Cause Of Osteoporosis Research Articles

Identification of a Novel Osteogenetic Oligodeoxynucleotide (osteoDN) That Promotes Osteoblast Differentiation in a TLR9-Independent Manner.

Dysfunction of bone-forming cells, osteoblasts, is one of the causes of osteoporosis. Accumulating evidence has indicated that oligodeoxynucleotides (ODNs) designed from genome sequences have the potential to regulate osteogenic cell fate. Such osteogenetic ODNs (osteoDNs) targeting and activating osteoblasts can be the candidates of nucleic acid drugs for osteoporosis. In this study, the ODN library derived from the Lacticaseibacillus rhamnosus GG genome was screened to determine its osteogenetic effect on murine osteoblast cell line MC3T3-E1. An 18-base ODN, iSN40, was identified to enhance alkaline phosphatase activity of osteoblasts within 48 h. iSN40 also induced the expression of osteogenic genes such as Msx2, osterix, collagen type 1α, osteopontin, and osteocalcin. Eventually, iSN40 facilitated calcium deposition on osteoblasts at the late stage of differentiation. Intriguingly, the CpG motif within iSN40 was not required for its osteogenetic activity, indicating that iSN40 functions in a TLR9-independent manner. These data demonstrate that iSN40 serves as a novel osteogenetic ODN (osteoDN) that promotes osteoblast differentiation. iSN40 provides a potential seed of the nucleic acid drug that activating osteoblasts for osteoporosis therapy.

Reversing the imbalance in bone homeostasis via sustained release of SIRT-1 agonist to promote bone healing under osteoporotic condition

The imbalance of bone homeostasis is the root cause of osteoporosis. However current therapeutic approaches mainly focus on either anabolic or catabolic pathways, which often fail to turn the imbalanced bone metabolism around. Herein we reported that a SIRT-1 agonist mediated molecular therapeutic strategy to reverse the imbalance in bone homeostasis by simultaneously regulating osteogenesis and osteoclastogenesis via locally sustained release of SRT2104 from mineral coated acellular matrix microparticles. Immobilization of SRT2104 on mineral coating (MAM/SRT) harnessing their electrostatic interactions resulted in sustained release of SIRT-1 agonist for over 30 days. MAM/SRT not only enhanced osteogenic differentiation and mineralization, but also attenuated the formation and function of excessive osteoclasts via integrating multiple vital upstream signals (β-catenin, FoxOs, Runx2, NFATc1, etc.) in vitro. Osteoporosis animal model also validated that it accelerated osteoporotic bone healing and improved osseointegration of the surrounding bone. Overall, our work proposes a promising strategy to treat osteoporotic bone defects by reversing the imbalance in bone homeostasis using designated small molecule drug delivery systems.

Abstract #1178966: A Rare Case of Idiopathic Osteoporosis with COL10A1 and COL27A1 Genetic Mutations in a Premenopausal Woman

The association between bone mineral density (BMD) and fracture differs in premenopausal women when compared to the postmenopausal women. Irrespective of the BMD, any fragility fracture in those aged 20-50 requires evaluation for secondary causes of osteoporosis. In the absence of secondary causes, idiopathic osteoporosis (IOP) is considered. We present a case of a premenopausal woman with IOP whose mutational analysis revealed variants in COL10A1 and COL27A1. These genetic mutations are found in Schmid-type metaphyseal chondrodysplasia (SMCD) and Steel syndrome, respectively. To our knowledge, this is the first case report establishing a linkage between these specific mutations and IOP. A 36-year-old Hispanic woman with a history of fragility fracture of the lumbar spine at age 23 was referred to Endocrinology for further evaluation. Dual-energy x-ray absorptiometry (DEXA) reported a Z-score of -3.0 in L1-L4, consistent with osteoporosis of the lumbar spine. A careful history, physical examination, and laboratory evaluation ruled out secondary causes of osteoporosis. In the interim, the patient presented a recurrent fragility fracture of the left proximal humerus requiring surgical intervention where bone marrow (BM) was obtained for cytology. BM cytology was found normocellular without increase in blasts or lymphocytes. Notably, the mutational analysis revealed heterozygous variants of uncertain significance (VUS) in COL10A1 [variant c682 c >T (p.Pro228Ser)] and COL27A1 [variant c.1814 c >T (p.Thr 6605 Met)]. Whole exome sequencing was not able to be performed due to insurance issues. The most common secondary causes of premenopausal bone loss include estrogen deficiency as seen in hypogonadism, drug exposure such as glucocorticoids, malabsorption disorders like celiac disease, hyperthyroidism, hypercalciuria, hyperparathyroidism, and disturbances in calcium and vitamin D metabolism. Osteoporosis with no known secondary causes is known as IOP. IOP is a disorder with multiple proposed mechanisms including impairment in growth hormone and insulin like growth factor axis, osteoblast dysfunction, and genetic mutations. Mutational analysis in selected IOP cases, have shown pathogenic variants and VUS in LRP5, LRP6, COL1A1, COL1A2, PLS3, WNT1, DKK1, FKBP10, HGD, SLC34A3. Our patient was found with heterozygous VUS in COL10A1 and COL27A1. These genetic mutations are found in (SMCD) and Steel syndrome, respectively. These rare osteochondrodysplasias, more commonly found in childhood, are associated with skeletal abnormalities including scoliosis, congenital hip dislocations, short stature, and characteristic facial features. More importantly, COL10A1 encodes the alpha 1 chain of collagen type X which is involved in growth plate function, and COL27A1 gene encodes a member of the fibrillar collagen family involved in the calcification of cartilage and the transition of cartilage to bone. To our knowledge, COL10A1 and COL27A1 mutations have not been yet associated as primary causes of IOP. We report this case aiming for further research to identify additional genetic etiologies of IOP.

