Pathophysiology Of Osteoporosis Research Articles

A novel small molecule effectively ameliorates estrogen deficiency-induced osteoporosis by targeting the gut-bone signaling axis

Postmenopausal osteoporosis stems mainly from estrogen deficiency leading to a gut microbiome-dependent disruption of host systemic immunity. However, the underlying mechanisms of estrogen deficiency-induced bone loss remain elusive and novel pharmaceutical intervention strategies for osteoporosis are needed. Here we reveal that ovariectomy (ovx)-induced estrogen deficiency in C57BL/6 mice causes significant disruption of gut microbiota composition, consequently leading to marked destruction of intestinal barrier function and gut leakage. As a result, signals transportation between intestinal microbiota and T cells from the gut to bone marrow is identified to contribute to osteoclastogenesis in ovx mice. Notably, we show that icariside I (GH01), a novel small molecule naturally occurring in Herbal Epimedium, has potential to alleviate or prevent ovx-induced bone loss in mice through regulation of gut-bone signaling axis. We find that GH01 treatment can effectively restore the gut microbiota composition, intestinal barrier function and host immune status markedly altered in ovx mice, thus significantly ameliorating bone loss and osteoporosis. These findings not only provide systematic understanding of the gut-immunity-bone axis-associated pathophysiology of osteoporosis, but also demonstrate the high potential of GH01 for osteoporosis treatment by targeting the gut-bone signaling axis.

Meta-Analysis Reveals Compositional and Functional Microbial Changes Associated with Osteoporosis.

Over the past decade, the role of the gut microbiota in many disease states has gained a great deal of attention. Mounting evidence from case-control and observational studies has linked changes in the gut microbiota to the pathophysiology of osteoporosis (OP). Nonetheless, the results of these studies contain discrepancies, leaving the literature without a consensus on osteoporosis-associated microbial signatures. Here, we conducted a comprehensive meta-analysis combining and reexamining five publicly available 16S rRNA partial sequence data sets to identify gut bacteria consistently associated with osteoporosis across different cohorts. After adjusting for the batch effect associated with technical variation and heterogeneity of studies, we observed a significant shift in the microbiota composition in the osteoporosis group. An increase in the relative abundance of opportunistic pathogens Clostridium sensu stricto, Bacteroides, and Intestinibacter was observed in the OP group. Moreover, short-chain-fatty-acid (SCFA) producers, including members of the genera Collinsella, Megasphaera, Agathobaculum, Mediterraneibacter, Clostridium XIV, and Dorea, were depleted in the OP group relative to the healthy control (HC) group. Lactic acid-producing bacteria, including Limosilactobacillus, were significantly increased in the OP group. The random forest algorithm further confirmed that these bacteria differentiate the two groups. Furthermore, functional prediction revealed depletion of the SCFA biosynthesis pathway (glycolysis, tricarboxylic acid [TCA] cycle, and Wood-Ljungdahl pathway) and amino acid biosynthesis pathway (methionine, histidine, and arginine) in the OP group relative to the HC group. This study uncovered OP-associated compositional and functional microbial alterations, providing robust insight into OP pathogenesis and aiding the possible development of a therapeutic intervention to manage the disease. IMPORTANCE Osteoporosis is the most common metabolic bone disease associated with aging. Mounting evidence has linked changes in the gut microbiota to the pathophysiology of osteoporosis. However, which microbes are associated with dysbiosis and their impact on bone density and inflammation remain largely unknown due to inconsistent results in the literature. Here, we present a meta-analysis with a standard workflow, robust statistical approaches, and machine learning algorithms to identify notable microbial compositional changes influencing osteoporosis.

Hormone-Related and Drug-Induced Osteoporosis: A Cellular and Molecular Overview.

