Bone Demineralization and Vertebral Fractures in Endogenous Cortisol Excess: Role of Disease Etiology and Gonadal Status
Libuse Tauchmanovà, Rosario Pivonello, Carolina Di Somma, Riccardo Rossi, Maria Cristina De Martino, Luigi Camera, Michele Klain, Marco Salvatore, Gaetano Lombardi, and Annamaria Colao
Departments of Molecular and Clinical Endocrinology and Oncology (L.T., R.P., C.D.S., R.R., M.C.D.M., G.L., A.C.) and Biomorphological and Functional Sciences (L.C., M.K., M.S.), Federico II University of Naples, 80131 Naples, Italy
Introduction: The effects of endogenous cortisol (F) excess on bone mass and vertebral fractures have still not been thoroughly investi- gated. The aim of this cross-sectional case-control study was to in- vestigate factors influencing bone demineralization and vertebral fractures in different conditions of F excess, i.e. Cushing’s disease and adrenal and ectopic Cushing’s syndrome.
Materials and Methods: Eighty consecutive patients and 80 con- trols were prospectively enrolled: 37 patients (21 females) with pi- tuitary ACTH-secreting adenoma, 18 (14 females) with adrenocortical adenoma, 15 (11 females) with adrenal carcinoma of mixed secretion, and 10 (three females) with ectopic ACTH secretion. The groups had similar age. At diagnosis, bone mineral density (BMD) was deter- mined by the dual-energy x-ray absorptiometry technique at the lum- bar spine (L1-L4) and femoral neck; vertebral fractures were inves- tigated by standard spinal radiographs.
Results: When comparing the groups with different etiology of F excess, the patients with ectopic ACTH secretion had higher F and
lower BMD values than the other subgroups. Morning F (P = 0.03) and testosterone levels (P = 0.04) correlated with lumbar BMD. Ver- tebral fractures were found in 61 (76%) of the patients, were multiple in 52 (85%) of the cases, and clinically evident in 32 (52%). Only multiple fractures were more frequent in patients with ectopic ACTH hypersecretion (P < 0.05). Lumbar spine BMD was the best predictor of vertebral fractures (P < 0.01). Surprisingly, amenorrheic and eu- menorrheic women had similar BMD values and fracture prevalence.
Conclusion: A high prevalence (76%) of vertebral fracture was re- vealed, regardless of the etiology of the patients’ hypercortisolism. The harmful effects of F excess at the spine were partly counterbal- anced by the increased androgen production but were not affected by gonadal status in women. (J Clin Endocrinol Metab 91: 1779-1784, 2006)
T HE SYNDROME OF glucocorticoid excess, first de- scribed in 1932 by Harvey Cushing, is recognized as one of the most important causes of bone loss (1). Cortisol (F) exerts direct and indirect effects on bone, enhancing its re- sorption and inhibiting its formation (2, 3-5). Glucocorticoid excess directly inhibits the differentiation of pluripotent mes- enchymal cells toward the osteoblastic lineage, directing them into the adipocytic pathway (6). It reduces the produc- tion of growth factors and bone matrix proteins and de- creases calcium absorption (7). Bone fractures, the main com- plication of osteoporosis, are well recognized as a dose- dependent effect in patients on glucocorticoid treatment and have been described as a presenting symptom of endogenous F excess (8,9). A high incidence of nontraumatic fractures in the period preceding the diagnosis of Cushing’s syndrome was described in 104 patients in a retrospective study by Vestergaard et al. (10).
The negative effects of F on the bone probably depend on
Abbreviations: ALP, Alkaline phosphatase; BMD, bone mineral den- sity; BMI, body mass index; DHEAS, dehydroepiandrosterone sulfate; E2, 17-B-estradiol; F, cortisol; iPTH, intact PTH; T, testosterone; UFF, urinary free F.
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the degree of its excess, whereas sex steroids have anabolic effects. The relationship between F and sex steroids may be complex in patients with endogenous hypercortisolism. It is well known that F excess alone inhibits the gonadal axis in both genders (3, 5); nevertheless, the production of dehy- droepiandrosterone sulfate (DHEAS) and androstenedione is generally increased in ACTH-dependent hypercortisolism and frequently high in adrenocortical carcinomas, together with the testosterone (T) levels. Androstenedione, DHEAS, and T are usually low in adrenal adenomas (11, 12). Estro- gens may be increased in subjects with adrenal carcinomas but are frequently low in women with ACTH excess and adrenal adenomas (13, 14). Androgen excess has been found to exert protective effects on bone mass in women with polycystic ovary syndrome, counterbalancing the harmful effects of amenorrhea (15, 16). With regard to the effects of estrogens, corticosteroid treatment and Cushing’s syndrome have been shown to cause more severe bone damage in postmenopausal than reproductive-aged women (17, 18). Nevertheless, it is still unclear whether any protective bone effects of androgens or estrogens can occur in patients with endogenous F excess. Few data are currently available on the effects of mixed F, androgen, and estrogen excess on bone mass and the prevalence of vertebral fractures.
