Imbalance In Bone Turnover Research Articles

Identification of differentially expressed genes, signaling pathways and immune infiltration in postmenopausal osteoporosis by integrated bioinformatics analysis

BackgroundPostmenopausal osteoporosis is a systemic metabolic disorder typified by an imbalance in bone turnover, where bone resorption supersedes bone formation. This imbalance primarily arises from a decline in bone mass induced by estrogen deficiency, and an elevated risk of fractures resulting from degradation of bone microstructure. Despite recognizing these changes, the precise causative factors and potential molecular pathways remain elusive. In this study, we aimed to identify differentially expressed genes (DEGs), associated pathways, and the role of immune infiltration in osteoporosis, leveraging an integrated bioinformatics approach to shed light on potential underlying molecular mechanisms. MethodsWe retrieved the expression profiles of GSE230665 from the Gene Expression Omnibus database, comprising 15 femur samples, including 12 postmenopausal osteoporosis samples and 3 normal controls. From the aggregated microarray datasets, we derived differentially expressed genes (DEGs) for further bioinformatics analysis. We used WGCNA, analyzed DEGs, PPI, and conducted GO analysis to identify pivotal genes. We then used the CIBERSORT method to explore the degree of immune cell infiltration within femur specimens affected by postmenopausal osteoporosis. To probe into the relationship between pivotal genes and infiltrating immune cells, we conducted correlation analysis. ResultsWe identified a total of 12,204 DEGs. Among these, 12,157 were up-regulated, and 47 were down-regulated. GO and KEGG pathway analyses indicated that these DEGs predominantly targeted cellular protein localization activity and associated signaling pathways. The protein-protein interaction network highlighted four central hub-genes: RPL31, RPL34, EEF1G, and BPTF. Principal component analysis indicated a positive correlation between the expression of these genes and resting NK cells (as per CIBERSORT). In contrast, the expression of RPL31, RPL34, and EEF1G showed a negative correlation with T cells (gamma delta per CIBERSORT). ConclusionsImmune infiltration plays a role in the development of osteoporosis.

P080 Print and online news representations of osteoporosis and its treatment in the UK: a framing analysis

Abstract Background/Aims Osteoporosis is a common condition which weakens bones, meaning bones can break easily. Breaking a bone may be a painful experience with significant physical, psychological, and social impact. Experts have recently proposed the “osteoporosis crisis” meaning those at risk are not being identified and for those who are, treatment uptake remains low. It is unclear what is driving the crisis. One influence may be news media, as news can impact on health beliefs and behaviours. This study aimed to investigate how osteoporosis and its treatment are represented in UK print and online news. Methods First, to explore the amount of newspaper coverage of osteoporosis compared to other long-term conditions (LTCs), a ProQuest search of twelve highly circulated newspapers between the 1st of October 2019 and the 30th of September 2020 was conducted, using the keyword “osteoporosis” and keywords relating to eight other LTCs. Next, the search on articles relating to osteoporosis was extended by using the search function on each newspaper’s website. The articles containing the keyword “osteoporosis” were subject to an inductive framing analysis. Analysis involved identifying dominant frames and components within them including problem definition, causal attribution, moral evaluation, and treatment recommendation. Results From the ProQuest comparison search, fewer articles were published containing the keyword “osteoporosis” (n = 148) compared to any of the other LTCs (“rheumatoid arthritis” (n = 194) to “cancer” (n = 9,644)). A total of 218 articles from ProQuest and online news platforms were identified for the framing analysis. Three dominant frames were present: Biomedical (n = 53 articles), Lifestyle (n = 47 articles) and Human-Interest (n = 118 articles). Osteoporosis was presented as a problem of menopause and ageing across all frames. The cause was attributed to either an imbalance in bone turnover (biomedical), poor diet and inactivity (lifestyle) and often disordered eating and menopause (human-interest). Moral evaluations of osteoporosis included descriptions of osteoporosis as a serious condition (biomedical), women were often described as vulnerable (lifestyle), and people with the condition were described as disabled, elderly and suffering (human-interest). Treatment recommendations highlighted pharmacological treatment (biomedical), or prevention through lifestyle choices (lifestyle). Human-interest stories included celebrity perspectives which were characterised by wealthy, glamorous and royal individuals and events, and lay stories which presented shocking or unusual cases and described those with the condition as victims and sufferers. Conclusion This study found that osteoporosis receives little media attention compared to other LTCs. There was little overlap between biomedical, and lifestyle components which reinforce osteoporosis as either a serious condition requiring medical intervention or as a self-inflicted condition controllable through individual actions. Human-interest stories highlighted pain and suffering of those afflicted. Results will inform focus groups exploring audience perceptions of media about osteoporosis and contribute to recommendations for reporting osteoporosis in the media. Disclosure R. Turner: None. C. Jinks: Grants/research support; CJ is part funded by the NIHR Applied Research Collaboration (ARC) West Midlands. S. Holohan: None. Z. Paskins: Grants/research support; ZP is funded by the National Institute for Health Research (NIHR) (Clinician Scientist Award (CS-2018-18-ST2- 010)/NIHR Academy).

