Bone Disease Research Articles

Use of a newly developed minimally invasive bilateral fixed angle locking system in the treatment of pathological pelvic fractures: a case series

BackgroundMetastatic bone disease (MBD) and its complications have a significant impact on patients’ quality of life. Pathological fractures are a particular problem as they affect patient mobility and pose a high risk of non-union. The pelvis is frequently affected by MBD and its fixation is challenging. We present a case series of three pathological sacral fractures treated with a new minimally invasive bilateral fixed angle locking system.Case presentationCase 1 and 2 suffered a pathological transforaminal sacral fracture without adequate trauma in stage 4 carcinomas (gastric cancer and breast cancer). Both were initially treated with non-surgical treatment, which had only a limited effect and led to imminent immobility. Both were operated on with fluoroscopic navigation and underwent transsacral SACRONAIL® stabilisation according to CT morphology (S1 + S2 and S1 respectively). Immediately after the operation, pain decreased and mobilisation improved. Case 3 had a pathological transalar sacral fracture during the 2nd cycle of chemotherapy due to non-Hodgkin’s lymphoma. He soon became immobile and could only move in a wheelchair. The operation was performed with CT navigation due to the very small corridors and an implant was inserted in S1 and S2. The patient reported immediate pain relief and his ability to walk improved over the following months. Despite continued chemotherapy, no wound complications occurred.ConclusionsThe cases show the advantages of the minimally invasive bilateral fixed angle locking system SACRONAIL® in the treatment of patients with pathological sacral fractures. It allows immediate full weight bearing and the risk of secondary surgical complications is low. All cases showed an improvement in pain scores and mobility.

ALKBH5 regulates etoposide-induced cellular senescence and osteogenic differentiation in osteoporosis through mediating the m6A modification of VDAC3.

Osteoporosis, a common bone disease in older individuals, involves the progression influenced by N6-methyladenosine (m6A) modification. This study aimed to elucidate the effects of VDAC3 m6A modification on human bone mesenchymal stromal cell (BMSC) senescence and osteogenic differentiation. BMSCs were treated with etoposide to induce senescence. Senescence was assessed by β-galactosidase staining and quantitative real-time PCR (qPCR), and osteogenic differentiation was evaluated using Western blot, alkaline phosphatase, and alizarin red S staining. VDAC3 and ALKBH5 expression were quantified by qPCR, and their interaction was assessed by RNA immunoprecipitation (RIP) and luciferase reporter assay. m6A methylation was analyzed using the Me-RIP assay. VDAC3 expression was significantly decreased in etoposide-treated BMSCs (1.00 ± 0.13 vs. 0.26 ± 0.06). VDAC3 overexpression reduced etoposide-induced senescence and promoted osteogenic differentiation. ALKBH5 overexpression inhibited VDAC3 m6A modification (1.00 ± 0.095 vs. 0.233 ± 0.177) and its stability. ALKBH5 knockdown decreased etoposide-induced senescence and promoted osteogenic differentiation, effects that were reversed by VDAC3 knockdown. YTHDF1 was identified as the m6A methylation reader, and its overexpression inhibited VDAC3 stability. We demonstrated that ALKBH5 inhibited osteogenic differentiation of etoposide-induced senescent cells through the inhibition of VDAC3 m6A modification, and YTHDF1 acted as the m6A methylation reader. These findings provide a novel theoretical basis for the treatment of osteoporosis.

Long Term Outcomes of Pain, Disability and Quality of Life in Open vs Minimally Invasive Surgery of Transforaminal Lumbar Interbody Fusion

Objective: This study aims to evaluate the short- and long-term outcomes—specifically in terms of pain, disability, and quality of life—between minimally invasive surgery (MIS) and open transforaminal lumbar interbody fusion (TLIF) for treating lumbar spondylolisthesis. Study Design and Setting: A prospective cohort study was carried out at Liaquat National Hospital & Medical College, Karachi, and a teaching institution in South Asia. The study included patients with chronic back pain for over three months, unresponsive to medical treatment or accompanied by radicular symptoms, with MRI-confirmed grade I and II degenerative lumbar spondylolisthesis, lateral recess stenosis, and unilateral disc herniation. Patients with spinal metastasis, previous surgeries, inflammatory arthritis, or metabolic bone diseases were excluded. Methodology: The outcomes of MIS-TLIF and open-TLIF were assessed using the Visual Analog Scale (VAS), Oswestry Disability Index (ODI), and SF-36 quality of life scores at 1, 6, and 24 months postoperatively. Results: Among 93 patients, 35 underwent open-TLIF and 58 received MIS-TLIF. MIS-TLIF resulted in significantly less blood loss and faster recovery. At four weeks, the MIS group had lower VAS and ODI scores, and higher SF-36 scores. Similar trends continued at six months, with improvements in ODI and SF-36. By 24 months, the MIS group maintained lower ODI scores, though VAS and SF-36 scores were comparable. Conclusion: MIS-TLIF shows superior outcomes, especially in the early postoperative phase, with reduced morbidity and improved quality of life, making it a preferable option in resource-limited settings.

Integrating deep phenotyping with genetic analysis: a comprehensive workflow for diagnosis and management of rare bone diseases.

