Study of twice-weekly injections of Teriparatide by comparing efficacy with once-weekly injections in osteoporosis patients: the TWICE study.

A 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial (the TWICE study) conducted in Japanese primary osteoporosis patients with a high risk of fractures demonstrated that a 28.2-µg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-µg once-weekly regimen of teriparatide, while also improving safety. INTRODUCTION: While a 56.5-µg once-weekly regimen of teriparatide has high efficacy for osteoporosis, treatment continuation rates are low, with one of the major causes being adverse drug reactions such as nausea or vomiting. The TWICE study was therefore conducted to investigate whether a twice-weekly regimen with 28.2-µg teriparatide can provide comparable efficacy to the 56.5-µg once-weekly regimen while improving safety. METHODS: A 48-week, multicenter, randomized, double-blind, double-dummy, active-controlled, non-inferiority trial was conducted in Japan. Patients with primary osteoporosis aged ≥ 65 years at high risk of fractures (n = 553) were randomly allocated to the 28.2-µg twice-weekly group (n = 277) or the 56.5-µg once-weekly group (n = 276). The primary endpoint was the percentage change in lumbar spine (L2-L4) bone mineral density (BMD) at final follow-up. RESULTS: The percentage changes in lumbar spine (L2-L4) BMD at final follow-up in the 28.2-µg twice-weekly and 56.5-µg once-weekly groups were 7.3% and 5.9%, respectively; the difference (95% confidence interval [CI]) in percentage change was 1.3% (0.400-2.283%). Since the lower limit of the 95% CI was above the pre-specified non-inferiority margin (- 1.6%), non-inferiority of the 28.2-µg twice-weekly group was demonstrated. Adverse drug reactions were significantly less frequent in the 28.2-µg twice-weekly group (39.7% vs 56.2%; p < 0.01); the incidence of major adverse drug reactions was lower, and the number of subjects who discontinued due to adverse drug reactions was less in the 28.2-µg twice-weekly group. CONCLUSIONS: A 28.2-µg twice-weekly regimen of teriparatide can provide comparable efficacy to a 56.5-µg once-weekly regimen while improving safety. CLINICAL TRIAL REGISTRATION: JapicCTI-163477 .

Physical states of surface and core lipids in lipid emulsions and apolipoprotein binding to the emulsion surface.

Plasma triglyceride-rich lipoproteins vary in lipid composition during their metabolism. We investigated the effects of the lipid composition of emulsion particles, specifically those of cholesterol enrichment and core replacement (replacing core triglyceride with cholesteryl oleate), on the physical states of surface and core lipids. Steady-state and time-resolved fluorescence anisotropies were measured in lipid emulsions using 1,6-diphenylhexatriene to probe the core and 1,6-diphenylhexatriene analogues for the outer and inner hydrophobic portions of surface phospholipids. In the absence of cholesterol, core replacement had little effect on the surface rigidity, despite the large difference in core mobility. However, core replacement caused a marked increase in surface rigidity in the presence of cholesterol. Quenching experiments using the fluorescent cholesterol analogue, dehydroergosterol, indicated that core replacement allowed surface dehydroergosterol to redistribute from the inner to the outer regions in the emulsion surface. These results indicated that core replacement modulates the surface properties of the emulsion particles through the redistribution of cholesterol in the surface layers. Furthermore, core replacement significantly decreased the binding of apolipoprotein E to the emulsion surface, whereas the binding of apolipoprotein CII responded to the cholesterol enrichment. This binding behavior of exchangeable apolipoproteins may closely correlate with the location of surface cholesterol and the mobility of core lipids.