Transcriptomic Signature and Pro-Osteoclastic Secreted Factors of Abnormal Bone-Marrow Stromal Cells in Fibrous Dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants of GNAS encoding for Gαs and leading to excessive cyclic adenosine monophosphate signaling in bone-marrow stromal cells (BMSCs). The effect of Gαs activation in the BMSC transcriptome and how it influences FD lesion microenvironment are unclear. We analyzed changes induced by Gαs activation in the BMSC transcriptome and secretome. RNAseq analysis of differential gene expression of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, was performed, and the transcriptomic profiles of both models were combined to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. To assess the modulation of several key secreted factors in FD pathogenesis, cytokines and other factors were measured in culture media. Cytokines were also screened in a collection of plasma samples from patients with FD, and positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers, were found. These data support the pro-inflammatory, pro-osteoclastic behavior of FD BMSCs and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

Transcriptomic signature and pro-osteoclastic secreted factors of abnormal bone marrow stromal cells in fibrous dysplasia.

Fibrous dysplasia (FD) is a mosaic skeletal disorder caused by somatic activating variants in GNAS, encoding for Gαs, which leads to excessive cAMP signaling in bone marrow stromal cells (BMSCs). Despite advancements in our understanding of FD pathophysiology, the effect of Gαs activation in the BMSC transcriptome remains unclear, as well as how this translates into their local influence in the lesional microenvironment. In this study, we analyzed changes induced by Gαs activation in BMSC transcriptome and performed a comprehensive analysis of their production of cytokines and other secreted factors. We performed RNAseq of cultured BMSCs from patients with FD and healthy volunteers, and from an inducible mouse model of FD, and combined their transcriptomic profiles to build a robust FD BMSC genetic signature. Pathways related to Gαs activation, cytokine signaling, and extracellular matrix deposition were identified. In addition, a comprehensive profile of their secreted cytokines and other factors was performed to identify modulation of several key factors we hypothesized to be involved in FD pathogenesis. We also screened circulating cytokines in a collection of plasma samples from patients with FD, finding positive correlations of several cytokines to their disease burden score, as well as to one another and bone turnover markers. Overall, these data support a pro-inflammatory, pro-osteoclastic behavior of BMSCs bearing hyperactive Gαs variants, and point to several cytokines and other secreted factors as possible therapeutic targets and/or circulating biomarkers for FD.

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.

Fibrous dysplasia in children and its management.

PURPOSE OF REVIEW: The purpose of this review is to provide a comprehensive overview into the diagnosis and management of fibrous dysplasia (FD) in children. RECENT FINDINGS: FD is a mosaic disorder arising from somatic Gα s variants, leading to impaired osteogenic cell differentiation. Fibro-osseous lesions expand during childhood and reach final disease burden in early adulthood. The mainstay of treatment focuses on surgical correction of skeletal deformities, physiatric care, and medical management of associated hyperfunctioning endocrinopathies. Bisphosphonates may be helpful to treat bone pain, but do not alter lesion quality or progression. Emerging evidence suggests that the RANKL inhibitor denosumab may be effective in improving lesion activity and mineralization, however further studies are needed to determine the potential utility of this and other novel therapies, particularly in children with FD. SUMMARY: Management of children with FD has unique challenges related to skeletal growth and age-related lesion progression. Inclusion of children in clinical research is critical to develop effective treatment strategies to treat FD lesions and prevent their development.

Serum Phosphorus as a Driver of Skeletal Morbidity in Fibrous Dysplasia.

