S P E C I A L C l i n i c a l
C a s e
F E A T U R E S e m i n a r
Recovery From SIADH-Associated Osteoporosis: A Case Report Anne-Sophie Sejling, Anne-Luise Thorsteinsson, Ulrik Pedersen-Bjergaard, and Pia Eiken Department of Cardiology, Nephrology, and Endocrinology (A.-S.S., A.-L.T., U.P.-B., P.E.), Nordsjællands Hospital, DK-3400 Hillerød, Denmark; Faculty of Health Sciences (A.-S.S.), University of Southern Denmark, DK-5000 Odense, Denmark; and Faculty of Health Sciences (U.P.-B., P.E.), University of Copenhagen, DK-2200 Copenhagen, Denmark
Introduction: Recent studies show an association between hyponatremia and osteoporosis. We have previously reported a case of severe male osteoporosis due to chronic syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we provide a follow-up on this case after cure of the condition that further supports the causal relationship. The Case: A 38-year-old man had been diagnosed with severe osteoporosis most likely due to chronic SIADH. The SIADH was believed to be idiopathic. A magnetic resonance imaging scan, however, revealed a tumor in the sinus, and biopsies showed an esthesioneuroblastoma, immunohistochemically positive for antidiuretic hormone (ADH). After the tumor was removed, ADH and sodium levels normalized. A dual-energy x-ray absorptiometry scan performed 7 months after the patient’s last surgery showed a significant spontaneous improvement in bone mineral density in the lumbar vertebrae. Conclusion: This case provides evidence for a causal relationship between SIADH and chronic hyponatremia and impaired bone metabolism that can lead to severe secondary osteoporosis. The effect on bone metabolism is at least partially reversible. (J Clin Endocrinol Metab 99: 3527–3530, 2014)
he syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a common cause of hyponatremia and is characterized by inappropriately elevated levels of vasopressin, which reduces water excretion and decreases the concentration of sodium in serum (1, 2). SIADH can be caused by malignant disease, pulmonary disorders, disorders of the central nervous system, or drugs, or it can be hereditary (3). Idiopathic forms of SIADH are diagnosed by exclusion (4). Studies suggest a relation between hyponatremia and hip fractures (5), falls (6), and osteoporosis (7, 8). We have previously described the case of a man who was diagnosed with severe osteoporosis at age 36, where the only plausible explanation is that the osteoporosis is secondary to chronic SIADH (9). We now report a follow-up on the
T
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received February 26, 2014. Accepted May 21, 2014. First Published Online June 27, 2014
doi: 10.1210/jc.2014-1572
patient that further supports the hypothesis that the loss of bone mineral density (BMD) was caused by SIADH.
The Case The patient, a 38-year-old man, was diagnosed with idiopathic SIADH in 1996 at the age of 22 (Figure 1). At the time of diagnosis, secondary SIADH was ruled out by a normal magnetic resonance imaging (MRI) scan of the cerebrum and a normal x-ray of the thorax. His sodium levels in the blood remained low during the next 12 years, and he did not receive any treatment for his SIADH except for occasional admissions due to seizures caused by low sodium. At the age of 34, the patient experienced back Abbreviations: ADH, antidiuretic hormone; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; MRI, magnetic resonance imaging; SIADH, syndrome of inappropriate secretion of ADH.
