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Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI.

ABSTRACT: Children with osteogenesis imperfecta (OI) type VI often have high fracture rates despite the current standard treatment with bisphosphonates. Subcutaneous injections of denosumab have been proposed as an alternative treatment approach, but safety data on denosumab in children are limited. Here we describe fluctuations in bone and mineral metabolism during denosumab treatment in four children with OI type VI who started denosumab (basic protocol: 1 mg per kg body mass every 3 months) between 1.9 and 9.0 years of age, after having received intravenous bisphosphonates previously. All four children developed hypercalciuria during active denosumab therapy. In two children aged 3.9 and 4.6 years, episodes of hypercalcemia were observed between 7 and 12 weeks after the preceding denosumab injection. During times when the interval between denosumab injections was increased to 6 months for clinical reasons, lumbar spine bone mineral density z-scores decreased rapidly. It appears that the duration of action of denosumab is short and variable in children with OI type VI. These observations call into question the concept that denosumab can be used as a stand-alone alternative to bisphosphonates to treat children with OI.

SUBMITTER: Trejo P

PROVIDER: S-EPMC5881132 | biostudies-literature | 2018 Mar

REPOSITORIES: biostudies-literature

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Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI.

Trejo Pamela P Rauch Frank F Ward Leanne L

Journal of musculoskeletal & neuronal interactions 20180301 1

Children with osteogenesis imperfecta (OI) type VI often have high fracture rates despite the current standard treatment with bisphosphonates. Subcutaneous injections of denosumab have been proposed as an alternative treatment approach, but safety data on denosumab in children are limited. Here we describe fluctuations in bone and mineral metabolism during denosumab treatment in four children with OI type VI who started denosumab (basic protocol: 1 mg per kg body mass every 3 months) between 1.9 ...[more]

PMID: 29504582

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Project description:BACKGROUND:Osteogenesis imperfecta (OI) is a rare disease leading to hereditary bone fragility. Nearly 90% of cases are caused by mutations in the collagen genes COL1A1/A2 (classical OI) leading to multiple fractures, scoliosis, short stature and nonskeletal findings as blue sclera, hypermobility of joints, bone pain and delayed motor function development. Bisphosphonates are used in most moderate and severely affected patients assuming that an increase of bone mineral density might reduce fractures and bone pain in patients with OI. Denosumab as a RANK ligand antibody inhibiting osteoclast maturation has been approved for osteoporosis treatment in adults. First data from small clinical trials promised a high efficacy of Denosumab in children with OI. Aim of this analysis was a retrospective evaluation of an individualized biomarker-associated treatment regime with Denosumab in 10 children with classical OI which were followed for 1?year after their participation in a pilot trial with Denosumab. Therefore urinary deoxypyridinoline levels were evaluated frequently as an osteoclastic activity marker and depending on that levels Denosumab injections were scheduled individually. METHODS:Ten patients (age range: 6.16-12.13?years; all participated in the former OI-AK phase 2 trial (NCT01799798)) were included in the follow-up period. Denosumab was administered subcutaneously depending on the individual urinary excretion course of deoxypyridinoline (DPD/Crea) as osteoclastic activity marker with 1?mg/kg body weight. DPD/Crea levels were evaluated before denosumab administration and afterwards. If patients present after an initial decrease after injection with a re-increase up to the DPD/crea level before Denosumab injection next dosage was planned. Changes of areal bone mineral density (aBMD) using dual energy x-ray absorptiometry of the lumbar spine after 12?month was evaluated. Safety was assessed by bone metabolism markers and side effect reporting. RESULTS:During follow-up mean relative change of lumbar aBMD was -?6.4%. Lumbar spine aBMD z-Scores decreased from -?1.01?±?2.61 (mean?±?SD) to -?1.91?±?2.12 (p?=?0.015). Mobility changed not significantly (GMFM-88 -6.49?±?8.85% (p?=?0.08). No severe side effects occurred. Dose intervals could be extended in the mean from 12?weeks previously to 20.3?weeks. CONCLUSIONS:On average, it was possible to prolong the intervals between drug administrations and to reduce the total dose about by 25% without a decrease of mobility or change of vertebral shape despite a reduction of lumbar aBMD during 1?year of biomarker-directed Denosumab treatment. Further trials are necessary to balance side effects and highest efficacy in children.

Dataset Information

Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI.

Publications

Hypercalcemia and hypercalciuria during denosumab treatment in children with osteogenesis imperfecta type VI.

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