Kassim Javaid

Vitamin D supplementation in pregnancy: a systematic review.

BACKGROUND It is unclear whether or not the current evidence base allows definite conclusions to be made regarding the optimal maternal circulating concentration of 25-hydroxyvitamin D [25(OH)D] during pregnancy, and how this might best be achieved. OBJECTIVES To answer the following questions: (1) What are the clinical criteria for vitamin D deficiency in pregnant women? (2) What adverse maternal and neonatal health outcomes are associated with low maternal circulating 25(OH)D? (3) Does maternal supplementation with vitamin D in pregnancy lead to an improvement in these outcomes (including assessment of compliance and effectiveness)? (4) What is the optimal type (D2 or D3), dose, regimen and route for vitamin D supplementation in pregnancy? (5) Is supplementation with vitamin D in pregnancy likely to be cost-effective? METHODS We performed a systematic review and where possible combined study results using meta-analysis to estimate the combined effect size. Major electronic databases [including Database of Abstracts of Reviews of Effects (DARE), Centre for Reviews and Dissemination (CRD), Cochrane Database of Systematic Reviews (CDSR) and the Health Technology Assessment (HTA) database] were searched from inception up to June 2012 covering both published and grey literature. Bibliographies of selected papers were hand-searched for additional references. Relevant authors were contacted for any unpublished findings and additional data if necessary. Abstracts were reviewed by two reviewers. INCLUSION AND EXCLUSION CRITERIA SUBJECTS pregnant women or pregnant women and their offspring. EXPOSURE either assessment of vitamin D status [dietary intake, sunlight exposure, circulating 25(OH)D concentration] or supplementation of participants with vitamin D or food containing vitamin D (e.g. oily fish). OUTCOMES offspring - birthweight, birth length, head circumference, bone mass, anthropometry and body composition, risk of asthma and atopy, small for gestational dates, preterm birth, type 1 diabetes mellitus, low birthweight, serum calcium concentration, blood pressure and rickets; mother - pre-eclampsia, gestational diabetes mellitus, risk of caesarean section and bacterial vaginosis. RESULTS Seventy-six studies were included. There was considerable heterogeneity between the studies and for most outcomes there was conflicting evidence. The evidence base was insufficient to reliably answer question 1 in relation to biochemical or disease outcomes. For questions 2 and 3, modest positive relationships were identified between maternal 25(OH)D and (1) offspring birthweight in meta-analysis of three observational studies using log-transformed 25(OH)D concentrations after adjustment for potential confounding factors [pooled regression coefficient 5.63 g/10% change maternal 25(OH)D, 95% confidence interval (CI) 1.11 to 10.16 g], but not in those four studies using natural units, or across intervention studies; (2) offspring cord blood or postnatal calcium concentrations in a meta-analysis of six intervention studies (all found to be at high risk of bias; mean difference 0.05 mmol/l, 95% CI 0.02 to 0.05 mmol/l); and (3) offspring bone mass in observational studies judged to be of good quality, but which did not permit meta-analysis. The evidence base was insufficient to reliably answer questions 4 and 5. LIMITATIONS Study methodology varied widely in terms of study design, population used, vitamin D status assessment, exposure measured and outcome definition. CONCLUSIONS The evidence base is currently insufficient to support definite clinical recommendations regarding vitamin D supplementation in pregnancy. Although there is modest evidence to support a relationship between maternal 25(OH)D status and offspring birthweight, bone mass and serum calcium concentrations, these findings were limited by their observational nature (birthweight, bone mass) or risk of bias and low quality (calcium concentrations). High-quality randomised trials are now required. STUDY REGISTRATION This study is registered as PROSPERO CRD42011001426. FUNDING The National Institute for Health Research Health Technology Assessment programme.

