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Tumor-induced osteomalacia masking primary hyperparathyroidism
Tumor-induced osteomalacia masking primary hyperparathyroidism Dawn M. Elfenbein, MD, MPH,a Thomas J. Weber, MD,b and Randall P. Scheri, MD,a Durham, NC
From the Departments of Surgerya and Medicine,b Duke University Hospital, Durham, NC
OSTEOMALACIA IS A METABOLIC BONE DISORDER that is characterized by inadequate skeletal mineralization caused by deficiencies of either calcium or phosphorus or secondary to other factors that inhibit normal mineral deposition in the presence of normal calcium and phosphorus levels. The presence of osteomalacia is suggested by musculoskeletal symptoms, such as diffuse pain, bony tenderness, diffuse muscular weakness, and an overall decline in functional status. Symptoms alone, however, are often nonspecific, and additional testing, including laboratory testing and radiographic imaging, may be indicated. Biochemical abnormalities may include low serum concentrations of phosphorus or calcium and increased alkaline phosphatase activity, although laboratory studies may not be revealing. Low bone density, pseudofractures (ie, stress fractures), and technetium-99 bone scintigraphy that reveals multiple abnormal areas of increased radiotracer uptake are some radiologic findings characteristic of osteomalacia.1 Common causes of osteomalacia include deficiencies of vitamin D and phosphorus, with rarer causes being chronic renal failure, renal tubular acidosis, and medications, such as bisphosphonates or anticonvulsants. One very unusual cause is tumor-induced osteomalacia (TIO), which is generally caused by benign mesenchymal neoplasms that overexpress the phosphaturic factor fibroblast growth factor23 (FGF-23). TIO is curable if the responsible neoplasm is resected. Hyperparathyroidism is an almost universally benign, often asymptomatic endocrine disorder characterized by an increased serum calcium concentration and inappropriately normal or increased parathyroid hormone (PTH) level. It is Accepted for publication August 29, 2012. Reprint requests: Dawn M. Elfenbein, MD, MPH, Duke University Hospital, General Surgery, DUMC 3443, Durham, NC 27710. E-mail: [email protected]. Surgery 2012;152:1256-8. 0039-6060/$ - see front matter Ó 2012 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2012.08.062
1256 SURGERY
associated with osteoporosis, recurrent nephrolithiasis, and nonspecific symptoms, such as fatigue. Primary hyperparathyroidism is most often caused by a single adenoma, but multiple gland hyperplasia can occur in genetically and medically predisposed individuals. Conversely, secondary hyperparathyroidism may be caused by a reflexive increase in PTH secondary to relative hypocalcemia in patients with chronic kidney disease (CKD). We present a rare case of TIO that presented symptomatically with very low serum phosphorus levels in a patient with a history of nephrolithiasis, chronic kidney disease, and presumed secondary hyperparathyroidism who developed severe hypercalcemia after resection of a mesenchymal neoplasm. CASE REPORT A 67-year-old man presented to the endocrine clinic with an accelerating several-year history of myalgias, arthralgias, and progressive fatigue. He had a history of osteoporosis, CKD, secondary hyperparathyroidism, nephrolithiasis, and vitamin D insufficiency. Pertinent medications included cholecalciferol and risedronate. Laboratory values revealed low serum levels of phosphorus (1.4 mg/ dL) but normal calcium and 25-hydroxy-vitamin D levels. In light of his clinical symptoms, the low serum phosphorus, and an increased 24-hour urine phosphorus excretion (1,403 mg/day; normal, <1,300), a diagnosis of TIO was entertained. Serum FGF-23 level was found to be markedly increased at 2,520 RU/mL. Risedronate was stopped, elemental phosphorus replacement and calcitriol were started, and an octreoscan revealed localized uptake in his right mid-thigh (Fig). The soft tissue mass in the thigh was resected without complications. On postoperative day 1, his serum phosphorus (3 mg/dL) and calcium (9.2 mg/ dL) were normal. Pathology was consistent with a phosphaturic mesenchymal neoplasm. Ten days postoperatively he presented with worsening fatigue. Laboratory values revealed a markedly increased serum calcium level of 13.4 mg/dL, normal phosphorus of 3.2 mg/dL,
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Surgery Volume 152, Number 6
Figure. Osteoscan. Abnormal uptake is seen in the medial right thigh, best seen on the anterior views in the first and third panels.