Phenotypes play a fundamental role in medical genetics, serving as external manifestations of underlying genotypes. Deep phenotyping, a cornerstone of precision medicine, involves precise multi-system phenotype assessments, facilitating disease subtyping and genetic understanding. Despite their significance, the field lacks standardized protocols for accurate phenotype evaluation, hindering clinical comprehension and research comparability. We present a comprehensive workflow of deep phenotyping for rare bone diseases from the Genetics Clinic of Skeletal Deformity at Peking Union Medical College Hospital. Our workflow integrates referral, informed consent, and detailed phenotype evaluation through HPO standards, capturing nuanced phenotypic characteristics using clinical examinations, questionnaires, and multimedia documentation. Genetic testing and counseling follow, based on deep phenotyping results, ensuring personalized interventions. Multidisciplinary team consultations facilitate comprehensive patient care and clinical guideline development. Regular follow-up visits emphasize dynamic phenotype reassessment, ensuring treatment strategies remain responsive to evolving patient needs. In conclusion, this study highlights the importance of deep phenotyping in rare bone diseases, offering a standardized framework for phenotype evaluation, genetic analysis, and multidisciplinary intervention. By enhancing clinical care and research outcomes, this approach contributes to the advancement of precision medicine in the field of medical genetics.

Opportunistic Screening for Low Bone Mineral Density in Adults with Cystic Fibrosis Using Low-Dose Computed Tomography of the Chest with Artificial Intelligence.

Background: Cystic fibrosis bone disease (CFBD) is a common comorbidity in adult people with cystic fibrosis (pwCF), resulting in an increased risk of bone fractures. This study evaluated the capacity of artificial intelligence (AI)-assisted low-dose chest CT (LDCT) opportunistic screening for detecting low bone mineral density (BMD) in adult pwCF. Methods: In this retrospective single-center study, 65 adult pwCF (mean age 30.1 ± 7.5 years) underwent dual-energy X-ray absorptiometry (DXA) of the lumbar vertebrae L1 to L4 to determine BMD and corresponding z-scores and completed LDCTs of the chest within three months as part of routine clinical care. A fully automated CT-based AI algorithm measured the attenuation values (Hounsfield units [HU]) of the thoracic vertebrae Th9-Th12 and first lumbar vertebra L1. The ability of the algorithm to diagnose CFBD was assessed using receiver operating characteristic (ROC) curves. Results: HU values of Th9 to L1 and DXA-derived BMD and the corresponding z-scores of L1 to L4 showed a strong correlation (all p < 0.05). The area under the curve (AUC) for diagnosing low BMD was highest for L1 (0.796; p = 0.001) and Th11 (0.835; p < 0.001), resulting in a specificity of 84.9% at a sensitivity level of 75%. The HU threshold values for distinguishing normal from low BMD were <197 (L1) and <212 (Th11), respectively. Conclusions: Routine LDCT of the chest with the fully automated AI-guided determination of thoracic and lumbar vertebral attenuation values is a valuable tool for predicting low BMD in adult pwCF, with the best results for Th11 and L1. However, further studies are required to define clear threshold values.

Lipocalin-2 as a marker of inflammation, bone density, and triglyceride-glucose index for new-onset arthritis patients in Mosul, Iraq.

Lipocalin-2 is an acute phase-associated adipokine that can serve as an inflammatory and biomarker indicator of cartilage deterioration in osteoarthritis. However, its role in the musculoskeletal system remains not fully understood. Hence, this study aimed to evaluate lipocalin-2 and its relationship with markers of inflammation (Interferon-gamma, ESR, and CRP), bone density (vitamin D3 and calcium), and the triglyceride-glucose index in new-onset arthritis patients in Mosul, Iraq. This study included 125 participants aged 20 to 65, divided into two groups. The Arthritis Patient Group comprised 70 participants (37 females and 33 males) attending the Bone Diseases Consultation Unit at the Ibn Sina Teaching Hospital in Mosul, Iraq. The Control Group comprised 31 females and 24 males. Ethical approval was obtained from the Iraqi Ministry of Health - Nineveh Health (No. 2022095). Commercial ELISA kits were used to measure serum lipocalin-2, Interferon-gamma, ESR, and CRP as inflammation markers, vitamin D3, and calcium as bone density markers. Moreover, the Triglyceride Glucose (TYG) Index was evaluated. The findings revealed a significant increase in lipocalin-2 levels in males compared to females, with LCN-2 increasing with age. Arthritis patients showed a significant increase (72%) in lipocalin-2 levels. Inflammatory indicators (erythrocyte sedimentation rate, C-reactive protein, interferon-gamma) displayed significant increases (46%, 1200%, and 581%, respectively). Glucose (23%), triglycerides (71%), and TYG index (21%) also exhibited significant increases. Meanwhile, bone density indicators (vitamin D3 and calcium) found a significant decrease (53% and 20%, respectively) in arthritis patients. Linear correlation coefficient (R) analysis revealed a significant positive relationship between lipocalin-2 and indicators of inflammation, glucose, TG, and TYG index. This study's findings suggest that LCN-2 serum levels were higher in patients with new-onset arthritis than in controls in Mosul, and LCN-2 serum increased in males compared with females and getting older serum LCN-2 increased for the patients and control groups. Furthermore, a significant correlation was found between the Triglyceride Glucose Index, which measures metabolic disorders, and serum LCN-2 levels and inflammatory indicators in new-onset arthritis patients in Mosul, Iraq.

Superscan Pattern on Bone Scintigraphy: A Comprehensive Review

Background/Objectives: The superscan pattern is a characteristic finding on bone scintigraphy, associated with a variety of metabolic bone diseases, malignancies, and other conditions. This pattern is characterized by a diffuse and intense uptake of radiotracer throughout the entire skeleton. Despite being a relatively rare finding, the superscan pattern can have significant clinical implications. Methods: This comprehensive review summarizes the available literature on the superscan pattern, focusing on its pathophysiology, clinical significance, and differential diagnoses. Relevant studies and case reports were analyzed to outline the diagnostic challenges associated with the interpretation of bone scintigraphy featuring the superscan pattern. Results: The literature highlights the clinical significance of the superscan pattern in various metabolic and oncologic conditions. Misinterpretation of this pattern can lead to diagnostic challenges, especially in distinguishing it from other pathologic conditions. Differential diagnosis remains crucial in the accurate interpretation and subsequent management of patients with this finding. Conclusions: This review provides a comprehensive overview of the superscan pattern on bone scintigraphy, aiming to assist clinicians in recognizing and managing this rare yet clinically important finding.

