Successful Treatment of Tumor-Induced Osteomalacia due to an Intracranial Tumor by Fractionated Stereotactic Radiotherapy

Abstract

Context:

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome, characterized by tumor secretion of fibroblast growth factor-23 (FGF23) causing hypophosphatemia due to renal phosphate wasting. TIO is usually caused by small, benign, difficult-to-localize, mesenchymal tumors. Although surgery with wide excision of tumor borders is considered the “gold standard” for definitive therapy, it can be associated with considerable morbidity depending on the location. To date, radiation therapy has not been considered as an effective treatment modality in TIO.

Objective:

A 67-year-old female presented with multiple nontraumatic fractures, progressive bone pain, and muscle weakness for 4 years. She was found to have biochemical evidence of urinary phosphate wasting with low serum phosphorus, low-normal serum calcium, normal 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D, and high serum FGF23 levels. TIO was diagnosed. Selective venous sampling for FGF23 confirmed that a 1.7-cm left frontal mass, radiographically similar to a meningioma, was the causative tumor. She declined surgery due to fear of complications and instead underwent fractionated stereotactic radiotherapy for 6 weeks.

Results:

In less than 4 years after radiation therapy, she was successfully weaned off phosphorus and calcitriol, starting from 2 g of oral phosphorus daily and 1 μg of calcitriol daily. Her symptoms have resolved, and she has not had any new fractures.

Conclusions:

Stereotactic radiotherapy was an effective treatment modality for TIO in our patient. Fractionated stereotactic radiation therapy represents an alternative to surgery for patients with TIO who are not surgical candidates or who decline surgery.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that is characterized by phosphate wasting due to increased levels of a circulating phosphatonin, fibroblast growth factor-23 (FGF23). In patients with TIO, tumor cells produce FGF23 that leads to urinary phosphate wasting through decreased expression of sodium-phosphate cotransporters (types 2a and 2c) in the proximal renal tubule. FGF23 also decreases expression of 1-α-hydroxylase (1), decreasing the conversion of 25-hydroxyvitamin D [25(OH) vitamin D] to its active form, 1,25 dihydroxyvitamin D [1,25(OH)₂ vitamin D], and consequently lowering absorption of phosphorus and calcium from the gut. This may lead to secondary hyperparathyroidism.

Hence, TIO is characterized by low serum phosphorus, low urinary phosphorus reabsorption, low or inappropriately normal 1,25(OH)₂ vitamin D, high or inappropriately normal FGF23, and occasionally secondary hyperparathyroidism.

Clinically, patients present with weakness, fatigue, diffuse aches, and bone pain from osteomalacia (2). In addition, patients with TIO may develop multiple fractures. TIO often causes severe morbidity and can be debilitating.

TIO is typically, but not universally, caused by benign mesenchymal tumors (2–6). These tumors are usually small and are sometimes difficult to localize (2). A stepwise approach for localization of these tumors has been proposed (2). First, functional imaging, such as 111-indium octreotide scintigraphy combined with single photon emission computed tomography (CT)/CT, with or without F-18-fluorodeoxyglucose (FDG) positron-emission tomography (PET)/CT or 68Ga-DOTANOC PET/CT followed by anatomical imaging (CT and/or magnetic resonance imaging [MRI]) is recommended. If the results of the above tests are nonconclusive, venous sampling with FGF23 measurements should be considered (2).

Treatment of TIO usually includes both medical and surgical approaches. Patients with TIO are treated medically with phosphorus and calcitriol supplementation until they have surgical therapy. Some patients also require calcium and vitamin D supplementation. The goal of therapy is to achieve low-normal serum phosphorus and 1,25(OH)₂ vitamin D levels while preventing complications of secondary hyperparathyroidism and hypercalciuria. Long-term medical therapy carries potential risks of hyperparathyroidism, nephrocalcinosis, and nephrolithiasis. Thus, periodic surveillance is recommended (2).

Surgery is traditionally considered the “gold standard” for definitive therapy for patients with TIO (2, 4, 6). Wide margin excision of the tumor borders is advised to prevent persistence or recurrence of TIO because tumors are often not encapsulated, and the true margin of the tumor is frequently beyond what is suggested radiographically (2, 7). Therefore, surgery may be associated with some morbidity, even with small and benign tumors, depending on the tumor location.

