Orthopedic Surgical Treatment of Patients with Tumor‐induced Osteomalacia Located in the Hip Bones: A Retrospective Analysis of 10 Years in a Single Center

Objective The orthopedic surgical treatment strategies for patients with tumor‐induced osteomalacia (TIO) require improvement, especially for patients where the causative tumors are located in surgically challenging areas, requiring a greater degree of in‐depth investigation. This work aims to summarize and investigate clinical features and orthopedic surgical treatment effects of patients with tumor‐induced osteomalacia (TIO), whose causative tumors are located in the hip bones. Methods A retrospective analysis was conducted on the clinical data of all patients diagnosed with culprit tumors located in the hip bones who underwent surgical treatment at the orthopedic bone and soft tissue tumor sub‐professional group of Peking Union Medical College Hospital from January 2013 to January 2023. This retrospective study summarized the clinical data, preoperative laboratory test results, imaging findings, surgery‐related data, perioperative changes in blood phosphorus levels, and postoperative follow‐up data of all patients who met the inclusion criteria. Normally distributed data are presented as mean and standard deviation, while non‐normally distributed data are shown as the means and 25th and 75th interquartile ranges. Results The clinical diagnostic criteria for TIO were met by all 16 patients, as confirmed by pathology after surgery. Among the 16 patients, we obtained varying degrees of bone pain and limited mobility (16/16), often accompanied by difficulties in sitting up, walking, and fatigue. An estimated 62.5% (10/16) of patients had significantly shorter heights during the disease stages. All 16 patients underwent surgical treatment for tumors in the hip bones, totaling 21 surgeries. In the pathogenic tumor, there were 16 cases of skeletal involvement and none of pure soft tissue involvement. Out of the 16 patients, 13 cases had a gradual increase in blood phosphorus levels following the latest orthopedic surgery, which was followed up for 12 months to 10 years. Due to unresolved conditions after the original surgery, four patients received reoperation intervention. Two cases of refractory TIO did not improve in their disease course. Conclusion In summary, the location of the causative tumor in the hip bone is hidden and diverse, and there is no defined orthopedic surgical intervention method for this case in clinical practice. For patients with TIO where the tumors are located in the hip bones, surgical treatment is difficult and the risk of postoperative recurrence is high. Careful identification of the tumor edge using precise preoperative positioning and qualitative diagnosis is crucial to ensure adequate boundaries for surgical resection to reduce the likelihood of disease recurrence and improve prognosis.


Introduction
2][3] The major clinical signs include muscle weakness, bone pain, and in severe cases, skeletal deformities, pathological fractures, and mobility disorders, which have a substantial impact on the quality of life and normal life among patients. 4,54][5][6] The early disease stages can often be misdiagnosed as ankylosing spondylitis, primary osteoporosis, or spinal degeneration. 1,2TIO-causing tumors can be surgically removed with an accurate diagnosis and identification, typically resulting in an effective correction of hypophosphatemia and significant alleviation of symptoms.
Determination of the tumor location as well as the improvement of clinical symptoms and laboratory indicators following surgical resection are key to establishing TIO diagnosis. 7,8Disease-causing tumors are widely distributed in the human body and can arise in subcutaneous tissues, limb bones and joints, spine, soft tissues, palms, and toes.2][3] More than half of intraosseous tumors that cause TIO are found in the long bones of the lower extremities, and a majority of them grow eccentrically.A few tumors involve the cortical bone, causing its osteolytic destruction.[3]9 The causative tumors for TIO are mostly benign tumors originating from mesenchymal tissue, with lesions located within bone or soft tissue.For some TIO patients, the location of the culprit tumor is hidden and the culprit tumor may grow slowly, complicating diagnosis or delaying treatment.The orthopedic surgical strategy for patients with TIO is a recent development, and the diagnosis, treatment, and prognosis of patients with causative tumors in different locations may vary. 10This is especially true when tumors are situated in surgically difficult regions, such as the hip bones, and presents challenges for orthopedic surgeons.Therefore, the surgical treatment of such tumors is an important issue that requires further in-depth research.
This study primarily focuses on clinical characteristics, early diagnosis, and treatment of TIO's causative tumor in the hip bone.The results of this study will: (i) provide an important reference for the development of orthopedic surgical expertise for the treatment of TIO patients with culprit tumors located in surgically challenging areas, such as the hip bones; (ii) improve the intraoperative procedures and the level of treatment for TIO patients with causative tumors located in the hip bone region, including determination of the tumor resection boundary; and (iii) further enhance diagnostic and therapeutic expertise to improve both the clinical diagnosis and treatment level of patients with culprit tumors located in surgically challenging areas such as the hip bones.

