Novel bioactive compounds in the treatment of osteoporosis: chemistry-driven discovery from preclinical validation to clinical translation
Abstract
Osteoporosis affects an estimated 200 million people worldwide. Fragility fractures of the hip, spine, and wrist carry high mortality and impose a heavy socioeconomic burden. Bisphosphonates, denosumab, selective estrogen receptor modulators (SERMs), teriparatide, abaloparatide, and the recent sclerostin antibody romosozumab have improved clinical outcomes, but unmet needs remain. Long-term antiresorptive use is complicated by atypical femoral fractures and osteonecrosis of the jaw; denosumab discontinuation causes rebound bone loss; romosozumab carries a cardiovascular caution. Persistence on therapy beyond 1 year is low, and no oral osteoanabolic agent has reached the clinic. Against this background, medicinal chemistry is producing a wave of next-line compounds. These include rationally designed small molecules and peptidomimetics targeting the Wnt pathway, calcium-sensing receptor antagonists (calcilytics) intended to mimic pulsatile parathyroid hormone, refined cathepsin K inhibitors, modulators of activin and myostatin signaling, and bone-targeted nanomedicines. Plant-derived scaffolds with anti-osteoporotic activity, particularly icariin, icaritin, genistein, naringin, resveratrol, curcumin, oleanolic acid, psoralen, and berberine, are being optimized chemically to address poor bioavailability. Senolytic combinations and PROTAC-based degraders represent newer modes of action. This review examines the chemistry behind these compounds, their structure-activity…
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