Phosphaturic mesenchymal tumor demonstrated by 68Ga-DOTATATE PET/CT in a patient: a case report.

Tumor-induced osteomalacia (TIO) is a paraneoplastic syndrome caused by abnormally high levels of fibroblast growth factor 23 (FGF-23), most commonly produced and secreted by small phosphaturic mesenchymal tumors (PMT). These tumors can show various anatomic locations throughout soft tissue and bone. The presence of the tumor itself rarely causes symptoms. Nonspecific symptoms such as muscle weakness and musculoskeletal pain are related to the developing hypophosphatemia and osteomalacia as a secondary effect of the increased circulating levels of FGF-23. Therefore, as the initial presentation can mimic a wide range of metabolic or inflammatory diseases, proper diagnosis is often delayed. Localization of the tumor is crucial, as its complete surgical resection is the only curative treatment. Whole-body functional imaging targeting the overexpression of somatostatin receptors (SSTR) on the surface of the PMT cells, is a highly specific and sensitive imaging method to detect the primary tumor site. Here, we discuss a case of TIO in a patient initially presenting with symptoms of inflammatory spondyloarthritis. SSTR positron emission imaging using 68Ga-DOTATATE was central in diagnosing and localizing the primary tumor.

Two Cases of Improved Bone Mineral Density Following Treatment of Hypophosphatemic Osteomalacia Due to FGF23 Excess.

Excess fibroblast growth factor-23 (FGF23) causes renal phosphorous wasting and impaired activation of vitamin D leading to osteomalacia. Tumor-induced osteomalacia (TIO) is a rare cause of FGF23-mediated hypophosphatemia. We present 2 patients with FGF23-mediated hypophosphatemia who had low bone mineral density (BMD) at diagnosis and remarkable improvements in BMD with treatment. Patient 1 is a 43-year-old man who had years of progressive pain, difficulty ambulating, and multiple fractures. Patient 2 is a 48-year-old nonverbal man with autism and intellectual disability who had months of progressively declining mobility, presumed pain, and multiple fractures. Workup in both cases revealed hypophosphatemia, evidence of renal phosphorous wasting, and elevated FGF23. Patient 1 was diagnosed with TIO when imaging identified a subcutaneous left flank mass and excision resulted in rapid symptom improvement; he experienced a 96% increase in lumbar spine (LS) BMD after surgery. Patient 2 has had multiple scans over several years, but no FGF23-secreting tumor has been identified. He has been maintained on medical treatment with phosphorous and calcitriol with improvement in functioning and 48% increase in LS BMD. Both patients had improvements in BMD with treatment, with more pronounced improvement in the patient with TIO managed surgically.

A case report of Tumor-Induced Osteomalacia (TIO) caused by central giant cell granuloma.

Introduction: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome defined by severe hypophosphatemia, bone loss, fractures, and muscle weakness. Identifying of the tumor site is often difficult. The primary treatment for Tumor-induced osteomalacia (TIO) is currently surgical resection. Removing the primary tumor is the most definitive treatment for this disease. Methods: Here we describe the case of a 32-year-old man who exhibited sever muscle weakness and pain that had continued for three years. The patient has three sisters and one brother, all of whom are completely healthy and free of bone and muscle problems.Laboratory data indicate low serum phosphorus, normal serum and urine calcium level, besides raised alkaline phosphatase level. Due to elevated phosphorus levels in the urine and the lack of an alternative source for phosphorus excretion, along with the absence of short stature, bone deformities, and a negative family history that might suggest the potential for Tumor-induced osteomalacia (TIO), an octreotide scan was performed to the localized the tumor site. The scan, corroborated by CT and MRI scans, displayed absorption in the right maxillary sinus. Surgical excision of the lesion confirmed it to be a central giant cell granuloma. Results: Following surgery and without receiving any other treatment, the patient's phosphorus levels and clinical condition improved compared to before the surgical treatment. Subsequently, the symptoms of muscle weakness and skeletal pain significantly diminished, and the patient regained the ability to move. Conclusion: Tumor enucleation was conducted, and the pathological examination of the maxillary sinus lesion unveiled a central Giant cell granuloma. The patient had clinical and laboratory improvement after surgery. This finding confirmed our diagnosis of a paraneoplastic hypophosphatemia associated with a giant cell granuloma.

