Continuous treatment with odanacatib for up to 8 years in postmenopausal women with low bone mineral density: a phase 2 study.

UNLABELLED: The efficacy and safety of weekly oral odanacatib (ODN) 50 mg for up to 8 years were assessed in postmenopausal women with low bone mineral density (BMD). Treatment with ODN for up to 8 years resulted in continued or maintained increases in BMD at multiple sites and was well tolerated. INTRODUCTION: ODN is a selective inhibitor of cathepsin K. In a 2-year phase 2b study (3/10/25/50 mg ODN once weekly [QW] or placebo) and extensions (50 mg ODN QW or placebo), ODN treatment for 5 years progressively increased BMD and decreased bone resorption markers in postmenopausal women with low BMD ( ClinicalTrials.gov NCT00112437). METHODS: In this prespecified interim analysis at year 8 of an additional 5-year extension (years 6 to 10), patients (n = 117) received open-label ODN 50 mg QW plus weekly vitamin D3 (5600 IU) and calcium supplementation as needed. Primary end points were lumbar spine BMD and safety. Patients were grouped by ODN exposure duration. RESULTS: Mean (95 % confidence interval [CI]) lumbar spine BMD changes from baseline were 4.6 % (2.4, 6.7; 3-year continuous ODN exposure), 12.9 % (8.1, 17.7; 5 years), 12.8 % (10.0, 15.7; 6 years), and 14.8 % (11.0, 18.6; 8 years). Similar patterns of results were observed for BMD of trochanter, femoral neck, and total hip versus baseline. Geometric mean changes from baseline to year 8 for bone resorption markers were approximately -50 % (uNTx/Cr) and -45 % (sCTx), respectively (all groups); bone formation markers remained near baseline levels. No osteonecrosis of the jaw, delayed fracture union, or morphea-like skin reactions were reported. CONCLUSIONS: Treatment with ODN for up to 8 years resulted in gains in BMD at multiple sites. Bone resorption markers remained reduced, with no significant change observed in bone formation markers. Treatment with ODN for up to 8 years was well tolerated.

Regional fat mass by DXA: high leg fat mass attenuates the relative risk of insulin resistance and dyslipidaemia in obese but not in overweight postmenopausal women.

OBJECTIVE: To investigate the influence of regional fat mass (FM) on insulin resistance and dyslipidaemia in obese postmenopausal women (BMI >30 kg/m(2)) compared to overweight women (BMI <30 kg/m(2)). Leg FM may attenuate the increased risk of cardiovascular disease and diabetes imposed by increased trunk FM in normal and overweight postmenopausal women. MATERIAL AND METHODS: Cross-sectional and consecutively referred patients comprising 63 obese and 36 overweight postmenopausal women. Body composition and regional FM by dual X-ray absorptiometry (DXA), fasting glucose, fasting insulin and C-peptide, insulin resistance by homeostasis model assessment (HOMA-IR), insulin sensitivity by quantitative insulin sensitivity check index (QUICKI) and metabolic clearance rate (MCRestOGTT), insulin secretion (HOMAsecr) and serum lipids were assessed. RESULTS: In obese subjects, leg FM was favourably associated with HOMA-IR (p<0.05), QUICKI (p<0.05), fasting glucose (p<0.05), fasting insulin (p<0.05), HOMAsecr (p<0.05) and total cholesterol/HDL ratio (p<0.05). Trunk FM was unfavourably associated with MCRestOGTT (p<0.01), QUICKI (p<0.05) and fasting insulin (p<0.05). Compared to leg FM, leg/trunk FM ratio was more strongly associated with fasting insulin (p<0.001), fasting C-peptide (p<0.001), HOMA-IR (p<0.001), MCRestOGTT (p<0.001), QUICKI (p<0.001), HOMAsecr (p<0.001), fasting glucose (p<0.01) and triglycerides (p<0.01). Stepwise multiple regression demonstrated that leg/trunk FM ratio was the most important variable with partial R (2) = 0.26 (p<0.001) for HOMA and R (2) = 0.37 (p<0.001) when QUICKI was used as the dependent variable. In overweight women, no associations between fat mass and parameters of insulin resistance or dyslipidaemia were found. CONCLUSIONS: A high leg/trunk FM ratio as measured by DXA may give relative protection against diabetes and cardiovascular disease in obese postmenopausal women, but not in overweight women.

