Diffuse and Prolonged Bone Pain Revealing Tumor‐Induced Osteomalacia: A Case Report

ABSTRACT

Tumor‐induced osteomalacia should be considered in patients with unexplained bone pain and fractures. Advanced imaging, such as Ga68‐DOTATATE PET/CT, enables precise tumor localization, and surgical excision can rapidly normalize phosphate metabolism and resolve symptoms, underscoring the importance of early diagnosis and intervention.

1. Introduction

Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome characterized by renal phosphate wasting, which leads to hypophosphatemia and impaired bone mineralization [1, 2]. The condition is most often associated with small, benign mesenchymal tumors that secrete excess fibroblast growth factor 23 (FGF23), a hormone integral to phosphate homeostasis [1, 3]. Elevated FGF23 levels decrease renal tubular phosphate reabsorption and inhibit the enzyme 1α‐hydroxylase, resulting in reduced synthesis of 1,25‐dihydroxyvitamin D [4, 5]. This biochemical cascade ultimately culminates in osteomalacia, with patients frequently presenting with diffuse bone pain, muscle weakness, and, in advanced cases, pathological fractures [6].

The pathophysiology of TIO underscores a unique interplay between an indolent neoplasm and significant systemic metabolic disturbances [7, 8]. Despite the typically benign histological nature of these tumors, their systemic effects are profound [9, 10]. The clinical presentation is often insidious, with symptoms overlapping those of other metabolic bone diseases, frequently leading to delays in diagnosis [6, 11]. Advances in biochemical testing now facilitate the early detection of hallmark hypophosphatemia and the inappropriately normal or low levels of 1,25‐dihydroxyvitamin D [12]. Nonetheless, localizing the small culprit lesions remains a diagnostic challenge. Recent improvements in imaging—particularly with functional modalities such as positron emission tomography (PET) using novel tracers—have enhanced the detection and localization of these elusive tumors, thereby enabling timely surgical intervention [1, 11].

In this case report, we describe a patient whose clinical presentation and laboratory findings raised suspicion for TIO. Through a comprehensive workup—including detailed biochemical analyses and advanced imaging studies—the responsible tumor was successfully identified and resected. Postoperative follow‐up revealed normalization of serum phosphate levels and significant improvement in the patient's symptoms. This case highlights the challenges of diagnosing TIO and underscores the importance of a team‐based approach to care. It also serves as a reminder to consider TIO when patients present with unexplained bone pain, as early recognition and treatment can make all the difference [1, 3, 6].

2. Case History/Examination

A 47‐year‐old man presented to the outpatient department of endocrinology with a 2 year history of progressive difficulty walking. The patient reported requiring a walking frame even before undergoing surgery, with his mobility worsening significantly in the month preceding his current evaluation. He also complained of chronic bilateral pain in the back, knees, ankles, and heels, persisting for several years. He denied experiencing constitutional symptoms such as fever, significant weight loss, or night sweats (B symptoms).

His medical history was notable only for surgery related to discopathy 3 years prior to referral and a right fibular fracture approximately 2 years prior. The cause of the fracture was unclear, and the patient denied any history of limb trauma. He underwent limb casting and was considered a candidate for orthopedic surgery because of the fibular fracture (Figure 1).

FIGURE 1.

Right leg X‐ray. Transverse fracture of the right fibula.

A two‐phase bone scintigraphy performed 2 years earlier revealed multiple foci of increased perfusion and osteoblastic activity in the axial skeleton and multiple appendicular sites, including the right tibial plateau and fibula (Figure 2). Additionally, magnetic resonance imaging (MRI) of the right knee performed at the same time suggested a subacute stress fracture of the tibial plateau, although the patient reported no history of trauma to the knees in the past several years (Figure 3). On physical examination, the patient appeared to have a modestly below‐average height and was obese (BMI: 32 kg/m²). He was hemodynamically stable but exhibited a pale complexion. An approximately 3 × 1 cm non‐tender mass was palpated in the right hemithorax at the level of the 5th rib. The remainder of the thoracoabdominal examination was unremarkable. Muscle strength in the lower limbs was diminished (3/5), though distal arterial pulses were normal (Tables 1 and 2).

