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Endocrine Care |
Department of Endocrinology and Metabolism, Leiden University Medical Center, 2300 RC Leiden, The Netherlands
Address all correspondence and requests for reprints to: Dr. F. Roelfsema, Department of Endocrinology and Metabolism, Leiden University Medical Center, Box 9600, 2300 RC Leiden, The Netherlands. E-mail: roelfsema{at}rullf2.medfac.leidenuniv.nl
Abstract
We conducted a randomized controlled trial in osteoporotic adult GH-deficient (GHD) patients to assess whether additional treatment with a bisphosphonate would further favorably influence parameters of bone turnover and bone mineral density measurements (BMD). All patients were receiving stable recombinant human (rhGH) replacement therapy for 4 yr at the start of the study. Eighteen GHD patients with osteoporosis were randomized to continue their rhGH maintenance dose or to receive combination therapy with rhGH and alendronate for 12 months. All patients were calcium and vitamin replete, and there were no changes in calcium, vitamin D, or hormone replacement therapy for the duration of the study. At baseline there were no significant differences between the alendronate and the control group in parameters of bone turnover, BMD, or prevalence of vertebral fractures. Childhood-onset and adult-onset GHD were equally distributed between the groups, with no statistical differences in age and gender or other parameters between groups. Mean serum osteocalcin, serum bone-specific alkaline phosphatase, and urinary N-telopeptide/creatinine ratio were within the normal range at the start of the study. In the alendronate group all measured parameters of bone turnover, i.e. bone-specific alkaline phosphatase, osteocalcin, and urinary N-telopeptide/creatinine ratio, significantly decreased after 6 months, with no further decrease thereafter. No changes were observed in the control group. In the alendronate-treated patients serum bone-specific alkaline phosphatase decreased from 10.9 ± 0.9 to 6.8 ± 0.7 µg/L at 6 months (P < 0.001), serum osteocalcin decreased from 3.9 ± 0.4 to 1.7 ± 0.3 µg/L (P < 0.001), and the urinary N-telopeptide/creatinine ratio decreased from 27.3 ± 7.0 to 6.4 ± 0.8 nmol/mmol (P = 0.01). In this group, lumbar spine BMD significantly increased from baseline by 3.4% at 6 months (P = 0.001) and by 4.4% at 12 months (P < 0.001) of treatment, with no further significant increase between 6 and 12 months (P = 0.217). No changes in lumbar spine BMD were observed in the control group. There were no significant changes in femoral neck BMD in either group for the duration of the study. No incident vertebral or peripheral fractures were documented in either group at the end of the study.
In summary, this is the first report indicating that treatment with alendronate was able to significantly increase BMD at the lumbar spine in GHD patients with osteoporosis receiving stable rhGH replacement for 4 yr. This increase was significantly greater in alendronate-treated patients than in patients maintained on rhGH. The increase in lumbar spine BMD in the alendronate-treated patients was associated with a decrease in the measured markers of bone turnover, whereas these markers did not change further in the patients maintained on rhGH. This controlled study suggests that additional treatment with alendronate in GHD patients with osteoporosis receiving stable rhGH replacement therapy is effective in increasing BMD at the lumbar spine. Further investigation is required to assess whether rhGH replacement alone or combined treatment with rhGH and alendronate is able to reduce the increased fracture risk associated with GHD.
IN ADULTS, GH deficiency (GHD) is associated with impaired psychological well-being and an altered body composition characterized by increased total weight and fat mass and increased waist to hip ratio. In addition, GHD adults have decreased muscle strength and muscle mass and a low bone turnover (1). This syndrome is also associated with increased mortality due to cardiovascular disease (2). The positive effect of recombinant human GH (rhGH) replacement therapy on these parameters is well established (3, 4), although there are as yet no data on the ability of this therapy to reduce the elevated mortality risk.
