The use of GH in OI has two main reasons: the first is to stimulate bone metabolism increasing in particular bone apposition, and the second is to increase statural growth. But GH has also a positive action on collagen metabolism in particular.

Experimental data show a positive action of GH on collagen metabolism: it stimulates the expression in osteoblast cultures of IGF-I and IGFBP-3, which in turn regulate the synthesis of type I collagen, and osteoblasts from various species respond to IGF by accelerating the proliferation and increasing DNA and collagen synthesis. Moreover, GH-somatomedin axis activity has been studied in children with OI, and a hypoactivity (with not a true GH deficit) of this axis was found in about one half of patients studied (J Clin Endocrinol Metab 1993;76:251-6) while serum concentrations of IGF-I were found mostly in the low normal physiological range.

The criteria to evaluate the efficacy of GH therapy are: the fracture index per year, growth velocity, action on bone markers metabolism, bone histomorphometry and bone density. All this indexes have the tendency to ameliorate at the time of puberty in OI, and this fact is a factor that may confound the possible positive results of a therapeutic trial.

One of the first attempts to treat OI with GH were done more than 20 years ago by Kruse and Kuhlencordt who treated two severe patients and found an increase of periosteal new bone formation and intracortical bone resorption by histo-morphometry with enhanced relative osteoblastic activity.

After this work, there are in literature no experiences until the preliminary results in a limited number of patients treated with GH or clonidine (a pituitary GH secretagogue) in 1993 by Marini et al.(J Clin Endocrinol Metab 1993;76:251-6). Continuing the GH experience, this group treated 20 patients with OI type III and IV, aged 5-12 years after a complete endocrine evaluation (Utrecht 1996). During treatment (initial dose of 0.2 mg/kg/week in 6 divided doses, doubled after 6 months) there where no change in the fracture rate, no significant changes of bone density and a significant increase in IGF-I and IGFBP-3 levels during treatment for all the treated group. While type III patients did not show a response in terms of growth and no trends in bone formation or resorption parameters, a growth response was found in 2/3 of Type IV OI patients, with significant increase of Oc and PICP levels and of bone histomorphometric parameters for this responder group. Moreover the results of pre-treatment endocrine evaluation are not predictive of the responder group.

Sillence and colleagues (Utrecht 1996) treated 15 prepubertal OI type I and IV patients, aged 7.6-13.9 years (0.2 mg/kg/week in 6 divided doses for 2 years), with a small decrease in annual fracture, also in patients who remained prepubertal at completion. All subjects achieved an increase in their height SDs, more pronounced in type I patients (+ 0.63 in type I vs + 0.55 in type IV). At the end of treatment, total body and lumbar (L2-L4) BMD mean Z scores decreased, as in untreated patients, but increased in absolute values. As a secondary effect, all subjects reported increased vigour and mobility during the study. The positive height growth, the increase in skeletal volume and BMD and subsequent reduction in fracture frequency would appear to confer significant therapeutic benefit. No correlations were seen between procollagen abnormalities and response or complications from growth hormone therapy.

Our Group evaluated the efficacy of one year of GH treatment (0.2 mg/kg/week in 6 divided doses) in patients affected by type I OI with an ascertained quantitative defect in type I collagen synthesis (J Pediatr 1996; 129: 432-439). During GH treatment the fracture risk did not change, markers of bone apposition (i.e. Oc and PICP levels) and bone density increased significantly and height velocity was significantly higher in treated patients in comparison to the pretreatment period and to the untreated group. We had an improvement in the well-being state, muscular performances and motor abilities. Body composition, as measured by DXA, changed during treatment, with an increase in lean body mass respect to fat mass.

From these results we decided to continue GH experience with a second group of patients with OI type I (n=14) and also a few OI type III (n=7) and IV (n=1) patients who asked treatment. In these patients (n=22) we evaluated GH IGF-I axis and GH secretion by two functional tests: arginine and clonidine. We found an insufficient growth hormone response (peak < 8 ng/ml) and low IGF-I levels in 6 patients (36 %) with type I, 2 (29 %) with type III and in the patient with type IV OI. We treated only patients with growth hormone deficient response, using a higher dosage of GH (0.4 mg/kg/week in 6 divided doses). In patients with type I OI we repeated the same good results of the preceeding study (significant increase in bone density, height velocity and lean body mass, with no change of the fracture risk) after 2 years of treatment, while in the 2 type III patients we had no positive influence on bone markers and bone density measurements in the same period. The patient with type IV OI experienced a worsening of pre-exixting vertebral deformities and back pain, stopping treatment after 6 months.

From all these results, we can conclude that GH, is a useful therapy in moderate forms of OI (type I-IV), where it has demonstrated a positive action on bone turnover, bone mineral content and height velocity rate without increasing the fracture risk in the short term period. However, patients during GH therapy have an improvement of the well-being state, muscular performances and motor abilities and this fact increases physical activity and consequently fracture risk in some cases. Patients with preexisting scoliosis or bone deformity must be treated with particular caution.

The selection of patients for GH treatment, on the basis of biochemical and molecular studies is a key factor. In fact, in the case of a mutation causing structural alterations in the type I collagen molecule, leading to secretion of this molecule to the matrix, GH treatment is, in our opinion, inadvisable.

In the next future GH will be probably associated in pharmacologic (0.4 mg/kg/week) and not substitutive doses with other factors decreasing bone resorption (i.e bisphosphonate) or stimulating bone formation. However, protocols using the association GH-bisphosphonate, also in cyclic regimen, are at the moment only at the initial state.


Reference: Proceedings of the 7th International Conference on Osteogenesis Imperfecta. Montreal, Canada, 1999.