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Original Article |
Departments of Medical Sciences (P.G., S.L.), Surgical Sciences (H.M.), and Radiology (M.P.-M.), University Hospital, S-75185 Uppsala; and Department of Endocrinology (A.G.N.), Sahlgrenska University Hospital, SE-41345 Göteborg, Sweden
Address all correspondence and requests for reprints to: Peter Gillberg, M.D., Ph.D., Division of Endocrinology, Department of Internal Medicine, Örebro University Hospital, SE-701 85 Örebro, Sweden. E-mail: peter.gillberg{at}medsci.uu.se.
Abstract
We have investigated the effects of GH treatment on bone turnover, bone size, bone mineral density (BMD), and bone mineral content (BMC) in 29 men, 27–62 yr old, with idiopathic osteoporosis. The patients were randomly assigned to treatment with GH, either as continuous treatment with daily injections of 0.4 mg GH/d (group A, n = 14) or as intermittent treatment with 0.8 mg GH/d for 14 d every 3 months (group B, n = 15). All patients were treated with GH for 24 months, with a follow-up period of 12 months, and also received 500 mg calcium and 400 U vitamin D3 daily during all 36 months. Fasting morning urine and serum samples were obtained for assay of IGF-I, bone markers, and routine laboratory tests at baseline, after 1, 12, 24, and 36 months. Body composition, BMD, and BMC were determined by dual-energy x-ray absorptiometry at baseline and every 6 months. After 2 yr, there was an increase in BMD in lumbar spine (by 4.1%) in group A, and in total body (by 2.6%) in group A and (by 2.7%) in group B. BMC of the total body and lean body mass increased, whereas fat mass decreased in both treatment groups. After 36 months, the BMD and BMC in lumbar spine and total body had increased further in both groups. We conclude that 2 yr of intermittent or continuous treatment with GH in men with idiopathic osteoporosis results in an increase in BMD and BMC that is sustained for at least 1 yr post treatment.
GH HAS AN ANABOLIC effect on bone, in vitro (1) as well as in vivo (2). GH excess, as in acromegaly, has been shown to result in increased bone turnover (3) and bone mineral density (BMD) (4). GH deficiency (GHD) of childhood-onset (5) and of adult-onset (6) is associated with reduced BMD. It has been shown that GH treatment of such patients activates bone remodeling and results in increased BMD (7, 8). Serum levels of the GH-dependent growth factors IGF-I and IGF-binding protein 3 are reduced but positively correlated to BMD in men with idiopathic osteoporosis (9, 10, 11). Moreover, a positive correlation between serum IGF-I levels and BMD has been noted in healthy men (12, 13).
GH and IGF-I have been suggested as possible anabolic agents in the treatment of osteoporosis (14). GH treatment for 1 yr has been shown to stimulate bone turnover in elderly osteoporotic women (15, 16), and short-term GH and IGF-I treatment increases bone formation and resorption markers in elderly healthy women (17) as well as in men with idiopathic osteoporosis (18, 19). However, none of these studies have demonstrated any significant effect of GH or IGF-I treatment on BMD.
The experiences from patients with GHD suggest that continuous GH treatment results in increased BMD, but it has also been shown that stimulation of bone metabolism with GH for as short a time period as 7 d results in an enhancement of bone formation markers for several weeks thereafter (20). Experimental studies on bone in animals have also shown that GH increases cortical thickness and has the potential to increase bone size (21, 22). In this present study, we therefore have investigated the effects of continuous and intermittent GH treatment for 2 yr on bone turnover, BMD, and bone size in men with idiopathic osteoporosis.
Subjects and Methods
Study design
A total of 29 men, 27–62 yr old, with idiopathic osteoporosis (i.e. without any clinical or laboratory sign of other causes of osteoporosis) were investigated at the Osteoporosis Research Center of the Department of Medical Sciences, University Hospital, Uppsala, Sweden. These patients had been referred to the osteoporosis unit because of suspected osteoporosis. Bone mineralization defects were excluded by bone biopsies after tetracycline labeling, and osteoporosis was defined as BMD in L2–L4 or in the femoral neck of no more than -2.5 SD of the mean BMD in a young male reference population and/or at least 1 osteoporotic fracture.
