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Cyclical pamidronate infusions increase bone mass in children suffering from osteogenesis imperfecta. The histological basis for these effects remains unknown. Therefore, we compared parameters of iliac bone histomorphometry from 45 patients before and after 2.4 +/- 0.6 years of pamidronate treatment (age at the time of the first biopsy, 1.4-17.5 years; 23 girls). Although biopsy size did not change significantly (P = 0.30), cortical width increased by 88%. Cancellous bone volume increased by 46%. This was due to a higher trabecular number, whereas trabecular thickness remained stable. Bone surface-based indicators of cancellous bone remodeling decreased by 26-75%. There was no evidence for a mineralization defect in any of the patients. These results suggest that, in the growing skeleton, pamidronate has a twofold effect. In remodeling, bone resorption and formation are coupled and consequently both processes are inhibited. However, osteoclasts and osteoblasts are active on different surfaces (and are thus uncoupled) during modeling of cortical bone. Therefore resorption is selectively targeted, and continuing bone formation can increase cortical width.
Introduction
Osteogenesis imperfecta (01) is a genetic disorder with increased bone fragility and low bone mass. The most commonly used classification distinguishes four clinical types (1). 01 type I comprises patients with absence of bone deformities. Type II is lethal in the perinatal period. 01 type III is the most severe form in children surviving the neonatal time. These patients have extremely short stature and limb and spine deformities secondary to multiple fractures. Patients with mild to moderate bone deformities and variable short stature are classified as OI type IV.
In the majority of patients with OI, the disease can be linked to mutations in one of the two genes coding for collagen type I ot chains (COL1A1 and COL1A2) (2). However, in some patients no such mutations are detectable. The lack of a mutation affecting collagen type 1 therefore does not rule out a diagnosis of OI.
OI is characterized by a variety of bone tissue abnormalities (3). Iliac bone biopsy specimens of these patients are small and have thin cortices, suggesting a defect in cortical bone modeling. The number of trabeculae in the cancellous compartment is low and the activity of cancellous bone remodeling is elevated. The thickness of trabeculae increases less with age...