Low bone mineral density (BMD) and subsequent skeletal fragility have emerged as a long-term complication of phenylketonuria (PKU).

To determine if there are differences in BMD and body composition between male and female participants with PKU.

From our randomized, crossover trial [1] of participants with early-treated PKU who consumed a low-phenylalanine (Phe) diet combined with amino acid medical foods (AA-MF) or glycomacropeptide medical foods (GMP-MF), a subset of 15 participants (6 males, 9 females, aged 15–50 y, 8 classical and 7 variant PKU) completed one dual energy X-ray absorptiometry (DXA) scan and 3-day food records after each dietary treatment. Participants reported lifelong compliance with AA-MF. In a crossover design, 8 participants (4 males, 4 females, aged 16–35 y) provided a 24-h urine collection after consuming AA-MF or GMP-MF for 1–3 weeks each.

Male participants had significantly lower mean total body BMD Z-scores (means ± SE, males = − 0.9 ± 0.4; females, 0.2 ± 0.3; p = 0.01) and tended to have lower mean L1–4 spine and total femur BMD Z-scores compared to female participants. Only 50% percent of male participants had total body BMD Z-scores above − 1.0 compared to 100% of females ( p = 0.06). Total femur Z-scores were negatively correlated with intake of AA-MF ( r = − 0.58; p = 0.048). Males tended to consume more grams of protein equivalents per day from AA-MF (means ± SE, males: 67 ± 6 g, females: 52 ± 4 g; p = 0.057). Males and females demonstrated similar urinary excretion of renal net acid, magnesium and sulfate; males showed a trend for higher urinary calcium excretion compared to females (means ± SE, males: 339 ± 75 mg/d, females: 228 ± 69 mg/d; p = 0.13). Females had a greater percentage of total fat mass compared to males (means ± SE, males: 24.5 ± 4.8%, females: 36.5 ± 2.5%; p = 0.047). Mean appendicular lean mass index was similar between males and females. Male participants had low-normal lean mass based on the appendicular lean mass index.

Males with PKU have lower BMD compared with females with PKU that may be related to higher intake of AA-MF and greater calcium excretion. The trial was registered at www.clinicaltrials.gov as NCT01428258 .