Bone health in patients with IL-6 receptor deficiency

Inborn errors of immunity (IEI) often include musculoskeletal abnormalities. The interleukin-6 (IL-6) pathway has a complex role in bone metabolism, with evidence for both bone formation and resorption. Signal Transducer and Activator of Transcription 3 (STAT3), a downstream effector of IL-6 signaling, is crucial for bone development, as shown in Hyper IgE syndrome. This study aimed to characterize bone health in patients with IL-6 receptor deficiency, clarifying the effects of disrupted IL-6 signaling. We prospectively enrolled seven patients from three related families with genetically confirmed IL-6 receptor deficiency (IL6R c.494G > C) for a single cross-sectional assessment. Clinical, laboratory, and radiological data were collected, including growth parameters, musculoskeletal examination, serum bone markers (CTX—C-terminal telopeptide of type I collagen; P1NP—amino-terminal propeptide of type I procollagen), metabolic markers (calcium, ALK-P, vitamin D), and bone density in patients older than five years. Among seven patients (median age 10.6 years), ALK-P was elevated in five and CTX in four, indicating increased bone turnover and resorption. P1NP was elevated in only one patient. Bone density revealed osteopenia in two older patients, while the remainder had normal measurements. Anthropometric data showed variable BMI SDS values. In this small cohort, IL-6 receptor deficiency was associated with elevated bone turnover and osteopenia in older patients, consistent with a high-turnover, uncoupled bone remodeling state characterized by elevated markers of both osteoblast activation and bone resorption alongside a discordantly low P1NP. While these findings should be interpreted with caution given the limited sample size, they offer preliminary observations regarding the skeletal consequences of disrupted IL-6 signaling and contribute to the understanding of bone health in IEI.