Fracture incidence and changes in quality of life in women with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO).

UNLABELLED: In this observational study of women with an inadequate clinical outcome to osteoporosis therapy, those with a fracture at baseline were more likely to sustain an incident fracture and have a worse health-related quality of life than those without prior fracture. INTRODUCTION: The Observational Study of Severe Osteoporosis (OSSO) was designed to assess the fracture incidence and health-related quality of life (HRQoL) in women with an inadequate clinical outcome to osteoporosis therapy. METHODS: Post-menopausal women (N=1,885) with established osteoporosis and an inadequate clinical response to osteoporosis drug therapy defined as: a) a fragility fracture despite therapy for one year (index fracture, N=988), or b) discontinued drug therapy due to adverse effects and/or non-compliance (N=897), were assessed during one year for HRQoL using the EQ-5D and the QUALEFFO questionnaires. RESULTS: One hundred and sixty-six (8.8%) women had a total of 209 incident fractures (1,139 fractures/10,000 women-years). Women with an index fracture were more likely to sustain an incident fracture than those without prior fractures (hazard ratio 1.91; 95% CI: 1.37-2.66; p<0.001). Co-morbidities or antidepressant use at baseline also increased the risk of incident fracture. Median total EQ-5D Health State Values and QUALEFFO scores were worse in women with an incident fracture regardless of index fracture status. The worst scores were reported in the EQ-5D sub-domains of self-care, usual activities and pain/discomfort. CONCLUSIONS: Women with an inadequate response to osteoporosis therapy had a high rate of incident fracture which had an adverse impact on HRQoL.

The aldosterone to renin ratio in the evaluation of patients with incidentally detected adrenal masses.

Incidentally discovered adrenal masses are diagnosed with increasing frequency, especially among patients with hypertension. Thus, a reliable screening test for primary hyperaldosteronism (PA) is essential to avoid unnecessary diagnostic procedures to this population. The aim of the present study is the evaluation of aldosterone to renin ratio (ARR), using plasma renin concentration, in the diagnostic algorithm of patients with adrenal incidentaloma. A total of 123 individuals were studied: 17 patients with proven PA (age 55.5 +/- 1.4 years), 27 patients with nonfunctioning adrenal incidentaloma (age 60.3 +/- 1.8 years, 14 hypertensives and 13 normotensives) and 79 control subjects (age 58.7 +/- 1.4 years, 27 hypertensives and 52 normotensives). A receiver operating characteristic (ROC) analysis disclosed that an ARR > or =32 combines a sensitivity of 100% with a specificity of 96.2% for the diagnosis of PA. No difference in AlphaRR between hypertensive and normotensive individuals harbouring an adrenal incidentaloma and hypertensive and normotensive controls was found. Patients with adrenal incidentalomas with subtle glucocorticoid hypersecretion demonstrated similar ARR compared to patients with normal cortisol secretion. In conclusion, ARR is reliable for the exclusion of PA in patients with adrenal incidentalomas. Furthermore, subtle aldosterone hypersecretion, as indicated by increased ARR, in patients with adrenal incidentalomas is not associated with the presence of hypertension or subtle glucocorticoid hypersecretion.

Leptin alterations in the course of sepsis in humans.

Neuroendocrine response to sepsis may be divided into acute and prolonged phase. As leptin is implicated in the stress response, leptin's profile during both phases, and the possible relationships between leptin and the neuroendocrine response to sepsis were investigated. Thirty adult patients with sepsis in an intensive care unit were studied. Blood samples were collected at the acute and the prolonged phases. In acute sepsis, leptin levels were higher in patients than in controls (10.2 +/- 2.5 vs. 4.1 +/- 1.2 ng/ml, p =0.01) and correlated positively with insulin levels and insulin resistance. A decline in leptin levels was found during prolonged sepsis (from 10.2 +/- 2.5 to 6.2 +/- 1.7 ng/ml, p=0.001), which was not related to survival (p=0.913). At the onset of sepsis, leptin levels increased in correlation with insulin and insulin resistance, possibly indicating a cause-effect relationship. However, the decline in leptin levels during the prolonged phase of sepsis was not related either to survival or to metabolic and hormonal changes.

Characterization of patients with an inadequate clinical outcome from osteoporosis therapy: the Observational Study of Severe Osteoporosis (OSSO).

