title: Pamidronate does not adversely affect bone intrinsic material properties in children with osteogenesis imperfecta.
abstract: Cyclical intravenous pamidronate therapy increases bone mass in children with osteogenesis imperfecta (OI), but the effect on the intrinsic material properties of bone is unknown at present. Thus, a possible influence of pamidronate treatment on bone quality at the material level might negate the beneficial effects of the gain in bone mass and lead to bone fragility in the long term. In the present study, we used transiliac bone biopsy samples and assessed the intrinsic material properties of the bone tissue at the micron-level by combined backscattered electron imaging and nanoindentation. Paired iliac bone samples from 14 patients (age 3 to 17 years) with severe OI before and after 2.5 +/- 0.5 years (mean +/- SD) of pamidronate treatment as well as age-matched controls were examined. Bone histomorphometry was performed in all samples and confirmed an increase of bone mass in treated patients. Backscattered electron imaging was used to measure the weighted mean calcium content (Ca(Mean)), the most frequent calcium content (Ca(Peak)), the variation in mineralization (Ca(Width)) and the amount of lowly mineralized areas (Ca(Low)) that correspond to sites of primary mineralization. Nanoindentation was performed in a subgroup of 6 patients and 6 controls to determine hardness and elastic modulus. Compared to controls, untreated OI patients had a significantly higher degree of bone matrix mineralization (Ca(Peak) +7%, P < 0.001) and a strong reduction of Ca(Low) (-38%, P < 0.001) despite enhanced bone formation, as well as increased hardness (+21%, P < 0.01) and elastic modulus (+13%, P < 0.01). However, none of these parameters was significantly altered by the subsequent pamidronate treatment. This shows that OI bone is stiffer and more mineralized and that, despite the enhanced bone formation rate in these patients, areas of primary mineralization are hardly visible. We also conclude that pamidronate treatment in children with OI does not have an adverse effect on the intrinsic material properties of bone and, as a consequence, that a long-term administration of the drug might not increase brittleness and fragility of the bone matrix. The antifracture effectiveness of pamidronate treatment in OI, as shown in previous clinical studies, has to be explained by the increase of mainly cortical bone volume.
authors.affiliation: Ludwig Boltzmann Institute of Osteology at the Hanusch Hospital of WGKK and AUVA Trauma Centre Meidling, 4th Med. Dept., Hanusch Hospital, Heinrich Collin Str. 30, A-1140 Vienna, Austria.
authors.forename: Markus
authors.initials: M
authors.lastname: Weber
authors.forename: Paul
authors.initials: P
authors.lastname: Roschger
authors.forename: Nadja
authors.initials: N
authors.lastname: Fratzl-Zelman
authors.forename: Thomas
authors.initials: T
authors.lastname: Schöberl
authors.forename: Frank
authors.initials: F
authors.lastname: Rauch
authors.forename: Francis H
authors.initials: FH
authors.lastname: Glorieux
authors.forename: Peter
authors.initials: P
authors.lastname: Fratzl
authors.forename: Klaus
authors.initials: K
authors.lastname: Klaushofer
mesh_terms: D000293:Adolescent; D015519:Bone Density / Q000187:drug effects*; D002648:Child; D002675:Child, Preschool; D004164:Diphosphonates / Q000009:adverse effects / Q000494:pharmacology*; D004548:Elasticity; D005260:Female; D006801:Humans; D008297:Male; D010013:Osteogenesis Imperfecta / Q000188:drug therapy* / Q000473:pathology; D000077268:Pamidronate; D013314:Stress, Mechanical
chemical_list: D004164:Diphosphonates; D000077268:Pamidronate