Mild hyponatremia is not associated with degradation of trabecular bone microarchitecture despite bone mass loss.

CONTEXT: Hyponatremia is associated with increased risk of osteoporosis and fractures. The impact of hyponatremia on non-invasive indices of bone quality, however, is unknown. OBJECTIVE: To evaluate whether trabecular bone microarchitecture, assessed non-invasively by trabecular bone score (TBS), is altered in patients with hyponatremia. METHODS: We conducted a cross-sectional analysis of the population-based 2005-2008 cycles of the National Health and Nutrition Examination Survey (NHANES), in which TBS measurement was performed. The main outcome measures were TBS values and bone mineral density (BMD) T-scores at the lumbar spine, total hip and femoral neck. RESULTS: A total of 4204 subjects aged 50 years or older were included (4041 normonatremic, 163 hyponatremic - 90.8% with mild hyponatremia). Univariate analyses did not show any difference in TBS between patients with and without hyponatremia (1.308 ± 0.145 vs 1.311 ± 0.141, p = 0.806). Hyponatremic subjects had lower BMD T-score at total hip (-0.70 ± 1.46 vs -0.13 ± 1.32, p < 0.001) and femoral neck (-1.11 ± 1.26 vs -0.72 ± 1.14, p = 0.004), while no difference was observed at lumbar spine (-0.27 ± 1.63 vs -0.31 ± 1.51, p = 0.772). After adjustment for relevant confounders, hyponatremia was confirmed as an independent predictor of lower BMD T-score at the total hip (ß=-0.20, 95%CI:[-0.39, -0.02], p = 0.029), while the significance was lost at the femoral neck (p = 0.308). Again, no association between hyponatremia and lumbar spine BMD (p = 0.236) or TBS (p = 0.346) was observed. CONCLUSIONS: Hyponatremia, at least in mild forms, is not associated with a degradation of trabecular microarchitecture, assessed non-invasively by TBS. An independent association between hyponatremia and loss of bone mass is confirmed, particularly at the total hip.

Evaluating adherence, tolerability and safety of oral calcium citrate in elderly osteopenic subjects: a real-life non-interventional, prospective, multicenter study.

BACKGROUND: Osteoporosis is a common concern in the elderly that leads to fragile bones. Calcium supplementation plays a crucial role in improving bone health, reducing fracture risk, and supporting overall skeletal strength in this vulnerable population. However, there is conflicting evidence on the safety of calcium supplements in elderly individuals. AIM: The aim of this study was to evaluate the adherence, safety and tolerability of calcium citrate supplementation in elderly osteopenic subjects. METHODS: In this non-interventional, prospective, multicenter study, subjects received daily 500 mg calcium citrate supplementation for up to one year. Adherence was calculated based on compliance and persistence. Safety was assessed through adverse reactions (ARs), deaths, and clinical laboratory evaluations. RESULTS: A total of 268 Caucasian subjects (91.4% female, mean age 70 ± 4.5 years) participated in the study. Mean adherence to treatment was 76.6 ± 29.5% and half of subjects had an adherence of 91% and ~ 33% of participants achieved complete (100%) adherence. ARs were reported by nine (3.9%) subjects, primarily gastrointestinal disorders, with no serious ARs. The frequency of all adverse events (including ARs) was significantly higher in subjects with adherence of < 80% (41.6%; 32/77) vs. those with adherence ≥ 80% (11%; 16/145, p < 0.0001). Both systolic and diastolic blood pressure decreased from baseline to follow-up visit (change of -2.8 ± 13.9 mmHg, p = 0.0102 and -2.1 ± 10.4 mmHg, p = 0.0116, respectively). CONCLUSION: This study demonstrated favorable adherence to calcium citrate supplementation in elderly osteopenic subjects. The occurrence of ARs, though generally mild, were associated with lower adherence to calcium supplementation.

Trabecular bone score as a marker of skeletal fragility across the spectrum of chronic kidney disease: a systematic review and meta-analysis.

