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The Journal of Clinical Endocrinology & Metabolism Vol. 82, No. 10 3303-3307
Copyright © 1997 by The Endocrine Society

Original Studies

Serum Markers of Bone and Collagen Turnover in Patients with Cushing’s Syndrome and in Subjects with Adrenal Incidentalomas

G. Osella, M. Terzolo, G. Reimondo, A. Piovesan, A. Pia, A. Termine, P. Paccotti and A. Angeli

Dipartimento di Scienze Cliniche e Biologiche, Cattedra di Medicina Interna, Azienda Ospedaliera S. Luigi, Università di Torino, Torino, Italy

Address all correspondence and requests for reprints to: Dr. Giangiacomo Osella, Clinica Medica Generale, Azienda Ospedaliera S. Luigi, Regione Gonzole 10, 10043 Orbassano (TO), Italy.


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The aim of this study was to assess serum levels of some markers of bone turnover and collagen synthesis in 22 patients with adrenal incidentalomas (AI), a model of silent glucocorticoid excess, and to compare the results with those obtained in 18 patients with Cushing’s syndrome (CS). Osteocalcin (BGP), bone isoenzyme of alkaline phosphatase, carboxy-terminal propeptide of type I procollagen, and carboxy-terminal cross-linked telopeptide of type I collagen were measured as biochemical indexes of bone turnover, and amino-terminal propeptide of type III procollagen was determined as an index of collagen synthesis. Two groups of healthy volunteers evenly matched for sex, age, and menstrual status were used for a case-control analysis of AI and CS groups, respectively. Patients with AI showed a slight, albeit significant, reduction in serum BGP and a mild increase in carboxy-terminal cross-linked telopeptide of type I collagen levels compared with controls [median, 6.6 vs. 7.8 ng/mL (P < 0.05) and 4.2 vs. 3.1 µg/L (P < 0.01), respectively]. No significant differences were found when comparing the other markers. Patients with CS had BGP, bone isoenzyme of alkaline phosphatase, and amino-terminal propeptide of type III procollagen levels significantly lower than control values [median, 3.0 vs. 7.3 ng/mL (P < 0.0001); 4.4 vs. 11.5 µg/L (P < 0.01); 2.2 vs. 4.3 µg/L (P < 0.0001), respectively], but no significant difference in the other markers.

These results confirm a clear inhibition of osteoblastic activity in CS and could suggest an enhanced bone metabolism in patients with AI. The degree of impairment of bone turnover in patients with AI does not seem enough to recommend surgery (removal of the adrenal adenoma) in the absence of other indications.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE UNEXPECTED discovery of an adrenal mass on abdominal computed tomography (CT) is a relatively frequent event, occurring in about 0.3–5% of scans (1). By definition, patients with incidentally discovered adrenal masses (adrenal incidentalomas) do not display any sign or symptom of overt hypercortisolism, but a refined laboratory investigation is able to disclose subclinical hypercortisolism with a remarkable frequency (2, 3, 4, 5, 6). Such a condition has been defined as pre-Cushing’s syndrome, but the rate of progression, if any, to clinically overt disease is still unknown (7, 8). It is presently unclear if a slight glucocorticoid excess may increase the risk for osteoporosis because bone metabolism has not been studied in detail (5, 9).

An indirect assessment of bone turnover and collagen synthesis can be achieved by measurement of specific biochemical markers. Osteocalcin [bone Gla protein (BGP)], the major noncollagenous protein produced by osteoblasts, is a widely employed index of bone formation (10, 11, 12). Another classic marker of osteoblastic activity is the bone isoenzyme of alkaline phosphatase (bALP) (13). Carboxy-terminal propeptide of type I procollagen (PICP) is an extension peptide cleaved during the synthesis of type I procollagen, and its concentrations reflect stoicheiometrically the bone collagen production (14). Conversely, serum carboxy-terminal cross-linked telopeptide of type I collagen (ICTP) reflects bone collagen catabolism and is considered a marker of bone resorption (15). Circulating levels of the amino-terminal propeptide of type III procollagen (PIIINP) are thought to reflect collagen synthesis in soft tissues (16, 17).