Osteoporosis resulting from an imbalance of bone turnover between resorption and formation is a critical health issue worldwide. Estrogen deficiency following a nature aging process is the leading cause of hormone-related osteoporosis for postmenopausal women, while glucocorticoid-induced osteoporosis remains the most common in drug-induced osteoporosis. Other medications and medical conditions related to secondary osteoporosis include proton pump inhibitors, hypogonadism, selective serotonin receptor inhibitors, chemotherapies, and medroxyprogesterone acetate. This review is a summary of the cellular and molecular mechanisms of bone turnover, the pathophysiology of osteoporosis, and their treatment. Nuclear factor-κβ ligand (RANKL) appears to be the critical uncoupling factor that enhances osteoclastogenesis. In contrast, osteoprotegerin (OPG) is a RANKL antagonist secreted by osteoblast lineage cells. Estrogen promotes apoptosis of osteoclasts and inhibits osteoclastogenesis by stimulating the production of OPG and reducing osteoclast differentiation after suppression of IL-1 and TNF, and subsequent M-CSF, RANKL, and IL-6 release. It can also activate the Wnt signaling pathway to increase osteogenesis, and upregulate BMP signaling to promote mesenchymal stem cell differentiation from pre-osteoblasts to osteoblasts rather than adipocytes. Estrogen deficiency leads to the uncoupling of bone resorption and formation; therefore, resulting in greater bone loss. Excessive glucocorticoids increase PPAR-2 production, upregulate the expression of Dickkopf-1 (DKK1) in osteoblasts, and inhibit the Wnt signaling pathway, thus decreasing osteoblast differentiation. They promote osteoclast survival by enhancing RANKL expression and inhibiting OPG expression. Appropriate estrogen supplement and avoiding excessive glucocorticoid use are deemed the primary treatment for hormone-related and glucocorticoid-induced osteoporosis. Additionally, current pharmacological treatment includes bisphosphonates, teriparatide (PTH), and RANKL inhibitors (such as denosumab). However, many detailed cellular and molecular mechanisms underlying osteoporosis seem complicated and unexplored and warrant further investigation.

Osteoporoza

Osteoporosis is the most frequent metabolic bone disease. It is characterized by decreased bone strength and bone fractures and consequently decreased quality of life with increased morbidity and mortality. It affects the population of postmenopausal women and older people of both gender, but also patients with other primary diseases. Modern diagnostic procedures such as bone mineral density measurement, trabecular bone score (TBS) measurement, and fracture assessment risk score (FRAX) enable early diagnosis and treatment in high-risk patients. The complex etiology and pathophysiology of osteoporosis require secondary causes to be differentiated from primary osteoporosis before the most optimal treatment is initiated. The treatment should be personalized. Two methods of treatment are antiresorptive treatment aimed toward the inhibition of bone degradation and anabolic treatment with stimulation of new bone formation. Ideally, the prevention of fractures should be the treatment of choice, otherwise, prevention of new fractures and improvement of life is the therapeutic goal. Bisphosphonates are the first line antiresorptive treatment together with denosumab, a monoclonal human antibody against RANK ligand (receptor activator of nuclear factor kappa B). Teriparatide, an N-terminal parathormone fragment, is the dominant anabolic drug. Vitamin D deficiency is a widespread problem and contributes to bone mass decrement and increased risk for fractures. With further advancements in understanding the biology of bone tissue, new therapeutic agents are expected in the treatment of patients with osteoporosis.

ODP090 Fragility Fractures and Osteoporosis Screening in Patients with Chronic Lymphocytic Leukemia