Cytokines, bone turnover markers and weight change in candidates for lung transplantation.

Weight loss in chronic obstructive pulmonary disease (COPD) is associated with increased morbidity and may negatively affect bone mineral density. Increased serum levels of cytokines such as tumour necrosis factor (TNF)-alpha have been associated with weight loss and with bone resorption. We studied the association between systemic inflammation, markers for bone turnover and recent weight change in underweight (n=48) and normal-weight patients (n=23) candidates for lung transplantation where the majority (56%) had COPD. Osteoporosis or osteopenia was present in all the diagnostic groups. The resulting model of linear regression in COPD patients showed that for the 1-CTP (a marker of bone resorption) model, the total variation of 61% was explained by recent weight change, sTNF-alpha receptor(R)II, dose of prednisolon and age. The resulting model of linear regression in the whole group of patients showed that the total variation of 72% was explained by recent weight change, sTNF-alpha RI, diagnosis (COPD/other diagnosis), dose of prednisolon and C-reactive protein. In conclusion, our results showed that serum concentration of 1-CTP was positively associated with sTNF-alpha receptor II and negatively with recent weight change in patients with advanced COPD. Recent weight loss in both the underweight and normal-weight patients showed to be a more important contributor than recent weight loss only in underweight patients for explaining variations in 1-CTP.

The effect of 6 months supplementation with conjugated linoleic acid on insulin resistance in overweight and obese.

BACKGROUND: Contradicting results have been published regarding the effect of conjugated linoleic acid (CLA) on insulin resistance. However, only a few studies have used the euglycemic hyperinsulinemic clamp method, which is considered the standard for measuring insulin resistance. OBJECTIVE: To evaluate if CLA as a mixture of the main isomers trans-10 cis-12 and cis-9 trans-11 affects the insulin resistance in healthy overweight and obese male and female adults. DESIGN: The main study was a randomized, double-blind, placebo-controlled trial with change in body composition as primary end point comprising 118 subjects receiving supplementation with either placebo (olive oil) or CLA (Clarinol) for 6 months. A sub-population of 49 subjects agreed additionally to participate in an euglycemic hyperinsulinemic clamp study at baseline and after 6 months of supplementation with study drug. The primary outcome was the change in glucose uptake (M) as measured by the hyperinsulinemic euglycemic glucose clamp method. Secondary outcomes were the correlates between insulin resistance and changes in body composition or blood chemistry parameters. Forty-one subjects completed the clamp test at both time points. RESULTS: The median M of the CLA group was 11.0 mg min(-1) lean body mass (lbm)(-1) (n=24) at baseline, 10.3 mg min(-1) lbm(-1) (n=24) after 6 months, and the median difference was +0.21 mg min(-1) lbm(-1) (n=24). The median M of placebo group was 8.4 mg min(-1) lbm(-1) at baseline and 9.3 mg min(-1) lbm(-1) after 6 months and the median difference was -0.22 mg min(-1) lbm(-1) (n=17). No significant (P<0.05) differences were found within groups or between groups. Likewise, the glucose uptake insulin concentration ratio during clamp (M/I) was independent of treatment and time. Homeostasis model assessment (HOMA) and quantitative insulin sensitivity check index derived from fasting glucose and insulin were also independent of treatment and time, and HOMA for the clamp population (n=49) corresponded well with HOMA for the per protocol population (n=83). Correlation analysis showed that changes in M were inversely correlated to changes in glucohemoglobin (P=0.002), but did not correlate with changes in either glucose, insulin, insulin c-peptide, leptin, adiponectin or percent body fat. CONCLUSIONS: CLA does not affect glucose metabolism or insulin sensitivity in a population of overweight or obese volunteers.

Body composition analysis by dual X-ray absorptiometry: in vivo and in vitro comparison of three different fan-beam instruments.

