title: Tenofovir disoproxil fumarate and an optimized background regimen of antiretroviral agents as salvage therapy: impact on bone mineral density in HIV-infected children.
abstract: OBJECTIVE
  Tenofovir disoproxil fumarate, a nucleotide analog HIV reverse transcriptase inhibitor with demonstrated activity against nucleoside-resistant HIV, is approved for use in adults but not children. Metabolic bone abnormalities have been seen in young animals given high-dose tenofovir and HIV-infected adults that were treated with oral tenofovir disoproxil fumarate. However, tenofovir disoproxil fumarate is being used in children despite a lack of bone safety data. We hypothesized that, given the higher rate of bone turnover that is associated with normal skeletal growth, the potential for TDF-related bone toxicity may be greater in children than in adults.
  
  
  METHODS
  Fifteen highly antiretroviral-experienced HIV-infected children who were 8 to 16 years of age (mean +/- SD: 12 +/- 2) and required a change in therapy received tenofovir disoproxil fumarate 175 to 300 mg/m2 per day (adult dose equivalent) as part of highly active antiretroviral therapy for up to 96 weeks. Bone mineral density of the lumbar spine, femoral neck, and total hip by dual-energy x-ray absorptiometry and blood and urine markers of bone metabolism were measured at 0, 24, 48, 72, and 96 weeks.
  
  
  RESULTS
  Median z score (SD score compared with age, gender, and ethnicity-matched control subjects) of the lumbar spine, femoral neck, and total hip were decreased from baseline at 24 weeks and 48 weeks and then stabilized. Lumbar spine bone mineral apparent density (which estimates volumetric bone mineral density independent of bone size) z scores also decreased at 24 weeks. Absolute decreases in bone mineral density were observed in 6 children; the mean age of these children was significantly younger than the bone mineral density stable group (10.2 +/- 1.1 vs 13.2 +/- 1.8 years). The change in lumbar spine bone mineral density correlated with decreases in HIV plasma RNA during treatment. Metabolic markers of bone formation and resorption were variable. Two children in whom tenofovir disoproxil fumarate was discontinued because of bone loss that exceeded protocol allowances demonstrated partial or complete recovery of bone mineral density by 96 weeks.
  
  
  CONCLUSIONS
  Tenofovir disoproxil fumarate use in children seems to be associated with decreases in bone mineral density that, in some children, stabilize after 24 weeks. Increases in bone markers and calcium excretion suggest that tenofovir disoproxil fumarate may stimulate bone resorption. Bone turnover is higher in children than in older adolescents and adults because of skeletal growth, potentially explaining the greater effect seen in young children. Decreases in bone mineral density correlate with decreases in viral load and young age, suggesting that young responders may be at greater risk for bone toxicity.
authors.affiliation: HIV and AIDS Malignancy Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
authors.forename: Rachel I
authors.initials: RI
authors.lastname: Gafni
authors.forename: Rohan
authors.initials: R
authors.lastname: Hazra
authors.forename: James C
authors.initials: JC
authors.lastname: Reynolds
authors.forename: Frank
authors.initials: F
authors.lastname: Maldarelli
authors.forename: Antonella N
authors.initials: AN
authors.lastname: Tullio
authors.forename: Ellen
authors.initials: E
authors.lastname: DeCarlo
authors.forename: Carol J
authors.initials: CJ
authors.lastname: Worrell
authors.forename: John F
authors.initials: JF
authors.lastname: Flaherty
authors.forename: Kitty
authors.initials: K
authors.lastname: Yale
authors.forename: Brian P
authors.initials: BP
authors.lastname: Kearney
authors.forename: Steven L
authors.initials: SL
authors.lastname: Zeichner
mesh_terms: D000225:Adenine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000627:therapeutic use; D000293:Adolescent; D000367:Age Factors; D044966:Anti-Retroviral Agents / Q000627:therapeutic use*; D015519:Bone Density / Q000187:drug effects*; D001846:Bone Development / Q000187:drug effects; D002648:Child; D005260:Female; D015658:HIV Infections / Q000188:drug therapy*; D006801:Humans; D008297:Male; D063065:Organophosphonates / Q000009:adverse effects* / Q000627:therapeutic use; D016879:Salvage Therapy; D000068698:Tenofovir
chemical_list: D044966:Anti-Retroviral Agents; D063065:Organophosphonates; D000068698:Tenofovir; D000225:Adenine