Altered Bone Mineral Research Articles

Impact of Different Anti-Hyperglycaemic Treatments on Bone Turnover Markers and Bone Mineral Density in Type 2 Diabetes Mellitus Patients: A Systematic Review and Meta-Analysis.

Diabetic bone disease (DBD) is a frequent complication in patients with type 2 diabetes mellitus (T2DM), characterised by altered bone mineral density (BMD) and bone turnover marker (BTMs) levels. The impact of different anti-diabetic medications on the skeleton remains unclear, and studies have reported conflicting results; thus, the need for a comprehensive systematic review is of paramount importance. A systematic search was conducted in PubMed and the Cochrane Library. The primary outcomes assessed were changes in BMD in relation to different anatomical sites and BTMs, including mainly P1NP and CTX as well as OPG, OCN, B-ALP and RANK-L. Risk of bias was evaluated using the JADAD score. The meta-analysis of 19 randomised controlled trials comprising 4914 patients showed that anti-diabetic medications overall increased BMD at the lumbar spine (SMD: 0.93, 95% CI [0.13, 1.73], p = 0.02), femoral neck (SMD: 1.10, 95% CI [0.47, 1.74], p = 0.0007) and in total hip (SMD: 0.33, 95% CI [-0.25, 0.92], p = 0.27) in comparison with placebo, but when compared with metformin, the overall effect favoured metformin over other treatments (SMD: -0.23, 95% CI [-0.39, -0.07], p = 0.004). GLP-1 receptor agonists and insulin analogues seem to improve BMD compared to placebo, while SGLT2 inhibitors and thiazolidinediones (TZDs) showed no significant effect, although studies' number cannot lead to safe conclusions. For BTMs, TZDs significantly increased P1NP levels compared to placebo. However, no significant differences were observed for CTX, B-ALP, OCN, OPG, and RANK-L between anti-diabetic drugs and metformin or placebo. High heterogeneity and diverse follow-up durations among studies were evident, which obscures the validity of the results. This review highlights the variable effects of anti-diabetic drugs on DBD in T2DM patients, emphasising the need for long-term trials with robust designs to better understand these relationships and inform clinical decisions.

Do Clinical Parameters Reflect Local Bone Metabolism in Heterotopic Ossification After Septic or Aseptic THA?

Do Clinical Parameters Reflect Local Bone Metabolism in Heterotopic Ossification After Septic or Aseptic THA?

The choice of region of interest after spinal procedures alters bone mineral density measurements.

Vertebrae affected by artifacts, such as metallic implants or bone cement, should be excluded when measuring the spine bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). Exclusion may be performed using two methods: first, the affected vertebrae are included in the region of interest (ROI) and subsequently excluded from the analysis; second, the affected vertebrae are completely excluded from the ROI. This study aimed to investigate the influence of metallic implants and bone cement on BMD with and without the inclusion of artifact-affected vertebrae in the ROI. DXA images of 285 patients, including 144 with spinal metallic implants and 141 who had undergone spinal vertebroplasty from 2018 to 2021, were retrospectively reviewed. Spine BMD measurements were performed when the images were evaluated using two different ROIs for each patient during the same examination. In the first measurement, the affected vertebrae were included in the ROI; however, the affected vertebrae were excluded from the BMD analysis. In the second measurement, the affected vertebrae were excluded from the ROI. Differences between the two measurements were evaluated using a paired t-test. Among 285 patients (average age, 73 years; 218 women), spinal metallic implants led to an overestimation of bone mass in 40 of 144 patients, whereas bone cement resulted in an underestimation of bone mass in 30 of 141 patients when the first measurement was compared with the second measurement. The opposite effect occurred in 5 and 7 patients, respectively. Differences in results between the inclusion and exclusion of the affected vertebrae in the ROI were statistically significant (p<0.001). Spinal implants or cemented vertebrae included in the ROI might significantly alter BMD measurements. Additionally, different materials were associated with varying modifications in BMD. The inclusion of affected vertebrae in the ROI may notably alter BMD measurements, even when they are excluded from the analysis. This study suggests that the vertebrae affected by spinal metallic implants or bone cement should be excluded from the ROI.

