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Original Studies |
Division of Endocrinology and Metabolism (T.B., Y.G., E.R.F., C.S.), Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland; Laboratorium voor Experimentele Geneeskunde en Endocrinologie (R.B.), Katholieke Universiteit Leuven, B-3000 Leuven, Belgium
Address correspondence and reprint requests to: Dr. Tarcisio Bianda, Division of Endocrinology and Metabolism, Department of Internal Medicine, University Hospital, CH-8091 Zürich, Switzerland.
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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-hydroxylase activity
in vivo. |
Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Aging is associated with decreasing serum concentrations of GH and IGF-I (15), a decrease in skeletal muscle and bone mass (16, 17), a decline in creatinine clearance and serum 1,25-(OH)2D3 levels (18, 19), and with an increase in PTH levels. Some of the actions of GH on the kidney may also be mediated by IGF-I; the latter has been reported to increase glomerular filtration rate and the production of 1,25-(OH)2D3 in healthy humans (20, 21). However, the role of IGF-I in the regulation of 1,25-(OH)2D3 in GH-deficient patients is not known.
To investigate the effects of IGF-I (and GH) on bone metabolism and on 1,25-(OH)2D3 production, we conducted a cross-over short-term treatment with both peptide hormones in adults with GHD.
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Subjects and Methods |
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Eight patients (48 ± 14 yr of age, range 25–72 yr, BMI
25.2 ± 3.7 kg/m2, 3 men and 5 women) with adult onset
of GHD were studied after obtaining written informed consent. GHD was
diagnosed by history and by low serum level of IGF-I. All subjects had
completed growth and puberty at the time of diagnosis, and all had GH
deficiency of at least 2 yr duration. None had previously received GH
substitution therapy, and the previous hormone replacement therapy was
maintained unchanged. One subject (patient 5) had noninsulin-dependent
diabetes mellitus (NIDDM), treated with diet and a sulfonylurea, and a
moderate renal insufficiency (creatinine of 150 µmol/L). The study
protocol had been approved by the ethics committee of the University
Hospital of Zürich. Patient characteristics are shown in Table 1
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)The study consisted of two periods of five days each, during which the subjects received continuous sc infusion of 5 µg/kg/h rhIGF-I or sc injections of GH (0.03 IU/kg/daily at 2000 h) in a crossover, randomized fashion. The patients were instructed not to change their diet or life-style. They were seen as outpatients and remained engaged in their normal daily activities during the study. Body weight and blood pressure were measured and side effects recorded at each clinic visit. Baseline blood chemistries were sampled for three consecutive days before starting treatment, and a wash-out period of ten weeks was also protocolled. After a 10-h overnight fast, blood samples were drawn at 0800 h for determinations of total serum IGF-I, glucose, calcium, albumin, phosphate, creatinine, osteocalcin, carboxyterminal propeptide of type I procollagen (PICP), aminoterminal propeptide of type I procollagen (PINP), PTH, 1,25-(OH)2D3, and Vitamin D binding protein (DBP). A 2-h fasting urine collection served for the determination of calcium, total and free deoxypyridinoline, phosphate, and creatinine excretion.
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Total serum levels of IGF-I and of 1,25-(OH)2D3 were measured by radioimmunoassay, DBP using radial immunodiffusion, and the free calcitriol index calculated as the molar ratio of the concentrations of total 1,25-(OH)2D3 and DBP as previously described (21).
Intact PTH and osteocalcin levels in serum were measured using two-site immunoradiometric assays (IRMA, Nichols Institute, San Juan Capistrano, CA).
Serum levels of PICP and PINP were measured with recently developed RIA kits (Orion Diagnostica, Espoo, Finland) (Mellko 1990). The lower detection limit of the tests is 1.2 µg/L and 2 µg/L, respectively.
Serum calcium, phosphate, albumin, and creatinine were analyzed according to standard laboratory methods. Serum calcium was corrected for individual variations in serum albumin using the formula: corrected serum calcium (mmol/L) = measured serum calcium (mmol/L) + 0.02 x [40 - measured albumin (g/L)]. Plasma glucose was measured as previously described (22).