Abstract Chronic lymphocytic leukemia (CLL) and osteoporosis are diseases of older adults with high prevalence rates. CLL infiltrates the bone marrow, increasing bone resorption and demineralization which contribute to the pathophysiology of osteoporosis. Despite this, there are limited clinical data describing the association of CLL with osteoporosis and fracture risk. We hypothesized that osteoporosis and fragility fractures (FF) are common in patients with CLL. The Huntsman Cancer Institute (HCI) has a CLL database which includes all patients diagnosed with CLL since January 1, 2000 and received care at the HCI. Patients included were identified from the CLL database with ICD-9 and 10 codes associated with osteopenia, osteoporosis and/or presence of a FF. Of the 57 patients included, 67% were female (n=38) with a mean age of 69 ± 10 years and 93% Caucasian. 60% (n=34) had RAI stage of 0-1 with genetic changes noted as follows: Del(13q) 46% (n=26), Del(17p) 7% (n=4), Del(11q) 5% (n=3), and Trisomy 12 14% (n=8). IGVH mutation was present in 31.6% of patients (n=18). 47% (n=25) of patients were treated with chemotherapy, of which Rituximab (n=14), Bendamustine (n=7), Cyclophosphamide (n=5), and Ibrutinib (n=5) were the most frequently used. 58.5% (n=32) had a history of FF, with 84% occurring in the spine (n=27/32). Assessment for Vitamin D deficiency and hyperparathyroidism were performed in 54% (n=31) and 21% (n=12) of the cohort respectively. Even though every patient in the study either had a diagnosis of osteoporosis by ICD code or FF, only 44% (n=25) of patients had an available DXA scan for our review, and only 31% (n=18) received treatment for osteoporosis. Of those with a DXA, the worst T score was in the right femoral neck (T score -1.9, IQR -1.5 to -2.5) with 44% (n=14/32) either having T scores in the normal or osteopenic range. Interestingly, FF was associated with higher T scores in the spine (FF spine T score -1. 0±1.5 vs no FF T score -2.2±0.8, p=0. 03). Clinical factors associated with FF were male sex (83% men vs 46% women, p<0. 01) and positive smoking history (93% smokers vs 46% non-smokers, p<0. 01). Use of chemotherapy and hip T scores were not associated with FF. The data from our study suggests that patients with CLL are predisposed to axial fragility fractures despite non-osteoporotic T scores. In addition, osteoporosis screening with DXA is under-utilized in the CLL population, despite meeting age-appropriate screening guidelines. Increased awareness and screening for axial fragility fractures, especially in men and smokers, should be recommended in the long term follow up of patients with CLL. Further study is needed to understand the pathophysiology of osteoporosis and FF in patients with CLL to develop improved methods for prevention of these morbid fractures. Presentation: No date and time listed

Mechanisms of estrogen deficiency-induced osteoporosis based on transcriptome and DNA methylation.

Osteoporosis is a disease that impacts the elderly. Low estrogen is related to changes in DNA methylation and consequent alterations in gene expression, leading to a new direction in research related to the pathophysiology of osteoporosis. We constructed an Ovariectomized (OVX) mouse model in our study, and the mouse models had osteoporosis based on the phenotype and methylation levels in the mouse's bone. Furthermore, the methylation level of the OVX mice was significantly changed compared to that of SHAM mice. Therefore, we performed genome-level analysis on the mouse model using transcriptome and Whole Genome Bisulfite Sequencing (WGBS) by combining the data of two omics and discovered that the changes in gene expression level caused by osteoporosis primarily focused on the decrease of bone and muscle development and the activation of the immune system. According to intersection analysis of methylation and transcriptome data, the differentially expressed genes and pathways are consistent with the differentially expressed methylation locations and regions. Further, the differentially expressed methylation sites were mainly concentrated in promoters, exons, and other critical functional regions of essential differentially expressed genes. This is also the primary cause of gene differential expression variations, indicating that estrogen deficiency might regulate gene expression by altering methylation modification, leading to osteoporosis. We demonstrated the clinical value of methylation modification research, and these findings would improve the current understanding of underlying molecular mechanisms of osteoporosis incidence and development and provide new ideas for early detection and treatment of osteoporosis.

The pathophysiology of osteoporosis in obesity and type 2 diabetes in aging women and men: The mechanisms and roles of increased bone marrow adiposity.

Osteoporosis is defined as a systemic skeletal disease characterized by decreased bone mass and micro-architectural deterioration leading to increased fracture risk. Osteoporosis incidence increases with age in both post-menopausal women and aging men. Among other important contributing factors to bone fragility observed in osteoporosis, that also affect the elderly population, are metabolic disturbances observed in obesity and Type 2 Diabetes (T2D). These metabolic complications are associated with impaired bone homeostasis and a higher fracture risk. Expansion of the Bone Marrow Adipose Tissue (BMAT), at the expense of decreased bone formation, is thought to be one of the key pathogenic mechanisms underlying osteoporosis and bone fragility in obesity and T2D. Our review provides a summary of mechanisms behind increased Bone Marrow Adiposity (BMA) during aging and highlights the pre-clinical and clinical studies connecting obesity and T2D, to BMA and bone fragility in aging osteoporotic women and men.

