Journal of the Neurological Sciences 347 (2014) 391–392
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Response to letter to the Editor Vitamin D supplementation in multiple sclerosis: Making a case for clarity Keywords: Vitamin D Multiple sclerosis Safety Toxicity
Dear Editor, You recently published a letter by Dr. Fragoso and colleagues [1] that provided a short description of 21 patients with relapsing remitting multiple sclerosis (MS) who were treated with “high dose” vitamin D and experienced subsequent adverse events. Fragoso et al. [1] note the limited data on vitamin D dosing and the limited evidence to date for efficacy of vitamin D in mitigating MS disease activity. They state their view that vitamin D should not be used as a replacement for approved disease-modifying therapies. We concur with these statements. However, we disagree with Fragoso et al. regarding their claim about the lack of safety of vitamin D in MS. The 21 patients summarized in the Letter were exposed to doses of vitamin D ranging from 8000 IU/day to extremely high supra-physiological doses of 150,000 IU/day of vitamin D, all considered “high dose”. This is an exceptionally broad range of vitamin D doses that would be expected to produce a very wide range of serum 25-hydroxyvitamin D [25(OH)D] concentrations, and the highest doses far exceed doses considered “safe.” Vitamin D doses up to 10,000 IU/d have been demonstrated to be safe in healthy men [2] and one open-label trial of vitamin D in men and women with MS demonstrated the safety of a dose-escalation protocol from 4000–40,000 IU/day (mean 14,000 IU/day) over one year [3]. Furthermore, of the 5 published randomized, controlled, double-blind trials of vitamin D supplementation in the management of MS, none observed hypercalcemic effects of vitamin D supplementation [4–8] even in patients treated with 40,000 IU/d of vitamin D and achieving mean serum 25(OH)D concentrations of 400 nmol/L [3]. There is no evidence to support either the safety or the efficacy of doses above 40,000 IU/day. Vitamin D toxicity manifests biochemically as hypercalciuria, hypercalcemia, hyperphosphatemia and suppressed PTH. However, Fragoso et al., describe hypercalcemia in only five of the 21 patients, suggesting that other patients were not actually “vitamin D toxic.” To associate the signs and symptoms described in the letter with vitamin D toxicity, biochemical studies evaluating concurrent serum 25(OH)D concentrations and their relationship to serum and urine calcium levels should have been provided. Furthermore, given that the most common cause of hypercalcemia is hyperparathyroidism (primary or secondary), inclusion of PTH levels would have clarified whether all of the five patients with hypercalcemia were actually “vitamin D toxic” rather than hyperparathyroid. Also, in the absence of an underlying susceptibility to hypervitaminosis D (e.g. sarcoidosis or other granulomatous disease), a dose of
http://dx.doi.org/10.1016/j.jns.2014.10.003 0022-510X/© 2014 Elsevier B.V. All rights reserved.
8000 IU/d would not be expected to produce hypercalcemia [9]. Thus, because the authors did not provide the vitamin D doses, the serum 25-hydroxyvitamin D [25(OH)D] concentrations associated with hypercalcemia in the five patients, or other biochemical and clinical information critical to interpreting these relationships, we cannot draw conclusions about the dose of vitamin D or the serum 25(OH)D level associated with vitamin D toxicity in these MS patients. Our other major concern relates to the authors' assertion that the neurologic worsening experienced by the patients was due to vitamin D intoxication. We suggest that the more likely explanation relates to the escalation of disease activity following cessation of diseasemodifying therapy. There is a wealth of biological evidence that supports the safety of vitamin D as part of the management in neurological diseases. Lack of evidence pertaining to the efficacy of vitamin D with respect to MS disease activity or progression should not discourage responsible vitamin D supplement intake in MS, given the risk of vitamin D insufficiency in MS patients, and the increased risk for osteoporosis and fracture in MS patients [10]. The Institute of Medicine currently suggests that up to 4000 IU/day of vitamin D is unlikely to cause toxicity even in healthy individuals and the Endocrine Society of North America has specified 10,000 IU/d as a safe upper level of intake. We would therefore suggest that vitamin D supplementation up to this amount is safe for most individuals, and has a benefit in terms of bone health. Future studies will inform on whether vitamin D can exert a positive effect on MS disease activity. Given current evidence-based rationale for the use of approved disease-modifying therapies, studies of vitamin D will require an “add-on” design with careful