BACKGROUND: Dual X-ray absorptiometry (DXA) is the preferred method for measuring body composition in clinical practice, but interchange between devices may pose problems with the interpretation of results. OBJECTIVE: To establish conversion equations for body composition variables between three fan-beam DXA systems. METHODS: Body composition was assessed in 21 subjects using Lunar Expert (Expert), Lunar Prodigy (Prodigy) and Hologic Delphi W (Delphi). Weekly measurements of Hologic whole body phantom 164 were performed. RESULTS: There were no significant differences between DXA-measured means of body weight, fat mass and lean body mass. Bland-Altman analysis revealed that Lunar Expert increasingly overestimated fat mass with increasing total mass (p<0.001) relative to Delphi and Prodigy, while Delphi produced a constant underestimation of fat mass. Correlations between scale weights and DXA-measured body weights, and between DXA-measured body weights and the sum of fat masses, lean body masses and bone mineral contents (BMC) between the three instruments, were excellent (Rsqr 0.998-0.910; p<0.001). Conversion factors to Prodigy for Expert and Delphi were respectively 1.003 and 1.011 for total body mass, 0.954 and 1.079 for fat mass, 1.018 and 0.967 for lean body mass and 1.049 and 1.136 for BMC (Rsqr 0.999-0.991; p<0.001). Standard error of estimate (SEE) for the slopes ranged from 0.20% to 2.10%. Phantom studies revealed stable instrument function with CV% commonly<2%, except for lean mass for Delphi (5.5%). CONCLUSIONS: Despite the significant differences in measurement of body composition between DXA fan-beam instruments, clinically relevant conversion factors can be established.

Quantitative ultrasound and bone mineral density: discriminatory ability in patients with rheumatoid arthritis and controls with and without vertebral deformities.

BACKGROUND: Quantitative ultrasound (QUS) is a reliable tool for discriminating between subjects with and without vertebral deformities in postmenopausal osteoporosis. Less is known about osteoporosis caused by inflammatory diseases or corticosteroid use. OBJECTIVES: (1). To compare in patients with rheumatoid arthritis the ability of QUS and dual energy x ray absorptiometry (DXA) to discriminate between those with and without vertebral deformities; (2). to explore whether the results are similar in population based controls. METHODS: Standardised lateral radiographs of the spine were obtained from 210 patients with rheumatoid arthritis aged over 50 years and 210 individually matched controls. Vertebral deformities were assessed morphometrically and semiquantitatively. All participants underwent bone measurements by DXA (Lunar Expert) and QUS (Lunar Achilles+). Receiver operating curve (ROC) analysis was used to compare the discriminating ability of BMD and QUS measurements in patients and controls with and without vertebral deformities. Analyses were repeated in patients stratified according to corticosteroid use. RESULTS: For all bone measurements except lumbar spine in the rheumatoid arthritis group, BMD discriminated significantly between the patients with and without vertebral deformities, and the results were similar to those obtained in controls. Among current corticosteroid users, neither QUS nor DXA could discriminate between subjects with and without vertebral deformities. CONCLUSIONS: These findings support QUS as an alternative tool for identifying patients at risk of having vertebral deformities in rheumatoid arthritis, although results should be interpreted with caution in current users of corticosteroids.

Sustained effects of pioglitazone vs. glibenclamide on insulin sensitivity, glycaemic control, and lipid profiles in patients with Type 2 diabetes.

