Zoledronate after denosumab discontinuation: Is repeated administrations more effective than single infusion?

BACKGROUND: After Denosumab (Dmab) discontinuation C-terminal telopeptide (CTX) levels increase, bone mineral density (BMD) decreases and multiple vertebral fractures (FX) may occur with relevant impact on women's health. A sequential therapy with bisphosphonates is recommended and the European Calcified Tissue Society (ECTS) proposed repeated zoledronate (ZOL) administrations in patients with persistently high CTX levels, although the efficacy of this schedule is unknown. In this retrospective study we describe BMD changes and FX rate in 52 patients managed according to the ECTS recommendations. METHODS: We measured CTX levels and administered ZOL after one month from Dmab withdrawal (t0). After 6 months (t1), we administered a second ZOL infusion, if CTX levels were ≥280 ng/L. BMD changes and FX rate were assessed on average after 17 months from Dmab withdrawal. RESULTS: 75% of patients repeated ZOL infusion. In this group spine BMD declined significantly (-5.5 ± 5.6%), while it remained stable in the group with CTX levels <280 ng/L (-0.1 ± 5.5%, p = 0.008). All fractured patients (9.6%) had received >5 Dmab injections and two ZOL infusions. The BMD worsening after Dmab withdrawal was associated with CTX t1 (OR 2.9, IQR 1.3-6.6, p = 0.009) and spine BMD gain during Dmab therapy corrected for the number of Dmab injections (OR 3.0, IQR 1.2-7.2, p = 0.014). A CTX level at t1 > 212 ng/L had 100% sensitivity in predicting the BMD loss. CONCLUSIONS: In patients with uncontrolled CTX levels after Dmab withdrawal, two ZOL infusions at 6 months apart do not prevent BMD loss and FX.

Italian Guidelines for the Management of Sporadic Primary Hyperparathyroidism.

AIM: This guideline (GL) is aimed at providing a clinical practice reference for the management of sporadic primary hyperparathyroidism (PHPT) in adults. PHPT management in pregnancy was not considered. METHODS: This GL has been developed following the methods described in the Manual of the Italian National Guideline System. For each question, the panel appointed by Associazione Medici Endocrinology (AME) and Società Italiana dell'Osteoporosi, del Metabolismo Minerale e delle Malattie dello Scheletro (SIOMMMS) identified potentially relevant outcomes, which were then rated for their impact on therapeutic choices. Only outcomes classified as "critical" and "important" were considered in the systematic review of evidence. Those classified as "critical" were considered for the clinical practice recommendations. RESULTS: The present GL provides recommendations about the roles of pharmacological and surgical treatment for the clinical management of sporadic PHPT. Parathyroidectomy is recommended in comparison to surveillance or pharmacologic treatment in any adult (outside of pregnancy) or elderly subject diagnosed with sporadic PHPT who is symptomatic or meets any of the following criteria: • Serum calcium levels >1 mg/dL above the upper limit of normal range. • Urinary calcium levels >4 mg/kg/day. • Osteoporosis disclosed by DXA examination and/or any fragility fracture. • Renal function impairment (eGFR <60 mL/min). • Clinic or silent nephrolithiasis. • Age ≤50 years. Monitoring and treatment of any comorbidity or complication of PHPT at bone, kidney, or cardiovascular level are suggested for patients who do not meet the criteria for surgery or are not operated on for any reason. Sixteen indications for good clinical practice are provided in addition to the recommendations. CONCLUSION: The present GL is directed to endocrinologists and surgeons - working in hospitals, territorial services or private practice - and to general practitioners and patients. The recommendations should also consider the patient's preferences and the available resources and expertise.

Carotid intima-media thickness in surgically or conservatively managed patients with primary hyperparathyroidism.

