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Summary : This narrative review summarises the recommendations of a Working Group of the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) for the conduct and reporting of real-world evidence studies with a focus on osteoporosis research. Purpose: Vast amounts of data are routinely generated at every healthcare contact and activity, and there is increasing recognition that these real-world data can be analysed to generate scientific evidence. Real-world evidence (RWE) is increasingly used to delineate the natural history of disease, assess real-life drug effectiveness, understand adverse events and in health economic analysis. The aim of this work was to understand the benefits and limitations of this type of data and outline approaches to ensure that transparent and high-quality evidence is generated. Methods: A ESCEO Working Group was convened in December 2022 to discuss the applicability of RWE to osteoporosis research and approaches to best practice. Results: This narrative review summarises the agreed recommendations for the conduct and reporting of RWE studies with a focus on osteoporosis research. Conclusions: It is imperative that research using real-world data is conducted to the highest standards with close attention to limitations and biases of these data, and with transparency at all stages of study design, data acquisition and curation, analysis and reporting to increase the trustworthiness of RWE study findings. [ABSTRACT FROM AUTHOR]

Summary: Systematic review and meta-analysis of the effect of moderate- to high-dose vitamin D supplementation in pregnancy on offspring bone mineralisation found a positive effect of vitamin D supplementation on offspring bone mineral density (BMD) at age 4–6 years, with a smaller effect on bone mineral content. Purpose: A systematic review and meta-analysis was performed to assess the effect of pregnancy vitamin D supplementation on offspring bone mineral density (BMD) in childhood. Methods: A literature search was conducted for published RCTs of antenatal vitamin D supplementation with assessment of offspring BMD or bone mineral content (BMC) by dual-energy X-ray absorptiometry (DXA) using MEDLINE and EMBASE up to 13th July 2022. Risk of bias was assessed using the Cochrane Risk of Bias 2 tool. Study findings were grouped in two age groups of offspring assessment: neonatal period and early childhood (3–6 years). Random-effects meta-analysis of the effect on BMC/BMD at 3–6 years was performed using RevMan 5.4.1, yielding standardised mean difference (SMD) (95% CI). Results: Five RCTs were identified with offspring assessment of BMD or BMC; 3250 women were randomised within these studies. Risk of bias was low in 2 studies and "of concern" in 3. Supplementation regimes and the control used (3 studies used placebo and 2 used 400 IU/day cholecalciferol) varied, but in all studies the intervention increased maternal 25-hydroxvitamin D status compared to the control group. Two trials assessing BMD in the neonatal period (total n = 690) found no difference between groups, but meta-analysis was not performed as one trial represented 96.4% of those studied at this age. Three trials assessed offspring whole-body-less-head BMD at age 4–6 years. BMD was higher in children born to mothers supplemented with vitamin D [0.16 SD (95% confidence interval 0.05, 0.27), n = 1358] with a smaller effect on BMC [0.07 SD (95% CI − 0.04, 0.19), n = 1351]. Conclusions: There are few RCTs published to address this question, and these are inconsistent in methodology and findings. However, meta-analysis of three trials suggests moderate- to high-dose vitamin D supplementation in pregnancy might increase offspring BMD in early childhood, but further trials are required to confirm this finding. (Prospero CRD42021288682; no funding received). [ABSTRACT FROM AUTHOR]

Childhood osteoporosis leads to increased propensity to fracture, and thus is an important cause of morbidity, pain and healthcare utilisation. Osteoporosis in children may be caused by a primary bone defect or secondary to an underlying medical condition and/or its treatment. Primary osteoporosis is rare, but there is an increasing number of children with risk factors for secondary osteoporosis. Therefore it is imperative that all paediatricians are aware of the diagnostic criteria and baseline investigations for childhood osteoporosis to enable timely referral to a specialist in paediatric bone health. This review will discuss the approach to diagnosis, investigation and management of childhood osteoporosis, with particular consideration to advances in molecular diagnosis of primary bone disorders, and current and emerging therapies for fracture reduction. [ABSTRACT FROM AUTHOR]