J Clin Endocrinol Metab, October 2014, 99(10):3527–3530
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J Clin Endocrinol Metab, October 2014, 99(10):3527–3530
condition, the patient had a new MRI of the cerebrum in 2012. This scan showed a tumor in the maxillary sinus. The tumor was removed in September 2012 and turned out to be an esthesioneuroblastoma, Hyams’ grade 1, with positive immunohistochemical staining for antidiuretic hormone (ADH). The Figure 1. Timeline. The patient was diagnosed with SIADH in 1996. He received no treatment for his condition. In 2008, he was diagnosed with severe osteoporosis. In 2012, he staining for the other pituitary horwas diagnosed with esthesioneuroblastoma. The tumor had produced ADH. After the mones was negative. The patient underremoval of the tumor, the SIADH was cured. The patient was treated with zoledronic acid went a second surgery 1 month later, injections in 2010 and 2011 and had DXA scans in 2008, 2011, and 2013. after computed tomography and MRI pain, and an MRI scan of the vertebrae column showed scans had shown residual tumor tissue. The tumor was compression fractures at Th9 –11 and L2. A dual-energy staged as a Kadish type B. The patient subsequently unx-ray absorptiometry (DXA) scan showed a Z-score of derwent radiation therapy. After the treatment, the vaso⫺3.9 at the lumbar spine (L3–L4) and a Z-score of ⫺1.5 pressin and sodium levels started to normalize, and the in the total hip. He had no other known risk factors for SIADH condition was cured (Table 1). osteoporosis, and no other cause was found after a thorSeven months after the second surgery and 2 years after ough physical examination, extensive lab tests, and inves- the last zoledronic acid injection, a new DXA scan was tigations including pituitary hormones, T, and M-compo- performed. It showed a pronounced increment in Z-score nent (9). The laboratory results did, however, show from ⫺3.8 to ⫺2.8 at the lumbar spine (L3–L4), correelevated urinary excretion of calcium and sodium, and sponding to 16% compared to the scan in 2011, and 18% plasma vasopressin levels were inappropriately elevated, compared to the baseline scan in 2008. In the total hip, the consistent with the diagnosis of SIADH. The patient was Z-score changed from ⫺1.1 to ⫺1.3. This negative change started on supplements with vitamin D and calcium as well of 2.1% was insignificant. as treatment with 5-mg zoledronic acid per year, and he received two doses in June 2010 and August 2011, respectively. After the second dose, the patient has received cal- Discussion cium and vitamin D supplements, but no antiosteoporotic treatment or any other medication. In May 2011, 11 We have described a case where a patient was cured from months after the first zoledronic acid treatment, a DXA SIADH caused by an endocrine sinus tumor that remained scan showed a small change in BMD in the lumbar spine occult for a long period. Sinus esthesioneuroblastomas are (Z score, ⫺3.8; 2.4% change) and the total hip (Z score, rare, but the association between esthesioneuroblastoma ⫺1.1; 6% change). The symptoms from SIADH had not and SIADH is well described (10 –14). In this case, the patient suffered from SIADH for 16 years before it was changed. As part of a second diagnostic workup of the SIADH resolved. As described previously in detail, this has most Table 1.
Laboratory Results
Plasma Levels
Before Surgery
2 wk After Second Surgery
1 mo After Second Surgery
6 mo After Second Surgery
Vasopressin, pmol/L (0 –1.51) Sodium, mmol/L (137–144) Calcium, mmol/L (1.18 –1.32) Potassium, mmol/L (3.5– 4.6) Magnesium, mmol/L (0.71– 0.94) Phosphate, mmol/L (0.71–1.53) Albumin, g/L (36 – 48) Creatinine, mol/L (60 –105) Hemoglobin, mmol/L (8.3–10.5) 25-Hydroxyvitamin D, nmol/L (⬎50) PTH, pmol/L (1.6 – 6.9) Renin, mIU/L (⬍31) Aldosterone, pmol/L (50 –360) Alkaline phosphatase, U/L (35–105)
8.6 120 1.13 4.3 0.72 0.74 48 58 9.3 98 6.8 4.4 1246 60
5.8 140 1.24 4.9 0.85 1.08 47 85 76 10
2.5 142 1.17 4.2 0.79 1.11 47 84 9.1 80 5.3
63
66
⬍0.53 137 1.22 4.9 0.85 1.25 47 85 9.7 80 6.4 3 51 43
Data in parentheses indicate normal values.
