Vitamin D Attenuates Fibrotic Properties of Fibrous Dysplasia-Derived Cells for the Transit towards Osteocytic Phenotype.

Fibrous dysplasia (FD) poses a therapeutic challenge due to the dysregulated extracellular matrix (ECM) accumulation within affected bone tissues. In this study, we investigate the therapeutic potential of 1,25-dihydroxyvitamin D3 (1,25(OH)2D3) in managing FD by examining its effects on FD-derived cells in vitro. Our findings demonstrate that 1,25(OH)2D3 treatment attenuates the pro-fibrotic phenotype of FD-derived cells by suppressing the expression of key pro-fibrotic markers and inhibiting cell proliferation and migration. Moreover, 1,25(OH)2D3 enhances mineralization by attenuating pre-osteoblastic cellular hyperactivity and promoting maturation towards an osteocytic phenotype. These results offer valuable insights into potential treatments for FD, highlighting the role of 1,25(OH)2D3 in modulating the pathological properties of FD-derived cells.

RANKL inhibition reduces lesional cellularity and Gαs variant expression and enables osteogenic maturation in fibrous dysplasia.

Fibrous dysplasia (FD) is a rare, disabling skeletal disease for which there are no established treatments. Growing evidence supports inhibiting the osteoclastogenic factor receptor activator of nuclear kappa-B ligand (RANKL) as a potential treatment strategy. In this study, we investigated the mechanisms underlying RANKL inhibition in FD tissue and its likely indirect effects on osteoprogenitors by evaluating human FD tissue pre- and post-treatment in a phase 2 clinical trial of denosumab (NCT03571191) and in murine in vivo and ex vivo preclinical models. Histological analysis of human and mouse tissue demonstrated increased osteogenic maturation, reduced cellularity, and reduced expression of the pathogenic Gαs variant in FD lesions after RANKL inhibition. RNA sequencing of human and mouse tissue supported these findings. The interaction between osteoclasts and mutant osteoprogenitors was further assessed in an ex vivo lesion model, which indicated that the proliferation of abnormal FD osteoprogenitors was dependent on osteoclasts. The results from this study demonstrated that, in addition to its expected antiosteoclastic effect, denosumab reduces FD lesion activity by decreasing FD cell proliferation and increasing osteogenic maturation, leading to increased bone formation within lesions. These findings highlight the unappreciated role of cellular crosstalk between osteoclasts and preosteoblasts/osteoblasts as a driver of FD pathology and demonstrate a novel mechanism of action of denosumab in the treatment of bone disease.TRIAL REGISTRATION: ClinicalTrials.gov NCT03571191.

Efficacy of antiresorptive agents in fibrous dysplasia and McCune Albright syndrome, a systematic review and meta-analysis.

Fibrous dysplasia (FD) is a rare skeletal disorder in which normal bone is replaced by a fibro-osseous tissue, resulting in possible deformities and fractures. The aim of this systematic review and meta-analysis was to synthesize the available evidence on the use of antiresorptive drugs in FD in terms of changes in bone turnover markers (BTMs), bone mineral density (BMD), and reducing pain. Three databases were searched in October 2022, with an update in July 2023. Of the 1037 studies identified, 21 were retained after eligibility assessment. A random-effects model was used to calculate global effect size and the corresponding standard error. Pamidronate and Denosumab were the most reported drugs in a total of 374 patients assessed. The initiation of treatments was accompanied by an average reduction of 40.5% [CI95% -51.6, -29.3] in the bone resorption parameters, and 22.0% [CI95% -31.9, -12.1] in the parameters of bone formation after 6-12 months. BMD was increased in both FD lesions and in the unaffected skeleton. Pain was reduced by 32.7% [CI95% -52.7, -12.6] after 6-12 months of treatment, and by 44.5% [CI95% -65.3, -23.6] after a mean 41.2 months of follow-up. The variation in pain was highly correlated to variation in bone resorption (R2 = 0.08, p < 0.0001) and formation parameters (R2 = 0.17, p < 0.0001). This study supports the overall efficacy of antiresorptive therapies in terms of reducing bone remodeling, improving bone density, and pain in FD.

