Hippokratia 2013, 17(1):7-11
Medical Department, Rehabilitation Center Amyntaio, General Hospital of Florina, Greece
Multiple sclerosis affects central nervous system leading to disability. Among other complications the deterioration of body composition is usually neglected and increases the risk for diseases such as coronary heart disease, non-insulin dependent diabetes mellitus, lipid abnormalities and bone loss leading to fractures in this population. Body mass index values, the effect of spasticity, the increased number of drugs used and the relationship between skeletal muscle and bone which interacts with impaired motor function leading to body composition alterations in multiple sclerosis are reviewed.
Keywords: Multiple sclerosis, body composition, bone, muscle, fat, rehabilitation
Corresponding author: Yannis Dionyssiotis, MD, PhD, Amyntaio, 53200, Florina, Greece, tel: +302386350312, +306946469759, e-mail: email@example.com
Multiple sclerosis (MS) leads to muscle weakness, co-ordination and balance problems, as well as sensation disorders, visual and cognitive deficits and gradual limitation of functioning1. All these disability conditions lead further to immobilisation associated with profound changes in body composition. The potential risks involved in these changes i.e. loss of lean tissue mass (LM) and bone mineral density (BMD) vs. gain in fat mass (FM) in body composition have implications for the health of the disabled individuals2.
Body fat has been identified as a significant predictor of mortality in humans making body composition measurement to quantify nutritional and health status an important issue for human health3-5. Moreover, some disorders such as carbohydrate intolerance, insulin resistance, lipid abnormalities, and heart disease occur prematurely and at a higher prevalence in disabled populations and may be related to adverse changes in body composition that result from immobilization and skeletal muscle denervation6.
Generally, among lesions of the central nervous system (CNS) there are differences on the evolution or not of the disease (i.e. progressive multiple sclerosis vs. complete paraplegia), the type of injury (i.e. spinal lesion with a level of injury vs. upper motor neuron lesion), life expectancy, the residual mobility and functionality, the ability to walk and stand (i.e. incomplete paraplegia-paraparesis vs. quadriplegia-tetraparesis) and drug treatment (i.e. frequent corticosteroid therapy in multiple sclerosis vs. long-term therapy with anticoagulants in paraplegia). In addition, there are differences in the degree of spasticity which is likely to play a regulatory role in maintaining bone density7,8. Moreover, another issue is the element of fatigue and muscle weakness in disabilities, especially in diseases like multiple sclerosis, which significantly reduces the mobility of these patients9.
There is an inverse relationship between activity levels in disabled subjects depending on the degree of mobility impairment leading to reduced physical activity10. This is the case in MS: the reduced activity need to be accompanied by a reduction in energy intake otherwise body fat will increase11. Individuals with MS were reported to have a poor exercise tolerance, which was related to an increased energy cost when exercising on a treadmill, depending mainly on spasticity12. In individuals with MS who walked at their own preferred walking speed using assistive devices although functional electrical stimulation reduced the metabolic energy cost of walking, the cost remained significantly greater compared to that of controls13. Conversely, others found that the energy cost was not increased14 and oxygen costs did not differ in persons with MS and mild disability from healthy subjects during a graded exercise on a cycle ergometer15. Recently published data are showing that the energy cost of self-paced walking in mildly disabled individuals with MS was higher, inversely related to the walking speed and directly related to the degree of disability, than that of control subjects16.
The relative difference in energy expenditure between individuals with multiple sclerosis (MS) and able-bodied subjects is probably lower than the relative difference in physical activity, because individuals with MS have a higher energy expenditure of physical activity10.
Subjects with those motor disorders often face problems of depression and limit mobility17. The dependency on mobility devices, common in all disabilities, and the frequent periods of immobilization after multiple operative procedures contribute to the hypoactivity status of such subjects. It could be assumed that, under these conditions, body composition may be significantly compromised18.
On the other hand the clinical manifestations of a disease such as MS could be variable; i.e. a severe form of MS can result in a wheelchair bound patient vs. patient with a more appropriate walking gait pattern vs. patient unable to walk at all and most of the time of the day bedridden19,20.
Therefore, the purpose of this review is to present body composition alterations of ambulatory and non-ambulatory subjects with MS.
