Ultrasonographic measures of synovitis in an early phase clinical trial: a double-blind, randomised, placebo and comparator controlled phase IIa trial of GW274150 (a selective inducible nitric oxide synthase inhibitor) in rheumatoid arthritis.

OBJECTIVES: To test the sensitivity to change of ultrasonographic endpoints in early phase clinical trials in subjects with active rheumatoid arthritis (RA). METHODS: A double-blind, placebo and comparator controlled, randomised, two-centre study investigated the effect on synovial thickness and vascularity of 28 days repeat daily oral dosing of 60 mg of the inducible nitric oxide synthase inhibitor GW274150 or 7.5 mg prednisolone in RA. Fifty patients with DAS28 scores ≥4.0 were assigned to 3 treatment arms of 17, 19 and 14 (on placebo, GW274150 and prednisolone respectively). Synovial thickness and vascularity of all 10 metacarpophalangeal joints were assessed by ultrasonography using a semi-quantitative scale at baseline (Day 1), Day 15 and Day 28. Vascularity was also measured quantitatively by power Doppler area. RESULTS: At Day 28, the GW274150 group showed a trend towards reduction in synovial thickness compared with placebo, with an adjusted mean decrease of 33% (p=0.072); the prednisolone group decreased significantly by 44% (p=0.011). Similarly, there was a trend to reduced synovial vascularity with GW274150 by 42% compared with placebo (p=0.075); prednisolone resulted in a statistically significant decrease of 55% (p=0.012). There was a 55% decrease in power Doppler area for GW274150, compared with placebo although the result was not statistically significant (p=0.375). Prednisolone 7.5 mg resulted in a highly statistically significant decrease of 95% (p=0.003). CONCLUSIONS: This study advocates the use of ultrasonographic measures of metacarpophalangeal joint synovitis as an endpoint for clinical studies assessing therapeutic potential of new compounds in small patient cohorts over 28 days.

Cumulative exposure to estrogen and psychosis: a peak bone mass, case-control study in first-episode psychosis.

The organizational structural effects of estrogen may be cumulative and permanent by impacting on neurodevelopment, giving rise to "neuroprotective" effects and eventually reduction of psychosis risk. Reduction in bone mineral density (BMD, in g/cm2), as a biological marker of reduced cumulative exposure to estrogen, may be a marker of increased psychosis risk. A sample of 19 first-episode female psychosis patients with minimal previous antipsychotic exposure (mean 10 weeks) and 20 female controls underwent advanced fan-beam dual X-ray absorptiometry (DXA) to assess lumbal spine BMD of the region of L1-L4. Mean BMD was around one standard deviation lower in patients (1.13, S.D.=0.10) than in controls (1.25, S.D.=0.12; p=0.0021), and 84% of patients scored below the median value of the controls (OR=5.3, 95% CI: 1.2, 24.2). The results are compatible with the hypothesis that psychosis in women may be associated causally with a reduced protective effect of estrogen over the course of development.

Association of collagen type I alpha1 gene polymorphism with bone mineral density in osteoporotic women in Serbia.

BACKGROUND: The collagen type I alpha1 (COLIA1) gene encodes for a major bone protein and is a strong candidate for genetic control of bone mineral density (BMD). COLIA1 gene polymorphism is associated with reduced BMD and increased fracture incidence. The aim of this study was to analyze the relationship between COLIA1 gene polymorphism and BMD in Serbian women. METHODS: The women were divided into groups according to their DEXA phenotypes. They included 39 osteoporotic, 36 osteopenic, and 33 women with normal BMD. Single nucleotide polymorphism (G to T substitution) within the Sp1-binding site in the first intron of the COLIA1 gene was assessed by polymerase chain reaction (PCR) followed by single-stranded conformation polymorphism (SSCP) analysis. RESULTS: The genotype frequencies for the whole group were 67.6% GG homozygotes, 24.1% GT heterozygotes, and 8.3% TT homozygotes and were not in Hardy-Weinberg equilibrium (HWE). Significant deviation from HWE was found only in the osteopenic group (p = 0.0007), where a higher number of homozygotes was found. Comparison of the allele frequencies showed no significant differences between three groups of tested women. CONCLUSIONS: The presence of the T allele in the genotype has no influence on BMD in the osteoporotic group of women. The observed deviation in the osteopenic group needs to be investigated further.

[Bone mineral density in patients with juvenile idiopathic arthritis].