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.

A novel approach for the prevention of ionizing radiation-induced bone loss using a designer multifunctional cerium oxide nanozyme.

The disability, mortality and costs due to ionizing radiation (IR)-induced osteoporotic bone fractures are substantial and no effective therapy exists. Ionizing radiation increases cellular oxidative damage, causing an imbalance in bone turnover that is primarily driven via heightened activity of the bone-resorbing osteoclast. We demonstrate that rats exposed to sublethal levels of IR develop fragile, osteoporotic bone. At reactive surface sites, cerium ions have the ability to easily undergo redox cycling: drastically adjusting their electronic configurations and versatile catalytic activities. These properties make cerium oxide nanomaterials fascinating. We show that an engineered artificial nanozyme composed of cerium oxide, and designed to possess a higher fraction of trivalent (Ce3+) surface sites, mitigates the IR-induced loss in bone area, bone architecture, and strength. These investigations also demonstrate that our nanozyme furnishes several mechanistic avenues of protection and selectively targets highly damaging reactive oxygen species, protecting the rats against IR-induced DNA damage, cellular senescence, and elevated osteoclastic activity in vitro and in vivo. Further, we reveal that our nanozyme is a previously unreported key regulator of osteoclast formation derived from macrophages while also directly targeting bone progenitor cells, favoring new bone formation despite its exposure to harmful levels of IR in vitro. These findings open a new approach for the specific prevention of IR-induced bone loss using synthesis-mediated designer multifunctional nanomaterials.

The influence of antineoplastic agents on the peri-implant bone around osseointegrated titanium implants: an in vivo histomorphometric and immunohistochemical study.

The interaction between antineoplastic drugs used for treating cancer and non-affected tissues remains poorly assessed and may be critical for maintaining the quality of life for patients during and after treatment. This pre-clinical study evaluated the effects of cisplatin (CIS) and 5-fluorouracil (5-FU) on the peri-implant repair process around osseointegrated titanium implants installed in the tibiae of rats. Were used 90 male rats, randomly divided into three groups (n = 30): physiological saline solution (PSS), CIS, and 5-FU. Titanium implants (4.0 × 2.2mm) were inserted in both tibiae of all animals at day 0. The animals received either PSS, CIS, or 5-FU at 35 and 37days. Euthanasia was performed at 50, 65, and 95days after surgery. Histometric (bone/implant contact [BIC]) and bone area fraction occupancy (% BAFO), histological, and immunohistochemical (for bone morphogenetic protein 2/4 [BMP2/4], Runt-related transcription factor 2 [RUNX2], osteocalcin [OCN], and tartrate-resistant acid phosphatase [TRAP]) analyses were performed. Data were statistically analyzed. Groups CIS and 5-FU presented lower BIC and lower BAFO as compared with PSS in all time points. The imbalance in bone turnover was observed by the lower number of BMP2/4-, RUNX2-, and OCN-positive cells/mm2 and the higher number of TRAP-positive cells/mm in groups CIS and 5-FU as compared with PSS in all time points. Persistent and exacerbated inflammation was observed in groups CIS and 5-FU. Both antineoplastic agents interfered negatively in the bone turnover around osseointegrated titanium implants. Closer and more careful follow-up of patients with osseointegrated implants that will undergo chemotherapy with either CIS or 5-FU shall be performed.

