The purpose of this randomized, double-masked, placebo-controlled study was to determine the efficacy and safety of risedronate in the prevention of vertebral fractures in postmenopausal women with established osteoporosis. The study was conducted at 80 study centers in Europe and Australia. Postmenopausal women (n = 1226) with two or more prevalent vertebral fractures received risedronate 2.5 or 5 mg/day or placebo; all subjects also received elemental calcium 1000 mg/day, and up to 500 IU/day vitamin D if baseline levels were low. The study duration was 3 years; however, the 2.5 mg group was discontinued by protocol amendment after 2 years. Lateral spinal radiographs were taken annually for assessment of vertebral fractures, and bone mineral density was measured by dual-energy X-ray absorptiometry at 6-month intervals. Risedronate 5 mg reduced the risk of new vertebral fractures by 49% over 3 years compared with control (p<0.001). A significant reduction of 61% was seen within the first year (p = 0.001). The fracture reduction with risedronate 2.5 mg was similar to that in the 5 mg group over 2 years. The risk of nonvertebral fractures was reduced by 33% compared with control over 3 years (p = 0.06). Risedronate significantly increased bone mineral density at the spine and hip within 6 months. The adverse-event profile of risedronate, including gastrointestinal adverse events, was similar to that of control. Risedronate 5 mg provides effective and well-tolerated therapy for severe postmenopausal osteoporosis, reducing the incidence of vertebral fractures and improving bone density in women with established disease.

A polarized human clonal intestinal cell line exhibiting mucus secretion (Cl.16E) was used to study the expression and function of vasoactive intestinal peptide (VIP) receptors in mucus-secreting cells. Cl.16E cells expressed one class of receptors with a KD of 0.13 nM and a capacity of 67 fmol/mg protein. Covalent labeling of receptors followed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis showed a receptor protein with a Mr of 63,000 in Cl.16E cells. VIP stimulated adenylate cyclase activity in membranes from Cl.16E cells with an ED50 of 0.06 nM. In conditions where carbachol stimulated mucin secretion from filter-grown Cl.16E cells, VIP, dibutyryl adenosine 3',5'-cyclic monophosphate (DbcAMP), or forskolin did not alter basal secretion. However, VIP strongly potentiated carbachol-induced mucin secretion, since carbachol alone and VIP plus carbachol induced a 1.6- and 3.6-fold increase of mucin secretion above basal, respectively. This potentiating effect of VIP was mimicked by DbcAMP or forskolin. It was observed for VIP concentrations in the 0.1-100 nM range (ED50, 2 nM). VIP elicited a dramatic increase of intracellular cAMP levels in filter-grown Cl.16E cells with a dose-response curve (ED50, 4 nM) very similar to that observed for the modulation of mucin secretion. These studies suggest that the clonal cell line Cl.16E may be an invaluable cellular model for evaluating the neurohormonal control of mucus secretion.

The human colonic epithelial cell line Cl.16E grows in culture as a polarized monolayer which differentiates at confluency into typical goblet cells secreting their mucin content into the culture medium. Polyclonal antibodies raised against these mucins were used in an ELISA to measure the amount of mucins secreted by the Cl.16E cells. Carbachol caused a transient and significant increase in mucus secretion with a maximal stimulation occurring at 30 min. A dose-dependent effect was found with a maximal stimulation with 10-3M carbachol. This effect was inhibited by atropine. These results indicate that the effects of carbachol are mediated by muscarinic receptors present on mucus-secreting epithelial cells.

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