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From The Clinical Research Centers |
Neuroendocrine Unit and General Clinical Research Center, Massachusetts General Hospital, and Harvard Medical School, Boston, Massachusetts 02114; and Dallas Diabetes and Endocrine Center and the University of Texas Southwestern Medical Center (H.B.A.B.), Dallas, Texas 75230
Address all correspondence and requests for reprints to: Beverly M. K. Biller, M.D., Neuroendocrine Unit, Massachusetts General Hospital, Fruit Street, Bulfinch 457B, Boston, Massachusetts 02114. E-mail: bbiller{at}partners.org
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Abstract |
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In contrast to the effect on body composition, BMD did not reverse toward pretreatment baseline after discontinuation of GH. Bone density at the hip continued to rise during PL administration, showing a significant increase (0.0014 ± 0.00042, g/cm2·month; P = 0.005) between months 18–36. Every bone site except two (radial BMD and total bone mineral content), including those without a significant increase in BMD during the 18 months of GH administration, showed a net increase over the entire 36 months. Therefore, there is a critical differential response of the duration of GH action on different body composition compartments. Physiological GH administration has a persistent effect on bone mass 18 months after discontinuation of GH.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Numerous reports evaluating the metabolic effects of GH replacement have shown increased lean mass and decreased fat mass as well as marked increases in bone turnover, both resorption, and bone formation, in GHD patients (16, 17, 18, 19, 20, 21, 22, 23, 24, 25). The effect of GH replacement on bone mass has been controversial, with several studies showing no change, and a few showing a decrease in bone mineral density (BMD) during therapy. Key factors contributing to the discrepant findings include age of onset of GHD, dose, gender of subjects, severity of osteopenia, and, most importantly, duration of therapy. All of the studies in which patients were administered GH for at least 18 months report an improvement in bone density. In studies spanning 18 months to 4 yr, increases in BMD range from 2–10% at the lumbar spine and from 2.4–6.7% at the femoral neck (24, 25, 26, 27, 28, 29, 30, 31). It is unknown whether this effect can be sustained or what the timing of the reversibility of the effect might be after discontinuation of GH in patients with adult-onset GHD. This information is essential in understanding the physiology of differential effects of GH therapy on body composition and in the development of chronic long term vs. intermittent therapeutic strategies using GH. We therefore sought to investigate the effect on regional bone mass and body composition of withdrawal of long term GH therapy.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Forty men (median age, 51 yr; range, 24–64 yr) with a history
of adult-onset pituitary disorders were recruited from the
Massachusetts General Hospital Neuroendocrine Clinical Center and from
surrounding communities. Details regarding the study and results of the
initial 18 months of treatment in 32 of the patients have been
previously reported (24, 32). Clinical characteristics of the patients
are shown in Table 1
, with the majority
of patients having GHD (confirmed by 2 stimulation tests) as a result
of pituitary adenomas or craniopharyngiomas. Replacement doses of
glucocorticoids, gonadal steroids, or thyroid hormone were unchanged
for at least 6 months before study entry.
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Protocol
This was a randomized, placebo-controlled, single blind, 36-month cross-over study. Patients were assigned to receive recombinant human GH (Nutropin, Genentech, Inc., South San Francisco, CA) or placebo (PL). Group 1 denotes those patients who were initially randomized to GH, and group 2 refers to those patients initially receiving PL. At 18 months of therapy, group 1 patients crossed over to PL, and group 2 patients crossed over to receive GH. Return visits for insulin-like growth factor I (IGF-I) monitoring and dose adjustment in the GH and PL groups occurred at the same intervals as during the initial 18 months of the study (24).
The initial daily dose was 10 µg/kg·day, self-administered sc at bedtime, and patients returned at regular intervals for measurement of serum IGF-I as previously described (24). If the serum IGF-I level was above the normal gender- and age-adjusted range, the patient’s dose was reduced by 25%. If the IGF-I level was below the age-adjusted normal range, the patient’s dose was increased by 25%. To maintain patient blinding, each patient receiving PL was asked to make a 25% dose reduction during the first 6 months of therapy. Drug compliance was assessed by vial count, monitoring of medication diaries, and rise in IGF-I during GH therapy.
Bone density and body composition
Dual energy x-ray absorptiometry was used to measure BMD, lean body mass, and percentage of body fat as previously described (24).
Statistical analysis
A random intercepts model was used to analyze change from month 18 and baseline for the body composition variables in group 1. This model estimates the mean change aggregated over months 24, 30, and 36. It contains a fixed intercept and a random intercept for each patient.
