing era). We found that in 2020 in-hospital mortality was significantly higher than in 2019 (17.4% vs. 5.3%, p = 0.009) as well as length of in-hospital stay (LOS) (12.7 ± 6.8 vs. 11 ± 6.2, p = 0.04). Finally, we performed a logistic regression analysis of the major determinants of mortality in the entire study population, which highlighted an association between mortality, being bedridden (ß = 1.4, p = 0.004), respiratory failure (ß = 1.5, p = 0.001), glomerular filtration rate (ß = -0.16, p = 0.03) and hospitalization in the COVID-19 outbreak era (ß = 1.6, p = 0.005). Our study highlights how the COVID-19 epidemic may have caused an increase in mortality and LOS even in patients not directly suffering from this infection.

Interrelations between clinical-psychological features and bone mineral density changes in post-menopausal women undergoing anti-osteoporotic treatment: a two-year follow-up.

Introduction: Psychological features have been bidirectionally associated with osteoporosis, but it is still unclear whether patient's anxiety fluctuations during the anti-osteoporotic treatment can have an impact on bone mineral density (BMD) variation. The aim of this study was to investigate the interrelations between psychological distress features, such as anxiety, depression, health-related QoL (HRQoL) and bone health in women receiving anti-osteoporotic treatment. Methods: 192 post-menopausal osteoporotic women were treated with alendronate or risedronate according to the standard procedure. The levels of anxiety, depression, and perceived HRQoL, along with BMD, were assessed at baseline and at a 2-year follow-up. Results: At the end of the study, the patients showed a statistically significant increase of both psychic and somatic anxiety (p<0.0001) and exhibited a worsening of depressive symptoms (p<0.0001), whereas HRQoL showed no change. BMD improved and no incident fractures occurred. BMD variation (ΔBMD) at lumbar spine was significantly associated with anxiety levels (r=0.23, p=0.021). Multiple regression analysis showed that both patients' worsening anxiety levels (ß = -0.1283, SE=0.06142, p=0.04) and their treatment adherence (ß=0.09, SE=0.02, p=0.0006) were independently associated with ΔBMD. Discussion: The findings of the current follow-up study suggest that BMD in post-menopausal women undergoing anti-osteoporotic treatment was predicted by treatment adherence and anxiety change over time.

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

Introduction: Hypophosphatasia (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. Methods: There 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. Results: There 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. Discussion: We 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.

When the FRAX(®) test is applied to controlled clinical trials.

FRAX(®) is a computer-based algorithm developed by the World Health Organization Collaborating Centre for Metabolic Bone Diseases in Sheffield (UK). This algorithm calculates fracture probability from easily obtained clinical risk factors in men and women: age, sex, body mass index and dichotomized variables comprising prior fragility fracture, parental history of hip fracture, current tobacco smoking, use of long-term oral glucocorticoid, rheumatoid arthritis, other causes of secondary osteoporosis and high alcohol consumption (femoral neck bone mineral density can be optionally input to enhance fracture risk prediction). The output of FRAX(®) is the 10-year probability of a major osteoporotic fracture (hip, clinical spine, humerus or wrist fracture) and the 10-year probability of hip fracture.Recently various Authors have re-evaluated the effectiveness of drugs approved for postmenopausal osteoporosis to test whether they are more effective in women with higher FRAX(®) probabilities.

Therapeutic Options for the Management of Aromatase Inhibitor- Associated Bone Loss.

BACKGROUND: Breast cancer is the most commonly occurring cancer in women worldwide. Early breast cancer is a kind of invasive neoplasm that has not proliferated beyond the breast or the axillary lymph nodes. Current therapeutic strategies for breast cancer mainly include local therapies such as surgery or radiotherapy and systemic therapies like chemotherapy, endocrine, and targeted therapy. Nowadays, the adjuvant treatment for hormone receptor-positive early breast cancer in postmenopausal women remains the main effective systemic therapy which can improve disease- free survival and overall survival; it involves several endocrine treatment regimens, including Selective Estrogen Receptor Modulators (SERMs), Aromatase Inhibitors (AIs), or a combination of them. AIs have been shown to be more effective in preventing recurrence in postmenopausal women with early breast cancer when compared with tamoxifen, thus representing the standard of care for adjuvant endocrine therapy. Although AIs are usually well-tolerated, they can have some side effects. Apart from the appearance of arthralgias or myalgias and cardiovascular events, AI therapies, reducing already low endogenous postmenopausal estradiol levels, cause increased bone loss and increase fracture risk in postmenopausal women. OBJECTIVES: The objective of this review is to evaluate the therapeutic options in the management of Aromatase Inhibitor-Associated Bone Loss (AIBL). METHODS: We reviewed the current literature dealing with different therapeutic options in the treatment of AIBL. RESULTS: Clinical practice guidelines recommend a careful evaluation of skeletal health in all women with breast cancer before AI therapy initiation. Adequate calcium and vitamin D intake have also been suggested. Pharmacological attempts to minimize AI-related bone loss have focused on the use of antiresorptive agents, such as bisphosphonates and denosumab to protect bone integrity and reduce the risk of fractures. Furthermore, clinical trials have shown that by making the bone microenvironment less susceptible to breast cancer metastasis, these drugs are able to increase disease- free survival. CONCLUSIONS: AI, that are the pillar of the systemic treatment for patients with hormone receptorpositive breast cancer, are associated with different side effects, and in particular, osteoporosis and fractures. Both bisphosphonates and denosumab are able to prevent this negative effect.