Medical management of osteoarthritis

Osteoarthritis is a common, chronic, musculoskeletal disorder. Symptomatic osteoarthritis, particularly of the knee and hip, is the most common cause of musculoskeletal disability in elderly people. In the Western world it ranks fourth in health impact among women and eighth among men.1 Given this high prevalence, therapeutic approaches to treatment will have to be shared between primary and secondary care. A range of non-surgical interventions has been proposed as components of such a therapeutic strategy. #### Summary points Osteoarthritis is a major cause of pain and disability in Western populations The prevalence of osteoarthritis necessitates a “shared care” approach to management between general practitioners and hospital specialists Several non-surgical interventions to alleviate pain and disability in lower limb osteoarthritis are now available: Non-pharmacological measures (education, social support, physiotherapy, and occupational therapy) Pharmacological measures (simple analgesics, non-steroidal anti-inflammatory drugs, COX-2 inhibitors, topical non-steroidal anti-inflammatory drugs, and capsaicin) Intra-articular therapy: corticosteroids, hyaluronic acid derivatives, and tidal irrigation These interventions have been evaluated to varying degrees, but they can be incorporated into an algorithm for the management of osteoarthritis #### Therapeutic options in osteoarthritis ##### Non-pharmacological treatment Education (patient and spouse or family) Social support (telephone contact) Physiotherapy (aerobic exercises, muscle strengthening, and patellar strapping) Occupational therapy (aids and appliances, joint protection) Weight loss Acupuncture Transcutaneous electrical nerve stimulation (TENS) ##### Pharmacological treatment Simple analgesia Non-steroidal anti-inflammatory drugs COX-2 inhibitors (cyclo-oxygenase-2 selective non-steroidal anti-inflammatory drugs) Topical (non-steroidal anti-inflammatory drugs, capsaicin) Chondroprotective agents ##### Intra-articular treatment Corticosteroids Hyaluronans Tidal irrigation Systematic reviews and controlled clinical trials were located through Medline and BIDS 1991-9, searching under the key words: osteoarthritis; guidelines; glucosamine; capsaicin; physiotherapy, occupational therapy, acupuncture, drug therapy, education, intra-articular injection, heat, cold, rehabilitation, epidemiology, therapy. When available, the most recent reviews or meta-analyses are cited; if not available, individual controlled trials were included and methodological shortcomings discussed. We did not perform assessments of quality of individual reviews. Semiquantitative estimates …

Association of vitamin D status with knee pain and radiographic knee osteoarthritis

OBJECTIVE The objective of the present study was to explore the association of serum vitamin D concentration and polymorphism in the vitamin D receptor (VDR), with knee pain and radiographic knee osteoarthritis (OA) among men and women in a large population-based UK cohort study. METHODS Seven hundred and eighty-seven participants in the Hertfordshire Cohort Study (399 men, 388 women; mean age 65.6±2.7 years) underwent a questionnaire on knee pain and radiographic knee examination. This study examined the association of Fok1, Cdx2 and Apa1 polymorphism in the gene for the VDR and serum 25(OH)D concentration with knee pain and radiographic knee OA by a generalized estimating equations population averaged logistic regression analysis in the Hertfordshire Cohort Study. RESULTS There were no associations of Fok1, Cdx2 and Apa1 polymorphisms of the VDR with knee OA except for Aa for Apa1 compared with AA [Odds ratio (OR) 0.59, 95% confidence interval (CI) 0.36-0.95, P=0.031]. While, ff for Fok1 (OR 1.60, 95% CI 1.07-2.39, P=0.022) and AA for Cdx2 polymorphism (OR 2.21, 95% CI 1.07-4.56, P=0.032) was significantly associated with higher prevalence of knee pain compared with FF for Fok1 and GG for Cdx2, respectively. None of these are statistically significant after adjusting for the three polymorphisms tested. 25(OH)D level was not significantly associated with radiographic knee OA, while, low tertile of 25(OH)D level tended to be associated with knee pain compared with high tertile of 25(OH)D level. CONCLUSION The present cross-sectional study using a large-scale population from the Hertfordshire Cohort study indicated that vitamin D may be associated with pain rather than radiographic change, but the evidence for an association between vitamin D genetic variation and pain in knee OA is very weak in the present study. Further replication of our results will be required to elucidate the association of vitamin D and knee OA.