This cross-sectional, case-control study aimed at investi- gating the risk factors for bone demineralization and verte-
bral fractures in endogenous glucocorticoid excess of differ- ent etiologies.
Subjects and Methods
Study design
In this cross-sectional, case-control study, we have analyzed deter- minants of bone demineralization and vertebral fractures in glucocor- ticoid excess of different etiologies. We took into consideration the gender, anthropomorphic features, estimated disease duration, serum F, T, androstenedione, DHEAS, and 17-B-estradiol (E2) levels, and the ratios among serum F, androgens, and E2. All determinations were performed at the diagnosis of Cushing’s syndrome. The study was performed according to the procedures indicated by the Helsinki II Declaration. All enrolled subjects gave their informed consent to par- ticipate in the study.
Subjects
From January 1996 to June 2003, 80 consecutive patients with en- dogenous F excess were referred to our department and prospectively enrolled in this study. The diagnosis of F excess was made on the basis of the typical clinical signs and symptoms and inappropriately elevated values of serum F and urinary free F (UFF) excretions. Additional in- vestigations included assays of circulating ACTH, FSH, LH, and pro- lactin levels, a low-dose 2-mg dexamethasone suppression test in all cases, and a high-dose 8-mg dexamethasone suppression test in all patients with ACTH-dependent Cushing’s syndrome; pituitary mag- netic resonance imaging or adrenal computed tomography was performed as appropriate. A whole-body scintigraphy with 111In-DTPA- D-phe1-octreotide was performed in patients with suspected ectopic ACTH hypersecretion; areas of abnormal uptake were then evaluated by com- puted tomography scan to confirm the presence of lesions. Among the 80 patients, histology confirmed the diagnosis of pituitary ACTH-secreting adenoma in 37 (microadenoma in 30 and macroadenoma in seven) of them, F-secreting adrenocortical adenoma in 18, mixed F- and androgen-secreting adrenocortical adenoma in four, mixed secreting carcinoma in 11, and ectopic ACTH excess due to bronchial carcinoid in eight patients. In the remaining two patients, a diagnosis of ectopic ACTH syndrome was sus- pected, but the tumor site is still unknown. Disease duration was estimated around the interval between the symptom onset mentioned by the patients when specifically asked (i.e. weight gain, appearance of striae rubrae, in- crease in blood pressure, etc.) and the diagnosis. Patients were considered to have hyperandrogenism when at least one of the androgens (T, DHEAS, or androstenedione) was 2 sD above the mean of the controls. Women were considered amenorrheic when menstrual cycles did not occur at regular intervals and E2 levels were below the normal range for the early follicular phase.
For each patient enrolled, a control subject matched for age, gender, and body mass index (BMI) was selected and included in the data analysis. Eighty subjects with eucortisolism were recruited among the patients with euthyroid goiter (TSH, 1-2.5 U/liter). Age was matched within 1 yr of the birth date, and BMI was matched within ±1.5 kg/m2. None of the 160 subjects had previously taken drugs known to interfere with bone metabolism, oral contraceptive, or hormonal replacement therapy, nor used to drink more than four cups of coffee per day and/or two alcohol-containing beverages per day.
Assessment of bone density and turnover
Serum calcium, phosphorus, creatinine, alkaline phosphatase (ALP), albumin, intact PTH (iPTH), and osteocalcin were determined after at least 8 h fasting, whereas urinary calcium and hydroxyproline excretion were measured in 24-h urine collection and corrected for creatinine excretion. Bone mineral density (BMD) at the lumbar spine (L1-L4 in anteroposterior scan) and femoral neck was determined by dual-energy x-ray absorptiometry using Hologic QDR 1000 densitometer (Hologic, Inc., Waltham, MA). Because of mixed (male and female) population, individual BMD values were expressed as Z scores. The coefficient of variation for the dual-energy x-ray absorptiometry technique was less than 1.5% for the lumbar spine and less than 1.8% for the femoral neck. The reference population adopted in this study was the international pooled sample provided by the manufacturer; their data, however, did not differ significantly from those obtained on a local sample in a study
performed when the device was set up (19). Quality control was main- tained by daily scanning of an anthropomorphic spine phantom. A systematic review of each BMD was performed, and artifacts from fractured vertebral bodies, kyphosis, and scoliosis were excluded from the evaluation. No patient had imbedded metal at the lumbar vertebrae or severe joint disease at the L1-L4 segments.