The aim of the present study was to evaluate the above-mentioned serum markers of bone turnover and collagen synthesis in patients with adrenal incidentalomas (AI), a model of silent glucocorticoid excess, and in patients with Cushing’s syndrome (CS). The effects of silent glucocorticoid excess were assessed and compared to those of overt hypercortisolism.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Twenty-two patients with an incidentally discovered adrenal mass (9 men and 13 women, aged 25–73 yr; median, 54.5) were enrolled in the study after giving their informed consent (Table 1Go). Adrenal masses were detected serendipitously by abdominal imaging studies performed for reasons other than suspected adrenal disease. Abdominal CT scan with iv contrast medium was performed in all patients. Biochemical screening aimed to exclude pheochromocytoma or aldosterone-producing adenoma was performed in all patients. They were also given the following endocrine evaluation: 1) measurement of serum cortisol at 4-h intervals over 24 h, 2) measurement of the 24-h excretion of urinary free cortisol, 3) measurement of dehydroepiandrosterone sulfate (DHEA-S) at 0800 h, 4) overnight dexamethasone suppression test (1 mg, orally, at 2300 h and measurement of serum cortisol at 0800 h the following morning), and 5) CRH stimulation test (100 µg, iv, as a bolus at 0900 h with measurement of ACTH and cortisol at -15, 0, 10, 20, 30, 45, and 60 min). Premenopausal women were tested in the early follicular phase of the menstrual cycle.


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  		Table 1. Demographic characteristics of patients with incidentally discovered adrenal masses (incidentalomas)

 
Eighteen patients with active Cushing’s syndrome (3 men and 15 women; aged 15–64 yr; median, 36) were studied (Table 2Go). The diagnosis of CS was made by the clinical picture and was confirmed by standard endocrine evaluation. The etiological diagnosis of CS (ACTH-secreting pituitary adenoma in 10 cases, adrenal adenoma or ACTH-independent macronodular hyperplasia in 6 cases, and ectopic ACTH secretion in 2 cases) was based on ACTH measurements and dynamic testing. Selective inferior petrosal sinus sampling for ACTH measurement was performed in 9 patients to ascertain the diagnosis. In all patients surgical outcome confirmed previous etiological diagnosis. Serum and urinary cortisol were measured by RIA (Sorin Biomedica, Saluggia, Italy), serum DHEA-S was measured by RIA (Diagnostic Systems Laboratories, Webster, TX), and plasma ACTH was measured by immunoradiometric assay (Nichols Institute, San Juan Capistano, CA).


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  		Table 2. Demographic characteristics of patients with active Cushing’s syndrome

 
Blood samples for markers of bone and collagen turnover were obtained in the morning in three groups of healthy subjects. Two groups of healthy volunteers evenly matched for sex, age (±1 yr), and menstrual status, were used for a case-control analysis of AI and CS groups, respectively. Moreover, serum BGP, bALP, ICTP, PICP, and PIIINP levels were determined in a third group of 236 healthy subjects [143 men (aged 18–84 yr; median, 41), 52 premenopausal women (aged 20–50 yr; median, 30), and 41 menopausal women (aged 45–83 yr; median, 59)] to calculate the 3rd and 97th percentiles of distribution for each variable. Serum BGP was measured by RIA (CIS Diagnostici, Santhiá, Italy); serum bALP was determined by immunoradiometric assay (Hybritech, Liege, Belgium); and serum PICP, ICTP, and PIIINP were measured by RIA (Farmos Diagnostica, Ounsalo, Finland). The detection limits were 1 ng/mL, 2.0 µg/L, 25 µg/L, 0.5 µg/L, and 0.2 µg/L, respectively. All hormone assays were performed in duplicate in the same assay session. Sera were immediately separated and stored at -20 C until assayed. Intra- and interassay coefficients of variation for all of the above-mentioned assays were below 8% and 12%, respectively. Because criteria for normal distribution were not satisfied at the Wilk-Shapiro test, statistical analysis was performed using nonparametric methods (Mann-Whitney U test, Kruskall-Wallis ANOVA by ranks for numerical variables, and {chi}2 test for categorical variables). Spearman rank correlation was performed as appropriate. Levels of statistical significance were set at P < 0.05. Data are expressed as the median and range.


