Energy metabolism and ketogenic diets: What about the skeletal health? a narrative review and a prospective vision for planning clinical trials on this issue

The existence of a common mesenchymal cell progenitor shared by bone, skeletal muscle, and adipocytes cell progenitors, makes the role of the skeleton in energy metabolism no longer surprising. Thus, bone fragility could also be seen as a consequence of a “poor” quality in nutrition. Ketogenic diet was originally proven to be effective in epilepsy, and long-term follow-up studies on epileptic children undergoing a ketogenic diet reported an increased incidence of bone fractures and decreased bone mineral density. However, the causes of such negative impacts on bone health have to be better defined. In these subjects, the concomitant use of antiepileptic drugs and the reduced mobilization may partly explain the negative effects on bone health, but little is known about the effects of diet itself, and/or generic alterations in vitamin D and/or impaired growth factor production. Despite these remarks, clinical studies were adequately designed to investigate bone health are scarce and bone health related aspects are not included among the various metabolic pathologies positively influenced by ketogenic diets. Here, we provide not only a narrative review on this issue, but also practical advice to design and implement clinical studies on ketogenic nutritional regimens and bone health outcomes. Perspectives on ketogenic regimens, microbiota, microRNAs, and bone health are also included

Source Attribution of Human Campylobacteriosis Using Whole-Genome Sequencing Data and Network Analysis

Campylobacter spp. are a leading and increasing cause of gastrointestinal infections world-wide. Source attribution, which apportions human infection cases to different animal species and food reservoirs, has been instrumental in control-and evidence-based intervention efforts. The rapid increase in whole-genome sequencing data provides an opportunity for higher-resolution source attribution models. Important challenges, including the high dimension and complex structure of WGS data, have inspired concerted research efforts to develop new models. We propose network analysis models as an accurate, high-resolution source attribution approach for the sources of human campylobacteriosis. A weighted network analysis approach was used in this study for source attribution comparing different WGS data inputs. The compared model inputs consisted of cgMLST and wgMLST distance matrices from 717 human and 717 animal isolates from cattle, chickens, dogs, ducks, pigs and turkeys. SNP distance matrices from 720 human and 720 animal isolates were also used. The data were collected from 2015 to 2017 in Denmark, with the animal sources consisting of domestic and imports from 7 European countries. Clusters consisted of network nodes representing respective genomes and links representing distances between genomes. Based on the results, animal sources were the main driving factor for cluster formation, followed by type of species and sampling year. The coherence source clustering (CSC) values based on animal sources were 78%, 81% and 78% for cgMLST, wgMLST and SNP, respectively. The CSC values based on Campylobacter species were 78%, 79% and 69% for cgMLST, wgMLST and SNP, respectively. Including human isolates in the network resulted in 88%, 77% and 88% of the total human isolates being clustered with the different animal sources for cgMLST, wgMLST and SNP, respectively. Between 12% and 23% of human isolates were not attributed to any animal source. Most of the human genomes were attributed to chickens from Denmark, with an average attribution percentage of 52.8%, 52.2% and 51.2% for cgMLST, wgMLST and SNP distance matrices respectively, while ducks from Denmark showed the least attribution of 0% for all three distance matrices. The best-performing model was the one using wgMLST distance matrix as input data, which had a CSC value of 81%. Results from our study show that the weighted network-based approach for source attribution is reliable and can be used as an alternative method for source attribution considering the high performance of the model. The model is also robust across the different Campylobacter species, animal sources and WGS data types used as input

