The effects of parathyroid hormone, alendronate, or both in men with osteoporosis.

BACKGROUND: Because parathyroid hormone increases both bone formation and bone resorption, it is possible that combining parathyroid hormone with an antiresorptive agent will enhance its effect on bone mineral density. METHODS: We randomly assigned 83 men who were 46 to 85 years of age and had low bone density to receive alendronate (10 mg daily; 28 men), parathyroid hormone (40 microg subcutaneously daily; 27 men), or both (28 men). Alendronate therapy was given for 30 months; parathyroid hormone therapy was begun at month 6. The bone mineral density of the lumbar spine, proximal femur, radial shaft, and total body was measured every six months with the use of dual-energy x-ray absorptiometry. Trabecular bone mineral density of the lumbar spine was measured at base line and month 30 by means of quantitative computed tomography. Serum alkaline phosphatase levels were measured every six months. The primary end point was the rate of change in the bone mineral density at the posteroanterior spine. RESULTS: The bone mineral density at the lumbar spine increased significantly more in men treated with parathyroid hormone alone than in those in the other groups (P<0.001 for both comparisons). The bone mineral density at the femoral neck increased significantly more in the parathyroid hormone group than in the alendronate group (P<0.001) or the combination-therapy group (P=0.01). The bone mineral density of the lumbar spine increased significantly more in the combination-therapy group than in the alendronate group (P<0.001). At 12 months, changes in the serum alkaline phosphatase level were significantly greater in the parathyroid hormone group than in the alendronate group or the combination-therapy group (P<0.001 for both comparisons). CONCLUSIONS: Alendronate impairs the ability of parathyroid hormone to increase the bone mineral density at the lumbar spine and the femoral neck in men. This effect may be attributable to an attenuation of parathyroid hormone-induced stimulation of bone formation by alendronate.

Receptor-mediated adenylyl cyclase activation through XLalpha(s), the extra-large variant of the stimulatory G protein alpha-subunit.

XLalpha(s), the large variant of the stimulatory G protein alpha subunit (Gsalpha), is derived from GNAS1 through the use of an alternative first exon and promoter. Gs(alpha) and XLalpha(s) have distinct amino-terminal domains, but are identical over the carboxyl-terminal portion encoded by exons 2-13. XLalpha(s) can mimic some functions of Gs(alpha), including betagamma interaction and adenylyl cyclase stimulation. However, previous attempts to demonstrate coupling of XLalpha(s) to typically Gs-coupled receptors have not been successful. We now report the generation of murine cell lines that carry homozygous disruption of Gnas exon 2, and are therefore null for endogenous XLalpha(s) and Gs(alpha) (Gnas(E2-/E2-)). Gnas(E2-/E2-) cells transfected with plasmids encoding XLalpha(s) and different heptahelical receptors, including the beta2-adrenergic receptor and receptors for PTH, TSH, and CRF, showed agonist-mediated cAMP accumulation that was indistinguishable from that observed with cells transiently coexpressing Gs(alpha) and these receptors. Our findings thus indicate that XLalpha(s) is capable of functionally coupling to receptors that normally act via Gs(alpha).