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Background: Findings from the Maternal Vitamin D Osteoporosis Study (MAVIDOS) trial demonstrated a positive effect of gestational cholecalciferol supplementation on offspring bone mineral density (BMD) at age 4 y. Demonstrating the persistence of this effect is important to understanding whether maternal vitamin D supplementation could be a useful public health strategy to improving bone health., Objectives: We investigated whether gestational vitamin D supplementation increases offspring BMD at ages 6-7 y in an exploratory post-hoc analysis of an existing trial., Methods: In the MAVIDOS randomized controlled trial, pregnant females <14 wk' gestation with a singleton pregnancy and serum 25-hydroxyvitamin D 25-100nmol/l at 3 United Kingdom hospitals (Southampton, Sheffield, and Oxford) were randomly assigned to either 1000 IU/d cholecalciferol or placebo from 14 to 17-wk gestation until delivery. Offspring born at term to participants recruited in Southampton were invited to the childhood follow-up at ages 4 and 6-7 y. The children had a dual-energy X-ray absorptiometry (DXA, Hologic discovery) scan of whole-body-less-head (WBLH) and lumbar spine, from which bone area, bone mineral content (BMC), BMD, and bone mineral apparent density (BMAD) were derived. Linear regression was used to compare the 2 groups adjusting for age, sex, height, weight, duration of consumption of human milk, and vitamin D use at 6-7 y., Results: A total of 454 children were followed up at ages 6-7 y, of whom 447 had a usable DXA scan. Gestational cholecalciferol supplementation resulted in higher WBLH BMC [0.15 SD, 95% confidence interval (CI): 0.04, 0.26], BMD (0.18 SD, 95% CI: 0.06, 0.31), BMAD (0.18 SD, 95% CI: 0.04, 0.32), and lean mass (0.09 SD, 95% CI: 0.00, 0.17) compared with placebo. The effect of pregnancy cholecalciferol on bone outcomes was similar at ages 4 and 6-7 y., Conclusions: Supplementation with cholecalciferol 1000 IU/d during pregnancy resulted in greater offspring BMD and lean mass in mid-childhood compared with placebo in this exploratory post-hoc analysis. These findings suggest that pregnancy vitamin D supplementation may be an important population health strategy to improve bone health., Trial Registration Number: This trial was registered at the ISRCTN (https://doi.org/10.1186/ISRCTN82927713) as 82927713 and EUDRACT (https://www.clinicaltrialsregister.eu/ctr-search/trial/2007-001716-23/results) as 2007-001716-23., Competing Interests: Conflict of interest RJM has received travel bursaries from Kyowa Kirin unrelated to this work. EMC has received travel bursaries or lecture fees from Eli Lilly, Pfizer, Thornton and Ross, and UCB, unrelated to this work. KMG has received reimbursement for speaking at conferences sponsored by companies selling nutritional products, and is part of an academic consortium that has received research funding from Abbott Nutrition, Nestec, BenevolentAI Bio Ltd., and Danone, outside the submitted work. MKJ reports consultancy and speaker fees from UCB, Amgen, and Kyowa Kirin. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier, and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Theramex, Shire, Consilient Healthcare, Kyowa Kirin, and Internis Pharma, outside the submitted work. KAW received Honoraria from Abbott Nutrition unrelated to this work. IS, SRC, and SD declare no conflicts of interest related to the submitted work., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Person-centered approaches to measuring severity of multimorbidity (≥ 2 chronic conditions) can help clinicians assess the individual experience of multimorbidity and inform effective caregiving and intervention strategies. We examine how limitations in everyday activities attributable to specific chronic conditions act independently and in tandem to influence individual perceptions of multimorbidity severity., Methods: Data from the Panel Study of Income Dynamics (2005-2021) were used to investigate self-reported limitations in normal daily activities resulting from nine chronic conditions (hypertension, arthritis, diabetes, heart condition [heart disease/heart attack], cancer, lung disease, stroke, depression, and memory loss) in 4 318 adults aged 55-95 (18 878 person-wave observations). We used descriptive and inferential analyses to estimate limitations resulting from specific conditions, limitations attributable to condition combinations, and the contribution of comorbid conditions to condition-specific and overall severity. Follow-up analyses addressed mortality selection using inverse probability weighting and examined cancer type and cancer status/treatment modality among respondents reporting cancer diagnosis., Results: Of the more prevalent conditions, arthritis was associated with the most severe limitations to normal activities. Memory loss was the least frequent condition reported but resulted in the most severe limitations, and as a comorbid condition, increased limitations reported for most conditions. Inverse probability weighting adjusted models revealed heterogeneity in estimates for some conditions including cancer and cancer survivors tended to report less lethal cancers that were cured or in remission., Conclusions: Our results suggest that efforts to prevent and treat arthritis and support cognitive function may reduce the severity of multimorbidity experienced by the individual., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Excessive production of Transforming Growth Factor β (TGFβ) is commonly associated with dominant and recessive forms of OI. Previous reports have indicated that administration of TGFβ-targeted antibodies maybe of potential therapeutic benefit to OI patients. However, direct targeting of TGFβ is likely to cause multiple adverse effects including simulation of autoimmunity. In the current study we use patient-derived normal and OI fibroblasts, osteoblasts and OIM mouse models to determine the effects of Losartan, an angiotensin II receptor type 1 (AT1) antagonist, on TGFβ signalling and bone morphology in OI. In OIM mice bred on a mixed background administration of 0.6 g/L losartan for 4 weeks was associated with a significant reduction in TGFβ from 79.2 g/L in the control to 60.0 ng/ml following losartan ( p  < 0.05), reduced osteoclast activity as measured by CTX from 275.9 ng/ml in the control to 157.2 ng/ml following 0.6 g/L of losartan (p < 0.05) and increased cortical bone thickness ( P  < 0.001). Furthermore in OIM mice bred on a C57BL/6 background 0.6 g/L losartan increased trabecular bone volume in the tibiae ( P  < 0.05) and the vertebrae ( P  < 0.01), increased cortical bone thickness ( P  < 0.001) reduced the trabecular pattern factor ( P  < 0.01 and P < 0.001 for the tibiae and vertebrae respectively), reduced osteoclast ( P  < 0.05) and osteoblast (P < 0.01) numbers as well as reducing the area of bone covered by these cell types. Interestingly, losartan did not affect immune cells infiltrating into bone, nor did this drug alter TGFβ signalling in normal or OI fibroblasts. Instead, losartan reduced SMAD2 phosphorylation in osteoblasts, inhibiting their ability to differentiate. Our data suggest that losartan may be an effective treatment for the bone-associated dysmorphia displayed in OI whilst minimising potential adverse immune cell-related effects., Competing Interests: NJB is global chief investigator of the Ultragenyx-funded studies (ORBIT, COSMIC) of setrusumab in children and young adults with OI and has consulted with Alexion, Mereo and Rampart and has been DMEC chair for a Pfizer study (recifercept in achondroplasia). No other authors have relevant conflicts of interest to declare., (© 2024 The Authors.)

Background: The rapidly growing field of multimorbidity research demonstrates that changes in multimorbidity in mid- and late-life have far reaching effects on important person-centered outcomes, such as health-related quality of life. However, there are few organizing frameworks and comparatively little work weighing the merits and limitations of various quantitative methods applied to the longitudinal study of multimorbidity., Methods: We identify and discuss methods aligned to specific research objectives with the goals of (i) establishing a common language for assessing longitudinal changes in multimorbidity, (ii) illuminating gaps in our knowledge regarding multimorbidity progression and critical periods of change, and (iii) informing research to identify groups that experience different rates and divergent etiological pathways of disease progression linked to deterioration in important health-related outcomes., Results: We review practical issues in the measurement of multimorbidity, longitudinal analysis of health-related data, operationalizing change over time, and discuss methods that align with 4 general typologies for research objectives in the longitudinal study of multimorbidity: (i) examine individual change in multimorbidity, (ii) identify subgroups that follow similar trajectories of multimorbidity progression, (iii) understand when, how, and why individuals or groups shift to more advanced stages of multimorbidity, and (iv) examine the coprogression of multimorbidity with key health domains., Conclusions: This work encourages a systematic approach to the quantitative study of change in multimorbidity and provides a valuable resource for researchers working to measure and minimize the deleterious effects of multimorbidity on aging populations., (© The Author(s) 2024. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Existing research suggests that children who experience poverty and hospitalization in early childhood are at risk of developing behavior problems. We examined whether the association between early childhood hospitalization and children's internalizing and externalizing behaviors were moderated by family poverty status and child sex. Participants included 224 children from the National Institute of Child Health and Human Development Study of Early Child Care and Youth Development. There was no direct association between hospitalization and problematic behaviors. Poverty status during early childhood, but not child sex, significantly moderated the association between hospitalization and externalizing problems. Findings support the need for community programs that promote an integrative approach to healthcare for families experiencing poverty., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Background: Observational studies relating maternal 25-hydroxyvitamin D status to timing and mode of delivery have reported inconsistent results. We assessed the effect of antenatal cholecalciferol supplementation on the incidence of preterm birth, delivery mode and post-partum haemorrhage (PPH)., Methods: MAVIDOS was a randomized, double-blind, placebo-controlled trial of 1000 IU/day cholecalciferol from 14 weeks' gestation until delivery. Gestational age, mode of delivery [categorized as spontaneous vaginal delivery (SVD), instrumental (including forceps and vacuum extraction) or Caesarean section] and PPH (>500 ml estimated blood loss) were determined from medical records., Results: A total of 965 women participated in the study until delivery. Gestation at birth and incidence of preterm birth (cholecalciferol 5.7%, placebo 4.5%, P = 0.43) were similar between the two treatment groups. SVD (versus instrumental or Caesarean delivery) was more likely in women randomized to cholecalciferol [Relative Risk (RR) 1.13, 95% confidence interval (CI) 1.02,1.25] due to lower instrumental (RR 0.68, 95%CI 0.51,0.91) but similar risk of Caesarean delivery (RR 0.94, 95%CI 0.74,1.19). PPH was less common in women randomized to cholecalciferol [32.1% compared with placebo (38.1%, P = 0.054) overall], but similar when stratified by delivery mode., Conclusions: Antenatal cholecalciferol supplementation did not alter timing of birth or prevalence of preterm birth but demonstrated a possible effect on the likelihood of SVD., (© The Author(s) 2022. Published by Oxford University Press on behalf of Faculty of Public Health.)