To our knowledge, only two case reports of successful alternative definitive therapies for TIO are described in the literature (8, 9). One described a case of a 40-year-old female with TIO due to a tumor in the right femoral head that was treated with CT-guided radiofrequency ablation. Surgery might have resulted in total hip arthroplasty; thus, to avoid this morbidity, an alternative approach was used. The patient had resolution of both clinical and biochemical abnormalities within a few weeks after CT-guided radiofrequency ablation. There was no recurrence up to 12 months later (8).

The second case report was a 51-year-old man with TIO due to a mesenchymal tumor in the pelvis that was treated by CT-guided percutaneous ethanol ablation and cryoablation. He had a history of total hip arthroplasty due to a proximal hip fracture before the TIO diagnosis. Wide excision of the tumor was recommended. However, alternative definitive therapy was pursued to avoid a potential need for revision of the hip arthroplasty with hemipelvic stabilization. The patient had rapid improvement of his symptoms and normalization of laboratory findings within days of the CT-guided percutaneous ethanol and cryoablation. The recovery persisted at 1 year of follow-up (9).

To date, radiation therapy has not been considered a successful treatment modality of TIO based on the available evidence in the literature reviewed (2). There are three case reports using this treatment approach. One report from Japan described a 48-year-old man with TIO due to a malignant mesenchymal tumor of the tongue. He underwent two surgical resections, but the tumor recurred. Because a third resection may have resulted in significant morbidity, he was treated with radiotherapy (66 Gy). The residual tumor and lymph nodes decreased in size, but hypophosphatemia persisted 2 years later (4).

Another report concerned a 63-year-old female with TIO due to a hemangiopericytoma of the maxillary sinus. She was treated with a partial resection of the tumor that led to partial short-term clinical and biochemical improvement. When the TIO symptoms recurred, the residual tumor was resected via craniotomy. She then underwent radiation therapy with selective embolization. The patient died after surgery and had no improvement in laboratory values or symptoms (10).

A third case report described a 34-year follow-up of a man with TIO due to an intracranial hemangiopericytoma. This aggressive tumor was treated with multiple resections, embolizations, octreotide therapy, gamma knife, and fractionated stereotactic radiotherapy. The tumor recurred despite all these therapies. Finally, he received chemotherapy with dasatinib, a tyrosine kinase inhibitor that led to clinical and radiological stability of the tumor at 2 years. That case report focused on the neurological manifestations and the tumor size (11).

We present here the case of a female with TIO due to a frontal lobe tumor, presumed to be a meningioma. She declined surgery due to fear of potential complications and instead was treated with fractionated stereotactic radiotherapy, which resulted in elimination of signs and symptoms of osteomalacia.

Case Report

A 60-year-old Caucasian female presented in 2006 with multiple nontraumatic fractures. She had a history of insufficiency fractures of sacral bones, pubic rami, multiple ribs, a clavicle, and femoral neck bilaterally. She also had marked thoracic kyphosis due to multiple vertebral compression fractures. She reported progressive bone pain and muscle weakness for 4 years, which had rendered her wheelchair-bound. Her past medical history included hypertension, anxiety, and what was described as “severe osteoporosis.” She had been treated with alendronate for 4 years before our evaluation.

Initial laboratory workup included the following serum levels: phosphorus, 1.8 mg/dL (normal range, 2.5–4.9); calcium, 8.7 mg/dL (8.5–10.5); 1,25(OH)₂ vitamin D, 36 pg/mL (15–60); 25(OH) vitamin D, 30 ng/dL (20–100); and PTH, 87 pg/mL (11–67) (Table 1). She had low bone mineral density (BMD) as assessed by dual-energy x-ray absorptiometry (DXA). Lumbar spine BMD was 0.620 g/cm² with a T-score of −3.4. Hip BMD was 0.567 g/cm² with a T-score of −3.7 (Table 2).

Table 1.

Laboratory Values and Medications

	Reference Range	Units	2006	2007	2008	2009b	2010	2011	2012	2013
Laboratory value
Serum calciuma	8.5–10.5	mg/dL	8.6	8.6	8.4	9.4	9.2	8.9	9.2	9.1
Serum phosphorusa	2.7–4.5	mg/dL	1.8	2.2	2.5	2.8	2.5	3.5	3.5	3.3
FGF23 (measured by full-length assay)	10–50	pg/mL		132	123
FGF23 (measured by C-terminal assay)	<180	RU/mL							134
PTH	11–67	pg/dL	87	38	121				19
25(OH) vitamin D	20–100	ng/mL	23		28		52		51
1,25(OH)2 vitamin D	15–60	pg/mL	22		12				60
Medicationc
Phosphorus (K-Phos Neutra)	1 tablet	250 mg	8	8	8	8	4	4	2	0
Calcitriol	1 tablet	0.25 μg	2	2	2	2	1	1	1	0
Calcium	1 tablet	600 mg	3	3	3	3	3	3	3	3
Vitamin D	1 tablet	400 IU	3	3	3	3	3	3	3	3

^aLaboratory values average over 1 year.