AIMS: This study compared the effects of 52 weeks' treatment with pioglitazone, a thiazolidinedione that reduces insulin resistance, and glibenclamide, on insulin sensitivity, glycaemic control, and lipids in patients with Type 2 diabetes. METHODS: Patients with Type 2 diabetes were randomized to receive either pioglitazone (initially 30 mg QD, n = 91) or micronized glibenclamide (initially 1.75 mg QD, n = 109) as monotherapy. Doses were titrated (to 45 mg for pioglitazone and 10.5 mg for glibenclamide) to achieve glycaemic targets during the next 12 weeks: fasting blood glucose of < or = 7 mmol/l and 1-h postprandial blood glucose of < or = 10 mmol/l. Patients were maintained on the titrated dose for 40 weeks. RESULTS: Pioglitazone significantly increased insulin sensitivity compared with glibenclamide, as assessed by homeostasis model assessment (17.0% vs. -13.0%; P < 0.001), quantitative insulin sensitivity check index (0.011 vs. -0.007; P < 0.001) and fasting serum insulin (-1.3 pmol/l vs. 23.8 pmol/l; P = 0.007). The glibenclamide group had significantly lower HbA1c than the pioglitazone group after 12 weeks of therapy (7.8% vs. 8.3%, P = 0.015), but significantly higher HbA1c after 52 weeks of therapy (7.8% vs. 7.2%, P = 0.001). Pioglitazone significantly (vs. glibenclamide) increased mean HDL-C (P < 0.001), decreased mean triglycerides (P = 0.019), and decreased mean atherogenic index of plasma (AIP; P = 0.001) and mean total cholesterol/HDL-C (P = 0.004), without significantly elevating mean total cholesterol or mean LDL-C compared with glibenclamide. CONCLUSIONS These data suggest that the effects of pioglitazone are more sustained than those of glibenclamide for improving insulin sensitivity in patients with Type 2 diabetes, and that 52 weeks' treatment with pioglitazone has favourable effects on glycaemic control and lipoprotein profile.

Vitamin D deficiency, bone mineral density and weight in patients with advanced pulmonary disease.

OBJECTIVE: To study the influence of underweight, body composition and vitamin D deficiency on bone mineral density in patients with advanced pulmonary disease. DESIGN: Cross-sectional study with time span for inclusion set at 5 years. SETTING: The clinical work and biochemical analyses were carried out at Rikshospitalet University Hospital, Norway. Analyses for vitamin D metabolites and bone markers were carried out at Aker University Hospital, and bone measurements at Clinic of Osteoporosis. SUBJECTS: Seventy-one candidates for lung transplantation (63% chronic obstructive pulmonary disease, 42 underweight and 29 normal weight) were included. MAIN OUTCOME MEASURES: Body composition, bone mineral density at lumbar spine and femur neck, serum concentration of calcidiol and vitamin D intake. RESULTS: Subnormal calcidiol levels were present in 52% of the underweight patients and 69% of the normal-weight patients. The resulting models of linear regression showed that for the lumbar spine T scores model, the total variation of 16.7% was explained by group (underweight/normal weight), sex and age. For the femur neck T scores model, the total variation of 20.4% was explained by the interaction of underweight and vitamin D deficiency (with borderline significance) and by arm muscle circumference percentage of standard. In patients with normal calcidiol levels, the median intake of vitamin D was 17 microg in the underweight patients and 11 microg in the normal-weight patients. CONCLUSIONS: Vitamin D deficiency was common in both underweight and normal-weight patients, but only in the underweight patients, an association between vitamin D deficiency and reduced femur neck T scores was indicated.

Self reported non-vertebral fractures in rheumatoid arthritis and population based controls: incidence and relationship with bone mineral density and clinical variables.

OBJECTIVE: To compare the incidence of self reported non-vertebral fractures after RA diagnosis between female patients with RA and control subjects, and to explore possible associations between non-vertebral fractures and bone mineral density (BMD), disease, and demographic factors. METHODS: 249 women (mean age 63.0 years) recruited from a county register of patients with RA and population controls (n = 249) randomly selected after matching for age, sex, and residential area were studied. Data on previous non-vertebral fractures were obtained from a detailed questionnaire, and BMD was measured at the hip and spine. RESULTS: 53 (21.3%) patients with RA had had 67 fractures after RA diagnosis, the corresponding numbers for controls were 50 (20.1%) and 60 (odds ratio (OR) for paired variables for overall fracture history 1.09, 95% CI 0.67 to 1.77). The overall fracture rates per 100 patient-years were 1.62 and 1.45, respectively, but self reported hip fractures were increased in RA (10 v 2, OR 9.0, 95% CI 1.2 to 394.5). Patients with a positive fracture history had longer disease duration, were more likely to have at least one deformed joint, and had lower age and weight adjusted BMD than those with no fracture history. In logistic regression analysis, fracture history was independently related to BMD only. CONCLUSIONS: With the probable exception of hip fractures, non-vertebral fractures do not seem to be a substantial burden in RA. Similar independent relationships between levels of BMD and fracture history were found in patients with RA and in population based controls.

