Treatment with intravenous bisphosphonates in children and adolescents with Osteogenesis Imperfecta: are we towards a consensus of a protocol?

In the current issue of JRPMS, Dr Sarantis and colleagues report the interesting case of a Greek patient, a 7 years-old boy, with Osteogenesis Imperfecta due to a novel COL1A1 mutation. The authors also provide insight into their protocol of pharmacological treatment with iv zolendronic acid, a topic of increasing interest in the field, as there is currently no consensus regarding choice of pharmacological agent, dosing or even duration of treatment. Osteogenesis Imperfecta (OI) literally means “imperfect bone birth” in Latin, as derived from the original Greek word οστεογένεση (ὀστοῦν = bone + γένεσις = birth). It was termed by Vrolik in 1849 and represents a genetic disorder with multiple genotypes and phenotypes. OI is caused by mutations either of the COL1A1 or COL1A2 genes (in reportedly 85% of the cases) encoding the pro-α1 or α2 chains of type-I collagen or of other genes (i.e WNT1, LRP5, BMP1, CRTAP, P3H1/LEPRE1) involved in osteoblast differentiation or post-translational modification/transport of type I collagen. Type-I collagen is the major protein of bone, constituting by large its organic part, but exists also in significant quantities in tendons, ligaments, skin, sclerae and dentin. Patients with OI have lower quantity and/or quality of type-I collagen, thus presenting with multiple clinical phenotypes that usually include low-energy fractures, bone deformities, joint hypermobility, bone pain, short stature, and in some cases blue sclerae, dentinogenesis imperfecta and premature hearing loss. According to the original classification of Sillence, OI can be distinguished in four predominant types (I-IV). Type I is the milder form with usually no deformities, type II is the lethal form resulting in perinatal death, type III is the most severe in surviving neonates with multiple fractures and deformities, and type IV is intermediate in severity between types I and III with moderate deformities and short stature. Pharmacological treatment of OI in various clinical settings reportedly depends upon the age of the patient at the time of diagnosis as well as the severity of the disease, and there is currently no consensus regarding a treatment regimen of choice. In the past, unsuccessful attempts to control the disease have been made with vitamins, sodium fluoride, calcitonin or even growth hormone. Twenty years ago, Glorieux and colleagues reported the use of intravenous pamidronate (a second-generation nitrogen-containing bisphosphonate) in children with severe osteogenesis imperfecta. Ever since, there have been a few reports regarding the short-term effects of pamidronate treatment in various dosing regimens for sometimes up to 4 years in small numbers of patients with OI. These studies, comprising groups of children with OI types I, III and IV all reported significant increases in lumbar spine areal bone mineral density (BMD). One study reported beneficial effects on lumbar spine BMD during treatment for 2-9 years. A very interesting study with iliac bone histomorphometry in 45 patients with OI suggested that after 2 years of treatment, iv pamidronate in different doses and dose regimens according to the age, induced significant increases in cortical width (88%, p<0.001) and average cancellous bone volume (46%, p<0.001) that was entirely due to an increase in trabecular number, while trabecular thickness remained unchanged. Bone formation rate (BFR/BS), osteoid thickness, and other markers of trabecular bone remodelling all significantly decreased (p<0.001), and the authors concluded that pamidronate has a 2-fold effect on the growing skeleton, by inhibiting bone remodelling-induced trabecular bone resorption while preserving bone formation of cortical bone due to bone modelling. One study reported that iv pamidronate given for 4 years led to a statistically