Presentation of hypoparathyroidism in Italy: a nationwide register-based study.

PURPOSE: We sought to assess the clinical presentation of hypoparathyroidism (HypoPT) in Italy. METHODS: We performed a nationwide study retrieving data from the hospital discharge ICD-9 codes database of the Italian Health Ministry, from 2007 through 2017. The codes corresponding to diagnosis of cardiovascular disease, cancer, infection, renal failure, psychiatric disease, upper airway tract infection and pneumonia, seizures, nephrolithiasis, cognitive impairment, cerebral calcifications, skin disorders, fracture, and cataract were retrieved when associated with the diagnosis of HypoPT (252.1). We excluded codes corresponding to diagnoses of cancer of the neck region. In-hospital mortality rate was calculated. We retrieved the same data from an age- and sex-matched non-HypoPT control population. RESULTS: Fourteen thousand five hundred seventy-nine hospitalizations for HypoPT and controls were analyzed. Hospitalization for cardiovascular disease, cancer, infection, renal failure, seizures, nephrolithiasis, cerebral calcifications (p < 0.0001), and cognitive impairment (p < 0.05) were more common in HypoPT compared to controls. Mean age of HypoPT with cardiovascular disease, cancer, and renal failure was younger compared to controls (p < 0.0001). The OR of hospitalization for cardiovascular disease, cancer, renal failure, seizures (OR 2, 40, 48  and 1.6, respectively), and nephrolithiasis (OR 1.6) were significant in HypoPT compared to non-HypoPT. The OR of hospitalization for infection and cognitive impairment were significant only in HypoPT women (OR 1.3 and 2.3, respectively). In-hospital mortality rate was lower in HypoPT vs controls (0.5% and 3.7%; p < 0.0001). CONCLUSION: Hospitalizations for cardiovascular disease, cancer, and renal failure are more prevalent and occur at a younger age in HypoPT vs non-HypoPT. Hospitalizations for seizures and nephrolithiasis are frequent in HypoPT; those for infection and cognitive impairment are more common in HypoPT women.

Twenty-four hour Holter ECG in normocalcemic and hypercalcemic patients with hyperparathyroidism.

PURPOSE: To investigate the occurrence of arrhythmias in patients with normocalcemic (NC) primary hyperparathyroidism (PHPT) compared to both hypercalcemic PHPT patients and control subjects by means of 24-h Holter ECG. METHODS: Thirteen NCPHPT postmenopausal patients were enrolled and age-matched with 13 hypercalcemic PHPT patients and 13 controls. Every subject underwent basal ECG, 24-h Holter ECG and mineral metabolism biochemical evaluation. RESULTS: PHPT patients had higher mean serum calcium levels compared to both NCPHPT and controls; there was no difference in mean serum calcium levels between NCPHPT and controls. Both NCPHPT and PHPT patients had significantly higher mean PTH levels compared with controls. There were no differences in ECG parameters between the three groups, except for QTc interval. PHPT patients had normal QTc interval values, but significantly shorter mean values compared with those of controls and NCPHPT patients. During 24-h Holter ECG recording, 100% of PHPT patients had supraventricular premature beats (SVPBs), compared to 46% of NCPHPT (p = 0.005) and to 53% of controls (p = 0.01). PHPT patients experienced ventricular premature beats (VPBs) (69.2%) vs 15% of NCPHPT patients (p = 0.01) and 23% of controls (p = 0.04). There was no difference between NCPHPT and controls subjects concerning occurrence of both VPBs and SVPBs. CONCLUSIONS: NCPHPT patients did not experience an increased occurrence of arrhythmias compared to controls, while PHPT patients showed an increased occurrence compared to both controls and NCPHPT. Our findings are most probably related to the short QTc interval caused by hypercalcemia observed in PHPT patients, but not in NCPHPT.

Efficacy of a gluten-free diet in reducing the widespread pain index and symptom severity scale in patients affected by fibromyalgia.

