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March 29, 2016; 86 (13) Article

Reduced bone resorption and increased bone mineral density in women with restless legs syndrome

Mehmet Ali Cikrikcioglu, Yahya Sekin, Gulistan Halac, Elif Kilic, Siddika Kesgin, Senay Aydin, Nihal Ozaras, Onur Akan, Kenan Celik, Jamshid Hamdard, Mehmet Zorlu, Cumali Karatoprak, Mustafa Cakirca, Muharrem Kiskac
First published February 26, 2016, DOI: https://doi.org/10.1212/WNL.0000000000002521
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Abstract

Objective: To investigate bone resorption and formation markers as well as bone mineral density in women with restless legs syndrome (RLS).

Methods: This was a prospective cross-sectional case-control study involving drug-naive women with RLS and age- and body mass index (BMI)–matched female controls. Routine blood analyses, markers of bone formation, procollagen 1 n-terminal peptide, bone resorption, c-telopeptide of type 1 collagen (CTX), sclerostin, and bone mineral density (BMD) were compared between the 2 groups. Pregnant or breastfeeding women and individuals with comorbidities other than iron deficiency, type 2 diabetes mellitus, or hypertension were excluded.

Results: A significant increase in lumbar BMD was found among 78 women with RLS as compared to 78 age- and BMI-matched controls (p = 0.001). The proportion of patients with osteopenia as defined by a lumbar T score was significantly lower among patients with RLS (p = 0.040). CTX and sclerostin were significantly lower in patients with RLS (p = 0.006 and p = 0.011, respectively), as were the levels of 25-hydroxy vitamin D3, calcemia, and free T3 (p = 0.017, p = 0.017, and p = 0.002, respectively).

Conclusions: Despite lower 25-hydroxy vitamin D3, patients with RLS had lower bone resorption markers, higher lumbar BMD, and lower frequency of lumbar osteopenia. As patients with RLS make movements night and day to decrease the severity of their symptoms, they unconsciously perform exercise, which may potentially explain the better bone profile among patients with RLS than in controls.

GLOSSARY

BMD=
bone mineral density;
BMI=
body mass index;
CBC=
complete blood count;
CTX=
C-telopeptide of type 1 collagen;
IRLSSG=
International Restless Legs Syndrome Study Group;
PINP=
procollagen 1 N-terminal peptide;
RLS=
restless legs syndrome

Restless legs syndrome (RLS) is a sensory-motor disorder characterized by intense, unpleasant, and disagreeable sensations (paresthesia and dysesthesia) in the extremities (mostly in the legs) that tend to begin or worsen in the evening or at night during periods of rest and are relieved by movement.1 It affects nearly 5%–15% of adults.1 An increase in sympathetic nervous system activity as well as increased nocturnal urinary cortisol excretion have been reported in patients with RLS when compared with controls.2,3 Both cortisol and sympathetic nervous system are known to negatively affect bone metabolism.4,5 To our knowledge, no previous studies have examined bone resorption and formation markers and bone mineral density in patients with RLS. Thus, we analyzed telopeptide of type 1 collagen (CTX) and sclerostin (markers of bone resorption), procollagen 1 N-terminal peptide (PINP) (a marker of bone formation), and bone mineral density (BMD) in patients with RLS.6

METHODS

Study design and study population.

The study was designed as a prospective, cross-sectional, case-control study. Female patients with drug-naive idiopathic RLS consecutively admitted to The Neurology Clinic of Bezmialem Vakif University between April 2014 and March 2015 were enrolled in this study if they met the inclusion/exclusion criteria and provided written informed consent for this study. Similarly, age and body mass index (BMI)–matched women successively attending the internal medicine outpatient department during the same time period served as controls if they met the inclusion and exclusion criteria in addition to providing written informed consent.

Inclusion criteria.

Drug-naive (i.e., no previous use of iron, dopamine agonists, opioids, or antiepileptics) female patients with RLS between 18 and 75 years of age meeting the 4 diagnostic criteria proposed by the International Restless Legs Syndrome Study Group (IRLSSG) and diagnosed with RLS with or without iron deficiency anemia comprised the patient group.7 The control group consisted of RLS-free women, with or without iron deficiency anemia.

