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The aims of the present study were to investigate how changes in the cumulative dose and the frequency of dosing influence the short-term antiresorptive efficacy of oral ibandronate treatment and whether serial measurements of bone markers could provide a useful diagnostic tool for the revelation of noncompliance to established treatments with antiresorptive drugs. Study participants were 200 healthy women 50-70 years old (mean 63.1 years) with a lumbar spine BMD t-score of -1 to -5. Women were randomly allocated to receive treatment with oral ibandronate according to one of the following eight dosing regimes: (1) 2.5 mg daily for 84 days; (2) 20 mg weekly for 84 days; (3) 2.5 mg daily for 28 days + no treatment for 56 days; (4) 2.5 mg daily for 28 days + 2.5 mg weekly for 56 days; (5) 2.5 mg daily for 28 days + 2.5 mg three times weekly for 56 days; (6) 2.5 mg daily for 14 days + 2.5 mg three times weekly for 56 days; (7) 2.5 mg three times weekly for 84 days; (8) no treatment for 168 days. Study parameters were the serum concentration of the C-terminal telopeptide of collagen type I (s-CTX, resorption marker) and N-MID osteocalcin (formation marker) measured by enzyme-linked immunosorbent assay. Oral treatment with ibandronate 20 mg weekly (cumulative dose 240 mg) resulted in greater final inhibition in s-CTX and area under the curve (AUC) compared to the 2.5 mg daily treatment (cumulative dose 210 mg), indicating that as long as optimal doses are administered the frequency of dosing has secondary importance for overall efficacy. When the cumulative dose was 130 mg or less, the final degree of inhibition was still the function of the cumulative dose, but the overall efficacy estimated by the AUC was also under the influence of the frequency of dosing. These observations suggest that serial measurements of s-CTX may provide a useful diagnostic tool for the early revelation of suboptimal dosing or noncompliance to already optimized therapies with antiresorptive agents.

Since effective prevention and treatment of osteoporosis demands a high degree of long-term compliance, optimization of the dosing regimen in terms of efficacy and convenience of drug intake is a critical issue of oral bisphosphonate treatment. The purpose of the present study was to investigate whether the efficacy of the treatment with oral ibandronate, 2.5 mg daily, can be maintained if changing the postdose fast from 60 to 30 min. This was a 48-week, multicenter, open-label, randomized, parallel-group noninferiority study. Subjects were postmenopausal women 55-80 years old with lumbar spine (L1-L4) bone mineral density (BMD) corresponding to a T score < or =2.5. Women were randomly assigned to take 2.5 mg ibandronate exactly 30 or 60 min before breakfast. Lumbar spine and proximal femur (trochanter, femoral neck, total hip) BMD were measured by dual energy X-ray absorptiometry; serum osteocalcin and creatinine-corrected urinary C-telopeptide of type I collagen (u-CTX/Cr) excretion were measured by ELISA. After 48 weeks of treatment, the relative increase in lumbar spine BMD from baseline in the 30-min fast group was lower than that in the 60-min fast group (3.07% versus 4.95%, one-sided 97.5% CI = -2.89%) such that the prespecified noninferiority criteria were not met. The mean relative increases in BMD at the trochanter (3.04% versus 4.36%), femoral neck (1.82% versus 2.19%), and total hip (2.35% versus 3.21%) in the 30-min fast group were also lower than those in the 60-min fast group. Less suppression of the markers of bone turnover (u-CTX/Cr, -48.5% vs -61.8%; serum osteocalcin, -34.8% vs 43.8%) was observed in the 30-min compared with the 60-min group. In conclusion, if reducing the postdose fasting interval, dose-increase compensation would likely to be required to maintain efficacy of oral ibandronate treatment. Another potential solution for improving the convenience with bisphosphonate treatment is expected from weekly or monthly dosing regimens currently under clinical investigations.

Recent in vitro and animal studies suggest that cholesterol and its metabolites inhibit the functional activity of osteoblasts and thereby induce reduced bone mineralization. However, scant information is available on the clinical implication of these findings with special regard to postmenopausal bone loss. Therefore, the aim of the present study was to investigate cross-sectional and longitudinal associations between serum cholesterol, bone mineral density (BMD), and bone turnover in 340 postmenopausal women aged 50-75 years (mean 59 years), who were followed for 8.3 +/- 1.1 years. BMD in the lumbar spine, distal forearm, and total hip was measured by dual energy X-ray absorptiometry. Other study variables were physical measures, serum cholesterol, serum markers of bone turnover, and self-reported information on various risk factors for osteoporosis. At baseline, serum cholesterol showed significant negative correlation with BMD at the lumbar spine (r = -0.21, P < 0.0001) and distal forearm (r = -0.14, P = 0.013), but not at the hip. No associations of serum cholesterol with serum osteocalcin (r = 0.054, P = 0.317) and CTX (r = -0.027, P = 0.623) were, however, noted. After adjustment for age and BMI, the negative correlation remained significant at the lumbar spine (r = -0.16, P = 0.004), but not at the distal forearm (r = -0.018, P = 0.738). At the end of the 8-year follow-up, the correlation between serum cholesterol and spine BMD was not observed. Those with the largest increases in serum cholesterol, however, showed the greatest decreases in spine BMD independently of the changes in BMI (r = -0.16, P = 0.004). The correlation between the changes in serum cholesterol and the simultaneous changes in osteocalcin (r = 0.081, P = 0.140) and CTX (r = 0.042, P = 0.441) were statistically insignificant. Thus, our results suggest that the weak associations between spine BMD and serum cholesterol can be explained by the fact that both variables are simultaneously affected by estrogen deficiency rather than by a direct influence of serum cholesterol on osteoblast function.

The purpose of the study was to investigate the influence of preactivation, wall tension and geometry on the reactivity of porcine coronary arteries to nifedipine and extracellular Ca(2+) in vitro. Porcine large coronary arteries were mounted as ring and cylindrical preparations and studied by wire- and balloon-based techniques. The sensitivity and maximal responses to nifedipine were more pronounced in 25 mM K(+) compared to 10 microM prostaglandin F(2alpha)-contracted preparations. Vascular sensitivity to nifedipine and Ca(2+) was enhanced under isometric compared to isobaric conditions. Under isometric conditions in the presence of 25 mM K(+), coronary rings were more sensitive to nifedipine, but less sensitive to Ca(2+) compared to cylindrical segments. In cylindrical segments, circumferential and axial tension increases augmented the extracellular Ca(2+)-dependent spontaneous resting tone and the sensitivity to extracellular Ca(2+). Coronary rings showed no resting tone at various resting tensions. These results suggest that preactivation, wall tension and vessel geometry are important determinants of Ca(2+)-influxes via nifedipine-sensitive voltage-gated Ca(2+) channels. Furthermore, axial wall tension appears to be a modulator of nifedipine-insensitive transmembrane Ca(2+)-influx that may play a role for the tone and reactivity in large coronary arteries.