Frontiers in Endocrinology · Nov 3, 2026
Significant bone mineral density improvement following sequential Romosozumab-Denosumab therapy in a postmenopausal woman with Multicentric Osteolysis, Nodulosis, and Arthropathy (MONA) syndrome
By Matteo Corbetta, Silvia Carrara, Silvia Vai et al.
Background Genetic factors play a significant role in determining bone metabolism and fracture risk. MMP2 plays a critical role in extracellular matrix remodelling and bone metabolism. Pathogenic MMP2 variants cause Multicentric Osteolysis, Nodulosis and Arthropathy (MONA) syndrome, a rare autosomal recessive skeletal disorder characterized by defective extracellular matrix remodelling and progressive osteolysis. Although skeletal involvement is a hallmark of MONA syndrome, osteoporosis and fragility fractures in adults with MONA syndrome remain poorly characterized; similarly, evidence regarding bone-targeted therapies is extremely limited. Case presentation A 57-year-old woman was referred for severe osteoporosis and multiple fragility fractures. Despite skeletal abnormalities since adolescence, the diagnosis remained unrecognized until adulthood, when a pathogenic biallelic MMP2 variant was detected in her peripheral blood. She experienced fragility fractures since early adulthood, followed by six vertebral fractures over a two-year period after menopause with progressive decline in bone mineral density (BMD). A single intravenous infusion of zoledronic acid induced a severe and prolonged acute-phase reaction with generalized joint stiffness. Progressive vertebral collapse prompted initiation of romosozumab, followed by denosumab. Romosozumab was associated with a substantial increase in BMD and stabilization of vertebral deformities, with no new fractures observed. During the subsequent 18-month treatment with denosumab, no incident fragility fractures occurred. The male sibling harboured the same MMP2 variant, experienced fragility fractures and vertebral deformities, and a similar severe reaction to zoledronic acid. Conclusions MONA syndrome is associated with increased bone fragility in adulthood, potentially worsening skeletal deformities and increasing inability. Menopause should be considered a critical phase, warranting closer attention to bone health and fracture prevention. Treatment with zoledronic acid may deserve caution in adults with MONA syndrome, while sequential treatment with romosozumab followed by denosumab may be effective in improving bone mineral density and preventing fragility fractures in individuals with MONA syndrome and osteoporosis.