Poor cognitive function and osteoporosis commonly co-exist in later life. In women, this is often attributed to post-menopausal estrogen loss. However, a common early life origin for these conditions and the associations between cognitive function and bone mineral density (BMD) in childhood have not previously been explored. We examined these relationships at age 6–7 years in the Southampton Women's Survey (SWS) mother-offspring cohort. Child occipitofrontal circumference (OFC), a proxy for brain volume, intelligence quotient (IQ) [Wechsler Abbreviated Scale of Intelligence] and visual recognition and working memory [CANTAB® Delayed Matching to Sample (DMS) and Spatial Span Length (SSP), respectively] were assessed. Whole-body-less-head (WBLH) and lumbar spine dual-energy X-ray absorptiometry [Hologic Discovery] (DXA) were performed to measure bone area (BA), bone mineral content (BMC), BMD and bone mineral apparent density (BMAD). Linear regression was used to examine associations between age and sex standardized variables (β represent standard deviation (SD) difference per SD of cognitive function). DXA was performed in 1331 children (mean (SD) age 6.8 (0.33) years, 51.5 % male), with OFC, IQ, DMS and SSP assessed in 1250, 551, 490 and 460, respectively. OFC (β = 0.25 SD/SD, 95%CI 0.20,0.30), IQ (β = 0.11 SD/SD, 95%CI 0.02,0.19), and DMS (β = 0.11, SD/SD, 95%CI 0.01,0.20) were positively associated with WBLH BA, with similar associations for lumbar spine BA. OFC and DMS were also positively associated with WBLH BMC, but only OFC was associated with BMD (WBLH: β = 0.38 SD/SD, 95%CI 0.33,0.43; LS: β = 0.19 SD/SD, 95%CI 0.13,0.24). Childhood brain volume was positively associated with measures of skeletal size and BMD, whereas IQ and memory were associated only with skeletal size. These findings suggest that common early life determinants for skeletal growth and BMD and cognitive function should be explored to identify potential early-life approaches to preventing osteoporosis and cognitive decline. • We explored the associations between cognitive function and BMD in children. • Head circumference, IQ and working memory were associated with skeletal size. • Only head circumference, and not IQ or memory, was associated with BMD. • Common determinants for skeletal growth and cognitive function should be explored. [ABSTRACT FROM AUTHOR]

Vitamin D has important roles in calcium metabolism and in the prevention of rickets and osteomalacia; low levels of 25-hydroxyvitamin D are common in the general population and amongst pregnant women. Whilst there is a wealth of observational evidence linking vitamin D deficiency to a wide range of disease outcomes, there are currently few high-quality randomised controlled trials to confirm any causal associations, although many are currently in progress. Furthermore, currently, the vast majority of published guidelines recommend standard supplemental vitamin D doses for children and pregnant women, yet there is increasing recognition that individual characteristics and genetic factors may influence the response to supplementation. As such, future research needs to concentrate on documenting definite beneficial clinical outcomes of vitamin D supplementation, and establishing personalised dosing schedules and demonstrating effective approaches to optimising initiation and adherence. [ABSTRACT FROM AUTHOR]

Osteoporosis constitutes a major public health problem, through its association with age-related fractures, particularly of the hip, vertebrae, distal forearm and humerus. Substantial geographic variation has been noted in the incidence of osteoporotic fractures worldwide, with Western populations (North America, Europe and Oceania), reporting increases in hip fracture throughout the second half of the 20th century, with a stabilisation or decline in the last two decades. In developing populations however, particularly in Asia, the rates of osteoporotic fracture appears to be increasing. The massive global burden consequent to osteoporosis means that fracture risk assessment should be a high priority among health measures considered by policy makers. The WHO operational definition of osteoporosis, based on a measurement of bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), has been used globally since the mid-1990s. However, although this definition identifies those at greatest individual risk of fracture, in the population overall a greater total number of fractures occur in individuals with BMD values above the threshold for osteoporosis diagnosis. A number of web-based tools to enable the inclusion of clinical risk factors, with or without BMD, in fracture prediction algorithms have been developed to improve the identification of individuals at high fracture risk, the most commonly used globally being FRAX®. Access to DXA, osteoporosis risk assessment, case finding and treatment varies worldwide, but despite such advances studies indicate that a minority of men and women at high fracture risk receive treatment. Importantly, research is ongoing to demonstrate the clinical efficacy and cost-effectiveness of osteoporosis case finding and risk assessment strategies worldwide. The huge burden caused by osteoporosis related fractures to individuals, healthcare systems and societies should provide a clear impetus for the progression of such approaches. [ABSTRACT FROM AUTHOR]

