Association between radius axial low-frequency ultrasound velocity and bone fragility in primary hyperparathyroidism.

CONTEXT: Radius quantitative ultrasound measurement, that utilized a portable low-frequency (VLF) axial transmission ultrasound for assessing the properties of radius cortical bone in a non PHPT population revealed a possible role as a screening tool prior to DXA to evaluate fragility fracture. OBJECTIVE: To evaluate this portable ultrasound device as a screening tool of skeletal fragility in PHPT patients. METHODS: We enrolled 117 postmenopausal women with PHPT. Every subject had a DXA of femur, lumbar spine, non-dominant distal 1/3 radius, TBS measurement, VLF with a portable device and spine x- ray. RESULTS: The mean age of the patients was 68 ± 10 years. The measurement of agreement between radius DXA and VLF was: K = 0.43, p < 0.001. A lower radius US T-score, also adjusted for years since menopause and BMI, was associated with osteoporosis identified with DXA at lumbar and/or femoral neck sites: OR = 1.852 (CI 1.08, 3.18). All fractures were associated with femoral neck T-score: OR = 1.89 (95% CI 1.24, 2.89), as well as with total hip T-score: OR = 1.65 (95% CI 1.09, 2.50), and years since menopause: OR = 1.25 (95% CI 1.02, 1.54).Morphometric vertebral fractures were associated with years since menopause: OR = 1.28 (95% CI 1.02,1.61), femoral neck T-score OR = 1.96 (95% CI 1.227, 3.135), total hip T-score OR = 1.64 (95% CI 1.04, 2.60), TBS OR = 0.779 (95% CI 0.60-0.99), both ultra-distal radius T-score: OR = 1.50 (95% CI 1.05, 2.156), and radius US T-score: OR = 1.67 (95% CI 1.09, 2.56). CONCLUSIONS: VLF could be used for screening purposes prior to DXA to evaluate PHPT fracture risk, only in conditions in which DXA measurement cannot be performed.

Effect of 2 Years of Monthly Calcifediol Administration in Postmenopausal Women with Vitamin D Insufficiency.

BACKGROUND: We assessed the long-term (24 months) efficacy and safety of monthly calcifediol (0.266 mg) in the correction and maintenance of total 25(OH)D levels in postmenopausal women with basal values <30 ng/mL. METHODS: We initially enrolled 45 consecutive patients during the period September 2019-September 2020. After an initial visit, patients were instructed to return at 3, 6, 9, 12 and 24 months for measuring serum total 25(OH)D, ionised calcium, creatinine and isoenzyme of alkaline phosphatase (bALP). Here, we report only the per-protocol analysis, because the COVID-19 pandemic precluded adherence to the scheduled visits for some patients. RESULTS: The patients' mean age was 62.4 ± 9.0 years. Mean basal 25(OH)D levels were 20.5 ± 5.3 ng/mL. There was a continuous increase of mean 25(OH)D values (p for trend < 0.001). However, mean values at month 24 (36.7 ± 15.9) were not significantly different in respect to values at month 12 (41.2 ± 11.18). At 24 months, only 1 out 19 patients had a value <20 ng/mL. There was a significant decrease with time of mean values of bALP (p < 0.0216), with no significant changes between 12 and 24 months. No significant changes were observed as far as ionised calcium or creatinine were concerned. CONCLUSIONS: The long-term administration of calcifediol maintains stable and sustained 25(OH)D concentrations, with no safety concerns.

Nutrition, Vitamin D, and Calcium in Elderly Patients before and after a Hip Fracture and Their Impact on the Musculoskeletal System: A Narrative Review.

Hip fractures are a major health issue considerably impacting patients' quality of life and well-being. This is particularly evident in elderly subjects, in which the decline in bone and muscle mass coexists and predisposes individuals to fall and fracture. Among interventions to be implemented in hip fractured patients, the assessment and management of nutritional status is pivotal, particularly in subjects older than 65. Nutrition plays a central role in both primary and secondary preventions of fracture. An adequate protein intake improves muscle mass and strength and the intestinal absorption of calcium. Other nutrients with recognized beneficial effects on bone health are calcium, vitamins D, K, and C, potassium, magnesium, folate, and carotenoids. With reference to calcium, results from longitudinal studies showed that the consumption of dairy foods has a protective role against fractures. Moreover, the most recent systematic reviews and meta-analyses and one umbrella review demonstrated that the combination of calcium and vitamin D supplementation significantly reduces hip fracture risk, with presumed higher efficacy in older and institutionalized subjects. Owing to these reasons, the adequate intake of calcium, vitamin D, protein, and other macro and micronutrients has been successfully implemented in the Fracture Liaison Services (FLSs) that represent the most reliable model of management for hip fracture patients. In this narrative review, papers (randomized controlled trials, prospective and intervention studies, and systematic reviews) retrieved by records from three different databases (PubMed, Embase, and Medline) have been analyzed, and the available information on the screening, assessment, and management of nutritional and vitamin D status and calcium intake in patients with hip fractures is presented along with specific prevention and treatment measures.

