Rare Skeletal Disorder Research Articles

Lower limb maltorsion and acetabular deformity in children and adolescents with X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is a rare monogenetic skeletal disorder. Lower limb deformities contribute substantially to impaired gait quality and burden of disease in patients with XLH. Standardized data regarding onset and severity of lower limb maltorsion are unavailable. This study aimed to evaluate lower limb maltorsion using rotational magnetic resonance imaging (MRI) and computed tomography (CT). Rotational MRI and CT of children and adolescents with verified XLH were evaluated retrospectively. Femoral and tibial torsion, acetabular anteversion, and axial acetabular coverage were measured and compared with published age-adapted radiographic, clinical measurements and MRI data, respectively. Fifteen patients (mean age, 10.7 years) were included in the study. Decreased femoral torsion was observed in 47% (14/30 femora) and femoral retrotorsion in 17% (5/30 femora). Ten of 13 hips with coxa vara deformity presented with decreased femoral antetorsion. Reduced external tibial torsion manifested in 64% (18/28 tibiae). Abnormal axial femoral head coverage was present in 67% (20/30 hips), whereas 53% (16/30 hips) showed increased acetabular anteversion. Femoral and tibial torsional pathologies were found in children and adolescents with XLH. The occurrence of severe femoral retrotorsion in a 2-year-old child prior to ambulation raises questions regarding the biomechanical impact of gait on the development of torsional deformities in XLH.

Evolution and Spatiotemporal Expression of ankha and ankhb in Zebrafish.

Craniometaphyseal Dysplasia (CMD) is a rare skeletal disorder that can result from mutations in the ANKH gene. This gene encodes progressive anksylosis (ANK), which is responsible for transporting inorganic pyrophosphate (PPi) and ATP from the intracellular to the extracellular environment, where PPi inhibits bone mineralization. When ANK is dysfunctional, as in patients with CMD, the passage of PPi to the extracellular environment is reduced, leading to excess mineralization, particularly in bones of the skull. Zebrafish may serve as a promising model to study the mechanistic basis of CMD. Here, we provide a detailed analysis of the zebrafish Ankh paralogs, Ankha and Ankhb, in terms of their phylogenic relationship with ANK in other vertebrates as well as their spatiotemporal expression patterns during zebrafish development. We found that a closer evolutionary relationship exists between the zebrafish Ankhb protein and its human and other vertebrate counterparts, and stronger promoter activity was predicted for ankhb compared to ankha. Furthermore, we noted distinct temporal expression patterns, with ankha more prominently expressed in early development stages, and both paralogs also being expressed at larval growth stages. Whole-mount in situ hybridization was used to compare the spatial expression patterns of each paralog during bone development, and both showed strong expression in the craniofacial region as well as the notochord and somites. Given the substantial overlap in spatiotemporal expression but only subtle patterning differences, the exact roles of these genes remain speculative. In silico analyses predicted that Ankha and Ankhb have the same function in transporting PPi across the membrane. Nevertheless, this study lays the groundwork for functional analyses of each ankh paralog and highlights the potential of using zebrafish to find possible targeted therapies for CMD.

Multicentric Osteolysis Nodulosis and Arthropathy (MONA): A Case Series and Review of the Literature.

Multicentric Osteolysis Nodulosis and Arthropathy (MONA) is a rare skeletal disorder driven by mutations in the MMP2 gene, leading to bone and joint degradation. This case series presents three unique MONA cases, highlighting clinical, radiological, and genetic aspects. These insights shed light on the complexities of MONA, aiding early diagnosis and multidisciplinary management. Case 1 is a 13-year-old male, born to consanguineous parents, presented with a 5-year history of progressive joint deformities, pain, and difficulty walking. Initially diagnosed as juvenile idiopathic arthritis (JIA), despite treatment, his symptoms persisted. Examination revealed multiple clinical findings, including joint contractures and nodules. Genetic analysis identified a pathogenic variant in the MMP2 gene, confirming MONA. Case 2 and Case 3 were two siblings, aged 12 and 17 years respectively, who presented progressive joint contractures in their hands and feet since early childhood. Clinical examinations revealed contractures and subcutaneous nodules. Genetic analysis confirmed MONA with a shared homozygous pathogenic MMP2 variant, emphasising the genetic basis of this rare disorder.