Urinary free deoxypyridinoline was measured using a competitive enzyme immunoassay (Pyrilinks-D kit, Metra Biosystems, Inc., Mountain View, CA), and values were expressed relative to creatinine excretion. Urinary total deoxypyridinoline was measured using high performance liquid chromatography. Urinary calcium, phosphate, and creatinine were analyzed according to standard laboratory methods. Fasting urinary calcium excretion (UCa), expressed as UCa V/GFR (mmol/L) = UCa x PCr/UCr was calculated from 2-h fasting urine collections. The ratios of deoxypyridinoline/creatinine (Dpyr/creatinine, nmol/mmol) and calcium/creatinine were also calculated from 2-h fasting urine samples. All samples from each patient were analyzed in a single assay to avoid interassay variation.
Statistics
Results are expressed as mean ± SD. The results were analyzed using the two-tailed Wilcoxon’s rank-sum test for paired difference.
A P value of less than 0.05 was considered statistically significant.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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All subjects tolerated the treatments well and completed the study. No episode of hypoglycemia and no significant changes in blood pressure were observed. During the GH-treatment blood glucose increased markedly in patients P2 and P5 (the diabetic patient). A generalized, nonpitting sc edema with a weight gain of 4 kg developed in one patient (P6) during IGF-I treatment, but regressed after the end of the treatment.
Baseline values
Baseline values of serum IGF-I and all other measured parameters
were similar at the start of each treatment period (
Figs. 2–5).
Apart from the low IGF-I levels, i.e. 7.5 ± 2.5
(IGF-I) vs. 7.8 ± 2.8 (GH) nmol/L, all of these serum
values were within the normal range.
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Serum IGF-I. GH treatment led to a less pronounced increase of
serum IGF-I levels than IGF-I treatment. Serum IGF-I level rose
significantly from 7.5 ± 2.5 to 77 ± 22.3 (IGF-I)
(P < 0.02) and from 7.7 ± 1.2 to 24.1 ±
7.9 nmol/L (GH) (P < 0.02), respectively (Fig. 2
).
Biochemical markers of bone turnover
The effects of either treatment on biochemical markers of bone
formation and resorption are shown in Figures 3 and 4.
Bone formation. A slight but significant increase in serum osteocalcin levels was observed after three days of each treatment: during IGF-I from 3.9 ± 1.8 to 4.9 ± 2.1 µg/L (P < 0.02) and during GH from 4.1 ± 2.5 to 5.2 ± 3.1 µg/L (P < 0.02). One week after stopping treatment the osteocalcin levels were back to baseline. The type I procollagen fragments, serum PICP and PINP, rose quickly and markedly during IGF-I therapy from 85 ± 27 (baseline) to 135 ± 29 µg/L (P < 0.02), and from 30.6 ± 16.4 (baseline) to 54.7 ± 21.8 µg/L (P < 0.02), respectively, and were back to the baseline two days after treatment end. During GH treatment, PICP levels rose from 86 ± 26 to 113 ± 29 µg/L (P < 0.02) and PINP levels from 31.9 ± 20.1 to 45.2 ± 24.2 µg/L, and remained elevated until two days after treatment end.
Bone resorption. The urinary free Dpyr/creatinine ratio increased from 4.3 ± 1.2 (baseline) to 5.8 ± 1.8 nmol/mmol (P < 0.02) after three days of IGF-I treatment and remained significantly elevated above baseline until one week (P < 0.02) after the end of treatment, whereas with GH, the maximal level (5.3 ± 1.5 nmol/mmol) was reached one day after stopping treatment, followed by a rapid return to baseline. Urinary total Dpyr/creatinine ratio remained unchanged during both treatment periods. The fasting urinary calcium/creatinine ratio rose from 0.11 ± 0.06 (baseline) to 0.37 ± 0.27 (IGF-I) (P < 0.02) and from 0.13 ± 0.09 to 0.26 ± 0.19 mmol/mmol (GH) (P < 0.02) after 4–5 days of treatment, respectively. Likewise, UCa V/GFR rose from 0.014 ± 0.008 (baseline) to 0.031 ± 0.020 (IGF-I) (P < 0.02) and from 0.014 ± 0.012 to 0.026 ± 0.021 mmol/L (GH) (P < 0.03), respectively.