Denosumab Use in Adults With Fibrous Dysplasia: Case Reports and Review of the Literature.

OBJECTIVE: In fibrous dysplasia (FD) of the bone, a gain-of-function mutation in the G-nucleotide binding protein alpha subunit results in constitutively active cyclic adenosine monophosphate. Downstream effects include formation of disorganized cortex and bone marrow fibrosis. Patients with FD experience bone pain and are at risk of fracture. Bisphosphonates are traditionally used to manage pain with mixed results. We sought to report denosumab use in patients with FD at our institution and summarized the existing literature on denosumab use in FD. METHODS: We retrospectively identified patients with FD who were treated with denosumab at our institution, describing patient characteristics and outcomes. We reviewed the existing literature on denosumab use in patients with FD. RESULTS: Patient 1 was diagnosed with FD at the age of 17 years and took bisphosphonates with initial improvement in pain. Pain eventually worsened; therefore, she received 4 doses of denosumab. Patient 2 was diagnosed with FD after a fall and was treated with bisphosphonates, reporting some initial improvement in bone pain. A few years later, the pain recurred, and he received 3 doses of denosumab. Both patients tolerated denosumab well but experienced no improvement in pain. On literature review, although some serious side effects were noted, patients experienced a decline in bone turnover markers, and most reported improvement in bone pain with denosumab. CONCLUSION: Denosumab is a promising therapy for managing symptoms of FD. Further studies are needed to determine the optimal dose and duration of treatment. Its long-term effect on FD lesions remains unclear.

Effects of zoledronic acid therapy in fibrous dysplasia of bone: a single-center experience.

Objective: Fibrous dysplasia (FD) is a rare bone disorder that can involve any part of the skeleton, leading to bone pain, deformities, and fractures. Treatment with intravenous bisphosphonates has been used with variable results. Therefore, we aimed to evaluate the effects of zoledronic acid (ZA) therapy in patients with monostotic or polyostotic FD. Methods: The medical records of thirteen patients with FD evaluated between 2015 and 2020 were retrospectively analyzed. In the subgroup of patients treated with ZA (n = 7), data on pain relief, changes in bone turnover markers (BTMs), and adverse events following ZA infusions were retrieved. Moreover, radiological changes in response to treatment were recorded in patients who underwent radiological follow-up. Results: Of the patients, 5 (38%) presented with monostotic whereas 8 (62%) had polyostotic FD. Bone pain was a common finding (69%), and most patients (62%) exhibited elevated baseline BTMs. Partial or complete pain relief was reported in 6 of 7 patients treated with ZA. BTMs, especially C-telopeptide of type I collagen (CTX), significantly decreased after therapy (change rate: -61.8% [IQR -71, -60%]), and median CTX levels were significantly lower than at baseline (0.296 ng/mL [0.216, 0.298] vs. 0.742 ng/mL [0.549, 0.907], respectively; P = 0.04). No radiological improvement was observed in cases with radiological follow-up (n = 3). No serious adverse effects of ZA were reported. Conclusion: ZA treatment was well tolerated and provided beneficial effects in relieving bone pain and reducing BTMs, especially CTX. Our data reinforce the role of ZA in the treatment of FD-related bone pain.

Inhibition of IL-6 in the treatment of fibrous dysplasia of bone: The randomized double-blind placebo-controlled TOCIDYS trial.

Increased interleukin-6 (IL-6) has been observed in the bone tissue of fibrous dysplasia of bone/McCune-Albright syndrome (FD/MAS) and is possibly involved in the increased bone destruction and bone pain characterizing this disease. The TOCIDYS trial was a randomized, placebo-controlled, 1 year, cross-over, proof-of-concept trial, conducted in patients not responding to bisphosphonates, using monthly intra-venous tocilizumab (a monoclonal antibody to the IL-6 receptor) at 8 mg/kg or a matching placebo for 6 months. Over the following 6 months, they received tocilizumab if they first had placebo, and vice-versa. We measured change in serum CTX after 6 months of treatment, compared with baseline (primary endpoint). Other endpoints were the change in bone pain, change in P1NP, bone alkaline phosphatase, osteocalcin and ICTP, and variation of quality of life. The analysis relied on ANOVA, with sequence of treatment, period and treatment as factors and accounting for a potential carry-over effect. We have randomized 8 patients with FD/MAS in each sequence who all completed the first 6 months treatment period. During the second 6 months period, 3 patients stopped therapy, so the efficacy analysis set included 13 patients. We observed no significant change in serum CTX and other biochemical markers of bone turnover between the tocilizumab and placebo groups. There was no significant change in the level of bone pain on tocilizumab, although 3 patients had a sharp decrease in pain while on active drug, with progressive relapse on placebo for 2 of them, but with some degree of improvement in a few patients while on placebo. The SF-36 quality of life scale was not significantly changed. We conclude that tocilizumab does not decrease bone turnover in FD/MAS when administered in patients who fail to respond to bisphosphonates. Tocilizumab does not reduce bone pain in most patients, but a substantial effect in a subset cannot be ruled out in this trial powered for markers but not for pain.

