Risk of Hip Fracture and PPI Use in Kidney Transplant Recipients

Increased mortality, decreased mobility, and loss of independence are all associated with hip fracture. For patients with end-stage renal disease (ESRD), the risk of hip fracture is considerably elevated compared with that of the general population. The time immediately following kidney transplantation is particularly high-risk for hip fracture due to pre-existing chronic kidney disease and the associated mineral bone disease, corticosteroid exposure, and osteoporosis.

Proton pump inhibitors (PPIs) are frequently prescribed as peptic ulcer prophylaxis in the period immediately following kidney transplantation. A significant proportion of kidney transplant recipients remain on PPI therapy beyond the immediate post-transplantation period. Omeprazole is the seventh, sixth, and fifth most prescribed drug in the first, second, and third year post-transplantation, respectively.

Use of PPIs has been linked to increased risk for fracture in the general population. However, according to Colin R. Lenihan, MB Bch, PhD, and colleagues, there are few data on the link between use of PPIs and the risk of hip fracture in the kidney transplantation population. The researchers recently conducted a retrospective nested matched case-control study to challenge the null hypothesis of no association between PPI use and post-transplantation hip fracture in a contemporary cohort of kidney transplant recipients in the United States. Study results were reported in the American Journal of Kidney Diseases [2017;69(5):595-601].

Eligible study participants were all first-time kidney transplant recipients recorded and contributing to the US Renal Data System while having a functioning kidney transplant January 1, 2007, to December 31, 2011. The researchers identified 231 cases of hip fracture that met the stated inclusion and exclusion criteria. Those cases were matched with 15,575 controls; the number of matched controls per case ranged between one and 225, with a median of 56.

There was a higher prevalence of diabetes mellitus, cardiovascular disease, cerebrovascular disease, arrhythmia, and rheumatologic disease among cases than controls. Use of steroids, mammalian target of rapamycin inhibitors, cyclosporine, azathioprine, and bisphosphonate was higher among cases than controls. The mean difference in age between cases and controls was 1.7 years; mean difference in time since transplantation was 0.3 years, reflecting good matching within the prespecified bounds (3 years for age and 1 year for time since transplantation).

In the 12 months prior to the index date, 65.4% of cases and 57.4% of controls filled a prescription for a PPI; 34.6% of cases and 28.9% of controls filled prescriptions for a PPI covering at least 292 of 365 days (>80%) before the index date (defined as higher PPI users).

Unadjusted odds ratios (ORs) of hip fracture associated with any, lesser, and higher PPI use compared with no use were 1.55 (95% confidence interval [CI], 1.18-2.05), 1.45 (95% CI, 1.04-2,02), and 1.65 (95% CI, 1.20-2.27), respectively. Following adjustment for baseline demographic, clinical, and pharmacologic variables, analysis showed an association between hip fracture status and any and high PPI use (ORs, 1.39; 95% CI, 1.04-1.84, and 1.41; 95% CI, 1.02-1.95, respectively).

A formal test for interaction between any prior calcineurin inhibitor use and any PPI use resulted in nonsignificant results (P>.99).

The researchers cited some limitations to the study, including the retrospective design that creates the possibility of residual confounding and the possibility that some PPI users may have been missed due to the availability of over-the-counter PPIs. In addition, some data were missing, including (1) the use of alternative peptic ulcer prophylaxis/anti–gastroesophageal reflux agents; (2) use of calcium, vitamin D, and other treatments related to bone health; and (3) smoking status.

The researchers summarized their findings by saying, “We found that PPI use was associated with increased odds of hip fracture in kidney transplant recipients. Our findings argue for a more judicious approach to prescription of PPIs in this population.”

Takeaway Points

  1. Researchers recently conducted a retrospective nested matched case-control study to examine evidence that specifically links use of a proton pump inhibitor with the risk of hip fracture in recipients of kidney transplant.
  2. In the year before the index date, 65.4% of those in the cases group and 57.4% of those in the control group were prescribed a PPI; further, 34.6% of cases and 28.9% of controls had a PPI prescribed for >80% of the year prior to the index date.
  3. Following adjustment for baseline demographic, clinical, and pharmacologic variables, any and higher PPI use was associated with hip fracture: odds ratios 1.39 and 1.41, respectively.