Osteoporosis screening in people with airways disease.

We tested associations between risk factors and bone mineral density in airways disease subjects, and developed a clinical screening tool to identify people who could benefit from bone mineral density testing. Subjects were recruited through hospital outpatients and pharmacies (Newcastle, n = 172). With survey refinement, we then tested a revised tool in a second sample (Adelaide, n = 317). Study factors included oral/inhaled corticosteroid use, asthma severity, respiratory admissions, physical activity, percent predicted forced expiratory volume in one second (FEV1), body mass index, and smoking history. Outcomes were bone mineral density of lumbar vertebra (L2-4) and total (or neck of) femur. Analysis was logistic regression with generation of a simple screening algorithm based upon coefficients. Scoring algorithm risk factors for T-score of < - 2.0: age > or = 68 = 10 points, bone mineral density < 20 = 25, weight < 60 kg = 20, 60-69 kg = 10, > or = 80 cigarette pack years = 15, low-level leisure activity = 5, area under receiver operator curve 0.83. For a cut-off score of 10, sensitivity was 91.2%, specificity 53.9%, positive and negative predictive values 52.3 and 91.7%, and 67.2% were correctly classified. In conclusions, our model has acceptable sensitivity, although limited specificity. Use of this tool may reduce unnecessary referrals for bone mineral density measurement.

Randomized controlled trial of alendronate in airways disease and low bone mineral density.

BACKGROUND: Patients with airways disease have been demonstrated to be at risk of osteoporosis, and this is likely to be multifactorial. Our aim was to identify patients with low bone mineral density (BMD) using a screening program, and then evaluate the benefit of daily alendronate. METHOD: Subjects with hip or lumbar spine baseline T-scores < - 2.5, or Z-score < - 1.0 commenced on alendronate/calcium (10 mg/600 mg day) or placebo/calcium, in a double blind randomized controlled trial. BMD by dual emission X-ray absorptiometry (lumbar vertebrae 2-4, neck of femur, total femur) was repeated after 12 months, with adverse events recorded. RESULTS: 145 subjects (74 male, 71 female, mean age 67, median FEV1 1.0 litres = 43% of predicted) were enrolled; 66 alendronate/calcium, 79 placebo/calcium with 24 and 26 withdrawals, respectively. Per protocol but not intention to treat analysis of covariance demonstrated statistically significant improvements in T and Z scores for lumbar spine bone mineral density (P = 0.035, P = 0.040), with no improvement demonstrated at the hip. CONCLUSIONS: Improvement in bone mineral density has been demonstrated at the lumbar spine, but not hip, by per protocol analysis, with daily alendronate, at 12 months.

Skeletal site bone mineral density heterogeneity in women and men.

The heterogeneity of skeletal bone mineral density, measured on a single dual-energy X-ray absorptiometer, was examined in a large cohort of 7050 women and 702 men referred for investigation of osteoporosis. The men were significantly older (64.8 +/- 13.2 vs 60.2 +/- 11.5 years) and had an increased prevalence of nontraumatic fractures (ODR: 2.18; 95% CI: 1.82-2.61). The detection rate (sensitivity) for any osteoporosis (spine or hip) in women was 87.1% and 45.1% when assessed at the anteroposterior (AP) spine and femoral neck respectively. The corresponding osteoporosis detection rate in men was 69.3% and 67.5% at the AP spine and femoral neck respectively. Age-related AP spine degenerative changes increased significantly and at a similar rate for both women and men. Misclassification, that is osteoporosis (T-score < -2.5) at one site and normal (T-score > -1) bone mass at the other, was low in both genders (< 4.5%), but 3.1 (95% CI: 2.1-4.6) times more likely in women when the diagnosis was based on the femoral neck compared with the AP spine. Our findings suggest that there are significant age- and gender-related bone mineral density differences between the spine and hip skeletal sites which have to be considered if only one site is selected for investigation.

Reproducibility of DXA: potential impact on serial measurements and misclassification of osteoporosis.

