The neglected association between schizophrenia and bone fragility: a systematic review and meta-analyses.

Schizophrenia is associated with increased risk of medical comorbidity, possibly including osteoporosis, which is a public health concern due to its significant social and health consequences. In this systematic review and meta-analysis, we aimed to determine whether schizophrenia is associated with bone fragility. The protocol for this review has been registered with PROSPERO (CRD42020171959). The research question and inclusion/exclusion criteria were developed and presented according to the PECO (Population, Exposure, Comparison, Outcome) framework. Schizophrenia was identified from medical records, DSM-IV/5 or the ICD. The outcomes for this review were bone fragility [i.e., bone mineral density (BMD), fracture, bone turnover markers, bone quality]. A search strategy was developed and implemented for the electronic databases. A narrative synthesis was undertaken for all included studies; the results from eligible studies reporting on BMD and fracture were pooled using a random effects model to complete a meta-analysis. The conduct of the review and reporting of results adhered to PRISMA guidelines. Our search yielded 3103 studies, of which 29 met the predetermined eligibility criteria. Thirty-seven reports from 29 studies constituted 17 studies investigating BMD, eight investigating fracture, three investigating bone quality and nine investigating bone turnover markers. The meta-analyses revealed that people with schizophrenia had lower BMD at the lumbar spine [standardised mean difference (SMD) -0.74, 95% CI -1.27, -0.20; Z = -2.71, p = 0.01] and at the femoral neck (SMD -0.78, 95% CI -1.03, -0.53; Z = -6.18, p ≤ 0.001). Also observed was a higher risk of fracture (OR 1.43, 95% CI 1.27, 1.61; Z = 5.88, p ≤ 0.001). Following adjustment for publication bias, the association between schizophrenia and femoral neck BMD (SMD -0.63, 95% CI -0.97, -0.29) and fracture (OR 1.32, 95% CI 1.28, 1.35) remained. Significantly increased risk of bone fragility was observed in people with schizophrenia. This association was independent of sex, participant number, methodological quality and year of publication.

Lithium use and bone health in women with bipolar disorder: A cross-sectional study.

INTRODUCTION: Several psychiatric disorders and medications used to treat them appear to be independently associated with skeletal deficits. As there is increasing evidence that lithium possesses skeletal protective properties, we aimed to investigate the association between lithium use and bone health in a group of women with bipolar disorder. METHOD: Women with bipolar disorder (n = 117, 20+ years) were recruited from south-eastern Australia. Bipolar disorder was confirmed using a clinical interview (SCID-I/NP). Bone mineral density (BMD; g/cm2 ) was measured at the spine, hip and total body using dual-energy x-ray absorptiometry and low bone mass determined by BMD T-score of <-1.0. Weight and height were measured, socioeconomic status (SES) determined and information on medication use and lifestyle factors self-reported. Linear and logistic regression were used to test associations between lithium and (i) BMD and (ii) low bone mass, respectively. RESULTS: Thirty-five (29.9%) women reported current lithium use. Lithium users and non-users differed in regard to SES and BMD; otherwise, groups were similar. After adjustments, mean BMD among lithium users was 5.1% greater at the spine (1.275 [95% CI 1.229-1.321] vs. 1.214 [1.183-1.244] g/cm2 , p = 0.03), 4.2% greater at the total hip (0.979 [0.942-1.016] vs. 0.938 [0.910-0.966] g/cm2 , p = 0.03) and 2.2% greater at the total body (1.176 [1.148-1.205] vs. 1.150 [1.129-1.171] g/cm2 , p = 0.08) compared to participants not receiving lithium. Lithium users were also less likely to have low bone mass (22.9% vs. 43.9%, p = 0.031). Associations persisted after adjustment for confounders. CONCLUSION: These data suggest lithium is associated with greater BMD and reduced risk of low bone mass in women with bipolar disorder. Research into the underlying mechanisms is warranted.

Biofabrication of functional bone tissue: defining tissue-engineered scaffolds from nature.

