Bone Histology And Histomorphometry In Osteogenesis Imperfecta (OI).

Frank Rauch, Rose Travers, Francis H. Glorieux
Genetics Unit, Shriners Hospital and McGill University, Montreal, Canada.

Very little is known about the mechanisms by which the molecular defects underlying OI are linked to the clinical manifestations of the disease. In particular, there is a gap in knowledge on the tissue-level characteristics of OI in children. The largest series of iliac crest histomorphometric data published to date included nine and four pediatric OI patients, respectively (Baron et al, Ped Res 1983;17:204; Ste-Marie et al, J Clin Pathol 1984;37:1081). Both studies reported decreased bone volume and increased bone remodeling in children with OI. However, these studies were too small for more detailed analyses and no data are available on histomorphometric differences between OI types and changes with age. In the present study, we qualitatively and quantitatively evaluated tetracycline-labeled biopsies from 89 children and adolescents with the clinical diagnosis of OI. Results were compared to those of age-matched individuals without metabolic bone disease and of children with idiopathic juvenile osteoporosis (IJO).

Our series included biopsies from 70 patients (age 2 to 13 years) with 'classical' OI (types I: n=32; type III: n=11; type IV: n=27). These were compared to control biopsies from 27 age-matched children. In biopsies from OI patients, the decrease in core size, cortical width and cancellous bone volume was readily apparent. As seen under polarized light, the lamellar pattern was usually preserved. Inspection of the tetracycline labels under fluorescent light did not reveal obvious disturbances of the mineralization process.

Quantitative evaluation revealed that decreased cancellous bone volume was partly due to a decrease in the number of trabeculae. Regression analysis showed that the number of trabeculae per mm cross-section did not change with age in either controls or OI patients. Thus, while trabecular number is low, there was no indication that OI patients lose trabeculae during development. By exclusion, this indicates that fewer trabeculae are produced. The second determinant of cancellous bone volume is trabecular thickness. Trabecular thickness was within the reference range for all 19 OI patients below 5 years of age. However, while trabecular thickness increased markedly with age in the control population, there was diminished trabecular thickening in OI type I and no thickening at all in types III and IV. The failure to increase trabecular thickness during development explains why cancellous bone mass of OI patients increasingly falls behind that of healthy children. As to differences between OI types, children with type I disease had a higher cancellous bone volume than type III and IV patients. This was entirely due to higher trabecular number in type I, whereas the thickness of trabeculae was similar in all three types.

In all classical OI types, cancellous bone metabolism was markedly increased. Indicators of bone formation and resorption (osteoid surface, osteoblast surface, mineralizing surface, erosive surface and osteoclast surface) were both increased without evidence for the predominance of one process over the other. The yearly turnover of cancellous bone was between 40% (type I) and 120% (type III) higher than in healthy controls. Thus, the increase in bone turnover correlated with the severity of the disease.

Biopsies were also obtained from 19 OI patients, who either clinically or histologically did not fit into the pattern of the classical types. Among these were 7 children aged 5 to 13 years, who had ossification of the interosseous membrane, a predisposition to hyperplastic callus formation and who did not have mutations in the COL1A1 genes. The histologic appearance was clearly different from that in classical OI. Lamellae appeared irregular and had a coarsened appearance under polarized light. Osteoid seams were thinner than in patients with classical OI and bone turnover was not increased. Bone remodeling in these patients was characterized by a normal activation rate of remodeling units, but impaired bone formation within individual remodeling units.

Another group of non-classical OI consisted of 6 children (age 3 to 18 years) who were moderately to severely affected and who were clinically indistinguishable from type IV OI. However, the histologic appearance was clearly different from all other forms of OI, as there was a lack of lamellation and very thick osteoid seams were present. A similar histologic phenotype with dramatically increased osteoid surface and thickness, but preserved lamellation, was present in two girls.

Finally, we examined biopsies from four OI patients (age 2.7 to 4.2 years) from a Native American community. In this population the disease follows a recessive pattern of inheritance and maps to chromosome 3p22-24.1. The histologic picture is very similar to that of OI type I in both qualitative and quantitative terms, showing that the tissue level manifestations of OI are not specific for collagen defects, but can be the result of mutations in other genes. In order to characterize the differences between IJO and OI, we examined biopsies from 9 children (age 10 to 12 years) with typical IJO. In these children, cancellous bone volume was decreased to a similar extent as in OI type I. However, all bone surface based parameters of bone formation were markedly lower than in OI. The yearly turnover of cancellous bone in IJO was 33% lower than in healthy controls and about 50% lower than in OI type I.

In conclusion, bone histomorphometry is an important tool for clinical studies on OI, as it provides information that cannot be obtained by any other method. Appreciation of this technique will help to understand the impact of molecular and cellular defects on the higher levels of biologic organization. Furthermore, the analysis of bone biopsies allows to detect distinct forms of OI, thus refining the classification of this group of disorders.

Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999.