Immunoporosis: Role of immune system in the pathophysiology of different types of osteoporosis.

Osteoporosis is a skeletal system disease characterized by low bone mass and altered bone microarchitecture, with an increased risk of fractures. Classical theories hold that osteoporosis is essentially a bone remodeling disorder caused by estrogen deficiency/aging (primary osteoporosis) or secondary to diseases/drugs (secondary osteoporosis). However, with the in-depth understanding of the intricate nexus between both bone and the immune system in recent decades, the novel field of “Immunoporosis” was proposed by Srivastava et al. (2018, 2022), which delineated and characterized the growing importance of immune cells in osteoporosis. This review aimed to summarize the response of the immune system (immune cells and inflammatory factors) in different types of osteoporosis. In postmenopausal osteoporosis, estrogen deficiency-mediated alteration of immune cells stimulates the activation of osteoclasts in varying degrees. In senile osteoporosis, aging contributes to continuous activation of the immune system at a low level which breaks immune balance, ultimately resulting in bone loss. Further in diabetic osteoporosis, insulin deficiency or resistance-induced hyperglycemia could lead to abnormal regulation of the immune cells, with excessive production of proinflammatory factors, resulting in osteoporosis. Thus, we reviewed the pathophysiology of osteoporosis from a novel insight-immunoporosis, which is expected to provide a specific therapeutic target for different types of osteoporosis.

Mechanisms of Systemic Osteoporosis in Rheumatoid Arthritis.

Rheumatoid arthritis (RA), an autoimmune disease, is characterized by the presence of symmetric polyarthritis predominantly of the small joints that leads to severe cartilage and bone destruction. Based on animal and human data, the pathophysiology of osteoporosis, a frequent comorbidity in conjunction with RA, was delineated. Autoimmune inflammatory processes, which lead to a systemic upregulation of inflammatory and osteoclastogenic cytokines, the production of autoantibodies, and Th cell senescence with a presumed disability to control the systemic immune system’s and osteoclastogenic status, may play important roles in the pathophysiology of osteoporosis in RA. Consequently, osteoclast activity increases, osteoblast function decreases and bone metabolic and mechanical properties deteriorate. Although a number of disease-modifying drugs to treat joint inflammation are available, data on the ability of these drugs to prevent fragility fractures are limited. Thus, specific treatment of osteoporosis should be considered in patients with RA and an associated increased risk of fragility fractures.

Integrated Bioinformatic Analysis of the Shared Molecular Mechanisms Between Osteoporosis and Atherosclerosis.

BackgroundOsteoporosis and atherosclerosis are common in the elderly population, conferring a heavy worldwide burden. Evidence links osteoporosis and atherosclerosis but the exact underlying common mechanism of its occurrence is unclear. The purpose of this study is to further explore the molecular mechanism between osteoporosis and atherosclerosis through integrated bioinformatic analysis.MethodsThe microarray data of osteoporosis and atherosclerosis in the Gene Expression Omnibus (GEO) database were downloaded. The Weighted Gene Co-Expression Network Analysis (WGCNA) and differentially expressed genes (DEGs) analysis were used to identify the co-expression genes related to osteoporosis and atherosclerosis. In addition, the common gene targets of osteoporosis and atherosclerosis were analyzed and screened through three public databases (CTD, DISEASES, and GeneCards). Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed by Metascape. Then, the common microRNAs (miRNAs) in osteoporosis and atherosclerosis were screened out from the Human microRNA Disease Database (HMDD) and the target genes of whom were predicted through the miRTarbase. Finally, the common miRNAs–genes network was constructed by Cytoscape software.ResultsThe results of common genes analysis showed that immune and inflammatory response may be a common feature in the pathophysiology of osteoporosis and atherosclerosis. Six hub genes (namely, COL1A1, IBSP, CTSD, RAC2, MAF, and THBS1) were obtained via taking interaction of different analysis results. The miRNAs–genes network showed that has-let-7g might play an important role in the common mechanisms between osteoporosis and atherosclerosis.ConclusionThis study provides new sights into shared molecular mechanisms between osteoporosis and atherosclerosis. These common pathways and hub genes may offer promising clues for further experimental studies.

