Restless leg syndrome as a complication of primary hyperparathyroidism: insights from a retrospective study.

INTRODUCTION: Restless leg syndrome (RLS) is an invalidating neurological disorder with a complex, largely unknown pathophysiology. While RLS is observed in Parkinson's disease and in renal failure, idiopathic cases are common. Limited reports associate RLS with parathyroid hormone (PTH). This study analyzes a cohort of patients with primary hyperparathyroidism (PHPT) and chronic post-surgical hypoparathyroidism (hypo PTH), to investigate RLS prevalence, and associated risk factors. METHODS: Ninety-five patients (54 PHPT, 41 hypo PTH) were consecutively enrolled at the bone metabolism outpatient clinic. The revised IRLSSG diagnostic criteria were used to diagnose RLS, with assessments conducted through face-to-face interviews and neurological examination. When RLS was confirmed, the RLS severity scale was applied. Retrospective records included calcium-phosphate metabolism-related parameters, surgery details, renal lithiasis, fragility fractures, and densitometric features (T-score). RESULTS: RLS was diagnosed in 22.2% PHPT patients, compared to 4.9% of patients with hypo PTH (p = 0.02). Of RLS diagnosed patients, 91.7% had a history of parathyroidectomy, compared to 47.6% of patients without RLS (p = 0.01). Most of the operated patients reported that surgery determined an improvement of symptoms; however, mean score severity of RLS at our evaluation was 15/40, defined as moderate. PTH and calcium levels were not statistically associated to the presence of RLS. CONCLUSION: Our study suggests that PHPT may be one of the etiologies of RLS. Parathyroidectomy alleviates symptoms in the vast majority of the cases but does not remove them.

DXA-based bone strain index in normocalcemic primary hyperparathyroidism.

The trabecular and cortical bone assessed by bone strain index seems not to be significantly affected in NHPT. INTRODUCTION: The natural history and bone involvement of normocalcemic hyperparathyroidism (NHPT) are not fully clarified yet. The bone strain index (BSI) is a deformation index based on the finite element method and can be applied to DXA scans. In this study, we aim to assess BSI in subjects with NHPT. METHOD: A case-control study included 170 subjects: 40 subjects with NHPT, 50 subjects with primary hypercalcemic hyperparathyroidism (PHPT), and 80 controls (age- and sex-matched with the NPTH group). RESULTS: Lumbar spine (LS) bone mineral density (BMD), femoral neck (FN) BMD, total hip (TH) BMD, and TBS were similar between NHPT and both PHPT and controls. FN-BSI was lower in NHPT compared to PHPT (1.52 ± 0.31 vs 1.72 ± 0.42 p = 0.031) while there were no differences between NHPT and controls. TH-BSI was lower in NHPT compared to PHPT (1.36 ± 0.23 vs 1.52 ± 0.34, p = 0.030), while there were no differences between NHPT and controls. LS-BSI was not different between NHPT and both PHPT and controls. CONCLUSION: The trabecular and cortical bones assessed by BSI seem not to be significantly impaired in NHPT. Further prospective studies are needed to confirm these findings and to give an insight into the natural history of NHPT to improve knowledge and management of this condition.

Evaluating the effect of calcifediol supplementation on seizure frequency in people with drug-resistant epilepsy.

The well-known neuroprotective role and involvement of vitamin D in the function of the central nervous system has raised the speculation about the possible antiseizure effect of vitamin D supplementation. This issue is crucial when considering people with epilepsy (PWE), who frequently display vitamin D deficiency, but nowadays data are still unconclusive. In our study, we enrolled 25 adult patients affected by drug-resistant epilepsy and hypovitaminosis D to test the effect of Calcifediol on seizure frequency after 6 months of supplementation. Our findings evidenced that Calcifediol administration completely restored 25-hydroxy vitamin D (25-OHD) and intact parathyroid hormone (iPTH) serum values (p < 0.001 for both) without significant changes of median seizure frequency (-6.1%). Anyway, we observed some rate of PWE responders (32%) to Calcifediol supplementation. Further randomized controlled trials with larger subjects 'samples will be needed to verify the possible antiseizure effect of vitamin D.