CONTEXT: The impairment of bone microarchitecture is a key determinant of skeletal fragility in patients with chronic kidney disease (CKD). Trabecular bone score (TBS) has been developed as a reliable non-invasive index of bone quality. However, its utility in this setting is still debated. OBJECTIVE: The aim of this systematic review and meta-analysis was to summarize the available evidence about TBS as a marker of skeletal fragility across the spectrum of CKD. METHODS: PubMed/Medline, EMBASE and Cochrane Library databases were systematically searched until July 2023 for studies reporting data about TBS in patients with CKD. Effect sizes were pooled through a random-effect model. RESULTS: Compared to controls, lower TBS values were observed in CKD patients not on dialysis (-0.057, 95%CI:[-0.090, -0.024], p < 0.01), in dialysis patients (-0.106, 95%CI:[-0.141, -0.070], p < 0.01) and in kidney transplant recipients (KTRs) (-0.058, 95%CI:[-0.103, -0.012], p = 0.01). With respect to fracture risk, TBS was able to predict incident fractures in non-dialysis patients at unadjusted analyses (hazard ratio (HR) per standard deviation decrease: 1.45, 95%CI:[1.05,2.00], p = 0.02), though only a non-significant trend was maintained when fully adjusting the model for FRAX® (HR = 1.26, 95%CI:[0.88,1.80], p = 0.21). Dialysis patients with prevalent fractures had lower TBS values compared to unfractured ones (-0.070, 95% CI:[-0.111, -0.028], p < 0.01). Some studies supported a correlation between TBS and fracture risk in KTRs, but results could not be pooled due to the lack of sufficient data. CONCLUSIONS: CKD patients are characterized by an impairment of bone microarchitecture, as demonstrated by lower TBS values, across the whole spectrum of kidney disease. TBS can also be helpful in the discrimination of fracture risk, with lower values being correlated with a higher risk of prevalent and incident fractures.

Bone safety of dual-release hydrocortisone in patients with autoimmune primary adrenal insufficiency.

Background: Conventional glucocorticoids (C-GC) replacement regimens have a detrimental effect on skeletal health in patients with adrenal insufficiency (AI), ultimately leading to an increased fracture risk. The novel dual-release hydrocortisone (DR-HC) formulations are characterized by a more favourable safety profile on various clinical endpoints. Data comparing the impact of C-GC and DR-HC on bone, however, are scarce. Methods: Twenty-seven patients with autoimmune primary AI (PAI; 13 treated with C-GC and 14 treated with DR-HC) were evaluated to compare bone-related parameters between the two treatment groups. Results: No significant differences between the two treatments groups were observed with respect to bone turnover markers. Patients treated with C-GC showed a lower bone mineral density (BMD) at lumbar spine (LS; 0.791 ± 0.195 vs. 0.942 ± 0.124 g/cm2, p=0.025) and at femoral neck (FN; 0.633 ± 0.114 vs. 0.716 ± 0.088 g/cm2, p=0.045). Moreover, they were characterized by a lower trabecular bone score (TBS; 1.236 ± 0.035 vs. 1.383 ± 0.030, p=0.004) and by a higher mean number of vertebral fractures per patient (0.75 vs. 0 fractures, p=0.002). TBS was the best predictor of fracture risk, with a pseudo-R2 of 0.593; moreover, at mediation analysis, it was able to fully explain the observed detrimental effect of C-GC, compared to DR-HC, on fracture risk. Conclusions: These results suggest that DR-HC is associated with less bone-related complications compared to C-GC in patients with PAI. Moreover, TBS seems to play a pivotal role in the mediation of the relationship between glucocorticoid treatment regimens and fracture risk.

Recurrence and mortality rate in an Italian multi-center case series of parathyroid atypical adenomas and carcinomas.