CONTEXT: Current evidence of cardiovascular (CV) risk in primary hyperparathyroidism (PHPT) is still inconsistent. OBJECTIVE: To prospectively investigate changes of early atherosclerosis in patients with PHPT undergoing parathyroidectomy (PTx) or conservative management, according to Consensus criteria. METHODS: Biochemical parameters of PHPT, CV risk factors (systolic and diastolic blood pressure-BP-, total-, HDL- and LDL-cholesterol, triglyceride, glycosilated hemoglobin, and HOMA-IR), and carotid intima-media thickness (IMT) and plaque were assessed in 52 consecutive postmenopausal PHPT patients both at baseline and ≥24 months after surgery (PTx: n = 22) or conservative management (no-PTx: n = 30). RESULTS: At baseline, PTx and no-PTx showed comparable age, BMI, renal function, 25(OH)D levels, and did not differ for CV risk factors, IMT and plaques, nor for the prevalence of smoking, diabetes mellitus, antihypertensive or statin therapy, while differing for all parameters characterizing PHPT. Follow-up length in PTx was longer (p = 0.004) than in no-PTx. Parameters characterizing PHPT significantly improved ≥24 months after surgery, whereas in no-PTx serum phosphate slightly decreased and PTH increased. Systolic and diastolic BP increased at follow-up in both groups, while other CV risk factors did not significantly vary. In PTx IMT did not significantly vary after surgery (0.85 ± 0.14 to 0.89 ± 0.22 mm, p = 0.366), whereas it significantly increased in no-PHPT (0.80 ± 0.18 to 0.93 ± 0.23 mm, p = 0.008), even adjusting for BP values. Plaque prevalence and incidence did not significantly differ in the two groups. CONCLUSION: Our results suggest that in postmenopausal PHPT patients subclinical atherosclerosis could be halted by PTx, whereas it worsens over time in not operated patients with milder disease.

Increased Risk of Vertebral Fractures in Patients With Mild Autonomous Cortisol Secretion.

CONTEXT: The risk of vertebral fractures (VFx) in patients with adrenal incidentalomas (AI) and mild autonomous cortisol secretion (MACS) is debated. OBJECTIVE: To evaluate the VFx prevalence and incidence in patients with AI and MACS. METHODS: This cross-sectional and longitudinal study using retrospective data from 4 Italian endocrinology units included 444 patients (cross-sectional arm) and 126 patients (longitudinal arm, 24.9 ± 5.3 months follow-up) to evaluate prevalent and incident VFx, respectively, in patients with MACS (MACS-yes) and without MACS (MACS-no). The main outcome measures were serum cortisol after a 1-mg dexamethasone test (F-1mgDST), bone mineral density (BMD) by dual-energy x-ray absorptiometry at spine (LS) and femur (FN), and VFx presence by x-ray. RESULTS: Cross-sectional arm: 214 and 230 patients were MACS-yes and MACS-no, respectively, based on F-1mgDST >1.8 µg/dL (50 nmol/L). Patients with MACS had higher VFx prevalence (62.6%) than those without MACS (22.9%, P < .001); MACS was associated with prevalent VFx (odds ratio, 5.203; 95% CI, 3.361-8.055; P < .001; relative risk [RR] 2.07), regardless of age, body mass index, gender distribution, LS-BMD, and presence of type 2 diabetes mellitus (T2D). Longitudinal arm: 66 and 60 patients were MACS-no and MACS-yes, respectively. Patients without MACS showed higher number of incident VFx (36.4%) than patients without MACS (10.0%, P < .001); MACS was associated with the presence of an incident VFx (RR 4.561; 95% CI, 1.600-13.003; P = .005) regardless of age, LS-BMD, gender distribution, presence of prevalent VFx, and T2D. Results were confirmed in women and men when separately evaluated. CONCLUSION: Women and men with AI and MACS are at higher risk of VFx.

Calcium-phosphate homeostasis and insulin resistance in men.

