Publications by authors named "Nicola Napoli"

147 Publications

Gain-of-function Lrp5 Mutation Improves Bone Mass and Strength and Delays Hyperglycemia in a Mouse Model of Insulin-Deficient Diabetes.

J Bone Miner Res 2021 Apr 8. Epub 2021 Apr 8.

Department of Medicine, Division of Bone and Mineral Diseases, Musculoskeletal Research Center.

High fracture rate and high circulating levels of the Wnt inhibitor, sclerostin have been reported in diabetic patients. We studied the effects of Wnt signaling activation on bone health in a mouse model of insulin-deficient diabetes. We introduced the sclerostin-resistant Lrp5 mutation, associated with high bone mass, in mice carrying the Ins2 mutation (Akita), which results in loss of beta cells, insulin deficiency and diabetes in males. Akita mice accrue less trabecular bone mass with age relative to wild type. Double heterozygous Lrp5 /Akita mutants have high trabecular bone mass and cortical thickness relative to wild type animals, as do Lrp5 single mutants. Likewise, the Lrp5 mutation prevents deterioration of biomechanical properties occurring in Akita mice. Notably, Lrp5 /Akita mice develop fasting hyperglycemia and glucose intolerance with a delay relative to Akita mice (7-8 vs. 5-6 weeks, respectively), despite lack of insulin production in both groups by 6 weeks of age. Although insulin sensitivity is partially preserved in double heterozygous Lrp5 /Akita relative to Akita mutants up to 30 weeks of age, insulin-dependent pAKT activation in vitro is not altered by the Lrp5 mutation. While white adipose tissue depots are equally reduced in both compound and Akita mice, the Lrp5 mutation prevents brown adipose tissue whitening that occurs in Akita mice. Thus, hyperactivation of Lrp5-dependent signaling fully protects bone mass and strength in prolonged hyperglycemia and improves peripheral glucose metabolism in an insulin independent manner. Wnt signaling activation represents an ideal therapeutic approach for diabetic patients at high risk of fracture. This article is protected by copyright. All rights reserved.
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http://dx.doi.org/10.1002/jbmr.4303DOI Listing
April 2021

Bone fragility in patients with diabetes mellitus: A consensus statement from the working group of the Italian Diabetes Society (SID), Italian Society of Endocrinology (SIE), Italian Society of Gerontology and Geriatrics (SIGG), Italian Society of Orthopaedics and Traumatology (SIOT).

Nutr Metab Cardiovasc Dis 2021 Feb 4. Epub 2021 Feb 4.

Department of Human Sciences and Promotion of the Quality of Life, San Raffaele Roma Open University, Rome, Italy; Department of Endocrinology, Nutrition and Metabolic Diseases, IRCCS MultiMedica, Milan, Italy.

Bone fragility is one of the possible complications of diabetes, either type 1 (T1D) or type 2 (T2D). Bone fragility can affect patients of different age and with different disease severity depending on type of diabetes, disease duration and the presence of other complications. Fracture risk assessment should be started at different stages in the natural history of the disease depending on the type of diabetes and other risk factors. The risk of fracture in T1D is higher than in T2D, imposing a much earlier screening and therapeutic intervention that should also take into account a patient's life expectancy, diabetes complications etc. The therapeutic armamentarium for T2D has been enriched with drugs that may influence bone metabolism, and clinicians should be aware of these effects. Considering the complexity of diabetes and osteoporosis and the range of variables that influence treatment choices in a given individual, the Working Group on bone fragility in patients with diabetes mellitus has identified and issued recommendations based on the variables that should guide screening of bone fragility and management of diabetes and bone fragility: (A)ge, (B)MD, (C)omplications, (D)uration of disease, & (F)ractures (ABCD&F). Consideration of these parameters may help clinicians identify the best time for screening, the appropriate glycaemic target and anti-osteoporosis drug for patients with diabetes at risk of or with bone fragility.
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http://dx.doi.org/10.1016/j.numecd.2021.01.019DOI Listing
February 2021

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

J Clin Med 2021 Mar 2;10(5). Epub 2021 Mar 2.

Unit of Endocrinology and Diabetes, Campus Bio-Medico University, 00128 Rome, Italy.

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.
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http://dx.doi.org/10.3390/jcm10050996DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957889PMC
March 2021

Testosterone Therapy Effects on Bone Mass and Turnover in Hypogonadal Men with Type 2 Diabetes.

J Clin Endocrinol Metab 2021 Mar 18. Epub 2021 Mar 18.

Division of Endocrinology, Diabetes and Metabolism, Baylor College of Medicine, One Baylor Plaza, Houston, TX, USA.

Context: Male hypogonadism is associated with low bone mineral density (BMD) and increased fragility fracture risk. Patients with type 2 diabetes (T2D) have relatively higher BMD, but greater fracture risk.

Objective: Evaluate the skeletal response to testosterone therapy in hypogonadal men with T2D compared to hypogonadal men without T2D.