Exclusion criteria.

Exclusion criteria included the following conditions: pregnancy, lactation, chronic kidney disease ≥ stage 3, diagnosis of mood disorder or psychosis, use of antidepressant or antipsychotic drugs or lithium, antiepileptic or opioid or dopaminergic drug use, alcoholism, drug addiction, hypophyseal dysfunction, thyroid dysfunction, primary parathyroid dysfunction, adrenal dysfunction, use of oral contraceptives, postmenopausal hormone replacement therapy, being bedridden, presence of bone prosthesis or orthosis, major surgical intervention, history of bone fracture, chronic and acute infections, cerebrovascular accident, ischemic heart disease, heart failure, chronic obstructive lung disease, asthma, obstructive sleep apnea syndrome, malabsorption syndromes, dementia, Parkinson disease, multiple sclerosis, inflammatory bowel disease, collagen tissue disorders, sarcoidosis, chronic hepatitis, portal hypertension, chronic corticosteroid and immunosuppressive therapy, hemolytic anemias, hematologic malignancy, and solid tumors.

Blood sampling and analysis.

Venous blood sampling was carried out in the early morning hours after overnight fasting. On the same day, complete blood count (CBC), biochemistry, 25-hydroxy vitamin D3, parathyroid hormone, ferritin, and thyroid hormone analyses were performed. For ELISA assay, venous blood samples were left for 20 minutes to allow clotting and then centrifuged at 1,500 g for 15 minutes. The sera were stored at −80°C for 12 months and thawed at room temperature at the day of analysis. CBC analysis was done with Sysmex XT 1800i apparatus (Roche, Kobe, Japan). Biochemical analyses were carried out using a COBAS 8000 apparatus (Roche, Tokyo, Japan) and COBAS-C system kits. The 25-hydroxy vitamin D3 analysis was carried out with COBAS E 601 hormone analyzer (Roche) using Roche kits (Mannheim, Germany). Thyroid hormone levels were analyzed with Advia (Tarrytown, NY) Centaur kit, and parathormone levels were analyzed with intact parathormone kit (Bayswater, Victoria, Australia). Ferritin levels were analyzed with ferritin kits (Bayswater) using an Advia (Dublin, Ireland) Centaur device. The serum concentrations of human PINP were measured with ELISA kit, according to protocols provided by the manufacturers (Human PINP ELISA kit, ref no.: DZE201121351; lot no.: 201410; Sunred Biological Technology, Shanghai, China). Serum concentrations of human CTX were measured with ELISA kit, according to protocols provided by the manufacturers (Human CTX-1 ELISA kit, ref no.: DZE201121350; lot no.: 201410; Sunred Biological Technology). Serum concentrations of human sclerostin were measured with ELISA kit, in line with the manufacturer's recommended protocols (Human SOST Elisa Kit, ref no.: DZE201125418; lot no.: 201503; Sunred Biological Technology). Multiskan FC Microplate Photometer (Thermo Fisher Scientific, Waltham, MA) was used for reading at 450 nm. The ELISA results were expressed in ng/mL.

Measurement of BMD.

BMD was measured at L1-L4 lumbar vertebra and in left proximal femur using dual energy x-ray absorptiometry technique with a DPX–Lunar trademark device (General Electric Healthcare, Cleveland, OH).

Patient assessments.

Medical history and family history were obtained from each person enrolled in the study. The time before the patient had been diagnosed with RLS or the period in which each patient had RLS without any treatment was questioned (duration of disease). The severity of RLS symptoms was determined via the John Hopkins RLS Severity Scale and the RLS Severity Scale, which was developed by the IRLSSG.8,9 Smoking status, age at menarche, menopause status (spontaneous or surgical menopause, age at menopause), number of miscarriages or curettages, duration of breastfeeding, number of births, monthly income of family, education status, employment status (employed vs not employed), and status of retirement were determined. A systemic physical examination was performed in each study participant. Regular use of medications and comorbidities were recorded. Also, arterial blood pressure was measured in all subjects from the right arm using a mechanical sphygmomanometer after 15 minutes of rest in the early morning hours, i.e., before blood samples were obtained. BMI was calculated using the following formula: BMI = body weight (kg)/height × height (m).

