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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2004-1650
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The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 6 3371-3380
Copyright © 2005 by The Endocrine Society

Growth Hormone Replacement Is Important for the Restoration of Parathyroid Hormone Sensitivity and Improvement in Bone Metabolism in Older Adult Growth Hormone-Deficient Patients

H. D. White, A. M. Ahmad, B. H. Durham, A. Patwala, P. Whittingham, W. D. Fraser and J. P. Vora

Department of Diabetes and Endocrinology (H.D.W., A.M.A., A.P., P.W., J.P.V.), Royal Liverpool University Hospital, Liverpool L7 8XP, United Kingdom; and Department of Clinical Biochemistry (B.H.D., W.D.F.), Royal Liverpool University Hospital, Liverpool L69 3GA, United Kingdom

Address all correspondence and requests for reprints to: Dr. Helen White, Department of Diabetes and Endocrinology, Link 7C, Royal Liverpool University Hospital, Prescot Street, Liverpool L7 8XP, United Kingdom. E-mail: h.white{at}ukf.net.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Alterations in PTH circadian rhythm and PTH target-organ sensitivity exist in adult GH-deficient (AGHD) patients and may underlie the pathogenesis of AGHD-related osteoporosis. GH replacement (GHR) results in increased bone mineral density, but its benefit in AGHD patients over 60 yr old has been debated.

To examine the effect of age on changes in PTH circadian rhythm and target-organ sensitivity after GHR, we recruited 22 AGHD patients (12 were <60 yr of age, and 10 were >60 yr of age). Half-hourly blood samples were collected for PTH, calcium, phosphate, nephrogenous cAMP (marker of renal PTH activity), type-I collagenß C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker) before and after 1, 3, 6, and 12 months of treatment with GHR.

Significant PTH circadian rhythms were present in both age groups throughout the study. After GHR, PTH decreased and nephrogenous cAMP, adjusted calcium, and bone turnover markers increased in both groups, suggesting increased PTH target-organ sensitivity. In younger patients, the changes were significant after 1 month of GHR, but, in older patients, the changes were delayed until 3 months, with maximal changes at 12 months.

Older AGHD patients derive benefit from GHR in terms of improvement in PTH sensitivity and bone metabolism. Their response appears delayed and may explain why previous studies have not shown a positive effect of GHR on bone mineral density in older AGHD patients.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ADVANCING AGE IS associated with a decline in spontaneous and stimulated GH secretion, thereby leading to an age-related reduction in serum GH and IGF-I concentrations (1, 2, 3, 4). After puberty, GH secretion reduces by approximately 14% for each decade of adult life in both men and women and is compounded by a simultaneous reduction in serum GH half-life (5). In parallel with decreased GH concentrations, healthy elderly individuals have an increased prevalence of osteoporosis compared with gender-matched younger subjects (6, 7, 8). Osteoporosis is also a feature of adult GH deficiency syndrome (AGHD) (9). As such, it has been hypothesized that the ageing process may be due to a relative GH deficiency state (8).

Older patients (>60 yr old) with hypothalamic-pituitary disease develop GH deficiency distinct from the natural decline in GH secretion associated with ageing (10), with significantly lower 24-h GH secretion, arginine-stimulated GH response, and IGF-I concentrations than age-matched controls (10). It has been suggested that the development of AGHD after the attainment of peak bone mass does not result in a reduction in bone mineral density (BMD) greater than that of an age- and gender-matched population (11, 12). However, it is recognized that GH is required not only to reach, but also to maintain, peak bone mass, thereby providing a mechanism for the development of osteoporosis in AGHD, whatever the age of onset (13, 14). There is no significant difference in the prevalence of osteoporotic fractures between older and younger patients with AGHD (15). Furthermore, bone turnover is lower (11, 16) and osteoporotic fracture rates are 2.66-fold higher in AGHD patients over 60 yr of age, compared with an age-matched healthy control population (15), indicating the presence of bone pathology additional to that observed in the general elderly population. To date, the majority of studies determining the effect of GH replacement (GHR) on bone metabolism have focused on younger AGHD patients (17, 18, 19, 20), and little data exist in older patients, prompting some authors to question the benefit of GHR in older AGHD patients (11, 21).

PTH is important in the control of bone metabolism (22, 23), and previous studies have suggested that patients with AGHD have alterations in PTH circadian rhythmicity and a reduction in the sensitivity of the kidney and bone to its effects (24). In combination, both mechanisms may be responsible for the reduction in bone turnover and the development of osteoporosis associated with AGHD (24). AGHD results in abnormalities of renal phosphate handling, which may also contribute to the pathogenesis of AGHD-related osteoporosis (24). GHR leads to increases in the maximal renal tubular phosphate reabsorption, sensitivity of the target organs to PTH, and bone turnover, all of which are likely to be important in the improvement in BMD reported following GHR treatment (25).

