Publications by authors named "Salvatore Minisola"

158 Publications

Stimulation of Treg Cells to Inhibit Osteoclastogenesis in Gorham-Stout Disease.

Front Cell Dev Biol 2021 27;9:706596. Epub 2021 Aug 27.

Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Gorham-Stout disease (GSD) is a very rare syndrome displaying excessive bone erosion and vascular lesion. Due to the rarity of the disease and to the limited studies, its etiopathogenesis is not entirely known. The involvement of immune system in the progressive osteolysis was recently suggested. Indeed, extensive reciprocal interactions between the immune and skeletal systems have been demonstrated. This study aimed to evaluate alterations of immune cells in GSD. An increase of CD8+ cells and reduction of CD4+ and CD4+CD25+CD127 cells was revealed in patients. Interestingly, patients' regulatory T cells maintain the ability to respond to extracellular stimuli and to regulate osteoclastogenesis; GSD cells proliferate under aCD3/CD28 signal reaching similar levels to those observed in control culture and exert their immunomodulatory activity on effector T cells. GSD Treg cells preserved their inhibitory effects on the osteoclastogenesis. These results suggest that stimulation of Treg cells could open the way for the identification and testing of new therapeutic approaches for patients affected by GSD.
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http://dx.doi.org/10.3389/fcell.2021.706596DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8430039PMC
August 2021

Vitamin D3 and 25(OH)D3: an open debate.

Am J Clin Nutr 2021 09;114(3):1251

From the Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy (SM, e-mail: VDM; CC; JP; LC; CS).

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http://dx.doi.org/10.1093/ajcn/nqab254DOI Listing
September 2021

A Prospective Open-Label Observational Study of a Buffered Soluble 70 mg Alendronate Effervescent Tablet on Upper Gastrointestinal Safety and Medication Errors: The GastroPASS Study.

JBMR Plus 2021 Jul 17;5(7):e10510. Epub 2021 May 17.

Rheumatology Service Hospital del Mar, Passeig Marítim and IMIM (Hospital del Mar Medical Research Institute), Parc de Recerca Biomèdica de Barcelona Barcelona Spain.

Upper gastrointestinal (GI) side effects are a main reason for discontinuing bisphosphonate treatment, an important therapeutic option for osteoporosis patients. Consequently, the development of novel formulations with improved tolerability is warranted. In this multicenter prospective, observational, postauthorization safety study conducted in Italy and Spain, postmenopausal women (PMW) with osteoporosis (naïve to bisphosphonates) were treated weekly with a buffered soluble alendronate 70 mg effervescent (ALN-EFF) tablet (Binosto®) and followed for 12 ± 3 months. Information was collected on adverse events (AEs), medication errors, persistence, and compliance using the Morisky-Green questionnaire. Patients ( = 1028) aged 67 ± 9 years (mean ± SD) received ALN-EFF weekly. The cumulative incidence of upper GI AEs (oesophageal toxicity, gastritis, gastric ulcers, and duodenitis) related to ALN-EFF (primary endpoint) was 9.6% (95% confidence interval [CI] 7.9-11.6%), the vast majority being of mild intensity. The most frequently occurring upper GI AEs related to ALN-EFF were dyspepsia (2.7%), gastroesophageal reflux disease (2.4%), and nausea (2.2%). None of the relevant upper GI AEs listed in the primary endpoint and no serious AEs were reported. At least one medication error occurred in 29.9% (95% CI 27.1-32.8%) of patients. However, the majority of medication errors were associated with administration instructions applicable to any oral bisphosphonate and only seven medication errors were associated with the ALN-EFF formulation. ALN-EFF was discontinued in 209 of 1028 (20.3%) patients. The most frequent reasons for discontinuation were AEs related to ALN-EFF (46.9%) and patients' decision (42.6%). Compliance with ALN-EFF was high, reflected by a mean Morisky-Green score of 92.8 ± 18.6. PMW with osteoporosis treated with ALN-EFF in a real-world setting experienced few upper GI AEs. In addition, they had a low discontinuation and high compliance compared with other formulations, suggesting that ALN-EFF may increase patient satisfaction and therefore long-term adherence and efficacy. © 2021 The Authors. published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10510DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8260812PMC
July 2021

Challenges in the management of tumor-induced osteomalacia (TIO).

Bone 2021 11 18;152:116064. Epub 2021 Jun 18.