Secondary Osteoporosis and Metabolic Bone Diseases.

Fragility fracture is a worldwide problem and a main cause of disability and impaired quality of life. It is primarily caused by osteoporosis, characterized by impaired bone quantity and or quality. Proper diagnosis of osteoporosis is essential for prevention of fragility fractures. Osteoporosis can be primary in postmenopausal women because of estrogen deficiency. Secondary forms of osteoporosis are not uncommon in both men and women. Most systemic illnesses and organ dysfunction can lead to osteoporosis. The kidney plays a crucial role in maintaining physiological bone homeostasis by controlling minerals, electrolytes, acid-base, vitamin D and parathyroid function. Chronic kidney disease with its uremic milieu disturbs this balance, leading to renal osteodystrophy. Diabetes mellitus represents the most common secondary cause of osteoporosis. Thyroid and parathyroid disorders can dysregulate the osteoblast/osteoclast functions. Gastrointestinal disorders, malnutrition and malabsorption can result in mineral and vitamin D deficiencies and bone loss. Patients with chronic liver disease have a higher risk of fracture due to hepatic osteodystrophy. Proinflammatory cytokines in infectious, autoimmune, and hematological disorders can stimulate osteoclastogenesis, leading to osteoporosis. Moreover, drug-induced osteoporosis is not uncommon. In this review, we focus on causes, pathogenesis, and management of secondary osteoporosis.

Yangonin treats inflammatory osteoporosis by inhibiting the secretion of inflammatory factors and RANKL expression.

As the main cause of osteoporosis, abnormal activity of osteoclasts could disrupt the balance between bone resorption and formation. Moreover, up-regulation of nuclear factor-kappa ligand (RANKL) expression by chronic inflammation-mediated inflammatory factors might contribute to the differentiation of osteoclast precursor cells. Therefore, an anti-inflammatory agent named yangonin was presented for inhibiting osteoclast and relieving inflammatory osteoporosis through down-regulating inflammatory factors. We established a model of macrophage inflammation and then verified the anti-inflammatory effect of yangonin. The inhibitory effect of yangonin on osteoclasts was detected by tartrate-resistant acid phosphatase (TRAP) staining, Western blotting and quantitative real-time PCR (qRT-PCR). Finally, micro-CT, TRAP and hematoxylin-eosin (HE) staining were used to show the effect of yangonin on inflammatory osteoporosis in vivo. Our results suggested that yangonin was able to reduce the secretion of inflammatory factors, down-regulate osteoclast-related genes such as TRAP, RANKL, cathepsin K (CTSK) and nuclear factor-activated T-cell 1 (NFATc1). Furthermore, it was demonstrated that yangonin could suppress the function of inflammatory cytokines in osteoclast differentiation and reporting, wherein NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways were involved. In an in vivo study, we implied that yangonin has a relieving effect on inflammatory osteoporosis. Our research shows that yangonin down-regulates inflammatory factors and inhibits the bone-breaking effect of inflammation through NF-κB, AKT and downstream c-Fos/NFATc1 signaling pathways to achieve the purpose of treating inflammatory osteoporosis.

