Several studies in humans have also demonstrated the effects of GH on bone (Table 9.1). In a study examining the effects of rhGH on circulating levels of several catabolic hormones, Fleming et al. in 1992 demonstrated that 0.2 mg/kg/day of rhGH given to six children with large burns (>40 % TBSA) significantly elevated IGF-1 levels [22]. The hypothesis that rhGH improves the impaired bone turnover state associated with severe burns was derived from these observations and from several studies including those in which rhGH was administered to children with GH deficiency [23]. These studies demonstrated that rhGH increases the levels of IGF-1 [24], BMD [25], osteocalcin [24–26], and type I procollagen propeptide (PICP) [25].

In 1995, Klein et al. studied bone histomorphometry and biochemistry following large severe burns (>42 % TBSA) in 24 pediatric patients. Five of these patients received 0.2 mg/kg/day of subcutaneous rhGH to improve wound healing during their in-patient treatment period [7]. No histomorphometric or biochemical differences were seen between the treatment and control groups. However, this study’s small sample size and lack of randomization limit its applicability at a pediatric population level. Therefore, better designed prospective studies with larger sample sizes were performed to further investigate the effect of GH on bone.

In 1998, Klein et al. performed the first study testing the hypothesis that rhGH improves bone turnover in burned children [23]. In this randomized double-blind controlled trial, 19 children with large burns (>40 % TBSA) were treated with either subcutaneous rhGH (0.2 mg/kg/day, n = 10) or saline (n = 9) from admission to wound healing completion. Blood levels of IGF-1, IGFBP-3, IGFBP-4, IGFBP-5, osteocalcin, and serum procollagen type I C-terminal peptide (PICP) were measured on admission and on completion of wound healing. These measures were then correlated with lumbar BMD. On completion of wound healing, IGF-1 and IGFBP-3 levels were significantly higher in the rhGH-treated group. IGFBP-4 (an inhibitor of the anabolic effects of GH on bone and other tissues) was raised on admission and continued to increase beyond the normal range, regardless of rhGH administration. Serum concentrations of IGFBP-5 (a binding protein that may link IGF-1 to bone), osteocalcin, and PICP did not differ significantly between the study groups. These findings suggest that short-term acute treatment with rhGH does not increase bone formation, but this may have been secondary to the short study treatment period. There is also a possibility that increased keratinocyte production of IGFBP-4 during wound healing may have inhibited IGF-1. These findings necessitated larger-scale studies with longer rhGH treatment periods.

Hart et al. randomized 72 severely burned children (>40 % TBSA) to receive either rhGH or saline in their double-blinded study [27]. Treatment with rhGH (0.05 mg/kg) or control was continued for 1 year post-burn. Only 40 children completed the study: 19 within the treatment and 21 in the control groups, respectively. Height, lean body mass (LBM), BMC, and serum levels of GH, IGF-1, and IGFBP-4 and -5, among other markers, were determined at discharge, 6, 9, and 12 months post-burn. Children treated with rhGH demonstrated a significant increase in height compared to controls at 12 months (1.4 ± 1.5 cm versus 7.9 ± 2.1 cm) (p < 0.05). Both groups showed bone loss for the first 6 months. However, the control group demonstrated no further change in BMC, whereas the rhGH-treated children continued to gain BMC. The difference between the BMC of both groups neared significance at 6 months (p = 0.06) and reached significance at the 12-month time point (p < 0.05). Unlike Klein et al.’s findings [23], IGF-1, IGFBP-4, and IGFBP-5 levels did not differ between groups. However, there was concordance with their finding that IGFBP-4 levels remained persistently elevated throughout the trial. Osteocalcin levels remained low despite rhGH therapy, signifying low or no bone formation. Hart’s study demonstrated that low dose rhGH for 1 year post-burn increased linear growth, LBM, and BMC. Although no rise in IGF-1 was shown, this finding is not enough to disprove the suggested IGF-1-mediated mechanism of GH [27]. LBM increased approximately 3 months before BMC—these results do not exclude the possibility that BMC rises were stimulated by skeletal loading. Although a limitation of this study was the large drop-out rate, the numbers of children completing the trial were similar for both groups, reducing bias [27].