Body composition alterations in multiple sclerosis
In patients with MS not many studies investigated body mass index (BMI), which is a person’s weight in kilograms divided by his height in meters squared. Nevertheless, BMI was found statistically less as to age comparable controls21. Both total body fat and mass percent showed consistent significant dependence on BMI, as among normal subjects. Multiple linear regression analysis of bone mineral percent at all studied sites showed consistent dependence on BMI (increased with higher BMI) for both MS and control subjects22.Recently, a Swedish population-based case-control study which investigated subjects’ BMIs regarding MS risk found that subjects whose BMI exceeded 27 kg/m2 at age 20 had a two-fold increased risk of developing MS compared with normal weight subjects. This result suggests a connective link between the obesity and the increasing MS incidence as recorded in some countries23. In line with these results another study found that obesity at age 18 (BMI>30 kg/m2) was associated with a greater than twofold increased risk of MS in women24.
In disabled conditions, the accuracy of skeletal muscle measured by DXA may be compromised when muscle atrophy is present. A lower ratio of muscle to adipose-tissue-free mass indicates a lower proportion of muscle in the fat-free soft tissue mass14.This is confirmed from studies in spinal cord injured (SCI) subjects: cross sectional area of skeletal muscle in the thighs after SCI is extensively reduced25. If this is the case, muscle mass would be overestimated by prediction models that assume that muscle represents all or a certain proportion of the fat-free soft tissue mass, i.e. in spinal cord injured subjects26.
No significant difference between ambulatory MS patients and non MS controls in body composition was found despite lower physical activity in ambulatory MS patients11. In MS subjects, there was no significant relation between any of the body composition measures and the level of disability as measured by the Expanded Disability Status Scale (EDSS), a method of quantifying disability in MS27. Others found no difference in body fat percent between ambulatory MS patients and lower physical activity in ambulatory MS patients vs. controls21,28. A possible explanation for the similar body composition may be lower energy intake in MS individuals who are ambulatory and greater energy cost of physical activity (walking) in MS than it is with non MS controls11.
A significant inverse relation between free fat mass (FFM) and EDSS score when ambulatory and non ambulatory MS subjects were combined was found21. On the contrary, when only ambulatory subjects were included no significant inverse relation between FFM percent and EDSS score was found11. It would seem apparent that non ambulatory patients with MS and controls would strengthen the inverse relation between FFM and EDSS score. In ambulatory MS subjects the finding of no relation between EDSS score and body fat percent was also explained in the study of Sioka et al which showed that ambulatory patients with MS had similar body composition compared with control individuals in respect to fat and lean mass, except in the lower extremities of female patients, where increased percentage of fat and reduced lean mass was found. According to the authors, a possible etiology for the gender difference observed includes the generally work related increased habitual mobility of male compared with female patients22. Moreover, studies suggested that worsening of MS symptoms was associated with significantly and moderately lower levels of self-reported physical activity independent of EDSS scores29. All these findings suggest that the level of disability in ambulatory individuals with MS does not predict body composition because MS would likely have a much greater effect on physical activity than on energy intake. This suggests that a significant level of disability does not force these individuals to be physically inactive and does not result in a greater body fat content. On the other side, there is inconsistent evidence of an inverse association between the neurological factor and cardio respiratory fitness in the MS population. According to Motl and Goldman the researchers have not examined the possibility that neurological disability is associated with cardio respiratory fitness independently of physical activity. This is important as physical inactivity has been associated with neurological disability in persons with MS30.
There are many detrimental manifestations of excess body fat, such as hyperlipidemia, insulin resistance, and type II diabetes11. The largest component of FFM is muscle mass31. If muscle mass is lower in individuals with MS than in controls, this might explain the impaired ability to ambulate and perform other activities of daily living. Muscle fiber size from biopsy specimens of the tibialis anterior was 26% smaller than that from specimens of control subjects32. Thus, at least for this small muscle, muscle mass was lower in MS. This relationship may not hold true for other muscle groups or for whole-body muscle mass11.