Low bone mineral density measurements (BMD) and an increase in fracture risk have been reported in GHD patients (5, 6, 7), although others, including ourselves, could not confirm these findings (8, 9, 10). The discrepancy in BMD measurements and hence in the incidence of osteoporosis result from the heterogeneous origin of GH deficiency in adults with GHD (adult or childhood onset) and on the presence or absence of other secondary causes of osteoporosis, such as corticosteroid excess or uncorrected estrogen or testosterone deficiency. In GHD adults with childhood-onset GHD, a low bone mass may be due to inability to achieve peak bone mass in adolescence and the low attained final body height (11). During rhGH replacement therapy significant increases in BMD are observed after 12–18 months of treatment (6, 7, 10, 12) and up to 4 yr of therapy (13, 14, 15). The increases are reported to be at a rate of about 1%/yr. Whether these increases in BMD are maintained over the longer term remains to be established.
In GHD patients, the increase in BMD during rhGH replacement occurs at the same rate in patients with a low BMD as in those with a normal BMD (8, 16) or even at a somewhat higher rate (10, 12, 15). However, the increase in BMD achieved by rhGH replacement is modest compared with that achieved by other therapies in the management of osteoporosis. Treatment with the oral bisphosphonate alendronate thus increased lumbar spine BMD by 9% after 3 yr of treatment at a mean rate of 3%/yr (17). This treatment also reduced the incidence of vertebral fractures and hip fractures by 48% in postmenopausal osteoporosis (17), an important parameter for evaluating the efficacy of osteoporosis treatment, which is not (yet) available for rhGH replacement therapy. The effect of adding a bisphosphonate to long-term rhGH replacement at a stable maintenance dose is not known. Bone turnover increases in the first 6 months of GH replacement treatment, and the resulting initial decline in BMD can be reversed by the addition of a bisphosphonate (18). After the first year of rhGH replacement a new steady state is achieved, probably favoring bone formation resulting in documented modest, but steady, increases in BMD for at least 4 yr of continuous rhGH replacement (13, 14, 15). Whether adding a bisphosphonate to this new steady state would positively or negatively affect BMD is not known. Interestingly, in a controlled study of patients with postmenopausal osteoporosis, combining rhGH with a bisphosphonate attenuated the beneficial effect of the latter on BMD (19). In the present randomized controlled study our aim was to assess whether the addition of alendronate, a nitrogen-containing bisphosphonate, to long-term rhGH replacement at stable doses would positively or negatively affect BMD in GHD patients with osteoporosis.
Subjects and Methods
Patients
Patients included in this study (n = 18) were selected from
the previously described cohort of 60 GHD adults treated with rhGH
replacement (20) on the basis of osteoporosis
(t-score, less than -2 at the femoral neck and/or lumbar
spine). At the start of the study, all patients had received 4 yr of
rhGH replacement at a mean daily dose of 1.6 IU (0.53 mg), ranging from
0.8–2.4 IU/day (0.26–0.8 mg). The substitution dose was stable for at
least 3 yr before inclusion. All patients were vitamin D replete, as
shown in Table 2
, and had oral calcium intake of at least 1200 mg
daily. None of the patients had renal or hepatic dysfunction, and none
had been previously treated with bisphosphonates. Sex hormone
replacement therapy, which was given as required, was not changed for
at least 2 yr before entry in the study. The local ethics committee
approved the study, and all patients gave their informed consent for
participation in the study.
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Patients were randomly allocated to receive additional bisphosphonate treatment with a daily dose of 10 mg alendronate (alendronate group), or not (control group), after stratification for adult-onset and childhood-onset GHD. All patients continued rhGH replacement therapy at stable maintenance doses, which remained unchanged for the duration of the study. Calcium, vitamin D supplementation, and other substitution therapy also remained unchanged in all patients for 1-yr study period. The primary end points of the study were changes in biochemical markers of bone turnover, changes in BMD measurements at the lumbar spine and femoral neck sites, as well as the incidence of new vertebral fractures after 1 yr of treatment.
