Patients with bladder cancer who underwent radical cystectomy and urinary diversion demonstrated an increased risk for bone fracture, according to results of a population-based study.
Radical cystectomy and urinary diversion may cause chronic metabolic acidosis, potentially leading to long-term bone loss in patients with bladder cancer. However, the association between radical cystectomy and fracture risk had not been established.
Amit Gupta, MD, MPH, of the departments of urology and epidemiology at University of Iowa, and colleagues used the SEER-Medicare–linked database from 2000 through 2007 to identify 50,520 patients with stage 0 through stage III bladder cancer. Researchers assessed the association between radical cystectomy and risk for fracture at any site.
Gupta and colleagues determined 4,878 (9.6%) patients in the cohort had cystectomy and urinary diversion.
During median follow-up of 41 months, 10,872 patients experienced a fracture. Of them, 792 had undergone cystectomy and urinary diversion, and 10,080 had not undergone cystectomy.
Median time to fracture was 16.6 months from cystectomy (interquartile range, 6.2-35.4) among patients who underwent cystectomy and 21.8 months (interquartile range, 8.3-42.2) from cancer diagnosis among those who did not undergo cystectomy.
The fracture rate was 6.55 per 100 person-years in the cystectomy group vs. 6.39 per 100 person-years among those who did not undergo cystectomy.
After controlling for disease and patient characteristics, researchers determined cystectomy was associated with a 21% increased risk for fracture (adjusted HR=1.21; 95% CI, 1.1-1.32).
The increased risk for fracture was most apparent among patients aged 66 to 69 years (adjusted HR=1.83; 95% CI, 1.47-2.29), followed by those aged 75 to 79 years (adjusted HR=1.29; 95% CI, 1.08-1.53) and those aged 70 to 74 years (adjusted HR=1.13; 95% CI, 0.93-1.37).
The increased risk for fracture was most apparent among patients with stage 0 disease (adjusted HR=1.48; 95% CI, 1.1-1.99), followed by those with stage III disease (adjusted HR=1.39; 95% CI, 1.09-1.77), stage I disease (adjusted HR=1.27; 95% CI, 1.11-1.44) and stage II disease (adjusted HR=1.04; 95% CI, 0.86-1.25).
“Interestingly, patients who had cystectomy seemed to have fewer risk factors for fracture at the time of cancer diagnosis, given that they were generally younger, had fewer comorbidities, were less likely to have chronic kidney disease and had a lower incidence for fractures in the year before diagnosis,” Gupta and colleagues wrote. “Despite these favorable characteristics, after cystectomy their risk for fracture was increased by 21%, compared with their peers who did not have cystectomy. These findings emphasize the need to monitor bone health and to conduct trials of prophylactic therapies that may reduce the risk of fracture in these patients.”
Disclosure: The researchers report no relevant financial disclosures.
Eila C. Skinner
There has long been a suspicion that urinary diversion with bowel might result in loss of bone. Studies in the 1970s and 1980s suggested that chronic metabolic acidosis along with vitamin-D resistance could cause long-term loss of bone calcium in patients following urinary diversion. However, studies in patients have been conflicting, and the majority have not been able to demonstrate a consistent loss of bone density, abnormal calcium metabolism or other clinically significant effects in cystectomy patients, even with long-term follow-up. These studies have been limited by small numbers and the difficulty of agreeing on a measurable endpoint.
In this study, Gupta and colleagues used the SEER–Medicare database to identify the risk of fracture in patients with non-metastatic bladder cancer, comparing those who underwent cystectomy with those who did not. After risk-adjusting for other known causes of osteoporosis, they identified a 20% increase in the risk of fracture in the cystectomy group.
These two groups were not completely comparable: the cystectomy patients were younger and healthier, were less likely to have renal dysfunction or prior fracture, had higher grade and stage disease, and were more likely to receive chemotherapy. It is interesting that the excess risk of fracture was observed in the first few months after diagnosis and the difference increased slowly over time. The early onset may be in part due to other effects of the surgery, such as the decreased activity, and nutrition deficit that are common for the first 2 to 3 months following cystectomy. Interestingly, continent urinary diversion was not any worse than ileal conduit.
The next question is whether intervention can prevent the risk of fracture in this population. Suggested interventions such as sodium bicarbonate or potassium citrate supplementation, dietary modification, calcium and vitamin D supplement, exercise, and medications such as bisphosphonates all could be tried. Ideally, these will be tested in a prospective fashion.