- Email: [email protected]
Vitamin D Deficiency Masquerading as Metastatic Cancer: A Case Series
CLINICAL INVESTIGATION
Vitamin D Deficiency Masquerading as Metastatic Cancer: A Case Series Jawaad S. Khokhar, MD, Allan S. Brett, MD and Ami Desai, MD
Abstract: Patients with vitamin D deficiency can present with nonspecific bone pain and findings on radionuclide bone scanning that may suggest metastatic malignancy. In this report, we present 4 such cases, in which clinicians initially pursued diagnoses of metastatic malignancy and did not consider vitamin D deficiency and osteomalacia in the differential diagnosis. Eventual recognition of vitamin D deficiency and provision of supplementation resulted in prompt resolution of symptoms for each patient. In appropriate cases, timely consideration of a diagnosis of vitamin D deficiency can mitigate the anxiety associated with undergoing an evaluation for cancer. Key Indexing Terms: Vitamin D deficiency; Osteomalacia; Radionuclide imaging. [Am J Med Sci 2009;337(4):245–247.]
V
itamin D deficiency in the general population has received increasing attention in recent years.1,2 Early signs of vitamin D deficiency in adults may be subtle, and may include bone pain, fatigue, and generalized muscle weakness. Observational data have suggested a high incidence of vitamin D deficiency among adults with persistent nonspecific musculoskeletal pain.3 Over time, vitamin D deficiency may progress to clinically evident osteomalacia, which may cause lesions on radionuclide bone scans4,5 that raise concern about metastatic malignancy. In this report, we present 4 patients who presented with nonspecific bone pain and underwent bone scanning. In each case, the history and scintigraphic findings initially suggested metastatic malignancy to clinicians caring for these patients. Eventually, each of these patients was diagnosed with vitamin D deficiency. To our knowledge, a case series of vitamin D deficiency masquerading as metastatic cancer has not been published previously.
CASE REPORTS Case 1 A 67-year-old woman with a history of osteoarthritis and seizure disorder (treated with phenytoin) presented with diffuse musculoskeletal pain that she did not perceive to be centered in her joints. She reported recent falls because of weakness and leg pain. Hip and pelvis x-rays revealed possible pseudofractures of the proximal femurs. Laboratory testing showed hypocalcemia (7.8 mg/dL), hypophosphatemia (2.0 mg/dL), normal albumin (4.0 g/dL), elevated alkaline phosphatase (654 U/L, normal ⬍110), and normal creatinine (1.0 mg/dL). A radiologist interpreted a radionuclide bone scan as showing “scattered foci of increased activity in the appendicular skeleton and ribs, compatible with metastatic disease” (Figure 1A). Percutaneous biopsy of an area of decreased attenuation in the sternum [noted on computed tomography (CT) scanning] was From the Department of Medicine (JSK, ASB), University of South Carolina School of Medicine; and Department of Medicine (AD), Feinberg School of Medicine, Northwestern University. Submitted May 7, 2008; accepted in revised form August 6, 2008. Correspondence: Allan S. Brett, MD, Department of Medicine, University of South Carolina School of Medicine, 2 Medical Park, Suite 502, Columbia, SC 29203 (E-mail: [email protected]).