Statistical methods.

Numerical variables were presented as means with standard deviation, and nominal variables were presented as ratios. Participants of the study were divided into RLS and control groups. Nominal independent variables were compared between the groups using the χ2 test. One-sample Kolmogorov-Smirnov test was performed to determine if the continuous (numerical) independent variables were normally distributed or not. In comparison of groups, independent continuous variables with normal distribution were compared with Student t test, whereas independent continuous variables without normal distribution were compared with Mann-Whitney U test. Bivariate correlations were sought and linear regression analysis was also performed. Power calculations for the study were performed after completion of study procedures. A 2-tailed p value of <0.05 was considered to be statistically significant.

Standard protocol approvals, registrations, and patient consents.

The study was approved by Bezmialem Vakif University Medical Faculty Ethics Committee, and all participants recruited to the study gave informed consent. The study was performed in accordance with the 2009 Helsinki Declaration.

RESULTS

There were 78 female patients with RLS and 78 female controls in the study. The mean age was 45.7 ± 11.7 years (range 21–75). The mean BMI was 28.6 ± 4.5 kg/m2 (range 19.6–40). The 2 groups were similar in terms of age and BMI (table 1).

View this table:
Table 1

Comparison of groups in terms of demographic variables, blood pressure, RLS severity score, and disease duration

The age at menarche, proportion of individuals at menopause, age at menopause, frequency of surgical menopause, number of births, number of miscarriages or curettages, and total duration of breastfeeding were comparable across the 2 groups (tables 1 and 2).

View this table:
Table 2

Demographic features, medicine regularly used, RLS severity, vitamin D, and t score status among the participants of the study

The 2 groups were similar in terms of monthly family income, education status, employment status (employed vs not employed), and retirement status (tables 1 and 2).

There were no significant differences between groups in terms of the proportion of cigarette smokers and ex-smokers, blood pressures, occurrence of hypertension or diabetes, HbA1C and fasting blood glucose levels, and regular use of medications (tables 1–3).

View this table:
Table 3

Rutin blood analysis results, bone biomarkers, and bone mineral density findings in both groups

Patients with RLS had significantly lower blood calcium, 25-hydroxy vitamin D3, sclerostin, and CTX and higher lumbar BMD than controls (table 3). PINP and femur BMD were comparable between the 2 groups (table 3).

Significant deficiency of 25-hydroxy vitamin D3 was detected in 83% of the overall study population (table 2). Although more patients in the RLS group had 25-hydroxy vitamin D3 deficiency, the difference was not significant (table 2).

There were significantly fewer individuals with osteopenia, as reflected by the lumbar T scores, among patients with RLS (table 2). A similar number of individuals in both groups had osteoporosis according to lumbar and femoral T scores, and a similar number of individuals in both groups had osteopenia according to the femoral T score (table 2).

Thyroid-stimulating hormone and FT4 were similar in the study groups, although FT3 was significantly lower in the RLS group (table 3).

No significant differences could be detected between the 2 groups with respect to the results of other routine blood analyses (table 3).

According to Johns Hopkins RLS severity criteria, mild or moderate severity was present in 75% of the patients, while the patient group consisted of participants with moderately severe RLS with regard to IRLSSG RLS severity score (tables 1 and 2). The mean duration of disease was 45 ± 44.5 months (range 8–360 months).

There was a negative bivariate correlation between IRLSSG severity score and calcemia, between IRLSSG severity score and CTX, and between IRLSSG severity score and sclerostin (r = −0.173, p = 0.029; r = −0.244, p = 0.002; and r = −0.271, p = 0.010, respectively). There was a positive bivariate correlation between IRLSSG severity score and lumbar BMD (r = 0.214, p = 0.007). A negative bivariate correlation between the duration of disease and CTX, between the duration of disease and sclerostin, and between the duration of disease and calcemia (r = −0.185, p = 0.020; r = −0.171, p = 0.050; and r = −0.190, p = 0.016, respectively) was observed. There was positive bivariate correlation between the duration of disease and lumbar BMD (r = 0.190, p = 0.018).