Long-term efficacy and safety of percutaneous ethanol injection (PEI) in cystic thyroid nodules: A systematic review and meta-analysis.

BACKGROUND: Percutaneous ethanol injection (PEI) is used for the treatment of benign cystic thyroid nodules. This systematic review and meta-analysis aimed to obtain strong evidence of its long-term efficacy and safety. METHODS: PubMed, CENTRAL, Scopus and Web of Science databases were searched until November 2020 for studies reporting data on volume reduction rate (VRR), compressive symptoms and cosmetic concerns. Associated complications were assessed. A random-effects model was designed to pool the data. RESULTS: Out of 385 papers, nine studies evaluating 1667 nodules were finally included. Overall, VRR at 6, 12, 24, 36, 60 and 120 months was 77%, 81%, 72%, 68%, 74% and 69%, respectively. Significant reductions in the compressive symptoms and cosmetic concerns were observed. No permanent complications were observed. CONCLUSIONS: The present meta-analysis showed that PEI could significantly reduce the volume of benign cystic thyroid nodules. This reduction was already effective at 6 months post-treatment, and the effect was stable over time.

Dipeptidyl Peptidase 3 Activity as a Promising Biomarker of Bone Fragility in Postmenopausal Women.

The dipeptidyl peptidase 3 (Dpp3) is a ubiquitous zinc-dependent aminopeptidase, participating in the activation or degradation of signaling peptides and in the Keap1−Nrf2 antioxidant pathway. The absence of Dpp3 in the Dpp3 knockout mouse model causes increased osteoclast activity, altered osteogenic function, sustained oxidative stress in the bone tissue, and bone loss. We aimed to assess the association of Dpp3 activity with bone fragility in postmenopausal osteoporosis and the impact of denosumab on enzymatic activity. We conducted a two-phase study including 69 postmenopausal women with severe osteoporosis and 36 postmenopausal women without osteometabolic conditions, as controls (cross-sectional phase). Subjects with severe osteoporosis were assessed at baseline and 14 days after the first denosumab administration (prospective phase). The results showed significant reduction in serum Dpp3 activity (expressed as nmoles of formed product/mg proteins/min) in patients vs. controls (0.791 ± 0.232 vs. 1.195 ± 0.338; p < 0.001), and significant association with bone mass at the femoral neck (r = 0.28, p = 0.02) in patients prior to treatment. We found a negative correlation between C-terminal telopeptide (CTX) or N-terminal pro-peptide of type 1 procollagen (P1NP) levels and Dpp3 activity (respectively, r = −0.29, p = 0.012; and r = −0.2572, p = 0.033). Dpp3 activity did not change after denosumab injection. Our findings support a critical role played by Dpp3 in bone homeostasis as a potential bone protective factor. Additional clinical studies in larger cohorts might explore the implementation of Dpp3 assessment as a biomarker of bone health status.

Bone Quality as Measured by Trabecular Bone Score in Normocalcemic Primary Hyperparathyroidism.