OBJECTIVE: Dietary interventions to improve fibromyalgia (FM) symptoms reported conflicting results. This study aimed to treat FM patients with a gluten-free diet (GFD), alternated with a non-restricted gluten-containing diet, followed by a rechallenge of the GFD. METHODS: Twenty postmenopausal women with FM and no history of celiac disease participated. A GFD was assigned for 6 months. This was followed by 3 months of a non-restricted gluten-containing diet and then a new GFD for another 6 months. At each visit, the widespread pain index (WPI) and the symptom severity scale (SS) scores were evaluated. RESULTS: The mean age of the patients enrolled was 53.9±10 years. None of the patients had a diagnosis of irritable bowel disease, although they reported vague gastrointestinal symptoms. After 6 months of a GFD, a statistically significant reduction was observed for the WPI (10.3±1.8 vs 7.7±1.4; p<0.0001) and the SS scale (6.4±1.8 vs 4.15±1.6; p=0.0002). The D percentage reduction of the WPI after 6 months of GFD was -24%±9%, while for the SS scale, it was -36%±21%. The following reintroduction of a gluten-containing diet brought about a statistically significant rise in the absolute SS scale and WPI, as well as a D modification of the WPI (21%±13%) and of the SS scale (74%±90%). The rechallenge of the GFD showed a significant improvement in absolute and D WPI (-24%±7%) and SS (-36%±11%). No modifications to the body mass index were found. CONCLUSIONS: A GFD improved FM symptoms evaluated with WPI and SS. This was confirmed for the first time, also with a rechallenge of the GFD that followed a non-restricted gluten-containing diet.

Study of the link between hemotopoietic and skeletal systems in patients attending a referral center for osteoporosis.

PURPOSE: To investigate the link between hematopoietic and skeletal tissues in patients with fragility fractures. METHODS: We retrospectively analyzed the medical records of women older than 40 years who attended the Bone Disease Unit of "Sapienza" University of Rome for their first visit for osteoporosis from January 2020 to June 2022. RESULTS: Fragility fractures were found in 61.8% of the sample. In particular, vertebral fractures in 35.5%, femoral fractures in 6.3%, Colles fractures in 16.5% and non-vertebral non-hip in 42.5%. Fractured patients were significantly older compared to non-fractured, had lower mean values of lumbar spine (p = 0.01), and femoral neck BMD (p = 0.007). A red blood cell distribution width (RDW) value higher than 15% was observed four times more in those with fractures compared to non-fractured patients (8.9% vs 2%, p = 0.01) and was associated with vertebral fracture after adjusting for age, BMI, menopause, nutritional status, smoking, osteoporosis and anemia (OR = 4.1, 95% CI 1.6-11.4, p = 0.003). Hematocrit was negatively associated with hip fracture also adjusting for age, BMI, menopause, nutritional status, smoking, osteoporosis (p = 0.025). CONCLUSION: Our study demonstrates that RDW values were significantly associated with vertebral fracture and hematocrit with hip fracture. Since both parameters are included in the initial evaluation of patients with suspected bone fragility, our results should push doctors to look at these values with no incremental cost for national health services.

Biclonal gammopathy of undetermined significance in a patient with systemic lupus erythematosus and antiphospholipid syndrome.

The case of a patient suffering from systemic lupus erythematosus with associated antiphospholipid antibody syndrome is described. In this patient, on protein electrophoresis, two monoclonal immunoglobulin G λ and k peaks were seen, defining a condition of biclonal gammopathy of undetermined significance (BGUS). This condition is extremely rare, especially in chronic inflammatory rheumatic diseases. The criteria of a BGUS are defined. We also underline how this condition can be the expression of a concomitant unrecognized cancer, a possible amyloidosis or an infectious process.

Higher serum levels of a cathepsin K-generated periostin fragment are associated with fractures in postmenopausal women with primary hyperparathyroidism: a pilot study.

