Denosumab as a Potential Disease-Modifying Treatment in Indolent Systemic Mastocytosis-Related Osteoporosis

Indolent systemic mastocytosis (ISM) is a rare clonal disorder characterized by mast cell proliferation and release of inflammatory mediators affecting multiple organs, including the skeleton, frequently causing osteoporosis. We present the case of a 78-year-old woman with a longstanding history of cutaneous mastocytosis who developed systemic symptoms including gastrointestinal discomfort and flushing. Laboratory evaluation revealed elevated serum tryptase level of 28.7 ng/mL (SI: 28.7 μg/L) (reference range, <11 ng/mL [SI: < 11 μg/L]), a positive <i>KIT</i> D816V pathogenic variant (testing to confirm somatic vs germline origin was not available), and increased urinary prostaglandin D2. Bone marrow biopsy confirmed ISM. Despite long-term bisphosphonate therapy, she sustained a low-trauma vertebral fracture, prompting transition to denosumab in 2021. Over 3 years of treatment, the patient experienced a 7% increase in lumbar spine bone mineral density and a sustained decrease in serum tryptase levels to 12.0 to 14.3 ng/mL (SI: 12.0-14.3 μg/L), suggesting improved bone health and potential reduction in systemic mast cell burden. This case highlights the challenges in managing ISM-related osteoporosis and suggests a dual benefit of denosumab in improving bone mineral density and potentially reducing mast cell activity.