Bilateral femoral shaft fractures in osteomalacia: A case report and literature review.

INTRODUCTION AND IMPORTANCE: When two non-traumatic femoral shaft fractures happen at the same time, they are usually not caused by high-energy trauma or medical conditions like osteomalacia caused by poor nutrition, long-term bisphosphonate medication use, or steroid use. Because this phenomenon is connected to inadequate bone mineralization and bone metabolism, it occurs when a bone is consistently under high stress. CASE PRESENTATION: A 40-year-old lady with a medical history of osteomalacia, including continuous vitamin D replacement therapy, showed up at the emergency room complaining of discomfort and swelling in her right thigh caused by a fall. During the emergency examination, X-rays showed a subtrochanteric fracture with a short oblique fracture line and a displaced oblique fracture in the right femoral shaft, but no fragmentation in the left femoral shaft. Osteomalacia caused the bilateral femoral shaft fracture in which the patient was identified as being displaced. We planned a surgical correction that included a closed reduction with intramedullary nailing and distal static screws on the right side, as well as intramedullary nailing followed by locking screw insertion on the left. Following the operation, the avoidance of bisphosphonate medications gained precedence. CLINICAL DISCUSSION: Patients of any age who come with bone pain, non-traumatic fractures, and muscle weakness should have their blood vitamin D, ALP levels, and BMD evaluated for osteomalacia. If a conventional X-ray shows normal, an MRI or bone scan of both hips is recommended to rule out any underlying fatigue fractures. Finding and treating the underlying cause of osteomalacia can help improve the prediction. CONCLUSION: Intramedullary nailing with screws is the most effective treatment for femoral shaft fractures. Improving patient outcomes relies on identifying and treating the underlying cause of osteomalacia. Given the patient's history and condition, avoiding bisphosphonate medicines following surgery was a primary priority in this case.

A Rare Case of Phosphaturic Mesenchymal Tumor Distal Femur in a Young Female.

Introduction: Phosphaturic mesenchymal tumors (PMTs) are rare bone neoplasms with diverse clinical presentations, often posing diagnostic challenges. Case Report: We describe the case of a 37-year-old female schoolteacher with a PMT localized in the distal femur. Diagnostic indicators included hypophosphatemia, hyperphosphaturia, elevated fibroblast growth factor-23 levels, and clinical symptoms of osteomalacia. Surgical management involved tumor resection and limb salvage surgery with a megaprosthesis. The post-operative period was uneventful, leading to a stable discharge. On follow-up, the patient showed no signs of recurrence, regained full ambulation, remained pain-free, and resumed teaching comfortably. Conclusion: This case highlights the importance of considering PMT in patients with unusual clinical symptoms, accompanied by hypophosphatemia, hyperphosphaturia, and osteomalacia, and demonstrates successful surgical management, leading to a favorable outcome.

FGF23-secreting sinonasal tumour presenting with acute subdural haemorrhage and tumour-induced osteomalacia.

A female in her 50s developed a headache, collapsed and was noted to have an acute atraumatic subdural haemorrhage (SDH) requiring surgical evacuation and intracranial pressure-directed therapy. Her background included recurrent epistaxis, severe generalised bone pain and multiple insufficiency fractures and an undifferentiated autoimmune connective tissue disease. Chronic hypophosphataemia, elevated alkaline phosphatase and raised fibroblast growth factor 23 (FGF23) were also noted. An MRI head and subsequent 68Ga CT/positron emission tomography scan demonstrated an intensely avid tumour in the right ethmoid sinus, extending intracranially. Phosphate was aggressively replaced, and alfacalcidol was initiated to circumvent the effects of FGF23 on her kidneys and bone minerals. The tumour was biopsied and then definitively resected via combined endonasal and craniotomy approaches, resulting in good clinical improvement. FGF23 titre and serum phosphate both normalised leaving the diagnosis of a phosphaturic mesenchymal tumour-secreting FGF23, leading to tumour-induced osteomalacia.