Comparison of ultrasound and X-ray absorptiometry bone measurements in a case control study of female rheumatoid arthritis patients and randomly selected subjects in the population.

To compare quantitative ultrasound (QUS) and dual-energy X-ray absorptiometry (DXA) bone measurements in female rheumatoid arthritis (RA) patients and controls were randomly selected from the population; secondly, to examine disease and demographic factors associated with these bone measurements. In a total of 115 RA patients (mean age 63.0 years) and 115 age- and gender-matched controls demographic and clinical variables were collected and heel QUS parameters [speed of sound (SOS), broadband ultrasound attenuation (BUA) and stiffness index (SI)] as well as DXA bone mineral density (BMD) at spine and hip were measured. The differences in QUS and DXA measurements between RA patients and controls were tested both on a group and on an individual level. Univariate and multivariate statistical tests were applied to explore for associations to the bone measurements. In the RA patients mean disease duration was 16.6 years, erythrocyte sedimentation rate 23.6 mm/h, M-HAQ 1.68, 28-swollen joint count 7.7, 18-deformed joint count 4.5, 50.0% were rheumatoid factor (RF) positive and 44.2% were current users of prednisolone. All bone measurements were reduced in RA patients compared with controls (SOS 1.9%, BUA 9.4%, SI 19.5%, femoral neck BMD 7.4%, total hip BMD 7.5%, spine L2-L4 BMD -3.0%). Only at spine was the BMD reduction not statistically significant ( P=0.21). In the subgroup of never users of prednisolone SOS was decreased by 1.4%, BUA by 3.7%, SI by 11.0, femoral neck BMD by 2.7%, and total hip BMD by 0.6%, whereas for spine L2-L4 BMD was increased by 4.3% and only for SOS and SI was the decrease statistically significant. The QUS discriminated better than DXA between patients and controls on a group level, but this difference in favor of QUS disappeared on an individual level when the measurement errors were taken into account. Age, BMI, RF and deformed joint count, but not corticosteroids, were independently associated with at least one of the QUS and one of the DXA measures; however, the association between disease-related variables was stronger with the QUS bone measures than with the DXA bone measures. The results for the quantitative QUS bone measures seem to mainly reflect bone mass. Disease-related variables in multivariate analysis remained independently associated with all QUS measures even when adjusting for DXA bone measures. Further studies are needed to examine if QUS may reflect other aspects than bone mass and be a potential better predictor for fracture risk in RA and corticosteroid-induced osteoporosis.

Clinical decision rules in rheumatoid arthritis: do they identify patients at high risk for osteoporosis? Testing clinical criteria in a population based cohort of patients with rheumatoid arthritis recruited from the Oslo Rheumatoid Arthritis Register.

BACKGROUND: Preliminary clinical criteria based on age, inflammation, and immobility have been proposed to identify which patients with rheumatoid arthritis (RA) should be examined by dual energy x ray absorptiometry (DXA) to diagnose osteoporosis. The three item criteria have not been evaluated in male patients with RA or in the entire female RA population. OBJECTIVES: (1) To test the proposed criteria in a cohort of men and women thought to be representative of the entire underlying RA population. (2) To develop clinical decision rules, which could be applied to all patients with RA irrespective of corticosteroid use. METHODS: Clinical and demographic data were collected from a total of 287 representative patients with RA (235 (82%) women, 52 (18%) men, age range 25.3-73.1 years) from the Oslo RA register (completeness 85%). Bone mineral density (BMD) was measured in spine L2-4 (anterior-posterior view) and femoral neck by DXA. The criteria were applied and sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) were calculated. RESULTS: Mean age (SD) for the women and men with RA was 56.8 (11.0) years and 61.5 (10.2) years; disease duration was 15.5 (9.5) years and 14.7 (8.6) years. Of the women 163 (69%) were postmenopausal. One hundred and seventeen (50%) women and 28 (54%) men fulfilled the three item criteria. For the diagnosis of osteoporosis (T score

Data driven attempt to create a clinical algorithm for identification of women with rheumatoid arthritis at high risk of osteoporosis.

