Published Ahead of Print on February 26, 2016 as 10.1212/WNL.0000000000002532
EDITORIAL
Strong bones and restless legs New data about bone remodeling in women with RLS
Linda A. Hershey, MD, Disorders of bone metabolism are a common concern PhD for older women, since there are known associations Mehmet Akif Karan, MD among bone loss, sex, and age.1 Women with restless legs syndrome (RLS) who have not yet been treated with medication have signs of increased sympathetic Correspondence to nervous system activity.2 The autonomic nervous sysDr. Hershey: tem appears to be a major regulator of bone mineral [email protected] density (BMD) through signals sent to osteoblasts, and increased sympathetic activity is associated with Neurology® 2016;86:1–2 more osteoporosis in older women because of decreased osteoblast proliferation.3 These observations created a plausible hypothesis that there would be a higher incidence of osteopenia or osteoporosis in drug-naive women with RLS. In a new study reported in this issue of Neurology®, Cikrikcioglu et al.4 examined this relationship and found no evidence to support this hypothesis. In fact, they discovered the opposite result in their case-control study: an increase in lumbar BMD in 78 women with RLS, compared to 78 age-matched and body mass index (BMI)– matched controls. There was a positive bivariate correlation between duration of RLS and lumbar BMD. They also studied 2 markers of bone resorption, c-telopeptide of type 1 collagen (CTX) and sclerosin, and found lower levels in women with RLS. There were negative bivariate correlations between the severity of RLS and bone resorption markers. There are several strengths of this study. It was a prospective, cross-sectional examination of drugnaive women with RLS. Those who had mood disorders, neurodegenerative diseases, or medications to treat those disorders were excluded. Therefore, the patients with RLS who were studied had primary, not secondary, disease. Those who had thyroid problems, collagen diseases, chronic kidney disease, chronic lung disease, fractures, and bone prostheses were also excluded. Patients with RLS were matched with controls with respect to BMI. This is important, since body mass has a protective effect on osteoporosis and osteopenia.1 Process variables (CTX, sclerosin, and vitamin D3) were assessed in addition to the primary endpoint of BMD. Cikrikcioglu et al.4 also found vitamin D3 deficiency in slightly more of their patients with RLS
compared to age-matched controls, which is consistent with the observations of other recent studies. For example, Wali et al.5 have shown that vitamin D3 levels were low in 12 adults with RLS and that vitamin supplementation improved the median RLS severity score from 26 at baseline to 10 after the correction of vitamin D levels. Jimenez-Jimenez et al.6 analyzed a possible relationship between 2 vitamin D receptor polymorphisms and the risk for RLS. They discovered that patients with RLS carrying the rs731236G allele had an earlier age at onset of RLS and those with the rs731236GG allele had higher severity scores for RLS. Kim et al.7 recently recognized genetic variations in the vitamin D receptor in association with osteoporosis among patients with chronic lung disease. Since osteopenia and osteoporosis are conditions usually seen later in life, and fracture risk is agedependent,8 the inclusion of younger women in this study might complicate the analysis of the results (the age range was from 21 to 75 years). Another weakness of the study was the cross-sectional design, since this limits the possibility of making statements about causality. Nevertheless, this study is an important first step in the direction of our understanding the role of bone remodeling in women with RLS. STUDY FUNDING No targeted funding reported.
DISCLOSURE Dr. Hershey is a PI on a Forum study and is coinvestigator on an Alzheimer’s Association grant, an OU College of Nursing grant, an OU Norman Faculty Investment grant, an OUHSC VP for Research grant, and an OUHSC Presbyterian Health Foundation grant. She has received honoraria for educational presentations and for online publications. Dr. Karan reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Freitas PM, Garcia Rosa ML, Gomes AM, et al. Central and peripheral body fat mass have a protective effect on osteopenia or osteoporosis in adults and elderly. Osteoporos Int Epub 2015 Dec 9. 2. Cikrikcioglu MA, Hursitoglu M, Erkal H, et al. Oxidative stress and autonomic nervous system functions in restless legs syndrome. Eur J Clin Invest 2011;41:734–742. 3. Kajimura D, Hinoi E, Ferron M, et al. Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual. J Exp Med 2011;208:841–851.