consideration of dosing. In clinical trials and in clinical practice, we suggest screening of patients for conditions associated with altered vitamin D metabolism and, in doses above the 10,000 IU/d, monitoring of serum and urine calcium levels and serum 25(OH)D levels. In summary, we concur with Fragoso et al. that irresponsible and sensationalized descriptions of potential new treatments for MS in the media or medical literature can be hazardous. However, we also assert that this Letter to the Editor is problematic in that it makes easily refutable and unsubstantiated claims regarding the lack of evidence for safety of vitamin D in MS and purportedly demonstrates the apparent toxicity of “high dose” vitamin D in MS while failing to provide the requisite evidence to support this claim. This Letter does not provide enough usable information on vitamin D toxicity and, with its overarching recommendation of caution, is more likely to be of harm than help. Sincerely, Conflict of interest The authors report no conflicts of interest. References [1] Fragoso YD, Adoni T, Damasceno A, de Albuquerque Damasceno CA, Ferreira ML, Finkelzstejn A, et al. Unfavorable outcomes during treatment of multiple sclerosis with high doses of vitamin D. J Neurol Sci Aug 24 2014;346:341–2.
392
Response to letter to the Editor
[2] Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204–10. [3] Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R, et al. A phase I/II doseescalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010;74: 1852–9. [4] Mosayebi G, Ghazavi A, Ghasami K, Kokhaei Y J and, P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest 2011;40:627–39. [5] Stein MS, Liu Y, Gray OM, Baker JE, Kolbe SC, Ditchfield MR, et al. A randomized trial of high-dose vitamin D2 in relapsing remitting multiple sclerosis. Neurology 2011; 77:1611–8. [6] Kampman MT, Steffensen LH, Mellgren SI, Jørgensen L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler 2012;18:1144–51. [7] Soilu-Hanninen M, Aivo J, Lindström BM, Elovaara I, Sumelahti ML, Färkkilä M, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2012;83:565–71. [8] Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H. Effects of adjunct low-dose vitamin D on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult Scler Int 2012;2012:452541. [9] Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007;85:6–18. [10] Marrie RA, Hanwell HE. General health issues in multiple sclerosis: comorbidities, secondary conditions, and health behaviors. Continuum (Minneap Minn) 2013;19: 1046–57.
S. Kimball Pure North S'Energy Foundation, Calgary, Alberta, Canada H.E. Hanwell Peter Gilgan Centre for Research and Learning, 686 Bay Street Rm 8-9840, Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada E-mail address: [email protected].
J.M. Burton University of Calgary, Departments of Clinical Neurosciences and Community Health Sciences, Hotchkiss Brain Institute, Calgary, Alberta, Canada R.P. Heaney Creighton University, Omaha, NE, United States M.F. Holick Physiology and Biophysics, Boston University School of Medicine, Boston, MA, United States B. Hollis Medical University of South Carolina, Department of Pediatrics, Charleston, SC, United States R. Lewanczuk University of Alberta, Department of Medicine, Division of Endocrinology, Edmonton, Alberta, Canada N. Makhani Yale School of Medicine, Pediatrics (Neurology) and Neurology, New Haven, CT, United States S. Venkateswaran University of Ottawa, Children's Hospital of Eastern Ontario, Department of Pediatrics, Ottawa, Ontario, Canada 26 September 2014
Contents lists available at ScienceDirect
Journal of the Neurological Sciences journal homepage: www.elsevier.com/locate/jns
Response to letter to the Editor Vitamin D supplementation in multiple sclerosis: Making a case for clarity Keywords: Vitamin D Multiple sclerosis Safety Toxicity
Dear Editor, You recently published a letter by Dr. Fragoso and colleagues [1] that provided a short description of 21 patients with relapsing remitting multiple sclerosis (MS) who were treated with “high dose” vitamin D and experienced subsequent adverse events. Fragoso et al. [1] note the limited data on vitamin D dosing and the limited evidence to date for efficacy of vitamin D in mitigating MS disease activity. They state their view that vitamin D should not be used as a replacement for approved disease-modifying therapies. We concur with these statements. However, we disagree with Fragoso et al. regarding their claim about the lack of safety of vitamin D in MS. The 21 patients summarized in the Letter were exposed to doses of vitamin D ranging from 8000 IU/day to extremely high supra-physiological doses of 150,000 IU/day of vitamin D, all considered “high dose”. This is an exceptionally broad range of vitamin D doses that would be expected to produce a very wide range of serum 25-hydroxyvitamin D [25(OH)D] concentrations, and the highest doses far exceed doses considered “safe.” Vitamin D doses up to 10,000 IU/d have been demonstrated to be safe in healthy men [2] and one open-label trial of vitamin D in men and women with MS demonstrated the safety of a dose-escalation protocol from 4000–40,000 IU/day (mean 14,000 IU/day) over one year [3]. Furthermore, of the 5 published randomized, controlled, double-blind trials of vitamin D supplementation in the management of MS, none observed hypercalcemic effects of vitamin D supplementation [4–8] even in patients treated with 40,000 IU/d of vitamin D and achieving mean serum 25(OH)D concentrations of 400 nmol/L [3]. There is no evidence to support either the safety or the efficacy of doses above 40,000 IU/day. Vitamin D toxicity manifests biochemically as hypercalciuria, hypercalcemia, hyperphosphatemia and suppressed PTH. However, Fragoso et al., describe hypercalcemia in only five of the 21 patients, suggesting that other patients were not actually “vitamin D toxic.” To associate the signs and symptoms described in the letter with vitamin D toxicity, biochemical studies evaluating concurrent serum 25(OH)D concentrations and their relationship to serum and urine calcium levels should have been provided. Furthermore, given that the most common cause of hypercalcemia is hyperparathyroidism (primary or secondary), inclusion of PTH levels would have clarified whether all of the five patients with hypercalcemia were actually “vitamin D toxic” rather than hyperparathyroid. Also, in the absence of an underlying susceptibility to hypervitaminosis D (e.g. sarcoidosis or other granulomatous disease), a dose of
http://dx.doi.org/10.1016/j.jns.2014.10.003 0022-510X/© 2014 Elsevier B.V. All rights reserved.
8000 IU/d would not be expected to produce hypercalcemia [9]. Thus, because the authors did not provide the vitamin D doses, the serum 25-hydroxyvitamin D [25(OH)D] concentrations associated with hypercalcemia in the five patients, or other biochemical and clinical information critical to interpreting these relationships, we cannot draw conclusions about the dose of vitamin D or the serum 25(OH)D level associated with vitamin D toxicity in these MS patients. Our other major concern relates to the authors' assertion that the neurologic worsening experienced by the patients was due to vitamin D intoxication. We suggest that the more likely explanation relates to the escalation of disease activity following cessation of diseasemodifying therapy. There is a wealth of biological evidence that supports the safety of vitamin D as part of the management in neurological diseases. Lack of evidence pertaining to the efficacy of vitamin D with respect to MS disease activity or progression should not discourage responsible vitamin D supplement intake in MS, given the risk of vitamin D insufficiency in MS patients, and the increased risk for osteoporosis and fracture in MS patients [10]. The Institute of Medicine currently suggests that up to 4000 IU/day of vitamin D is unlikely to cause toxicity even in healthy individuals and the Endocrine Society of North America has specified 10,000 IU/d as a safe upper level of intake. We would therefore suggest that vitamin D supplementation up to this amount is safe for most individuals, and has a benefit in terms of bone health. Future studies will inform on whether vitamin D can exert a positive effect on MS disease activity. Given current evidence-based rationale for the use of approved disease-modifying therapies, studies of vitamin D will require an “add-on” design with careful consideration of dosing. In clinical trials and in clinical practice, we suggest screening of patients for conditions associated with altered vitamin D metabolism and, in doses above the 10,000 IU/d, monitoring of serum and urine calcium levels and serum 25(OH)D levels. In summary, we concur with Fragoso et al. that irresponsible and sensationalized descriptions of potential new treatments for MS in the media or medical literature can be hazardous. However, we also assert that this Letter to the Editor is problematic in that it makes easily refutable and unsubstantiated claims regarding the lack of evidence for safety of vitamin D in MS and purportedly demonstrates the apparent toxicity of “high dose” vitamin D in MS while failing to provide the requisite evidence to support this claim. This Letter does not provide enough usable information on vitamin D toxicity and, with its overarching recommendation of caution, is more likely to be of harm than help. Sincerely, Conflict of interest The authors report no conflicts of interest. References [1] Fragoso YD, Adoni T, Damasceno A, de Albuquerque Damasceno CA, Ferreira ML, Finkelzstejn A, et al. Unfavorable outcomes during treatment of multiple sclerosis with high doses of vitamin D. J Neurol Sci Aug 24 2014;346:341–2.