Asia-Pacific Consensus Recommendations on X-Linked Hypophosphatemia: Diagnosis, Multidisciplinary Management, and Transition From Pediatric to Adult Care.

X-linked hypophosphatemia (XLH) is a rare, inherited, multisystem disorder characterized by hypophosphatemia that occurs secondary to renal phosphate wasting. Mutations in PHEX gene (located at Xp22.1) in XLH alter bone mineral metabolism, resulting in diverse skeletal, dental, and other extraskeletal abnormalities that become evident in early childhood and persist into adolescence and adult life. XLH impacts physical function, mobility, and quality of life, and is associated with substantial socioeconomic burden and health care resource utilization. As the burden of illness varies with age, an appropriate transition of care from childhood and adolescence to adulthood is necessary to meet growth-related changes and minimize long-term sequelae of the condition. Previous XLH guidelines that encompassed transition of care have focused on Western experience. Regional differences in resource availability warrant tailoring of recommendations to the Asia-Pacific (APAC) context. Hence, a core expert panel of 15 pediatric and adult endocrinologists from nine countries/regions across APAC convened to formulate evidence-based recommendations for optimizing XLH care. A comprehensive literature search on PubMed using MeSH and free-text terms relevant to predetermined clinical questions on diagnosis, multidisciplinary management, and transition of care of XLH revealed 2171 abstracts. The abstracts were reviewed independently by two authors to shortlist a final of 164 articles. A total of 92 full-text articles were finally selected for data extraction and drafting the consensus statements. Sixteen guiding statements were developed based on review of evidence and real-world clinical experience. The GRADE criteria were used to appraise the quality of evidence supporting the statements. Subsequently, a Delphi technique was utilized to rate the agreement on statements; 38 XLH experts (15 core, 20 additional, 3 international) from 15 countries/regions (12 APAC, 3 EU) participated in the Delphi voting to further refine the statements. Statements 1-3 cover the screening and diagnosis of pediatric and adult XLH; we have defined the clinical, imaging, biochemical, and genetic criteria and raised red flags for the presumptive and confirmatory diagnosis of XLH. Statements 4-12 tackle elements of multidisciplinary management in XLH such as therapeutic goals and options, composition of the multidisciplinary team, follow-up assessments, required monitoring schedules, and the role of telemedicine. Treatment with active vitamin D, oral phosphate, and burosumab is discussed in terms of applicability to APAC settings. We also expound on multidisciplinary care for different age groups (children, adolescents, adults) and pregnant or lactating women. Statements 13-15 address facets of the transition from pediatric to adult care: targets and timelines, roles and responsibilities of stakeholders, and process flow. We explain the use of validated questionnaires, desirable characteristics of a transition care clinic, and important components of a transfer letter. Lastly, strategies to improve XLH education to the medical community are also elaborated in statement 16. Overall, optimized care for XLH patients requires prompt diagnosis, timely multidisciplinary care, and a seamless transfer of care through the coordinated effort of pediatric and adult health care providers, nurse practitioners, parents or caregivers, and patients. To achieve this end, we provide specific guidance for clinical practice in APAC settings. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Craniosynostosis in Patients With X-Linked Hypophosphatemia: A Review.

Craniosynostosis is a rare condition of skull development, manifesting during fetal and early infant development, and is usually congenital. Craniosynostosis secondary to metabolic disorders, such as X-linked hypophosphatemia (XLH), is less common and is typically diagnosed later than congenital craniosynostosis. XLH is a rare, progressive, and lifelong hereditary phosphate-wasting disorder characterized by loss of function of the phosphate-regulating endopeptidase homologue, X-linked gene, which is associated with premature fusion of cranial sutures due to abnormal phosphate metabolism (hypophosphatemia) and altered bone mineralization or elevated levels of fibroblast growth factor 23. This targeted literature review of 38 articles seeks to provide an overview of craniosynostosis in individuals with XLH. The objectives of this review are to increase awareness of the prevalence, presentation, and diagnosis of craniosynostosis in XLH; examine the spectrum of craniosynostosis severity in XLH; discuss the management of craniosynostosis in those with XLH; recognize the complications for patients with XLH; and identify what is known about the burden of craniosynostosis for individuals with XLH. The presentation of craniosynostosis in individuals with XLH tends to manifest slightly later than congenital craniosynostosis and can vary in severity and appearance, making diagnosis difficult and resulting in inconsistent clinical outcomes. Consequently, craniosynostosis in patients with XLH is an underreported and potentially underrecognized condition. There have been no studies investigating the effects of craniosynostosis on the quality of life of people with XLH. Despite a growing awareness among researchers and experienced clinicians, there are still improvements to be made in general awareness and timely diagnosis of craniosynostosis in XLH. The XLH community would benefit from further study into the prevalence of craniosynostosis, the effect of XLH medical therapy on the development of craniosynostosis, and the effects of craniosynostosis on quality of life. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Prevalence of anticonvulsant-induced vitamin D deficiency