Introduction: There are few data regarding the clinical outcome of patients with parathyroid carcinoma (PC) and atypical adenoma (AA) after surgery. Aim of our study was to investigate disease recurrence and mortality rate as well as their predictors in a series of patients with PC or AA. Methods: Clinical and biochemical parameters, histological features, incidence of disease recurrence and mortality rate were retrospectively assessed in 39 patients (51% males, mean age 56.2 ± 17.2 years) diagnosed with PC (n=24) or AA (n=15) and followed up for 6.8 ± 5.0 years after surgery. Results: No differences in baseline characteristics were registered between the two groups, except for higher KI67 values in PC than AA (6.9 ± 3.9% vs 3.4 ± 2.1%, p<0.01). Eight patients (21%) experienced recurrence after a mean follow-up of 5.1 ± 2.7 years, with higher relapse rate in PC than AA (25% vs 13%), though this difference did not reach statistical significance. Mortality rate was 10% in the whole sample, without significant differences between PC and AA. Relapsing cases had been undergone the most extensive surgery more frequently and they had a higher mortality rate in comparison to non relapsing patients (38% vs 6% and 38% vs 3%, respectively, p<0.03 for both). In comparison to survivors, deceased patients were submitted to the most extensive surgery more frequently (50% vs 9%), they were older (74.8 ± 4.6 vs 53.2 ± 16.3 years), and they had higher KI67 values (11.7 ± 4.9 vs 4.8 ± 2.8, p<0.03 for all comparisons). Conclusions: During seven-year follow-up after surgery, no significant differences in recurrence and mortality rate were observed between PC and AA patients. Death was associated with disease relapse, older age and higher KI67 values. These findings suggest a similar and careful long-term follow-up in both parathyroid tumors, especially in older patients, and emphasize the need of further studies in large cohorts to throw light on this crucial clinical issue.

Adrenocortical, somatotropic, and antidiuretic response to nasal glucagon in healthy subjects.

OBJECTIVE: The glucagon stimulation test involves the peptide intramuscular or subcutaneous administration for the diagnosis of hypopituitarism. To date, no data are available regarding its intranasal formulation. Our study intended to investigate the role of intranasal glucagon as a potential stimulus test for the evaluation of the corticotropic, somatotropic, and antidiuretic axes. DESIGN: Non-randomized, single-blinded, cross-over study including 10 healthy subjects (50% women). METHODS: All participants underwent 2 days of testing, and intranasal glucagon or placebo was administered. At baseline, every 15' up to +90', and then every 30' up to +180', a blood sample was taken for adrenocorticotropic hormone (ACTH), cortisol, growth hormone (GH), copeptin, glucose, insulin, sodium, potassium, and plasma osmolarity. At baseline and at the end of the test, urinary osmolarity was evaluated as well. RESULTS: After administration of both glucagon and placebo, ACTH and cortisol values decreased progressively (P < 0.001), but in the drug group, the reduction in cortisol was less accentuated up to +90' (P < 0.05). Growth hormone values decreased after placebo administration (P < 0.001); on the other hand, after glucagon, an increasing, yet non-significant trend was observed (P = 0.096) with the difference between the two groups evident starting from +120' onwards (P < 0.005). The placebo administration led to a reduction of copeptin, while its stability was observed after glucagon administration. Six subjects developed hypokalemia (ie, potassium <3.5 mmol/L) post-glucagon, with the nadir at 45' (3.6 [3.2-3.8] mmol/L) significantly correlated with the immediate post-glycemic rise insulin peak (Spearman's rho -0.719; P = 0.019). No significant differences were observed compared to the other analytes tested. CONCLUSIONS: Intranasal glucagon administration is not an effective stimulus for hypophyseal secretion. Hypokalemia secondary to hyperinsulinemic rebound appears to be a frequent complication of its acute administration.

Trabecular Bone Score as an Index of Bone Fragility in Patients with Acromegaly: A Systematic Review and Meta-Analysis.