Osteolytic mystery: A rare case of pathologic fracture from a phosphaturic mesenchymal tumor in hip and femur.

Phosphaturic mesenchymal tumor (PMT) is a rare tumor causing bone complications and myopathy. Histologically, PMT displays a mix of spindled cells, osteoclast-like giant cells, basophilic matrix, and flocculent or "grungy" calcification. Here we describe a case of PMT in the right hip and proximal femur, initially suspected to be multiple myeloma, presenting with osteolytic lesions and elevated alkaline phosphatase. Tests for malignancy were negative, but a subsequent biopsy confirmed PMT. The patient underwent hip biopsy, femur resection, and hemiarthroplasty, with follow-up MRI recommended.

Biopsies from patients with sacral insufficiency fracture are characterized by low bone matrix mineralization and high turnover.

Sacral insufficiency fractures are known to occur primarily in older women without adequate trauma. While an association with low bone mineral density (ie, osteoporosis) has been reported, more detailed information on local bone quality properties in affected patients is not available. In the present study, core biopsies were obtained from the S1 sacral ala in patients with a bilateral sacral insufficiency fracture (type IV according to the fragility fractures of the pelvis classification) who required surgical stabilization. Dual energy X-ray absorptiometry (DXA) and laboratory bone metabolism analyses were performed. For comparison, control biopsies were acquired from skeletally intact age- and sex-matched donors during autopsy. A total of 31 biopsies (fracture: n = 19; control: n = 12) were evaluated by micro-computed tomography, histomorphometry on undecalcified sections, and quantitative backscattered electron imaging (qBEI). DXA measurements showed mean T-scores in the range of osteoporosis in the fracture cohort (T-scoremin -2.6 ± 0.8). Biochemical analysis of bone metabolism parameters revealed high serum alkaline phosphatase and urinary deoxypyridinoline/creatinine levels. In the biopsies, a loss of trabecular microstructure along with increased osteoid values were detected in the fracture patients compared with controls (osteoid volume per bone volume 5.9 ± 3.5 vs. 0.9 ± 0.5%, p <.001). We also found evidence of microfractures with chronic healing processes (ie, microcallus) as well as pronounced hypomineralization in the biopsies of the fracture cohort compared with the controls as evidenced by lower CaMean measured by qBEI (22.5 ± 1.6 vs. 24.2 ± 0.5 wt%, p =.003). In conclusion, this high-resolution biopsy study provides evidence of local hypomineralization in patients with sacral insufficiency fractures, pointing to reduced fracture resistance but also a distinct phenotype other than the predominant loss of trabeculae as in postmenopausal osteoporosis. Our data highlight the importance of therapies that promote bone mineralization to optimally treat and prevent sacral insufficiency fractures.

PTH like substance secreting mesenchymal tumor causing oncogenic osteomalacia; unravelling the difficulties in localization - A report of 2 cases.

Background: Oncogenic osteomalacia is a rare paraneoplastic association of Phosphaturic mesenchymal tumor (PMT) secreting excessive levels of a PTH like substance. They usually remain undiagnosed and patients suffer for years. The rarity of this tumor and its non-specific clinical presentations poses great challenge to the treating surgeons. Its management is poorly described in literature. We report two of such rare cases without much diagnostic delay. Case report: We had 2 cases; A 53-year-old south east Asian male with 6 months of debilitating pain over multiple sites, and another 44-year-old male patient with complaints of low back ache, and pain over both lower and upper limbs for 1.5 years. Both had low serum phosphorus and elevated FGF-23 values, but all other parameters were normal. A PMT was suspected and confirmed on a Ga68- DOTATOC scan in both cases, and on complete excision, their symptoms and the altered blood parameters got normalized. Histology was consistent with PMT. Conclusion: Accurate and timely diagnosis of a PMT with non-specific features are extremely challenging, but not without solutions. Even though a tumor of rarity, with the appropriate imaging modalities like Ga68- DOTATOC scan, and estimation of FGF-23 and serum phosphorus levels, they can be diagnosed. Once identified, complete removal is often curative within a few months.