Damage to bone leads to pain and loss of movement in the musculoskeletal system. Although bone can regenerate, sometimes it is damaged beyond its innate capacity. Research interest is increasingly turning to tissue engineering (TE) processes to provide a clinical solution for bone defects. Despite the increasing biomimicry of tissue-engineered scaffolds, significant gaps remain in creating the complex bone substitutes, which include the biochemical and physical conditions required to recapitulate bone cells' natural growth, differentiation and maturation. Combining advanced biomaterials with new additive manufacturing technologies allows the development of 3D tissue, capable of forming cell aggregates and organoids based on natural and stimulated cues. Here, we provide an overview of the structure and mechanical properties of natural bone, the role of bone cells, the remodelling process, cytokines and signalling pathways, causes of bone defects and typical treatments and new TE strategies. We highlight processes of selecting biomaterials, cells and growth factors. Finally, we discuss innovative tissue-engineered models that have physiological and anatomical relevance for cancer treatments, injectable stimuli gels, and other therapeutic drug delivery systems. We also review current challenges and prospects of bone TE. Overall, this review serves as guide to understand and develop better tissue-engineered bone designs.

Antipsychotic medication use and fracture: a case-control study.

It has been reported that antipsychotic use is associated with lower bone mineral density and bone quality. We aimed to determine whether antipsychotic use is associated with fracture risk in a population-based sample of adults living in the Barwon Statistical Division, south-eastern Australia. In this case-control study, 1458 participants (51.8% women) with radiologically confirmed fracture between June 1st 2012 and May 31st 2013 (cases) were compared with 1795 participants (46.5% women) without fracture (controls) for the same time period. Medication use, medical history and lifestyle factors were documented by self-report. Multivariable binary logistic regression was used to explore associations between antipsychotic use and fracture following adjustment for possible confounders. In women, antipsychotic use was identified for 20 of 755 (2.6%) cases and 10 of 834 (1.2%) controls (p = 0.034) and in men, antipsychotic use was identified for 13 of 703 (1.8%) cases and 5 of 961 (0.5%) controls (p = 0.010). Following adjustments, antipsychotic use was associated with a 3.0-fold increased risk of fracture in men and a 2.3-fold increased risk of fracture in women. Patterns persisted after exclusion of participants with non-fragility fractures and self-reported schizophrenia. While future research exploring underlying mechanisms is needed, regular monitoring of bone health in antipsychotic users is suggested.

Antipsychotic medication use in association with quantitative heel ultrasound (QUS).

Purpose: Antipsychotic medication use has been associated with decreased bone mineral density; however, less is known whether antipsychotics affect other parameters of bone health. Therefore, the aim of this study was to investigate the association between antipsychotic medication use and quantitative heel ultrasound (QUS) in a population based sample of men and women. Methods: Thirty-one antipsychotic users and 155 non-users matched for age and sex were drawn from the Geelong Osteoporosis Study. QUS was undertaken and included the parameters: Broadband ultrasound attenuation (BUA), speed of sound (SOS) and stiffness index (SI). Current medication use, lifestyle factors, anthropometry and socio-economic status were collected. Generalized Estimation Equation models were conducted to determine associations between antipsychotic medication use and each of the QUS parameters, adjusting for covariates. Results: Antipsychotic users were less active, consumed less alcohol, were more likely to smoke and take antidepressants; otherwise, the groups were similar. After adjusting for age, sex and weight, antipsychotic users had a 7.7 % lower mean BUA [108.70 (95 % CI 104.26-113.14) vs. 116.42 (95 % CI 115.48-117.37) dB/MHz, p = 0.005] and 7.4 % lower mean SI [89.92 (95 % CI 86.89-92.95) vs. 97.30 (95 % CI 96.48-98.12) %, p < 0.001] compared to non-users. Differences in mean SOS between antipsychotic users and non-users failed to reach statistical significance (p = 0.07). Conclusion: Antipsychotic use was associated with lower QUS parameters. The risk of bone deterioration should be considered when antipsychotics are prescribed.

Antipsychotic-induced bone loss: the role of dopamine, serotonin and adrenergic receptor signalling.