Objectives: Multimorbidity, also referred to as multiple chronic conditions (MCCs), is the concurrent presence of 2 or more chronic health conditions. Increasing multimorbidity represents a substantial threat to the health of aging populations. Recent trends suggest greater risk of poor health and mortality among later-born cohorts, yet we are unaware of work examining cohort differences in multimorbidity among aging U.S. adults., Methods: We examine intercohort variation in MCC burden in adults aged 51 years and older using 20 years (n = 33,598; 1998-2018) of repeated assessment drawn from the Health and Retirement Study. The index of MCCs included 9 chronic conditions (heart disease, hypertension, stroke, diabetes, arthritis, lung disease, cancer excluding skin cancer, high depressive symptoms, and cognitive impairment). We used linear mixed models with various approaches to estimate age/period/cohort effects to model intercohort patterns in MCC burden. We also explored variation in the specific conditions driving cohort differences in multimorbidity., Results: More recent cohorts had greater MCC burden and developed multimorbidity at earlier ages than those born to prior generations. The burden of chronic conditions was patterned by life-course sociodemographic factors and childhood health for all cohorts. Among adults with multimorbidity, arthritis and hypertension were the most prevalent conditions for all cohorts, and there was evidence that high depressive symptoms and diabetes contributed to the observed cohort differences in multimorbidity risk., Discussion: Our results suggest increasing multimorbidity burden among more recently born cohorts of aging U.S. adults and should inform policy to address diminishing health in aging populations., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: Biochemical and haematological testing is recommended in the United Kingdom when inflicted injury is suspected. We examined the associations of test results with radiologically-confirmed fracture(s), and between test results, in a large retrospective observational cohort., Methods: Infants up to age two years presenting with suspected inflicted injury, without clinically or radiologically apparent bone disease, and where a skeletal survey was undertaken during the period 1st August 2013 to 31st December 2020, were included. Biochemical parameters: corrected calcium (cCa); phosphate (P); alkaline phosphatase (ALP); parathyroid hormone (PTH); 25-hydroxyvitamin D (25D); and haematological parameters: haemoglobin (Hb); mean corpuscular haemoglobin (MCH); mean corpuscular haemoglobin content (MCHC); mean corpuscular volume (MCV); platelet count were collated together with the results of the radiological assessments., Findings: Of 332 eligible infants (190 male), 142 (84 male) had fracture(s) and/or intracranial injury. Mean PTH in the non-fracture group (n measured 50/190) was 27.3 ng/l; in those with intracranial injury alone (n measured 9/23) was 39.4 ng/l; in those with fracture alone (n measured 62/84) was 45.0 ng/l; and in those with fracture and intracranial injury (n measured 20/35) 51.8 ng/l. F-test of multiple means = 0.0369. There was no difference in 25D between the groups., Interpretation: PTH was raised in infants who had fracture(s), intracranial injury or both. A single raised PTH may not necessarily be an indicator of prior disturbed skeletal health in these circumstances. The relevance of vitamin D status and interpretation of data from biochemical testing should be informed by the overall presentation in suspected inflicted injury cases. A single raised PTH may be a consequence of the child's injuries rather than prior disturbed bone health., (Copyright © 2022 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Secreted protein, acidic, cysteine rich ( SPARC )-related osteogenesis imperfecta (OI), also referred to as OI type XVII, was first described in 2015, since then there has been only one further report of this form of OI. SPARC is located on chromosome 5 between bands q31 and q33. The encoded protein is necessary for calcification of the collagen in bone, synthesis of extracellular matrix and the promotion of changes to cell shape., Methods: We describe a further two patients with previously unreported homozygous SPARC variants with OI: one splice site; one nonsense pathogenic variant. We present detailed information on the clinical and radiological phenotype and correlate this with their genotype. There are only two previous reports by Mendozo-Londono et al and Hayat et al with clinical descriptions of patients with SPARC variants., Results: From the data we have obtained, common clinical features in individuals with OI type XVII caused by SPARC variants include scoliosis (5/5), vertebral compression fractures (5/5), multiple long bone fractures (5/5) and delayed motor development (3/3). Interestingly, 2/4 patients also had abnormal brain MRI, including high subcortical white matter changes, abnormal fluid-attenuated inversion in the para-atrial white matter and a large spinal canal from T10 to L1. Of significance, both patients reported here presented with significant neuromuscular weakness prompting early workup., Conclusion: Common phenotypic expressions include delayed motor development with neuromuscular weakness, scoliosis and multiple fractures. The data presented here broaden the phenotypic spectrum establishing similar patterns of neuromuscular presentation with a presumed diagnosis of 'myopathy'., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

The current study aimed to investigate the association between grandparenting and cognitive function over time in noncustodial grandparents in China and the United States. Lagged dependent variable (LDV) approach and linear regression models were applied to analyze a sample of 1,411 Chinese and 6,579 American adults aged 65 and above from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2013) and the U.S. Health and Retirement Study (HRS, 2012-2014). Grandparenting involvement was associated with less decline in episodic memory for grandparents and greater level of grandparenting had no negative effect on mental status and global cognitive function in noncustodial grandparents in China and the United States. The impact of grandparenting on cognitive function was conditioned on caregiving intensity, gender, urban/rural residence, and nation. Findings of the study suggest that greater attention on grandparenting facilitation might yield improved research, social support, policy, and interventions on cognitive health for the general older population.

In the Maternal Vitamin D Osteoporosis Study (MAVIDOS) randomized trial, vitamin D supplementation in pregnancy did not lead to greater neonatal bone mass across the trial as a whole, but, in a prespecified secondary analysis by season of birth, led to greater neonatal bone mass among winter-born babies. Demonstrating persistence of this effect into childhood would increase confidence in a long-term benefit of this intervention. We investigated whether antenatal vitamin D supplementation increases offspring bone mineralization in early childhood in a prespecified, single-center follow-up of a double-blinded, multicenter, randomized controlled clinical trial based in the UK (MAVIDOS). A total of 1123 women in early pregnancy with a baseline 25-hydroxyvitamin D level 25-100 nmol/L from three research centers (2008-2014) were randomized to 1000 IU/d cholecalciferol or matched placebo from 14 weeks of gestation to delivery. Offspring born at the Southampton, UK research center were assessed at age 4 years (2013-2018). Anthropometry and dual-energy X-ray absorptiometry (DXA) were performed (yielding whole body less head [WBLH] bone mineral content [BMC], areal bone mineral density [aBMD], bone area [BA], and body composition). Of 723 children, 564 (78.0%) children attended the 4-year visit, 452 of whom had a useable DXA. Maternal vitamin D supplementation led to greater WBLH aBMD in the children compared with placebo (mean [95% confidence interval {CI}]: supplemented group: 0.477 (95% CI, 0.472-0.481) g/cm 2 ; placebo group: 0.470 (95% CI, 0.466-0.475) g/cm 2 , p  = 0.048). Associations were consistent for BMC and lean mass, and in age- and sex-adjusted models. Effects were observed across the whole cohort irrespective of season of birth. Maternal-child interactions were observed, with a greater effect size among children with low milk intake and low levels of physical activity. Child weight, height, and body mass index (BMI) were similar by maternal randomization group. These findings suggest a sustained beneficial effect of maternal vitamin D supplementation in pregnancy on offspring aBMD at age 4 years, but will require replication in other trials. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research., Competing Interests: EMC reports honoraria/travel support from Eli Lilly, Pfizer, and UCB outside the submitted work. NJB reports remuneration from Internis Pharmaceuticals Ltd, outside the submitted work. ATP reports grants from Versus Arthritis, Medical Research Council, National Institute for Health Research, Bupa Foundation, BBSRC, and EU outside the submitted work. KMG reports reimbursement for speaking at Nestle Nutrition Institute conferences, grants from Abbott Nutrition & Nestec, outside the submitted work; in addition, KMG has a patent Phenotype Prediction pending, a patent Predictive Use of CpG Methylation pending, and a patent Maternal Nutrition Composition pending, not directly related to this work. MKJ reports personal fees from Stirling Anglia, Consilient Health and Internis, outside the submitted work. RE reports grants from Amgen, grants and personal fees from IDS, grants from Alexion, grants and personal fees from Roche, personal fees from GSK Nutrition, personal fees from Mereo, personal fees from Sandoz, grants and personal fees from Nittobo, personal fees from AbbVie, personal fees from Samsung, personal fees from Haoma Medica, personal fees from Elsevier, personal fees from CL Bio, personal fees from FNIH, personal fees from Viking, personal fees from UCSF, personal fees from Biocon, from Lyramid, outside the submitted work. CC reports personal fees from ABBH, Amgen, Eli Lilly, GSK, Medtronic, Merck, Novartis, Pfizer, Roche, Servier and Takeda, outside the submitted work. NCH reports personal fees, consultancy, lecture fees and honoraria from Alliance for Better Bone Health, AMGEN, MSD, Eli Lilly, Servier, Shire, UCB, Consilient Healthcare, Kyowa Kirin and Internis Pharma, outside the submitted work. RJM, SD, SRC, JSGK, SHK, RF, SVG, IS, AP, and HMI have nothing to disclose. Of the MAVIDOS group: N. Arden has received honoraria, held advisory board positions (which involved receipt of fees), and received consortium research grants, respectively, from: Merck, grants from Roche, personal fees from Smith & Nephew, Nicox, Flexion, grants from Bioiberica, Novartis, and personal fees from Bioventus and Freshfields, outside the submitted work. M.Z. Mughal has received lecture fees from Abbott Nutrition & Thornton & Ross, outside the submitted work. A. Carr, M. Clynes, E. Dennison, D. Reid, and S. Woolford have nothing to disclose., (© 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.)