Background. Epilepsy is a common disease in children and adults, requiring long-term or lifelong use of antiepileptic drugs (AEDs) in 60% of cases. Enzyme-inducing and enzyme-inhibiting AEDs may have a negative effect on vitamin D metabolism. However, at present, standard treatment protocols for patients with epilepsy include no nutrients and vitamin-mineral vitamin D containing complexes.Objective: to analyze studies on the prevalence of vitamin D deficiency induced by AEDs intake in patients with epilepsy.Material and methods. The search for full-text publications in Russian and English was carried out in еLibrary, PubMed/ MEDLINE, ClinicalKey, Google Scholar databases, covering the last five years. The analysis included 9 domestic and 54 foreign epidemiological studies assessing prevalence of AED-induced vitamin D deficiency and, consequently, altered bone mineralization and osteomalacia/osteoporosis.Results. Both in children and adults, the prevalence of AED-induced vitamin D deficiency reaches 40% and even higher. The region of residence of patients with epilepsy does not significantly affect this indicator. Impaired bone mineralization is associated with AED-induced vitamin D deficiency and requires the inclusion of vitamin D in the protocols of disease-modifying epilepsy therapy in children and adults.Conclusion. The results of the review showed high relevance of the discussed interdisciplinary problem and need to introduce laboratory screening of vitamin D deficiency among pediatric and adult patients with epilepsy.

Distribution of Bone Mineral Density in the Ankle Joint: Correlation with Hindfoot Alignment

Category: Ankle; Basic Sciences/Biologics; Hindfoot Introduction/Purpose: Abnormal Hindfoot Alignment (HA) has been correlated with increased complication rates in ankle fusion or replacement. Altered Bone Mineral Density (BMD) due to abnormal stress distribution could be predisposing factor for those unwanted outcomes. The objective of this study was to assess spatial distribution of BMD around the ankle joint in patients with normal or abnormal HA using cone beam Weight Bearing CT. Methods: Retrospective comparative study including 81 ankles allocated into 3 groups based on the Foot Ankle Offset (FAO): 27 normal (0%5%). groups were comparable by age (p=0.967), Body Mass Idex (p=0.669), sex (p=0.820) and side (p=0.708). Semi- automatic segmentation (BoneLogic, Disior) was applied to identify bones. Tibia and talus were digitally compartmented in medial (M) and lateral (L) volumes relative to the median sagittal plane. Mean Hounsfield Unit (HU) value per compartment was used to assess BMD and to calculate the Medial over Lateral HU ratio (M/L-HU). Comparisons among the three groups were performed using one-way ANOVA, Kruskal-Wallis and Chi2 tests. Results: Mean +- standard deviation HU values in the compartments in normal cases were 495.2+-110 (medial tibia), 495.6+- 108.1 (lateral tibia), 368.9+-80.3 (medial talus), 448.2+-90.6 (lateral talus) and 686.7+-120.4 (fibula). Upon comparison of the mean BMD value for each compartment in the three groups, the difference did not achieve statistical significance. Conversely, the tibia HU-M/L ratio (0.88+-0.14 in valgus cases, 0.99 +- 0.08 in normally-aligned cases and 1.04+-0.08 in varus cases) and the talar HU- M/L ratio (0.68+-0.18 in valgus cases, 0.82+-0.08 in normally-aligned cases and 0.96+-0.20 in varus cases) were significantly different in the three groups (p&lt;0.001). Conclusion: We found that the BMD in distal tibia, fibula and the talus varies with hindfoot alignment. The increased HU medio- lateral ratio in varus cases was consistent with a greater medial bone density in the tibia and talus, while the decreased ratio found in valgus cases suggested a more lateral concentration in both bones. This data supports the role of WBCT in analyzing BMD distribution. This method could be clinically useful in ankle OA to evaluate bone quality for such considerations as surgical indications or implant positioning.

