ContextPrognostic biomarkers for monitoring bone health in adolescents with 21‐hydroxylase deficiency (21OHD) are needed.ObjectivesTo assess associations between concentrations of baseline bone turnover markers (BTMs) including osteocalcin (OC) and type‐I collagen C‐terminal telopeptide (CTX) and changes in lumbar spine bone mineral density (LSBMD) in adolescents with classic 21OHD.Designs and patientsA retrospective‐prospective study of 33 adolescents with classic 21OHD who had baseline data for LSBMD, bone age (BA), and BTM concentrations.MethodsBTM concentrations were converted into z‐scores according to BA. We measured LSBMD at the follow‐up study visit and calculated the annual percentage change in LSBMD (%∆LSBMD).ResultsAt baseline, participants (55% female, 79% Tanner 5) had mean (±SD) age of 14.6 ± 3.6 years, BA 16.7 ± 2.9 years, and average glucocorticoid (GC) dose 17.3 ± 5.6 mg/m2/day of hydrocortisone equivalent. The mean follow‐up duration was 14.4 ± 5.6 months. Median (Q1–Q3) %∆LSBMD was 3.6% (0–8.5)/year. %∆LSBMD was similar among genders or 21OHD subtypes. Prednisolone versus hydrocortisone replacement resulted in lower %∆LSBMD (p = .004). %∆LSBMD was increased across tertiles of CTX z‐score (p = .014). %∆LSBMD correlated negatively with GC dose (p = .01) and positively with CTX and OC z‐scores (p < .01). In regression analyses, only CTX z‐score positively associated with %∆LSBMD (p = .003), adjusting for sex, BA, body mass index, testosterone, 25‐hydroxyvitamin D, and GC type and dose.ConclusionsHigher GC dose and the use of prednisolone were associated with decreased LSBMD accrual in adolescents with 21OHD. CTX z‐score independently associated with LSBMD accrual, suggesting its potential for prognostic bone biomarker.