Design, Method And Participants: Single arm, open-label clinical (NCT01378299) trial involving 105 men (40-74 years old), with average morning testosterone<300ng/dl. Subjects were injected intramuscularly with testosterone cypionate (200mg) every 2 weeks for 18 months. Testosterone and estradiol assessed by liquid-chromatography/mass-spectroscopy; serum C-telopeptide (CTX), osteocalcin and sclerostin by ELISA; A1C by high performance liquid chromatography, areal BMD (aBMD) and body composition by dual-energy x-ray absorptiometry; tibial volumetric BMD (vBMD) and bone geometry by peripheral quantitative computed tomography.

Results: Among our population of hypogonadal men, 49 had T2D and 56 were non-T2D. After 18 months of testosterone therapy, there were no differences in circulating testosterone and estradiol between the groups. Hypogonadal men with T2D had increased osteocalcin, reflecting increased osteoblast activity, compared to non-T2D men (p<0.01). T2D men increased lumbar spine aBMD (p<0.05), total area at 38% tibia (p<0.01) and periosteal and endosteal circumferences at the same site (p<0.01 for both). T2D men had reduced tibial vBMD (p<0.01), but with preserved bone mineral content (p=0.01). Changes in A1c or body composition were similar between the 2 groups.

Conclusions: Testosterone therapy results in greater improvements in the skeletal health of hypogonadal men with T2D than their non-diabetic counterparts.
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http://dx.doi.org/10.1210/clinem/dgab181DOI Listing
March 2021

In Men With Obesity, T2DM Is Associated With Poor Trabecular Microarchitecture and Bone Strength, and Low Bone Turnover.

J Clin Endocrinol Metab 2021 Feb 4. Epub 2021 Feb 4.

Division of Endocrinology, Diabetes and Metabolism at Baylor College of Medicine, Houston, TX, USA.

Introduction: Obesity and type 2 Diabetes (T2D) are both associated with greater bone mineral density (BMD) but increased risk of fractures. The effect of the combination of both conditions on bone metabolism, microarchitecture and strength in the obese population remains unknown.

Methods: Data from 112 obese men were collected. Bone turnover and biochemical markers were measured by enzyme-linked immunosorbent assay (ELISA), body composition and BMD at all sites were assessed by dual energy X-ray absorptiometry (DXA), whereas bone microarchitecture and strength (stiffness and failure load) were measured by high-resolution peripheral computed tomography (HR-pQCT). Data were compared among metabolically healthy obese (MHO) and metabolically unhealthy obese (MUHO) with and without T2D and between obese without and with T2D.

Results: Compared to MHO and MUHO without T2D, MUHO with T2D had significantly lower levels of osteocalcin ((7.49±3.0 and 6.03±2.47, vs 4.24±2.72 ng/ml, respectively, p=0.003) and C-terminal telopeptide of type I collagen (CTx) (0.28±0.10 and 0.29±0.13 vs. 0.21±0.15 ng/ml, respectively, p=0.02). Dividing our subjects simply into those with and without T2D showed that obese men with T2D had significantly lower levels of osteocalcin (p=0.003) and CTx (p=0.005), greater trabecular separation at the tibia and radius (p=0.03 and p=0.04, respectively) and lower tibial failure load and stiffness (both p=0.04), relative to obese men without T2D.

Conclusion: In men, the combination of obesity and T2D is associated with reduced bone turnover, poorer trabecular bone microarchitecture and bone strength compared to those who are obese but without T2D suggesting worse bone disease.
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http://dx.doi.org/10.1210/clinem/dgab061DOI Listing
February 2021

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

Int J Endocrinol 2021 15;2021:8902367. Epub 2021 Jan 15.

Unit of Endocrinology and Diabetes, University Campus Bio-Medico, Rome, Italy.

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.
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http://dx.doi.org/10.1155/2021/8902367DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7822697PMC
January 2021

Nutritional Therapy for Athletes with Diabetes.

J Funct Morphol Kinesiol 2020 Nov 13;5(4). Epub 2020 Nov 13.

Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, 00128 Rome, Italy.

Diabetes is a worldwide disease also affecting the sports field. The two main forms of diabetes, namely type 1 diabetes (T1D) and type 2 diabetes (T2D), differ in both their pathological and pharmacological characteristics and thus require a distinct nutritional treatment. Diet plays an important role in the management of athletes with diabetes and is crucial to achieving their best performance. This review aims to investigate the objectives of nutritional therapy before, during and after training, in order to improve the best composition of macronutrients during meals. In this review, we provide a brief overview of recent studies about nutritional approaches to people with diabetes for performance optimization and for the control of diabetes-related complications. Thereafter, we discuss the differences between macronutrients and dietary intake before, during and after training. It can be concluded that each sport has particular characteristics in terms of endurance and power, hence demanding a specific energy expenditure and consequent nutritional adjustments. Therefore, the management of athletes with diabetes must be personalized and supported by medical professionals, including a diabetologist, physiologist and a nutritionist.
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http://dx.doi.org/10.3390/jfmk5040083DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739333PMC
November 2020

Beneficial Effects of Physical Activity in Diabetic Patients.

J Funct Morphol Kinesiol 2020 Sep 4;5(3). Epub 2020 Sep 4.

Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Via Alvaro del Portillo 21, 00128 Rome, Italy.

One of the main goals of diabetic therapy is to achieve the best metabolic control to prevent the development and progression of potential complications. A multidisciplinary approach characterized by the combination of diet, physical activity (PA) and drug therapy with oral and injectable (non-insulin) pharmacological agents, is desirable to optimize metabolic control. The aim of this review is to explain the contribution of PA and its beneficial effects on patients affected by type 1 (T1D) and type 2 diabetes (T2D). We provide an overview of evidence on the effects of PA for the main two types of diabetes mellitus (DM) to identify the right level of PA to be recommended. We discuss the physiological and clinical role of PA in people with DM. It can be concluded that the objective of antidiabetic therapy should be the achievement and optimization of metabolic control through a multidisciplinary approach involving non-pharmacological therapy such as diet and PA, which has a crucial role.
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http://dx.doi.org/10.3390/jfmk5030070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7739324PMC
September 2020

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

The impact of type 2 diabetes on the development of tendinopathy.

Diabetes Metab Res Rev 2020 Oct 27. Epub 2020 Oct 27.

Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy.

Tendinopathy is a chronic and often painful condition affecting both professional athletes and sedentary subjects. It is a multi-etiological disorder caused by the interplay among overload, ageing, smoking, obesity (OB) and type 2 diabetes (T2D). Several studies have identified a strong association between tendinopathy and T2D, with increased risk of tendon pain, rupture and worse outcomes after tendon repair in patients with T2D. Moreover, consequent immobilization due to tendon disorder has a strong impact on diabetes management by reducing physical activity and worsening the quality of life. Multiple investigations have been performed to analyse the causal role of the individual metabolic factors occurring in T2D on the development of tendinopathy. Chronic hyperglycaemia, advanced glycation end-products, OB and insulin resistance have been shown to contribute to the development of diabetic tendinopathy. This review aims to explore the relationship between tendinopathy and T2D, in order to define the contribution of metabolic factors involved in the degenerative process and to discuss possible strategies for the clinical management of diabetic tendinopathy.
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http://dx.doi.org/10.1002/dmrr.3417DOI Listing
October 2020

Liver fibrosis score, physical frailty, and the risk of dementia in older adults: The Italian Longitudinal Study on Aging.

Alzheimers Dement (N Y) 2020 24;6(1):e12065. Epub 2020 Aug 24.

Clinica Medica "Frugoni" and Geriatric Medicine-Memory Unit University of Bari Aldo Moro Bari Italy.

Introduction: Liver fibrosis increases progressively with aging and has been associated with poorer cognitive performance in middle-aged and older adults. We investigated the relationships between a non-invasive score for advanced liver fibrosis (non-alcoholic fatty liver disease [NAFLD] fibrosis score [NFS]) and dementia risk. We also assessed physical frailty, a common geriatric condition which is associated to dementia. We tested the joint effects of physical frailty and fibrosis on dementia incidence.

Methods: A total of 1061 older adults (65 to 84 years), from the Italian Longitudinal Study on Aging, were prospectively evaluated for the risk of dementia in a period between 1992 and 2001. Liver fibrosis was defined according to the NFS. Physical frailty was assessed according to the Fried's criteria. Cox proportional hazards models were used to estimate the short- and long-term risk of overall dementia, associated to the NFS, testing the effect modifier of physical frailty status.

Results: Older adults with only high NFS (F3-F4) did not exhibit a significant increased risk of overall dementia. Over 8 years of follow-up, frail older adults with high NFS had an increased risk of overall dementia (hazard ratio [HR]: 4.23; 95% confidence interval [CI]: 1.22 to 14.70,  = .023). Finally, physically frail older adults with low albumin serum levels (albumin < 4.3 g/dL) and with advanced liver fibrosis (F3-F4 NFS) compared to those with lower liver fibrosis score (F0-F2 NFS) were more likely to have a higher risk of overall dementia in a long term-period (HR: 16.42; 95% CI: 1.44 to 187.67,  = .024).

Discussion: Advanced liver fibrosis (F3-F4 NFS) could be a long-term predictor for overall dementia in people with physical frailty. These findings should encourage a typical geriatric, multidisciplinary assessment which accounts also for the possible co-presence of frail condition in older adults with chronic liver disease and liver fibrosis.
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http://dx.doi.org/10.1002/trc2.12065DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7443742PMC
August 2020

Analysis of hepatic stiffness after viral eradication in a population with chronic hepatitis C treated with DAAs.

Med Clin (Barc) 2021 04 9;156(7):317-323. Epub 2020 Aug 9.

Department of Interdisciplinary Medicine, University of Bari, Bari, Italy. Electronic address:

Introduction And Objectives: Despite chronic hepatitis C (CHC) is still a global burden as the high morbidity and mortality, the recently approved direct-acting antivirals (DAAs) permit a very high rate of sustained virologic response (SVR) in these patients. The clinical improvement due to viral eradication is being documented, however it is not clear why a subset of patients does not benefit in terms of fibrosis regression or hepatocellular carcinoma (HCC) development. Aim of the study was to assess the hepatic stiffness regression at SVR24 and detect factors impacting stiffness course.