Calcium released by osteoclastic resorption stimulates autocrine/paracrine activities in local osteogenic cells to promote coupled bone formation.

A major cause of osteoporosis is impaired coupled bone formation. Mechanistically, both osteoclast-derived and bone-derived growth factors have been previously implicated. Here, we hypothesize that the release of bone calcium during osteoclastic bone resorption is essential for coupled bone formation. Osteoclastic resorption increases interstitial fluid calcium locally from the normal 1.8 mM up to 5 mM. MC3T3-E1 osteoprogenitor cells, cultured in a 3.6 mM calcium medium, demonstrated that calcium signaling stimulated osteogenic cell proliferation, differentiation, and migration. Calcium channel knockdown studies implicated calcium channels, Cav1.2, store-operated calcium entry (SOCE), and calcium-sensing receptor (CaSR) in regulating bone cell anabolic activities. MC3T3-E1 cells cultured in a 3.6 mM calcium medium expressed increased gene expression of Wnt signaling and growth factors platelet-derived growth factor (PDGF), vascular endothelial growth factor (VEGF), and bone morphogenic protein-2 (BMP 2). Our coupling model of bone formation, the receptor activator of nuclear factor-κΒ ligand (RANKL)-treated mouse calvaria, confirmed the role of calcium signaling in coupled bone formation by exhibiting increased gene expression for osterix and osteocalcin. Critically, dual immunocytochemistry showed that RANKL treatment increased osterix-positive cells and increased fluorescence intensity of Cav1.2 and CaSR protein expression per osterix-positive cell. The above data established that calcium released by osteoclasts contributed to the regulation of coupled bone formation. CRISPR/Cas-9 knockout of Cav1.2 in osteoprogenitor cells cultured in basal calcium medium caused a >80% decrease in the expression of downstream osteogenic genes, emphasizing the large magnitude of the effect of calcium signaling. Thus, calcium signaling is a major regulator of coupled bone formation.

DXA FRAX® May Differ Significantly and Substantially To Web FRAX®

Osteoporosis and the associated fractures are a major global health burden for patients, their social network and societies. Access to quality risk assessment, diagnosis and treatment is heterogeneous and inadequate around the globe. Many algorithms have been developed for deciding who to test, assessing fracture risk, when to intervene, and how to monitor the effects of interventions. FRAX® has become the dominant fracture risk assessment tool worldwide which estimates the average 10 year risk of major osteoporotic fracture risk and hip fracture, and is recommended by our global partners: ISCD and IOF. A particular attraction of the FRAX® algorithm is that on-line calculations can be made with or without DXA testing, which is particularly attractive when access to DXA is limited or non-existent. In our centre public waiting times for non-urgent DXA are up to 10 years, so reducing unnecessary testing is a laudable and overarching service goal. A recent Japanese study comparing 4 FRAX calculation tools suggested little difference exists. However in our unit we have noticed at times very different results when using the Ireland embedded DXA-FRAX® tool to the Web-FRAX® Ireland tool. 1) To Compare DXA-FRAX® to Web-FRAX® 10-year estimates for MOF and HF. 2) To Compare Web-FRAX® 10-year estimates for MOF and HF with and without DXA-measured T-scores. We used a sub-group of the DXA-HIP Cohort as previously published to gain initial insights into DXA-FRAX® to Web-FRAX® as part of a larger calibration and validation project, which has been approved by our hospitals Ethics and Research Committee. All scans are performed and reported by staff trained to ISCD standards and recommendations. At the time of reporting DXA-FRAX® scores are calculated as part of the analysis as recommended by ISCD and IOF, and more recently Web-FRAX® for Ireland has been calculated and stored with and without BMD data. All data are cleaned, merged, anonymized and stored for analysis. Summary cross-sectional data, and comparison of differences were completed using absolute and relative scales, and Bland-Altman Plots for agreement between measures. Weights were reduced to 125kg for the on-line tool and age to 90 years when values exceeded these thresholds. Data on 588 adults aged ≥40 years were available of whom 108 (18%) were men. Mean age was 67 years, BMI: 28kg/m2, 249 had a prior fracture, 64 a parental hip fracture, 40 smokers, 42 taking glucocorticoid therapy, 39 had rheumatoid arthritis, 5 were excess alcohol users while 107 had other FRAX®-listed secondary causes of osteoporosis. Mean WF femoral neck BMD T-score was -1.4. Mean MOF DXA-FRAX® was 15.3 (SD:11.1) compared to 12.6 (SD:8.5) for Web-FRAX®, while HF means were 6.7 (SD:8.4) Vs 3.8 (SD:5.5) respectively. Bland-Altman plots showed there was much greater discrepancy for men, and those with higher risk estimates. Comparisons between DXA-FRAX® and Web-FRAX® revealed similar results. Significant differences exist in results of DXA-FRAX® and Web-FRAX® for Ireland, particularly for men and those with higher risk estimates so these results should be interpreted cautiously. Reassuringly results were similar for those deemed at lower risk and for women.

