Caje Moniz

A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the prevent recurrence of osteoporotic fractures study

PURPOSE We conducted a 5-year, double-blind, randomized, placebo-controlled study to determine whether salmon calcitonin nasal spray reduced the risk of new vertebral fractures in postmenopausal women with osteoporosis. SUBJECTS AND METHODS A total of 1,255 postmenopausal women with established osteoporosis were randomly assigned to receive salmon calcitonin nasal spray (100, 200, or 400 IU) or placebo daily. All participants received elemental calcium (1,000 mg) and vitamin D (400 IU) daily. Vertebral fractures were assessed with lateral radiographs of the spine. The primary efficacy endpoint was the risk of new vertebral fractures in the salmon calcitonin nasal spray 200-IU group compared with the placebo group. RESULTS During 5 years, 1,108 participants had at least one follow-up radiograph. A total of 783 women completed 3 years of treatment, and 511 completed 5 years. The 200-IU dose of salmon calcitonin nasal spray significantly reduced the risk of new vertebral fractures by 33% compared with placebo [200 IU: 51 of 287, placebo: 70 of 270, relative risk (RR) = 0.67, 95% confidence interval (CI): 0.47- to 0.97, P = 0.03]. In the 817 women with one to five prevalent vertebral fractures at enrollment, the risk was reduced by 36% (RR = 0.64, 95% CI: 0.43- to 0.96, P = 0.03). The reductions in vertebral fractures in the 100-IU (RR = 0.85, 95% CI: 0.60- to 1.21) and the 400-IU (RR = 0.84, 95% CI: 0.59- to 1.18) groups were not significantly different from placebo. Lumbar spine bone mineral density increased significantly from baseline (1% to 1. 5%, P<0.01) in all active treatment groups. Bone turnover was inhibited, as shown by suppression of serum type-I collagen cross-linked telopeptide (C-telopeptide) by 12% in the 200-IU group (P <0.01) and by 14% in the 400-IU group (P<0.01) as compared with placebo. CONCLUSION Salmon calcitonin nasal spray at a dose of 200 IU daily significantly reduces the risk of new vertebral fractures in postmenopausal women with osteoporosis.

Efavirenz is associated with severe vitamin D deficiency and increased alkaline phosphatase

Objective(s):To identify factors (including exposure to specific antiretroviral drugs) associated with severe vitamin D deficiency (VDD) in HIV-infected individuals and to explore the effects of severe VDD and antiretroviral drug exposure on serum alkaline phosphatase (ALP) as surrogate marker of bone turnover. Design:Cross-sectional survey of vitamin D status among HIV-infected patients attending for routine clinical care at a large London HIV clinic. Methods:Severe VDD was defined as 25(OH)D levels of less than 10 μg/l (<25 nmol/l). Multivariate logistic regression analysis was used to identify factors associated with severe VDD and upper quartile ALP levels. Results:Vitamin D levels were measured in 1077 patients and found to be suboptimal in 91%. One-third of patients had severe VDD. Black ethnicity, sampling in winter, nadir CD4 cell count less than 200 cells/μl, and exposure to combination antiretroviral therapy were associated with severe VDD. In analyses restricted to patients on combination antiretroviral therapy, current efavirenz use was significantly associated with severe VDD [adjusted odds ratio 2.0 (95% confidence interval 1.5–2.7)]. Current tenofovir [adjusted odds ratio 3.5 (95% confidence interval 2.3–5.2)] and efavirenz use [adjusted odds ratio 1.6 (95% confidence interval 1.02–2.4)], but not severe VDD [odds ratio 1.1 (0.8–1.5)], were associated with increased bone turnover (upper quartile ALP). Conclusion:Efavirenz was associated with severe VDD, a condition associated with multiple adverse health outcomes, and efavirenz and tenofovir with increased ALP. The clinical significance of these findings requires further investigation, given the widespread use of efavirenz and tenofovir in first-line combination antiretroviral therapy.

Metabolic bone disease is present at diagnosis in patients with inflammatory bowel disease

Aim : To establish whether bone disease is present at diagnosis in inflammatory bowel disease and to identify contributory metabolic abnormalities.