The patients were randomly assigned to treatment with recombinant human GH (Genotropin; Pharmacia \|[amp ]\| Upjohn, Inc., Uppsala, Sweden), 1.2 U (0.4 mg) daily (group A) or 2.4 U (0.8 mg) daily for 14 d every third month (group B) given as sc injections at bedtime for 24 months, with a follow-up period of 12 months after cessation of the GH treatment. All patients received daily supplementation with 500 mg calcium and 400 U vitamin D3 during all 36 months.
At baseline, all investigations were performed on two consecutive days, with follow-up visits after 1, 6, 12, 18, 24, 30, and 36 months. Fasting morning urine and serum samples were obtained for assays of IGF-I, markers for bone turnover, and routine laboratory tests. In group B, laboratory analyses were performed before the next treatment period, except at the 12-month visit, when samples were assessed also after the 2-wk treatment. BMD, body composition, and body weight (BW) were determined by dual-energy x-ray absorptiometry (DXA), with two measurements at baseline and then every 6 months. Lateral x-rays of the thoracic and lumbar spine were taken at baseline and after 24 months, to record incident fractures during the study. Radiograms of the right hand were obtained at baseline and after 24 months, to evaluate changes in cortical thickness of the second metacarpal.
Eighteen of the patients had previously sustained clinically diagnosed fractures. These consisted of 17 patients with vertebral fractures and 1 patient with bilateral hip fractures. According to the spine x-rays at baseline, 19 of the 29 patients had signs of 1 or more prevalent vertebral fractures. Thus, a total of 20 patients, 10 in each group, had suffered from osteoporotic fractures before study start. Any new fractures during the study were recorded at each follow-up visit.
Informed consent was given by all subjects after a thorough review of the study protocol, which was approved by the Ethical Committee of the Faculty of Medicine, University of Uppsala, and the Medical Products Agency, Uppsala, Sweden.
Laboratory analyses
IGF-I in serum was measured by an immunoradiometric assay after formic acid-ethanol extraction (Nichols Institute Diagnostics, San Juan Capistrano, CA). Osteocalcin was measured in serum by RIA using a commercial kit (CIS-Bio International, ORIS group, Gif-Sur-Yvette Cedex, France) with intra- and interassay coefficients of variation (CV) no more than 6.6%. Free deoxypyridinoline cross-links (DPD), expressed per mole creatinine in second void urine (DPD/Cr), were measured by a competitive ELISA (Pyrilin KS-D; Metra Biosystems, Mountain View, CA), where both the intra- and interassay CV were less than 5%.
Intact PTH in serum was determined by a sandwich radioimmunometric method (Nichols Institute Diagnostics) with a normal range of 12–55 ng/liter and intra- and interassay variations of 2.9% and 3.5%, respectively. Serum levels of 1,25-dihydroxy cholecalciferol (1,25 (OH)2 vit D3) were measured by Medilab (Täby, Sweden), using a competitive radioreceptor assay (INCSTAR Corp., Stillwater, MN) with intra- and interassay variations of 14.1 and 26%, respectively.
BMD and body composition
BMD (g/cm2) and bone mineral content (BMC, g) were determined by DXA of the total body, the lumbar spine (L2–L4), and the proximal femur, with DPX-L equipment (Lunar Corp., Madison, WI). All DXA scans were analyzed by the same investigator (H.M.). The "compare" feature in the software package was used for all lumbar spine measurements. The investigator who analyzed the DXA measurements was blinded for the different treatment regimes. All analyses were performed continuously; and, at the end of the study, all scans were reanalyzed for each individual.
Lean body mass (LBM), total body fat mass, and BW were obtained from the total body DXA measurements.
Mean values for BMD, BMC, and body composition were calculated from the duplicate measurements at baseline.
Radiography
Lateral spine x-rays of the thoracic and lumbar spine were performed as part of the clinical routine at baseline and after 2 yr. Vertebral fractures were diagnosed according to conventional clinical criteria.