Over recent decades, the perception of osteoporosis has changed from that of an inevitable consequence of ageing, to that of a well characterised and treatable chronic non-communicable disease, with major impacts on individuals, healthcare systems and societies. Characterisation of its pathophysiology from the hierarchical structure of bone and the role of its cell population, development of effective strategies for the identification of those most appropriate for treatment, and an increasing armamentarium of efficacious pharmacological therapies, have underpinned this evolution. Despite this marked progress, individuals who experience a fragility fracture remain under-treated in many areas of the world, and there is substantial need for investment both in secondary and primary prevention globally. In this brief article, we give an overview of the pathogenesis of osteoporosis, and summarise current and future approaches to its assessment and treatment. [ABSTRACT FROM AUTHOR]

Background Fractures are common in childhood, and there is considerable variation in the reported incidence across European countries, but few data relating to ethnic and geographic differences within a single country. We therefore aimed to determine the incidence of childhood fractures in the United Kingdom (UK), and to describe age-, ethnicity- and region- specific variations. Methods The Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 7% of the UK population. The occurrence of a fracture between 1988 and 2012 was determined from the CPRD for all individuals < 18 years of age, and used to calculate fracture incidence rates for age, sex and ethnicity. Regional fracture incidence rates were also calculated based on general practitioner location within 14 Strategic Health Authorities (SHA) within the UK. Results The overall fracture incidence rate was 137 per 10,000 person-years (py). This was higher in boys (169 per 10,000 py) than girls (103 per 10,000 py) and white children (150 per 10,000 py) compared to those of black (64 per 10,000 py) and South Asian (81 per 10,000 py) ethnicity. Marked geographic variation in incidence was observed. The highest fracture rates were observed in Wales, where boys and girls had 1.82 and 1.97 times greater incidence, respectively, than those residing in Greater London. Conclusion In the period 1988–2012, there was marked geographic and ethnic variation in childhood fracture incidence across the UK. These findings also implicate lifestyle and socio-economic differences associated with location and ethnicity, and are relevant to policy makers in the UK and internationally. [ABSTRACT FROM AUTHOR]

Over recent decades, the perception of osteoporosis has changed from that of an inevitable consequence of ageing, to that of a well characterised and treatable chronic non-communicable disease, with major impacts on individuals, healthcare systems and societies. Characterisation of its pathophysiology from the hierarchical structure of bone and the role of its cell population, development of effective strategies for the identification of those most appropriate for treatment, and an increasing armamentarium of efficacious pharmacological therapies, have underpinned this evolution. Despite this marked progress, individuals who experience a fragility fracture remain under-treated in many areas of the world, and there is substantial need for investment both in secondary and primary prevention globally. In this brief article, we give an overview of the pathogenesis of osteoporosis, and summarise current and future approaches to its assessment and treatment. [ABSTRACT FROM AUTHOR]