Dental Profile of Brazilian Patients with Rare Skeletal Genetic Disorders: Clinical Features and Associated Factors.

The aim of this study is to compare the dental profiles of Brazilian patients with rare genetic skeletal disorders and normotypical patients. A cross-sectional study was carried out with 210 individuals aged between 2 and 54 years old [105 with rare diseases (Mucopolysaccharidosis/MPS n = 27 and Osteogenesis Imperfecta/OI n = 78) and 105 without rare diseases] and their parents/caregivers. The parents/caregivers answered a questionnaire about individual aspects of their child and the dental profile was identified from questions related to dental history and the presence/absence of dental problems. The patients' oral cavity was also examined by three examiners for dental caries, malocclusion, gingivitis, and dental anomalies. The average age of individuals with a rare disease was 14.1 years (±12.2) and the median was 9.5 years. Participants who had already used the public health system (SUS) dental care services had a 2.24 times higher chance of belonging to the group with a rare disease (OR = 2.24; 95% CI: 1.07-4.89). Patients with rare diseases are 14.86 times more likely to have difficulty receiving dental treatment (OR = 14.86; 95% CI: 5.96-27.03) and 10.38 times more likely to have one or more dental problems (OR = 10.38; 95% CI: 1.95-35.17). Individuals with rare disorders have a greater history of difficulty in accessing dental treatment, using the SUS, and were diagnosed with more dental problems compared to normotypical individuals.

Arthroscopic Management of Dysplasia Epiphysealis Hemimelica (Trevor Disease) of the Ankle

Dysplasia epiphysealis hemimelica (Trevor disease) is a rare skeletal development disorder of childhood, characterized by irregular ossification centers, which may develop together or individually, leading to asymmetric epiphyseal cartilage overgrowth, affecting 1 side of the epiphyses or the epiphyses equivalents (the medial side being affected twice as often as the lateral), until skeletal maturity is reached. Trevor disease around the ankle is locally aggressive with a poor outcome, especially in tumors involving the articular surface. The purpose of this Technical Note is to describe the details of arthroscopic management of dysplasia epiphysealis hemimelica (Trevor disease) of the ankle.

Rare genetic skeletal disorders: Evolving terminology, therapies, education and advocacy

In the US, rare diseases are defined as disorders affecting fewer than 200,000 US residents or disorders for which there is no reasonable expectation that drug development costs will be recoverable by US sales. Almost 800 of the approximately 10,000 defined rare diseases are bone disorders. Until recently, their rarity and heterogeneity have unfortunately hindered their exploration at both clinical and scientific levels. However, wider availability of genetic testing, development of new surgical and pharmaceutical treatment options, and patient advocacy have motivated efforts to study, diagnose, and treat these disorders. Thus, care of the patient with a rare skeletal disorder is now evolving rapidly. This report presents a brief summary of important developments in skeletal disorders impacting bone quality and frequently co-managed by pediatric orthopaedic surgeons. Key Concepts(1)Although a “cure” is not yet available for most rare bone disease patients, new agents are frequently being advanced as new genes and their products are identified as molecules to target.(2)Medical therapies, often combined with surgical interventions and physical therapy, are reducing pain and increasing function in many pediatric orthopaedic patients with rare bone disorders.(3)New tools for physician education and patient management are increasingly available to assist the pediatric orthopaedic surgery community.

Deciphering the Genomic Complexity of Acromesomelic Dysplasia Type Maroteaux: Insights from a Consanguineous Pakistani Family

