Aims

This project will, which will form the basis of an Arthritis Research UK Clinical Research Fellowship for Anupama Nandagudi, will use the mother participants in ALSPAC to investigate whether increased bone turnover explains the link between CVD and osteoporosis:-

(i) Using a cross sectional design, we will confirm that carotid intimal thickness (cIMT) is associated with hip BMD, as measured in the first mothers' clinic comprising predominantly premenopausal women, independently of shared risk factors.

(ii) We will investigate whether cIMT is related to bone turnover, as assessed by beta-CTX measured on blood samples obtained at the same time funded by this fellowship, and whether any association observed explains that between cIMT and hip BMD as described in (i).

(iii) Using a prospective design, we will determine whether cIMT is related to pQCT parameters as assessed at the distal and mid radius in the second mothers' clinic two years later. In particular, we will determine whether these associations involve phenotypes suggestive of increased bone resorption, and if so, whether these relationships are explained by associations with beta-CTX as described in (ii).

(iv) Whether shared genetic risk factors also contribute to the relationship between CVD and osteoporosis will be examined as follows:-

a. We will investigate whether genetic markers for cIMT as identified in recent GWA studies are also related to hip BMD, pQCT variables and/or beta-CTX.

b. We will determine whether genetic markers for bone phenotypes identified in recent GWA studies are also associated with cIMT.

c. We will determine whether associations between cIMT and bone outcomes observed above are explained by shared genetic risk factors which we identify.

d. Whether associations between cIMT, bone phenotypes and genetic factors which we find can be replicated in other populations with equivalent genotypic and phenotypic data will be investigated based on other cohorts (eg Young Finns, Twins UK).

Hypothesis

Prevalent subclinical CVD predicts future fractures and bone loss (1). As well as shared risk factors, this may reflect common pathological mechanisms such as increased bone turnover, which is the subject of the present proposal

Exposure variable

Subclinical CVD as reflected by cIMT as measured at the first mothers' clinic

Outcome Variables

Hip BMD (first mothers' clinic)

Beta-CTX (first mothers' clinic)

Trabecular BMD, as measured by pQCT at the distal radius (second mothers' clinic)

Cortical bone parameters, as measured by pQCT at the mid-radius (second mothers' clinic)

Confounders

Lifestyle risk factors (smoking, HRT use, physical activity, alcohol)

Constitutional risk factors (BP, BMI, fat mass (including intramuscular fat mass as measured by pQCT), age of menopause)

Blood measures (CRP, IL-6, LDL, VLDL, HDL, leptin, adiponectin)

References

(1) Uyl D, Nurmohamed MT, van Tuyl LHD, Raterman HG, Lems WF 2010 (Sub)clinical cardiovascular disease is associated with increased bone loss and fracture risk; A systematic review of the association between cardiovascular disease and osteoporosis. Arthritis Research and Therapy 13 (1) Article Number: R5.