SUBSTITUTION OF ALUMINIUM SALTS BY MAGNESIUM SALTS IN CONTROL OF DIALYSIS HYPERPHOSPHATAEMIA

For two years all 28 patients undergoing hospital haemodialysis were switched from a dialysate magnesium (Mg) of 0.85 mmol/l to one containing none. Oral aluminium hydroxide was discontinued, and magnesium carbonate was substituted as a phosphate binder. After 24 months on this regimen predialysis aluminium concentration had fallen significantly. There was no significant change in predialysis phosphate, which remained above the normal range; nor was there evidence of increased secondary hyperparathyroidism as judged by parathyroid hormone immunoassay and biochemical or clinical criteria. Predialysis Mg concentrations tended to fall towards the normal range. Aluminium-containing phosphate binders seem to be unnecessary for the control of dialysis hyperphosphataemia. Magnesium carbonate may be an alternative and less toxic compound.

Rapid development of sensitive, high-throughput, quantitative and highly selective mass spectrometric targeted immunoassays for clinically important proteins in human plasma and serum

OBJECTIVES The aim of this study was to develop high-throughput, quantitative and highly selective mass spectrometric, targeted immunoassays for clinically important proteins in human plasma or serum. DESIGN AND METHODS The described method coupled mass spectrometric immunoassay (MSIA), a previously developed technique for immunoenrichment on a monolithic microcolumn activated with an anti-protein antibody and fixed in a pipette tip, to selected reaction monitoring (SRM) detection and accurate quantification of targeted peptides, including clinically relevant sequence or truncated variants. RESULTS In this report, we demonstrate the rapid development of MSIA-SRM assays for sixteen different target proteins spanning seven different clinically important areas (including neurological, Alzheimers, cardiovascular, endocrine function, cancer and other diseases) and ranging in concentration from pg/mL to mg/mL. The reported MSIA-SRM assays demonstrated high sensitivity (within published clinical ranges), precision, robustness and high-throughput as well as specific detection of clinically relevant isoforms for many of the target proteins. Most of the assays were tested with bona-fide clinical samples. In addition, positive correlations, (R2 0.67-0.87, depending on the target peptide), were demonstrated for MSIA-SRM assay data with clinical analyzer measurements of parathyroid hormone (PTH) and insulin growth factor 1 (IGF1) in clinical sample cohorts. CONCLUSIONS We have presented a practical and scalable method for rapid development and deployment of MS-based SRM assays for clinically relevant proteins and measured levels of the target analytes in bona fide clinical samples. The method permits the specific quantification of individual protein isoforms and addresses the difficult problem of protein heterogeneity in clinical proteomics applications.

Genetic studies of a family with hereditary hyperparathyroidism–jaw tumour syndrome

Familial hyperparathyroidism may occur as familial isolated hyperparathyroidism (FIHP) or as part of an inherited syndrome, in particular multiple endocrine neoplasia types 1 and 2 A (MEN1, MEN2A) and hyperparathyroidism–jaw tumour (HPT–JT) syndrome. The localization of the genes responsible for these syndromes has enabled genetic screening of families with primary hyperparathyroidism (PHPT) to be carried out. This has important clinical implications in terms of individual follow‐up and management. We previously reported a large FIHP family with an increased risk of parathyroid cancer and excluded its linkage to MEN1, MEN2 and PTH genes. Here we re‐analysed this family and performed genetic linkage to the HPT–JT locus in chromosome 1q21‐q32. Loss of heterozygosity studies of 1q21‐q32, 11q13 and X chromosome were also performed.

Dissociation of Bone Turnover in Anorexia Nervosa

Biochemical markers were measured to assess bone turnover in a cross-sectional study of 43 patients with anorexia nervosa; 28 were at their first assessment (untreated) with a body mass index (BMI) (median interquartile range) of 13·3 (2) kg/m2. A second group of 15 patients undergoing treatment (treated) had a median BMI of 17·6 (2·8) kg/m2. The median, interquartile range of urinary deoxypyridinoline (DPyd), a bone resorption marker, was raised in both groups compared with an age-matched control population [DPyd = 17·8 (15·2), 17·5 (16·4) and 9·2 (4·0) nmol/mmol creatinine, respectively]. Serum type 1 collagen carboxyterminal propeptide (P1CP), a marker of bone formation, was similar to controls in the untreated patients [112 (29) and 112 (78·5)ng/ml, respectively], but was significantly raised in the treated patients [163 (219)ng/ml, P < 0·05]. A second group of 21 patients was followed prospectively, on admission and during 8 weeks of intensive inpatient care (BMI on admission and after 8 weeks was 13·0 (2) and 16·7 (3) kg/m2, respectively). The resorption marker, serum type 1 collagen carboxyterminal telopeptide (1CTP) was raised on admission and remained high during treatment. P1CP and osteocalcin levels were similar to control levels on admission but increased with treatment, and after 8 weeks were 40% and 63% higher respectively than on admission. These findings suggest that in untreated anorexia nervosa there was uncoupling of bone turnover as bone resorption markers were raised without a concomitant increase in bone formation markers. As the condition was treated and patients gained weight, the formation markers also increased, leading to a more balanced, although higher, bone turnover.