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.

Bone loss after discontinuation of denosumab: the devil is in the details.

A 47-year-old postmenopausal woman with osteoporosis was treated with denosumab, which was discontinued due to side effects. She was therefore transitioned to a yearly intravenous infusion of zoledronic acid. An increase in bone turnover markers together with bone loss at the lumbar spine was observed before the second infusion, suggesting an overshooting of bone resorption due to denosumab discontinuation. On physical examination, the patient was restless and reported having lost about 10 kg since the last visit. A solitary left inferior thyroid nodule was noted on neck palpation. Circulating thyroid hormone levels were elevated, with suppressed thyroid-stimulating hormone. A thyroid scan showed increased uptake in the left inferior nodule with suppression of the remainder of the thyroid gland. A diagnosis of hyperthyroidism due to toxic adenoma was made. The patient was treated with radioactive iodine ablation, with consequent complete normalization of thyroid function. She continued yearly treatment with zoledronic acid. She remained clinically well with no further fractures. Bone turnover markers were appropriately suppressed and bone mineral density increased in the spine and hip. This case illustrates how the overshooting phenomenon following denosumab discontinuation may be compounded by the development of secondary conditions, which can result in suboptimal response to antiresorptive osteoporosis medications.

Analysis of circulating osteoclast and osteogenic precursors in patients with Gorham-Stout disease.

PURPOSE: Gorham-Stout disease is a very rare disorder characterized by progressive bone erosion and angiomatous proliferation; its etiopathogenesis is still unknown, and diagnosis is still performed by exclusion criteria. The alteration of bone remodeling activity has been reported in patients; in this study, we characterized circulating osteoclast and osteogenic precursors that could be important to better understand the osteolysis observed in patients. METHODS: Flow cytometry analysis of PBMC (Peripheral Blood Mononuclear Cells) was performed to characterize circulating osteoclast and osteogenic precursors in GSD patients (n = 9) compared to healthy donors (n = 55). Moreover, ELISA assays were assessed to evaluate serum levels of bone markers including RANK-L (Receptor activator of NF-κB ligand), OPG (Osteoprotegerin), BALP (Bone Alkaline Phosphatase) and OCN (Osteocalcin). RESULTS: We found an increase of CD16-/CD14+CD11b+ and CD115+/CD14+CD11b+ osteoclast precursors in GSD patients, with high levels of serum RANK-L that could reflect the increase of bone resorption activity observed in patients. Moreover, no significant alterations were found regarding osteogenic precursors and serum levels of BALP and OCN. CONCLUSION: The analysis of circulating bone cell precursors, as well as of RANK-L, could be relevant as an additional diagnostic tool for these patients and could be exploited for therapeutic purposes.

Effect of Antidiabetic Drugs on Bone Health in Patients with Normal Renal Function and in Chronic Kidney Disease (CKD): Insight into Clinical Challenges in the Treatment of Type 2 Diabetes.

Among the metabolic changes occurring during the course of type 2 diabetes (T2DM) and diabetic kidney disease (DKD), impaired bone health with consequent increased fracture risk is one of the most complex and multifactorial complications. In subjects with diabetic kidney disease, skeletal abnormalities may develop as a consequence of both conditions. In the attempt to define a holistic approach to diabetes, potential effects of various classes of antidiabetic drugs on the skeleton should be considered in the setting of normal kidney function and in DKD. We reviewed the main evidence on these specific topics. Experimental studies reported potential beneficial and harmful effects on bone by different antidiabetics, with few data available in DKD. Clinical studies specifically designed to evaluate skeletal effects of antidiabetics have not been performed; notwithstanding, data gleaned from randomized controlled trials and intervention studies did not completely confirm observations made by basic research. In the aggregate, evidence from meta-analyses of these studies suggests potential positive effects on fracture risk by metformin and glucagon-like peptide-1 receptor agonists, neutral effects by dipeptidyl peptidase-4 inhibitors, sodium-glucose cotransporter-2 inhibitors, and sulfonylureas, and negative effects by insulin and thiazolidinediones. As no clinical recommendations on the management of antidiabetic drugs currently include fracture risk assessment among the main goal of therapy, we propose an integrated approach with the aim of defining a patient-centered management of diabetes in chronic kidney disease (CKD) and non-CKD patients. Future clinical evidence on the skeletal effects of antidiabetics will help in optimizing the approach to a personalized and more effective therapy of diabetes.