Objectives: In the context of a lack of national consensus on the benefits of skull base imaging in children with osteogenesis imperfecta (OI), this study aims to analyse and correlate the clinical symptoms and radiological images of children with severe OI., Methods: A retrospective case notes and image analysis was carried out on children with complex OI between 2012 and 2018 at a specialist tertiary centre. Data were collected on patient demographic factors, clinical data, imaging findings (presence of Wormian bones, platybasia, basilar impression (McGregor's technique) and basilar invagination (McRae's technique)), and clinical features at the time of imaging., Results: Of the 127 patients in the OI database, 94 were included. A total of 321 radiographs, 21 CT scans and 39 MRI scans were analysed. Average frequency of radiographs was 8 per 10 years. Of the 94 patients, 58 (62%), 10 (11%), 1 (1%) demonstrated platybasia, basilar impression, and basilar invagination, respectively. Of the radiographs analysed, platybasia, basilar impression, basilar invagination, and the presence of Wormian bones, could not be evaluated in 71 (22.3%), 48 (15.2%), 61 (19.5%) and 28 (9.4%) radiographs respectively (due to poor positioning, anatomical abnormalities, and poor image quality). Of the 140 radiographs with platybasia, 17 (12%) also demonstrated basilar impression compared to only 3 (2.9%) out of the 99 without platybasia (p = 0.03). No significant associations were seen between the presence of Wormian bones and basilar impression. Of the 39 MRIs, additional information on CSF flow rate, spinal cord signal and cerebellar morphology was reported in 14 (36%). There was a lack of concordance between MRI and matched radiographs in 7.1% (1/14) and 36% (5/14) for platybasia and basilar impression respectively, with full concordance for basilar invagination. Fewer than 5% had positive clinical symptoms/signs at the time of imaging; 2% (7/321) had macrocephaly, 0.6% (2/321) headache, all other neurological features were absent). Clinical features were not documented in >85% of patients., Conclusion: The apparent low prevalence of clinical symptoms and signs and of radiologically identified cranio-cervical abnormalities, suggests that current levels of serial imaging may be excessive. Until larger prospective studies clarify these issues, we suggest a clinical pathway for base of skull imaging which proposes a risk stratification approach to radiographic frequency and suggests parameters for proceeding to MRI., (Copyright © 2021 Elsevier Inc. All rights reserved.)

eHealth literacy is a critical factor that influences caregivers' well-being. The purpose of this study is to examine the association between eHealth literacy, education, and caregiver burden among Chinese caregivers of older adults with cognitive impairment. Data came from structured interviews with 300 primary family caregiver-care recipient dyads in Wuhan, China. We used logistic regression to examine the association between eHealth literacy, education, and caregiver burden. An interaction effect between eHealth literacy and education on caregiver burden was identified. eHealth literacy was positively associated with caregiver burden among caregivers with less than a high school education, but not among those with a high school education or above. eHealth literacy is salient in the burden experienced by caregivers with low education. eHealth literacy needs to be enhanced with health information verification from health professionals and programs to support caregiving efficacy to realize its positive impact on caregivers' mental health.

To identify potentially modifiable risk-factors in the age-related disablement process, we examined the association between change in mobility limitations and multimorbidity and how dietary quality moderates this association. Information from 3320 adults aged 65 and older in 2012 was drawn from the Health and Retirement Study and the Health Care and Nutrition Study. Mobility limitations reported in 2012 and change in mobility limitations from 2012 to 2014 were regressed on multimorbidity measured as number of chronic conditions in 2012, dietary quality measured in 2013 using the Alternative Healthy Eating Index-2010 (AHEI-2010), and their interaction term using Poisson regression. Respondents reported an average of 2.9 (SD, 2.9) mobility limitations in 2012 and 3.1 (SD, 3.0) mobility limitations in 2014, an average of 2.64 (SD, 1.4) chronic conditions in 2012, and mean AHEI-2010 score in 2013 of 57.1 (SD, 10.9). Greater AHEI-2010 scores were associated with fewer mobility limitations at baseline (p < .001) and slower progression of mobility limitations over the two-year observational window (p < .001). For those with AHEI-2010 scores ≥48.4, dietary quality appeared to moderate the association between multimorbidity and change in mobility limitations. These results suggest that improving dietary quality may be an effective means of reducing the progression of mobility limitations among older adults and that dietary quality may modify the effect of multimorbidity on progressive disablement. Our work adds to research supporting dietary quality as a potentially intervenable factor in the reduction of disablement in aging populations., (Copyright © 2021. Published by Elsevier Inc.)

Background: The pattern of change in maternal bone turnover throughout pregnancy is poorly characterized., Objectives: We investigated changes across pregnancy in a marker of maternal bone resorption, urinary C-terminal telopeptide of type I collagen (CTX), the influence of gestational vitamin D supplementation, and associations between CTX and maternal postnatal bone indices., Methods: MAVIDOS (the Maternal Vitamin D Osteoporosis Study) is a randomized, double-blind, placebo-controlled trial of 1000 IU cholecalciferol/d compared with placebo from 14 weeks of gestation to birth. Maternal second-void urinary α- and β-CTX were measured (ELISA) at 14 and 34 weeks of gestation; DXA was performed within 2 wk postpartum. The Mann-Whitney Rank Sum test, Spearman's rank correlation, and linear regression were used to compare median CTX values within and between groups from early to late pregnancy, and associations with maternal bone outcomes., Results: In total, 372 women had CTX and 25-hydroxyvitamin D [25(OH)D] measured in early and late pregnancy. CTX at 14 and 34 weeks of gestation were correlated in both placebo (r = 0.31) and cholecalciferol (r = 0.45) groups (P < 0.0001). Median CTX increased from 14 to 34 weeks of gestation in both groups (n = 372 total) [placebo (n = 188): from 223.6 to 449.7 μg/mmol creatinine; cholecalciferol (n = 184): from 222.3 to 419.3 μg/mmol creatinine; P = 0.03 for placebo compared with cholecalciferol difference in CTX at 34 weeks of gestation]. The conditional mean ± SD increase in CTX [z-score (SD)] from early to late pregnancy was greater in the placebo group (n = 188) than in the cholecalciferol group (n = 184) (placebo: 0.16 ± 0.92; cholecalciferol: -0.16 ± 1.06; P-difference < 0.01). Higher CTX at 34 weeks of gestation was associated, similarly in both groups, with lower maternal total hip and lumbar spine bone mineral content and bone mineral density (BMD) (e.g., lumbar spine BMD: β = -0.02 g · cm-2 · SD-1 increase in CTX; 95% CI: -0.027, -0.002 g · cm-2 · SD-1; P = 0.02, n = 283)., Conclusions: Maternal urinary CTX, a bone resorption marker, rises through pregnancy, although to a lesser degree with gestational cholecalciferol supplementation, and is inversely associated with maternal bone mass postpartum.This trial was registered at www.isrctn.com as ISRCTN 82927713 and eudract.ema.europa.eu as EudraCT 2007-001716-23., (© The Author(s) 2021. Published by Oxford University Press on behalf of the American Society for Nutrition.)

Objectives: Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; extra-skeletal features in OI include blue sclerae, dentinogenesis imperfecta, skin laxity and joint hyper-extensibility. Most patients with OI are thought to have a low bone mass but contrary to expectations there are certain forms of OI with high bone mass which this study explores in further detail., Method: A cohort of n = 6 individuals with pathogenic variants in BMP1 and the C-propeptide cleavage variants in COL1A1 were included in this study. Detailed clinical and radiological phenotyping was done and correlated with genotype to identify patterns of clinical presentation and fracture history in this cohort of patients. This data was compared to previously reported literature in this group., Results: 2 patients with BMP1 and 4 patients with pathogenic variants in C-propeptide region in COL1A1 were deep-phenotyped as part of this study and 1 patient with C-propeptide variant in COL1A1 , showed low bone mineral density. In those with an elevated bone mineral density, this became even more apparent on bisphosphonate therapy. Patients in this cohort had variable clinical presentation ranging from antenatal presentation to more of an insidious course resulting in later confirmation of genetic diagnosis up to 19 years of age., Conclusions: Patients with pathogenic variants in the C-propeptide region of COL1A1/A2 and BMP1 appear to have a high bone mass phenotype with increased sensitivity to bisphosphonate therapy. It is important to closely monitor patients with these genotypes to assess their response to therapy and tailor their treatment regime accordingly., Competing Interests: The authors declare that they have no known competing financialinterestsor personal relationships that could have appeared to influence the work reported in this paper., (© 2021 Published by Elsevier Inc.)