In linear regression analysis, while there was no correlation between the dependent variable, i.e., lumbar BMD, and the independent variables, i.e., age at menarche, number of births, number of miscarriages or curettage, duration of breastfeeding, employment status (employed vs not employed), cigarette smoking, calcemia, phosphatemia, creatinine, albumin, 25-hydroxy vitamin D3, transferrin saturation rate, duration of disease, and IRLSSG severity score, a significant correlation between the dependent variable, i.e., lumbar BMD, and the independent variables, i.e., presence of RLS, presence of menopause, BMI, and monthly family income, was found (table 4).

View this table:
Table 4

Linear regression analysis (dependent variable was lumbar bone mineral density)

In linear regression analysis, no correlation between the dependent variable, i.e., calcemia, and the independent variables, i.e., creatinine, 25-hydroxy vitamin D3 level, C-reactive protein, HbA1c, duration of disease, IRLSSG RLS severity score, number of births, number of miscarriages or curettage, and duration of breastfeeding, could be detected. On the other hand, there was significant correlation between the dependent variable, i.e., calcemia, and the independent variables, including serum phosphorus, presence of RLS, and presence of menopause (table 5).

View this table:
Table 5

Linear regression analysis (dependent variable was calcemia)

The estimated statistical power of the study was 100% based on the Student t test used to compare the BMD between patients and controls.

DISCUSSION

Bone resorption markers (sclerostin and CTX) were lower, BMD was higher, and proportion of individuals with osteopenia was lower among patients with RLS in our study. This was contrary to our hypothesis at the outset of the study, since sympathetic activity is associated with the activation of osteoclasts and inhibition of osteoblasts, and since excessive cortisol is known to induce osteoporosis.4,5

Movement, walking, mental work, and excitement during the day transiently decrease or eliminate RLS symptoms in patients with RLS.2 These physical and mental activities increase sympathetic activity,10,11 with a resultant increase in cortisol release. Cortisol further increases the sympathetic nervous system activation by positive feedback.2 This increased sympathetic activity and cortisol release might exert positive effects on dopaminergic activity in brain.2 Functional dopamine deficiency in patients with RLS might transiently be alleviated and RLS symptoms might transiently disappear through this mechanism.2 This may form the basis of the observed increase in the level of physical or mental activities in patients with RLS that may occur knowingly or unknowingly.2 Studies examining the heart rate variability in these patients also demonstrated increased sympathetic nervous system activity.2 The exact mechanisms responsible for the increase in the severity of RLS symptoms during night hours remain unidentified.2 In humans, the circadian rhythm of cortisol secretion is paralleled with that of dopamine,2 which is reversed in RLS symptomatology.2 One potential explanation for physiologically decreased nocturnal dopamine secretion involves the decreased cortisol release and increased parasympathetic nervous system activation,2 in association with increased RLS symptoms at night.2 Patients with RLS have a disposition for continuously moving in bed and striking their legs against the bed in an effort to get rid of RLS symptoms until early morning hours, i.e., at the time of peak cortisol levels.2 On the other hand, such aberrations might disturb circadian rhythm of cortisol secretion and impair autonomic nervous system functions through decreased parasympathetic activity and increased nocturnal cortisol secretion. Previously, low-dose corticosteroid infusions have been reported to decrease nocturnal RLS symptoms.12 Recently, it has been demonstrated that patients with RLS have higher urinary cortisol excretion throughout the night when compared with a control group.3 The better bone findings in our patients with RLS than in controls may be accounted for by the increased physical activity in the night and morning hours that may serve as a form of unintended exercise. Although this increased motility augments sympathetic activity and cortisol release, it may also produce positive effects on bone due to an exercise effect.13,14

Sclerostin is a molecule released from osteocytes that has negative effects on bone formation.14 It has been demonstrated that sclerostin decreases with exercise and in parallel to this, bone formation increases.14 Lower serum sclerostin levels in women with RLS might support the notion that increased motility is responsible for the positive bone metabolism.

