-Halogenated analogues of the anti-resorptive bisphosphonate risedronate (5, Ris) and its phosphonocarboxylate cognate (7, 3-PEHPC) were synthesized and compared with 5, 7, and the corresponding desoxy analogues in bone mineral affinity and mevalonate pathway inhibition assays. The Ris (5e−h) and 3-PEHPC (7e−h) analogues had decreased bone mineral affinity, confirming that the -OH group in 5and 7enhances bone affinity. The 5-halo-analogues potently inhibited farnesyl pyrophosphate synthase (FPPS) with IC50values from 16 (-F) to 340 (-Br) nM (5, 6 nM). In contrast, 7-halo-analogues were ineffective versus FPPS (IC50> 600 M), but inhibited Rab geranylgeranyl transferase (RGGT) (IC5016−35 M) similarly to 7itself (IC5024 M). The -F analogue 7ewas 1−2 times as active as 7in J774 cell viability and Rab11 prenylation inhibition assays. [ABSTRACT FROM AUTHOR]