Objective: Existing research suggests walnut intake may be associated with better cognitive function in older adults, yet few studies utilise longitudinal data from observational studies of ageing populations. Our objective was to estimate the association between whole walnut intake and cognitive change in a representative sample of older Americans., Design: Secondary analysis of the Health and Retirement Study and Health Care and Nutrition Study. Walnut consumption was defined as a categorical measure (none, low intake (0·01-0·08 1 oz. servings per day) and moderate intake (>0·08 1 oz. servings per day)) and cognitive function was measured using the Telephone Interview for Cognitive Status. Latent growth modelling estimated the association between walnut consumption and trajectories of cognitive status over a 4-year observational period. Sensitivity analyses assessing non-random dropout and Monte Carlo power analyses were conducted to contextualise results., Setting: The USA., Participants: A sample of 3632 US adults aged 65 years and older., Results: Those reporting any walnut consumption had greater cognitive scores at baseline than those not consuming walnuts (low walnut consumption, b = 1·53, se = 0·21, P < 0·001; moderate walnut consumption, b = 2·22, se = 0·27, P < 0·001), but walnut consumption was not associated with cognitive change. Walnut consumption was positively associated with socioeconomic status and health behaviours as well as intake of nutrients identified to have neuroprotective benefits., Conclusions: We identified an association between walnut consumption and cognitive function in older adults, although we did not find that walnut consumption was protective against age-related cognitive decline.

Objective: The purpose of the study was to examine the association between dietary lutein and zeaxanthin (L + Z) intake and immediate word recall (IWR) and delayed word recall (DWR), and to identify the major contributors to dietary L + Z intake in a recent and representative sample of the older US population., Design: In this cross-sectional analysis, multivariate path analytic models estimated the association between L + Z consumption and cognitive performance while adjusting for covariates., Setting: Observations were drawn from the 2014 Health and Retirement Study, a nationally representative panel study of older US adults, and the 2013 Health Care and Nutrition Study, which assessed dietary intake via FFQ in a subsample of respondents., Participants: The analytic sample included 6390 respondents aged ≥50 years., Results: L + Z intake was 2·44 ± 2·32 mg/d on average, and L + Z intake differed significantly across quartiles (P < 0·001). For example, average L + Z intake in Q1 was 0·74 ± 0·23 mg/d and in Q4 was 5·46 ± 2·88 mg/d. In covariate adjusted models, older adults in the highest quartiles of L + Z intake had significantly greater IWR and DWR scores than those in the lowest quartile. Leafy vegetables, cruciferous vegetables, dark yellow vegetables, fish and seafood, legumes, eggs and fruit were significant and meaningful predictors of dietary L + Z intake., Conclusion: A high consumption of vegetables, fish and seafood, legumes, eggs and fruit is associated with a higher intake of L + Z and greater word recall among older adults.

Bone health in children with osteogenesis imperfecta is monitored using radiographs and dual-energy X-ray absorptiometry, which have limitations. High-resolution peripheral quantitative CT can non-invasively derive bone microarchitectural data. Children with severe osteogenesis imperfecta have fragile deformed bones, and positioning for this scan can be difficult. We assessed the feasibility of high-resolution peripheral quantitative CT in nine children aged 9-15 years with osteogenesis imperfecta and compared results with dual-energy X-ray absorptiometry and with healthy controls. All nine recruited children were successfully scanned and showed no preference for either modality. It therefore appears feasible to perform high-resolution peripheral quantitative CT in children with osteogenesis imperfecta aged 9 years and older. Future studies should focus on understanding the clinical implications of the technology in this patient cohort.

This article provides an overview of the current knowledge on hypophosphatasia-a rare genetic disease of very variable presentation and severity-with a special focus on adolescents and adults. It summarizes the available information on the many known mutations of tissue-nonspecific alkaline phosphatase (TNSALP), the epidemiology and clinical presentation of the disease in adolescents and adults, and the essential diagnostic clues. The last section reviews the therapeutic approaches, including recent reports on enzyme replacement therapy (EnzRT).

Objective: To estimate latent dietary profiles in a community-dwelling sample of older Americans and identify associations between dietary profile membership and individual demographic, socio-economic and health characteristics., Design: Secondary analysis of the 2012 Health and Retirement Study (HRS) and linked 2013 Health Care and Nutrition Study (HCNS). Latent profile analysis identified mutually exclusive subgroups of dietary intake and bivariate analyses examined associations between dietary profile membership, participant characteristics and nutrient intakes., Setting: USA., Participants: An analytic sample of 3558 adults aged 65 years or older., Results: Four dietary profiles were identified with 15·5 % of the sample having a 'Healthy' diet, 42·0 % consuming a 'Western' diet, 29·7 % having a diet consisting of high intake of all food groups and 12·7 % reporting relatively low intake of all food groups. Members of the 'Healthy' profile reported the greatest socio-economic resources and health, and members of the 'Low Intake' profile had the fewest resources and worst health outcomes. Macronutrient and micronutrient intakes varied across profile although inadequate and excessive intakes of selected nutrients were observed for all profiles., Conclusions: We identified dietary patterns among older Americans typified by either selective intake of foods or overall quantity of foods consumed, with those described as 'Low Intake' reporting the fewest socio-economic resources, greatest risk of food insecurity and the worst health outcomes. Limitations including the presence of measurement error in dietary questionnaires are discussed. The causes and consequences of limited dietary intake among older Americans require further study and can be facilitated by the HRS and HCNS.

Background and Objectives: The purpose of the present study is to examine the socioeconomic correlates of adherence to minimum mineral intake recommended by the Chinese Dietary Guidelines during each trimester of pregnancy among Chinese women., Methods and Study Design: A total of 567 pregnant women with foetal age of 6 - 12 weeks were recruited from nine community health centres and three hospitals. Cross-sectional survey data were collected using structured interviews and questionnaires. Mineral intake was calculated from food consumption reported on 24-hour dietary reviews using the Chinese Food Composition Metrics. Logistic regression models were estimated to assess the relationship between sociodemographic factors and adherence to mineral intake recommendations for each trimester., Results: Significant predictors of adherence to mineral intake recommendations include: (1) age (zinc: OR=1.09, p<0.05; copper: OR=1.11, p<0.05), having bachelor's degree (copper: OR=2.23, p<0.05; phosphorus: OR=2.23, p<0.01), and household income ≥5,000RMB (potassium: OR=2.51, p<0.001; phosphorus: OR=1.91, p<0.05) during the first trimester, (2) being employed (zinc: OR=0.54, p<0.001; selenium: OR=0.53, p<0.05) and household income ≥5,000 RMB (zinc: OR=1.86, p<0.05) during the second trimester, and (3) husband/partner with associate degree or vocational school education (selenium: OR=3.26, p<0.01) and household income of 3,000-4,999 RMB (potassium: OR=1.71, p<0.05; zinc: OR=1.48, p<0.05) during the third trimester., Conclusions: To our knowledge, this is the first study that examines the relationship between socioeconomic factors and mineral intake among Chinese pregnant women at three trimesters. Findings highlight the importance of considering individuals' socioeconomic status to develop personalized interventions to prevent undernutrition among this population.

Objective: Existing research supports a positive relationship between egg intake and cognitive function in older populations, although the impact of whole egg consumption on multi-domain cognitive function and cognitive decline in representative samples of older adults has not been described. We examined the association between egg consumption, cognitive performance, and cognitive change in a representative sample of U.S. adults aged 65 and older. Methods: We drew observations from the 2012 and 2014 Health and Retirement Study and the recently released 2013 Health Care and Nutrition Study. The analytic sample contained 3835 respondents, representing a weighted population of 37,806,082 community-dwelling adults aged 65 and older in 2013. Multivariate path analytic models were used to estimate the association between egg consumption groups (none, ≤ 1 serving per week, 2-6 servings per week, ≥ 7 servings per week) and cognitive performance across domains of working memory, executive function, and global mental status. First-order autoregressive models were used to estimate cognitive change over the 2-year observational period. Follow-up analyses examined associations between egg consumption group, dietary patterns, and nutrient intake. Results: On average, older adults consumed 0.34 eggs per day ( SD  = 0.36). Although bivariate analyses suggested that moderate egg consumers had the best cognitive performance at baseline assessment, egg consumption was not associated with cognitive performance or cognitive change when adjusting models for covariates known to have a robust association with cognitive health. Conclusions: Our results suggest that egg consumption does not benefit, nor is detrimental to, the cognitive health of older adults. Further studies of whole egg consumption and cognitive performance would benefit from controlled experimental settings, longer follow-up periods to measure cognitive change, and assessment of both community-dwelling and institutionalized older adults.

We have previously demonstrated inverse associations between maternal 25(OH)-vitamin D status and perinatal DNA methylation at the retinoid-X-receptor-alpha (RXRA) locus and between RXRA methylation and offspring bone mass. In this study, we used an existing randomized trial to test the hypothesis that maternal gestational vitamin D supplementation would lead to reduced perinatal RXRA locus DNA methylation. The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicenter, double-blind, randomized, placebo-controlled trial of 1000 IU/day cholecalciferol or matched placebo from 14 weeks' gestation until delivery. Umbilical cord (fetal) tissue was collected at birth and frozen at -80°C (n = 453). Pyrosequencing was used to undertake DNA methylation analysis at 10 CpG sites within the RXRA locus (identified previously). T tests were used to assess differences between treatment groups in methylation at the three most representative CpG sites. Overall, methylation levels were significantly lower in the umbilical cord from offspring of cholecalciferol-supplemented mothers, reaching statistical significance at four CpG sites, represented by CpG5: mean difference in % methylation between the supplemented and placebo groups was -1.98% (95% CI, -3.65 to -0.32, p = 0.02). ENCODE (Encyclopedia of DNA Elements) evidence supports the functionality of this locus with strong DNase hypersensitivity and enhancer chromatin within biologically relevant cell types including osteoblasts. Enrichment of the enhancer-related H3K4me1 histone mark is also seen in this region, as are binding sites for a range of transcription factors with roles in cell proliferation, response to stress, and growth factors. Our findings are consistent with previous observational results and provide new evidence that maternal gestational supplementation with cholecalciferol leads to altered perinatal epigenetic marking, informing mechanistic understanding of early life mechanisms related to maternal vitamin D status, epigenetic marks, and bone development. © 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc., (© 2018 The Authors. Journal of Bone and Mineral Research Published by Wiley Periodicals Inc.)