Genetic aspects underlying the normocalcemic and hypercalcemic phenotypes of primary hyperparathyroidism.

PURPOSE: Hypercalcemic primary hyperparathyroidism (PHPT) is a common endocrine disorder that has been very well characterized. In contrast, many aspects of normocalcemic primary hyperparathyroidism (NPHPT) such as natural history, organ damage, and management are still matter of debate. In addition, both the pathophysiology and molecular basis of NPHPT are unclear. We investigated whether PHPT and NPHPT patient cohorts share the same pattern of genetic variation in genes known to be involved in calcium and/or bone metabolism. RESEARCH DESIGN AND METHODS: Genotyping for 9 single nucleotide polymorphisms (SNPs) was performed by Real-Time PCR (TaqMan assays) on 27 NPHPT and 31 PHPT patients evaluated in a tertiary referral Center. The data of both groups were compared with 54 in house-controls and 503 subjects from the 1000 Genomes Project. All groups were compared for allele/haplotype frequencies, on a single locus, two loci and multi-locus basis. RESULTS: The NPHPT group differed significantly at SNPs in OPG and ESR1. Also, the NPHPT cohort was peculiar for pairwise associations of genotypes and for the overrepresentation of unusual multilocus genotypes. CONCLUSIONS: Our NPHPT patient set harbored a definitely larger quota of genetic diversity than the other samples. Specific genotypes may help in defining subgroups of NPHPT patients which deserve ad hoc clinical and follow-up studies.

The Mutual Interplay between Bone, Glucose and Lipid Metabolism: The Role of Vitamin D and PTH.

BACKGROUND: We sought to investigate the mutual interplay between bone, glucose and lipid metabolism in a wide cohort of community-based subjects. METHODS: We studied 1240 blood donors (F/M ratio 1/3.2, mean age 41.9 ± 11.7 SD). Serum ionized (Ca++), magnesium (Mg++), 25-hydroxy-vitamin D [25(OH)D], PTH-1-84, 1,25-dihydroxyvitamin D [1,25(OH)2D], total cholesterol (C), HDL-C, triglycerides and glucose were measured and LDL-C levels were calculated in all subjects. RESULTS: 25(OH)D negatively correlated with BMI (R = -0.11), PTH (R = -0.16) (p < 0.0001), total C (R = -0.06, p < 0.05) and triglycerides (R = -0.13, p < 0.0001) and positively with 1,25(OH)2D (R = 0.12) and creatinine (R = 0.17) (p < 0.0001). Serum PTH positively correlated with total C (R = 0.08, p < 0.01), LDL-C (R = 0.1, p < 0.001), triglycerides (R = 0.09, p < 0.01) and glucose (R = 0.15, p < 0.0001) and negatively with HDL-C (R = -0.09, p < 0.01). The odds of showing abnormal serum triglycerides and HDL-C increased as 25(OH)D decreased (p < 0.0001 and p < 0.03) and PTH increased (p < 0.03 and p = 0.05), while the odds of showing abnormal LDL-C levels increased in association with elevated PTH (p < 0.01). CONCLUSION: Vitamin D, PTH, glucose and lipid metabolism are mutually influenced. Hypovitaminosis D predisposes toward worsening lipid profiles through the actions of PTH, while serum PTH levels per se associate with higher glucose and LDL-C levels.

Occipital bone and tumor-induced osteomalacia: a rare tumor site for an uncommon paraneoplastic syndrome.

