Pamidronate does not adversely affect bone intrinsic material properties in children with osteogenesis imperfecta
Introduction
Osteogenesis imperfecta (OI) is a heterogeneous heritable disorder that is characterized by low bone mass and increased bone fragility [1]. In most patients, the disease is caused by mutations in one of the two genes that code for collagen type I alpha chains (COL1A1 and COL1A2) [1]. Whereas the genetic background of OI and the resulting defects in collagen structure have become increasingly well characterized, there is still little understanding of the mechanisms leading to the marked bone fragility in OI [2]. In particular, it is not clear to what extent the increased susceptibility to bone fractures results from diminished bone mass or rather is the consequence of impaired bone material quality.
Iliac bone samples of children with OI are abnormally small, have thin cortices and a low amount of trabecular bone [3]. The activity of both bone formation and bone resorption is increased and the lamellar organization of trabeculae appears disordered, reflecting a disturbed bone matrix architecture [1]. One study has found that children with OI have hypermineralized bone matrix [4]. Similar observations have been made in the oim, a murine model of moderate-to-severe OI. The bones of these animals exhibit an abnormally high calcium concentration but a low amount and poorly cross-linked collagen fibrils [5], leading to increased hardness of the matrix combined with reduced mechanical strength [6], [7], [8].
In the past few years, therapy with intravenous pamidronate has been reported to increase bone mass and to decrease fracture rates in children with severe OI [1]. Histomorphometric studies suggest that the increase in bone mass is due to higher cortical thickness and a larger number of trabeculae [9]. While the improvement in fracture incidence probably can be explained by the increase in bone mass, it is not known to what extent the treatment also affects the intrinsic material properties of the bone matrix.
Intrinsic material properties of bone tissue are defined by the composition of the organic matrix and its degree of mineralization at the ultrastructural level and are independent of bone mass, geometry and trabecular structures. At the present time, little is known about the quality of bone formed in the course of pamidronate therapy. However, this question is of crucial importance since bisphosphonates are known to increase the degree and homogeneity of mineralization in patients with postmenopausal osteoporosis [10], [11]. The bone matrix of OI patients is known to be already hypermineralized prior to therapy [1]. Therefore, there are concerns that bisphosphonate treatment might further increase the brittleness and therefore fragility of OI bone [12].
In a previous study, we have shown that alendronate treatment does not alter the mechanical and material properties of bone in the oim mouse model, a rather encouraging perspective for the bisphosphonate therapy in children with OI [13]. But until now, there is no evidence that the same is true in treated children. One difficulty is that biomechanical properties of bone cannot be studied in humans by conventional methods like whole-bone bending tests. To determine bone stiffness and hardness within bone biopsies, we used nanoindentation, a well-established technique to assess the intrinsic mechanical properties of human bone and cartilage [14], [15], [16].
In the present study, we compare bone histomorphometric data, the degree of mineralization of the bone matrix and the mechanical properties of bone material in 14 children with OI. Paired iliac bone samples were taken and evaluated before and after a 2.5-year pamidronate therapy as well as in age-matched controls.
Section snippets
Subjects
The study population comprised 14 patients (6 girls, 8 boys) with moderate to severe OI that were treated at the Shriners Hospital for Children in Montreal. These subjects are a subgroup of the cohort whose histomorphometric results during pamidronate treatment have been reported earlier [9]. The distribution of OI types was as follows: Type I, N = 4; type III, N = 3; type IV, N = 7. Collagen type I mutations were assessed as described previously [17]. Mutations were found in 12 of these
Results
The histomorphometric and densitometric results showed the expected increase in bone mass and cortical thickness in OI patients during pamidronate treatment, as previously described [9]. Pretreatment iliac bone samples of OI patients were smaller than those of control patients (Table 1, Fig. 2A), had thinner cortices and less trabecular bone (Table 1, Fig. 2B), but higher trabecular bone formation rates. Cortical width increased during pamidronate treatment (Table 1, Fig. 2C). Cancellous bone
Discussion
The present study focused on the intrinsic bone material quality in children affected with severe osteogenesis imperfecta (OI types III and IV) and treated with the bisphosphonate pamidronate. Summarizing the results obtained in the present study, the following picture emerges: in agreement with previous studies on OI patients and on the OI murine (oim) model [1], [6], [7], the bone matrix appears to be more highly mineralized, leading to a higher stiffness and hardness of the bone material as
Acknowledgments
We thank Rose Travers for histomorphometric analyses at the Genetics Unit of Shriners Hospital for Children, Montreal, and Gerda Dinst, Phaedra Messmer, Sonja Lueger for careful sample preparations and qBEI measurements at the bone material laboratory of the Ludwig Boltzmann-Institute of Osteology, Vienna, Austria. This study was supported by the Shriners of North America, by the AUVA (Austrian Social Insurance for Occupational Risk), by the WGKK (Social Health Insurance Vienna) and the FWF
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