Bone Metabolism Alteration in Patients with Inflammatory Bowel Disease.

Background: Metabolic bone disease is a common disorder, but there is a lack of data on it in patients with inflammatory bowel disease (IBD). Methods: In this prospective, one-centre study, we assessed bone mineral and vitamin D alterations in 187 IBD patients (119 with Crohn’s disease (CD) and 68 with ulcerative colitis (UC)). Results: While 81.3% of the patients had vitamin D deficiency, 14.2% of them had a severe deficiency. Elevated serum PTH concentrations were found in 14.9% of the patients. Only in 4.1% of cases was there an elevated level of a serum marker for bone formation (osteocalcin), whereas in 14.4% of cases, the bone resorption marker (CTX) was raised. The concentration of phosphate in urine was higher in the CD than in the UC group (51.20 vs. 31.25; p = 0.003). PTH was negatively associated with vitamin D level. Among the patients receiving corticosteroids, the CTX and CRP median levels were higher (0.49 vs. 0.38; p = 0.013 and 6.45 vs. 2.2; p = 0.029, respectively) compared with the group who did not receive them. Urine phosphate levels were lower (48.60 vs. 26.00; p = 0.005), as were osteocalcin (15.50 vs. 23.80; p < 0.001), and PTH (29.05 vs. 36.05; p = 0.018). Conclusions: Bone mineral alterations were common in patients with IBD, mostly in the CD patients. This may be associated with poor absorption, making CD patients vulnerable to changes in bone mineralization. Vitamin D supplementation remains crucial, especially when taking corticosteroids.

Protective effect of Spirulina against bone fragility induced by Garcinia cambogia in high-fat diet induced obese rats

The present work evaluated the protective effects of Spirulina against the bone fragility caused by Garcinia cambogia in high-fat diet induced obese rats. High-fat diet and high-fat emulsion (HFD+HFE) were administered via oral gavage to 30 six-week-old female Sprague Dawley rats for six weeks to induce obesity, except for a normal group (n = 6). Following four weeks of treatment, the diet-induced obese groups were orally administered, daily, with (1) G. cambogia (GC); (2) Spirulina (S); and (3) G. cambogia + Spirulina (GC+S). The normal and obese control groups were treated with equal volumes of 0.9% saline water. It was found that GC significantly decreased body mass index (BMI) below the obese range (0.68 g/cm2). Additionally, GC altered bone mineral density (BMD), increased phosphate and calcium levels, and decreased maximum force and mineral apposition rates (MAR) as compared to the obese control group (p &lt; 0.05). Bone fragility caused by GC was confirmed by the decrease in bone formation marker osteocalcin (OCN), as well as an increase in bone resorption receptor activator of nuclear factor kappa-B ligand (RANKL) and tartrate-resistant acid phosphatase type 5b (TRAP5b) as compared to the obese control group. Spirulina also decreased the BMI of the obese rats. Spirulina also increased blood bone markers, BMD, maximum force, and Young’s modulus. Rats supplemented with GC+S demonstrated higher double-labelled surface (dLS/BS) and MAR as compared to those in the GC group (p &lt; 0.05). Meanwhile, the S group demonstrated improvement in all dynamic histomorphometric indices. S and GC+S groups demonstrated bone formation upregulation and bone resorption downregulation, thus indicating a bone protective effect of Spirulina. Overall, GC treatment led to bone fragility. GC+S treatment significantly augmented bone formation and mineralisation in obese rats as compared to the GC treatment alone. Rats in the S group demonstrated effective weight reduction while showing no destructive effects on the bone.

How Do Drugs Affect the Skeleton? Implications for Forensic Anthropology.

