Dual-Energy X-ray Absorptiometry Predictors of Vertebral Deformities in Beta-Thalassemia Major.

Vertebral fractures in beta-thalassemia major are increasingly found because of the longer life expectancy of patients, with a major negative impact on their quality of life. We performed a retrospective cross-sectional study to investigate the prevalence of vertebral deformities in thalassemic patients and to identify their best dual-energy X-ray absorptiometry (DXA) predictor among trabecular bone score (TBS), bone mineral density (BMD), and Z-score. Eighty-two outpatients with beta-thalassemia major on regular conventional treatment were studied at a single academic center. All patients underwent plain thoracic-lumbar spine X-rays and lumbar DXA to assess the number and the severity of vertebral deformities (Genant's method), the spinal deformity index, lumbar spine DXA parameters (BMD, TBS, and Z-score), and the presence of platyspondyly. Twenty-nine patients (35%) had vertebral deformities and showed significantly lower TBSs than the remainders (1.141 ± 0.083 vs 1.254 ± 0.072, p < 0.0001). The analysis of variance of the TBS between the group of patients without vertebral deformities (spinal deformity index = 0) and the remaining groups showed a significant difference (p < 0.001). The TBS had better sensitivity (86.2%), specificity (75.5%), and diagnostic accuracy (79.3%) than BMD and Z-score in discriminating patients with and without vertebral deformities. Combining the TBS with the BMD or the Z-score showed that the diagnostic accuracy of the first in discriminating patients with and without vertebral deformities improved from 79.3% to 85.4% and 87.8%, respectively. The presence of platyspondyly was a significant predictor of vertebral deformities in the multivariate model. Vertebral deformities in well-treated patients with beta-thalassemia major are common and are often unrecognized. In our hands, the TBS was better than the BMD and the Z-score in predicting vertebral deformities. Plain X-rays of the spine should be performed also in asymptomatic patients, especially when the TBS is low.

Increased osteoprotegerin levels in Cushing's syndrome are associated with an adverse cardiovascular risk profile.

CONTEXT: Patients with Cushing's syndrome (CS) have a mortality rate four times higher than age- and sex-matched subjects, mainly due to cardiovascular events. Serum osteoprotegerin (OPG) levels are increased in patients with cardiovascular disease and/or excess bone resorption. OBJECTIVE: The aim of the study was to assess serum OPG and soluble receptor activator of nuclear factor-kappaB ligand (sRANKL) levels in CS and their possible relationship with coronary risk profile. DESIGN AND SETTING: We conducted a cross-sectional study at a tertiary referral center. PATIENTS: We studied 48 adult patients with CS and 48 age- and sex-matched controls. Twenty-six patients had pituitary-dependent CS; five patients had CS caused by ectopic ACTH secretion; and 17 patients had adrenal-dependent CS, accounted for by cortisol-secreting adenoma (n = 9), ACTH-independent macronodular bilateral adrenal hyperplasia (n = 4), or World Health Organization stage II cortisol-secreting carcinoma (n = 4). Patients underwent assessment of the absolute coronary risk and measurement of bone mineral density by dual-energy x-ray absorptiometry. Serum OPG and total sRANKL were measured by ELISA. RESULTS: Serum OPG (but not sRANKL) levels were significantly higher in CS patients than in controls (P < 0.01). In patients, serum OPG showed a positive correlation with age (r = 0.36; P = 0.01). OPG levels were higher in patients with the metabolic syndrome [median, 1262 (range, 199-2306) pg/ml vs. 867 (412-2479) pg/ml; P = 0.03], and showed a positive correlation with the absolute coronary risk (r = 0.36; P = 0.01). Serum OPG levels were higher in patients with pituitary-dependent CS in comparison with adrenal-dependent CS. CONCLUSIONS: In patients with CS, serum OPG levels are increased and appear to be associated with coronary risk.

Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis.

Glucocorticoid (GC)-induced osteoporosis is the leading form of secondary osteoporosis. Bone loss can be rapid. However, longitudinal studies at the very beginning of treatment are scarce. Patients relapsing from multiple sclerosis are treated with high-dose, short-term iv GCs. A number of them are young, without concomitant disease affecting bone and with no substantial impairment of mobility. Such patients were selected for the present study. Thirteen patients suffering from multiple sclerosis [11 females, two males; age 32 +/- 2 yr (mean +/- se)] and receiving iv methylprednisolone 15 mg/kg daily for 10 d completed the study. We measured serum osteocalcin (OC), aminoterminal propeptide of type I collagen (PINP), bone isoform of alkaline phosphatase (bALP), carboxyterminal telopeptide of type I collagen (CTX), and urinary calcium/creatinine ratio (uCa/Cr) during the 10-d cycle and 3 months later. Dual-energy x-ray absorptiometry and calcaneal quantitative ultrasonometry were performed before and 6 months after therapy. We found an immediate, impressive fall of OC and PINP (-80 +/- 3 and -54 +/- 5% at d 2, respectively), which persisted throughout the whole treatment period (P < 0.0001 for both markers). bALP levels showed only a modest decrease at d 6 (-19 +/- 7%, P < 0.05), with subsequent return to baseline in d 7-10. After 3 months, OC, PINP, and bALP levels rose to +51 +/- 22, +37 +/- 16 (not significant), and +61 +/- 17% (P < 0.01) with respect to baseline, respectively. uCa/Cr and CTX showed a progressive, marked increase during treatment, peaking at d 7-9 (+92 +/- 44 and +149 +/- 63%, respectively), with subsequent decrement at d 10 (P < 0.01 and P < 0.05, respectively) despite continuing GC administration. After 3 months, uCa/Cr and CTX levels were also higher than baseline. No change in quantitative ultrasonometry parameters and bone mineral density was observed 6 months after therapy. In conclusion, high-dose, short-term iv GC regimens cause an immediate and persistent decrease in bone formation and a rapid and transient increase of bone resorption. Our data also support the concept that discontinuation of such regimens is followed by a high bone turnover phase.