interpreted as “negative for neoplasm.” Additional search for a primary malignancy (including mammography, abdominal CT, and chest CT) was negative. Six weeks after the workup had been initiated, vitamin D deficiency was considered. Levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were both low (7 ng/mL and 7 pg/mL, respectively). Intact parathyroid hormone (PTH) level was markedly elevated (641 pg/mL; normal 14 –72 pg/mL). The patient was treated with oral vitamin D (ergocalciferol 50,000 IU daily for 5 days and then weekly for 5 weeks, followed by 1000 IU of vitamin D3 daily) and calcium supplementation. Her bone pain and weakness resolved within several months. Serum calcium levels rose to 8.9 mg/dL at 3 months and 9.7 mg/dL at 9 months; alkaline phosphatase declined to 272 U/L. Case 2 A 64-year-old woman presented with diffuse musculoskeletal pain. At the age of 58, she had undergone gastric bypass surgery because of severe obesity. At the age of 59, she underwent modified radical mastectomy for an estrogen receptor-positive T1N0M0 right breast carcinoma and received tamoxifen postoperatively. Sixteen months after the mastectomy, she presented with low back pain, myalgias, and fatigue. Alkaline phosphatase was 231 U/L (normal 39 –117 U/L). A bone scan, obtained because of concern about metastatic malignancy, revealed areas of increased activity in the right hip, the right inferior pubic ramus, and multiple left ribs, interpreted as consistent with metastases. Mammography of the left breast and CT scans of the chest, abdomen, and pelvis were negative; specifically, CT imaging of bone scan abnormalities was unremarkable, and no biopsies were obtained. During the next several years, she continued to experience waxing and waning diffuse musculoskeletal pain. CT scans of chest, abdomen, and pelvis were done on 2 more occasions, and mammography was done yearly; all these studies remained negative. At the age of 64, she consulted another physician with worsening pain, especially prominent in her rib cage. She had lost about 100 pounds since her gastric bypass surgery, but she remained severely obese (body mass index, 47.1 kg/m2). Vitamin D deficiency was now considered. Serum calcium was 7.8 mg/dL, phosphorus 3.1 mg/dL, creatinine 0.7 mg/dL, albumin 4.0 g/dL, and alkaline phosphatase 220 U/L (normal ⬍130 U/L). Serum 25-hydroxyvitamin D was undetectable (less than 4 ng/mL), and PTH was elevated (338 pg/mL; normal 10 – 65 pg/mL). The patient was treated with oral vitamin D (ergocalciferol 50,000 IU weekly for 4 weeks, then monthly) and supplemental calcium. At 3 months, her rib pain had resolved. On repeat laboratory testing, 25-hydroxyvitamin D was 11 ng/mL, calcium 8.5 mg/dL, phosphorus 3.5 mg/dL, alkaline phosphatase 184 U/L, and PTH 248 pg/mL. Her ergocalciferol dose was then increased to 50,000 IU twice weekly. Four months later, her 25-hydroxyvitamin D level was still low (15 ng/mL), but she remained pain-free. Case 3 A 58-year-old woman presented with the chief complaint “my bones hurt,” and described several months of diffuse pain,
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FIGURE 1. Bone scans (technetium-99m-methylene diphosphonate) for cases 1, 3, and 4. Arrows indicate areas of abnormally increased activity. (A) Posterior view of case 1, showing multiple lesions in the ribs and a lesion in the left femur. (B) Anterior view of case 3, showing increased activity in the left ilium. (C, D) Posterior views of case 4, showing abnormalities in the ribs, left sacroiliac area, and left pubic rami.
especially in the lower extremities. She had a history of localized right breast cancer at the age of 36 (and had undergone bilateral mastectomies), and localized left renal cell carcinoma (resected at the age of 49). Serum calcium was 9.4 mg/dL, albumin 4.6 g/dL, phosphorus 3.0 mg/dL, alkaline phosphatase 116 U/L (normal ⬍110 U/L), and creatinine 0.8 mg/dL. Because of the cancer history, a bone scan was performed; it showed an area of slightly increased activity in the left ilium (Figure 1B). Magnetic resonance imaging revealed a marrow signal abnormality in this area, interpreted as “suspicious for metastatic disease.” A CT-guided biopsy was negative for malignancy. In addition, a chest x-ray and abdominal CT scan were normal. At this point, vitamin D deficiency was considered. The serum 25-hydroxyvitamin D level was undetectable (⬍7 ng/mL), but PTH was normal (52 pg/mL; normal 14 –72 pg/mL). Oral vitamin D supplementation (ergocalciferol, 50,000 IU weekly) and calcium supplementation were begun. Two months later the patient reported that her bone pain had disappeared, at which time the 25-hydroxyvitamin D was 70 ng/mL, calcium 9.9 mg/dL, and phosphorus 3.1 mg/dL. Case 4 A 58-year-old woman presented with several months of fatigue and diffuse pain that was especially prominent in her legs. Past medical history included wrist and rib fractures after falls during the previous several years. Calcium was 8.7 mg/dL, alkaline phosphatase was 154 U/L (normal 30 –115 U/L; predominantly bone source on fractionation), blood urea nitrogen 16 mg/dL, and creatinine 1.5 mg/dL. Dual-energy x-ray absorptiometry demonstrated osteoporosis at the hips and spine. Bone scan revealed abnormalities in the ribs bilaterally, the left sacroiliac joint, and the left pubic rami (Figures 1C and 1D); these findings raised concern about metastatic malignancy, possibly complicated by insufficiency or traumatic fractures. However, no primary malignancy was obvious from history, physical examination, laboratory testing (including serum protein electrophoresis), and mammography. One month later, vitamin D deficiency was con-
246
sidered. Serum 25-hydroxyvitamin D was 16 ng/mL, and PTH was 110 pg/mL (normal 10 – 65 pg/mL). The patient was treated with oral vitamin D (ergocalciferol, 50,000 IU weekly for a month, followed by 800 IU of vitamin D3 daily) and calcium supplements, and her generalized pain resolved over several months. Two months later, the 25-hydroxyvitamin D level was 46 ng/mL.