CONTEXT: Fibrous dysplasia (FD) results in fractures, pain, and deformities. Abnormal osteoprogenitor cells overproduce FGF23, leading to hyperphosphaturia in most patients and frank hypophosphatemia in a subset. Studies suggest hypophosphatemia is associated with increased FD-related morbidity. However, the relationship between phosphorus and skeletal complications has not been investigated, and the optimal therapeutic target has not been determined. OBJECTIVE: Characterize the impact of serum phosphorus on FD-related morbidity and identify levels associated with increased skeletal complications. METHODS: Natural history study with 240 subjects at a clinical research center who had ≥1 fasting phosphorus level, determined as age- and sex-adjusted Z-scores. Subjects were categorized based on frank hypophosphatemia (Z-score ≤ -2; n = 48); low-normophosphatemia (> -2 to ≤ -1; n = 66); and high-normophosphatemia (> -1 to ≤ 2; n = 125). Main outcomes were fractures, orthopedic surgeries, and scoliosis. RESULTS: Subjects with frank and low-normophosphatemia had increased fracture and surgery rates vs high-normophosphatemia. The prevalence of moderate to severe scoliosis was similarly higher in the frank and low-normophosphatemia groups. In a subanalysis of patients matched for Skeletal Burden Score ≥35, fracture and surgery rates remained higher in the frank hypophosphatemia group, suggesting association between phosphorus and skeletal complications is not explained by differences in FD burden alone. CONCLUSION: Both frank hypophosphatemia and low-normophosphatemia are associated with increased FD-related complications. This supports FGF23-mediated hypophosphatemia as a driver of skeletal morbidity, which may impact a larger proportion of the FD/McCune-Albright syndrome population than previously recognized. These findings enable clinicians to identify at-risk patients and will inform development of prospective studies to determine optimal therapeutic targets.

Phenotyping Pain in Patients With Fibrous Dysplasia/McCune-Albright Syndrome.

CONTEXT: Pain is a poorly managed aspect in fibrous dysplasia/McCune-Albright syndrome (FD/MAS) because of uncertainties regarding the clinical, behavioral, and neurobiological underpinnings that contribute to pain in these patients. OBJECTIVE: Identify neuropsychological and neurobiological factors associated with pain severity in FD/MAS. DESIGN: Prospective, single-site study. PATIENTS: Twenty patients with FD/MAS and 16 age-sex matched healthy controls. INTERVENTION: Assessments of pain severity, neuropathic pain, pain catastrophizing (pain rumination, magnification, and helplessness), emotional health, and pain sensitivity with thermal quantitative sensory testing. Central nervous system (CNS) properties were measured with diffusion tensor imaging, structural magnetic resonance imaging, and functional magnetic resonance imaging. MAIN OUTCOME MEASURES: Questionnaire responses, detection thresholds and tolerances to thermal stimuli, and structural and functional CNS properties. RESULTS: Pain severity in patients with FD/MAS was associated with more neuropathic pain quality, higher levels of pain catastrophizing, and depression. Quantitative sensory testing revealed normal detection of nonnoxious stimuli in patients. Individuals with FD/MAS had higher pain tolerances relative to healthy controls. From neuroimaging studies, greater pain severity, neuropathic pain quality, and psychological status of the patient were associated with reduced structural integrity of white matter pathways (superior thalamic radiation and uncinate fasciculus), reduced gray matter thickness (pre-/paracentral gyri), and heightened responses to pain (precentral, temporal, and frontal gyri). Thus, properties of CNS circuits involved in processing sensorimotor and emotional aspects of pain were altered in FD/MAS. CONCLUSION: These results offer insights into pain mechanisms in FD/MAS, while providing a basis for implementation of comprehensive pain management treatment approaches that addresses neuropsychological aspects of pain.

Management of RANKL-mediated Disorders With Denosumab in Children and Adolescents: A Global Expert Guidance Document.

CONTEXT: Denosumab is an effective treatment for many receptor activator of nuclear factor kappa-B ligand (RANKL)-mediated disorders but there are potential safety considerations and limited data to guide its use in children and adolescents. OBJECTIVE: This document seeks to summarize the evidence and provide expert opinion on safe and appropriate use of denosumab in pediatric RANKL-mediated disorders. PARTICIPANTS: Ten experts in pediatric bone and mineral medicine from 6 countries with experience in the use of denosumab participated in the creation of this document. EVIDENCE: Data were sourced from the published literature, primarily consisting of case reports/series and review articles because of the lack of higher level evidence. Expert opinion of the authors was used substantially when no published data were available. CONCLUSION: Denosumab is an effective treatment for RANKL-mediated disorders in children and adolescents but is often not curative and, in some cases, is best used in conjunction with surgical or other medical treatments. Careful multidisciplinary planning is required to define the goals of treatment and expert oversight needed to manage the risk of mineral abnormalities. Substantive, collaborative research efforts are needed to determine optimal treatment regimens and minimize risks.