BACKGROUND: Osteoporotic fractures remain a major public health problem. Currently available osteoporosis therapies significantly reduce the risk of fractures, but up to 50% of patients have an inadequate clinical outcome to therapy. AIM: To describe the clinical and quality of life (QOL) of a study population meeting a proposed definition of inadequate clinical outcome to osteoporosis therapy, recruited for the Observational Study of Severe Osteoporosis (OSSO). DESIGN: Cross-sectional, observational study. METHODS: Post-menopausal women with osteoporosis (n = 2314) were divided into Group 1 (those who had previously experienced a fragility fracture despite osteoporosis drug therapy for at least 12 months) (n = 1309, 57%), or Group 2 (those who had previously discontinued osteoporosis drug therapy due to non-compliance or side-effects) (n = 1005; 43%). Baseline clinical characteristics, quality of life (QOL) and osteoporosis/falls risk factors were analysed. RESULTS: The overall population had low BMD (mean +/- SD T-score at lumbar spine -3.1 +/- 1.1), and risk factors for fracture such as previous fractures (67.8%), family history (15.1%), and prolonged glucocorticoid use (17.5%). QOL was poor: total QUALEFFO and EQ-5D scores were 46.8 +/- 18.7, and 0.50 +/- 0.33, respectively. Patients in Group 1 had higher age and body mass index, fewer hours of exercise, more previous fragility fractures and falls, and poorer QOL scores. DISCUSSION: Our definition of inadequate clinical outcome from osteoporosis drug therapy identifies a severe osteoporosis cohort with poor QOL and increased fracture risk. Using such a definition may lead to earlier recognition of inadequate clinical outcome to osteoporosis therapy, and improved interventions and results.

Evaluation of GH reserve in patients with adrenal incidentalomas and biochemical evidence of subclinical autonomous glucocorticoid hypersecretion.

OBJECTIVE: Although it is well established that overt hypercortisolism in patients with active Cushing's syndrome leads to a profound suppression of stimulated GH secretion, the role of subclinical autonomous glucocorticoid hypersecretion (SAGH), currently detected with increasing frequency in patients with adrenal incidentalomas, on GH secretory reserve has received little attention. The aim of the present study was to evaluate whether SAGH in patients presented with adrenal incidentalomas has a negative effect on GH secretory reserve. DESIGN AND PATIENTS: Sixteen patients with overt Cushing's syndrome (CS) and 36 patients with adrenal incidentalomas were investigated. The latter group was further divided in 23 patients who demonstrated an adequate suppression of cortisol levels (of < 70 nmol/l) following the low-dose dexamethasone suppression test (LDDST) and in 13 patients, who failed to suppress (cortisol levels post-LDDST > 70 nmol/l). The former group was defined as normocortisolaemic (NC) and the latter group as representing patients with SAGH. The combined pyridostigmine + GHRH test (PD + GHRH) was used to assess the GH secretory reserve of these patients. RESULTS: Peak GH levels following PD + GHRH administration were significantly lower in CS patients compared to both the NC and SAGH group of patients with adrenal incidentalomas (2.2 +/- 0.7 vs. 18.9 +/- 2.6 and 21.5 +/- 3.6 microg/l, respectively, P < 0.05); no difference was observed in peak GH responses between the NC and SAGH group of patients. A subnormal GH response (defined as GH(max) < 12.8 microg/l) was observed in all 16 patients with CS. However, only seven NC and three SAGH patients failed to respond adequately. Correlation analysis revealed a negative correlation between peak GH response to PD + GHRH and plasma cortisol concentrations in CS patients (R =-0.6, P = 0.012), while in patients with adrenal incidentalomas such a correlation was absent. Contrary to patients with CS in whom body mass index (BMI) was not correlated to peak GH, a significant negative correlation between peak GH response to PD + GHRH and BMI was disclosed in patients with adrenal incidentalomas (R =-0.49, P = 0.003). In these patients, again contrary to CS patients, a significant negative correlation was also found between peak GH post PD + GHRH and age (R = -0.46, P = 0.002). CONCLUSIONS: In conclusion, our results provide evidence that, contrary to patients with overt CS, SAGH does not affect the GH secretory response to provocative stimulation.

Symptomatic pheochromocytoma with normal urinary catecholamine metabolites.

A 61-year old female presented with paroxysmal hypertension and a 4.5cm left adrenal mass on CT scan. Repeated measurements of 24-hour urinary fractionated metanephrines, total catecholamines and vanillylmandelic acid (VMA) were within normal range. A further scintigraphic study with (131)I -metaiodobenzylguanidine ((131)I-MIBG) revealed selective concentration of the radiotracer, corresponding to the CT mass. After adequate preoperative treatment, successful surgical excision of the tumor was performed and the pathological examination confirmed the diagnosis of a cystic pheochromocytoma with a 2cm solid tumor. On reevaluation three months later using (131)I-MIBG, no evidence of remaining or recurrent disease was found. The patient, off any antihypertensive medication, reported mild recurrent hypertension and panic attacks that were adequately controlled with antidepressants. This is a rare case of a symptomatic pheochromocytoma without elevated urine catecholamines and metanephrines. According to the literature, plasma free metanephrines would be the ideal test for biochemical detection of the tumor. However, in the event that they are not available and there is a high clinical suspicion for the presence of pheochromocytoma, as in our patient, we suggest performance of a functional nuclear medicine study, such as (131)I-MIBG, to confirm the clinical diagnosis.