DISCUSSION In this report, we describe 4 patients who presented with nonspecific pain perceived to arise in bone. Clinicians initially considered the possibility of metastatic malignancy in all patients, 2 of whom had previous histories of localized, surgically resected, cancers. Each patient underwent radionuclide bone scintigraphy, the results of which further heightened concerns about bone metastases, and 2 patients underwent bone biopsy. Eventually, vitamin D deficiency was diagnosed in all cases. Remarkably, these 4 patients were encountered during a 16-month period in the small practices of 2 general internists and 2 internal medicine residents. Thus, vitamin D deficiency masquerading as possible metastatic cancer is presumably common in primary care practice. However, to our knowledge only 3 such cases—none from the United States— have been published previously in single-case reports.6 – 8 Vitamin D deficiency is generally defined as a 25hydroxyvitamin D level less than 20 ng/mL. However, some experts consider levels between 20 and 30 ng/mL as reflecting relative insufficiency of vitamin D, because levels in this range may be associated with increased secretion of parathyroid hormone and reduced intestinal transport of calcium.1 The prevalence of clinically important vitamin D deficiency in the United States is unclear. Studies have suggested especially high prevalence in institutionalized elderly populations, postmenopausal women, patients with osteoporosis, and populations described as black or African-American.9 –11 Mechanisms that may result in vitamin D deficiency include reduced skin synVolume 337, Number 4, April 2009
Vitamin D Deficiency
thesis (eg, from inadequate exposure to sunlight and dark skin pigmentation), decreased bioavailability (eg, from malabsorptive states such as celiac disease and gastric bypass surgery), increased catabolism (eg, secondary to anticonvulsant drugs), urinary loss (eg, with nephrotic syndrome), decreased synthesis of 25-hydroxyvitamin D (in liver disease), and decreased synthesis of 1,25-dihydroxyvitamin D (in renal disease).1 Serum vitamin D levels are inversely correlated with body mass index in observational studies,12 possibly through sequestration of vitamin D in fat. Even at a sunny southern U.S. latitude (Arizona), a recent study demonstrated that 25% of subjects had 25-hydroxyvitamin D levels less than 20 ng/mL.13 Among our cases, patient 1 was taking phenytoin, patient 4 had documented osteoporosis, 2 patients (cases 1 and 3) were black, and 2 were white (cases 2 and 4); all were postmenopausal women. Patient 2 had undergone gastric bypass surgery but remained severely obese. Although her 25-hydroxyvitamin D level rose only modestly (from an undetectable level to 15 ng/mL) during the first 7 months of treatment, her bone pain resolved rapidly; this observation suggests a physiologic effect of supplementation even when serum levels remain suboptimal. Malabsorption of vitamin D after gastric bypass surgery has been described repeatedly in the literature. For example, in a recent study of 136 patients, the mean serum 25-hydroxyvitamin D level was 14.6 ng/mL an average of 4.5 years after bariatric surgery; fully onethird of these patients had levels less than 8 ng/mL, and some remained deficient despite high-dose vitamin D supplementation.14 In celiac disease, another relatively common cause of malabsorption, a 69% prevalence of low 25-hydroxyvitamin D levels has been reported.15 Osteomalacia is a manifestation of severe and prolonged vitamin D deficiency. Laboratory abnormalities may include elevated alkaline phosphatase, elevated PTH (reflecting secondary hyperparathyroidism), and low calcium and phosphorus levels. Our cases suggest that these abnormalities may occur in various combinations. For example, only patients 1 and 2 had clearly subnormal calcium levels, and case 3 had an undetectable 25hydroxyvitamin D level but normal calcium and PTH levels. Interpretation of vitamin D levels are complicated by variability among assays,16 with high pressure liquid chromatography considered the most accurate. Chemiluminescent assays were used in cases 1 and 3, and liquid chromatography-mass spectrometry was used in cases 2 and 4. On plain x-rays, patients with vitamin D deficiency and osteomalacia may demonstrate pseudofractures, which were present in case 1 but not recognized initially. As noted in each of our cases, radionuclide