Individual variation in adaptive immune responses and risk of hip fracture – A NOREPOS population-based cohort study

T-cell mediated immune responses may affect bone homeostasis, and subsequently the risk of fracture, through multiple pathways. Little is known about how individual variation in these responses contributes to the risk of fracture on a population-level. Tuberculin skin tests (TST) are likely one of the few tests directly reflecting in vivo T-cell responses to have been conducted on a population-scale, as part of the effort to prevent the spread of tuberculosis. The aim of this study was to estimate the impact of individual variation in these immune responses on the risk of hip fracture in the general population. The hypothesis was that individuals with a tendency towards pro-inflammatory responses have an increased risk of fracture.We used data from the compulsory nationwide Norwegian mass tuberculosis screening and BCG vaccination programme during 1963-1975, which covered an estimated 80-85% of the population. This data included results from standardized TST, as well as timing and status of BCG vaccination. Individuals aged 14-30 years at the time of TST measurement and born 1940-1960 were included in the current analysis. All included individuals had a negative TST followed by BCG vaccination in the past, and had no signs of tuberculosis upon examination. TST results at the screening were recorded in millimetres, and later categorized according to clinical guidelines (positive/negative). Our cohort constitutes 248 551 individuals who were alive and living in Norway at the start of the NORHIP database in 1994. This database includes records on all hospitalizations due to hip fractures in Norway during 1994-2013 (follow-up). Risk estimates were adjusted for county, BMI, age and time between BCG-TST, using Cox regression models. There were 3580 incident hip fractures during follow-up (first fractures), with a median age at the time of fracture of 61 years (range 36-73). Men with a positive TST had a 22% (HR 1.22, 95% CI 1.02-1.44) increased adjusted risk of hip fracture compared to men with a negative TST. This association was strengthened in sensitivity analyses limited to either those born 1945-1960 (post WW2) or aged 11-14 years at BCG vaccination (school vaccination). No clear association was observed in women. We conclude that men with a negative tuberculin skin test after BCG vaccination have a reduced risk of hip fracture decades later. Women do not demonstrate similar associations, potentially due to sex specific differences in immune responses.