Introduction Although it has been suggested that overweight and obese children have an increased risk of fracture, recent studies in post-menopausal women have shown that the relationship between obesity and fracture risk varies by fracture site. We therefore assessed whether adiposity and overweight/obesity prevalence differed by upper limb fracture site in children. Methods Height, weight, BMI, triceps and subscapular skinfold thickness (SFT) were measured in children aged 3–18 years with an acute upper limb fracture. Data was compared across three fracture sites (hand, forearm and upper arm/shoulder [UA]), and to published reference data. Results 401 children (67.1% male, median age 11.71 years, range 3.54–17.27 years) participated. 34.2%, 50.6% and 15.2% had fractures of the hand, forearm and UA, respectively. Children with forearm fractures had higher weight, BMI, subscapular SFT and fat percentage z-scores than those with UA fractures (p < 0.05 for all). SFT and fat percentage z-scores were also higher in children with forearm fractures compared to hand fractures, but children with hand and UA fractures did not differ. Overweight and obesity prevalence was higher in children with forearm fractures (37.6%) than those with UA fractures (19.0%, p = 0.009). This prevalence was also higher than the published United Kingdom population prevalence (27.9%, p = 0.003), whereas that of children with either UA (p = 0.13) or hand fractures (29.1%, p = 0.76) did not differ. These differences in anthropometry and overweight/obesity prevalence by fracture site were evident in boys, but not present in girls. Conclusion Measurements of adiposity and the prevalence of overweight/obesity differ by fracture site in children, and in particular boys, with upper limb fractures. [ABSTRACT FROM AUTHOR]

Vitamin D status has been increasingly associated with wide-ranging clinical outcomes. There is now a wealth of observational studies reporting on its associations with obstetric complications, including pre-eclampsia, gestational diabetes and the mode and timing of delivery. The findings are inconsistent, and currently there is a lack of data from high-quality intervention studies to confirm a causal role for vitamin D in these outcomes. This is similarly true with regards to fetal development, including measures of fetal size and skeletal mineralisation. Overall, there is an indication of possible benefits of vitamin D supplementation during pregnancy for offspring birthweight, calcium concentrations and bone mass as well as for reduced maternal pre-eclampsia. However, for none of these outcomes is the current evidence base conclusive, and the available data justify the instatement of high-quality randomised placebo controlled trials in a range of populations and health care settings to establish the potential efficacy and safety of vitamin D supplementation to improve particular outcomes. [ABSTRACT FROM AUTHOR]

Background Studies in childhood suggest that both body composition and early postnatal growth are associated with bone mineral density (BMD). However, little is known of the relationships between longitudinal changes in fat (FM) and lean mass (LM) and bone development in pre-pubertal children. We therefore investigated these associations in a population-based mother-offspring cohort, the Southampton Women's Survey. Methods Total FM and LM were assessed at birth and 6–7 years of age by dual-energy x-ray absorptiometry (DXA). At 6–7 years, total cross-sectional area (CSA) and trabecular volumetric BMD (vBMD) at the 4% site (metaphysis) of the tibia was assessed using peripheral quantitative computed tomography [pQCT (Stratec XCT-2000)]. Total CSA, cortical CSA, cortical vBMD and strength–strain index (SSI) were measured at the 38% site (diaphysis). FM, LM and bone parameters were adjusted for age and sex and standardised to create within-cohort z-scores. Change in LM (ΔLM) or FM (ΔFM) was represented by change in z -score from birth to 7 years old and conditioned on the birth measurement. Linear regression was used to explore the associations between ΔLM or ΔFM and standardised pQCT outcomes, before and after mutual adjustment and for linear growth. The β -coefficient represents SD change in outcome per unit SD change in predictor. Results DXA at birth, in addition to both DXA and pQCT scans at 6–7 years, were available for 200 children (48.5% male). ΔLM adjusted for ΔFM was positively associated with tibial total CSA at both the 4% ( β = 0.57SD/SD, p < 0.001) and 38% sites ( β = 0.53SD/SD, p < 0.001), cortical CSA ( β = 0.48SD/SD, p < 0.001) and trabecular vBMD ( β = 0.30SD/SD, p < 0.001), but not with cortical vBMD. These relationships persisted after adjustment for linear growth. In contrast, ΔFM adjusted for ΔLM was only associated with 38% total and cortical CSA, which became non-significant after adjustment for linear growth. Conclusion In this study, gain in childhood LM was positively associated with bone size and trabecular vBMD at 6–7 years of age. In contrast, no relationships between change in FM and bone were observed, suggesting that muscle growth, rather than accrual of fat mass, may be a more important determinant of childhood bone development. [ABSTRACT FROM AUTHOR]

