A Three-Year Longitudinal Study Comparing Bone Mass, Density, and Geometry Measured by DXA, pQCT, and Bone Turnover Markers in Children with PKU Taking L-Amino Acid or Glycomacropeptide Protein Substitutes

In patients with phenylketonuria (PKU), treated by diet therapy only, evidence suggests that areal bone mineral density (BMDa) is within the normal clinical reference range but is below the population norm. Aims: To study longitudinal bone density, mass, and geometry over 36 months in children with PKU taking either amino acid (L-AA) or casein glycomacropeptide substitutes (CGMP-AA) as their main protein source. Methodology: A total of 48 subjects completed the study, 19 subjects in the L-AA group (median age 11.1, range 5–6 years) and 29 subjects in the CGMP-AA group (median age 8.3, range 5–16years). The CGMP-AA was further divided into two groups, CGMP100 (median age 9.2, range 5–16years) (n = 13), children taking CGMP-AA only and CGMP50 (median age 7.3, range 5–15years) (n = 16), children taking a combination of CGMP-AA and L-AA. Dual X-ray absorptiometry (DXA) was measured at enrolment and 36 months, peripheral quantitative computer tomography (pQCT) at 36 months only, and serum blood and urine bone turnover markers (BTM) and blood bone biochemistry at enrolment, 6, 12, and 36 months. Results: No statistically significant differences were found between the three groups for DXA outcome parameters, i.e., BMDa (L2–L4 BMDa g/cm2), bone mineral apparent density (L2–L4 BMAD g/cm3) and total body less head BMDa (TBLH g/cm2). All blood biochemistry markers were within the reference ranges, and BTM showed active bone turnover with a trend for BTM to decrease with increasing age. Conclusions: Bone density was clinically normal, although the median z scores were below the population mean. BTM showed active bone turnover and blood biochemistry was within the reference ranges. There appeared to be no advantage to bone density, mass, or geometry from taking a macropeptide-based protein substitute as compared with L-AAs.

Effects of 8 years of growth hormone treatment on scoliosis in children with Prader-Willi syndrome

Objective: Scoliosis is frequently seen in children with Prader-Willi syndrome (PWS). There is still concern that growth hormone (GH) treatment might increase the risk of onset or progression of scoliosis. Short-term data suggested no adverse effects of GH on scoliosis, but long-term effects of GH treatment on development of scoliosis in PWS are unknown. This study investigated the effects of 8 years of GH treatment on scoliosis in children with PWS. Design: Open-label, prospective cohort study in 103 children with PWS receiving GH for eight years. Prevalence and severity of scoliosis were compared to a group of 23 age-matched GH untreated children with PWS. Methods: Spine X-rays and DEXA-scans were performed, and Cobb angel was measured by two independent observers. Results: After 8 years of GH treatment, at median age of 10.8 years, prevalence of scoliosis was 77.7%. No difference in prevalence or severity of scoliosis was found between GH-treated and age-matched untreated children with PWS (P=0.409 and p=0.709, respectively). Height SDS and trunkLBM were significantly higher in GH-treated children. Higher bone mineral density of the lumbar spine was found in children without scoliosis after 8 years of GH. Bone mineral apparent density of lumbar spine (BMADLS) SDS was associated with lower Cobb angle (r=-0.270, p=0.008). Conclusions: Eight years of GH treatment has no adverse effects on prevalence and severity of scoliosis in children with PWS until 11 years of age. As BMADLS SDS is inversely associated with Cobb angle, it is pivotal to optimize BMD-status in children with PWS.

Bone Development in Transgender Adolescents Treated With GnRH Analogues and Subsequent Gender-Affirming Hormones