   Results
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 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
The size of incidentally discovered adrenal masses on CT measurement ranged from 1.7–3.5 cm (median, 2.5), and it was stable after a 12-month follow-up. During this period the patients remained clinically asymptomatic, and no sign of overt hypercortisolism or extraadrenal malignancy became manifest. All of the masses showed CT features typical of adrenocortical adenomas (small size, smooth margins, low density, and absent or mild enhancement after iv contrast medium). Tables 3Go and 4Go show the levels of serum markers of bone and collagen turnover in the two groups of patients (AI and CS) and in their respective matched controls. Patients with AI showed a slight, albeit significant, reduction in serum BGP and a mild increase in ICTP levels compared with controls. No significant differences were found when comparing the other markers. Patients with CS showed BGP, bALP, and PIIINP levels significantly lower than control values, but no significant difference in the other markers. Individual data of patients with AI and CS are presented in Figs. 1Go and 2Go. The abnormalities of the hypothalamic-pituitary-adrenal axis detected in patients with AI are summarized in Table 5Go. An inverse correlation (r = -0.65; P < 0.01) was found between 24-h mean serum cortisol levels and serum PIIINP in patients with CS. No significant correlation was present between serum or urinary cortisol and DHEA-S, on the one hand, and bone markers, on the other, in both groups of patients.


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  		Table 3. Serum markers of bone and collagen turnover in 22 patients with adrenal incidentalomas and 22 sex- and age-matched normal subjects

 

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  		Table 4. Serum markers of bone and collagen turnover in 18 patients with Cushing’s syndrome and 18 sex- and age-matched normal subjects

 


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  		Figure 1. BGP levels (upper panel) and bALP levels (lower panel) in patients with CS and AI. Patients are stratified for sex and menstrual status. The shaded area represents the reference range (3rd and 97th percentiles of the control population).

 


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  		Figure 2. ICTP levels (upper panel) and PIIINP levels (lower panel) in patients with CS and AI. Patients are stratified for sex and menstrual status. The shaded area represents the reference range (3rd and 97th percentiles of the control population).

 

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  		Table 5. Abnormalities of HPA axis in patients with adrenal incidentalomas

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Bone loss due to cortisol excess has a multifactorial origin where the direct inhibitory effect played by glucocorticoids on osteoblastic activity is the central feature (18, 19, 20). Indirect evidence of suppressed bone formation in patients with CS arises from the observation of reduced serum BGP levels (21), which return to normal after correction of cortisol excess (21, 22). Secondary hyperparathyroidism due to reduced intestinal calcium absorption and increased urinary calcium excretion is likely to cause increased osteoclastic activity in CS (23, 24, 25). Recently, Hermus et al. found an increased hydroxyproline/creatinine ratio in premenopausal females with CS compared with age-matched controls, but ICTP levels were not different in the two groups (26). To the best of our knowledge, no further data about bone resorption markers in CS are available in the literature.

In unselected series of AI patients, a disturbance of the hypothalamic-pituitary-adrenal axis resulting from partial adrenal autonomy was frequently observed (4, 5, 6, 7, 8). Therefore, a mild degree of hypercortisolism, insufficient to cause a clinically recognizable syndrome, could be detected in a remarkable number of incidentally discovered adenomas (27). In the present series, the diagnosis of adenoma is confidently tenable, even in the absence of histological confirmation, on the basis of CT criteria and follow-up data (28, 29).