Simple SummaryForensic anthropologists analyze human remains to assist in the identification of the deceased, predominantly by assessing age-at-death, sex, stature, ancestry and any unique identifying features. Whilst methods have been established to create this biological profile of the skeleton, these may be influenced by a number of factors. This paper, for the first time, provides an overview from a reading of the clinical and pharmacological literature to explore whether the intake of drugs can affect the skeleton and whether these may have implications for forensic anthropology casework. In effect, drugs such as tobacco, heroin, and prescription medications can alter bone mineral density, can increase the risk of fractures, destroy bone and changes to the dentition. By considering how drugs can affect the skeleton, forensic anthropologists can be aware of this when attempting to identify the deceased.Forensic anthropologists rely on a number of parameters when analyzing human skeletal remains to assist in the identification of the deceased, predominantly age-at-death, sex, stature, ancestry or population affinity, and any unique identifying features. During the examination of human remains, it is important to be aware that the skeletal features considered when applying anthropological methods may be influenced and modified by a number of factors, and particular to this article, prescription drugs (including medical and non-medical use) and other commonly used drugs. In view of this, this paper aims to review the medical, clinical and pharmacological literature to enable an assessment of those drug groups that as side effects have the potential to have an adverse effect on the skeleton, and explore whether or not they can influence the estimation of age-at-death, sex and other indicators of the biological profile. Moreover, it may be that the observation of certain alterations or inconsistencies in the skeleton may relate to the use of drugs or medication, and this in turn may help narrow down the list of missing persons to which a set of human remains could belong. The information gathered from the clinical and medical literature has been extracted with a forensic anthropological perspective and provides an awareness on how several drugs, such as opioids, cocaine, corticosteroids, non-steroidal anti-inflammatory drugs, alcohol, tobacco and others have notable effects on bone. Through different mechanisms, drugs can alter bone mineral density, causing osteopenia, osteoporosis, increase the risk of fractures, osteonecrosis, and oral changes. Not much has been written on the influence of drugs on the skeleton from the forensic anthropological practitioner perspective; and this review, in spite of its limitations and the requirement of further research, aims to investigate the current knowledge of the possible effects of both prescription and recreational drugs on bones, contributing to providing a better awareness in forensic anthropological practice and assisting in the identification process of the deceased.

A survey on the incidence of common musculoskeletal side effects among the patients taking long-term anti-ulcerant therapies in Bangladesh

BackgroundProton pump inhibitors (PPIs) and H2 blockers are commonly prescribed medications to treat ulcers in the stomach and the upper part of the small intestine and prescribed for some other common gastrointestinal complications such as gastroesophageal reflux disease, esophagitis, irritable bowel syndrome, and dyspepsia. Previous studies claimed that, apart from other side effects, these anti-ulcerant therapies significantly altered bone mineral density by interfering with intestinal reabsorption of minerals and vitamin B12, and the most widely prescribed PPIs were significantly associated with increased risks of hip and spine fractures. However, the potential skeletal side effects of these antiulcerants are unknown in Bangladesh. MethodsTo examine safety concerns of anti-ulcer therapies and their impact on musculoskeletal health among patients in Bangladesh, the present work surveyed 200 patients in five different hospitals from December 2019 to February 2020. ResultsThe current study revealed that most respondents (95 %) received PPIs for gastrointestinal indications while the rest were taking H2 receptor antagonists for their gastric ailments. Most patients taking PPIs alone (> 3 years; 95 % of respondents) claimed some unusual musculoskeletal side effects, such as weakness, flank pain, spasm of hands and feet, muscle aches, numbness, and tremor. About 61 % of patients taking PPIs experienced low back pain whereas the respondents with neck pain and knee joint pain were 10 % and 7 %, respectively. However, few osteopenia and osteoporotic incidences have been also recorded. Although further studies are required to confirm the impact of these antiulcerants on the bone, these patient responses suggest that these musculoskeletal side effects might have some links with altered bone metabolism. ConclusionsIt is possible that anti-ulcerant therapies may worsen the bone metabolism of patients suffering from osteoporosis or other bone disorders, and awareness and precautions should be raised among the patients and clinicians for the careful administration of PPIs to patients suffering from bone disorders.

New Generation of Meso and Antiprogestins (SPRMs) into the Osteoporosis Approach.