Impact of altitude on the development of low bone mineral density and osteoporosis in individuals aged 50 years and older: protocol for a multicentre prospective cohort study.

INTRODUCTION: Osteoporotic fractures are a leading cause of disability and contribute significantly to medical care costs worldwide. Variations in bone mineral density and the risk of osteoporosis are notably influenced by altitude. This study aims to longitudinally examine individuals with osteoporosis and low bone mass at three different altitudes (low, high and very high) to understand the effects of high-altitude environments on bone density. METHODS AND ANALYSIS: This multicentre, prospective cohort study will involve 893 participants divided into three groups based on altitude: low (500-1500 m), high (2500-4500 m) and very high (4500-5500 m). Participants will undergo comprehensive diagnostic assessments, including demographic data collection, structured questionnaires, medical examinations and clinical laboratory tests. Follow-up visits will occur annually for a minimum of 5 years. The primary outcome will be changes in bone mineral density values. Secondary outcomes will include the incidence of osteoporosis and osteoporotic fractures. Cox proportional hazard models will be used to calculate the risk associated with osteoporotic events and related fractures. ETHICS AND DISSEMINATION: The study has been approved by the Institutional Review Board of the Hospital of Chengdu Office of People's Government of Tibetan Autonomous Region (No: 2024-70). The acquired insights will be disseminated via academic forums, scholarly articles and stakeholder engagement sessions. TRIAL REGISTRATIONNUMBER: ChiCTR2300078872.

Latent metabolic bone disease, skeletal dysplasia and other conditions related to low bone formation among 38 patients with subtrochanteric femoral fractures: a retrospective observational study.

Subtrochanteric femoral fracture is rare and intractable due to the possible association with low bone formation. Retrospective analysis of 38 patients with subtrochanteric femoral fractures revealed that four patients suffered from disorders related to low bone formation and there were specific treatments for two of them. PURPOSE: The main aim of this study was to detect latent metabolic bone diseases and skeletal dysplasia associated with low bone formation among patients with morphologic atypical femoral fracture (AFF). A second aim was to evaluate the frequency of recognized risk factors, such as antiresorptive agents, glucocorticoids, and age. METHODS: Clinical information was retrospectively analyzed among 38 Japanese patients who were admitted to the Department of Orthopedic Surgery and Spinal Surgery and the Division of Emergency and Critical Care Medicine at the University of Tokyo Hospital with diagnoses of subtrochanteric fractures between February 2012 and March 2022. RESULTS: Among 38 patients (including 30 females), 21 patients were aged 75 and over. Ten patients had past oral glucocorticoid use, and 18 had past antiresorptive agent use. Two patients were diagnosed with hypophosphatemic osteomalacia after the development of fractures. One patient was suspected to be a carrier of a loss-of-function variant of alkaline phosphatase, biomineralization associated (ALPL), and one other patient had previously been genetically diagnosed with pycnodysostosis. Among four patients with a diagnosis or suspicion of these metabolic bone diseases and skeletal dysplasia, four had past clinical fractures, two had past subtrochanteric femoral fractures, and two had subtrochanteric femoral fractures on both sides. CONCLUSION: If clinicians encounter patients with morphologic AFF, latent diseases related to low bone formation should be carefully differentiated because appropriate treatment may prevent delayed union and recurrent fractures. Additionally, it may be desirable to exclude these bone diseases in advance before initiating long-term use of antiresorptive agents in osteoporotic patients by screening with serum alkaline phosphatase levels to reduce the risk of morphologic AFF.

Long-term Evolution of Hypophosphatemia and Osteomalacia in a Patient With Multiple Myeloma.

