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.

Evidence that Sensitivity to Growth Hormone (GH) Is Growth Period and Tissue Type Dependent: Studies in GH-Deficient lit/lit Mice

“…Consistent with the human clinical data using GH-deficient subjects (7,8,(11)(12)(13)(14)(15)37), we have found that GHdeficient lit/lit mice exhibit a significant decrease in BMD and that treatment of these mice with GH caused a significant increase in BMD. In terms of the magnitude of BMD change caused by GH treatment, it is remarkable that 2 wk of GH treatment increased total body BMD by as much as 15% when it was administered between d 42-55 in lit/lit mice.…”

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].…”

“…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]. Several studies have found an early increases (3-6 months) in markers of both bone formation and resorption in the patients treated with GH for GHD; and these increases were correlated with the increase in growth rate [3][4][5][6][7]. Tobiume et al [3] found a strong link between the percentage increase in bone-specific ALP at 3 months and the change in height velocity SD after one year of treatment.…”

“…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].…”

Bone development during GH and GnRH analog treatment

“…In a randomized clinical trial, treatment with GnRH agonist was used to increase adult height in adolescents with short stature and normally timed puberty (39). In this study, the principal adverse event in the GnRH-agonist group was reduced lumbosacral BMD during treatment and inadequate catch-up accretion of bone mineral after treatment (mean lumbar vertebral BMD at the time adult height was achieved, 1.6^1.2 S.D.…”