OBJECTIVE: The impact of normocalcemic hyperparathyroidism (NHPT) on bone quality remains largely unexplored. We aimed to investigate the usefulness of trabecular bone score (TBS) assessment in NHPT and the accuracy of TBS in predicting vertebral fractures (VFs) in NHPT. METHODS: In this multicentric cross-sectional study, we assessed the TBS in 47 subjects with NHPT, 41 with primary hyperparathyroidism (PHPT), and 39 age- and sex-matched control subjects. RESULTS: TBS values did not differ among the 3 groups. The prevalence of low TBS (TBS < 1.2) was 23.4% in NHPT, 26.8% in PHPT, and 15.4% in controls, without statistically significant differences between groups. However, we found a lower lumbar spine Z-score adjusted for TBS (LS Z-score∗TBS) in PHPT participants when compared with controls (-0.48 ± 1.06 vs 0.07 ± 0.93, P = .017). In NHPT group, LS Z-score∗TBS did not detect patients with overall VFs (threshold, -0.15; area under the curve, 0.45; 95% CI, 0.253-0.648; accuracy, 55.3%). Instead, it was useful for moderate-severe VFs (threshold, 0.55; area under the curve, 0.81; 95% CI, 0.62-0.996; accuracy, 83%). In PHPT subjects also, TBS did not predict VFs. CONCLUSION: In NHPT, TBS is not reduced. When adjusted for TBS, the LS Z-score might predict moderate-to-severe VFs.

Calcium citrate: from biochemistry and physiology to clinical applications.

Adequate daily calcium intake should normally be achieved by dietary sources. Since low calcium diets are quite common in subjects that do not reach the recommended intake and particularly those at risk of fractures, calcium supplements may become necessary. Different forms of calcium salts are available, but products containing calcium citrate and calcium carbonate complexes are the most frequently used. Although only limited evidence on the efficacy and long-term safety of calcium citrate is available, these supplements may represent a valuable product for the management of different chronic pathological conditions. The aim of this review was to evaluate the current and potential clinical applications of calcium citrate. In particular, we focused on the use of calcium citrate supplementation in subjects with osteoporosis or in bariatric patients. Other pathological conditions that could benefit calcium citrate supplementation may include achloridria, chronic hypoparathyroidism and hypocitraturic subjects with moderate/high risk of nephrolithiasis. Indeed, citrate salts are widely used in the treatment of nephrolithiasis, since they have shown an inhibitory effect on kidney stone formation and recurrence.

Romosozumab versus parathyroid hormone receptor agonists: which osteoanabolic to choose and when.

Osteoanabolic agents are used as a first line treatment in patients at high fracture risk. The PTH receptor 1 (PTH1R) agonists teriparatide (TPTD) and abaloparatide (ABL) increase bone formation, bone mineral density (BMD), and bone strength by activating PTH receptors on osteoblasts. Romosozumab (ROMO), a humanized monoclonal antibody against sclerostin, dramatically but transiently stimulates bone formation and persistently reduces bone resorption. Osteoanabolic agents increase BMD and bone strength while being more effective than antiresorptives in reducing fracture risk in postmenopausal women. However, direct comparisons of the antifracture benefits of osteoanabolic therapies are limited. In a direct comparison of TPTD and ABL, the latter resulted in greater BMD increases at the hip. While no differences in vertebral or non-vertebral fracture risk were observed between the two drugs, ABL led to a greater reduction of major osteoporotic fractures. Adverse event profiles were similar between the two agents except for hypercalcemia, which occurred more often with TPTD. No direct comparisons of fracture risk reduction between ROMO and the PTH1R agonists exist. Individual studies have shown greater increases in BMD and bone strength with ROMO compared to TPTD in treatment-naïve women and in women previously treated with bisphosphonates. Some safety aspects, such as a history of tumor precluding the use of PTH1R agonists, and a history of major cardiovascular events precluding the use of ROMO, should also be considered when choosing between these agents. Lastly, convenience of administration, reimbursement by national health systems and length of clinical experience may influence patient choice.

From sampling to cellblock: The fully automated journey of cytological specimens.