The relative effects of both peptide hormones on bone formation versus
resorption are shown in Table 2.
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Serum phosphate and albumin remained unchanged during both treatments. Total calcium, corrected for albumin, increased slightly but not significantly during both treatments from 2.19 ± 0.08 to 2.25 ± 0.07 mmol/L during IGF-I, and from 2.20 ± 0.07 to 2.23 ± 0.07 mmol/L during GH, respectively. Serum PTH levels remained unchanged during both treatment periods.
A significant increase in serum total
1,25-(OH)2D3 levels was observed after 3 days
of IGF-I treatment from 43.2 ± 14.7 to 61.7 ± 29.8
(P < 0.02) and after 5 days of GH treatment from
45.7 ± 14.7 to 66.2 ± 33.8 pg/ml (P <
0.04). 24 hours after stopping treatment total
1,25-(OH)2D3 levels were back to the baseline
(Fig. 5). DBP remained unchanged during both treatment periods.
Consequently, the free calcitriol index rose from 1.63 ±
0.49 x 10-5 to 2.31 ± 0.71 x
10-5 (IGF-I) (P < 0.02) and from
1.70 ± 0.44 x 10-5 to 2.28 ± 0.88
x 10-5 (P < 0.03) (GH),
respectively.
Kidney function
Serum creatinine levels fell only during IGF-I therapy, from
107.5 ± 28.7 (baseline) to 89.5 ± 22.7 µmmol/L
(P < 0.02), whereas there was no significant decrease
during GH therapy (103.3 ± 18.7 vs. 98.8 ± 22.0 µmol/L)
(Fig. 5). Serum urea levels fell during both treatments, from 6.7
± 3.4 (baseline) to 4.6 ± 3.0 (IGF-I) (P <
0.02) and from 5.9 ± 2.0 to 4.5 ± 2.9 mmol/L (GH)
(P < 0.02), respectively.
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Stimulatory effects of GH on bone turnover have been well documented in healthy adult humans (24) and in patients with GHD (10, 11, 12), and some but not all revealed a beneficial effect of GH treatment on bone mineral content (25, 26, 27). In patients lacking functional GH receptors (type Laron dwarfs) IGF-I therapy affects longitudinal bone growth (28, 29, 30). It is evident that GH and IGF-I play an important role in the acquisition of peak bone mass, but the effects of IGF-I on bone metabolism and mineral density in the adult are less clear. IGF-I administration stimulates bone turnover in men with osteoporosis (31), in osteopenic women with anorexia nervosa (32), and in postmenopausal women (33, 34). In contrast, no report has been published on the effects of IGF-I treatment on bone turnover of GH-deficient adults. Bone turnover is decreased in GH-deficient adults as assessed by histomorphometry and biochemical markers, and increased by GH treatment (9, 35). Whether the action of GH on bone results from the hormonal effects of circulating IGF-I, from autocrine/paracrine effects of IGF-I, or from IGF-I-independent GH effects is unknown.
In our study both IGF-I and GH treatment led to a rapid and pronounced
stimulation of bone collagen production. We found a significant
increase in PICP and PINP levels after three days of hormonal treatment
and a return to baseline within one week after the end of treatment.
The serum osteocalcin levels were also significantly increased by both
hormones after three days, but less markedly as compared with the type
I collagen propeptides. In agreement, other studies have found slight
(31, 32) or no changes (33, 36) of serum osteocalcin in response to IGF
treatment. Interestingly, the percentage increase in formation
parameters largely exceeded their effects on resorption markers during
both treatment periods, as shown in Table 2. The trial was designed to monitor not
only the different response of bone formation and resorption markers
during the treatment, but particularly to control whether activation of
bone turnover would be characterized by an osteoclast activation
followed by a potentially sustained increase of osteoblast activity.