The reproducibility of bone mineral density (BMD) measurements by dual-energy X-ray absorptiometry (DXA), based on 12 successive monthly determinations, was assessed in a group of 24 subjects (23 postmenopausal women, 1 man) using six trained operators. The variability (S2A) was calculated from both duplicate operator measurements and the standard error of estimate from nonparametric regression of the individual subject series. Robust estimates of SA from the 90th percentile of the sampling distribution of variances were calculated for the spine (25 mg/cm2), femur neck (20 mg/cm2) and total femur (15.5 mg/cm2) using the bootstrap technique. The critical difference for a significant decrease (p = 0.05) at the spine, femoral neck and total femur was estimated at 57, 46 and 36 mg/cm2 respectively. Estimation of S2A allowed calculation of the probability that the true BMD, for an observed BMD near the osteoporosis diagnostic threshold (T-score < -2.5), is not misclassified. Analysis of covariance established a significant operator-subject interaction at all sites, but only the total femur was associated with a significant difference between operators. The percentage of body fat was a significant covariate for the spine and total femur regions. ANOVA showed that the greater proportion of variance was instrument-related. The limitations of DXA as an analytical method are discussed.

The clinical role of quantitative ultrasound in assessing fracture risk and bone status.

Quantitative ultrasound (QUS) analysis of calcaneal bone is useful to quantify fracture risk, and in monitoring response to treatment and identifying bone changes associated with disease and medication. However, diagnosis of osteoporosis by QUS measurements remains contentious, but the problems are due to the limitations of the present T-scores rather than the technique. QUS offers the potential for the widespread detection of low bone mass and subsequent management and prevention of fracture.

Femur BMD bias associated with DPX-IQ reanalysis of DPX-acquired scan files.

Bone mineral density values calculated by DPX-IQ software reanalysis of original DPX software analyzed scans were compared at the femur region. Based on the results for 24 subjects each scanned on 12 different occasions, a significant bias at all sites--neck, Ward's triangle and trochanter--ranging from -0.7% (neck) to -2.1% (trochanter) was found. For the trochanter site 16 of the 24 subjects had significantly lower mean BMD values after DPX-IQ reanalysis, a trend also noted at the neck and Ward's triangle. Although it has been recommended that scans analyzed with DPX software do not require DPX-IQ reanalysis, our findings strongly indicate that DPX-IQ reanalysis is essential to minimize total error during follow-up BMD determinations.

Patient attitudes to commonly promoted medical interventions.

OBJECTIVE: To survey attitudes about three "best practice" medical interventions (hormone replacement therapy [HRT], thrombolysis for acute myocardial infarction [THROM] and coronary artery by-pass surgery [CABS]) in a sample of patients, and identify factors associated with those attitudes. SETTINGS: Metropolitan tertiary care hospital outpatient clinics (survey 1, April 1997), two general practice surgeries (survey 2, May 1997), and one general practice surgery (survey 3, October 1997). DESIGN: Patients completed a questionnaire while waiting for their clinical consultation. Attitude scores were measured on an 11-category Likert scale ranging from -5 (definitely would not) to +5 (definitely would) for acceptance of proposed medication or surgery. PARTICIPANTS: 85 (participation rate, 85%), 77 (94%) and 95 (97%) in surveys 1, 2 and 3, respectively. Surveys 1 and 2 constituted the primary study group (n = 162). Patients aged > or = 50 years or reporting heart disease were excluded from the HRT analyses; patients aged > or = 65 years were excluded from the THROM and CABS analyses. RESULTS: The median attitude scores for HRT (n = 58), THROM and CABS (n = 111) were -2.95 (95% CI, -5 to -2.1), -0.5 (95% CI, -0.9 to 0) and -0.1 (95% CI, -0.5 to +1.3), respectively. Decreasing the risk-benefit ratio fourfold for HRT in survey 3 (n = 68) increased the median score to -0.75 (95% CI, -2.3 to 0). CONCLUSIONS: Patients do not view favourably the risk-benefit ratio of the three surveyed medical interventions. These attitudes may present a major impediment to most primary prevention programs.

Nitroglycerin tolerance in human vessels: evidence for impaired nitroglycerin bioconversion.