Julius-Maximilians University, Brettreichstr. 11, 97074 Würzburg, Germany. Electronic address:

Tumor-induced osteomalacia (TIO), also known as oncogenic osteomalacia, is a rare acquired paraneoplastic disease, which is challenging to diagnose and treat. TIO is characterized by hypophosphatemia resulting from excess levels of tumor-secreted fibroblast growth factor 23 (FGF23), one of the key physiological regulators of phosphate metabolism. Elevated FGF23 results in renal phosphate wasting and compromised vitamin D activation, ultimately resulting in osteomalacia. Patients typically present with progressive and non-specific symptoms, including bone pain, multiple pathological fractures, and progressive muscle weakness. Diagnosis is often delayed or missed due to the non-specific nature of complaints and lack of disease awareness. Additionally, the disease-causing tumour is often difficult to detect and localize because they are often small, lack localizing symptoms and signs, and dwell in widely variable anatomical locations. Measuring serum/urine phosphate should be an inherent diagnostic component when assessing otherwise unexplained osteomalacia, fractures and weakness. In cases of hypophosphatemia with inappropriate (sustained) phosphaturia and inappropriately normal or frankly low 1,25-dihydroxy vitamin D, differentiation of the potential causes of renal phosphate wasting should include measurement of FGF23, and TIO should be considered. While patients experience severe disability without treatment, complete excision of the tumour is typically curative and results in a dramatic reversal of symptoms. Two additional key current unmet needs in optimizing TIO management are: (1 and 2) the considerable delay in diagnosis and consequent delay between the onset of symptoms and surgical resection; and (2) alternative management. These may be addressed by raising awareness of TIO, and taking into consideration the accessibility and variability of different healthcare infrastructures. By recognizing the challenges associated with the diagnosis and treatment of TIO and by applying a stepwise approach with clear clinical practice guidelines, patient care and outcomes will be improved in the future.
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http://dx.doi.org/10.1016/j.bone.2021.116064DOI Listing
November 2021

Epidemiology of Tumor-Induced Osteomalacia in Denmark.

Calcif Tissue Int 2021 Aug 5;109(2):147-156. Epub 2021 Apr 5.

Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

Tumor-induced osteomalacia (TIO) is a rare, acquired condition of phosphate wasting due to phosphaturic mesenchymal tumors. Because the incidence and prevalence of TIO is unknown, we conducted an observational cohort study using national Danish health registers for the period 2008 to 2018 to obtain such information. The study also aimed to describe the demographics of the TIO population and the prognosis. The operational definition was based on hypophosphatemia or adult osteomalacia diagnoses, combined with prescriptions used in the initial management and procedures consistent with advanced imaging used for locating tumors. The incidence of TIO in Denmark was found to be below 0.13 per 100,000 person years for the total population of the country and 0.10 per 100,000 in adult-onset disease. The prevalence of TIO was estimated to be no more than 0.70 per 100,000 persons for the total population and 0.43 per 100,000 in adults. In 2018, there were a maximum of nine new cases of TIO in Danish adults. Mortality was low but few patients fulfilled the protocol cure criterion during the observation period. TIO has no ICD-10 code and limitations to the study include lack of information on serum biochemistry and on the use of phosphate supplements. Strengths include the use of long-term longitudinal, national hospital and prescription data from a country with universal healthcare. Given the very small patient population with TIO and the known delay to diagnosis and cure, management of patients with suspected TIO should be centralized.
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http://dx.doi.org/10.1007/s00223-021-00843-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8273058PMC
August 2021

Consensus on clinical management of tumor-induced osteomalacia.

Chin Med J (Engl) 2021 Apr 1;134(11):1264-1266. Epub 2021 Apr 1.

Department of Endocrinology, Key Laboratory of Endocrinology, State Key Laboratory of Complex Severe and Rare Diseases, NHC, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, China.

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http://dx.doi.org/10.1097/CM9.0000000000001448DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8183716PMC
April 2021

FGF23 functions and disease.

Minerva Endocrinol (Torino) 2021 Apr 1. Epub 2021 Apr 1.

Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Rome, Italy.

The main function of fibroblast growth factor 23 (FGF23) is the regulation of phosphate metabolism through its action on the sodium-dependent phosphate cotransporters in the proximal renal tubules. Additionally, FGF23 interacts with vitamin D and parathyroid hormone in a complex metabolic pathway whose detailed mechanisms are still not clear in human physiology and disease. More recently, research has also focused on the understanding of mechanisms of FGF23 action on organs and system other than the kidneys and bone, as well as on its interaction with other metabolic pathways. Collectively, the new evidence are successfully used for the clinical evaluation and management of FGF23-related disorders, for whom which new therapies with many potential applications are now available.
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http://dx.doi.org/10.23736/S2724-6507.21.03378-2DOI Listing
April 2021

Challenges in Diagnosing of Normocalcemic Primary Hyperparathyroidism.

Endocr Pract 2021 Jun 8;27(6):644. Epub 2021 Mar 8.

Department of Clinical, Internal, Anesthesiologic, and Cardiovascular Sciences, Sapienza University, Viale del Policlinico 155, 00161, Rome, Italy.

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http://dx.doi.org/10.1016/j.eprac.2021.02.018DOI Listing
June 2021

Dysregulated miRNAs in bone cells of patients with Gorham-Stout disease.

