This prospective analysis evaluated the association of BMD measures with incident prostate cancer in a cohort of older men with no history of PCa. Unexpectedly, we found that higher BMD of the total body was significantly related to reduced risk for prostate cancer. No associations were observed for hip and spine BMD measures with PCa. Additionally, total body BMD was inversely associated with the development of high-grade, but not low-grade disease. A similar but weaker association was observed for total hip BMD with high-grade PCa.
The direction of the association of total body BMD with prostate cancer was contrary to our initial hypothesis. This finding lends support to results from the NHANES I Epidemiologic Follow-up Survey where a decline in prostate cancer risk, although not significant, was observed with higher quartiles of bone density, determined using radiographic absorptiometry. In that study, compared to the lowest BMD quartile, the age, race, and BMI-adjusted rate ratios across BMD quartiles were 0.63 (95% CI: 0.37–1.07) for the second, 0.86 (95% CI: 0.49–1.49) for the third, and 0.72 (95% CI: 0.38–1.38) for the highest quartile (11
Our results were discordant with those from the Tobago Prostate Survey and the Framingham Study, where higher bone density was associated with an increased prostate cancer risk (10
). The Tobago study evaluated Afro-Caribbean men, and reported a significant trend of higher prostate cancer prevalence with increasing total hip BMD quartiles, in men aged 60–79 years. Compared to men in the lowest quartile of BMD, those in the highest quartile had a two-fold higher odds of prostate cancer (OR= 2.12, 95% CI: 1.21–3.71). No such associations were observed in younger men in this cohort (10
). Notably, total hip BMD in this population was higher than that observed for African-American men in NHANES III by approximately one standard deviation (17
). This may be reflective of a higher exposure to endogenous sex steroid hormones and growth factors. The Framingham study involved 100 cases of prostate cancer, diagnosed at a median age of 75.2 years. It reported a higher risk of PCa in the upper two quartiles of radiogrammetrically-determined metacarpal cortical width, assessed at a mean age of 61 years (12
). While these findings were adjusted for important risk factors such as age and BMI, they may be prone to residual confounding by factors such as family history of prostate cancer and calcium and vitamin D intakes, which were not collected in the above studies.
Sex steroids are important regulators of skeletal growth and maintenance of BMD in both men and women (18
). In the Swedish arm of the MrOS cohort, free testosterone was found to be a positive predictor of bone density at the total body, total hip, femur trochanter, and arm (20
). Androgens are also thought to stimulate cell proliferation of the prostate epithelium and were related to increased risk of PCa in some prospective epidemiologic studies (2
). While the direction of association observed in our study does not provide a direct evidence for the role of endogenous sex hormones in the link between BMD and prostate cancer, it suggests a possible involvement of other pathophysiological mechanisms.
Poor vitamin D status may be a common denominator for the inverse association between BMD and prostate cancer risk. Low levels of vitamin D are known to have detrimental effects on bone density (21
) and have been implicated in prostate carcinogenesis. In-vivo evidence suggests that calcitriol has anti- proliferative and chemopreventive effects in PCa (22
). Additionally, in some epidemiologic studies, low levels of vitamin D metabolites have been assocaited with increased prostate cancer risk (23
Inflammation may also be involved in the link between BMD and prostate cancer. Pro-inflammatory cytokines have been implicated in osteoporosis and increased fractures risk (25
). Interleukin-6 was shown to stimulate osteoclasts, thereby increasing the rates of bone remodeling and bone loss (26
). Inflammation is also suggested to play a role in prostate carcinogenesis (27
). In the MrOS cohort, self-reported history of prostatitis was found to be positively associated with prevalent prostate cancer (OR= 5.4, 95% CI 4.4–6.6) (28
), raising the possibility that chronic inflammation within the prostate may contribute to the pathogenesis of prostate cancer. Owing to the complex multifactorial pathogenesis of prostate cancer and bone mineralization, it is likely that more than one biological mechanism is involved in their link.
Interestingly, in our secondary analysis, the relationship of BMD measures with prostate cancer was limited to high-grade tumors. To our knowledge, our study was the first to investigate the relationship of bone density with tumor grade in PCa. Therefore, no other data are available for direct comparison. Vitamin D insufficiency may be involved in this association. Recent results from the Physician’s Health Study have indicated that low levels of both 25(OH) D and 1,25(OH)2
D were related to increased risk of aggressive PCa. However, no such associations were observed for non-aggressive disease (24
The observed associations were specific to BMD of the total body as well as the total hip, in the case of high grade disease. The lack of association at the spine may be related to the sensitivity of DXA technology to extra-osseous calcification, such as aortic calcification and degenarative osteoarthritic changes, which get incorporated in the region of interest and lead to a falsely increased bone density of the spine.
Interestingly, we observed that men with incident PCa were younger and had a higher level of physical activity, compared to men who did not develop the disease. This may be a reflection of increased awareness to prostate cancer screening and prevention in PCa cases, as triggered by their stronger family history of the disease.
Our results extend previous findings by longitudinally examining the association of prostate cancer and tumor grade with bone density at different skeletal sites. Our study had the benefit of a rigorous adjudication of prostate cancer cases, determination of BMD using a state-of-the-art method, and adjustment of results for a comprehensive set of risk factors for PCa, including calcium intake, family history of PCa, physical activity, and statin use. Limitations of our analysis include the unavailability of serum measurements of vitamin D and sex hormones on the full population, and the generalizability of findings to other populations due to the inclusion of a well-functioning cohort of mainly older white men.
In conclusion, we observed an unexpected inverse association between total body bone density and the risk of prostate cancer in older men who did not have a prior history of the disease. Further research is needed to confirm the direction of the relationship and to elucidate the pathophysiological mechanisms involved in the link between BMD and prostate cancer.