BMPs in bone regeneration: Less is more effective, a paradigm-shift

• This review recalls the history of BMP2 from its discovery to its clinical application.
• After more than 125 years BMP2 is still not fully understood: open questions and possibilities are highlighted.
• Antagonist-insensitive BMP2 or the interplay of BMP2 and mechano-biology could be future strategies to improve the efficacy and safety of this growth factor in clinical use.

Worldwide, the clinical application of BMP2 (bone morphogenetic protein 2) has helped an increasing number of patients achieve bone regeneration in a clinical area lacking simple solutions for difficult bone healing situations. In this review, the historical aspects and current critical clinical issues are summarized and positioned against new research findings on efficacy and function of BMP2. Knowledge concerning how the dose of this growth factor as well as its interaction with mechanical loading influences the efficacy of bone regeneration, might open possible future strategies in cases where bony bridging is unachievable so far. In conclusion, it is apparent that there is a substantial need for continued basic research to unravel the details of its function and the underlying signaling pathways involved, to make BMP2 even more relevant and safe in daily clinical use, even though this growth factor has been known for more than 125 years.