OBJECTIVES: To examine relations between osteoporosis and low bone mass and demographic and clinical variables in patients with rheumatoid arthritis (RA), in an attempt to develop a data driven clinical tool for identification of patients at high risk of osteoporosis. METHODS: All patients were recruited from a county based register and were examined cross sectionally with a variety of clinical and health status measures as well as bone density measures (anteroposterior spine L2-4, total hip, and femoral neck). Associations between osteoporosis (T score < or = -2.5SD) and low bone mass (T score < or = -1SD), on the one hand, and demographic and clinical measures, on the other, were examined bivariately and by logistic regression analyses. RESULTS: 394 patients with a mean age of 54.8 years were examined. The percentages having osteoporosis/low bone mass were 16.8/45.8, 14.7/54.5 and 14.7/55.5 in spine L2-4, total hip, and femoral neck, respectively. Osteoporosis and low bone mass were bivariately related to age, body mass index (BMI), disease duration, disease process measures, presence of deformed joints, physical disability, current use of corticosteroids, and history of non-vertebral fracture. In multivariate analyses, age >60 years, low BMI, and current use of corticosteroids were consistently related to osteoporosis and to low bone mass at all sites. The presence of deformed joints was associated with osteoporosis at the total hip, and a history of previous non-vertebral fracture with osteoporosis at the femoral neck. The Modified Health Assessment Questionnaire (MHAQ) > or = 1.5 and non-vertebral fracture were also independently associated with low bone mass at the hip. The logistic regression analyses models could, however, only predict osteoporosis with a sensitivity of about 50-60% and a specificity of 80-90% at the various measurement sites, and low bone mass with a sensitivity and specificity of about 70%. CONCLUSION: Consideration of demographic and disease markers may be of some help in predicting presence of osteoporosis or low bone mass, but a combination of markers cannot be used as a clinical tool with sufficient sensitivity and specificity for the identification of osteoporosis or low bone mass in patients with RA.

The Sp1 binding site polymorphism in the collagen type I alpha 1 (COLIA1) gene is not associated with bone mineral density in healthy children, adolescents, and young adults.

Up to 85% of the variance in bone mineral density (BMD) is genetically determined. A putative candidate gene involved in the regulation of bone mass is the COLIA1 gene encoding type I collagen, which is the major protein of bone. We examined possible allelic influences of a G to T COLIA1 gene polymorphism in a recognition site for the transcription factor Sp1 on: (i) gain of forearm BMD using single photon absorptiometry (SPA); and (ii), BMD of the forearm, spine, hip, and whole body with dual X-ray absorptiometry (DXA). At baseline, 269 healthy boys and girls aged 8.2-16.5 years were eligible for the study. Forearm BMD measurements obtained at baseline and after 3.8+/-0.1 years (+/-s.d.) were used to calculate the annual percentage change in BMD. Calcium intake and physical activity were determined by a detailed questionnaire at baseline and after 1 year. Essentially no significant differences in forearm BMD gain or in BMD assessed at the forearm, spine, and whole body were observed among the three COLIA1 genotypes. In conclusion, the data indicate that the polymorphism at the Sp1 site in the COLIA1 gene is not associated with BMD or gain of forearm BMD in healthy boys and girls.

Bone mineral density and frequency of osteoporosis in female patients with rheumatoid arthritis: results from 394 patients in the Oslo County Rheumatoid Arthritis register.