Laboratory investigations
Blood and urine samples were collected at baseline and at 6 and 12 months from starting of the study. Serum calcium, albumin, phosphate, parameters of renal and liver function, and urinary calcium and creatinine excretion were measured by automated techniques. The serum insulin-like growth factor I (IGF-I) concentration was measured by RIA (INCSTAR Corp., Stillwater, MN) after extraction and purification on ODS-silica columns. The detection limit of this assay is 1.5 nmol/L, and the interassay coefficient of variation was below 11%. IGF-I was expressed as the SD score from age-related normal values as determined in the same laboratory. Circulating intact PTH was measured with an immunoradiometric assay on the Immulite (Diagnostic Products, Los Angeles, CA) with a detection limit of 0.1 pmol/L and an interassay coefficient of variation of 5–6%. An RIA was used for osteocalcin measurements (INCSTAR Corp.), with a detection limit of 0.2 µg/L and an interassay coefficient of variation between 7 - 9.5%. Reference ranges for males are 3.2–12.2 µg/L and for females 2.7–11.5 µg/L. Serum bone-specific alkaline phosphatase was measured by an immunoradiometric assay (Ostase Hybritech, Tandem R, Hybritech, Inc., San Diego, CA). The detection limit was 2 µg/L, and the intraassay coefficient of variation was 7–8% (all samples were measured in the same assay). Normal values were 3.7–20.9 µg/L (male), 2.9–14.5 µg/L (premenopausal women), and 3.8–22.6 µg/L (postmenopausal women).
Urinary cross-links of type I collagen, N-telopeptide, were measured by Osteomark enzyme-linked immunosorbent assay (Ostex International, Inc., Seattle, WA) from a morning void urine. Results are expressed as urinary N-telopeptide/creatinine ratio. The intraassay variation coefficient was 6–7% (all samples were measured in one assay), and normal values ranged from 3–63 (males) and 5–65 (females) nmol/mmol creatinine.
BMD measurements
BMD was measured at the lumbar spine and both femoral neck sites using dual x-ray absorptiometry (model 4500, Hologic, Inc., Waltham, MA) at baseline and at 6 and 12 months of treatment. The femoral neck BMD used for evaluation was the average of the left and right femoral neck BMDs.
Radiological investigations
Lateral x-rays of the lumbar and thoracic spine were performed at baseline and at 12 months and assessed for the presence of vertebral fractures. This was defined as a 20% decrease in anterior, middle, or posterior height of a vertebra. In addition, a questionnaire was used for evaluation of the incidence of nonvertebral fractures.
Statistics
Values were expressed as the mean ± SEM unless otherwise mentioned. To identify differences between randomized treatment groups over time, multivariate ANOVA for repeated measures was used. For evaluating changes over time within the alendronate and control groups, the changes were calculated separately and analyzed with univariate ANOVA for repeated measures with appropriate contrasts. Statistics were performed using SPSS for Windows 9.0 and Systat 9.0 (SPSS, Inc., Chicago, IL). P < 0.05 was considered significant.
Results
Baseline evaluation
Biochemistry. Eleven men and 7 women, equally distributed
between the alendronate and the control groups, were included in the
study. Mean age was 57.9 ± 2.8 yr. There were no statistical
differences in any of the parameters studied at baseline between the 2
groups. All patients had normal serum PTH concentrations. The mean
serum IGF-I concentration was 22.9 ± 1.9 nmol/L, and the mean IGF
SD score was +1.2 ± 0.4, indicating adequate rhGH
substitution. Mean serum osteocalcin was within the normal range in
both groups, but 2 alendronate-treated patients and 3 control patients
had low serum osteocalcin concentrations at baseline. Serum
bone-specific alkaline phosphatase was within the normal range in 17
patients and was elevated in 1 control patient. The mean urinary
N-telopeptide concentration was 34.1 ± 10.2 nmol/mmol creatinine,
and 2 patients (1 in each group) had elevated levels at the start of
the study. Clinical and biochemical characteristics of the 2 treatment
groups are shown in Tables 1 and 2
.
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Radiological investigations. Six preexisting vertebral fractures were documented in five patients. All had been asymptomatic. Three patients reported peripheral fractures before the start of the study (two alendronate-treated patients and one control patient), all after adequate trauma.
Changes during the year of treatment
Treatment was well tolerated, and none of the patients had to be withdrawn from the study because of development of side-effects.