The combined cortical thickness (CCT) of the second metacarpal bone of the right hand was calculated to evaluate any changes during the treatment period. Standardized conventional radiography was performed twice on each patient. The first examination was made before treatment, with follow-up 2 yr later, shortly after finishing treatment. The radiographs were performed with the right hand placed flat on the screen; and the same film-screen combination, the same x-ray room, and a film-focus-distance of 100 cm were used at each occasion. Two radiographs were taken at each occasion, with two prechosen exposures: 40 kV, 5 mA; and 40 kV, 10 mA. The reason for choosing two exposures was to get at least one well exposed image from each examination, independent of the patients bone quality. One film from each examination was evaluated, and the same exposure was chosen for analysis of both pre- and posttreatment examinations in each patient. The two images were then analyzed identically in a digitalization table, at the same time, by the same investigator (M.P.-M.), without knowledge of dates of examination.
The CCT was calculated by subtracting the diameter of the cancellous bone from the outer diameter measured at the midcarpal transverse axis of the second metacarpal bone, according to a method described previously (23). In our laboratory, the intraindividual CV of the midcarpal diameter measurements was 5.13%, and the interindividual CV of the CCT calculations was 12.9%.
Statistics
All statistics were performed using the software StatView version 4.5 from Abacus Concepts, Inc. (Berkeley, CA). Repeated-measures ANOVA was used to compare the treatment response within and between the two groups. Post hoc tests were made using the Fisher least-squares difference test to determine where statistical differences occurred. Within each group, Student’s two-tailed paired t test was used to assess changes over time. Simple regression analyses were performed to evaluate linear relationships between study parameters at baseline. Significance was accepted at P 
0.05.
Results
Baseline characteristics
Table 1
shows the baseline characteristics for the patients included in the study. There were no differences between the treatment groups in any aspect at baseline. At baseline, there was a positive correlation between the serum IGF-I level and the total body BMD (r = 0.39, P = 0.04), BMC (r = 0.56, P = 0.002) and LBM (r = 0.41, P = 0.03), and CCT of the second metacarpal (r = 0.39, P = 0.05).
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After 6 months of GH treatment, there was a reduction in lumbar spine BMD, by 3.0%, in group A (Fig. 1). After 24 months of treatment, there was an increase in BMD in lumbar spine by 4.1% in group A and in total body by 2.6% in group A and 2.7% in group B. There were increases in lumbar spine BMC in group A and in total body BMC in both groups after 24 months of active treatment (Fig. 2). There were no significant changes in femoral neck BMD or BMC.
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and 2). The BMD in lumbar spine had then increased by 4.6% in group A and by 6.6% in group B and in total body by 3.7% and 3.2% in the two groups, respectively, compared with baseline. Also BMC continued to increase up to 36 months, at which time the BMC in the lumbar spine and the total body had increased by 6.6% and 4.0%, respectively, in group A and by 8.3% and 3.3%, respectively, in group B, compared with baseline (Fig. 2). After 24 months of GH treatment, LBM was significantly increased in both study groups, compared with baseline. No further change in LBM was detected after cessation of GH treatment. In group B, LBM remained statistically significant from baseline at 36 months (Table 2).
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Effect of GH treatment on markers for bone remodeling and serum IGF-I
After 1 month of GH treatment, there was an increase in serum osteocalcin levels, which was also seen after 24 and 36 months in both treatment groups (Table 2). The urinary DPD/Cr excretion was also increased in both groups after 1 month; however, after 12 and 24 months, it was only significantly increased in group A. After 12 months, the DPD/Cr excretion was analyzed immediately after the GH treatment period in group B. DPD/Cr levels were then significantly increased (7.4 ± 1.8 mmol/mol), compared with baseline. At 36 months, the DPD/Cr excretion had returned to baseline levels in both groups (Table 2). The serum ALP levels and the urinary calcium excretion were not affected by the GH treatment in any of the groups (data not shown). There was no difference between the two groups in the effect of GH treatment, with regard to biochemical variables.
In group A, the serum levels of 1,25 (OH)2 vit D3 were increased throughout the study, compared with baseline. In group B, the increase in 1,25 (OH)2 vit D3 was significant only at 24 months (Table 2).
Serum IGF-I levels were elevated between 43% and 55% throughout the study in group A (Table 2). The IGF-I levels immediately after a treatment period in group B were measured after 12 months and were then increased by 60% (266 ± 92 µg/liter vs. 166 ± 23 µg/liter). At 36 months, the IGF-I levels were significantly reduced in both groups, compared with baseline (Table 2).