Inclusion and Exclusion Criteria
Inclusion criteria included: (i) clinical manifestations with continuously worsening bone pain symptoms, often starting at weight-bearing joint sites (including feet, hips, knees, ankles, chest and waist); (ii) laboratory examination with preoperative existing hypophosphatemia; (iii) bone pain symptoms gradually improving and blood phosphorus levels rapidly increasing after resection of oncogenic tumors; (iv) imaging examination through magnetic resonance imaging or CT, whole body bone imaging, octreoscan or octreotide SPECT-CT, or 68 Ga-DOTATATE PET/CT examination of the responsible lesion, the location and adjacent relationship of the culprit tumor can be detected, confirming that the suspected pathogenic tumor is located in the hip bone and surrounding area; and (v) Pathological examination confirming that the tumor responsible for resection is pathogenic tumor of TIO.
Exclusion criteria included: (i) patients who have not received surgical treatment or have surgical contraindications; (ii) cases with incomplete clinical data; and (iii) osteomalacia caused by other factors.

General Information
This study included surgical treatment-related data from all consecutive patients with TIO located at the hip bone region who underwent surgical treatment in the orthopedic bone and soft tissue tumor sub-professional group of Peking Union Medical College Hospital from January 2013 to January 2023.The age, gender, symptoms and signs, bone pain location, height shortening during the disease stage, the occurrence of pathological fractures during the course, and history of orthopedic surgery unrelated to causative tumors after disease onset were statistically analyzed.We also analyzed information on the distribution of pathogenic tumor sites.
Imaging Examination.Preoperative bone density, limb and trunk X-ray, surgical area B-ultrasound, CT, MRI, wholebody bone imaging, octreoscan or octreotide SPECT-CT, 68 Ga-DOTATATE PET/CT examination for qualitative and localized diagnosis, assisting in the formulation of surgical plans and the assessment of surgical risks.
Pathological Diagnosis.The excised tumor tissue samples were sent for examination during surgery.After surgery, the tumor tissue sections were removed for H.E. staining and immunohistochemistry staining.The nature and pathological characteristics of the lesion were diagnosed by an experienced physician from the Department of Pathology.
The normalization of blood phosphorus levels in patients after surgery is considered indicative of effective surgical resection.In cases where disease recurrence or unresolved symptoms are observed during the follow-up process, further localization or other treatment options should be performed according to the diagnosis and treatment flowchart of the TIO orthopedic surgical treatment strategy. 10

Statistical Analysis
All normally distributed data of this study were described with mean and standard deviation.Non-normally distributed data were described as the median and 25th and 75th interquartile ranges (Q25, Q75).A MedCalc Statistical Software version 15.2.2 (MedCalc Software, Ostend, Belgium) was used to complete data processing and statistical analyses.

General Characteristics
Table 1 presents the basic clinical characteristics of all 16 patients.In total, nine male and seven female patients with a mean age (and standard deviation) of 41.5 AE 11.0 years (range, 24 to 55 years) were included in this retrospective study.The mean duration of symptoms before initial accurate diagnosis was 80.8 (30.0, 126.0) months (range, one to 25 years) (Figure 1).The follow-up duration was from 12 to 120 months.Clinical symptoms included bone pain (100%), fractures (56.3%) (Figure 2), and muscle weakness or fatigue (93.8%).

Laboratory Examination
All patients had varying degrees of hypophosphatemia before surgery (Table 2) Preoperatively, the average blood phosphorus level of patients included in this study was 0.41 AE 0.10 mmol/L.

Localization of the Causative Tumor
All causative tumors were identified by a stepwise approach involving multiple imaging modalities.Before surgery, 14 patients underwent octreoscan or octreotide SPECT-CT, and 13 patients completed PET/CT (11 patients for 68 Ga-DOTATATE PET/CT).Additionally, 14 patients completed the MRI examination of the location of the pathogenic tumor, and the other two patients underwent a CT examination of the lesion site.The anatomical schematic diagram shown in Figure 3 shows the distribution of culprit tumors in all 16 patients with TIO.

Surgical Treatment
As shown in Table 2, 16 patients underwent 21 surgeries, with four patients undergoing second or third operations for unresolved or relapsed conditions.One female patient (patient two) accepted parathyroidectomy due to tertiary hyperparathyroidism.Thereafter, her serum calcium normalized, whereas, serum P remained low.The overall cure rate was 81.3% (13/16) for surgical treatment of TIO with causative tumors in the hip bones.