392
Response to letter to the Editor
[2] Heaney RP, Davies KM, Chen TC, Holick MF, Barger-Lux MJ. Human serum 25hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 2003;77:204–10. [3] Burton JM, Kimball S, Vieth R, Bar-Or A, Dosch HM, Cheung R, et al. A phase I/II doseescalation trial of vitamin D3 and calcium in multiple sclerosis. Neurology 2010;74: 1852–9. [4] Mosayebi G, Ghazavi A, Ghasami K, Kokhaei Y J and, P. Therapeutic effect of vitamin D3 in multiple sclerosis patients. Immunol Invest 2011;40:627–39. [5] Stein MS, Liu Y, Gray OM, Baker JE, Kolbe SC, Ditchfield MR, et al. A randomized trial of high-dose vitamin D2 in relapsing remitting multiple sclerosis. Neurology 2011; 77:1611–8. [6] Kampman MT, Steffensen LH, Mellgren SI, Jørgensen L. Effect of vitamin D3 supplementation on relapses, disease progression, and measures of function in persons with multiple sclerosis: exploratory outcomes from a double-blind randomised controlled trial. Mult Scler 2012;18:1144–51. [7] Soilu-Hanninen M, Aivo J, Lindström BM, Elovaara I, Sumelahti ML, Färkkilä M, et al. A randomised, double blind, placebo controlled trial with vitamin D3 as an add on treatment to interferon beta-1b in patients with multiple sclerosis. J Neurol Neurosurg Psychiatry 2012;83:565–71. [8] Shaygannejad V, Janghorbani M, Ashtari F, Dehghan H. Effects of adjunct low-dose vitamin D on relapsing-remitting multiple sclerosis progression: preliminary findings of a randomized placebo-controlled trial. Mult Scler Int 2012;2012:452541. [9] Hathcock JN, Shao A, Vieth R, Heaney R. Risk assessment for vitamin D. Am J Clin Nutr 2007;85:6–18. [10] Marrie RA, Hanwell HE. General health issues in multiple sclerosis: comorbidities, secondary conditions, and health behaviors. Continuum (Minneap Minn) 2013;19: 1046–57.
S. Kimball Pure North S'Energy Foundation, Calgary, Alberta, Canada H.E. Hanwell Peter Gilgan Centre for Research and Learning, 686 Bay Street Rm 8-9840, Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada E-mail address: [email protected].
J.M. Burton University of Calgary, Departments of Clinical Neurosciences and Community Health Sciences, Hotchkiss Brain Institute, Calgary, Alberta, Canada R.P. Heaney Creighton University, Omaha, NE, United States M.F. Holick Physiology and Biophysics, Boston University School of Medicine, Boston, MA, United States B. Hollis Medical University of South Carolina, Department of Pediatrics, Charleston, SC, United States R. Lewanczuk University of Alberta, Department of Medicine, Division of Endocrinology, Edmonton, Alberta, Canada N. Makhani Yale School of Medicine, Pediatrics (Neurology) and Neurology, New Haven, CT, United States S. Venkateswaran University of Ottawa, Children's Hospital of Eastern Ontario, Department of Pediatrics, Ottawa, Ontario, Canada 26 September 2014