MAVIDOS Maternal Vitamin D Osteoporosis Study: study protocol for a randomized controlled trial. The MAVIDOS Study Group

MAVIDOS is a randomised, double-blind, placebo-controlled trial (ISRCTN82927713, registered 2008 Apr 11), funded by Arthritis Research UK, MRC, Bupa Foundation and NIHR.BackgroundOsteoporosis is a major public health problem as a result of associated fragility fractures. Skeletal strength increases from birth to a peak in early adulthood. This peak predicts osteoporosis risk in later life. Vitamin D insufficiency in pregnancy is common (31% in a recent Southampton cohort) and predicts reduced bone mass in the offspring. In this study we aim to test whether offspring of mothers supplemented with vitamin D in pregnancy have higher bone mass at birth than those whose mothers were not supplemented.Methods/DesignWomen have their vitamin D status assessed after ultrasound scanning in the twelfth week of pregnancy at 3 trial centres (Southampton, Sheffield, Oxford). Women with circulating 25(OH)-vitamin D levels 25-100 nmol/l are randomised in a double-blind design to either oral vitamin D supplement (1000 IU cholecalciferol/day, n = 477) or placebo at 14 weeks (n = 477). Questionnaire data include parity, sunlight exposure, dietary information, and cigarette and alcohol consumption. At 19 and 34 weeks maternal anthropometry is assessed and blood samples taken to measure 25(OH)-vitamin D, PTH and biochemistry. At delivery venous umbilical cord blood is collected, together with umbilical cord and placental tissue. The babies undergo DXA assessment of bone mass within the first 14 days after birth, with the primary outcome being whole body bone mineral content adjusted for gestational age and age. Children are then followed up with yearly assessment of health, diet, physical activity and anthropometric measures, with repeat assessment of bone mass by DXA at age 4 years.DiscussionAs far as we are aware, this randomised trial is one of the first ever tests of the early life origins hypothesis in human participants and has the potential to inform public health policy regarding vitamin D supplementation in pregnancy. It will also provide a valuable resource in which to study the influence of maternal vitamin D status on other childhood outcomes such as glucose tolerance, blood pressure, cardiovascular function, IQ and immunology.

Subchondral bone attrition may be a reflection of compartment-specific mechanical load: The MOST Study

Introduction Subchondral bone attrition (SBA), a feature of osteoarthritis, may be caused by excess focal load to bone, and/or inadequate bone quality to withstand loads through the joint. This study evaluated the effects of malalignment, which can cause focal excessive load, and systemic bone density on the presence and incidence of SBA. Methods The Multicenter Osteoarthritis Study is a cohort of individuals who have or are at high risk of knee osteoarthritis. Baseline alignment and bone mineral density (BMD) measures were assessed. Baseline and 30-month knee magnetic resonance images were graded for SBA (grade 0–3) using the whole-organ magnetic resonance imaging score. The study evaluated the association of alignment in medial and lateral compartments, respectively, and systemic BMD with baseline presence of SBA and incident SBA using logistic regression and adjusting for age, sex and body mass index. Results Of 1253 participants (mean age 62 years, mean BMI 30, 61% women), 33% had baseline SBA and 44% had knee osteoarthritis. Associations between the presence and incidence of SBA with malalignment in both compartments were noted (odds ratios (95% CI) 2.9 (2.1 to 4.0) and 1.9 (1.2 to 2.9), respectively, for varus knees in the medial compartment; 4.5 (2.8 to 7.1) and 2.1 (1.1 to 4.1), respectively, for valgus knees in the lateral compartment). Low BMD was not associated with SBA. Conclusions The presence and incidence of SBA are associated with malalignment in a compartment-specific manner, but not with low BMD. SBA may be a marker of increased load experienced by overlying cartilage, which may contribute to increased forces transmitted to the cartilage due to alteration in subchondral bone.