7293 An Unusual Case Of Adult-Onset Heterozygous HHRH In A Male With Normal Phosphorus And Severe Osteoporosis

Abstract Disclosure: M. El Najjar: None. A. Sabet: None. D. Willard: None. Introduction: Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is a rare genetic disorder characterized by renal phosphate wasting, which can affect bone metabolism. Although onset is typically in childhood, adult-onset forms have been described, and the manifestation depends on the zygosity of each patient. Most commonly, adults with HHRH demonstrate markedly reduced bone density and multiple fractures. Heterozygotes have milder presentations with mild hypophosphatemia, hypercalciuria, and nephrolithiasis, usually without bone disease; however, it is less well characterized. Case report: A 73-year-old man suffered an L1 vertebral compression fracture while playing golf. Bone mineral density testing revealed T-scores of -0.9 at the lumbar spine and -3.4 at the femoral neck (Z-score -2.6). He started alendronate 70 mg weekly for osteoporosis treatment. A year later, the patient sustained an L3 vertebral compression fracture while on treatment with no improvement in his bone density. His family history was remarkable for osteoporosis in his mother but no nephrolithiasis or hypercalcemia. Physical examination was unremarkable. Laboratory evaluation was notable for a 1,25-dihydroxyvitamin D of 87 pg/mL (18-72 pg/mL) , a 24-hour urine calcium of 240 mg/g Cr (30-210 mg/g),a serum PTH of 9 pg/mL (16-77 pg/ml) , but otherwise a normal serum calcium level of 9.4 mg/dL (8.6-10.3 mg/dL) and serum phosphate level of 2.2 mg/dl (2.1-4.3 mg/dl). Genetic testing revealed heterozygosity for SLC34A3 mutation, which is associated with HHRH. The patient discontinued alendronate and started 250 mg phosphorus supplementation 4 times daily. At 6 months follow up, he reported improvement in his body aches, and biochemical testing showed normalization of his 24-hour urine calcium to 171 mg/g Cr and serum PTH to 21 pg/mL. Repeat bone density scan after 1 year of phosphorus supplementation showed T-scores of -0.3 at the lumbar spine (5.8% increase) and -2.6 at the femoral neck (15.5% increase). Clinical Lesson: HHRH is an autosomal recessive hypophosphatemic rickets associated with mutations of the SLC34A3 sodium-phosphate cotransporter, where it is believed that selective phosphate wasting leads to increased calcitriol, in contrast to other forms of hypophosphatemic rickets, causing increased intestinal calcium absorption and resulting hypercalciuria. Adult-onset forms of HHRH have been described in heterozygous carriers of the SLC34A3 mutation and usually present with low to low-normal phosphate levels, hypercalciuria, and nephrolithiasis but without bone disease. However, clinical variations of heterozygous carriers have also been recognized, and therefore are likely underdiagnosed. Our patient’s serum phosphorus level was within the normal range, and hypophosphatemic rickets could have been missed if a more extensive laboratory evaluation had not been performed. Presentation: 6/1/2024

7949 Unraveling a Unique Presentation of Paget’s Disease of Bone

Abstract Disclosure: S. Puri: None. L. Bovee: None. R. Narla: None. Background: Paget's Disease of Bone (PDB) is a disorder characterized by rapid bone destruction and repair, which results in distortion of bone architecture. PDB occurs most commonly in adults over 55 and of European descent. PDB presents with both lytic and sclerotic lesions, predominantly in the axial skeleton. Serum alkaline phosphatase (ALP) levels and bone turnover markers (BTMs) are typically elevated in PDB. Clinical Case: A 53-year-old African-American woman with a history of breast cancer, PTSD, depression, and obesity (BMI 37) presented with worsening back pain over the past six months. Her pain would start at the center of her back and radiate to her left lower extremity. She endorsed rapid weight loss and night sweats and had lumbar bony tenderness on exam, prompting a spinal MRI. Spinal MRI was significant for diffuse sclerosis of the L3 vertebral body only. The radiology report provided a broad differential for this finding, including metastases, lymphoma, infection, PDB, and hemangioma. Due to progression of the patient’s back pain and concern for possible malignancy, a whole-body SPECT was completed which showed isolated tracer uptake into the L3 vertebral body extending into the pedicles and spinous process. Similar findings were noted on bone scans dating back to 2001. Per the radiology report, the presence of sclerosis with minimal expansion is most suggestive of PDB. Endocrinology was consulted for guidance on treatment and surveillance imaging for this patient. The endocrinology team discussed the case with radiology, who confirmed that the patient’s imaging findings had classic features of PDB. Bone specific ALP (B-ALP) and procollagen type 1 amino-terminal propeptide (P1NP) as bone turnover markers (BTMs) were within normal limits. A DEXA scan is pending to evaluate for concurrent osteoporosis. Clinical Lessons: PDB was favored as the most likely diagnosis primarily due to the sclerotic appearance of the patient’s vertebral lesion on imaging, radicular symptoms, and exam finding of bony point tenderness. Other diagnoses, such as metastatic disease, were considered and were thought to be unlikely given that the vertebral lesion is monostotic and stable. This case highlights the necessity of carefully evaluating radiographic findings and clinical history in the diagnosis of PDB. In this case, the patient was from a demographic group unlikely to have PDB and, unexpectedly, did not have elevated BTMs. It is important to consider PDB on the differential diagnosis in cases such as this because PDB can present in myriad ways and in a variety of patient populations. Presentation: 6/2/2024