However, the effects of IGF-I on bone formation do not appear to be
secondary to an initial increase in bone resorption, as observed in the
more common states of increased bone turnover in adults, such as PTH
excess or sex steroid withdrawal. Moreover, we observed a quick return
of the measured parameters to baseline levels and no further changes
during the subsequent weeks, in contrast with the prolonged effects of
IGF-I found by Johansson et al. (37) in an osteoporotic
patient. The stimulatory effects of IGF-I on bone formation in
GH-deficient patients suggest an intrinsic action of this peptide on
osteoblasts. In fact, IGF-I has been shown to support proliferation,
differentiation, and matrix synthesis in cultures of osteoblast-like
cells and bone organ cultures. In vitro, IGF-I is a potent
stimulator of the production of type I collagen, the main structural
protein of bone (4, 38, 39). IGF-I was also found to increase
procollagen 1(I) mRNA expression both in osteoblasts
in vitro and in bone in vivo (14, 39, 40).
Osteoblasts express type I IGF receptors and are responsible for bone formation. By contrast, IGF-I has not been shown to exert a direct effect on the activity of mature osteoclasts. The increase in resorption markers possibly reflects an indirect osteoclast activation mediated by a stimulation of osteoblasts, as shown in vitro (41).
Both GH and IGF-I increase glomerular filtration rate (20, 42) and
production of 1,25-(OH)2D3 in vivo
(21, 43, 44). IGF-I stimulates the production of
1,25-(OH)2D3 by kidney cells in
vitro (45). However, the effects of IGF-I on
1,25-(OH)2D3 production have not been tested in
GH-deficient human subjects. The results of the present study provide
further evidence that IGF-I stimulates the production of
1,25-(OH)2D3 independently of GH. The lack of
any concomitant change in PTH, phosphate, and calcium levels, which are
important regulators of renal 1-hydroxylase is compatible with a
direct stimulatory effect of IGF-I on 1-hydroxylase. Our findings in
GH-deficient patients support the notion that IGF-I mediates the
stimulatory effect of GH on 1,25-(OH)2D3
production independently of circulating PTH, as recently suggested
(46). The increased total and free concentrations of
1,25-(OH)2D3 did not significantly change serum
calcium and circulating PTH levels. Urinary calcium is known to be more
sensitive than serum calcium in detecting actions of increased levels
of circulating 1,25-(OH)2D3. The observed rise
in urinary calcium may reflect increased net uptake by the gut and/or
increased net efflux from the skeleton. We cannot answer the question
why PTH secretion was not decreased despite significant elevation of
1,25-(OH)2D3 and a trend for a rise in serum
calcium. Speculatively, GH and IGF-I might downregulate the expression
of calcium-sensing receptors or influence the expression of PEX (a
phosphate-regulating gene with homology to endopeptidases located on
the X chromosome) and the activity (or secretion) of its
putative substrate, phosphatonin, in target tissues.
The age-related concomitant decline of IGF-I concentrations in serum, human cortical bone (47, 48), and of renal synthesis of 1,25-(OH)2D3 (18) could contribute to the decrease in cortical bone mass in aged persons of both sexes. Administration of GH or IGF-I increases serum IGF-I and the production of collagen in bone as well as the production of 1,25-(OH)2D3 by the kidneys, indicating that these tissues are (and remain upon aging) responsive to the two hormones. GH and IGF-I may also prevent the senile component of osteoporosis, which appears to result mainly from defective bone formation. Only long-term clinical trials will tell us whether the IGF-I effects on bone metabolism are sustained and lead to an increase in bone mass.
Conclusions: our data demonstrate that IGF-I administration, similarly
to GH, stimulates bone metabolism and the production of
1,25-(OH)2D3 in GH-deficient adults. Because
the increase in markers of bone formation was not preceded by an
increase in resorption markers, IGF-I may exert a direct anabolic
effect on bone forming cells in vivo. IGF-I appears also to
stimulate renal 1-hydroxylase activity directly, as PTH, calcium,
and phosphate remained unchanged.
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Acknowledgments |
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Footnotes |
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Received June 26, 1997.
Revised September 17, 1997.
Accepted September 25, 1997.
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References |
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