BACKGROUND AND AIMS: Data on P homeostasis in insulin resistance (IR) are still conflicting. We investigated calcium-phosphate homeostasis parameters in men with/without IR. METHODS AND RESULTS: 177 volunteers (aged 61.62 ± 12.11), whose body mass index (BMI) was 29.97 ± 6.35, were studied. On fasting blood and spot urine samples, we measured serum creatinine, sodium (sNa), potassium (sK), chloride (sCl), calcium (sCa), phosphate (sP), alkaline phosphatase total activity (ALP), glucose, insulin, parathyroid hormone (PTH), 25-hydroxy-vitamin D [25(OH)D], and urinary electrolytes corrected for creatinine (uNa/Cr, uK/Cr, uCl/Cr, uCa/Cr, and uP/Cr). Through the QUICKI index, we separated subjects with (IR+, n = 68) or without (IR-, n = 109) IR, and their parameters were compared. Associations were assessed by age-adjusted partial correlation, whose coefficients were compared by Fisher's transform. IR + had higher sP (3.54 ± 0.65 vs. 3.35 ± 0.47, p = 0.044) and lower uCa/Cr levels (0.073 ± 0.056 vs. 0.095 ± 0.072, p = 0.047) than IR-. BMI correlated with sP (r = 0.21, p < 0.05) and PTH (r = 0.29, p < 0.01). QUICKI negatively correlated with sCa (r = -0.22, p < 0.05) and positively with uCa/Cr (r = 0.21, p < 0.05), in turn correlating with uNa/Cr (r = 0.45, p < 0.001). In both groups, uCa/Cr correlated with eGFR and uNa/Cr (p < 0.05 to p < 0.001). In IR + only, sP correlated with BMI, PTH with insulin, and uP/Cr (p < 0.05 for all). IR+ and IR-coefficients differed (p < 0.05 to p < 0.001) for the correlation of sP with BMI and of PTH with insulin and uP/Cr. CONCLUSION: The higher sP and lower uCa/Cr levels found in men with IR + suggest that IR could modulate calcium-phosphate homeostasis, likely by affecting their renal handling.

The degree of cortisol secretion is associated with diabetes mellitus and hypertension in patients with nonfunctioning adrenal tumors.

BACKGROUND: Similarly to cortisol-secreting adrenal tumors, also non-functioning adrenal tumors (NFAT) may be associated with an increased cardiovascular risk. We assessed in NFAT patients: (i) the association between hypertension (HT), diabetes mellitus (DM), obesity (OB), dyslipidemia (DL) and cardiovascular events (CVE) and cortisol secretion; (ii) the cut-off of the cortisol secretion parameters for identifying NFAT patients with a worse cardiometabolic profile. PATIENTS AND METHODS: In 615 NFAT patients (with cortisol levels after 1 mg overnight dexamethasone suppression test, F-1mgDST < 1.8 µg/dL [50 nmol/L]) F-1mgDST and adrenocorticotroph hormone (ACTH) levels and data on HT, DM, OB, DL and CVEs prevalence were retrospectively collected. RESULTS: HT, DM and HT plus DM were associated with F-1mgDST levels (area under the ROC curve: 0.588 ± 0.023, 0.610 ± 0.028, 0.611 ± 0.033, respectively, p < 0.001 for all comparisons) but not with ACTH. The cut-off for identifying patients with either HT or DM or HT plus DM was set at ≥ 1.2 µg/dL (33 nmol/L). As compared with patients with F-1mgDST < 1.2 µg/dL (n = 289), patients with F-1mgDST 1.2-1.79 µg/dL (33-49.4 nmol/L) (n = 326) had lower ACTH levels (17.7 ± 11.9 vs 15.3 ± 10.1 pg/mL, respectively, p = 0.008), older age (57.5 ± 12.3 vs 62.5 ± 10.9 years, respectively, p < 0.001), and higher prevalence of HT (38.1% vs 52.5% respectively p < 0.001), DM (13.1% vs 23.3%, respectively, p = 0.001), HT plus DM (8.3% vs 16.9%, respectively, p < 0.002) and CVE (3.2% vs 7.3%, respectively, p = 0.028). F-1mgDST 1.2-1.79 µg/dL was associated with either HT (odd ratio, OR, 1.55, 95% confidence interval, 95% CI 1.08-2.23, p = 0.018) or DM (OR 1.60, 95% CI 1.01-2.57, p = 0.045) after adjusting for age, gender, OB, DL, and DM (for HT) or HT (for DM), and with the presence of HT plus DM (OR 1.96, 95% CI 1.12-3.41, p = 0.018) after adjusting for age, gender, OB and DL. CONCLUSIONS: In NFAT patients, F-1mgDST 1.2-1.79 µg/dL seems to be associated with a higher prevalence of HT and DM and a worse cardiometabolic profile, even if the poor accuracy of these associations suggests caution in interpreting these results.

Secondary Osteoporosis: A Still Neglected Condition.

The condition of "secondary osteoporosis" is defined as a bone loss that results from specific well-defined clinical disorders [...].