BACKGROUND: Acromegaly is characterized by impaired bone quality and increased fracture risk. However, due to the pathophysiology of acromegalic osteopathy, bone mineral density (BMD) does not represent a reliable predictor for fragility fractures in this setting. Trabecular bone score (TBS) has been recently evaluated as an alternative index of skeletal fragility in acromegalic patients. However, no conclusive data are still available in this regard. METHODS: PubMed/Medline, EMBASE, Cochrane Library, Ovid, and CINAHL databases were systematically searched until June 2022 for studies reporting data either about the comparison of TBS values between acromegalic patients and non-acromegalic controls or about the relationship - within acromegalic patients - between TBS values and fracture risk. Effect sizes were pooled through a random-effect model. RESULTS: Eight studies were eligible for inclusion in the meta-analysis, encompassing 336 acromegalic patients and 490 non-acromegalic controls. Overall, TBS was significantly lower in acromegalic patients compared to controls (-0.089, 95% CI: [-0.111, -0.067], p < 0.01), irrespective of acromegaly disease activity and gonadal status. With respect to fracture risk, TBS was significantly lower in acromegalic patients with vertebral fractures than in those without (-0.099, 95% CI: [-0.166, -0.032], p < 0.01). CONCLUSION: In this meta-analysis, we specifically assessed the role of TBS as an index of bone quality and fracture risk in patients with acromegaly. Our results support the notion that TBS could be of value in the assessment and management of skeletal fragility in acromegalic patients, especially in light of the poor information provided in this setting by BMD.

Comparison of the diagnostic accuracy of 18F-Fluorocholine PET and 11C-Methionine PET for parathyroid localization in primary hyperparathyroidism: a systematic review and meta-analysis.

BACKGROUND: Primary hyperparathyroidism is characterized by an autonomous hypersecretion of parathyroid hormone by one or more parathyroid glands. Preoperative localization of the affected gland(s) is of key importance in order to allow minimally invasive surgery. At the moment, 11C-Methionine and 18F-Fluorocholine PET studies appear to be among the most promising second-line localization techniques; their comparative diagnostic performance, however, is still unknown. METHODS: PubMed/Medline and Embase databases were searched up to October 2020 for studies estimating the diagnostic accuracy of 11C-Methionine PET or 18F-Fluorocholine PET for parathyroid localization in patients with primary hyperparathyroidism. Pooled sensitivity and positive predictive value were calculated for each tracer on a 'per-lesion' basis and compared using a random-effect model subgroup analysis. RESULTS: In total, 22Twenty-two studies were finally considered in the meta-analysis. Of these, 8 evaluated the diagnostic accuracy of 11C-Methionine and 14 that of 18F-Fluorocholine. No study directly comparing the two tracers was found. The pooled sensitivity of 18F-Fluorocholine was higher than that of 11C-Methionine (92% vs 80%, P < 0.01), while the positive predictive value was similar (94% vs 95%, P = 0.99). These findings were confirmed in multivariable meta-regression models, demonstrating their apparent independence from other possible predictors or confounders at a study level. CONCLUSION: This was the first meta-analysis that specifically compared the diagnostic accuracy of 11C-Methionine and 18F-Fluorocholine PET for parathyroid localization in patients with primary hyperparathyroidism. Our results suggested a superior performance of 18F-Fluorocholine in terms of sensitivity, while the two tracers had comparable accuracy in terms of positive predictive value.

Long-Term Efficacy of Intensive Zoledronate Therapy and Predictors of Retreatment in Paget's Disease of Bone.