Antipsychotics are commonly used in treating psychiatric disorders. These medications primarily target dopamine the serotonin receptors, they have some affinity to adrenergic, histamine, glutamate and muscarinic receptors. There is clinical evidence that antipsychotic use decreases BMD and increases fracture risk, with dopamine, serotonin and adrenergic receptor-signalling becoming an increasing area of focus where the presence of these receptors in osteoclasts and osteoblasts have been demonstrated. Osteoclasts and osteoblasts are the most important cells in the bone remodelling and the bone regeneration process where the activity of these cells determine the bone resorption and formation process in order to maintain healthy bone. However, an imbalance in osteoclast and osteoblast activity can lead to decreased BMD and increased fracture risk, which is also believed to be exacerbated by antipsychotics use. Therefore, the aim of this review is to provide an overview of the mechanisms of action of first, second and third generation antipsychotics and the expression profiles of dopamine, serotonin and adrenergic receptors during osteoclastogenesis and osteoblastogenesis.

Lipopolysaccharide-binding protein and bone health: data from a population-based sample of men.

We aimed to investigate the association between serum lipopolysaccharide-binding protein (LBP) and bone health in men. LBP was associated with lower bone density at the mid-forearm and the quantitative heel ultrasound measure, broadband ultrasound attenuation, for heavier participants. Data do not support clear associations between serum LBP and bone health. INTRODUCTION: The objective of this study was to investigate the association between serum lipopolysaccharide-binding protein (LBP) and potential downstream effects on skeletal density, quality, and turnover in a population-based sample of men. METHODS: This cross-sectional study utilised data from 1149 men (aged 20-96 year) enrolled in the Geelong Osteoporosis Study. Blood samples were obtained and lipopolysaccharide-binding protein (LBP), bone resorption marker, C-telopeptide (CTx), and formation marker, type 1 procollagen amino-terminal-propeptide (P1NP), were measured. Bone mineral density (BMD) was measured using dual-energy X-ray absorptiometry. Stiffness Index (SI), broadband ultrasound attenuation (BUA), and speed of sound (SOS) were derived from quantitative heel ultrasound (QUS). Linear regression models were developed to test associations between log-transformed LBP (ln-LBP), BMD, QUS, and bone turnover, after adjusting for potential covariates. RESULTS: Serum LBP ranged from 1.07-208.53 ng/mL (median 16.53 ng/mL). Those with higher levels were older, less mobile, and had lower BMD at the mid-forearm, otherwise, groups were similar. Before and after adjustment for age, ln-LBP was associated with lower BMD at the spine, total body, and mid-forearm. Further adjustment for weight attenuated associations at the spine and total body, yet the relationship at the mid-forearm was sustained (ß - 0.014 ± 0.004, p = 0.001). SOS and SI were not associated with ln-LBP either before or after adjustment for age; however, weight was identified as an effect modifier in the relationship between ln-LBP and BUA. An association was observed for those weighing greater than 82.7 kg (ß 3.366 ± 0.929, p < 0.001), after adjustment for potential covariates. Neither bone turnover marker was associated with ln-LBP. CONCLUSION: Our data do not support a clear association between serum LBP and measures of bone health in this sample of men.

Bipolar disorder and bone health: A case-control study.

BACKGROUND: Bipolar disorder (BD) is associated with significant psychological and physical comorbidity. Yet little is known about the bone health of individuals with BD. Thus, we aimed to investigate the association between BD and bone health in a population-based sample of women. METHODS: Women with a history of BD (cases; n = 117) were recruited from public and private health care settings and controls, without BD, were drawn from the Geelong Osteoporosis Study (n = 909). BD was identified using a semi-structured clinical interview (SCID-I/NP). Bone mineral density (BMD) was measured at the spine, femoral neck and total body using dual energy x-ray absorptiometry, and bone quality by quantitative heel ultrasound and included the following parameters: Speed of Sound (SOS), Broadband Ultrasound Attenuation (BUA) and Stiffness Index (SI). Weight and height were measured and information on medication use and lifestyle was obtained. RESULTS: Adjusted mean BMD among the cases was 4.3% lower at the hip and 1.6% lower at the total body compared to controls. Age was an effect modifier at the spine. Among women <50 years, mean spine BMD for cases was 3.5% lower than controls. No differences in spine BMD for those ≥50 years were detected. Cases also had a 1.0%, 3.2% and 7.8% lower adjusted mean SOS, BUA and SI compared to controls, respectively. LIMITATIONS: Course, chronicity and recovery of BD were not explored in relation to bone health. CONCLUSION: These data suggest BD is associated with low bone quantity and quality in women. Replication and research into underlying mechanisms is warranted.