Radiology
There were no significant changes in CCT of the second metacarpal in any of the groups during the study (Table 2). According to the spine x-rays after 2 yr of GH treatment, no new vertebral compression fractures were detected.
Adverse events during the study
Most patients experienced mild and transient side effects of the GH treatment, presumably related to fluid retention. The GH dose had to be permanently reduced to 0.8 U (0.3 mg)/d in two patients in group A, after a short treatment period, because of swelling of the hands and headache. These side effects resolved after dose reduction. Three patients in group A withdrew from the study before 24 months: one patient, after 12 months, because of a spontaneous hip fracture; and two patients, after 12 and 18 months, respectively, because of personal reasons. One patient in group B, with intermittent treatment, was withdrawn from the study after only 6 months because of a myocardial infarction. This event occurred 2 months after the second 2-wk treatment period and was considered unrelated to the GH treatment.
Discussion
In this study, treatment of men with idiopathic osteoporosis with GH, at doses of 1.2 U (0.4 mg)/d continuously or 2.4 U (0.8 mg)/d for 2 wk every third month, had no positive effect on BMD in lumbar spine or total body for the first 12 months but was followed by an increase in BMD and BMC by 24 and 36 months. Only a few previous reports have been published in which osteoporotic patients have been treated with GH. Short-term GH treatment of postmenopausal women with spinal osteopenia or osteoporosis have been shown to activate bone remodeling, with increases in both bone formation and resorption markers (17, 24, 25). Considerably higher doses of GH were used than in the present study; but in both our study groups, there were signs of activated bone remodeling, according to the biochemical markers in serum and urine.
In two recent studies, elderly osteoporotic women were treated with GH for 1 yr (15, 16). They experienced the same lack of BMD response at the lumbar spine and total body as we found; in fact, a decrease in BMD in femoral neck was noted in the study by Sääf et al. (16), which also is in line with our findings of a reduction in lumbar spine BMD after 6 months. Sugimoto et al. (15) continued to observe the patients for 1 yr post treatment; and by that time, the BMD in lumbar spine and distal radius had increased significantly, compared with pretreatment levels. A similar further increase in BMD and BMC has been noted 12–18 months after discontinuation of GH replacement in adult GHD men (26, 27). This was also seen in our study, where the BMD in lumbar spine and total body continued to increase up to 12 months after cessation of GH treatment. Thus, these data, in combination with the findings of protracted effects of GH on serum osteocalcin levels, could support the theory that GH treatment initializes bone remodeling cycles with a relatively greater enhancement of bone formation, as indicated by bone histomorphometric analyzes performed on GHD men treated with GH for 1 yr (28).
The serum osteocalcin levels remained significantly increased also 1 yr post treatment in both groups, indicating a prolonged effect on serum osteocalcin levels and also possibly on bone formation. A similar prolonged effect, for 30–177 d post treatment in serum osteocalcin levels, has been noted in previous short-term studies of GH treatment of osteoporotic subjects (18, 24) and in healthy young men (20), and this provides a rationale for intermittent GH therapy. The effect of GH treatment on bone resorption markers seems to be more transient, according to the results of the present and previous studies (18, 24).
In an effort to combine GH as an activator of bone formation in sequence with calcitonin as an inhibitor of bone resorption, Gonelli et al. (29) used the concept of activate-depress-free-repeat and studied 30 postmenopausal women who were divided into 3 groups. One group received GH for 7 d, followed by calcitonin for 21 d, and then 61 d without treatment, with a total duration of 24 months. In the other 2 groups, either GH or calcitonin was exchanged for placebo. In this study, patients in the group that received GH alone showed a significant reduction in BMD in lumbar spine and femoral shaft. Aloia et al. (30) treated 14 women with postmenopausal osteoporosis, with either GH daily for 2 months followed by calcitonin for 3 months, or with only calcitonin given intermittently, with a total duration of treatment of 24 months in both groups. In the group receiving GH and calcitonin, there was an increase in total body calcium, whereas no change was noted in BMC in the forearm.