Hyperhomocysteinemia in patients with Cushing's syndrome.

We evaluated serum homocysteine concentrations and the C677T polymorphism of the gene encoding for methylene tetrahydrofolate reductase, a key enzyme for homocysteine metabolism, in 57 patients with Cushing's syndrome, 41 with active disease, and 16 in remission after successful surgery and 105 blood donors. The patients with active Cushing's syndrome had significantly higher serum homocysteine levels and lower folate concentrations than either the patients in remission or controls. The presence of a statistically significant difference in homocysteine concentrations among the three groups was confirmed after adjustment for confounding variables. In a multiple regression model, homocysteine levels were significantly associated with midnight serum cortisol levels (beta = 0.33, P = 0.01), which is the most sensitive marker of endogenous hypercortisolism, and serum folate levels (beta = -0.32, P = 0.02). The distribution of methylene tetrahydrofolate reductase genotypes was not different between patients and controls. In conclusion, active hypercortisolism is associated with hyperhomocysteinemia and reduced serum folate concentrations, whereas the patients in remission have homocysteine concentrations comparable with healthy subjects. Low serum folate concentrations do not fully account for the increase in homocysteine levels that are positively correlated with cortisol levels. Hyperhomocysteinemia may be key to the prothrombotic state and increased cardiovascular risk of Cushing's syndrome.

Cortisol secretion, bone health, and bone loss: a cross-sectional and prospective study in normal non-osteoporotic women in the early postmenopausal period.

OBJECTIVE: The aim of the study was to evaluate the relationship between cortisol secretion, bone health, and bone loss in a cohort of normal women in the early postmenopausal period. METHODS: We measured lumbar and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA) and heel ultrasound parameters in 82 healthy, nonosteoporotic (lumbar T-score ≥-2.0) women (median age 52.5 years, range 42-61). These women were examined in two sessions, 1 year apart, in the early postmenopausal period (onset of menopause between 6 and 60 months). Parameters of the hypothalamic-pituitary-adrenal (HPA) axis function were morning serum cortisol, morning and midnight salivary cortisol, 24-h urinary free cortisol (UFC), serum cortisol after 0.5 and 1 mg overnight dexamethasone, and DHEA-S. RESULTS: In multiple regression analyses, the following significant inverse correlations were found: i) lumbar BMD and either 24-h UFC (P<0.005) or morning serum cortisol (P<0.05), ii) total femur and femoral neck BMD with morning serum cortisol (P=0.05 and P<0.05), and iii) heel ultrasound stiffness index and midnight salivary cortisol (P<0.005). The annual rate of change in lumbar and femoral BMD did not correlate with any of the above-mentioned hormonal variables. No difference was found in the parameters of HPA axis function in slow (loss of BMD <1%) vs fast (loss of BMD ≥3%) bone losers. CONCLUSIONS: HPA axis may contribute to postmenopausal bone health, but differences in cortisol secretion do not influence the differential rate of bone loss between slow and fast bone losers in the early postmenopausal period, at least in healthy women.

Circulating osteoprotegerin and soluble RANK ligand in systemic sclerosis.

OBJECTIVE: .Microvascular damage is an early pathogenetic event in systemic sclerosis (SSc). The receptor activator of nuclear factor-kappaB ligand (RANKL)/RANK/osteoprotegerin (OPG) system is involved in vascular biology. Our aim was to assess OPG and soluble RANKL (sRANKL) serum levels in patients with SSc and healthy controls. METHODS: Sixty patients with SSc (median age 58, range 31-72 yrs) and 60 healthy subjects matched for age, sex, and menopausal status were recruited. Serum OPG, sRANKL, soluble vascular cell adhesion molecule (sVCAM; marker of endothelial activation/injury), and bone turnover markers were measured. Bone mineral density in patients was assessed and cardiovascular/coronary risk was estimated. RESULTS: OPG was similar in the 2 groups, while sRANKL and sRANKL/OPG ratio was higher in patients (p = 0.01 for both). sVCAM was markedly higher in patients (p < 0.001). OPG levels correlated positively with age in both patients (Spearman R = 0.50, p < 0.001) and controls (R = 0.56, p < 0.001). In patients, OPG was lower in men and higher in those with active ulcers or calcinosis. sRANKL levels were higher in patients treated with platelet aggregation inhibitors, and correlated negatively with densitometric measures. 25-hydroxyvitamin D levels were significantly lower in patients (p < 0.001). In patients, OPG levels correlated positively with cardiovascular and coronary risk (R = 0.28, p = 0.05 and R = 0.34, p < 0.01, respectively) and were higher in patients with hypertension and left ventricular hypertrophy. sVCAM levels correlated positively with cardiovascular and coronary risk (R = 0.27, p = 0.06, and R = 0.38, p < 0.01, respectively). CONCLUSION: Higher sRANKL levels and sRANKL/OPG ratio in patients with SSc are likely to be a consequence of altered bone microenvironment. We show a dissociation between the well established marker of endothelial activation/injury, sVCAM, and the alleged marker of vascular damage, OPG, in patients with SSc. Further studies are needed to better ascertain the relationships of the RANKL/RANK/OPG system with the progression of macro- and microvascular damage.