Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen synthesis

doi:10.1016/S0022-3476(96)70077-X

The Journal of Pediatrics

Volume 129, Issue 3, September 1996, Pages 432-439

https://doi.org/10.1016/S0022-3476(96)70077-X Get rights and content

Abstract

OBJECTIVES: We studied growth rate, bone density, and bone metabolism in patients affected by type I osteogenesis imperfecta (OI) with quantitative defect in type I collagen synthesis during treatment with human growth hormone (hGH), being aware of its collagen-stimulating synthesis activity in vitro. STUDY DESIGN: Fourteen patients (6 boys; ages 4.8 to 10.8 years) were studied. Any structural alteration in the collagen chains was excluded, and reduced production of structurally normal type I collagen (increase in type III/type I collagen; reduction in the messenger ribonucleic acid α1[I]/α2[I] ratio) was demonstrated. The patients were divided into two groups comparable in sex, age, height, and clinical severity of OI; seven patients (three boys) were treated for 12 months with hGH at a dosage of 0.2 mg/kg per week (0.6 IU/kg per week), in six injections subcutaneously, and seven were followed as control subjects. Auxologic data were measured every 3 months, and bone age was determined at the start, after 1 year of treatment, and 1 year after its completion. Every 3 months, serum insulin-like growth factor type I, osteocalcin, carboxyterminal propeptide of type I procollagen, alkaline phosphatase, calcium, and phosphorus levels and urinary hydroxyproline and calcium levels were determined. Bone mass measurements were carried out at the start of the study in all patients and repeated after 12 months in treated patients at the lumbar spine by dual-energy x-ray absorptiometry and by anteroposterior (second, third, and fourth lumbar vertebrae) and lateral (third lumbar vertebra) scan. Results were expressed as areal (anteroposterior and lateral) bone density (in milligrams per square centimeter) and as calculated true density (in milligrams per cubic centimeter). RESULTS: After 12 months, linear growth velocity in treated patients increased significantly in comparison with the pretreatment period (from 3.57 ± 0.55 to 6.04 ± 0.69 cm/yr; p <0.05) and with the untreated group (p <0.05). Bone age did not advance faster than chronologic age. The fracture index per year was low before treatment, and during therapy no patient had any fractures. Serum osteocalcin levels were statistically lower than in control subjects before treatment and increased significantly after 12 months (3.3 ± 1.0 vs 2.1 ± 0.9 nmol/L; p <0.05). Serum levels of carboxyterminal propeptide of type I procollagen were significantly lower than normal values before treatment (164.6 ± 46.7 vs 310.3 ± 97.6 ng/ml; p <0.05) and rose, but not significantly, during and after treatment. Before therapy, patients with OI had significantly lower lumbar anteroposterior, lateral, and calculated true bone density than the normal population of the same sex compared for both age and height. After hGH treatment, bone density increased significantly in the lumbar spine, in anteroposterior and lateral scans (+2.6% ± 2.5% and +9.8% ± 14.0%, respectively; p <0.05), and in calculated true bone density (+11.4% ± 6.7%; p <0.05). CONCLUSIONS: From our results, we conclude that hGH treatment in moderate OI does not increase the fracture risk in treated patients in the short term, significantly increases the rate of linear growth velocity, and increases bone turnover and mineral content in trabecular bone at the lumbar spine. (J PEDIATR 1996;129:432-9)

Section snippets

Patients

Fourteen patients (6 boys, 8 girls; age range, 4.8 to 10.8 years) affected by type I OI took part in the study. The patients were some of a greater number of patients (N = 130) followed up by the Italian Multicentric OI Study Group. Informed consent was obtained from the parents of each patient before the start of the study protocol.

In the probands suitable for the hGH treatment from a clinical point of view, the collagen synthesis of dermal fibroblasts was studied in vitro to rule out the

RESULTS

Table II shows clinical data of patients before, during, and after treatment. All patients remained prepubertal during the treatment period. During therapy none of the treated patients presented evidence of fracture or inexplicable pain. No patient had any clinical evidence of kyphoscoliosis.

After 12 months, linear growth velocity in our treated patients increased significantly compared with the pretreatment period (from 3.57 ± 0.55 to 6.04 ± 0.69 cm/yr; p <0.05) and compared with the untreated

DISCUSSION

OI is a heterogeneous syndrome from genetic, biochemical, and clinical points of view.¹ In our patients we excluded the presence of a structural defect in collagen chains and demonstrated an increase in the type III/type I collagen ratio and a reduction in the α1(I)/α2(I) mRNA ratio, thus confirming the reduced production of structurally normal type I collagen.3, 12

In these cases, we considered the possibility of hGH treatment to increase collagen synthesis, having observed its stimulating

Acknowledgements

We thank the Italian Association for Osteogenesis Imperfecta for encouragement and support (Telethon Italia, grant E.013). Dr. Franco Stanzial is also acknowledged for his participation at the initial stage of the project.

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^☆: From Clinica Pediatrica, Istituto di Semeiotica e Nefrologia Medica, Istituto di Biologia e Genetica, Università di Verona, Verona, Italy, and Centro per lo Studio delle Malattie del Tessuto Connettivo, Dipartimento di Biochimica, Università di Pavia, Pavia, Italy

^☆☆: Supported in part by the Italian Association for Osteogenesis Imperfects (Telethon Italia, grant E.013).

^★: Reprint requests: Franco Antoniazzi, MD, Clinica Pediatrica, Università di Verona, Policlinico Borgo Roma, I-37134 Verona, Italy.

^★★: 0022-3476/96/$5.00 + 0 9/21/75042

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Growth hormone treatment in osteogenesis imperfecta with quantitative defect of type I collagen synthesis☆,☆☆,★,★★

Abstract

Section snippets

Patients

RESULTS

DISCUSSION

Acknowledgements

Matrix

Adv Pediatr

J Pediatr

J Pediatr

Bone

J Pediatr

J Pediatr

Bone [Bone and Mineral

Osteogenesis imperfecta

Genetic heterogeneity in osteogenesis imperfecta

J Med Genet

Osteogenesis imperfecta type I: molecular heterogeneity for COL1A1 null alleles of type I collagen

Am J Hum Genet

Increased activity of insulin-like growth factor (IGF) in osteoblastic cells in the presence of growth hormone (GH): positive correlation with the presence of the GH-induced IGF-binding protein BP-3

Endocrinology

Regulatory effects of insulin-like growth factors I and II on bone collagen synthesis in rat calvarial cultures

Endocrinology

The growth hormone and somatomedin axis in short children with osteogenesis imperfecta

J Clin Endocrinol Metab

A base substitution at IVS-19 3’-end splice junction causes exon 20 skipping in proα2(I) collagen mRNA and produces mild osteogenesis imperfecta

Hum Genet

Defective splicing of mRNA from one COL1A1 allele of type I collagen in nondeforming (type I) osteogenesis imperfecta

J Clin Invest

Nonoperative treatment of osteogenesis imperfecta: orthotic and mobility management

Clin Orth Rel Res

Radiologic atlas of skeletal development of the hand and wrist