Pathological Diagnosis and Postoperative Follow-up
The histopathology results of tissues from all 21 surgeries (100%) were consistent with phosphaturic mesenchymal tumors.The histologic features of a phosphaturic mesenchymal tumor included tumor cells infiltrating between bone trabeculae; bland, spindled to stellate-shaped cells with extremely few mitoses in most cases; a very well-developed capillary network; and calcification of the matrix of the tumor in an unusual "grungy" or flocculent fashion.
In most cases, the serum P level normalized after a mean of 5.9 AE 2.7 days (range, 2-11 days) postoperatively (Table 3).The follow-up period ranged from 12 months to 10 years.Among the 16 patients, only two patients experienced limited left foot dorsiflexion after surgery and one patient suffered from right hip infection after the operation.Additionally, all 16 patients included one recurrent case and two refractory TIO cases.Among the 16 patients, 15 underwent lesion resection and bone cement reconstruction (Figure 4), whereas one patient underwent complete pelvic tumor resection (type I, Enneking classification) and was subsequently clinically cured (Figure 5).For cases which postoperative recovery does not improve, neutral phosphorus solution and active vitamin D treatment was administered, and the condition was closely monitored.So far, patients with TIO, managed by our team were regularly followed up

Discussion
2][13] To date, most research has focused on the disease pathogenesis, changes in bone metabolism, preoperative diagnosis, and postoperative follow-up of patients with TIO.Relatively little attention has been paid to orthopedic surgical treatment strategy, despite its importance in patient prognosis.In April 2024, our team authored the first review of the preoperative evaluation and orthopedic surgical strategies used for patients with TIO, published in the Journal of Bone Oncology. 10In this study, we summarized and analyzed the clinical features and orthopedic surgical treatment effects of patients with TIO in our institution, whose culprit tumors are located in the hip bones.2][13] Most of the causative tumors are benign, and a majority can be cured after complete surgical resection.Therefore, it is particularly important to actively search for the responsible tumor.The majority of TIO was found in the limbs, followed by the head, neck, and maxillofacial region.Patients with culprit tumors located in the hip bone region are relatively rare, and the local anatomical structure is complex, which poses certain difficulties in qualitative localization diagnosis.5][16] Because somatostatin receptor is highly expressed in most of these tumors, octreotide imaging (somatostatin receptor tracer imaging) is fundamental for the localization of preliminary tumors.However, octreotide SPECT/CT and 68 Ga-DOTATATE PET/CT examination are inadequate for locating lesions; it cannot fully meet the needs of a preoperative understanding of the relationship between the tumor and its surrounding tissues.5][16] Of note, not all tumors have somatostatin receptor expression on the surface; moreover, both the literature and our experience confirmed that the negative octreotide scan and 68 Ga-DOTATATE PET/CT examination could not completely exclude the possibility of TIO.1,12 Before identifying the primary tumor, oral neutral phosphorus preparation and oral active vitamin D are temporarily necessary to improve clinical symptoms.Blood phosphorus may increase to a normal range in this case.
Surgical Tips for Patients with TIOs with Culprit Tumors Located in Hip Bones Hip bone has a complex anatomical structure.The causative tumor for TIO in the hip bone is highly unusual in the clinic, with no previous international diagnosis and treatment reports as well as experience.Thus, clinical treatment is considerably challenging.In our investigation, the causative tumor of all patients had skeletal involvement.Based on our diagnosis and treatment experience, the postoperative recurrence rate and proportion of refractory TIO cases with bone involvement are significantly higher than those with soft tissue tumors. 11,17Therefore, four patients in this study underwent reoperation and two refractory cases together with one recurrent case did not receive clinical cure in recent followup.9][20][21] At present, the clinical treatment principle of culprit tumor in hip bone is to eliminate the tumor and adjacent tumor tissue, reduce the risk of local recurrence, and incidence of complications, as well as maximize the recovery of limb function.9][20][21][22] However, clinical experience suggests that even if the patients with TIO in the hip bones agree to open surgical resection, there is still a risk of local recurrence or negative pathological results.Therefore, selecting an acceptable surgical procedure for treating causative tumors in the hip bones and improving the effect of surgical treatment is a thorny problem confronted by orthopedics doctors.
4][25][26] In cases where complete removal of the causative tumor is feasible, surgical boundaries are set at least 0.5 cm beyond the tumor margin.Surgeons must exercise discretion during the procedure, as overly conservative resection may lead to disease recurrence, while overly extensive resection may damage bone structure, affecting local stability and postoperative motor function.Furthermore, high-temperature cautery around the lesion is an option to deactivate any residual tumors and minimize disease recurrence.For patients with phosphaturic mesenchymal tumor (PMT) in the hip bone, due to the complex anatomical structure of this region and the existence of local anatomical variations in patients, special attention should be paid to identifying important anatomical structures, including nerves, blood vessels, muscles, tendons, ligaments, and spermatic cords to prevent the occurrence of secondary injuries.In this study, two patients experienced limited foot dorsiflexion after surgery.The