The only difference between fractured and non-fractured postmenopausal women with PHPT of same sex, age, and BMI was a significantly mean higher serum k-periostin level. K-periostin value was associated with fracture at any site (odds ratio 1.044, 95% CI 1.005-1.091, p = 0.03). INTRODUCTION: To assess serum k-periostin fragment levels in patients with primary hyperparathyroidism (PHPT), fractured and non-fractured matched for sex, age, and body mass index. METHODS: Twenty-five Caucasian fractured postmenopausal women with PHPT (group Fx) and 25 PHPT non-fractured (group NFx) were enrolled. Each patient underwent DXA scan at lumbar, hip, and forearm, spine X-ray, and biochemical evaluation of calcium metabolism. For k-periostin analyses, we utilized a specific ELISA test that detects CatK-generated fragment levels in the bloodstream. RESULTS: We found no difference in mean BMD and bone turnover marker values between Fx and NFx groups. Prevalence of osteoporosis was not significantly different in Fx vs NFx (72% vs 60%, p = 0.55). Among Fx, 16% reported multiple fractures, 28% morphometric vertebral fractures, 4% femoral fractures, 28% non-vertebral non-femoral fractures, and 8% wrist fractures. The only detectable difference between Fx and NFx group was a significantly mean higher k-periostin serum level (46.2 ± 21.4 vs 34.7 ± 13.5 ng/ml, p = 0.02). K-periostin was associated with fracture at any site (odds ratio 1.044, 95% CI 1.005-1.091, p = 0.03). No difference in mean k-periostin values was found between patients with vertebral fracture vs those with non-vertebral fracture, and between those with multiple fractures vs those with single fracture. CONCLUSION: Serum k-periostin is significantly associated with fracture in PHPT. If confirmed by further studies, k-periostin could be considered a new marker of bone fragility in PHPT, independently of BMD.

Efficacy of gluten-free diet in patients with rheumatoid arthritis.

Recent research has increasingly shown that depending on the foods we eat, gut flora may be affected by an inflammatory or anti-inflammatory response, thus playing an important role in inflammatory autoimmune diseases, such as rheumatoid arthritis or gastroenterological disorders. Gluten seems to be a glycoprotein with a clinically relevant inflammatory effect. Several observational studies and anecdotal cases reported a correlation between gluten and various diseases, including autoimmune diseases, such as rheumatoid arthritis. This study aimed to evaluate whether gluten-free diet could be effective in controlling inflammation and ongoing rheumatoid arthritis symptoms. We report 4 cases of patients with long-standing rheumatoid arthritis with no response to several conventional and biotechnological drugs, treated with a gluten-free diet concurrently with the drug therapy. Our patients presented different degrees of response to the diet, in terms of disease remission and improvement of symptoms. Our cases confirm that a gluten-free diet may improve symptoms of rheumatoid arthritis, even in patients resistant to conventional drug therapies.

Lumbar spine bone mineral density and trabecular bone score-adjusted FRAX, but not FRAX without bone mineral density, identify subclinical carotid atherosclerosis.

PURPOSE: Osteoporosis and atherosclerosis share common risk factors. Aim of this study was to test if FRAX (which is an algorithm that can identify subjects at risk of fracture), without or with BMD values, also adjusted for trabecular bone score (TBS) was able to identify subclinical atherosclerosis, evaluated by measurement of carotid intima media thickness (cIMT ≥ 0.9 mm) as compared to DXA values. METHODS: Ninety postmenopausal women underwent DXA measurement and cIMT evaluation. For each patient, the FRAX algorithm for major osteoporotic fracture (M) and for hip fracture (H) without BMD was computed, together with FRAX with BMD and TBS-adjusted FRAX. Serum levels of osteoprotegerin, sRANKL, and interleukin-6 were also measured. RESULTS: There were no differences in anthropometric parameters and cardiovascular risk factors between subjects with cIMT ≥ 0.9 mm (35% of subjects, group A) compared to those with cIMT < 0.9 mm (group B). The prevalence of osteoporosis and FRAX BMD, TBS-adjusted FRAX both for M and H were higher in group A compared to group B. The best ROC curves to identify subjects with a cIMT ≥ 0.9 mm were: lumbar spine T-score, with a threshold of - 2.5 SD (area under the curve, AUC 0.64; p = 0.02) with a sensibility of 50% and a specificity of 76%; TBS-adjusted FRAX H with a sensibility of 50% and a specificity of 72% (AUC 0.64; p = 0.01 with a threshold of 3%). Interleukin-6 positively correlated with FRAX BMD H and M. CONCLUSIONS: FRAX without BMD does not identify subclinical carotid atherosclerosis, while lumbar spine T-score and TBS-adjusted FRAX H similarly detected it with higher specificity for T-score.

Vertebral fracture assessment (VFA) for monitoring vertebral reshaping in children and adolescents with osteogenesis imperfecta treated with intravenous neridronate.