Receptor activator of nuclear factor κB (RANK) and its ligand (RANKL) play key roles in bone metabolism and the immune system. The RANK/RANKL complex has also been shown to be critical in the formation of mammary epithelia cells. The female hormones estradiol and progesterone closely control the action of RANKL with RANK. Blood concentration of these sex hormones in the postmenopausal period leads to an increase in RANK/RANKL signaling and are a major cause of women’s osteoporosis, characterized by altered bone mineralization. Knowledge of the biochemical relationships between hormones and RANK/RANKL signaling provides the opportunity to design novel therapeutic agents to inhibit bone loss, based on the anti-RANKL treatment and inhibition of its interaction with the RANK receptor. The new generation of both anti- and mesoprogestins that inhibit the NF-κB-cyclin D1 axis and blocks the binding of RANKL to RANK can be considered as a potential source of new RANK receptor ligands with anti-RANKL function, which may provide a new perspective into osteoporosis treatment itself as well as limit the osteoporosis rise during breast cancer metastasis to the bone.

Mechano-chemical regulation of bat wing bones for flight

Distal phalanges in bat wings have been hypothesized to be cartilaginous to allow for flight. We provide new evidence on how bat wing development might facilitate flight though protein-based regulation of bone mineralization and lead to more deflection at phalanx than humerus. Between Pteropus poliocephalus and Pteropus hypomelanus, two large bat species, we detected 112 proteins including 11 associated with mineralization and analyzed their distribution between the wing bones. Here, in contrast to previous reports, we found no cartilage-specific proteins and demonstrate that distal phalanges in bat wings are in fact low density bone that contain collagen I (the main constituent of bone's organic matrix) and proteins associated with mineralization in bone such as osteomodulin, bone-specific protein osteocalcin. The functional relevance of these changes was explored by measuring changes in mineral (crystal sizes, packing and density), material (Young's modulus and hardness) and structural characteristics. Consistent with changes in proteins associated with mineralization, mineral crystal thickness and alignment decreased from humerus to phalanges, and the mineral platelets were less densely packed along the wing length. Crystal thickness was negatively correlated with proteins associated with inhibition of mineralization as well as with two types of small leucine-rich proteoglycans, indicating the mineral growth and maturity is down regulated by these proteins independent of mineral quantity. The Young's modulus decreased across the wing and was significantly correlated with bone mineral density. Thus, the results from two bat species, studied here, demonstrate progressive alterations in bone mineralization occur in concert with the changes in secretion of bone regulatory proteins along the wing length. This altered mineralization together with structural changes serve to lighten the limb bone and optimize biomechanical properties conducive to flight.

Bone mineral density and long-term progression of aortic valve and mitral annular calcification: The Multi-Ethnic Study of Atherosclerosis

Background and aimsBone and mineral metabolism has been implicated in the pathophysiology of cardiac valve calcification. Whether bone demineralization, a common aging-related disorder, promotes calcific valve disease remains uncertain. We tested the hypothesis that low bone mineral density (BMD) is associated with greater incidence/progression of cardiac valve calcification in the Multi-Ethnic Study of Atherosclerosis. MethodsUsing linear mixed-effects models, we related baseline measurement of BMD of the thoracic vertebrae by computed tomography (CT) in 6768 participants to serial CT assessments of aortic valve calcification (AVC) and mitral annular calcification (MAC) obtained over a >10-year period. ResultsAfter multivariable adjustment, lower BMD (per SD decrement) was associated with accelerated increase in AVC over time in women (0.76 [95% CI 0.42,1.09] Agatston -units [AU]/year) and men (1.41 [95% CI 0.48,2.33] AU/year), as well as for MAC in women (3.22 [95% CI 1.16,5.28] AU/year) and men (3.59 [95% CI 2.09,5.09] AU/year). Significant effect modification was observed, with more pronounced BMD-related acceleration of AVC and MAC progression in older or white participants of one or both sexes, as well as by estimated glomerular filtration rate, though the latter differed by sex for AVC and MAC. ConclusionsIn this multi-ethnic cohort, low thoracic BMD was significantly, but modestly, associated with increased AVC and MAC progression. This suggests that altered bone mineral metabolism does not have a major impact on calcific valve disease in the general population, but the possibility of a more meaningful influence in higher-risk individuals with osteoporosis will require further investigation.