Megavoltage pituitary irradiation lowers but seldom leads to safe GH levels in acromegaly: a long-term follow-up study.

Radiotherapy (RT) has long been used in the treatment of acromegaly, but confusion regarding the definition of biochemical cure has hampered interpretation of previous reports on the outcome of this treatment. In the present study we present additional data using the currently accepted criteria of biochemical cure in a large group of patients followed up by our department. Forty-six acromegalic patients were treated with external beam megavoltage RT and followed up for a mean of 7.6 years (range 2-22 years). Only four patients had had previous surgical treatment by either transsphenoidal or transfrontal routes. Following RT, mean basal GH levels decreased from 30.9 ng/ml (5-96 ng/ml) to 11.5 ng/ml (1-36 ng/ml) at 10 years of follow up with a further fall to 6.1 ng/ml (1-29 ng/ml) in those patients followed up for more than 10 years. As a result, although mean GH levels of less than 5 ng/ml were achieved in 9/28 (30.1%) at 5 years, 6/19 (31.6%) at 10 years, and in 6/11 (54.5%) of those patients followed up for more than 10 years post-RT, only 0/28 (0%), 7/28 (25%), 4/19 (21%) and 1/11 (1%) achieved GH levels of <2.5 ng/ml at 2, 5. 10 and >10 years following RT. Thus, in the whole series only 10/48 (20.8%) patients showed a decrease of GH level to less than 2.5 ng/ml at their latest follow up. Hypopituitarism as a result of RT was only infrequently observed in this series; gonadal deficiency developed in 12 (26.6%) patients, thyrotrophin (TSH) deficiency in 3 (6.6%) and adrenocorticotrophin deficiency in 2 (4.4%). In conclusion, megavoltage RT is an effective treatment for the control of GH hypersecretion in acromegaly, with a continuing lowering effect for several years following RT but seldom leads to safe GH levels.

Does acromegaly really predispose to an increased prevalence of gastrointestinal tumours?

OBJECTIVE: The few published prospective studies suggest a strong association of colonic tumours with acromegaly, but include small numbers of patients. In addition, the upper gastrointestinal tract of these patients has never been prospectively studied. The aim of the present study was to investigate the incidence of gastric and colonic tumours in a large cohort of acromegalic patients. DESIGN: Acromegalic patients consecutively admitted to an Endocrinology Department for diagnosis and follow-up, were submitted to gastroscopy and colonoscopy, to identify those harbouring gastrointestinal tumours. PATIENTS: Over a 5-year period, 54 out of 61 patients (78% with active disease) received colonoscopy and 42 out of 61 gastroscopy. No patient had a past history of gastrointestinal malignancy. MEASUREMENTS: All polypoid lesions found at colonoscopy and gastroscopy were separately recorded and biopsied. RESULTS: No case of gastrointestinal cancer or gastric polyp was discovered. Nineteen patients (35%) had 1-8 colonic polyps, including 5 (9.3%) with adenomas. When compared to patients with a normal colon, those with polyps were significantly older (44.5 +/- 14.2 vs 52.1 +/- 10.9 years, P = 0.047), but the duration of acromegaly (10.8 +/- 8.4 vs 10.9 +/- 7.1 years, P = 0.9) and the number of patients with active disease were similar in both groups. CONCLUSIONS: Acromegalic patients do not have an increased incidence of gastric tumours. The observed significant variation in the prevalence of colonic adenomas (9-35%, P = 0.03) and cancer (0-15%, P = 0.017), between our patients and those of the published prospective studies with similar demographic characteristics, suggest that environmental and hereditary factors may be more important than the presence of acromegaly.

Calcium metabolism in diabetes mellitus: effect of improved blood glucose control.