PURPOSE: The study was aimed at monitoring vertebral bodies changes with the use of Vertebral Fracture Assessment (VFA) in children and adolescents affected by osteogenesis imperfecta (OI) during treatment with intravenous neridronate. METHODS: 60 children and adolescents (35 males and 25 females; age 1-16 years) with OI type I, III and IV were included in the study. Intravenous neridronate was administered at the dose of 2 mg/kg every 3 months in all patients. Lumbar spine (LS) bone mineral density (BMD) and VFA by dual X-ray absorptiometry (DXA) were assessed every 6 months up to 24 months during treatment. VFA with vertebral morphometry (MXA) was used to calculate the three indices of vertebral deformity: wedging, concavity and crushing. Serum calcium, phosphate, parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D], total alkaline phosphatase (ALP), bone alkaline phosphatase (BALP) and urinary C-terminal telopeptide of type 1 collagen (CTx) were measured at any time point. RESULTS: Mean LS BMD values significantly increased at 24 months compared to baseline (p < 0.0001); the corresponding Z-score values were -1.28 ± 1.23 at 24 months vs -2.46 ± 1.25 at baseline; corresponding mean Bone Mineral Apparent Density (BMAD) values were 0.335 ± 0.206 vs 0.464 ± 0.216. Mean serum levels of ALP, BALP and CTx significantly decreased from baseline to 24 months. By MXA, we observed a significant 19.1% reduction of the mean wedging index of vertebral reshaping at 12 months, and 38.4% at 24 months (p < 0.0001) and of the mean concavity index (16.3% at 12 months and 35.9% at 24 months; p < 0.0001). Vertebral reshaping was achieved for 66/88 (75%) wedge fractures and 59/70 (84%) concave fractures, but there were 4 incident mild fractures. Finally, VF rate was reduced at 24 months compared to baseline: 37/710 (5.2%) vs 158/710 (22.2%). CONCLUSION: Our study demonstrates the utility of VFA as a safe and alternative methodology in the follow-up of children and adolescents with OI.

Psoriatic spondyloarthritis and Sjögren syndrome: a casual association?

The association between Sjögren syndrome (SS) and psoriatic arthritis (PsA) is rare. Herein, we report a case of SS in a PsA patient with the mutilans variant. A 67-year old woman developed PsA with progressive articular destruction up to the typical deformation of 'telescoping fingers' in the distal phalanges. Psoriatic onychopathy presented ten years after the osteolytic damage in the hands. This late appearance led to delayed diagnosis and therapy, and, consequently, worsened the articular destruction. Thereafter, the patient developed a typical SS with clinical symptoms, such as xerophthalmia and xerostomia. This diagnosis was confirmed by positive diagnostic tests, such as Schirmer test, ANA, and anti-SSA/Ro and anti-SSB/La antibodies. A potential association between the two diseases is discussed.

Vitamin D screening.

At present, there is no need and no sufficient evidence to support universal screening for vitamin D status. There are four categories of subjects in whom there is no requirement for screening, since a number of studies indicate beneficial effects of vitamin D supplementation; these are represented by children and adolescents, pregnant women, patients taking bone active drugs and subjects with documented hypovitaminosis D. In the remaining subjects, the utilization of adequate questionnaires will target with sufficient sensitivity and specificity those with hypovitaminosis D. These must be first supplemented and, at a later time, serum 25(OH)D assay should be requested to confirm attainment of sufficiency, independently of the threshold chosen. This strategy will cut costs deriving from both widespread use of vitamin D assays and vitamin D supplementation.

Long-term bone mineral density changes after surgical cure of patients with tumor-induced osteomalacia.