Patients And Methods: Hepatic stiffness assessed by acoustic radiation force impulse (ARFI) and anthropometric- and biochemical parameters were retrospectively collected by 166 CHC patients treated with DAAs, form baseline and SVR24.

Results: Viral eradication significantly improved overall hepatic stiffness and other related hepatitis hallmarks such as ALT, AST, γGT, platelets count, AST to Platelets ratio Index (APRI), total- and LDL cholesterol. The multiple regression analysis showed that patients with baseline glucose > 110mg/dl presented a stiffness regression significantly lower when compared to low glucose patients (<110mg/dl), moreover baseline HbA1c strongly correlated with DeltaStiffness. 7 patients (4.2%) developed HCC and importantly, presented hyperglycaemia and no stiffness regression nor platelets count recover.

Conclusions: Although viral eradication with DAAs entails overall benefits, glycaemic decompensation negatively affects fibrosis regression and probably facilitates HCC development.
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http://dx.doi.org/10.1016/j.medcli.2020.04.050DOI Listing
April 2021

Sclerostin Regulation, Microarchitecture, and Advanced Glycation End-Products in the Bone of Elderly Women With Type 2 Diabetes.

J Bone Miner Res 2020 12 2;35(12):2415-2422. Epub 2020 Oct 2.

Unit of Endocrinology and Diabetes, Departmental Faculty of Medicine and Surgery, Campus Bio-Medico University of Rome, Rome, Italy.

Increased circulating sclerostin and accumulation of advanced glycation end-products (AGEs) are two potential mechanisms underlying low bone turnover and increased fracture risk in type 2 diabetes (T2D). Whether the expression of the sclerostin-encoding SOST gene is altered in T2D, and whether it is associated with AGEs accumulation or regulation of other bone formation-related genes is unknown. We hypothesized that AGEs accumulate and SOST gene expression is upregulated in bones from subjects with T2D, leading to downregulation of bone forming genes (RUNX2 and osteocalcin) and impaired bone microarchitecture and strength. We obtained bone tissue from femoral heads of 19 T2D postmenopausal women (mean glycated hemoglobin [HbA1c] 6.5%) and 73 age- and BMI-comparable nondiabetic women undergoing hip replacement surgery. Despite similar bone mineral density (BMD) and biomechanical properties, we found a significantly higher SOST (p = .006) and a parallel lower RUNX2 (p = .025) expression in T2D compared with non-diabetic subjects. Osteocalcin gene expression did not differ between T2D and non-diabetic subjects, as well as circulating osteocalcin and sclerostin levels. We found a 1.5-fold increase in total bone AGEs content in T2D compared with non-diabetic women (364.8 ± 78.2 versus 209.9 ± 34.4 μg quinine/g collagen, respectively; p < .001). AGEs bone content correlated with worse bone microarchitecture, including lower volumetric BMD (r = -0.633; p = .02), BV/TV (r = -0.59; p = .033) and increased trabecular separation/spacing (r = 0.624; p = .023). In conclusion, our data show that even in patients with good glycemic control, T2D affects the expression of genes controlling bone formation (SOST and RUNX2). We also found that accumulation of AGEs is associated with impaired bone microarchitecture. We provide novel insights that may help understand the mechanisms underlying bone fragility in T2D. © 2020 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4153DOI Listing
December 2020

MECHANISMS IN ENDOCRINOLOGY: Vitamin D and COVID-19.

Eur J Endocrinol 2020 Nov;183(5):R133-R147

Institute of Endocrine and Metabolic Sciences, San Raffaele, Vita-Salute University and IRCCS Hospital, Milano, Italy.

The SARS-CoV-2 virus responsible for the COVID-19 pandemic has generated an explosion of interest both in the mechanisms of infection leading to dissemination and expression of this disease, and in potential risk factors that may have a mechanistic basis for disease propagation or control. Vitamin D has emerged as a factor that may be involved in these two areas. The focus of this article is to apply our current understanding of vitamin D as a facilitator of immunocompetence both with regard to innate and adaptive immunity and to consider how this may relate to COVID-19 disease. There are also intriguing potential links to vitamin D as a factor in the cytokine storm that portends some of the most serious consequences of SARS-CoV-2 infection, such as the acute respiratory distress syndrome. Moreover, cardiac and coagulopathic features of COVID-19 disease deserve attention as they may also be related to vitamin D. Finally, we review the current clinical data associating vitamin D with SARS-CoV-2 infection, a putative clinical link that at this time must still be considered hypothetical.
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http://dx.doi.org/10.1530/EJE-20-0665DOI Listing
November 2020

Computed Tomography Highlights Increased Visceral Adiposity Associated With Critical Illness in COVID-19.

Diabetes Care 2020 10 4;43(10):e129-e130. Epub 2020 Aug 4.

Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Rome, Italy

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http://dx.doi.org/10.2337/dc20-1333DOI Listing
October 2020

Bone Turnover Markers Do Not Predict Fracture Risk in Type 2 Diabetes.