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doi: 10.1210/jc.2014-1572
likely led to the development of severe osteoporosis (9). Treatment with zoledronic acid had no effect on bone density as long as the SIADH condition persisted, but a pronounced spontaneous increment in BMD, in particular in the lumbar spine, was observed after reversal of SIADH by radical removal of the tumor. All scans were performed at the same center at the same machine (Delphi SL; Hologic), which has a precision error at 1.2% at the L1–L4 level and 1.3% in total femur (15). The software also remained the same. It is unlikely that the improvement in BMD is caused by the previous administration of zoledronic acid because there was no increase in BMD 1 year after the first administration. This is supported by data from a study by Boonen et al (16) that showed that the most pronounced effect of zoledronic acid on BMD in men occurs within the first 6 months. Similar results have been obtained in women (17). An association between hyponatremia and osteoporosis has been shown in the last couple of years. Studies have shown that the frequency of hyponatremia was higher in patients who suffered a fracture compared to controls after a fall and that hyponatremic patients are more than twice as likely to sustain a bone fracture (18, 19). In accordance, data from the third National Health and Nutrition Examination Survey showed a positive linear association between sodium levels in the serum and femoral neck BMD in hyponatremic participants over the age of 50 years (7). However, an association between hyponatremia and fractures mediated by reduced BMD still needs to be demonstrated in a prospective clinical trial because the Rotterdam Study showed that an association between mild hyponatremia and risk of fractures was not explained by differences in BMD (20). Still, studies by Verbalis et al (7) and Barsony et al (8) have provided potential mechanistic data by showing that hyponatremia stimulates bone resorption and osteoclast formation in rats and cultured cells, and Tamma et al (21) have shown that ADH negatively regulates osteoblasts and stimulates osteoclasts in genetically modified mice. This finding indicates that patients’ osteoporosis could be a result of the high ADH levels. The spinal preponderance of the osteoporosis in this case resembles that of osteoporosis secondary to other endocrine causes such as Cushing’s syndrome (22–24). Also in this condition, reversibility of osteoporosis has been described after surgical elimination of the syndrome (25, 26). However, the time course to complete BMD normalization differs from study to study (27, 28), and a study by Randazzo et al (29) questioned whether the secondary osteoporosis is fully reversible. It will therefore be very
jcem.endojournals.org
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interesting to follow this patient to see whether his BMD normalizes completely with time. It is noteworthy that the plasma aldosterone levels also normalized after the removal of the tumor. It is possible that it also had a beneficial effect on the BMD because hyperaldosteronism has been shown to be associated with bone loss in rats (30). The fact that the osteoporosis was reversible upon normalization of sodium homeostasis provides evidence for the need for normalizing sodium levels in patients with chronic hyponatremia. SIADH can be managed with fluid restriction, but not all patients are compliant to this treatment. In this case, vasopressin receptor antagonist may be indicated. However, further studies are warranted to address whether vasopressin receptor antagonists have an effect on calcium homeostasis and BMD and, if so, whether hyponatremia-induced osteoporosis can be avoided.
Conclusion This case provides evidence for a causal relationship between chronic hyponatremia due to SIADH and development of clinically significant osteoporosis. The severe side effects on bone metabolism are at least partially reversible by normalization of sodium homeostasis.
Acknowledgments Address all correspondence and requests for reprints to: AnneSophie Sejling, Endocrine Section 0652, Department of Cardiology, Nephrology, and Endocrinology, Nordsjællands Hospital, Dyrehavevej 29, DK-3400-Hillerød, Denmark. E-mail: [email protected]. Disclosure Summary: A.-S.S., A.-L.T., and U.P.-B. have nothing to disclose. P.E. has served in advisory boards for Eli Lilly, MSD, and Amgen and has received lecture fees from Lilly, Amgen, and GlaxoSmithKline.
References 1. Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. Am J Med. 1957;23: 529 –542. 2. Gross P. Clinical management of SIADH. Ther Adv Endocrinol Metab. 2012;3:61–73. 3. Ellison DH, Berl T. Clinical practice. The syndrome of inappropriate antidiuresis. N Engl J Med. 2007;356:2064 –2072. 4. Esposito P, Piotti G, Bianzina S, Malul Y, Dal Canton A. The syndrome of inappropriate antidiuresis: pathophysiology, clinical management and new therapeutic options. Nephron Clin Pract. 2011; 119:c62– c73.