Growth and bone development.

Osteoporosis is a major cause of morbidity and mortality through its association with age-related fractures. Although most effort in fracture prevention has been directed at retarding the rate of age-

Defining incident radiographic hip osteoarthritis for epidemiologic studies in women

OBJECTIVE To evaluate definitions of radiographic hip osteoarthritis (RHOA) for use in longitudinal epidemiologic studies of disease incidence in women. METHODS We studied 5,839 women from the Study of Osteoporotic Fractures who had had serial pelvic radiographs obtained (mean of 8.3 years apart) and who were followed up (mean followup 7.1 years from the time of the second radiograph) for evaluation of clinical outcomes. Definitions of RHOA were assessed for construct validity (association with symptoms and signs at the time of the second radiograph) and predictive validity (association with total hip replacement [THR] and signs and symptoms a mean of 7.1 years later). Odds ratios (ORs) and 95% confidence intervals were calculated to assess the strength of association using logistic regression. RESULTS The cumulative incidence of RHOA ranged from 2.2% to 11.7%. All definitions displayed significant construct validity; the most consistent was found for composite definitions that required the concurrent presence of 2 or more individual radiographic features and definitions based on stringent criteria for joint space narrowing. All definitions except minimum joint space < or =2.5 mm displayed consistent predictive validity. Composite definitions had the strongest associations with THR (OR 10.5-18.5) and hip pain (OR 2.6-2.9). The hips identified as having OA by each definition varied, with especially small overlap between findings using definitions based on osteophytes and those using definitions based on joint space narrowing alone. CONCLUSION Most definitions of incident RHOA display good construct and predictive validity. Composite definitions have the best overall performance, and definitions requiring the presence of both osteophytes (in particular, femoral osteophytes) and joint space narrowing would be recommended for most epidemiologic and genetic studies.

INTRAUTERINE GROWTH AND POSTNATAL SKELETAL DEVELOPMENT: FINDINGS FROM THE SOUTHAMPTON WOMEN'S SURVEY

We have previously demonstrated associations between fetal growth in late pregnancy and postnatal bone mass. However, the relationships between the intrauterine and early postnatal skeletal growth trajectory remain unknown. We addressed this in a large population-based mother-offspring cohort study. A total of 628 mother-offspring pairs were recruited from the Southampton Womens Survey. Fetal abdominal circumference was measured at 11, 19 and 34 weeks gestation using high-resolution ultrasound with femur length assessed at 19 and 34 weeks. Bone mineral content was measured postnatally in the offspring using dual-energy X-ray absorptiometry at birth and 4 years; postnatal linear growth was assessed at birth, 6, 12, 24, 36 and 48 months. Late pregnancy abdominal circumference growth (19-34 weeks) was strongly (P < 0.01) related to bone mass at birth, but less robustly associated with bone mass at 4 years. Early pregnancy growth (11-19 weeks) was more strongly related to bone mass at 4 years than at birth. Postnatal relationships between growth and skeletal indices at 4 years were stronger for the first and second postnatal years, than the period aged 2-4 years. The proportion of children changing their place in the distribution of growth velocities progressively reduced with each year of postnatal life. The late intrauterine growth trajectory is a better predictor of skeletal growth and mineralisation at birth, while the early intrauterine growth trajectory is a more powerful determinant of skeletal status at age 4 years. The perturbations in this trajectory which influence childhood bone mass warrant further research.

The failing medial compartment in the varus knee and its association with CAM deformity of the hip.