FASEB J 2021 03;35(3):e21424

Bone Physiopathology Research Unit, Genetics and Rare Diseases Research Division, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Gorham-Stout disease (GSD) is a very rare disease characterized by increased bone erosion with angiomatous proliferation. The mechanisms underlying this disorder have not been deeply investigated. Due to its rarity, no guidelines are currently available for treatment and management of GSD. We recently evaluated the cellular alterations of the bone remodeling in patients showing that osteoclast precursors displayed increased ability to differentiate into osteoclasts and that affected osteoclasts resorb bone more actively than control cells. Moreover, osteoblasts isolated from a patient showed a defective ability to form mineralized nodules. In this paper, we investigated the molecular pathways involved in the cellular defects of GSD bone cells. For this study, we recruited nine patients and performed miRNome analysis of bone cells. Between the 178 miRNAs robustly expressed in GSD osteoclasts, significant modulation of three miRNAs (miR-1246, miR-1-3p, and miR-137-3p) involved in the regulation of osteoclast formation and activity or in the angiomatous proliferation was found in patients' cells. Interestingly, miR-1246 was also up-regulated in serum exosomes from patients. Analysis of miRNAs from patient osteoblasts suggested alteration of miR-204a-5p, miR-615-3p and miR-378a-3p regulating osteoblast function and differentiation. The resulting miRNA pattern may help to understand better the mechanisms involved in GSD and to identify new potential therapeutic targets for this rare disease.
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http://dx.doi.org/10.1096/fj.202001904RRDOI Listing
March 2021

Vertebral Fracture Assessment in Postmenopausal Women With Postsurgical Hypoparathyroidism.

J Clin Endocrinol Metab 2021 04;106(5):1303-1311

Department of Radiological Sciences, Oncology and Pathology, Sapienza University of Rome, Viale Regina Elena, Rome, Italy.

Context: Hypoparathyroidism is a rare endocrine disorder whose skeletal features include suppression of bone turnover and greater volume and width of the trabecular compartment. Few and inconsistent data are available on the prevalence of vertebral fractures (VF).

Objective: To evaluate the prevalence of VF assessed by vertebral fracture assessment (VFA) in postmenopausal women with chronic postsurgical hypoparathyroidism.

Design: Cross-sectional study.

Setting: Ambulatory referral center.

Patients Or Other Participants: Fifty postmenopausal women (mean age 65.4 ± 9 years) with chronic postsurgical hypoparathyroidism and 40 age-matched healthy postmenopausal women (mean age 64.2 ± 8.6).

Main Outcome Measures: Lumbar spine, femoral neck, and total hip bone mineral density were measured by dual X-ray absorptiometry (Hologic Inc., USA) in all subjects. Site-matched spine trabecular bone score was calculated by TBS iNsight (Medimaps, Switzerland). Assessment of VF was made by VFA (iDXA, Lunar GE, USA) using the semiquantitative method and the algorithm-based qualitative assessment.

Results: All-site BMD values were higher in the hypoparathyroid vs the control group. By VFA, we observed a 16% prevalence of VF in hypoparathyroid women vs 7.5% in control subjects. Among those with hypoparathyroidism who fractured, 5 (62.5%) had grade 1 wedge, 2 (25%) had grade 2 wedge, and 1 (12.5%) had grade 2 wedge and grade 2 biconcave VF. In the hypoparathyroid group, 57% with VFs and 32% without VFs had symptoms of hypoparathyroidism.

Conclusion: We demonstrate for the first time that in postmenopausal women with chronic postsurgical hypoparathyroidism, VFs are demonstrable by VFA despite normal BMD.
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http://dx.doi.org/10.1210/clinem/dgab076DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8063231PMC
April 2021

Osteomalacia and Vitamin D Status: A Clinical Update 2020.

JBMR Plus 2021 Jan 21;5(1):e10447. Epub 2020 Dec 21.

Bone and Mineral Research Laboratory, Division of Endocrinology Diabetes & Bore and Mineral Disorders, Henry Ford Hospital Detroit MI USA.

Historically, rickets and osteomalacia have been synonymous with vitamin D deficiency dating back to the 17th century. The term osteomalacia, which literally means soft bone, was traditionally applied to characteristic radiologically or histologically documented skeletal disease and not just to clinical or biochemical abnormalities. Osteomalacia results from impaired mineralization of bone that can manifest in several types, which differ from one another by the relationships of osteoid (ie, unmineralized bone matrix) thickness both with osteoid surface and mineral apposition rate. Osteomalacia related to vitamin D deficiency evolves in three stages. The initial stage is characterized by normal serum levels of calcium and phosphate and elevated alkaline phosphatase, PTH, and 1,25-dihydroxyvitamin D [1,25(OH)D]-the latter a consequence of increased PTH. In the second stage, serum calcium and often phosphate levels usually decline, and both serum PTH and alkaline phosphatase values increase further. However, serum 1,25(OH)D returns to normal or low values depending on the concentration of its substrate, 25-hydroxyvitamin D (25OHD; the best available index of vitamin D nutrition) and the degree of PTH elevation. In the final stage, hypocalcemia and hypophosphatemia are invariably low with further exacerbation of secondary hyperparathyroidism. The exact,or even an approximate, prevalence of osteomalacia caused by vitamin D deficiency is difficult to estimate, most likely it is underrecognized or misdiagnosed as osteoporosis. Signs and symptoms include diffuse bone, muscle weakness, and characteristic fracture pattern, often referred to as pseudofractures, involving ribs, scapulae, pubic rami, proximal femurs, and codfish-type vertebrae. The goal of therapy of vitamin D-deficiency osteomalacia is to alleviate symptoms, promote fracture healing, restore bone strength, and improve quality of life while correcting biochemical abnormalities. There is a need for better understanding of the epidemiology of osteomalacia. Simplified tools validated by concurrent bone histology should be developed to help clinicians promptly diagnose osteomalacia. © 2020 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10447DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7839817PMC
January 2021

Imaging technologies in the differential diagnosis and follow-up of brown tumor in primary hyperparathyroidism: Case report and review of the literature.