Skeletal System Biology and Smoke Damage: From Basic Science to Medical Clinic.

Cigarette smoking has a negative impact on the skeletal system, as it reduces bone mass and increases fracture risk through its direct or indirect effects on bone remodeling. Recent evidence demonstrates that smoking causes an imbalance in bone turnover, making bone vulnerable to osteoporosis and fragility fractures. Moreover, cigarette smoking is known to have deleterious effects on fracture healing, as a positive correlation between the daily number of cigarettes smoked and years of exposure has been shown, even though the underlying mechanisms are not fully understood. It is also well known that smoking causes several medical/surgical complications responsible for longer hospital stays and a consequent increase in the consumption of resources. Smoking cessation is, therefore, highly advisable to prevent the onset of bone metabolic disease. However, even with cessation, some of the consequences appear to continue for decades afterwards. Based on this evidence, the aim of our review was to evaluate the impact of smoking on the skeletal system, especially on bone fractures, and to identify the pathophysiological mechanisms responsible for the impairment of fracture healing. Since smoking is a major public health concern, understanding the association between cigarette smoking and the occurrence of bone disease is necessary in order to identify potential new targets for intervention.

The Effect of Tobacco Smoking on Bone Mass: An Overview of Pathophysiologic Mechanisms.

Recent evidence demonstrates that tobacco smoking causes an imbalance in bone turnover, leading to lower bone mass and making bone vulnerable to osteoporosis and fracture. Tobacco smoke influences bone mass indirectly through alteration of body weight, parathyroid hormone-vitamin D axis, adrenal hormones, sex hormones, and increased oxidative stress on bony tissues. Also, tobacco smoke influences bone mass through a direct effect on osteogenesis and angiogenesis of bone. A RANKL-RANK-OPG pathway is an essential regulatory pathway for bone metabolism and its importance lies in its interaction with most of the pathophysiologic mechanisms by which smoking influences bone mass. Both first- and secondhand smoke adversely affect bone mass; smoking cessation seems to reverse the effect of smoking and improve bone health. Recent advances in research on bone turnover markers could advance scientific knowledge regarding the mechanisms by which smoking may influence bone mass.

Clinical immunity in bone and joints.

The immune system and bone metabolism influence each other. An imbalance in the immune system, resulting in inflammatory stimuli may induce an imbalance in bone turnover via induction of osteoclast differentiation and inhibition of osteoblast differentiation, leading to various pathological conditions including osteoporosis. T-cell subsets, helper T (Th)1 and Th17, which activate the immune system, induce osteoclasts, whereas regulatory T (Treg) cells, responsible for immunosuppression, inhibit osteoclastic differentiation. In addition, inflammatory cytokines, such as the tumor necrosis factor (TNF), also cause an imbalance in bone turnover, induction of osteoclasts and inhibition of osteoblasts. Treatments targeting the immune system may regulate abnormalities in bone metabolism, while also controlling immune abnormalities. In rheumatoid arthritis (RA), a representative autoimmune disease, immune abnormality and accompanying prolongation of synovial inflammation cause bone and cartilage destruction, periarticular osteoporosis, and systemic osteoporosis. Joint damage and osteoporosis in RA occur through totally different mechanisms. Stimulation by inflammatory cytokines induces the expression of the receptor activator for nuclear factor-κB ligand (RANKL) in T cells and synovial cells, thereby inducing bone destruction due to osteoblast-independent osteoclast maturation. However, biological products targeting TNF or interleukin-6 not only control disease activity, but also inhibit joint destruction. However, these biological products are not effective for osteoporosis. Conversely, anti-RANKL antibody inhibits osteoporosis and bone destruction, but exerts no influence on RA disease activity. Such differences in therapeutic efficacy may indicate the necessity for rethinking current theories on the mechanism of bone metabolism abnormality and joint destruction. Understanding the mechanisms underlying these pathologies via commonalities existing between the immune system and the metabolic system may lead to the development of new treatments.