^bYear during which fractionated stereotactic radiation therapy occurred.

^cDoses of medications presented in number of tablets per day.

Table 2.

BMD Based on DXA

	Spine BMD, g/cm2	T-score	BMD Change vs Baseline, %	Hip BMD, g/cm2	T-score	BMD Change vs Baseline %
2005	0.620	−3.4		0.567	− 3.7
11/2007a	0.840	−1.9	+35.5	0.584	− 2.9	+3
09/2008	0.963	−0.8	+55.3	0.718	−1.8	+26.6
09/2012a	0.934	−1.0	+50.6	0.873	−0.6	+54

There was a significant increase in the patient's BMD in both spine and hip within 7 years of therapy.

^aThe same DXA scan machine (HOLOGIC).

Because her workup revealed low serum phosphorus with low-normal serum calcium, normal 1,25(OH)₂ vitamin D, and mildly elevated PTH, the suspicion of hypophosphatemic osteomalacia was high. Her bone-specific alkaline phosphatase was elevated at 354 U/L (46–67). Her fractional excretion of phosphorus was high at 28% (<5%), thus confirming renal phosphate wasting. Her serum FGF23 level of 132 pg/mL (10–50) established FGF23-dependent phosphate wasting disorder consistent with TIO (because there was no family history of hypophosphatemic disorders, rickets, or short stature and no personal history of exposure to renal tubular toxins, such as heavy metals or chemotherapy agents).

She was treated with oral phosphate (initially 2 g or 8 tablets per day of K-Phos Neutral), calcitriol (1 μg/d), calcium (1800 mg/d), and cholecalciferol (1200 IU/d). The doses of these medications were titrated to maintain serum levels of phosphorus, calcium, 25(OH) vitamin D, and 1,25(OH)₂ vitamin D within normal limits (Table 1). Alendronate was discontinued after the diagnosis of TIO was established.

Symptoms of weakness, fatigue, and bone aches resolved after starting medical therapy, and she has not had new fractures. She has not developed complications of long-term calcium, phosphorus, and calcitriol administration.

She had multiple tumor localization studies that included CT scans, MRI scans, octreoscan, FGD-PET/CT scan, and tumor sestamibi scan. Octreoscan revealed a lesion in the skull that was previously identified and presumed to be a 17 × 13 × 15-mm meningioma based on radiographic appearance. Thus, an intracranial tumor was thought to be the possible cause of TIO (Figure 1). However, because meningiomas are known to be octreotide positive and there was limited knowledge about meningiomas causing TIO at the time of the workup, she had selective venous sampling for FGF23 (12–14). The study revealed a clear step-up in the FGF23 levels as the frontal mass was approached anatomically (Figure 2). This was consistent with the diagnosis of TIO due to intracranial tumor. The patient declined biopsy of the mass, and the tissue diagnosis of the mass remains unknown.

Figure 1.

Imaging studies. A, CT scan of the head revealed a 17 × 13 × 15-mm medial left frontal mass suggestive of meningioma. B, MRI of the head confirmed the lesion. C, Octreoscan was positive for an intracranial lesion corresponding to the left frontal mass. D, FDG-PET demonstrated generalized increased uptake by the brain. E, MRI of the head in 2009 before fractionated stereotactic radiation therapy. F, MRI of the head 1 year after fractionated stereotactic radiation therapy in 2010 revealed stable in size tumor with multiple small hemorrhages within it.

Figure 2.

Selective venous sampling for FGF23. There was a significant step-up in FGF23 concentration as the suspected tumor was approached anatomically.

The patient was offered surgical removal of the mass via craniotomy; however, she declined because of fear of complications. Instead she underwent fractionated stereotactic radiotherapy in 2009. She received 60 Gy of radiation in divided doses during a 5-week period. She elected to have small doses of radiation over time rather than a single higher dose.

