Three-drug combination therapy to prevent glucocorticoid-associated osteonecrosis in patients with systemic lupus erythematosus: a proof-of-concept study.

BACKGROUND

Systemic lupus erythematosus (SLE) is a major underlying disease of glucocorticoid-associated osteonecrosis of the femoral head (ONFH). Despite its clinical significance, no prophylactic treatment has been established to prevent ONFH in patients receiving systemic glucocorticoid therapy.

OBJECTIVES

To investigate the efficacy and safety of a three-drug combination therapy consisting of clopidogrel sulfate, pitavastatin calcium hydrate, and tocopherol acetate, administered concurrently with initial glucocorticoid therapy to prevent ONFH in patients with SLE.

DESIGN

A multicenter, single-arm, interventional clinical trial conducted as an advanced medical treatment approved by the Ministry of Health, Labor and Welfare of Japan.

METHODS

This study was conducted at 12 sites in Japan between August 2014 and March 2024. Patients with SLE who required initial glucocorticoid therapy (⩾0.5 mg/kg/day of prednisolone) received the three study drugs concurrently with glucocorticoids for 90 days. Magnetic resonance imaging of both hip joints was performed 180 days after initiation of glucocorticoid therapy to determine ONFH occurrence. The primary endpoint was ONFH incidence, and safety and potential risk factors were also evaluated using logistic regression analysis.

RESULTS

Of the 50 enrolled patients, 43 completed the 90-day regimen. ONFH was identified in 8 of 43 patients (18.6%), which was below the threshold incidence of 25% based on the historical control, suggesting a potential signal of reduced incidence (p = 0.1664). Treatment-emergent adverse events were observed in 19 patients; the only severe adverse event was a drug eruption in one patient. The exploratory analysis identified the period of drinking as a significant risk factor for ONFH occurrence.

CONCLUSION

The findings demonstrate the feasibility and acceptable safety of this three-drug combination therapy. Although the results should be regarded as preliminary and hypothesis-generating, they suggest a potential signal that warrants further investigation in adequately powered randomized controlled trials.

TRIAL REGISTRATION: Clinical trial for the control of osteonecrosis of the femoral head secondary to the initial corticosteroid treatment in patients with systemic lupus erythematosus (UMIN000008230; https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000009636).