Despite the current debate on the best therapeutic approach, i.e. symptomatic vs intensive strategy, one zoledronate (Zol) infusion is effective in most patients with Paget's disease of bone (PDB), whereas few need retreatment, whose predictors are not well established. We aimed to evaluate long-term efficacy of intensive Zol therapy and predictors of retreatment in PDB. Pagetic complications, clinical and biochemical response to Zol together with frequency of retreatment were retrospectively assessed in forty-seven PDB patients (age, mean ± SD: 72.5 ± 8.9 years, M/F: 24/23; symptomatic/asymptomatic: 16/31). Statistical analysis for retreatment prediction were based on Mann-Whitney U test, Pearson's Χ2 and ROC curve analysis. During seven-year follow-up, all patients achieved pain relief and only one underwent arthroplasty. Bone alkaline phosphatase (BAP) detected three non-responder (6%) and six relapsing (13%) patients needing retreatment. Retreated patients had less old age (66.1 ± 11.2 vs 74.0 ± 7.7 years), higher frequency of polyostotic disease (78% vs 40%) and higher baseline (96.5 ± 24.8 vs 44.9 ± 27.7 mcg/l) and post-Zol nadir BAP levels (24.7 ± 24.1 vs 8.1 ± 4.1 mcg/l) than patients treated once (p < 0.05 for all comparisons). In multivariate analysis both serum baseline and post-Zol nadir BAP significantly predicted retreatment (OR 1.09, 95%CI 1.01-1.17 and 1.29, 1.03-1.62, respectively), with ROC curve analysis showing the greatest accuracies for threshold values of 75.6 and 9.9 mcg/l (sensitivity 88 and 90%, specificity 94 and 86%, AUC 0.92 and 0.93, respectively). Our data in mostly asymptomatic, metabolically active PDB patients treated with intensive Zol therapy show a negligible incidence of pagetic complications and long-term optimal disease control, with BAP being the best predictor of retreatment.

Fracture risk assessment in an Italian group of transgender women after gender-confirming surgery.

INTRODUCTION: Bone health is a critical issue in transgender women (TW) health care. Conflicting results have been reported on bone status after gender-confirming surgery (GCS). No recent data in Italian TW are available. MATERIALS AND METHODS: The aim of this cross-sectional study was to evaluate fracture risk, lumbar spine BMD and 25OH vitamin D (25OHD) levels in a population of TW on estrogen replacement therapy (ERT) after GCS. We retrospectively analyzed a group of 57 TW, aged 45.3 ± 11.3 years, referred to our Gender Dysphoria Clinic, at least 2 years after GCS. Anthropometric parameters, patient compliance to ERT, biochemical and hormonal assessment, lumbar spine BMD and fracture risk were evaluated. RESULTS: Prevalence of low bone mass (Z-score ≤ -2) was 40% according to the natal gender. In this group, 17ß-estradiol levels were significantly lower (median 21 pg/ml [25th-75th percentile 10.6-48.5] vs 63 pg/ml [38.5-99.5]; p < 0.001) and a higher prevalence of low compliance to ERT was recorded (83% vs 29%; p < 0.0001) compared to those with higher bone mass. An intermediate-high fracture risk was found in 14% of the sample. A high percentage (93%) of hypovitaminosis D was present. CONCLUSIONS: TW on ERT have a high prevalence of low bone mass, significantly associated with low estradiol levels and low compliance to ERT. A high prevalence of hypovitaminosis D was highlighted. Considering that one out of seven TW showed an intermediate-high 10-year fracture risk, such risk assessment may be considered to prevent and manage osteoporosis in this clinical setting.

Treatment of Acromegalic Osteopathy in Real-life Clinical Practice: The BAAC (Bone Active Drugs in Acromegaly) Study.

BACKGROUND: Vertebral fractures (VFs) are a frequent complication of acromegaly, but no studies have been so far published on effectiveness of antiosteoporotic drugs in this clinical setting. OBJECTIVE: To evaluate whether in real-life clinical practice bone active drugs may reduce the risk of VFs in patients with active or controlled acromegaly. STUDY DESIGN: Retrospective, longitudinal study including 9 tertiary care endocrine units. PATIENTS AND METHODS: Two hundred and forty-eight patients with acromegaly (104 males; mean age 56.00 ±â€…13.60 years) were evaluated for prevalent and incident VFs by quantitative morphometric approach. Bone active agents were used in 52 patients (20.97%) and the median period of follow-up was 48 months (range 12-132). RESULTS: During the follow-up, 65 patients (26.21%) developed incident VFs in relationship with pre-existing VFs (odds ratio [OR] 3.75; P < .001), duration of active acromegaly (OR 1.01; P = .04), active acromegaly at the study entry (OR 2.48; P = .007), and treated hypoadrenalism (OR 2.50; P = .005). In the entire population, treatment with bone active drugs did not have a significant effect on incident VFs (P = .82). However, in a sensitive analysis restricted to patients with active acromegaly at study entry (111 cases), treatment with bone active drugs was associated with a lower risk of incident VFs (OR 0.11; P = .004), independently of prevalent VFs (OR 7.65; P < .001) and treated hypoadrenalism (OR 3.86; P = .007). CONCLUSIONS: Bone active drugs may prevent VFs in patients with active acromegaly.

