Abstract
Multiple sclerosis (MS) is a chronic inflammatory-demyelinating disease of the nervous system. There has been mounting evidence showing that MS is associated with increased risk of osteoporosis and fractures. The development of osteoporosis in MS patients can be related to the cumulative effects of various factors. This review summarizes the common risk factors and physiologic pathways that play a role in development of osteoporosis in MS patients. Physical inactivity and reduced mechanical load on the bones (offsetting gravity) is likely the major contributing factor for osteoporosis in MS. Additional possible factors leading to reduced bone mass are low vitamin D levels, and use of medications such as glucocorticoids and anticonvulsants. The role of the inflammatory processes related to the underlying disease is considered in the context of the complex bone metabolism. The known effect of different MS disease-modifying therapies on bone health is limited. An algorithm for diagnosis and management of osteoporosis in MS is proposed.
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References
Compston A, Coles A. Multiple sclerosis. Lancet. 2008;372(9648):1502–17.
Sa MJ. Physiopathology of symptoms and signs in multiple sclerosis. Arq Neuropsiquiatr. 2012;70(9):733–40.
Weinstock-Guttman B, et al. Risk of bone loss in men with multiple sclerosis. Mult Scler. 2004;10(2):170–5.
Hearn AP, Silber E. Osteoporosis in multiple sclerosis. Mult Scler. 2010;16(9):1031–43.
Zorzon M, 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(7):550–6.
Marrie RA, et al. A cross-sectional study of bone health in multiple sclerosis. Neurology. 2009;73(17):1394–8.
Sioka C, Kyritsis AP, Fotopoulos A. Multiple sclerosis, osteoporosis, and vitamin D. J Neurol Sci. 2009;287(1–2):1–6.
Gibson JC, Summers GD. Bone health in multiple sclerosis. Osteoporos Int. 2011;22(12):2935–49.
Josyula S, et al. The nervous system’s potential role in multiple sclerosis associated bone loss. J Neurol Sci. 2012;319(1–2):8–14.
Ye S, Wu R, Wu J. Multiple sclerosis and fracture. Int J Neurosci. 2013;123(9):609–16.
Levis S, Theodore G. Summary of AHRQ’s comparative effectiveness review of treatment to prevent fractures in men and women with low bone density or osteoporosis: update of the 2007 report. J Manag Care Pharm. 2012;18(4 Suppl B):S1–15 (discussion S13).
Cosman F, et al. Fracture history and bone loss in patients with MS. Neurology. 1998;51(4):1161–5.
Nieves J, et al. High prevalence of vitamin D deficiency and reduced bone mass in multiple sclerosis. Neurology. 1994;44(9):1687–92.
Ozgocmen S, et al. Vitamin D deficiency and reduced bone mineral density in multiple sclerosis: effect of ambulatory status and functional capacity. J Bone Miner Metab. 2005;23(4):309–13.
Achiron A, et al. Bone strength in multiple sclerosis: cortical midtibial speed-of-sound assessment. Mult Scler. 2004;10(5):488–93.
Moen SM, et al. Low bone mass in newly diagnosed multiple sclerosis and clinically isolated syndrome. Neurology. 2011;77(2):151–7.
Heaney RP. Pathophysiology of osteoporosis. Endocrinol Metab Clin North Am. 1998;27(2):255–65.
Sipos W, et al. Pathophysiology of osteoporosis. Wien Med Wochenschr. 2009;159(9–10):230–4.
Luis Neyro J, Jesus Cancelo M, Palacios S. Inhibition of RANK-L in the pathophysiology of osteoporosis. Clinical evidences of its use. Ginecol Obstet Mex. 2013;81(3):146–57.
Negishi-Koga T, et al. Suppression of bone formation by osteoclastic expression of semaphorin 4D. Nat Med. 2011;17(11):1473–80.
Korn T. Pathophysiology of multiple sclerosis. J Neurol. 2008;255(Suppl 6):2–6.
Manolagas SC, Jilka RL. Bone marrow, cytokines, and bone remodeling. Emerging insights into the pathophysiology of osteoporosis. N Engl J Med. 1995;332(5):305–11.
McLean RR. Proinflammatory cytokines and osteoporosis. Curr Osteoporos Rep. 2009;7(4):134–9.
Altintas A, et al. The role of osteopontin: a shared pathway in the pathogenesis of multiple sclerosis and osteoporosis? J Neurol Sci. 2009;276(1–2):41–4.
Vogt MH, et al. Increased osteopontin plasma levels in multiple sclerosis patients correlate with bone-specific markers. Mult Scler. 2010;16(4):443–9.
Slavov GS, et al. Vitamin D immunomodulatory potential in multiple sclerosis. Folia Med (Plovdiv). 2013;55(2):5–9.
Munger KL, et al. Vitamin D intake and incidence of multiple sclerosis. Neurology. 2004;62(1):60–5.
George PM, et al. Pharmacology and therapeutic potential of interferons. Pharmacol Ther. 2012;135(1):44–53.
Abraham AK, et al. Mechanisms of interferon-beta effects on bone homeostasis. Biochem Pharmacol. 2009;77(12):1757–62.
