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ARTICLES: M. A. Mikati, L. Dib, B. Yamout, R. Sawaya, A. C. Rahi, and G. El-Hajj Fuleihan Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone Neurology 2006; 67: 2005-2014 [Abstract] [Full text] [PDF]

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Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone

Zulfi Haneef, Mercedes Jacobson   (22 March 2007)

Reply from the Authors

Mohamad A Mikati, Lea Dib, Bassem Yamout, Raja Sawaya, Amal C. Rahi, and Ghada El-Hajj Fuleihan   (22 March 2007)

Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone 22 March 2007
Zulfi Haneef, Temple University Hospital 3401 North Broad Street, Philadelphia, PA 19122, Mercedes Jacobson Send Correspondence to journal: Re: Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone zulfihaneef{at}gmail.com Zulfi Haneef, et al.	We read the article by Mikati et al with interest. [1] The authors compared low dose to high dose vitamin D treatment of Anti-Epileptic Drug (AED)-induced bone loss. It is commendable that the authors have undertaken a long-term trial to clarify inconsistencies from previous trials which have have been short-term and not shown statistical significance. Some details regarding the adult subjects merit further clarification. The control group received a lower dose of vitamin D as giving placebo would have been unethical. Higher dose vitamin D caused higher serum levels and earlier improvement of bone mineral density (BMD). The conclusion that “higher dose vitamin D substantially improves BMD” implies superiority over lower dose therapy. However, it is notable that the BMD improved to a lesser extent in the low dose group. A longer follow-up may attenuate this disparity, which seems intuitive considering that BMD changes occur over long periods. After a one-year follow-up, the authors found that “in view of the smaller than anticipated difference in BMD between the two treatment groups (in the range of 1% rather than 7%) our study turned out to be underpowered to detect treatment differences”. Until a definite advantage of higher dose therapy with reduction in clinical fractures is proven, lower dose therapy should not be deemed inferior. Reduction in fracture risk, rather than higher vitamin D levels or BMD, should ultimately guide treatment decisions for the clinician and ethical decisions for the future researcher. Another concern is the suboptimal calcium intake in either group. The authors contend that the trial “was meant to be a vitamin D rather than a calcium/ vitamin D trial”. Vitamin D acts in concert with calcium to improve bone health. With adequate vitamin D, calcium intake of 800 mg/day may be needed (average 608 mg/d in this study). [2] We believe that the response to vitamin D should be viewed with caution. A third area of potential bias is that the high dose group was significantly younger than the low dose group (25 Vs 31 years, p 0.01). The younger age could have produced a more robust response. It is well known that the balance between bone formation and loss shifts to increased bone loss at the age of 30. [3] References 1. Mikati MA, Dib L, Yamout B, Sawaya R, Rahi AC, El-Hajj Fuleihan G.Two randomized vitamin D trials in ambulatory patients on anticonvulsants: Impact on bone. Neurology, 2006; 67: 2005 - 2014. 2. Steingrimsdottir L, Gunnarsson O, Indridason OS, Franzson L, Sigurdsson G. Relationship between serum parathyroid hormone levels, vitamin D sufficiency, and calcium intake. JAMA. 2005 ;294:2336-41. 3. National Osteoporosis Foundation. http://www.nof.org/osteoporosis/bonehealth.htm Disclosure: The authors report no conflicts of interest.
Reply from the Authors 22 March 2007
Mohamad A Mikati, American University of Beirut Medical Center PO Box: 11-0236 Riad El Solh 11072020 Beirut Lebanon, Lea Dib, Bassem Yamout, Raja Sawaya, Amal C. Rahi, and Ghada El-Hajj Fuleihan Send Correspondence to journal: Re: Reply from the Authors mamikati{at}aub.edu.lb Mohamad A Mikati, et al.	We thank Drs. Haneef and Jacobson for their comments. Higher dose vitamin D in adults significantly increased BMD at several sites, whereas low dose did not. [1] The Conclusion of the Abstract conveys the information regarding the substantial increments in BMD with the high dose in adults. We have specifically avoided the comparison of the high dose to the low dose in the Abstract due to the limitations of the study, as we outlined. [1] These limitations include the lower than anticipated study power due to the observed differences in BMD changes between the two doses, the low calcium intake of the study group, and the relatively short study duration. We agree that treatment strategies should ultimately be guided by fractures and other symptoms resulting from AED related bone disease--rather than bone density--as the outcome. In our experience, these may not be uncommon. [4] However, such evidence could only be obtained through large, multi-center randomized trials with lengthy follow up, which are very difficult to implement. Until then, our study provides useful information regarding the efficacy of two doses of vitamin D. Age could be a potential confounder for the observed BMD changes; because of the differences in age and treatment duration, between adults in the low and high dose groups, that regression analyses were implemented. As described in our Results, adjusting for age and treatment duration did not influence the effect of treatment doses on the percentage change in BMD at any skeletal site. Therefore, the observed differences in treatment effect in adults were unlikely to be due to age differences. The understanding of bone metabolism in patients on anti-epileptic drugs is still unclear. [4] These include pathophysiology of bone loss [5], relative impact of age, vitamin D, treatment duration, type and mode of therapy [4], and the optimal treatment strategy including the optimal dose of vitamin D1. [5-7] There is a need for large, multi-center studies to advance the state of knowledge in this challenging field. [4] References 4. Mikati MA, Hanna-Wakim R. Symptomatic antiepileptic drug associated vitamin D deficiency in non-institutionalized patients; an under-diagnosed disorder. Lebanese Medical Journal 2003;51:71-74. 5. Farhat G, Yamout B, Mikati M, Demirjian S, Sawaya R, El-Hajj Fuleihan G. Effect of antiepileptic drugs on bone density in ambulatory patients. Neurology 2002; 58:1348-1353. 6. Fitzpatrick L. Pathophysiology of bone loss in patients receiving anticonvulsant therapy. Epilepsy Behav 2004; 5(suppl 2): S3-S15. 7. Drezner MK. Treatment of anticonvulsant drug-induced bone disease. Epilepsy Behav 2004; (suppl 2): S41-S47. Disclosure: The authors report no conflicts of interest.