Pathophysiology and Management of Type 2 Diabetes Mellitus Bone Fragility

Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone fragility fractures compared to nondiabetic subjects. This increased fracture risk may occur despite normal or even increased values of bone mineral density (BMD), and poor bone quality is suggested to contribute to skeletal fragility in this population. These concepts explain why the only evaluation of BMD could not be considered an adequate tool for evaluating the risk of fracture in the individual T2DM patient. Unfortunately, nowadays, the bone quality could not be reliably evaluated in the routine clinical practice. On the other hand, getting further insight on the pathogenesis of T2DM-related bone fragility could consent to ameliorate both the detection of the patients at risk for fracture and their appropriate treatment. The pathophysiological mechanisms underlying the increased risk of fragility fractures in a T2DM population are complex. Indeed, in T2DM, bone health is negatively affected by several factors, such as inflammatory cytokines, muscle-derived hormones, incretins, hydrogen sulfide (H2S) production and cortisol secretion, peripheral activation, and sensitivity. All these factors may alter bone formation and resorption, collagen formation, and bone marrow adiposity, ultimately leading to reduced bone strength. Additional factors such as hypoglycemia and the consequent increased propensity for falls and the direct effects on bone and mineral metabolism of certain antidiabetic medications may contribute to the increased fracture risk in this population. The purpose of this review is to summarize the literature evidence that faces the pathophysiological mechanisms underlying bone fragility in T2DM patients

Pathophysiology and Management of Type 2 Diabetes Mellitus Bone Fragility

Individuals with type 2 diabetes mellitus (T2DM) have an increased risk of bone fragility fractures compared to nondiabetic subjects. This increased fracture risk may occur despite normal or even increased values of bone mineral density (BMD), and poor bone quality is suggested to contribute to skeletal fragility in this population. These concepts explain why the only evaluation of BMD could not be considered an adequate tool for evaluating the risk of fracture in the individual T2DM patient. Unfortunately, nowadays, the bone quality could not be reliably evaluated in the routine clinical practice. On the other hand, getting further insight on the pathogenesis of T2DM-related bone fragility could consent to ameliorate both the detection of the patients at risk for fracture and their appropriate treatment. The pathophysiological mechanisms underlying the increased risk of fragility fractures in a T2DM population are complex. Indeed, in T2DM, bone health is negatively affected by several factors, such as inflammatory cytokines, muscle-derived hormones, incretins, hydrogen sulfide (H2S) production and cortisol secretion, peripheral activation, and sensitivity. All these factors may alter bone formation and resorption, collagen formation, and bone marrow adiposity, ultimately leading to reduced bone strength. Additional factors such as hypoglycemia and the consequent increased propensity for falls and the direct effects on bone and mineral metabolism of certain antidiabetic medications may contribute to the increased fracture risk in this population. The purpose of this review is to summarize the literature evidence that faces the pathophysiological mechanisms underlying bone fragility in T2DM patients

Bone fragility in gastrointestinal disorders

Osteoporosis is a common systemic disease of the skeleton, characterized by compromised bone mass and strength, consequently leading to an increased risk of fragility fractures. In women, the disease mainly occurs due to the menopausal fall in estrogen levels, leading to an imbalance between bone resorption and bone formation and, consequently, to bone loss and bone fragility. Moreover, osteoporosis may affect men and may occur as a sequela to different diseases or even to their treatments. Despite their wide prevalence in the general population, the skeletal implications of many gastrointestinal diseases have been poorly investigated and their potential contribution to bone fragility is often underestimated in clinical practice. However, proper functioning of the gastrointestinal system appears essential for the skeleton, allowing correct absorption of calcium, vitamins, or other nutrients relevant to bone, preserving the gastrointestinal barrier function, and maintaining an optimal endocrine-metabolic balance, so that it is very likely that most chronic diseases of the gastrointestinal tract, and even gastrointestinal dysbiosis, may have profound implications for bone health. In this manuscript, we provide an updated and critical revision of the role of major gastrointestinal disorders in the pathogenesis of osteoporosis and fragility fractures. © 2022 by the authors. Licensee MDPI, Basel, Switzerland

