Is there an association of bone mineral density and risk of breast cancer in postmenopausal Saudi women?

Several studies revealed an association between high bone mineral density (BMD) and the increased risk for developing breast cancer (BC). Aim: Explore if there is an association between BMD and BC risk in postmenopausal Saudi (PMS) women. Material and Method: In a retrospective cohort study of 1145 PMS women age range from 46 – 85 year (mean = 55 year). The average time period of menopause 4 years.We reviewed BMD of all patients performed between October 2012 and November 2018. All patients had BMD measurements of lumbar spine L2-L4 and right femoral neck in gm/cm². Results: The T-score was used for analysis of the results. Among the total patient studied 195 (17%) were found to have BC group 1 (G1) while 950 (93%) without BC group 2(G2). Analysis of lumbar spine T-score in G1 showed that: 29 % had osteoporosis, 37% osteopenia and 34% had normal BMD and in G2 40% had osteoporosis, 31% osteopenia and 29 had normal values. Results showed prevalence of osteoporosis in G1 was significantly lower than in G2 (p =0.002) while there was no significant difference between the two groups with osteopenia and normal BMD results (p = 0.06 and 0.205 respectively). Conclusion: PMS women with BC had higher BMD at time of diagnosis compared to their counterpart without BC.

A novel computational strategy for DNA methylation imputation using mixture regression model (MRM)

Background DNA methylation is an important heritable epigenetic mark that plays a crucial role in transcriptional regulation and the pathogenesis of various human disorders. The commonly used DNA methylation measurement approaches, e.g., Illumina Infinium HumanMethylation-27 and -450 BeadChip arrays (27 K and 450 K arrays) and reduced representation bisulfite sequencing (RRBS), only cover a small proportion of the total CpG sites in the human genome, which considerably limited the scope of the DNA methylation analysis in those studies. Results We proposed a new computational strategy to impute the methylation value at the unmeasured CpG sites using the mixture of regression model (MRM) of radial basis functions, integrating information of neighboring CpGs and the similarities in local methylation patterns across subjects and across multiple genomic regions. Our method achieved a better imputation accuracy over a set of competing methods on both simulated and empirical data, particularly when the missing rate is high. By applying MRM to an RRBS dataset from subjects with low versus high bone mineral density (BMD), we recovered methylation values of ~ 300 K CpGs in the promoter regions of chromosome 17 and identified some novel differentially methylated CpGs that are significantly associated with BMD. Conclusions Our method is well applicable to the numerous methylation studies. By expanding the coverage of the methylation dataset to unmeasured sites, it can significantly enhance the discovery of novel differential methylation signals and thus reveal the mechanisms underlying various human disorders/traits.

FRI0540 DIFFERENT ASSOCIATION BETWEEN BONE MINERAL DENSITY AND OSTEOARTHRITIS ACCORDING TO THE SITE OF OSTEOARTHRITIS

Background:Osteoarthritis (OA) and osteoporosis (OP) are both high prevalence at old age, and there are various reports on the association between the two diseases. Some studies have shown that high bone mineral density (BMD) is a risk factor for OA incidence, while others have mentioned the possibility of OP contributing to onset of hip OA. Recent study described that higher BMD reduce the risk of hip OA and raise the risk of knee OA. So, the relationship between BMD and OA or the effects of BMD on different OA site are not clear yet.Objectives:In this study, we investigated the association between BMD and radiographic OA using representative sample data of Korean adults.Methods:The study included 6345 subjects aged 50 years or older who underwent BMD measurements using dual-energy X-ray absorptiometry and X-rays of at least one site of the spine, hip, and knee in the Korean National Health and Nutrition Examination Survey conducted in 2010-2011. OA was defined according to radiographic finding (KL grade ≥ 2). Weighted multivariable logistic regression was used to analyze the association between BMD and OA. Since gender differences are evident, men and women were analyzed separately.Results:Spine OA was about 60% in both men and women, and hip OA was about 35% in men but only 1% in women. Knee OA was 76% in women and 58% in men. In men, the risk of OA increased 1.24 times as BMD increased by 1 g/cm2. By site, knee and spine OA were statistically significant in relation to BMD, but hip OA was not statistically significant. In women, the association between BMD and knee and hip OA was insignificant. In spine OA, the risk of OA increased 1.2 times when BMD increased by 1 g/cm2.Conclusion:In conclusion, high BMD increased the risk of knee and spine OA in men, but did not affect hip OA. In women, high BMD increased the risk of spine OA. Differences in the mechanism of OA development by site are thought to be possible explanations for the differences in the association between BMD and OA.Disclosure of Interests:None declared