This paper reports our personal experience filling the gap regarding changes of bone mineral density after surgical treatment in patient suffering from tumor-induced osteomalacia. INTRODUCTION: No systematic data are available regarding long-term bone mineral density (BMD) changes after surgical cure of patients with tumor-induced osteomalacia. METHODS: From October 2001 through April 2018, we studied 10 consecutive patients (mean age ± SD, 45.5 ± 13.8 years; 5 males and 5 females) with tumor-induced osteomalacia. We evaluated BMD when initially presented at our Center and after surgical removal of the tumor. RESULTS: Basal BMD and corresponding Z-score values (mean values ± SD) measured by DXA were as follows: L1-L4 = 0.692 ± 0.15 g/cm2, Z-score = - 2.80 ± 1.60; femur neck 0.447 ± 0.10 g/cm2, Z-score = - 2.66 ± 0.93; total femur = 0.450 ± 0.08 g/cm2, Z-score = -3.04 ± 0.85). Furthermore, Trabecular Bone Score (TBS) was evaluated in three patients (basal values, 0.990 ± 0.32). Seven patients were intermittently followed after surgical excision of the tumor while supplemented with cholecalciferol and calcium salts; the remaining three were lost to follow-up. There was a striking increase of BMD values that peaked at 26.7 ± 6.50 months: L1-L4 = 1.289 ± 0.247 g/cm2, p < 0.001, Z-score + 1.75 ± 1.42; femur neck = 0.890 ± 0.235 g/cm2, p = 0.028, Z-score = + 0.50 ± 1.40; total femur = 0.834 ± 0.150 g/cm2, p = 0.005, Z-score = - 0.74 ± 1.14. In patients with the greatest bone involvement at lumbar site, there was a striking increase of an average 1.5% (p < 0.01) in respect to baseline Z-score value for each additional month of observation during the first 2-3 years post-surgery. An improvement of trabecular microarchitecture was also documented (TBS, 1.255 ± 0.16). CONCLUSION: This is the first case series documenting an impressive increase of BMD at both lumbar and femoral sites, together with an improvement of trabecular microarchitecture as documented by TBS. This is the consequence of huge mineralization of the large amount of osteoid tissue after resolution of the disease.

Patients' reasons for adhering to long-term alendronate therapy.

We aimed to determine patients' reasons for continuing alendronate therapy over 5 years by administering a questionnaire. Bone mineral density, fractures, drugs, Charlson comorbidity index, and lifestyle factors were also considered. Education and awareness of the disease appeared highly associated with good alendronate adherence while worsening health status with discontinuation. INTRODUCTION: Aim of this study was to investigate patients' reasons for adhering to long-term alendronate therapy (more than 5 years), as data is not available in the current literature regarding the reasons behind long-term adherence. METHODS: We studied 204 long-term adherent alendronate users: 65 postmenopausal outpatients still adherent (group C, years on treatment = 8.70 ± 1.31) were compared to 139 age-matched patients who discontinued therapy (group S, years on treatment = 8.64 ± 1.43). We evaluated main biochemical parameters, BMD values, fractures, and Charlson comorbidity index (CCI). A questionnaire was administered to analyze the reasons for long-term adherence. RESULTS: There were no significant differences between groups concerning baseline DXA values, number of fractures, and CCI. A higher education level was observed in group C (C 54% vs S 35% of patients, p = 0.001). At the time of interview, there was a significantly higher number of patients with a CCI of two in group S compared to the beginning of treatment (56% vs 43%, p = 0.04), together with a higher number of patients taking more than 3 drugs (22% vs 11%, p = 0.01) compared to basal evaluation. Forty-seven percent of patients reported new diseases during the treatment as the main reason for stopping alendronate. A multivariate, stepwise logistic regression analysis showed that awareness of the disease was highly associated with adherence (OR = 0.20; 95% CI 0.045-0.93, p = 0.04) followed by higher education (OR = 0.526, 95% CI 0.345-0.801, p = 0.003). Worsening of CCI was associated with discontinuation (OR = 2.75, 95% CI 1.033-7.324, p = 0.04). CONCLUSIONS: Education and disease awareness are associated with long-term alendronate adherence while competing health problems negatively impact adherence.

Associations between radius low-frequency axial ultrasound velocity and bone fragility in elderly men and women.