Predictors of risk of fracture in inflammatory bowel diseases: a prospective study using FRAX score.

BACKGROUND: Despite the well-known risk of osteoporosis and bone fractures among patients with inflammatory bowel diseases, the WHO FRAX tool has been used in a limited number of studies in this specific population. The purpose of this study was to search for predictors of risk of fractures assessed by FRAX score. METHODS: We prospectively calculated FRAX score for hip and major osteoporotic fractures in inflammatory bowel disease patients consecutively recruited. RESULTS: The mean risk of hip fractures at 10 years, for the 80 recruited patients, resulted 1.4%, while the mean risk of major osteoporotic fractures was 7.8%. The risk of hip fractures was 1.3% among the 30 Crohn's disease patients versus 1.4% (P=0.82) among 50 ulcerative colitis patients. A prolonged use of corticosteroids correlated with a tendency to a greater risk of hip fracture (r=0.38, P=0.08). Patients with normal erythrocyte sedimentation rate (ESR) values had a risk of osteoporotic hip fractures of 0.75%, while those with high ESR values had a risk of 1.86% (P=0.04). Regarding the risk of major bone fractures, patients with normal ESR values had a risk of 5.9%, versus a risk of 18% in those with elevated ESR (P=0.03). CONCLUSIONS: The correlation between increase of inflammatory markers and increased risk of osteoporotic fractures and the lack of difference between Crohn's disease and ulcerative colitis suggest a central role of inflammation over malabsorption in this population.

Increased frequency of impaired fasting glucose and isolated systolic hypertension in Paget's disease of bone.

PURPOSE: Scanty data about glucose metabolism and hypertension have been reported in Paget's disease of bone (PDB) to be related with increased cardiovascular mortality. The aim of the present study was to evaluate glucose and blood pressure levels in PDB, looking for their association with disease severity. METHODS: We performed an observational cross-sectional study in 54 patients with PDB and 54 age, sex and BMI-matched controls. Glucose and blood pressure levels and parameters of bone and mineral metabolism were assessed. RESULTS: Patients with PDB showed increased glucose levels (6.3 ± 1.7 vs 5.3 ± 1.4 mmol/l, p < 0.001) and prevalence of impaired fasting glucose (14.8%, 5.3-24.3 vs 1.9%, 0-5.4, p < 0.02) as well as enhanced systolic blood pressure (145.9 ± 21.3 vs 132.9 ± 18.9 mmHg, p < 0.005), pulse pressure (69.6 ± 20.0 vs 56.0 ± 16.9 mmHg, p < 0.01) and prevalence of isolated systolic hypertension (46.3%, 33.0-59.6 vs 16.7%, 6.7-26.6, p < 0.003) in comparison to controls. Moreover, we found a positive association of (1) glucose levels with ionized calcium and bone alkaline phosphatase; (2) both systolic and pulse pressure with total and bone alkaline phosphatase (p < 0.05). By multiple linear regression analysis (R2 = 0.26; p < 0.05) serum ionized calcium correlated with glucose levels (ß = 0.44; p < 0.04), after adjusting for age and BMI. CONCLUSIONS: Our study shows increased fasting glucose, systolic and pulse pressure levels as well as enhanced prevalence of impaired fasting glucose and isolated systolic hypertension in PDB, potentially accounting for increased cardiovascular mortality. Furthermore, our findings suggest high serum calcium and/or increased bone alkaline phosphatase as a link between PDB and cardio-metabolic disorders.