Treatment of fibrous dysplasia: focus on denosumab.

INTRODUCTION: Fibrous dysplasia (FD) is a rare bone disease that is associated with various endocrine conditions, such as McCune Albright syndrome. It manifests as abnormal osteolysis, multiple fractures, or deformities that are reported during disease course. The receptor activator of nuclear factor-kappa B (RANK)/RANK ligand (RANKL) pathway is upregulated in FD and can be targeted with denosumab, a blocking monoclonal antibody. AREAS COVERED: Preclinical and clinical data on the scientific rationale for using denosumab in FD and on the efficacy and safety of this therapy for this condition have been reviewed, in addition to other therapies. EXPERT OPINION: Denosumab is a potential therapeutic agent against FD. A combined synergic approach involving theranostics might increase its therapeutic potential.

RANKL inhibition halts lesion progression and promotes bone remineralization in mice with fibrous dysplasia.

Fibrous dysplasia (FD) is a rare bone disease caused by GNAS mutation in skeletal stem cells, typically originating from and worsening in childhood. Till now, no cure for FD exists despite the well-recognized etiology. Studies have demonstrated that osteoclastogenesis hyperactivity is caused by elevated RANKL expression, making RANKL inhibition a potential therapy. Although a human monoclonal anti-RANKL antibody, denosumab, has been used in FD patients, the effects and mechanisms of RANKL inhibition for FD treatment require assessment. Denosumab is expensive and can only be injected. Therefore, formulating an oral-administered, cost-effective medicine is encouraged. In the current study, we evaluated the effects of a small-molecule RANKL inhibitor, AS2676293, on a transgenic FD mouse model. AS2676293 effectively suppressed osteoclastogenesis and halted FD progression. The pre-existing bone defects were primarily replaced by newly formed mineralized bone after two weeks of AS2676293 administration. The potent RANKL inhibitory effect and easier route of delivery make AS2676293 a promising target therapy of FD. Results from our study suggested that RANKL inhibition is effective in halting FD progression and promoting bone remineralization, which could benefit the patients with early onset of FD.

Successful treatment with denosumab for pelvic fibrous dysplasia: A case report and review of the literature.

RATIONALE: Fibrous dysplasia is a rare disorder that results in fractures, pain, and disability and can affect any bone in the body. The treatment of symptomatic fibrous dysplasia is determined based on the affected bones. Although some lesions are often too extensive for surgical procedures, there are currently no effective or recommended medical treatments available for them. PATIENT CONCERNS: A 27-year-old woman developed right buttock pain and was diagnosed with a bone tumor in the right ilium. Clinical images revealed an expansive osteolytic lesion with thinning of the cortex and cystic change from the acetabulum to the sacroiliac joint. DIAGNOSIS: An incisional biopsy was performed, and the lesion was diagnosed as cystic fibrous dysplasia. Occasional osteoclast-like giant cells and woven bone were observed. The patient had no evidence of polyostotic lesions or findings of McCune-Albright syndrome. Biochemical blood test results showed no obvious abnormal values, except for an increase in serum tartrate-resistant acid phosphatase 5b to 459 mU/dL. INTERVENTIONS: Since surgical treatment appeared to be challenging, she was treated with denosumab with decreased dose-intensity schedules. OUTCOMES: The administration of denosumab caused osteosclerosis within the lesion, resulting in the elimination of bone pain. The patient received denosumab treatment for 18 months. Pain relief and lesion radiodensity were maintained for 9 months after denosumab discontinuation. The serum level of tartrate-resistant acid phosphatase 5b was measured to monitor the response to denosumab, which was suppressed during denosumab treatment. LESSONS: We described successful denosumab treatment in a patient with cystic fibrous dysplasia (FD) who maintained efficacy for 9 months after treatment. Although the use of denosumab in fibrous dysplasia is currently off-label, our experience with this patient supports the potential of denosumab therapy for patients for whom surgical treatment is challenging.

