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.

Osteoporotic Hip Fracture Prediction: Is T-Score-Based Criterion Enough? A Hip Structural Analysis-Based Model.

At present, the current gold-standard for osteoporosis diagnosis is based on bone mineral density (BMD) measurement, which, however, has been demonstrated to poorly estimate fracture risk. Further parameters in the hands of the clinicians are represented by the hip structural analysis (HSA) variables, which include geometric information of the proximal femur cross section. The purpose of this study was to investigate the suitability of HSA parameters as additional hip fracture risk predictors. With this aim, twenty-eight three-dimensional patient-specific models of the proximal femur were built from computed tomography (CT) images and a sideways fall condition was reproduced by finite element (FE) analyses. A tensile or compressive predominance based on minimum and maximum principal strains was determined at each volume element and a risk factor (RF) was calculated. The power of HSA variables combinations to predict the maximum superficial RF values was assessed by multivariate linear regression analysis. The optimal regression model, identified through the Akaike information criterion (AIC), only comprises two variables: the buckling ratio (BR) and the neck-shaft angle (NSA). In order to validate the study, the model was tested on two additional patients who suffered a hip fracture after a fall. The results classified the patients in the high risk level, confirming the prediction power of the adopted model.

The Italian Observational Study on Severe Osteoporosis (ISSO): 24-month results on incidence of fractures and adherence to treatment.

OBJECTIVES: To estimate the proportion of patients with very severe osteoporosis (those covered by the reimbursement criteria of the Italian National Health Service) experiencing new vertebral and non-vertebral fragility fractures in the first 24 months of a new anti-osteoporosis treatment. METHODS: Prospective observational study in men and post-menopausal women (aged > 21 years) initiating anti-osteoporosis treatment for very severe osteoporosis. Eligibility was based on teriparatide (TPD) reimbursement criteria in Italy: incident of vertebral or hip fracture during anti-resorptive treatment (minimum 1 year), or at least three prevalent severe vertebral fractures, or two prevalent severe vertebral fractures and a historical proximal hip fracture. Incidence of new clinical vertebral and non-vertebral fractures was documented by original x-rays and/or radiological reports, and a post-hoc analysis compared data from the TPD monotherapy population versus the total treated group. RESULTS: Overall, 767 patients (mean age 72.8 years, 90.7% women) were enrolled in the study, of whom 628, 538, 419 and 424 attended visits at 6, 12, 18 and 24 months, respectively. The most commonly prescribed therapy was TPD (single-agent; 64.5%), then bisphosphonates and other anti-resorptives (33.3%). A combination of different oral treatments was given to 22.5% of the patients. Overall treatment adherence at 24 months was 65.7%. In a post-hoc analysis, the overall incidence of new clinical vertebral and non-vertebral fractures in the total treated population was, respectively, 4.7% and 2.3% in the first 6 months; 1.8% and 1.6% in the 6-12 month period; 2.9% and 1.4% in the 12-18 month period; and 2.2% and 1.0% in the 18-24 month period. CONCLUSIONS: In patients with very severe osteoporosis, the risk of new vertebral and non-vertebral fractures declined after the first 6 months and remained low throughout the study.

Percutaneous vertebroplasty in osteoporotic patients: an institutional experience of 1,634 patients with long-term follow-up.

PURPOSE: To assess long-term clinical outcome of percutaneous vertebroplasty (PV). MATERIALS AND METHODS: PV was performed in 1,634 patients (1,387 women; median age 73 years ± 9.3) with painful osteoporotic vertebral compression fractures (VCFs). All patients had back pain that persisted for ≥ 2 months with a concordant magnetic resonance imaging study. After PV, medical therapy for osteoporosis was continued, and patients were prospectively evaluated (follow-up 11.8-44.9 months, mean 25.0 months). Visual analog scale (VAS), Oswestry Disability Index (ODI), analgesic drug use, and use of external brace support were recorded at baseline and during follow-up. New occurrences of symptomatic vertebral fractures were recorded. RESULTS: The mean VAS score of 7.94 significantly improved to 1.12 at the primary endpoint (P < .001). Differences in patterns of analgesic usage compared with baseline values were highly statistically significant (marginal homogeneity test, P < .001). Median ODI values of 82% before treatment significantly decreased to 6% (P < .001). Before intervention, 1,279 patients wore a brace; 1,167 (91.2%) patients did not wear a brace after PV (χ(2) = 31.005, P < .0001). A new painful fracture with a significant higher proportion of contiguous vertebrae (63.6%) occurred in 214 (13.1%) patients (z = 7.59, P = .025). CONCLUSIONS: PV can provide durable pain relief and improvement in ambulation in patients with VCFs.