Table. Biochemical studies of the patient Thigh tumor excision Initial presentation
Preoperative
Parathyroidectomy
10 days Postoperative postoperatively
PTH (pg/mL) Not measured Not measured Not measured Ca (mg/dL) Not measured 9.8 9.2 iCa (mmol/L) Not measured Not measured 1.23 PO4 (mg/dL) 1.4 Not measured 3 FGF-23 2,520 Not measured 202 (RU/mL) Cr (mL/dL) 1.3 1.6 1.3
218 13.4 1.79 3.2 156 1.4
Preoperative
Postoperative
145 11.3 1.47 3.7 Not measured Not 1.5
10 days postoperatively
32 9.4 1.26 3.9 measured Not 1.6
30 10.4 1.33 3.6 measured 1.9
Ca, Serum calcium; Cr, serum creatinine; FGF-23, fibroblast growth factor-23; iCa, ionized calcium; PO4, serum phosphorus; PTH, parathyroid hormone.
and increased PTH of 218 pg/mL (Table). He was given intravenous fluids and furosemide, started on cinacalcet, and discharged once the serum level of calcium was only mildly increased. On follow-up, he had persistent fatigue, increased calcium and PTH levels, and was referred to endocrine surgery. Ultrasonography and technetium-99 Sestamibi scan identified a left-sided parathyroid adenoma
that was removed (630 mg); serial intraoperative PTH levels decreased >50% and to normal limits after resection. The next morning, his PTH was 32 mg/mL, his ionized calcium was normal (1.26 mmol/L), and his calcium was normal (9.4 mg/dL). On follow-up, his symptoms of fatigue had resolved, but he still had signs of persistent disease with mildly increased serum calcium
1258 Elfenbein, Weber, and Scheri
and inappropriately high PTH levels that have been treated with low-dose cinacalcet. DISCUSSION It has been through the study of rare phosphatewasting neoplasms as described here that the hormone FGF-23 was first described a decade ago.2 FGF-23 is the principle regulator of serum phosphate, and its mechanism of action is fairly well understood. Dietary phosphorus and 1,25(OH)2D3 simulate secretion of FGF-23 by osteocytes and osteoblasts. FGF-23 binds to its cognate FGF-23 receptor (FGFR) in the renal distal convoluted tubule, in concert with the obligate cofactor Klotho, where it increases phosphate excretion through downregulation of the type 2a sodium phosphorus cotransporter, and downregulates 1 alpha-hydroxylation of 25(OH)D2.3 Both these effects actively decrease serum phosphorus levels. PTH also plays a role in phosphate homeostasis. In the process of mobilizing calcium from bones, phosphate is mobilized and excreted renally. PTH also downregulates the NaPi type 2a sodium phosphorus cotransporter. The actions of FGF-23 and PTH may be interdependent, based on recent study that found that the agent cinacalcet can be used to treat hypophosphatemia in patients with unresectable TIO.4 In addition, parathyroid cells also express the FGFR. In rat and bovine cells, the action of FGF-23 on normal parathyroid tissue appears be to decrease the synthesis of PTH.5 In our patient, we suspect that his phosphaturic mesenchymal neoplasm was longstanding. In addition, he likely had coexistent primary hyperparathyroidism because of his history of nephrolithiasis. Based on his clinical presentation, we postulate that the removal of his phosphaturic neoplasm ‘‘unmasked’’ and accelerated his hypercalcemic
Surgery December 2012
disorder. A rare soft tissue neoplasm coexisting with a parathyroid adenoma is more likely than rapid transformation of secondary to tertiary hyperparathyroidism in a patient with CKD. He had a clear adenoma both by preoperative imaging and by gross and microscopic pathology, and he had marked improvement of symptoms after removal of this adenoma. In the subsequent weeks after operation, he maintained persistent biochemical disease without symptoms. It is possible that his remaining glands had some degree of hypercellularity versus hyperplasia from longstanding, high serum levels of FGF-23. TIO is a rare disorder that has taught us much about phosphorus regulation through the discovery of FGF-23. Primary hyperparathyroidism is most often caused by a single gland that secretes an inappropriate level of PTH in the setting of borderline high or frankly abnormal serum calcium. The description of these 2 entities occurring concomitantly is rare. Future investigations of FGF23 should focus on the interplay between FGF-23 and PTH regulatory pathways. REFERENCES 1. Schapira D, Izhak OB, Nachtigal A, Burstein A, Shalon RB, Shagrawi I, et al. Tumor-induced osteomalacia. Semin Arthritis Rheum 1995;25:35-46. 2. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001;98:6500-5. 3. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008;118:3820-8. 4. Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT. Cinacalcet in the management of tumorinduced osteomalacia. J Bone Miner Res 2007;22:931-7. 5. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goet R, Kuro-o M, Mohammadi M, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007;117:4003-8.