Whole-body-less-head (WBLH) is the recommended skeletal region of interest (ROI) for dual-energy X-ray absorptiometry (DXA) assessment of bone mineral density (BMD) in children. Historically it has been suggested that the skull is less responsive than the rest of the skeleton to stimuli that affect BMD but there are few published data to support this notion. We compared the associations of BMD with anthropometric, body composition, diet, and activity variables across various ROI. Children from the Southampton Women's Survey (SWS) mother-offspring cohort participated at age 6–7 years, including measurement of height, weight, and whole-body and lumbar spine (LS) BMD by DXA (Hologic Discovery). Physical activity was assessed by accelerometry (Actiheart) and diet by interviewer-led questionnaire. BMD was measured in the following skeletal ROI: whole-body, skull, WBLH and lower limbs (all derived from the whole-body scan) and LS. 1218 children participated. Height z-score, weight z-score, lean mass and milk intake were associated with skull BMD, but associations were weaker than observed for other ROI; for example, the association between lean mass and skull BMD was β (95% CI) 0.11 (0.08, 0.14) SD/kg, compared with 0.32 (0.30, 0.34), 0.38 (0.37, 0.40) and 0.23 (0.21, 0.25) SD/kg for whole body, WBLH and lumbar spine, respectively. Relationships with whole-body BMD were attenuated compared with WBLH. Associations between skull BMD and anthropometry, body composition and dietary variables were weaker than for other DXA sites. These findings support, and importantly provide a quantitative basis for, the recommendation that the skull should be excluded from whole-body DXA analyses in children. • Exclusion of the skull from whole body DXA scans in children has been recommended. • Associations with anthropometry were weaker for skull BMD than BMD at other sites. • Quantitative support for head exclusion from whole-body DXA scans is provided. [ABSTRACT FROM AUTHOR]

Summary Rates of fracture worldwide are changing. Using the Clinical Practice Research Datalink (CPRD), age, and gender, geographical, ethnic and socioeconomic trends in fracture rates across the United Kingdom were studied over a 24-year period 1988–2012. Previously observed patterns in fracture incidence by age and fracture site were evident. New data on the influence of geographic location, ethnic group and socioeconomic status were obtained. Introduction With secular changes in age- and sex-specific fracture incidence observed in many populations, and global shifts towards an elderly demography, it is vital for health care planners to have an accurate understanding of fracture incidence nationally. We aimed to present up to date fracture incidence data in the UK, stratified by age, sex, geographic location, ethnicity and socioeconomic status. Methods The Clinical Practice Research Datalink (CPRD) contains anonymised electronic health records for approximately 6.9% of the UK population. Information comes from General Practitioners, and covers 11.3 million people from 674 practices across the UK, demonstrated to be representative of the national population. The study population consisted of all permanently registered individuals aged ≥ 18 years. Validated data on fracture incidence were obtained from their medical records, as was information on socioeconomic deprivation, ethnicity and geographic location. Age- and sex-specific fracture incidence rates were calculated. Results Fracture incidence rates by age and sex were comparable to those documented in previous studies and demonstrated a bimodal distribution. Substantial geographic heterogeneity in age- and sex adjusted fracture incidence was observed, with rates in Scotland almost 50% greater than those in London and South East England. Lowest rates of fracture were observed in black individuals of both sexes; rates of fragility fracture in white women were 4.7 times greater than in black women. Strong associations between deprivation and fracture risk were observed in hip fracture in men, with a relative risk of 1.3 (95% CI 1.21–1.41) in Index of Multiple Deprivation category 5 (representing the most deprived) compared to category 1. Conclusions This study presents robust estimates of fracture incidence across the UK, which will aid decisions regarding allocation of healthcare provision to populations of greatest need. It will also assist the implementation and design of strategies to reduce fracture incidence and its personal and financial impact on individuals and health services. [ABSTRACT FROM AUTHOR]