Assessment of vertebral fractures
All patients were evaluated for back pain and height changes as clinical symptoms of vertebral fractures. Potential asymptomatic ver- tebral compression fractures were investigated in all patients by stan- dard spinal radiographs in anterior-posterior and lateral positions of the vertebrae Th4-L4. A prevalent fracture was defined in accordance with previous studies, with a 20% difference in anteroposterior, middle- posterior, or posterior-posterior adjacent ratio (20, 21). Vertebral collapse was defined as wedge-shaped, biconcave, or completely collapsed bod- ies (20, 21). Because most patients had a very severe demineralization of the vertebral bodies, it was impossible to use the digitalized technique for vertebral body measurement. An analysis of radiographic films was independently performed in chronological order by two operators: a skeletal radiologist (L.C.) and an endocrinologist trained in osteoporosis management (L.T.). They were blind to the status of case/control and origin of F excess. The validity of each finding was established by both operators for the detection of the presence and number of fractures; the interobserver agreement was calculated using k statistics, and results were good (k = 0.87).
Assays
Hormone determinations were performed with the same commercial kits for the whole study period: F, T, E2, and DHEA-S by Immulite and solid-phase chemoluminescent enzyme immunoassay (Diagnostic Prod- ucts Corp., Los Angeles, CA); androstenedione by RIA Diagnostic Sys- tems Laboratories (Webster, TX); FSH and LH by RIA using Biodata kits (Rimini, Italy); and prolactin by RIA using Radim kits (Pomezia, Italy). iPTH and serum osteocalcin levels were measured by RIA (Nichols Institute Diagnostics, San Clemente, CA). Hydroxyproline excretion was measured with HPLC. Blood chemistry profile, including levels of cal- cium, phosphorus, ALP, 24-h urinary calcium excretion, and creatinine, were analyzed using a standard autoanalyzer.
Statistical analysis
The statistical analysis was performed by the SPSS Inc. (Chicago, IL) package (release 13.0) and StatsDirect statistical software (release 2.5.2, StatsDirect Ltd., Cheshire, UK). Data distribution was analyzed by the Kolmogorov-Smirnov test. To compare data for continuous variables, ANOVA followed by Bonferroni test as post hoc test or Kruskal-Wallis H test followed by Dwass-Steel-Chritchlow-Fligner test (22) were used, according to the data distribution. Categorical variables were compared by using the Pearson’s x2 test. The data were compared between patients and controls, between patients with and without fractures, and between subgroups of patients with different etiology of F excess. Age, BMI, estimated disease duration, urinary F excretion, and circulating levels of F, androgens, and E2 were considered as potential predictive factors for BMD by the linear regression analysis. All these parameters plus BMD were included in the evaluation of risk factors for vertebral fractures by the logistic regression. The step-wise forward selection was used for both procedures. Predictive factors of vertebral fractures have been evaluated by the receiver operating characteristic analysis on the dif- ferent parameters considering the value associated with the maximal diagnostic accuracy (maximal sum of sensitivity and specificity). Sta- tistical significance was set at 5%.
Results
Anthropometrical and endocrine profiles (Table 1)
Age was similar in all groups of patients, whereas the estimated disease duration was shorter in patients with ec- topic ACTH secretion and adrenal carcinomas when com- pared with the other subgroups (P < 0.01). BMI was higher in the patients with isolated F excess due to adrenal adenoma
| Variable | ACTH-secreting pituitary adenoma | Adrenal adenoma | Adrenal carcinoma | Ectopic ACTH excess | Controls |
|---|---|---|---|---|---|
| No. of subjects | 37 | 18 | 15 | 10 | 80 |
| Female/male | 21/16 | 14/4 | 11/4 | 3/7 | 49/31 |
| Age (yr) | 38 (18-58) | 38 (22-66) | 41.5 (27-58) | 42 (29-52) | 39 (18-66) |
| BMI (kg/m2) | 26.9 (21-40.2) | 28.3 (21.3-40.4) | 28.2 (21-33) | 27 (21.6-33.7) | 27 (21-40) |
| Estimated disease | 19 (8-26)ª | 21 (7-25)ª | 8.3 (5-13) | 8.1 (4-11) | |
| duration (months) | |||||
| No. of amenorrheic women | 9/21 (42.8%) | 6/14 (42.8%) | 4/11 (36.4%) | 2/3 (66%) | 6/49 (12%) |
| F 0800 h (nmol/liter) | 725.6 (276-1,344)b,c | 619 (544-1,173)d | 560 (328-957)6 | 690 (469-1,724)b,c | 364 (260-482) |
| UFF excretion (nmol/24 h) | 1,504 (326-9,290)ª,c | 1,496 (306-4,139)d | 1,847 (323-6,208)c | 5,132 (1,270-14,987)b,c | 423 (179-331) |
| DHEAS (mol/liter) | 8.3 (2.6-18)6 | 1.6 (1.3-5.8)b,e | 20 4.3-99)b,e | 9 (5.9-19.5)6 | 6.5 (4.3-8.4) |
| Androstenedione (nmol/liter) | 12.2 (3.5-34.9)b | 3.14 (0.34-19.2)e | 27 (3.8-58)b | 23 (6.8-69)b | 4.0 (1-7.7) |
| Male T (nmol/liter) | 7.7 (4.1-13)d | 5.5 (3.2-7.8)b,e | 18 (12-36) | 9 (5-14.5)d | 19.4 (12-35) |
| Female T (nmol/liter) | 6.1 (3.2-10)b | 0.9 (0.3-1.3)b,e | 5 (1.4-52)d | 6.8 (3.1-13)b | 2.42 ± 0.52 |
| Female E2 (pmol/liter) | 124 (55-191) | 159 (53-716) | 352 (132-1,534)be | 121 (55-147) | 147 ± 18.8 |
Data are expressed as median and range. Reference ranges: F, 140-680 nmol/liter; UFF excretion, 55-300 nmol/24 h; DHEAS, 1.3-6.7 umol/liter; androstenedione, 3.0-6.0 nmol/liter; male T, 10-35 nmol/liter; female T, less than 3.5 nmol/liter; E2, 70-220 pmol/liter.