The aim of this study was to investigate the effect of age on PTH circadian rhythm, PTH sensitivity, and bone turnover in patients with untreated AGHD and to determine the role of GHR in older AGHD patients, in terms of changes in PTH sensitivity, bone mineral metabolism, and bone turnover.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

Twenty-two patients with severe AGHD were recruited to the study. Twelve patients (six men) were younger than 60 yr of age at recruitment (mean ± SEM: 48.2 ± 2.4 yr, range 26–57 yr), and 10 patients (five men) were older than 60 yr (mean ± SEM: 63.8 ± 1.2 yr, range 60–68 yr). The number of patients recruited to the study was determined from a power calculation performed using data from our previous studies (25). The SD of the mean change in PTH in our previous studies was 1.9 pg/ml. The difference of interest for PTH was 5.7 pg/ml. The standardized difference (2x difference of interest/SD) was 6, which resulted in a power greater than 95% when at least 10 patients were recruited to each group, using the normogram presented by Altman (26). Equal numbers of men and women were recruited to each group, thereby eliminating the effect of gender on the outcome. Patients were recruited in equal numbers per month over a 6-month period.

Severe AGHD was defined as a peak GH response of less than 9 mU/liter (3 µg/liter) to hypoglycemia [blood glucose <40 mg/dl (2.2 mmol/liter)] induced during an insulin stress test. All patients had undergone pituitary surgery and were subsequently diagnosed with hypopituitarism. Patients were naive to previous treatment with GHR and were optimally replaced on all other pituitary hormones. In particular, all women recruited to the study were on combined estrogen and progesterone replacement if serum estradiol levels were less than 40 pg/ml (150 pmol/liter). Baseline characteristics of each patient are shown in Table 1Go.


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  		TABLE 1. Patient diagnoses and demographics

 
Methods

Before the commencement of GHR, all patients were hospitalized at 1300 h for a period of 25 h. An indwelling venous cannula was inserted in the antecubital fossa of each patient at the time of admission, and blood samples were collected every half hour from 1400 h on the day of admission to 1400 h the following day. Samples were centrifuged immediately at –4 C, and serum was separated to be frozen at –70 C for later analysis. Urine samples were collected at 3-hourly intervals between 1400 and 2300 h and between 0800 and 1400 h, and aliquots were stored at –20 C for later analysis. Each patient was served standardized hospital meals at 0800, 1200, 1800, and 2200 h. Subjects remained recumbent during 2300–0800 h and slept during this period.

After baseline sampling, GH was commenced at a standard daily dose of 0.2 mg, which was self-injected using an automated pen device at 2200 h every night. GH dose was titrated 2 wk after commencement, by increments of 0.1 mg/d, according to IGF-I concentration, with the aim of maintaining IGF-I within 2 SD values (SDS) of the age-related reference range (IGF SDS). Study visits were repeated 1, 3, 6, and 12 months after the initiation of GHR. The Royal Liverpool University Hospital Ethics Committee approved the study, and written informed consent was obtained from each patient before recruitment.

Biochemistry

Serum calcium, phosphate, creatinine, and albumin were measured on all samples by the standard autoanalyzer method (Hitachi 747; Roche Diagnostics, Lewes, UK). Serum calcium was adjusted for albumin (27). Serum adjusted calcium (ACa) has been shown to strongly correlate with ionized calcium and has been found to be precise in subjects with calcium and albumin within the reference range (27, 28). Plasma PTH (1–84) was measured on all samples using a commercial assay (Nichols Institute, San Juan Capistrano, CA), with a detection limit of 4.8 pg/ml and intra- and interassay coefficients of variance (CVs) of less than 7% across the working range.

Serum 1,25-dihydroxyvitamin D [1,25(OH)2D] was extracted by acetonitrile, purified through C18-OH reverse phase column, and measured by RIA (Nichols Institute Diagnostics) with tritiated recovery on each sample. The intraassay CV was less than 9% and the interassay CV was less than 12% across the working range, with a detection limit of 6 ng/ml. Serum 25-hydroxyvitamin D (25-OHD) was measured using an RIA kit (Diasorin, Inc., Stillwater, MN) after acetonitrile extraction. The intraassay CV was less than 8%, and the interassay CV was less than 11%, with a detection limit of 1.6 ng/ml.

Plasma concentration of type-I collagenß C-telopeptide (ßCTX), a marker of bone resorption, and procollagen type-I amino-terminal propeptide (PINP), a marker of bone formation, were measured using electrochemiluminescence assays (ELECSYS; Roche Diagnostics). The intraassay CV and interassay CV for ßCTX were less than 4% and less than 5%, respectively, across the working range, with a detection limit of 0.01ng/ml; and the intraassay CV and interassay CV for PINP were less than 2% and less than 2.5%, respectively, across the working range, with a detection limit of 4 µg/liter.

Urine creatinine, calcium, and phosphate were analyzed on all samples using standard laboratory methods (Roche Diagnostics). The renal threshold for maximum tubular phosphate reabsorption rate (TmPO4/GFR; mg/dl of GFR) was derived from the normogram by Walton and Bijvoet (29).