Bone toxicity induced by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and the retinoid system: A causality analysis anchored in osteoblast gene expression and mouse data

Dioxin exposures impact on bone quality and osteoblast differentiation, as well as retinoic acid metabolism and signaling. In this study we analyzed associations between increased circulating retinol concentrations and altered bone mineral density in a mouse model following oral exposure to 2,3,7,8-tetrachlordibenzo-p-dioxin (TCDD). Additionally, effects of TCDD on differentiation marker genes and genes involved with retinoic acid metabolism were analysed in an osteoblast cell model followed by benchmark dose-response analyses of the gene expression data. Study results show that the increased trabecular and decreased cortical bone mineral density in the mouse model following TCDD exposure are associated with increased circulating retinol concentrations. Also, TCDD disrupted the expression of genes involved in osteoblast differentiation and retinoic acid synthesis, degradation, and nuclear translocation in directions compatible with increasing cellular retinoic acid levels. Further evaluation of the obtained results in relation to previously published data by the use of mode-of-action and weight-of-evidence inspired analytical approaches strengthened the evidence that TCDD-induced bone and retinoid system changes are causally related and compatible with an endocrine disruption mode of action.

Home-Based Telehealth Exercise Intervention in Early-On Survivors of Childhood Acute Lymphoblastic Leukemia: Feasibility Study.

BackgroundAcute lymphoblastic leukemia is the most common type of pediatric cancer. Acute lymphoblastic leukemia causes an altered bone mineral homeostasis state, which can contribute to osteopenia, and bone fractures, most commonly vertebral fractures. With the increasing number of childhood cancer survivors, late adverse effects such as musculoskeletal comorbidities are often reported and are further influenced by inactive lifestyle habits. Physical activity has been shown to increase the mechanical workload of the bone, mitigating bone impairment in other cancer-specific populations.ObjectiveThis interventional pilot study aims to investigate the use of telehealth to deliver a home-based exercise intervention for early-on survivors of bone marrow–related hematological malignancies and to assess its impact on survivors’ musculoskeletal and functional health.MethodsWe aimed to recruit a group of 12 early-on survivors of acute lymphoblastic leukemia, within 6 months to 5 years of treatment, to participate in and complete the proposed telehealth intervention with a parent. The 16-week intervention included 40 potential home-based physical activity interventions supervised by a kinesiologist through a telehealth internet platform, with monthly progression. Patients were recruited to the cohort if they were able to participate in the intervention during the first month (minimum 12 weeks of intervention). Evaluation before and after the intervention protocol highlighted differences in functional capacities and musculoskeletal health of patients using mechanography, peripheral quantitative computed tomography, 6-minute walk test, and grip force test.ResultsThe recruitment rate for the intervention was low (12/57, 21% of contacted patients). Of 12 patients, 3 were excluded (1=relapse, 1=failure to meet technical requirements, and 1=abandoned). The 9 patients who completed the intervention (6 girls; mean age 10.93, SD 2.83 years; mean BMI 21.58, SD 6.55 kg/m2; mean time since treatment completion 36.67, SD 16.37 months) had a mean adherence of 89% and a completion rate of 75%. In addition, these patients showed functional improvements in lower limb muscle force and power as well as in the 6-minute walk test distance. Participants also showed improved bone health after the intervention on the following parameters: bone mineral content, stress-strain index, total and cortical cross-sectional area at the 14% site (P=.03, P=.01, P=.01, and P=.001, respectively) and 38% site of the tibia (P=.003, P=.04, P=.001, and P=.003, respectively).ConclusionsHigh adherence and participation rates suggest that telehealth is a feasible method to deliver exercise interventions to young early-on survivors of acute lymphoblastic leukemia. The proposed intervention seems promising in providing benefits to patients’ functional performance and bone health, but a large-scale study is needed to confirm this assumption.

Incidental Skeletal Findings on Sodium-fluoride Positron Emission Tomography: A Collection of Benign Tumors

Sodium-fluoride (NaF) positron emission tomography (PET) is a sensitive method to detect altered bone mineralization. Its increasing use in routine clinical practice for metastatic bone disease has also resulted in the detection or characterization of incidental benign bone lesions. A spectrum of NaF PET scan cases with benign bone tumors are presented in this article, including whole body PET bone scan and selected PET/computed tomography (CT), CT, or magnetic resonance imaging (MRI) of the region of interest. The reader will be able to improve their knowledge related to the clinical presentation of these entities, some are rare and recognize based on NaF PET and CT/MRI patterns by reviewing these cases.