From the Departments of Surgerya and Medicine,b Duke University Hospital, Durham, NC
OSTEOMALACIA IS A METABOLIC BONE DISORDER that is characterized by inadequate skeletal mineralization caused by deficiencies of either calcium or phosphorus or secondary to other factors that inhibit normal mineral deposition in the presence of normal calcium and phosphorus levels. The presence of osteomalacia is suggested by musculoskeletal symptoms, such as diffuse pain, bony tenderness, diffuse muscular weakness, and an overall decline in functional status. Symptoms alone, however, are often nonspecific, and additional testing, including laboratory testing and radiographic imaging, may be indicated. Biochemical abnormalities may include low serum concentrations of phosphorus or calcium and increased alkaline phosphatase activity, although laboratory studies may not be revealing. Low bone density, pseudofractures (ie, stress fractures), and technetium-99 bone scintigraphy that reveals multiple abnormal areas of increased radiotracer uptake are some radiologic findings characteristic of osteomalacia.1 Common causes of osteomalacia include deficiencies of vitamin D and phosphorus, with rarer causes being chronic renal failure, renal tubular acidosis, and medications, such as bisphosphonates or anticonvulsants. One very unusual cause is tumor-induced osteomalacia (TIO), which is generally caused by benign mesenchymal neoplasms that overexpress the phosphaturic factor fibroblast growth factor23 (FGF-23). TIO is curable if the responsible neoplasm is resected. Hyperparathyroidism is an almost universally benign, often asymptomatic endocrine disorder characterized by an increased serum calcium concentration and inappropriately normal or increased parathyroid hormone (PTH) level. It is Accepted for publication August 29, 2012. Reprint requests: Dawn M. Elfenbein, MD, MPH, Duke University Hospital, General Surgery, DUMC 3443, Durham, NC 27710. E-mail: [email protected]. Surgery 2012;152:1256-8. 0039-6060/$ - see front matter Ó 2012 Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.surg.2012.08.062
1256 SURGERY
associated with osteoporosis, recurrent nephrolithiasis, and nonspecific symptoms, such as fatigue. Primary hyperparathyroidism is most often caused by a single adenoma, but multiple gland hyperplasia can occur in genetically and medically predisposed individuals. Conversely, secondary hyperparathyroidism may be caused by a reflexive increase in PTH secondary to relative hypocalcemia in patients with chronic kidney disease (CKD). We present a rare case of TIO that presented symptomatically with very low serum phosphorus levels in a patient with a history of nephrolithiasis, chronic kidney disease, and presumed secondary hyperparathyroidism who developed severe hypercalcemia after resection of a mesenchymal neoplasm. CASE REPORT A 67-year-old man presented to the endocrine clinic with an accelerating several-year history of myalgias, arthralgias, and progressive fatigue. He had a history of osteoporosis, CKD, secondary hyperparathyroidism, nephrolithiasis, and vitamin D insufficiency. Pertinent medications included cholecalciferol and risedronate. Laboratory values revealed low serum levels of phosphorus (1.4 mg/ dL) but normal calcium and 25-hydroxy-vitamin D levels. In light of his clinical symptoms, the low serum phosphorus, and an increased 24-hour urine phosphorus excretion (1,403 mg/day; normal, <1,300), a diagnosis of TIO was entertained. Serum FGF-23 level was found to be markedly increased at 2,520 RU/mL. Risedronate was stopped, elemental phosphorus replacement and calcitriol were started, and an octreoscan revealed localized uptake in his right mid-thigh (Fig). The soft tissue mass in the thigh was resected without complications. On postoperative day 1, his serum phosphorus (3 mg/dL) and calcium (9.2 mg/ dL) were normal. Pathology was consistent with a phosphaturic mesenchymal neoplasm. Ten days postoperatively he presented with worsening fatigue. Laboratory values revealed a markedly increased serum calcium level of 13.4 mg/dL, normal phosphorus of 3.2 mg/dL,
Elfenbein, Weber, and Scheri 1257
Surgery Volume 152, Number 6
Figure. Osteoscan. Abnormal uptake is seen in the medial right thigh, best seen on the anterior views in the first and third panels.
