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Laboratorio Sperimentale di Ricerche Endocrinologiche Istituto Auxologico Italiano, IRCCS Milano 20122, Italy Bruno Ambrosi Istituto di Scienze Endocrine Ospedale Maggiore IRCCS Università di Milano Milano 20122, Italy
We read the paper entitled "Serum Markers of Bone and Collagen Turnover in Patients with Cushing’s Syndrome and in Subjects with Adrenal Incidentalomas" by Osella et al. (1), and we would like to make some comments on this issue.
In their study, the authors suggest that patients with adrenal
incidentaloma are a model of silent glucocorticoids excess. We are
aware that most of these patients actually show different abnormalities
of steroid secretion, i.e. high 17
-hydroxyprogesterone
(17-OHP) response to ACTH, low dehydroepiandrosterone sulfate (DHEA-S)
levels, mild glucocorticoid excess, as already widely documented.
However, the presence of subtle hypercortisolism is typical of the
subset of patients who are commonly defined as affected with
"preclinical or subclinical" Cushing’s syndrome. Although the
hormonal criteria identifying the preclinical condition are not as yet
univocally defined, it is likely that a continuous spectrum of
abnormalities does exist, encompassing patients with really silent
incidentaloma, or mild glucocorticoid alterations, or even active
Cushing’s syndrome.
In their paper, Osella et al. (1) describe the existence of alterations of bone metabolism in a nonhomogeneous group of patients, since a "silent glucocorticoid excess" was not demonstrated for all subjects. Indeed, nine patients did not disclose any steroid alterations, and five showed only a reduction of DHEA-S levels; the remaining eight had different degrees of cortisol abnormalities (from very subtle, as in case no. 2, to more evident ones), suggesting the probability of a preclinical Cushing’s syndrome.
In our experience, markers of bone and collagen turnover were evaluated in patients with incidentaloma and compared with the results obtained in those with either active or preclinical Cushing’s syndrome. A significant decrease of bone-GLA protein (BGP) and aminoterminal propeptide of type III procollagen (PIIINP) levels was found in patients with Cushing’s syndrome (2, 3), in line with the data by Osella et al. (1). By contrast, our results differ as far bone resorption activity is concerned. In fact, we found a significant reduction of carboxyterminal cross-linked telopeptide of type I collagen (ICTP) levels (3), indicating an overall inhibition of bone turnover, which could contribute to bone loss. A plausible explanation for this discordance might be attributed to the different age range and/or the duration of the disease, as the etiological diagnosis and the radioimmunoassay methods were similar in both series. In this respect, it has been shown that exogenous steroids exert different effects on bone resorption, depending on the duration of treatment (i.e. early stimulation after short therapy, inhibition after more prolonged administration) (4). Therefore, the uncoupling between bone resorption and formation parameters in the study by Osella et al. (1) might be the early (and/or transient) expression of the negative effects of steroid excess on bone.
Notably, similar findings (reduced bone and collagen turnover) were also observed in patients with preclinical Cushing’s syndrome, indicating that bone and collagen impairment may occur before the onset of active Cushing’s syndrome (5).
As far as our series of 35 patients with adrenal incidentaloma is concerned (3), serum BGP (4.2 ± 0.5 ng/mL) and ICTP levels (2.9 ± 0.2 ng/mL) were significantly lower than in normal subjects, while serum PIIINP concentration did not differ from that of controls. However, mean BGP and PIIINP levels were lower in patients with Cushing’s syndrome than in those with incidentaloma. It is important to emphasize that markedly suppressed BGP levels (<2.0 ng/mL), similar to those recorded in active Cushing’s syndrome, were found in a subset of 9 of 35 patients who had a heterozygous 21-hydroxylase deficiency. Therefore, it would be of interest to know whether the lowest BGP levels reported in adrenal incidentaloma by Osella et al. (1) were detected in patients with a similar 21-hydroxylase deficiency; this aspect might also account for the differences observed in ICTP levels between our study (3) and that by Osella et al. (1).
In conclusion, we believe that the impairment in markers of bone and collagen turnover may be considered as a precocious sign of an abnormal pattern of steroid secretion and may therefore contribute to the selection of those patients who require more accurate follow-up. Further studies, aimed at evaluating bone mineral density and/or bone histomorphometry, are requested for better understanding the true clinical meaning of alterations in markers of bone and collagen turnover.
Footnotes
Address correspondence to: Bruno Ambrosi, MD, Institute of Endocrine Sciences, Ospedale Maggiore, University of Milan, Via F. Sforza, 35-20122 Milan, Italy.
Received November 20, 1997.
References
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