Use of antipsychotic medication and its relationship with bone mineral density: A population-based study of men and women.

Background: Schizophrenia has been shown to be associated with reduced bone mineral density (BMD) and higher fracture risk. However, less is known whether antipsychotic treatment is associated with reduced BMD. Thus, we aimed to examine associations between antipsychotic use and BMD among men and women drawn from the general population. Methods: This cross-sectional study involved 793 women and 587 men enrolled in the Geelong Osteoporosis Study (GOS). BMD was determined using dual-energy X-ray absorptiometry at the spine and hip. Information regarding socio-economic status (SES), current medication and/or supplementation use, lifestyle factors, and anthropometry was collected. Association between antipsychotic use and BMD was determined using linear regression after adjusting for potential confounders. Results: Of the group, 33 women (4.2%) and 16 men (2.7%) currently used antipsychotics. Age was identified as an effect modifier in the association between antipsychotic use and BMD for women. Amongst women aged < 60 years, adjusted mean BMD was 11.1% lower at the spine [1.139 (95%CI 1.063-1.216) vs. 1.250 (95%CI 1.223-1.277) g/cm2, p = 0.005] for antipsychotic users compared to non-users. At the hip, age, weight, and smoking adjusted mean BMD was 9.9% lower [0.893 (95%CI 0.837-0.950) vs. 0.992 (95%CI 0.976-1.007) g/cm2, p < 0.001] for antipsychotic users in comparison with non-users. The pattern persisted following further adjustments. There was no association detected between antipsychotic use and BMD for women aged 60 years and over and for men. Conclusion: Our data suggest that antipsychotic medication use is associated with reduced BMD in younger women but not older women or men.

Anticonvulsant use and fracture: a case-control study.

OBJECTIVES: We aimed to investigate fracture risk associated with anticonvulsant use in a population-based sample of men and women. METHODS: Data from 1,458 participants (51.8% women) with a radiologically confirmed incident fracture (cases) were compared to 1,796 participants (46.5% women) without fracture (controls). Lifestyle factors, medication use and medical history were self-reported. Associations between anticonvulsant use and fracture were explored using binary logistic regression following adjustment for confounders. RESULTS: In men, fracture cases and controls differed in age, smoking history, education, alcohol use, and gonadal hormone supplementation. In women, fracture cases and controls differed by previous fracture history, alcohol use, physical activity levels and use of anti-fracture agents. After adjustment for age, pooled anticonvulsant use was associated with a 3.4-fold higher risk of fracture in men and a 1.8-fold higher risk in women. Following further adjustments for confounders these patterns persisted; a 2.8-fold higher fracture risk in men and a 1.8-fold higher fracture risk in women. CONCLUSIONS: Anticonvulsant use was associated with increased fracture risk, independent of demographic, lifestyle, medical and medication related factors. While further studies exploring potential underlying mechanisms are warranted, regular monitoring of bone health in anticonvulsant users with risk factors may be useful.

Anticonvulsant use and bone health in a population-based study of men and women: cross-sectional data from the Geelong Osteoporosis Study.

BACKGROUND: Anticonvulsant use has been linked to bone deficits in specific patient populations. We studied the association between anticonvulsant use and bone health in a population-based sample of men and women. METHODS: Data from 926 men (24-73 yr) and 1070 women (21-94 yr) participating in the Geelong Osteoporosis Study were included. Bone mineral density (BMD, g/cm2) of the PA-spine and total hip was measured using dual-energy X-ray absorptiometry (Lunar). Bone quality was determined using quantitative heel ultrasound (QUS). Anthropometry was conducted and socioeconomic status was determined. Medication and lifestyle information was obtained via questionnaire. Linear regression was used to test associations between anticonvulsant use and bone health before and after adjustment for potential confounders. RESULTS: Seventeen (1.8%) men and 20 (1.9%) women reported anticonvulsant use. In men, anticonvulsant users had 9.1% lower adjusted mean BMD at the spine and hip compared to non-users. Body mass index was an effect modifier at the spine. Anticonvulsant users also had 1.8% lower speed of sound (SOS), 10.6% lower broadband ultrasound attenuation (BUA) and 13.7% lower stiffness index (SI) compared to non-users. In women, BMD tended to be lower at the hip compared to non-users as with the bone quality measure, BUA. No significant associations were observed at the spine or the other bone quality measures, SOS and SI. CONCLUSION: Our data suggest that bone quantity and quality, assessed using BMD and QUS, are lower for men and possibly women who use anticonvulsants. While further exploration into potential mechanisms is needed, our findings suggest that monitoring bone health among users of anticonvulsants is warranted.

