We synthesized a directed library of compounds to explore the structure-activity relationships of peroxisome proliferator-activated receptor δ (PPARδ) activation relative to mesenchymal stem cell (MSC) osteogenesis. Our scaffold used para-substituted cinnamic acids as a polar headgroup, a heteroatom and heterocycle core connecting units, and substituted phenyl groups for the lipophilic tail. Compounds were screened for their ability to increase osteogenesis in MSCs, and the most promising were examined for subunit specificity using a quantitative PPAR transactivation assay. Six compounds were selected for in vivo studies in an ovariectomized mouse model of human postmenopausal osteoporosis. Four compounds improved bone density in vivo, with two (12d and 31a) having activity comparable to that of GW0742, a well-studied PPARδ-selective agonist. 31a (2-methyl-4-[N-methyl-N-[5-methylene-4-methyl-2-[4-(trifluoromethyl)phenyl]thiazole]]aminocinnamic acid) had the highest selectivity for PPARδ compared to other subtypes, its selectivity far exceeding that of GW0742. Our results confirm that PPARδ is a new drug target for possible treatment of osteoporosis via in situ manipulation of MSCs.