In recent years, technological innovation have emerged to standardize pathology laboratory processes and reduce the handling of diagnostic samples. Among them is an automatic tissue embedding system that eliminates the need for manual activity in tissue paraffin embedding, thereby improving sample preservation. Unfortunately, this system cannot be used for cytological specimens due to the lack of an effective holder to support the procedure steps. In this study, we evaluated the performance of a commercial polymer matrix to enable and standardize the automatic paraffin embedding of cytological material from different organs and sources. Cytological samples from 40 patients were collected on the matrices and submitted for fully automatic workflow preparation, from formalin fixation until paraffin block, using the Sakura embedding system. Our results demonstrated the feasibility of the automated procedure, from loading cytological sample onto the matrix to obtaining the paraffin cellblock, thereby avoiding manual manipulation of cellular material. All samples resulted adequately processed and paraffin-embedded showing satisfactory tissue permeation by processing reagents, optimal preservation of cytoplasmic and nuclear details, and good quality of staining results on paraffin sections. Automated embedding of cytological samples eliminates the risk of lost specimens, reduces laboratory burden, standardizes procedures, increases diagnostic yield, and ultimately improves patients' management.

Risk and management of osteoporosis due to inhaled, epidural, intra-articular or topical glucocorticoids.

Glucocorticoids (GCs) are widely used by several specialties for the treatment of a variety of diseases and conditions. The unfavorable effect of oral GCs on bone health is well-documented. The ensuing from their use glucocorticoid-induced osteoporosis (GIOP) is the most common cause of medication-induced osteoporosis and fractures. It is uncertain, however, if, and in what extent, GCs administered by other routes affect the skeleton. In the present review, we quote current evidence on the effect of inhaled GCs, epidural and intra-articular steroid injections, and topical GCs on bone outcomes. Although evidence is limited and weak, it seems that a small proportion of the administered GCs may be absorbed, enter the systemic circulation, and adversely affect the skeleton. Potent GCs, higher doses, and longer treatment duration seem to infer the greater risk for bone loss and fractures. There are scarce data, and only for inhaled GCs, regarding the efficacy of antiosteoporotic medications in patients receiving GCs through routes other than oral. Further studies are needed to clarify the relationship between GC administration through these routes and bone outcomes and to help establishing guidelines for the optimal management of such patients.

Leg restlessness and hyperparathyroidism in Parkinson's disease, a further clue to RLS pathogenesis?

Background: Non-motor manifestations are the main features of Parkinson's disease (PD). These have been associated with vitamin D abnormalities, but the role of parathormone (PTH) is still obscure. Among the non-motor symptoms of PD, the pathogenesis of restless leg syndrome (RLS) is still debated, but it has been associated with the vitamin D/PTH axis in other disease models. Our study deepens the association between vitamin D and PTH with the prevalence of non-motor symptoms of PD and explores such a relationship in patients reporting leg restlessness. Methods: Fifty patients with PD were extensively investigated with motor and non-motor scales. Data on serum levels of vitamin D, PTH, and related metabolites were obtained, and patients were stratified as having vitamin D deficiency or hyperparathyroidism according to standardized criteria. Results: Overall, 80% of patients with PD exhibited low vitamin D levels, and hyperparathyroidism was diagnosed in 45%. The analysis of the non-motor symptoms profile using the non-motor symptom questionnaire (NMSQ) revealed 36% of leg restlessness, a main feature of RLS. This was significantly associated with worse motor symptoms, quality of sleep, and quality of life. Moreover, it was associated with hyperparathyroidism (OR: 3.48) and with PTH levels, independent of vitamin D, calcium/phosphate levels, and motor status. Conclusion: Our results suggest a significant association between the vitamin D/PTH axis and leg restlessness in PD. PTH has a putative role in nociceptive modulation, and previous evidence on hyperparathyroidism has suggested a possible interrelation with RLS. Further investigations are necessary to add PTH to the non-dopaminergic non-motor landscape of PD.

Real-Time Evaluation of Thyroid Cytology Using New Digital Microscopy Allows for Sample Adequacy Assessment, Morphological Classification, and Supports Molecular Analysis.

