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Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Histomorphometry and CT of 51 paired iliac crest biopsy specimens from women treated with teriparatide revealed significant increases in cancellous bone volume, cancellous bone connectivity density, cancellous bone plate-like structure, and cortical thickness, and a reduction in marrow star volume. Introduction:We studied the ability of teriparatide (rDNA origin) injection , TPTD] to improve both cancellous and cortical bone in a subset of women enrolled in the Fracture Prevention Trial of postmenopausal women with osteoporosis after a mean treatment time of 19 months. This is the first report of a biopsy study after treatment with teriparatide having a sufficient number of paired biopsy samples to provide quantitative structural data. Methods: Fifty-one paired iliac crest bone biopsy specimens (placebo [n ϭ 19], 20 g teriparatide [n ϭ 18], and 40 g teriparatide [n ϭ 14]) were analyzed using both two-dimensional (2D) histomorphometry and three-dimensional (3D) microcomputed tomography (CT). Data for both teriparatide treatment groups were pooled for analysis. Results and Conclusions: By 2D histomorphometric analyses, teriparatide significantly increased cancellous bone volume (median percent change: teriparatide, 14%; placebo, Ϫ24%; p ϭ 0.001) and reduced marrow star volume (teriparatide, Ϫ16%; placebo, 112%; p ϭ 0.004). Teriparatide administration was not associated with osteomalacia or woven bone, and there were no significant changes in mineral appositional rate or wall thickness. By 3D cancellous and cortical bone structural analyses, teriparatide significantly decreased the cancellous structure model index (teriparatide, Ϫ12%; placebo, 7%; p ϭ 0.025), increased cancellous connectivity density (teriparatide, 19%; placebo, Ϫ14%; p ϭ 0.034), and increased cortical thickness (teriparatide, 22%; placebo, 3%; p ϭ 0.012). These data show that teriparatide treatment of postmenopausal women with osteoporosis significantly increased cancellous bone volume and connectivity, improved trabecular morphology with a shift toward a more plate-like structure, and increased cortical bone thickness. These changes in cancellous and cortical bone morphology should improve biomechanical competence and are consistent with the substantially reduced incidences of vertebral and nonvertebral fractures during administration of teriparatide.

In a recent study of women with postmenopausal osteoporosis, treatment with teriparatide for a median of 19 months increased bone mineral density and decreased the risk of vertebral and nonvertebral fractures. Using the same cohort, the current study evaluated the relationship between these therapeutic effects and the patient's baseline age, vertebral bone mineral density, and prevalent vertebral fractures. In women over 65 years of age, treatment resulted in a greater increase in vertebral bone mineral density than in younger women (treatment-byage interaction, p ‫؍‬ 0.037), but baseline age had no effect on the relative risk reduction for vertebral fractures (treatment-by-age interaction, p ‫؍‬ 0.558). In women receiving placebo (with calcium and vitamin D), there was an inverse relationship between baseline vertebral bone mineral density and vertebral fracture risk. When compared across bone mineral density tertiles, the effects of teriparatide on the relative risk for developing new vertebral fractures and increase in vertebral bone mineral density did not differ significantly (p ‫؍‬ 0.817 and p ‫؍‬ 0.615, respectively). Teriparatide treatment significantly decreased vertebral fracture risk in patients with a vertebral bone mineral density T score of less than -3.3 or a score between -2.1 and -3.3 (p < 0.001 and p ‫؍‬ 0.027, respectively) and showed a trend toward reduced fracture risk in the group with a T score greater than -2.1 (p ‫؍‬

This paper discusses multiple testing procedures in dose-response clinical trials with primary and secondary endpoints. A general gatekeeping framework for constructing multiple tests is proposed, which extends the Dunnett test [Journal of the American Statistical Association 1955; 50: 1096-1121] and Bonferroni-based gatekeeping tests developed by Dmitrienko et al. [Statistics in Medicine 2003; 22:2387-2400]. The proposed procedure accounts for the hierarchical structure of the testing problem; for example, it restricts testing of secondary endpoints to the doses for which the primary endpoint is significant. The multiple testing approach is illustrated using a dose-response clinical trial in patients with diabetes. Monte-Carlo simulations demonstrate that the proposed procedure provides a power advantage over the Bonferroni gatekeeping procedure. The power gain generally increases with increasing correlation among the endpoints, especially when all primary dose-control comparisons are significant.