Abstract
Immune-mediated bone loss significantly impacts fracture risk in patients with autoimmune disease, but to what extent individual variations in immune responses affect fracture risk on a population level is unknown. To examine how immune responses relate to risk of hip fracture, we looked at the individual variation in a post-vaccination skin test response that involves some of the immune pathways that also drive bone loss. From 1963 to 1975, the vast majority of the Norwegian adult population was examined as part of the compulsory nationwide Norwegian mass tuberculosis screening. These examinations included standardized tuberculin skin tests (TSTs). Our study population included young individuals (born 1940 to 1960 and aged 14 to 30 years at examination) who had all received Bacille Calmette-Guerin (BCG) vaccination after a negative TST at least 1 year prior and had no signs of tuberculosis upon clinical examination. The study population ultimately included 244,607 individuals, whose data were linked with a national database of all hospitalized hip fractures in Norway from 1994 to 2013. There were 3517 incident hip fractures during follow-up. Using a predefined Cox model, we found that men with a positive or a strong positive TST result had a 20% (hazard ratio [HR] = 1.20, 95% confidence interval [CI] 1.01-1.44) and 24% (HR = 1.24, 95% CI 1.03-1.49) increased risk of hip fracture, respectively, compared with men with a negative TST. This association was strengthened in sensitivity analyses. Total hip bone mineral density (BMD) was available for a limited subsample and similarly revealed a non-significantly reduced BMD among men with a positive TST. Interestingly, no such clear association was observed in women. An increased immune response after vaccination is associated with an increased risk of hip fracture decades later among men, possibly because of increased immune-mediated bone loss. © 2020 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
Highlights
The term osteoimmunology was coined in 2000(1) and has become a shorthand for the interplay between bone and immune system
Our results showed that men with a positive TST after Bacille Calmette-Guerin (BCG) vaccination at a young age had a slightly increased risk of hip fracture later in life, potentially mediated through increased immunemediated bone loss
A similar sex-specific difference has previously been described for C-reactive protein (CRP) and bone mineral density (BMD),(29) and there are indications that men and women have differing immune responses toward tuberculin/tuberculosis.[30]. The impact of female reproductive health on immune activity may be important to consider
Summary
The term osteoimmunology was coined in 2000(1) and has become a shorthand for the interplay between bone and immune system. A large part of this interplay is facilitated by cytokines released from activated T cells, which affect bone remodeling in different ways. Most activated T cells release cytokines that inhibit rather than stimulate bone loss.[2,3] T-helper cell. The tuberculin skin test (TST) has been employed since the early 20th century primarily to detect infection with tuberculosis[11] and to document the immunological reaction to the Bacille Calmette-Guerin (BCG) vaccine. The test is conducted by intracutaneously applying antigens derived from tubercle bacilli. This produces a skin induration if the individual has undergone a prior sensitization toward the injected antigens, commonly from a BCG vaccination or much less common from environmental mycobacteriae or tuberculosis infection
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