Thyroid cytological examination, a key tool in preoperative thyroid nodule evaluation, is specific and accurate; some drawbacks are due to inadequate or indeterminate cytological reports and there is a need for an innovative approach overcoming the limits of traditional cytological diagnostics. Fluorescence laser confocal microscopes (FCM) is a new optical technique for allowing immediate digital imaging of fresh unfixed tissues and real-time assessment of sample adequacy and diagnostic evaluation for small biopsies and cytological samples. Currently, there are no data about the use of FCMs in the field of thyroid nodular pathology. The aims of this study were to test FCM technology for evaluating the adequacy of FNA samples at the time of the procedure and to assess the level of concordance between FCM cytological evaluations, paired conventional cytology, and final surgical histology. The secondary aim was to define the integrity of nucleic acids after FCM evaluation through NGS molecular analysis. Sample adequacy was correctly stated. Comparing FCM evaluation with the final histology, all cases resulting in malignant or suspicious for malignancy at FCM, were confirmed to be carcinomas (PPV 100%). In conclusion, we describe a successful application of FCM in thyroid preoperative cytological evaluation, with advantages in immediate adequacy assessment and diagnostic information, while preserving cellular specimens for permanent morphology and molecular analysis, thus improving timely and accurate patient management.

An eXplainable Artificial Intelligence analysis of Raman spectra for thyroid cancer diagnosis.

Raman spectroscopy shows great potential as a diagnostic tool for thyroid cancer due to its ability to detect biochemical changes during cancer development. This technique is particularly valuable because it is non-invasive and label/dye-free. Compared to molecular tests, Raman spectroscopy analyses can more effectively discriminate malignant features, thus reducing unnecessary surgeries. However, one major hurdle to using Raman spectroscopy as a diagnostic tool is the identification of significant patterns and peaks. In this study, we propose a Machine Learning procedure to discriminate healthy/benign versus malignant nodules that produces interpretable results. We collect Raman spectra obtained from histological samples, select a set of peaks with a data-driven and label independent approach and train the algorithms with the relative prominence of the peaks in the selected set. The performance of the considered models, quantified by area under the Receiver Operating Characteristic curve, exceeds 0.9. To enhance the interpretability of the results, we employ eXplainable Artificial Intelligence and compute the contribution of each feature to the prediction of each sample.

Calcium Citrate Versus Calcium Carbonate in the Management of Chronic Hypoparathyroidism: A Randomized, Double-Blind, Crossover Clinical Trial.

In hypoparathyroidism (HypoPT), calcium supplementation is virtually always required, although the disease is likely to be associated with an increased risk of nephrolithiasis. The use of calcium citrate (Ca-Cit) theoretically could have a positive impact on the nephrolithiasis risk because citrate salts are used to reduce this risk. Our objective was to evaluate the potential therapeutic advantage of Ca-Cit in comparison with calcium carbonate (CaCO3 ) in HypoPT, on nephrolithiasis risk factors, as well as to their ability to maintain desirable serum calcium levels. We also evaluated these preparations on quality of life (QOL). This randomized, double-blind, crossover trial recruited 24 adults with postsurgical chronic hypoparathyroidism at Campus Bio-Medico University of Rome. Participants were randomized 1:1 to Ca-Cit or CaCO3 for 1 month and then crossed over to the other treatment for another month. The primary outcomes were changes in albumin-adjusted serum calcium and in ion activity product of calcium oxalate levels (AP[CaOx] index). Secondary efficacy outcomes included changes in SF-36 survey score, fatigue score, constipation, and adverse events. No difference in terms of AP(CaOx) index was observed between the two groups. However, Ca-Cit was associated with a significant reduction in the oxalate/creatinine ratio compared with CaCO3 (-2.46 mmol/mol [SD 11.93] versus 7.42 mmol/mol [SD 17.63], p = 0.029). Serum calcium and phosphorus concentration was not different between the two calcium preparations. Ca-Cit was associated with less constipation (p = 0.047). No difference was found in QOL scores. Although Ca-Cit did not modify the AP(CaOx) index when compared with CaCO3, it was associated with a reduction in urinary oxalate excretion that could have a potential beneficial effect on nephrolithiasis risk. These results are likely to have clinical implications in HypoPT, particularly those who do not tolerate CaCO3 and those affected by nephrolithiasis. A longer-term experience is needed to confirm these findings. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Clinical Use of Raman Spectroscopy Improves Diagnostic Accuracy for Indeterminate Thyroid Nodules.