FIGURE 2.

Two‐phase Bone Scintigraphy. Whole‐body blood pool demonstrating increased blood pooling in the proximal right tibia (tibial plateau), left ankle, and both calcanei (A). Increased perfusion in shoulders, bilateral ribs, both sacroiliac joints, and right tibial.

FIGURE 3.

Right knee magnetic resonance imaging (MRI). Linear area within the tibial plateau with adjacent mild bone marrow edema in coronal proton density–weighted (A), sagittal T1‐weighted (B), and sagittal T2‐weighted (C) sequences.

TABLE 1.

Vital signs and Body Mass Index on physical examination.

Examination parameter	Patient value/finding	Reference value	Unit of measurement	Notes/abbreviation
General appearance	Obese, pale	N/A	N/A	Not applicable
Blood pressure	135/85	< 120/80	mmHg	Systolic/diastolic
Heart rate	85	60–100	bpm	Beats per minute
Respiratory rate	19	14–20	Breaths/min
Temperature	36.9	36.5–37.5	°C	36.8
Oxygen saturation	96%	Varies by individual	%
BMI (Body mass index)	32	18.5–24.9	kg/m2	Obese

TABLE 2.

General physical examination findings.

Examination parameter	Finding	Notes/abbreviation
Head and neck	Pale conjunctiva, otherwise unremarkable	N/A
Thorax	Non‐tender mass in the right hemithorax, otherwise unremarkable	N/A
Abdomen	Unremarkable	N/A
Limbs	Normal upper limb force (5/5), Diminished lower limb muscle force (3/5), Otherwise unremarkable	Muscle Force Scale: 0–5, 5 being normal

3. Diagnostic Assessment

Considering the patient's history and physical examination, the differential diagnoses include hyperparathyroidism, X‐linked hypophosphatemia, metastatic bone disease, vitamin d deficiency, paget's disease, multiple myeloma, and tumor‐induced osteomalacia (TIO).

At the time of admission, serum phosphate levels were reported to be 2.4 mg/dL (normal range: 2.6–4.5 mg/dL), whereas calcium levels were measured at 8.5 mg/dL (normal range: 8–11.5 mg/dL). Vitamin D level was 32 ng/mL (normal range: 30–80 ng/mL), and parathyroid hormone (PTH) and creatinine levels were within the normal range. Analysis of a 24 h urine sample (1500 cc) revealed phosphorus excretion of 2331 mg and calcium excretion of 33 mg, with normal ranges of 400–1300 mg/24 h for phosphorus and< 300 mg/24 h for calcium. Tubular Reabsorption of Phosphate (TRP) was calculated to be about 0.011 (≈1.1%), which is markedly low (normal range: 85%–95%), indicating severe renal phosphate wasting. Serum protein electrophoresis (SPEP) results were as follows: Albumin 58.8%, Alpha‐1 3.5%, Alpha‐2 7.4%, Beta‐1 6.5%, Beta‐2 5.9%, and Gamma 17.9% (Table 3).

TABLE 3.

Laboratory findings.

Laboratory test	Patient value	Reference value	Unit of measurement
White blood cell count (WBC)	6.6	4.5–11.3	x1000/cumm a
Hemoglobin (Hb)	14	13.2–18	g/dL b
Platelet count (PLT)	219	140–450	x1000/cumm a
Serum phosphate	2.4	2.6–4.5	mg/dL c
Serum calcium	8.5	8–11.5	mg/dL c
Serum vitamin D	32	30–80	ng/mL d
Parathyroid hormone (PTH)	40.6	10–65	pg/mL e
Thyroid‐stimulating hormone (TSH)	2.8	0.25–5.6	μU/mL f
Serum creatinine	1.2	0.7–1.3	mg/dL c
Urine phosphorus	2331	400–1300	mg/24h g
Urine calcium	33	< 300	mg/24h g
Urine creatinine	1178	600–2000	mg/24h g
Serum protein Electrophoresis (SPEP)	Albumin: 58.8%, Alpha‐1: 3.5%, Alpha‐2: 7.4%, Beta‐1: 6.5%, Beta‐2: 5.9%, Gamma: 17.9%	Varies by individual	%
Serum alkaline phosphatase	2164	80–306	U/L h

^a Thousands per cubic millimeter.