Multiple Rebound-Associated Vertebral Fractures after Denosumab Discontinuation: Is Prompt Antiresorptive Therapy Always Recommended,Even When the Risk of Fracture Seems Low? A Case Report.

BACKGROUND: Non-osteoporotic patients with endocrine-sensitive breast cancer are often treated with denosumab only during the anti-aromatase treatment, and when the anti-aromatase therapy is discontinued, no antiresorptive drug is prescribed. This case report clearly shows how even a patient with a low risk of fractures could have multiple rebound vertebral fractures after denosumab discontinuation. CASE PRESENTATION: We report the case of a 60-year-old woman who suffered from multiple vertebral fractures only seven months after discontinuation of denosumab that had been administered to prevent bone loss related to three years of aromatase inhibitors as adjuvant therapy for breast cancer. No antiresorptive therapy was prescribed at the time of denosumab discontinuation, assuming that the patient had a low absolute risk of fracture after the withdrawal of the aromatase inhibitor. CONCLUSION: This case underlines the relative irrelevance of bone mineral density and clinical algorithms in predicting the risk of rebound-associated vertebral fractures after denosumab discontinuation and the strong recommendation to always switch to another antiresorptive therapy (such as zoledronic acid) immediately at the time of denosumab discontinuation.

Improving the Hip Fracture Risk Prediction Through 2D Finite Element Models From DXA Images: Validation Against 3D Models.

Osteoporotic fracture incidence represents a major social and economic concern in the modern society, where the progressive graying of the population involves an highly increased fracture occurrence. Although the gold standard to diagnose osteoporosis is represented by the T-score measurement, estimated from the Bone Mineral Density (BMD) using Dual-energy X-ray Absorptiometry (DXA), the identification of the subjects at high risk of fracture still remains an issue. From this perspective, the purpose of this work is to investigate the role that DXA-based two-dimensional patient-specific finite element (FE) models of the proximal femur, in combination with T-score, could play in enhancing the risk of fracture estimation. With this aim, 2D FE models were built from DXA images of the 28 post-menopausal female subjects involved. A sideways fall condition was reproduced and a Risk of Fracture ( RF ^ ) was computed on the basis of principal strains criteria. The identified RF ^ was then compared to that derived from the CT-based models developed in a previous study. The 2D and 3D RF ^ turned out to be significantly correlated (Spearman's ρ = 0.66, p < 0.001), highlighting the same patients as those at higher risk. Moreover, the 2D RF ^ resulted significantly correlated with the T-score (Spearman's ρ = -0.69, p < 0.001), and managed to better differentiate osteopenic patients, drawing the attention to some of them. The Hip Structural Analysis (HSA) variables explaining the majority of the variance of the 2D and 3D fracture risk were the same as well, i.e., neck-shaft angle and narrow neck buckling ratio. In conclusion, DXA-based FE models, developable from currently available clinical data, appear promising in supporting and integrating the present diagnostic procedure.

Novel mutation of PPOX gene in a patient with abdominal pain and syndrome of inappropriate antidiuresis.

PURPOSE: Acute porphyrias are metabolic disorders of heme biosynthesis characterized by acute life-threatening attacks. The diagnosis is often missed since clinical presentation is aspecific mimicking other medical and surgical conditions. Variegate porphyria (VP) is an autosomal dominant inherited disease with incomplete penetrance due to decreased activity of the Protoporphyrinogen Oxydase (PPOX) gene; most VP mutations are family specific. We report the case of a 40 year-old woman who presented many times to the emergency department complaining of unexplained abdominal pain and laboratory investigations showed repeatedly hyponatremia. Syndrome of inappropriate antidiuresis (SIAD) was confirmed and measurement of urine porphobilinogen and delta-aminolevulinic acid disclosed the diagnosis of acute porphyria. The genetic analysis of PPOX gene was performed. METHODS: The entire coding sequence and exon/intron boundaries of PPOX gene were amplified in 5 different Polymerase Chain Reaction (PCR) fragments. In silico prediction of the pathogenicity of the mutation was determined by using different tools, Polyphen2, SNPs&GO, SNPs3D. RESULTS: The genetic analysis of PPOX gene revealed a novel missense variant c.1376 G > A (p.Cys459Tyr) in heterozygous state. The same variant was later found in one of her cousins with skin lesions and other three younger asymptomatic relatives. We provided evidence that this novel mutation is likely to be pathogenetic. CONCLUSIONS: Our case highlights the importance of considering VP in the differential diagnosis of SIAD and underlines the role of genetic screening in the management of such patients. The finding of a novel mutation of PPOX gene in our index case has allowed to recognize an affected family.