Study protocol for the systematic review and meta-analyses of the association between schizophrenia and bone fragility.

INTRODUCTION: Individuals with schizophrenia are known to be at higher risk of comorbid conditions, both physical and psychological. Osteoporosis is possibly one of these, leading to public health concerns due to higher rates of associated mortality and morbidity. We aim to systematically search all available evidence across electronic databases regarding the relationship between schizophrenia and bone fragility. METHODS AND ANALYSIS: A systematic search of the research databases CINAHL, MEDLINE Complete, Embase and PsycINFO will be conducted and identified papers reviewed for eligibility, with a second reviewer confirming inclusions. Searches will be run from database inception to 1 October 2020 and supplemented by the hand checking of references of identified articles. A previously published scoring system will be used for assessing the methodological quality and risk of bias. A meta-analysis is planned. ETHICS AND DISSEMINATION: Due to including published literature only, ethical permission will not be necessary. Results of this study will be published in a relevant scientific journal and presented at a conference in the field of interest. PROSPERO REGISTRATION NUMBER: CRD42020171959.

Dietary tryptophan and bone health: a cross-sectional, population-based study.

Tryptophan metabolites influence bone. We aimed to investigate the relationship between dietary tryptophan and bone health in a population-based sample of men and women. Following adjustment for age, dietary tryptophan was not associated with bone quantity or quality, suggesting a non-critical role of superfluous tryptophan on the skeleton. PURPOSE: Tryptophan metabolites, such as serotonin, influence bone. We sought to determine the relationship between dietary intake of tryptophan and bone health in a population-based study of men and women. METHODS: Participants (1033 women and 900 men, aged 20-98 years) enrolled in the Geelong Osteoporosis Study (GOS) were investigated. Dietary information was collected using a validated questionnaire. Tryptophan levels were calculated (mg/day) in accordance with Food Standards Australia and New Zealand and dichotomised according to the median. Bone mineral density (BMD; g/cm2) was measured at the spine (postero-anterior projection) and total hip using dual-energy X-ray absorptiometry. Stiffness index (SI), broadband ultrasound attenuation (BUA) and speed of sound (SOS) were derived from quantitative heel ultrasound. Linear regression models were used to test associations between dietary tryptophan and bone health, after adjustment for potential confounders. RESULTS: Tryptophan intakes ranged from 112 to 3796 mg/day (median 1035) in men and 115-2869 mg/day (median 885) in women. In men older than 45 years and women, a high tryptophan intake was associated with greater hip BMD compared to participants with a low tryptophan intake (p = 0.002 and p = 0.04, respectively); however, these relationships were attenuated by age (all p > 0.05). Participants with high tryptophan intake had greater BUA and SI compared to participants with low tryptophan intake (men; BUA, p = 0.02 and SI, p = 0.02, and women; BUA, p = 0.03 and SI, p = 0.08), yet also attenuated by age (all p > 0.05). CONCLUSION: No association was found between tryptophan intake and bone health in this population, which suggests a non-critical role of superfluous tryptophan consumption on the skeleton.

Bone health in bipolar disorder: a study protocol for a case-control study in Australia.