bone scans frequently reveal focal areas of increased uptake in the ribs, long bones, and pelvis. However, bone scan abnormalities have been reported in most areas of the appendicular and axial skeleton in patients with osteomalacia. These findings are frequently nonspecific and may be confused with neoplastic, inflammatory, or other metabolic conditions (including the secondary hyperparathyroidism associated with chronic renal failure).4,5 Our report has inherent limitations. First, osteoporotic fractures could have contributed to the clinical presentation in our patients. However, locations of some of the bone scan abnormalities in our patients were not typical for osteoporotic fractures, and each of our patients presented with diffuse bone pain that was not limited to abnormal areas of bone scans. Second, only 2 patients underwent bone biopsy to rule out malignancy. However, none of our patients have shown clinical evidence of metastatic cancer during 25, 10, 10, and 17 months of follow-up, respectively, since
© 2009 Lippincott Williams & Wilkins
our initial encounters. The striking improvement in symptoms with vitamin D therapy in all cases suggests that vitamin D deficiency was a major etiologic factor. Third, these patients were not evaluated and treated systematically according to a research protocol; we encountered them randomly after other primary care physicians had evaluated them initially, and they returned to their primary care physicians within our facilities after vitamin D deficiency was identified. Hence, treatment regimens and follow-up laboratory testing were not uniform. Fourth, because all patients improved clinically, their primary care physicians did not repeat bone scans after treatment. In conclusion, in 4 patients with diffuse bone pain encountered during a brief period, clinicians initially overlooked the possibility of vitamin D deficiency and initiated evaluations for metastatic malignancy. Our series suggests that primary care physicians should have a low threshold for considering a diagnosis of vitamin D deficiency in any patient presenting with unexplained musculoskeletal pain and an abnormal bone scan, including those with a remote history of treated cancer. In such cases, timely evaluation for vitamin D deficiency can mitigate the anxiety associated with undergoing an evaluation for cancer. REFERENCES 1. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266 – 81. 2. Reginster J-Y. The high prevalence of inadequate serum vitamin D levels and implications for bone health. Curr Med Res Opin 2005;21:579 – 86. 3. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463–70. 4. El-Desouki MI, Othman SM, Fouda MA. Bone mineral density and bone scintigraphy in adult Saudi female patients with osteomalacia. Saudi Med J 2004;25:355– 8. 5. Fogelman I, McKillop JH, Bessent RG, et al. The role of bone scanning in osteomalacia. J Nucl Med 1978;19:245– 8. 6. Gray MR, Leinster SJ, Al-Janabi M, et al. Osteomalacia mimicking metastases: a treatable cause of bone pain. J R Coll Surg Edinb. 1992;37:344–5. 7. Cardano S, Cornaglia G, Monteverde AI. A worrisome scintigraphy. Recenti Prog Med 2006;97:393– 6. 8. Ahmed M, Faraz HA, Almahfouz A, et al. A case of vitamin D deficiency masquerading as occult malignancy. Ann Saudi Med 2006;26:231–6. 9. Lips P, Hosking D, Lippuner K, et al. The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med 2006;260:245–54. 10. Holick MF, Siris ES, Binkley N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90:3215–24. 11. Alsafwah S, Laguardia SP, Nelson MD, et al. Hypovitaminosis D in African Americans residing in Memphis, Tennessee with and without heart failure. Am J Med Sci 2008;335:292–7. 12. Goldner WS, Stoner JA, Thompson J, et al. Prevalence of vitamin D insufficiency and deficiency in morbidly obese patients: a comparison with non-obese controls. Obes Surg 2008;18:145–50. 13. Jacobs ET, Alberts DS, Foote JA, et al. Vitamin D insufficiency in southern Arizona. Am J Clin Nutr 2008;87:608 –13. 14. Abbasi AA, Amin M, Smiertka JK, et al. Abnormalities of vitamin D and calcium metabolism after surgical treatment of morbid obesity: a study of 136 patients. Endocr Pract 2007;13:131– 6. 15. Kemppainen T, Kroger H, Janatuinen E, et al. Osteoporosis in adult patients with celiac disease. Bone 1999;24:249 –55. 16. Binkley N, Krueger D, Cowgill CS, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab 2004;89:3152–7.