ª P < 0.01 vs. groups with adrenal carcinoma and ectopic ACTH excess.
b P < 0.001 vs. controls.
€ P < 0.05 vs. groups with Cushing’s syndrome due to adrenal adenoma or carcinoma.
d P < 0.05 vs. controls.
e P < 0.05 vs. all other groups of patients.
f Determined in early follicular phase in women with cycles.
(P < 0.05 vs. all other groups). Women were more frequently affected by F excess than men in all subgroups except for the ectopic ACTH secretion, where men were more frequently represented. The ratio of amenorrheic vs. eumenorrheic women in each subgroup was similar.
Higher serum and urinary F levels, serum androstenedione, and DHEAS levels were found in ectopic and pituitary ACTH hypersecretion than in adrenal adenomas and carcinomas. An- drostenedione and DHEAS were lower in adrenal adenomas than in the other subgroups (P < 0.05). DHEAS and E2 were higher in adrenal carcinomas than in the other groups (P < 0.05); E2 was similar among men and women with carcinomas, indicating that most adrenal malignancies produce small to
large amounts of E2. T was lower in men with Cushing’s dis- ease, adrenal adenoma, and ectopic ACTH secretion than in those with adrenal carcinoma (P < 0.05). The latter one was similar to controls. Women with adrenal carcinoma, pituitary, and ectopic ACTH hypersecretion had T levels significantly higher (P < 0.05) than controls, whereas those with adrenal adenoma had lower values (P < 0.05).
Assessment of bone density and turnover (Table 2)
Calcium, phosphorus, iPTH, and vitamin D values did not differ between controls and patients of any subgroup. Serum osteocalcin levels were lower and hydroxyproline excretion
| Variable | ACTH-secreting pituitary adenoma | Adrenal adenoma | Adrenal carcinoma | Ectopic ACTH excess | Controls |
|---|---|---|---|---|---|
| No. of subjects | 37 | 18 | 15 | 10 | 80 |
| Serum calcium (mmol/liter) | 2.36 ± 0.13 | 2.38 ± 0.15 | 2.34 ± 0.14 | 2.39 ± 0.16 | 2.33 ± 0.11 |
| Albumin (g/dl) | 3.99 ± 0.44 | 4.06 ± 0.36 | 3.86 ± 0.5 | 4.28 ± 0.3 | 4.1 ± 0.3 |
| Urinary calcium excretion (mg/24 h) | 182 + 95 | 215 ± 88 | 171 ± 44 | 192 ±62 | 166 ± 73 |
| iPTH (ng/liter) | 43.4 ± 12 | 40.2 ± 14 | 38 ± 15 | 44.5 ±13 | 41.2 ± 16 |
| Osteocalcin (ng/ml) | 1.5 ± 0.5ª | 2.3 ± 0.7 | 2.4 ± 0.9 | 1.2 ± 0.4ª | 8.9 ± 2.46 |
| ALP (U/liter) | 153 ± 52 | 174.5 ±58 | 185 ± 61 | 187 + 49 | 168 ± 58 |
| Creatinine (pmol/liter) | 86 ± 8.6 | 88 ± 8.9 | 90 ± 9 | 87 ± 8.7 | 82 ± 9.8 |
| Hydroxyprolinuria (pmol/m2) | 135 ± 41.5 | 129 ± 36 | 127.5 ±32 | 137 + 40 | 102 + 166 |
| Lumbar Z score (SD) | -1.97 (-5.15 to -0.06) | -1.8 (-4 to -0.36) | -1.8 (-2.9 to 0.9) | -3.53 (-4.9 to -3.0)" | -0.03 ± 1.1ª |
| Femoral Z score (SD) | -1.04 (-2.6 to 0.3) | -1.5 (-2.6 to 1.2) | -0.8 (-2.3 to 0.7) | -0.6 (-2.45 to -0.2) | 0.05 ± 0.8b |
| Prevalence (%) of any vertebral fracture | 29 (78%) | 12 (67%) | 10 (67%) | 10 (100%) | 1 (1.3%)d |
| Clinical fracturese | 15 (52%) | 6 (60%) | 4 (40%) | 7 (70%) | 0 (0%)b |
| Multiple fracturese | 25 (86%) | 9 (75%) | 8 (80%) | 10 (100%) | 0 (0%)d |
Data are expressed as mean + SD or median and range, as appropriate.