Another reason for skeletal muscle alterations is glucocorticoid usage. The prolonged duration of of glucocorticoid use causes catabolism of skeletal muscle. Decreased amino acid transport into muscle and increased glutamine synthesis with resultant muscle atrophy are some of the concomitant effects of glucocorticoid use on skeletal muscle. Endogenous glucocorticoid excess also produces generalized osteoporosis, most prevalent in trabecular-rich skeletal regions21.
Beside corticosteroids, immunomodulatory, antiepileptic and antidepressant drugs usually used in individuals with MS, high incidence of vitamin D deficiency, molecular mechanisms and disuse-loss of mechanical stimuli in bone all have an impact on bone integrity (most believe that immobilization of these patients is a minor factor in the etiology of osteoporosis as compared to the remaining factors)17.
Subjects with MS have multiple risk factors for osteoporosis, a disease characterized by low bone mass and destruction of the microarchitecture of bone tissue, resulting in increased bone fragility and susceptibility to fractures33. Although, there are several studies of bone mass in women with multiple sclerosis, higher rates of osteopenia and osteoporosis have been reported in women with spina bifida or spinal cord injury with lower T-scores compared to women with other types of disability. The finding that women with serious disabilities have low bone density is not surprising and is probably related to the lack of activity (reduced mobility, reduced loading on bone) and worsening of the disability34.
There is a high incidence of vitamin D deficiency in MS patients and is determined by levels of 25-hydroxy vitamin D <20ng/ml35. The reasons might be due to a combination of low dietary vitamin D intake and avoidance of sun exposure, because MS symptoms may worsen resulting from fatigue upon heat exposure in these patients.
Reduced mobility has been implicated as an important factor in bone loss in patients suffering from multiple sclerosis (MS) and it seems to greatly influence the BMD of the femur36,37. Immobilization due to motor paralysis caused by lesion of the central nervous system contributes to bone changes which are: (a) the lack of the normal load applied to bone in the upright position and (b) the reduced number and intensity of muscle contractions. A severe form of MS can result in a wheelchair bound patient a clinical manifestation equivalent to paraplegia but another MS patient may have an appropriate walking gait pattern (i.e. using ankle foot orthosis) or may also be bedridden19. However, the high proportion of ambulatory patients with bone loss suggests additional non-mechanical factors38. So far, spasticity is considered by many researchers, to play a regulatory role in maintaining bone density7. Only one MS study assessed the relation of spasticity and bone strength, measured by quantitative ultrasound of cortical bone, using tibial speed of sound (SOS, m/sec) parameter at midpoint of the tibial shaft and found preserved bone strength in MS patients and increased SOS related to spasticity in a subgroup of female patients39.
Low testosterone alone in these populations does not explain bone loss and no clear impact of smoking or alcohol abuse on decreased bone mass could be established40. Molecular mechanisms could also be the case in inflammatory or autoimmune disorders like MS: receptor activator of nuclear factor kappa B ligand (RANKL) stimulates osteoclastogenesis and the same do cytokines, such as TNF-α, IL-1, or IL-11, all produced by T-cells activation, leading to bone destruction. On the contrary, osteoprotegerin (OPG) is an osteoclastogenesis inhibitory factor preventing the function from RANKL. In MS this system is disturbed in favour of RANKL41,42. The effects of immunomodulatory therapy (IMT) on bone mineral density (BMD) measured by dual energy X-ray absorptiometry (DXA) in patients with MS who received different IMTs (interferon beta-1a, interferon beta-1b, and Glatiramer in 3% combined with high-dose pulse corticosteroid therapy) suggested that IMT may have a protective effect on bone in patients with MS even in the presence of pulse steroid therapy43. The RANK-RANKL interaction plays an important role in bone remodelling and immune function and mammary gland development. There is a link between bone turnover regulation and inflammatory immune cells in conjunction with various cytokines and hormones which induces endogenous interferon beta (IFN-beta) and osteoclastogenesis via induction of the c-fos gene 44,45. The bond of IFN-beta to its biological receptor causes finally an inhibition of c-fos protein production and osteoclast proliferation and differentiation46.