Vitamin D Status and SARS-CoV-2 Infection and COVID-19 Clinical Outcomes

Background: Several studies suggest an association between serum 25-hydroxyvitamin D (25OHD) and the outcomes of Severe Acute Respiratory Syndrome Corona-Virus-2 (SARS-CoV-2) infection, in particular Coronavirus Disease-2019 (COVID-19) related severity and mortality. The aim of the present meta-analysis was to investigate whether vitamin D status is associated with the COVID-19 severity, defined as ARDS requiring admission to intensive care unit (ICU) or mortality (primary endpoints) and with the susceptibility to SARS-CoV-2 and COVID-19-related hospitalization (secondary endpoints). Methods: A search in PubMed, ScienceDirect, Web of Science, Google Scholar, Scopus, and preprints repositories was performed until March 31th 2021 to identify all original observational studies reporting association measures, or enough data to calculate them, between Vitamin D status (insufficiency <75, deficiency <50, or severe deficiency <25 nmol/L) and risk of SARS-CoV-2 infection, COVID-19 hospitalization, ICU admission, or death during COVID-19 hospitalization. Findings: Fifty-four studies (49 as fully-printed and 5 as pre-print publications) were included for a total of 1,403,715 individuals. The association between vitamin D status and SARS-CoV2 infection, COVID-19 related hospitalization, COVID-19 related ICU admission, and COVID-19 related mortality was reported in 17, 9, 27, and 35 studies, respectively. Severe deficiency, deficiency and insufficiency of vitamin D were all associated with ICU admission (odds ratio [OR], 95% confidence intervals [95%CIs]: 2.63, 1.45–4.77; 2.16, 1.43–3.26; 2.83, 1.74–4.61, respectively), mortality (OR, 95%CIs: 2.60, 1.93–3.49; 1.84, 1.26–2.69; 4.15, 1.76–9.77, respectively), SARS-CoV-2 infection (OR, 95%CIs: 1.68, 1.32–2.13; 1.83, 1.43–2.33; 1.49, 1.16–1.91, respectively) and COVID-19 hospitalization (OR, 95%CIs 2.51, 1.63–3.85; 2.38, 1.56–3.63; 1.82, 1.43–2.33). Considering specific subgroups (i.e., Caucasian patients, high quality studies, and studies reporting adjusted association estimates) the results of primary endpoints did not change. Interpretations: Patients with low vitamin D levels present an increased risk of ARDS requiring admission to intensive care unit (ICU) or mortality due to SARS-CoV-2 infection and a higher susceptibility to SARS-CoV-2 infection and related hospitalization

Future directions for the management of pain in osteoarthritis.

Osteoarthritis (OA) is the predominant form of arthritis worldwide, resulting in a high degree of functional impairment and reduced quality of life owing to chronic pain. To date, there are no treatments that are known to modify disease progression of OA in the long term. Current treatments are largely based on the modulation of pain, including NSAIDs, opiates and, more recently, centrally acting pharmacotherapies to avert pain. This review will focus on the rationale for new avenues in pain modulation, including inhibition with anti-NGF antibodies and centrally acting analgesics. The authors also consider the potential for structure modification in cartilage/bone using growth factors and stem cell therapies. The possible mismatch between structural change and pain perception will also be discussed, introducing recent techniques that may assist in improved patient phenotyping of pain subsets in OA. Such developments could help further stratify subgroups and treatments for people with OA in future

Validation of the clinical consensus recommendations on the management of fracture risk in postmenopausal women with type 2 diabetes

Background and aims: Bone fragility is recognized as a complication of type 2 diabetes (T2D). However, the fracture risk in T2D is underestimated using the classical assessment tools. An expert panel suggested the diagnostic approaches for the detection of T2D patients worthy of bone-active treatment. The aim of the study was to apply these algorithms to a cohort of T2D women to validate them in clinical practice. Methods and results: The presence of T2D-specific fracture risk factors (T2D ≥ 10 years, ≥1 T2D complications, insulin or thiazolidinedione use, poor glycaemic control) was assessed at baseline in 107 postmenopausal T2D women. In all patients at baseline and in 34 patients after a median follow-up of 60.2 months we retrospectively evaluated bone mineral density and clinical and morphometric vertebral fractures. No patient was treated with bone-active drug. Following the protocols, 34 (31.8%) and 73 (68.2%) patients would have been pharmacologically and conservatively treated, respectively. Among 49 patients without both clinical fractures and major T2D-related risk factors, who would have been, therefore, conservatively followed-up without vertebral fracture assessment, only one showed a prevalent vertebral fracture (sensitivity 90%, negative predictive value 98%). The two patients who experienced an incident fracture would have been pharmacologically treated at baseline. Conclusions: The clinical consensus recommendations showed a very good sensitivity in identifying T2D postmenopausal women at high fracture risk. Among those with treatment indication as many as 13% of patients experienced an incident fracture, and, conversely, among those without treatment indication no incident fractures were observed