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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2005-1602
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 3 913-919
Copyright © 2006 by The Endocrine Society

Effect of Active Acromegaly and Its Treatment on Parathyroid Circadian Rhythmicity and Parathyroid Target-Organ Sensitivity

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

Department of Diabetes and Endocrinology (H.D.W., A.M.A., S.C., A.P., 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
 
Context: Patients with active acromegaly have increased bone turnover and skeletal abnormalities. Biochemical cure of acromegaly may represent a functional GH-deficient state and result in cortical bone loss. Reduced PTH target-organ sensitivity occurs in adult GH deficiency and may underlie the associated development of osteoporosis.

Objective: We examined the effect of active and treated acromegaly on PTH concentration and target-organ sensitivity.

Patients: Ten active acromegalic subjects (GH nadir > 0.3 µg/liter after 75-g oral glucose load and IGF-I above age-related reference range) and 10 matched controls participated in the study.

Design: Half-hourly blood and 3-h urine samples were collected on patients and controls for 24 h. Samples were analyzed for PTH, calcium (Ca), nephrogenous cAMP (NcAMP, a marker of PTH renal activity), ß C-telopeptide (bone resorption marker), and procollagen type-I amino-terminal propeptide (bone formation marker). Serum calcium was adjusted for albumin (ACa). Eight acromegalic subjects who achieved biochemical cure (GH nadir < 0.3 µg/liter after 75-g oral glucose load and IGF-I within reference range) after standard surgical and/or medical treatment reattended and the protocol repeated.

Results: Active acromegalic subjects had higher 24-h mean PTH, NcAMP, ACa, urine Ca, ß C-telopeptide, and procollagen type I amino-terminal propeptide (P < 0.05), compared with controls. Twenty-four-hour mean PTH increased (P < 0.001) in the acromegalic subjects after treatment, whereas NcAMP and ACa decreased (P < 0.05).

Conclusion: Increased bone turnover associated with active acromegaly may result from increased PTH concentration and action. Biochemical cure of acromegaly results in reduced PTH target-organ sensitivity indicated by increased PTH with decreased NcAMP and ACa concentrations. PTH target-organ sensitivity does not appear to return to normal after successful treatment of acromegaly in the short term and may reflect functional GH deficiency.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
ACROMEGALY IS ASSOCIATED with skeletal changes that are characterized by appositional bone growth, increased bone dimensions, and increased bone turnover (1, 2). Total bone mass is increased in bone biopsies of patients with acromegaly, and histomorphometric studies have revealed an increase in bone matrix resorption and formation surfaces (3). Bone mineral density is normal or elevated in eugonadal patients with active acromegaly (4, 5, 6, 7, 8). Long-term successful treatment of acromegaly appears to result in loss of cortical bone (9).

PTH is an important regulator of bone remodeling (10, 11). The anabolic action of PTH on bone requires the presence of GH (11), and a strong correlation between PTH concentration and bone turnover markers in active and treated acromegaly has led to the suggestion that the effect of GH on bone turnover may be mediated by PTH (12). An increase in PTH, vitamin D, calcium, and phosphate concentration has been identified in active acromegaly (2, 13, 14), but the relationship of these changes to the underlying pathogenesis of bone disease in acromegaly has not been fully elucidated. Successful treatment of acromegaly results in a reduction in markers of bone turnover (12, 15), but previous reports on the effect of PTH have been inconsistent, with an increase, decrease, or no change in concentration reported (5, 12, 15, 16, 17). Healthy subjects exhibit an endogenous PTH circadian rhythm (18), with a nocturnal rise in concentration and a morning nadir. As such, measurement of PTH by venesection at a single variable time point is unreliable (19, 20) and may account for the differences in PTH concentration previously reported in patients with treated acromegaly (5, 12, 15, 16, 17).

Transsphenoidal resection of the GH-secreting pituitary adenoma is the conventional treatment for acromegaly, and where cure is not achieved, adjunctive pituitary radiotherapy, somatostatin analogs, and more recently GH receptor antagonists are used (21, 22, 23). Adequacy of treatment is assessed by measurement of GH nadir after an oral glucose challenge and IGF-I estimation. Modern surgical and medical therapies facilitate aggressive acromegaly management, and as a result it has been suggested that patients may be at risk of developing a functional GH deficiency (24).