Glucocorticoid (GC)-induced osteoporosis (OP-GC) is the main type of secondary osteoporosis47-52. The mechanisms of GCs action in bone has been studied extensively. Prolonged treatment with glucocorticoids results in increased risk of fractures, evident at 3 months, regardless of changes in BMD. High dose, short-term i.v. treatment with GCs leads directly to reduction of bone formation and increased bone resorption, as indicated by markers of bone turnover53,54. In the study of Zorzon et al, osteopenia was found especially in MS women who received high dose methylprednisolone pulses (HDMP) in relapses period55. On the contrary, another study disputed the aforementioned result. This study, investigating the effect of intravenous (i.v.) administration of glucocorticoids in MS patients, found no clear effect on bone loss: besides, they reported an increase in BMD of the lumbar spine51.
Moreover, with the use of enzyme-inducing antiepileptic drugs (AEDs) bone loss is accelerated by the metabolism of vitamin D3 leading to decreased calcium absorption, secondary hyperparathyroidism, greater bone resorption, and a continuous negative feedback.
Studies support a relationship between selective serotonin reuptake inhibitors (SSRI) use in depression and lower BMD/change in BMD both in cross-sectional and longitudinal analyses56.
Other important issues determining the alterations of body composition are the completeness of lesions (an absence of sensory or motor function below the neurological level, including the lowest sacral segment), because body composition seems to be better in subjects with incomplete lesions (partial preservation of motor and/or sensory function below the neurological level, including the lowest sacral segment) i.e. in MS most subjects having a clinical outcome equivalent to incomplete tetraplegia or paraplegia and aging which contributes to major detrimental alterations of body composition57-59.
Dietary changes, individualized physical activity programs and medication should be taken into account in therapy when we deal with this subgroup of subjects. However, self-management of dietary changes to improve weight control and disease should be the case, which means that the patients need to follow diets with lower energy intake and at the same time to eat regularly foods rich in nutrients60.
We need to keep in mind that healthy BMI values often underestimate body fat and may mask the adiposity, and spasticity did not defend skeletal muscle mass and bone, supporting the concept that in neurologic disabilities, the myopathic muscle could not recognize correctly the stimulation because of the neurogenic injury.8 The relationship between skeletal muscle and impaired motor function in MS subjects remains still unclear. According to Kent-Braun et al, it seems that chronically reduced maximum discharge rates and altered or incomplete motor unit activation may induce changes in skeletal muscle characteristics33.
Moreover, disabled subjects mostly transfer much of the weight-bearing demands of daily activities to their upper extremities reducing the weight-bearing of the affected paralyzed muscles triggering a cycle of added muscle atrophy which interacts with the continuous catabolic action caused by the neurogenic factor.
Although the ranking system of the World Health Organization (WHO) created for postmenopausal osteoporosis focused mainly on healthy people, most authors classify disabled subjects according to the WHO criteria. At the same time, despite the increased number of risk factors in people with multiple sclerosis there aren’t guidelines on the BMD measurements. An explanation about the problem of terminology according bone loss was given in a recently published paper for SCI 17: “bone loss” is probably not specific enough, and might imply that the change in bone status is being recorded over time, while “osteoporosis” below the level of injury must be used with caution, especially in quadriplegia, paraplegia and/or equivalent diseases, a concept supported by the maintenance of bone in the spine in regions below the level of the lesion because of weight bearing in the seated position (i.e. in a wheelchair), and compressive stress of the fusion materials used following injury in the injured area (i.e. in traumatic paraplegia).
Further research about body composition in MS is needed and more longitudinal studies to quantitate and monitor body composition changes and to modify our therapeutic interventions. The most important issue related to body composition is how to promote optimal body weight to reduce risk of diseases such as coronary heart disease, non-insulin dependent diabetes mellitus, lipid abnormalities and fractures because of bone loss.
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article.
Conflict of Interest
There was no conflict of interest related to this manuscript.
1. Rietberg MB, Brooks D, Uitdehaag BMJ, Kwakkel G. Exercise therapy for multiple sclerosis. Cochrane Database Syst Rev. 2005: CD003980.
2. Jones LM, Goulding A, Gerrard DF. DEXA: a practical and accurate tool to demonstrate total and regional bone loss, lean tissue loss and fat mass gain in paraplegia. Spinal Cord. 1998; 36: 637-640.
