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Fibrous dysplasia (FD) is a rare bone disease caused by postzygotic somatic activating mutations in the GNAS gene, which lead to constitutive activation of adenylyl cyclase, and elevated levels of cyclic AMP, which act on downstream signaling pathways, and cause normal bone to be replaced with fibrous tissue and abnormal (woven) bone. The bone disease may occur in one bone (monostotic), multiple bones (polyostotic), or in combination with hyperfunctioning endocrinopathies and hyperpigmented skin lesions (in the setting of McCune-Albright Syndrome). FD is common in the craniofacial skeleton, causing significant dysmorphic features, bone pain, and dental anomalies. This review summarizes the pathophysiology, clinical findings and treatment of FD, with an emphasis on the craniofacial and oral manifestations of the disease.

Fibrous dysplasia of bone (FD) is a mosaic disease caused by mutations in GNAS. Constitutive activation of the a-subunit of the G s stimulatory protein (Gas) leads to dysregulated proliferation of bone marrow stromal cells (BMSCs), generating expansile lesions of fibrotic tissue and abnormal bone. Local bone remodeling regulation by BMSCs is also altered, and FD tissue is characterized by abundant osteoclast-like cells that may be essential for lesion expansion. Animal models show local expression of RANKL in bone lesions, and treatment with the RANKL neutralizing antibody denosumab decreased lesion expansion rate in a patient with aggressive FD. However, the role of RANKL/osteoprotegerin (OPG) in FD pathophysiology is not yet understood. We measured serum levels of RANKL, OPG, and inactive RANKL-OPG complexes in FD patients of known disease burden and in healthy volunteers (HVs). RANK, RANKL, and Ki67 immunohistochemistry were assessed in FD tissue. Cultured FD and HV BMSCs were stimulated with prostaglandin E 2 (PGE 2 ) and 1,25 vitamin D 3 to increase RANKL expression, and media levels of RANKL and OPG were measured. Osteoclastogenic induction by FD or HV BMSCs was assessed in co-cultures with HV peripheral monocytes. FD patients showed a 16fold increase in serum RANKL compared to HVs. OPG was moderately increased (24%), although RANKL/OPG ratio was 12-fold higher in FD patients than in HVs. These measurements were positively correlated with the skeletal burden score (SBS), a validated marker of overall FD burden. No differences in serum inactive RANKL-OPG complexes were observed. In FD tissue, RANKLþ and Ki67þ fibroblastic cells were observed near RANKþ osteoclasts. High levels of RANKL were released by FD BMSCs cultures, but were undetectable in HV cultures. FD BMSC released less OPG than HV BMSCs. FD, but not HV BMSCs, induced osteoclastogenesis in monocyte co-cultures, which was prevented by denosumab addition. These data are consistent with the role of RANKL as a driver in FD-induced osteoclastogenesis.

Background The mainstay of treatment for craniofacial fibrous dysplasia is surgical; however, optimal indications and techniques are poorly understood, particularly in polyostotic disease and McCune-Albright syndrome. This study investigated surgical indications and risk factors for recurrence in a large cohort. Methods One hundred thirty-three craniofacial fibrous dysplasia subjects in a natural history study were evaluated. Radiographic studies, operative reports, and clinical records were reviewed. Results Thirty-six subjects underwent 103 craniofacial procedures (mean, 2.8 operations per subject), with 13.5 ± 10.5-year follow-up (range, 0 to 39 years). The most common indication was craniofacial deformity (n = 61 operations), including 36 initial operations (59 percent) and 26 reoperations (41 percent). Mean time to reoperation was 3.4 ± 3.2 years (range, 0.3 to 13.3 years). Re-growth occurred after 42 operations (68 percent), and was more frequent after operations in subjects with McCune-Albright syndrome growth hormone excess [22 of 25 operations (88 percent)] than without growth hormone excess [15 of 36 operations (58 percent); p = 0.02]. Of 11 subjects with growth hormone excess, nine (82 percent) were undiagnosed at the time of their initial operation. Regrowth was more frequent after debulking procedures [31 of 38 (82 percent)] than after more aggressive reconstructions [nine of 20 (45 percent); p = 0.007]. Eleven subjects underwent treatment for aneurysmal bone cysts, with recurrence in one subject. Eleven subjects underwent biopsies and none had complications or regrowth. Conclusions Craniofacial fibrous dysplasia regrowth and reoperation are common, particularly after debulking procedures. Outcomes are favorable for aneurysmal bone cysts and biopsies. McCune-Albright syndrome growth hormone excess is a risk factor for regrowth, and may be underdiagnosed in surgical patients. Surgeons should be aware of appropriate screening for endocrinopathies in fibrous dysplasia. These findings highlight the importance of a multidisciplinary approach to craniofacial fibrous dysplasia, and individualized care with long-term follow-up. CLINICAL QUESTION/LEVEL OF EVIDENCE Therapeutic, IV.

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Purpose Osteonecrosis of the jaw (ONJ) is an established side effect of intravenous bisphosphonates and other anti-resorptive medications. Although bisphosphonates are frequently prescribed for patients with the skeletal disorder fibrous dysplasia (FD), there are no reports of ONJ in this population. This has led some to conclude that FD patients are at low risk for the development of bisphosphonate-related ONJ. Patients and Methods Patients were evaluated as part of a longstanding FD natural history study at the NIH. Results Out of 76 FD patients who were treated with bisphosphonates, four developed ONJ (5.4%). Three patients developed ONJ in areas of FD bone, and one in an area of normal bone. All four patients had features known to be associated with ONJ in the general population, including long-term, high dose, intravenous bisphosphonate treatment, periodontal and endodontic infections, and dentoalveolar surgical procedures. Conclusions These cases establish ONJ as a potential complication of bisphosphonate treatment in patients with FD. The presence of established risk factors for ONJ in this group of FD patients suggests that high risk individuals may be identified prior to the development of ONJ. Clinicians should use caution in prescribing bisphosphonates to FD patients, and should do so only for established indications.

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