Effective NSAID treatment indicates that hyperprostaglandinism is affecting the clinical severity of childhood hypophosphatasia

Background: Hypophosphatasia (HP) is an inborn error of bone
metabolism characterized by a genetic defect in the gene encoding
the tissue-nonspecific alkaline phosphatase (TNSALP). There is a
lack of knowledge as to how the variability and clinical severity
of the HP phenotype (especially pain and walking impairment) are
related to metabolic disturbances or impairments, subsequent to the
molecular defect. Methods: We analyzed the changes in clinical
symptoms and the prostaglandin (PG) metabolism in response to
treatment with non-steroidal anti-inflammatory drugs (NSAIDs) in
six children affected by childhood HP. In addition, by exposing HP
fibroblasts to pyridoxal phosphate and/or calcium pyrophosphate in
vitro, we analyzed whether the alterations in PG levels are
sequelae related to the metabolic defect. Results: Childhood HP
patients, who often complain about pain in the lower limbs without
evident fractures, have systemic hyperprostaglandinism. Symptomatic
anti-inflammatory treatment with NSAIDs significantly improved
pain-associated physical impairment. Calcium pyrophosphate, but not
pyridoxal phosphate, induced cyclooxygenase-2 (COX-2) gene
expression and PG production in HP and normal fibroblasts in vitro.
Conclusion: Clinical features of childhood HP related to pain in
the lower legs may be, at least in part, sequelae related to
elevated PG levels, secondary to the primary metabolic defect.
Consequently, NSAID treatment does improve the clinical features of
childhood HP.