P1446DIFFUSE IDIOPATHIC SKELETAL HYPEROSTOSIS IN PATIENTS UNDERGOING MAINTENANCE HEMODIALYSIS

Background and Aims Diffuse idiopathic skeletal hyperostosis (DISH) is an idiopathic degenerative disease characterized by ossification of spinal ligaments and entheses, especially in the anterior longitudinal ligament. The ankylosed spine is prone to fracture with minor trauma and may result in spinal cord injury. It is usually asymptomatic and often diagnosed incidentally by computed tomography or other imaging methods. Several reports have revealed DISH as a risk factor for stroke, cardiovascular disease, and metabolic disorders, such as diabetes mellitus, hyperinsulinemia, obesity, dyslipidemia, and hyperuricemia. However, there are few reports of DISH in patients with end stage kidney disease (ESKD) requiring hemodialysis. Epidemiology, etiology and risk factors of DISH in patients with ESKD are unknown. We aimed to examine the prevalence and predictors of DISH in maintenance hemodialysis patients. Method This was a case-control study using patients who received maintenance hemodialysis in our hospital in December 2018. The prevalence of DISH at enrollment was evaluated according to Resnick and Niwayama criteria by computed tomography (CT). The criteria is defined as follows: (1) Flowing ossification along the anterolateral aspect of at least four contiguous vertebral bodies, (2) Relative preservation of intervertebral disc height in the involved segment, (3) Absence of apophyseal joint bony ankylosis and sacroiliac joint erosion. We excluded patients who could not receive chest CT or with a history of thoracic spine surgery. Fisher exact tests were used to evaluate the relationships between categorical variables, and Kruskal-Wallis or Mann-Whitney U tests were used to evaluate continuous variables. We performed logistic regression analyses to identify variables that had a statistically significant association with DISH, as measured by the estimated odds ratio (OR) with the 95% confidence interval (CI). Results A total of 395 consecutive patients were treated with maintenance hemodialysis in our hospital in December 2018. After excluding 4 patients who could not receive chest CT and 2 patients with a history of thoracic spine surgery, the remaining 389 patients were analyzed. The median age was 70 years, and 61.2% of patients were men. One hundred and twenty-three (31.6%) patients were diagnosed with DISH. We assigned them to the DISH group and other 266 patients to the control group. The patients with DISH were significantly more likely to have advanced age, male sex, high body weight, high bone mineral density, prior vertebral fracture, and diabetic nephropathy. Multivariate analysis showed that having DISH was significantly associated with advanced age (OR 1.06, 95%CI 1.03-1.09, P<0.001), high bone mineral density (OR1.02, 95%CI 1.00-1.03, P=0.03), prior vertebral fracture (OR3.22, 95%CI 1.23-8.41, P=0.017), diabetic nephropathy (OR 2.00, 1.03-3.90, P=0.041). Conclusion The prevalence of DISH in maintenance hemodialysis patients was high. Advanced age, male sex, high body weight, high bone mineral density, prior vertebral fracture, and diabetic nephropathy were identified as a risk factor for DISH. Physicians involved in hemodialysis treatment should be aware of the existence of DISH as one of the comorbidities in the elderly ESKD patients.

Coumarin Boosts Optimal Bone Remodeling Through Blocking AGE-RAGE Interaction in Diabetic Osteoblasts and Osteoclasts

Objectives Accumulating evidence has shown that the risk of osteoporotic fractures is increased in patients with diabetes mellitus despite normal or high bone mineral density. Thus, diabetes-induced bone fragility has been recently recognized as a diabetic complication. Because the fracture risk is independent of the reduction in bone mineral density, deterioration of the bone quality may be the main cause of bone fragility. Coumarin is naturally found in many plants as phenylpropanoids and present in tonka beans at notably high concentrations. The purpose of this study was to identify that hyperglycemia-mediated advanced glycation end-product (AGE) resulted in impaired bone remodeling and to examine whether coumarin was capable of preventing diabetic osteoporosis through boosting bone remodeling. Methods The in vitro study employed osteoblastic MC3T3-E1 cells that were exposed to 33 mM glucose for 6 days in the presence of 1–20 μM coumarin. Alkaline phosphatase (ALP) activity was quantitatively determined in osteoblastic cells by using stable p-nitrophenyl phosphate. In addition, murine macrophage Raw 264.7 cells were differentiated to multi-nucleated osteoclasts with receptor activator of nuclear factor-κΒ ligand (RANKL) in 33 mM glucose and 1–20 μM coumarin for 5 days. Results High glucose attenuated the ALP activity of osteoblastic cells, which was enhanced by treating 1–20 μM coumarin to cells. On the other hand, 33 mM glucose diminished TRAP and bone resorption activity in RANKL-differentiated osteoclasts, indicating that osteoclast activation was impaired under diabetic conditions. On the contrary, coumarin elevated osteoclastic differentiation and activation. In addition, coumarin ameliorated aberrant bone remodeling in osteoblasts and osteoclasts evoked by AGE. Together, coumarin improved bone remodeling impaired in diabetic osteoblasts and osteoclasts though suppressing interaction of AGE and its receptor. Conclusions These findings suggest the possibility that coumarin might be a potential agent for the treatment of diabetic osteoporosis. Funding Sources This work was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (MSIT) (2019R1A2C1003218).

Osteopetrorickets Presenting with Failure to Thrive and Hypophosphatemia

Osteopetrosis is a rare group of bone disorders characterized by defective osteoclast bone resorption causing high bone mineral density. A high bone mineral density in combination with defective skeletal mineralization results in a phenotype of osteopetrorickets. We present a rare presentation of infantile osteopetrorickets in an 8-week-old female who presented with failure to thrive, hypophosphatemia, anemia, and thrombocytopenia. A skeletal survey showed increased bone density with rachitic changes. She was found to have a homozygous T-cell immune regulator 1 (TCIRG1) pathogenic mutation consistent with osteopetrosis. This highlights the importance of a clinical suspicion of osteopetrosis with this symptom constellation.