Bone Rep 2021 Jun 30;14:100745. Epub 2020 Dec 30.

Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Italy.

Brown tumors are osteolytic lesions associated with hyperparathyroidism (HPT). They may involve various skeletal segments, but rarely the cranio-facial bones. We report a case of a young boy with a swelling of the jaw secondary to a brown tumor presenting as the first manifestation of primary HPT (PHPT). He was found to have brown tumor located in the skull, as well. Different imaging technologies were employed for the diagnosis and follow-up after parathyroidectomy. We enclose a review of the literature on the employment of such imaging technologies in the differential diagnosis of osteolytic lesions. A multidisciplinary approach comprising clinical, laboratory and imaging findings is essential for the differential diagnosis of brown tumor in PHPT.
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http://dx.doi.org/10.1016/j.bonr.2020.100745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7815655PMC
June 2021

ECHOCARDIOGRAPHIC FINDINGS IN PATIENTS WITH NORMOCALCEMIC PRIMARY HYPERPARATHYROIDISM COMPARED WITH FINDINGS IN HYPERCALCEMIC PRIMARY HYPERPARATHYROID PATIENTS AND CONTROL SUBJECTS.

Endocr Pract 2021 Jan 18;27(1):21-26. Epub 2020 Nov 18.

Department of Clinical, Internal, Anesthesiologic and Cardiovascular Sciences, Sapienza University, Rome, Italy.

Objective: There are no data regarding echocardiographic parameters in patients with normocalcemic primary hyperparathyroidism (NCPHPT). We compared the echocardiographic findings in postmenopausal women with NCPHPT with those in patients with hypercalcemic primary hyperparathyroidism (PHPT) and controls.

Methods: Seventeen consecutive Caucasian postmenopausal women with NCPHPT were compared with 20 women with hypercalcemic PHPT and 20 controls. Obesity, diabetes, kidney failure, and previous cardiovascular diseases were considered exclusion criteria. Each patient underwent biochemical evaluation, bone mineral density scan, and echocardiographic measurements. Patients with parathyroid disorders underwent kidney ultrasound evaluation.

Results: Patients with PHPT had significantly higher mean total serum calcium, ionized calcium, 24-hour urinary calcium, and parathyroid hormone and lower mean phosphorus levels compared with those in the controls (all P < .05). The only differences between patients with NCPHPT and PHPT were significantly lower mean total serum calcium, ionized calcium, and 24-hour urinary calcium and higher phosphorus levels in patients with NCPHPT (all P < .05). The only biochemical difference between patients with NCPHPT and the controls was a higher level of mean parathyroid hormone in patients with NCPHPT. There were no differences in cardiovascular risk factors between patients with NCPHPT and PHPT and the controls. Hypertension was the most frequent cardiovascular risk factor, diagnosed in 65% of patients with PHPT. This high prevalence was not statistically significant compared with that observed in patients with NCPHPT (59%) and in the controls (30%). Echocardiography parameters were not different between patients with NCPHPT and PHPT and the controls when subdivided according to the presence of hypertension (ANOVA followed by Bonferroni correction).

Conclusion: In a population with a low cardiovascular risk, we found no differences in cardiovascular risk factors and echocardiographic parameters between patients with NCPHPT and PHPT and the controls.
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http://dx.doi.org/10.4158/EP-2020-0405DOI Listing
January 2021

Rheumatoid arthritis, bone and drugs: a dangerous interweave.

Ann Rheum Dis 2021 Jan 17. Epub 2021 Jan 17.

Department of Clinical, Internal, Anaesthesiological and Cardiovascular Sciences, Sapienza University of Rome, Roma, Italy.

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http://dx.doi.org/10.1136/annrheumdis-2020-219545DOI Listing
January 2021

Underdiagnosis and undertreatment of osteoporotic patients admitted in internal medicine wards in Italy between 2010 and 2016 (the REPOSI Register).

Endocrine 2021 02 12;71(2):484-493. Epub 2021 Jan 12.

Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences, "Sapienza" University of Rome, Rome, Italy.

Purpose: To evaluate clinical features, treatments, and outcomes of osteoporotic patients admitted to internal medicine and geriatric wards compared with non-osteoporotic patients (REPOSI registry).

Methods: We studied 4714 patients hospitalized between 2010 and 2016. We reported age, sex, educational level, living status, comorbidities and drugs taken, Cumulative Illness Rating Scale (CIRS), Barthel Index, Short-Blessed Test, 4-item Geriatric Depression Scale, serum hemoglobin, creatinine, and clinical outcomes. Osteoporosis was defined based on the diagnoses recorded at admission, according to the following ICD9: 733, 805-813, 820-823.

