Pathophysiology Of Bone Loss Research Articles

Substance P blocks ovariectomy-induced bone loss by modulating inflammation and potentiating stem cell function.

Osteoporosis is an age-related disease caused by imbalanced bone remodeling resulting from excessive bone resorption. Osteoporosis is tightly linked with induction of chronic inflammation, which activates osteoclasts and impairs osteoprogenitor in bone marrow. T helper 17 (Th17) cells have been recently recognized as one of major inducers in the pathophysiology of bone loss by secreting IL-17. Thus, modulation of Th17 development is anticipated to affect the progression of osteoporosis.Substance P (SP) is reported to provide anti-inflammatory effects by controlling immune cell profile and also, promote restoration of damaged stem cell niches—the bone marrow—by repopulating BMSCs or potentiating its paracrine ability. This study aimed to explore the therapeutic effects of systemically injected SP on ovariectomy (OVX)-induced osteoporosis.Resultantly, SP injection obviously blocked OVX-induced impairment of bone microarchitecture and reduction of the mineral density. In osteoporotic condition, SP could ameliorate chronic inflammation by promoting Treg cell polarization and inhibiting the development of osteoclastogenic Th17 cells. Moreover, SP could rejuvenate stem cell and enable stem cells to repopulate and differentiate into osteoblast.Collectively, our study strongly suggests that SP treatment can block osteoporosis and furthermore, SP treatment provides therapeutic effect on chronic disease with inflammation and stem cell dysfunction.

Pathophysiology of Bone Loss in Patients with Prostate Cancer Receiving Androgen-Deprivation Therapy and Lifestyle Modifications for the Management of Bone Health: A Comprehensive Review.

Androgen-deprivation therapy (ADT) is a systemic therapy administered for the management of advanced prostate cancer (PCa). Although ADT may improve survival, long-term use reduces bone mass density (BMD), posing an increased risk of fracture. Considering the long natural history of PCa, it is essential to preserve bone health and quality-of-life in patients on long-term ADT. As an alternative to pharmacological interventions targeted at preserving BMD, current evidence recommends lifestyle modifications, including individualized exercise and nutritional interventions. Exercise interventions include resistance training, aerobic exercise, and weight-bearing impact exercise, and have shown efficacy in preserving BMD. At the same time, it is important to take into account that PCa is a progressive and debilitating disease in which a substantial proportion of patients on long-term ADT are older individuals who harbor axial bone metastases. Smoking cessation and limited alcohol consumption are commonly recommended lifestyle measures in patients receiving ADT. Contemporary guidelines regarding lifestyle modifications vary by country, organization, and expert opinion. This comprehensive review will provide an evidence-based, updated summary of lifestyle interventions that could be implemented to preserve bone health and maintain quality-of-life throughout the disease course of PCa.

Osteoclastic miR-301-b knockout reduces ovariectomy (OVX)-induced bone loss by regulating CYDR/NF-κB signaling pathway

Postmenopausal osteoporosis (PMOP) is a frequent bone disorder responsible for an increased risk of disability to millions of individuals in the world. For identifying novel and effective targets to treat this disease, it is essential to explore the underlying molecular mechanisms. MicroRNAs (miRNAs) have been widely investigated due to their involvement in the pathophysiology of bone loss. In this study, we attempted to elucidate the role of miR-301-b in murine osteoclastogenesis. We found that miR-301-b expression was increased in the bone tissues from PMOP patients, along with up-regulated nuclear factor of activated T cells c1 (NFATC1), which were confirmed in ovariectomy (OVX)-induced mouse bone specimens and bone marrow-derived macrophages (BMMs). Osteoclastogenesis was found to be obviously suppressed by miR-301-b inhibitor, whereas being further promoted in BMMs transfected with miR-301-b mimic. The animal studies showed that osteoclastic miR-301-b knockout markedly up-regulated the bone mass by reducing osteoclastogenesis. Mechanistically, we found that cylindromatosis (CYLD) was a direct target of miR-301-b at the post-transcriptional level during osteoclastogenesis. The enhanced expression of CYLD led to a reduction of phosphorylated nuclear factor κB (NF-κB), along with remarkably decreased tumor necrosis factor-α (TNF-α) and interleukin-1β (IL-1β). Finally, osteoclastic miR-301-b ablation evidently inhibited OVX-induced osteoclastogenesis, exhibiting protective effects against bone loss in rodent animals. Therefore, results in the study reported an important mechanism for osteoclastogenesis progression regulated by miR-301-b/CYLD/NF-κB pathway, which may be an effective therapeutic target for PMOP treatment.