RANK-L inhibitor as a promising agent for refractory extensive craniofacial fibrous dysplasia: A case report.

BACKGROUND: McCune-Albright syndrome is a rare disorder characterized by polyostotic fibrous dysplasia (FD), café-au-lait skin pigmentation, and endocrine dysfunction. Extensive FD in the craniofacial region can present significant challenges in terms of disease control and carries a high risk of permanent visual impairment. METHODS: We present a case of medically and surgically resistant FD that required nine optic nerve decompressions. RESULTS: The condition was ultimately controlled with the use of the denosumab agent. CONCLUSION: The case highlights the importance and potential efficacy of denosumab in resistant FD management, particularly in cases involving sensitive organs.

Lesion Expansion in Gnathic Fibrous Dysplasia: Natural History, Indicators of Progression, and Response to Bisphosphonates.

Fibrous dysplasia (FD) is characterized by expansile fibro-osseous lesions that may occur in association with endocrinopathies as part of McCune-Albright syndrome (MAS). Craniofacial FD is a significant source of morbidity and most commonly involves the gnathic bones. There is a critical need to understand the natural history and risk factors for gnathic FD progression to develop preventative trials and identify candidates for intervention. The purpose of this study was to characterize gnathic FD lesion expansion and to identify risk factors associated with lesion growth. Patients with gnathic FD and serial CT imaging were evaluated. Volumetric analyses of CT scans were performed using MIM Encore software. Generalized mixed model analysis was used to account for intra-subject correlation, with FD lesion volume as the dependent variable. In addition to age, effects of MAS-associated endocrinopathies, sex, disease severity, and bisphosphonate treatment were evaluated. A total of 104 total lesions in 52 patients were characterized longitudinally. Median age at initial scan was 8.8 years (range 3.4-18.8), and median age at final scan was 16.8 years (range 6.9-33.4 years). The median number of scans per subject was 4 (range 2-14). FD lesion volume increased with age (2.50 cm3 /yr, 95% confidence interval [CI] 1.95-3.04, p < 0.001). However, lesion expansion rate decreased over time (-0.05 cm3 /yr, 95% CI -0.07 to 0.04, p < 0.001). Mandibular lesions tended to expand at a greater rate than maxillary lesions (p < 0.001). Growth hormone excess was associated with accelerated expansion rate (p = 0.002). Other MAS-associated endocrinopathies, pubertal status, sex, weight, lesion density, disease severity, and bisphosphonate treatment were not associated with lesion volume or expansion. Gnathic FD lesion expansion is most rapid in younger children and declines as patients approach adulthood. The availability of quantitative natural history data will guide clinicians in identifying patients who are candidates for medical and surgical interventions and clinical trials for preventative therapies. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

An inducible explant model of osteoclast-osteoprogenitor coordination in exacerbated osteoclastogenesis.

Elucidating a basic blueprint of osteoclast-osteoblast coordination in skeletal remodeling and understanding how this coordination breaks down with age and disease is essential for addressing the growing skeletal health problem in our aging population. The paucity of simple, activatable, biologically relevant models of osteoclast-osteoblast coordination has hindered our understanding of how skeletal remolding is regulated. Here, we describe an inducible ex vivo model of osteoclast-osteoblast progenitor coordination. Induction activates the release of osteoclastogenic factors from osteoprogenitors, which elicits the differentiation and fusion of neighboring preosteoclasts. In turn, multinucleated osteoclasts release soluble coupling factors, RANK+ extracellular vesicles and promote osteoprogenitor proliferation, recapitulating aspects of perturbed coordination in diseases underpinned by excessive osteoclast formation. We expect this model to expedite the investigation of cell-cell fusion, osteoclast-osteoblast progenitor coordination, and extracellular vesicle signaling during bone remodeling and offer a powerful tool for evaluating signaling cascades and novel therapeutic interventions in osteoclast-linked skeletal disease.

