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The MAC forms a lytic pore in the membrane of target cells and is a key effector of the innate immune system. Excessive complement activation has been implicated in chronic inflammation, which is a well-established risk factor for increased fracture susceptibility. Although other components of the complement system have been linked to bone mass regulation, the role of C9 is unknown. The aim of the present study was to determine the role of C9 for bone health. To determine the role of circulating, mainly liver-derived, C9 in humans, we conducted Mendelian randomization (MR) using a single-SNP instrument and performed genetic colocalization analyses. Genetically predicted higher circulating C9 levels were causally associated with increased risk of forearm fractures and fractures at any bone site. Colocalization analyses supported these findings. Mechanistic studies were performed in mice. As expected, high C9 expression was observed in the liver, while the expression was low in cortical bone and no expression was observed in trabecular bone. Adult female mice with global C9 deletion (\n                    <jats:italic>C9<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    ) exhibited lower vertebral trabecular bone volume fraction due to a decreased trabecular number, but they were partly protected against ovariectomy-induced trabecular bone loss. No skeletal phenotype was observed in the femur or in male\n                    <jats:italic>C9<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    mice. In conclusion, high genetically determined circulating C9 is causally linked to increased fracture risk in humans. In mice, global inactivation of\n                    <jats:italic>C9<\/jats:italic>\n                    <jats:sup>\u2212\/\u2212<\/jats:sup>\n                    affects vertebral trabecular bone in a sex-specific and context-dependent manner.\n                  <\/jats:p>","DOI":"10.1007\/s00223-026-01515-9","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T08:28:09Z","timestamp":1775118489000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Role of Complement Component 9 in Bone Health: Causal Evidence in Humans and Mechanistic Studies in Mice"],"prefix":"10.1007","volume":"117","author":[{"given":"Claes","family":"Ohlsson","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anna E.","family":"T\u00f6rnqvist","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Karin H.","family":"Nilsson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maria","family":"Nethander","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jianyao","family":"Wu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lei","family":"Li","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antti","family":"Koskela","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7982-7438","authenticated-orcid":false,"given":"Sofia","family":"Mov\u00e9rare-Skrtic","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,2]]},"reference":[{"key":"1515_CR1","doi-asserted-by":"publisher","first-page":"53","DOI":"10.1016\/j.smim.2018.01.001","volume":"37","author":"Y Modinger","year":"2018","unstructured":"Modinger Y, Loffler B, Huber-Lang M, Ignatius A (2018) Complement involvement in bone homeostasis and bone disorders. 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