Fibro-osseous lesions can be divided into three main categories: FD, cemento-ossifying fibroma (COF), and COD. Histopathologically, FD is characterized by irregularly shaped trabeculae of immature bone within a cellular fibrous stroma. The trabeculae are typically curvilinear, resembling Chinese characters, and lack osteoblastic rimming, which help clinicians easily differentiate FD from COF and COD. However, COF and COD are histologically similar; both are characterized by fibrovascular connective tissue containing mineralized products, such as immature woven bone, lamellar bone, and cementum-like particles. Peripheral osteoid or osteoblastic rimming is commonly observed in both lesions. However, COF exhibits less significant intralesional hemorrhage than does COD, and COD tends to exhibit “ginger root” bone trabeculae.

Few studies have described florid-type COD extending beyond the tooth-bearing area to the bilateral condyles. The rare presentation prompted us to consider familial gigantiform cementoma (FGC) as a differential diagnosis. FGC and COD exhibit overlapping histopathological features, necessitating clinical and radiographic evaluations for accurate diagnosis. According to the fifth edition of the World Health Organization classification for odontogenic and maxillofacial bone tumors [7], FGC typically develops in young patients (e.g., adolescents), leading to rapid expansion of all four jaw quadrants and ultimately resulting in facial deformities. FGC does not exhibit a predilection for sex or ethnicity. However, COD predominantly develops in middle-aged women; approximately 90% of all COD cases involve this population. Black women have the highest risk of COD, followed by East Asian and White women [8]. Similar to FGC, florid-type COD can be inherited or occur sporadically [9]. In our case, the lesion was confined to the mandible of a middle-aged woman with no family history of jawbone lesions. Furthermore, the lesion exhibited slow progression over decades, which differs from the rapid growth typically observed in FGC. Genetic analyses have revealed that FGC results from an autosomal dominant mutation in ANO5—a mutation that does not occur in familial COD, ossifying fibroma, or polyostotic FD [10].

COF is generally regarded as a neoplastic lesion with a well-demarcated margin separating it from normal bone [11]. Biopsy typically indicates a firm mass. Conversely, COD is characterized by fragile, fragmented tissue; patients with COD are susceptible to hemorrhage in the mixed radiographic stage, which is consistent with the clinical findings in our case. Syndromic ossifying fibroma (also called hyperparathyroidism-jaw tumor) frequently involves mutations in the tumor suppressor gene HRPT2 (known as CDC73) [12]. However, our patient had normal parathyroid function. Aggressive subtypes of ossifying fibroma—for example, psammomatoid ossifying fibroma and trabecular ossifying fibroma—predominantly develop in childhood and are classified as juvenile ossifying fibroma. Against the aforementioned background, a final diagnosis of florid-type COD with condylar involvement and multiple different calcification stages spreading the whole mandible was made in the present case.

Most patients with focal COD do not require biopsy or treatment. Few standard treatment protocols are available for extensive COD with limited surgical options. Nevertheless, many studies have highlighted the efficacy of denosumab in treating FD, giant cell bone tumors, and aneurysmal bone cysts [13,14,15]. The pathophysiology of FD involves the replacement of normal bone tissue with fibrous tissue resulting from GNAS mutations, which are exclusive to FD and can facilitate its differentiation from other fibro-osseous lesions such as COD and COF [16, 17]. The GNAS mutation results in the release of osteoblastic factors that promote the formation of immature osteoblasts. These osteoblasts release osteoclastic factors such as receptor activator of nuclear factor-κB ligand (RANKL), osteoprotegerin, macrophage colony-stimulating factor, and interleukin-6, which activate proinflammatory macrophages and osteoclast differentiation [18]. Denosumab, a human monoclonal antibody targeting RANKL, reduces osteoclastic activity and improves clinical outcomes in FD. However, COD has a distinct pathophysiology and is confined to the jawbone. The craniofacial bone originates from neural crest mesenchymal cells; various signaling pathways, such as the Wnt and bone morphogenic protein pathways, regulate the formation of craniofacial bone [19]. A study reported that COD is driven by mutations in genes involved in the Ras/mitogen-activated protein kinase pathway [20]. However, in the aforementioned study, only 28% of all patients with COD (5 of 18 patients) had these mutations.

Very few treatment options are available for extensive COD involving the entire mandible; moreover, only a limited number of articles have reported COD cases. In patients with bone lesions such as FD, aneurysmal bone cysts, and giant cell tumors, denosumab has yielded promising results, such as pain relief, tumor volume control, and bone lesion ossification [5, 21]. Although the pathophysiology varies across these bone diseases, blocking the RANKL pathway to modulate bone turnover appears to be beneficial. Denosumab is the only approved therapeutic agent for inoperable giant cell granulomas or adjunct in operable cases, as demonstrated in an open-label phase II trial [22]. Although few clinical trials have evaluated the efficacy of denosumab in treating FD and aneurysmal bone cysts, some case series have reported favorable outcomes with this agent [6, 23]. As an alternative treatment option in our case, denosumab facilitated mineralization of a large, destructive COD lesion. To the best of our knowledge, this is the first reported case of denosumab use in COD. Further studies are required to clarify the pathophysiology of COD and the potential of denosumab for clinical use.