BACKGROUND: The basis for progressive attenuation of the effects of organic nitrates during long-term therapy (nitrate tolerance) remains controversial; proposed mechanisms include impaired nitrate bioconversion resulting in decreased release of nitric oxide (NO) from nitrates and/or increased NO clearance through a reaction with incrementally generated superoxide (O(2)(-)). METHODS AND RESULTS: Patients undergoing elective coronary artery bypass were randomized to receive 24 hours of intravenously infused nitroglycerin (NTG; nitrate group) or no nitrate therapy (control group). Discarded segments of the internal mammary artery and saphenous vein were used to examine (1) vascular responsiveness to NTG, sodium nitroprusside, and the calcium ionophore A23187; (2) bioconversion of NTG to 1,2- and 1,3-glyceryl dinitrate; and (3) the generation of O(2)(-). Responses to NTG were reduced 3- to 5-fold in vessels from the nitrate group compared with control vessels (P:<0. 01 for both types of segments), whereas responses to sodium nitroprusside and A23187 were unchanged. Tissue content of 1, 2-glyceryl dinitrate was lower (P:=0.012) in the saphenous veins from the nitrate group than in those from the control group. O(2)(-) generation was greater (P:<0.01) in internal mammary artery samples from the nitrate group than in those from the control group. However, incremental O(2)(-) generation induced by an inhibitor of superoxide dismutase did not affect NTG responses. CONCLUSIONS: NTG tolerance in patients with coronary artery disease is nitrate-specific and is associated with evidence of impaired NTG bioconversion. Tolerance was associated with incremental O(2)(-) generation, but short-term elevation of O(2)(-) did not affect NTG responsiveness, suggesting increased NO clearance by O(2)(-) has a minimal contribution to tolerance.

Mutants of 11beta-hydroxysteroid dehydrogenase (11-HSD2) with partial activity: improved correlations between genotype and biochemical phenotype in apparent mineralocorticoid excess.

Mutations in the kidney isozyme of human 11-hydroxysteroid dehydrogenase (11-HSD2) cause apparent mineralocorticoid excess, an autosomal recessive form of familial hypertension. We studied 4 patients with AME, identifying 4 novel and 3 previously reported mutations in the HSD11B2 (HSD11K) gene. Point mutations causing amino acid substitutions were introduced into a pCMV5/11HSD2 expression construct and expressed in mammalian CHOP cells. Mutations L179R and R208H abolished activity in whole cells. Mutants S180F, A237V, and A328V had 19%, 72%, and 25%, respectively, of the activity of the wild-type enzyme in whole cells when cortisol was used as the substrate and 80%, 140%, and 55%, respectively, of wild-type activity when corticosterone was used as the substrate. However, these mutant proteins were only 0.6% to 5.7% as active as the wild-type enzyme in cell lysates, suggesting that these mutations alter stability of the enzyme. In regression analyses of all AME patients with published genotypes, several biochemical and clinical parameters were highly correlated with mutant enzymatic activity, demonstrated in whole cells, when cortisol was used as the substrate. These included the ratio of urinary cortisone to cortisol metabolites (R(2)=0.648, P<0.0001), age at presentation (R(2)=0.614, P<0.0001), and birth weight (R(2)=0.576, P=0.0004). Approximately 5% conversion of cortisol to cortisone is predicted in subjects with mutations that completely inactivate HSD11B2, suggesting that a low level of enzymatic activity is mediated by another enzyme, possibly 11-HSD1.

Effect of hypercortisolism and ACTH on the metabolism of cortisol.

The effects of hypercortisolemia and ACTH on the metabolism of cortisol in congenital adrenal hyperplasia, Cushing's syndrome, and exogenous ACTH and cortisol administration were investigated by analysis of the respective urinary tetrahydro-metabolites of cortisol (THF and aTHF) and cortisone (THE) by capillary gas chromatography. The results for the patients with congenital adrenal hyperplasia establish that ACTH hypersecretion in the absence of an associated marked elevation of plasma cortisol does not cause inhibition of the 11beta-OHSD enzyme. In contrast elevated plasma cortisol levels (adrenal adenoma or intravenous cortisol administration) in the presence of suppressed ACTH secretion leads to significant inhibition of the peripheral conversion of cortisol to cortisone. The latter results are equivalent to the mode of cortisol metabolism noted during clinical states of ACTH hypersecretion and hypercortisolemia (Cushing's disease, ectopic ACTH syndrome and ACTH administration). The overall findings provide convincing evidence that ACTH hypersecretion is not associated with specific in vivo inhibition of 11beta-OHSD enzyme activity.

