José A. Amado

Seasonal deficiency of vitamin D in children : A potential target for osteoporosis-preventing strategies?

Peak bone mass attained after skeletal growth is a major determinant of the risk of developing osteoporosis later in life, hence the importance of nutritional factors that contribute to bone mass gain during infancy and adolescence. An adequate supply of vitamin D is essential for normal bone homeostasis. This study was undertaken to determine what the levels are of 25‐hydroxyvitamin D (25(OH)D) that may be considered desirable in children and to assess if normal children maintain these levels throughout the year. Vitamin D metabolites and parathyroid hormone (PTH) serum levels were measured in 21 children in March and October, prior to and after the administration of a daily supplement of 25(OH)D (40 μg for 7 consecutive days). There were inverse correlations between basal 25(OH)D levels and supplementation‐induced changes in serum 1,25(OH)2D (r = 0.57, p < 0.05) and PTH (r = 0.41, p < 0.05). When basal levels of 25(OH)D were below 20 ng/ml, the supplement induced an increase in serum 1,25(OH)2D; with basal 25(OH)D under 10–12 ng/ml, the supplement also decreased serum PTH. The lowest serum level of 25(OH)D in 43 normal children studied in summer was 13 ng/ml. Those results suggested that the lowest limit for desirable levels of 25(OH)D in children was somewhere between 12 and 20 ng/ml. However, 31% of 51 normal children studied in winter had levels below 12 ng/ml, and 80% had levels lower than 20 ng/ml. Those children are likely to have suboptimal bioavailability of vitamin D, which might hamper their achievement of an adequate peak bone mass. Since cutaneous synthesis of vitamin D is rather limited in winter, oral vitamin D supplementation should be considered.

Weight gain induced by haloperidol, risperidone and olanzapine after 1 year: Findings of a randomized clinical trial in a drug-naïve population

BACKGROUND There is little information about weight gain induced by antipsychotics at long-term. OBJECTIVE To quantify the weight gain induced by first (haloperidol) and second generation antipsychotics (olanzapine and risperidone) in a cohort of drug-naïve subjects after 1 year of treatment. METHODS This is a prospective, randomized clinical trial, including a representative sample of first episode psychotic incident cases from a population area of 555.000 people. The main outcome measures were changes in body weight and body mass index at 3 months and at 12 months. Both a per protocol analysis and an intention to treat analysis were conducted. RESULTS A total of 164 drug-naïve patients were included. At 12 months 144 patients were evaluated. Of them, 66% completed the protocol and 34% needed treatment switch. We found statistically significant differences in weight gain at 3 months: 3.8 kg (+/-4.1) for haloperidol, 5.9 kg (+/-5.1) for risperidone and 8.4 kg (+/-5.0) for olanzapine (F=7.045; p=0.002). After 1 year the difference in weight gain had disappeared: 9.7 kg (+/-5.7) for haloperidol, 8.9 kg (+/-8.8) for risperidone and 10.9 kg (+/-7.2) for olanzapine (F=0.817; p=0.445). CONCLUSIONS Drug-naïve patients experience an extraordinary weight gain after 1 year of treatment with haloperidol, olanzapine or risperidone. The main difference among these treatments is the pattern of weight gain but not the final amount of weight gain.

Plasma Leptin and TNF-α Levels in Chronic Hepatitis C Patients and Their Relationship to Hepatic Fibrosis

The aim of this study was to examine the possible relationship between the plasma levels of leptin and tumor necrosis factor (TNF)-α and the stage of hepatic fibrosis in a cohort of patients with chronic hepatitis C. Leptin and TNF levels were measured by RIA in 135 patients and in 75 age- and sex-matched controls. Liver disease was evaluated by the stage of fibrosis and the extent of inflammatory infiltrate in the liver biopsy. Leptin levels correlated with BMI values in healthy controls and in patients with chronic hepatitis C (men, r = 0.61, P = 0.0001; women, r = 0.68, P = 0.003). Leptin levels increased as hepatic fibrosis stage progressed both in male and in female patients (P < 0.001); also, TNF levels were higher in patients with an advanced stage of fibrosis (P = 0.006). In these patients, levels of leptin increased according to the progression of the stage of fibrosis; these data suggest that leptin may play a role in the regulation of hepatic fibrosis.