Multiple myeloma commonly manifests with symptoms arising from the involvement of various organs, particularly the bone and kidneys. In this report, we detail the case of a 44-year-old man who was diagnosed with multiple myeloma associated with reduced bone density. He exhibited clinical findings of osteomalacia due to Fanconi syndrome (characterized clinically by bone pain and proximal weakness and biochemically by elevated serum alkaline phosphatase, hypophosphatemia, hypouricemia, and glucosuria). With phosphate replacement, there was a notable improvement in bone pain, osteomalacia, and bone mineral density. Nevertheless, the patient continued to experience renal wasting of phosphate, uric acid, and glucose despite achieving remission from multiple myeloma for nearly 2 years. Our case highlights several important clinical features of myeloma-associated Fanconi syndrome, including the need to recognize this complication to appropriately treat the underlying bone disease while avoiding osteoclast inhibitors and the long-term persistence of the proximal renal tubulopathy despite achieving remission from myeloma and correction of osteomalacia.

Tumor-Induced Osteomalacia: A Case Report.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome with a variable presentation. We present a case of a 55-year-old female who presented with pain in the bilateral hip region for the last two years. On routine biochemical evaluation, she was found to have hypophosphatemia with an X-ray of the bilateral hip region showing an acute stress fracture in the bilateral intertrochanteric region of the femur. An evaluation for the cause of hypophosphatemia revealed renal phosphate loss with low percentage tubular reabsorption of phosphate (% TRP) of 83% (reference range: 85-95%), with tubular maximum phosphate reabsorption per unit glomerular filtration rate (TmP/GFR) of 2.07 mg/dL (reference range: 2.5-4.5 mg/dL (0.67 mmol/L; range: 0.84-1.23 mmol/L)). Further evaluation revealed elevated levels of intact fibroblast growth factor, 445.7 pg/mL (reference range: 23-95 pg/mL). A 68-Gallium DOTA-1-Nal3-octreotide (DOTANOC) PET-CT revealed a focal increased tracer uptake with a lytic lesion at the lateral metaphyseal aspect of the proximal right tibia, suspicious of somatostatin receptor avid mesenchymal tumor, leading to the diagnosis of TIO. Definitive treatment with complete surgical excision of the tumor was done. Postoperatively, her phosphorus level was within the normal target range even without oral phosphate supplementation. While it is a rare condition, a proper and systemic workup can lead to timely diagnosis and management of this debilitating benign condition.

Hypophosphatemic osteomalacia due to cadmium toxicity in silverware industry: A curious case of aches and pains.

Hypophosphatemic osteomalacia in an adult often gives clinical diagnostic challenges. Usually, they are caused by either tumor-induced osteomalacia or due to genetically mediated hypophosphatemia, particularly X-linked hypophosphatemia. However, heavy metal toxicity, leading to global proximal renal tubular dysfunction, is a rare cause, and in particular, cadmium toxicity is rarely encountered in clinical practice. The presence of bony pain and neurological deficit, along with a classical exposure history, provides the diagnostic clue. In this background, here we present a middle-aged man who had severe bony pains all over his body and lower back stiffness for five years. He underwent an initial workup as a suspected spondyloarthropathy but was later on, found to have hypophosphatemic osteomalacia and severe proximal renal tubular dysfunction. Further, the workup revealed elevated FGF-23. His occupational history revealed prolonged exposure to cadmium fumes in the silverware industry. He improved moderately with treatment; however, significant renal damage is still present. This case highlights the importance of considering cadmium toxicity in proper clinical and occupational contexts in the evaluation of hypophosphatemic osteomalacia in an adult.

Burosumab treatment of X-linked hypophosphatemia patients: interim analysis of the SUNFLOWER longitudinal, observational cohort study.