Purpose: This study delves into the genetic basis of Acromesomelic Dysplasia (AMD), a rare skeletal disorder, particularly focusing on the Maroteaux type within a consanguineous Pakistani family. The purpose is to explore the genetic landscape beyond known mutations and understand the underlying causes of AMD.
 Methodology: A comprehensive approach was adopted, combining detailed clinical examinations with advanced genomic methodologies. Ethical clearance was obtained, and pedigree design facilitated the identification of affected individuals. Molecular techniques including DNA extraction and linkage analysis were conducted to investigate known AMD-related genes such as NPR2, BMPR1B, GDF5, GALNS, GLB1, and GHR. Whole-genome sequencing was emphasized despite financial constraints to uncover potential novel genetic loci associated with AMD.
 Findings: Despite exhaustive analysis, no mutations in known AMD-related genes were identified within the studied family. Linkage analysis did not correlate with any known genetic loci, suggesting the presence of unidentified genetic elements contributing to AMD. Autosomal recessive inheritance was confirmed through pedigree and molecular scrutiny, highlighting the complexity of AMD genetics.
 Unique Contribution to Theory, Policy and Practice: This research underscores the importance of employing advanced genomic strategies, such as whole-genome sequencing, in decoding rare genetic disorders like AMD. By revealing the limitations of current diagnostic approaches and advocating for collaborative efforts and resource pooling, this study contributes to the advancement of genetic counseling, therapeutic interventions, and precision medicine in rare genetic disorders.

First case of Hajdu-Cheney syndrome in Lithuania caused by novel NOTCH2 gene likely pathogenic variant

Hajdu-Cheney syndrome (HCS) is an extremely rare autosomal dominant skeletal disorder. The prevalence rate of less than 1 case per 1,000,000 newborns and only 50 cases were reported in the medical literature. HCS is characterized by progressive bone resorption in the distal phalanges (acro-osteolysis), progressive osteoporosis, distinct craniofacial changes, dental anomalies, and occasional association with renal abnormalities. HCS is caused by pathogenic variants in the NOTCH2 gene, 34th exon. We report first familial case of HCS caused by likely pathogenic variant of NOTCH2 gene c.6449delC, p.(Pro2150LeufsTer5).

Gorham–Stout disease started with recurrent bilateral exudative pleuritis: case description and literature review

Gorham–Stout disease is an extremely rare skeletal disorder of unknown etiology manifested by multiple foci of osteolysis (“vanishing bone disease”) and lymphangiomatosis. Osteolysis can occur in any part of the skeleton (skull, facial skeleton, ribs, clavicula, spine, pelvic bones, bones of the upper and lower extremities). Approximately half of the patients develop pleural effusion, accompanied by respiratory abnormalities. We describe a case of Gorham-Stout disease with recurrent bilateral exudative pleuritis as a first and most prominent sign, while the bone lesions at the vertebral bodies, ribs and sternum proceeded without active complaints and were an accidental finding during chest computer tomography. Timely diagnosis of the disease depends on the awareness of doctors of various specialties and careful reading of imaging results.

Health-related quality of life and associated risk factors in patients with Multiple Osteochondromas: a cross-sectional study

PurposeTo evaluate the health-related quality of life and associated risk factors for Multiple Osteochondromas patients.MethodsA cross-sectional, observational study was conducted from May to December 2022 during the routine visit to the referral center for rare skeletal disorders. All patients with Multiple Osteochondromas aged ≥ 3 years were included. EuroQol 5-dimension questionnaires, and demographic, clinical, and surgical history data were collected. Descriptive statistics, Fisher’s exact test, One-sample t-test, Spearman’s correlation, and multiple linear and logistic regression were performed to analyze the data. Results are reported following STROBE guidelines.ResultsA total of 128 patients were included in the study, with a mean age of 14 [SD, 10] years. The mean EQ-5D Index Value was 0.863 [SD, 0.200] and the EQ-VAS was 84 [SD, 19] with a positive correlation between two scores [r = 0.541, p < 0.001]. Patients frequently referred problems in pain/discomfort [78.8%], anxiety/depression [50%], and usual activities [38.8%] dimensions. Increasing age was the common risk factor for health-related quality of life [p < 0.000], as well as Index Value and VAS scores were significantly lower in surgical patients [p = 0.001 and p < 0.001, respectively].ConclusionIncreasing age and surgical procedures were found highly associated with reduced health-related quality of life in Multiple Osteochondromas patients. Our findings provide relevant information to support the establishment of patient-centered healthcare pathways and pave the way for further research into medical and non-medical therapeutic strategies for these patients.

