Urinary calcium and bone resorption markers during three years of denosumab treatment in Pediatric osteogenesis imperfecta

Osteogenesis Imperfecta (OI) is a rare genetic disorder predominantly resulting from mutations in COL1A1 and COL1A2. Denosumab, a monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand (RANKL) inhibits osteoclast differentiation and activation and thereby bone resorption. Despite its efficacy as an anti-resorptive therapy, concerns of rebound hypercalcemia limit its clinical use. This investigation was part of the multicenter trial NCT02352753, which was terminated early due to calcium-related adverse events. We implemented a sub-study to investigate dynamics of bone resorption markers and calcium and the precise timepoint of rebound during denosumab therapy in OI patients. 40 participants between 2 to 16 yr received subcutaneous denosumab (1 mg/kgBW) every six months for three years. Calcium supplementation was started on the day of denosumab injection. Spot urine samples were collected at weeks 2, 8, 12, 16, 18, 20, and 22 post-injection in every treatment cycle to measure urinary bone resorption markers (NTX and DPD), calcium and creatinine. Calcium supplementation was ended when urinary Ca/Creatinine ratios reached age-specific thresholds. Denosumab effectively suppressed bone resorption within the first two months post-injection. However, after 8 wk, uNTX and DPD levels re-increased again, reaching baseline levels after three months, followed by a mild rebound after four months. Average duration of Ca supplementation was 10 wk, two patients developed mild nephrocalcinosis. In conclusion, we saw that rebound of bone resorption emerges as early as 4 mo after denosumab injection. Continuous monitoring of calcium levels and careful handling of calcium supplementation is mandatory during therapy, but Ca-related side effects can still occur.