Subclinical Cushing's syndrome.

Subclinical Cushing's syndrome (CS) is attracting increasing interest since the serendipitous discovery of an adrenal mass has become a rather frequent event owing to the routine use of sophisticated radiologic techniques. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50% of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner that is not fully restrained by pituitary feedback, in 5 to 20% of cases depending on study protocols and diagnostic criteria. The criteria for qualifying subclinical cortisol excess are controversial and presently there is no consensus on a gold standard for the diagnosis of this condition. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipemia has been described in patients with subclinical CS; however, there is still no clear demonstration of the long-term complications of this condition whose management remains largely empirical. Either adrenalectomy or careful observation associated with treatment of the metabolic syndrome have been suggested as treatment options.

Subclinical Cushing's syndrome in adrenal incidentalomas.

This article reviews the available evidence on subclinical Cushing's syndrome in patients who have adrenal incidentalomas. The authors' aim is to present up-to-date information on the most relevant issues of subclinical Cushing's syndrome by addressing the many uncertainties and controversies surrounding this ill-defined endocrine condition.

The fat body mass increase after adjuvant androgen deprivation therapy is predictive of prostate cancer outcome.

Androgen deprivation therapy (ADT) leads to important changes in body composition. No data are currently available about the relationship between these treatment-related changes and patient outcome. Using dual-energy X-ray absorptiometry, bone mineral density (BMD), fat body mass (FBM), and lean body mass (LBM) were determined at baseline, and after 1 and 2 years in 53 non-metastatic prostate cancer (PC) patients with high-risk disease treated with adjuvant ADT. Changes in these parameters were correlated with patient outcome in terms of adverse skeletal events, disease recurrence, and overall survival. ADT led to a significant decrease in BMD (p < 0.03) and LBM (p < 0.03), and an increase in FBM, (p < 0.0001). Changes in BMD failed to show any relationship with time to skeletal-related events (SRE), disease recurrence, and death. FBM increase was a significant predictor of higher risk of SRE [hazard ratio (HR) 3.024, 95 % CI 1.004-10.353, p < 0.02], higher risk of death (HR 2.373, 95 % CI 1.012-5.567, p = 0.04), and a non-significant higher risk of disease recurrence (HR 2.219, 95 % CI 0.956-5.150, p = 0.13). LBM decrease did not correlate with either time to SRE or survival, while a non-significant association with disease recurrence (HR 1.550, 95 % CI 0.670-3.605, p = 0.06) was observed. The early increase in FBM may provide predictive information of poor outcome in PC patients given ADT. These data suggest that the adoption of early preventive measures aiming to reduce fat increase can potentially reduce the morbidity and mortality 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.

Adrenal incidentaloma: a new cause of the metabolic syndrome?

