Optimizing bone health in lymphoma survivors: denosumab superiority to alendronate for R-CHOP-like therapy (the DENOSULY phase III randomized controlled trial).

Glucocorticoid-induced osteoporosis (GIOP) poses a critical long-term complication for lymphoma survivors, with cumulative incidence of fractures following R-CHOP-like therapy. Existing GIOP guidelines, typically based on chronic low-dose steroid use, are insufficient for managing this acute, high-risk toxicity of lymphoma therapy-related GIOP (LTR-GIOP). This prospective, multi-center, phase 3 randomized controlled trial (n=100; median age 74-years) compared the efficacy and safety of denosumab versus alendronate in newly diagnosed lymphoma patients receiving R-CHOP-like therapy. Patients were randomized into two groups: one received a total of two subcutaneous injections of denosumab every 6 months, and the other received oral alendronate once a week for 12 months. This study was named DENOSULY and the cases were collected by the Hokuriku Hematology Oncology Study Group. The primary endpoint was the percentage change in lumbar spine (LS) bone mineral density (BMD) at 12 months. Consequently, denosumab demonstrated superiority over alendronate in LS(L1-L4) BMD change (denosumab: +2.8%±4.4% vs. alendronate: -1.3%±5.6%; p=0.0010). Crucially, denosumab also showed superiority at the femoral neck (denosumab: +2.8%±5.8% vs. alendronate: -3.6%±10.3%; p=0.0020), a site where superiority is infrequently demonstrated in non-LTR-GIOP comparisons. Denosumab achieved stronger suppression of the bone resorption marker TRACP-5b (p=0.0003). Since denosumab showed significant superiority over alendronate at both the lumbar spine and femoral neck, denosumab may be the preferred agent in LTR-GIOP. Recognizing R-CHOP recipients as a very high-risk population, our findings underscore the need for immediate, enhanced prophylaxis with denosumab to prevent LTR-GIOP and improve long-term survivorship and quality of life. This trial was registered at www.umin.ac.jp as UMIN000038881.