7027 A Rare And Multifactorial Etiology Of Severe Parathyroid Hormone Independent Hypercalcemia In An Adult Female With Rett Syndrome

Abstract Disclosure: M.I. Foo: None. M. Thompson: None. Background: Symptomatic hypercalcemia is a rare, but potentially life-threatening disorder. Although dehydration is an unusual cause of severe hypercalcemia, in the appropriate clinical setting dehydration may amplify underlying mild or moderate hypercalcemia to dangerous levels.Case: A 46-year-old non-verbal, non-mobile Caucasian female with Rett Syndrome (RS) with Stage III Chronic Kidney Disease (CKD3) who is dependent on percutaneous endoscopic gastrostomy (PEG) tube for nutrition and known PTH independent hypercalcemia of unknown etiology presented to the hospital with intractable vomiting and constipation, an outpatient serum calcium level of 16.0 mg/dL, and serum creatinine 4.03 mg/dL (baseline 1.2 mg/dL). Initial laboratory assessment revealed elevated corrected serum calcium levels (15.7 mg/dL), with appropriately suppressed PTH levels (12.5 pg/mL) and hypernatremia (146 mmol/L). Thyroid function tests, both Vitamin D 1,25(OH)2D and D 25(OH)D levels and PTH-RP were normal. Computed tomography of the abdomen and pelvis revealed bilateral nephrolithiasis and moderate stool burden, but no evidence of malignancy or granulomatous disease. Skeletal scintigraphy was also without evidence of osseous metastatic disease or Paget’s disease of bone. An in-depth interview with the patient’s caregiver uncovered that the patient had a relative intolerance to enteral hydration and had been receiving minimal water flushes prior to admission, contributing to severe dehydration. Hypercalcemia was ultimately ascribed to prolonged immobilization due to RS compounded by inadequate fluid intake and auto-diuresis secondary to hypercalciuria in the setting of CKD (prior baseline eGFR 45 mL/min/1.73m2).Outcome: The patient's hypercalcemia improved after a multidisciplinary and multi-directed approach involving intravenous and enteral fluid resuscitation, calcitonin, furosemide, and ultimately zoledronic acid following improvement in creatinine with fluid resuscitation. The dietary service employed a strategy of 24-hour enteral feeding, increasing both the frequency and amount of enteral water, which the patient tolerated well, and provided her with a new pump for home use. Education on monitoring tube feed tolerance and providing adequate enteral hydration was provided to both the caregiver and group home. On discharge, eGFR stabilized at 33 mL/min/1.73m2 and corrected calcium stabilized at 10.0–10.4 mg/dl. She was provided with an endocrinology follow-up to continue bisphosphonate therapy.Discussion: Hypercalcemia of immobility should remain a differential diagnosis in severe hypercalcemia, especially PEG tube dependent patients with underlying kidney disease. This case highlights the importance of thorough history taking and a multidisciplinary strategy to guarantee optimal care and mitigate potential adverse outcomes in medically complex patients. Presentation: 6/2/2024

6976 Early-Onset Paget's Disease- A Unique Presentation In A Young Female With Elevated Alkaline Phosphatase And Low Back Pain

Abstract Disclosure: F. El Sayed: None. Background Paget disease of bone is an age-related disorder characterized by abnormal growth in certain bones, leading to changes in size and shape. Commonly affecting the skull, spine, pelvis, and long bones, it is more prevalent in men, those over 55, with a family history, and of European ancestry. The prevalence of Paget's disease of bone is approximately 2-3% in individuals over 55 in the United States and Europe, with higher rates in those of European descent. Symptoms, such as pain and deformities, may arise from the condition itself or complications like arthritis. While Paget disease can cause visible abnormalities and fractures in affected bones, most individuals remain asymptomatic. Diagnosis often involves blood tests measuring alkaline phosphatase levels, bone scans, and x-rays. Case Presentation We present the case of a 34-year-old woman who sought evaluation due to persistently elevated alkaline phosphatase (ALP) levels in the thousands. The abnormality was discovered during routine blood work conducted during her pregnancy in 2020, and subsequent investigation revealed a chronic elevation for over three years. The patient reported chronic lower back pain but denied other neurological symptoms. Quantification of ALP Bone showed elevated levels at 629, with normal aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels, as well as within-range calcium and gamma-glutamyl transferase (GGT). A whole-body bone scan revealed marked radio tracer uptake in the calvarium, raising concerns for Paget's disease. The patient received a one-time infusion of Zoledronic acid (5 mg), leading to a significant decrease in ALP levels to 182 after three months. Subsequent examination by an Ear, Nose, and Throat (ENT) specialist unveiled bilateral extra bone deposition and mild hearing loss in the right ear, adding a unique dimension to the patient's presentation. This case highlights the importance of a comprehensive approach to diagnose and manage Paget's disease, even in younger individuals with atypical symptoms. Discussion and conclusion Paget's disease presenting in young adults with back pain can be a diagnostic challenge due to its atypical occurrence in this age group. Although back pain is a common symptom, the underlying cause might not immediately be linked to Paget's disease, which typically affects older individuals. However, when encountering persistent back pain in young adults, especially when accompanied by elevated alkaline phosphatase levels, clinicians should consider Paget's disease as a potential differential diagnosis. Further investigation, including imaging studies and bone scans, becomes crucial to confirm the presence of Paget's disease and initiate appropriate management strategies to mitigate its impact on the patient's health and quality of life. Presentation: 6/2/2024