X-linked hypophosphatemia (XLH) is a genetic disease that results in excessive FGF23, chronic hypophosphatemia, and musculoskeletal abnormalities, with affected patients experiencing symptoms such as bone pain, bone deformity, fracture, and pseudofracture. Burosumab is a fully human monoclonal antibody that binds to FGF23, improving lowered serum 1,25(OH)2D and phosphate levels in patients with XLH. There are insufficient data on the use of burosumab, its safety, and the outcomes of treated patients in a real-world setting. The SUNFLOWER (Study of longitUdinal observatioN For patients with X-Linked hypOphosphatemic rickets/osteomalacia in collaboration With Asian partnERs) study is an ongoing longitudinal, observational cohort study of patients with XLH in Japan and South Korea. Enrollment occurred between April 2018 and December 2020. This interim analysis compared the background characteristics of patients who received burosumab with those who did not, and assessed improvements in biomarkers, physical and motor function, health-related quality-of-life (HRQOL) and other patient-reported outcome (PRO) measures, as well as the safety of burosumab treatment in 143 Japanese patients from 15 institutions over 6 mo. The patients had a median [interquartile range] age of 17.5 [11.0, 38.8] yr and 98 (68.5%) were female. Among patients aged <18 and ≥18 yr, 40/73 (54.8%) and 25/70 (35.7%) received burosumab, respectively. More patients aged ≥18 who received burosumab had bone pain at baseline vs those not treated with burosumab (6/25, 24.0% vs 2/45, 4.4%, p=.021). Patients treated with burosumab had improved serum phosphate and 1,25(OH)2D levels; moreover, rickets severity and HRQOL/PRO measures, such as pain, appeared to improve over 6 mo of burosumab treatment, and no new safety concerns were identified. This study identified trends in the background characteristics of patients with XLH who receive burosumab in real-world clinical practice. Furthermore, the results support the use of burosumab therapy in real-world settings.

Iron and bones: effects of iron overload, deficiency and anemia treatments on bone.

Iron is a vital trace element and exerts opposing effects on bone in both iron overload and iron deficiency situations. Remarkably, iron supplementation through intravenous infusion in patients with iron deficiency can also have detrimental effects on bone in special cases. The diverse mechanisms underlying these effects and their manifestations contribute to the complexity of this relationship. Iron overload impacts both bone resorption and formation, accelerating bone resorption while reducing bone formation. These effects primarily result from the direct action of reactive oxygen species (ROS), which influence the proliferation, differentiation, and activity of both osteoclasts and osteoblasts differently. This imbalance favors osteoclasts and inhibits the osteoblasts. Simultaneously, multiple pathways, including bone morphogenic proteins, RANK ligand, and others, contribute to these actions, leading to a reduction in bone mass and an increased susceptibility to fractures. In contrast, iron deficiency induces low bone turnover due to energy and co-factor deficiency, both of which require iron. Anemia increases the risk of fractures in both men and women. This effect occurs at various levels, reducing muscular performance and, on the bone-specific level, decreasing bone mineral density. Crucially, anemia increases the synthesis of the phosphaturic hormone iFGF23, which is subsequently inactivated by cleavage under physiological conditions. Thus, iFGF23 levels and phosphate excretion are not increased. However, in specific cases where anemia has to be managed with intravenous iron treatment, constituents-particularly maltoses-of the iron infusion suppress the cleavage of iFGF23. As a result, patients can experience severe phosphate wasting and, consequently, hypophosphatemic osteomalacia. This condition is often overlooked in clinical practice and is often caused by ferric carboxymaltose. Ending iron infusions or changing the agent, along with phosphate and vitamin D supplementation, can be effective in addressing this issue.

Metabolic Bone Disease.

Metabolic bone diseases encompass a group of disorders characterized by abnormalities in bone metabolism, structure, or mineralization. These disorders negatively impact overall health and quality of life and place individuals at high risk for fracture, which may increase morbidity and mortality. Clinicians should understand who is at risk for these disorders, select individuals who warrant further workup, determine appropriate laboratory and imaging evaluation, interpret results in a clinical context, and choose an optimal management strategy based on the individual patient.

Hypophosphatemic rickets and short stature.