Biochemical markers of bone turnover. There were no
significant changes in parameters of bone resorption (N-telopeptide) or
bone formation (bone-specific alkaline phosphatase, osteocalcin) during
the 1-yr study period in patients receiving stable maintenance doses of
rhGH for 4 yr and not receiving additional alendronate treatment
(control group). In contrast, all measured parameters of bone turnover
significantly decreased in patients receiving additional alendronate
treatment. The urinary N-telopeptide/creatinine ratio thus
significantly decreased from baseline at 6 months (P =
0.013) and 12 months (P = 0.02) of treatment, with no
significant difference between the 6 and 12 month values. At the 6
month time point, the N-telopeptide/creatinine ratio had decreased by
70.2 ± 4% in the alendronate group and by 1.4 ± 17% in
the control group (P = 0.002), and at 12 months this
ratio was decreased by 70 ± 8.2% and 16.7 ± 15%,
respectively (P = 0.006; Fig 1). In alendronate-treated patients, the
serum osteocalcin concentration was significantly lower at 6 and 12
months compared with baseline (P < 0.001 and
P = 0.005, respectively), also without a further
decrease between 6 and 12 months of treatment. The percent decrease in
osteocalcin concentration was more pronounced in the alendronate than
in the control group, but this failed to reach statistical significance
(P = 0.065). Serum bone-specific alkaline phosphatase
was significantly lower at 6 (P < 0.001) and 12 months
(P = 0.001) compared with baseline in the
alendronate-treated patients (Fig. 1 and Table 3). The decrease in serum bone-specific
alkaline phosphatase concentration was significantly higher in the
alendronate-treated patients compared with the control patients at 6
and 12 months (P = 0.001 and P = 0.001,
respectively; Fig. 1).
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and
Table 3).
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Incidence of fractures. No new vertebral or peripheral fractures developed in either group during the 12-month study period.
Discussion
The present study was performed to assess the effect of combined use of rhGH replacement and oral bisphosphonate treatment in patients with GHD, two therapies with established efficacy in increasing BMD when, respectively, administered in the correction of GHD or osteoporosis. The efficacy of oral bisphosphonates is established in the management of primary and secondary osteoporosis in men and women (17, 21). They result in a decrease in bone turnover, an increase in BMD, and a clear decrease in fracture risk. The effect of rhGH on BMD in non-GHD patients with postmenopausal osteoporosis is modest (22) and it is not known whether rhGH therapy decreases fracture risk in non-GHD patients.
The beneficial effects of rhGH on the skeleton are well established in GHD patients. After an initial decline in BMD within the first few months of rhGH replacement, BMD increases at a rate of 1–2%/yr (6, 8, 12, 13, 23), and this effect has been shown to be sustained for up to 3–4 yr of rhGH replacement therapy (13, 14, 15, 23). There are no currently available data for longer term rhGH replacement. Whereas bisphosphonates decrease overall bone turnover, GH initially increases bone turnover, hence the early bone loss. Both agents have thus been shown to have opposite mechanisms of action, which may interact favorably or unfavorably. Combining a bisphosphonate to rhGH in postmenopausal osteoporosis is less effective than the use of a bisphosphonate alone (19). In contrast, addition of a bisphosphonate at the start of rhGH replacement therapy has been shown to favorably counteract the initial transient deleterious effect of the increased bone turnover induced by rhGH treatment (18). The question arises as to whether addition of a bisphosphonate at a later stage in the course of rhGH replacement therapy, when a new steady state of bone turnover is achieved under rhGH maintenance therapy, would have deleterious, beneficial, or no additional effect to that of rhGH on bone metabolism.