Effect of a bisphosphonate and selective estrogen receptor modulator on bone remodeling in streptozotocin-induced diabetes and ovariectomized rat model

Background ContextDiabetes and menopause can cause severe osteoporosis. In general, menopause and diabetes can lead to an imbalance in bone turnover, which results in secondary osteoporosis. However, the efficacy of antiresorptive drugs against this form of osteoporosis has not been extensively evaluated. ObjectiveThe aim of this study was to determine the changes in vertebral bone remodeling when postmenopausal osteoporosis is accompanied by diabetes and to compare the efficacy of bisphosphonates and selective estrogen-receptor modulators (SERMs) against these outcomes. Study designStreptozotocin-induced diabetic, ovariectomized Sprague-Dawley rats were used as the disease model. Alendronate and raloxifene were used as the bisphosphonate and SERM, respectively. MethodsWe divided 62 female rats into five groups: (1) control (n=14), (2) DM (diabetes) (n=12), (3) DM+OVX (diabetes+ovariectomy) (n=12), (4) DM+OVX+A (diabetes+ovariectomy+alendronate) (n=12), and (5) DM+OVX+R (diabetes+ovariectomy+raloxifene) (n=12). Serum biochemical markers of bone turnover, including osteocalcin and the C-telopeptide of type I collagen (CTX-1), were analyzed. We measured histomorphometric parameters of the fourth lumbar vertebrae using microcomputed tomography. Mechanical strength was evaluated by a compression test. ResultsIn the DM and DM+OVX group, only the levels of osteocalcin significantly decreased compared with those of the control group at 8 weeks after OVX. At 12 weeks, the serum CTX-1 levels in the DM+OVX+A and DM+OVX+R groups were significantly lower than those of the DM+OVX group, but there were no changes in the levels of osteocalcin. Bone mineral density and mechanical strength were higher in the DM+OVX+A and DM+OVX+R groups than in the DM and DM+OVX groups (p<.05). ConclusionsEven if postmenopausal osteoporosis is accompanied by diabetes in this animal model, both alendronate and raloxifene seem to show antiresorptive effects, decreased bone turnover rates, and improved bone mechanical strength. Therefore, alendronate and raloxifene are effective in the treatment of osteoporosis even for bone loss caused by DM and postmenopausal osteoporosis.

Bone adaptation to mechanical loading in a mouse model of reduced peripheral sensory nerve function

Underlying mechanisms contributing to the imbalance in bone turnover during osteoporosis remain only partially explained. Reduced sensory nerve function may contribute to this imbalance, as sensory neuropeptides affect the activity of osteoblasts and osteoclasts in vivo, especially during bone adaptation. In this study, we investigated bone adaptation in mice following two weeks of tibial compression (peak magnitude 3 N or 7 N). To induce decreased sensory nerve function, mice were treated with capsaicin as neonates. We hypothesized that decreased sensory nerve function would diminish the adaptation of bone to mechanical loading, assessed with μCT and dynamic histomorphometry. We found that tibial compression induced significant changes in cortical microarchitecture that depended on compression magnitude and location along the length of the tibia; in contrast, there was no effect of loading on trabecular bone of the tibial metaphysis. Tibial compression significantly increased periosteal, and decreased endosteal, bone formation. Contrary to our initial hypothesis, capsaicin-treated mice generally displayed a similar, if not larger, adaptive response to mechanical loading, including greater increases in bone mineral content and mineral apposition rate. To integrate mechanical loading of bone with sensory nerve activation, we examined whether concentration of the neuropeptides calcitonin gene-related peptide (CGRP) and substance P (SP) in bone were affected following 1 or 5 days of 5 N tibial compression or hindlimb unloading. We found that 1 day of tibial compression significantly increased CGRP concentrations in bone, and hindlimb unloading also exhibited a trend toward increased CGRP in bone. These results may suggest a role of sensory nerves in the bone adaptation response to the mechanical environment, though this remains unclear.

