Objectives: Denosumab (Dmab) is a monoclonal antibody targeting RANKL administered by sub-cutaneous injection. Recent reports have raised concern about the rebound phenomenon (hypercalcemia and increases in bone turnover markers, BTM) following Dmab in adults, and during treatment in children with osteogenesis imperfecta. The purpose of this report was to explore this phenomenon in children with osteoporosis associated with lower bone turnover.
Methods: In this one-year pilot study (NCT02632916), children 4 to 16 years with low-trauma fractures due to osteoporosis were randomized 1:1 to receive ZA 0.025 mg/kg or Dmab 1 mg/kg every 6 months (two doses). Serum ionized calcium and BTM were collected on the day before each dose (c-telopeptide of type I collagen (CTX), and bone-specific alkaline phosphatase (BSALP)). BTM were expressed as age- and gender-matched z-scores (Z).
Results: Ten children completed the study (four with glucocorticoid-treated Duchenne muscular dystrophy (DMD) and one with juvenile osteoporosis (JO) in each group, all boys). At baseline, the two boys with JO had a bone formation rate/bone surface by trans-iliac biopsies at Z −3.3 and −1.0. In DMD at baseline, the mean ± standard deviation serum CTXZ and BSALPZ were −2.6±0.3 and −2.9±0.6, respectively. There were no episodes of hypercalcemia preceding any treatment doses. CTXZ increased between baseline and six months, or between six and 12 months, in 5/5 boys on Dmab (greatest median change during either time period 22%; range 11, 165%) vs 4/5 on ZA (median change 11%; range 4, 14%). The BSALPZ increased in 3/5 boys on Dmab (median change 3%; range −17, 49%) vs 3/5 (median change 12%, range −6.0, 15). On Dmab, the CTXZ was below −2.0 in all but one patient with DMD (Z −1.7 for this patient) at 12 months, but was above-average (Z+0.3) for the patient with JO.
Discussion: In this pilot study, CTXZ increased above baseline more frequently on Dmab compared with ZA. BTM increases were greatest in the patient with JO on Dmab. In contrast, boys with DMD on Dmab had minimal BTM increases; furthermore, BTM remained low in DMD at 12 months.
Disclosure: Leanne Ward has been a consultant to and participated in clinical trials with Novartis Pharmaceuticals and Amgen Inc.