The proton pump inhibitor, lansoprazole, prevents the development of non-traumatic osteonecrosis of the femoral head: an experimental and prospective clinical trial

Ima Kosukegawa,Motohisa Yamamoto,Satoshi Nagoya,Toshihiko Yamashita,Hiroki Takahashi,Shunichiro Okazaki,Chisako Suzuki,Junya Shimizu

doi:10.1007/s00590-020-02622-5

Abstract

BackgroundAn effective prevention strategy for osteonecrosis of the femoral head (ONFH) has yet to be established. We previously reported that the innate immune system via the toll-like receptor (TLR) response induced by corticosteroids leads to the development of ONFH and that repression of IRF7 activity by an inhibitor could interfere with the development of ONFH while maintaining the therapeutic effect of the corticosteroids.ObjectiveIn the present study, we hypothesize that lansoprazole has the potential to suppress IRF7 activity and prevent corticosteroid-induced ONFH in rats. Furthermore, we conducted a preliminary clinical trial to prevent corticosteroid-induced ONFH in autoimmune disease patients.MethodsMale Wistar rats were randomly divided into four groups. On Day 1, each rat was injected with TLR4 ligand (LPS) or TLR7 ligand (imiquimod), followed by methylprednisolone with or without lansoprazole on Day 2. They were killed at 1 or 14 days after the last injection.We prospectively recruited 30 patients requiring primary high-dose corticosteroid treatment for immune diseases. All patients were administered lansoprazole, starting the night before corticosteroid treatment began. MRI was performed before corticosteroid treatment, and at 4, 12 and 24 weeks afterward.ResultsIn rats, co-treatment of lansoprazole with corticosteroids significantly repressed both IRF7 activity and the development of ONFH. Moreover, in the human patients, the incidence of ONFH was significantly decreased from 53.4 to 13.3%.ConclusionsAlthough the present study is preliminary, the results show that co-treatment of lansoprazole with corticosteroids prevents ONFH development. Lansoprazole may be both safe and effective in preventing osteonecrosis of the femoral head in patients needing corticosteroid treatment.

Highlights

High-dose corticosteroid therapy for inflammatory diseases and alcohol-abuse was reported to be a risk factor for non-traumatic osteonecrosis of the femoral head (ONFH) [1,2,3]
We previously reported corticosteroid-induced ONFH rat models treated with a toll-like receptor (TLR) ligand and corticosteroid and that TLR signaling pathways contribute to the pathogenesis of corticosteroid-induced ONFH in rats [8, 9]
We reported that ONFH results from the activation of nuclear factor kappa B (NF-κB) and interferon regulatory factor 7 (IRF7) via the TLR signaling pathways, followed by a subsequent repression in NF-κB activity by corticosteroid treatment, whereas IRF7 activity is unaffected by corticosteroid treatment

Summary

Introduction

High-dose corticosteroid therapy for inflammatory diseases and alcohol-abuse was reported to be a risk factor for non-traumatic osteonecrosis of the femoral head (ONFH) [1,2,3]. We used a historical control group (14 men and 44 women, mean age 45.2 years) of patients from the same institute, who were the subject of a previous report [20]. Their underlying diseases were SLE (n = 16), IgG4-related disease The maximal mean prednisolone dosage was 45.2 mg/day, excluding 3 days of treatment at 1000 mg/day in ten patients These parameters, excluding gender consistency (p < 0.01, Fisher’s exact test), were not significantly different compared to the LPZ treatment group (age: p = 0.06, Mann–Whitney test, underlying diseases: p = 0.09, Chi-square test, maximal steroid dosage: p = 0.76, Mann–Whitney test).

Experimental results

Discussion

Conclusions

Compliance with ethical standard