A number of patients with adrenal incidentaloma are exposed to a slight degree of cortisol excess resulting from functional autonomy of the adrenal mass (usually a cortical adenoma). At present, there are only scant data on the unwanted effects of this endocrine condition referred to as subclinical Cushing's syndrome. The aim of the present study was to look for some features of the metabolic syndrome in patients with incidental adrenal adenoma. Forty-one patients (9 men and 32 women) bearing adrenal incidentaloma with typical computed tomography features of cortical adenoma were studied. For both patients and controls, exclusion criteria were age equal to 70 yr or greater, previous history of fasting hyperglycemia, or impaired glucose tolerance (IGT), severe hypertension, current use of medication or concomitant relevant illnesses, and body mass index (BMI) equal to 30 kg/m(2) or greater. Forty-one patients with euthyroid multinodular goiter accurately matched for sex, age, and BMI served for a 1:1 case-control analysis. The study design included an oral glucose tolerance test (75 g) and an endocrine workup aimed at the study of the hypothalamic-pituitary-adrenal axis. Age and BMI were fully comparable between patients (54.0 +/- 10.7 yr, 23.8 +/- 2.4 kg/m(2)) and controls (52.2 +/- 11.6 yr, 23.5 +/- 2.8 kg/m(2)). Fasting glucose and fasting insulin levels were not different between the two groups (4.96 +/- 0.61 mmol/liter vs. 4.88 +/- 0.58 mmol/liter; 67 +/- 34 pmol/liter vs. 59 +/- 32 pmol/liter), but the 2-h postchallenge glucose was significantly higher in patients than in controls (7.43 +/- 2.49 mmol/liter vs. 6.10 plus minus 1.44 mmol/liter, P = 0.01). Fifteen patients (36%) reached the World Health Organization criteria for IGT and two other patients (5%) reached those for diabetes, and 14% of the controls qualified for IGT (P = 0.01). No difference in the lipid pattern was seen between the two groups, but either systolic or diastolic blood pressure were higher in patients (135.4 +/- 15.5 mm Hg vs. 125.0 +/- 15.6 mm Hg, P = 0.003; 82.9 +/- 9.1 mm Hg vs. 75.3 +/- 6.6 mm Hg, P < 0.0001). We calculated the whole-body insulin sensitivity index derived from the oral glucose tolerance test that was significantly reduced in the patients (4.3 +/- 1.7 vs. 5.7 +/- 2.5, P = 0.01). In a multiple regression analysis, 2-h glucose was associated with BMI and midnight cortisol values (r(2) = 0.36, P = 0.002). The comparison of the patients with nonfunctioning adenoma (n = 29) with those with subclinical Cushing's syndrome (n = 12) yielded significant differences as to 2-h glucose and triglyceride levels, which were significantly higher in the second group (7.02 +/- 1.76 mmol/liter vs. 8.72 +/- 3.17 mmol/liter, P = 0.03; 1.06 +/- 0.4 mmol/liter vs. 1.73 +/- 0.96 mmol/liter, P = 0.002), but the insulin sensitivity index was conversely reduced (5.2 +/- 1.4 vs. 2.9 +/- 1.2, P < 0.0001). In conclusion, many patients with incidental adrenal adenoma display altered glucose tolerance, that may be explained by reduced insulin sensitivity, and increased blood pressure levels in comparison with carefully age- and BMI-matched controls. The slight hypercortisolism observed in some such patients may significantly contribute to this state of insulin resistance. Midnight serum cortisol appears as a sensitive marker of the metabolic effects of subclinical 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.

Subclinical Cushing's syndrome: [review]

Subclinical Cushing's syndrome (CS) is attracting increasing interest since the serendipitous discovery of an adrenal mass has become a rather frequent event owing to the routine use of sophisticated radiologic techniques. Cortical adenoma is the most frequent type of adrenal incidentaloma accounting for approximately 50 percent of cases in surgical series and even greater shares in medical series. Incidentally discovered adrenal adenomas may secrete cortisol in an autonomous manner that is not fully restrained by pituitary feedback, in 5 to 20 percent of cases depending on study protocols and diagnostic criteria. The criteria for qualifying subclinical cortisol excess are controversial and presently there is no consensus on a gold standard for the diagnosis of this condition. An increased frequency of hypertension, central obesity, impaired glucose tolerance, diabetes and hyperlipemia has been described in patients with subclinical CS; however, there is still no clear demonstration of the long-term complications of this condition whose management remains largely empirical. Either adrenalectomy or careful observation associated with treatment of the metabolic syndrome have been suggested as treatment options.

A síndrome de Cushing subclínica (SCS) tem atraído interesse cada vez maior desde que a descoberta casual de uma massa adrenal se tornou um evento freqüente devido ao emprego rotineiro de técnicas sofisticadas de imagem. O adenoma cortical é o tipo mais freqüente de incidentaloma adrenal, correspondendo a cerca de 50 por cento dos casos em séries cirúrgicas e até mais do que isso em séries médicas. Adenomas adrenais descobertos incidentalmente podem secretar cortisol de maneira autônoma ou não controlada totalmente pelo feedback hipofisário, em 5 a 20 por cento dos casos, dependendo do protocolo de estudo e dos critérios diagnósticos. Os critérios para qualificar um excesso subclínico de cortisol são controversos e atualmente não existe consenso a respeito de "padrão ouro" para o diagnóstico dessa condição. Em pacientes com SCS, tem sido descrita uma freqüência elevada de hipertensão, obesidade central, intolerância à glicose, diabetes e hiperlipemia; entretanto, ainda não existe uma evidente demonstração de complicações a longo prazo dessa condição, cujo manejo permanece amplamente empírico. Tanto a adrenalectomia como a observação cuidadosa, associada com o tratamento da síndrome metabólica, têm sido sugeridos como opções terapêuticas.