Reduced bone mass occurring with increased frequency in diabetes mellitus has been attributed to poor blood glucose control but the pathogenetic mechanisms remain unknown. To evaluate the role of calcium metabolism, 59 patients with diabetes and normal renal function (22 Type 1, 37 Type 2) were studied. In all patients plasma calcium (Ca), serum phosphate (PO4), serum parathyroid hormone (PTH), and 24-h urinary calcium (uCa) were determined under both poor and improved control (for at least 7 days) as ascertained by four blood glucose determinations daily. Improvement of blood glucose control (p = 0.001) was associated with reduction of uCa both in Type 1 (6.9 +/- 1 vs 4.9 +/- 0.9 mmol day-1, mean +/- SEM, p = 0.02) and in Type 2 patients (4.2 +/- 0.4 vs 3.2 +/- 0.4 mmol day-1, mean +/- SEM, p = 0.002). Considerably more Type 1 patients (10 out of 22) had PTH values below the detection limit (1.5 pmol l-1) during poor than during improved control (2 out of 22). Comparison between the two types of diabetes showed that in Type 1 under poor control, Ca and PTH were lower (p = 0.03), while uCa was higher (p = 0.003), and after improved control, only uCa continued to be higher (p = 0.035). These findings suggest that increased uCa excretion in association with 'functional hypoparathyroidism' (especially in Type 1 diabetes) is observed during poor blood glucose control, and may be one of the factors leading to reduced bone mass in diabetes mellitus.

Effect of 131I treatment on the calcitonin response to calcium infusion in hyperthyroid patients.

OBJECTIVE: The objective was to evaluate the effect of 131I treatment for hyperthyroidism on calcitonin secretion by thyroid C-cells. DESIGN: Determination of basal calcitonin levels and calcitonin secretory reserve before and after 131I administration. PATIENTS: Seventeen hyperthyroid patients (15 female, two male) were studied before, and 2 months after 131I treatment, and 12 of these patients were restudied 8 months after 131I treatment. MEASUREMENTS: Calcitonin response was assessed by measuring basal and post calcium infusion calcitonin levels. Basal TSH, T3, and T4 levels were also determined at each study. RESULTS: The rise of plasma calcium resulted in statistically significant increase of plasma calcitonin levels before 131I treatment (10.9 +/- 2.4 pmol/l), while this response was significantly diminished 2 and 8 months after treatment (2.6 +/- 0.7 and 1.6 +/- 0.3 pmol/l, respectively). No correlation was found between the calcitonin response and age or plasma TSH. CONCLUSION: Our results demonstrate that 131I treatment for hyperthyroidism may seriously damage thyroid C-cells and cause calcitonin deficiency.

Estimation of glycated fetal hemoglobin in normal cord blood by isoelectric focusing. Correlation with maternal glycated hemoglobin and birth weight.

Glycated fractions of hemoglobin F and A (F1, A1c) were measured simultaneously in cord and maternal blood, respectively, in 109 normal women at delivery using an isoelectric focusing, method in polyacrylamide gel plates. Cord blood hemoglobin F1 values (mean +/- SD) were 5.92 +/- 1.09% and maternal blood hemoglobin A1c values were 6.51 +/- 0.92%. The difference was statistically highly significant (p less than 0.001) and their values were also significantly correlated (p less than 0.001). Moreover, both values were also well correlated with those of maternal blood glucose (p less than 0.01), actual birth weight (p less than 0.01) and birth weight ratio (p less than 0.01). It is concluded that hemoglobin F1 can be successfully separated and measured by isoelectric focusing. However HbF1 estimation seems to have no obvious advantages against the maternal HbA1c measurement as an index of fetal exposure to glucose during the last weeks of pregnancy.

Calcium balance in osteoporotic patients on long-term oral calcium therapy with and without sex hormones.

1. The effect of a high calcium intake (1 mmol day-1 kg-1) alone or with the concomitant administration of oestradiol and testosterone derivatives was monitored by serial calcium balances in 48 patients with osteoporosis of various types. 2. On high calcium alone there was an increase (P less than 0.001) in both total calcium balance and net calcium absorption as compared with values on a simulated home intake. This effect was sustained for periods up to 10 years (mean 3.5 years) by the addition of the hormones. 3. Discontinuation of the hormones (only) produced a significant decrease in both calcium balance and nett absorption but both were still increased when compared with the initial values under simulated home calcium intake. 4. No significant change in the urinary calcium output was observed under any of the regimens.

Effect of digitalis on diminished baroreceptor sensitivity in diabetics.

The baroreceptor sensitivity was estimated in 50 normal controls (Group A) and in 50 diabetics of comparable age (Group B). The technique used was infusion of angiotensin (0.5 microgram/min) and measurement of the bradycardic response resulting from the increase of blood pressure. The slope was used as an index of baroreceptor sensitivity. Diabetics had significantly lower baroreceptor sensitivity and a higher resting heart rate. Sensitivity decreased with age in both groups. The reproducibility of the method was excellent. Deslanoside-C (0.8 mg) significantly increased the baroreceptor sensitivity in 11 normal controls and 9 diabetics. Very low sensitivity was found in 26 diabetics who had no evidence of orthostatic hypotension, neuropathy, or retinopathy. However all 17 patients with the above findings had very low sensitivity.