In contrast to acromegaly, adult GH deficiency (AGHD) is associated with a reduction in bone turnover and increased prevalence of osteoporosis (25). Abnormalities in PTH circadian rhythmicity, together with a reduction in target-organ sensitivity to the effects of PTH, have been consistently reported in AGHD (19, 20, 25, 26). It has been suggested that the changes in PTH circadian rhythmicity and target-organ sensitivity reported in AGHD may underlie development of reduced bone turnover and bone loss (19, 20). This, therefore, provides the rationale for examining PTH circadian rhythm and sensitivity in active acromegalics, in whom bone turnover and GH levels are increased (1, 2) and in treated acromegalics, in whom a functional GH deficiency may exist (24).

PTH target-organ sensitivity and circadian rhythmicity, and their correlation with bone turnover, have not previously been described in active or treated acromegaly. The aim of our study was to examine the effect of active acromegaly and its treatment on PTH circadian rhythm, PTH target-organ sensitivity, calcium, phosphate, and bone turnover and compare the data with that obtained from a group of age and gender matched healthy controls.


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

The study was carried out in accordance with the Declaration of Helsinki and approved by the Royal Liverpool University Hospital Ethics Committee. Written informed consent was obtained from each patient and healthy control before recruitment. 10 patients (five men) with active acromegaly [defined as GH nadir > 0.3 µg/liter (1 mU/liter) after 75-g oral glucose load and IGF-I above the age-related reference range] and 10 healthy controls (five men) were recruited to the study. Healthy controls were friends or relatives of staff working within the department. There was no significant difference in age (mean ± SD) between the acromegalic patients and healthy controls (55.7 ± 12.2 yr vs. 59.2 ± 10.3 yr, respectively, P = 0.61). Patients received standard conventional treatment with transsphenoidal surgery plus adjunctive radiotherapy/medical therapy where cure was not attained (as defined above) with tests performed 6 wk after surgery (Table 1Go). In patients who received adjunctive treatment, IGF-I was monitored at monthly intervals, and GH response to oral glucose loading was reassessed when IGF-I entered the reference range. Eight of the 10 acromegalic patients (four men) achieved biochemical cure within 12 months of study commencement (as defined above). Dynamic assessment of residual pituitary function was made in all the acromegalic patients before study visits, and pituitary hormones were clinically and biochemically optimally replaced where necessary. In particular, sex steroids were replaced in all women found to be deficient in gonadotrophins, as per our usual practice and in line with guidance form the United Kingdom Department of Health Chief Medical Officer. Three of the five acromegalic women required estrogen therapy: one woman who previously had a hysterectomy received estrogen alone, whereas the other two received combined estrogen and progesterone therapy. Two of the five healthy women controls were postmenopausal and were taking sex steroid replacement as prescribed by their family doctor, as part of their routine care. A lifestyle and dietary assessment of all patients and healthy controls was made before the study visits to ensure all subjects had adequate calcium and vitamin D intake.


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  		TABLE 1. Individual patient characteristics and management

 
We used a GH nadir of less than 0.3 µg/liter (1 mU/liter) in response to oral glucose loading as the definition of biochemical cure of our patients. Although the consensus guidelines published in February 2000 suggest a nadir of less than 1 µg/liter (3 mU/liter) is adequate to define biochemical cure (23), it has since been argued that this cut-off is too high (27). Because the advent of more sensitive GH RIAs and the increasing recognition of the morbidity and mortality caused by active acromegaly, it has been suggested that a lower GH nadir of less than 0.3 µg/liter (1 mU/liter) after oral glucose loading may be more appropriate (27).

All active acromegalics and healthy controls were admitted to the Metabolic Bone Unit of the Royal Liverpool University Hospital at 1300 h for a period of 25 h. Acromegalic patients were admitted before treatment and after biochemical cure. 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/plasma was separated to be frozen at –70 C for later analysis. Urine samples were collected at 3-h intervals between 1400 and 2300 h and 0800 and 1400 h, and aliquots of these samples were stored at –20 C for later analysis. Each patient was served with standardized hospital meals at 0800, 1200, 1800, and 2200 h. Subjects remained recumbent during 2300–0800 h and slept during this period.

Biochemistry

Serum GH concentration was measured using the Advantage chemiluminescence system (Nichols Institute Diagnostics, Nijmegen, The Netherlands). The assay is calibrated against WHO HGH International Standard WHO 80/505 and displays a bias of +3.3% against the United Kingdom External Quality Assessment Scheme. Coefficient of variation (CV) was less than 5%. Serum 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 (28). Intra- and interassay CVs were 1.6 and 6.4%, respectively.

