Osteoclast indices in osteogenesis imperfecta: systematic review and meta-analysis

Background: Osteogenesis imperfecta (OI) is a rare bone fragility disorder caused by mutations in genes that encode collagen type I or affect its processing. Alterations in bone resorbing osteoclasts were suggested to contribute to OI pathophysiology. We aimed to systematically identify studies reporting measures of osteoclast formation and function in patients and mouse models of OI, to quantify OI-induced changes. Results: The systematic search of Medline, OVID and Web of Science identified 798 unique studies. After screening, we included for meta-analysis 23 studies reporting osteoclast parameters in 310 OI patients of 9 different types and 16 studies reporting osteoclast parameters in 406 animals of 11 different OI mouse models. The standardized mean difference was used as the effect size, random effects meta-analysis was performed using R-studio. In OI patients, collagen degradation markers were significantly higher in patients with OI compared to age-matched control with the effect size of 1.23 [Confidence interval (CI): 0.36, 2.10]. Collagen degradation markers were the most elevated in the 3 to 7-year-old age group, and in patients with more severe forms of OI. Bone histomorphometry demonstrated the trends for higher osteoclast numbers, 1.16 [CI: -0.22, 2.55], and osteoclast surface, 0.43 [CI: -0.63; 1.49], and significantly higher eroded surface, 3.24 [CI: 0.51, 5.96] compared to the aged-match control. In OI mice, meta-analysis demonstrated significant increases in collagen degradation markers, 1.59 [CI: 1.07, 2.11]; in osteoclast numbers, 0.94 [CI: 0.50, 1.39], osteoclast surface, 0.73 [CI:0.22, 1.23], and eroded surface 1.31[CI: 0.54, 2.08]. The largest differences were in OI mice with the mutations in Col1a1 and Col1a2 genes. There were no differences between males and females in clinical or animal studies. Conclusions: Quantitative estimates of changes in osteoclast indices and their variance for patients with OI are important for planning future studies. We confirmed that similar changes are observed in mice with OI, supporting their translational utility.