Rare Case of a Dyggve-Melchior-Clausen Syndrome Revealed by a Spinal Cord Compression

Dyggve-Melchior-Clausen syndrome (DMSC) is an rare autosomal recessive skeletal disorder that belongs to the category of spondyloepiphyseal dysplasia. The present work reports a case of DMCS in a nine- year-old kid who was admitted for spinal cord compression accompanied by mental retardation and dysmorphic syndrome. The patient had shown a C1-C2 dislocation with compression of the bulbo-medullary junction, platyspondyly with double ondulation of all the vertebral endplates, widely open acetabulums and epi- metaphyseal dysplasia of the femoral heads. Discussion: The syndrome is clinically characterized by a staturo- ponderal delay of varying severity. Radiological characteristics consist of a scalloped appearance of the iliac wings, spondyloepimetaphyseal dysplasia and platyspondyly. The diagnosis of Dyggve-Melchior-Clausen syndrome can be suspected after a clinical evaluation, a detailed patient history, and identification of characteristic clinical and radiological signs.

Clinical features and genetic analysis of a case series of skeletal ciliopathies in a prenatal setting

BackgroundShort-rib polydactyly syndrome (SRPS) refers to a group of lethal skeletal dysplasias that can be difficult to differentiate between subtypes or from other non-lethal skeletal dysplasias such as Ellis-van Creveld syndrome and Jeune syndrome in a prenatal setting. We report the ultrasound and genetic findings of four unrelated fetuses with skeletal dysplasias.MethodsSystemic prenatal ultrasound examination was performed in the second or third trimester. Genetic tests including GTG-banding, single nucleotide polymorphism (SNP) array and exome sequencing were performed with amniocytes or aborted fetal tissues.ResultsThe major and common ultrasound anomalies for the four unrelated fetuses included short long bones of the limbs and narrow thorax. No chromosomal abnormalities and pathogenic copy number variations were detected. Exome sequencing revealed three novel variants in the DYNC2H1 gene, namely NM_001080463.2:c.6809G > A p.(Arg2270Gln), NM_001080463.2:3133C > T p.(Gln1045Ter), and NM_001080463.2:c.337C > T p.(Arg113Trp); one novel variant in the IFT172 gene, NM_015662.3:4540-5 T > A; and one novel variant in the WDR19 gene, NM_025132.4:c.2596G > C p.(Gly866Arg). The genotypes of DYNC2H1, IFT172 and WDR19 and the phenotypes of the fetuses give hints for the diagnosis of short-rib thoracic dysplasia (SRTD) with or without polydactyly 3, 10, and 5, respectively.ConclusionOur findings expand the mutation spectrum of DYNC2H1, IFT172 and WDR19 associated with skeletal ciliopathies, and provide useful information for prenatal diagnosis and genetic counseling on rare skeletal disorders.

A novel missense mutation identified in a rare skeletal disorder acromesomelic dysplasia in India

A novel missense mutation identified in a rare skeletal disorder acromesomelic dysplasia in India

Gorham-Stout disease

Gorham-Stout disease (GSD), also called vanishing bone disease, is an extremely rare skeletal disorder characterized by destruction of osseous matrix due to a massive process of osteolysis and proliferation of blood and lymph vessels, followed by a lack of deposition of new bone matrix. GSD can occur either at the level of a single bone or affect several bones, although the bones of the upper part of the skeletal system, especially at maxillofacial level, seem to be preferentially involved. To date, the diagnosis of GSD, mainly based on radiographic and histological analyses, is often made by excluding the presence of other diseases. Unfortunately, despite the several studies on GSD that have been carried out since its discovery, the pathogenesis of this disease is still unknown. Consequently, the therapies currently used are mainly aimed at keeping the disease under control, trying to avoid its progression, but they are not decisive, and this is in fact due to the lack of knowledge of its pathogenetic and pathophysiological bases. This concise review aims to provide a brief overview of the state of the art of current research regarding the etiopathogenesis of GSD and the discovery and development of new and different diagnostic and therapeutic methods. KEY WORDS: GSD, lymph vessel, blood vessel, bone cells

A Rare Skeletal Disorder, Fibrous Dysplasia: A Review of Its Pathogenesis and Therapeutic Prospects.