Objectives: It is well established that UK Asians typically have lower vitamin D levels than Caucasians. It is also known that vitamin D binding protein (DBP) is lower in some races than Caucasians. To investigate how ethnicity, skin colour and genetic variation affect the response to vitamin D (15000 IU) administered to young Asian and Caucasian men., Design: Prospective, single-centre clinical trial., Participants: Sixty young men (18-25 year) of Asian (n = 30) and Caucasian (n = 30) origin., Measurements: We measured serum calcium, phosphate, magnesium, alkaline phosphatase, albumin, parathyroid hormone; total 25 hydroxyvitamin D (25OHD); calculated and directly measured free 25OHD; DBP at baseline and 4 weeks; DBP genotype, skin colour (Fitzpatrick scale), dietary vitamin D and calcium intake at baseline; and urine calcium:creatinine ratio at baseline, 1 and 4 weeks., Results: At baseline, Asians had lower serum total 25OHD (26.4 [13.7] vs 34.1 [12.3] nmol/L P = 0.0272) and DBP (6.7 [3.4] vs 9.6 [4.4] nmol/L; P = 0.0065) but similar free 25OHD (16.7 [10.4] vs 17.8 [7.5] pmol/L P = 0.6530). After dosing, total 25OHD rose similarly in each group (≈56 nmol/L), but measured free 25OHD rose more in Asians (18.1 [9.4] vs 12.2 [13.3] pmol/L P = 0.0464). Lower DBP at baseline, possibly reflecting genotype differences, was associated with a greater change in measured free 25OHD in Caucasians, but not in Asians., Conclusions: Asian compared with Caucasian males had a larger increment in measured free 25OHD following 150 000 units vitamin D3, possibly reflecting differences in DBP affinity for 25OHD. Ethnicity should be considered when devising guidelines for the treatment of vitamin D deficiency., (© 2018 John Wiley & Sons Ltd.)

Bone disease in the neonatal period has often been regarded as an issue affecting premature infants, or a collection of rare and ultra-rare disorders that most neonatologists will see only once or twice each year, or possibly each decade. The emergence of targeted therapies for some of these rare disorders means that neonatologists may be faced with diagnostic dilemmas that need a rapid solution in order to access management options that did not previously exist. The diagnostic modalities available to the neonatologist have not changed a great deal in recent years; blood tests and radiographs still form the mainstays with other techniques usually reserved for research studies, but rapid access to genomic testing is emergent. This paper provides an update around diagnosis and management of bone problems likely to present to the neonatologist., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Both food insecurity and comorbidity have been identified as precursors to functional limitation in older adults, yet whether food insecurity modifies the progression from chronic disease to disability has not been assessed. We examined 5986 respondents age 50 and older drawn from the 2012-2014 Health and Retirement Study (HRS) and 2013 Health Care and Nutrition Study (HCNS). Mobility limitations reported in 2014 and change in mobility limitations from 2012 to 2014 were regressed on measures of food insecurity, number of chronic conditions, and their interaction terms using Poisson regression. Around 17.3% of the sample was identified as food insecure. In 2012, respondents reported an average of 1.9 (SD = 1.5) chronic conditions and 2.4 mobility limitations (SD = 3.0). In 2014, individuals reported an average of 2.5 (SD = 3.1) mobility limitations. Food insecurity was associated with a greater number of mobility limitations (IRR = 1.20, 95% CI: 1.11-1.29, p < .001) and more rapid increase in mobility limitations over the two-year observational period (IRR = 1.06, 95% CI: 1.00-1.11, p = .047). Food security status also modified the association between comorbidity and both mobility limitation outcomes, with the food secure exhibiting a stronger positive association between chronic conditions and mobility limitations than the food insecure. The food insecure tended to have more mobility limitations than the food secure when few chronic conditions were reported. Our results suggest that food insecurity is associated with prevalence and change in mobility limitations among older adults., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Idiopathic Juvenile Osteoporosis (IJO) refers to significantly lower than expected bone mass manifesting in childhood with no identifiable aetiology. IJO classically presents in early pubertal period with multiple fractures including metaphyseal and vertebral crush fractures, and low bone-mass., Methods: Here we describe two patients and provide information on their clinical phenotype, genotype and bone material analysis in one of the patients., Results: Patient 1: 40-year old adult male diagnosed with IJO in childhood who re-presented with a hip fracture as an adult. Genetic analysis identified a pathogenic PLS3 hemizygous variant, c.1765del in exon 16. Patient 2: 15-year old boy with multiple vertebral fractures and bone biopsy findings suggestive of IJO who also has a diagnosis of autism spectrum disorder. Genetic analysis identified a maternally inherited PLS3 pathogenic c.1295T>A variant in exon 12. Analyses of the transiliac bone sample revealed severe reduction of trabecular volume and bone turnover indices and elevated bone matrix mineralisation., Discussion: We propose that genetic testing for PLS3 should be undertaken in patients presenting with a current or previous history of IJO as this has implications for genetic counselling and cascade screening. The extensive evaluation of the transiliac biopsy sample of Patient 2 revealed a novel bone phenotype., Conclusion: This report includes a review of IJO and genetic causes of osteoporosis, and suggests that existing cases of IJO should be screened for PLS3. Through analysis of bone material properties in Patient 2, we can conclude that PLS3 does have a role in bone mineralisation., (© 2018 Wiley Periodicals, Inc.)

Objective: Few studies have examined the impact of cancer treatment on cognitive trajectories in the growing population of older adults diagnosed with and surviving cancer. This study examined whether recent cancer and its treatment accelerated memory decline in older adults., Materials and Methods: We conducted a secondary analysis of observations drawn from the Health and Retirement Study (2002-2012), a population-based sample of older adults in the United States. Changes in immediate (IWR) and delayed word recall (DWR) scores were estimated by latent growth modeling in individuals who never had cancer (n=10,939) or had been diagnosed with cancer between 2000 and 2002 and received treatment with some combination of radiation and/or surgery (n=240), chemotherapy only (n=34), or chemotherapy and some combination of radiation and/or surgery (n=64)., Results: In the period immediately following treatment, individuals reporting a recent cancer treated with chemotherapy and surgery/radiation experienced significantly more rapid decline in IWR (b =-0.34, SE =0.17, p=0.047) and DWR (b=-0.38, SE=0.19, p=0.049) than the non-cancer group. Sensitivity analyses addressing mortality selection and memory-related disease at baseline attenuated the strength of these associations. There were no other statistically significant differences in estimated linear or quadratic slope by cancer status or treatment., Conclusion: Our results support a potential association between recent cancer treatment and trajectories of memory decline in older adults and provide guidance on the interpretation of statistical estimates from panel studies of health and aging., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objectives: Osteogenesis Imperfecta (OI) is a heterogeneous condition mainly characterised by bone fragility; intelligence is reported to be normal. However, a minority of children seen also show symptomology consistent with an 'Autism Spectrum Disorder'. A joint genetics and psychology research study was undertaken to identify these patients using 'Gold Standard' research tools: Autism Diagnostic Inventory Revised (ADI-R); Autism Diagnostic Observation Schedule (ADOS) and undertake genetic analyses in them., Method: A cohort of n  = 7 children with autistic traits and severe/complex OI were recruited to the study. The study was set-up to explore whether there was a genetic link between bone fragility and autism in a sub-set of patients with bone fragility identified with autism traits in our complex/severe OI clinic. This was not set-up as a prevalence study but rather an exploration of genetics in association with ADI/ADOS confirmed ASD and bone fragility., Adi& Ados: Standardised tools were used to confirm autism diagnosis. ADI and ADOS were completed by the Clinical Psychologist; ADI comprises a 93 item semi-structured clinical review with a diagnostic algorithm diagnosing Autism; ADOS is a semi-structured assessment of socialisation, communication and play/imagination which also provides a diagnostic algorithm., Exome Sequencing: In patients recruited, those that fulfilled research criteria for diagnosis of autism using above tools were recruited to trio whole exome sequencing (WES)., Results: one patient had compound heterozygous variants in NBAS ; one patient had a variant in NRX1 ; one patient had a maternally inherited PLS3 variant; all the other patients in this cohort had pathogenic variants in COL1A1/COL1A2 ., Conclusions: Although, not set out as an objective, we were able to establish that identifying autism had important clinical and social benefits for patients and their families in ensuring access to services, appropriate schooling, increased understanding of behaviour and support., Lay Summary: It is important for clinicians looking after children with brittle bone disease, also referred to as Osteogenesis Imperfecta (OI) to be aware of early features of developmental delay/autistic traits especially with severe forms of OI as the emphasis is on their mobility and bone health. Ensuring appropriate assessment and access to services early-on will enable these patients to achieve their potential. Further investigations of genomics in bone fragility in relation to autism are required and dual diagnosis is essential for high quality clinical and educational provision.