In the current study, although bone resorption markers (i.e., CTX and sclerostin) were lower and lumbar BMD was higher in patients with RLS, bone formation markers (PINP) and BMD at the femur neck were similar to those in the controls. The cycle of bone resorption and formation occurs in the trabecular bone, which constitutes a higher proportion of the total bone mass in the vertebrae as compared to other bones of the body, leading to a more rapid bone turnover in this anatomical site.15,16 The fact that most of our patients had RLS of moderate severity with relatively short disease duration may explain lower levels of bone resorption markers and higher lumber vertebral BMD in our study. Probably, more severe RLS symptoms and longer duration of disease would have led to higher femoral neck BMD and bone formation markers (PINP) among patients with RLS than among controls.

Certain bivariate correlations observed in the current study are consistent with the findings of decreased bone resorption and increased lumbar BMD in patients with RLS. The longer duration of disease and higher severity of RLS symptoms were associated with higher lumbar BMD and lower serum sclerostin and CTX levels.

Calcemia was lower in female participants with RLS. The 25-hydroxy vitamin D3 level was also lower in patients with RLS. In linear regression analysis, while calcemia was not correlated with 25-hydroxy vitamin D3 level, it was found to be correlated with serum phosphorus (could reflect the nutritional status), presence of RLS, and presence of menopause. As the severity of RLS and duration of disease increased, calcemia became lower. The lower calcium levels in the RLS group might be related to increased physical activity in RLS. Turgut et al.17 previously reported lower ionized calcium levels in sportsmen than in sedentary individuals. Since immobility is associated with the development of hypercalcemia, increased activity level might lead to lower calcium levels in patients with RLS.18 However, it should also be noted that in contrast with studies suggesting decreased calcemia levels with exercise, others found increased calcemia as a result of physical activity.17,19,–,21

Interestingly, despite lower serum 25-hydroxy vitamin D3, patients with RLS had higher lumbar BMD, contrary to what might be expected: i.e., lower 25-hydroxy vitamin D3 should be associated with lower BMD. The bone mass and the amount of mineralization in bone matrix are among the determinants of BMD. Although mineralization of bone matrix was lower in patients with RLS, higher lumbar BMD might have resulted from a higher bone mass. Also in a previous study, lower 25-hydroxy vitamin D3 levels were demonstrated in patients with RLS than the controls.22

In our study, although FT3 was within the normal range in the RLS group, it was significantly lower than in the control group. Increased physical and sympatho-adrenal activity might produce low FT3.23,–,25

In linear regression analysis, in addition to the already established risk factors associated with osteoporosis such as BMI, age, monthly family income, and presence of menopause, we also explored other independent variables such as the presence of RLS, duration of disease, and RLS severity score. Consequently, the independent variable of lumbar vertebral BMD was found to be associated with presence of menopause, monthly family income, BMI, and the presence of RLS.

One of the limitations of the current study is the absence of BMD measurements in upper extremities, tibia, and calcaneus. Patients with RLS exhibit increased mobility especially in the form of walking, rotation in bed, and beating the legs to the bed. Performing BMD measurements at the above-mentioned anatomical sites could have provided additional support for our conclusions.

Better bone findings were found among patients with RLS in our study. The unintended increase in the physical activity level of patients with RLS in the day and night hours could be responsible for the observed positive effects on bone.

AUTHOR CONTRIBUTIONS

Dr. Cikrikcioglu, Dr. Ozaras, Dr. Halac: study concept and design, statistical analysis, final approval of participants to include in the study, writing of the manuscript. Dr. Sekin, Dr. Aydin, Dr. Akan, Dr. Celik, Dr. Zorlu, Dr. Kiskac, Dr. Cakirca, Dr. Hamdard: screening, evaluation, and examination of participants to recruit to study. Dr. Kilic, Dr. Kesgin: ELISA analyzing, blood sampling and storing supervision, contribution to discussion. Dr. Karatoprak: important contribution to discussion.

STUDY FUNDING

Supported by BAP (scientific research support fund of Bezmialem Vakif University).

DISCLOSURE

The authors report no disclosures relevant to the manuscript. Go to Neurology.org for full disclosures.

Footnotes

  • Go to Neurology.org for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

  • Editorial, page 1179

  • Received July 20, 2015.
  • Accepted in final form November 25, 2015.

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