Results: Twelve percent of the patients had a preadmission diagnosis of osteoporosis. Only 20% of these had been prescribed oral bisphosphonates; 34% were taking vitamin D supplements. Osteoporotic patients were significantly older, with lower BMI, higher CIRS, and taking more drugs. They were significantly more depressed, less independent, with a higher severity of cognitive impairment compared with non-osteoporotic patients. At discharge, the number of patients receiving treatment for osteoporosis did not change. Length of stay and inhospital mortality did not differ between groups. Osteoporotic patients were more frequently nonhome discharged compared with those without osteoporosis (14.8 vs. 7.9%, p = 0.0007), mostly discharged to physical therapy or rehabilitation (8.8 vs. 2.5% of patients, p < 0.0001). Among osteoporotic patients deceased 3 months after discharge, the number of those treated with vitamin D, with or without calcium supplements, was significantly lower compared with survivors (12 vs. 32%, p = 0.0168).

Conclusions: The diagnosis of osteoporosis is poorly considered both during hospital stay and at discharge; osteoporotic patients are frailer compared to non-osteoporotic patients.
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http://dx.doi.org/10.1007/s12020-020-02553-5DOI Listing
February 2021

Controversies in Vitamin D: A Statement From the Third International Conference.

JBMR Plus 2020 Dec 10;4(12):e10417. Epub 2020 Nov 10.

Department of Medicine, Endocrinology Division, College of Physicians and Surgeons Columbia University New York NY USA.

The Third International Conference on Controversies in Vitamin D was held in Gubbio, Italy, September 10-13, 2019. The conference was held as a follow-up to previous meetings held in 2017 and 2018 to address topics of controversy in vitamin D research. The specific topics were selected by the steering committee of the conference and based upon areas that remain controversial from the preceding conferences. Other topics were selected anew that reflect specific topics that have surfaced since the last international conference. Consensus was achieved after formal presentations and open discussions among experts. As will be detailed in this article, consensus was achieved with regard to the following: the importance and prevalence of nutritional rickets, amounts of vitamin D that are typically generated by sun exposure, worldwide prevalence of vitamin D deficiency, the importance of circulating concentrations of 25OHD as the best index of vitamin D stores, definitions and thresholds of vitamin D deficiency, and efficacy of vitamin D analogues in the treatment of psoriasis. Areas of uncertainly and controversy include the following: daily doses of vitamin D needed to maintain a normal level of 25OHD in the general population, recommendations for supplementation in patients with metabolic bone diseases, cutaneous production of vitamin D by UVB exposure, hepatic regulation of 25OHD metabolites, definition of vitamin D excess, vitamin D deficiency in acute illness, vitamin D requirements during reproduction, potential for a broad spectrum of cellular and organ activities under the influence of the vitamin D receptor, and potential links between vitamin D and major human diseases. With specific regard to the latter area, the proceedings of the conference led to recommendations for areas in need of further investigation through appropriately designed intervention trials. © 2020 The Authors. published by Wiley Periodicals LLC. on behalf of American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbm4.10417DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7745884PMC
December 2020

Looking for new anabolic treatment from rare diseases of bone formation.

J Endocrinol 2021 02;248(2):R29-R40

Bone Physiopathology Unit, Genetics and Rare Diseases Research Area, Bambino Gesù Children's Hospital, IRCCS, Rome, Italy.

Bone remodelling is a complex mechanism regulated by osteoclasts and osteoblasts and perturbation of this process leads to the onset of diseases, which may be characterised by altered bone erosion or formation. In this review, we will describe some bone formation-related disorders as sclerosteosis, van Buchem disease, hypophosphatasia and Camurati-Engelmann disease. In the past decades, the research focused on these rare disorders offered the opportunity to understand important pathways regulating bone formation. Thus, the identification of the molecular defects behind the etiopathology of these diseases will open the way for new therapeutic approaches applicable also to the management of more common bone diseases including osteoporosis.
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http://dx.doi.org/10.1530/JOE-20-0285DOI Listing
February 2021

Measuring serum calcium: Total, albumin-adjusted or ionized?

Clin Endocrinol (Oxf) 2021 Aug 15;95(2):267-268. Epub 2020 Nov 15.

Department of Clinical, Internal, Anesthesiological and Cardiovascular Sciences (SCIAC), Sapienza' Rome University, Rome, Italy.

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http://dx.doi.org/10.1111/cen.14362DOI Listing
August 2021

Xerostomia, gustatory and olfactory dysfunctions in patients with COVID-19.

Am J Otolaryngol 2020 Nov - Dec;41(6):102721. Epub 2020 Sep 10.

Department of Orofacial Sciences, University of California San Francisco, San Francisco, CA, USA.

Background: The novel Coronavirus Disease-19 (COVID-19) continues to have profound effect on global health. Our aim was to evaluate the prevalence and characterize specific symptoms associated with COVID-19.