Summary: Background: Evidence linking prenatal maternal vitamin D supplementation with the offspring's risk of atopic eczema is inconsistent, with most data coming from observational studies. Objectives: To examine the influence of maternal cholecalciferol supplementation during pregnancy on the risk of atopic eczema in the offspring at ages 12, 24 and 48 months. Methods: Within the UK Maternal Vitamin D Osteoporosis Study (MAVIDOS) double‐blind, randomized placebo‐controlled trial, we examined the relationship of maternal vitamin D supplementation during pregnancy with offspring atopic eczema at ages 12, 24 and 48 months. In MAVIDOS, pregnant women were allocated to either cholecalciferol 1000 IU per day or matched placebo, taken from around 14 weeks' gestation until delivery, with the primary outcome of neonatal whole‐body bone mineral content. The prevalence of atopic eczema in the offspring was ascertained at ages 12 (n = 635), 24 (n = 610) and 48 (n = 449) months, based on the UK Working Party criteria for the definition of atopic dermatitis. The trial was registered with ISRCTN (82927713) and EudraCT (2007‐001716‐23). Results: The characteristics of mothers and offspring were similar between the intervention and placebo groups, apart from longer breastfeeding duration in the intervention group. Adjusting for breastfeeding duration, offspring of mothers who received cholecalciferol 1000 IU daily had a lower odds ratio (OR) of atopic eczema at age 12 months [OR 0·55, 95% confidence interval (CI) 0·32–0·97, P = 0·04]; this effect weakened and was not statistically significant at ages 24 months (OR 0·76, 95% CI 0·47–1·23) or 48 months (OR 0·75, 95% CI 0·37–1·52). The statistical interaction of intervention and breastfeeding duration in relation to eczema at age 12 months was not significant (P = 0·41), but stratification showed reduced infantile eczema risk in the intervention group for infants breastfed for ≥ 1 month (OR 0·48, 95% CI 0·24–0·94, P = 0·03) but not in those breastfed for < 1 month (OR 0·80, 95% CI 0·29–2·17, P = 0·66). Conclusions: Our data provide the first randomized controlled trial evidence of a protective effect of antenatal cholecalciferol supplementation on the risk of infantile atopic eczema, with the effect potentially being via increased breast milk cholecalciferol levels. The findings support a developmental influence on atopic eczema, and point to a potentially modifiable perinatal influence on atopic eczema. What is already known about this topic?There are currently no antenatal interventions proven to reduce the incidence of infantile atopic eczema in the general population.However, observational studies have led to speculation that antenatal vitamin D supplementation may be beneficial. [ABSTRACT FROM AUTHOR]

Pregnancy 25-hydroxyvitamin D [25(OH)D] concentrations are associated with maternal and fetal health outcomes. Using physiological human placental perfusion and villous explants, we investigate the role of the placenta in regulating the relationships between maternal 25(OH)D and fetal physiology. We demonstrate active placental uptake of 25(OH)D3 by endocytosis, placental metabolism of 25(OH)D3 into 24,25-dihydroxyvitamin D3 and active 1,25-dihydroxyvitamin D [1,25(OH)2D3], with subsequent release of these metabolites into both the maternal and fetal circulations. Active placental transport of 25(OH)D3 and synthesis of 1,25(OH)2D3 demonstrate that fetal supply is dependent on placental function rather than simply the availability of maternal 25(OH) D3. We demonstrate that 25(OH)D3 exposure induces rapid effects on the placental transcriptome and proteome. These map to multiple pathways central to placental function and thereby fetal development, independent of vitamin D transfer. Our data suggest that the underlying epigenetic landscape helps dictate the transcriptional response to vitamin D treatment. This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself. These data demonstrate a complex interplay between vitamin D and the placenta and will inform future interventions using vitamin D to support fetal development and maternal adaptations to pregnancy. [ABSTRACT FROM AUTHOR]