BACKGROUND AND OBJECTIVE: Molecular analysis of thyroid fine-needle aspiration (FNA) specimens is believed to improve the management of indeterminate nodules. Raman spectroscopy (RS) can differentiate benign and malignant thyroid lesions in surgically removed tissues, generating distinctive structural profiles. Herein, the diagnostic performance of RS was tested on FNA biopsies of thyroid gland. DESIGN: Prospective, blinded, and single-center study. METHODS: We enrolled 123 patients with indeterminate or more ominous cytologic diagnoses (TIR3A-low-risk indeterminate lesion, TIR3B-high-risk indeterminate lesion, TIR4-suspicious of malignancy, TIR5-malignant). All subjects were surgical candidates (defined by international guidelines) and submitted to FNA procedures for RS analysis. We compared RS data, cytologic findings, and final histologic assessments (as reference standard) using various statistical techniques. RESULTS: The distribution of our study population was as follows: TIR3A:37, TIR3B:32, TIR4:16, and TIR5:38. In 30.9% of patients, histologic diagnoses were benign. For predicting thyroid malignancy in FNA samples, the overall specificity of RS was 86.8%, with 86.5% specificity in indeterminate cytologic categories. In patients with high-risk ultrasound categories, the specificity of RS increased to 87.5% for TIR3A, reaching 100% for TIR3B. Benign histologic diagnoses accounted for 72.9% of patients classified as TIR3A and 31.3% of those classified as TIR3B. Based on positive RS testing, unnecessary surgery was reduced to 7.4% overall (TIR3A-33.3%, TIR3B-6.7%). CONCLUSIONS: This premier use of RS for thyroid cytology confirms its role as a valuable diagnostic tool and a valid alternative to molecular studies, capable of improving the management of indeterminate nodules and reducing unnecessary surgery.

Unraveling the Effects of Carotenoids Accumulation in Human Papillary Thyroid Carcinoma.

Among the thyroid cancers, papillary thyroid cancer (PTC) accounts for 90% of the cases. In addition to the necessity to identify new targets for PTC treatment, early diagnosis and management are highly demanded. Previous data indicated that the multivariate statistical analysis of the Raman spectra allows the discrimination of healthy tissues from PTC ones; this is characterized by bands typical of carotenoids. Here, we dissected the molecular effects of carotenoid accumulation in PTC patients by analyzing whether they were required to provide increased retinoic acid (RA) synthesis and signaling and/or to sustain antioxidant functions. HPLC analysis revealed the lack of a significant difference in the overall content of carotenoids. For this reason, we wondered whether the carotenoid accumulation in PTC patients could be related to vitamin A derivative retinoic acid (RA) biosynthesis and, consequently, the RA-related pathway activation. The transcriptomic analysis performed using a dedicated PCR array revealed a significant downregulation of RA-related pathways in PTCs, suggesting that the carotenoid accumulation in PTC could be related to a lower metabolic conversion into RA compared to that of healthy tissues. In addition, the gene expression profile of 474 PTC cases previously published in the framework of the Cancer Genome Atlas (TGCA) project was examined by hierarchical clustering and heatmap analyses. This metanalysis study indicated that the RA-related pathways resulted in being significantly downregulated in PTCs and being associated with the follicular variant of PTC (FV-PTC). To assess whether the possible fate of the carotenoids accumulated in PTCs is associated with the oxidative stress response, the expression of enzymes involved in ROS scavenging was checked. An increased oxidative stress status and a reduced antioxidant defense response were observed in PTCs compared to matched healthy thyroids; this was possibly associated with the prooxidant effects of high levels of carotenoids. Finally, the DepMap datasets were used to profile the levels of 225 metabolites in 12 thyroid cancer cell lines. The results obtained suggested that the high carotenoid content in PTCs correlates with tryptophan metabolism. This pilot provided novel possible markers and possible therapeutic targets for PTC diagnosis and therapy. For the future, a larger study including a higher number of PTC patients will be necessary to further validate the molecular data reported here.