Background: Cole-Carpenter syndrome (CCS) is commonly classified as a rare Osteogenesis Imperfecta (OI) disorder. This was following the description of two unrelated patients with very similar phenotypes who were subsequently shown to have a heterozygous missense mutation in P4HB ., Objectives: Here, we report a 3-year old female patient with severe OI who on exome sequencing was found to carry the same missense mutation in P4HB as reported in the original cohort. We discuss the genetic heterogeneity of CCS and underlying mechanism of P4HB in collagen production., Methods: We undertook detailed clinical, radiological and molecular phenotyping in addition, to analysis of collagen in cultured fibroblasts and electron microscopic examination in the patient reported here., Results: The clinical phenotype appears consistent in patients reported so far but interestingly, there also appears to be a definitive phenotypic clue (crumpling metadiaphyseal fractures of the long tubular bones with metaphyseal sclerosis which are findings that are uncommon in OI) to the underlying genotype ( P4HB variant)., Discussion: P4HB (Prolyl 4-hydroxylase, betasubunit) encodes for PDI (Protein Disulfide isomerase) and in cells, in its tetrameric form, catalyses formation of 4-hydroxyproline in collagen. The recurrent variant in P4HB , c.1178A>G, p.Tyr393Cys, sits in the C-terminal reactive centre and is said to interfere with disulphide isomerase function of the C-terminal reactive centre. P4HB catalyses the hydroxylation of proline residues within the X-Pro-Gly repeats in the procollagen helical domain. Given the inter-dependence of extracellular matrix (ECM) components in assembly of a functional matrix, our data suggest that it is the organisation and assembly of the functional ECM that is perturbed rather than the secretion of collagen type I per se., Conclusions: We provide additional evidence of P4HB as a cause of a specific form of OI-CCS and expand on response to treatment with bisphosphonates in this rare disorder., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

There is increasing evidence of persistent effects of early life vitamin D exposure on later skeletal health; linking low levels in early life to smaller bone size in childhood as well as increased fracture risk later in adulthood, independently of later vitamin D status. A major determinant of bone mass acquisition across all ages is mechanical loading. We tested the hypothesis in an animal model system that early life vitamin D depletion results in abrogation of the response to mechanical loading, with consequent reduction in bone size, mass and strength during both childhood and adulthood. A murine model was created in which pregnant dams were either vitamin D deficient or replete, and their offspring moved to a vitamin D replete diet at weaning. Tibias of the offspring were mechanically loaded and bone structure, extrinsic strength and growth measured both during growth and after skeletal maturity. Offspring of vitamin D deplete mice demonstrated lower bone mass in the non loaded limb and reduced bone mass accrual in response to loading in both the growing skeleton and after skeletal maturity. Early life vitamin D depletion led to reduced bone strength and altered bone biomechanical properties. These findings suggest early life vitamin D status may, in part, determine the propensity to osteoporosis and fracture that blights later life in many individuals.

Objectives: Our first objective was to estimate empirically-derived subgroups (latent profiles) of observed carbohydrate, protein, and fat intake density in a nationally representative sample of older U.S. adults. Our second objective was to determine whether membership in these groups was associated with levels of, and short term change in, physical mobility limitations., Design and Setting: Measures of macronutrient density were taken from the 2013 Health Care and Nutrition Study, an off-year supplement to the Health and Retirement Study, which provided indicators of physical mobility limitations and sociodemographic and health-related covariates., Participants: 3,914 community-dwelling adults age 65 years and older., Measurements: Percent of daily calories from carbohydrate, protein, and fat were calculated based on responses to a modified Harvard food frequency questionnaire. Latent profile analysis was used to describe unobserved heterogeneity in measures of carbohydrate, protein, and fat density. Mobility limitation counts were based on responses to 11 items indicating physical limitations. Poisson regression models with autoregressive controls were used to identify associations between macronutrient density profile membership and mobility limitations. Sociodemographic and health-related covariates were included in all Poisson regression models., Results: Four latent subgroups of macronutrient density were identified: "High Carbohydrate", "Moderate with Fat", "Moderate", and "Low Carbohydrate/High Fat". Older adults with the lowest percentage of daily calories coming from carbohydrate and the greatest percentage coming from fat ("Low Carbohydrate/High Fat") were found to have greater reported mobility limitations in 2014 than those identified as having moderate macronutrient density, and more rapid two-year increases in mobility limitations than those identified as "Moderate with Fat" or "Moderate"., Conclusion: Older adults identified as having the lowest carbohydrate and highest fat energy density were more likely to report a greater number of mobility limitations and experience greater increases in these limitations than those identified as having moderate macronutrient density. These results suggest that the interrelation of macronutrients must be considered by those seeking to reduce functional limitations among older adults through dietary interventions., Competing Interests: The authors declare no conflicts of interest

Skeletal deformity and bone fragility are the hallmarks of the brittle bone dysplasia osteogenesis imperfecta. The diagnosis of osteogenesis imperfecta usually depends on family history and clinical presentation characterized by a fracture (or fractures) during the prenatal period, at birth or in early childhood; genetic tests can confirm diagnosis. Osteogenesis imperfecta is caused by dominant autosomal mutations in the type I collagen coding genes (COL1A1 and COL1A2) in about 85% of individuals, affecting collagen quantity or structure. In the past decade, (mostly) recessive, dominant and X-linked defects in a wide variety of genes encoding proteins involved in type I collagen synthesis, processing, secretion and post-translational modification, as well as in proteins that regulate the differentiation and activity of bone-forming cells have been shown to cause osteogenesis imperfecta. The large number of causative genes has complicated the classic classification of the disease, and although a new genetic classification system is widely used, it is still debated. Phenotypic manifestations in many organs, in addition to bone, are reported, such as abnormalities in the cardiovascular and pulmonary systems, skin fragility, muscle weakness, hearing loss and dentinogenesis imperfecta. Management involves surgical and medical treatment of skeletal abnormalities, and treatment of other complications. More innovative approaches based on gene and cell therapy, and signalling pathway alterations, are under investigation.

Context: Single-nucleotide polymorphisms (SNPs) in genes related to vitamin D metabolism have been associated with serum 25-hydroxyvitamin D [25(OH)D] concentration, but these relationships have not been examined following antenatal cholecalciferol supplementation., Objective: To determine whether SNPs in DHCR7, CYP2R1, CYP24A1, and GC are associated with the response to gestational cholecalciferol supplementation., Design: Within-randomization group analysis of the Maternal Vitamin D Osteoporosis Study trial of antenatal cholecalciferol supplementation., Setting: Hospital antenatal clinics., Participants: In total, 682 women of white ethnicity (351 placebo, 331 cholecalciferol) were included. SNPs at rs12785878 (DHCR7), rs10741657 (CYP2R1), rs6013897 (CYP24A1), and rs2282679 (GC) were genotyped., Interventions: 1000 IU/d cholecalciferol from 14 weeks of gestation until delivery., Main Outcome Measure: 25(OH)D at randomization and 34 weeks of gestation were measured in a single batch (Liaison; Diasorin, Dartford, UK). Associations between 25(OH)D and the SNPs were assessed by linear regression using an additive model [β represents the change in 25(OH)D per additional common allele]., Results: Only rs12785878 (DHCR7) was associated with baseline 25(OH)D [β = 3.1 nmol/L; 95% confidence interval (CI), 1.0 to 5.2 nmol/L; P < 0.004]. In contrast, rs10741657 (CYP2R1) (β = -5.2 nmol/L; 95% CI, -8.2 to -2.2 nmol/L; P = 0.001) and rs2282679 (GC) (β = 4.2 nmol/L; 95% CI, 0.9 to 7.5 nmol/L; P = 0.01) were associated with achieved 25(OH)D status following supplementation, whereas rs12785878 and rs6013897 (CYP24A1) were not., Conclusions: Genetic variation in DHCR7, which encodes 7-dehyrocholesterol reductase in the epidermal vitamin D biosynthesis pathway, appears to modify baseline 25(OH)D. In contrast, the response to antenatal cholecalciferol supplementation was associated with SNPs in CYP2R1, which may alter 25-hydroxylase activity, and GC, which may affect vitamin D binding protein synthesis or metabolite affinity., (Copyright © 2017 Endocrine Society)