INTRODUCTION: Little is known about the bone health of adults with bipolar disorder, aside from evidence purporting bone deficits among individuals with other mental illnesses, or those taking medications commonly used in bipolar disorder. In this paper, we present the methodology of a case-control study which aims to examine the role of bipolar disorder as a risk factor for bone fragility. METHODS AND ANALYSIS: Men and women with bipolar disorder (~200 cases) will be recruited and compared with participants with no history of bipolar disorder (~1500 controls) from the Geelong Osteoporosis Study. Both cases and controls will be drawn from the Barwon Statistical Division, south-eastern Australia. The Structured Clinical Interview for DSM-IV-TR Research Version, Non-patient edition is the primary diagnostic instrument, and psychiatric symptomatology will be assessed using validated rating scales. Demographic information and detailed lifestyle data and medical history will be collected via comprehensive questionnaires. Participants will undergo dual energy X-ray absorptiometry scans and other clinical measures to determine bone and body composition. Blood samples will be provided after an overnight fast and stored for batch analysis. ETHICS AND DISSEMINATION: Ethics approval has been granted from Barwon Health Research Ethics Committee. Participation in the study is voluntary. The study findings will be disseminated via peer-reviewed publications, conference presentations and reports to the funding body.

Bipolar disorder and bone health: A systematic review.

BACKGROUND: Bipolar disorder is a chronic, episodic mental illness, affecting around 2.4% of the population worldwide. Psychological and/or physiological comorbidities are a common consequence, and osteoporosis is one such possible comorbidity. Thus, this systematic review aimed to collate, evaluate, and discuss the literature examining the link between bipolar disorder and bone health. METHODS: We conducted an e-search of PubMed/OVID/MEDLINE, PsychINFO and CINAHL to identify studies that investigated associations between bipolar disorder and bone in adults aged ≥18. Two reviewers determined eligibility according to pre-determined criteria, and methodological quality was assessed using a previously published methodological scoring system. Due to heterogeneity, a best-evidence synthesis was performed. RESULTS: Our search yielded 1409 articles, of which three (all cohorts) met predetermined criteria. The studies from Taiwan and the United States of America analysed administrative data, albeit spanning different years, and comprised a total of 344,497 participants. No studies investigating bone quantity or quality were identified. Bipolar disorder was associated with an increased risk of fracture (range 20-80%); and fracture-free survival time for those with bipolar disorder decreased substantially with advancing age, and for women (10-30% shorter than men). Fracture incidence per 1000 person years (py) was 21.4 and 10.8 in those with and without bipolar disorder, respectively. LIMITATIONS: Limited data and marked methodological heterogeneity prevented the pooling of these data for a numerical synthesis. CONCLUSIONS: Increased fracture risk was observed in individuals with bipolar disorder, independent of older age, sex, comorbidities and medication use. The operative mechanisms, risk and treatment factors warrant further enquiry.

Selective Serotonin Reuptake Inhibitors (SSRIs) and Markers of Bone Turnover in Men.

Selective serotonin reuptake inhibitors (SSRIs) have been shown to have a clinically significant impact on bone metabolism. To explore this further, we aimed to determine whether these agents are associated with serum markers of bone turnover utilising a population-based sample of men (n = 1138; 20-96 year) participating in the Geelong Osteoporosis Study. Blood samples were obtained and the bone resorption marker, C-telopeptide (CTx) and formation marker, type 1 procollagen amino-terminal-propeptide (PINP) were measured. Anthropometry and socio-economic status (SES) were determined and information on medication use and lifestyle was obtained via questionnaire. Lifetime mood disorders were assessed using semi-structured clinical interviews. Thirty-seven (3.3%) men reported using SSRIs. Age was an effect modifier in the association between SSRIs and markers of bone turnover. Among younger men (20-60 year; n = 557), adjusted mean CTx and PINP values were 12.4% [16.7 (95% CI 14.6-18.8) vs 19.1 (95% CI 18.7-19.4) pg/ml, p = 0.03] and 13.6% [5.6 (95% CI 4.9-6.3) vs 6.4 (95% CI 6.3-6.6) pg/ml, p = 0.02] lower among SSRI users compared to non-users, respectively. No differences in SSRI use and markers of bone turnover were detected among older men (61-94 year; all p > 0.05). These patterns persisted after further adjustment for activity, alcohol, smoking, SES, depression, bone active medications and other antidepressants. Our data suggest that SSRI use is associated with alterations in bone turnover markers among younger men. The observed decreases in both CTx and PINP are likely to contribute to a low bone turnover state and increased skeletal fragility with this potential imbalance between formation and resorption resulting in subsequent bone loss.