See page XXX From the Department of Neurology (L.A.H.), University of Oklahoma Health Sciences Center, Oklahoma City; and Division of Geriatrics (M.A.K.), Istanbul Medical School, Capa, Turkey. © 2016 American Academy of Neurology
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
4.
5.
6.
2
Cikrikcioglu MA, Sekin Y, Halac G, et al. Reduced bone resorption and increased bone mineral density in women with restless legs syndrome. Neurology 2016; 86:xx–xx. Wali S, Shukr A, Boudal A, Alsaiari A, Krayem A. The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep Breath 2015;19:579–583. Jimenez-Jimenez FJ, Garcia-Martin E, Alonso-Navarro H, et al. Association between vitamin D receptor rs731236 (Taq1) polymorphism and risk for restless legs syndrome
Neurology 86
7.
8.
in Spanish Caucasian population. Medicine 2015;94: e2125. Kim SW, Lee JM, Ha JH, et al. Association between vitamin D receptor polymorphisms and osteoporosis in patients with COPD. Int J Chron Obstr Pulm Dis 2015;10:1809– 1817. Boskey AL, Donnelly E, Boskey E, et al. Examining the relationship between bone tissue composition, compositional heterogeneity and fragility fracture: a matched case controlled FTIRI study. J Bone Miner Res Epub 2015 Dec 4.
March 29, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Strong bones and restless legs: New data about bone remodeling in women with RLS Linda A. Hershey and Mehmet Akif Karan Neurology published online February 26, 2016 DOI 10.1212/WNL.0000000000002532 This information is current as of February 26, 2016 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2016/02/26/WNL.0000000000 002532.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Autonomic diseases http://www.neurology.org//cgi/collection/autonomic_diseases Endocrine http://www.neurology.org//cgi/collection/endocrine Restless legs syndrome http://www.neurology.org//cgi/collection/restless_legs_syndrome
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
EDITORIAL
Strong bones and restless legs New data about bone remodeling in women with RLS
Linda A. Hershey, MD, Disorders of bone metabolism are a common concern PhD for older women, since there are known associations Mehmet Akif Karan, MD among bone loss, sex, and age.1 Women with restless legs syndrome (RLS) who have not yet been treated with medication have signs of increased sympathetic Correspondence to nervous system activity.2 The autonomic nervous sysDr. Hershey: tem appears to be a major regulator of bone mineral [email protected] density (BMD) through signals sent to osteoblasts, and increased sympathetic activity is associated with Neurology® 2016;86:1–2 more osteoporosis in older women because of decreased osteoblast proliferation.3 These observations created a plausible hypothesis that there would be a higher incidence of osteopenia or osteoporosis in drug-naive women with RLS. In a new study reported in this issue of Neurology®, Cikrikcioglu et al.4 examined this relationship and found no evidence to support this hypothesis. In fact, they discovered the opposite result in their case-control study: an increase in lumbar BMD in 78 women with RLS, compared to 78 age-matched and body mass index (BMI)– matched controls. There was a positive bivariate correlation between duration of RLS and lumbar BMD. They also studied 2 markers of bone resorption, c-telopeptide of type 1 collagen (CTX) and sclerosin, and found lower levels in women with RLS. There were negative bivariate correlations between the severity of RLS and bone resorption markers. There are several strengths of this study. It was a prospective, cross-sectional examination of drugnaive women with RLS. Those who had mood disorders, neurodegenerative diseases, or medications to treat those disorders were excluded. Therefore, the patients with RLS who were studied had primary, not secondary, disease. Those who had thyroid problems, collagen diseases, chronic kidney disease, chronic lung disease, fractures, and bone prostheses were also excluded. Patients with RLS were matched with controls with respect to BMI. This is important, since body mass has a protective effect on osteoporosis and osteopenia.1 Process variables (CTX, sclerosin, and vitamin D3) were assessed in addition to the primary endpoint of BMD. Cikrikcioglu et al.4 also found vitamin D3 deficiency in slightly more of their patients with RLS
compared to age-matched controls, which is consistent with the observations of other recent studies. For example, Wali et al.5 have shown that vitamin D3 levels were low in 12 adults with RLS and that vitamin supplementation improved the median RLS severity score from 26 at baseline to 10 after the correction of vitamin D levels. Jimenez-Jimenez et al.6 analyzed a possible relationship between 2 vitamin D receptor polymorphisms and the risk for RLS. They discovered that patients with RLS carrying the rs731236G allele had an earlier age at onset of RLS and those with the rs731236GG allele had higher severity scores for RLS. Kim et al.7 recently recognized genetic variations in the vitamin D receptor in association with osteoporosis among patients with chronic lung disease. Since osteopenia and osteoporosis are conditions usually seen later in life, and fracture risk is agedependent,8 the inclusion of younger women in this study might complicate the analysis of the results (the age range was from 21 to 75 years). Another weakness of the study was the cross-sectional design, since this limits the possibility of making statements about causality. Nevertheless, this study is an important first step in the direction of our understanding the role of bone remodeling in women with RLS. STUDY FUNDING No targeted funding reported.