” P < 0.05 vs. all other groups of patients.
b P < 0.05 vs. all groups of patients.
c P < 0.01 vs. all other groups of patients.
d P < 0.01 vs. all groups of patients.
e The percentage of clinical and multiple fractures was calculated as a subset of patients with any fracture. Reference ranges: calcium, 2.2-2.6 mmol/liter; ALP, 98-275 U/liter; creatinine, less than 133 umol/liter; albumin, 3.6-5.2 g/dl; osteocalcin, 2-22 ng/ml; PTH, 10-75 ng/liter; hydroxyproline excretion, 60-190 pmol/m2.
f P < 0.05 vs. ectopic ACTH hypersecretion.
higher in patients than controls (P < 0.05). Osteocalcin was lower in patients with pituitary and ectopic ACTH secretion than in those with adrenal tumors (P < 0.05).
Both lumbar (P < 0.01) and femoral BMD (P < 0.05) values were significantly lower in patients than controls. Gender- and age-corrected lumbar BMD was lower in the group with ectopic ACTH secretion (P < 0.01 vs. all groups) but similar among the others.
Assessment of vertebral fractures (Table 2)
Vertebral fractures were found in 61 (76%) patients, with multiple involvement of thoracic and / or lumbar vertebrae in 52 (85%). Clinically symptomatic collapsed vertebrae were found in 32 (52%) patients; they were associated with pain, functional limitation, and height shortening by 3-10 cm of final stature. Twenty-nine patients (48% of those with frac- tures) had asymptomatic fractures, which were multiple in 22 (76%) of them. The fractures involved the thoracic verte- bral bodies in 52% of patients, the lumbar vertebrae in 23% of patients, and both thoracic and lumbar bodies in 25% of cases. Seven patients with vertebral fractures (11%) had val- ues of lumbar BMD within the normal range. The prevalence of any and clinical fractures did not differ among the groups with different disease etiology, whereas multiple fractures were more frequent in patients with ectopic ACTH hyper- secretion when compared with those with adrenal tumors (P < 0.05).
When comparing the patients with fractures with those without fractures, the first group had decreased lumbar BMD (0.83 ± 0.14 vs. 1.03 ± 0.19 g/cm2; P < 0.001), whereas both groups presented similar age, BMI, and endocrine parameters.
Predictive factors for bone loss and fractures
Lumbar and femoral BMD correlated with morning F (r = -0.36, P = 0.03 and r = - 0.4, P = 0.02, respectively) and total T (r = 0.35, P = 0.04 and r = 0.58; P = 0.015, respectively), whereas femoral BMD showed a trend also with DHEAS (r = 0.47; P = 0.06). There was no correlation between BMD and E2 values.
By logistic regression analysis, vertebral fractures were predicted by lumbar BMD values (B = 0.61; P < 0.001). Among the different parameters evaluated to distinguish those with a predictive value, lumbar BMD was the only one statistically significant at receiver operating characteristic analysis with the area under the curve of 0.87 ± 0.07 (95% confidence interval, 0.74-1.008; P = 0.001). Lumbar BMD value of 0.823 g/cm2 indicated the cutoff to distinguish pa- tients with and without vertebral fractures with a sensitivity of 100% and specificity of 53%.
Surprisingly, there were no differences in lumbar BMD Z score (-1.96 ± 1.14 vs. - 1.61 ± 1.13; P = 0.367) and prev- alence of fractures [18 of 21 (86%) vs. 16 of 28 (57%); P = 0.1] between amenorrheic and eumenorrheic women. Their F and androgen levels did not differ significantly as well as those of E2 (191 ± 209 vs. 261 ± 305 pmol/liter; P = 0.3).
Discussion
This is the first systematic evaluation of both symptomatic and nonsymptomatic vertebral fractures and their risk fac- tors in a large population of patients with endogenous F excess. A high prevalence (76%) of vertebral fractures was revealed, regardless of the different etiology of patients’ hy- percortisolism. A lower lumbar BMD was a predictor for vertebral fractures.
