Alendronate for the treatment of osteoporosis in men. (33/3016)

BACKGROUND: Despite its association with disability, death, and increased medical costs, osteoporosis in men has been relatively neglected as a subject of study. There have been no large, controlled trials of treatment in men. METHODS: In a two-year double-blind trial, we studied the effect of 10 mg of alendronate or placebo, given daily, on bone mineral density in 241 men (age, 31 to 87 years; mean, 63) with osteoporosis. Approximately one third had low serum free testosterone concentrations at base line; the rest had normal concentrations. Men with other secondary causes of osteoporosis were excluded. All the men received calcium and vitamin D supplements. The main outcome measures were the percent changes in lumbar-spine, hip, and total-body bone mineral density. RESULTS: The men who received alendronate had a mean (+/-SE) increase in bone mineral density of 7.1+/-0.3 percent at the lumbar spine, 2.5+/-0.4 percent at the femoral neck, and 2.0+/-0.2 percent for the total body (P<0.001 for all comparisons with base line). In contrast, men who received placebo had an increase in lumbar-spine bone mineral density of 1.8+/-0.5 percent (P<0.001 for the comparison with base line) and no significant changes in femoral-neck or total-body bone mineral density. The increase in bone mineral density in the alendronate group was greater than that in the placebo group at all measurement sites (P<0.001). The incidence of vertebral fractures was lower in the alendronate group than in the placebo group (0.8 percent vs. 7.1 percent, P=0.02). Men in the placebo group had a 2.4-mm decrease in height, as compared with a decrease of 0.6 mm in the alendronate group (P=0.02). Alendronate was generally well tolerated. CONCLUSIONS: In men with osteoporosis, alendronate significantly increases spine, hip, and total-body bone mineral density and helps prevent vertebral fractures and decreases in height.  (+info)

Prediction of disease progression in early rheumatoid arthritis by ICTP, RF and CRP. A comparative 3-year follow-up study. (34/3016)

OBJECTIVE: To test the predictive value of the cross-linked carboxyterminal telopeptide of type I collagen (ICTP; a marker of type I collagen degradation), rheumatoid factor (RF) and C-reactive protein (CRP) for disease progression in patients with early rheumatoid arthritis (RA) METHOD: We tested the value of baseline values of RF, CRP and ICTP for the prediction of radiological joint progression over 3 yr in 63 consecutive patients with early RA who were treated with the 'saw-tooth strategy'. RESULTS: Age- and sex-adjusted risks as odds ratios (95% confidence intervals) of elevated serum ICTP, RF positivity and increased CRP for progressive joint disease (defined as an increase of > 20 in Larsen's index on radiographs of the hands and feet) were 3.9 (1.3, 11.9), 3.9 (1.0, 15.5) and 2.6 (0.9, 7.5), respectively. Better prediction was achieved when the tests were used in combination, and where there was both elevated ICTP and positive RF the odds ratio was 9.1 (2.5, 32.9). This test combination showed good sensitivity and specificity (71 and 77%, respectively), with a positive predictive value of 65% and a likelihood ratio of 3.1. CONCLUSION: This kind of risk profile, in which the tests used reflect different aspects of the disease process, may be useful in early disease assessment to find patients who will need the most active drug therapy.  (+info)

Synergistic cooperation between Sp1 and Smad3/Smad4 mediates transforming growth factor beta1 stimulation of alpha 2(I)-collagen (COL1A2) transcription. (35/3016)

Transforming growth factor-beta1 (TGFbeta) is a strong activator of extracellular matrix accumulation. TGFbeta stimulates the gene coding for human alpha2(I)-collagen (COL1A2) by inducing binding of an Sp1-containing complex to an upstream promoter element (TGFbeta responsive element or TbRE) that contains a CAGA box. Here we report that the CAGA box of the TbRE is the binding site of the Smad3/Smad4 complex, and that the binding of the complex is required for TGFbeta-induced COL1A2 up-regulation. Recombinant Smad3 and Smad4 bind in vitro to the CAGA box of COL1A2; TGFbeta treatment of cultured fibroblasts induces Smad3/Smad4 binding to the TbRE; transient overexpression of Smad3 and Smad4 in fibroblasts transactivates TbRE-driven transcription; and COL1A2 gene up-regulation by TGFbeta is abolished in cells stably transfected with plasmids that express dominant negative forms of Smad3 or Smad4. In Sp1-deficient Drosophila Schneider cells, there was cooperative synergy between Smad3/Smad4 and Sp1 at the TbRE site. The analysis also emphasized the requirement of both Sp1- and Smad-binding sites for optimal promoter transactivation. In cells stably transfected with a plasmid expressing a dominant negative form of Sp1, the synergy was shown to be promoter-specific and dependent on the binding of Sp1 to the TbRE. Interestingly, overexpression of dominant negative Sp1 was found to block the antagonistic signal of tumor necrosis factor-alpha on COL1A2 transcription, as well. These results provide the first linkage between the Smad3 and Smad4 proteins and TGFbeta stimulation of type I collagen biosynthesis.  (+info)