The comparison of a cohort of patients in whom full-blown glucocorticoid excess was invariably present with one of the patients exposed to variable degrees of mild hypercortisolism provided interesting results. BGP levels were clearly suppressed in our patients with CS compared with those in both healthy subjects and patients with AI. Conversely, only a slight reduction of BGP levels in AI was found in the case-control analysis. This figure could reflect the different types of hypercortisolism in patients with AI and CS. There is general agreement that BGP levels are reduced in CS (21, 22, 30); the only exception is the study by Hermus et al. (26).

In the present study, bALP levels were reduced in CS patients, and this finding confirms that osteoblastic activity is inhibited in overt hypercortisolism. On the contrary, bALP did not differ between patients with AI and age-matched controls. This divergent behavior suggests that BGP is more sensitive than bALP to the actions of glucocorticoids.

PICP, another marker of bone formation, was not altered by either overt or silent hypercortisolism. The discrepancy between BGP-bALP and PICP is not surprising, as it is believed that they reflect different osteoblastic activities (11, 12, 14). PICP is probably less responsive to hormone influences because it remains unmodified in presence of sustained GH excess, where BGP is clearly elevated (31).

When looking at ICTP, a marker of bone resorption, no difference was found between patients with CS and healthy subjects, whereas patients with AI showed higher levels than age-matched controls. These findings suggest that osteoclastic activity is not enhanced in CS, whereas it seems to be increased in AI. The age difference between the two groups could offer a possible explanation: the impact of slight hypercortisolism on the bone of elderly subjects (postmenopausal women in about half of the cases) could be more profound than that of overt hypercortisolism on young bone. It is conceivable that glucocorticoids could more easily induce secondary hyperparathyroidism in elder people, in whom dietary calcium intake and intestinal absorption are often insufficient. Another possibility is that glucocorticoids recruit osteoclasts and at the same time dampen their activity (32). These actions may be dissociated according to a dose-dependent relationship. In the presence of slight cortisol excess, as in patients with AI, only the recruitment of new osteoclasts may be operative. On the other hand, clearly elevated cortisol levels, such as those observed in CS, may also blunt the activity of the newly recruited osteoclasts.

The behavior of PIIINP was parallel that of BGP. We confirmed our previous observation of reduced PIIINP levels in patients with CS (30) as a consequence of the antianabolic effect of increased cortisol concentrations on soft tissue collagen. The mild hypercortisolism displayed by patients with AI is not sufficient to affect soft tissues. This finding fits well with the clinical observation that atrophy of the epidermis and its underlying connective tissue is a well known feature of CS patients, but not of those with AI.

The lack of correlations between bone markers and hormone variables in patients with AI is not surprising, as no correlation was found in patients with overt CS in the present or in a previous series (30). Other factors, such as age of onset and duration of the hypercortisolemic state, may be important. In steroid-treated patients, bone loss seems to be maximal during the first 6–12 months of treatment (33, 34). It is, therefore, possible that markers of bone turnover are correlated with endocrine variables only in an early phase of the disease.

To the best of our knowledge, there is only one report on serum parameters of bone and collagen turnover in patients with AI (35). The outcome of the present study is only in partial agreement with that of the previous one. Differences in demographic characteristics of patients could be a possible explanation for the observed discrepancies. However, the lack of data on bone mineral density is a limit of the present as well as the previous study.

In conclusion, the slight cortisol hypersecretion of patients with AI could be responsible for the impaired bone formation and increased bone resorption. However, the degree of impairment of bone turnover, gauged by analysis of specific serum markers, does not seem enough to recommend removal of the adrenal adenoma in the absence of other indications.

Received January 30, 1997.

Revised June 3, 1997.

Accepted June 17, 1997.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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