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Vitamin D Deficiency Masquerading as Metastatic Cancer: A Case Series Jawaad S. Khokhar, MD, Allan S. Brett, MD and Ami Desai, MD
Abstract: Patients with vitamin D deficiency can present with nonspecific bone pain and findings on radionuclide bone scanning that may suggest metastatic malignancy. In this report, we present 4 such cases, in which clinicians initially pursued diagnoses of metastatic malignancy and did not consider vitamin D deficiency and osteomalacia in the differential diagnosis. Eventual recognition of vitamin D deficiency and provision of supplementation resulted in prompt resolution of symptoms for each patient. In appropriate cases, timely consideration of a diagnosis of vitamin D deficiency can mitigate the anxiety associated with undergoing an evaluation for cancer. Key Indexing Terms: Vitamin D deficiency; Osteomalacia; Radionuclide imaging. [Am J Med Sci 2009;337(4):245–247.]
V
itamin D deficiency in the general population has received increasing attention in recent years.1,2 Early signs of vitamin D deficiency in adults may be subtle, and may include bone pain, fatigue, and generalized muscle weakness. Observational data have suggested a high incidence of vitamin D deficiency among adults with persistent nonspecific musculoskeletal pain.3 Over time, vitamin D deficiency may progress to clinically evident osteomalacia, which may cause lesions on radionuclide bone scans4,5 that raise concern about metastatic malignancy. In this report, we present 4 patients who presented with nonspecific bone pain and underwent bone scanning. In each case, the history and scintigraphic findings initially suggested metastatic malignancy to clinicians caring for these patients. Eventually, each of these patients was diagnosed with vitamin D deficiency. To our knowledge, a case series of vitamin D deficiency masquerading as metastatic cancer has not been published previously.
CASE REPORTS Case 1 A 67-year-old woman with a history of osteoarthritis and seizure disorder (treated with phenytoin) presented with diffuse musculoskeletal pain that she did not perceive to be centered in her joints. She reported recent falls because of weakness and leg pain. Hip and pelvis x-rays revealed possible pseudofractures of the proximal femurs. Laboratory testing showed hypocalcemia (7.8 mg/dL), hypophosphatemia (2.0 mg/dL), normal albumin (4.0 g/dL), elevated alkaline phosphatase (654 U/L, normal ⬍110), and normal creatinine (1.0 mg/dL). A radiologist interpreted a radionuclide bone scan as showing “scattered foci of increased activity in the appendicular skeleton and ribs, compatible with metastatic disease” (Figure 1A). Percutaneous biopsy of an area of decreased attenuation in the sternum [noted on computed tomography (CT) scanning] was From the Department of Medicine (JSK, ASB), University of South Carolina School of Medicine; and Department of Medicine (AD), Feinberg School of Medicine, Northwestern University. Submitted May 7, 2008; accepted in revised form August 6, 2008. Correspondence: Allan S. Brett, MD, Department of Medicine, University of South Carolina School of Medicine, 2 Medical Park, Suite 502, Columbia, SC 29203 (E-mail: [email protected]).
interpreted as “negative for neoplasm.” Additional search for a primary malignancy (including mammography, abdominal CT, and chest CT) was negative. Six weeks after the workup had been initiated, vitamin D deficiency was considered. Levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin D were both low (7 ng/mL and 7 pg/mL, respectively). Intact parathyroid hormone (PTH) level was markedly elevated (641 pg/mL; normal 14 –72 pg/mL). The patient was treated with oral vitamin D (ergocalciferol 50,000 IU daily for 5 days and then weekly for 5 weeks, followed by 1000 IU of vitamin D3 daily) and calcium supplementation. Her bone pain and weakness resolved within several months. Serum calcium levels rose to 8.9 mg/dL at 3 months and 9.7 mg/dL at 9 months; alkaline phosphatase declined to 272 U/L. Case 2 A 64-year-old woman presented with diffuse musculoskeletal pain. At the age of 58, she had undergone gastric bypass surgery because of severe obesity. At the age of 59, she underwent modified radical mastectomy for an estrogen receptor-positive T1N0M0 right breast carcinoma and received tamoxifen postoperatively. Sixteen months after the mastectomy, she presented with low back pain, myalgias, and fatigue. Alkaline phosphatase was 231 U/L (normal 39 –117 U/L). A bone scan, obtained because of concern about metastatic malignancy, revealed areas of increased activity in the right hip, the right inferior pubic ramus, and multiple left ribs, interpreted