J Bone Miner Res 2020 12 29;35(12):2363-2371. Epub 2020 Sep 29.

Department Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Type 2 diabetes (T2D) is characterized by increased fracture risk despite higher BMD and reduced bone turnover. BMD underestimates fracture risk in T2D, but the predictive role of bone turnover markers (BTMs) on fracture risk in T2D has not been explored. Thus, we sought to determine whether BTMs predict incident fractures in subjects with T2D. For this case-cohort study, we used data from the Health, Aging, and Body Composition (Health ABC) Study of well-functioning older adults, aged 70 to 79 years at baseline (April 1997-June 1998). The case-cohort sample consisted of (i) the cases, composed of all 223 participants who experienced incident fractures of the hip, clinical spine, or distal forearm within the first 9 years of study follow-up; and (ii) the subcohort of 508 randomly sampled participants from three strata at baseline (T2D, prediabetes, and normoglycemia) from the entire Health ABC cohort. A total of 690 subjects (223 cases, of whom 41 were in the subcohort) were included in analyses. BTMs (C-terminal telopeptide of type I collagen [CTX], osteocalcin [OC], and procollagen type 1 N-terminal propeptide [P1NP]) were measured in archived baseline serum. Cox regression with robust variance estimation was used to estimate the adjusted hazard ratio (HR) for fracture per 20% increase in BTMs. In nondiabetes (prediabetes plus normoglycemia), fracture risk was increased with higher CTX (HR 1.10; 95% confidence interval [CI], 1.01 to 1.20 for each 20% increase in CTX). Risk was not increased in T2D (HR 0.92; 95% CI, 0.81 to 1.04; p for interaction .045). Similarly, both OC and P1NP were associated with higher risk of fracture in nondiabetes, but not in T2D, with p for interaction of .078 and .109, respectively. In conclusion, BTMs did not predict incident fracture risk in T2D but were modestly associated with fracture risk in nondiabetes. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4140DOI Listing
December 2020

Are We Ready to Use Teriparatide to Treat Medication-Related Osteonecrosis of the Jaw in Clinical Practice?

J Clin Oncol 2020 09 13;38(26):2949-2951. Epub 2020 Jul 13.

Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico, University of Rome, Rome, Italy.

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http://dx.doi.org/10.1200/JCO.20.01633DOI Listing
September 2020

The D-side of COVID-19: musculoskeletal benefits of vitamin D and beyond.

Endocrine 2020 08 6;69(2):237-240. Epub 2020 Jul 6.

Unit of Endocrinology and Diabetes, Department of Medicine, Campus Bio-Medico University of Rome, Via Alvaro di Portillo 21, 00128, Rome, Italy.

Coronavirus 2019 disease (COVID-19) mostly adversely affects the elderly, a population at higher risk for low serum 25-hydroxyvitamin D (25(OH)D) levels. In this viewpoint, we highlight the well-known musculoskeletal properties of vitamin D, which are particularly relevant in the context of COVID-19, suggesting further potential benefits through extra-skeletal effects. Maintaining optimal 25(OH)D is crucial to prevent falls, frailty and fractures in elderly patients, with low activity levels due to lockdown, or who are relatively immobilized during hospitalization and after discharge for prolonged periods of time. Hypovitaminosis D is also associated with susceptibility to respiratory infections, admissions to the intensive care unit, and mortality. We underscore the importance of achieving desirable serum 25(OH)D in COVID-19 elderly patients, to ensure beneficial musculoskeletal effects and possibly respiratory effects of vitamin D, in the context of COVID-19.
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http://dx.doi.org/10.1007/s12020-020-02407-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7338117PMC
August 2020

Managing fragility fractures during the COVID-19 pandemic.

Nat Rev Endocrinol 2020 09;16(9):467-468

Kogod Center on Aging and Division of Endocrinology, Mayo Clinic, Rochester, MN, USA.

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http://dx.doi.org/10.1038/s41574-020-0379-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7288256PMC
September 2020

Impact of Improvement in Walking Speed on Hospitalization and Mortality in Females with Cardiovascular Disease.

J Clin Med 2020 Jun 5;9(6). Epub 2020 Jun 5.

General Directorship for Public Health and Integration Policy, Emilia-Romagna Region, 40133 Bologna, Italy.

Cardiovascular disease (CVD) is the principal cause of death in women. Walking speed (WS) is strongly related with mortality and CVD. The rate of all-cause hospitalization or death was assessed in 290 female outpatients with CVD after participation in a cardiac rehabilitation/secondary prevention program (CR/SP) and associated with the WS maintained during a moderate 1 km treadmill-walk. Three-year mortality rates were 57%, 44%, and 29% for the slow (2.1 ± 0.4 km/h), moderate (3.1 ± 0.3 km/h), and fast (4.3 ± 0.6 km/h) walkers, respectively, with adjusted hazard ratios (HRs) of 0.78 ( 0.24) and 0.55 ( 0.03) for moderate and fast walkers compared to the slow walkers. In addition, hospitalization or death was examined four to six years after enrollment as a function of the change in the WS of 176 patients re-assessed during the third year after baseline. The rates of hospitalization or death were higher across tertiles of reduced WS, with 35%, 50%, and 53% for the high (1.5 ± 0.3 km/h), intermediate (0.7 ± 0.2 km/h), and low tertiles (0.2 ± 0.2 km/h). Adjusted HRs were 0.79 ( 0.38) for the intermediate and 0.47 ( 0.02) for the high tertile compared to the low improvement tertile. Improved walking speed was associated with a graded decrease in hospitalization or death from any cause in women undergoing CR/SP.
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http://dx.doi.org/10.3390/jcm9061755DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7357156PMC
June 2020

T-Score as an Indicator of Fracture Risk During Treatment With Romosozumab or Alendronate in the ARCH Trial.