Association between osteoporosis Knowledge and Food Habits in Female University Students of Lahore

Background: Osteoporosis is a general metabolic disorder which causes many musculoskeletal issues and reduces the quality of life in the elderly population which usually progresses at the age between 30 to 40 years in both males and females. Recent studies suggested some of the associated factors like age, low bone mineral density, sex family history of fracture, less dietary intake of vitamin D, and abnormal thyroid function, these factors are the leading cause of osteoporosis especially in females. It is also indicated that along with other associated factors poor living style, malnutrition and the bad food habits leads to form osteoporosis which contributes in the loss of bone mass in post-menopausal stage of women Objective: To determine the association between osteoporosis knowledge and food habits in female university students of Lahore. Methodology: After the approval from the research committee of University an analytical cross sectional study was conducted using the Osteoporosis knowledge assessment tool (OKAT) &Adolescent food habits checklist tool (AFHC) to collect data from 138 students. The collection of data was carried by online Google forms because the university was closed due to the pandemic situation. Results: Mean knowledge score was found 9.9 with SD 4.8. Majority of the participants were found having average Knowledge good Knowledge (33.3% and 32.6%). Mean AFHC score was found 12.1 with SD±4.5. Increasing score indicates higher good food habits’ value and r value indicates that there is association between osteoporosis knowledge and food habits. Conclusion: This study concluded that there is a strong positive correlation between osteoporosis knowledge and food habits.

The Role of Senescence-Associated Secretory Phenotype in Bone Loss.

As the population of most nations have a large proportion of older individuals, there is an increase in the prevalence of osteoporosis. Consequently, scientists have focused their attention on the pathogenic mechanisms of osteoporosis. Owing to an increase in studies on cellular senescence in recent years, research has begun to focus on the function of the senescent microenvironment in osteoporosis. With chronic inflammation, senescent cells in the bone marrow secrete a series of factors known as senescence-associated secretory phenotype (SASP) factors, acting on their own or surrounding healthy cells and consequently exacerbating ageing.The components of the SASP may differ depending on the cause of osteoporosis. This review aimed to summarize the relationship between SASP factors and osteoporosis and suggest new insights into the mechanistic investigation of osteoporosis.

Activation of osteoblast ferroptosis via the METTL3/ASK1-p38 signaling pathway in high glucose and high fat (HGHF)-induced diabetic bone loss.

Diabetes mellitus (DM) and osteoporosis are two common diseases that may develop as a cause-and-effect relationship since the incidence of osteoporotic fractures is significantly increased in DM patients. However, the pathophysiology of diabetic osteoporosis is yet to be clearly understood. Iron overload has been reported to lead to bone loss and closely related to osteoporosis. In this study, we hypothesized that high glucose and high fat (HGHF) may induce osteoblastic ferroptosis for the pathogenesis of diabetic osteoporosis and explored the possible molecular mechanisms behind. Using the diabetic rat model established by HGHF feeding with a subsequent intraperitoneal injection of a single low dose of streptozocin, we found that the serum ferritin level (a biomarker for body iron store) was significantly elevated in HGHF-fed rats and the expression of SLC7A11 and GPX4 (inhibitory marker proteins for ferroptosis) was markedly attenuated in the bone tissue of the rats with diabetic bone loss as compared to the normal rats. In an osteoblast cell model, treatment of pre-osteoblastic MC3T3-E1 cells with high glucose and palmitic acid (HGPA) not only suppressed osteoblast differentiation and mineralization but also triggered ferroptosis-related osteoblastic cell death. m6 A-seq revealed that m6 A methylation on ASK1 was 80.9-fold higher in HGPA-treated cells. The expression of p-ASK1 and p-p38 was also significantly elevated in the HGPA-treated cells. Knockout of METTL3 (methyltransferase-like 3), one of the major m6 A methyltransferases, in MC3T3-E1 cells not only abrogated HGPA-induced activation of ASK1-p38signaling pathway but also attenuated the level of ferroptosis. Therefore, HGHF-induced ferroptosis in osteoblasts may be the main cause of osteoporosis in DM via activation of METTL3/ASK1-p38signaling pathway, and inhibition of ferroptosis in osteoblasts may provide a potential therapeutic strategy for diabetic osteoporosis.