Nephrogenous cAMP (NcAMP), which is a reliable index of PTH activity at the level of the kidney (30), was determined from the formula: NcAMP = (SCr x UcAMP/Ucr) – PcAMP, where NcAMP is expressed as nanograms per milliliter GFR, SCr is serum creatinine in milligrams per deciliter, UcAMP is urine cAMP in nanograms per milliliter, Ucr is urine creatinine in milligrams per deciliter, and PcAMP is plasma cAMP in nanograms per milliliter. Plasma cAMP (PcAMP) was measured by RIA (BIOTRAC cAMP; Amersham Pharmacia Biotech, Little Chalfont, UK). The intraassay CV was less than 8% and the interassay CV was less than 10% across the working range, with a detection limit of 5 ng/ml. Urine cAMP (UcAMP) was measured by in-house RIA as previously described (31). The intra- and interassay CVs were less than 8 and 10%, respectively, with a detection limit of 0.2 ng/ml. Creatinine clearance (in milliliters per minute) was calculated from the formula (urine flow rate in milliliters per minute x serum creatinine in milligrams per deciliter)/urine creatinine in milligrams per deciliter).

IGF-I was measured with a specific RIA in the presence of a large excess of IGF-II (Mediagnost, Tübingen, Germany) to block the interference of IGF-binding proteins (32). Intra- and interassay CVs were 1.6 and 6.4%, respectively. The IGF-I normal ranges were established with a cohort of 450 healthy adults (age 18–80 yr; 225 men). The distribution of the values obtained was log normal; consequently, the measured values were log-transformed before additional calculations. Means and SD of the log IGF-I values were calculated for age intervals (10 yr). Best-fit regression curves were then derived for means and mean minus SD. IGF SDS were then calculated using the formula log IGF-1 – mean/SD.

Statistical analysis

To determine the circadian rhythm parameters of PTH and phosphate, individual and population-mean cosinor analysis was performed using Chronolab 3.0 (Universdad de Vigo, Pontevedra, Spain), a software package for analyzing biological time series by least-squares estimation (33). The software provides the following circadian parameters: 1) midline estimate statistic of rhythm (MESOR), defined as the rhythm-adjusted mean or the average value of rhythmic function fitted into the data; 2) acrophase, defined as the lag between a defined reference time (1400 h of the first day in our study when the fitted period is 24 h) and time of peak value of the crest time in the cosine curve fitted to the data; and 3) amplitude, defined as half the extent of rhythmic change in a cycle approximated by the fitted cosine curve (difference between the maximum value measured at acrophase and the MESOR of the fitted curve).

General linear model ANOVA for repeated measures was used to analyze the data. To allow for multiple comparisons, Student’s t test for paired data with Bonferroni’s correction was then applied to determine the significance of the intraage differences between visits, and Student’s t test for unpaired data was used to determine the significance of inter-age differences. For all analyses, P < 0.05 was considered significant. Values are expressed as the mean ± SEM unless otherwise stated.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
IGF and GH dose

There was no significant difference in duration of disease (10.7 ± 2.4 vs. 7.8 ± 1.7 yr, P = 0.58) or body mass index (29.5 ± 1.1 vs. 34.6 ± 2.6 kg/m2, P = 0.06) between the younger and older AGHD patients, respectively. At baseline, the IGF SDS was –3.17 ± 0.51 in the younger group and –2.72 ± 1.17 in the older group (P = 0.38). The largest increase in IGF SDS was between 0 and 1 month in both age groups [–0.54 ± 0.56 at 1 month (P = 0.003) for patients <60 yr; –0.38 ± 0.96 at 1 month (P = 0.002) for patients >60 yr; P = 0.69 for difference in IGF SDS between the age groups at 1 month]. Thereafter, there was no significant change in IGF SDS in either group. In addition, there was no significant difference between the groups in IGF SDS or GH dose (0.32 ± 0.02 mg in younger patients vs. 0.29 ± 0.03 mg in older patients, P = 0.86). Patient 4 required temporary down-titration of GH dose during month 4 of the study due to symptoms of carpel tunnel syndrome. No other adverse events were recorded.