8305 Assessing The Relationship Between Oral Health And Bone Disease Among Post-menopausal Women

Abstract Disclosure: N. Tahir: None. S. Ahmad: None. K. Batra: None. A. Gupta: None. K.E. Izuora: Research Investigator; Self; Novo Nordisk. Background: Menopause is associated with significant bone loss and worsening oral health, especially periodontal disease (PD). The purpose of this study was to understand the relationship between oral health and bone loss and the factors that influence this relationship. This will help better understand their pathophysiology and provide guidance for more appropriate care. Methods: ​​This cross-sectional study included post-menopausal women undergoing routine bone density evaluation at a diagnostic radiology center. After participants signed informed consent, histories were collected via an investigator-administered questionnaire, the oral cavity was inspected for teeth loss and PD, and a bone density assessment, interpreted by a radiologist, was obtained. The significance level was set at 5% and data were analyzed using chi-square and logistic regression tests. Results: In a sample of 100 eligible participants, the mean age and body mass index (BMI) were 68.17 ± 8.33 years and 29.59 ± 6.13 kg/m2 respectively. Twenty-three participants (23.0%) had T2DM, 29 (29.0%) had &amp;lt; 20 natural teeth and 17 (17.0%) had normal bone mineral density. In an unadjusted simple logistic regression, age, BMI, race/ethnicity, number of natural teeth, history of PD, and history of osteoporotic fracture were associated with bone loss. However, in the binary logistic regression, the only significant predictors of bone loss included age (aOR 1.171, p&amp;lt;0.001), BMI (aOR 0.763, p&amp;lt;0.001), and the history of osteoporotic fractures (aOR 21.273, p=0.021). Conclusion: Clinical variables associated with bone loss in our study included older age, lower BMI, and history of osteoporotic fracture. These are established risk factors for bone loss. Although unadjusted results suggest a relationship between oral health measures and bone loss, these relationships were not present when other factors were included in a multivariate model. These findings suggest PD by itself may not be a risk factor for bone loss but may reflect the similarity in the risk factors for both conditions. Presentation: 6/3/2024

6483 Diaphyseal Medullary Stenosis With Malignant Fibrous Histiocytoma: A Rare Skeletal Dysplasia/Sarcoma Syndrome

Abstract Disclosure: A. Grover: None. C.R. Ferreira: None. R.I. Gafni: None. S. Jumani: None. M.T. Collins: None. K.L. Roszko: None. I.R. Hartley: None. Introduction: Diaphyseal medullary stenosis with malignant fibrous histiocytoma (DMS-MFH) is a rare autosomal dominant syndrome associated with pathologic fractures, myopathy, premature hair graying, and aggressive osteosarcomas. DMS-MFH has been linked to genetic variants in the methylthioadenosine phosphorylase (MTAP) gene, which encodes an enzyme in the methionine salvage and polyamine synthesis pathway. This pathway is implicated in other skeletal fragility disorders, such as Snyder-Robinson syndrome, suggesting a still undefined role of this pathway in bone biology. We describe a kindred with DMS-MFH and identify diagnostic challenges. Case: A 53-year-old perimenopausal woman presented with four fragility fractures over one year. Relevant history included premature hair graying, esophageal strictures, and nephrolithiasis. The patient’s bone formation markers were slightly elevated; bone resorption markers were within reference range. Her only osteoporosis risk factor was perimenopausal status. Bone series showed a diffuse heterogeneous appearance of the long bones with a mixed lytic/sclerotic appearance. DEXA scan revealed osteopenia. Family history was significant for 2 sons with aggressive osteosarcomas diagnosed in their late teens; one died at age 20. The other son is currently 39-years-old with recurrent osteosarcomas in three different limbs. The family also has a multigenerational history of severe bone fragility, muscle weakness, and premature hair graying. The patient, her living son, and his father underwent genome sequencing that identified a variant in MTAP (c.885A&amp;gt;G; p.(R295=)) in the patient and son. This variant was previously reported in three other families with DMS-MFH and has been shown to alter splicing. Notably, commercial genetic testing did not report this as a relevant variant, and diagnosis required independent analysis of the raw sequence data. Based on these findings, the patient and her son were diagnosed with DMS-MFH. Given the bone fragility with elevated bone turnover markers we treated the patient with yearly zoledronic acid infusions with no subsequent fractures. Surveillance for osteosarcoma is also being performed with annual whole-body MRI. Conclusion: DMS-MFH has been reported in only five families to date. The sixth family described here has clinical characteristics similar to the other kindreds. Due to high risk of aggressive osteosarcoma, timely diagnosis is imperative to decrease morbidity and mortality. Commercial genome sequencing may miss this diagnosis, so targeted genetic testing should be pursued. As more cases are identified, characterization of affected families may enhance our understanding of the natural history of the disease and guide surveillance and treatment strategies. Presentation: 6/2/2024

8410 Lipid modification enhances the calcemic and bone building effects of injected PTH(1-14) and PTH(1-11) fragment peptides in mice

