The Effects of Obesity on Bone Structure and Strength
Condition: Osteoporosis; Obesity
MeSH terms: Osteoporosis; Obesity
Study type: Observational

Summary: 
      High body weight is protective against hip and spine fracture, but has been found to increase
      the risk of humerus, foot and ankle fracture. Increasing understanding of the actions of
      adipokines on bone suggests that there may be complex effects on different aspects of bone
      geometry and microarchitecture and that these effects may vary depending on whether
      adipokines act directly on bone cells or through the central nervous system and between
      cortical and trabecular compartments. Previous research is limited by the use of areal
      dual-energy x-ray absorptiometry (DXA) scans which may be inaccurate in obese populations due
      to increased body thickness.

      The aim of this study is to investigate the effect of obesity on bone mineral density, bone
      geometry, bone microarchitecture and bone strength of the hip, lumbar spine, distal radius
      and tibia.

      This is an observational, cross-sectional study of normal weight and obese individuals
      matched by age, gender, height, postcode and smoking. The total number of subjects will be
      240; men and premenopausal women ages 25 to 40 years and men and postmenopausal women ages 55
      to 75 years. DXA, high-resolution peripheral computed tomography (HR-pQCT), quantitative
      computed tomography (QCT) and finite element analysis will be used to assess bone structure
      and strength. Biochemical markers of bone turnover and hormones related to bone metabolism
      will also be measured in order to identify potential mediators of the effects of obesity on
      bone structure and strength.

      A sub-study has been included to evaluate the interaction of fracture risk and cardiovascular
      risk in obese and non-obese individuals. There is evidence of an interaction between bone
      mineral density (BMD) and cardiovascular risk and test the hypothesis that there are common
      pathways linking BMD and cardiovascular risk, including fat secretion of inflammatory
      cytokines e.g. interleukin-1 and adipokines e.g. leptin and adiponectin. Ultrasound based
      assessments of vascular function will be used to assess cardiac risk and relate these
      measures to bone density.

      Obese individuals have lower circulating levels of 25OHD. This may be due to poor nutritional
      intake, reduced sunlight exposure or the vitamin D being stored in fat tissue. The
      investigators will measure levels of 25OHD in lean, overweight and obese men and women to
      examine whether 25(OH)D is related to age or gender and whether low 25OHD in obesity affects
      bone health in subsets of lean, overweight and obese participants of different ages.
    

Detailed description: 
      This is a single centre, observational, cross-sectional, case-controlled study to determine
      the effects of obesity on bone structure and strength. Cases will be obese individuals and
      controls will be lean individuals. Overweight individuals will increase the applicability of
      the vitamin D sub-study to the general population. Cases will be individually matched to
      controls by gender, age, height, first part of postcode (e.g. S5, S10) and smoking, listed in
      order of priority. Individually matched controls will reduce the influence of potential
      confounding factors on the data collected. Blinding is not applicable to this study design.

      Participants aged 25-40 years will attend for two visits:

      Visit 1 - Consent, questionnaire, anthropometric measurements (height, weight, waist-to-hip
      ratio (WHR), triceps skinfold), tympanic temperature, blood sampling, neuromuscular function
      tests (chair stand test, narrow walk test and grip strength) Visit 2 - Anthropometric
      measurements (height, weight), pregnancy test, measurement of supine abdominal thickness, hip
      width measurement, DXA (whole body, spine, hip), HR-pQCT (tibia, radius), QCT (spine and
      hip).

      Participants aged 55-75 years will attend for three visits; visits 1 and 2 as for the younger
      participants, and an additional visit to form the cardiovascular sub-study:

      Visit 3 - Anthropometric measurements (height, weight), blood pressure, cardiovascular risk
      measurements (abdominal aortic calcification (AAC), flow mediated dilatation (FMD), carotid
      intima-media thickness (CIMT), pulse wave velocity (PWV) and ABPI).

      Due to the seasonality of vitamin D levels, the vitamin D sub-study must be completed in the
      summer months. Participants who have completed the main study prior to August 2012 and have
      given their consent to be contacted regarding future research will be invited to participate
      in the vitamin D sub-study by telephone and subsequently sent written information about the
      vitamin D sub-study. Volunteers will be invited to attend for one additional visit between
      August 2012 and October 2012.

      Future participants (those yet to consent to taking part in the main study) will be invited
      to participate in the vitamin D sub-study prior to consenting to the main study. As vitamin D
      levels are affected by seasonality, the substudy components can be completed at visit 1 of
      the main study for participants who attend for their first study visit between August 2012
      and October 2012. However, participants attending for visit 1 of the main study between
      October 2012 and April 2013 will be invited to attend for an additional visit to complete the
      vitamin D sub-study in summer/autumn 2013.

      Participation in the vitamin D sub-study will require a small blood sample to be taken and
      the completion of diet and sun exposure questionnaires.

      The effect of obesity on bone structure will be determined by comparing the measures of BMD,
      bone microarchitecture and geometry in the obese study group with the lean group. The effects
      of obesity on bone strength will be determined using Finite element analysis (FEA). Outcomes
      from the neuromuscular function tests will be compared between the lean and obese groups to
      determine the effect of obesity on lower extremity strength, balance, coordination and
      flexibility. Hormones and bone turnover markers will be compared in lean and obese
      participants and any associations between hormones and bone turnover markers and measures of
      bone structure and strength will be identified.

      The relationship between cardiovascular risk and BMD will be assessed by comparing the
      measures of FMD, CIMT, PWV, AAC and ABPI in the obese sub-study group with the lean sub-study
      group. The interactions between cardiovascular risk and fracture risk will be studies using
      the surrogate imaging for atherosclerosis risk.

      Comparisons of the levels of hormones, inflammatory markers and other biochemical factors
      will be made between the lean and obese participants and tests will be made for associations
      between these measures and measures of cardiovascular risk.

      The primary outcome in the main study will be mean difference in hip BMD between obese and
      lean individuals.

      Secondary outcomes will be mean difference in cross-sectional moment of inertia, cortical and
      trabecular BMD, bone microarchitecture and geometry and neuromuscular function between lean
      and obese individuals, association between BMD and cardiovascular risk and association
      between body weight and circulating 25(OH)D.
    

Observational model: Ecologic or Community
Time perspective: Cross-Sectional
Sampling method: Non-Probability Sample
Study population: 
        Healthy Caucasians Recruited from South Yorkshire, UK
      
Biospecimen description: 
      Serum, plasma, urine, DNA
    
Keywords: Bone; Vitamin D; Cardiovascular