BONE DENSITOMETRY AND BIOCHEMICAL BONE REMODELING MARKERS IN TYPE 1 DIABETES MELLITUS

Bone mineral density (BMD) at the lumbar spine, quantified by dual energy X-ray absorptiometry, and biochemical bone remodeling markers (serum alkaline phosphatase, osteocalcin, tartrate-resistant acid phosphatase and urinary hydroxyproline) have been studied in 94 patients with diabetes mellitus aged 18-62 years. BMD was normal (1.13 +/- 0.02 g/cm2 in patients vs. 1.16 +/- 0.12 g/cm2 in controls), although it was found to be negatively correlated with HbA1, microalbuminuria, age and the duration of the disease. Serum alkaline phosphatase (188 +/- 75 I.U./l vs. 168 +/- 42 I.U./1; P < 0.03), serum tartrate-resistant acid phosphatase (14.3 +/- 4.3 I.U./l vs. 11.7 +/- 3.7 I.U./l; P < 0.0001) and urinary hydroxyproline (0.018 +/- 0.016 mmol/mmol creatinine vs. 0.011 +/- 0.008 mmol/mmol creatinine; P < 0.001) were higher in diabetics than in controls. Serum osteocalcin was lower (2.5 +/- 1.3 ng/ml vs. 3.4 +/- 1.2 ng/ml; P < 0.0001). No relationship was found between bone remodeling markers and BMD. It is concluded that lumbar BMD is normal in type 1 diabetic patients, although the degree of metabolic control, age and duration of the disease may affect it. In the light of the biochemical markers, bone remodeling may be disturbed in diabetes, but such disturbance seems to be unimportant regarding BMD.

Successful treatment of shoulder pain syndrome due to supraspinatus tendinitis with transdermal nitroglycerin. A double blind study

&NA; We have conducted a prospective double blind randomized and placebo controlled clinical study in 20 patients with shoulder pain syndrome caused by supraspinatus tendinitis to determine whether transdermal nitroglycerin (NTG) has analgesic action in this condition. In a randomized manner we used a 5‐mg NTG (Nitroplast®) patch per day over 3 days or similar placebo patches applied in the most painful area. Patients were evaluated before treatment was initiated and after 24 and 48 h. The assessment was made blindly by the same clinical investigator. The follow‐up showed a significant decrease in intensity of pain at 24 h (7.05 ± 0.4 to 4.5 ± 0.5) and 48 h (2 ± 0.3) in the NTG group (P < 0.003). No changes were observed in the placebo group. The mean pain duration, activity of the extremity and hours of sleep also improved in the NTG group, with no significant modification in the placebo group. Two patients experienced headache as a side effect 24 h after treatment was started. Patients in the NTG group remained free of symptoms when they were assessed 15 days later. We conclude that NTG is useful in the treatment of shoulder pain syndrome caused by supraspinatus tendinitis and that this treatment could be a useful approach to the management of this common disturbance and probably also in other tendon musculoskeletal disorders.

Glucose and lipid disturbances after 1 year of antipsychotic treatment in a drug-naive population

OBJECTIVE This study examined the main metabolic side effects induced by antipsychotic treatment in a cohort of first episode drug-naïve subjects after the first year of treatment. METHODS A randomized, open-label, prospective clinical trial was conducted. Participants were 164 consecutive subjects included in a first episode program and never treated with antipsychotic medication. Patients were assigned to haloperidol, olanzapine or risperidone. The main outcome measures were changes at 1 year in fasting glucose parameters (glucose, insulin levels and insulin resistance index) and changes in fasting lipid parameters (total cholesterol, triglycerides, LDL cholesterol, HDL cholesterol). RESULTS 144 of the total sample were evaluated at 1 year. There was a statistically significant increase in the mean values of insulin levels, insulin resistance index, total cholesterol, LDL-cholesterol and triglycerides. No pathological values in fasting glucose plasma levels were found at baseline and there were no changes after 1 year. Weight gain was positively correlated with changes in insulin levels, insulin resistance index and triglyceride levels. We did not detect statistically significant differences between treatments in any of the parameters evaluated. CONCLUSIONS Fasting glycaemia and insulin concentrations at baseline do not support the hypothesis that schizophrenia is associated with an underlying abnormality in glucose metabolism. The changes in insulin and lipid parameters at 1 year seem to be related to the magnitude of weight gain. There were no significant differences between haloperidol, olanzapine and risperidone concerning metabolic adverse effects after the first year of treatment.