Patients with ectopic and pituitary ACTH hypersecretion had more severe F excess than those with adrenal adenomas or carcinomas. Androgen excess (high DHEAS, andro- stenedione, and female T) was present in patients with pi- tuitary and ectopic Cushing, whereas the excess of andro- gens plus estrogens was revealed in patients with adrenal carcinoma. F and total T correlated with both lumbar and femoral BMD in our patients, whereas Minetto et al. (23) showed a significant correlation between DHEAS and BMD at either lumbar spine or femoral neck.
Surprisingly, serum androgens were similar in men and women with overt Cushing’s syndrome. Moreover, in our experience, amenorrheic and eumenorrheic women had sim- ilar bone density and prevalence of fractures. Although their E2 values overlapped, the lack of any relationship among E2, BMD, and fractures in this study can likely be explained by the negative bony effects of overt hypercortisolism, which overwhelm the positive effects of estrogens in this particular population. Because the decrease in estrogen levels in the general population is the most important cause of bone loss and the number of women included in each patient group in this study was relatively small, some milder correlation may have been missed. As a matter of fact, Karavitaki et al. (18) have documented reduced forearm BMD in 16 postmeno- pausal but not in 13 premenopausal women with Cushing’s syndrome; nevertheless, peripheral and axial skeleton may have different behavior during the F excess.
Our data suggested that among the risk factors considered for bone loss, spinal bone status worsened proportionally with the degree of F excess, being partly influenced by in- creased androgen levels but not directly by E2.
As concerning the etiology of F excess, lower lumbar BMD and a higher frequency of multiple fractures were observed in patients with ectopic ACTH excess, whereas there was no statistical difference between subjects with pituitary or ad- renal Cushing’s disease. This is in contrast with a previous finding by Ohmori et al. (24) who reported a greater bone loss in patients with pure F excess due to adrenal adenomas compared with those with Cushing’s disease and attributed this difference to the protective effect of androgens.
Concerning the fractures, the prevalence revealed by this study is not so surprising because Chiodini et al. (25) have recently reported a prevalence of vertebral fractures as high as 43% in premenopausal and 78% in postmenopausal women with subclinical hypercortisolism due to adrenal in- cidentaloma. Male patients were more frequently affected by clinically evident fractures. Thoracic vertebrae were more frequently fractured than the lumbar ones. However, there are no data on predictive factors for fractures in endogenous hypercortisolism. On the other hand, in patients with exog- enous F excess, a daily dose was found to be a strong pre-
dictor of vertebral fractures by Van Staa et al. (26), whereas combined effects of higher doses, longer duration, and a continuous pattern of exposure increased the relative risk for vertebral and nonvertebral fractures in the study by Stein- buch et al. (27). Overt endogenous F excess is likely more severe than that caused by corticosteroid treatments because only some of the patients on steroid therapy develop typical symptoms of hypercortisolism.
The high prevalence of multiple vertebral fractures de- tected in the current study at diagnosis of F excess is of particular clinical relevance because they are irreversible. An increase in BMD ranging from 14-79% has been reported in patients successfully treated for endogenous F excess (28- 30), and fracture incidence decreased after glucocorticoid treatment withdrawal (26). These findings point out the ne- cessity of a very precocious preventive treatment to reduce, at least partially, the detrimental effects of F excess on the bone. In fact, the use of calcium, vitamin D, and bisphos- phonates is recommended for the prevention of bone loss in chronic users of corticosteroids (31, 32), and we previously reported that bisphosphonate treatment counterbalanced the negative effects of hypercortisolism in patients with active Cushing’s disease (33).
Although lumbar BMD was found to be a predictive factor for vertebral fractures, this study confirms that patients with either exogenous or endogenous F excess are at risk for symptomatic and nonsymptomatic vertebral fractures even at normal densitometric values, and a radiography of the spine is required to assess the morphology of vertebral bodies.
In conclusion, this study confirms and extends previous observations on the negative early and dose-dependent ef- fects of endogenous F excess on bone density and bone turn- over (10, 34-36). The harmful effects of hypercortisolism on the spine were partly counterbalanced by an increased an- drogen production in both genders but not by female go- nadal status. Among the groups with different etiology of F excess, the patients with ectopic ACTH secretion had higher F, lower lumbar BMD values, and more frequent multiple fractures. Any vertebral fracture was present in 76% of the patients at diagnosis of Cushing’s syndrome, regardless of its etiology. The best preventive intervention should include a very early diagnosis of F excess, simultaneous bone status evaluation, and a prompt preventive treatment. Unfortu- nately, it is not an easy task in a common clinical practice.