PTH

At baseline, the 24-h mean PTH concentration was significantly higher in the older group than in the younger group [42.3 ± 0.8 pg/ml (4.45 ± 0.08 pmol/liter) vs. 40.6 ± 0.7 pg/ml (4.27 ± 0.07 pmol/liter), P < 0.001; Fig. 1Go]. After 1 month of GHR, 24-h mean PTH concentration decreased significantly in the younger group [39.0 ± 0.7 pg/ml (4.10 ± 0.07 pmol/liter), P < 0.001]. It remained below baseline at all subsequent visits: 38.6 ± 0.7 pg/ml (4.06 ± 0.07 pmol/liter) at 3 months; 35.1 ± 0.7 pg/ml (3.69 ± 0.07 pmol/liter) at 6 months; and 38.8 ± 0.7 pg/ml (4.08 ± 0.07 pmol/liter) at 12 months, all P < 0.005 compared with baseline. In the older patients, 24-h mean PTH concentration decreased significantly after 3 months of GHR [40.7 ± 0.8 pg/ml (4.28 ± 0.08 pmol/liter), P < 0.001, compared with baseline], after which PTH concentration stayed significantly below baseline [40.0 ± 0.9 pg/ml (4.21 ± 0.09 pmol/liter) and 35.9 ± 1.0 pg/ml (3.78 ± 0.11 pmol/liter) for both 6- and 12-month visits, respectively, P < 0.001]. The maximum percentage decrease in 24-h mean PTH concentration occurred after 6 months of GHR in the younger group (11.9 ± 1.1%) and at 12 months in the older group (14.8 ± 1.1%), but the percentage decrease was not significantly different between the groups (P = 0.07).



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  		FIG. 1. Conversion factors for SI units are: x0.105 for PTH, x0.250 for ACa, x0.323 for serum phosphate, x0.323 for TmPO4, x0.417 for 1,25(OH)2D, x0.4 for 25OHD. *, P < 0.05 within age group compared with baseline. **, P < 0.01 within age group compared with baseline. ***, P < 0.001 within age group compared with baseline. +, P < 0.05 between age groups compared with baseline. ++, P < 0.01 between age groups compared with baseline. +++, P < 0.001 between age groups compared with baseline.

 
Individual and population cosinor analyses demonstrated significant PTH circadian rhythms for all patients at all visits (P < 0.001; Fig. 2Go). Before the commencement of GHR, the mean PTH MESOR was significantly higher in the older than in younger patients [42.9 ± 2.7 pg/ml (4.52 ± 0.28 pmol/liter) vs. 40.4 ± 2.0pg/ml (4.25 ± 0.21 pmol/liter), P = 0.04], but there was no significant difference in the amplitude [5.4 ± 2.4 pg/ml (0.57 ± 0.25 pmol/liter) vs. 6.0 ± 1.0 pg/ml (0.63 ± 0.10 pmol/liter) for older and younger patients respectively, P = 0.53] or acrophase (–161 ± 45 vs. –161 ± 48 degrees for older and younger patients, respectively, P = 0.72). The PTH MESOR decreased significantly by 1 month of GHR in the younger patients [38.1 ± 2.0 pg/ml (4.01 ± 0.21 pmol/liter)] and 3 months in the older patients [41.2 ± 2.8 pg/ml (4.34 ± 0.29 pmol/liter)] (both P < 0.05, compared with baseline). Maximum changes in PTH MESOR occurred at 6 months [34.9 ± 2.7 pg/ml (3.67 ± 0.28 pmol/liter)] and at 12 months [36.5 ± 2.1 pg/ml (3.84 ± 0.22 pmol/liter)] for younger and older patients respectively, with no significant difference in the percentage decrease observed (P = 0.09). The amplitude and acrophase of the PTH circadian rhythm did not differ significantly between the groups or within the groups at the follow-up visits.



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  		FIG. 2. Cosinor-derived PTH rhythms before and 12 months after GHR. Bold lines represent younger patients and dotted lines represent older patients before (A) and after (B) 12 months GHR. Arrows (bold, younger patients; dotted, older patients) represent the acrophase in degrees. PTH expressed as picograms per milliliter (conversion factor to picomoles per liter x0.105)

 
PTH circadian rhythmicity was maintained in both age groups at all visits. A sustained peak in PTH concentration was observed between 1400 and 2300 h in both groups before GHR (Fig. 3Go). The maximum percentage increase in PTH concentration between 1400 and 2300 h (or percentage increase of afternoon/evening peak, calculated from [(maximum value between 1400 and 2300 h – nadir value between 1400 and 2300 h)/nadir value between 1400 and 2300 h x 100]) at baseline was 25.2 and 28.1%, in the younger and older patients, respectively (P = 0.68), and did not change significantly in either group after GHR. The mean percentage change in PTH concentration between 1400 and 2300 h [(value at each time point – 1400 h value)/1400-h value x 100] decreased significantly at 1 month in the younger patients (P = 0.01) and at 6 months in the older patients (P = 0.004, compared with baseline). Thus, a reduction in mean percentage increase in PTH concentration between 1400 and 2300 h, without significant change in the maximum percentage increase in the afternoon/evening peak, indicated a narrower peak after GHR, occurring at 1 and 6 months in younger and older patients, respectively.



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  		FIG. 3. Twenty-four-hour PTH profiles. PTH expressed as picograms per milliliter (conversion factor to picomoles per liter x 0.105)

 
At baseline, there was no significant difference in mean PTH concentration between 1400 and 2300 h and 2300 and 0800 h in either group (Table 2Go). After GHR, 2300- to 0800-h mean PTH concentration became significantly higher than the 1400- to 2300-h mean PTH concentration at 1 month in younger patients (P = 0.002) and 6 months in older patients (P = 0.01), with a significant difference persisting to the end of the study (P = 0.008 and P = 0.04 for younger and older patients, respectively, compared with baseline).