Bone mineral density and height gain in children with chronic cholestatic liver disease undergoing transplantation.

Background. Osteodystrophy is a well-described complication of chronic liver disease. Previous reports in adults and children undergoing liver transplantation (LT) were discordant, with the former showing no improvement of bone disease in the first year after transplantation and the latter demonstrating remarkable benefit from it. Our aim was to perform a pilot study on osteodystrophy in children undergoing LT and evaluate the contribution of growth on bone mineral density (BMD) changes. Methods. We studied six patients (two male), with a median age at transplantation of 8.8 (range 3.8–16.6) years. Indications for transplantation were biliary atresia and progressive familial intrahepatic cholestasis (three patients each). BMD was studied with dual-energy x-ray absorptiometry and biochemical markers of liver and bone function in patients before and at 3, 6, and 12 months after LT. Results. Median L2-L4 spinal BMD was 0.54 g/cm2 (range 0.29–0.87) before LT, and 0.58 g/cm2 (0.27–0.86) at 3 months, 0.66 g/cm2 (0.36–1.00) at 6 months, and 0.76 g/cm2 (0.44–1.02) at 12 months after LT (P =0.005). Median height was 133 (range 93–167) cm before LT, and 134 (93–167) at 3 months, 136 (97–167) at 6 months, and 139 (102–167) at 12 months after LT. There was direct correlation between height gain and total body BMD improvement (r =0.929, P =0.007). Conclusion. BMD in children with chronic cholestatic liver disease improves remarkably by 12 months after LT. Catch-up growth in children can account for the different effect of LT on bone density between adult and pediatric populations in the first year after surgery.

Successful control of hyperparathyroidism in patients on continuous ambulatory peritoneal dialysis using magnesium carbonate and calcium carbonate as phosphate binders.

To avoid the use of aluminium as a phosphate binder, patients on CAPD who were stable were dialysed against a peritoneal dialysis fluid which was magnesium free. A mixture of calcium and magnesium carbonate was used as a phosphate binder over a period in excess of 1 year. Vitamin D analogues were used in the majority. Results show satisfactory control of hyperparathyroidism with mean parathyroid hormone concentration for the group of 121 pg/ml (normal < 100 pg/ml), calcium concentration of 2.41 mmol/l, magnesium 0.97 mmol/l, phosphate 1.36 mmol/l and aluminium 0.35 mmol/l (normal < 0.2 mumol/l). These results were as good as and better in some respects than a minority using calcium carbonate alone or remaining on aluminium hydroxide, the latter remaining on Mg-containing CAPD fluid.

High-dose fish oil and antioxidants in Crohn's disease and the response of bone turnover: a randomised controlled trial.

Crohns disease is associated with altered bone turnover that may be influenced by nutritional status, the systemic inflammatory response, cytokine production by circulating (peripheral blood) mononuclear cells (PBMC) and antioxidant micronutrient intake. High-dose fish oil is associated with reductions in disease relapse and inflammatory markers, and modulates PBMC function. The effect of fish oil plus antioxidants on bone turnover and PBMC function (the production of interferon-gamma and prostaglandin E2) in Crohns disease was investigated in a randomised-controlled trial. Patients with currently or recently raised biochemical markers of inflammation (C-reactive protein > or = 6.9 mg/l or erythrocyte sedimentation rate > or =18 mm/h) received fish oil (providing 2.7 g/d EPA and DHA) and antioxidants (vitamins A, C and E, and Se) (n 31) or placebo (n 30) for 24 weeks. Bone turnover was assessed by measuring the concentrations of urinary deoxypyridinoline (bone resorption) and serum osteocalcin (bone formation). Fish oil plus antioxidants were associated with increases in EPA, DHA Se in plasma (all P < 0.01), and with a reduction in interferon-gamma production by mitogen-stimulated PBMC, which demonstrated a negative correlation with deoxypyridinoline/creatinine:osteocalcin ratio (r - 0.33, P = 0.009). There were no differences between the groups at 24 weeks in the response of deoxypyridinoline or osteocalcin or their ratio, or in nutritional status. Dietary supplementation in Crohns disease with high intakes of EPA and DHA, as fish oil, plus antioxidants was associated with a modulated production of interferon-gamma by PBMC but not altered indices of bone turnover.