The increasing use of dual-energy X-ray absorptiometry (DXA) in children has led to the need for robust reference data for interpretation of scans in daily clinical practice. Such data need to be representative of the population being studied and be "future-proofed" to software and hardware upgrades. The aim was to combine all available pediatric DXA reference data from seven UK centers to create reference curves adjusted for age, sex, ethnicity, and body size to enable clinical application, using in vivo cross-calibration and making data back and forward compatible. Seven UK sites collected data on GE Lunar or Hologic Scanners between 1996 and 2012. Males and females aged 4 to 20 years were recruited (n = 3598). The split by ethnic group was white 2887; South Asian 385; black Afro-Caribbean 286; and mixed heritage 40. Scans of the total body and lumbar spine (L 1 to L 4 ) were obtained. The European Spine Phantom was used to cross-calibrate the 7 centers and 11 scanners. Reference curves were produced for L 1 to L 4 bone mineral apparent density (BMAD) and total body less head (TBLH) and L 1 to L 4 areal bone mineral density (aBMD) for GE Lunar Prodigy and iDXA (sex- and ethnic-specific) and for Hologic (sex-specific). Regression equations for TBLH BMC were produced using stepwise linear regression. Scans of 100 children were randomly selected to test backward and forward compatibility of software versions, up to version 15.0 for GE Lunar and Apex 4.1 for Hologic. For the first time, sex- and ethnic-specific reference curves for lumbar spine BMAD, aBMD, and TBLH aBMD are provided for both GE Lunar and Hologic scanners. These curves will facilitate interpretation of DXA data in children using methods recommended in ISCD guidelines. The databases have been created to allow future updates and analysis when more definitive evidence for the best method of fracture prediction in children is agreed. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Background: Osteogenesis imperfecta (OI), the commonest inherited bone fragility disorder, affects 1 in 15,000 live births resulting in frequent fractures and reduced mobility, with significant impact on quality of life. Early diagnosis is important, as therapeutic advances can lead to improved clinical outcome and patient benefit., Report: Whole exome sequencing in patients with OI identified, in two patients with a multi-system phenotype, compound heterozygous variants in NBAS (neuroblastoma amplified sequence). Patient 1: NBAS c.5741G>A p.(Arg1914His); c.3010C>T p.(Arg1004*) in a 10-year old boy with significant short stature, bone fragility requiring treatment with bisphosphonates, developmental delay and immunodeficiency. Patient 2: NBAS c.5741G>A p.(Arg1914His); c.2032C>T p.(Gln678*) in a 5-year old boy with similar presenting features, bone fragility, mild developmental delay, abnormal liver function tests and immunodeficiency., Discussion: Homozygous missense NBAS variants cause SOPH syndrome (short stature; optic atrophy; Pelger-Huet anomaly), the same missense variant was found in our patients on one allele and a nonsense variant in the other allele. Recent literature suggests a multi-system phenotype. In this study, patient fibroblasts have shown reduced collagen expression, compared to control cells and RNAseq studies, in bone cells show that NBAS is expressed in osteoblasts and osteocytes of rodents and primates. These findings provide proof-of-concept that NBAS mutations have mechanistic effects in bone, and that NBAS variants are a novel cause of bone fragility, which is distinguishable from 'Classical' OI., Conclusions: Here we report on variants in NBAS, as a cause of bone fragility in humans, and expand the phenotypic spectrum associated with NBAS. We explore the mechanism underlying NBAS and the striking skeletal phenotype in our patients., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Prompt and accurate diagnosis of skeletal dysplasias can play a crucial role in ensuring appropriate counseling and management (both antenatal and postnatal). When a skeletal dysplasia is detected during the antenatal period, especially early in the pregnancy, it can be associated with a poor prognosis. It is important to make a diagnosis in antenatal presentation of skeletal dysplasias to inform diagnosis, predict prognosis, provide accurate recurrence risks, and options for prenatal genetic testing in future pregnancies. Prenatal ultrasound scanning is a useful tool to detect several skeletal dysplasias and sonographic measurements serve as reliable indicators of lethality. The lethality depends on various factors including gestational age at which features are identified, size of the chest and progression of malformations. Although, it is important to type the skeletal presentation as accurately as possible, this is not always possible in an antenatal presentation and it is important to acknowledge this uncertainty. In the case of a live birth, it is always important to reassess the infant. Osteogenesis imperfecta (OI) is a heterogeneous group of disorders characterized by fragile bones. Here, we report an infant with severe OI born following a twin pregnancy in whom the bone disease is caused by a heterozygous pathogenic mutation, c.4160C >T, p.(Ala1387Val) located in the C-propeptide region of COL1A1. An assumption of lethality antenatally complicated his management in early life. We discuss this patient with particular emphasis on the neonatal presentation of a severe skeletal dysplasia and the lessons that may be learned in such situations. © 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Context: Current approaches to antenatal vitamin D supplementation do not account for interindividual differences in 25-hydroxyvitamin D (25(OH)D) response., Objective: We assessed which maternal and environmental characteristics were associated with 25(OH)D after supplementation with cholecalciferol., Design: Within-randomization-group analysis of participants in the Maternal Vitamin D Osteoporosis Study trial of vitamin D supplementation in pregnancy., Setting: Hospital antenatal clinics., Participants: A total of 829 pregnant women (422 placebo, 407 cholecalciferol). At 14 and 34 weeks of gestation, maternal anthropometry, health, and lifestyle were assessed and 25(OH)D measured. Compliance was determined using pill counts at 19 and 34 weeks., Interventions: 1000 IU/d of cholecalciferol or matched placebo from 14 weeks of gestation until delivery., Main Outcome Measure: 25(OH)D at 34 weeks, measured in a single batch (Diasorin Liaison)., Results: 25(OH)D at 34 weeks of gestation was higher in the women randomized to vitamin D (mean [SD], 67.7 [21.3] nmol/L) compared with placebo (43.1 [22.5] nmol/L; P < .001). In women randomized to cholecalciferol, higher pregnancy weight gain from 14 to 34 weeks of gestation (kg) (β = -0.81 [95% confidence interval -1.39, -0.22]), lower compliance with study medication (%) (β = -0.28 [-0.072, -0.48]), lower early pregnancy 25(OH)D (nmol/L) (β = 0.28 [0.16, 0.40]), and delivery in the winter vs the summer (β = -10.5 [-6.4, -14.6]) were independently associated with lower 25(OH)D at 34 weeks of gestation., Conclusions: Women who gained more weight during pregnancy had lower 25(OH)D in early pregnancy and delivered in winter achieved a lower 25(OH)D in late pregnancy when supplemented with 1000 IU/d cholecalciferol. Future studies should aim to determine appropriate doses to enable consistent repletion of 25(OH)D during pregnancy.

Osteogenesis Imperfecta (OI) is an inherited bone fragility disorder most commonly associated with autosomal dominant mutations in the type I collagen genes. Autosomal recessive mutations in a number of genes have also been described, including the BMP1 gene that encodes the mammalian Tolloid (mTLD) and its shorter isoform bone morphogenic protein-1 (BMP1). To date, less than 20 individuals with OI have been identified with BMP1 mutations, with skeletal phenotypes ranging from mild to severe and progressively deforming. In the majority of patients, bone fragility was associated with increased bone mineral density (BMD); however, the full range of phenotypes associated with BMP1 remains unclear. Here, we describe three children with mutations in BMP1 associated with a highly variable phenotype: a sibship homozygous for the c.2188delC mutation that affects only the shorter BMP1 isoform and a further patient who is compound heterozygous for a c.1293C>G nonsense mutation and a c.1148G>A missense mutation in the CUB1 domain. These individuals had recurrent fractures from early childhood, are hypermobile and have no evidence of dentinogenesis imperfecta. The homozygous siblings with OI had normal areal BMD by dual energy X-ray absorptiometry whereas the third patient presented with a high bone mass phenotype. Intravenous bisphosphonate therapy was started in all patients, but discontinued in two patients and reduced in another due to concerns about increasing bone stiffness leading to chalk-stick fractures. Given the association of BMP1-related OI with very high bone material density, concerns remain whether anti-resorptive therapy is indicated in this ultra-rare form of OI.© 2016 Wiley Periodicals, Inc., (© 2016 Wiley Periodicals, Inc.)

Unlabelled: Debilitating rickets-like lower limb deformities are common in children throughout the world, particularly in Malawi, Africa where the causes are unknown. We have identified that Blount disease and calcium deficiency rickets are the likely causes of these deformities and propose calcium supplementation as a potential treatment of Malawian rickets., Introduction: Surgical correction of rickets-like lower limb deformities is the most common paediatric operation performed at Beit Cure Orthopaedic Hospital, Malawi. The aim of this study was to investigate the aetiology of these deformities., Methods: Children with a tibio-femoral angle of deformity >20° were enrolled (n = 42, 3.0-15.0 years). Anthropometric and early life and well-being data were collected. Early morning serum and urine samples were collected on the morning of the operation for markers of calcium and phosphate homeostasis. Knee radiographs were obtained, and the children were diagnosed with either Blount (BD, n = 22) or evidence of rickets disease (RD, n = 20). As BD is a mechanical rather than metabolic disease, BD were assumed to be biochemically representative of the local population and thus used as a local reference for RD., Results: There were no differences in anthropometry or early life experiences between BD and RD. Parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, total alkaline phosphatase and urinary phosphate were significantly higher and serum phosphate, 25-hydroxyvitamin D (25OHD) and tubular maximal reabsorption of phosphate significantly lower in RD than BD. There was no difference in serum calcium, fibroblast growth factor 23 or markers of iron status between groups. All children had 25OHD > 25 nmol/L., Conclusions: Vitamin D deficiency is not implicated in the aetiology of RD or BD in Malawian children. The cause of RD in Malawi is likely to be dietary calcium deficiency leading to elevated PTH resulting in increased losses of phosphate from the bone and glomerular filtrate. The causes of BD remain unclear; there was no evidence in support of previously suggested risk factors such as being overweight or starting to walk early. Prior to surgical intervention, supplementation with calcium should be considered for children with RD., Competing Interests: Compliance with ethical standards Conflicts of interest None.

Long-term bisphosphonate (BP) therapy in adults with osteoporosis is associated with atypical femoral fractures, caused by increased material bone density and prolonged suppression of bone remodeling which may reduce fracture toughness. In children with osteogenesis imperfecta (OI), long-term intravenous BP therapy improves bone structure and mass without further increasing the already hypermineralized bone matrix, and is generally regarded as safe. Here we report a teenage girl with OI type IV, who was started on cyclical intravenous pamidronate therapy at age 6 years because of recurrent fractures. Transiliac bone biopsy revealed classical structural features of OI but unusually low bone resorption surfaces. She made substantial improvements in functional ability, bone mass, and fracture rate. However, after 5 years of pamidronate therapy she started to develop recurrent, bilateral, nontraumatic, and proximal femur fractures, which satisfied the case definition for atypical femur fractures. Some fractures were preceded by periosteal reactions and prodromal pain. Pamidronate was discontinued after 7 years of therapy, following which she sustained two further nontraumatic femur fractures, and continued to show delayed tibial osteotomy healing. Despite rodding surgery, and very much in contrast to her affected, untreated, and normally mobile mother, she remains wheelchair-dependent. The case of this girl raises questions about the long-term safety of BP therapy in some children, in particular about the risk of oversuppressed bone remodeling with the potential for microcrack accumulation, delayed healing, and increased stiffness. The principal concern is whether there is point at which benefit from BP therapy could turn into harm, where fracture risk increases again. This case should stimulate debate whether current adult atypical femoral fracture guidance should apply to children, and whether low-frequency, low-dose cyclical, intermittent, or oral treatment maintenance regimens should be considered on a case-by-case basis. © 2016 American Society for Bone and Mineral Research., (© 2016 American Society for Bone and Mineral Research.)

