Bone Markers and Bone Mineral Density during Growth Hormone Treatment in Children with Growth Hormone Deficiency

Abstract

Growth hormone (GH) has a positive impact on muscle mass, growth and bone formation. It is known to interact with the bone-forming unit, with well-documented increases in markers of bone formation and bone resorption within weeks of the start of GH therapy. These changes relate significantly to short-term growth rate, but it is not evident that they predict long-term response to GH therapy. The consequences of GH deficiency (GHD) and GH replacement therapy on bone mineral density (BMD) have been difficult to interpret in children because of the dependency of areal BMD on height and weight. Some studies have tried to overcome this problem by calculating volumetric BMD, but results are conflicting. The attainment of a normal peak bone mass in an individual is considered important for the future prevention of osteoporosis. From the limited data available, it appears difficult to normalize bone mass totally in GH-deficient individuals, despite GH treatment for long periods. Studies to date examining the interaction between GH and bone have included only small numbers of individuals, making it difficult to interpret the study findings. It is hoped that these issues can be clarified in future research by the direct measurement of bone density (using quantitative computer tomography). Mineralization is only one facet of bone strength, however; other important components (e.g. bone structure and geometry) should be addressed in future paediatric studies. Future studies could also address the importance of the degree of GHD in childhood; how GH dose and insulin-like growth factor-I levels achieved during therapy relate to the final outcome; whether or not the continuation of GH therapy after the attainment of final height may further enhance bone mass; whether the timing and dose of other treatments (e.g. sex hormone replacement therapy) are critical to the outcome; and whether GHD in childhood is associated with an increased risk of fracture.

Short‐term changes in bone formation markers following growth hormone (GH) treatment in short prepubertal children with a broad range of GH secretion

“…This is the first study, to our knowledge, to investigate all three bone formation markers for which assays are available (PINP, BALP and osteocalcin) in children receiving GH treatment. The results from this cohort of short prepubertal children demonstrate and confirm previous studies, that these circulating bone formation markers, as analysed with a fully automated immunoassay system, increased on a short‐term basis during GH treatment. The GH‐mediated short‐term changes demonstrated for PINP, BALP and osteocalcin correlated with the growth response during GH treatment, thus reflecting the cellular response of GH.…”

“…Previous studies have shown that bone formation and resorption markers were either low or normal at baseline prior to GH treatment in children with GH deficiency . Strong correlations have also been found between increased bone marker levels and changes in growth rate, and it has been suggested that bone markers should be assessed 3 months after the initiation of GH treatment as they may explain variations in growth response …”

Skeletal effects of growth hormone and insulin-like growth factor-I therapy

“…This effect can be seen both in mice, in which GH overexpression increases BMD (Saban et al, 1996) and lit/lit GH-deficient or GHR knockout mice have poor peak BMD (Mohan et al, 2003; Sims et al, 2000; Sjögren et al, 2000), and in humans, in which childhood onset GH deficiency leads to decreased BMD and increased fracture risk in adulthood (de Boer et al, 1994; Holmes et al, 1994; Rosén et al, 1997; Simpson et al, 2002). GH supplementation in normal human subjects increases levels of serum bone formation markers (Holloway et al, 1994), and treatment of both animals and patients deficient in GH significantly increases their reduced BMD (Bouillon and Prodonova, 2000; Cowell et al, 2000; Simpson et al, 2002). Many of these effects of GH, however, are dependent upon age and growth period; GH deficiency leads to a 4-fold greater reduction in BMD during postpubertal growth than during prepubertal growth (Mohan et al, 2003), an effect which may be explained in part by the failure of GH to appropriately activate hepatic gene transcription in prepubertal rats (Choi and Waxman, 2000).…”

Morphological Determinants of Femoral Strength in Growth Hormone-Deficient Transgenic Growth-Retarded (Tgr) Rats

“…Childhood GHD, which is often diagnosed with less stringent criteria, (5–7) is also associated with impaired bone mineral accumulation and turnover, (8,9) and if uncorrected through puberty, may result in reduced peak bone mass in young adult life (10,11) . The extent to which failure to achieve adequate peak bone mass in late adolescence and early adulthood leads to an increased risk of subsequent osteoporosis and bone fracture remains unclear (12) …”