An 18-month-old male presented with gross motor delay and poor growth (weight z-score -2.21, length z-score -4.26). Radiographs showed metaphyseal irregularities suggesting metaphyseal dysplasia and sagittal craniosynostosis. Biochemical evaluation supported hypophosphatemic rickets [serum phosphorus 2.3 mg/dL (reference range (RR) 4.3-6.8), alkaline phosphatase 754 unit/L (RR 156-369)] due to renal phosphate wasting (TmP/GFR 4.3 mg/dL, normal for age 4.3-6.8), with C-terminal fibroblast growth factor 23 (FGF23) 125 RU/mL (>90 during hypophosphatemia suggests FGF23-mediated hypophosphatemia). Treatment was initiated with calcitriol and phosphate. Genetic analysis showed a pathogenic variant of FGF23: c.527G > A (p.Arg176Gln) indicative of autosomal dominant hypophosphatemic rickets (ADHR). Consistent with reports linking iron deficiency with the ADHR phenotype, low ferritin was detected. Following normalization of ferritin level (41 ng/mL) with oral ferrous sulfate replacement, biochemical improvement was demonstrated (FGF23 69 RU/mL, phosphorus 5.0 mg/dL and alkaline phosphatase 228 unit/L). Calcitriol and phosphate were discontinued. Three years later, the patient demonstrated improved developmental milestones, linear growth (length Z-score -2.01), radiographic normalization of metaphyses, and stabilization of craniosynostosis. While the most common cause of hypophosphatemic rickets is X-linked hypophosphatemia, other etiologies should be considered as treatment differs. In ADHR, normalization of iron leads to biochemical and clinical improvement.

The role of GDF5 in regulating enthesopathy development in the Hyp mouse model of XLH.

X-linked hypophosphatemia (XLH) is caused by mutations in PHEX, leading to rickets and osteomalacia. Adults affected with XLH develop a mineralization of the bone-tendon attachment site (enthesis), called enthesopathy, which causes significant pain and impaired movement. Entheses in mice with XLH (Hyp) have enhanced bone morphogenetic protein (BMP) and Indian hedgehog (IHH) signaling. Treatment of Hyp mice with the BMP signaling blocker palovarotene attenuated BMP/IHH signaling in Hyp entheses, thus indicating that BMP signaling plays a pathogenic role in enthesopathy development and that IHH signaling is activated by BMP signaling in entheses. It was previously shown that mRNA expression of growth/differentiation factor 5 (Gdf5) is enhanced in Hyp entheses at P14. Thus, to determine a role for GDF5 in enthesopathy development, Gdf5 was deleted globally in Hyp mice and conditionally in Scx + cells of Hyp mice. In both murine models, BMP/IHH signaling was similarly decreased in Hyp entheses, leading to decreased enthesopathy. BMP/IHH signaling remained unaffected in WT entheses with decreased Gdf5 expression. Moreover, deletion of Gdf5 in Hyp entheses starting at P30, after enthesopathy has developed, partially reversed enthesopathy. Taken together, these results demonstrate that while GDF5 is not essential for modulating BMP/IHH signaling in WT entheses, inappropriate GDF5 activity in Scx + cells contributes to XLH enthesopathy development. As such, inhibition of GDF5 signaling may be beneficial for the treatment of XLH enthesopathy.

X-linked hypophosphatemia (XLH) is a rare bone disorder that leads to short stature and poorly mineralized bones. As adults, patients with XLH often develop a mineralization of the bone-tendon attachment site, called enthesopathy, which results in significant pain. We previously showed that Achilles bone-tendon attachment sites (entheses) in mice with XLH (Hyp) have an enthesopathy characterized by increased bone morphogenetic protein (BMP) signaling. In the current studies, we show that treating Hyp mice with the BMP signaling inhibitor palovarotene prevents enthesopathy, demonstrating that the increased BMP signaling in Hyp entheses leads to enthesopathy development. We also reported that gene expression of Gdf5, which activates BMP signaling, is enhanced in Hyp entheses. Therefore, to determine if the enhanced Gdf5 expression leads to the increased BMP signaling seen Hyp entheses, Gdf5 was deleted from Hyp mice and also deleted specifically in the entheses of Hyp mice. In both mouse models, enthesopathy development was attenuated, demonstrating that the increased Gdf5 expression in Hyp entheses plays a role in enthesopathy development. These data indicate that blocking GDF5 and BMP signaling may prevent enthesopathy in patients with XLH.