[DRUG CORRECTION OF THE STRUCTURAL AND FUNCTIONAL STATUS OF BONE TISSUE IN PATIENTS WITH FIBROUS DYSPLASIA].

In a significant number of patients with fibrous dysplasia, among various orthopedic pathologies, bone pain, its deformation and pathological fractures, disorders of bone tissue and its metabolism are leading. Issues of correction of clinical and orthopedic manifestations of the disease and changes in the structural and functional state of bone tissue are insufficiently studied and need improvement The purpose of the study is to improve drug antiosteoporotic therapy for patients with fibrous dysplasia in order to reduce their pain, improve the condition of bone tissue and its metabolism. In the department of pediatric traumatology and orthopedics of the SI "ITO NAMSU" in the period from 2015 to 2020, 16 patients with FD were treated (with polyosal form - 6 patients, with Albright syndrome - 5, with Campanacci syndrome - 5), who have been used drug antiosteoporotic therapy, in particular with the use of antiresorbents (pamidronic acid preparations). The age of patients ranged from 6 to 28 years, 13 patients were children. Qualitative and quantitative assessment of the therapy results and reduction of pain was performed by applying the "VAS" scale, improving the condition of bone tissue and its metabolism by studying the mineral density of bone tissue and markers of bone metabolism. The article presents the rationale, general principles and features of antiosteoporotic therapy; indications and contraindications to it; calculations of doses and schemes of application of these or those drugs, including from group of bisphosphonates at a fibrous dysplasia. The presented drug therapy has been successfully tested in 16 patients with fibrous dysplasia. The effectiveness of the treatment is confirmed by the reduction or elimination of pain, stopping the progression of pathological bone disease of the lower limbs, improving structural condition of bone tissue and its metabolism. The results of drug therapy in patients with fibrous dysplasia indicates its effectiveness and appropriateness of use, which is shown by the relief of pain, improving the structural condition of bone tissue and its metabolism.

Safety of therapy with and withdrawal from denosumab in fibrous dysplasia and McCune-Albright syndrome: an observational study.

Denosumab (Dmab) treatment can benefit patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS) by suppressing the receptor activator of nuclear factor κB ligand (RANKL)-mediated increased bone resorption. However, limited data of two pediatric cases indicate that a rebound phenomenon may occur after withdrawal. Therefore we studied the safety of Dmab discontinuation in FD/MAS. Thirty-seven patients using Dmab, mostly after unsuccessful bisphosphonate (BP) treatment, were included. Health records were screened for pain scores, side effects, and bone turnover markers (BTMs) (calcium, alkaline phosphatase [ALP], procollagen 1 N-terminal propeptide [P1NP], and ß-crosslaps [B-CTX, also termed ß-C-terminal telopeptide]) during treatment, and for BTMs and clinical rebound effects after withdrawal. BTM levels after withdrawal were compared to pretreatment values. Data were calculated as median (interquartile range [IQR]). BTMs normalized in two-thirds of patients and pain scores decreased significantly during treatment (p = 0.002). One patient (2.7%) developed osteonecrosis of the jaw. Sixteen patients discontinued Dmab treatment after a median of 1.6 years (IQR 1.0 years) because of insufficient effect on pain (n = 10, 63%), side effects (n = 4, 25%), or other reasons (n = 4, 25%). Follow-up posttreatment was 3.2 (2.8) years, wherein no fractures, pain flares, or lesion progression occurred. Calcium remained normal in all but one patient, who had a mild asymptomatic hypercalcemia (2.73 mmol/L) 5 months after discontinuation. ALP passed pretreatment levels in five of 11 patients (46%), increased most after 6 months by 18 (43) U/L, and returned to baseline levels thereafter. P1NP exceeded pretreatment levels in four of nine patients (44%), CTX in eight of nine patients (89%). P1NP rose most after 3 months and stabilized thereafter. CTX showed the highest relative elevation. Patients with high pretreatment levels responding well to Dmab seemed to have the highest rebound. These results suggest beneficial effects of Dmab on pain and BTMs, and show a biochemical but asymptomatic rebound phenomenon after withdrawal in adults with FD/MAS, mainly in case of high pretreatment levels, good response, and multiple injections. Further studies on the safety of Dmab and withdrawal are needed and ongoing. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Denosumab for craniofacial fibrous dysplasia: duration of efficacy and post-treatment effects.