During the first year after radiation, she had a 50% reduction in oral phosphorus requirement, and thereafter about 25% per year of the initial dose. By less than 4 years after radiation therapy, oral phosphorus and calcitriol had been discontinued, and renal phosphate wasting had resolved completely. Initially in 2006, her 24-hour urinary phosphorus was 750.8 mg/24 h (400–1300) when her serum phosphorus concentration was 1.8 mg/dL with fractional excretion of phosphate 28%; in healthy individuals, it should be less than 5% when serum phosphate is low. In 2013, when she completely discontinued phosphorus and calcitriol supplementations, her 24-hour urinary phosphorus was 467 mg/24 h with serum phosphorus of 2.8 mg/dL, and fractional excretion of phosphate was 9.2% (5–20%). Her FGF23 also decreased to the normal reference range over time. It was elevated at 132 and 123 pg/mL (10–50) when measured by full length assay in 2007 and 2008. In 2012, her FGF23 was within normal limits at 134 RU/mL (<180) when measured by C-terminal assay. The tumor size had remained stable, but was accompanied by evidence of multiple small hemorrhages within the tumor on MRI 1 year after radiation therapy (Figure 1). She has not had more fractures, and her BMD has increased by nearly 50% (Table 2).

Discussion

We present a case of successful treatment of TIO due to an intracranial tumor by fractionated stereotactic radiation therapy. This is the first case report that describes the therapeutic effectiveness of fractionated stereotactic radiotherapy in the management of TIO.

We hypothesize that the therapeutic response to radiation was achieved by compromising the tumor's blood flow, resulting in tumor necrosis that led to decreased FGF23 production.

Historically, radiation therapy was not considered an effective treatment modality for TIO, probably because of the overall benign, well-differentiated, and slowly proliferating tumor characteristics. Interestingly, in all three previously mentioned case reports utilizing radiation therapy for treatment of TIO, radiation therapy was used in patients with rather aggressive malignant tumors. On the other hand, our patient had a tumor with benign appearance and behavior, which did not cause any neurological deficits. Considering the need for a wide-margin excision to prevent recurrence of TIO caused by intracranial tumors, a traditional surgical approach in this case could possibly have led to significant morbidity.

Intracranial tumors in general are considered to be rare causes of TIO, with only a few cases reported (11, 13, 15, 16). Although the radiological appearance was that of a meningioma, the histological type of the intracranial tumor in our patient remains to be elucidated because she has declined biopsy. Although radiological appearance of the mass was consistent with meningioma, it may not be the case. A recent report described a tumor that radiologically resembled a meningioma that turned out to be a low-grade phosphaturic mesenchymal tumor, mixed connective tissue variant, the most common histological variant of tumors that cause TIO (11). Interestingly, when our patient was initially evaluated, there was no evidence in the literature of TIO due to meningiomas.

Our case also represents an example of long-term follow-up of medical therapy for TIO. Our patient's symptoms of bone pain and weakness improved gradually with medical therapy only and resolved before she underwent radiotherapy. Her very low bone mass on her first DXA scan in 2005 reflects osteomalacia, not osteoporosis. Phosphorus and calcitriol supplementations alone led to a dramatic increase in BMD (more than 50%) due to mineralization of the unmineralized osteoid. That magnitude of change in BMD would have been unusual for osteoporosis.

One of the challenges of long-term medical therapy is the risk of complications and therefore the necessity of periodic lab work monitoring to prevent those complications. The risk of complications is proportional to the duration of the therapy as well as other factors. With careful monitoring, our patient has not developed nephrocalcinosis or nephrolithiasis after more than 6 years of therapy with calcium, phosphorus, and calcitriol.

Successful cure of TIO in our patient is supported by normalization of fraction of phosphorus excretion upon complete discontinuation of phosphorus and calcitriol. The effect of radiation therapy is not immediate and may take years for its entire effect; however, for selected patients it may be the treatment modality of choice.

Risks and benefits of radiation therapy should be considered in patients undergoing this therapy. Patients like ours who have TIO due to intracranial tumor are at risk for pituitary irradiation and consequently may develop panhypopituitarism as well as some cognitive impairment. Those potential complications are individual and depend on the location of the tumor itself as well as the radiation modality that is used.

Because the recognition of TIO and the ability to localize the associated tumors has improved over the years, novel therapeutic modalities are currently under investigation as well. Surgery remains the gold standard for definitive treatment of patients with TIO. However, when surgery might be associated with severe morbidity, or the patient is not a surgical candidate, we propose considering fractionated stereotactic radiation therapy in addition to medical treatment as an alternative to surgery for patients with TIO.