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The Journal of Clinical Endocrinology & Metabolism Vol. 85, No. 2 549-555
Copyright © 2000 by The Endocrine Society

Original Studies

Use of Long-Term Intravenous Phosphate Infusion in the Palliative Treatment of Tumor-Induced Osteomalacia

S. Jim Yeung, Ian E. McCutcheon, Pamela Schultz and Robert F. Gagel

Sections of Endocrine Neoplasia and Hormonal Disorders (S.J.Y., P.S., R.F.G.) and Neurosurgery (I.E.M.), University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030

Address all correspondence and requests for reprints to: Robert F. Gagel, M.D., Section of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Box 15, Houston, Texas 77030.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Case Report
 Discussion
 References
 
Tumor-induced osteomalacia is characterized by paraneoplastic defects in vitamin D metabolism, proximal renal tubular functions, and phosphate transport. The resulting hypophosphatemia can cause generalized pain and muscle weakness, which significantly affect the quality of life of the patients. Palliative treatment with calcium, vitamin D, and phosphate replacement is indicated for patients in whom the causative tumor cannot be completely resected. In this report we describe a case of tumor-induced osteomalacia in whom adequate oral doses of phosphate could not be used because of gastrointestinal side-effects. Long term (3–6 months) iv phosphate infusion delivered by ambulatory infusion pumps in combination with oral calcium and vitamin D was used successfully to decrease pain and increase muscle strength. Careful monitoring of serum calcium, phosphate, and creatinine levels and reliable microinfusion technology have allowed the long term use of iv phosphate infusion without serious morbidity. This patient received repeated (three times) phosphate infusions over 8 yr, resulting in laboratory and symptomatic improvement after each course. However, this patient did suffer two episodes of central venous catheter-related infection. Because of potentially serious complications, such as severe hypocalcemia, calcified right ventricular thrombi, and nephrocalcinosis, long term iv phosphate infusion should be reserved for patients who cannot tolerate adequate doses of oral phosphate and for whom the benefits outweigh the risks.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Case Report
 Discussion
 References
 
TUMOR-INDUCED osteomalacia (tumor-induced hypophosphatemic rickets) is a syndrome characterized by hypophosphatemia, low plasma 1,25-dihydroxyvitamin D3 levels, and clinical osteomalacia (1, 2, 3, 4, 5, 6). This syndrome is thought to be caused by humoral factors produced by one of several tumor types that inhibit renal tubular reabsorption of phosphate, other proximal renal tubular functions, and 1{alpha}-hydroxylation of 25-hydroxyvitamin D3. Resolution of the syndrome after tumor removal (7, 8, 9, 10, 11, 12, 13, 14) and reproduction of the syndrome by tumor xenografting in athymic mice (15, 16, 17) and bioassays of tumor cell-conditioned culture media (18, 19, 20, 21, 22) or tumor extracts (16) provide support for this hypothesis.

Patients suffering from tumor-induced osteomalacia often have symptoms of generalized pain and muscle weakness. Osteopenia and pseudofractures occur frequently, and osteomalacia can be demonstrated by bone biopsy. Severe loss of bone mass may lead to fractures (23, 24). Characteristic biochemical findings include hypophosphatemia, hyperphosphaturia, and an elevated serum alkaline phosphatase level. This clinical syndrome is distinct from hypophosphatemia associated with hematogenous malignancies, in which light chain nephropathy causes phosphate wasting (25).

The neoplasms reported to cause this syndrome, the majority of which are nonmalignant, include schwannoma (11), fibroma (9, 10, 14), dermatofibroma (19), hemangiopericytomas (7, 15, 26, 27, 28, 29), neurilemoma (30), osteosarcoma (31), osteoblastoma (32), chondroblastoma (33), chondrosarcoma (34), sclerosing hemangiomas (20), giant cell tumor (35), malignant fibrous histocytoma (36), and fibrosarcoma (14). In a review of 72 cases (1), more than one third of the tumors were classified as vascular tumors, and half of these were hemangiopericytomas. In another review of 100 cases (30), 87% of the cases were benign, 50% were vascular in origin, and 50% of the tumors were located in skeletal tissues. Weidner summarized the pathological features of these mesenchymal tumors and coined the name phosphaturic mesenchymal tumor (5, 37). Subsequent reports have emphasized that this syndrome may be associated not only with mesenchymal tumors but also with prostate carcinoma (38, 39, 40, 41) and perhaps small cell cancers of the lung (42, 43) and trachea (44), but a definite causal relationship has not been established between tumor-induced osteomalacia and prostate or small cell cancer.