Benzofuran pyran hybrid prevents glucocorticoid induced osteoporosis in mice via modulation of canonical Wnt/β-catenin signaling.

Glucocorticoid induced osteoporosis (GIOP) is the second most leading cause of osteoporosis. We have identified a compound, a benzofuran pyran hybrid compound 4e that has osteogenic potential and we wanted to assess its efficacy in GIOP in male mice. We assessed the effect of dexamethasone and compound 4e on primary osteoblasts using various cell based and immunofluorescence assays. For in vivo studies we administered methylprednisolone and compound 4e as a prophylactic measure in male Balb/c mice for 28 days and then evaluated the effect on bone microarchitecture by microCT, bone formation by histology along with clinically relevant bone markers. Compound 4e preserved osteoblast differentiation as evident by higher ALP positive cells and mineralization in compound treated groups. Compound 4e also increased the expression of osteogenic genes. This compound guarded β-catenin expression both in vitro and in vivo as confirmed by western blot and immunofluorescence assays. This led to the preservation of bone microarchitecture and cortical thickness at 2.5 mg kg−1 and 5 mg kg−1 doses. Further compound 4e enhanced bone formation rate and regulated osteocyte death. The osteogenic potential of compound 4e was reflected by an increased level of serum marker osteocalcin and decreased levels of SOST and CTX-I. Overall, Compound 4e is able to overcome the catabolic effect of dexamethasone on bone by targeting the canonical WNT/β-catenin signaling as evidenced by both in vitro and in vivo studies.

A retrospective study on the etiological exploration of osteoporosis in aging men in a French geriatric setting

IntroductionOsteoporosis in older men is common and causes significant mortality and morbidity. Some data suggest that conditions leading to bone fragility, including osteoporosis, are under-identified and undertreated in men. Additionally, 50% of the causes of osteoporosis are secondary in men. The latest Endocrine Society and different Rheumatology Societies Guidelines recommend additional laboratory investigations in men with osteoporosis so as to treat them more efficiently. Main goal of the studyOur aim was to determine whether men managed in our geriatrics center, diagnosed with osteoporosis, underwent investigations to determine the aetiology of osteoporosis and other bone fragility conditions and what the secondary causes were. Materials and methodWe conducted a monocentric, retrospective study including all men seen at the geriatric consult in 2016 diagnosed with osteoporosis. For each patient, we evaluated our clinical practice, whether common secondary causes were sought-after and what these aetiologies were. ResultsAmong the 121 men with a diagnosis of osteoporosis seen at the geriatric consult at the Lille University Hospital in 2016, only 51 had undergone further investigations. Among the 3 major secondary causes were identified: 17.6% glucocorticoid induced, 13.7% treatment induced hypogonadism, 11.7% late onset hypogonadism. ConclusionsA more efficient etiological assessment of osteoporosis in older men could be achieved and would improve management for our patients. This can be achieved by a better knowledge of the recommendations for etiological assessment of bone fragility and osteoporosis and a dedicated consultation within the geriatric sector.

Research progress on the correlation between primary aldosteronism and bone metabolism

Primary aldosteronism is a clinical syndrome characterized by hypertension, with or without hypokalemia, low renin and hyperaldosteronism, which is a common endocrine hypertension due to adrenal cortical lesions and excessive autonomic aldosteronism, resulting in increased retention of sodium and potassium and volume load. Studies have shown that aldosterone overdose increases the risk of cardiovascular disease, renal insufficiency, diabetes, metabolic syndrome and even death. In recent years, studies have pointed out that patients with primary aldosteronism have increased urinary calcium and elevated parathyroid hormone, and the prevalence of osteoporosis and fracture is higher than that of essential hypertension and healthy people. Primary aldosteronism may be a secondary cause of osteoporosis, but the specific pathogenesis remains unclear. This article reviews the correlation of bone metabolism and possible pathogenesis of primary aldosteronism.