Abstract Disclosure: J. Höppner: None. H. Noda: None. A. Khatri: None. H. Jüppner: None. T.J. Gardella: None. PTH analogs with improved actions in vivo are of interest as potential treatment options for bone and mineral ion diseases such as hypoparathyroidism and osteoporosis. The efficacies in vivo of conventional PTH peptides are generally limited by rapid rates of clearance from the circulation (t1/2 = ∼ 5-30 minutes) and relatively short-dwell times on the receptor (PTH1R). This is especially true for small fragment analogs, such as M (modified)-PTH(1-14), and M-PTH(1-11), which have only been shown to be active in vitro. We explored whether PTH fragment peptide efficacy in vivo could be enhanced by addition of a lipid chain (e.g., a C15 palmitoyl chain (palm)) to either the peptide C-terminus or to the side chain of the amino acid residue at position 11 or 13. The C-tail lipid modifications were specifically designed to promote binding to serum albumin, and hence extend circulation half-life, while the lipid chains at sidechains of residue positions 11 and 13 were designed, based on structural models, to anchor the ligand to the receptor in situ -- i.e. by projection of the acyl chain between two adjacent transmembrane helices and into the surrounding plasma membrane -- to thereby extend receptor dwell time. Assessment of cAMP signaling potencies in HEK293/hPTH1R/glosensor cells revealed that both types of lipid modifications can preserve agonist potency, and that the lipid extensions at position 11 or 13 can indeed prolong receptor dwell times, as shown by extended durations of cAMP signaling after initial binding of Palm 11 or 13-modified M-PTH(1-14) and M-PTH(1-11) peptide fragment. Single subcutaneous injection of either Palm-13-M-PTH(1-14) or Palm-11-M-PTH(1-11) into mice resulted in prolonged increases in blood serum calcium levels, while 14 days of daily injection resulted in profound increases in bone mass, as measured by uCT, and marked increases in blood levels of the bone turnover markers CTX1 and P1NP, whereas non-lipidated M-PTH(1-14) control peptides were inactive in vivo. Peptide lipidation thus holds promise as a strategy to employ in the design of new PTH analogs with improved efficacies in vivo. Presentation: 6/1/2024

7630 Incidental Calvarial Brown Tumor in an ESRD patient with seizures

Abstract Disclosure: K.N. Pereira: None. V. mehta: None. S. Sekaran: None. M. Renzu: None. Brown Tumor [BT], also known as Osteitis fibrosa cystica [OFC], is a rare tertiary manifestation of hyperparathyroidism [HPTH]. BT commonly affects the maxilla/mandible, long bones and spine and presents as lytic bone lesions on imaging. Among the crania-facial bones, the maxilla, palate, temporal bone, nasal cavity, orbital bone and paranasal sinuses are affected. We describe a case of a 37 year old African-American female with extensive medical history including ESRD on hemodialysis who initially presented to the hospital with hypertensive emergency in the setting of 1 week of missed dialysis. During her presentation, she had an unexplained seizure which led to further workup with imaging. CT head revealed findings suspicious of renal osteodystrophy as well as a discrete lucency at the calvarial vertex suggestive of a brown tumor. Endocrinological studies were noted to have very high PTH levels with hypercalcemia, hyperphosphatemia and vitamin D deficiency indicative of tertiary hyperparathyroidism. Based on her clinical presentation, labs and imaging, her bone disease including BT and pathologic fractures, was deemed to be due to tertiary hyperparathyroidism in the setting of ESRD, which were not amenable to surgical intervention. Extensive literature review did not reveal any reported BTs in the calvarial vertex. This case emphasizes on the holistic approach to diagnosis of BTs and underlines that fact that BT can occur in any cortical bone including unusual presentation sites like the calvarial vertex. Presentation: 6/3/2024

6874 A Rare Case Of Hereditary 1,25 (OH)2D Resistant Rickets

Abstract Disclosure: G. Umarji: None. F. Thelmo: None. S.A. Jabbour: None. Vitamin D-dependent rickets type 2A (VDDR2A) also known as hereditary 1,25 (OH)2D resistant rickets is due to biallelic loss-of-function mutations in the gene encoding vitamin D receptor on chromosome 12q13.11, thus, it represents a true form of tissue resistance to vitamin D. It is a scarce form of rickets with approximately only 120 cases reported. A 37-year-old male was referred to endocrinology by neurosurgery for evaluation of metabolic bone disease. Seven years ago, he was in a car accident which resulted in a lumbar spine injury causing radiculopathy and severe low back pain leading to lumbar spine decompression/fusion. However, he suffered from nonunion of bones and had to undergo another surgery a year later with recurrent postoperative nonunion of bones. During the operation, the surgeon noticed that his spine seemed demineralized. He had a history of multiple minor fractures in childhood, decreased hearing in left ear for two years, fragile teeth for many years, and some hair loss since age 30. Physical exam showed a height of 1.82 m, weight 89.3 kg with body mass index of 26 kg/m2, broken teeth, no leg bowing and normal stance. Laboratory results showed normal renal function, thyroid function tests and testosterone level, corrected calcium 8.3 mg/dL (8.7-10.2), 25-OH-vitamin D 54 ng/mL (30-100), phosphorus 2.8 mg/dL (2.8-4.1), intact parathyroid hormone 65 pg/mL (15-65), bone-specific alkaline phosphatase 21 mcg/L (4-27), 24-hour urine calcium 156 mg/day (100-300), 24-hour urine phosphorus 1,752 mg/day (390-1,425), FGF-23: 93 RU/mL (44-215) and 1,25 (OH)2D 92 pg/mL (24-81.5). Dual absorptiometry of the lumbar spine and hip showed osteopenia with Z scores of -2.2 and -1.2 respectively. Genetic testing for metabolic bone disease panel showed heterozygous mutation in VDR gene at nucleotide position c.146+9dup associated with autosomal recessive VDDR2A. We present a very rare form of vitamin D resistant rickets. As many patients with VDDR2A are unable to respond to any form of vitamin D, it is suggested that VDDR2 be more appropriately described as hereditary 1,25 (OH)2D resistant rickets (HVDRR), hereditary resistance to 1,25 (OH)2D, or even pseudovitamin D-deficiency type IIA (PDDR IIA). Clinical features include severe rickets, bone pain, hypotonia, dental caries and alopecia. Biochemical features include hypocalcemia, hypophosphatemia, normal to elevated alkaline phosphatase, normal 25(OH)D and importantly, elevated 1,25-(OH)2D levels. Management is with high doses of calcium and vitamin D therapy. While rare, this disease highlights the need for a comprehensive evaluation of metabolic bone diseases and a thorough understanding of calcium and vitamin D metabolism. Presentation: 6/2/2024