Acknowledgments
We are indebted to Mr. Alfonso Gruosso for his help in editing the manuscript and to Dr. Francesco Manguso for his statistical expertise.
Received March 16, 2005. Accepted February 23, 2006.
Address all correspondence and requests for reprints to: Annamaria Colao, M.D., Ph.D., Department of Molecular, Clinical Endocrinology, and Oncology, Federico II University of Naples, via Sergia Pansini 5, 80131 Naples, Italy. E-mail: colao@unina.it.
This work was partially supported by the Italian Minister of Research and University in Rome (Grant 2004062974).
All of the authors have nothing to declare.
References
1. Cushing H 1932 The basophil adenomas of the pituitary body and their clinical manifestation (pituitary basophilism). Bull Johns Hopkins Hosp 50:137-195
2. Canalis E 1996 Mechanisms of glucocorticoid action in bone: implications for glucocorticoid-induced osteoporosis. J Clin Endocrinol Metab 81:3441-3447
3. Borelli A, Leite MO, Correa PH, Jorgetti V, Marcondes JA, Batalha JR, Cintra AB, Wajchenberg BL 1992 Bone histomorphometry in Cushing’s syndrome. J Endocrinol Invest 15:783-787
4. Reid IR 1998 Glucocorticoid effects on bone. J Clin Endocrinol Metab 83: 1860-1861 (Editorial)
5. Lukert BP, Raisz LG 1990 Glucocorticoid-induced osteoporosis: pathogenesis and management. Ann Int Med 112:352-364
6. Pereira RM, Delany AM, Canalis E 2001 Cortisol inhibits the differentiation and apoptosis of osteoblasts in culture. Bone 28:484-490
7. Rubin MR, Bilezikian JP 2002 The role of parathyroid hormone in the patho- genesis of glucocorticoid-induced osteoporosis: a reexamination of the evi- dence. J Clin Endocrinol Metab 87:4033-4041
8. Khanine V, Fournier JJ, Requeda E, Luton JP, Simon F, Crouzet 2000 Os- teoporotic fractures at presentation of Cushing’s disease: two case reports and literature review. Joint Bone Spine 67:341-345
9. Freehill AK, Lenke LG 1999 Severe kyphosis secondary to glucocorticoid- induced osteoporosis in a young adult with Cushing’s disease. A case report and literature review. Spine 24:189-193
10. Vestergaard P, Lindholm J, Jorgensen JO, Hagen C, Hoeck HC, Laurberg P, Rejnmark L, Brixen K, Kristensen LO, Feldt-Rasmussen U, Mosekilde L 2002 Increased risk of osteoporotic fractures in patients with Cushing’s syndrome. Eur J Endocrinol 146:51-56
11. Lado-Abeal J, Rodriguez-Arnao J, Newell-Price JDC, Perry LA, Grossman AB, Besser GM, Trainer PJ 1998 Menstrual abnormalities in women with Cushing’s disease are correlated with hypercortisolemia rather than raised circulating androgen levels. J Clin Endocrinol Metab 83:3083-3088
12. Barbetta L, Dall’Asta C, Re T, Colombo P, Travaglini P, Ambrosi B 2001 Androgen secretion in ectopic ACTH syndrome and in Cushing’s disease: modifications before and after surgery. Horm Metab Res 33:596-601
13. Kaltsas GA, Korbonits M, Isidori AM, Webb JAW, Trainer PJ, Monson JP, Besser GM, Grossman AB 2000 How common are polycystic ovaries and the polycystic ovarian syndrome in women with Cushing’s syndrome? Clin En- docrinol (Oxf) 53:493-500
14. Fitzpatric LA 1994 Glucocorticoid-induced osteoporosis. In: Marcus R, ed. Osteoporosis. Boston: Blackwell Scientific; 202-226
15. Castelo-Branco C, Gomez O, Pons F, Martinez de Osaba MJ, Balasch J, Antoni Vanrell J 2003 Secreting ovarian tumors may protect women from osteoporosis. Gynecol Oncol 88:149-152
16. Adami S, Zamberlan N, Castello R, Tosi F, Gatti D, Moghetti P 1998 Effect of hyperandrogenism and menstrual cycle abnormalities on bone mass and bone turnover in young women. Clin Endocrinol (Oxf) 48:169-173
17. Sipahi S, Tuzun S, Ozaras R, Calis HT, Tuzun F, Karayel T 2004 Bone mineral density in women with sarcoidosis. J Bone Miner Metab 22:48-52
18. Karavitaki N, Ioannidis G, Giannakopoulos F, Mavrokefalos P, Thalassinos N 2004 Evaluation of bone mineral density of the peripheral skeleton in pre- and postmenopausal women with newly diagnosed endogenous Cushing’s syndrome. Clin Endocrinol (Oxf) 60:264-270