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  		TABLE 2. Mean PTH concentrations (pg/ml) at 1400–2300 h and 2300–0800 h

 
The nocturnal/early morning rise in PTH concentration (or maximum percentage increase in PTH concentration between 2300 and 0800 h [(maximum value between 2300 and 0800 h – 2300 h value)/2300 h value x 100]) was significantly higher in the younger group at baseline (20.6 vs. 14.5%, P = 0.02). After GHR, the nocturnal/early morning rise in PTH concentration increased in both groups, reaching significance at 3 months in the younger patients (29.7%, P = 0.007 compared with baseline) and at 6 months in the older patients (20.8%, P = 0.03). The nocturnal/early morning rise in PTH remained significantly higher in the younger group at the end of the study (35.4 vs. 24.9%, P < 0.001).

NcAMP

At the beginning of the study, the older group had a significantly higher 24-h mean NcAMP than the younger group (16.2 ± 1.6 vs. 12.6 ± 1.7 ng/ml GFR, P = 0.048). NcAMP levels increased significantly after 1 month GHR in the younger group (20.8 ± 2.0 ng/ml GFR, P = 0.001) and after 3 months in the older group (24.8 ± 2.0 ng/ml GFR, P < 0.001). At visits subsequent to 1 month in the younger group, NcAMP decreased back toward baseline and by 12 months was not significantly different from baseline (11.8 ± 1.8 ng/mlGFR, P = 0.77). Mean NcAMP remained significantly above baseline in the older group at 6 and 12 months (25.2 ± 1.8 and 25.4 ± 1.8 ng/ml GFR, respectively, P < 0.001). The maximum percentage increase in mean NcAMP occurred after 1 and 12 months of GHR in the younger and older patients, respectively, and was not significantly different between the groups (65.0 ± 4.3 and 56.7 ± 5.4%, respectively, P = 0.09).

Serum adjusted calcium (ACa)

Twenty-four-hour mean ACa was significantly higher at baseline in the older than in the younger patients [9.28 ± 0.2 mg/dl (2.32 ± 0.004 mmol/liter) vs. 9.24 ± 0.02 mg/dl (2.31 ± 0.004 mmol/liter), P = 0.004]. In the younger group, serum ACa increased significantly, reaching a maximum after 1 month of GHR [9.52 ± 0.02 mg/dl (2.38 ± 0.004 mmol/liter, P < 0.001], and decreasing to below baseline at 6 months [9.12 ± 0.02 mg/dl (2.28 ± 0.004 mmol/liter), P < 0.001 compared with baseline]. After 3 months of GHR in the older group, 24-h mean ACa increased significantly [9.40 ± 0.02 mg/dl (2.35 ± 0.004 mmol/liter), P < 0.001], reaching a maximum by 6 months [9.52 ± 0.02 mg/dl (2.38 ± 0.005 mmol/liter), P < 0.001] and returning to baseline by 12 months [9.28 ± 0.02 mg/dl (2.32 ± 0.004 mmol/liter), P = 0.98 compared with baseline]. The percentage change for maximum ACa increase was not significantly different between the groups (3.0 ± 0.2 vs. 2.6 ± 0.2% for the younger and older patents respectively, P = 0.07).

Serum phosphate (PO4)

In the older group, 24-h mean serum PO4 was significantly lower at baseline [3.19 ± 0.03 mg/dl (1.03 ± 0.010 mmol/liter) vs. 3.44 ± 0.02 mg/dl (1.11 ± 0.008 mmol/liter), P < 0.001] and at all subsequent visits [3.38 ± 0.03 mg/dl (1.09 ± 0.010 mmol/liter) vs. 3.88 ± 0.02 (1.25 ± 0.008 mmol/liter); at 1 month, P < 0.001; 3.60 ± 0.03 mg/dl (1.16 ± 0.010 mmol/liter) vs. 3.97 ± 0.02 mg/dl (1.28 ± 0.008 mmol/liter); at 3 months, P < 0.001; 3.50 ± 0.03 mg/dl (1.13 ± 0.010 mmol/liter) vs. 3.78 ± 0.02 mg/dl (1.22 ± 0.008 mmol/liter); at 6 months, P < 0.001; 3.63 ± 0.03 mg/dl (1.17 ± 0.010 mmol/liter) vs. 3.78 ± 0.02 mg/dl (1.22 ± 0.008 mmol/liter); and at 12 months, P < 0.001]. After initiation of GHR, serum PO4 increased significantly in both age groups by 1 month (P < 0.001), to reach a maximum at 3 months (P < 0.001). Thereafter, 24-h mean PO4 concentration decreased significantly (P < 0.01) but remained above baseline in both groups of patients (P < 0.001). Although the maximum serum PO4 concentration was significantly higher in the younger patients (P < 0.001), there was no significant difference in maximal percentage PO4 increase between the groups (16.0 ± 0.8 vs. 17.1 ± 1.2% for younger and older groups, respectively, P = 0.43). All patients had significant PO4 circadian rhythms at all visits (P < 0.001).