3. Bender R, Trautner C, Spraul M, Berger M. Assessment of excess mortality in obesity. Am J Epidemiol. 1998; 147: 42-48.
4. Seidell JC, Verschuren WM, van Leer EM, Kromhout D. Overweight, underweight, and mortality. A prospective study of 48.287 men and women. Arch Intern Med. 1996; 156: 958-963.
5. Van Der Ploeg GE, Withers RT, Laforgia J. Percent body fat via DEXA: comparison with a four-compartment model. J Appl Physiol. 2003; 94: 499-506.
6. Spungen AM, Adkins RH, Stewart CA, Wang J, Pierson RN Jr, Waters RL et al. Factors influencing body composition in persons with spinal cord injury: a cross-sectional study. J Appl Physiol. 2003; 95: 2398–2407.
7. Dionyssiotis Y, Lyritis GP, Mavrogenis AF, Papagelopoulos PJ. Factors influencing bone loss in paraplegia. Hippokratia. 2011; 15: 54-59.
8. DionyssiotisY. Body Composition in Disabilities of Central Nervous System. El Maghraoui A (ed), Dual Energy X-Ray Absorptiometry, InTech, Rijeka, 2012, 75-94.
9. Krupp LB, Serafin DJ, Christodoulou C. Multiple sclerosis-associated fatigue. Expert Rev Neurother. 2010; 10: 1437-1447.
10. Rimmer JH, Riley B, Wang E, Rauworth A, Jurkowski J. Physical activity participation among persons with disabilities: barriers and facilitators. Am J Prev Med. 2004; 26: 419-425.
11. Lambert CP, Lee Archer R, Evans WJ. Body composition in ambulatory women with multiple sclerosis. Arch Phys Med Rehabil. 2002; 83: 1559-1561.
12. Olgiati R, Jacquet J, Di Prampero PE. Energy cost of walking and exertional dyspnea in multiple sclerosis. Am Rev Respir Dis. 1986; 134: 1005-1010.
13. Paul L, Rafferty D, Young S, Miller L, Mattison P, McFadyen A. The effect of functional electrical stimulation on the physiological cost of gait in people with multiple sclerosis. Mult Scler. 2008; 14: 954-961.
14. Tantucci C, Massucci M, Piperno R, Grassi V, Sorbini CA. Energy cost of exercise in multiple sclerosis patients with low degree of disability. Mult Scler. 1996; 2: 161–167.
15. Morrison EH, Cooper DM, White LJ, Larson J, Leu SY, Zaldivar F, et al. Ratings of perceived exertion during aerobic exercise in multiple sclerosis. Arch Phys Med Rehabil. 2008; 89: 1570–1574.
16. Franceschini M, Rampello A, Bovolenta F, Aiello M, Tzani P, Chetta A. Cost of walking, exertional dyspnoea and fatigue in individuals with multiple sclerosis not requiring assistive devices. J Rehabil Med. 2010; 42: 719-723.
17. Dionyssiotis Y. Bone loss and fractures in multiple sclerosis: focus on epidemiologic and physiopathological features. Int J Gen Med. 2011; 4: 505-509.
18. Chad KE, McKay HA, Zello GA, Bailey DA, Faulkner RA, Snyder RE. Body composition in nutritionally adequate ambulatory and non-ambulatory children with cerebral palsy and a healthy reference group. Dev Med Child Neurol. 2000; 42: 334-339.
19. Dionyssiotis Y. Spinal cord injury-related bone impairment and fractures: an update on epidemiology and physiopathological mechanisms. J Musculoskelet Neuronal Interact. 2011; 11: 257-265.
20. Dionyssiotis Y. Bone Loss in Spinal Cord Injury and Multiple Sclerosis. Stone JH, Blouin M, (eds), International Encyclopedia of Rehabilitation, Center for International Rehabilitation Research Information and Exchange (CIRRIE), 2011.
21. Formica CA, Cosman F, Nieves J, Herbert J, Lindsay R. Reduced bone mass and fat-free mass in women with multiple sclerosis: effects of ambulatory status and glucocorticoid Use. Calcif Tissue Int. 1997; 61:129-133.
