Universität zu Köln

Hoyer-Kuhn, Heike, Rehberg, Mirko, Netzer, Christian, Schoenau, Eckhard and Semler, Oliver ORCID: 0000-0003-0029-7556 (2019). Individualized treatment with denosumab in children with osteogenesis imperfecta - follow up of a trial cohort. Orphanet J. Rare Dis., 14 (1). LONDON: BMC. ISSN 1750-1172

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Hoyer-Kuhn, Heike UNSPECIFIED UNSPECIFIED UNSPECIFIED Rehberg, Mirko UNSPECIFIED UNSPECIFIED UNSPECIFIED Netzer, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Schoenau, Eckhard UNSPECIFIED UNSPECIFIED UNSPECIFIED Semler, Oliver UNSPECIFIED orcid.org/0000-0003-0029-7556 UNSPECIFIED
URN:	urn:nbn:de:hbz:38-141212
DOI:	10.1186/s13023-019-1197-z
Journal or Publication Title:	Orphanet J. Rare Dis.
Volume:	14
Number:	1
Date:	2019
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1750-1172
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language GIANT-CELL TUMOR; POSTMENOPAUSAL WOMEN; BONE TURNOVER; PAMIDRONATE; FRACTURES; EFFICACY; THERAPY; MARKERS; SAFETY; HEALTH Multiple languages Genetics & Heredity; Medicine, Research & Experimental Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/14121