Bone loss induced by cancer treatments in breast and prostate cancer patients

Cancer and cancer therapies are a major factor risk for osteoporosis due to bone loss and deterioration of bone microarchitecture. Both factors contribute to a decrease in bone strength and, consequently, increased bone fragility and risk of fracture. Cancer-associated bone loss is a multifactorial process, and optimal interdisciplinary management of skeletal health, accurate assessment of bone density, and early diagnosis are essential when making decisions aimed at reducing bone loss and fracture risk in patients who have received or are receiving treatment for cancer. In this document, a multidisciplinary group of experts collected the latest evidence on the pathophysiology of osteoporosis and its prevention, diagnosis, and treatment with the support of the Spanish scientific society SEOM. The aim was to provide an up-to-date and in-depth view of osteoporotic risk and its consequences, and to present a series of recommendations aimed at optimizing the management of bone health in the context of cancer.

Osteoporosis epidemiology using international cohorts.

To provide an update on the most important new cohort studies within osteoporosis and their bearing on clinical management and directions for future research. We identified a collection of new observational cohort studies - including new reports from already established large cohorts - and intervention studies providing new insights into osteoporosis pathophysiology, risk finding, intervention, and treatment barriers. Recent cohort studies in osteoporosis highlight the importance of timely identification and treatment of people who are at high risk of suffering osteoporotic fractures. Physical performance is a strong indicator of fracture risk and one that is tightly linked to a number of chronic conditions, not least inflammatory conditions like rheumatoid arthritis. Advances in case finding may involve opportunistic screening for low bone mineral density and vertebral fractures of radiology images obtained for other purposes, polygenic risk scores, and routinely collected medication and comorbidity information.

Deregulated Clusterin as a Marker of Bone Fragility: New Insights into the Pathophysiology of Osteoporosis.

Clusterin (CLU) is a secreted heterodimeric glycoprotein expressed in all organism fluids as well as in the intracellular matrix that plays key roles in several pathological processes. Its recent involvement in muscle degeneration of osteoporotic patients led to investigation of the role of CLU in bone metabolism, given the biochemical and biomechanical crosstalk of the bone–muscle unit. Quantitative real time-polymerase chain reaction (qRT-PCR) analysis of CLU expression was performed in both osteoblasts and Peripheral Blood Mononuclear Cells (PBMCs) from osteoporotic patients (OP) and healthy individuals (CTR). Furthermore, immunohistochemical analysis on femoral head tissues and enzyme-linked immunosorbent assay (ELISA) in plasma samples were performed to investigate CLU expression pattern. Finally, genotyping of CLU rs11136000 polymorphism has also been performed by qRT-PCR assays to explore a possible association with CLU expression levels. Data obtained showed a significantly increased expression level of secreted CLU isoform in PBMCs and osteoblasts from OP patients. Immunohistochemical analysis confirms the increased expression of CLU in OP patients, both in osteocytes and osteoblasts, while plasma analysis reveals a statistically significant decrease of CLU levels. Unfortunately, no functional association between CLU expression levels and the presence of CLU rs11136000 polymorphism in OP patients was found. These data suggest a potential role played by CLU as a potential biomarker for the diagnosis and prognosis of OP progression.

The Rising Era of "Immunoporosis": Role of Immune System in the Pathophysiology of Osteoporosis.

Discoveries in the last few years have emphasized the existence of an enormous breadth of communication between bone and the immune system in maintaining skeletal homeostasis. Originally, the discovery of various factors was assigned to the immune system viz. interleukin (IL)-6, IL-10, IL-17, tumor necrosis factor (TNF)-α, receptor activator of nuclear factor kappa B ligand (RANKL), nuclear factor of activated T cells (NFATc1), etc., but now these factors have also been shown to have a significant impact on osteoblasts (OBs) and osteoclasts (OCs) biology. These discoveries led to an alteration in the approach for the treatment of several bone pathologies including osteoporosis. Osteoporosis is an inflammatory bone anomaly affecting more than 500 million people globally. In 2018, to highlight the importance of the immune system in the pathophysiology of osteoporosis, our group coined the term “immunoporosis”. In the present review, we exhaustively revisit the characteristics, mechanism of action, and function of both innate and adaptive immune cells with the goal of understanding the potential of immune cells in osteoporosis. We also highlight the Immunoporotic role of gut microbiota (GM) for the treatment and management of osteoporosis. Importantly, we further discuss whether an immune cell-based strategy to treat and manage osteoporosis is feasible and relevant in clinical settings.