Context Hormonal interventions in adolescents with gender dysphoria may have adverse effects, such as reduced bone mineral accrual. Objective To describe bone mass development in adolescents with gender dysphoria treated with gonadotropin-releasing hormone analogues (GnRHa), subsequently combined with gender-affirming hormones. Design Observational prospective study. Subjects 51 transgirls and 70 transboys receiving GnRHa and 36 transgirls and 42 transboys receiving GnRHa and gender-affirming hormones, subdivided into early- and late-pubertal groups. Main Outcome Measures Bone mineral apparent density (BMAD), age- and sex-specific BMAD z-scores, and serum bone markers. Results At the start of GnRHa treatment, mean areal bone mineral density (aBMD) and BMAD values were within the normal range in all groups. In transgirls, the mean z-scores were well below the population mean. During 2 years of GnRHa treatment, BMAD stabilized or showed a small decrease, whereas z-scores decreased in all groups. During 3 years of combined administration of GnRHa and gender-affirming hormones, a significant increase of BMAD was found. Z-scores normalized in transboys but remained below zero in transgirls. In transgirls and early pubertal transboys, all bone markers decreased during GnRHa treatment. Conclusions BMAD z-scores decreased during GnRHa treatment and increased during gender-affirming hormone treatment. Transboys had normal z-scores at baseline and at the end of the study. However, transgirls had relatively low z-scores, both at baseline and after 3 years of estrogen treatment. It is currently unclear whether this results in adverse outcomes, such as increased fracture risk, in transgirls as they grow older.

The effect of GnRH analogue treatment on bone mineral density in young adolescents with gender dysphoria: findings from a large national cohort

Background More young people with gender dysphoria (GD) are undergoing hormonal intervention starting with gonadotropin-releasing hormone analogue (GnRHa) treatment. The impact on bone density is not known, with guidelines mentioning that bone mineral density (BMD) should be monitored without suggesting when. This study aimed to examine a cohort of adolescents from a single centre to investigate whether there were any clinically significant changes in BMD and bone mineral apparent density (BMAD) whilst on GnRHa therapy. Methods A retrospective review of 70 subjects aged 12–14 years, referred to a national centre for the management of GD (2011–2016) who had yearly dual energy X-ray absorptiometry (DXA) scans. BMAD scores were calculated from available data. Two analyses were performed, a complete longitudinal analysis (n=31) where patients had scans over a 2-year treatment period, and a larger cohort over the first treatment year (n=70) to extend the observation of rapid changes in lumbar spine BMD when puberty is blocked. Results At baseline transboys had lower BMD measures than transgirls. Although there was a significant fall in hip and lumbar spine BMD and lumbar spine BMAD Z-scores, there was no significant change in the absolute values of hip or spine BMD or lumbar spine BMAD after 1 year on GnRHa and a lower fall in BMD/BMAD Z-scores in the longitudinal group in the second year. Conclusions We suggest that reference ranges may need to be re-defined for this select patient cohort. Long-term BMD recovery studies on sex hormone treatment are needed.

Older age at Initiation of Antiretroviral Therapy Predicts Low Bone Mineral Density in Children with perinatally-infected HIV in Zimbabwe

BackgroundPerinatally-acquired HIV infection commonly causes stunting in children, but how this affects bone and muscle development is unclear. We investigated differences in bone and muscle mass and muscle function between children with HIV (CWH) and uninfected children.SettingCross-sectional study of CWH (6–16 years) receiving antiretroviral therapy (ART) for >6 months and children in the same age-group testing HIV-negative at primary health clinics in Zimbabwe.MethodsFrom Dual-energy X-ray Absorptiometry (DXA) we calculated total-body less-head (TBLH) Bone Mineral Content (BMC) for lean mass adjusted-for-height (TBLH-BMCLBM) Z-scores, and lumbar spine (LS) Bone Mineral Apparent Density (BMAD) Z-scores.ResultsThe 97 CWH were older (mean age 12.7 vs. 10.0 years) and therefore taller (mean height 142cm vs. 134cm) than those 77 uninfected. However, stunting (height-for-age Z-score≤-2) was more prevalent in CWH (35% vs. 5%, p<0.001). Amongst CWH, 15% had low LS-BMAD (Z-score ≤-2) and 13% had low TBLH-BMCLBM, vs. 1% and 3% respectively in those uninfected (both p≤0.02). After age, sex, height and puberty adjustment, LS-BMAD was 0.33 SDs (95%CI −0.01, 0.67; p=0.06) lower in CWH, with no differences in TBLH-BMCLBM, lean mass or grip strength by HIV status. However, there was a strong relationship between age at ART initiation and both LS-BMAD Z-score (r=-0.33, p=0.001) and TBLH-BMCLBM Z-score (r=-0.23, p=0.027); for each year ART initiation was delayed a 0.13 SD reduction in LS-BMAD was seen.ConclusionSize-adjusted low bone density is common in CWH. Delay in initiating ART adversely affects bone density. Findings support immediate ART initiation at HIV diagnosis.