EPO Treatment for Anemia Ups Fracture Risk in Patients on Dialysis

Pam Harrison

May 17, 2021

Erythropoietin-stimulating agents — widely used to treat anemia in end-stage renal disease (ESRD) — increase the risk of hip fracture in patients on dialysis, and the higher the dose, the greater the risk, the first study of its kind indicates.

In an analysis of claims data from 1997 through to 2013 of 747,832 patients receiving dialysis, hip fracture rates mirrored increases and decreases of average weekly erythropoietin (EPO) doses over the study interval. Specifically, hip fracture rates increased from 12 per 1000 patient-years in 1997 to 18.9 per 1000 patient-years in 2004, after which they declined to 13.1 per 1000 patient-years in 2013.

These trends matched average EPO doses used over the same interval, which increased from 11,900 units/week in 1997 to 18,300 units/week in 2004, after which they declined to 8800 units/week by 2013.

"Overall, results of our present study indicate that EPO treatment of hemodialysis patients and, in particular, changes in the average doses of EPO used for this treatment over time may have contributed to the changing trends in hip fracture incidence observed among ESRD patients during the past three decades," write Sukanya Suresh of the National Institutes of Health, Bethesda, Maryland, and colleagues. The study was published online May 5 in the Journal of Bone and Mineral Research.

"Patients with renal failure can benefit from EPO treatment; however, as with all medications, a full understanding of potential drug-associated risks favors the likelihood that a positive risk-benefit balance can be achieved with EPO treatment," senior author Constance Tom Noguchi, PhD, of the National Institute of Diabetes and Digestive and Kidney Diseases, added in a statement.

Retrospective Cohort Study

The retrospective cohort study included patients on hemodialysis enrolled in the United States Renal Data System between 1997 and 2013.

"Fracture rates for patients treated with EPO doses of 50 to < 150, 150 to < 300, and ≥ 300 units/kg/week were compared to those of patients treated with EPO doses < 50 units/kg/week," the researchers explain.

After adjusting for potential confounders, including body mass index (BMI), the risk of hip fracture for patients treated with 50 to < 150 units/kg/week were only slightly greater at 8% compared with those treated with doses < 50 units/kg/week.

However, for patients treated with 150 to < 300 units/kg/week, hip fracture risk was 22% greater than those treated with < 50 units/kg/week, while for those treated with ≥ 300 units/kg/week, risk of hip fracture was 41% higher than those treated with the lowest dose of EPO.

Other factors that predicted a higher risk of hip fracture included age ≥ 65 years, female gender, White race, BMI < 25 kg/m2, diabetes as the cause of ESRD, duration of dialysis < 2 years, and elevated comorbidity score.

"Conversely, a BMI ≥ 30 was predictive of a decreased fracture risk," they add.

The investigators point out that EPO treatment has not previously been reported to be a risk factor for hip fracture in patients with renal failure, or indeed, in any other patient group.

That said, a recent epidemiologic study did find that high endogenous levels of EPO were associated with increased fracture risk in elderly Swedish men with normal renal function. This finding — along with those from the current study — are also consistent with results from animal studies that have shown elevated EPO levels can induce bone loss.

Dose-intensive EPO treatment in patients on dialysis was also independent of hemoglobin values, as the authors point out.

"There is no question that patients with renal failure can benefit from EPO treatment with decreased exposure to blood transfusions and improvements in activity tolerance and a sense of well-being," Suresh and colleagues state.

"Nevertheless, findings of the present study provide further justification for minimizing the doses of EPO used to treat patients with renal failure and for avoiding high doses, using EPO to ameliorate rather than correct anemia," they stress.

The authors have reported no relevant financial relationships.

J Bone Miner Res. Published online May 5, 2021. Full text

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