19. Del Puente A, Heyse SP, Mandes MG, Mantova D, Carpinelli A, Nutile G, Oriente P 1998 Epidemiology of osteoporosis in women in southern Italy. Aging Clin Exp Res 10:53-58
20. Minne HW, Leidig G, Wüster C, Siromachhkostov L, Baldauf G, Bickel R, Sauer P, Lojen M, Ziegler R 1988 A newly defined spine deformity index (SDI) to quantitative vertebral crush fractures in patients with osteoporosis. Bone Miner J 3:335-349
21. Melton LJ, Kan SH. Frye KM, Wahner HW, O’Fallon WM, Riggs B 1989 Epidemiology of vertebral fractures in women. Am J Epidemiol 124:1000-1011
22. Critchlow DE, Fligner MA 1991 On distribution-free multiple comparisons in the one-way analysis of variance. Commun Stat Theor Methods 20:127-139
23. Minetto M, Reimondo G, Osella G, Ventura M, Angeli A, Terzolo M 2004 Bone loss is more severe in primary adrenal than in pituitary-dependent Cushing’s syndrome. Osteoporos Int 11:855-861
24. Ohmori N, Nomura K, Ohmori K, Kato Y, Itoh T, Takano K 2003 Osteoporosis is more prevalent in adrenal than in pituitary Cushing’s syndrome. Endocr J 50:1-7
25. Chiodini I, Guglielmi G, Battista C, Carnevale V, Torlontano M, Cammista M, Trischitta V, Scillitani A 2004 Spinal volumetric bone mineral density and vertebral fractures in female patients with adrenal incidentalomas: the effects of subclinical hypercortisolism and gonadal status. J Clin Endocrinol Metab 89:2237-2241
26. Van Staa TP, Leufkens HGM, Abenhaim L, Zhang B, Cooper C 2000 Use of corticosteroids and risk of fractures. J Bone Miner Res 15:993-1000
27. Steinbuch M, Youket TE, Cohen S 2004 Oral glucocorticoid use is associated with an increased risk of fracture. Osteoporos Int 15:323-328
28. Di Somma C, Pivonello R, Loche S, Faggiano A, Klain M, Salvatore M, Lombardi G, Colao A 2003 Effect of 2 years of cortisol normalization on the impaired bone mass and turnover in adolescent and adult patients with Cush- ing’s disease: a prospective study. Clin Endocrinol (Oxf) 58:302-308
29. Catargi B, Tabarin A, Basse-Cathalinant B, Ducassou D, Roger P 1996 De- velopment of bone mineral density after cure of Cushing’s syndrome. Ann Endocrinol (Paris) 57:203-208
1784 J Clin Endocrinol Metab, May 2006, 91(5):1779-1784
Tauchmanovà et al. · Bone Status in Endogenous Hypercortisolism
30. Hermus AR, Smals A, Swinkels LM, Huysmans DA, Pieters GF, Sweep CF, Corstens FH, Kloppenborg PW 1995 Bone mineral density and bone turnover before and after cure of Cushing’s syndrome. J Clin Endocrinol Metab 80: 2859-2865
31. Canalis E, Bilezikian JP, Angeli A, Giustina A 2004 Perspectives on glu- cocorticoid-induced osteoporosis. Bone 34:593-598
32. Compston J 2003 Glucocorticoid-induced osteoporosis. Horm Res 60 (Suppl 3):77-79
33. Di Somma C, Colao A, Pivonello R, Klain M, Faggiano A, Tripodi FS, Merola B, Salvatore M, Lombardi G 1998 Effectiveness of chronic treatment with alendronate in the osteoporosis of Cushing’s disease. Clin Endocrinol (Oxf) 48:655-662
34. Chiodini I, Carnevale V, Tortolano M, Fusilli S, Guglielmi G, Pileri M,
Modoni S, Di Giorgio A, Liuzzi A, Minisola S, Cammisa M, Trischitta V, Scillitani A 1998 Alteration of bone turnover and bone mass at different skeletal sites due to pure glucocorticoid excess: study in eumenorrheic patients with Cushing’s syndrome. J Clin Endocrinol Metab 83:1863-1867
35. Tauchmanovà L, Rossi R, Nuzzo V, del Puente A, Esposito A, Pizzi C, Fonderico F, Lupoli G, Lombardi G 2001 Bone loss determined by quantitative ultrasonometry correlates with the disease activity in patients with different degree of endogenous glucocorticoid excess due to adrenal mass. Eur J En- docrinol 145:241-247
36. Sartorio A, Conti A, Ferrero S, Giambona S, Re T, Passini E, Ambrosi B 1998 Evaluation of markers of bone and collagen turnover in patients with active and preclinical Cushing’s syndrome and in patients with adrenal incidenta- loma. Eur J Endocrinol 138:146-152
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