A Bone Remodelling Model Based on Generalised Thermodynamic Potentials and Optimisation Applied to a Trabecula with Cyclic Loading

Background: Bone diseases caused by an imbalance of bone turnover represent a major public health concern worldwide. Studies involving bone remodelling mechanisms can assist in the treatment of osteoporosis, osteopenia and in cases of fractures. In recent decades several authors have developed bone remodelling models.Aim: The aim of this study is to propose a model based on the thermodynamic framework to describe the process of bone remodelling. A secondary aim is to model a trabecula subjected to cyclic loading and calibrate the model with experimental data.Methods: Thermodynamic potentials are used to generate the functions of state based on internal scalar variables. The evolution of the variables in time is determined by dissipation potentials, which are created through the use of convex analysis. Constitutive equations are solved with mathematical programming algorithms and the numerical implementation of this theory uses the Finite Elements Method for spatial discretization.Results: The proposed theory was applied to a one-dimensional example, and two situations (an undamaged material and an initially damaged material) were simulated. The one-dimensional example shows a microscopic view of a trabecula under the influence of a growing load cycle throughout 1200 days. This dynamic process may represent the rehabilitation of an athlete, starting with light exercises up to a very heavy physical activity.Conclusions: The model was able to represent one bone remodelling cycle in the trabecula. Although it is not yet possible to obtain an experimental curve of a traction testin vivo, thein silicomodel showed a process of damage that is similar to the static test of the literature. The results also suggest a modification in the equation adopted for the Helmholtz potential shown here. This study presents a consistent thermodynamic formalism for bone remodelling, which may allow further contributions as the incorporation of chemical reactions, mass transference and anisotropic damage.

Paget’s disease: clinical update

Paget's disease is a chronic disorder of bone remodeling, characterized by an abnormal increase of osteoclast and, hence, osteoblast activity. The imbalance of bone turnover results in the formation of unhealthy and fragile bone. It also leads to impairment of adjacent joints and to a risk of various complications. Current research focuses on the elucidation of the etiologic role viral infection and predisposing genetic factors. Paget's disease is commonly discovered by chance; its suspicion is raised either by high level of alkaline phosphatase or by the X-ray of the pathological bone. Bisphosphonates have proven to be effective in controlling disease activity because they inhibit osteoclast function. Their use is recommended when bone-derived serum alkaline phosphatase is high and/or when disease localizations are highly suspected for the development of complications.

Mechanisms of Cancer-induced Bone Pain

Cancer-induced bone pain (CIBP) is common and challenging to treat. Common therapies, such as opioids, radiotherapy and bisphosphonates, are often only partially effective. CIBP is a different entity to inflammatory or neuropathic pain and needs to be considered as such. This overview examines the mechanisms of CIBP; the imbalance of bone turnover, peripheral and central nervous involvement and key neurochemical mediators. The current understanding of the underlying pathophysiology of CIBP is discussed.

Serotonin biosynthesis block builds bone

osteoporosis act by inhibiting the resorption of bone, and novel agents that could safely increase bone formation on a long-term basis could have a major impact on disease treatment and prevention. Now, writing in Nature Medicine, Ducy and colleagues show that specifically inhibiting biosynthesis of gut-derived serotonin (GDS) can increase bone formation and prevent or reverse this disease in rodents. Osteoporosis is characterized by decreased bone density and strength, leading to an increased risk of fracture. It is most prevalent in post-menopausal women, as reduced oestrogen levels lead to an imbalance in bone turnover, which is mediated by bone-resorbing osteoclasts and bone-building osteoblasts. As GDS is a powerful inhibitor of the proliferation of osteoblasts and bone formation, the authors proposed that blocking GDS biosynthesis could be a new therapeutic strategy for osteoporosis. To test this hypothesis, they used LP533401, a small-molecule inhibitor of tryptophan hydroxylase 1 (TPH1) — the initial enzyme in GDS biosynthesis — that is currently being investigated in clinical trials for irritable bowel syndrome. First, they confirmed the capacity of LP533401 to inhibit GDS production using TPH1-expressing cells and showed that mice fed with LP533401 for 3 days exhibited a dose-dependent decrease in serum serotonin concentration. In addition, by analysing the crystal structure of the enzymatic domain and using three-dimensional modelling, LP533401 was found to inhibit TPH1 activity partly by interacting with two key residues near the catalytic site, Tyr235 and Phe241. The compound was then assessed in mice immediately after ovariectomy, which provides a model for the development of osteoporosis in post-menopausal women. Control mice developed an osteopaenia, whereas mice fed with LP533401 once daily for 28 days exhibited a major elevation in bone formation parameters, resulting in a higher bone mass. Furthermore, the compound rescued established osteopaenia in mice that were left untreated for 2 or 6 weeks following ovariectomy. The authors next compared LP533401 to parathyroid hormone (PTH), which is the only current treatment capable of stimulating bone synthesis and reversing osteoporosis. However, PTH must be injected daily and can only be used for 2 years. Ovariectomized rats were allowed to develop a severe osteopaenia over 3 or 12 weeks and then given either oral LP533401 or high-dose PTH injections for 4 weeks. Like PTH, LP533401 fully rescued the osteopaenia, increased osteoblast number and bone formation rate. LP533401 also increased the mass of load-bearing long bones, but not as efficiently as PTH, although bone integrity, architecture and quality were similarly restored. Importantly, LP533401 did not affect brain serotonin content in these experiments — which is crucial as brain-derived serotonin and GDS oppositely influence bone formation — nor did it exert any adverse effects on the gastrointestinal tract or on haemostasis. It therefore seems that inhibitors of GDS synthesis could have the potential to become a new class of anabolic drugs for osteoporosis. Sarah Crunkhorn

