<p>This mini-review provides a critical evaluation of calcium-based metal–organic frameworks (Ca-MOFs) and heterometallic Ca/Sr-MOFs, emphasizing their potential in therapeutic delivery and their role in bone regeneration, mediated by multifaceted modulation of bone biology and remodeling. Although these frameworks display favorable properties such as structural versatility, low cytotoxicity, and intrinsic bioactivity, their actual translational potential has not been sufficiently clarified. Here, we highlight how Ca- and Ca/Sr-MOFs differ from other bioactive MOFs: in vitro studies consistently demonstrate their ability to stimulate mineralization and support drug release, yet convincing in vivo validation remains scarce. By analyzing synthetic strategies, stability and solubility profiles, as well as the role of specific ligands with osteogenic relevance, this review identifies both the strengths and the unresolved challenges of these systems. The unique contribution of this work lies in distinguishing genuine opportunities for Ca/Sr-MOFs in bone tissue engineering from overstated claims, thereby outlining realistic directions for future research toward clinically relevant applications.</p> Graphical abstract <p></p>