^b Grams per deciliter.

^c Milligrams per deciliter.

^d Nanograms per milliliter.

^e Picograms per milliliter.

^f microunits per milliliter.

^g Milligrams per 24 h.

^h Units per liter.

Because of normal calcium, PTH, and Vitamin D levels, hyperparathyroidism and vitamin D deficiency were considered unlikely. X‐linked hypophosphatemia was also deemed improbable because of the adult‐onset of symptoms. Additionally, Paget's disease, multiple myeloma, and metastatic bone disease were ruled out on the basis of normal renal function, normal SPEP results, the absence of B‐symptoms, lack of hypercalcemia, and the absence of focal lytic/sclerotic lesions in pelvic and knee X‐rays (Figure 4).

FIGURE 4.

Pelvic and lower limb X‐rays. No focal lytic or sclerotic lesions identified on pelvic (A) and lower legs (B) radiographs.

Following the initiation of oral phosphate supplementation (1000 mg of phosphorus, three times daily) and calcitriol (0.25 mcg, three times daily), daily serum sampling was performed as part of routine monitoring. Calcium levels gradually increased to 9.0 mg/dL. However, serum phosphate levels remained low, ranging between 2.5 and 3.0 mg/dL.

Ultrasound of the upper chest wall on the right side revealed a solid‐cystic mass with irregular borders and lobules, located 6 mm beneath the skin surface (Figure 5). The solid components exhibited hypovascularity. The mass is highlighted on the chest CT scan (Figure 6).

FIGURE 5.

Ultrasound of the mass. Solid‐cystic mass measuring 33 × 16 mm located on upper chest wall.

FIGURE 6.

Chest CT scan. The mass is highlighted with yellow arrows.

A vertex‐to‐mid‐thigh positron emission tomography‐computed tomography (PET/CT) scan using 68Ga‐DOTATATE detected a multi‐loculated, 68Ga‐DOTATATE‐avid soft tissue lesion in the right anterior chest wall (Figure 7 and Video 1). The findings were suggestive of a phosphaturic mesenchymal tumor. Unfortunately, evaluation of fibroblast growth factor 23 (FGF23) levels was not feasible because of the lack of appropriate laboratory facilities. No abnormal 68Ga‐DOTATATE uptake was observed in the brain, head and neck, thorax, mediastinum, axillary regions, abdomen, or pelvis. However, a 1.4 cm 68Ga‐DOTATATE‐uptaking lesion was detected in the left adrenal. The patient had normal blood pressure and denied palpitations, headaches, or sweating. Laboratory results showed serum potassium 4.1 mEq/L (normal: 3.5–5.0), urine metanephrine 121 μg/g creatinine (normal: 0–300), and normetanephrine 238 μg/g creatinine (normal: 0–400), excluding pheochromocytoma. Subclinical Cushing syndrome was ruled out by a low‐dose dexamethasone suppression test (morning serum cortisol 1.3 μg/dL; normal: < 1.8) after 1 mg dexamethasone at 11:00 PM. Findings were consistent with an adrenal incidentaloma (Figure 7).

FIGURE 7.

Ga68‐DOTATATE‐PET/CT SCAN. Soft tissue lesion in the right anterior chest wall (white arrow) (A). A lesion of 1.4 cm in size, exhibiting 68Ga‐DOTATATE uptake, identified in the left adrenal gland, which is consistent with an incidentaloma (green arrow) (B).