Recent advances in periodontitis, a prototypic osteo-immunological disease

Periodontitis is a highly prevalent infect-inflammatory disease that can lead to bone destruction, tooth mobility and finally, tooth loss if left untreated. The pathophysiology of bone loss in inflammatory conditions, such as periodontitis, has not been completely elucidated yet, but it appears that inflammation shifts the balance between bone resorption and bone formation in favor of bone loss. Besides the classical T helper cell populations (Th1 and Th2), which contribute to periodontitis, new T cell subsets have been defined and are now implicated in the pathogenesis of periodontitis. Th17 cells are strongly correlated with tissue destruction while regulatory T cells (Tregs) act as immune-modulatory cells. In addition to control immune reactions, several immune cell types directly affect bone cell activity, promoting bone resorption and suppressing bone formation. In this context, the RANKL/OPG (receptor activator of nuclear factor κB ligand/osteoprotegerin) ratio is increased in the inflamed periodontium, which stimulates osteoclastogenesis and bone resorption. More recently, inflammation has been associated with suppressed osteoblast differentiation and bone formation which is at least partially dependent on reduced Wnt signaling. This review aims to highlight the role of host response in inflammatory bone loss during periodontitis, emphasizing the role of Th17 and Treg cells and their relationship with RANKL/OPG and Wnt signaling, in order to better understand the network between skeletal and immune systems from the periodontal point of view.

Pathophysiology of Bone Loss: Growth and loss, changes in microarchitecture, molecular mechanism, hormonal regulation, nutritional influence

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Estrogen treatment does not reduce fractures?

Estrogen treatment does not reduce fractures?

Bone Mass and Mineral Metabolism Alterations in Adult Celiac Disease: Pathophysiology and Clinical Approach

Osteoporosis affects many patients with celiac disease (CD), representing the consequence of calcium malabsorption and persistent activation of mucosal inflammation. A slight increase of fracture risk is evident in this condition, particularly in those with overt malabsorption and in postmenopausal state. The adoption of a correct gluten-free diet (GFD) improves bone derangement, but is not able to normalize bone mass in all the patients. Biomarkers effective in the prediction of bone response to gluten-free diet are not yet available and the indications of guidelines are still imperfect and debated. In this review, the pathophysiology of bone loss is correlated to clinical aspects, defining an alternative proposal of management for this condition.

THU0383 Osteoporosis in Epilepsy and Multiple Sclerosis Patients.

BackgroundOsteoporosis is the most common type of bone disease. There is recent mounting evidence indicating that patients with multiple sclerosis (MS) and epilepsy (EP) have decreasing bone mineral density (BMD)...

Marrow Fat and Bone—New Perspectives

There is growing interest in the relationship between bone mineral density, bone strength, and fat depots. Marrow adipose tissue, a well-established component of the marrow environment, is metabolically distinct from peripheral fat depots, but its functional significance is unknown. In this review, we discuss animal and human data linking the marrow adipose tissue depot to parameters of bone density and integrity as well as the potential significance of marrow adipose tissue in metabolic diseases associated with bone loss, including type 1 diabetes mellitus and anorexia nervosa. Potential hormonal determinants of marrow adipose tissue are also discussed. We conclude that whereas most animal and human data demonstrate an inverse association between marrow adipose tissue and measures of bone density and strength, understanding the functional significance of marrow adipose tissue and its hormonal determinants will be critical to better understanding its role in skeletal integrity and the role of marrow adipose tissue in the pathophysiology of bone loss.

Updated evidence-based screening and treatment of osteoporosis in spinal cord injured patients