Serum calcium (Ca), phosphate (PO4), creatinine (Cr) and albumin (ACa) were measured on all samples by the standard autoanalyzer method (Hitachi 747, Roche Diagnostics, Lewes, UK). Serum Ca was adjusted for albumin as previously described (29, 30). Serum PTH (1–84) was measured on all samples using a commercial assay (Nichols Institute, San Juan Capistrano, CA), with a detection limit of 0.5 pmol/liter and intra- and interassay CVs of less than 7%.

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%, with a detection limit of 15 nmol/liter.

Plasma concentration of type I collagen-ß 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 immunoassays (ELECSYS, Roche Diagnostics). The intraassay CV and interassay CV for ßCTX was less than 4% and less than 5%, respectively, with a detection limit of 0.01 ng/ml, and the intraassay CV and interassay CV for PINP was less than 2% and less than 2.5%, respectively, with a detection limit of 4 µg/liter.

Urine Cr, Ca, and PO4 were analyzed on all samples using standard laboratory methods (Roche Diagnostics). The renal threshold for maximum tubular PO4 reabsorption rate (TmPO4/glomerular filtration rate (GFR); mmol/liter of GFR) was derived from the normogram by Walton and Bijvoet (31). Nephrogenous cAMP (NcAMP), which is a reliable index of PTH activity at the level of the kidney (32), was determined from the formula: NcAMP = (SCr x UcAMP)/(Ucr – PcAMP), where NcAMP is expressed as nmol/liter GFR, SCr is serum creatinine in µmol/liter, UcAMP is urine cAMP in micromoles per liter, UCr is urine creatinine in millimoles per liter, and PcAMP is plasma cAMP in nanomoles per liter. Urine cAMP (UcAMP) was measured by in-house RIA methods as previously described (19). The intra- and interassay CVs were less than 8 and 10%, respectively, with a detection limit of 0.2 µmol/liter. 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%, with a detection limit of 5 nmol/liter.

Statistical analysis

Individual and population-mean cosinor analyses, to determine circadian rhythm parameters of PTH and phosphate, were performed using Chronolab 3.0 (Universdade de Vigo, Vigo, Spain) (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. Student’s t test for unpaired data, with Bonferroni’s correction to allow for multiple comparisons, was then applied to determine the significance of differences between the acromegalic and control groups. Student’s t test for paired data, with Bonferroni’s correction, was used to determine the difference before and after treatment in the acromegalic patients. Patients who did not achieve biochemical cure were excluded from the active acromegalic group when comparisons were being made with the treated acromegalic group. Correlations were sought using Pearson’s linear correlation coefficient. 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
 
Active acromegaly

Patients with active acromegaly had significantly higher 24 h-mean PTH concentration (P < 0.001) in the presence of significantly higher NcAMP (P = 0.002), ACa (P < 0.001) and 1,25(OH)2D (P = 0.007) than healthy controls (Table 2Go). Urine CaCr ratio was significantly higher in patients with active acromegaly (P < 0.001). Serum PO4 and TmPO4 were significantly higher in patients with active acromegaly (both P < 0.001), whereas urine PO4Cr ratio was significantly lower (P = 0.008). Both measured markers of bone turnover were significantly higher in the active acromegalics, compared with controls (P < 0.001). PTH and NcAMP correlated significantly with markers of bone turnover in the active acromegalics (r = 0.65 for PTH and type I collagen ß C-telopeptide (ßCTX), P = 0.008; r = 0.71 for PTH and PINP, P = 0.006; r = 0.78 for NcAMP and PINP, P = 0.03; and r = 0.75 for NcAMP and CTX, P = 0.02). There was no significant difference in any of the analyses between men and women.