Postoperative Follow-up
Postoperatively, patients should be closely followed up to monitor blood phosphorus levels.9][30] Based on the experience of the guidelines, it is important to locate the suspected causative tumor for further diagnosis if the blood phosphorus levels remain lower than the normal value. 3,4,9,17The standardized regular follow-up after surgery is important, and whether the postoperative disease relapses or not, warrants the attention of orthopedic surgeons.For patients with tumor-induced osteomalacia (TIO), surgical resection of the responsible tumor is the preferred treatment.In cases where surgical removal of the tumor is challenging or not feasible, image-guided ablation offers a viable alternative, being effective, minimally invasive, and safe. 19,31Cowan et al. 32 suggested that CT-guided cryoablation can expand the treatment options for TIO patients, particularly beneficial for those unwilling or unsuitable for surgery.Global guidelines for TIO recommend oral phosphate combined with active vitamin D or burosumab for cases where tumor resection is not possible, aiming to regulate calcium and phosphorus homeostasis, alleviate hypophosphatemia, and halt disease progression. 9,33inacalcet may be considered for patients unable to tolerate phosphate solution or suffering from secondary hyperparathyroidism.Notably, recent research focus in TIO treatment has revolved around anti-FGF-23 monoclonal antibodies, such as burosumab, which bind to FGF23, inhibiting its activity and signaling pathways, thereby enhancing phosphorus reabsorption and serum vitamin D levels, ultimately improving bone mineralization. 34,35rengths and Limitations Despite presenting the extremely rare cases of PMT in the hip bone as well as summarizing the experience of diagnosis and treatment, this study still has many shortcomings: (i) first, the number of cases recruited in the analysis is relatively small, despite being the largest clinical analysis report of PMTs resulting from TIO location in the hip bone so far; (ii) this study is a single center study, though we have presented all the cases from our team over the past 10 years; (iii) this study is a retrospective study, which can lead to bias in the research results; and (iv) we have only reported therapeutic effect of short-term and medium-term follow-up; the long-term therapeutic effect warrants further confirmation.

Conclusion
I n conclusion, TIO with an oncogenic tumor in the hip bone is an uncommon bone metabolic disease, and its onset and progression will severely impact the quality of life of patients.The occurrence and progression of this disease will impose a significant physical and mental burden to patients, and a huge economic burden to society.Clinicians should improve their understanding of the disease, combined with clinical manifestations, imaging examination, pathological diagnosis, and other techniques to improve diagnosis accuracy and take reasonable therapy to improve prognosis.The etiology, pathogenesis, diagnosis, treatment, and prognosis of TIO need additional investigation to bring benefit to these patients.

F
Progressive pain of both lower limbs for more than 2 years and fatigue for more than 1 year 24 Pain in the dorsum of both feet, lateral side of right leg, groin of right lower limb, lateral side of left knee joint and left shoulder bone pain occurred for 2 years and cystic space occupying lesion of right iliac joint was found for 5 months 24Lateral right foot, ankle joint, knee joint, hip joint, waist and back, anterior chest ribs, orthopedic clinic and endocrinology, and their condition is relatively stable.

FIGURE 1
FIGURE 1 Time distribution map of disease progression from onset todiagnosis for all patients included in this study.

CasesFIGURE 2
FIGURE 2The distribution diagram of the locations where fractures/ insufficiency fractures occurred in patients included in this study during the course of the disease.

FIGURE 3
FIGURE 3 Anatomical distribution map of the hip bones where the responsible tumors were located (Created with BioRender.com,and the license to publish from the BioRender has been obtained).

FIGURE 4 FIGURE 5
FIGURE 4 Case 1 (A) The octreoscan showing the suspected culprit tumor in left acetabular region.(B) The 68 Ga-DOTATATE PET/CT revealing high intake in the left acetabulum.(C, D) MRI of the hip revealing the mass, which was highly indicative of the causative tumor.(E, F) The postoperative X-ray of the pelvis.(G) Serum phosphorus levels elevated to the normal range after the operation.

TABLE 1
General data and clinical manifestations of TIO patients with culprit tumors located in the hip bones.

TABLE 1 Continued
Note: "-" represents the information is not available.;Abbreviations: F, Female; M, Male; m, month.

TABLE 3
Changes of blood phosphorus level in TIO patients with culprit tumors in the hip bones.

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NUMBER 8• AUGUST, 2024 ORTHOPEDIC SURGERY OF TIO PATIENTS WITH CAUSATIVE TUMORS IN HIP BONES

TABLE 4
Clinical review of four previously published causative tumors for TIO in the acetabular regions.or posterolateral approach is recommended due to the particularity of anatomical location.The full grasp of the local anatomical structure determine the incidence of intraoperative complications.