VIDEO 1.

Download video file ^{(1.3MB, mp4)}

Ga68‐DOTATATE‐PET/CT Scan. Soft tissue lesion localized on the 5th rib, with a maximum size of 3 cm and a maximum standardized uptake value (SUVmax) of 15.2. Left adrenal incidentaloma is also visible. Video content can be viewed at https://onlinelibrary.wiley.com/doi/10.1002/ccr3.72235.

4. Conclusions and Results (Outcome and Follow‐Up)

The patient underwent excision of the mass. After tumor excision, symptoms (including diffuse bone pain and inability to walk) rapidly resolved and the patient was able to walk without any helping device. Follow‐up laboratory revealed normal phosphate and calcium levels in serum.

Histopathological examination of the excisional biopsy specimen revealed a benign mesenchymal tumoral growth with heterogeneous components, including benign fatty tissue, cellular areas of plump spindle cell proliferation with mild pleomorphism and no mitosis, areas with vascular proliferation, and loose myxoid stroma or light blue background with some anucleated blue globules. Hemosiderin deposits, lymphocytic infiltration, and areas of hemorrhage were noted. Lymph node tissue was also seen with no significant pathologic changes. There was no evidence of malignancy in the specimen. Findings consistent with a benign lipomatous tumor, suggestive of myxolipoma (Figure 8). Immunohistochemical analyses, including fibroblast growth factor 23 staining and somatostatin receptor expression, could not be performed because of the unavailability of necessary laboratory facilities. Although histopathology is suggestive of a myxolipoma, the clinical presentation and rapid biochemical normalization post‐resection are consistent with a phosphaturic mesenchymal tumor (PMT). Given the lack of immunohistochemical confirmation, we cannot definitively classify this lesion as a PMT, but it represents a histologic variant contributing to tumor‐induced osteomalacia (Figure 9).

FIGURE 8.

Hematoxylin–eosin (H&E) staining. Sections show proliferation of plump spindle cells and adipose tissue in myxoid and highly vascularized stroma. x100 (A). x400 (B).

FIGURE 9.

Timeline figure. PTH = Parathyroid hormone.

5. Discussion

Tumor‐induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which FGF23‐secreting tumors cause renal phosphate wasting, osteomalacia, and often long diagnostic delays [13, 14]. In our patient, this typical combination of hypophosphatemia, bone pain, and fractures was present but initially unrecognized, illustrating how easily TIO can be overlooked [13]. The clinical presentation of TIO is often insidious, with patients experiencing nonspecific symptoms such as bone pain, muscle weakness, and fractures, which can lead to significant diagnostic delays [13, 14].

Our 47‐year‐old patient had a 2‐year history of progressive gait disturbance and chronic multifocal bone pain, yet his symptoms were initially attributed to degenerative spine disease and stress fractures. Biochemical evaluation ultimately revealed hypophosphatemia with inappropriately normal 1,25‐dihydroxyvitamin D levels, confirming TIO, whereas Ga68‐DOTATATE PET/CT successfully localized a small chest wall tumor that had been missed on earlier evaluations [13, 14, 15]. However, we were unable to measure serum FGF23 levels or perform immunohistochemistry on the resected tumor, which represents a limitation in definitively confirming the tumor's precise nature.

Complete surgical excision of the culprit tumor is considered the definitive treatment for TIO and usually leads to rapid normalization of phosphate metabolism [14]. In our patient, resection of the chest wall lesion resulted in prompt correction of serum phosphate and dramatic improvement in mobility, highlighting the curative potential of surgery when the tumor is accurately localized [13, 14, 15].

For patients in whom the tumor cannot be localized or resected, long‐term medical therapy with phosphate salts, active vitamin D analogues, or the anti‐FGF23 antibody burosumab can improve biochemical control and symptoms [13, 15, 16, 17]. In our case, complete surgical removal of the tumor achieved full biochemical and clinical remission, so additional targeted medical therapy was not required [13, 14, 15, 16].

