Long-bone changes after pamidronate discontinuation in children and adolescents with osteogenesis imperfecta.

Cyclical intravenous pamidronate is a widely used symptomatic therapy in moderate to severe osteogenesis imperfecta (OI). The effects of treatment discontinuation on long bone development have not been characterized. In this observational study we used peripheral quantitative computed tomography to assess the radius at the distal metaphysis and at the diaphysis in 23 young OI patients (11 female) who had received pamidronate for at least 3 years. Measurements were performed twice, at the time of treatment discontinuation (when the age of the patients ranged from 5.9 to 21.3 years) and at an average of 1.9 years (range 1.5 to 2.4 years) later. At the time of pamidronate discontinuation, all but one of the patients who were below 15 years of age (n=14) had a positive age- and sex-specific z-score for bone mineral content (BMC) at the metaphysis, resulting in a mean z-score of +2.0 (SD=1.0) for this subgroup. In contrast, patients aged 15 years or older (n=9) had an average metaphyseal BMC z-score of -1.5 (SD=1.5). After pamidronate discontinuation, metaphyseal BMC z-score decreased by an average of 2.4 (SD=2.0) in the whole group. The change in BMC z-score was growth-dependent, as BMC z-scores decreased by about 2 or more in all patients in whom distal radius growth plates were open when pamidronate was discontinued. In contrast, none of the 11 patients with closed distal radius growth plates experienced a decrease in metaphyseal BMC z-score by more than 2. At the diaphysis, the average BMC z-score was low at the time of the last pamidronate infusion [z-score -1.7 (SD=1.4)]. After pamidronate discontinuation, the average diaphyseal BMC z-score decreased by only 0.3 (SD=0.4). In summary, this study shows that the effect of pamidronate discontinuation is much larger at the radial metaphysis than at the diaphysis and is dependent on growth. Metaphyseal bone tissue added by longitudinal growth after treatment discontinuation has a lower density than tissue created during treatment. It is possible that this produces zones of localized bone fragility after pamidronate treatment is stopped in growing children.

High and low density in the same bone: a study on children and adolescents with mild osteogenesis imperfecta.

Children and adolescents with osteogenesis imperfecta (OI) generally have low bone mineral density (BMD) at the lumbar spine and hip. However, the effects of the disease on diaphyseal bone have not been well characterized, even though long-bone fractures are common in such patients. In this study on 42 fully mobile children and adolescents with mild OI (age 6-19 years; 17 girls), lumbar spine, radius (metaphysis and diaphysis) and second metacarpal (diaphysis) were analyzed using dual-energy X-ray absorptiometry, peripheral quantitative computed tomography and radiogrammetry, respectively. Bone mineral content at the lumbar spine, radial metaphysis and radial diaphysis was between 25% and 31% lower than in age-matched healthy children and adolescents. At the lumbar spine and radial metaphysis, bone size (as estimated from projection area and cross-sectional area, respectively) was normal or only slightly below the results expected for healthy individuals, whereas bone size was very small at the diaphyseal sites of the radius and the second metacarpal. Total volumetric BMD is defined as the ratio between bone mineral content and bone volume. Therefore, these differences in bone size between skeletal locations led to markedly discrepant results for total volumetric BMD. Total volumetric BMD was low at the lumbar spine (23% below result expected for healthy subjects of the same age) and the radial metaphysis (-15%) but elevated at the radial diaphysis (+25%; all differences to controls significant at P < 0.001). Despite high volumetric BMD, estimated bending strength at the radial diaphysis was very low. These results demonstrate that volumetric BMD can be abnormally high and low within the same bone in the same individual and highlight the fact that volumetric BMD at diaphyseal sites does not provide a good estimate of bone strength when bone size is abnormal.

The projection domain of MAP2b regulates microtubule protrusion and process formation in Sf9 cells.

The expression of microtubule-associated protein 2 (MAP2), developmentally regulated by alternative splicing, coincides with neurite outgrowth. MAP2 proteins contain a microtubule-binding domain (C-terminal) that promotes microtubule assembly and a poorly characterized domain, the projection domain (N-terminal), extending at the surface of microtubules. MAP2b differs from MAP2c by an additional sequence of 1372 amino acids in the projection domain. In this study, we examined the role of the projection domain in the protrusion of microtubules from the cell surface and the subsequent process formation in Sf9 cells. In this system, MAP2b has a lower capacity to induce process formation than MAP2c. To investigate the role of the projection domain in this event, we expressed truncated forms of MAP2b and MAP2c that have partial or complete deletion of their projection domain in Sf9 cells. Our results indicate that process formation is induced by the microtubule-binding domain of these MAP2 proteins and is regulated by their projection domain. Furthermore, the microtubule-binding activity of MAP2b and MAP2c truncated forms as well as the structural properties of the microtubule bundles induced by them do not seem to be the only determinants that control the protrusion of microtubules from the cell surface in Sf9 cells. Rather, our data suggest that microtubule protrusion and process formation are regulated by intramolecular interactions between the projection domain and its microtubule-binding domain in MAP2b.