Methods: This retrospective study included 326 patients with confirmed SARS-CoV-2 infection evaluated at the Emergency Department of the Umberto I Polyclinic Hospital, Rome, Italy between March 6th and April 30th, 2020. In order to assess xerostomia, olfactory and gustatory dysfunctions secondary to COVID-19, a telephone-based a modified survey obtained from the National Health and Nutrition Examination Survey (NHANES) 2013-2014 for taste and smell disorders and the Fox Questionnaire for dry mouth were administered to 111 patients (34%) after discharge between June 4th and June 12th.

Results: Taste dysfunction was the most common reported symptom (59.5%; n = 66), followed by xerostomia (45.9%; n = 51) and olfactory dysfunctions (41.4%; n = 46). The most severe symptom was olfactory dysfunction with a median severity score of 8.5 (range: 5-10). Overall 74.5% (n = 38) of patients with xerostomia, 78.8% (n = 52) of patients with gustatory dysfunctions and 71.1% (n = 33) of patients with olfactory dysfunctions reported that all symptoms appeared before COVID-19 diagnosis. Overall, the majority of patients reported one symptom only (45.9%, n = 51), 37 (33.3%) reported the association of two symptoms, and 23 (20.7%) patients reported the association of three symptoms at the same time.

Conclusion: Xerostomia, gustatory and olfactory dysfunctions may present as a prodromal or as the sole manifestation of COVID-19. Awareness is fundamental to identify COVID-19 patients at an early stage of the disease and limit the spread of the virus.
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http://dx.doi.org/10.1016/j.amjoto.2020.102721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7482593PMC
November 2020

Circulating Long Non-Coding RNA GAS5 Is Overexpressed in Serum from Osteoporotic Patients and Is Associated with Increased Risk of Bone Fragility.

Int J Mol Sci 2020 Sep 21;21(18). Epub 2020 Sep 21.

Department of Orthopedics and Traumatology, PTV Foundation, 00133 Rome, Italy.

Osteoporosis (OP) is a multifactorial disorder in which environmental factors along with genetic variants and epigenetic mechanisms have been implicated. Long non-coding RNAs (lncRNAs) have recently emerged as important regulators of bone metabolism and OP aetiology. In this study, we analyzed the expression level and the genetic association of lncRNA GAS5 in OP patients compared to controls. Quantitative RT-PCR analysis of GAS5 was performed on the serum of 56 OP patients and 28 healthy individuals. OP subjects were divided into three groups of analysis: 29 with fragility fractures of lumbar spine (OP_VF), 14 with fragility fractures of femoral neck (OP_FF) and 13 without fractures (OP_WF). Genotyping of the rs145204276 insertion/deletion polymorphism has also been performed by Restriction fragment length polymorphism (RFLP) and direct sequencing analyses. Expression of circulating GAS5 is significantly increased in OP patients compared to controls ( < 0.01), with a statistically higher significance in fractured OP individuals vs. healthy subjects ( < 0.001). No statistically significant change was found in female OP patients; conversely, GAS5 is upregulated in the subgroup of fractured OP women sera ( < 0.01) and in all OP males ( < 0.05). Furthermore, a direct correlation between GAS5 expression level and parathyroid hormone (PTH) concentration was found in OP patients ( = 0.2930; = 0.0389). Genetic analysis of rs145204276 revealed that the deletion allele was correlated with a higher expression of GAS5 in OP patients (0.22 ± 0.02 vs. 0.15 ± 0.01, ** < 0.01). Our results suggest circulating GAS5 as a putative biomarker for the diagnosis and prognosis of OP and OP-related fractures.
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http://dx.doi.org/10.3390/ijms21186930DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7554802PMC
September 2020

Inhibition of the RANKL with denosumab has no effect on circulating markers of atherosclerosis in women with postmenopausal osteoporosis: a pilot study.

Endocrine 2021 01 8;71(1):199-207. Epub 2020 Sep 8.

Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University of Rome, Viale del Policlinico 155, 00161, Rome, Italy.

Purpose: We evaluated the early effect of denosumab on circulating markers of atherosclerosis in women with postmenopausal osteoporosis.

Methods: Denosumab (60 mg) was administered subcutaneously every 6 months (m) in 27 women (mean age 75 ± 5 years) with postmenopausal osteoporosis and high cardiovascular risk for a total of 24 m. Zoledronic acid was administered in 6 age-matched women as a single intravenous dose. Serum levels of vascular cell adhesion protein 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), E and P selectin, CD-40 ligand (CD40L), interleukin-6 (IL-6), matrix metalloproteinase (MMP) 1 and 9, monocyte chemoattractant protein-1 (MCP-1), fibrinogen (FBG), and high sensitivity C-reactive protein (hs-CRP) were measured at baseline, 15 days (d), 2, 6 and 12 m after dosing. In the denosumab group, observation was extended to 24 m as secondary endpoint.

Results: Serum ICAM-1 levels showed significant increase in the zoledronic acid group (+18 ± 0.1%; p < 0.01) at 12 m. In the denosumab group, we observed a significant increase in serum CD40L (+2 ± 0.8%; p < 0.001), MMP-1 (+11 ± 0.4%, p < 0.02), and MMP-9 (+39.4 ± 0.8%, p < 0.01) at 24 m. There was a significant increase in serum FBG and hs-CRP in both groups at 12 m (denosumab:+2.2 ± 0.2% and +50.3 ± 1.6%; zoledronic acid: +9.4 ± 0.1 and +81.8 ± 0.8%; p < 0.01). No significant between-group differences were found.