A criticism of the studies by Klein, Hart, and their respective teams [23, 27] is that they neglected to assess whether GH resulted in functional improvements. Concerns were also raised about the possibility of the suppression of endogenous GH production secondary to extended rhGH treatment, resulting in a rebound phenomenon upon cessation of treatment. Przkora et al. addressed these concerns in a study to investigate functional improvements up to 2 years post-burn [28]. In this double-blinded study, children were randomized to receive daily doses of either rhGH (0.05 mg/kg) (n = 19) or control (n = 25) for 12 months from discharge. Follow-up was performed at 6, 12, 18, and 24 months post-burn. The following bone-related measurements were taken at each follow-up appointment: child height, LBM, BMC, GH, IGFBP-3, IGF-1, and osteocalcin (among other serum markers). Strength testing of children aged ≥7 years was also conducted on their dominant leg extensors. The percentage change in height from baseline was significantly higher in the rhGH-treated group from 12 months up to 24 months post-burn. Likewise, BMC in rhGH-treated patients continued to improve with a steeper gradient than in controls and was significantly greater from 12 to 24 months post-burn. Strength was significantly greater in the treated group at 12 months, but this effect did not persist after drug discontinuation. Although GH, IGF-1, and IGFBP-3 were all significantly increased in the treated group during the first 12 months, only IGF-1 was persistently elevated after the discontinuation of treatment (via mechanisms not yet elucidated). Osteocalcin was elevated 18 months post-burn in the treated group. No adverse effects were recorded. Up to 1 year after the discontinuation of rhGH treatment, no rebound phenomenon was observed.

Przkora’s study provided the first data on the functional improvements from rhGH treatment, including improved muscle strength and cardiac function. The rises in IGF-1 and IGFBP-3 following rhGH treatment are supportive of the hypothesis that GH acts through the IGF-1 complex. However, several study limitations were raised. There was no “healthy” control group with which expected development in the absence of morbidity could be compared. This study, like that by Hart et al., also suffered from a high drop-out rate. A possible explanation for this is that 70 % of the children treated at Shriners Hospital for Children (Galveston, USA), where both studies were performed, came from Mexico and this patient population does not tend to remain in the USA for the extended time period of the trial.

The positive effects of GH on bone health were further confirmed in a 2009 study by Branski et al. [29]. Burned children (>40 % TBSA) were randomized to receive either subcutaneous placebo (n = 94) or rhGH in doses of 0.05, 0.1, or 0.2 mg/kg (n = 101) for up to 12 months post-burn. The same bone-related markers described above were measured at discharge, 6, 9, 12, 18, and 24 months post-burn. The heights of patients receiving rhGH were significantly greater than controls from 9 to 24 months and approached normalcy (50th percentile) from 12 to 24 months. rhGH doses of 0.1 mg/kg led to the most sustained height gains whereas 0.2 mg/kg did not lead to any significant height improvement. As might be expected, 0.2 mg/kg doses led to the greatest increases in LBM, although this finding was only significantly better than the control group within the period of active treatment. Overall, BMC values did not differ significantly between the groups. Surprisingly, only the lower dose of 0.05 mg/kg led to significant differences in BMC in the two groups (12–24 months). Serum IGF-1 levels were only significantly higher in the entire rhGH group from 6 to 12 months post-burn. Only rhGH doses of 0.2 mg/kg resulted in significantly raised osteocalcin levels. Hence, no significant differences in osteocalcin levels were observed between the controls and the entire rhGH group. Two cases of hypercalcemia following 0.2 mg/kg doses of rhGH and one case of hyperglycaemia were the only adverse effects recorded. These results suggest that some effects of GH may be dose-related. For example, the decrease in BMC with 0.2 mg/kg/day rhGH was thought to be due to sustained suppression of parathyroid hormone and high bone turnover (as indicated by a raised osteocalcin) in this group. The authors therefore suggested using 0.2 mg/kg rhGH in the acute phase post-burn to maximize gains in LBM and 0.1 mg/kg rhGH for at least 1 year post-burn to maximize gains in other bone health indices.

These randomized placebo-controlled clinical trials provide high level evidence (level 1 on the American Society of Plastic Surgeons Evidence Rating Scale for Therapeutic Studies) [30] of the efficacy and safety of rhGH in improving bone health. Although this chapter has focused solely on bone health indices, GH has myriad other benefits to burned patients. These include improved cardiac function, improved muscle protein kinetics, maintained muscular growth, improved wound healing, and improved resting energy expenditure, denoting a less heightened metabolic state [31]. Considering the wide range of possible side effects of GH in children [32], only minor, easily correctible adverse affects were seen. Despite the apparent positive safety profile of rhGH, there remain concerns following recent trials in adults which demonstrated significantly higher mortality rates (up to 44 %) compared with controls when administered to adult ICU patients [33]. In addition, GH is administered subcutaneously, potentially reducing compliance. These issues, combined with rhGH treatment costs of approximately $18,000 per patient in the USA, have made alternative anabolic agents desirable.

Testosterone levels fall below baseline from approximately 60 days post-burn up to 3 years, suggesting the need for an anabolic replacement and/or augmentation [34, 35]. Animal models have supported the rationale for androgen supplementation. In 2000, Erben et al. showed that androgen-deficient orchidectomized rats suffered substantial global loss of trabecular bone and sustained increases in bone turnover [36]. Other studies have corroborated these results. Short-term androgen deficiency caused significant increases in markers of bone turnover in aged male rats [37]. Several androgens including testosterone and 5 alpha-dihydrotestosterone effectively prevented this rise in bone turnover.