Bone Disease in Long-Term Lung Transplant Survivors.

BACKGROUND: During the first two years after lung transplantation (LTx), the incidence of fragility fractures (FX) is estimated to be 15-50% and it is lower in patients with cystic fibrosis (CF) as compared with other end-stage lung diseases (nCF). The aim of our study is to compare the skeletal outcomes, after the first 2 years post-LTx, in long-term survivors with CF and nCF. MATERIALS AND METHODS: We evaluated the FX rate, the changes in bone mineral density (BMD) and trabecular bone score (TBS) in 68 patients (38 CF and 30 nCF) who underwent LTx in our center and with a follow-up after LTx longer than 5 years (7.3 ± 2.0 years). RESULTS: After the second year post-LTx: (i) the FX rate was lower than during the first two years post-LTx (4.4 vs. 20.6%, p = 0.004), with no difference between CF and nCF patients (5.3 vs. 3.3%, p = 0.589); (ii) BMD at lumbar spine, femoral neck and total hip remained stable (-1.6 ± 1.0 vs. -1.4 ± 1.1, p = 0.431, -1.8 ± 0.9 vs. -1.9 ± 0.9, p = 0.683, -1.5 ± 0.9 vs. -1.4 ± 0.9, p = 0.678, respectively) as well as TBS (1.200 ± 0.124 vs. 1.199 ± 0.205, p = 0.166). CONCLUSIONS: After the second year post-LTx, the skeletal complications become less frequent and have similar incidence in patients with CF and nCF.

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.

Optimization of a Monobromobimane (MBB) Derivatization and RP-HPLC-FLD Detection Method for Sulfur Species Measurement in Human Serum after Sulfur Inhalation Treatment.

(1) Background: Hydrogen sulfide (H2S) is a widely recognized gasotransmitter, with key roles in physiological and pathological processes. The accurate quantification of H2S and reactive sulfur species (RSS) may hold important implications for the diagnosis and prognosis of diseases. However, H2S species quantification in biological matrices is still a challenge. Among the sulfide detection methods, monobromobimane (MBB) derivatization coupled with reversed phase high-performance liquid chromatography (RP-HPLC) is one of the most reported. However, it is characterized by a complex preparation and time-consuming process, which may alter the actual H2S level; moreover, a quantitative validation has still not been described. (2) Methods: We developed and validated an improved analytical protocol for the MBB RP-HPLC method. MBB concentration, temperature and sample handling were optimized, and the calibration method was validated using leave-one-out cross-validation and tested in a clinical setting. (3) Results: The method shows high sensitivity and allows the quantification of H2S species, with a limit of detection of 0.5 µM. Finally, it can be successfully applied in measurements of H2S levels in the serum of patients subjected to inhalation with vapors rich in H2S. (4) Conclusions: These data demonstrate that the proposed method is precise and reliable for measuring H2S species in biological matrices and can be used to provide key insights into the etiopathogenesis of several diseases and sulfur-based treatments.

Novel Glial Cells Missing-2 (GCM2) variants in parathyroid disorders.

OBJECTIVE: The aim of this study was to analyze variants of the gene glial cells missing-2 (GCM2), encoding a parathyroid cell-specific transcription factor, in familial hypoparathyroidism and in familial isolated hyperparathyroidism (FIHP) without and with parathyroid carcinoma. DESIGN: We characterized 2 families with hypoparathyroidism and 19 with FIHP in which we examined the mechanism of action of GCM2 variants. METHODS: Leukocyte DNA of hypoparathyroid individuals was Sanger sequenced for CASR, PTH, GNA11 and GCM2 mutations. DNA of hyperparathyroid individuals underwent MEN1, CDKN1B, CDC73, CASR, RET and GCM2 sequencing. The actions of identified GCM2 variants were evaluated by in vitro functional analyses. RESULTS: A novel homozygous p.R67C GCM2 mutation which failed to stimulate transcriptional activity in a luciferase assay was identified in affected members of two hypoparathyroid families. Oligonucleotide pull-down assay and in silico structural modeling indicated that this mutant had lost the ability to bind the consensus GCM recognition sequence of DNA. Two novel (p.I383M and p.T386S) and one previously reported (p.Y394S) heterozygous GCM2 variants that lie within a C-terminal conserved inhibitory domain were identified in three affected individuals of the hyperparathyroid families. One family member, heterozygous for p.I138M, had parathyroid carcinoma (PC), and a heterozygous p.V382M variant was found in another patient affected by sporadic PC. These variants exerted significantly enhanced in vitrotranscriptional activity, including increased stimulation of the PTH promoter. CONCLUSIONS: We provide evidence that two novel GCM2 R67C inactivating mutations with an inability to bind DNA are causative of hypoparathyroidism. Additionally, we provide evidence that two novel GCM2 variants increased transactivation of the PTH promoter in vitro and are associated with FIHP. Furthermore, our studies suggest that activating GCM2 variants may contribute to facilitating more aggressive parathyroid disease.

