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However, recombinant human BMPs (rhBMPs) exhibit large inter-individual variations in local bone formation during clinical spinal fusion. Smurf1 ubiquitinates BMP downstream molecules for degradation. Here, we classify age-related osteoporosis based on distinct intraosseous BMP-2 levels and Smurf1 activity. One major subgroup with a normal BMP-2 level and elevated Smurf1 activity (BMP-2<jats:sup>n<\/jats:sup>\/Smurf1<jats:sup>e<\/jats:sup>) shows poor response to rhBMP-2 during spinal fusion, when compared to another major subgroup with a decreased BMP-2 level and normal Smurf1 activity (BMP-2<jats:sup>d<\/jats:sup>\/Smurf1<jats:sup>n<\/jats:sup>). We screen a chalcone derivative, i.e., 2-(4-cinnamoylphenoxy)acetic acid, which effectively inhibits Smurf1 activity and increases BMP signaling. For BMP-2<jats:sup>n<\/jats:sup>\/Smurf1<jats:sup>e<\/jats:sup> mice, the chalcone derivative enhances local bone formation during spinal fusion. After conjugating to an osteoblast-targeting and penetrating oligopeptide (DSS)<jats:sub>6<\/jats:sub>, the chalcone derivative promotes systemic bone formation in BMP-2<jats:sup>n<\/jats:sup>\/Smurf1<jats:sup>e<\/jats:sup> mice. 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