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5. Hagino T, Ochiai S, Watanabe Y, et al. Hyponatremia at admission is associated with in-hospital death in patients with hip fracture. Arch Orthop Trauma Surg. 2013;133:507–511. 6. Renneboog B, Musch W, Vandermergel X, Manto MU, Decaux G. Mild chronic hyponatremia is associated with falls, unsteadiness, and attention deficits. Am J Med. 2006;119:71.e1– e8. 7. Verbalis JG, Barsony J, Sugimura Y, et al. Hyponatremia-induced osteoporosis. J Bone Miner Res. 2010;25:554 –563. 8. Barsony J, Sugimura Y, Verbalis JG. Osteoclast response to low extracellular sodium and the mechanism of hyponatremia-induced bone loss. J Biol Chem. 2011;286:10864 –10875. 9. Sejling AS, Pedersen-Bjergaard U, Eiken P. Syndrome of inappropriate ADH secretion and severe osteoporosis. J Clin Endocrinol Metab. 2012;97:4306 – 4310. 10. Ow TJ, Bell D, Kupferman ME, Demonte F, Hanna EY. Esthesioneuroblastoma. Neurosurg Clin N Am. 2013;24:51– 65. 11. Senchak A, Freeman J, Ruhl D, Senchak J, Klem C. Low-grade esthesioneuroblastoma presenting as SIADH: a review of atypical manifestations. Case Rep Otolaryngol. 2012;2012:582180. 12. Gray ST, Holbrook EH, Najm MH, Sadow PM, Curry WT, Lin DT. Syndrome of inappropriate antidiuretic hormone secretion in patients with olfactory neuroblastoma. Otolaryngol Head Neck Surg. 2012;147:147–151. 13. Osterman J, Calhoun A, Dunham M, et al. Chronic syndrome of inappropriate antidiuretic hormone secretion and hypertension in a patient with olfactory neuroblastoma. Evidence of ectopic production of arginine vasopressin by the tumor. Arch Intern Med. 1986; 146:1731–1735. 14. Plasencia YL, Cortés MB, Arencibia DM, et al. Esthesioneuroblastoma recurrence presenting as a syndrome of inappropriate antidiuretic hormone secretion. Head Neck. 2006;28:1142–1146. 15. Shepherd JA, Fan B, Lu Y, Lewiecki EM, Miller P, Genant HK. Comparison of BMD precision for Prodigy and Delphi spine and femur scans. Osteoporos Int. 2006;17:1303–1308. 16. Boonen S, Reginster JY, Kaufman JM, et al. Fracture risk and zoledronic acid therapy in men with osteoporosis. N Engl J Med. 2012; 367:1714 –1723. 17. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007; 356:1809 –1822. 18. Gankam Kengne F, Andres C, Sattar L, Melot C, Decaux G. Mild
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hyponatremia and risk of fracture in the ambulatory elderly. QJM. 2008;101:583–588. Sandhu HS, Gilles E, DeVita MV, Panagopoulos G, Michelis MF. Hyponatremia associated with large-bone fracture in elderly patients. Int Urol Nephrol. 2009;41:733–737. Hoorn EJ, Rivadeneira F, van Meurs JB, et al. Mild hyponatremia as a risk factor for fractures: the Rotterdam Study. J Bone Miner Res. 2011;26:1822–1828. Tamma R, Sun L, Cuscito C, et al. Regulation of bone remodeling by vasopressin explains the bone loss in hyponatremia. Proc Natl Acad Sci USA. 2013;110:18644 –18649. Kawamata A, Iihara M, Okamoto T, Obara T. Bone mineral density before and after surgical cure of Cushing’s syndrome due to adrenocortical adenoma: prospective study. World J Surg. 2008;32: 890 – 896. Dobnig H, Stepan V, Leb G, Wolf G, Buchfelder M, Krejs GJ. Recovery from severe osteoporosis following cure from ectopic ACTH syndrome caused by an appendix carcinoid. J Intern Med. 1996; 239:365–369. Kristo C, Jemtland R, Ueland T, Godang K, Bollerslev J. Restoration of the coupling process and normalization of bone mass following successful treatment of endogenous Cushing’s syndrome: a prospective, long-term study. Eur J Endocrinol. 2006;154:109 –118. Tóth M, Grossman A. Glucocorticoid-induced osteoporosis: lessons from Cushing’s syndrome. Clin Endocrinol (Oxf). 2013;79: 1–11. Pocock NA, Eisman JA, Dunstan CR, Evans RA, Thomas DH, Huq NL. Recovery from steroid-induced osteoporosis. Ann Intern Med. 1987;107:319 –323. Manning PJ, Evans MC, Reid IR. Normal bone mineral density following cure of Cushing’s syndrome. Clin Endocrinol (Oxf). 1992;36:229 –234. Füto L, Toke J, Patócs A, et al. Skeletal differences in bone mineral area and content before and after cure of endogenous Cushing’s syndrome. Osteoporos Int. 2008;19:941–949. Randazzo ME, Grossrubatscher E, Dalino Ciaramella P, Vanzulli A, Loli P. Spontaneous recovery of bone mass after cure of endogenous hypercortisolism. Pituitary. 2012;15:193–201. Chhokar VS, Sun Y, Bhattacharya SK, et al. Loss of bone minerals and strength in rats with aldosteronism. Am J Physiol Heart Circ Physiol. 2004;287:H2023–H2026.