INTRODUCTION: Tumor-induced osteomalacia (TIO) is an uncommon paraneoplastic syndrome due to the overproduction of fibroblast growth factor 23 (FGF23). It is predominantly caused by mesenchymal tumors and cured upon their complete removal. Non-surgical treatment is an alternative option but limited to specific clinical conditions. METHODS: We report a challenging case of TIO caused by a tumor involving the occipital bone. We also performed a literature review of TIO caused by tumors localized at this site, focusing on clinical findings, treatment, and outcomes. RESULTS: The patient, a 62-year-old male, presented with a long-lasting history of progressive weakness. Biochemical evaluation revealed severe hypophosphatemia due to low renal tubular reabsorption of phosphate with raised intact FGF23 values. A 68 Ga-DOTATATE PET/TC imaging showed a suspicious lesion located in the left occipital bone that MRI and selective venous catheterization confirmed to be the cause of TIO. Stereotactic gamma knife radiosurgery was carried out, but unfortunately, the patient died of acute respiratory failure. To date, only seven additional cases of TIO have been associated to tumors located in the occipital bone. Furthermore, the tumor involved the left side of the occipital bone in all these patients. CONCLUSION: The occipital region is a difficult area to access so a multidisciplinary approach for their treatment is required. If anatomical differences could be the basis for the predilection of the left side of the occipital bone, it remains to be clarified.

Bone Marrow Adipose Tissue Is Increased in Postmenopausal Women With Postsurgical Hypoparathyroidism.

CONTEXT: Suppression of bone turnover, greater trabecular volume, and normal-high normal all-site bone mineral density (BMD) are hallmarks of postsurgical hypoparathyroidism (HypoPT). Impairment in the trabecular microarchitecture with possible higher risk of vertebral fractures (VF) in women with postmenopausal HypoPT has also been described. Currently, no data on bone marrow adipose tissue (BMAT) are available in HypoPT. OBJECTIVE: To assess BMAT by magnetic resonance imaging (MRI) and proton magnetic resonance spectroscopy (1H-MRS) in postmenopausal women with chronic postsurgical HypoPT. METHODS: This cross-sectional pilot study, conducted at an ambulatory referral center, included 29 postmenopausal women (mean age 66 ± 8.4 years) with postsurgical HypoPT and 31 healthy postmenopausal women (mean age 63 ± 8.5). Lumbar spine MRI was performed and BMAT was measured by applying PRESS sequences on the L3 body. Lumbar spine, femoral neck, and total hip BMD were measured by dual x-ray absorptiometry (DXA); site-matched spine trabecular bone score (TBS) was calculated by TBS iNsight (Medimaps, Switzerland); VF assessment was performed with lateral thoracic and lumbar spine DXA. RESULTS: Fat content (FC) and saturation level (SL%) were higher (P <.0001 and P <.001), while water content (W) was lower in HypoPT compared to controls (P <.0001). FC significantly correlated with years since menopause and body weight (P <.05) in HypoPT, while TBS negatively correlated with FC and SL% (P <.05) and positively with residual lipids (RL) and W (P <.05). CONCLUSION: We demonstrate for the first time that BMAT is increased in postmenopausal women with postsurgical hypoparathyroidism and negatively associated with trabecular microarchitecture.

Vitamin D in hypoparathyroidism: insight into pathophysiology and perspectives in clinical practice.

Hypoparathyroidism (HypoPT) is a rare endocrine disorder characterized by the absence or insufficient parathyroid hormone production resulting in chronic hypocalcemia. Complications of HypoPT include perturbation of several target organs. The conventional treatment consists of the administration of active vitamin D, namely calcitriol. Regarding vitamin D status, few data are available, mostly in HypoPT subjects supplemented with parent vitamin D. In addition, perturbation of vitamin D metabolism has been poorly investigated, as well as the contribution of altered vitamin D status on the clinical expression of the disease. The most recent consensus on the management of chronic HypoPT suggests the baseline evaluation of serum 25-hydroxy-vitamin D [25(OH)D] and supplementation with parent vitamin D with the aim to achieve and maintain serum 25(OH)D levels in the range of 30-50 ng/mL. The rationale for using supplementation with parent vitamin D (either ergocalciferol or cholecalciferol) in HypoPT would be to provide sufficient 25(OH)D substrate to the residual 1-α-hydroxylase activity, thus ensuring its conversion to active vitamin D in renal and extra-renal tissues. More data from experimental and clinical studies are needed for better assessing how these mechanisms may significantly influence metabolic control in HypoPT and eventually skeletal and extra-skeletal manifestation of the disease. Finally, future data will clarify how the currently available parent vitamin D compounds (ergocalciferol, cholecalciferol, calcifediol) would perform in addressing these specific issues.