Denosumab has been advocated as a potential treatment for the rare skeletal disorder fibrous dysplasia (FD); however, there is limited data to support safety and efficacy, particularly after drug discontinuation. We report a case of successful treatment of aggressive craniofacial FD with denosumab, highlighting novel insights into the duration of efficacy, surrogate treatment markers, and discontinuation effects. A 13-year-old girl presented with persistent pain and expansion of a maxillary FD lesion, which was not responsive to repeated surgical procedures or bisphosphonates. Pre-treatment biopsy showed high RANKL expression and localization with proliferation markers. Denosumab therapy was associated with improved pain, decreased bone turnover markers, and increased lesion density on computed tomography scan. During 3.5 years of treatment, the patient developed increased non-lesional bone density, and after denosumab discontinuation, she developed hypercalcemia managed with bisphosphonates. Pain relief and lesion stability continued for 2 years following treatment, and symptom recurrence coincided with increased bone turnover markers and decreased lesion density back to pre-treatment levels. This case highlights the importance of considering the duration of efficacy when treating patients with FD and other nonresectable skeletal neoplasms that require long-term management.

Denosumab Treatment for Giant Cell Tumors, Aneurysmal Bone Cysts, and Fibrous Dysplasia-Risks and Benefits.

PURPOSE OF REVIEW: This review summarizes current understanding of the role of denosumab, an inhibitor of receptor activator of nuclear kappa-B ligand (RANKL), in the management of 3 skeletal neoplasms: giant cell tumors, aneurysmal bone cysts, and fibrous dysplasia. RECENT FINDINGS: A growing body of literature supports denosumab use in giant cell tumors, a neoplasm in which RANKL plays a clear pathogenic role. Comparatively less data is available in aneurysmal bone cysts and fibrous dysplasia; however, the pathogenic similarity of these disorders to giant cell tumors, as well as encouraging preliminary data, suggests denosumab may be useful. Denosumab's inhibitory effects on bone turnover are fully reversible after drug discontinuation. This raises important unanswered questions for clinical management, including potential risks of tumor recurrence and bone turnover rebound. Denosumab is a promising potential treatment for skeletal neoplasms. However, its clinical use is impacted by ongoing safety concerns related to postdiscontinuation rebound, particularly in children. There is a critical need to understand denosumab treatment and discontinuation effects on tumor recurrence and to develop strategies for long-term treatment in patients who cannot be managed surgically.

Bisphosphonates for the treatment of fibrous dysplasia of bone.

INTRODUCTION: Fibrous dysplasia of bone (FD) is a rare congenital bone disease, due to a somatic mutation of GNAS. This mutation results in a defect of osteoblast differentiation and mineralization and also an increase in bone resorption by large active osteoclasts. Bone pain is present in half of patients and is the main determinant of quality of life of patients with FD. Bisphosphonates are known to reduce bone pain and reduce the risk of fracture in patients with bone metastases or Paget's disease. Bisphosphonates may have similar effects in FD. In this article, we have reviewed the therapeutic potential of bisphosphonates to reduce bone pain due to FD, improve bone strength and reduce the occurrence of fracture. MATERIAL AND METHODS: We have reviewed 234 articles examining the effect of bisphosphonates on FD/McCune Albright Syndrome with no date limit, in PubMed and selected the articles with highest quality of methodology. RESULTS: Pamidronate therapy significantly decreased bone pain and bone resorption (urinary NTX, urinary and serum CTX). Pamidronate may improve radiological lesions of FD patients (filling of osteolytic lesion and/or cortical thickening). This data with intravenous pamidronate, however, has been obtained from observational studies and no randomized controlled trial is available. Randomized placebo-controlled trials of oral bisphosphonates (alendronate or risedronate) have failed to demonstrate a significant decrease in bone pain over placebo. Several studies including one randomized controlled trial have shown an increase in bone mineral density (BMD) at FD sites with oral and intravenous bisphosphonate treatment. No effect on occurrence of fracture has been reported. CONCLUSION: In conclusion, intravenous bisphosphonates may be proposed to treat persistent, moderate to severe bone pain of FD, e.g., according to the guidelines from the FD/MAS International Consortium. Oral bisphosphonates should not be used in this indication.