22. Sioka C, Fotopoulos A, Georgiou A, Papakonstantinou S, Pelidou SH, Kyritsis AP, et al. Body composition in ambulatory patients with multiple sclerosis. J Clin Densitom. 2011; 14: 465-470.
23. Hedström AK, Olsson T, Alfredsson L. High body mass index before age 20 is associated with increased risk for multiple sclerosis in both men and women. Mult Scler. 2012; 18: 1334-1336.
24. Munger KL, Chitnis T, Ascherio A. Body size and risk of MS in two cohorts of US women. Neurology. 2009; 73: 1543-1550.
25. Castro MJ, Apple DF Jr, Hillegass EA, Dudley GA. Influence of complete spinal cord injury on skeletal muscle cross-sectional area within the first 6 months of injury. Eur J Appl Physiol Occup Physiol. 1999; 80: 373–378.
26. Modlesky CM, Bickel CS, Slade JM, Meyer RA, Cureton KJ, Dudley GA. Assessment of skeletal muscle mass in men with spinal cord injury using dual-energy X-ray absorptiometry and magnetic resonance imaging. J Appl Physiol. 2004; 96: 561-565.
27. Kurtzke JF. Rating neurologic impairment in multiple sclerosis: an expanded disability status scale (EDSS). Neurology. 1983; 33: 1444-1452.
28. Ng AV, Kent-Braun JA. Quantitation of lower physical activity in persons with multiple sclerosis. Med Sci Sports Exerc. 1997; 29: 517-523.
29. Motl RW, Arnett PA, Smith MM, Barwick FH, Ahlstrom B, Stover EJ. Worsening of symptoms is associated with lower physical activity levels in individuals with multiple sclerosis. Mult Scler. 2008; 14: 140-142.
30. Motl RW, Goldman M. Physical inactivity, neurological disability, and cardiorespiratory fitness in multiple sclerosis. Acta Neurol Scand. 2011; 123: 98-104.
31. Lohman TG. Applicability of body composition techniques and constants for children and youth. Pandolf KB (ed), Exercise and sport sciences reviews, Vol 14, Macmillan, New York, 1986, 325-357.
32. Kent-Braun JA, Ng AV, Castro M, Weiner MW, Gelinas D, Dudley GA, et al. Strength, skeletal muscle composition and enzyme activity in multiple sclerosis. J Appl Physiol. 1997; 83: 1998-2004.
33. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001; 285: 785-795.
34. Garland DE, Adkins RH, Stewart CA, Ashford R, Vigil D. Regional osteoporosis in women who have a complete spinal cord injury. J Bone Joint Surg Am. 2001; 83A: 1195-1200.
35. Nieves J, Cosman F, Herbert J, Shen V, Lindsay R. High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology. 1994; 44: 1687–1692.
36. Uebelhart D, Demiaux-Domenech B, Roth M, Chantraine A. Bone metabolism in spinal cord injured individuals and in others who have prolonged immobilisation. A review. Paraplegia. 1995; 33: 669–673.
37. Tüzün S, Altintaş A, Karacan I, Tangürek S, Saip S, Siva A. Bone status in multiple sclerosis: beyond corticosteroids. Mult Scler. 2003; 9: 600-604.
38. Cosman F, Nieves J, Komar L, Ferrer G, Herbert J, Formica C, et al. Fracture history and bone loss in patients with MS. Neurology. 1998; 51: 1161-1165.
39. Achiron A, Edelstein S, Ziev-Ner Y, Givon U, Rotstein Z, Barak Y. Bone strength in multiple sclerosis: cortical midtibial speed-of-sound assessment. Mult Scler. 2004; 10: 488-493.
40. Weinstock-Guttman B, Gallagher E, Baier M, Green L, Feichter J, Patrick K, et al. Risk of bone loss in men with multiple sclerosis. Mult Scler. 2004; 10: 170–175.
41. Zhao W, Liu Y, Cahill CM, Yang W, Rogers JT, Huang X. The role of T cells in osteoporosis, an update. Int J Clin Exp Pathol. 2009; 20: 544-552.