Long‐term surveillance is recommended in TIO to detect biochemical relapse or tumor recurrence, although optimal follow‐up intervals remain uncertain and should be individualized [13, 14, 15, 16, 17]. Our patient is being monitored with periodic assessments of serum phosphate and, when clinically indicated, imaging of the chest wall to ensure sustained remission and to address any late skeletal complications [13, 14, 15, 16, 17].

This case highlights the importance of thorough physical examination (because of missed evaluation of chest wall mass in the patient for years), and also considering TIO in patients with unexplained hypophosphatemia and osteomalacia, utilizing advanced imaging techniques for tumor localization, and the effectiveness of surgical resection in resolving the condition. Ongoing surveillance is crucial to ensure long‐term management and early detection of recurrence [13, 14, 15, 16, 17].

The clinical challenges in diagnosing and managing TIO are significant [15]. The rarity of the condition and the nonspecific nature of its symptoms often lead to delayed diagnosis [14, 15]. The average diagnostic delay can range from 2.5 to 28 years, as reported in various studies [13]. This delay can result in prolonged patient suffering and increased morbidity [14, 15].

Therefore, increasing clinicians' awareness of TIO and its clinical presentation is essential for timely diagnosis and treatment. The introduction of advanced imaging techniques, such as Ga68‐DOTATATE PET/CT, has significantly improved the localization of TIO‐causing tumors, reducing the diagnostic delay and facilitating curative surgical interventions [15, 16]. However, the accessibility and availability of these imaging modalities can vary, impacting the timely diagnosis and management of TIO [13, 15, 16].

In cases where the tumor cannot be localized or surgically resected, medical management with phosphate supplements and active vitamin D analogs can help manage symptoms and improve quality of life [13, 15, 16, 17]. Burosumab, an anti‐FGF23 antibody, has emerged as a promising therapy for patients with inoperable tumors or those who do not achieve remission after surgery [13, 14, 15, 16, 17]. Clinical trials have demonstrated the efficacy of burosumab in normalizing serum phosphate levels and improving clinical outcomes in TIO patients [13, 15, 16].

We believe that long‐term management of TIO requires a multidisciplinary approach, involving endocrinologists, radiologists, surgeons, and even other specialists. Regular follow‐up with biochemical assessments and imaging studies is crucial for monitoring recurrence and managing any residual symptoms [13, 14, 15, 16].

In conclusion, this case underscores the importance of considering TIO in patients with unexplained hypophosphatemia and osteomalacia. Utilizing advanced imaging techniques for tumor localization and the effectiveness of surgical resection in resolving the condition are critical [14, 15, 16]. Ongoing surveillance is essential to ensure long‐term management and early detection of recurrence [13, 14, 15, 16]. Increasing clinicians' awareness of TIO and its clinical presentation can lead to timely diagnosis and improved patient outcomes [4, 13, 14, 15, 16, 17].

Author Contributions

Rahman Amraei: conceptualization, data curation, formal analysis, investigation, methodology, project administration, resources, supervision, validation, visualization, writing – original draft, writing – review and editing. Amirmohammad Karimi: conceptualization, investigation, validation, visualization, writing – original draft, writing – review and editing. Samad Nazarpoor: conceptualization, data curation, formal analysis, investigation, methodology, validation, visualization, writing – original draft, writing – review and editing. Saeed Choobkar: conceptualization, investigation, writing – original draft.

Funding

This case report was conducted without any funding support.

Ethics Statement

This study was conducted in accordance with institutional and national ethics guidelines. Ethical approval was obtained from Lorestan University of Medical Sciences Ethics Committee.

Consent

Written informed consent was obtained from the patient for publication of this case report and any accompanying images.

Conflicts of Interest

The authors declare no conflicts of interest.

Data Availability Statement

Data supporting the findings of this case report are available from the corresponding author upon reasonable request.