J Bone Miner Res 2020 07 22;35(7):1333-1342. Epub 2020 May 22.

Service and Laboratory of Bone Diseases, Geneva University Hospital, Geneva, Switzerland.

In the Active-Controlled Fracture Study in Postmenopausal Women With Osteoporosis at High Risk (ARCH) clinical trial (NCT01631214), 1 year of romosozumab followed by alendronate reduced the risk of vertebral and nonvertebral fractures compared to alendronate alone in women with prevalent fracture. We performed post hoc analyses of data from patients in ARCH (romosozumab, n = 1739; alendronate, n = 1726) who had a baseline BMD measurement and received at least one open-label alendronate dose. We evaluated 1-year mean BMD and corresponding T-score changes; proportions of patients achieving T-scores > -2.5 at the total hip (TH), femoral neck (FN), and lumbar spine (LS); and group differences in fracture rates after 12 months, while all participants were on alendronate. Subsequently, we investigated the relationship between T-scores achieved at the TH, FN, and LS at 12 months and subsequent fracture incidence. At 1 year, mean change from baseline in TH BMD was 6.3% (T-score change 0.31) with romosozumab versus 2.9% (T-score change 0.15) with alendronate (p < .001). The proportion of patients with TH T-score > -2.5 increased from 34% at baseline to 55% after 1 year of romosozumab and from 32% at baseline to 44% after 1 year of alendronate. Compared with patients receiving alendronate in year 1, those receiving romosozumab had a 75% reduction in new or worsening vertebral fracture (p < .001) in year 2, and a 19% reduction in nonvertebral fracture (p = .120) and 40% reduction in hip fracture (p = .041) during the open-label period. TH and FN T-scores achieved at month 12 were associated with subsequent nonvertebral and vertebral fracture rates and the relationships were independent of treatment received. LS T-score at 12 months was associated with vertebral but not nonvertebral fracture risk. We conclude that 1 year of romosozumab leads to larger BMD gains versus alendronate, and that the T-score achieved with either therapy is related to subsequent fracture risk. These data support the use of T-score as a therapeutic target for patients with osteoporosis. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.3996DOI Listing
July 2020

Clinical, Biochemical, and Radiological Profile of Normocalcemic Primary Hyperparathyroidism.

J Clin Endocrinol Metab 2020 07;105(7)

UOS Malattie Metaboliche, Santa Maria Goretti Hospital, Latina, Italy.

Context: The clinical and radiological aspects of normocalcemic hyperparathyroidism (NHPT) are confounded by the differing methods used to rule out secondary hyperparathyroidism and by the small sample size.

Objective: To assess the clinical, biochemical, and radiological profile of NHPT compared with primary hyperparathyroidism (PHPT) and control subjects.

Design: Multicentric cross-sectional study.

Setting: Outpatient clinic.

Patients: 47 NHPT, 41 PHPT, and 39 age- and sex-matched control subjects.

Main Outcome Measures: Calcium metabolism and bone turnover markers (BTMs). Lumbar spine, total hip, femoral neck, one-third distal radius bone mineral density (BMD). Morphometric vertebral fracture (VF) assessed by dual-energy X-ray absorptiometry.

Results: NHPT patients had significantly higher parathyroid hormone, 25(OH)-vitamin D levels and lower calcium × phosphorus product than controls (P < .001). Compared with PHPT, the NHPT group had significantly higher 25(OH) vitamin D levels (P = .016). NHPT had BTM levels similar to controls and PHPT. NHPT, PHPT, and controls have similar lumbar spine and femoral neck BMD. NHPT and controls had a similar radial BMD, while patients with PHPT had a lower radial BMD than both patients with NHPT (P = .031) and controls (P < .05). Using the control group as the reference, after adjustment for interacting factors, there was no increase in risk of moderate-severe VF in NHPT (odds ratio [OR] 1.04, 95% confidence interval [CI] 0.25-4.55), while PHPT had an increased risk (OR 3.81,95% CI 1.15-15.12). Seventy-nine percent of NHPT and 59% of PHPT patients fulfilled the criteria for asymptomatic hyperparathyroidism.

Conclusions: The biochemical phenotype of NHPT is intermediate between PHPT and controls. In contrast, the bone phenotype resembles controls with normal bone turnover, no significant BMD impairment, and no increased risk of VF.
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http://dx.doi.org/10.1210/clinem/dgaa174DOI Listing
July 2020

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition.