OBJECTIVE: To examine the bone mineral density (BMD), frequency of osteoporosis, and risk factors for BMD reduction in a representative population of female rheumatoid arthritis (RA) patients ages 20-70 years. METHODS: BMD in the femoral neck, total hip, and spine L2-4 (anterior-posterior view) was measured in 394 RA patients recruited from a validated county RA register (completeness 85%) comprising 721 women ages 20-70 years. BMD was measured with dual-energy x-ray absorptiometry, and age-specific values were compared with pooled values from a European/US population of healthy subjects free from earlier fractures, chronic diseases, and medications influencing bone metabolism. A multiple linear regression model was used to determine individual predictors of BMD. RESULTS: No statistically significant differences were found in demographic, disease activity, disease severity, or health status parameters between the RA register patients in whom BMD was measured and the remaining register patients. Femoral neck BMD was significantly reduced by 4.2% in the age group 50-59 years, and by 5.0% in those ages 60-70 years. For BMD in the total hip, the significant reductions were 3.7%, 6.0%, and 8.5% in the age groups 40-49 years, 50-59 years, and 60-70 years, respectively. No significant reduction in spine L2-4 BMD was found. A 2-fold increased frequency of osteoporosis was observed in all 4 age groups of RA patients compared with the reference population, ranging from 0% to 28.6% in the femoral neck, 0% to 29.9% in the total hip, and 1.8% to 31.5% in the spine. Predictors of reduced BMD were as follows: at the femoral neck, older age, low body weight, current use of corticosteroids, greater physical disability (as measured by the modified Health Assessment Questionnaire [M-HAQ]), and presence of rheumatoid factor; at the total hip, older age, low weight, current use of corticosteroids, and higher M-HAQ disability score; and at the lumbar spine, older age, low weight, and current use of corticosteroids. CONCLUSION: Register-based prevalence data on BMD reduction in female RA patients ages 20-70 years are presented for the first time in this report, which demonstrates a 2-fold increase in osteoporosis in this representative population.

Reduced bone mineral density in male rheumatoid arthritis patients: frequencies and associations with demographic and disease variables in ninety-four patients in the Oslo County Rheumatoid Arthritis Register.

OBJECTIVE: To examine reductions in bone mineral density (BMD) and factors associated with reduced BMD in 94 male rheumatoid arthritis (RA) registry patients ages 20-70 years. METHODS: Dual-energy x-ray absorptiometry was used to measure BMD in the anteroposterior lumbar spine at L2-LA, the femoral neck, and the total hip, and clinical data were collected. The patients were recruited from a validated county RA registry (completeness 85%) comprising 192 men ages 20-70 years. Age-specific BMD values were compared with a pooled healthy European/United States population. Bivariate and multivariate analyses were performed to determine demographic and disease-related associations with BMD and reduced bone mass (Z score of < or =1 SD below the mean value in controls). RESULTS: A statistically significant BMD reduction was found only for the oldest age group (60-70 years): 5.2% reduction in the femoral neck and 6.9% in the total hip. No BMD reduction was found at L2-L4. The proportions (95% confidence intervals) of RA patients with Z scores of < or =1 SD below control (16% expected) were 30.9% (21.6-40.2) for L2-L4, 30.8% (95% CI 21.3-40.3) for the femoral neck, and 33.0% (95% CI 23.3-42.7) for the total hip. Disease activity and severity measures were, in general, not associated with BMD or reduced bone mass. CONCLUSION: A 2-fold statistically significant increased frequency of patients with reduced bone mass (Z score of < or =1 SD below control; 16% expected) was found for both the spine and the hip. The only significant reduction in BMD by age group was for the hip in patients who were ages 60-70 years, with no reduction in L2-LA BMD. Multivariate analyses did not reveal consistent associations between reduced BMD and demographic or disease variables.

Pattern of cancer in Indian patients hospitalized in Durban, South Africa.

In emigrants from less to more developed countries, consequent changes in environmental factors are associated, inter alia, with changes in occurrences of the chronic diseases of lifestyle. In South Africa, most immigrants from India arrived in the early 1900s. To learn of the current pattern of cancer in the descendants of these people, enquiries were made on several series of patients admitted to RK Khan Hospital in Durban. The results were then compared with those of patients admitted to Ambojogai Hospital, North West India, the ancestral home of the majority of South African Indians. The most prominent differences were the lower percentages in South African Indians in respect of cancers of the mouth/pharynx in both sexes and of cervical cancer, and their considerably higher percentages, principally in the cases of stomach cancer in both sexes, of prostate cancer in males and of breast cancer in females. Discussion of risk factors indicates that in such populations there could be some control over the rises in some cancers, and on reductions in others. However, endeavours at prevention are hindered not only by the lack of knowledge prevailing, but also by their general indifference; likewise, this is the case with western populations.

Lack of relationship between vitamin D receptor genotype and forearm bone gain in healthy children, adolescents, and young adults.