Therapy of this clinical syndrome is directed first toward resection of the tumor. A complete resection is curative and will result in reversal of all biochemical abnormalities (7, 8, 9, 10, 11, 12, 13, 14). When complete resection of the causative tumor is not successful or not possible, correction of the two major biochemical abnormalities, i.e. hypophosphatemia and 1,25-dihydroxyvitamin D3 deficiency) will often lead to clinical improvement (3, 6).

Although deficiency of 1,25-dihydroxyvitamin D3 and secondary hyperparathyroidism may contribute to renal phosphate loss, the degree of hypophosphatemia and phosphaturia in patients with tumor-induced osteomalacia cannot be completely accounted for by this mechanism (2). Normalization of vitamin D abnormalities by treatment with large doses of ergocalciferol or smaller doses of calcitriol can correct secondary hyperparathyroidism, but hypophosphatemia and phosphaturia persist in these patients. Nevertheless, vitamin D and calcium supplementation is an important component of therapy.

The second component is correction of hypophosphatemia. Phosphate supplementation is most commonly by oral phosphate administration. In general, oral phosphate therapy is well tolerated, although 5–10% of treated patients develop gastrointestinal symptoms, including nausea, vomiting, diarrhea, or abdominal pain. These side-effects are generally dose related, and doses required to normalize serum phosphate in patients with tumor-induced osteomalacia may not be tolerable. Alternatives to oral phosphate therapy are few. The use of parenteral phosphate therapy has been limited to life-threatening situations because of concerns about metastatic calcification, hypocalcemia, cardiac arrhythmia, and electrolyte disturbances. This report describes a case of tumor-induced osteomalacia, complicated by hyperparathyroidism, in which iv phosphate infusion was used repeatedly long term in combination with other therapies (i.e. parathyroid surgery, calcitriol and calcium supplementation) and contributed to improvement in biochemical and clinical parameters.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Case Report
 Discussion
 References
 
Intravenous phosphate infusion

Two hundred millimoles of potassium phosphate, U.S.P. (potassium, 4.4 mEq/L; phosphate, 3 mmol/L), was diluted in sodium chloride 70 mEq/L to a final volume of 200 mL (i.e. 1 mol/L phosphate). This concentrated solution was infused via central venous catheters at rates varying from 1–2 mL/h. The patient had central venous catheters inserted in the subclavian veins. The ambulatory infusion pump used was InfuMed (Medfusion, Inc., Duluth, GA). The infusion was titrated in 0.1 mL/h increments to maintain a serum phosphorus level of about 2 mg/dL.

Monitoring strategy

Close monitoring of serum phosphorus, calcium, magnesium, creatinine, sodium, and potassium is necessary during continuous iv infusion of phosphate. These laboratory measurements were obtained daily during the first week of therapy. After the serum phosphorus level had achieved the target value and stabilized, the monitoring frequency was decreased to once per week.


   Case Report
Top
 Abstract
 Introduction
 Materials and Methods
 Case Report
Discussion
 References
 
A white female first presented with a 2-yr history of progressive bone and muscle pain and weakness in 1977 at the age of 58 years. Laboratory evaluation showed hypophosphatemia, decreased tubular reabsorption of phosphate (Fig. 1DGo), and elevated alkaline phosphatase. Radiological studies showed generalized osteopenia (Fig. 2Go) and pseudofractures (Fig. 3Go) consistent with a diagnosis of hypophosphatemic rickets.



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  		Figure 1. Changes in serum phosphorus, alkaline phosphatase, serum creatinine, and tubular reabsorption of phosphate over time. In all eight panels, the black bars indicate the periods of continuous iv phosphate infusion. A–D show the data up to the partial resection of a mesenchymal tumor, and E–H show the data since the surgery. A and E, Serum phosphorus. The dotted line indicates the lower limit of normal. B and F, Serum creatinine. The dotted line indicates the upper limit of normal. C and G, Alkaline phosphatase. D and H, Maximum TmP/GF. The dotted line indicates the lower limit of normal.