Chronic arthritis leads to disturbances in the bone collagen network

IntroductionIn this study we used a mice model of chronic arthritis to evaluate if bone fragility induced by chronic inflammation is associated with an imbalance in bone turnover and also a disorganization of the bone type I collagen network.MethodsSerum, vertebrae and femur bones were collected from eight-month-old polyarthritis SKG mice and controls. Strength of the femoral bones was evaluated using three-point bending tests and density was assessed with a pycnometer. Bone turnover markers carboxy-terminal collagen cross-linking telopeptides (CTX-I) and amino-terminal propeptide of type I procollagen (PINP) were measured in serum. The organization and density of bone collagen were analyzed in vertebrae using second-harmonic generation (SHG) imaging with a two-photon microscope and trabecular bone microstructure was assessed by scanning electron microscope (SEM).ResultsFemoral bones of SKG mice revealed increased fragility expressed by deterioration of mechanical properties, namely altered stiffness (P = 0.007) and reduced strength (P = 0.006), when compared to controls. Accordingly, inter-trabecular distance and trabecular thickness as observed by SEM were reduced in SKG mice. PINP was significantly higher in arthritic mice (9.18 ± 3.21 ng/ml) when compared to controls (1.71 ± 0.53 ng/ml, P < 0.001). Bone resorption marker CTX-I was 9.67 ± 3.18 ng/ml in arthritic SKG mice compared to 6.23 ± 4.11 ng/ml in controls (P = 0.176). The forward-to-backward signal ratio measured by SHG was higher in SKG animals, reflecting disorganized matrix and loose collagen structure, compared to controls.ConclusionsWe have shown for the first time that chronic arthritis by itself impairs bone matrix architecture, probably due to disturbed bone remodeling and increased collagen turnover. This effect might predispose patients to bone fragility fractures.

The Effect of Bed Rest on Bone Turnover in Young Women Hospitalized for Anorexia Nervosa: A Pilot Study

Malnourished adolescents with anorexia nervosa (AN) requiring medical hospitalization are at high risk for skeletal insults. Even short-term bed rest may further disrupt normal patterns of bone turnover. The objective of the study was to determine the effect of relative immobilization on bone turnover in adolescents hospitalized for AN. This was a short-term observational study. The study was conducted at a tertiary care pediatric hospital. Twenty-eight adolescents with AN, aged 13-21 yr with a mean body mass index of 15.9 +/- 1.8 kg/m(2), were enrolled prospectively on admission. As per standard care, all subjects were placed on bed rest and graded nutritional therapy. Markers of bone formation (bone specific alkaline phosphatase), turnover (osteocalcin), and bone resorption (urinary N-telopeptides NTx) were measured. During the 5 d of hospitalization, serum osteocalcin increased by 0.24 +/- 0.1 ng/ml . d (P = 0.02). Urine N-telopeptides reached a nadir on d 3, declining -6.9 +/- 2.8 nm bone collagen equivalent per millimole creatinine (P = 0.01) but returned to baseline by d 5 (P > 0.05). Bone-specific alkaline phosphatase exhibited a decline that was strongly age dependent, being highly significant for younger subjects only [age 14 yr: -0.42 +/- 0.11 (P = 0.0002); age 18 yr: -0.03 +/- 0.08 (P = 0.68)]. Age had no effect on other outcome measures. Limitation of physical activity during hospitalization for patients with AN is associated with suppressed bone formation and resorption and an imbalance of bone turnover. Future interventional studies involving mechanical stimulation and/or weight-bearing activity are needed to determine whether medical protocols prescribing strict bed rest are appropriate.