Public perceptions and self-reported prevalence of osteoporosis in South Australia.

The self-reported prevalence of, and attitudes to and perceptions of, osteoporosis in the South Australian community were assessed using data collected as part of the 1995 South Australian Health Omnibus Survey (household interviews)--a clustered, self-weighting, multistage sample of households in metropolitan and country centers. The self-reported prevalence was 4.8 (95% CI: 3.7-5.8) and 1.4% (95% CI: 0.8-2.0) for women (n = 1531) and men (n = 1485) respectively. For individuals with osteoporosis, calcium was the favored treatment (52%), while 33% of women were on hormone replacement therapy. An appropriate definition of osteoporosis was given by 62% of women and 37% of men. The main risk factors were reported as lack of calcium and age. There was a significant association between knowledge of the definition of osteoporosis and identification of correct risk factors. A high perceived risk of osteoporosis was reported in 23% of women and 7% of men. Osteoporosis risk was assessed as higher in those who did not adopt recognized prevention measures. Perception of risk was not related to the individual's own risk factors. Self-reported prevalence of osteoporosis significantly underestimates the likely true prevalence and general awareness and knowledge is much lower for men than women. The importance of individual risk factors for osteoporosis are not understood by the general community.

Alternate site testing for HbA1c using the Primus CLC330 GHb analyzer.

OBJECTIVE: To determine whether the Primus high-pressure liquid chromatography (HPLC) is suited to alternate site testing (AST) for HbA1c in a hospital diabetes outpatient clinic. RESEARCH DESIGN AND METHODS: Patients were attending the clinic for routine management of their diabetes. A number of diabetic patients with uremia (n = 11) were also investigated. HbA1c levels were measured in the outpatient setting by the Primus HPLC and in a more limited study the DCA-2000 instrument using the new 6-min assay cartridge. HbA1c measurements were also performed with Pierce affinity minicolumns and a Bio-Rad Variant HPLC. RESULTS: The Primus HPLC assay had low imprecision of 2.3, 1.6, and 1.0% for HbA1c levels of 4.7, 7.3, and 11.1%, respectively, and was not prone to interference by carbamylated hemoglobin as found for the ion-exchange Variant HPLC method. Method comparison studies showed that the bias and proportional error between the Pierce affinity minicolumn procedure (standardized with respect to an external quality control program) and the Primus HPLC (Y) was -0.4 and 1.2% respectively (n = 32). Similarly the bias and proportional error between the Primus and DCA-2000 methods was 0.7 and -2.5%. The Primus was shown to give falsely elevated HbA1c concentrations if the time between sequential injections was > 28 min. CONCLUSIONS: The Primus HPLC has a decided advantage over specialty AST instruments, like the DCA-2000, in not only meeting AST requirements but also allowing rapid automated batch processing of all laboratory HbA1c samples.

Initiation of hormone replacement therapy after diagnosis of osteoporosis by bone densitometry.

The effect of osteoporosis, as diagnosed by bone densitometry, on general practitioners' decisions to initiate hormone replacement therapy (HRT) was assessed. Data for the study were collected by questionnaire from 147 women (> 40 years), previously referred for measurement of bone mineral density (BMD) at the proximal forearm. Among the women, at the time of BMD measurement, current and ever use of HRT was 35% and 50% respectively, and 25.2% were osteoporotic on the basis of their BMD level. HRT was more likely to be initiated by women who were told that their BMD was low (ODR 3.4; 95% CI 1.2-9.7); 37% of all women with osteoporosis were using HRT compared with 78% who were taking calcium supplements. Potential reasons for the low HRT prescription may include the nature of the BMD report, patient aversion to HRT and doctors' concern with the long-term side-effects of HRT.