Prostate Cancer Increases Fracture Risk Independent of Androgen Suppression

COPENHAGEN, Oct. 15 -- Prostate cancer has fracture risks of its own, over and above those of androgen-suppression therapy for the disease, found investigators here.

The disease is associated with a two-fold risk of any fracture, and a nearly four-fold risk for hip fracture, independent of androgen deprivation therapy or orchiectomy, reported Bo Abrahamsen, M.D., of Copenhagen University Hospital Gentofte, and colleagues, in a case-control study in the October issue of BJU International.

The increased risk is seen early after diagnosis and remains pronounced even in long-term survivors, they added.

"The risk of hip fracture was increased at all ages, but most strikingly in men aged 50 to 65 years, where hip fractures were eight times more likely than expected from age and previous fracture history," the investigators wrote.

"Our study showed that more than 3% of hip fractures in men aged 50 and over can be attributed to prostate cancer, and the risk remains even when men have recovered from the disease," said Dr. Abrahamsen.

He and his colleagues drew on the medical records system in Denmark to evaluate the risk of fracture attributable to prostate cancer, and the impact of exposure to prescribed gonadotrophin-releasing hormone agonists and androgen deprivation on fracture risk in a nationwide, population-based case-control cohort.

They extracted and merged data from the Danish National Hospital Discharge Register, the National Bureau of Statistics, and the National Prescriptions Database. They looked at information on 15,716 men 50 or older who were diagnosed with a fracture at any hospital in Denmark in 2000, and at 4,149 age-matched controls.

In all, 1.3% of controls and 2.5% of cases had a previous diagnosis of prostate cancer.

The authors found that prostate cancer was associated with an increased odds ratio for all fractures of 1.8 (95% confidence interval 1.6 to 2.1) and for hip fractures of 3.7 (95% CI 3.1 to 4.4). There was no increased risk of vertebral fractures, however.

"For hip fractures, the unadjusted excess risk was particularly pronounced in men aged 50 to 65 years, where the odds ratio was 9.2 (95% CI, 4.8 to 17.5), but the risk was increased at all ages including > 80 years, where the odds ratio was 1.7 (95% CI, 1.3-2.1). The risk of all fractures was doubled in all age categories," the authors wrote.

Among the 1,018 men with prostate cancer, 19% had been treated with orchiectomy, 9% had been prescribed androgen deprivation therapy, and 4% had received both before the time of the index fracture.

In this group "patients who had had orchiectomy or had filled at least one prescription for antihormonal medications in the period 1995 to 2000 up to the date of the index fracture had a greater risk of fracture, which was additive to the risk associated with the disease itself," the investigators wrote.

In an analysis adjusted for prostate cancer, age and previous fracture, the additional odds ratio for overall fractures was 1.7 (95% CI 1.2 to 2.5; P<0.01) for androgen deprivation, and 1.7 (95% CI 1.2 to 2.4, P<0.01) for orchiectomy.

Androgen deprivation was also associated with added risk for hip fracture, with an odds ratio of 1.9 (95% CI 1.2 to 3.0, P<0.05).

There was an increased risk for spinal fractures only in men with previous fractures, with an odds ratio of 2.1 (95% CI 1.2 to 4.9, P<0.01), but not with exposure to prostate cancer therapy, the authors noted.

"Both the present study and others indicate that fracture risk is further increased in patients with prostate cancer when they receive androgen deprivation therapy or have an orchiectomy. Thus, many fractures might be preventable," they wrote.

Therapies for reducing or preventing fractures in men being treated with androgen deprivation or castration include the use of bisphosphonates (pamidronate, chlodronate and zolendronic acid), estrogen, selective estrogen-receptor modifiers raloxifene and toremifene, endothelin-1 antagonists, selective matrix metalloproteinase inhibitors , and denosumab, the authors noted.

They acknowledge that the case-control design was a limitation of the study, in that they could not provide direct estimates of fracture or mortality rates.

They also noted that "we have very comprehensive information on all prescriptions redeemed by cases and controls, but this accounts for only a small proportion of their exposure to androgen deprivation therapy, as a very large proportion of such medications were provided directly by hospital departments. Therefore, many patients would have unrecorded iatrogenic hypogonadism. This will dilute the impact and reduce the apparent OR for androgen deprivation therapy on fractures."