A random slopes model was used to analyze bone density variables in group 1. This model contains a fixed intercept and slope in each 18-month period and a random intercept and slope for each patient in each period. This model was used to estimate the slope in period 2 (months 18–36) alone and the sum of the slopes in periods 1 (months 0–18) and 2 (months 18–36). The analysis plan was determined at the time the study was designed and is based on previous analyses of the effect of GH on the parameters studied. Data were analyzed by an intent to treat, and all available data were used.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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. A total of 25 patients completed the
study, of whom 13 were in group 1 and 12 were in group 2. In group 1
(GH
PL), 4 of the dropouts occurred during GH therapy and 3 during PL
treatment. Reasons for study discontinuation in group 1 during GH
administration were seizure after discontinuation of anticonvulsant
therapy, tachycardia, cerebrovascular accident, and a nonmedical
reason. Reasons for discontinuation in group 1 during PL were a decline
in systolic function, worsening depression, and a nonmedical reason. In
group 2 (PLGH), 3 of the dropouts occurred during PL administration
and 5 during GH therapy. Reasons for discontinuation in group 2 during
PL administration were pneumonia, untreated hypothyroidism, and a
nonmedical reason. Reasons for discontinuation in group 2 during GH
were nausea, fatigue, and joint pains; seizures (in a patient with
symptoms of possible seizures before GH); malaise and lightheadedness;
and lack of energy.
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All but one patient required dose reductions from the initial 10 µg/kg·day dose because of elevated IGF-I levels and/or side-effects. The one patient (in group 2) who did not require a dose reduction failed to have a significant increase in IGF-I when he was started on GH and later admitted to noncompliance. The mean dose of GH at 18 months for the group initially randomized to GH was 4.0 ± 2.0 µg/kg·day, and the mean GH dose at 36 months in the group initially randomized to PL was 4.1 ± 2.1 µg/kg·day. If the noncompliant patient who was thought to have remained on 10 µg/kg·day throughout the study is excluded from an evaluation of dose, the mean dose at 36 months was 3.6 ± 1.1 µg/kg·day.
Body composition
Body composition results are shown in Fig. 1. GH administration during the initial
18 months resulted in a significant decrease in body fat and an
increase in lean mass as previously reported (24). After
discontinuation of GH at 18 months and initiation of PL, there was a
significant increase (3.18 ± 0.44%; P = 0.0001)
in body fat to pretreatment values between months 18–36. Similarly,
after discontinuation of GH, lean mass decreased significantly
(-2133 ± 539 g; P = 0.0016). However, lean
mass remained significantly higher (1276 ± 502 g;
P = 0.0258) than baseline, on the average, between
months 24–36.
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The effect on BMD of GH administration for 18 months
followed by withdrawal for 18 months is shown in Table 3 and Fig. 2. The administration of GH for 18 months
resulted in increased BMD of the spine and femoral neck, as previously
reported (24). However, unlike body composition, which reverted toward
pretreatment baseline after discontinuation of GH, bone density did not
decrease. At the hip, bone density continued to increase significantly
(0.0014 ± 0.00042 g/cm2·month;
P = 0.0051) during PL administration between months
18–36. Likewise, total BMD and trochanter BMD rose significantly in
group 1 patients during PL administration [0.0014 ± 0.00053
g/cm2·month (P = 0.0158) and
0.0015 ± 0.00032 g/cm2·month
(P = 0.0003), respectively].
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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It has been recognized that adolescents who discontinue GH after achieving target height experience changes in body composition, such as increased body fat and decreased lean muscle (33, 34, 35, 36). However, the effect of GH withdrawal on body composition in adults has not been systematically addressed in adult-onset GHD patients. One small study (three men and five women) of patients with a history of childhood-onset GHD showed that body fat and lean mass returned to baseline by 3 months after discontinuation of 6 months of GH therapy (18). The current finding of the reversibility of GH effects on body composition in adults after withdrawal is important because it demonstrates that the beneficial effect of GH depends on sustained hormone administration.
Subjects with GHD of adult onset are shown to have lower bone mass than normal subjects in many, although not all, studies (7, 9, 10, 11, 12, 13, 27, 37, 38). Holmes et al. showed that both men and women with adult-onset GHD of at least 2 yr duration had highly significant reductions in lumbar spine and forearm bone density regardless of whether they had isolated GHD or combined GHD and gonadotropin deficiency (13). Colao et al. recently demonstrated that bone mass was reduced in subjects with very severe or severe GHD regardless of whether the patients had GHD alone or in association with other pituitary hormone deficits (14). The findings from these two studies suggest a specific effect of GH on bone. In addition, fracture rates 2–3 times higher than those in healthy controls have been reported in patients with GHD (15). However, several other investigators have not shown this degree of osteopenia among adult-onset GHD subjects (27, 37, 38).