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C a s e
F E A T U R E S e m i n a r
Recovery From SIADH-Associated Osteoporosis: A Case Report Anne-Sophie Sejling, Anne-Luise Thorsteinsson, Ulrik Pedersen-Bjergaard, and Pia Eiken Department of Cardiology, Nephrology, and Endocrinology (A.-S.S., A.-L.T., U.P.-B., P.E.), Nordsjællands Hospital, DK-3400 Hillerød, Denmark; Faculty of Health Sciences (A.-S.S.), University of Southern Denmark, DK-5000 Odense, Denmark; and Faculty of Health Sciences (U.P.-B., P.E.), University of Copenhagen, DK-2200 Copenhagen, Denmark
Introduction: Recent studies show an association between hyponatremia and osteoporosis. We have previously reported a case of severe male osteoporosis due to chronic syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we provide a follow-up on this case after cure of the condition that further supports the causal relationship. The Case: A 38-year-old man had been diagnosed with severe osteoporosis most likely due to chronic SIADH. The SIADH was believed to be idiopathic. A magnetic resonance imaging scan, however, revealed a tumor in the sinus, and biopsies showed an esthesioneuroblastoma, immunohistochemically positive for antidiuretic hormone (ADH). After the tumor was removed, ADH and sodium levels normalized. A dual-energy x-ray absorptiometry scan performed 7 months after the patient’s last surgery showed a significant spontaneous improvement in bone mineral density in the lumbar vertebrae. Conclusion: This case provides evidence for a causal relationship between SIADH and chronic hyponatremia and impaired bone metabolism that can lead to severe secondary osteoporosis. The effect on bone metabolism is at least partially reversible. (J Clin Endocrinol Metab 99: 3527–3530, 2014)
he syndrome of inappropriate secretion of antidiuretic hormone (SIADH) is a common cause of hyponatremia and is characterized by inappropriately elevated levels of vasopressin, which reduces water excretion and decreases the concentration of sodium in serum (1, 2). SIADH can be caused by malignant disease, pulmonary disorders, disorders of the central nervous system, or drugs, or it can be hereditary (3). Idiopathic forms of SIADH are diagnosed by exclusion (4). Studies suggest a relation between hyponatremia and hip fractures (5), falls (6), and osteoporosis (7, 8). We have previously described the case of a man who was diagnosed with severe osteoporosis at age 36, where the only plausible explanation is that the osteoporosis is secondary to chronic SIADH (9). We now report a follow-up on the
T
ISSN Print 0021-972X ISSN Online 1945-7197 Printed in U.S.A. Copyright © 2014 by the Endocrine Society Received February 26, 2014. Accepted May 21, 2014. First Published Online June 27, 2014
doi: 10.1210/jc.2014-1572
patient that further supports the hypothesis that the loss of bone mineral density (BMD) was caused by SIADH.
The Case The patient, a 38-year-old man, was diagnosed with idiopathic SIADH in 1996 at the age of 22 (Figure 1). At the time of diagnosis, secondary SIADH was ruled out by a normal magnetic resonance imaging (MRI) scan of the cerebrum and a normal x-ray of the thorax. His sodium levels in the blood remained low during the next 12 years, and he did not receive any treatment for his SIADH except for occasional admissions due to seizures caused by low sodium. At the age of 34, the patient experienced back Abbreviations: ADH, antidiuretic hormone; BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; MRI, magnetic resonance imaging; SIADH, syndrome of inappropriate secretion of ADH.