Background and Objective: Spinal cord injury (SCI) can result in a profound reduction in bone mineral density (BMD) and disturbances of the skeletal trabecular microarchitecture. The pathogenesis of osteoporosis after SCI is complex and differs from other forms of this problem. Low-impact fractures in SCI patients usually occur during accidents that should not normally cause fracture. The aim of this study is to review the latest works on evidence-based screening and treatment of osteoporosis in spinal cord injured patients. Methods: The MedLine andPubMed databases were used as the data source to identify studies from January 1, 1995 to August 1, 2012. Cross referencing of discovered articles was also performed. All of the evidences related to SCI-induced osteoporosis were extracted. Selected ones categorized into two main groups: screening and treatment. We designed search strategies using following keywords in both text word and subject heading forms: “Osteoporosis”, “bone loss”, “spinal cord injury”, “veteran”, “evidence”, and “screening, treatment”. According to the inclusion criteria, 92 studies were included. Results: Evidences for screening shows different modalities such as Dual energy X-ray absorptiometry (DEXA), Quantitative ultrasound (QUS) and Quantitative computed tomography (QCT), each with its own advantages and disadvantages. Treatment methods include bisphosphonates, vitamin D, Sclerostin monoclonal antibody, standing and walking, exercise, electrical muscle stimulation and cycling, vibration and ultrasound (US). Discussion: Research in SCI-induced bone loss is in its infancy. The exact pathogenesis of this debilitating complication has not yet been cleared. Furthermore, lack of sufficient evidences and guidelines makes it more difficult to recommend present knowledge for clinical practice purposes. Conclusions: Considering the high burden of this complication, more studies should be conducted to have a better understanding of the pathophysiology of bone loss in SCI. Future research on new drugs such as Denosumab, an anti-RANKL antibody, would be promising. Finally, health monitoring, accurate diagnosis and targeted treatments should be considered shortly after injury.

Alterations of bone geometry, density, microarchitecture, and biomechanical properties in systemic lupus erythematosus on long-term glucocorticoid: a case–control study using HR-pQCT

Compared to controls, HR-pQCT at distal radius of SLE patients on chronic glucocorticoid (SLE/GC) revealed reduced bone area, vBMD, deteriorated microarchitecture, and unevenly distributed stresses limited to cortical bone. Despite similar trabecular quality, whole bone strength decreased in patients. These alterations may partly explain high fracture rates in SLE/GC. To assess bone geometric, densitometric, microarchitectural, and biomechanical properties in patients with systemic lupus erythematosus (SLE) on long-term glucocorticoid (GC) (SLE/GC) as compared with healthy controls. A total of 180 female SLE patients and 180 healthy controls were in this cross-sectional study to assess areal bone mineral density (aBMD) by dual-energy X-ray absorptiometry. High-resolution peripheral quantitative computed tomography (HR-pQCT) and microfinite element analysis (μFEA) was performed at distal radius. In addition to significantly lower aBMD at femoral neck, total hip and lumbar spine, cortical area, average volumetric BMD (vBMD) and cortical vBMD also significantly reduced by 5.3, 5.7, to 1.9% in SLE patients, respectively. Deteriorations of cortical microarchitecture were pronounced in patients, with 6.3% reduction in cortical thickness and 13.6% higher in cortical porosity. Local stresses were more unevenly distributed through cortical bone in patients. SLE/GC patients had decreased whole bone stiffness, estimated failure load, and apparent modulus. Parameters related to trabecular bone density and microarchitecture were comparable between patients and controls. In SLE/GC patients, despite a reduction in bone area, vBMD and deteriorated microarchitecture and unevenly distributed stresses limited to the cortical compartment, whole bone strength decreased. HR-pQCT and μFEA were promising in elucidating the potential underlying pathophysiology of bone loss and propensity to fracture in SLE/GC and provide us additional information about alterations of bone quality which might better predict fracture risk beyond aBMD in SLE/GC.

Relationship of bone mineral density with disease activity and functional ability in patients with ankylosing spondylitis: a cross-sectional study

In ankylosing spondylitis, inflammatory activity probably plays a key role in the pathophysiology of bone loss. The aim of the study was to investigate the relationship of bone mineral density (BMD) at the lumbar spine and hip region with some measures of disease activity and functional ability in patients with ankylosing spondylitis. In 80 patients with established ankylosing spondylitis, disease activity and functional ability were determined by C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Bath Ankylosing Spondylitis Functional Index (BASFI). Spinal pain and patient global health were assessed using horizontal visual analog scale. BMD was measured by dual-energy X-ray absorptiometry. There was a significant negative correlation of bone density T scores with acute-phase reactants (i.e., patients with lower T scores had higher level of CRP and ESR). That relationship was reflected more reliably at proximal femur sites than at the lumbar spine. There were also significant differences in ESR, BASDAI, BASFI, spinal pain and global health between three groups of patients according to WHO classification of osteoporosis (normal, osteopenic and osteoporotic). Significantly, more patients with osteopenia at the lumbar spine had lower BASDAI index than those with normal BMD (P=0.030). Our results indicate an association of low BMD with high disease activity in patients with AS. Femoral BMD seems to be more associated with disease activity and functional ability than lumbar spine BMD.