Magnetic resonance imaging at 3.0-T in postmenopausal osteoporosis: a prospective study and review of the literature.

ObjectiveTo promote advanced research using magnetic resonance imaging (MRI) in the diagnosis of and screening for osteoporosis by looking for correlations among the T-scores measured by dual-energy X-ray absorptiometry (DEXA), the apparent diffusion coefficient (ADC) values on diffusion-weighted imaging (DWI), and the T1-weighted signal intensity values.Materials and MethodsThis was a prospective study of postmenopausal women with no contraindications to MRI and no history of cancer who underwent DEXA within 30 days before or after the MRI examination. A 3.0-T scanner was used in order to acquire sagittal sequences targeting the lumbar spine.ResultsThirteen women underwent DEXA and MRI. In two cases, the MRI was discontinued early. Therefore, the final sample comprised 11 patients. The ADC values and T1-weighted signal intensity were found to be higher in patients with osteoporosis. However, among the patients > 60 years of age with osteoporosis, ADC values were lower and T1-weighted signal intensity was even higher.ConclusionIt is unlikely that MRI will soon replace DEXA for the diagnostic workup of osteoporosis. Although DWI and ADC mapping are useful for understanding the pathophysiology of osteoporosis, we believe that T1-weighted sequences are more sensitive than is DWI as a means of performing a qualitative analysis of vertebral alterations.

Molecular insights for an anti-osteoporotic properties of Litsea glutinosa on Saos-2 cells: An in-vitro approach

Osteoporosis is a skeletal disease that is identified by the deterioration of micro-architecture of bone tissue, leading to enhanced bone brittleness and a consequential increase in fracture threat. There are many treatments available for osteoporosis such as bisphosphonate therapy, hormonal replacement therapy, herbal therapy etc. For decades, there are several herbs that are attributed to have anti-osteoporotic effects however the candidate genes involved in it remained unknown. In line with this, the present study is focused to elucidate the anti-osteoporotic property of Litsea glutinosa (LG). To understand the proliferative effect and identify involved players, gene expression was studied on the Saos-2 osteocytes in-vitro. The expression profile of candidate genes involved in different signaling pathways such as Egr-2, RUNX2, MAPK3, NFATc1, CREB, ERβ, along with proliferation and apoptotic markers in osteoporosis were selected for the study. The gene expression profile demonstrated a significant up-regulation of Egr-2, RUNX2, MAPK3, CREB, EBβ in the range of 1.5–2.2 folds, whereas NFATc1 was found to be down-regulated up to 0.4 times compared to control when treated with 250 μg/mL of LG. Besides this, anti-apoptosis effect of LG was also supported by flow cytometry results which also proved that LG induces proliferation and inhibits apoptosis, suggesting the proliferative role of LG. In conclusion, the present study gathers the potency of LG extract for its proliferative and anti-apoptotic effect on Saos-2 osteocytes and opens a new avenue for detailing the mechanistic actions of it on mitigating the pathophysiology of osteoporosis.