as consistent with metastases. Mammography of the left breast and CT scans of the chest, abdomen, and pelvis were negative; specifically, CT imaging of bone scan abnormalities was unremarkable, and no biopsies were obtained. During the next several years, she continued to experience waxing and waning diffuse musculoskeletal pain. CT scans of chest, abdomen, and pelvis were done on 2 more occasions, and mammography was done yearly; all these studies remained negative. At the age of 64, she consulted another physician with worsening pain, especially prominent in her rib cage. She had lost about 100 pounds since her gastric bypass surgery, but she remained severely obese (body mass index, 47.1 kg/m2). Vitamin D deficiency was now considered. Serum calcium was 7.8 mg/dL, phosphorus 3.1 mg/dL, creatinine 0.7 mg/dL, albumin 4.0 g/dL, and alkaline phosphatase 220 U/L (normal ⬍130 U/L). Serum 25-hydroxyvitamin D was undetectable (less than 4 ng/mL), and PTH was elevated (338 pg/mL; normal 10 – 65 pg/mL). The patient was treated with oral vitamin D (ergocalciferol 50,000 IU weekly for 4 weeks, then monthly) and supplemental calcium. At 3 months, her rib pain had resolved. On repeat laboratory testing, 25-hydroxyvitamin D was 11 ng/mL, calcium 8.5 mg/dL, phosphorus 3.5 mg/dL, alkaline phosphatase 184 U/L, and PTH 248 pg/mL. Her ergocalciferol dose was then increased to 50,000 IU twice weekly. Four months later, her 25-hydroxyvitamin D level was still low (15 ng/mL), but she remained pain-free. Case 3 A 58-year-old woman presented with the chief complaint “my bones hurt,” and described several months of diffuse pain,
The American Journal of the Medical Sciences • Volume 337, Number 4, April 2009
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Khokhar et al
FIGURE 1. Bone scans (technetium-99m-methylene diphosphonate) for cases 1, 3, and 4. Arrows indicate areas of abnormally increased activity. (A) Posterior view of case 1, showing multiple lesions in the ribs and a lesion in the left femur. (B) Anterior view of case 3, showing increased activity in the left ilium. (C, D) Posterior views of case 4, showing abnormalities in the ribs, left sacroiliac area, and left pubic rami.
especially in the lower extremities. She had a history of localized right breast cancer at the age of 36 (and had undergone bilateral mastectomies), and localized left renal cell carcinoma (resected at the age of 49). Serum calcium was 9.4 mg/dL, albumin 4.6 g/dL, phosphorus 3.0 mg/dL, alkaline phosphatase 116 U/L (normal ⬍110 U/L), and creatinine 0.8 mg/dL. Because of the cancer history, a bone scan was performed; it showed an area of slightly increased activity in the left ilium (Figure 1B). Magnetic resonance imaging revealed a marrow signal abnormality in this area, interpreted as “suspicious for metastatic disease.” A CT-guided biopsy was negative for malignancy. In addition, a chest x-ray and abdominal CT scan were normal. At this point, vitamin D deficiency was considered. The serum 25-hydroxyvitamin D level was undetectable (⬍7 ng/mL), but PTH was normal (52 pg/mL; normal 14 –72 pg/mL). Oral vitamin D supplementation (ergocalciferol, 50,000 IU weekly) and calcium supplementation were begun. Two months later the patient reported that her bone pain had disappeared, at which time the 25-hydroxyvitamin D was 70 ng/mL, calcium 9.9 mg/dL, and phosphorus 3.1 mg/dL. Case 4 A 58-year-old woman presented with several months of fatigue and diffuse pain that was especially prominent in her legs. Past medical history included wrist and rib fractures after falls during the previous several years. Calcium was 8.7 mg/dL, alkaline phosphatase was 154 U/L (normal 30 –115 U/L; predominantly bone source on fractionation), blood urea nitrogen 16 mg/dL, and creatinine 1.5 mg/dL. Dual-energy x-ray absorptiometry demonstrated osteoporosis at the hips and spine. Bone scan revealed abnormalities in the ribs bilaterally, the left sacroiliac joint, and the left pubic rami (Figures 1C and 1D); these findings raised concern about metastatic malignancy, possibly complicated by insufficiency or traumatic fractures. However, no primary malignancy was obvious from history, physical examination, laboratory testing (including serum protein electrophoresis), and mammography. One month later, vitamin D deficiency was con-
246
sidered. Serum 25-hydroxyvitamin D was 16 ng/mL, and PTH was 110 pg/mL (normal 10 – 65 pg/mL). The patient was treated with oral vitamin D (ergocalciferol, 50,000 IU weekly for a month, followed by 800 IU of vitamin D3 daily) and calcium supplements, and her generalized pain resolved over several months. Two months later, the 25-hydroxyvitamin D level was 46 ng/mL.