J Clin Endocrinol Metab, October 2014, 99(10):3527–3530
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Recovery From SIADH-Associated Osteoporosis
J Clin Endocrinol Metab, October 2014, 99(10):3527–3530
condition, the patient had a new MRI of the cerebrum in 2012. This scan showed a tumor in the maxillary sinus. The tumor was removed in September 2012 and turned out to be an esthesioneuroblastoma, Hyams’ grade 1, with positive immunohistochemical staining for antidiuretic hormone (ADH). The Figure 1. Timeline. The patient was diagnosed with SIADH in 1996. He received no treatment for his condition. In 2008, he was diagnosed with severe osteoporosis. In 2012, he staining for the other pituitary horwas diagnosed with esthesioneuroblastoma. The tumor had produced ADH. After the mones was negative. The patient underremoval of the tumor, the SIADH was cured. The patient was treated with zoledronic acid went a second surgery 1 month later, injections in 2010 and 2011 and had DXA scans in 2008, 2011, and 2013. after computed tomography and MRI pain, and an MRI scan of the vertebrae column showed scans had shown residual tumor tissue. The tumor was compression fractures at Th9 –11 and L2. A dual-energy staged as a Kadish type B. The patient subsequently unx-ray absorptiometry (DXA) scan showed a Z-score of derwent radiation therapy. After the treatment, the vaso⫺3.9 at the lumbar spine (L3–L4) and a Z-score of ⫺1.5 pressin and sodium levels started to normalize, and the in the total hip. He had no other known risk factors for SIADH condition was cured (Table 1). osteoporosis, and no other cause was found after a thorSeven months after the second surgery and 2 years after ough physical examination, extensive lab tests, and inves- the last zoledronic acid injection, a new DXA scan was tigations including pituitary hormones, T, and M-compo- performed. It showed a pronounced increment in Z-score nent (9). The laboratory results did, however, show from ⫺3.8 to ⫺2.8 at the lumbar spine (L3–L4), correelevated urinary excretion of calcium and sodium, and sponding to 16% compared to the scan in 2011, and 18% plasma vasopressin levels were inappropriately elevated, compared to the baseline scan in 2008. In the total hip, the consistent with the diagnosis of SIADH. The patient was Z-score changed from ⫺1.1 to ⫺1.3. This negative change started on supplements with vitamin D and calcium as well of 2.1% was insignificant. as treatment with 5-mg zoledronic acid per year, and he received two doses in June 2010 and August 2011, respectively. After the second dose, the patient has received cal- Discussion cium and vitamin D supplements, but no antiosteoporotic treatment or any other medication. In May 2011, 11 We have described a case where a patient was cured from months after the first zoledronic acid treatment, a DXA SIADH caused by an endocrine sinus tumor that remained scan showed a small change in BMD in the lumbar spine occult for a long period. Sinus esthesioneuroblastomas are (Z score, ⫺3.8; 2.4% change) and the total hip (Z score, rare, but the association between esthesioneuroblastoma ⫺1.1; 6% change). The symptoms from SIADH had not and SIADH is well described (10 –14). In this case, the patient suffered from SIADH for 16 years before it was changed. As part of a second diagnostic workup of the SIADH resolved. As described previously in detail, this has most Table 1.
Laboratory Results
Plasma Levels
Before Surgery
2 wk After Second Surgery
1 mo After Second Surgery
6 mo After Second Surgery
Vasopressin, pmol/L (0 –1.51) Sodium, mmol/L (137–144) Calcium, mmol/L (1.18 –1.32) Potassium, mmol/L (3.5– 4.6) Magnesium, mmol/L (0.71– 0.94) Phosphate, mmol/L (0.71–1.53) Albumin, g/L (36 – 48) Creatinine, mol/L (60 –105) Hemoglobin, mmol/L (8.3–10.5) 25-Hydroxyvitamin D, nmol/L (⬎50) PTH, pmol/L (1.6 – 6.9) Renin, mIU/L (⬍31) Aldosterone, pmol/L (50 –360) Alkaline phosphatase, U/L (35–105)
8.6 120 1.13 4.3 0.72 0.74 48 58 9.3 98 6.8 4.4 1246 60
5.8 140 1.24 4.9 0.85 1.08 47 85 76 10
2.5 142 1.17 4.2 0.79 1.11 47 84 9.1 80 5.3
63
66
⬍0.53 137 1.22 4.9 0.85 1.25 47 85 9.7 80 6.4 3 51 43
Data in parentheses indicate normal values.
