Urinary pyridinium collagen cross-links predict growth performance in children with idiopathic short stature and with growth hormone (GH) deficiency treated with GH. Skeletal metabolism during GH treatment.

Abstract

GH is able to promote longitudinal growth in children with GH-deficiency (GHD) and in some children with idiopathic short stature (ISS). The objectives of this study were to evaluate the predictive value of bone and collagen markers on the growth response to GH therapy in children with ISS and with GHD, and to characterize the effects of GH treatment on bone and collagen turnover in children with ISS and with GHD. Twenty prepubertal short, slowly growing, children treated with GH, 15 IU/m2 per week, were studied; of them 13 (10 males) had ISS and 7 (5 males) had GHD. An overnight 12-h urinary collection and a fasting morning blood sample were obtained at baseline, 1, 3, 6, and 12 months of treatment. Urinary levels of collagen cross-links, pyridinoline (Pyd) and deoxypyridinoline (Dpd), and circulating levels of osteocalcin, intact PTH, calcitonin, procollagen type III aminoterminal propeptide (PIIINP), insulin-like growth factor-I, and alkaline phosphatase were determined. Urinary collection was also obtained from 127 healthy children (51 males) aged 6-13 yr. In children with ISS, the changes in Dpd over 1 month of GH therapy were related to the changes in height velocity (HV) over 1 yr of therapy (r = 0.67; P < 0.05); the changes in Pyd after 1 month of GH treatment were related to the changes in HV at 6 months of GH treatment (r = 0.57; P < 0.05). All the other markers evaluated were not related to the HV changes in children with ISS. In children with GHD, the changes in Pyd and in Dpd after 1 month of GH treatment were positively related to the changes in HV after 12 months of therapy (r = 0.82; P < 0.05, and r = 0.82; P < 0.05, respectively). The changes in Pyd after 1 month were also related to the HV changes after 6 months of GH (r = 0.77; P < 0.05). Positive relationships between the HV after 6 months of GH and the increases of PIIINP (r = 0.80; P < 0.05) and osteocalcin (r = 0.77; P < 0.05) after 3 months of GH therapy were observed. All patients showed urinary Dpd and Pyd excretions in the normal range. In patients with ISS, Pyd (P < 0.05), Dpd (P < 0.05), osteocalcin (P < 0.01), PIIINP (P < 0.01), and alkaline phosphatase (P < 0.01) increased longitudinally during the GH treatment and the increments reached a maximum after 3-6 months of therapy. Patients with GHD showed an increase of the same markers but the increases occurred earlier, after 1 month of GH therapy. The collagen cross-links, Pyd and Dpd, could be helpful early markers in predicting the responsiveness to GH therapy in children with ISS and with GHD. GH treatment stimulates bone and collagen metabolism.

Biochemical Measurements of Bone Turnover in Children and Adolescents

“…In these children, OC, BAP and PICP concentrations are either normal or lower than in age-matched controls (Fig. 6) [12,13,26,41,83,115]. However, lower OC concentration in children with short stature was observed until the age of 10 years but not thereafter [18].…”

“…During GH treatment, increase of metabolic markers correlates with height velocity and predicts subsequent height gain. Predictive strength is greater for Pyr, DPyr, ICTP, PICP and BAP [12,26,27,41,43,54,115], whereas that of OC or total AP is weaker or nonsignificant [13,26,36,54]. Correlations of bone marker levels with areal BMD do not establish whether markers correlate with bone mineral accrual or with bone growth.…”

Serum procollagen type 1 amino-terminal propeptide (P1NP) as an early predictor of the growth response to growth hormone treatment: Comparison of intrauterine growth retardation and idiopathic short stature

“…Biochemical measurements of bone turnover may therefore be helpful in studies on the pathophysiology of defects of skeletal metabolism and growth. The markers of bone formation and resorption are either low [28] or normal [29] at baseline in patients with GHD and increase significantly on GH treatment [3][4][5][6][7]29]. The plasma concentrations of bone-specific alkaline phosphatase (ALP), osteocalcine and the carboxy-terminal propeptide of type 1 collagen (PICP), markers of bone formation, are also low in non-GHD patients such as those with hypophosphatemic rickets and osteogenosis imperfecta, and are increased significantly by GH [30,31].…”

“…Some studies have evaluated these markers in growth hormone (GH)-deficient (GHD) children treated with GH. As these concentrations increased significantly, with a strong correlation between them and the changes in growth rate, it was suggested that markers of bone formation and/or bone resorption should be assessed 3 months after the start of GH therapy in GHD children, as a prediction of the growth response to GH treatment [3][4][5][6][7]. This may be useful, as the response cannot be assayed by measuring insulin-like growth factor I (IGF I) [8,9].…”

“…The factors influencing these variations are still unclear. The effect of GH treatment on the bone turnover of ISS children has been evaluated in only 6 studies, to our knowledge [4,[10][11][12][13][14], whereas there are no reported data on the effects of GH on the bone turnover of children with IUGR.…”