INTRODUCTION: It is well known that juvenile idiopathic arthritis (JIA) as a chronic inflammatory disease with onset during the childhood, beside other complication, can lead to bone metabolism disturbance and osteoporosis. OBJECTIVE: To assess bone mineral density (BMD) in children with JIA and to identify factors playing role in bone mineral disturbance. METHODS: Seventy-five patients (26 male and 49 female) average disease duration 7.2 (2.4-16.8) years, and 73 age matched healthy control subjects (29 male and 44 female) participated in the study. Mean age of the groups was about 14.5 years. BMD was determined by dual x-ray absorptiometry (DEXA) of the lumbar spine (L2-L4). For further analysis we used the absolute value of BMD, expressed as g/cm2, Z score expressed as SD (relative value as standard deviation decline of normal BMD values of referent Italian population with identical age and gender), bone mineral content (BMC) as g/cm, and corrected BMD-BMDv as g/cm3. RESULTS: Z score in the group of patients was significantly lower (-1.02 +/- 1.6) in comparison to the control group (-0.09 +/- 1.4; p<0.001). BMD, BMDv and BMC were also statistically lower in patients with JIA. The lowest Z score was found in patients with systemic onset (-2.63 SD). Z score showed a statistically significant positive correlation with arthritis course (polyarticular course had lower Z score), body mass index and standard deviation score for height and weight. Statistically significant negative correlation was detected in regard to Z score and glucocorticoid (GC) treatment duration, GC cumulative dose, number of joints with limited range of motion, radiological stage and functional class. CONCLUSION: The results showed a decreased BMD in patients with JIA in comparison to the control group. Systemic onset, polyarthritis, longer treatment with GC and higher cumulative dosage, as well as higher damage level (functional status and radiological stage) are factors playing negative role in bone metabolism in children with JIA.

Effects of Alendronate on bone mass in women with osteoporosis.

This paper presents the results of a two-year study of the effects of alendronate (Fosamax) on bone mass in 187 women with osteoporosis, mean age 57.68 years. Bone mass, i.e. bone mineral density (BMD) was measured at the lumbar spine. Measurements were performed prior to treatment, one year and two years after treatment using the DEXA method. The BMD was examined in 65 women, mean age 54.02, taking calcium and vitamin D, and in 75 women mean age 57.16, without any therapy. The baseline BMD (T score) in the alendronate group was -2.87 SD, whereas in the two control groups it measured -1.86 SD and -2.02 SD, respectively. A significant improvement of bone mass, by 5.8%, was registered after a year of treatment with alendronate, and by 8.3% after two years. In patients receiving calcium and vitamin D, a significant increase of bone mass was established as well: by 2.9% after a year, but the values declined back to the baseline after the second year. In patients without any treatment the bone mass decreased by 0.6% after a year, and by 0.9% after the second year.

[Cyclic intravenous pamidronate in treatment of osteoporosis]. / Lecenje osteoporoze ciklicnom primenom pamidronata.

OBJECTIVE: To assess the efficacy and tolerability of cyclic intravenous pamidronate therapy in women with severe osteoporosis. MATERIAL AND METHODS: Bone mineral density (BMD) measurement was performed by dual-energy X-ray absorptiometry using LUNAR DPX-L device. Slow intravenous infusion regimens of pamidronate (30 mg) every three months were used in treatment of 240 women, in addition to supplemental Ca and vitamin D. Bone mineral density was measured from lumbar spine 1 year later (120 mg of pamidronate) in 195 women and 2 years later (240 mg of pamidronate) in 29 women. The placebo group included 63 women treated only with calcium and vitamin D. RESULTS: The average age of 240 women with severe osteoporosis was 61.2 +/- 9.5. All were postmenopausal, except for two of them. Their mean age at the onset of menopause was 46.2 +/- 5.6. Mean duration of menopause was 15.7 +/- 8.1. After 1 year of therapy, bone mineral density increased from 0.781 g/cm2 to 0.83 7 g/cm2 (p < 0.001), the mean increase bone mass was 7.2% (p < 0.0001). After 2 years, bone mineral density increased to 0.844 g/cm2, the improvement was 8.1% from baseline (p < 0.001). Bone mineral density in the placebo group, after one year, significantly increased (p = 0.046) from 0.966 g/cm2 to 1.004 g/cm2, the improvement was 3.9%. However, after two years, bone mineral density decreased to 0.973 g/cm2, and compared with baseline this change was 0.7% and not significant (p > 0.05). CONCLUSION: Pamidronate prevented further decrease of BMD in our patients with severe osteoporosis and also increased BMD in these patients. This safe and efficient drug is well tolerated.