 


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  		Figure 2. Development of osteopenia. Radiographs of lumbar spine of the patient described are shown. The dates of the radiographs are shown at the bottom of each panel. Cortical thinning is evident over time, and marked osteopenia can be clearly observed in the radiographs from 1976 and 1983.

 


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  		Figure 3. Pseudofracture. An arrow points to a pseudofracture in the scapula of the patient.

 
There was no prior history of alcohol abuse, excessive antacid use, or bone abnormality or fracture and no family history of bone diseases, hypophosphatemia, or Fanconi syndrome. Laboratory evaluation excluded intrinsic renal diseases, systemic acidosis, thyroid disease, hyperparathyroidism, exposure to heavy metals, and vitamin D abnormalities. Although tumor-induced osteomalacia was suspected, a detailed laboratory and radiological evaluation failed to identify a causative tumor at that time.

During the period from 1977–1991 she was managed with several therapeutic regimens. She was treated initially with oral calcium and vitamin D (50,000 U daily) for a period of 4 months. There was no improvement in serum phosphate or her symptoms on this regimen. Oral sodium phosphate ranging from 1–3 g elemental phosphorus/day was added to her regimen and continued until 1991. Compliance with the oral sodium phosphate regimen was poor because of gastrointestinal symptoms, and she was unable to tolerate more than 1.5 g elemental phosphorus/day, orally. The maximum vitamin D dose during this period was 100,000 U/day. In 1983, she was switched from ergocalciferol to calcitriol given orally in doses of 0.25–1 µg/day for the next 10 yr. She was also supplemented with 1.6 g elemental Ca/day. The medical regimen varied during this period, but remained within the parameters outlined above.

On this therapeutic regimen there was improvement of her serum phosphorus concentration, but at no point during this period was her serum phosphorus greater than 2.3 mg/dL, and most values ranged between 1.7–1.8 mg/dL. There was symptomatic improvement and a reduction of her serum alkaline phosphatase concentration from pretreatment values greater than 340 IU/L (normal, 38–126 IU/L) to values ranging from 212–282 IU/L, but it never completely normalized.

In February 1988, an osteoblastic area in the left acetabulum was noted (Fig. 4Go). A biopsy demonstrated osteomalacia. There was still no evidence of a causative tumor. In early 1991, she again presented with worsening bone pain and inability to ambulate or rise from a chair without assistance. She was noted to have a serum calcium concentration of 10.6 mg/dL, which was elevated from her baseline value of about 8.8 mg/dL. Her serum alkaline phosphatase concentration had also risen to more than 500 IU/L (Fig. 1BGo). She was found to have elevated midregion PTH (2400 pg/mL; normal range, 50–340 pg/mL) and N-terminal PTH (24 pg/mL; normal range, 4–19 pg/mL). Ultrasonographic examination revealed a 0.8 x 0.8 x 0.5-cm left neck mass. A parathyroid adenoma (Fig. 6Go) was subsequently removed with normalization of the serum calcium. An incidental papillary thyroid carcinoma was noted in the left lobe of the thyroid gland, leading to a left hemithyroidectomy.



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  		Figure 4. Blastic changes in the hip. The white arrow points to a blastic area in the left acetabulum of the patient described. This area was biopsied and shown to have changes consistent with osteomalacia. The black arrow points to a pseudofracture at the femoral neck with associated blastic changes.

 


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  		Figure 6. Histological features of the phosphaturic mesenchymal tumor. Photomicrographs of stained sections of the phosphaturic mesenchymal tumor are shown on the left at low (left upper panel) and high (left lower panel) magnifications. For comparison, photomicrographs of sections of the parathyroid adenoma resected from this patient are shown on the right at low (right upper panel) and high (right lower panel) magnifications. The morphological features of the phosphaturic mesenchymal tumor are those of a relatively bland spindle cell proliferation. The spindle cells demonstrate mild hyperchromasia and pleomorphism.