Vitamin D

There was no significant difference in baseline 1,25(OH)2D or 25OHD concentration [29.8 ± 3.0 pg/ml (71.5 ± 7.2 pmol/liter) vs. 31.5 ± 3.1 pg/ml (75.6 ± 7.7 pmol/liter), P = 0.74 for 1,25(OH)2D; 24.4 ± 1.0 ng/ml (61.1 ± 2.2 nmol/liter) vs. 23.6 ± 0.8 ng/ml (59.0 ± 2.1 nmol/liter), P = 0.50 for 25OHD] between the younger and older patients, respectively. 1,25(OH)2D increased significantly in both groups after 3 months GHR (P = 0.009 for younger patients, P = 0.03 for older patients). Percentage increase in 1,25(OH)2D at 3 months was significantly higher in the younger patients (35.3 ± 3.3 vs. 30.6 ± 2.7%, P = 0.03), but there was no significant difference in maximal percentage increase between the groups (48.7 ± 5.3 vs. 45.6 ± 4.7%, P = 0.08, for younger and older patients, respectively). 25OHD increased significantly in both groups after1 month GHR (P < 0.001), and there was no significant difference in maximal percentage increase (65.4 ± 7.3 vs. 60.7 ± 5.2%, P = 0.09) for younger and older patients, respectively.

Bone turnover markers

In the older patients, 24-h mean ßCTX and PINP were significantly lower at baseline (0.11 ± 0.01 vs. 0.21 ± 0.01 ng/ml and 29.5 ± 1.9 vs. 45.9 ± 1.3 µg/liter, respectively, P < 0.001) and remained lower for the duration of the study (P < 0.001, Fig. 1Go). After 1 month of GHR, both markers increased significantly in the younger patients (0.24 ± 0.01 ng/ml, P = 0.03 for ßCTX and 60.3 ± 1.3 µg/liter, P < 0.001 for PINP), reaching a maximum at 12 months (0.45 ± 0.01 ng/ml and 80.7± µg/liter, respectively, P < 0.001). In older patients, 24-h mean ßCTX and PINP increased significantly after 3 months of GHR (0.19 ± 0.01 ng/ml and 36.8 ± 1.9 µg/liter, respectively, P < 0.001) and reached a maximum at 12 months (0.20 ± 0.01 ng/ml and 48.9 ± 1.9 µg/liter, respectively, P < 0.001). The maximum percentage increase in serum ßCTX and PINP were significantly higher in the younger than in the older patients (117.9 ± 6.0 vs. 90.3 ± 6.5%, P = 0.003 for ßCTX and 76.0 ± 1.1 vs. 66.3 ± 2.0%, P < 0.001 for PINP).

During the first and third months of GHR, 24-h mean ßCTX increased by 14.5 ± 0.9 and 76.0 ± 1.3%, respectively, in the younger patients compared with increases of 29.3 ± 2.8 and 61.0 ± 2.5% in PINP; in the older patients, 24-h mean ßCTX increased by 27.8 ± 1.2 at 1 month and by 72.6 ± 1.8% at 3 months, whereas PINP increased only by 14.3 ± 2.2 at 1 month and 24.7 ± 2.5% at 3 months (P < 0.001 between differences in ßCTX and PINP in each age group at both time points). Of the total increase in ßCTX, 66.7 ± 9.4% occurred in the first 3 months of GHR in younger patients compared with 88.7 ± 8.0% in older patients (P = 0.002). However, 80.5 ± 7.4% of the total increase in PINP occurred in the initial 3 months of treatment in younger patients compared with only 38.9 ± 6.4% in older patients (P < 0.001).

Urine calcium excretion (UCa)

The urine calcium creatinine ratio was significantly lower in the older patients at baseline (0.30 ± 0.04 vs. 0.55 ± 0.03, P < 0.001). After GHR, the urine calcium creatinine ratio did not change significantly in the older patients (P = 0.90), but decreased significantly in the younger group, after 1 month (0.41 ± 0.03, P < 0.001), remaining below baseline for the remainder of the study (P < 0.01). At the end of the study period, the urine calcium creatinine ratio was not significantly different between the age groups (0.30 ± 0.04 vs. 0.39 ± 0.03 for older and younger patients, respectively, P = 0.1).

Urine phosphate excretion (UPO4)

Before GHR, there was no significant difference in urine phosphate creatinine ratio between the groups (1.79 ± 0.14 and 1.92 ± 0.11 for older and younger patients, respectively, P = 0.5). For the study duration, the phosphate creatinine ratio did not change significantly in the older patients (P = 0.7); however, in the younger patients, there was a significant increase after 3 months GHR (2.43 ± 0.11, P = 0.002), followed by a decrease below baseline after 6 months (1.66 ± 0.11, P = 0.02 compared with baseline).