Tumor-induced Osteomalacia: A Comprehensive Review.

Tumor-induced osteomalacia (TIO) is an ultrarare paraneoplastic syndrome due to overproduction of fibroblast growth factor 23 (FGF23), with profound effects on patient morbidity. TIO is an underdiagnosed disease, whose awareness should be increased among physicians for timely and proper management of patients. Symptoms reported by patients with TIO are usually nonspecific, thus rendering the diagnosis elusive, with an initial misdiagnosis rate of more than 95%. Biochemical features of TIO are represented by hypophosphatemia, increased or inappropriately normal levels of FGF23, and low to low normal circulating 1,25-dihydroxyvitamin D (1,25(OH)2D). Phosphaturic mesenchymal tumors are the pathological entities underlying TIO in most affected patients. There is now evidence that FN1-FGFR1 and FN1-FGF1 fusion genes are present in about half of tumors causing this paraneoplastic syndrome. Tumors causing TIO are small and grow slowly. They can occur in all parts of the body from head to toe with similar prevalence in soft tissue and bone. There are a number of functional and anatomical imaging techniques used for tumor localization; 68Ga DOTA-based technologies have better sensitivity. Surgery is the treatment of choice; several medical treatments are now available in case of inability to locate the tumor or in case of incomplete excision.

Impairment in muscle strength and its determinants in primary hyperparathyroidism: A study in postmenopausal women.

Neuromuscular impairment is described among the non-classical complications of primary hyperparathyroidism (PHPT). However, the extent of this complications and related mechanisms have not been fully addressed. The study aimed at assessing muscle strength and its main determinants in postmenopausal women with PHPT. We studied 48 postmenopausal women with PHPT (mean age 60.8 ± 5.6 SD years; BMI 25.6 ± 5.5 kg/m2) and 38 healthy postmenopausal women (mean age 58.6 ± 5.9; BMI 25.2 ± 3.5). In all subjects, the maximum voluntary contraction (MVC, Newton, N) was measured by Hand held Dynamometer (Kayser Italia srl, Livorno, Italy) and the lumbar spine, total hip, femoral neck, and non dominant distal one-third radius areal BMD (aBMD) by dual X-ray absorptiometry (DXA) (Hologic, Waltham, MA). Serum ionized calcium (Ca++), parathyroid hormone (PTH), phosphorus (P), and 25-hydroxyvitaminD [25(OH)D] levels were measured in both groups. A subgroup of 30 PHPT women agreed to participate to the follow-up sub-study and were re-assessed 24 months after parathyroidectomy (n = 15) or after baseline evaluation (n = 15). Patients with PHPT had significant lower MVC values compared to healthy women (p < 0.001). As expected, serum Ca++ and PTH levels were higher and P lower in PHPT compared to controls. We observed a significant association between MVC and total hip and one-third radius aBMD (R = 0.320 and 0.370, p < 0.05) and negative association with Ca++ (R = -0.340, p < 0.05) in the PHPT group; MVC was positively associated with one-third radius aBMD (R = 0.360, p < 0.05) and negatively with age, BMI and myostatin (R = -0.390, -0.340 and -0.450, p < 0.05) in the group of healthy women. The linear model using BMI, Ca++, P, 25(OH)D, PTH, myostatin, and aBMD as covariates showed that one-third radius aBMD was positively associated with MVC in PHPT patients (p < 0.02) and in healthy subjects (p < 0.001). Additionally, serum PTH and myostatin were negatively associated with MVC in healthy subjects (p < 0.03 and p < 0.01). The linear model showed that surgery was associated with an increase in MVC (p < 0.05) in PHPT patients after 24 months, all other variables being equal and by controlling for baseline values of MVC. Handgrip strength is significantly impaired in postmenopausal women with PHPT. Some common mechanisms influencing muscle function exist in PHPT and in healthy subjects; they are associated with the reduced aBMD at cortical sites. Hypercalcemia seems to be one of the main determinants of impairment in muscle strength in PHPT, while no role is played by myostatin.

Quality of Life in Primary Hyperparathyroidism.