 
Severe and persistent bone pain and hypophosphatemia after removal of the parathyroid adenoma despite maximum tolerated oral phosphate therapy led to the initiation of a continuous iv phosphate infusion. Initially, she received 48 mmol potassium phosphate infused over a 24-h period with the infusion rate adjusted to maintain her serum phosphorus between 2.5–3.5 mg/dL (Fig. 1AGo). The infusion was continued for almost 12 months before discontinuance. Within 2–3 months after the initiation of phosphate infusion, she was able to ambulate without assistance, and there was a continued fall in her serum alkaline phosphatase concentration during the first 6 months of phosphate infusion. This drop in alkaline phosphatase was most likely due to removal of the parathyroid adenoma rather than to the direct effect of phosphate infusion, because subsequent phosphate infusions did not change her serum alkaline phosphatase significantly. During the phosphate infusion, her midregion PTH and intact PTH measurements were normal. The infusion was continued until February 1992. At the time of discontinuance, she had improved symptomatically, with near-normal muscle strength and no bone pain. Bone mineral density measurements by dual energy x-ray absorptiometry demonstrated improvement in bone density in all measured areas [e.g. femoral neck, 0.330 g/cm2 (right) and 0.312 g/cm2 (left) on February 21, 1991 to 0.469 g/cm2 (right) and 0.474 g/cm2 (left) on February 20, 1992. However, radiographic evaluation at the time showed the previously noted pseudofractures without obvious changes.

There was concern throughout the infusion period regarding potential adverse effects of iv phosphate infusion. Frequent serum creatinine measurements demonstrated a transient rise in her serum creatinine concentration to 1.8 mg/dL (Fig. 1CGo). Examination for renal calcification by ultrasound demonstrated no evidence of calcification. Two episodes of fever and chills, attributed to venous catheter-related bacteremia, led to the removal of the subclavian central venous catheter in February 1992.

In June 1993, the patient again presented with renewed complaints of bone pain and a new complaint of pain in her neck. Radiographic evaluation demonstrated a lucent, destructive lesion involving the posterior spinous process and right lamina (Fig. 5Go) of the second cervical vertebra. A fine needle aspiration biopsy was performed and showed features characteristic of a benign spindle cell mesenchymal tumor (45). The aspirate contained tissue fragments and a large number of single spindle cells, which demonstrated mild hyperchromasia and pleomorphism. In addition, numerous vessels were seen as well as material that may be osteoid. There were not a significant number of mitoses seen. Immunohistochemical stains for cytokeratin, S-100 protein, neurofilament, and thyroglobulin were negative. Complete resection of the tumor was not possible because of the cervical instability such a resection would cause and close proximity to the vertebral artery. A partial resection was performed to protect the spinal cord from encroachment and to relieve nerve root compression of the second and third cervical spinal nerves. The surgical pathology showed a benign fibroma-like tumor consistent with phosphaturic mesenchymal tumors (Fig. 6Go) (5). After partial (~40–50% of the tumor) surgical removal, there was a transient increase in the serum phosphorus concentration (Fig. 1EGo) and a concurrent increase in the maximum renal tubular reabsorption of phosphorus per L glomerular filtrate (TmP/GF; Fig. 1HGo). However, within a few days both the serum phosphorus concentration and TmP/GF values had fallen back to baseline values. This transient decline was perhaps due to "stunning" of the tumor by surgical manipulation, as the extent of resection was unlikely to have significant biochemical impact over the long term. The size of the tumor was monitored subsequently by annual computed tomography scan.



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  		Figure 5. Mesenchymal tumor. A, Radiograph of the cervical spine of the patient. The arrow points to the lytic lesion at the ramus of the cervical vertebra. B, Computed tomograph of the cervical spine. The arrow points to the same lytic lesion.

 
In March 1994, she was restarted on the phosphate infusion because of renewed bone symptoms and a small rise in her alkaline phosphatase concentration (Fig. 1GGo). Her serum phosphate was normal during the iv infusion (Fig. 1EGo). On March 25, 1994, laboratory evaluation showed serum alkaline phosphatase activity of 108 IU/L, serum calcium of 8.7 mg/dL, serum phosphorus of 2.7 mg/dL, 25-hydroxyvitamin D of 100 ng/mL, 1,25-dihydroxyvitamin D of 85 pg/mL, and intact PTH of 27 pg/mL. Again, she responded clinically with resolution of bone pain and improvement in muscle strength. This infusion was continued until August 1994. In May 1996, her symptoms returned, and measurement of intact PTH (1738 pg/mL) and serum calcium (8.5 mg/dL) levels suggested secondary hyperparathyroidism. Her calcitriol dose was increased, and she received iv phosphate infusion again until September 1996. Her intact PTH level subsequently normalized.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Case Report
 Discussion
References
 