There are many studies that have addressed the impact of GH replacement on bone density. The majority of these were 3–12 months in duration, and results are highly variable, including an early decline in bone density in some cases (10, 17, 18, 19, 22, 23, 39, 40, 41, 42, 43, 44, 45). It has been theorized that the initial decline in BMD after short term GH treatment is due to increased remodeling, resulting in a higher proportion of newly formed, unmineralized osteoid (46). Because the bone-remodeling cycle spans many months, there may be a delayed improvement in BMD until the new bone is fully mineralized. Therefore, the results of longer term studies are particularly important to consider when evaluating the effect of GH on BMD. There are now 8 studies that included measurement of BMD in adult-onset GHD patients with a treatment duration of at least 18 months. Of these, 5 include a placebo arm as part of the study design; however, in all but the current study, the PL arm was only 6–9 months, followed by open label treatment (24, 28, 29, 30, 31). Importantly, all 8 of these studies evaluating the effect of long term GH therapy show significant increases in BMD, in the range of 2–10% over 18–48 months, particularly in the spine and hip (24, 25, 26, 27, 28, 29, 30, 31). In 1 recent study, 17 patients with adult-onset GHD were followed during 42 months of GH administration, and BMD was found to increase for up to 30–36 months, followed by a plateau (31).
The dose of GH is one of several variables that differ between studies and may influence the response of bone to GH administration. In some of the long term studies in adult-onset GHD patients, the dose was supraphysiological, as evidenced by elevated IGF-I levels (24, 25, 26, 27, 28, 29, 30, 31). One study that compared three doses, ranging from low to high, found no difference in the increase in bone mass regardless of which dose the patients received (27). In the current study, doses were adjusted carefully with the goal of physiological, rather than pharmacological, dosing, and a significant effect on BMD was seen.
In addition to the duration of therapy and GH dose, another variable that may impact on the potential benefit of GH on bone and account for some of the differences in results between studies is gender. No gender difference was observed in the percent increase in BMD in a study of men and women treated for 2 yr with GH (27). However, in one recent study, men had significant increases in bone mass with long term GH therapy, whereas women did not, despite receiving higher doses (30). There was a significantly greater increase in lumbar spine, femoral neck, and trochanter BMD in men than women treated with GH for several years (31). It has also been demonstrated that men exhibit a greater increase in serum bone markers (osteocalcin, carboxy-terminal propeptide of type I procollagen, and carboxy-terminal cross-linked telopeptide of type I collagen) than women, yet in one study, women had greater increases in total bone mineral content and BMD (25). In healthy normal subjects over age 55 yr, IGF-I levels are correlated with spine and hip BMD solely in women (47). Our study was designed to evaluate the effects of GH on only one gender to avoid this confounding variable. Similar data about GH withdrawal are now needed in women.
Our finding of a continuing rise in BMD among a large cohort of men with adult-onset GHD followed prospectively for 18 months after discontinuation of GH therapy has not been previously reported. In 1 study, several subjects who had received GH (without an increase in bone density) for 6 or 12 months in an earlier study were rerecruited for remeasurement of BMD 2 yr later. An increase was seen in BMD of the lumbar spine, Ward’s area, and trochanter in these subjects (3 men and 5 women) 24 months after the completion of GH treatment (26). The only other evaluations of BMD after GH discontinuation in adults were conducted in 2 small studies of subjects with childhood-onset GHD. One showed a return to the baseline subnormal BMD 1 yr after discontinuing 12 months of GH therapy (48). In contrast, Holmes et al. demonstrated a further increase in forearm cortical bone mineral content 1 yr after completing a 12-month course of GH replacement in 10 subjects (49). The current study is thus the only prospective evaluation of the effect on bone of discontinuing GH replacement in patients with adult-onset GHD.
The unexpected finding that BMD continues to rise long after cessation of GH replacement suggests that this hormone initiates the bone-remodeling process in men with adult-onset GHD, but is not required to sustain such an effect. It has been suggested that GH triggers initiation of the bone-remodeling cycle, which then continues regardless of whether GH exposure is continued (26). Markers of bone and collagen turnover can remain increased for many days after cessation of brief GH administration in normal volunteers and adult-onset GHD patients (50, 51). Interestingly, a similar finding related to withdrawal of PTH therapy has recently been reported. Women who had been administered 6–12 months of PTH to prevent bone loss from GnRH agonist therapy for endometriosis were restudied 1 yr after discontinuation of PTH. BMD increases were significantly greater in women who had completed PTH 1 yr earlier than in women who had taken GnRH analogs without PTH (52).
We have studied the effect of discontinuing physiological GH replacement on body composition, with differential responses to the duration of GH therapy seen in different compartments. Although body fat increases to pretreatment levels and lean mass declines nearly to baseline, there is a prolonged effect of GH administration on BMD even after the cessation of therapy. Further studies of the effect of GH on bone will need to explore the possible anabolic effects of GH therapy alone with both intermittent and continuous use or in combination with antiresorptive agents in GHD subgroups and in other patients with osteoporosis.
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Acknowledgments |
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Footnotes |
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Received August 20, 1999.
Revised November 30, 1999.
Accepted December 6, 1999.
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References |
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, group 2 (GH during the second 18 months).
Error bars represent ±SEM. The period of
withdrawal of GH for group 1 patients is denoted by the shaded
area. P = 0.0001 for the increase in body
fat and P = 0.0016 for the decrease in lean mass in
group 1 after cessation of therapy.