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doi: 10.1210/jc.2014-1572
likely led to the development of severe osteoporosis (9). Treatment with zoledronic acid had no effect on bone density as long as the SIADH condition persisted, but a pronounced spontaneous increment in BMD, in particular in the lumbar spine, was observed after reversal of SIADH by radical removal of the tumor. All scans were performed at the same center at the same machine (Delphi SL; Hologic), which has a precision error at 1.2% at the L1–L4 level and 1.3% in total femur (15). The software also remained the same. It is unlikely that the improvement in BMD is caused by the previous administration of zoledronic acid because there was no increase in BMD 1 year after the first administration. This is supported by data from a study by Boonen et al (16) that showed that the most pronounced effect of zoledronic acid on BMD in men occurs within the first 6 months. Similar results have been obtained in women (17). An association between hyponatremia and osteoporosis has been shown in the last couple of years. Studies have shown that the frequency of hyponatremia was higher in patients who suffered a fracture compared to controls after a fall and that hyponatremic patients are more than twice as likely to sustain a bone fracture (18, 19). In accordance, data from the third National Health and Nutrition Examination Survey showed a positive linear association between sodium levels in the serum and femoral neck BMD in hyponatremic participants over the age of 50 years (7). However, an association between hyponatremia and fractures mediated by reduced BMD still needs to be demonstrated in a prospective clinical trial because the Rotterdam Study showed that an association between mild hyponatremia and risk of fractures was not explained by differences in BMD (20). Still, studies by Verbalis et al (7) and Barsony et al (8) have provided potential mechanistic data by showing that hyponatremia stimulates bone resorption and osteoclast formation in rats and cultured cells, and Tamma et al (21) have shown that ADH negatively regulates osteoblasts and stimulates osteoclasts in genetically modified mice. This finding indicates that patients’ osteoporosis could be a result of the high ADH levels. The spinal preponderance of the osteoporosis in this case resembles that of osteoporosis secondary to other endocrine causes such as Cushing’s syndrome (22–24). Also in this condition, reversibility of osteoporosis has been described after surgical elimination of the syndrome (25, 26). However, the time course to complete BMD normalization differs from study to study (27, 28), and a study by Randazzo et al (29) questioned whether the secondary osteoporosis is fully reversible. It will therefore be very
jcem.endojournals.org
3529
interesting to follow this patient to see whether his BMD normalizes completely with time. It is noteworthy that the plasma aldosterone levels also normalized after the removal of the tumor. It is possible that it also had a beneficial effect on the BMD because hyperaldosteronism has been shown to be associated with bone loss in rats (30). The fact that the osteoporosis was reversible upon normalization of sodium homeostasis provides evidence for the need for normalizing sodium levels in patients with chronic hyponatremia. SIADH can be managed with fluid restriction, but not all patients are compliant to this treatment. In this case, vasopressin receptor antagonist may be indicated. However, further studies are warranted to address whether vasopressin receptor antagonists have an effect on calcium homeostasis and BMD and, if so, whether hyponatremia-induced osteoporosis can be avoided.
Conclusion This case provides evidence for a causal relationship between chronic hyponatremia due to SIADH and development of clinically significant osteoporosis. The severe side effects on bone metabolism are at least partially reversible by normalization of sodium homeostasis.
Acknowledgments Address all correspondence and requests for reprints to: AnneSophie Sejling, Endocrine Section 0652, Department of Cardiology, Nephrology, and Endocrinology, Nordsjællands Hospital, Dyrehavevej 29, DK-3400-Hillerød, Denmark. E-mail: [email protected]. Disclosure Summary: A.-S.S., A.-L.T., and U.P.-B. have nothing to disclose. P.E. has served in advisory boards for Eli Lilly, MSD, and Amgen and has received lecture fees from Lilly, Amgen, and GlaxoSmithKline.
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