Teriparatide, human PTH (1-34), a new therapy for osteoporosis, elicits markedly different skeletal responses depending on the treatment regimen. In order to understand potential mechanisms for this dichotomy, the present investigation utilized microarrays to delineate the genes and pathways that are regulated by intermittent (subcutaneous injection of 80 μg/kg/day) and continuous (subcutaneous infusion of 40 μg/kg/day by osmotic mini pump) PTH (1–34) for 1 week in 6-month-old female rats. The effect of each PTH regimen was confirmed by histomorphometric analysis of the proximal tibial metaphysis, and mRNA from the distal femoral metaphysis was analyzed using an Affymetrix microarray. Both PTH paradigms co-regulated 22 genes including known bone formation genes (i.e., collagens, osteocalcin, decorin, and osteonectin) and also uniquely modulated additional genes. Intermittent PTH regulated 19 additional genes while continuous treatment regulated 173 additional genes. This investigation details for the first time the broad profiling of the gene and pathway changes that occur in vivo following treatment of intermittent versus continuous PTH (1–34). These results extend previous observations of gene expression changes and reveal the in vivo regulation of BMP3 and multiple neuronal genes by PTH treatment. © 2005 Wiley-Liss, Inc.