TmPO4/GFR was significantly lower at baseline in the older patients (2.51 ± 0.06 mg/dl GFR (0.81 ± 0.02 mmol/liter GFR) vs. 2.85 ± 0.06 mg/dl GFR (0.92 ± 0.02 mmol/liter GFR), P < 0.001). In both groups, TmPO4/GFR increased significantly after 1 month of GHR (2.95 ± 0.06 mg/dl GFR (0.95 ± 0.02 mmol/liter GFR) and 3.41 ± 0.06 mg/dl GFR (1.10 ± 0.02 mmol/liter GFR) for older and younger patients, respectively, P < 0.001), and it remained above baseline for the duration of the study (P < 0.001). TmPO4/GFR remained lower in the older patients for the duration of the study (P < 0.001).

Creatinine clearance

There was no significant difference in creatinine clearance between the younger and older patients (127.9 ± 11.4 vs. 114.0 ± 8.2 ml/min, respectively, P = 0.45).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Untreated older adults with GH deficiency had a higher 24-h mean PTH, with concomitant higher mean NcAMP and serum ACa, and lower 24-h mean serum PO4, TmPO4/GFR and UCa compared with gender-matched younger AGHD patients. Bone turnover markers were lower in the older AGHD group, signifying a relative reduction in bone remodeling and suggesting a differential response of the kidney and bone to the effects of PTH in untreated older AGHD patients. A relative resistance of the parathyroid gland calcium sensing receptors has previously been reported in untreated AGHD compared with GHR patients (34). As a consequence, in untreated AGHD patients, larger changes in serum Ca need to be achieved before an adaptive response in PTH secretion can occur (34). The significantly higher 24-h mean PTH, NcAMP, and serum ACa observed in our older untreated AGHD patients may have occurred as a result of a greater parathyroid gland resistance in this group, which would allow serum Ca to remain relatively higher than in the younger patients without a reduction in PTH concentration.

After GHR, renal and skeletal PTH sensitivity increased in both older and younger AGHD patients, as indicated by a decrease in PTH concentration and by increases in NcAMP, ACa, 1,25(OH)2D, and bone turnover markers. In the younger patients, the increase in renal PTH sensitivity was observed after 1 month of GHR, when the change in NcAMP was maximal. In the older patients, significant increases in renal sensitivity to PTH were seen at 3 months of GHR and did not reach a maximum until 12 months. The maximal decrease in PTH occurred after 6 months of GHR in the younger group, and a new equilibrium state was observed, with NcAMP decreasing to baseline and serum adjusted calcium decreasing to below baseline. Although maximal changes in PTH, NcAMP, ACa, and 1,25(OH)2D occurred at 12 months in older patients, NcAMP excretion remained high, suggesting equilibrium had not yet been achieved. The magnitude of improvement in renal PTH sensitivity was similar in both age groups, with no significant difference in maximal percentage changes in PTH, NcAMP, ACa, and 1,25(OH)2D between the groups, but it is possible that GHR beyond 12 months would result in further changes in PTH sensitivity in the older patients. 1{alpha}-Hydroxylase activity is mediated by PTH and, therefore, the increase in 1,25(OH)2D observed in both groups may reflect the increase in PTH target-organ sensitivity seen after GHR (35). The significantly higher percentage increase in 1,25(OH)2D occurring at 3 months in the younger group may be a result of the earlier improvement in PTH target-organ sensitivity seen in this group. 25OHD is less well regulated than 1,25(OH)2D (36). The significant increase in 25OHD seen at 1 month in both groups mirrors the improvement in quality of life consistently reported after GHR and, thus, may reflect increased outdoor activity occurring as a result of the increased vitality and well-being observed after 1 month of GHR (37, 38, 39, 40, 41).

Bone turnover markers increased significantly after 1 month of GHR in the younger group and after 3 months treatment in the older group, suggesting a delay in bone cell response and sensitivity to the effects of PTH in the older group. In both groups, markers of bone turnover continued to increase for the duration of the study. The percentage increase in both bone markers was significantly higher in the younger group, but a similar increase in bone turnover might have been observed in both groups, had the study been of longer duration. Simultaneous changes in bone resorption and bone formation are important for maintenance of bone mass (42). The majority of bone resorption and formation increase in the younger patients, and bone resorption increase in the older patients, was complete by 3 months of GHR, but the majority of bone formation increase in the older group occurred between 3 and 12 months of GHR. In older AGHD patients, resorption relatively exceeded formation until after 3 months of GHR, suggesting a relative uncoupled state, which may have resulted in a negative equilibrium of bone turnover, thus providing a mechanism of delay in BMD improvement.