7984 A Challenging Case Of Hyperphosphatemic Familial Tumoral Calcinosis

Abstract Disclosure: T.G. de Souza: None. T.J. Weber: None. Introduction: Hyperphosphatemic Familial Tumoral Calcinosis (hFTC) is a rare, autosomal recessive metabolic disorder characterized by elevated serum phosphate levels and the accumulation of calcium phosphate deposits in soft tissues. There are fewer that 150 genetically confirmed cases in the literature. There are no consensus guidelines; therapeutic approaches are guided by case reports or series. This case serves to heighten awareness of therapeutic strategies including global health considerations for the disabled adult with a rare bone disorder. Case: A 32-year-old African-American woman presented to establish care for hFTC, for which she takes ibuprofen for disabling bilateral hip pain. hFTC was diagnosed in early childhood and managed at a large children’s hospital. Therapeutic modalities relied on operative resection of skin lesions on eruption. She describes cosanguinous parentage, consignment to foster care as a child and homelessness as an adult. She has not had adult endocrine care for her hFTC. Her medical comorbidities include major depressive disorder, PTSD and suicide attempt. She reports one uncle with hFTC noting that his phenotype was not significantly disabling and apparent recession of his lesions with age. Her parents did not have symptoms of hFTC. Radiographically, she had amorphous calcium deposits over both hips (her primary sites of severe pain), upper back (site of painless spontaneous eruptions), and left elbow without pain or skin penetration, as well as hyperostosis of the ilium bilaterally. She noticed waxing and waning of her eruptions with her menstrual cycle, such that lesions worsen in the luteal phase. Megestrol acetate also induced new eruptions. Examination shows brown staining to all teeth with several missing teeth. She had a marked lower extremity limb length discrepancy with severe restriction of hip abduction. Blood chemistries were grossly normal, including renal function, calcium, uric acid and PTH. Serum phosphorous was elevated at 5.2 (2.3 - 4.5 mg/dL). CT showed bilateral nephrocalcinosis. We instituted treatment with a low phosphorous diet, sevelamer to reduce intestinal phosphate absorption and acetazolamide to increase urinary phosphate excretion. For her pain and functional disability, we recommended continued NSAIDs, physical therapy and social work consultation to facilitate continued access to care. Conclusions: This case uniquely describes hFTC symptom fluctuation with the menstrual cycle, worsening with increased progesterone, suggesting a possible role of gonadal hormones on FGF-23 biology. It also highlights the socioeconomic burdens that can accompany rare bone disease, which become more pronounced as the patient achieves adulthood. Successful transition of care from pediatric to adult endocrinologist, in addition to engaging multi-disciplinary support, is essential in optimizing life-long care in hFTC. Presentation: 6/1/2024

7050 Effect of Spironolactone On Reducing Sugar-Induced Cellular Damage In MC3T3-E1 Osteoblastic Cells

Abstract Disclosure: S. Yun: None. H. Sang: None. S. Park: None. K. Suh: None. H. Kim: None. S. Chin: None. Background: In diabetes, prolonged hyperglycemia causes oxidative stress, resulting in pancreatic beta cells' dysfunction and diabetic complications. Oxidative stress can inhibit osteoblast differentiation and induce dysfunction and apoptosis. Spironolactone is an aldosterone antagonist used to treat hypertension and heart failure. In this study, we observed whether spironolactone can reduce osteoblast cytotoxicity and differentiation caused by oxidative stress induced by 2-deoxy-d-ribose (dRib). Methods: MC3T3-E1 cells were treated with spironolactone (0-100 uM) in the presence of 15 mM dRib. The cytotoxicity (lactate dehydrogenase, LDH) and differentiation (collagen content, alkaline phosphatase [ALP] activity, and mineralization) of osteoblasts, inflammatory cytokines (tumor necrosis factor-α [TNF-α], interleukin [IL]-6), oxidative stress (reactive oxygen species [ROS], mitochondrial superoxide), endoplasmic reticulum (ER) stress (activating transcription factor 6 [ATF-6], inositol-requiring 1 [IRE1]), mitochondrial function (mitochondrial membrane potential [MMP], adenosine triphosphate [ATP]), glyoxalase I activity, and glutathione (GSH) were measured. Results: Pretreatment of MC3T3-E1 osteoblastic cells with spironolactone prevented the dRib-induced cytotoxicity of osteoblasts and promoted differentiation of osteoblasts suppressed by dRib. Spironolactone significantly reduced dRib-induced inflammatory cytokines, ROS, mitochondrial superoxide, and ER stress. dRib-induced mitochondrial dysfunction was significantly improved by treatment with spironolactone. dRib is detoxified by the glyoxalase system. Pretreatment with spironolactone also increased the level of reduced GSH and the activity of glyoxalase I in dRib. Conclusion: Spironolactone could reduce dRib-induced cytotoxicity and promote differentiation in MC3T3-E1 osteoblastic cells by reducing oxidative stress and inflammatory cytokines, increasing mitochondrial biogenesis, and detoxifying dRib. These results suggest that spironolactone can be useful in the prevention and treatment of diabetic bone disease. Presentation: 6/1/2024