Thermostability of bone tissue after immobilization induced osteopenia in a rat model.

Immobilization of load-bearing bones results in imbalance of bone turnover followed by bone loss and impairment of its mechanical function. The question is whether immobilization induced bone loss is accompanied by deterioration of properties of the bone tissue components. Thermally induced transformations of collagen reflect the overall condition of the structure and cross-links in collagen network. The aim of the present study was to investigate whether immobilization induced osteopenia effects stability of collagen in bone tissue. Bone loss was developed by unilateral hindlimb immobilization in adult rats. Effects of unloading on cortical tissue from tibiae were studied after three weeks of unloading (I3R0) and four weeks after remobilization and free convalescence (I3R4) in both tibiae. Thermodynamic parameters of collagen degradation in bone were determined from differential scanning calorimetry (DSC) analysis of partially dehydrated cortical bone samples from tibiae in the range of temperatures from 60 degrees C up to 300 degrees C. All bone samples were thermally very stable showing first clear endothermal process with a peak temperature within a range from 150 degrees C to 169 degrees C, for different samples. The next endotherm, wider and flatter, was observed between 245-298 degrees C with a peak at 255 degrees C - 260 degrees C. There were significant side-to-side (right to left) differences for both endothermal processes in tibiae samples from experimental groups: I3R0 and I3R4. Immobilization of load-bearing bones influences stability of collagen in bone tissue. Free remobilization was not sufficient for recovery of thermal parameters of bone.

A prospective study of changes in bone turnover and bone density associated with regaining weight in women with anorexia nervosa

Anorexia nervosa (AN) is a condition of self-induced weight loss, associated with an intense fear of gaining weight. Previous studies have shown that bone density may increase with regaining and maintaining normal weight; however, relatively little is known about the changes in bone metabolism that occur during weight restoration. We describe the effect of weight restoration and maintenance of weight over 1 year on bone mineral density (BMD) and bone turnover. We recruited women from the eating disorders services at the South West London and St George's Mental Health NHS Trust, and the Priory and Charter Nightingale Hospitals in London, UK. Details of their AN, fracture history, menstrual history and exercise were obtained by interview and case note review. Morning samples of blood and second void urine were taken for biochemical analysis. BMD was measured by DXA at the lumbar spine (LS), femoral neck (FN), distal radius (RD) and total body bone mineral content (BMC). Patients then entered the treatment program, which includes re-feeding, dietary education and psychotherapy. Over a period of 42 months, we recruited 55 women who agreed to participate in this study and underwent baseline investigations. Of these, 15 (27%) subjects achieved and then maintained their target weight for the duration of the study. At baseline for all subjects (n=55) estradiol levels were lower than the normal reference ranges (both follicular and luteal phases) in 91% of the women. Bone specific alkaline phosphatase (BSAP) concentrations were lower than the premenopausal reference range in 55% of women, and urinary deoxypyridinoline (DPD) was above the premenopausal reference range in 78% of women. Baseline lumbar spine BMD was positively related to BMI (Pearson's r=0.29, P=0.04) and inversely related to bone turnover markers: urinary DPD (Pearson's r=-0.39, P=0.01 and serum BSAP (Pearson's r=-0.3, P=0.06). The 15 patients who regained and maintained weight were followed-up for a mean duration of 69 weeks (SD 7.3, range 54 to 84 weeks). Mean BMI increased from 14.2 (1.7) to 20.2 (0.77) kg/m2 and remained stable throughout follow-up. Menstruation resumed in 8 of the 15 women. Total body BMC and LS BMD increased significantly over the duration of follow-up (by 4.3% each), but FN BMD and distal radius remained stable. Lumbar spine bone area also increased significantly, whereas FN and distal radius did not. These changes were associated with a significant increase in BSAP (P=0.01), and a non-significant trend for a decrease in DPD (P=0.10). Our findings suggest that when women are at low body weight they are in a hypo-estrogenic state, which is associated with imbalance of bone turnover (high bone resorption and low bone formation). This is reversed with weight gain and persists as target weight is maintained and is associated with increases in BMC and BMD.