Osteoporosis Complications in Crohn's Disease Patients: Factors, Pathogenesis, and Treatment Outlines.

The causes of osteoporosis in Crohn’s disease (CD) are multifactorial; cytokines, steroids, and vitamin deficiency all have an essential role. It is imperative to distinguish the factors that contribute to bone resorption, potentially increasing the risk of low bone mineral density (BMD), osteoporosis, and fracture. However, the pathogenicity of osteoporosis associated with CD remains unclear. Although osteoporosis treatment may vary between bisphosphonate and corticosteroid, infliximab's efficacy, when combined with immune modulators, suppresses both CD symptoms and osteoporosis progression. In this review, we aim to understand the present pathogenicity of osteoporosis, including the factors pro-inflammatory cytokines, chronic steroid use, and malnutrition, developing osteoporosis in a different pathological way, and to assist the treatment lines implying a positive outcome of osteoporosis in CD patients.Osteoporosis is considered to be one of the early complications of CD where early detection can prevent osteoporosis progression. This can be done by utilizing dual-energy X-ray-absorptiometry (DEXA) to evaluate the Z-score and treat the existing factors that have a role in the progression of osteoporosis in CD patients.

AACE2021-A-1058: Evaluation of Bone Mineral Density in Various Thyroid Disorders

Thyrotoxicosis is a known cause of osteoporosis. It is known that thyroxin may be misused by some patients to cause regression of thyroid nodules resulting in iatrogenic thyrotoxicosis. Primary hypothyroid patients have shown increased risk of fractures with conflicting data regarding BMD changes in this group. This study aims to assess the bone mineral density changes in patients with various thyroid disorders and how these changes are related various factors like the duration and dose of levothyroxine, age, and thyroid status. a retrospective study of bone mineral density measurement using DEXA scan in 77 women with various thyroid disorders seen in Baghdad endocrinology outpatient clinic between 2018-2020. 15 patients with primary hyperthyroidism, 9 patients with simple thyroid nodule, and 53 patients with primary hypothyroidism were enrolled. Effect on Bone mineral density was analyzed with respect to primary diagnosis, duration of the disease and treatment, thyroid status, age and menopausal state. The highest prevalence of abnormal BMD (osteopenia and osteoporosis) was found in patients with hyperthyroidism (80%), followed by primary hypothyroidism (52%) and finally by simple nodular disease (33%). A normal BMD was more likely in those less than 45 years of age, premenopausal and those with simple nodule, and there was a statistically significant association of an underlying diagnosis of hyperthyroidism, age>45, and postmenopausal state with a low BMD state. Patients with hyperthyroidism had significantly higher rates of osteoporosis 46.6 % and osteopenia 33.3%, with only 20% had shown a normal BMD. Patients with primary hypothyroidism had a normal BMD only in 47% of cases, while 53% had a low abnormal BMD, with 41.5% demonstrating frank osteoporosis and 11.3% having osteopenia. Patients with simple thyroid nodule had significantly higher rates of normal BMD with 66%, while 33.3% had osteopenia with none having osteoporosis. While the current thyroid state of the patient did not show an association with abnormal BMD in both primary hyperthyroidism and primary hypothyroidism, there was a statistically significant association of osteopenia and subclinical hyperthyroid state in patients with thyroid nodules. Patients with hypothyroidism and abnormal BMD were more likely to be >45 years of age, postmenopausal, and used a higher dose of LT4*. This risk was not related to the duration of LT4 treatment or the TSH value. The duration of hyperthyroidism was significantly longer in patients with hyperthyroidism and low BMD compared to those with normal BMD (6 years compared to 1 year), while the duration of hypothyroidism treatment with levothyroxine in patients with primary hypothyroidism was similar (7 years) in both normal and low BMD groups. Primary hyperthyroidism carries the highest risk for low BMD among thyroid disorders, especially in postmenopausal women and long duration of disease. Patients with simple thyroid nodule have increased risk of osteopenia if their TSH is in the subclinical hyperthyroid state. Primary hypothyroid patients have an increased risk of osteoporosis and osteopenia especially in those above the age of 45, postmenopausal, and those requiring high doses of thyroxine. Bone status was not related to the thyroid state in primary hyperthyroidism and primary hypothyroidism.