The pathophysiology of immunoporosis: innovative therapeutic targets

The physiological balance between bone resorption and bone formation is now known to be mediated by a cascade of events parallel to the classic osteoblast-osteoclast interaction. Thus, osteoimmunology now encompasses the role played by other cell types, such as cytokines, lymphocytes and chemokines, in immunological responses and how they help modulate bone metabolism. All these factors have an impact on the RANK/RANKL/OPG pathway, which is the major pathway for the maturation and resorption activity of osteoclast precursor cells, responsible for osteoporosis development. Recently, immunoporosis has emerged as a new research area in osteoimmunology dedicated to the immune system's role in osteoporosis. The first part of this review presents theoretical concepts on the factors involved in the skeletal system and osteoimmunology. Secondly, existing treatments and novel therapeutic approaches to treat osteoporosis are summarized. These were selected from to the most recent studies published on PubMed containing the term osteoporosis. All data relate to the results of in vitro and in vivo studies on the osteoimmunological system of humans, mice and rats. Treatments for osteoporosis can be classified into two categories. They either target osteoclastogenesis inhibition (denosumab, bisphosphonates), or they aim to restore the number and function of osteoblasts (romozumab, abaloparatide). Even novel therapies, such as resolvins, gene therapy, and mesenchymal stem cell transplantation, fall within this classification system. This review presents alternative pathways in the pathophysiology of osteoporosis, along with some recent therapeutic breakthroughs to restore bone homeostasis.

The Pathophysiology of Osteoporosis after Spinal Cord Injury.

Spinal cord injury (SCI) affects approximately 300,000 people in the United States. Most individuals who sustain severe SCI also develop subsequent osteoporosis. However, beyond immobilization-related lack of long bone loading, multiple mechanisms of SCI-related bone density loss are incompletely understood. Recent findings suggest neuronal impairment and disability may lead to an upregulation of receptor activator of nuclear factor-κB ligand (RANKL), which promotes bone resorption. Disruption of Wnt signaling and dysregulation of RANKL may also contribute to the pathogenesis of SCI-related osteoporosis. Estrogenic effects may protect bones from resorption by decreasing the upregulation of RANKL. This review will discuss the current proposed physiological and cellular mechanisms explaining osteoporosis associated with SCI. In addition, we will discuss emerging pharmacological and physiological treatment strategies, including the promising effects of estrogen on cellular protection.

Effects of Ovariectomy and Exercise Training on Mineral Status in a High-Fat Diet-Induced Obesity Rat Model.

Osteoporosis is a growing public health issue for an aging society. Previous studies have found both beneficial and detrimental effects of obesity on bone health. The purpose of this study was to investigate the impact of estrogen deficiency and physical activity on bone and blood concentrations of macrominerals (Ca, P, and Mg) and microminerals (Zn, Se, Cu, and Fe) in a high-fat diet-induced obesity rat model. Forty-eight female Wistar rats were divided into six groups: sham-operated and ovariectomized rats that received a standard diet (SD), high-fat diet (HFD), or HFD accompanied by physical exercise. The effect of ovariectomy on bone minerals varied with diet. Ovariectomy significantly decreased femoral Ca and Mg in sedentary rats receiving a SD; femoral Se, Cu, Zn, and Fe in sedentary rats on HFD; and plasma Fe in both sedentary rats on SD and exercising rats on HFD. The interaction of ovariectomy and diet had the strongest impact on Mg and Se concentrations in femur. In ovariectomized rats, HFD showed to have a protective effect on bone mineralization (femoral Ca and Mg), and a negative one on antioxidant microminerals (femoral Se, Cu, and Zn). Physical activity reduced the decline of Se, Cu, Zn, and Fe in the femur of ovariectomized rats on HFD. In the current state of knowledge, it is difficult to suggest if decreased femoral levels of antioxidant microminerals may contribute to the pathophysiology of osteoporosis in obese individuals or just reflect the mineral status in the body.

Genetic Determinants Involved in the Osteoporosis Pathophysiology

Osteoporosis is a chronic disease characterized by decreased bone mass and distorted microarchitecture that leads to increased bone fragility making an individual prone to fractures. It is one of the most widely affected diseases worldwide that has the potential to cause serious morbidity, mortality and cost implications. It is a multifactorial disease that is influenced by the interaction between genetic, hormonal, nutritional and environmental factors. As it is a polygenic disorder, myriad genes influence the disease condition to a varied extent. The identification of genes or loci that effects the development of the disease will help not only in individualizing the prognosis, treatment and prevention of fractures but also in discovering novel therapeutic agents. The genetic association studies on osteoporosis have reported conflicting results. Well designed and efficiently conducted studies with enough power to detect variations in the interaction between various contributing factors of the disease in the homogenous population are needed to establish conclusive genotypic associations with the disease. The present review briefly summarizes the data published on the genes affecting osteoporosis development.