Coxa Vara Deformity in Fibrous Dysplasia/McCune-Albright Syndrome: Prevalence, Natural History and Risk Factors: A Two-Center Study.

This study aimed to evaluate the prevalence of and risk factors for coxa vara deformity in patients with fibrous dysplasia/McCune-Albright syndrome (FD/MAS). This study was conducted at the National Institutes of Health and Leiden University Medical Center. All patients with any subtype of FD/MAS, FD involving the proximal femur, one or more X-rays available and age <30 years were included. X-rays were scored for the neck-shaft angle (NSA). Varus deformity was defined as NSA <110 degrees or >10 degrees below age-specific values. Risk factors for deformity were assessed by nested case-control analysis, comparing patients and femurs with and without deformity, and by linear mixed effects model, modeling temporal NSA decrease (the natural course of the NSA) in non-operated femurs with two or more X-rays. Assessed variables included growth hormone excess, hyperthyroidism, hypophosphatemia, >25% of the femur affected, calcar destruction, radiolucency, and bilateral involvement. In total 180 patients were studied, 57% female. Mean ± SD baseline age was 13.6 ± 7.5 years; median follow-up 5.4 (interquartile range [IQR], 11.1) years. Sixty-three percent (63%) were diagnosed with MAS. A total of 94 patients were affected bilaterally; 274 FD femurs were analyzed; 99 femurs had a varus deformity (36%). In the nested case-control analysis, risk factors were as follows: presence of MAS (p < 0.001), hyperthyroidism (p < 0.001), hypophosphatemia (p < 0.001), high percentage of femur affected (p < 0.001), and calcar destruction (p < 0.001). The linear mixed effects model included 114 femurs, identified risk factors were: growth hormone excess (ß = 7.2, p = 0.013), hyperthyroidism (ß = 11.3, p < 0.001), >25% of the femur affected (ß = 13.2, p = 0.046), calcar destruction (ß = 8.3, p = 0.004), radiolucency (ß = 3.9, p = 0.009), and bilateral involvement (ß = 9.8, p = 0.010). Visual inspection of the graph of the model demonstrated most progression of deformity if NSA <120 degrees with age < 15 years. In conclusion, in tertiary care centers, the prevalence of FD/MAS coxa vara deformity was 36%. Risk factors included presence of MAS, high percentage of femur affected, calcar destruction, radiolucency, NSA <120 degrees and age < 15 years. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Craniofacial Fibrous Dysplasia: Clinical and Therapeutic Implications.

PURPOSE OF REVIEW: This study aims to review diagnosis, potential complications, and clinical management in craniofacial fibrous dysplasia. RECENT FINDINGS: Fibrous dysplasia (FD) is a rare mosaic disorder in which normal bone and marrow are replaced with expansile fibro-osseous lesions. Disease presents along a broad spectrum and may be associated with extraskeletal features as part of McCune-Albright syndrome (MAS). The craniofacial skeleton is one of the most commonly impacted areas in FD, and its functional and anatomical complexities create unique challenges for diagnosis and management. This review summarizes current approaches to diagnosis and management in FD/MAS, with emphasis on the clinical and therapeutic implications for the craniofacial skeleton.

Identification of GNAS Variants in Circulating Cell-Free DNA from Patients with Fibrous Dysplasia/McCune Albright Syndrome.