Fibrous dysplasia (FD) is a rare, non-hereditary skeletal disorder characterized by its chronic course of non-neoplastic fibrous tissue buildup in place of healthy bone. A myriad of factors have been associated with its onset and progression. Perturbation of cell-cell signaling networks and response outputs leading to disrupted building blocks, incoherent multi-level organization, and loss of rigid structural motifs in mineralized tissues are factors that have been identified to participate in FD induction. In more recent years, novel insights into the unique biology of FD are transforming our understandings of its pathology, natural discourse of the disease, and treatment prospects. Herein, we built upon existing knowledge with recent findings to review clinical, etiologic, and histological features of FD and discussed known and potential mechanisms underlying FD manifestations. Subsequently, we ended on a note of optimism by highlighting emerging therapeutic approaches aimed at either halting or ameliorating disease progression.

Indian patients with CHST3-related chondrodysplasia with congenital joint dislocations.

CHST3-related chondrodysplasia with congenital joint dislocations (CDCJD, #MIM 143095), is a rare genetic skeletal disorder caused by biallelic loss of function variants in CHST3. CHST3 is critical for the sulfation of chondroitin sulfate. This study delineates the clinical presentation of nine individuals featuring the key symptoms of CDCJD; congenital joint (knee and elbow) dislocations, short trunk short stature progressive vertebral anomalies, and metacarpal shortening. Additional manifestations include irregular distal femoral epiphysis, supernumerary carpal ossification centers, bifid humerus, club foot, and cardiac abnormalities. Sanger sequencing was carried out to investigate molecular etiology in eight patients and exome sequencing in one. Genetic testing revealed five homozygous variants in CHST3 (four were novel and one was previously reported). All these variants are located on sulfotransferase domain of CHST3 protein and were classified as pathogenic/ likely pathogenic. We thus report on nine individuals with CHST3-related chondrodysplasia with congenital joint dislocations from India and suggest monitoring the health of cardiac valves in this condition.

THU455 Sclerostin Inhibitor Use In The Medical Management Of Osteogenesis Imperfecta Type III

Abstract Disclosure: M.D. Lundholm: None. A. Derkyi: None. S. Talvacchio: None. J.C. Marini: Other; Self; Ultragenyx, Amgen Inc. L.Z. Khan: None. Background: Osteogenesis imperfecta (OI) is a rare collagen-related hereditary skeletal disorder with an increased fracture risk from minimal trauma, short stature, and bone deformity. OI is associated with defects in collagen structure or synthesis, high bone turnover, and paradoxical bone hypermineralization. The optimal medical therapies for bone health in these patients are unknown. Clinical Case: A 27-year-old woman with OI presented to clinic for bone health. She was diagnosed with OI type III by phenotype, collagen biochemistry, and genetic analyses (heterozygous for a COL1A1 Gly187Ala substitution) following fractures at age 4 mos. She experienced dozens of fractures, has had orthopedic hardware in bilateral femora, left tibia, humerus, and radius, and right tibia, as well as spine fusion at age 7 yrs. She had not fractured in over 3 yrs which she attributed to the stability of her automatic wheelchair. She had no family history of OI and had been in studies at the NIH; from ages 6-9 yrs she received pamidronate (1 mg/kg/cycle q3m) with BMD improvement. Presently, her vitals were normal, with height of 3’6” (25-50th percentile for type III OI females) and weight of 64 lbs (BMI 25.5 kg/m2). On exam she had blue sclera, midface hypoplasia, dentinogenesis imperfecta, severe kyphosis and scoliosis, and a barrel chest. She had normal calcium, PTH, and 25-OH vitamin D levels. Skull CT showed 1 mm increase in basilar invagination (16 to 17 mm). DEXA demonstrated progressive decline in radial BMD from 0.671 g/cm2 to 0.625 g/cm2 over 3 yrs (z-score -0.4 to -1.1) into the osteopenic range. For worsening bone disease, she is starting romosozumab 210 mg monthly. Discussion: While several agents increase BMD in OI, there are no placebo-controlled studies to show an effect on fracture rate. Bisphosphonates including pamidronate are used most commonly, with increased areal BMD, decreased bone turnover, but also increased mineralization of already brittle bone. Overall, two Cochran reviews failed to support decreased fracture rates from bisphosphonates, and there is risk of adynamic bone with chronic use. There is even less evidence for use of denosumab which is additionally associated with a rebound effect upon discontinuation. Sclerostin inhibitors are the newest agents with both anabolic and antiresorptive effects and good results in OI mouse models. Phase 2 data with sestrusumab showed increased BMD and decreased bone turnover. Ongoing studies are looking at sclerostin inhibitor use in adults and adolescents. From a practical standpoint, romosozumab has a shorter effect with quicker offset than bisphosphonates if needed to stop for fracture healing. Conclusion: Sclerostin inhibitors are an option for the medical treatment of OI. Further investigation is needed to determine long-term safety, optimal duration, and use of sclerostin inhibitors in combination with antiresorptive agents in OI. Presentation: Thursday, June 15, 2023