DISCLOSURE Dr. Hershey is a PI on a Forum study and is coinvestigator on an Alzheimer’s Association grant, an OU College of Nursing grant, an OU Norman Faculty Investment grant, an OUHSC VP for Research grant, and an OUHSC Presbyterian Health Foundation grant. She has received honoraria for educational presentations and for online publications. Dr. Karan reports no disclosures. Go to Neurology.org for full disclosures.
REFERENCES 1. Freitas PM, Garcia Rosa ML, Gomes AM, et al. Central and peripheral body fat mass have a protective effect on osteopenia or osteoporosis in adults and elderly. Osteoporos Int Epub 2015 Dec 9. 2. Cikrikcioglu MA, Hursitoglu M, Erkal H, et al. Oxidative stress and autonomic nervous system functions in restless legs syndrome. Eur J Clin Invest 2011;41:734–742. 3. Kajimura D, Hinoi E, Ferron M, et al. Genetic determination of the cellular basis of the sympathetic regulation of bone mass accrual. J Exp Med 2011;208:841–851.
See page XXX From the Department of Neurology (L.A.H.), University of Oklahoma Health Sciences Center, Oklahoma City; and Division of Geriatrics (M.A.K.), Istanbul Medical School, Capa, Turkey. © 2016 American Academy of Neurology
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
1
4.
5.
6.
2
Cikrikcioglu MA, Sekin Y, Halac G, et al. Reduced bone resorption and increased bone mineral density in women with restless legs syndrome. Neurology 2016; 86:xx–xx. Wali S, Shukr A, Boudal A, Alsaiari A, Krayem A. The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep Breath 2015;19:579–583. Jimenez-Jimenez FJ, Garcia-Martin E, Alonso-Navarro H, et al. Association between vitamin D receptor rs731236 (Taq1) polymorphism and risk for restless legs syndrome
Neurology 86
7.
8.
in Spanish Caucasian population. Medicine 2015;94: e2125. Kim SW, Lee JM, Ha JH, et al. Association between vitamin D receptor polymorphisms and osteoporosis in patients with COPD. Int J Chron Obstr Pulm Dis 2015;10:1809– 1817. Boskey AL, Donnelly E, Boskey E, et al. Examining the relationship between bone tissue composition, compositional heterogeneity and fragility fracture: a matched case controlled FTIRI study. J Bone Miner Res Epub 2015 Dec 4.
March 29, 2016
ª 2016 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Strong bones and restless legs: New data about bone remodeling in women with RLS Linda A. Hershey and Mehmet Akif Karan Neurology published online February 26, 2016 DOI 10.1212/WNL.0000000000002532 This information is current as of February 26, 2016 Updated Information & Services
including high resolution figures, can be found at: http://www.neurology.org/content/early/2016/02/26/WNL.0000000000 002532.full.html
Subspecialty Collections
This article, along with others on similar topics, appears in the following collection(s): Autonomic diseases http://www.neurology.org//cgi/collection/autonomic_diseases Endocrine http://www.neurology.org//cgi/collection/endocrine Restless legs syndrome http://www.neurology.org//cgi/collection/restless_legs_syndrome
Permissions & Licensing
Information about reproducing this article in parts (figures,tables) or in its entirety can be found online at: http://www.neurology.org/misc/about.xhtml#permissions
Reprints
Information about ordering reprints can be found online: http://www.neurology.org/misc/addir.xhtml#reprintsus
Neurology ® is the official journal of the American Academy of Neurology. Published continuously since 1951, it is now a weekly with 48 issues per year. Copyright © 2016 American Academy of Neurology. All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.
