Age-related osteopenia is characterized by a negative balance between bone resorption and formation. The anti-osteoporotic drug strontium ranelate was found to reduce bone resorption and to promote bone formation. Here, we investigated the implication of the calcium-sensing receptor (CaSR) in the response to strontium ranelate using osteoblasts from CaSR knockout [CaSR−/−] and wild-type [CaSR+/+] mice. We showed that calcium and strontium ranelates increased cell replication in [CaSR−/−] and [CaSR+/+] osteoblasts. Strontium ranelate rapidly increased ERK1/2 phosphorylation in [CaSR+/+] but not in [CaSR−/−] osteoblasts, indicating that strontium ranelate can act independent of the CaSR/ERK1/2 cascade to promote osteoblast replication. We also showed that strontium ranelate prevented cell apoptosis induced by serum deprivation or the pro-inflammatory cytokines IL-1β and TNF-α in [CaSR−/−] and [CaSR+/+] osteoblasts, indicating that CaSR is not the only receptor involved in the protective effect of strontium ranelate on osteoblast apoptosis. Strontium ranelate activated the Akt pro-survival pathway in [CaSR−/−] and [CaSR+/+] osteoblasts, and pharmacological inhibition of Akt abrogated the anti-apoptotic effect of strontium ranelate. Furthermore, both the proliferative and anti-apoptotic effects of strontium ranelate in [CaSR−/−] and [CaSR+/+] osteoblasts were abrogated by selective inhibition of COX-2. The results provide genetic and biochemical evidence that the effects of strontium ranelate on osteoblast replication and survival involve ERK1/2 and Akt signalling and PGE2 production, independent of CaSR expression. The finding that CaSR-dependent and CaSR-independent pathways mediate the beneficial effects of strontium ranelate on osteoblasts, provides novel insight into the mechanism of action of this anti-osteoporotic agent on osteoblastogenesis.