Combination of osteogenesis imperfecta and hypophosphatasia in three children with multiple fractures, low bone mass and severe osteomalacia, a challenge for therapeutic management

Osteogenesis imperfecta (OI) and hypophosphatasia (HPP) are rare skeletal disorders caused by mutations in the genes encoding collagen type I (COL1A, COL1A2) and tissue-non-specific isoenzyme of alkaline phosphatase (ALPL), respectively. Both conditions result in skeletal deformities and bone fragility although bone tissue abnormalities differ considerably. Children with OI have low bone mass and hypermineralized matrix, whereas HPP children develop rickets and osteomalacia.We report a family, father and three children, affected with growth retardation, low bone mass and recurrent fractures. None of them had rickets, blue sclera or dentinogenesis imperfecta. ALP serum levels were low and genetics revealed in the four probands heterozygous pathogenic mutations in COL1A2 c.838G > A (p.Gly280Ser) and in ALPL c.1333T > C (p.Ser445Pro). After multidisciplinary meeting, a diagnostic transiliac bone biopsy was indicated for each sibling for therapeutic decision.Bone histology and histomorphometry, as compared to reference values of children with OI type I as well as, to a control pediatric patient harboring the same COL1A2 mutation, revealed similarly decreased trabecular bone volume, increased osteocyte lacunae, but additionally severe osteomalacia. Quantitative backscattered electron imaging demonstrated that bone matrix mineralization was not as decreased as expected for osteomalacia.In summary, we observed within each biopsy samples classical features of OI and classical features of HPP. The apparent nearly normal bone mineralization density distribution results presumably from divergent effects of OI and HPP on matrix mineralization. A combination therapy was initiated with ALP enzyme-replacement and one month later with bisphosphonates. The ongoing treatment led to improved skeletal growth, increased BMD and markedly reduced fracture incidence.

862 Successful Surgical Management of Chylothorax Secondary to Gorham-Stout Disease

Abstract Introduction Gorham-Scout Disease (GSD) is a rare skeletal disorder of unknown aetiology characterised by progressive osteolysis and excessive lymphovascular proliferation. Chylothorax is a severe and life-threatening complication of GSD that confers a poor prognosis. Literature review reveals only one previous case of successful surgical management for chylothorax secondary to GSD. Case presentation A teenage asylum seeker presented with a large left pleural effusion on a background of chronic left flank collection secondary to lymphovascular malformation. Cytological analysis of the fluid drained from chest drain insertion confirmed a chylothorax. A posterior rib excision biopsy helped to confirm the diagnosis of GSD. She had VATS ligation of the thoracic duct and talc pleurodesis, however, due to recollection and ongoing symptomatic discomfort, she subsequently underwent left thoracotomy, decortication of lung and pleurectomy. These surgical interventions helped to stabilise the chylothorax with ongoing management for GSD related to radiotherapy and pain control via the administration of bisphosphonates. Conclusions GSD is a rare disease that can develop a number of severe complications including a chylothorax. Management via surgical and radiotherapeutic techniques can provide long term remission, however, other modalities may be needed in order to optimise analgesic requirements.

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 6-12months. 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.