Circulating collagen metabolites in systemic sclerosis. Differences between limited and diffuse form and relationship with pulmonary involvement. (36/3016)

OBJECTIVE: To study collagen metabolites in systemic sclerosis (SSc) and their relationship with clinical manifestations of the disease. METHODS: Forty-eight SSc patients, 13 with a diffuse form (dcSSc), 23 with a limited form (lcSSc) and 12 with suspected SSc not fulfilling the ACR criteria, and 31 healthy controls were examined. Serum concentrations of aminoterminal type III procollagen peptide (PIIINP), aminoterminal and carboxyterminal type I procollagen peptides (PINP and PICP) and cross-linked carboxyterminal telopeptide of collagen I (ICTP) were determined by radioimmunoassay. RESULTS: Increased serum concentrations of ICTP were found in SSc patients compared with controls. Distinctly higher levels of ICTP were observed in dcSSc than in lcSSc. High serum ICTP was correlated with skin score and acute phase reactants, and with reduced pulmonary function. Serum PIIINP concentration was elevated in both lcSSc and dcSSc. CONCLUSION: Augmented collagen catabolism accompanies the increased collagen synthesis in SSc. Serum ICTP concentration is a marker of this feature and also reflects clinical severity.  (+info)

Transforming growth factor beta in hypertensives with cardiorenal damage. (37/3016)

We investigated whether a relationship exists between circulating transforming growth factor beta -1 (TGF-beta(1)), collagen type I metabolism, microalbuminuria, and left ventricular hypertrophy in essential hypertension and whether the ability of the angiotensin II type 1 receptor antagonist losartan to correct microalbuminuria and regress left ventricular hypertrophy in hypertensives is related to changes in TGF-beta(1) and collagen type I metabolism. The study was performed in 30 normotensive healthy controls and 30 patients with never-treated essential hypertension classified into 2 groups: those with microalbuminuria (urinary albumin excretion >30 and <300 mg/24 h) associated with left ventricular hypertrophy (left ventricular mass index >116 g/m(2) for men and >104 g/m(2) for women) (group B; n=17) and those without microalbuminuria or left ventricular hypertrophy (group A; n=13). The measurements were repeated in all patients after 6 months of treatment with losartan (50 mg once daily). The serum concentration of TGF-beta(1) was measured by a 2-site ELISA method, and the serum concentrations of carboxy-terminal propeptide of procollagen type I (a marker of collagen type I synthesis) and carboxy-terminal telopeptide of collagen type I (a marker of collagen type I degradation) were measured by specific radioimmunoassays. The duration of hypertension and baseline values of blood pressure were similar in the 2 groups of patients. No differences in serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and carboxy-terminal telopeptide of collagen type I were found between normotensives and group A of hypertensives. Serum TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I were increased (P<0.05) in group B of hypertensives compared with group A of hypertensives and normotensives. No differences in carboxy-terminal telopeptide of collagen type I were found among the 3 groups of subjects. After treatment with losartan, microalbuminuria and left ventricular hypertrophy persisted in 6 patients (then considered nonresponders) and disappeared in 11 patients (then considered responders) from group B. Compared with nonresponders, responders exhibited similar control of blood pressure and higher (P<0.05) blockade of angiotensin II type 1 receptors (as assessed by a higher increase in plasma levels of angiotensin II). Whereas TGF-beta(1), carboxy-terminal propeptide of procollagen type I, and the ratio of carboxy-terminal propeptide of procollagen type I to carboxy-terminal telopeptide of collagen type I decreased (P<0.05) in responders, no changes in these parameters were observed in nonresponders. These findings show that an association exists between an excess of TGF-beta(1), stimulation of collagen type I synthesis, inhibition of collagen type I degradation, and cardiorenal damage in a group of patients with essential hypertension. In addition, our results suggest that the ability of losartan to blunt the synthesis of TGF-beta(1) and normalize collagen type I metabolism may contribute to protect the heart and the kidney in a fraction of patients with essential hypertension.  (+info)

