We demonstrate that 3-D conformal pelvic EBRT increases the risk of hip fracture by 76% in men over 65 years of age being treated for prostate cancer. To analyze the site-specific risk modification of the EBRT we also test the effect of EBRT on the risk of fall-related fractures outside the radiation field, specifically distal forearm fracture. Indeed, we show that whereas EBRT increased the risk of hip fracture it did not increase the risk of distal forearm fracture. As reference points, the added hip fracture risk due to EBRT treatment is similar in scale to the added risk from a 7 year increase in age (HR=1.097 per year) or having a Charlson comorbidity score of ≥2 vs. a score of 0 in our model, the risk imparted by a baseline diagnosis of osteoporosis, or the increased risk others have shown due to being a current smoker vs. never smoker.6
In absolute risk terms, 51 men need to be treated with EBRT to induce 1 hip fracture through 10 years of follow-up. Given that over 28% of the nearly 200,000 men diagnosed with prostate cancer each year receive EBRT, 3-D conformal EBRT may be linked to approximately 1,000 hip fractures each year.
We have previously shown that pelvic EBRT is a significant risk factor for hip fractures but not other fractures in women with gynecologic and colorectal malignancies.5
Similarly, the Stockholm trial of short-course radiotherapy for rectal cancer resulted in a doubling of fracture incidence in the radiated group for both men and women.18
The bony pelvis lies in close proximity to genitourinary pelvic organs and their lymphatics. Therefore, when radiation is used to treat the prostate and/or the pelvic lymph nodes, nearby bony structures are also irradiated.
Radiation damage occurs in the bone matrix, at the cellular level and at the vascular level.7
Radiation can lead to death of osteoblasts, osteocytes, and osteoclasts, resulting in a reduction in bone matrix production. In addition, radiation damage to the vascular supply to the bone may lead to further bone loss.9
Radiotherapy has been associated with fractures of the femur, pubic rami, and pubic symphysis; acetabular failure; and avascular necrosis of the hip.8, 9, 19
Adding to the complexity of the problem, fractures after radiotherapy are more difficult to treat; hip replacement after radiotherapy is associated with an increased risk of infection and malfunction.8, 20
This study did not analyze the association between IMRT and hip fractures. Prostate IMRT utilization has increased greatly over the last decade since it was first approved for payment by Medicare in 2002. Whereas some of the 3-D conformal EBRT beams pass through the hip en route
to the prostate (), IMRT can allow planners decrease the dose to the hip or completely avoid the hip when necessary without compromising dose to the prostate or increasing scatter to the rectum and bladder.21
This may translate into a lower risk for hip fracture with IMRT. However, we did not include IMRT in this analysis because it was introduced late in our study period and our Medicare claims follow-up would have been too short (3–4 years) to measure the long-term risk of hip fracture in this group.
EBRT Treatment Plan for Prostate Cancer. Note how lateral beams pass through the hip bones en route to the prostate. (From Kathryn Dusenbery, M.D., Department of Therapeutic Radiology, University of Minnesota)
AST is known to increase the risk of fractures.22
Because EBRT+AST combination therapy in high risk prostate cancer is known to improve survival compared to either treatment alone,13, 14, 16
we were interested in the combined effect of these modalities on the risk of hip fracture. As all cancer therapy should be aimed at balancing benefits and risks, an examination of the risk of combination therapy is important. As expected, hip and distal forearm fracture risk was highest in the group treated with AST alone (mean = 19 monthly doses). Although the addition of short course AST to EBRT (mean =11 monthly doses) did increase the risk of hip fracture by 40% compared to EBRT alone, the added effect of AST was not as dramatic as that seen at the higher number of doses used with AST monotherapy. Given that current trial evidence favors 36 months over 6 months of AST when combined with EBRT,14
it would be interesting to know how more AST doses affects hip fracture risk in the EBRT+AST group. However, a low number of events (hip fractures) in each group after stratification by the number of AST doses prevented us from investigating for such a dose-response relationship.
Certain limitations deserve mention. As our findings are based on a population of men > 65 years of age, conclusions may not be applicable in younger patients. Claims-based research can be an inexact measure of minor events; however, hip fracture nearly always results in acute hospitalization and claims-based methods have been shown to be valid in such disease models.23
It may be argued that the older age and higher number of comorbidities of our EBRT-treated cohort are evidence that men who select EBRT are generally more ill and at higher baseline risk for hip fracture. We have controlled for such a selection bias in two ways. First we demonstrate that EBRT-treated patients were not at higher risk for distal forearm fractures. In a way, distal forearm fracture serves as an internal control – if the increase in hip fracture risk seen in the EBRT-treated men was due to selection bias then one would expect their risk of distal forearm fracture to have been higher too. Second, our multivariate model demonstrates that after controlling for these other risk factors (e.g. age and comorbidities), EBRT still increases the risk of hip but not distal forearm fracture. Of note, there may be residual confounding due to differences in the prevalence of risk factors that we are not able to measure such as patient weight, smoking, glucocorticoid therapy, alcohol use and radiation dose to the hip -- some of these risk factors may be correlated with the receipt of EBRT. Finally, we were only able to exclude metastatic disease through 6 months after diagnosis. Should new bony metastases occur after 6 months these may result in fracture. This may confound measurement of our outcome if the likelihood of delayed metastatic disease differs between RP and EBRT-treated men. We controlled for the risk of confounding due to metastases by excluding men who initiated AST or underwent orchiectomy more than 6 months after diagnosis. Furthermore, previous studies have shown that even among men with advanced prostate cancer managed with AST, only 7–16% of fractures are due to metastases.24, 25
Randomized studies would be needed to confirm these findings. Such studies should have extended follow-up (10 years) and be of sufficient size to be powered to detect a difference in events that occur in <10% of men. These studies should control for the risk factors we were unable to directly measure.