Case Report: Evolution of KIT D816V-Positive Systemic Mastocytosis to Myeloid Neoplasm With PDGFRA Rearrangement Responsive to Imatinib.

Systemic mastocytosis (SM) is a rare neoplasm resulting from extracutaneous infiltration of clonal mast cells (MC). The clinical features of SM are very heterogenous and treatment should be highly individualized. Up to 40% of all SM cases can be associated with another hematological neoplasm, most frequently myeloproliferative neoplasms. Here, we present a patient with indolent SM who subsequently developed a myeloid neoplasm with PDGFRA rearrangement with complete response to low-dose imatinib. The 63-year-old patient presented with eosinophilia and elevated serum tryptase level. Bone marrow analysis revealed aberrant MCs in aggregates co-expressing CD2/CD25 and KIT D816V mutation (0.01%), and the FIP1L1-PDGFRA fusion gene was not identified. In the absence of 'B' and 'C' findings, we diagnosed an indolent form of SM. For 2 years after the diagnosis, the absolute eosinophil count progressively increased. Bone marrow evaluation showed myeloid hyperplasia and the FIP1L1-PDGFRA fusion gene was detected. Thus, the diagnosis of myeloid neoplasm with PDGFRA rearrangement was established. The patient was treated with imatinib 100 mg daily and rapidly obtained a complete molecular remission. The clinical, biological, and therapeutic aspects of SM might be challenging, especially when another associated hematological disease is diagnosed. Little is known about the underlying molecular and immunological mechanisms that can promote one entity prevailing over the other one. Currently, the preferred concept of SM pathogenesis is a multimutated neoplasm in which KIT mutations represent a "phenotype modifier" toward SM. Our patient showed an evolution from KIT mutated indolent SM to a myeloid neoplasm with PDGFRA rearrangement; when the eosinophilic component expanded, a regression of the MC counterpart was observed. In conclusion, extensive clinical monitoring associated with molecular testing is essential to better define these rare diseases and consequently their prognosis and treatment.

Impact of bone-active drugs and underlying disease on bone health after lung transplantation: A longitudinal study.

INTRODUCTION: the effect of bone-active drugs on the risk of fragility fractures (Fx), bone mineral density (BMD) and trabecular bone score (TBS) changes in patients receiving lung transplantation (LTx) is largely unknown. This study assessed the bone-active drugs effect in patients undergoing LTx both with (CF) and without (nCF) cystic-fibrosis. METHODS: We evaluated incident Fx, both clinical and morphometric vertebral Fx by spinal X-ray, BMD and trabecular bone score (TBS) in 117 patients (CF=50, nCF n = 67) before and 24-months after LTx. A bone-active therapy was proposed to all LTx candidates. RESULTS: 83.8% of patients started a bone-active drug. Lumbar-spine (LS) T-score improved significantly only in treated patients (-1.4 ± 1.0 vs -2.0±1.0, p = 0.0001), whereas femur BMD and TBS remained stable in treated and not treated subjects. The rate of incident Fx was 15.3%, with no difference between treated and not treated patients. After LTx, LS T-score improved significantly only in nCF group (-1.3 ± 1.0 vs -1.8 ± 1.1, p = 0.0001), while femur remained stable in both nCF and CF groups. Patients with CF showed a significant Z-TBS increase (-3.6 ± 1.7 vs -3.0 ± 1.7, p = 0.019) and a lower Fx incidence as compared with nCF patients (4.1% vs 24.2%, p  =0.003). Incident Fx were associated with nCF diagnosis (OR 7.300, CI95% 1.385-38.461, p = 0.019) regardless of prevalent Fx, previous glucocorticoid therapy and bone-active therapy introduced at least 6 months before LTx. CONCLUSIONS: A prompt medical intervention helps in preventing BMD loss after LTx. As compared with nCF patients, CF patients show a TBS increase and a lower Fx risk after LTx.