Alcohol intake and bone metabolism in elderly women. (38/3016)

BACKGROUND: Published reports on the effect of alcohol consumption on bone mineral density (BMD) are inconsistent. OBJECTIVE: The objective of this study was to examine the relation between alcohol intake and BMD, calcitropic hormones, calcium absorption, and other biochemical indexes of bone and mineral metabolism in elderly women. DESIGN: The results presented are derived from baseline observations of 489 elderly women (aged 65-77 y) recruited for an osteoporosis study. The nondrinking group comprised 297 women and the drinking group comprised 148 women. Furthermore, the effect of different alcohol intakes (28.6 to 57.2 to 142.9 g/wk) was studied. RESULTS: Women who consumed alcohol had significantly higher spine (10%), total body (4.5%), and midradius (6%) BMD than did nondrinkers. An alcohol intake >28.6 g/wk was associated with higher BMD; maximum effect was seen with an intake of >28.6 to +info)

Effects of aging on bone mineral content and bone biomarkers in female cynomolgus monkeys. (39/3016)

Age-related changes in bone mineral content and bone biomarkers were assessed over the complete lifespan of female cynomolgus monkeys. The bone mass of the lumbar spine increased linearly from birth to about 2.5 years of age, and this increase gradually slowed thereafter until a peak bone mass was achieved at 9 years of age. The bone mass stabilized after 9 years of age, showing no sign of further reduction with age. In contrast with the significant increase in bone mass before 2.5 years of age, significant decreases occurred in the serum concentrations of the following bone formation markers: intact osteocalcin, bone-specific alkaline phosphatase and amino-terminal propeptide of type I procollagen, but the serum concentration of carboxy-terminal propeptide of type I procollagen did not change significantly throughout the entire lifespan. Concerning the bone resorption markers, the levels of tartrate-resistant acid phosphatase fluctuated throughout the entire lifespan. The skeleton of an aging female monkey undergoes changes similar to those observed in senescent humans, but did not undergo the menopausal changes seen in women. The use of female cynomolgus monkeys to model human skeletal interventions should therefore be undertaken with consideration of the similarities and differences between cynomolgus monkeys and humans.  (+info)

Sp1 and Smad proteins cooperate to mediate transforming growth factor-beta 1-induced alpha 2(I) collagen expression in human glomerular mesangial cells. (40/3016)

The mechanism(s) by which Smads mediate and modulate the transforming growth factor (TGF)-beta signal transduction pathway in fibrogenesis are not well characterized. We previously showed that Smad3 promotes alpha2(I) collagen gene (COL1A2) activation in human glomerular mesangial cells, potentially contributing to glomerulosclerosis. Here, we report that Sp1 binding is necessary for TGF-beta1-induced type I collagen mRNA expression. Deletion of three Sp1 sites (GC box) between -376 and -268 or mutation of a CAGA box at -268/-260 inhibited TGF-beta1-induced alpha2(I) collagen promoter activity. TGF-beta1 inducibility was also blocked by a Smad3 dominant negative mutant. Chemical inhibition of Sp1 binding with mithramycin A, or deletion of the GC boxes, inhibited COL1A2 activation by Smad3, suggesting cooperation between Smad3 and Sp1 in the TGF-beta1 response. Electrophoretic mobility shift assay showed that Sp1 and Smads form complexes with -283/-250 promoter sequences. Coimmunoprecipitation experiments demonstrate that endogenous Sp1, Smad3, and Smad4 form complexes in mesangial cells. In a Gal4-LUC reporter assay system, Sp1 stimulated the TGF-beta1-induced transcriptional activity of Gal4-Smad3, Gal4-Smad4 (266), or both. Using the transactivation domain B of Sp1 fused to the Gal4 DNA binding domain, we show that, in our system, the transcriptional activity of this Sp1 domain is not regulated by TGF-beta1, but it becomes responsive to this factor when Smad3 is coexpressed. Finally, combined Sp1 and Smad3 overexpression induces marked ligand-independent and ligand-dependent promoter activity of COL1A2. Thus, Sp1 and Smad proteins form complexes and their synergy plays an important role in mediating TGF-beta1-induced alpha2(I) collagen expression in human mesangial cells.  (+info)