Background: Maternal vitamin D status has been associated with bone mass of offspring in many, but not all, observational studies. However, maternal vitamin D repletion during pregnancy has not yet been proven to improve offspring bone mass in a randomised controlled trial. We aimed to assess whether neonates born to mothers supplemented with vitamin D during pregnancy have greater whole-body bone mineral content (BMC) at birth than those of mothers who had not received supplementation., Methods: The Maternal Vitamin D Osteoporosis Study (MAVIDOS) was a multicentre, double-blind, randomised, placebo-controlled trial that recruited pregnant women from three study sites in the UK (Southampton, Oxford, and Sheffield). Eligible participants were older than 18 years, with a singleton pregnancy, gestation of less than 17 weeks, and a serum 25-hydroxyvitamin D (25[OH]D) concentration of 25-100 nmol/L at 10-17 weeks' gestation. P'articipants were randomly assigned (1:1), in randomly permuted blocks of ten, to either cholecalciferol 1000 IU/day or matched placebo, taken orally, from 14 weeks' gestation (or as soon as possible before 17 weeks' gestation if recruited later) until delivery. Participants and the research team were masked to treatment allocation. The primary outcome was neonatal whole-body BMC, assessed within 2 weeks of birth by dual-energy x-ray absorptiometry (DXA), analysed in all randomly assigned neonates who had a usable DXA scan. Safety outcomes were assessed in all randomly assigned participants. This trial is registered with the International Standard Randomised Controlled Trial registry, ISRCTN 82927713, and the European Clinical Trials Database, EudraCT 2007-001716-23., Findings: Between Oct 10, 2008, and Feb 11, 2014, we randomly assigned 569 pregnant women to placebo and 565 to cholecalciferol 1000 IU/day. 370 (65%) neonates in the placebo group and 367 (65%) neonates in the cholecalciferol group had a usable DXA scan and were analysed for the primary endpoint. Neonatal whole-body BMC of infants born to mothers assigned to cholecalciferol 1000 IU/day did not significantly differ from that of infants born to mothers assigned to placebo (61·6 g [95% CI 60·3-62·8] vs 60·5 g [59·3-61·7], respectively; p=0·21). We noted no significant differences in safety outcomes, apart from a greater proportion of women in the placebo group with severe post-partum haemorrhage than those in the cholecalciferol group (96 [17%] of 569 mothers in the placebo group vs 65 [12%] of 565 mothers in the cholecalciferol group; p=0·01). No adverse events were deemed to be treatment related., Interpretation: Supplementation of women with cholecalciferol 1000 IU/day during pregnancy did not lead to increased offspring whole-body BMC compared with placebo, but did show that 1000 IU of cholecalciferol daily is sufficient to ensure that most pregnant women are vitamin D replete, and it is safe. These findings support current approaches to vitamin D supplementation in pregnancy. Results of the ongoing MAVIDOS childhood follow-up study are awaited., Funding: Arthritis Research UK, Medical Research Council, Bupa Foundation, and National Institute for Health Research., (Copyright © 2016 Cooper et al. Open Access article distributed under the terms of CC BY. Published by Elsevier Ltd.. All rights reserved.)

This study examines the co-development of cognitive and physical function in older Americans using an age-heterogeneous sample drawn from the Health and Retirement Study (1998-2008). We used multiple-group parallel process latent growth models to estimate the association between trajectories of cognitive function as measured by immediate word recall scores, and limitations in physical function as measured as an index of functional mobility limitations. Nested model fit testing was used to assess model fit for the separate trajectories followed by estimation of an unconditional parallel process model. Controls for demographic characteristics, socioeconomic status, and chronic health conditions were added to the best-fitting parallel process model. Pattern mixture models were used to assess the sensitivity of the parameter estimates to the effect of selective attrition. Results indicated that favorable cognitive health and mobility at initial measurement were associated with faster decline in the alternate functional domain. The cross-process associations remained significant when we adjusted estimates for the influence of covariates and selective attrition. Demographic and socioeconomic characteristics were consistently associated with initial cognitive and physical health but had few relations with change in these measures.

We report a sibling-pair and a 4-year old child from two families with an atypical presentation in Osteogenesis imperfecta (OI). In the sib-pair, the older sibling initially came to medical attention due to a fracture history (Patient 1) and she was shown to have a COL1A2 mutation. In addition, she also had developmental delay, facial dysmorphism, and a history of frequent infections which led to a search for an alternate diagnosis. ArrayCGH revealed a 4.3 Mb duplication on chromosome 19q13.42q13.43, which was confirmed by FISH analysis. On further familial analysis, the younger sibling who had no previous fracture history was also found to have the COL1A2 mutation and tested positive for the 19q13.42q13.43 duplication (Patient 2). The 19q13 duplication appears to be the cause of intellectual disability in these siblings but given that this is a chromosomal duplication, it is still possible that there is an as yet unidentified cause that may account for the combined phenotype in this family. Patient 3 was a 4-year old child presenting with a femoral fracture, blue sclerae, developmental delay, and joint hypermobility. Genetic analyses confirmed a COL1A2 mutation but also revealed an 8.8 Mb deletion of 11q24.2q25, confirmed by G-band chromosome analysis. We discuss the differing phenotypes in patients presenting with atypical OI and stress the need to consider ancillary investigations in individuals presenting with heterogeneous phenotypic symptoms, not entirely attributable to OI., (© 2015 Wiley Periodicals, Inc.)

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity to fracture. Over 90% of patients with OI have a mutation in COL1A1/COL1A2, which shows an autosomal dominant pattern of inheritance. In-depth phenotyping and in particular, studies involving manifestations in the skin connective tissue have not previously been undertaken in OI. The aims of the study were to perform histological and ultrastructural examination of skin biopsies in a cohort of patients with OI; to identify common and distinguishing features in order to inform genotype-phenotype correlation; and to identify common and distinguishing features between the different subtypes of OI. As part of the RUDY (Rare Diseases in Bone, Joints and/or Blood Vessels) study, in collaboration with the NIHR Rare Diseases Translational Research Collaboration, we undertook a national study of skin biopsies in patients with OI. We studied the manifestations in the skin connective tissue and undertook in-depth clinical and molecular phenotyping of 16 patients with OI. We recruited 16 patients: analyses have shown that in type 1 collagen mutation positive patients (COL1A1/ COL1A2) (n-4/16) consistent findings included: variable collagen fibril diameter (CFD) and presence of collagen flowers. Histological examination in these patients showed an increase in elastic fibers that are frequently fragmented and clumped. These observations provide evidence that collagen flowers and CFD variability are consistent features in OI due to type 1 collagen defects and reinforce the need for accurate phenotyping in conjunction with genomic analyses.

The skeleton responds to mechanical stimulation. We wished to ascertain the magnitude and speed of the growing skeleton's response to a standardised form of mechanical stimulation, vibration. 36 prepubertal boys stood for 10 minutes in total on one of two vibrating platforms (high (>2 g) or low (<1 g) magnitude vibration) on either 1, 3 or 5 successive days (n=12 for each duration); 15 control subjects stood on an inactive platform. Blood samples were taken at intervals before and after vibration to measure bone formation (P1NP, osteocalcin) and resorption (CTx) markers as well as osteoprotegerin and sclerostin. There were no significant differences between platform and control groups in bone turnover markers immediately after vibration on days 1, 3 and 5. Combining platform groups, at day 8 P1NP increased by 25.1% (CI 12.3 to 38.0; paired t-test p=0.005) and bone resorption increased by 10.9% (CI 3.6 to 18.2; paired t-test p=0.009) compared to baseline. Osteocalcin, osteoprotogerin and sclerostin did not change significantly. The growing skeleton can respond quickly to vibration of either high or low magnitude. Further work is needed to determine the utility of such "stimulation-testing" in clinical practice., Competing Interests: The authors have no conflict of interest.

Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of bone formation, resulting in low bone mass and an increased propensity for fractures. It is a variable condition with a range of clinical severities. The histological and ultrastructural findings in the skin of patients with OI have not been described in detail in the previously published literature. Although protein analysis of cultured fibroblasts has historically been used in the diagnostic work-up of OI patients, other aspects of skin examination are not routinely performed as part of the diagnostic pathway in patients with OI. The aims of this study were to perform histological and ultrastructural examination of skin biopsies in patients with OI. This was to identify common and distinguishing features in the numerous genetically distinct subtypes of OI and compare the findings with those in patients who did not present with fractures, and to enable the use of the results thus obtained to aid in the diagnostic work-up of patients with OI. As part of a larger research study set-up to identify clinical features and natural history in patients with atypical features of OI, skin biopsy and examination (histology and electron microscopy) were undertaken. Genetic analysis and ancillary investigations were also performed to identify similarities within this group and to differentiate this group from the 'normal' population. At the end of this study, we were able to demonstrate that the histological and electron microscopic findings on a skin biopsy may be an indicator of the likelihood of identifying a pathogenic mutation in type 1 collagen genes. This is because patients with specific findings on examination, such as elastic fibre area fraction (on histological analysis), collagen fibril diameter variability, deviation from the expected mean and collagen flowers (on electron microscopy), are more likely to be positive on genetic analyses. This has, in turn, provided more insight into the pathways to direct gene testing and has reinforced the need for accurate phenotyping before undertaking further genetic investigations. The morphometric assessment of elastic fibre area fraction and ultrastructural findings from this study have provided us with a better understanding of OI and insights into the possible mechanism of these changes in the skin. Correlation of skin findings with the clinical phenotype as well as genetic testing has enabled understanding of the molecular pathogenesis and translation of changes at the genomic level to clinical phenotype.