DISCUSSION In this report, we describe 4 patients who presented with nonspecific pain perceived to arise in bone. Clinicians initially considered the possibility of metastatic malignancy in all patients, 2 of whom had previous histories of localized, surgically resected, cancers. Each patient underwent radionuclide bone scintigraphy, the results of which further heightened concerns about bone metastases, and 2 patients underwent bone biopsy. Eventually, vitamin D deficiency was diagnosed in all cases. Remarkably, these 4 patients were encountered during a 16-month period in the small practices of 2 general internists and 2 internal medicine residents. Thus, vitamin D deficiency masquerading as possible metastatic cancer is presumably common in primary care practice. However, to our knowledge only 3 such cases—none from the United States— have been published previously in single-case reports.6 – 8 Vitamin D deficiency is generally defined as a 25hydroxyvitamin D level less than 20 ng/mL. However, some experts consider levels between 20 and 30 ng/mL as reflecting relative insufficiency of vitamin D, because levels in this range may be associated with increased secretion of parathyroid hormone and reduced intestinal transport of calcium.1 The prevalence of clinically important vitamin D deficiency in the United States is unclear. Studies have suggested especially high prevalence in institutionalized elderly populations, postmenopausal women, patients with osteoporosis, and populations described as black or African-American.9 –11 Mechanisms that may result in vitamin D deficiency include reduced skin synVolume 337, Number 4, April 2009
Vitamin D Deficiency
thesis (eg, from inadequate exposure to sunlight and dark skin pigmentation), decreased bioavailability (eg, from malabsorptive states such as celiac disease and gastric bypass surgery), increased catabolism (eg, secondary to anticonvulsant drugs), urinary loss (eg, with nephrotic syndrome), decreased synthesis of 25-hydroxyvitamin D (in liver disease), and decreased synthesis of 1,25-dihydroxyvitamin D (in renal disease).1 Serum vitamin D levels are inversely correlated with body mass index in observational studies,12 possibly through sequestration of vitamin D in fat. Even at a sunny southern U.S. latitude (Arizona), a recent study demonstrated that 25% of subjects had 25-hydroxyvitamin D levels less than 20 ng/mL.13 Among our cases, patient 1 was taking phenytoin, patient 4 had documented osteoporosis, 2 patients (cases 1 and 3) were black, and 2 were white (cases 2 and 4); all were postmenopausal women. Patient 2 had undergone gastric bypass surgery but remained severely obese. Although her 25-hydroxyvitamin D level rose only modestly (from an undetectable level to 15 ng/mL) during the first 7 months of treatment, her bone pain resolved rapidly; this observation suggests a physiologic effect of supplementation even when serum levels remain suboptimal. Malabsorption of vitamin D after gastric bypass surgery has been described repeatedly in the literature. For example, in a recent study of 136 patients, the mean serum 25-hydroxyvitamin D level was 14.6 ng/mL an average of 4.5 years after bariatric surgery; fully onethird of these patients had levels less than 8 ng/mL, and some remained deficient despite high-dose vitamin D supplementation.14 In celiac disease, another relatively common cause of malabsorption, a 69% prevalence of low 25-hydroxyvitamin D levels has been reported.15 Osteomalacia is a manifestation of severe and prolonged vitamin D deficiency. Laboratory abnormalities may include elevated alkaline phosphatase, elevated PTH (reflecting secondary hyperparathyroidism), and low calcium and phosphorus levels. Our cases suggest that these abnormalities may occur in various combinations. For example, only patients 1 and 2 had clearly subnormal calcium levels, and case 3 had an undetectable 25hydroxyvitamin D level but normal calcium and PTH levels. Interpretation of vitamin D levels are complicated by variability among assays,16 with high pressure liquid chromatography considered the most accurate. Chemiluminescent assays were used in cases 1 and 3, and liquid chromatography-mass spectrometry was used in cases 2 and 4. On plain x-rays, patients with vitamin D deficiency and osteomalacia may demonstrate pseudofractures, which were present in case 1 but not recognized initially. As noted in each of our cases, radionuclide bone scans frequently reveal focal areas of increased uptake in the ribs, long bones, and pelvis. However, bone scan abnormalities have been reported in most areas of the appendicular and