Multiple myeloma screening within a fracture liaison service (FLS).

A key role of the Fracture Liaison Service (FLS) is screening for secondary causes of osteoporosis. In 2019, the Royal Osteoporosis Society recommended that all patients attending FLS who are recommended anti-osteoporosis therapy have universal screening for myeloma based on serum electrophoresis, serum free light chains and urine electrophoresis. Here, we examined the impact of universal myeloma screening within an FLS. We sampled all patients seen by the Oxfordshire FLS between January and April 2018. The completion rates and outcomes of screening were checked using the hospital and FLS databases. Of 950 patients identified by the FLS, 628 were eligible for MM screening; 473 (75%) of these were female, and the average age was 78.4years. Overall, 584 had some form of myeloma screening, of which 577 (92%) had serum electrophoresis, 525 (84%) had serum free light chains and 407 (65%) had urine electrophoresis measured. A total of 327 (59%) patients had complete screening. Three patients (0.5%) had newly diagnosed myeloma and were urgently referred to Haematology Services. Furthermore, 46 (8%) patients had a detectable serum paraprotein with a likely diagnosis of monoclonal gammopathy of uncertain significance (MGUS) and referred for community annual surveillance according to local guidelines. Addition of universal myeloma screening to laboratory testing identified myeloma in 1 per 195 patients, and its precursor state MGUS in 1 per 13 patients, which may have otherwise been missed. Further analysis with long-term follow-up is needed to clearly define the value of diagnosing MGUS within the FLS setting and establish the benefits vs. costs and methods to improve screening completion rates.

INTS7-ABCD3 Interaction Stimulates the Proliferation and Osteoblastic Differentiation of Mouse Bone Marrow Mesenchymal Stem Cells by Suppressing Oxidative Stress.

Increased adipocyte and decreased osteoblast differentiation, combined with the ectopic proliferation of bone marrow mesenchymal stem cells (BM-MSCs), represent the primary causes of osteoporosis. The dysregulation of numerous intracellular bioactive factors is responsible for the aberrant differentiation and growth of BM-MSCs. In this study, we focused on a new stimulative factor, integrator complex subunit 7 (INTS7), and its cooperative protein ATP-binding cassette subfamily D member 3 (ABCD3)/high-density lipoprotein-binding protein (HDLBP) in mouse BM-MSCs. We aimed to uncover the effects of the INTS7–ABCD3/HDLBP interaction on BM-MSC biological behaviors and the potential mechanism underlying these effects. Functional in vitro experiments showed that the suppression of the INTS7–ABCD3 interaction rather than HDLBP could impair BM-MSC proliferation and induce cell apoptosis. Moreover, Alizarin Red S and Oil Red O staining, respectively, revealed that INTS7 and ABCD3 knockdown but not HDLBP knockdown could decrease osteoblastic differentiation and accelerate the adipogenic differentiation of BM-MSCs. Mechanistically, reactive oxygen species (ROS) and histone γ-H2AX quantities significantly increased, whereas the levels of antioxidants declined due to INTS7 and ABCD3 inhibition in BM-MSCs. These findings indicated that the suppression of oxidative stress could be involved in the INTS7/ABCD3 co-regulatory mechanisms for BM-MSC proliferation and differentiation, identifying new potential candidates for osteoporosis therapy.

P013 Serum osteoprotegerin and RANKL in patients with Juvenile Idiopathic Arthritis and their correlation with bone mineral density

