In this large population-based study, we found that the use of ADT in the treatment of prostate cancer was associated with an increased risk of osteoporosis and fracture. The ADT group had a higher cumulative incidence of osteoporosis and fracture than the non-ADT group in the propensity score-matched cohort. In addition, the risk of osteoporosis and fracture increased as the duration of ADT increased, although concurrent use of anti-androgens did not increase the harmful effects of ADT.
Theories regarding osteoporotic fractures include the effect of increased bone turnover on bone strength, independent of reduced bone mineral density.21 Normal bone is in a state of equilibrium with ongoing bone formation and resorption mediated by osteoblasts and osteoclasts, respectively.22 Androgen deprivation induces testosterone and estrogen deficiency, increasing bone turnover and bone resorption, resulting in a decrease in the bone mineral density (BMD).23,24 Our previous meta-analysis showed that prostate cancer patients treated with ADT showed a significant decrease in the BMD compared to the controls.25 Large-scale population-based studies on the correlation between ADT and fracture have been conducted in several Western countries.7,17,18,26,27 Shahinian et al. conducted a study of 50,613 men who survived for more than 5 years after prostate cancer diagnosis, as recorded in the database of the National Cancer Institute's SEER program and Medicare.7 The authors reported that patients using ADT experienced fractures more frequently than those not using ADT, and there was a significant relationship between fracture risk and cumulative dose of ADT in the first year. Beebe-Dimmer et al. also investigated the association between ADT and fracture risk using the SEER-Medicare dataset.26 They reported that ADT in elderly men with prostate cancer increased the incidence of fractures, and the effect appeared to decrease with increasing time duration since the administration of the last dose of a GnRH agonist. Other population-based cohort studies conducted in Denmark, Canada, and New Zealand reported similar results.
Nevertheless, it is not known whether the effects of ADT on BMD and fractures vary among races. Morgans et al. compared BMD and fracture between African American and Caucasian men receiving ADT for prostate cancer to assess whether race-related ADT effects vary.19 They reported that the hip BMD was higher and the prevalence of vertebral fractures was lower in African American men receiving ADT for prostate cancer than in Caucasian men. Therefore, there may be a racial difference in the effect of ADT on fractures. A few studies have discussed the fracture risk among prostate cancer patients in the Asian population receiving ADT, and it is unclear whether ADT has a similar effect on the BMD of Asian patients with prostate cancer. Several studies have suggested that there are racial differences in the bone density and incidence of fractures between Asian and Caucasian women.28–30 Wu et al. conducted a study using the National Health Insurance Program of Taiwan.20 They showed that ADT or orchiectomy increased the risk of fracture in Chinese patients with prostate cancer. However, the 5-year fracture-free rates were 90.0% in the ADT group and 92.2% in the non-ADT group.20 It has been suggested that the effect of ADT on the decrease in the fracture-free rate in the Asian population may not be as marked as that reported in Western studies.7,18,31 In our study, the 5-year fracture-free rates in the ADT group were 88.26% compared with 93.78% in the non-ADT group. Our results did not differ significantly from those of other Western studies. Therefore, it is still questionable whether the effect of ADT on fracture risk varies according to race, and additional studies are required to validate these observations.
Evidence-based management for minimizing bone loss in prostate cancer patients with ADT is important.32 Bisphosphonates, a human monoclonal antibody (denosumab), and selective estrogen receptor modulators (e.g., raloxifene and toremifene) are available for the management of BMD loss by ADT.33 The National Comprehensive Cancer Network Guidelines has provided much evidence for the above treatments with respect to ADT-induced bone loss.34 Poon et al. found that all the drugs mentioned are effective in reducing the rate of bone loss in patients with non-metastatic prostate cancer using ADT, through a systematic review and network meta-analysis.33 Moreover, clinicians should encourage lifestyle interventions and provide information about nutritional supplements to prostate cancer patients using ADT.33 Meanwhile, clinicians administering ADT for prostate cancer patients should consider periodic BMD testing. The USA Endocrine Society and the National Comprehensive Cancer Network recommend BMD measurement in men aged 50–69 years with fracture risk factors such as use of ADT.34,35
Our study had several strengths. Our database included almost all prostate cancer patients in Korea during the study period, resulting in a large sample size with a relatively long follow-up period. Our study design, based on strict inclusion/exclusion criteria of the study cohort and meticulous matching by various covariates, may have been helpful in reducing confounding bias. Nevertheless, there were also some limitations. Claim data do not provide clinical information such as tumor stage, tumor grade, prostate specific antigen level, and BMD data. The probability of bone metastasis in the ADT group is high, and fractures related to bone metastasis could not be excluded from the analysis. However, fractures in prostate cancer due to bone metastases are known to account for only 7 to 16 percent of all fractures.36,37 Accordingly, the increased risk of fracture from ADT would be maintained even after excluding bone metastasis-related fractures. In addition, we did not distinguish between continuous ADT use and intermittent ADT use, which may have impacted the results.
In conclusion, the use of ADT was associated with an increased risk of osteoporosis and fracture in Korean patients with prostate cancer. Moreover, our results also indicate that the risk of osteoporosis and fracture increases as the duration of ADT increases. Clinicians who administer ADT for patients with prostate cancer should always be mindful of the risk of osteoporosis and fracture, avoid unnecessary ADT, and perform regular bone health check-ups. Meanwhile, further study investigating racial differences in the effects of ADT on fracture is needed.