Myeloma Cells Suppress Osteoblast Differentiation by Secreting a Soluble Wnt Inhibitor, sFRP-2.

Multiple myeloma (MM), a malignancy of plasma cells, develops in the bone marrow, and generates devastating bone destruction. Along with enhanced bone resorption, clinical evidence has also suggested suppression of bone formation as a contributing factor to the bone loss in MM. In contrast to recent understanding on mechanisms of osteolysis enahnced in MM, little is known about factors responsible for impaired bone formation. A canonical Wingless-type (Wnt) signaling pathway has recently been shown to play a critical role in osteoblast differentiation. Therefore, in the present study, we aimed to clarify mechanisms of suppression of osteoblast differentiation by MM cells with a particular focus on a canonical Wnt signaling pathway. Because several secreted Frizzled related protein (sFRP) and DKK family members are known as soluble Wnt antagonists, we first examined the expression of sFRP-1, 2 and 3 and DKK-1 in MM cell lines including U266, RPMI8226 and ARH77. All cell lines expressed sFRP-2 and sFRP-3 mRNA observed by RT-PCR. However, sFRP-1 was not expressed in any cell line, and Dkk-1 was expressed only in U266 cells at mRNA levels. We next conducted Western blot analyses for these factors and detected only sFRP-2 in immunoprecipitants of conditioned media as well as cell lysates of all these cell lines. However, no other factors were found at protein levels. Furthermore, sFRP-2 mRNA and protein expression was detected in most MM cells from patients with advanced or terminal stages of MM with bone destruction including plasma cell leukemia (3/4 and 8/10, respectively). In order to examine a biological role for sFRP-2, we added recombinant sFRP-2 to MC3T3-E1 cell culture together with BMP-2. Exogenous sFRP-2 partially suppressed alkaline phosphatase activity but almost completely mineralized nodule formation enhanced by BMP-2. Furthermore, sFRP-2 immunodepletion significantly restored mineralized nodule formation in MC3T3-E1 cells suppressed by RPMI8226 and ARH77 CM. These results suggest that sFRP-2 alone is able to suppress osteoblast differentiation induced by BMP-2 and that MM cell-derived sFRP-2 is among predominant factors responsible for defective bone formation in MM. Because MM cell-derived factors such as DKK-1, IGF-BP4 and IL-3 other than sFRP-2 have been implicated as an inhibitor of osteoblast differentiation, sFRP-2 may act alone or in combination with such other factors to potently suppress bone formation in MM. Taken together, MM cells may cause an imbalance of bone turnover with enhanced osteoclastic bone resorption and concomitantly suppressed bone formation, which leads to devastating destruction and a rapid loss of bone.

Ability of myeloma cells to secrete macrophage inflammatory protein (MIP)-1alpha and MIP-1beta correlates with lytic bone lesions in patients with multiple myeloma.

Macrophage inflammatory protein (MIP)-1alpha and MIP-1beta have been identified as candidates for multiple myeloma (MM)-derived bone-resorbing factors. To validate the clinical relevance of these observations, we investigated correlations between the ability of MM cells to secrete these chemokines and the extent of MM bone lesions as well as levels of biochemical bone markers in patients with MM. Patients with multiple bone lesions exhibited higher MIP-1alpha and MIP-1beta secretion from MM cells along with elevated urinary deoxypyridinoline (Dpd), without significant elevation of serum bone-specific alkaline phosphatase (BALP) or osteocalcin compared with those with minimal bone lesions. MIP-1alpha and MIP-1beta levels correlated positively with urinary Dpd and serum BALP but not with serum osteocalcin. These results provide further evidence for a causal role of MIP-1alpha and MIP-1beta in the development of lytic bone lesions, and suggest that MM cells suppress osteoblastic bone formation to cause an imbalance of bone turnover and development of destructive bone lesions.