In this study we found a significantly greater increase in lumbar spine BMD in the alendronate-treated patients compared with the patients maintained only on stable rhGH replacement therapy. As repeatedly shown with the use of a bisphosphonate in the setting of osteoporosis (24), the increase in BMD was coupled with a significant decrease in parameters of bone turnover. The differences in markers of bone turnover at baseline between the alendronate-treated and the nonalendronate-treated patient groups might indicate a less favorable equilibrium of bone formation and resorption in patients not receiving alendronate. However, these differences were not statistically significant, and there was also no significant difference in changes in BMD between groups over the 4 yr of rhGH replacement therapy preceding randomization (data not shown). Although the number of patients is small, these data indicate a beneficial effect of bisphosphonates in GHD patients with osteoporosis maintained on rhGH replacement. An analogy to the combination of an inhibitor of bone resorption (alendronate) and a potential stimulator of bone formation (rhGH) used in this study is that of the combined use of PTH with oral bisphosphonates. PTH potently stimulates bone turnover in favor of bone formation, thereby increasing BMD (24, 25). Treatment with rhPTH, followed by alendronate treatment, showed a greater increase in BMD than treatment with alendronate alone. In these osteoporotic patients, markers of bone turnover increased during rhPTH treatment and decreased below baseline after introduction of the antiresorptive agent alendronate (27, 28).
It has been shown that markers of bone turnover increase after the start of rhGH replacement (8, 29, 30), in line with the stimulatory effects of GH on both bone formation and resorption. During continuing rhGH replacement therapy these markers decrease, but remain above baseline values (13), pointing to a continuing increased bone turnover (8). In patients with postmenopausal osteoporosis treated with bisphosphonates, the degree of suppression of markers of bone turnover has been used to predict the increment in BMD (31). Although there was a high variation in bone-specific parameters between patients and in bone density, the significant correlation of N- telopeptide and bone alkaline phosphatase at 6 months with lumbar spine BMD increments at 6 and 12 months suggests that early changes in bone turnover markers may also be of value in predicting the long-term effect of alendronate treatment on the BMD in this population. It is of note that in the alendronate-treated patients suppression of bone turnover was maximal at 6 months, and suppression was sustained thereafter.
In this study changes at the femoral neck BMD were less pronounced than those at the lumbar spine. This is probably due to the duration of follow-up, as in most studies no or only a moderate increase in femoral neck BMD is observed in GHD patients in the first 18 months of rhGH treatment (32). It is also in keeping with the lack of early changes observed in postmenopausal osteoporosis after treatment with alendronate (17).
A question that remains unsolved is whether bisphosphonate treatment alone is able to increase BMD in the nonsubstituted GH-deficient patient with a low bone turnover state. Our policy is to supplement all GH-deficient patients so that we lack a non-rhGH-substituted control population to address this question and that of the potential additive effect of later treatment with rhGH replacement therapy in bisphosphonate-treated GHD patients (1). Nevertheless, one could probably expect favorable clinical results as shown in low bone turnover states associated with corticosteroid use as well as in a number of older patients with postmenopausal osteoporosis in which bisphosphonates have been shown to be effective in increasing BMD and decreasing fracture risk. Rosen et al. (33) reported a 3-fold increased fracture risk in a non-rhGH-substituted GHD population. An important issue that remains unanswered is whether rhGH replacement alone is able to decrease fracture risk in GHD patients. There were no incident fractures in the course of this study in either treatment group. However, due to the short duration of the study and the limited number of patients, we cannot comment on the incidence of new vertebral fractures during combination therapy.
In conclusion, in this study oral bisphosphonate treatment had an additive positive effect on lumbar spine BMD and bone markers in GHD patients with osteoporosis on a stable rhGH maintenance dose. Our data from this study suggest that in patients with GHD and osteoporosis, adding bisphosphonate treatment in the form of alendronate to stable rhGH maintenance therapy significantly decreased bone turnover and increased BMD after 1 yr of treatment. Longer-term studies on a larger study population are required to establish the potential additional effect of alendronate to that of rhGH replacement to reduce the increased risk of fractures associated with GHD.
Received December 28, 2000.
Revised March 2, 2001.
Accepted March 8, 2001.
References
This article has been cited by other articles:
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  A. Giustina, G. Mazziotti, and E. Canalis Growth Hormone, Insulin-Like Growth Factors, and the Skeleton Endocr. Rev., August 1, 2008; 29(5): 535 - 559. [Abstract] [Full Text] [PDF]
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