Denosumab Discontinuation and the Rebound Phenomenon: A Narrative Review.

Denosumab is a potent antiresorptive agent that substantially increases bone mineral density and reduces fracture rates at all skeletal sites for as long as it is administered. However, its favorable skeletal effects reverse quickly upon its discontinuation, because of a vast increase of osteoclast number and activity, which leads to a subsequent profound increase of bone turnover above pre-treatment values, a phenomenon commonly described as "rebound phenomenon". More importantly, most patients experience rapid, profound bone loss due to this burst of bone resorption that may lead in a minority of these patients to occurrence of fractures, especially multiple vertebral fractures. Therefore, subsequent antiresorptive treatment is mandatory, although the optimal regimen is yet to be clarified. In the present review, we outline what is currently known regarding the negative effects of denosumab discontinuation on different aspects of bone status, the factors that may affect them, and strategies to prevent them.

The Impact of Antiosteoporotic Drugs on Glucose Metabolism and Fracture Risk in Diabetes: Good or Bad News?

Osteoporosis and diabetes mellitus represent global health problems due to their high, and increasing with aging, prevalence in the general population. Osteoporosis can be successfully treated with both antiresorptive and anabolic drugs. While these drugs are clearly effective in reducing the risk of fracture in patients with postmenopausal and male osteoporosis, it is still unclear whether they may have the same efficacy in patients with diabetic osteopathy. Furthermore, as bone-derived cytokines (osteokines) are able to influence glucose metabolism, it is conceivable that antiosteoporotic drugs may have an effect on glycemic control through their modulation of bone turnover that affects the osteokines' release. These aspects are addressed in this narrative review by means of an unrestricted computerized literature search in the PubMed database. Our findings indicate a balance between good and bad news. Active bone therapies and their modulation of bone turnover do not appear to play a clinically significant role in glucose metabolism in humans. Moreover, there are insufficient data to clarify whether there are any differences in the efficacy of antiosteoporotic drugs on fracture incidence between diabetic and nondiabetic patients with osteoporosis. Although more studies are required for stronger recommendations to be issued, bisphosphonates appear to be the first-line drug for treatment of osteoporosis in diabetic patients, while denosumab seems preferable for older patients, particularly for those with impaired renal function, and osteoanabolic agents should be reserved for patients with more severe forms of osteoporosis.

Proton Pump Inhibitors and Fractures in Adults: A Critical Appraisal and Review of the Literature.

Despite the large number of patients worldwide being on proton pump inhibitors (PPIs) for acid-related gastrointestinal disorders, uncertainty remains over their long-term safety. Particularly, the potential side effects of these drugs on bone health have been evaluated in the last years. The purpose of our narrative review is to gather and discuss results of clinical studies focusing on the interactions between PPIs and fracture risk. Data generated mainly from nested case-control studies and meta-analysis suggest that long-term/high-dose PPIs users are characterized by an increased risk of fragility fractures, mainly hip fractures. However, in these studies, the PPIs-induced bone impairment is often not adjusted for different confounding variables that could potentially affect bone health, and exposure to PPIs was reported using medical prescriptions without adherence evaluation. The mechanisms of the PPI-related bone damage are still unclear, but impaired micronutrients absorption, hypergastrinemia, and increased secretion of histamine may play a role. Clinicians should pay attention when prescribing PPIs to subjects with a preexistent high risk of fractures and consider antiosteoporotic drugs to manage this additive effect on the bone. However, further studies are needed to clarify PPIs action on the bone.