The clinical course of this patient embodies many of the oft-reported characteristics of this tumor syndrome. The patient presented with classic osteomalacia caused by hypophosphatemia. Treatment with vitamin D and oral phosphate resulted in improvement, but led to the development of hyperparathyroidism, a clinical feature reported in this syndrome (46) as well as in X-linked hypophosphatemic rickets (47, 48, 49). Hyperparathyroidism is thought to result from the calcium-lowering effects of phosphate administration or an effect of phosphate on parathyroid growth and function. She is also typical in the sense that a considerable period of time elapsed between the onset of clinical symptoms and the diagnosis of a mesenchymal tumor (4, 24) despite concerted efforts to identify such a tumor.

The oral regimen received by this patient might have been suboptimal. Current recommendations for successful treatment of tumor-induced osteomalacia suggest 2–3 g oral phosphate and 2.5–5 µg calcitriol/day (6). Although this patient could not tolerate more than 1.5 g oral phosphate/day, it is not known whether higher calcitriol doses would have increased the effect of oral phosphate. Addition of calcium was intended to supplement calcium as the bone healed, but calcium is generally not required and may even have decreased the bioavailability of phosphate.

What is unique about this patient is the use of a continuous iv phosphate infusion to normalize the serum phosphorus concentration. Although there is considerable experience with the use of short term phosphate infusion for management of profound hypophosphatemia associated with severe malnutrition, alcoholism, or diabetic ketoacidosis (50, 51, 52), there is practically no information on long term phosphate infusion other than in the form of total parenteral nutrition. During the 1970s, iv phosphate was used for the management of hypercalcemia (53), but potentially life-threatening severe hypocalcemia (50, 51, 52, 54) and ectopic calcification led to the avoidance of this approach during subsequent decades. The development of small and reliable pump technology made it possible for us reexamine the use of long term iv phosphate infusion in the palliative treatment of patients with tumor-induced osteomalacia.

The indications for considering iv phosphate in this patient included the worsening of her osteomalacia as a result of combined hypophosphatemia and hyperparathyroidism. Oral phosphate therapy was not feasible because of her prior history of gastrointestinal symptoms and its inability to normalize the serum phosphorus concentration even after removal of a parathyroid adenoma. Her symptoms impacted negatively on her quality of life. Support for our decision to infuse phosphate iv is provided by the excellent clinical response. Her alkaline phosphatase concentration fell from a peak value of 935 mIU/mL to a value of 170 mIU/mL within 6 months after initiation of the phosphate infusion, a finding that could be attributable to normalization of her phosphate or, more likely, correction of her hyperparathyroidism. The patient and we were sufficiently convinced of the benefit of the phosphate therapy that we initiated several subsequent courses of therapy, with clinical improvement as a result of each infusion. It is important to note that iv phosphate infusion was initiated only after it became clear that serum phosphate could not be normalized by oral supplementation.

With the advancement in ambulatory infusion technology during the past decade, precise control of infusion rate is possible. The phosphate was given by infusion pump, and serum calcium and phosphate were carefully monitored because of the potential for development of hyperphosphatemia and profound hypocalcemia (54). Our experience with this patient suggests that our monitoring strategy was adequate to prevent serious complications. The short term complications encountered included a transient rise in serum creatinine and two episodes of venous catheter-related bacteremia.

Venous thrombosis is a well recognized complication of central venous catheters. In conjunction with phosphate infusion through a central venous catheter, a single case of calcified right atrial thrombus has been reported (55). Calcified thrombi associated with central venous catheters have been reported in patients chronically receiving total parenteral nutrition (56, 57, 58). The risks of a serious complication (calcified thrombus, bacteremia, hypocalcemia, etc.) should be balanced against the benefits of phosphate infusion in the decision-making process.

We conclude that iv phosphate therapy can be administered for extended periods of time for palliative treatment of tumor-induced osteomalacia. Such therapy should be reserved for patients who cannot tolerate oral phosphate therapy, and caution should be exercised to prevent excessive infusion of phosphate with consequent hypocalcemia and ectopic calcification.

Received February 17, 1999.

Revised July 22, 1999.

Revised October 22, 1999.

Accepted November 2, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Case Report
 Discussion
 References
 

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