Holloway et al. (31) conducted a study in which 84 healthy osteopenic women, 60 yr old and over, were treated cyclically with injections of recombinant GH (mean dose, approximately 1.2 mg/d) or its placebo, for 7 d, followed by injections of salmon calcitonin (100 U/d) or its placebo, for 5 d, and thereafter, 44 d of supplemental calcium only. This was repeated for 12 cycles, resulting in a 24-month study. This resulted in significant increases in BMD in lumbar spine, by 2.7% in the group treated with GH and calcitonin and by 1.7% in the group treated with GH and placebo. BMD in total hip also increased significantly, by 1.3%, in both the group treated with GH and placebo and in the group treated with calcitonin and placebo. No significant changes in BMD were noted in the groups treated with placebo alone. This indicates that cyclic GH treatment of osteopenic women, with or without calcitonin, increases BMD at clinically relevant sites. The reason for not obtaining similar results in the studies by Gonelli et al. (29) and Aloia et al. (30) could be attributable to the relatively small sizes of the treatment groups in these studies.
In the present study, the intermittent administration of GH in group B was followed only by a free interval of 10 wk before the next treatment cycle, with no depression of bone resorption, and the dosage was much lower than that used previously. This resulted in a significant increase in BMD in total body after 2 yr, by 2.7%. Furthermore, in our study, all subjects were men, eugonadal, and relatively young, compared with the previously mentioned studies of postmenopausal women without estrogen replacement therapy (15, 16). However, in a recent study by Landin-Wilhelmsen et al. (32), postmenopausal women with ongoing estrogen therapy were treated with continuous daily injections of GH, 1.0 U (0.3 mg) or 2.5 U (0.8 mg) for 3 yr. This treatment resulted in an increase in BMC in femoral neck, lumbar spine, and total body of up to 14% in the group treated with 2.5 U (0.8 mg)/d at 4 yr, i.e. 1 yr post treatment. A gender difference in the skeletal response to GH has been described in GHD patients (33), with women being less GH responsive than men, but the mechanism remains unclear. We found increases in BMD in lumbar spine and total body in the men who were intermittently treated that were larger than those found by Holloway et al. (31). This could be attributable to a gender difference and to the fact that the patients in our study had a lower mean BMD T-score (SD score compared with young, healthy males) and were younger than the osteopenic women.
Previous studies on the effect of GH on BMD have been performed mainly in patients with GHD. In these trials, GH replacement resulted in an increase in BMD of between 3.4% and 6.7% in various locations of the skeleton, with treatment periods of between 18 and 45 months (8, 34, 35, 36). The annual increase in BMD during GH treatment in the studies of GHD patients varies between 1.2 and 5.4%/yr in the lumbar spine, and it seems evident that a treatment period of 18–24 months is needed before any beneficial effect on BMD can be detected (34, 37, 38). Similarly, continuous treatment of healthy elderly women (39) and men (40), as well as of osteoporotic patients (41), for up to 12 months have not shown any beneficial effects on BMD. In the present study, a reduction in BMD was seen in the lumbar spine in group A after 6 months of treatment. This may be caused by an initial increase in activation frequency of bone remodeling, with a resulting increase in remodeling space, therefore requiring longer treatment periods to elucidate any positive effects of GH treatment on BMD. It is of interest to note that this initial reduction in BMD was not seen in the intermittently treated group in our study. This could be beneficial in considering GH treatment of men with idiopathic osteoporosis, because it may not be safe to further reduce BMD in subjects who are already osteoporotic.
In this present study, we could not detect any significant changes in CCT in the second metacarpal during the GH treatment period. It is known from experimental animal studies that GH treatment increases cortical thickness (22), and this has also been shown by histomorphometry after 12 months of GH replacement in GHD adult men (28). In cross-sectional studies of middle-aged and elderly men, age- related decreases in CCT of the second metacarpal of 0.31%–0.33% per year have been demonstrated (42, 43); so at best, GH perhaps prevented the normal age-related decline in CCT.
Throughout the whole treatment period, there were persistent increases in LBM in both groups in our study. This is well in line with previous observations in GH replacement of GHD men (33) and in GH treatment of elderly men (44). The increased LBM and the increased serum IGF-I concentrations show the effectiveness of the GH administration in both groups. The dose used in the group with continuous treatment was slightly lower than that usually recommended in GHD adults (45, 46), whereas the dose in the intermittently treated group was in the range of what is usually needed in GH replacement.