Fibrous dysplasia/McCune-Albright syndrome (FD/MAS) is a rare mosaic bone and endocrine disorder. Although most variants affect the GNAS R201 codon, obtaining a genetic diagnosis is difficult because not all cells harbor the variant, and an invasive biopsy may be required. We explored the presence of GNAS p.R201 variants in blood circulating cell free DNA (ccfDNA) using sensitive techniques of digital droplet polymerase chain reaction (PCR) (ddPCR) and competitive allele-specific TaqMan PCR (castPCR) in an effort to improve the genetic diagnosis of FD/MAS. We isolated ccfDNA from the plasma of 66 patients with a wide range of disease severity and performed both ddPCR and castPCR mutation analysis to search for GNAS p.R201H or R201C variants. We detected R201 variants in ccfDNA samples of 41 of 66 (62.1%) patients by either castPCR or ddPCR, and 45 of 66 (68.2%) of patients if the techniques were combined. Variant detection was more likely in patients with more severe disease. Skeletal disease burden score (SBS) was significantly higher in patients who had detectable variants, and SBS was a predictor of variant allele frequency. By ddPCR analysis, patients aged ≤30 years had higher detection rates, and higher variant allele frequencies, independent of disease burden. We detected variant DNA in only one patient with monostotic FD by ddPCR only. In summary, we have demonstrated that ccfDNA containing variant GNAS can be isolated from the plasma of patients with FD/MAS and that ddPCR and castPCR methods have similar variant detection rates. This methodology represents an important potential advancement in diagnosis for patients with FD/MAS, especially those younger than 30 years or with more severe disease. Published 2023. This article is a U.S. Government work and is in the public domain in the USA.

Precocious Puberty in a Boy With Bilateral Leydig Cell Tumors due to a Somatic Gain-of-Function LHCGR Variant.

Context: Autosomal dominant and rarely de novo gain-of-function variants in the LHCGR gene are associated with precocious male puberty, while somatic LHCGR variants have been found in isolated Leydig cell adenomas and Leydig cell hyperplasia. Bilateral diffuse Leydig cell tumor formation in peripheral precocious male puberty has not been reported. Case Description: We present a boy with gonadotropin-independent precocious puberty and rapid virilization beginning in infancy resistant to standard therapy. Treatment with abiraterone in addition to letrozole and bicalutamide proved effective. Bilateral diffuse Leydig cell tumors were identified at age 5 years. Results: Whole-genome sequencing of tumor and blood samples was performed. The patient was confirmed to have bilateral, diffuse Leydig cell tumors harboring the somatic, gain-of-function p.Asp578His variant in the LHCGR gene. Digital droplet polymerase chain reaction of the LHCGR variant performed in tumor and blood samples detected low levels of this same variant in the blood. Conclusion: We report a young boy with severe gonadotropin-independent precocious puberty beginning in infancy who developed bilateral diffuse Leydig cell tumors at age 5 years due to a somatic gain-of-function p.Asp578His variant in LHCGR. The gain-of-function nature of the LHCGR variant and the developmental timing of the somatic mutation likely play a role in the risk of tumor formation. Abiraterone (a CYP17A1 inhibitor), in combination with an antiandrogen, aromatase inhibitor, and glucocorticoid, appears to be an effective therapy for severe peripheral precocious puberty in boys.

Malignant Sarcomatous Degeneration of Craniofacial Fibrous Dysplasia.

BACKGROUND: Fibrous dysplasia (FD) is an uncommon bone disease characterized by the replacement of normal bone architecture with abnormal fibro-osseous connective tissue. Here, we discuss 2 cases of craniofacial FD, with malignant sarcomatous degeneration - a rare and morbid complication of the disease. CASE HISTORY: Two cases of craniofacial FD with malignant degeneration are presented. In the first, a 68-year-old male with a history of FD presented with acutely worsening left-sided facial pain and V2 and V3 hypoesthesia. Imaging findings suggested a large infratemporal fossa mass with biopsy demonstrating sarcomatous degeneration. Radical craniofacial resection achieved a gross total resection with likely microscopic disease. The patient was unable to tolerate adjuvant chemotherapy or radiation and succumbed to his disease 13 months following surgery.In the second case, a 36-year-old male with McCune-Albright Syndrome and craniofacial FD presented with acutely worsening left-sided headaches and midface hypoesthesia. Imaging revealed a heterogenous and expansile lesion with erosive changes in the left nasal cavity and infratemporal fossa. Pathology was suggestive of low grade sarcomatous degeneration. Given the extensive involvement of the skull base, the tumor was deemed unresectable, and the patient soon died following initiation of chemotherapy. CLINICAL RELEVANCE: Malignant sarcomatous transformation is a rare and challenging complication of craniofacial FD. Indolent onset, advanced spread at time of presentation, and close relationship with vital neurovascular structures are all hurdles for the treating clinician. The entity poses a diagnostic dilemma, as pathological analysis can be equivocal and may mimic nonmalignant processes, such as locally aggressive FD.