Association between bipolar spectrum disorder and bone health: a meta-analysis and systematic review protocol.

INTRODUCTION: Bipolar spectrum disorder is a chronic, episodic illness, associated with significant personal, social and economic burden. It is estimated to affect ∼2.4% of the population worldwide and is commonly associated with psychological and/or physiological comorbidities. Osteoporosis is one such comorbidity, a disease of bone that is asymptomatic until a fracture occurs. This systematic review attempts to capture, collate, assess and discuss the literature investigating the association between bipolar spectrum disorder and bone health. METHODS AND ANALYSIS: We aim to identify articles that investigate the association between bipolar spectrum disorder and bone health in adults by systematically searching the MEDLINE, PubMed, OVID and CINAHL databases. Two independent reviewers will determine eligibility of studies according to predetermined criteria, and methodological quality will be assessed using a previously published scoring system. A meta-analysis will be conducted, and statistical methods will be used to identify and control for heterogeneity, if possible. If numerical syntheses are prevented due to statistical heterogeneity, a best evidence synthesis will be conducted to assess the level of evidence for associations between bipolar spectrum disorder and bone health. ETHICS AND DISSEMINATION: Ethical permission will not be required for this systematic review since only published data will be used. This protocol will be registered with PROSPERO. Findings of the review will be published in a peer-reviewed scientific journal, and will be presented to clinical and population health audiences at national and international conferences.

DNA methylation and the social gradient of osteoporotic fracture: A conceptual model.

INTRODUCTION: Although there is a documented social gradient for osteoporosis, the underlying mechanism(s) for that gradient remain unknown. We propose a conceptual model based upon the allostatic load theory, to suggest how DNA methylation (DNAm) might underpin the social gradient in osteoporosis and fracture. We hypothesise that social disadvantage is associated with priming of inflammatory pathways mediated by epigenetic modification that leads to an enhanced state of inflammatory reactivity and oxidative stress, and thus places socially disadvantaged individuals at greater risk of osteoporotic fracture. METHODS/RESULTS: Based on a review of the literature, we present a conceptual model in which social disadvantage increases stress throughout the lifespan, and engenders a proinflammatory epigenetic signature, leading to a heightened inflammatory state that increases risk for osteoporotic fracture in disadvantaged groups that are chronically stressed. CONCLUSIONS: Our model proposes that, in addition to the direct biological effects exerted on bone by factors such as physical activity and nutrition, the recognised socially patterned risk factors for osteoporosis also act via epigenetic-mediated dysregulation of inflammation. DNAm is a dynamic modulator of gene expression with considerable relevance to the field of osteoporosis. Elucidating the extent to which this epigenetic mechanism transduces the psycho-social environment to increase the risk of osteoporotic fracture may yield novel entry points for intervention that can be used to reduce individual and population-wide risks for osteoporotic fracture. Specifically, an epigenetic evidence-base may strengthen the importance of lifestyle modification and stress reduction programs, and help to reduce health inequities across social groups. MINI ABSTRACT: Our conceptual model proposes how DNA methylation might underpin the social gradient in osteoporotic fracture. We suggest that social disadvantage is associated with priming of inflammatory signalling pathways, which is mediated by epigenetic modifications, leading to a chronically heightened inflammatory state that places disadvantaged individuals at greater risk of osteoporosis.

Effects of Depression and Serotonergic Antidepressants on Bone: Mechanisms and Implications for the Treatment of Depression.

Osteoporosis is a chronic skeletal disease marked by microarchitectural deterioration of the bone matrix and depletion of bone mineral density (BMD), with a consequent increased risk for fragility fractures. It has been frequently associated with depression, which is also a chronic and debilitating disorder with high prevalence. Selective serotonin reuptake inhibitors (SSRIs), first-line agents in the pharmacological treatment of mood and anxiety disorders, have also been shown to negatively affect bone metabolism. SSRIs are the most prescribed antidepressants worldwide and a large number of persons at risk of developing osteoporosis, including older patients, will receive these antidepressants. Therefore, a proper musculoskeletal evaluation of individuals who are being targeted for or using SSRIs is a priority. The aim of this article is to review the evidence regarding the effects of depression and serotonergic antidepressants on bone and its implications for clinical care.