{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T06:08:51Z","timestamp":1789711731145,"version":"4.0.1"},"reference-count":152,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T00:00:00Z","timestamp":1789689600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Chem."],"abstract":"<jats:p>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\u00a0year 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\u2013activity relationships, their preclinical pharmacology, and their progress through clinical evaluation. We pay particular attention to the failures (odanacatib, calcilytics, integrin antagonists, Src inhibitors) as well as the successes, because the lessons from attrition shape the chemistry choices that follow. We attempt to identify those chemistry-led strategies that have most reliably accelerated bench-to-bedside translation in bone disease, and those that have not.<\/jats:p>","DOI":"10.3389\/fchem.2026.1917991","type":"journal-article","created":{"date-parts":[[2026,9,18]],"date-time":"2026-09-18T05:36:16Z","timestamp":1789709776000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":0,"title":["Novel bioactive compounds in the treatment of osteoporosis: chemistry-driven discovery from preclinical validation to clinical translation"],"prefix":"10.3389","volume":"14","author":[{"given":"Honghui","family":"Fan","sequence":"first","affiliation":[{"name":"Department of Orthopedics, Shaoxing People\u2019s Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"School of Medicine, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Songtao","family":"Jin","sequence":"additional","affiliation":[{"name":"Department of Orthopedics, Shaoxing People\u2019s Hospital","place":["Shaoxing, Zhejiang, China"]},{"name":"School of Medicine, Shaoxing University","place":["Shaoxing, Zhejiang, China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2026,9,18]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","first-page":"40","DOI":"10.1016\/j.biocel.2008.06.010","article-title":"Potential therapeutic effects of curcumin, the anti-inflammatory agent, against neurodegenerative, cardiovascular, pulmonary, metabolic, autoimmune and neoplastic diseases","volume":"41","author":"Aggarwal","year":"2009","journal-title":"Int. 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