Zoledronic Acid in a Mouse Model of Human Fibrous Dysplasia: Ineffectiveness on Tissue Pathology, Formation of "Giant Osteoclasts" and Pathogenetic Implications.

We compared the effects of a nitrogen-containing bisphosphonate (N-BP), zoledronic acid (ZA), and an anti-mouse RANKL antibody (anti-mRANKL Ab) on the bone tissue pathology of a transgenic mouse model of human fibrous dysplasia (FD). For comparison, we also reviewed the histological samples of a child with McCune-Albright syndrome (MAS) treated with Pamidronate for 3 years. EF1α-GsαR201C mice with FD-like lesions in the tail vertebrae were treated with either 0.2 mg/kg of ZA at day 0, 7, and 14 or with 300 µg/mouse of anti-mRANKL Ab at day 0 and 21. All mice were monitored by Faxitron and histological analysis was performed at day 42. ZA did not affect the progression of the radiographic phenotype in EF1α-GsαR201C mice. FD-like lesions in the ZA group showed the persistence of osteoclasts, easily detectable osteoclast apoptotic activity and numerous "giant osteoclasts". In contrast, in the anti-mRANKL Ab-treated mice, osteoclasts were markedly reduced/absent, the radiographic phenotype reverted and the FD-like lesions were extensively replaced by newly formed bone. Numerous "giant osteoclasts" were also detected in the samples of the child with MAS. This study supports the hypothesis that osteoclasts per se, independently of their resorptive activity, are essential for development and expansion of FD lesions.

Age-Related Changes and Effects of Bisphosphonates on Bone Turnover and Disease Progression in Fibrous Dysplasia of Bone.

Fibrous dysplasia (FD) is a mosaic disease in which bone is replaced with fibro-osseous tissue. Lesions expand during childhood, reaching final burden by age 15 years. In vitro data suggest that disease activity decreases in adulthood; however, there is no clinical data to support this concept. Bone turnover markers (BTMs) have been used as markers of disease activity in FD; however, the natural history of BTM changes, the effects of antiresorptive treatment, and their association to clinical outcomes have not been described. The goals of this study are to describe 1) the natural history of FD disease activity and its association with pain; 2) the impact of bisphosphonates on the natural history of BTMs; and 3) the effect of bisphosphonates on progression of FD burden during childhood. Disease burden scores and alkaline phosphatase, osteocalcin, NTx, FGF23, and RANKL levels from 178 subjects in an FD/MAS natural history study were reviewed, including 73 subjects treated with bisphosphonates. BTMs, RANKL, and FGF23 demonstrated a sustained reduction with age. Bisphosphonate treatment did not significantly impact this age-dependent decrease in BTMs. Pain was more prevalent and severe in adults compared with children and was not associated with BTMs. In children, the progression of disease burden was not affected by bisphosphonates. In conclusion, FD is associated with an age-dependent decline in bone turnover and other markers of disease activity. Pain, in contrast, is more frequent and severe in adults with FD and is not related to bone turnover. Bisphosphonate treatment does not significantly impact the age-dependent decrease in bone turnover, nor does it prevent the progression of FD disease burden in children. These findings, in association with the established adverse effects of antiresorptives, should be considered when evaluating use and response to bisphosphonates in patients being treated for FD and in any study using BTMs as surrogate endpoints. © 2019 American Society for Bone and Mineral Research.