Proton Pump Inhibitors, But Not H2-receptor Antagonists, Are Associated With Incident Fractures Among Kidney Transplant Recipients

Abstract

Background. Fractures are a common and burdensome problem among kidney transplant recipients (KTRs). Proton pump inhibitors (PPIs) are frequently used after kidney transplantation and have been associated with increased fracture risk in the general population. This study aimed to determine whether PPI use is associated with incidence of major fractures in KTRs. Methods. Using the Wisconsin Allograft Recipient Database, we identified 155 KTRs with a major fracture that occurred at least 12 months after transplantation. Controls were selected using incidence-density sampling. Use of PPIs and histamine 2-receptor antagonists (H2RA) during the year before the index date were identified. Results. A total of 155 cases were matched to 685 controls. Within 1 year before the index date, 68% of cases and 52% of controls used a PPI, and 16% of cases and 11% of controls used an H2RA. PPI use was associated with higher incidence of major fractures in unadjusted analysis (odds ratio [OR], 2.4; 95% CI, 1.6-3.5) and in adjusted analyses controlling for demographic and transplant-related covariates and use of corticosteroids, bisphosphonates, vitamin D and calcium supplements (OR, 1.9; 95% CI, 1.2-3.1). H2RA use was not associated with incidence of major fractures in adjusted analyses (OR, 1.0; 95% CI, 0.5-1.8). The associations between PPI use and fractures remained similar in analyses limited to spine and hip fractures. Conclusions. Use of PPIs, but not H2RAs, is associated with a higher risk of major fractures among KTRs. Clinicians should individualize PPI use in KTRs, evaluating the risks and benefits of prescribing and continuing PPIs in KTRs.

Associations between Proton Pump Inhibitor and Histamine-2 Receptor Antagonist and Bone Mineral Density among Kidney Transplant Recipients

“…The lack of a significant association between PPI use and BMD decrease is in apparent conflict with previous studies that linked PPI use with greater risk of fractures in both the general population [11,12,14,26,27] and KTRs [16,17]. A meta-analysis involving 18 relevant observational studies in the general population showed PPI use modestly increased the risk of hip, spine, and any osteoporotic fracture [28].…”

“…Roughly half of KTRs receive PPIs or histamine-2 receptor antagonists (H2RAs) prophylaxis for gastric complications following transplantation, and some recipients remain on these therapies for years after transplantation [10]. Observational studies have found an association between high dose and long-term PPI therapy and fracture in the general population and in KTRs [11][12][13][14][15][16][17]. Results of studies examining the association between PPIs and change in bone mineral density (BMD) in the general population have been inconsistent [18][19][20].…”

Choice of Acid Suppressant Therapy and Long‐Term Graft Outcomes After Kidney Transplantation

“…16,17 Other transplant studies have demonstrated associations between PPI use and hypomagnesemia, Clostridium difficile infections, iron deficiency anemia, and increased fracture risk. [18][19][20][21][22][23][24] However, these studies did not compare PPIs to H2RAs [18][19][20][21][22] and included relatively small cohorts. 23,24 Most studies comparing the impact of PPI or H2RA use on renal function posttransplant report outcomes up to a year posttransplant.…”

“…[18][19][20][21][22][23][24] However, these studies did not compare PPIs to H2RAs [18][19][20][21][22] and included relatively small cohorts. 23,24 Most studies comparing the impact of PPI or H2RA use on renal function posttransplant report outcomes up to a year posttransplant. 14,15 Currently, the only study evaluating the effect of PPIs or H2RAs on long-term renal function demonstrated significantly worse kidney function in PPI treated patients but has not been published in full manuscript form.…”

“…Studies have demonstrated that the formulation of MPA may determine the effect of PPI co‐administration, with mycophenolate mofetil (MMF) exhibiting significantly decreased area under the curve that has not been consistently seen with enteric‐coated mycophenolate sodium (EC‐MPS), although reductions in the active metabolite mycophenolic acid glucuronide have not been shown to consistently be impacted by PPI therapy with either formulation 16,17 . Other transplant studies have demonstrated associations between PPI use and hypomagnesemia, Clostridium difficile infections, iron deficiency anemia, and increased fracture risk 18–24 . However, these studies did not compare PPIs to H2RAs 18–22 and included relatively small cohorts 23,24 .…”