7191 When Pain Is Misdiagnosed: A Case of Parathyroid Carcinoma Masked as Fibromyalgia

Abstract Disclosure: H. Pham: None. P.V. Kumar: None. S. Taylor: None. Parathyroid carcinoma is a rare and aggressive cause of hyperparathyroidism, typically associated with &amp;lt;1% of primary hyperparathyroidism cases. Incidence occurs mainly in the 5th decade of life, with less than 4% of all cases presenting in patients under age 30. Here, we highlight a case involving a 28-year-old woman with fibromyalgia who presented for worsening right shoulder pain in the setting of progressive, poorly characterized pain for the past year. Her initial physical exam was unremarkable aside from a non-tender left sided neck enlargement. However, her laboratory results were significant for corrected serum calcium of 15 mg/dL, serum phosphorus of 2.3 mg/dL, parathyroid hormone (PTH) &amp;gt;2500 pg/mL, and alkaline phosphatase 1604 units/L. X-ray of her right shoulder demonstrated mottled bone concerning for degenerative disease. Thyroid ultrasound revealed a complex cystic lesion posterior to the left thyroid lobe measuring 5.3 x 3.9 x 2.9 cm, worrisome for giant parathyroid adenoma. CT abdomen/pelvis showed diffuse osteosclerosis and innumerable lytic lesions, consistent with osteitis fibrosa cystica, as well as bilateral nephrolithiasis, likely medullary nephrocalcinosis. Her hypercalcemia was treated with aggressive hydration with normal saline and IV pamidronate. She underwent surgical resection of her parathyroid adenoma, which was unfortunately complicated by symptomatic hypocalcemia requiring prolonged care in the ICU. Her calcium levels did improve within a few days, and she was subsequently discharged with close outpatient follow-up. Final pathology report showed predominant thickened trabecular growth pattern with focal vascular invasion consistent with parathyroid carcinoma. Our patient’s case represents a rare presentation of parathyroid carcinoma in a young patient without any additional risk factors. Although atypical, her severe symptomatic hypercalcemia, nephrolithiasis, presence of large neck mass, and diffuse skeletal disease warranted immediate concern for malignant hyperparathyroidism instead of benign adenoma. Delayed diagnosis in our patient led to prolonged bone disease and severe complications. While hungry bone syndrome typically manifests post-parathyroidectomy in patients with end-stage renal disease, our patient experienced this complication in the setting of advanced, untreated hyperparathyroidism. We should consider hypercalcemia and hyperparathyroidism in our differential diagnosis for chronic pain, especially if pain remains uncontrolled with conservative measures. The most appropriate initial test for evaluation of hypercalcemia is a PTH level to distinguish between PTH-dependent and PTH-independent etiologies. Parathyroid carcinoma, even in young patients, should be considered when PTH is &amp;gt;3x upper limit of normal, serum calcium is &amp;gt;14, or skeletal and renal involvement is present. Presentation: 6/3/2024

7522 Effects of Trikafta On Bone Mineral Density And Body Composition In Patients With Cystic Fibrosis

Abstract Disclosure: N. Mon: None. S.S. Krishnasamy: None. G. Bakeerathan: None. L. Healy: None. E. Favier: None. S. Foushee: None. Background: Cystic fibrosis related bone disease (CFBD) is a common complication of adult Cystic fibrosis (CF) patients due to calcium, vitamin D and K malabsorption from exocrine pancreatic insufficiency, increased inflammatory cytokines, glucocorticoid therapy, delayed puberty, physical inactivity, and hypogonadism. Newer CF transmembrane conductance regulator (CFTR) modulator therapy elexacaftor/tezacaftor/ivacaftor (Trikafta) has proven benefit in pulmonary and nutritional outcomes. There is limited data on effects of Trikafta on bone health and body composition. The aim is to examine the effects of Trikafta on bone mineral density (BMD) at the lumbar spine (LS) and femoral neck (FN), and body composition in terms of fat free mass index (FFMI) and fat mass index (FMI) in our CF patients. Method: We conducted a cross sectional and retrospective review of 38 adults with CF (Ages 20-59, 28 males and 10 females) in our CF clinic. Body Mass Index (BMI), Body composition measured by bioelectric impedance analysis, BMD of LS and FN by Dual-energy X-ray absorptiometry, Vitamin D level, and forced expiratory volume in one second (FEV1 % predicted) in patients taking Trikafta were analyzed and compared with control CF group who were not on Trikafta. Results: 38 subjects on Trikafta, aged 33.29 ± 10.36 years with FEV1 % predicted 65.11± 28.14% were studied. Serum 25-hydroxyvitamin D level was 35.92 ± 18.52 ng/dL. Of the 38 study patients, 23 (60.53%) had a diagnosis of CF related diabetes (CFRD). Among the Trikafta cohort, 18 (50%) had low BMD with Z-scores ≤ -2.0 and 7 (19.44%) of them had Z score ≤ -1.0 and &amp;gt; -2.0. Compared with the control group, LS BMD 0.93 ± 0.16 g/cm2 and FN BMD 0.73± 0.13g/cm2 (p &amp;gt;0.05) were not improved significantly. BMI of study population 23.09 ± 4.21 kg/m2 (p &amp;lt;0.05) and FMI 6.11 ± 4.25 kg/m2 (p &amp;lt;0.05) increased significantly; however, there was a decrease in FFMI 9.60 ± 1.44 kg/m2 (p &amp;lt;0.05). Conclusion: Treatment with Trikafta in CF patients was associated with increases in BMI and fat mass index but decrease in fat free mass index. There was no statistically significant difference in BMD at LS and FN in our study cohort. This study has limitations in terms of gender differences within the study cohort, duration of Trikafta use in relation to bone mass, and also extent of glucocorticoid use among the study subjects. Larger prospective clinical trials are needed to study efficacy of Trikafta on CFBD. Presentation: 6/3/2024