An exploratory study in elderly women and men from the Geneva Retirees Cohort indicates that low-frequency quantitative ultrasound measurement at the radius captures aBMD, bone size, and cortical tissue mineral density and might be used for screening purposes prior to DXA to evaluate fracture risk. INTRODUCTION: The contribution of distal radius bone mineral density (BMD) and cortical microstructure to fracture risk has recently been demonstrated. In this exploratory study, we investigated whether low-frequency quantitative ultrasound measurement at the distal radius may capture the peripheral determinants of bone fragility assessed with dual-energy X-ray absorptiometry (DXA) and high-resolution peripheral quantitative computed tomography (HR-pQCT). METHODS: Low-frequency velocity (VLF) was measured at the radius using OsCare Sono®, a portable axial transmission ultrasonometer, in 271 community-dwelling postmenopausal women and men (age 71.5 ± 1.4 years) from the Geneva Retirees Cohort. Cortical (Ct) and trabecular (Tb) volumetric (v) BMD and microstructure at the distal radius were assessed by HR-pQCT, in addition to areal (a) BMD by DXA, at the same time point. RESULTS: VLF was highly correlated with aBMD at the distal third radius (r = 0.72, p < 0.001). For microstructure parameters, the highest correlation was observed with cortical area (r = 0.59, p < 0.001). VLF also captured bone geometry (total area) and cortical tissue mineral density independently of aBMD. In models adjusted for age and sex, VLF was significantly associated with prevalent low-trauma fractures [OR 95%CI for one SD decrease of VLF 1.50 (1.05, 2.14), p = 0.024], with discrimination performance comparable to femoral neck or distal radius aBMD. CONCLUSION: Measurement of VLF at the radius captures aBMD, bone size, and cortical tissue mineral density and might be used for screening purposes prior to DXA to evaluate fracture risk.

Clinical presentation and management of patients with primary hyperparathyroidism in Italy.

PURPOSE: Evaluation of the phenotype of primary hyperparathyroidism (PHPT), adherence to International Guidelines for parathyroidectomy (PTx), and rate of surgical cure. METHOD: From January 2014-January 2016, we performed a prospective, multicenter study in patients with newly diagnosed PHPT. Biochemical and instrumental data were collected at baseline and during 1-year follow-up. RESULTS: Over the first year we enrolled 604 patients (age 61 ± 14 years), mostly women (83%), referred for further evaluation and treatment advice. Five hundred sixty-six patients had sporadic PHPT (93.7%, age 63 ± 13  years), the remaining 38 (6.3%, age 41 ± 17  years) had familial PHPT. The majority of patients (59%) were asymptomatic. Surgery was advised in 281 (46.5%). Follow-up data were available in 345 patients. Eighty-seven of 158 (55.1%) symptomatic patients underwent PTx. Sixty-five (53.7%) of 121 asymptomatic patients with at least one criterion for surgery underwent PTx and 56 (46.3%) were followed without surgery. Negative parathyroid imaging studies predicted a conservative approach [symptomatic PHPT: OR 18.0 (95% CI 4.2-81.0) P < 0.001; asymptomatic PHPT: OR 10.8, (95% CI 3.1-37.15) P < 0.001). PTx was also performed in 16 of 66 (25.7%) asymptomatic patients without surgical criteria. Young age, serum calcium concentration, 24 h urinary calcium, positive parathyroid imaging (either ultrasound or MIBI scan positive in 75% vs. 16.7%, P = 0.001) were predictors of parathyroid surgery. Almost all (94%) of patients were cured by PTx. CONCLUSIONS: Italian endocrinologists do not follow guidelines for the management of PHPT. Negative parathyroid imaging studies are strong predictors of a non-surgical approach. PTx is successful in almost all patients.

Non classical complications of primary hyperparathyroidism.

Several studies suggested that the condition of primary hyperparathyroidism (PHPT) may be associated not only with the classical bone, kidney and gastrointestinal consequences, but also with cardiovascular, neuromuscular and articular complications, impaired quality of life and increased cancer risk. However, the only cardiovascular complications associated with PHPT, which seems to improve after parathyroidectomy, is left ventricular hypertrophy, while, data regarding the reversibility of hypertension, valve calcifications and increased vascular stiffness are inconsistent. Parathyroidectomy seems to ameliorate neuropsychological, cognitive disturbances and quality of life in moderate-severe PHPT, while data in mild PHPT are less clear. At variance, the effect of parathyroidectomy on neuromuscular and articular complications is still unknown, and no studies demonstrated a reduction of cancer risk after recovery from PHPT. Overall, to date, cardiovascular and neuropsychological evaluation are not recommended solely because of PHPT, nor cardiovascular disease, muscle weakness, and neuropsychological complications are indication for parathyroidectomy.