ESPE Yearbook of Paediatric Endocrinology

To read the full abstract: J Bone Miner Res. 2020 Apr 24. doi: https://pubmed.ncbi.nlm.nih.gov/32329913/

In brief: Hematopoietic stem cell transplantation remains the only curative treatment in children with severe osteopetrosis. According to this study, increased serum calcium and phosphate serve as good markers of successful engraftment, which leads to significant but incomplete normalization of bone mineral distribution and bone morphology.

Commentary: Osteopetrosis is a genetically heterogeneous group of skeletal disorders that share a common feature: increased bone mass due to deficient bone resorption by osteoclasts. High bone mass may lead to severe complications involving the hematological, neurological and other organ systems. Genetic causes of this rare bone disease are relatively well known and mutations in several genes related to osteoclast development and resorptive capacity have been described. Despite these scientific advances, little progress has been made in the therapeutic approaches for severely affected children. Hematopoietic stem cell transplantation (HSCT) remains the only curative treatment but its success rate and long-term effects are inadequately explored. This study is the first large cohort study evaluating long-term skeletal effects of HSCT in children with osteopetrosis. Altogether 35 children treated between 2003 and 2016 were included in this retrospective study; all but two underwent HSCT. Disease-causing mutations involved five genes but mutations in TCIRG1 accounted for more than half of the cases. Outcome was evaluated by clinical, hematological and biochemical parameters and by careful evaluation of plain radiographs.

The authors show that hematopoietic recovery after HSCT coincides with a peak in bone remodelling, evidenced by significant changes in serum calcium and phosphate levels. These electrolyte measurements are widely available and used for baseline and monitoring studies. They conclude that serum calcium and phosphate could be used as auxiliary indicators of engraftment in addition to neutrophil counts, platelet counts and donor chimerism. While complete blood counts are readily available, they are difficult to interpret as they are confounded by blood product transfusions.

All radiographs taken before 3 months post-HSCT and radiographs taken later were assessed for morphological and cortex-to-medullary density changes following HSCT. After the HSCT, radiographs of the femur were much less sclerotic overall and the medullary cavity was visibly less radiodense than the cortex, suggesting significant remodeling and bone mineral redistribution. Not only skeletal mineral density but also long bone morphology was strikingly changed following HSCT. Before HSCT, Erlenmeyer flask deformities could be clearly seen, especially in the distal femoral metaphysis, whereas later radiographs showed a gradual widening of the diaphysis and a narrowing of the metaphysis, transforming the Erlenmeyer flask deformity into a more normal, but not completely normal, morphology. The authors conclude that neither mineral distribution nor bone morphology were completely rescued following HSCT, suggesting that even after HSCT the patients may be vulnerable to skeletal and other complications related to hyperostosis.