Conclusions: 24-m treatment with denosumab has no effect on the circulating markers of atherosclerosis in women with postmenopausal osteoporosis. Fluctuation of serum ICAM-1, CD40L, MMPs, FBG and hs-CRP can be ascribed to perturbation of immunological mechanisms stimulated by denosumab and zoledronic acid.
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http://dx.doi.org/10.1007/s12020-020-02483-2DOI Listing
January 2021

Phosphate Metabolism.

Calcif Tissue Int 2021 01 9;108(1):1-2. Epub 2020 Aug 9.

Bone Metabolic Diseases Unit, Department of Biomedical, Experimental and Clinical Sciences, University of Florence, AOU Careggi, Florence, Italy.

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http://dx.doi.org/10.1007/s00223-020-00727-xDOI Listing
January 2021

Naso-Ethmoidal Phosphaturic Mesenchymal Tumor: A Rare Tumor Site for an Uncommon Paraneoplastic Syndrome.

Ear Nose Throat J 2020 Jul 30:145561320940869. Epub 2020 Jul 30.

Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1177/0145561320940869DOI Listing
July 2020

Diagnosis and management of hypocalcemia.

Endocrine 2020 09 4;69(3):485-495. Epub 2020 May 4.

Department of Clinical, Internal, Anesthesiology and Cardiovascular Sciences, Sapienza University, Rome, Italy.

The aim of this clinical narrative review is to summarize and critically appraise the literature on the differential diagnosis of hypocalcemia and to provide its correct management. Calcium is essential for muscle contraction and neurotransmitter release, but clinical manifestations of hypocalcaemia (serum calcium level <8 mg/dl; 2.12 mmol/L) may involve almost any organ and system and may range from asymptomatic to life-threating conditions. Disorders causing hypocalcemia can be divided into parathyroid hormone (PTH) and non-PTH mediated. The most frequent cause of hypocalcemia is postsurgical hypoparathyroidism, while a more comprehensive search for other causes is needed for appropriate treatment in the non PTH-mediated forms. Intravenous calcium infusion is essential to raise calcium levels and resolve or minimize symptoms in the setting of acute hypocalcemia. Oral calcium and/or vitamin D supplementation is the most frequently used as treatment of chronic hypocalcemia. In hypoparathyroidism, providing the missing hormone with the use of the recombinant human (rh) PTH(1-84) has been recently approved both by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This new therapy has the advantage of being effective for correcting serum calcium levels and significantly reducing the daily requirements of calcium and active vitamin D supplements. However, due to the high cost, a strict selection of candidates to this therapy is necessary. More challenging is the long-term hypocalcemia treatment, due to its associated complications. The development of long-acting recombinant human PTH will probably modify the management of chronic hypoparathyroidism in the future.
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http://dx.doi.org/10.1007/s12020-020-02324-2DOI Listing
September 2020

Skeletal protection in patients with primary hyperparathyroidism.

Lancet Diabetes Endocrinol 2020 05;8(5):352-353

Department of Clinical, Internal, Anaesthesiologic and Cardiovascular Sciences, Rome University, 00161 Rome, Italy.

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http://dx.doi.org/10.1016/S2213-8587(20)30103-0DOI Listing
May 2020

The Interplay Between Bone and Glucose Metabolism.

Front Endocrinol (Lausanne) 2020 24;11:122. Epub 2020 Mar 24.

Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Rome, Italy.

The multiple endocrine functions of bone other than those related to mineral metabolism, such as regulation of insulin sensitivity, glucose homeostasis, and energy metabolism, have recently been discovered. and murine studies investigated the impact of several molecules derived from osteoblasts and osteocytes on glucose metabolism. In addition, the effect of glucose on bone cells suggested a mutual cross-talk between bone and glucose homeostasis. In humans, these mechanisms are the pivotal determinant of the skeletal fragility associated with both type 1 and type 2 diabetes. Metabolic abnormalities associated with diabetes, such as increase in adipose tissue, reduction of lean mass, effects of hyperglycemia , production of the advanced glycation end products, diabetes-associated chronic kidney disease, and perturbation of the calcium-PTH-vitamin D metabolism, are the main mechanisms involved. Finally, there have been multiple reports of antidiabetic drugs affecting the skeleton, with differences among basic and clinical research data, as well as of anti-osteoporosis medication influencing glucose metabolism. This review focuses on the aspects linking glucose and bone metabolism by offering insight into the most recent evidence in humans.
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http://dx.doi.org/10.3389/fendo.2020.00122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105593PMC
February 2021

Bone Control of Muscle Function.

Int J Mol Sci 2020 Feb 11;21(4). Epub 2020 Feb 11.

Bone Physiopathology Unit, Genetics and Rare Diseases Research Area, Bambino Gesù Children's Hospital, 00165 Rome, Italy.

