A cross-sectional multicenter study of osteogenesis imperfecta in North America - results from the linked clinical research centers

Abstract

Osteogenesis imperfecta (OI) is the most common skeletal dysplasia that predisposes to recurrent fractures and bone deformities. In spite of significant advances in understanding the genetic basis of OI, there have been no large-scale natural history studies. To better understand the natural history and improve the care of patients, a network of Linked Clinical Research Centers (LCRC) was established. Subjects with OI were enrolled in a longitudinal study, and in this report, we present cross-sectional data on the largest cohort of OI subjects (n = 544). OI type III subjects had higher prevalence of dentinogenesis imperfecta, severe scoliosis, and long bone deformities as compared to those with OI types I and IV. Whereas the mean lumbar spine area bone mineral density (LS aBMD) was low across all OI subtypes, those with more severe forms had lower bone mass. Molecular testing may help predict the subtype in type I collagen-related OI. Analysis of such well-collected and unbiased data in OI can not only help answering questions that are relevant to patient care but also foster hypothesis-driven research, especially in the context of 'phenotypic expansion' driven by next-generation sequencing.

Keywords: bone mineral density in osteogenesis imperfecta; history study; longitudinal study; natural history study; osteogenesis imperfecta.

Fig. 1. Lumbar spine aBMD Z-scores in OI types I, III, and IV

A graphic display of the variation in LS aBMD Z-scores among different age groups in OI. ^*p<0.05, compared to OI I; ^**p<0.05, compared to OI I & IV. Error bars indicate +/− 1 SD.

Fig. 2. Lumbar spine aBMD Z-scores in OI types V, VI, VII, and other rare forms

Box plots comparing the LS aBMD Z-scores in types V, VI, VII, and unclassified & other OI types. The small sample size precluded further categorization by age. There were no differences in aBMD between the groups (p=0.1567).

Fig. 3. LS aBMD distribution by genotype

Box plots showing the interquartile ranges and the 5^th and 95^th centiles (error bars) for LS aBMD Z-scores for various OI subtypes. The type I collagen-related OI have been further categorized based on the type of mutations. Note that the mean aBMD is low across all subtypes.

Fig. 4. Correlation between aBMD and fractures in OI types I, III, and IV

The correlation between LS aBMD Z-scores and number of fractures in the preceding year show no statistically significant correlations in OI types I (r=0.01578; p=0.7554; n=392), III (r=0.05123; p=0.5800; n=119), and IV (r=−0.01979; p=0.7522; n=257). The number of fractures was calculated per subject. Data points may not represent the actual number of subjects due to graphic overlap of common points.