42. Kurban S, Akpinar Z, Mehmetoglu I. Receptor activator of nuclear factor kappaB ligand (RANKL) and osteoprotegerin levels in multiple sclerosis. Mult Scler. 2008; 14: 431-432.
43. Abraham AK, Ramanathan M, Weinstock-Guttman B, Mager DE. Mechanisms of interferon-beta effects on bone homeostasis. Biochem Pharmacol. 2009; 15: 1757-1762.
44. Liu C, Walter TS, Huang P, Zhang S, Zhu X, Wu Y, et al. Structural and functional insights of RANKL-RANK interaction and signaling. J Immunol. 2010; 184: 6910-6919.
45. Walsh MC, Kim N, Kadono Y, Rho J, Lee SY, Lorenzo J, et al. Osteoimmunology: interplay between the immune system and bone metabolism. Annu Rev Immunol. 2006; 24: 33-63.
46. Murthy JM. Antiepileptic drugs and bone health: dietary calcium and vitamin D the confounding factors. Neurol India. 2010; 58: 175–176.
47. Canalis E, Bilezikian JP, Angeli A, Giustina A. Perspectives on glucocorticoid-induced osteoporosis. Bone. 2004; 34: 593-598.
48. Canalis E, Mazziotti G, Giustina A, Bilezikian JP. Glucocorticoid-induced osteoporosis: pathophysiology and therapy. Osteoporos Int. 2007; 18: 1319-1328.
49. Lakatos P, Nagy Z, Kiss L, Horvath C, Takacs I, Foldes J, et al. Prevention of corticosteroid-induced osteoporosis by alfacalcidol. Z Rheumatol. 2000; 59 Suppl 1: 48-52.
50. Mazziotti G, Angeli A, Bilezikian JP, Canalis E, Giustina A. Glucocorticoid-induced osteoporosis: an update. Trends Endocrinol Metab. 2006; 17: 144-149.
51. Schwid SR, Goodman AD, Puzas JE, McDermott MP, Mattson DH. Sporadic corticosteroid pulses and osteoporosis in multiple sclerosis. Arch Neurol. 1996; 53: 753-757.
52. Shuhaibar M, McKenna MJ, Au-Yeong M, Redmond JM. Favorable effect of immunomodulator therapy on bone mineral density in multiple sclerosis. Ir J Med Sci. 2009; 178: 43-45.
53. De Vries F, Bracke M, Leufkens HG, Lammers JW, Cooper C, Van Staa TP. Fracture risk with intermittent high-dose oral glucocorticoid therapy. Arthritis Rheum. 2007; 56: 208-214.
54. Van Staa TP, Leufkens HG, Abenhaim L, Zhang B, Cooper C. Use of oral corticosteroids and risk of fractures. J Bone Miner Res. 2000; 15: 993-1000.
55. Zorzon M, Zivadinov R, Locatelli L, Giuntini D, Toncic M, Bosco A, et al. Long-term effects of intravenous high dose methylprednisolone pulses on bone mineral density in patients with multiple sclerosis. Eur J Neurol. 2005; 12: 550-556.
56. Haney EM, Warden SJ. Skeletal effects of serotonin (5-hydroxytryptamine) transporter inhibition: evidence from clinical studies. J Musculoskelet Neuronal Interact. 2008; 8: 133-145.
57. Garland DE, Stewart CA, Adkins RH, Hu SS, Rosen C, Liotta FJ, et al. Osteoporosis after spinal cord injury. J Orthop Res. 1992; 10: 371-378.
58. Demirel G, Yilmaz H, Paker N, Onel S. Osteoporosis after spinal cord injury. Spinal Cord. 1998; 36: 822-825.
59. Sabo D, Blaich S, Wenz W, Hohmann M, Loew M, Gerner HJ. Osteoporosis in patients with paralysis after spinal cord injury: A cross sectional study in 46 male patients with dual-energy X-ray absorptiometry. Arch Orthop Trauma Surg. 2001; 121: 75-78.
60. Groah SL, Nash MS, Ljungberg IH, Libin A, Hamm LF, Ward E, et al. Nutrient intake and body habitus after spinal cord injury: an analysis by sex and level of injury. J Spinal Cord Med. 2009; 32: 25-33.