Table. Biochemical studies of the patient Thigh tumor excision Initial presentation
Preoperative
Parathyroidectomy
10 days Postoperative postoperatively
PTH (pg/mL) Not measured Not measured Not measured Ca (mg/dL) Not measured 9.8 9.2 iCa (mmol/L) Not measured Not measured 1.23 PO4 (mg/dL) 1.4 Not measured 3 FGF-23 2,520 Not measured 202 (RU/mL) Cr (mL/dL) 1.3 1.6 1.3
218 13.4 1.79 3.2 156 1.4
Preoperative
Postoperative
145 11.3 1.47 3.7 Not measured Not 1.5
10 days postoperatively
32 9.4 1.26 3.9 measured Not 1.6
30 10.4 1.33 3.6 measured 1.9
Ca, Serum calcium; Cr, serum creatinine; FGF-23, fibroblast growth factor-23; iCa, ionized calcium; PO4, serum phosphorus; PTH, parathyroid hormone.
and increased PTH of 218 pg/mL (Table). He was given intravenous fluids and furosemide, started on cinacalcet, and discharged once the serum level of calcium was only mildly increased. On follow-up, he had persistent fatigue, increased calcium and PTH levels, and was referred to endocrine surgery. Ultrasonography and technetium-99 Sestamibi scan identified a left-sided parathyroid adenoma
that was removed (630 mg); serial intraoperative PTH levels decreased >50% and to normal limits after resection. The next morning, his PTH was 32 mg/mL, his ionized calcium was normal (1.26 mmol/L), and his calcium was normal (9.4 mg/dL). On follow-up, his symptoms of fatigue had resolved, but he still had signs of persistent disease with mildly increased serum calcium
1258 Elfenbein, Weber, and Scheri
and inappropriately high PTH levels that have been treated with low-dose cinacalcet. DISCUSSION It has been through the study of rare phosphatewasting neoplasms as described here that the hormone FGF-23 was first described a decade ago.2 FGF-23 is the principle regulator of serum phosphate, and its mechanism of action is fairly well understood. Dietary phosphorus and 1,25(OH)2D3 simulate secretion of FGF-23 by osteocytes and osteoblasts. FGF-23 binds to its cognate FGF-23 receptor (FGFR) in the renal distal convoluted tubule, in concert with the obligate cofactor Klotho, where it increases phosphate excretion through downregulation of the type 2a sodium phosphorus cotransporter, and downregulates 1 alpha-hydroxylation of 25(OH)D2.3 Both these effects actively decrease serum phosphorus levels. PTH also plays a role in phosphate homeostasis. In the process of mobilizing calcium from bones, phosphate is mobilized and excreted renally. PTH also downregulates the NaPi type 2a sodium phosphorus cotransporter. The actions of FGF-23 and PTH may be interdependent, based on recent study that found that the agent cinacalcet can be used to treat hypophosphatemia in patients with unresectable TIO.4 In addition, parathyroid cells also express the FGFR. In rat and bovine cells, the action of FGF-23 on normal parathyroid tissue appears be to decrease the synthesis of PTH.5 In our patient, we suspect that his phosphaturic mesenchymal neoplasm was longstanding. In addition, he likely had coexistent primary hyperparathyroidism because of his history of nephrolithiasis. Based on his clinical presentation, we postulate that the removal of his phosphaturic neoplasm ‘‘unmasked’’ and accelerated his hypercalcemic
Surgery December 2012
disorder. A rare soft tissue neoplasm coexisting with a parathyroid adenoma is more likely than rapid transformation of secondary to tertiary hyperparathyroidism in a patient with CKD. He had a clear adenoma both by preoperative imaging and by gross and microscopic pathology, and he had marked improvement of symptoms after removal of this adenoma. In the subsequent weeks after operation, he maintained persistent biochemical disease without symptoms. It is possible that his remaining glands had some degree of hypercellularity versus hyperplasia from longstanding, high serum levels of FGF-23. TIO is a rare disorder that has taught us much about phosphorus regulation through the discovery of FGF-23. Primary hyperparathyroidism is most often caused by a single gland that secretes an inappropriate level of PTH in the setting of borderline high or frankly abnormal serum calcium. The description of these 2 entities occurring concomitantly is rare. Future investigations of FGF23 should focus on the interplay between FGF-23 and PTH regulatory pathways. REFERENCES 1. Schapira D, Izhak OB, Nachtigal A, Burstein A, Shalon RB, Shagrawi I, et al. Tumor-induced osteomalacia. Semin Arthritis Rheum 1995;25:35-46. 2. Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U S A 2001;98:6500-5. 3. Quarles LD. Endocrine functions of bone in mineral metabolism regulation. J Clin Invest 2008;118:3820-8. 4. Geller JL, Khosravi A, Kelly MH, Riminucci M, Adams JS, Collins MT. Cinacalcet in the management of tumorinduced osteomalacia. J Bone Miner Res 2007;22:931-7. 5. Ben-Dov IZ, Galitzer H, Lavi-Moshayoff V, Goet R, Kuro-o M, Mohammadi M, et al. The parathyroid is a target organ for FGF23 in rats. J Clin Invest 2007;117:4003-8.