Hip Geometry Variation in Homozygous Ectonucleotide Pyrophosphatase/ Phosphodiesterase 1 (ENPP1) Deficient Patients

ENPP1 is an important regulator of skeletal and soft tissue mineralization. Mouse models have demonstrated a link between defective ENPP1 and altered bone mineralization, including osteopenia and mild osteomalacia. In humans, rare homozygous loss of ENPP1 leads to generalized arterial calcification of infancy (GACI), characterized by vascular, joint, and organ calcification, hypophosphatemic rickets/osteomalacia, and skin and retinal findings. Heterozygous ENPP1 deficiency has been described in early-onset osteoporosis and an ENPP1 polymorphism was found to be strongly associated with variation in hip geometry, as measured by DXA hip structural analysis (HSA). However, the overall skeletal phenotype of ENPP1-deficiency is not well characterized in affected individuals. In addition to bone density, DXA provides surrogate information about mechanical strength, resistance to compression, tension, and buckling, offering a non-invasive and clinically accessible tool to assess hip geometry. Parameters include cross-sectional area (CSA), cross-sectional moment of inertia (CSMI), subperiosteal width (SPW), endocortical width (ECW), cortical thickness (CT), section modulus (Z), and buckling ratio (BR)—each measured in the narrow neck (NN), intertrochanteric (IT), and femoral shaft (FS) regions. SPW and ECW increase with age and are correlated with bone fragility. In mice, CSA and CSMI are inversely correlated with bone fragility when assessed by biomechanical tests. However, the opposite correlation has been observed in patients with fractures. HSA by DXA was assessed in 7 homozygous ENPP1-deficient patients (age range 5–56 years) and in 73 sex- and age-matched controls. All ENPP1-deficient patients were hypophosphatemic, of which, 2 were receiving treatment. Given the small sample size, standardized test statistics (t-scores) were derived for 21 hip geometry parameters; comparisons between groups were performed using the Mann-Whitney test. The Benjamini-Hochberg test was used to correct for multiple comparisons with a false discovery rate (FDR) q-value threshold set at 0.15. Compared with controls, ENPP1-deficient patients had significant changes in structural and derived measures of strength. Increases were seen in NN SPW, NN ECW, and FS SPW, which are correlated with bone fragility. In contrast, the increases seen in FS CSA, FS Z, FS CSMI, and NN CSMI are associated with improved bone strength. Although a q-value threshold of 0.15 indicates that 15% (~1/7) of all significant discoveries will represent a false positive, most findings represented true discoveries. These findings suggest that ENPP1 influences bone structure and strength, supporting findings from the aforementioned ENPP1 polymorphism study describing increased SPW in the NN and FS regions. This work contributes to the nascent body of literature studying the impact of ENPP1 on skeletal homeostasis.

A regulatory variant at 3q21.1 confers an increased pleiotropic risk for hyperglycemia and altered bone mineral density

SummarySkeletal and glycemic traits have shared etiology, but the underlying genetic factors remain largely unknown. To identify genetic loci that may have pleiotropic effects, we studied Genome-wide association studies (GWASs) for bone mineral density and glycemic traits and identified a bivariate risk locus at 3q21. Using sequence and epigenetic modeling, we prioritized an adenylate cyclase 5 (ADCY5) intronic causal variant, rs56371916. This SNP changes the binding affinity of SREBP1 and leads to differential ADCY5 gene expression, altering the chromatin landscape from poised to repressed. These alterations result in bone- and type 2 diabetes-relevant cell-autonomous changes in lipid metabolism in osteoblasts and adipocytes. We validated our findings by directly manipulating the regulator SREBP1, the target gene ADCY5, and the variant rs56371916, which together imply a novel link between fatty acid oxidation and osteoblast differentiation. Our work, by systematic functional dissection of pleiotropic GWAS loci, represents a framework to uncover biological mechanisms affecting pleiotropic traits.

Effect of the supplementation of olive leaves and olive cake on growth performance and bone mineralisation of broiler chickens

Effect of the supplementation of olive leaves and olive cake on growth performance and bone mineralisation of broiler chickens