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic arthropathy of childhood and is associated with low bone mass, and may hasten the onset of osteoporosis later in life1. Bone loss occurs because of an imbalance between osteoclasts-activating factors like receptor activator of nuclear factor-κB ligand (RANKL) and its inhibitor osteoprotegerin (OPG) 2. Dual energy X-ray absorptiometry (DXA) is the preferred method for measuring bone mineral density (BMD) in children and to identify and follow individuals at risk for fracture 3. The objective is the Evaluation of serum levels of osteoprotegerin and RANKL and their correlation with BMD in JIA patients. Methods Forty JIA patients (according to the revised classification criteria of ILAR) and 40 healthy children individually matched for age, sex and race were included in this study. Children excluded from the study were those with primary and secondary causes of osteoporosis (such as chronic illness). All patients were assessed clinically by: age, sex, body mass index, type of JIA, disease duration and disease activity (by Juvenile Arthritis Disease Activity Score; JADAS 10). The functional disability was assessed by the Childhood Health Assessment Questionnaire (CHAQ). Blood samples were collected from JIA patients and healthy controls to determine serum levels of OPG and RANKL by ELISA. DXA scans were done using GE Healthcare Lunar DPX, Madison, Wisconsin. Bone mineral density of the L1-L4 lumbar spine and total body less head (TBLH) was evaluated in g/cm2 and expressed as Z score for age, sex according to the reference data given for this equipment. Results The study included 40 patients (25 females) with a mean age of 11.14 years and median disease duration of 2.5 years. As regard JIA type, 45% of patients were oligoarticular, 32.5% were polyarticular, and 22.5% were systemic JIA. Median JADAS 10 was 13.95. Patients (especially polyarticular JIA) had significantly higher serum RANKL levels and lower serum OPG and OPG/RANKL ratio when compared with controls (with p-value <0.001, 0.032 and <0.001 respectively). A diagnosis of low BMD (BMD Z-score ≤ -2) was given in 25% of patients (15% polyarticular and 10% systemic) by DXA of lumbar spine, and 20% (10% polyarticular and 10% systemic) by DXA of TBLH. On the other hand, no patient was given a diagnosis of osteoporosis (BMD Z-score ≤ -2 and a significant fracture history). Low BMD at lumbar spine and TBLH was negatively correlated with serum RANKL while positively correlated with OPG/RANKL ratio. Moreover, low BMD at lumbar spine was positively correlated with serum OPG level Conclusion High RANKL and low OPG levels appear to be associated with low bone mass in JIA patients. Patients with JIA (especially polyarticular and systemic subtype) are at increased risk of low bone mineral mass. Disclosure of Interests None declared

Bridging the gaps in secondary fracture prevention at a single center in Pakistan—compliance with the IOF best practice framework

The International Osteoporosis Foundation (IOF) formulated a set of best practice framework as an international benchmark for secondary fracture prevention (SFP) and fracture liaison services (FLS), delineating essential elements of service delivery. The aim of this audit was to assess compliance with the IOF standards for patients ≥ 50years presenting with fragility hip fractures at a tertiary care center in Pakistan. A retrospective sample of hip fracture cases from Jan 2019 to Dec 2019, treated at the section of Orthopedic Surgery, Aga Khan University, Karachi, was conducted. After excluding high energy trauma cases and patients younger than 50years of age, medical records were audited, using a pre-structured Performa based on IOF standards. Compliance level of 0, 1, 2, and 3 was recorded as defined by IOF. Microsoft excel was used for data analysis. A compliance level of 3 was recorded for patient identification and fall prevention services, whereas level 1 was attained for database maintenance for 25 (100%) cases. For medication initiation, level 0 was recorded for all the cases; however, 8 (32%) cases were prescribed calcium and vitamin D supplements. For the standards, including post-fracture assessment timing, evaluation of secondary causes of osteoporosis, multifaceted assessment, medication review, communication strategy, and long-term management, a level 0 was noted for 25 (100%) cases. Moreover, no recommended assessment guidelines were followed uniformly. The care gaps identified require substantial efforts to ensure adequate implementation of the overall best practice standards for SFP, necessitating the need for FLS initiation and establishment of fracture care pathway.

The role of TRPV channels in osteoporosis.

As the world's population ages, the treatment of osteoporosis is a major problem to be addressed. The cause of osteoporosis remains unclear. Ca2+ is not only an important component of bones but also plays a key role in osteoporosis treatment. Transient receptor potential vanilloid (TRPV) channels are one of the TRP channel families that is widely distributed in various organs, playing an important role in the physiological regulation of the human body. Bone formation and bone absorption may require Ca2+ transport via TRPV channels. It has been proven that the TRPV subtypes 1, 2, 4, 5, 6 (TRPV1, TRPV2, TRPV4, TRPV5, TRPV6) may affect bone metabolism balance through selective regulation of Ca2+. They significantly regulate osteoblast/osteoclast proliferation, differentiation and function. The purpose of this review is to explore the mechanisms of TRPV channels involved in regulation of the differentiation of osteoblasts and osteoclasts, as well as to discuss the latest developments in current researches, which may provide new clues and directions for an in-depth study of osteoporosis and other related bone metabolic diseases.