J Orthop Trauma 2020 Apr;34(4):e125-e141

Harvard Medical School, Musculoskeletal Research Center, Marcus Institute for Aging Research, Hebrew SeniorLife, Boston, MA, USA.

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fractureamong people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, andsubcutaneous pharmacotherapies are efficaciousandcanreduce risk of future fracture.Patientsneededucation,however, about thebenefitsandrisks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive butmay be beneficial for selected patients at high risk.Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the earlypost-fractureperiod,prompt treatment is recommended.Adequate dietary or supplemental vitaminDand calciumintake shouldbe assured. Individuals beingtreatedfor osteoporosis shouldbe reevaluated for fracture risk routinely, includingvia patienteducationabout osteoporosisandfracturesandmonitoringfor adverse treatment effects.Patients shouldbestronglyencouraged to avoid tobacco, consume alcohol inmoderation atmost, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease).
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http://dx.doi.org/10.1097/BOT.0000000000001743DOI Listing
April 2020

Favorable skeletal benefit/risk of long-term denosumab therapy: A virtual-twin analysis of fractures prevented relative to skeletal safety events observed.

Bone 2020 05 21;134:115287. Epub 2020 Feb 21.

University of Wisconsin-Madison, Madison, WI, USA.

Antiresorptive therapies reduce fracture risk; however, long-term bone turnover inhibition may raise concerns about rare, but serious, skeletal adverse events-atypical femoral fracture (AFF) and osteonecrosis of the jaw (ONJ). Denosumab, a fully human monoclonal antibody against RANKL, has demonstrated sustained low vertebral and nonvertebral fracture rates with low skeletal adverse event rates in the 3-year FREEDOM trial and its 7-year Extension (in which all subjects received open-label denosumab). In this analysis, we aimed to estimate fractures prevented relative to skeletal adverse events observed with 10 years of denosumab therapy. We modeled a hypothetical placebo group using the virtual-twin method, thereby allowing calculation of fractures prevented with denosumab treatment (relative to the virtual-placebo group) in the context of AFF or ONJ events observed in the long-term denosumab group. Estimated virtual-placebo and observed long-term denosumab exposure-adjusted fracture rates per 100,000 subject-years were calculated for fractures classified as clinical (3180 and 1777, respectively), major osteoporotic (2699 and 1525), vertebral (1879 and 901), and nonvertebral (2924 and 1528), and compared with observed AFF and ONJ in the long-term denosumab group (5 and 35 per 100,000 subject-years, respectively). The skeletal benefit/risk ratio (fractures prevented per adverse event observed) for clinical fractures was 281 (AFF) and 40 (ONJ). Based on this model, denosumab treatment for up to 10 years has a favorable skeletal benefit/risk profile when comparing fractures prevented per skeletal adverse event observed. Clinical trial registration: NCT00089791, NCT00523341.
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http://dx.doi.org/10.1016/j.bone.2020.115287DOI Listing
May 2020

Denosumab in postmenopausal women with osteoporosis and diabetes: Subgroup analysis of FREEDOM and FREEDOM extension.

Bone 2020 05 10;134:115268. Epub 2020 Feb 10.

School of Medicine, University of California San Francisco, San Francisco, CA, USA.

Purpose: Diabetes and osteoporosis occur frequently in older adults and are both associated with increased fracture risk. Denosumab treatment reduced new vertebral, nonvertebral, and hip fractures over 3 years, with continued low fracture incidence for up to 10 years in postmenopausal women with osteoporosis. However, its effects in diabetic subjects with osteoporosis have not yet been investigated.

Methods: Post hoc analysis of the 3-year, placebo-controlled FREEDOM study and 7-year Extension included postmenopausal women with osteoporosis and diabetes. Effects on BMD, vertebral, and nonvertebral fracture incidence were evaluated.

Results: Of 7808 subjects in FREEDOM, 508 with diabetes received denosumab (n = 266) or placebo (n = 242). Among those, BMD increased significantly with denosumab versus placebo in FREEDOM, and continued to increase during the Extension in long-term (continuing denosumab) and crossover (placebo to denosumab) denosumab subjects. In FREEDOM, denosumab-treated subjects with diabetes had significantly lower new vertebral fracture rates (1.6%) versus placebo (8.0%) (RR: 0.20 [95% CI 0.07-0.61]; p = .001). Nonvertebral fracture incidence was higher with denosumab (11.7%) versus placebo (5.9%) (HR: 1.94 [95% CI 1.00-3.77]; p = .046), although there were fewer hip fractures with denosumab (World Health Organization, 2017 [1]) than placebo (4; nonsignificant). During the first 3 years in FREEDOM Extension, new vertebral and nonvertebral fracture incidences were low in long-term and crossover denosumab diabetic groups (≤6%), consistent with the overall Extension population; yearly nonvertebral fracture incidence was comparable to the FREEDOM placebo group.