PTH plays an important role in bone metabolism (43, 44), and fluctuations in PTH concentration are necessary for physiological bone remodeling. In support of this concept, continuous PTH administration has a catabolic effect on bone metabolism, whereas intermittent administration is anabolic (22). Untreated AGHD patients have a sustained afternoon/evening PTH peak and reduced nocturnal PTH rise compared with healthy adults (24), and such changes in PTH circadian rhythm may be involved in the pathogenesis of osteoporosis in AGHD. Although circadian rhythmicity was maintained in all our patients, there were significant differences in the 24-h PTH profiles within and between the groups, before and after GHR. After GHR, both older and younger AGHD patients developed a significantly narrower afternoon/evening peak of PTH, significant day (1400–2300 h) to nocturnal (2300–0800 h) variation in PTH, and increase in nocturnal PTH peak. In older patients, these alterations in PTH rhythmicity occurred 6 months after GHR compared with 1 month in younger patients in the case of afternoon/evening PTH peak alterations and day/nocturnal variability, and 3 months for an increase in nocturnal peak. The delay in the older patients of changes in PTH circadian rhythm after GHR may have important consequences for the restoration of PTH target-organ sensitivity and normal bone metabolism.

Abnormalities in renal phosphate handling may contribute to the development of osteoporosis in AGHD (25). In health, TmPO4 is modulated by GH, through mechanisms independent of PTH and vitamin D (45). In AGHD, PO4 tubular resorption is reduced, leading to increased UPO4 (24) and a relative phosphate-deficient state, which is reversed by GHR (25). In our study, GHR resulted in significant increases in TmPO4/GFR and serum PO4 in both younger and older age groups, maximal at 1 and 3 months, respectively, and of similar magnitude in both groups. In the younger patients, UPO4 excretion increased significantly 3 months after GHR, coinciding with the significantly higher peak serum PO4. This higher PO4 excretion reflected the higher filtered PO4 load in this group. After 6 months of treatment, serum and urinary PO4 decreased as a new equilibrium was achieved.

The majority of studies looking at GHR and BMD in AGHD conclude that a treatment period of at least 2 yr is required before BMD increases significantly (46, 47, 48, 49). The ages of the patients in most of these studies are comparable with our younger group of patients (46, 47, 49). Maximal changes in PTH rhythmicity, and sensitivity occurred in our younger age group between 1 and 3 months of GHR but did not occur until 6 to 12 months in the older age group. Studies designed to observe the positive effect of GHR on BMD in older AGHD patients need to continue longer than 2 yr. The short duration of previous studies may explain the reported absence of significant change in BMD in older AGHD patients after GHR (50).

The consequences of AGHD are subjectively more apparent in the younger than older patients because of the reduction in GH secretion occurring during the natural ageing process (11, 51, 52). In particular, the increased prevalence of osteoporosis in healthy older patients compared with younger people may reduce the impact of AGHD-related changes in BMD in older patients. Indeed, it has been suggested that reduction in BMD is not a prominent feature in older patients with AGHD (53), resulting in debate regarding the use of GHR for older AGHD patients, particularly if prescribed for the maintenance of skeletal health (11, 21). However, BMD is only a surrogate marker of fracture risk when assessing the benefit of treatment. Fracture risk depends on bone quality, which as well as bone mineralization, takes into account bone size, turnover, and activation frequency of bone remodelling units. The prevalence of fracture rates in AGHD is not affected by age and is increased above that of an age matched healthy population (15, 54). It may be argued that osteoporotic fractures are more important clinically in an older population because of increased associated morbidity and mortality in this age group. We have shown that the abnormalities in PTH rhythmicity and renal sensitivity underlying the pathogenesis of AGHD-related osteoporosis respond to GHR by a similar, albeit delayed, magnitude in older and younger patients. In addition, we did not observe any additional adverse effects to GHR in our older population. Therefore, the administration of GHR may be beneficial, is appropriate, and should be encouraged in AGHD patients older than 60 yr to improve bone metabolism.


   Acknowledgments
 
We are grateful to all the nursing and clerical staff on the Metabolic Bone Unit, Royal Liverpool University Hospital, for all their help and support. We also thank Nick Hoyle (Roche) for the provision of bone marker kits, and Eli Lilly (Indianapolis, IN) and Pfizer (Ann Arbor, MI) for their support.


   Footnotes
 
First Published Online March 1, 2005

Abbreviations: ACa, Serum adjusted calcium; AGHD, adult GH deficiency; BMD, bone mineral density; ßCTX, type-I collagen ß C-telopeptide; CV, coefficient of variance; GHR, GH replacement; MESOR, midline estimate statistic of rhythm; NcAMP, nephrogenous cAMP; PINP, procollagen type-I amino-terminal propeptide; PcAMP, plasma cAMP; PO4, serum phosphate; SDS, SD score; UCa, urine calcium excretion; UcAMP, urine cAMP; UPO4, urine phosphate excretion.

Received August 18, 2004.

Accepted February 22, 2005.


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Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
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