Effect of antipsychotics on peptides involved in energy balance in drug-naive, psychotic patients after 1 year of treatment

Weight gain has become one of the most common and concerning side effects of antipsychotic treatment. The mechanisms whereby antipsychotics induce weight gain are not known. It has been suggested that peptides related to food intake and energy balance could play a role in weight gain secondary to antipsychotic therapy. To better understand the pathophysiology of antipsychotic-induced weight gain, we studied the effects of 3 antipsychotic drugs (haloperidol, olanzapine, and risperidone) on peptides involved in energy balance (insulin, ghrelin, leptin, adiponectin, visfatin, and resistin) in a population of drug-naive patients with first episode of psychosis. A significant increase in weight (10.16 kg [SD, 8.30 kg]; P < 0.001), body mass index (3.56 kg/m2 [SD, 2.89 kg/m2]; P < 0.001), and fasting insulin (3.93 &mgr;U/mL [SD, 3.93 &mgr;U/mL]; P = 0.028), leptin (6.76 ng/mL [SD, 7.21 ng/mL]; P < 0.001), and ghrelin (15.47 fmol/mL [SD, 47.90 fmol/mL]; P = 0.009) plasma levels were observed. The increments in insulin and leptin concentrations were highly correlated with the increment in weight and body mass index and seem to be a consequence of the higher fat stores. The unexpected increase in ghrelin levels might be related with the causal mechanism of weight gain induced by antipsychotics. Finally, the 3 antipsychotics had similar effects in all parameters evaluated.

Vertebral compression fractures and mineral metabolism in chronic obstructive lung disease.

Chronic obstructive lung disease has been reported as a cause of osteoporosis, though whether this association is due to the disease itself or to corticosteroid treatment has not been elucidated. We studied 44 male patients with chronic obstructive lung disease (mean (SD) FEV1 39% (14%) of predicted normal) who were not having long term corticosteroids. No differences in a vertebral deformity score or in metacarpal index were found between them and a control group of similar age. Indices of bone formation (serum osteocalcin) and bone resorption (urinary hydroxyproline) were normal and parathyroid hormone and 1,25-dihydroxyvitamin D were also normal. Serum 25-hydroxyvitamin D was decreased, indicating depleted vitamin D. Calcitonin concentrations were higher in the patient than in the control group of the same age. There was no increase in the prevalence of osteoporosis in patients with chronic obstructive lung disease who had not received long term corticosteroid treatment. Increased concentrations of calcitonin may protect the skeleton from the detrimental effect of hypovitaminosis D.

Association of the 163A/G and 1181G/C Osteoprotegerin Polymorphism with Bone Mineral Density

The aim of the study was to investigate the distribution of 163 A/G osteoprotegerin gene promoter and 1181 G/C osteoprotegerin exon 1 polymorphisms in a group of women with different hormonal status and to analyze their relationship with BMD. Osteoprotegerin polymorphisms and BMD were analyzed in 332 women (69 premenopausal and 263 postmenopausal). BMD was quantified at the lumbar spine (L 2-4), femoral neck, and total hip. Genotyping for the presence of different polymorphisms was performed using the Custom Taqman ((R)) SNP Genotyping assays. There were not significant differences in BMD according to 163 A/G genotype. However, significant differences in lumbar spine BMD were found according to 1181 G/C alleles. Thus, women with CC genotype had significant higher BMD at the lumbar spine than those with GC or GG genotype. No differences were found in femoral neck and total hip BMD. In age-adjusted models, the 1181 G/C OPG polymorphism explained 2.2% of BMD variance at the spine, 0.3% at the femoral neck, and 0.9% at the total hip in the whole group. In the subgroup of premenopausal women, the polymorphism was strongly related to spine BMD, and explained 11.5% of the variance, whereas body weight explained 7.9%. The 1181 G/C polymorphism was associated with lumbar spine BMD in Spanish women. Premenopausal women with the CC genotype had a higher BMD.

Plasma Adrenomedullin Levels in Type 1 Diabetes: Relationship with clinical parameters

OBJECTIVE To assess the relationship between plasma adrenomedullin (AM) levels and the presence of microvascular complications in type 1 diabetic patients. RESEARCH DESIGN AND METHODS We measured plasma AM and cAMP levels in 103 type 1 diabetic patients (46 without complications, 24 with retinopathy only, 14 with microalbuminuria but normal kidney function, and 19 with renal insufficiency) and 41 matched healthy control subjects. RESULTS Patients with renal insufficiency had higher levels of AM and cAMP than all other groups. Patients with only retinopathy showed a trend to have higher levels than patients without complications. There were no differences among all other groups. There was a significant correlation between AM and cAMP in the total diabetic group (rs = 0.36, P < 0.001) but not in the control group. In multiple regression analysis, plasma AM demonstrated significant relationships with creatinine clearance (β = −0.31, P = 0.004) and duration of the disease (β = 0.28, P = 0.008). CONCLUSIONS Plasma AM and cAMP are increased in type 1 diabetic patients with renal insufficiency. Creatinine clearance (CrClc) and duration of the disease are related to plasma AM levels in these patients.