Predictors of bone loss in childhood hematologic malignancies: a prospective study

Twenty-nine children with malignancies and age, gender-matched controls were prospectively studied over 14 months. Patients had higher parathyroid hormone (PTH) levels and fat mass, lower bone mass, and bone mass increments at follow-up than controls. Lean mass, age at diagnosis, systemic and intrathecal therapy were predictors of bone mass changes on adjusted analyses. Children with hematologic malignances have low bone mass. We prospectively investigated anthropometric, clinical, and hormonal predictors of changes in bone mass in children receiving cancer therapy. Twenty-nine children, mean age of 9 ± 2.9 years and 32 age and gender-matched controls, were studied. Seven had completed their course 40 ± 22 weeks prior, while 22 were still receiving therapy for 80 ± 28 weeks. Age at diagnosis, calcium intake, exercise activity, systemic corticosteroids in dexamethasone (Dex) dose, and methotrexate (MTX), and intrathecal MTX therapy received within follow-up period were assessed. Routine chemistries, PTH, 25-hydroxy vitamin D (25-OHD), bone remodeling markers, bone mass, and body composition were measured at baseline and 14 months. Patients had lower exercise activity, sun exposure, and bone markers levels than controls. They had higher PTH levels and fat mass, lower bone mass at the spine, hip, and total body, and lower increments at these sites on follow-up. Predictors of bone mass changes on univariate analyses were: age at diagnosis (R = -0.50 to -0.44, p < 0.05), Dex-MTX doses (R = -0.58 to -0.41, p < 0.05), intrathecal therapy (p < 0.03),% changes in lean mass (R = 0.37 to 0.54, p < 0.04), 25-OHD levels (R = 0.39, p < 0.03), and PTH levels (R = -0.47 to -0.41, p < 0.05). Lean mass, age at diagnosis, systemic and intrathecal therapy were predictors of bone mass changes on adjusted analyses. This study provides insight into the pathophysiology of bone loss in children receiving cancer therapy and possible interventions to optimize their skeletal health.

Secondary Osteoporosis in Patients with Juvenile Idiopathic Arthritis

Bone disease in patients with juvenile idiopathic arthritis (JIA) is associated with focal (joint erosion and juxtaarticular osteopenia) and systemic bone loss (generalized osteopenia or reduction of bone mass density). Pathophysiology of bone loss is multifactorial and involves particularly proinflammatory cytokines and deleterious effects of glucocorticoid therapy. Clinical studies in patients with JIA indicate excessive activation of osteoclastogenesis and reduction of bone formation. Reduction of physical activity, muscle atrophy caused by high disease activity, and compulsory restriction in movements are also associated with bone loss. In patients with JIA, the disease can be complicated by growth cartilage involvement and systemic or local growth retardation. In the absence of preventive measures, fragility fractures can occur even at an early age.

Pathophysiology of bone loss in the female athlete

Low bone mass is frequent among female athletes. The "female athlete triad" is a term that describes the interaction among energy availability, menstrual function, and bone metabolism that may lead to amenorrhea and osteopenia or osteoporosis. The main pathophysiologic mechanisms that lead to low bone mass in female athletes are low energy availability and functional hypothalamic amenorrhea. Increased energy expenditure and/or decreased energy intake, as well as the presence of eating disorders, are associated with low bone mass. In addition, menstrual dysfunction is quite common, especially among athletes competing in sports favoring leanness, and also associates with low bone mass. Screening for bone loss in female athletes should take place in the presence of amenorrhea or body mass index <18 kg/m(2) . Management of low bone mass aims to restore normal energy availability and nutritional habits. Hormone replacement therapy has no effect in abnormally underweight patients unless normal eating behaviors are restored.

Androgens and osteoporosis

The review is timely given recent advances regarding mechanisms of androgen action on bone cells and in humans. Osteoporosis in men is an important public health problem. An improved understanding of the role of androgens in the pathophysiology of bone loss will lead to new treatments. Androgen receptors are present in most bone cells. Testosterone acts on bone both directly via the androgen receptor and indirectly, following aromatization, via the oestrogen receptor. During skeletal modelling, ERalpha is critical for longitudinal bone growth. For periosteal growth and bone expansion, androgen receptor activation has a positive effect, whereas ERalpha activation is inhibitory. During skeletal remodelling, both receptor pathways generate similar and additive effects on bone.Androgen deficiency is a common secondary cause of osteoporosis in men and should be treated with testosterone, particularly in symptomatic men. However, lack of efficacy data for testosterone in osteoporosis means it is less useful as a first-line treatment in men with age-related declines in testosterone and osteoporosis, when other agents such as bisphosphonates and parathyroid hormone are effective. Randomized, placebo-controlled trials of testosterone therapy in men with age-related declines in testosterone and osteoporosis are needed, and should carefully evaluate potential risks, as well as its efficacy in reducing fractures and other health benefits.