Recent studies have suggested that genetic effects on bone mineral density (BMD) are related to allelic variation in the vitamin D receptor (VDR) gene. We examined 1) allelic influences of the VDR gene on BMD of the forearm, spine, hip, and whole body; and 2) allelic influences of the VDR gene on forearm BMD gain. Two hundred and seventy-three healthy boys and girls, aged 8.2-16.5 yr, at baseline were eligible. Forearm BMD was assessed with single photon absorptiometry at baseline. BMD gain was calculated as the annual percent change in BMD measured by single photon absorptiometry from the baseline and after 3.8 +/- 0.1 (+/-SD) yr. Calcium intake and physical activity were assessed by a detailed questionnaire at baseline and after 1 yr. VDR alleles were determined by BsaMI endonuclease restriction fragment analysis after PCR amplification. No significant differences in forearm BMD gain or in BMD assessed at the forearm, spine, hip, and whole body were observed among the three VDR genotypes. These findings did not change after adjusting for environmental factors such as calcium intake and physical activity or age, weight, height, and changes in weight and height during the observation period. In conclusion, our data do not support the idea that VDR genotypes are related to BMD gain or to BMD at the forearm, hip, spine, and whole body in healthy boys and girls, aged 8-21 yr. VDR genotyping is probably of little use for the detection of individuals who would benefit from increased calcium and physical activity to increase their peak bone densities.

Sandostatin LAR in acromegalic patients: long-term treatment.

We have evaluated the long term effects and safety of Sandostatin LAR, a long acting formulation of octreotide, during 18 subsequent injections given every fourth week to 14 octreotide-sensitive acromegalic patients. The dosages (20, 30, or 40 mg) were adjusted according to GH response, side-effects, or symptom relief and assessed on day 28 after each injection. We found a stable and consistent suppression of GH and insulin-like growth factor (IGF-I) during the entire study period. Daily mean GH levels were suppressed below 2 micrograms/L in 9, to between 2-5 micrograms/L in 3, and to between 5-10 micrograms/L in 2 patients. The corresponding IGF-I values were suppressed to below 500 micrograms/L in 9 patients and to between 500-1000 micrograms/L in the remaining 5 patients. Increasing the dosage of Sandostatin LAR from 20 to 30 mg had no obvious additional effect on GH suppression, but provided a further decrease in IGF-I levels. Forty milligrams of the drug had no additional effect on GH or IGF-I compared to 30 mg. Acromegalic signs and symptoms improved during treatment. Although the fluctuations of daily mean octreotide levels were high, dosage increments caused an increase in the average serum concentration in the individual patient. Pituitary tumor size reduction was seen in all previously untreated patients (n = 4). We found only minor changes in glucose metabolism (oral glucose tolerance test and hemoglobin A1C) during treatment, but no biologically relevant changes in thyroid function (TSH, T3, and free T4). One patient developed asymptomatic gallstones, and another acquired vitamin B12 deficiency during treatment. The drug is well tolerated during long term treatment. Sandostatin LAR may well be the future medical treatment of choice for acromegalic patients.

X chromosome inactivation pattern in female carriers of X linked hypophosphataemic rickets.

X linked hypophosphataemia (XLH) results from an abnormality of renal tubular phosphate reabsorption. The disorder is inherited as an X linked dominant trait and the gene has been mapped to Xp22.1-p22.2. A candidate gene (PEX) has recently been isolated. The most striking clinical features are growth retardation and skeletal abnormalities. As expected for X linked dominant disorders, females are less affected. However, such a gene dosage effect does not exist for renal phosphate reabsorption. Preferential X chromosome inactivation has been proposed as a possible explanation for this lack of gene dosage. We have examined the X inactivation pattern in peripheral blood cells from 12 females belonging to seven families with XLH using PCR analysis at the androgen receptor locus. The X inactivation pattern in these patients did not differ significantly from the pattern in 30 healthy females. The X inactivation pattern in peripheral blood cells does not necessarily reflect the X inactivation pattern in renal cells. However, the finding of a normal distribution of X inactivation in peripheral blood cells indicates that the similarity in the renal handling of phosphate in male and female patients is not related to a ubiquitous preferential X inactivation.