Quality of life is impaired in primary hyperparathyroidism (PHPT), regardless of the severity of the disease. Clinical studies have employed different instruments, including standardized and disease-specific questionnaires, and including patients with different phenotypes of PHPT. Neuropsychiatric symptoms and decline in cognitive status are common in PHPT. Patients may complain of these issues or they can be ascertained by questionnaires; they include depression, anxiety, impaired vitality, social and emotional functions, sleep disturbances, and altered mental function. Randomized controlled trials on the effects of surgical versus non-surgical treatments have collectively shown improvement in quality of life after parathyroidectomy, but results have been heterogeneous.

Classical and Nonclassical Manifestations of Primary Hyperparathyroidism.

This narrative review summarizes data on classical and nonclassical manifestations of primary hyperparathyroidism (PHPT). It is based on a rigorous literature search, inclusive of a Medline search for systematic reviews from 1940 to December 2020, coupled with a targeted search for original publications, covering four databases, from January 2013-December 2020, and relevant articles from authors' libraries. We present the most recent information, identify knowledge gaps, and suggest a research agenda. The shift in the presentation of PHPT from a predominantly symptomatic to an asymptomatic disease, with its varied manifestations, has presented several challenges. Subclinical nephrolithiasis and vertebral fractures are common in patients with asymptomatic disease. The natural history of asymptomatic PHPT with no end organ damage at diagnosis is unclear. Some observational and cross-sectional studies continue to show associations between PHPT and cardiovascular and neuropsychological abnormalities, among the different disease phenotypes. Their causal relationship is uncertain. Limited new data are available on the natural history of skeletal, renal, cardiovascular, neuropsychological, and neuromuscular manifestations and quality of life. Normocalcemic PHPT (NPHPT) is often diagnosed without the fulfillment of rigorous criteria. Randomized clinical trials have not demonstrated a consistent long-term benefit of parathyroidectomy (PTX) versus observation on nonclassical manifestations. We propose further refining the definition of asymptomatic disease, into two phenotypes: one without and one with evidence of target organ involvement, upon the standard evaluation detailed in our recommendations. Each of these phenotypes can present with or without non-classical manifestations. We propose multiple albumin-adjusted serum calcium determinations (albumin-adjusted and ionized) and exclusion of all secondary causes of high parathyroid hormone (PTH) when establishing the diagnosis of NPHPT. Refining the definition of asymptomatic disease into the phenotypes proposed will afford insights into their natural history and response to interventions. This would also pave the way for the development of evidence-based guidance and recommendations. © 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).

Characterization of Extracellular Vesicles in Osteoporotic Patients Compared to Osteopenic and Healthy Controls.

Extracellular vesicles (EVs) are mediators of a range of pathological conditions. However, their role in bone loss disease has not been well understood. In this study we characterized plasma EVs of 54 osteoporotic (OP) postmenopausal women compared to 48 osteopenic (OPN) and 44 healthy controls (CN), and we investigated their effects on osteoclasts and osteoblasts. We found no differences between the three groups in terms of anthropometric measurements and biochemical evaluation of serum calcium, phosphate, creatinine, PTH, 25-hydroxy vitamin D and bone biomarkers, except for an increase of CTX level in OP group. FACS analysis revealed that OP patients presented a significantly increased number of EVs and RANKL+ EVs compared with both CN and OPN subjects. Total EVs are negatively associated with the lumbar spine T-score and femoral neck T-score. Only in the OPN patients we observed a positive association between the total number of EVs and RANKL+ EVs with the serum RANKL. In vitro studies revealed that OP EVs supported osteoclastogenesis of healthy donor peripheral blood mononuclear cells at the same level observed following RANKL and M-CSF treatment, reduced the ability of mesenchymal stem cells to differentiate into osteoblasts, while inducing an increase of OSTERIX and RANKL expression in mature osteoblasts. The analysis of miRNome revealed that miR-1246 and miR-1224-5p were the most upregulated and downregulated in OP EVs; the modulated EV-miRNAs in OP and OPN compared to CN are related to osteoclast differentiation, interleukin-13 production and regulation of canonical WNT pathway. A proteomic comparison between OPN and CN EVs evidenced a decrease in fibrinogen, vitronectin, and clusterin and an increase in coagulation factors and apolipoprotein, which was also upregulated in OP EVs. Interestingly, an increase in RANKL+ EVs and exosomal miR-1246 was also observed in samples from patients affected by Gorham-Stout disease, suggesting that EVs could be good candidate as bone loss disease biomarkers. © 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).