Conclusion: Denosumab significantly increased BMD and decreased vertebral fracture risk in subjects with osteoporosis and diabetes. No reduction in nonvertebral fractures was observed.
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http://dx.doi.org/10.1016/j.bone.2020.115268DOI Listing
May 2020

Osteoarthritis and type 2 diabetes: From pathogenetic factors to therapeutic intervention.

Diabetes Metab Res Rev 2020 03 12;36(3):e3254. Epub 2019 Dec 12.

Department of Endocrinology and Diabetes, Campus Bio-Medico University of Rome, Rome, Italy.

Over the last decades, osteoarthritis (OA) and type 2 diabetes (T2D) prevalence increased due to the global ageing population and the pandemic obesity. They currently affect a substantial part of the Western world population and are characterized by enhancing the risk of disability and reduction of quality of life. OA is a multifactorial condition whose development derives from the interaction between individual and environmental factors: The best known primarily include age, female gender, genetic determinants, articular biomechanics, and obesity (OB). Given the high prevalence of OA and T2D and their association with OB and inflammation, several studies have been conducted to investigate the causative role of biological characteristics proper to T2D on the development of OA. This review aims to analyse the relationship between of OA and T2D, in order to explain the pathophysiological drivers of the degenerative process and to delineate possible targets to which appropriate treatments may be addressed in the near future.
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http://dx.doi.org/10.1002/dmrr.3254DOI Listing
March 2020

Effect of Aerobic or Resistance Exercise, or Both, on Bone Mineral Density and Bone Metabolism in Obese Older Adults While Dieting: A Randomized Controlled Trial.

J Bone Miner Res 2020 03 4;35(3):430-439. Epub 2019 Dec 4.

Division of Endocrinology, Diabetes, and Metabolism, Baylor College of Medicine, Houston, TX, USA.

Weight loss therapy of older adults with obesity is limited by weight loss-induced decrease in bone mineral density (BMD), which could exacerbate ongoing age-related bone loss and increase the risk for fractures. Therefore, it is recommended that weight loss therapy of older adults with obesity should include an intervention such as regular exercise to reduce the concomitant bone loss. However, the most appropriate exercise types to combine with weight loss therapy in this older population is unknown. In a randomized controlled trial, we performed a head-to-head comparison of aerobic or resistance exercise, or both, during matched ~10% weight loss in 160 older adults with obesity. We measured changes in BMD (total hip, femoral neck, trochanter, intertrochanter, one-third radius, lumbar spine) and bone markers. Changes between groups were analyzed using mixed-model repeated measures analyses of variance. After 6 months of intensive lifestyle interventions, BMD decreased less in the resistance group (-0.006 g/cm [-0.7%]) and combination group (-0.012 g/cm [-1.1%]) than in the aerobic group (-0.027 g/cm [-2.6%]) (p = 0.001 for between-group comparisons). Serum C-telopeptide, procollagen type 1 N-propeptide, and osteocalcin concentrations increased more in the aerobic group (33%, 16%, and 16%, respectively) than in the resistance group (7%, 2%, and 0%, respectively) and combination group (11%, 2%, and 5%, respectively) (p = 0.004 to 0.048 for between-group comparisons). Multiple regression analyses revealed that the decline in whole body mass and serum leptin were the independent predictors of the decline in hip BMD (multiple R = 0.45 [p < .001]). These findings indicate that compared with aerobic exercise, resistance and combined aerobic and resistance exercise are associated with less weight loss-induced decrease in hip BMD and less weight loss-induced increase in bone turnover. Therefore, both resistance and combined aerobic and resistance exercise can be recommended to protect against bone loss during weight loss therapy of older adults with obesity. (LITOE ClinicalTrials.gov number NCT01065636.) © 2019 American Society for Bone and Mineral Research. Published 2019. This article is a U.S. Government work and is in the public domain in the USA.
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http://dx.doi.org/10.1002/jbmr.3905DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7064383PMC
March 2020

Intervertebral disc degeneration: A focus on obesity and type 2 diabetes.

Diabetes Metab Res Rev 2020 01 16;36(1):e3224. Epub 2019 Nov 16.

Department of Orthopaedic and Trauma Surgery, Campus Bio-Medico University of Rome, Rome, Italy.

Obesity (OB) and type 2 diabetes (T2D) are among the most prevalent metabolic diseases. They currently affect a substantial part of the world population and are characterized by several systemic co-morbidities, including cardiovascular diseases, stroke, cancer, liver steatosis, and musculoskeletal disorders, by increasing the risk of developing osteoarthritis and intervertebral disc degeneration (IVDD). IVDD is a chronic, progressive process whose main features are disc dehydration, loss of disc height, and changes of load distribution across the spine, resulting in disc structure disruption and leading to low back pain onset. Given the high prevalence of these metabolic disorders and their association with IVDD, several studies have been conducted in order to investigate the causative role of biological and biomechanical characteristics proper to these conditions in the development of IVDD. This review aims to analyse the role of OB and T2D on IVDD, in order to clarify the pathophysiological drivers of the degenerative process and to delineate possible targets to which appropriate treatments may be addressed in the near future.
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http://dx.doi.org/10.1002/dmrr.3224DOI Listing
January 2020