One of the limitations of this study is the absence of a placebo-treated control group. Idiopathic osteoporosis in men is a relatively uncommon disease, and study subjects are scarce; and therefore, we conducted this trial as an open study, and all patients received active treatment. They were all treated with daily supplements of 500 mg calcium and 400 U vitamin D3 in addition to GH. However, the increases in BMD that were seen in the present study are of greater magnitude than that reported from treatment of elderly men with calcium and vitamin D alone (47), or in male placebo groups treated with calcium and vitamin D3 (48). Moreover, calcium and vitamin D3 treatment alone (47) resulted in a significant decrease in serum osteocalcin levels, indicating a reduction in bone remodeling; whereas the opposite changes in bone biomarkers were seen in the present study, indicating a stimulation of bone remodeling.
Other limitations of this study are the small sample sizes and small differences found in BMD and BMC. These increase the risk for statistical type II errors and might be a reason for the lack of a difference in treatment response between the two groups.
A barrier to GH as a plausible therapy for osteoporosis is that the improvements in BMD in this present and other studies are not as impressive as those usually seen with antiresorptive agents. However, changes in BMD during antiresorptive treatments are thought to be caused by filling in of remodeling space rather than to a true bone forming action (49). Male idiopathic osteoporosis has been shown to result primarily from a reduction in osteoblastic activity, with decreased bone formation and low bone turnover, in contrast to what is seen in postmenopausal osteoporosis that is caused by an increased osteoclast activity and increased bone resorption (50, 51). Thus, the ideal therapy for male idiopathic osteoporosis would be an anabolic agent such as GH. A second barrier to GH treatment is side effects. However, the side effects of GH treatment are well known from numerous studies in GHD and GH-sufficient subjects and are usually well tolerated and seldom cause interruption of treatment. A third barrier to GH treatment is that it has to be injected sc. This could possibly cause patients to hesitate to commence this treatment. However, no patient in this study, or in the study of 80 elderly women by Landin-Wilhelmsen et al. (32), dropped out because of side effects or because of problems related to the administration of GH. An alternative anabolic agent in treatment of male idiopathic osteoporosis is PTH. This hormone has been shown to be a potent stimulator of skeletal dynamics in men with idiopathic osteoporosis and to increase BMD substantially in lumbar spine and in femoral neck in men with idiopathic osteoporosis (51). However, PTH treatment of osteoporosis shares some disadvantages with GH treatment. PTH has to be injected sc, exactly as GH, and the treatment is also associated with side effects such as hypercalcemia and nausea. In addition, PTH has not been as widely used as GH, and long-term effects of PTH treatment are not as well known as for GH.
In conclusion, this study showed that GH treatment of men with idiopathic osteoporosis continuously, as well as intermittently, in combination with calcium and vitamin D3 for 2 yr resulted in an increase in BMD in lumbar spine and total body and an increase in total body BMC, which was sustained, and possibly also increased further, for at least 1 yr post treatment. The GH treatment did not have any effect on bone size, according to the method used in this study. The treatment was well tolerated and caused only few and mild transient side effects. This suggests that GH, intermittently or continuously, in combination with calcium and vitamin D3, could be considered in treatment of idiopathic osteoporosis in men. However, the absence of a placebo-treated control group strongly limits the conclusions that can be drawn about the efficacy of the treatment in this study; and double-blind, placebo-controlled studies are needed to further elucidate the effects of GH on BMD and fracture risk in male idiopathic osteoporosis.
Acknowledgments
We express our gratitude to Katharina Nisser, R.N. (osteoporosis unit, University Hospital, Uppsala, Sweden), for skillful technical assistance.
Footnotes
This work was supported by Pharmacia Sweden AB.
Abbreviations: BMC, Bone mineral content; BMD, bone mineral density; BW, body weight; CCT, combined cortical thickness; CV, coefficient of variation; DPD, free deoxypyridinoline cross-links; DPD/Cr, DPD expressed per mol creatinine in second void urine; DXA, dual-energy x-ray absorptiometry; GHD, GH deficiency; LBM, lean body mass; 1,25 (OH)2 vit D3, 1,25-dihydroxy cholecalciferol.
Received February 13, 2002.
Accepted July 31, 2002.
References
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