Bisphosphonates after denosumab withdrawal reduce the vertebral fractures incidence.

OBJECTIVE: Several studies showed the occurrence of vertebral fracture (VFx) in patients discontinuing denosumab (Dmab), suggesting the need of bisphosphonate (BPs) therapy to mitigate this VFx risk increase. However, the morphometric VFx (morphoVFx) incidence after Dmab discontinuation and the BPs effect on VFx risk in this setting are still a matter of debate. DESIGN: Retrospective, monocentric study. METHODS: In 120 patients (111 females) discontinuing Dmab, 19 have not been treated (non-treated group: 16 females, aged 63.5 ± 15.0 years) and 101 patients have been treated (treated group: 95 females, aged 70.0 ± 10.6 years) with BPs (28 alendronate (ALN); 73 zoledronate ZOL), single infusion), respectively. We evaluated the incidence of both clinical VFx and morphoVFx in treated group and non-treated group. RESULTS: Patients in treated group showed a 5.5% VFx incidence (n = 6, three clinical, three morpho VFx), which was anyway lower than non-treated group patients (n = 4, 21.1%, four clinical, three multiple, P = 0.029), despite a comparable FRAX score at the time of Dmab initiation. The logistic regression analysis showed that the VFx incidence was independently associated with the lack of BPs treatment (odds ratio: 13.9, 95% CI 1.7-111.1, P = 0.014), but not with the number of Dmab injections, age, duration of BPs before Dmab initiation, the BMD at Dmab withdrawal, and the prevalence of VFx at Dmab withdrawal. CONCLUSIONS: The Dmab withdrawal is associated with an increased risk of clinical but not morphometric VFx. Therapy with ALN or with a single ZOL treatment is partially effective in reducing the increased VFx risk after Dmab withdrawal.

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.

Dietary calcium intake in a cohort of individuals evaluated for low bone mineral density: a multicenter Italian study.

BACKGROUND: A low calcium intake is a well-known factor that influences the bone mineral density (BMD) maintenance. In the presence of inadequate calcium intake, secondary hyperparathyroidism develops, leading to an increased bone turnover and fracture risk. AIMS: To assess the dietary calcium intake in relation with osteoporosis and fragility fracture in a cohort of Italian individuals evaluated for low BMD. METHODS: A 7-day food-frequency questionnaire was administered to 1793 individuals, who were consecutively referred at the Centers of the Italian Society for Osteoporosis, Mineral Metabolism and Skeletal Diseases (SIOMMMS) for low BMD. RESULTS: In 30.3% and 20.9% of subjects, the calcium intake was inadequate (< 700 mg/day) and adequate (> 1200 mg/day), respectively. As compared with patients with adequate calcium intake, those with inadequate calcium intake were younger (65.5 ± 10.8 vs 63.9 ± 11.5 years, p = 0.03) and they more frequently reported adverse reactions to food (3.2% vs 7.2% p = 0.01) and previous major fragility fractures (20.8% vs 27.0%, p = 0.03). Patients with calcium intake < 700 mg/day showed a higher prevalence of diabetes mellitus, idiopathic hypercalciuria and food allergy/intolerance (8.1%, 5.1%, 7.2%, respectively) than patients with calcium intake > 700 mg/day (5.3%, 3.0%, 4.1%, respectively, p < 0.04 for all comparisons), also after adjusting for age, gender and body mass index. In 30.3% of fractured subjects, the calcium intake was < 700 mg/day. DISCUSSION: In Italy, a low calcium intake is highly prevalent in individuals at risk for low BMD. Importantly, an inadequate calcium intake is highly prevalent even in patients with history of fragility fractures. CONCLUSIONS: Only about a fifth of patients being assessed for low BMD in an Italian SIOMMMS referral Centre have an adequate calcium intake.

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.