medwireNews: Non-autosomal dominant (AD) inheritance and the presence of structural collagen defects are associated with reduced benefit of treatment with zoledronic acid in children with osteogenesis imperfecta, researchers report.
Mei Li (Peking Union Medical College Hospital, Beijing, China) and team attribute this association to the “more severe phenotypes” associated with these features and suggest that “[n]ew therapeutic agents are worth developing in these patients.”
Overall, femoral neck bone mineral density (BMD) increased from an average of 0.408 to 0.761 g/cm2 during treatment of the 201 children (135 boys) included in the study. Treatment was started at a median age of 5 years and continued for a median of 3 years.
However, while the 176 children with AD inheritance had an average 49.8% increase in femoral neck BMD after 6 months of treatment, those with non-AD inheritance (autosomal recessive or X-linked) had an increase averaging just 24.3%.
Likewise, the corresponding increases in BMD standard deviation scores were 3.80 versus 2.03 after 2 years of treatment and 4.46 versus 2.04 after 3 years.
Of note, children with non-AD inheritance had significantly higher baseline serum levels of the bone resorption marker β-isomerized carboxy-telopeptide of type I collagen (β-CTX) than those with AD inheritance, in line with a more severe disease process.
Among children with AD inheritance, the majority (94%) had mutations in genes encoding collagen (primarily COL1A1 and COL1A2), resulting in a quantitative reduction of collagen in 30%, structural defects in 45% and other changes in 25%.
The researchers found that β-CTX levels declined significantly less in patients with structural collagen changes versus a quantitative reduction at 6 months (22.7 vs 43.1%), 1 year (13.2 vs 36.4%) and 3 years (6.8 vs 33.0%).
In addition, children with collagen structural defects had a higher rate of new fractures than those with quantitative reductions during the first 2 years of treatment, at 35.1% versus 18.4%.
And in multiple linear regression analysis, having a quantitative reduction in collagen, rather than structural defects, was associated with a significantly improved response to zoledronic acid, as was a younger age at treatment initiation.
These two factors were also significantly predictive of having fewer new fractures during treatment.
The researchers say that structural collagen defects “may have more severe consequences for bone matrix structure” than a reduced amount of collagen, and note that even when the quantity of collagen is reduced there may still be “a relatively normal microenvironment” for bisphosphonates to act on.
They conclude in The Journal of Clinical Endocrinology & Metabolism that their findings “may help to predict [bisphosphonate] efficacy in [osteogenesis imperfecta] patients on the basis of pathogenic mutations.”
By Eleanor McDermid
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J Clin Endocrinol Metab 2022; doi:10.1210/clinem/dgac366