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  		TABLE 2. Serum and urine biochemistry in patients with active acromegaly and controls

 
Individual and population cosinor analysis demonstrated significant circadian rhythms for PTH and serum PO4 for all patients (P < 0.001; Fig. 1Go). The PTH MESOR of the circadian rhythm was significantly higher in the active acromegaly patients, compared with healthy controls [42.3 ± 3.9 pg/ml (4.45 ± 0.41 pmol/liter) vs. 30.4 ± 4.1 pg/ml (3.52 ± 0.43 pmol/liter) P = 0.03; Fig. 1Go], but there was no significant difference in PTH amplitude [6.5 ± 1.4 pg/ml (0.68 ± 0.15 pmol/liter) vs. 5.2 ± 1.0 pg/ml (0.55 ± 0.11 pmol/liter) P = 0.12] or acrophase (–169 ± 190 vs. – 153 ± 190, P = 0.84). There was no significant difference in PO4 MESOR [4.12 ± 0.37 mg/dl (1.33 ± 0.12 mmol/liter) vs. 3.88 ± 0.37 mg/dl (1.25 ± 0.12 mmol/liter) P = 0.06], amplitude [1.33 ± 0.40 mg/dl (0.43 ± 0.13 mmol/liter) vs. 0.65 ± 0.37 mg/dl (0.21 ± 0.12 mmol/liter) P = 0.09], or acrophase (–190.5 ± 40.70 vs. – 199.2 ± 41.60, P = 0.72) between the active acromegalics and controls, respectively.


Figure 1
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  		FIG. 1. PTH circadian rhythm.

 
The percent nocturnal increase in PTH concentration [calculated using the formula: (maximum PTH concentration-PTH concentration at 2200 h)/PTH concentration at 2200 h x 100] did not differ significantly between the groups (25.3 ± 2.1% in the acromegalic patients vs. 22.6 ± 2.7% in the healthy controls, P = 0.24).

Treated acromegaly

Figure 2Go shows the 24-h mean serum and urine biochemistry for the eight acromegalic patients who achieved biochemical cure, before and after treatment. The two acromegalic patients who did not achieve biochemical cure were excluded from the analyses, and therefore, the 24-h mean values were recalculated in the active acromegalic group using data obtained only from the eight patients who reached biochemical cure. The 24-h mean data for the control patients is also shown in Fig. 2Go.


Figure 2
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  		FIG. 2. Twenty-four-hour mean serum and urine biochemistry.

 
Attainment of biochemical cure in the acromegalic patients (n = 8) resulted in a significant reduction in IGF-I concentration (100.1 ± 7.7 nmol/liter vs. 28.6 ± 8.7 nmol/liter, P < 0.001). In addition, we observed a significant increase in 24-h mean PTH [44.4 ± 0.7 pg/ml (4.67 ± 0.07 pmol/liter) vs. 46.5 ± 0.6 pg/ml (4.89 ± 0.06 pmol/liter) P < 0.001] with significant decreases in NcAMP (34.5 ± 2.7 ng/ml GFR vs. 15.2 ± 2.2 ng/ml GFR, P < 0.001), ACa [9.28 ± 0.04 mg/dl (2.32 ± 0.01 mmol/liter) vs. 9.12 ± 0.04 mg/dl (2.28 ± 0.01 mmol/liter) P < 0.001], 1,25(OH)2D [31.1 ± 0.8 pg/ml (74.5 ± 1.9 nmol/liter) vs. 24.6 ± 1.0 pg/ml (59.0 ± 2.4 nmol/liter) P = 0.002], urine CaCr ratio (0.33 ± 0.04 vs. 0.20 ± 0.06, P = 0.007), ßCTX (0.71 ± 0.09 ng/ml vs. 0.39 ± 0.11 ng/ml, P < 0.001), and PINP (84.3 ± 1.2 µg/liter vs. 55.3 ± 1.6 µg/liter, P < 0.001) in the treated, compared with the active, acromegalics. Serum PO4 and TmPO4 significantly decreased after treatment [4.19 ± 0.03 mg/dl (1.35 ± 0.01 mmol/liter) vs. 3.44 ± 0.03 mg/dl (1.11 ± 0.01 mmol/liter) and 3.38 ± 0.03 mg/dl GFR (1.09 ± 0.01 mmol/liter GFR) vs. 2.60 ± 0.09 mg/dl GFR (0.84 ± 0.03 mmol/liter GFR), respectively, both P < 0.00]), whereas urine PO4Cr ratio increased significantly (1.81 ± 0.22 vs. 2.59 ± 0.23, P < 0.001). Twenty-four-hour mean PTH concentration was significantly higher in the treated acromegalics, compared with healthy controls (P < 0.001), whereas NcAMP, ACa, 1,25(OH)2D, and PINP were significantly lower (P < 0.05). ßCTX was also lower in the treated acromegalics than the controls, but this failed to reach significance (P = 0.09). Serum PO4 and TmPO4 were significantly lower in the treated acromegalics, compared with healthy controls (P < 0.001). There was no significant difference in urine calcium or phosphate excretion between the groups.