axial skeleton in patients with osteomalacia. These findings are frequently nonspecific and may be confused with neoplastic, inflammatory, or other metabolic conditions (including the secondary hyperparathyroidism associated with chronic renal failure).4,5 Our report has inherent limitations. First, osteoporotic fractures could have contributed to the clinical presentation in our patients. However, locations of some of the bone scan abnormalities in our patients were not typical for osteoporotic fractures, and each of our patients presented with diffuse bone pain that was not limited to abnormal areas of bone scans. Second, only 2 patients underwent bone biopsy to rule out malignancy. However, none of our patients have shown clinical evidence of metastatic cancer during 25, 10, 10, and 17 months of follow-up, respectively, since
© 2009 Lippincott Williams & Wilkins
our initial encounters. The striking improvement in symptoms with vitamin D therapy in all cases suggests that vitamin D deficiency was a major etiologic factor. Third, these patients were not evaluated and treated systematically according to a research protocol; we encountered them randomly after other primary care physicians had evaluated them initially, and they returned to their primary care physicians within our facilities after vitamin D deficiency was identified. Hence, treatment regimens and follow-up laboratory testing were not uniform. Fourth, because all patients improved clinically, their primary care physicians did not repeat bone scans after treatment. In conclusion, in 4 patients with diffuse bone pain encountered during a brief period, clinicians initially overlooked the possibility of vitamin D deficiency and initiated evaluations for metastatic malignancy. Our series suggests that primary care physicians should have a low threshold for considering a diagnosis of vitamin D deficiency in any patient presenting with unexplained musculoskeletal pain and an abnormal bone scan, including those with a remote history of treated cancer. In such cases, timely evaluation for vitamin D deficiency can mitigate the anxiety associated with undergoing an evaluation for cancer. REFERENCES 1. Holick MF. Vitamin D deficiency. N Engl J Med 2007;357:266 – 81. 2. Reginster J-Y. The high prevalence of inadequate serum vitamin D levels and implications for bone health. Curr Med Res Opin 2005;21:579 – 86. 3. Plotnikoff GA, Quigley JM. Prevalence of severe hypovitaminosis D in patients with persistent, nonspecific musculoskeletal pain. Mayo Clin Proc 2003;78:1463–70. 4. El-Desouki MI, Othman SM, Fouda MA. Bone mineral density and bone scintigraphy in adult Saudi female patients with osteomalacia. Saudi Med J 2004;25:355– 8. 5. Fogelman I, McKillop JH, Bessent RG, et al. The role of bone scanning in osteomalacia. J Nucl Med 1978;19:245– 8. 6. Gray MR, Leinster SJ, Al-Janabi M, et al. Osteomalacia mimicking metastases: a treatable cause of bone pain. J R Coll Surg Edinb. 1992;37:344–5. 7. Cardano S, Cornaglia G, Monteverde AI. A worrisome scintigraphy. Recenti Prog Med 2006;97:393– 6. 8. Ahmed M, Faraz HA, Almahfouz A, et al. A case of vitamin D deficiency masquerading as occult malignancy. Ann Saudi Med 2006;26:231–6. 9. Lips P, Hosking D, Lippuner K, et al. The prevalence of vitamin D inadequacy amongst women with osteoporosis: an international epidemiological investigation. J Intern Med 2006;260:245–54. 10. Holick MF, Siris ES, Binkley N, et al. Prevalence of vitamin D inadequacy among postmenopausal North American women receiving osteoporosis therapy. J Clin Endocrinol Metab 2005;90:3215–24. 11. Alsafwah S, Laguardia SP, Nelson MD, et al. Hypovitaminosis D in African Americans residing in Memphis, Tennessee with and without heart failure. Am J Med Sci 2008;335:292–7. 12. Goldner WS, Stoner JA, Thompson J, et al. Prevalence of vitamin D insufficiency and deficiency in morbidly obese patients: a comparison with non-obese controls. Obes Surg 2008;18:145–50. 13. Jacobs ET, Alberts DS, Foote JA, et al. Vitamin D insufficiency in southern Arizona. Am J Clin Nutr 2008;87:608 –13. 14. Abbasi AA, Amin M, Smiertka JK, et al. Abnormalities of vitamin D and calcium metabolism after surgical treatment of morbid obesity: a study of 136 patients. Endocr Pract 2007;13:131– 6. 15. Kemppainen T, Kroger H, Janatuinen E, et al. Osteoporosis in adult patients with celiac disease. Bone 1999;24:249 –55. 16. Binkley N, Krueger D, Cowgill CS, et al. Assay variation confounds the diagnosis of hypovitaminosis D: a call for standardization. J Clin Endocrinol Metab 2004;89:3152–7.
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