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Pharmacokinetic, pharmacodynamic, and pharmacogenetic determinants of osteonecrosis in children with acute

Jitesh D Kawedia1, Sue C Kaste, Deqing Pei

  • 1Department of Pharmaceutical Sciences, St Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105-2794, USA.

Blood
|December 15, 2010
PubMed

Insights

Glucocorticoid treatment for acute lymphoblastic leukemia causes osteonecrosis in children. Older age, intensive treatment, lower albumin, higher cholesterol, and poor dexamethasone clearance are risk factors. Genetic variations may also play a role.

Area of Science:

  • Pediatric Oncology
  • Pharmacogenomics
  • Bone Metabolism

Background:

  • Osteonecrosis is a serious complication of glucocorticoid therapy in children treated for acute lymphoblastic leukemia (ALL).
  • Early detection and risk factor identification are crucial for managing this adverse event.

Purpose of the Study:

  • To prospectively identify risk factors for symptomatic osteonecrosis in children undergoing ALL treatment.
  • To investigate the association of clinical, biochemical, pharmacokinetic, and genetic factors with osteonecrosis development.

Main Methods:

  • Prospective screening with magnetic resonance imaging (MRI) of hips and knees in 364 children with ALL.
  • Analysis of clinical data (age, treatment arm), serum lipids, albumin, cortisol, dexamethasone pharmacokinetics, and genome-wide germline genetic polymorphisms.
  • Statistical analysis to determine associations with symptomatic (grade 2-4) and severe (grade 3-4) osteonecrosis.

Main Results:

  • The cumulative incidence of any osteonecrosis was 71.8%, and symptomatic osteonecrosis was 17.6%.
  • Risk factors for symptomatic osteonecrosis included older age (>10 years) and more intensive ALL treatment.
  • Lower albumin, elevated cholesterol, and poor dexamethasone clearance were associated with symptomatic and severe osteonecrosis.
  • Genetic polymorphisms in ACP1 were significantly associated with osteonecrosis risk, lower albumin, and higher cholesterol.

Conclusions:

  • Older age, intensive treatment, altered lipid/albumin levels, and dexamethasone exposure are key factors in glucocorticoid-induced osteonecrosis in pediatric ALL.
  • The ACP1 gene polymorphism may contribute to osteonecrosis risk by influencing lipid metabolism and albumin levels.
  • These findings highlight the complex interplay of clinical, pharmacokinetic, and genetic factors in osteonecrosis development, guiding potential preventative strategies.

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