PTH correlated significantly with both PINP (r = 0.67, P = 0.007) and ßCTX (r = 0.61, P = 0.01), and NcAMP correlated significantly with PINP (r = 0.77, P = 0.04) and ßCTX (r = 0.73, P = 0.03) in the treated acromegalic patients. There was no significant difference in any of the analyses between men and women.

PTH and PO4 circadian rhythms were significant in all acromegalics who achieved biochemical cure (P < 0.001, Fig. 1Go). PTH MESOR was significantly higher [45.5 ± 3.6 pg/ml (4.79 ± 0.38 pmol/liter) vs. 41.9 ± 3.3 pg/ml (4.41 ± 0.35 pmol/liter) P = 0.047] and PO4 MESOR significantly lower [3.63 ± 0.37 mg/dl (1.17 ± 0.12 mmol/liter) vs. 4.96 ± 0.53 mg/dl (1.36 ± 0.17 mmol/liter) P = 0.009] after treatment, but there was no significant difference in the amplitude or acrophase of the PTH and PO4 circadian rhythms between the active and treated acromegalics.

Biochemical cure of acromegaly also resulted in a blunted nocturnal peak in PTH concentration (10.9 ± 2.7%), compared with both the active acromegalics and healthy controls (P < 0.001). The nocturnal rise in PTH concentration correlated positively with PINP and CTX in both the active and treated acromegalic patients (P < 0.05).


   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
Our patients with active acromegaly had significantly higher 24-h mean PTH, ACa, 1,25(OH)2D, and bone turnover markers than healthy controls, in the presence of a significantly higher 24-h mean NcAMP, suggesting increased PTH activity at the target organs in the active acromegalics. After biochemical cure, the acromegalic patients developed a reduction in PTH target-organ sensitivity, as indicated by a higher 24-h mean PTH concentration in the presence of lower NcAMP, ACa, 1,25(OH)2D, and bone turnover markers than both the active acromegalics and healthy controls. We have also shown that patients with both active and treated acromegaly exhibit a significant PTH circadian rhythm.

We did not demonstrate any gender difference in PTH or calcium metabolism, in either the active or treated acromegalics, although it is important to point out that the study was not powered to detect such differences. However, our findings are consistent with studies performed in healthy controls in which estrogen-deficient women were not recruited and gender differences in PTH and calcium were not observed (34, 35). Differences in PTH concentration and circadian rhythmicity between men and women have been reported only where the study population has included postmenopausal, estrogen-deficient women (36). All the women in our study were estrogen replete, and the estrogen status of all patients remained unchanged for the duration of the study, thereby excluding estrogen as a confounding factor in the differences observed in PTH circadian rhythmicity and target-organ sensitivity.

Temporal fluctuations in PTH concentration and maintenance of PTH circadian rhythmicity are important for the anabolic action of PTH on bone (37, 38). The action of PTH on its target organs depends on not only the concentration and circadian rhythm of PTH but also the sensitivity of the skeletal and bone receptors to the effect of PTH (19). NcAMP is a reliable indicator of PTH activity at the kidney and can therefore be used in conjunction with PTH concentration to determine renal PTH sensitivity (32).

Our study has demonstrated that patients with active acromegaly have a higher PTH concentration than healthy controls, resulting in increased activity at the bone and kidney, thereby explaining the previously reported increase in bone turnover and ACa. The higher ACa may be accounted for by a combination of increased calcium reabsorption at the renal tubules and PTH-mediated 1{alpha}-hydroxylation of 25-hydroxyvitamin D-promoting calcium absorption from the intestine. The higher PTH concentration in active acromegaly may occur as a result of GH-induced parathyroid gland hyperstimulation (39). In keeping with our data, other studies have also reported increased bone turnover and higher PTH, ACa, and 1,25(OH)2D concentrations in patients with active acromegaly, compared with healthy controls (2, 13, 14). We have shown significant correlations among PTH, NcAMP, and the nocturnal rise in PTH concentration and markers of bone turnover, providing further evidence that PTH and in particular the pattern of PTH secretion and the sensitivity of target organs to PTH may mediate the effect of GH on bone.