Bone and muscle represent a single functional system and are tightly connected to each other. Indeed, diseases characterized by alterations of muscle physiology have effects on bone remodeling and structure and vice versa. Muscle influence on bone has been deeply studied, and recent studies identified irisin as new molecule involved in this crosstalk. Muscle regulation by bone needs to be extensively investigated since in the last few years osteocalcin was recognized as a key molecule in the bone-muscle interaction. Osteocalcin can exist in two forms with different degrees of carboxylation. The undercarboxylated form of osteocalcin is a hormone released by the bone matrix during the osteoclast bone resorption and can bind its G-protein coupled receptor GPRC6A expressed in the muscle, thus regulating its function. Recently, this hormone was described as an antiaging molecule for its ability to regulate bone, muscle and cognitive functions. Indeed, the features of this bone-related hormone were used to test a new therapeutic approach for sarcopenia, since injection of osteocalcin in older mice induces the acquirement of physical abilities of younger animals. Even if this approach should be tested in humans, osteocalcin represents the most surprising molecule in endocrine regulation by the skeleton.
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http://dx.doi.org/10.3390/ijms21041178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7072735PMC
February 2020

Approach to patients with hypophosphataemia.

Lancet Diabetes Endocrinol 2020 02 7;8(2):163-174. Epub 2020 Jan 7.

Department of Internal Medicine and Medical Disciplines, Sapienza University of Rome, Rome, Italy.

Phosphate metabolism is an evolving area of basic and clinical research. In the past 15 years, knowledge on disturbances of phosphate homoeostasis has expanded, as has the discovery of new targeted therapies. Hypophosphataemia might be the biochemical finding in several diseases, and its clinical evaluation should initially focus on the assessment of pathophysiological mechanisms leading to low serum phosphate concentrations. Clinical consequences of hypophosphataemia can involve multiple organ systems and vary depending on several factors, the most important being the underlying disorder. This Review focuses on the approach to patients with hypophosphataemia and how underlying pathophysiological mechanisms should be understood in the evaluation of differential diagnosis. We define an algorithm for the assessment of hypophosphataemia and review the most up-to-date literature on specific therapies. Continuous research in this area will result in a better understanding and management of patients with hypophosphataemia.
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http://dx.doi.org/10.1016/S2213-8587(19)30426-7DOI Listing
February 2020

Psychotropic medications and proton pump inhibitors and the risk of fractures in the teriparatide versus risedronate VERO clinical trial.

Bone 2020 01 22;130:115113. Epub 2019 Oct 22.

Sapienza Rome University, Rome, Italy. Electronic address:

Background: VERO is a fracture endpoint study in women with established osteoporosis that showed reduction in the risks of new vertebral fractures (VFx) and clinical fractures in women randomized to teriparatide compared with risedronate. Patients on psychotropic drugs (hypnotics, benzodiazepines and antidepressants [selective serotonin- and norepinephrine-reuptake inhibitors: SSRIs and SNRIs]) and proton pump inhibitors (PPIs) may be at a higher risk of fractures. We studied the association of exposure to these medications with the risk of fractures in the VERO study cohort, including an assessment of their potential interactions with the assigned clinical trial drugs.

Methods: A total of 1360 postmenopausal women with at least 2 moderate or 1 severe VFx and bone mineral density T-score ≤-1.50 were randomized to subcutaneous daily teriparatide (20μg) or oral weekly risedronate (35mg) in a double-blind, double-dummy, 2-year trial. In thispost-hoc analysis, multivariable log-binomial and Cox proportional hazards regression models were used to estimate adjusted risk ratios (RR) or hazard ratios (HR) for the exposure to these concomitant medications with the occurrence of incident fractures. We also assessed treatment effect modifications on anti-fracture efficacy driven by the use of these medications.

Results: There were 406 (29.9 %), 347 (25.5 %) and 176 (12.9 %) subjects taking PPIs, benzodiazepines/hypnotics, and SSRIs/SNRIs during the study, respectively. For all fracture endpoints, the greater risk reduction of teriparatide versus risedronate did not significantly differ within the categories of psychotropic drugs and PPIs. Multivariable analysis showed that the risk of pooled new and worsened VFx was higher in PPI users than in non-PPI users (RR: 1.57; p=0.032), regardless of the study treatment. Benzodiazepine/hypnotic drug users showed an increased risk of clinical fractures (HR: 1.71; p=0.026) and non-vertebral fragility fractures (NVFFx, HR: 1.89; p=0.017), regardless of the study treatment. Increases in the risk of clinical fractures (HR: 1.93; p=0.018) and NVFFx (HR: 2.16; p=0.011) were also observed in SSRI/SNRI users, regardless of the study treatment.

Conclusion: In postmenopausal women with severe osteoporosis, the superior anti-fracture efficacy of teriparatide compared with risedronate was consistent regardless of psychotropic or PPI drugs use. Patients taking psychotropic drugs and PPIs showed a higher risk for NVFFx and VFx respectively, compared to those not on these medications.
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http://dx.doi.org/10.1016/j.bone.2019.115113DOI Listing
January 2020
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