469 Vitamin D signalling and metabolic pathways expression in breast cancer progression

With current treatments, men usually survive many years after being diagnosed with prostate cancer. However, without supportive care, the systemic effects of prostate cancer and therapies such as androgen deprivation therapy (ADT) can undermine skeletal integrity, resulting in skeletal complications that may erode quality of life (QOL). Prostate cancer patients are at risk for fractures from cancer treatment-induced bone loss. In addition, they are also at risk for pathologic fractures, severe bone pain, and other sequelae from bone metastases, which almost invariably occur during the progression of prostate cancer. This review investigates the incidence and pathophysiology of bone loss and skeletal morbidity in prostate cancer patients and reviews available treatment options for maintaining skeletal health throughout the continuum of care for these patients.Studies were identified through MEDLINE searches, review of bibliographies of relevant articles, and review of abstracts from national meetings.Several supportive care options are available to prevent generalized and localized bone loss, including calcium and vitamin D supplements and bisphosphonates. Oral calcium and vitamin D supplementation alone, however, appears to be insufficient to prevent bone loss during ADT. Zoledronic acid administered every 3 months during ADT or every 3 to 4 weeks for patients with bone metastases can reverse bone loss and reduce skeletal morbidity, respectively, in patients with prostate cancer.Skeletal complications contribute to the erosion of QOL in prostate cancer patients. Palliative care can provide important benefits to these patients. Some agents, such as zoledronic acid, may provide skeletal health benefits throughout the course of prostate cancer progression. Further investigations of the QOL impact of these benefits are warranted.

Clinical relevance of changes in bone metabolism in inflammatory bowel disease

Low bone mineral density is an established, frequent, but often neglected complication in patients with inflammatory bowel disease (IBD). Data regarding the diagnosis, therapy and follow-up of low bone mass in IBD has been partially extrapolated from postmenopausal osteoporosis; however, the pathophysiology of bone loss is altered in young patients with IBD. Fracture, a disabling complication, is the most important clinical outcome of low bone mass. Estimation of fracture risk in IBD is difficult. Numerous risk factors have to be considered, and these factors should be weighed properly to help in the identification of the appropriate patients for screening. In this editorial, the authors aim to highlight the most important clinical aspects of the epidemiology, prevention, diagnosis and treatment of IBD-related bone loss.

Iron inhibits hydroxyapatite crystal growth in vitro

Hemochromatosis is a known cause of osteoporosis in which the pathophysiology of bone loss is largely unknown and the role of iron remains questionable. We have investigated the effects of iron on the growth of hydroxyapatite crystals in vitro on carboxymethylated poly(2-hydroxyethyl methacrylate) pellets. This noncellular and enzyme-independent model mimics the calcification of woven bone (composed of calcospherites made of hydroxyapatite crystals). Polymer pellets were incubated with body fluid containing iron at increasing concentrations (20, 40, 60 μmol/L). Hydroxyapatite growth was studied by chemical analysis, scanning electron microscopy, and Raman microscopy. When incubated in body fluid containing iron, significant differences were observed with control pellets. Iron was detected at a concentration of 5.41- to 7.16-fold that of controls. In pellets incubated with iron, there was a ∼3- to 4-fold decrease of Ca and P and a ∼1.3- to 1.4-fold increase in the Ca/P ratio. There was no significant difference among the iron groups of pellets, but a trend to a decrease of Ca with the increase of iron concentration was noted. Calcospherite diameters were significantly lower on pellets incubated with iron. Raman microspectroscopy showed a decrease in crystallinity (measured by the full width of the half height of the 960 Δcm −1 band) with a significant increase in carbonate substitution (measured by the intensity ratio of 1071 to 960 Δcm −1 band). Energy dispersive x-ray analysis identified iron in the calcospherites. In vitro, iron is capable to inhibit bone crystal growth with significant changes in crystallinity and carbonate substitution.

Gut, inflammation and osteoporosis: basic and clinical concepts

Chronic inflammatory disorders such as inflammatory bowel diseases (IBD) affect bone metabolism and are frequently associated with the presence of osteoporosis. Bone loss is regulated by various mediators of the...