BACKGROUND Since 2011, the knee service at the Nuffield Orthopaedic Centre has been offering a neutralising medial opening wedge high tibial osteotomy (HTO) to a specific group of patients with genu varum and early knee osteoarthritis. An observation was made concerning this group of patients and the presence of CAM deformity at the hip. The aim of this study is to establish whether or not any association exists between the OA phenotype shared by our HTO group and the incidence of CAM deformity at the hip. METHODS A cross-sectional study was designed to estimate the prevalence of CAM-type lesions across different groups of individuals. Our HTO group (n=30) was compared to a pre-arthroplasty group (n=20) and control group (n=20). A total of 70 subjects were identified across the different groups all of whom had long-leg radiographs (LLRs) available for analysis. LLRs were analysed using an in house developed Matlab®-based (Matlab R2009b; MathWorks) software package for hip measurements and MediCAD® (Hectec GmbH, Germany) for lower limb alignment measurements. RESULTS The HTO group had a significantly higher prevalence of CAM lesions (57%) than both the pre-arthroplasty (40%) and control (30%) groups. This difference was maintained when results were adjusted for potential confounding factors (age, gender and laterality). Across the groups, individuals with tibia vara were more likely to have CAM-deformity of the hip (p=0.021). CONCLUSION Patients with symptomatic early knee OA and varus deformity of the knee have a high prevalence of CAM deformity in the hip.

27 The Neurohistology Of Painful And Pain-free Rotator Cuff Tendons

Introduction The relationship between rotator cuff tendon structure and pain symptoms is imperfect and icompletely understood.2 The inability to gather tendon-matched and age-matched control tissue from live donors has been a significant limiting factor in many previous studies.1 The aim of this study was to determine whether there were neurohistological differences between painful and pain-free rotator cuff tendons. Methods Supraspinatus tendon specimens were obtained by ultrasound guided biopsy from 9 patients with painful rotator cuff tendinopathy (RCT) resistant to conservative management (painful group) and 9 pain-free patients at over 6 years following subacromial decompression (SAD) (pain-free group). Pain symptoms were measured using the validated Oxford Shoulder Score (OSS). Structural tendon integrity was assessed ultrasonographically. Basic histological staining and immunohistochemistry was performed. Mann-Whitney U tests were used to test for differences between groups. Results The groups were similar in terms of age, sex and structural tendon abnormality. The painful group consisted of 7 males and 2 females, the pain-free group of 6 males and 3 females. The mean age of the painful group was 51 years and that of the pain-free group was 52 years. The median OSS in the painful group was 32 (range 23 to 36) and this was significantly lower (p = 0.0002) than the median OSS in the pain-free group (all 48). There were two partial thickness tears in both groups and no full thickness tears. There were no significant differences between groups in terms of cellularity, vascularity, proliferation and hypoxia inducible-factor 1α expression. The leucocyte count (% of CD45 positive cells) and macrophage count (% of CD206 positive cells) were increased in the painful group versus pain-free (p = 0.038 and 0.0004 respectively). The expression of metabotropic glutamate receptor 7 (mGluR7) was reduced in the painful group versus pain-free (p = 0.002), while the expression of the Kainate 1 receptor was increase in the painful group (p = 0.003). PGP 9.5 (a nerve marker) and Lactate Dehydrogenase (LDH) expression were increased in the painful group versus pain-free (p = 0.008 and 0.007 respectively). There were no significant differences in glutamate, the inotropic glutamate receptor (NMDAR1) and the metabotropic glutamate receptors (mGluR1 and 2) between groups. Discussion This study has shown that specific characteristics of tendon neurohistology are associated with the presence of shoulder pain. This provides strong evidence that the rotator cuff tendon is of key importance in the symptomatology of RCT. The mechanism behind these tendon differences is unclear. These findings are novel and improve our understanding of pain in RCT, and may help provide novel therapeutic targets. References 1 Dean BJ, Franklin SL, et al. A systematic review of the histological and molecular changes in rotator cuff disease. Bone Joint Res. 2012;1(7):158–166 2 Yamaguchi K, D. K. et al. The demographic and morphological features of rotator cuff disease. A comparison of asymptomatic and symptomatic shoulders. JBJS (Am). 2006;88(8):1699–1704