Production of 1,25(OH)2D is regulated by PTH-mediated 1{alpha}-hydroxylase activity in the kidney (40). The increase in PTH activity we observed in the kidney (as indicated by higher NcAMP, compared with controls) would account for the significantly higher 1,25(OH)2D seen in our and other studies (12, 16). In keeping with other studies (12, 16), our active acromegalics had a higher urine Ca excretion, compared with control patients, that may be explained by the increased glomerular filtered load of Ca resulting from the relatively higher ACa concentration.

GH regulates PO4 metabolism partly through its effect on PTH secretion. However, the predominant action of GH is PO4 retention that occurs through augmentation of intestinal PO4 absorption and increased renal PO4 reabsorption threshold (41, 42, 43), thereby resulting in a net positive PO4 balance and so increased serum PO4 concentration. This explains the significantly higher serum PO4 concentration seen in our active acromegalics, compared with controls. Urine PO4 excretion was significantly lower in the active acromegalics, compared with controls, as a result of increased renal tubular PO4 reabsorption, as evidenced by the significantly higher TmPO4.

Previous studies have reported an increase (12, 15), decrease (17), or no change (5, 16) in PTH concentration after treatment of acromegaly, inconsistencies that may reflect the single time point sampling methodology used in these studies (19). The circadian rhythm of PTH exhibits an early-morning decline and late-morning rise, with significant variation in concentration occurring between 0800 and 1100 h. Variation in sampling time in studies using single time point sampling methodology may lead to inconsistent results as previously shown (19, 20). We sampled patients over a 24-h period, which allowed us to study the PTH circadian rhythm in acromegaly and gain a truer reflection of the effect of acromegaly and its treatment on PTH concentration. Attainment of biochemical cure in our acromegalic patients resulted in an increase in 24-h mean PTH concentration, which together with the simultaneous reduction in 24-h NcAMP, ACa, 1,25(OH)2D, and bone turnover markers would indicate a reduction in PTH target-organ sensitivity. The reduction in 24-h mean serum PO4 and increase in urine PO4 may have occurred as a result of decreasing GH concentrations associated with the successful treatment of acromegaly, as demonstrated by the reduction in TmPO4, through mechanisms described previously.

In addition to a reduction in the sensitivity of target organs to the effect of PTH, attainment of biochemical cure also resulted in a reduced nocturnal rise in PTH of the treated acromegalics. The abnormalities in PTH circadian rhythm and reduction in PTH target-organ sensitivity in the treated acromegalics may underlie the reduction in bone turnover and subsequent long-term loss of cortical bone observed in previous studies. It has previously been suggested that aggressive treatment of acromegaly and reduction in IGF-I levels may result in a functional GH-deficient state (24). We previously reported a similar reduction in PTH target-organ sensitivity and abnormalities in PTH circadian rhythmicity in AGHD patients, a group that also have an increased prevalence of osteoporosis (19, 20, 44). The reduction in PTH target-organ sensitivity in the treated acromegalic patients may therefore be a result of a functional GH deficiency, induced by surgical and medical therapy, and is of clinical consequence because of the potential to develop osteoporosis in the long term. The results of these and previous data suggest that GH is an important regulator of PTH secretion and target-organ action (19, 20, 26, 39, 44, 45).

With the continuing development of novel agents in the treatment of acromegaly, with particular reference to GH receptor antagonists, it is expected that an increasing number of patients with active acromegaly will achieve biochemical cure, making the potential long-term side effects of treatment including the potential development of osteoporosis increasingly important. Further investigation of the long-term effect of aggressive acromegaly management on skeletal health and fracture risk is required. In addition, studies to examine the potential benefit of GH replacement in the prevention of osteoporosis would be helpful in determining the future management of such patients.


   Acknowledgments
 
We are grateful to the endocrine specialist nurses and all the clerical and nursing staff on the Metabolic Bone Unit at the Royal Liverpool University Hospital for all their help and support. We also thank Nick Hoyle (Roche) for the provision of bone marker kits.


   Footnotes
 
First Published Online December 13, 2005

Abbreviations: ACa, Serum-adjusted calcium; AGHD, adult GH deficiency; Ca, calcium; Cr, creatinine; ßCTX, collagen-ß C-telopeptide; CV, coefficient of variation; GFR, glomerular filtration rate; NcAMP, nephrogenous cAMP; 1,25(OH)2D, 1,25-dihydroxyvitamin D; PcAMP, plasma cAMP; PINP, procollagen type I amino-terminal propeptide; TmPO4, maximum tubular PO4 reabsorption rate.

Received July 19, 2005.

Accepted December 1, 2005.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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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.
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