Determination of FGF23 Levels for the Diagnosis of FGF23-Mediated Hypophosphatemia.

Fibroblast growth factor-23 (FGF23) measurement is a critical tool in the evaluation of patients with disordered phosphate homeostasis. Available laboratory reference ranges for blood FGF23 were developed using samples from normophosphatemic individuals. Reliance on such values can lead to misdiagnosis in patients with FGF23-mediated hypophosphatemia, such as X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO), in whom pathology-driving FGF23 levels can be in the "normal range." To determine FGF23 levels that are diagnostic for the identification of patients with FGF23-mediated hypophosphatemic disorders, we studied 149 patients with various disorders of FGF23-mediated and FGF23-independent hypophosphatemia and defined cut-off levels for both intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23) that can accurately distinguish between FGF23-mediated and FGF23-independent hypophosphatemia. In addition, to demonstrate the relationship between FGF23 and phosphate across the spectrum of human physiology, we assessed blood levels of FGF23 and phosphate in 434 patients with various forms of hypophosphatemia, hyperphosphatemia, and normophosphatemia. An intact FGF23 cut point of 27 pg/mL was 100% sensitive and specific in distinguishing FGF23-mediated from FGF23-independent hypophosphatemia, and a cFGF23 cut point of 90 RU/mL was 100% sensitive and specific in distinguishing specifically TIO from FGF23-independent hypophosphatemia. There was overlap in the cFGF23 range of 45-90 RU/mL between genetic forms of FGF23 excess and FGF23-independent hypophosphatemia, substantiating the superiority of iFGF23 over cFGF23 in making the diagnosis of FGF23-mediated hypophosphatemia. In this cohort, using the laboratory upper limit of normal for cFGF23 (180 RU/mL) would result in a misdiagnosis in more than half of patients with FGF23-mediated hypophosphatemia. In this, the largest study of FGF23 in chronic hypophosphatemia to date, we established iFGF23 and cFGF23 cut-off values to assist in the evaluation and diagnosis of hypophosphatemic conditions. © 2022 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Skeletal Disease Acquisition in Fibrous Dysplasia: Natural History and Indicators of Lesion Progression in Children.

Fibrous dysplasia (FD) is a rare mosaic disorder resulting in fractures, pain, and disability. Bone lesions appear during childhood and expand during skeletal growth. The rate at which FD lesions progress and the biochemical determinants of FD lesion formation have not been established, making it difficult to investigate and implement preventative therapies. The purpose of this study was to characterize FD lesion progression in children, and to identify clinical variables associated with progressive disease. Clinical data and imaging from an ongoing natural history study at the National Institutes of Health (NIH) were reviewed. 99m-Technetium methylene diphosphonate (99Tc-MDP) scans were used to determine Skeletal Burden Score (SBS), a validated quantitative scoring system. FD progression rate was determined by the change in the SBS in each patient per year. Thirty-one children had serial 99Tc-MDP scans, with a median age at first scan of 6 years (interquartile range [IQR] 4-8, range 2-10), and median follow-up 1.1 years (IQR 1.1-2.1, range 0.7-11.2). The median FD progression rate for the total group was 2.12 SBS units/year (IQR 0.81-2.94, range 0.05-7.81). FD progression rates were highest in children under age 8 years and declined with age (p = 0.03). Baseline disease severity was associated with subsequent disease progression (p = 0.009), with the highest FD progression rates in patients with moderate disease (baseline SBS 16-30), and lowest progression rates in those with severe disease (SBS ≥50). Serum levels of the bone formation marker osteocalcin were positively correlated with subsequent FD progression rate (p = 0.01, R = 0.58). There was no association between FD progression and baseline endocrinopathies, fractures, or surgery rates. FD lesions progress during childhood, particularly in younger children and those with moderate involvement. Osteocalcin may potentially serve as a biomarker for progressive disease. These findings may allow clinicians to investigate preventative therapies, and to identify children with FD who are candidates for early interventions. Published 2022. This article is a U.S. Government work and is in the public domain in the USA.