Moen SM, et al. Bone turnover and metabolism in patients with early multiple sclerosis and prevalent bone mass deficit: a population-based case-control study. PLoS One. 2012;7(9):e45703.
Thomas T, et al. Leptin acts on human marrow stromal cells to enhance differentiation to osteoblasts and to inhibit differentiation to adipocytes. Endocrinology. 1999;140(4):1630–8.
Gordeladze JO, et al. Leptin stimulates human osteoblastic cell proliferation, de novo collagen synthesis, and mineralization: impact on differentiation markers, apoptosis, and osteoclastic signaling. J Cell Biochem. 2002;85(4):825–36.
Ducy P, et al. Leptin inhibits bone formation through a hypothalamic relay: a central control of bone mass. Cell. 2000;100(2):197–207.
Elefteriou F, et al. Serum leptin level is a regulator of bone mass. Proc Natl Acad Sci USA. 2004;101(9):3258–63.
Ruhl CE, et al. Body mass index and serum leptin concentration independently estimate percentage body fat in older adults. Am J Clin Nutr. 2007;85(4):1121–6.
Friedman JM. The function of leptin in nutrition, weight, and physiology. Nutr Rev. 2002;60(10 Pt 2):S1–14 (discussion S68–84, 85–7).
Glauber HS, et al. Body weight versus body fat distribution, adiposity, and frame size as predictors of bone density. J Clin Endocrinol Metab. 1995;80(4):1118–23.
Wardlaw GM. Putting body weight and osteoporosis into perspective. Am J Clin Nutr. 1996;63(3 Suppl):433S–6S.
Carlton ED, Demas GE, French SS. Leptin, a neuroendocrine mediator of immune responses, inflammation, and sickness behaviors. Horm Behav. 2012;62(3):272–9.
Yadav VK, et al. A serotonin-dependent mechanism explains the leptin regulation of bone mass, appetite, and energy expenditure. Cell. 2009;138(5):976–89.
Veniant MM, LeBel CP. Leptin: from animals to humans. Curr Pharm Des. 2003;9(10):811–8.
De Rosa V, et al. Leptin neutralization interferes with pathogenic T cell autoreactivity in autoimmune encephalomyelitis. J Clin Invest. 2006;116(2):447–55.
Matarese G, et al. Requirement for leptin in the induction and progression of autoimmune encephalomyelitis. J Immunol. 2001;166(10):5909–16.
Budhiraja S, Chugh A. Neuromedin U: physiology, pharmacology and therapeutic potential. Fund Clin Pharmacol. 2009;23(2):149–57.
Sato S, et al. Central control of bone remodeling by neuromedin U. Nat Med. 2007;13(10):1234–40.
Shi YC, Baldock PA. Central and peripheral mechanisms of the NPY system in the regulation of bone and adipose tissue. Bone. 2012;50(2):430–6.
Khor EC, Baldock P. The NPY system and its neural and neuroendocrine regulation of bone. Curr Osteoporos Rep. 2012;10(2):160–8.
Inose H, et al. Efficacy of serotonin inhibition in mouse models of bone loss. J Bone Miner Res. 2011;26(9):2002–11.
Karsenty G, Yadav VK. Regulation of bone mass by serotonin: molecular biology and therapeutic implications. Annu Rev Med. 2011;62:323–31.
Yuan XQ, et al. Fluoxetine promotes remission in acute experimental autoimmune encephalomyelitis in rats. Neuroimmunomodulation. 2012;19(4):201–8.
Elefteriou F, et al. Leptin regulation of bone resorption by the sympathetic nervous system and CART. Nature. 2005;434(7032):514–20.
Shi Y, et al. Signaling through the M(3) muscarinic receptor favors bone mass accrual by decreasing sympathetic activity. Cell Metab. 2010;11(3):231–8.
Smith CJ, Fischer TH. Particulate and vapor phase constituents of cigarette mainstream smoke and risk of myocardial infarction. Atherosclerosis. 2001;158(2):257–67.
Didilescu AC, et al. The role of smoking in changing essential parameters in body homeostasis. Pneumologia. 2009;58(2):89–94.
Emre M, de Decker C. Effects of cigarette smoking on motor functions in patients with multiple sclerosis. Arch Neurol. 1992;49(12):1243–7.
Zivadinov R, et al. Smoking is associated with increased lesion volumes and brain atrophy in multiple sclerosis. Neurology. 2009;73(7):504–10.
Manouchehrinia A, et al. Tobacco smoking and disability progression in multiple sclerosis: United Kingdom cohort study. Brain. 2013;136(Pt 7):2298–304.
Hernan MA, Olek MJ, Ascherio A. Cigarette smoking and incidence of multiple sclerosis. Am J Epidemiol. 2001;154(1):69–74.
Brot C, Jorgensen NR, Sorensen OH. The influence of smoking on vitamin D status and calcium metabolism. Eur J Clin Nutr. 1999;53(12):920–6.
Fini M, et al. Role of obesity, alcohol and smoking on bone health. Front Biosci (Elite Ed). 2012;4:2686–706.
Borer KT. Physical activity in the prevention and amelioration of osteoporosis in women: interaction of mechanical, hormonal and dietary factors. Sports Med. 2005;35(9):779–830.
Mojtahedi MC, et al. Bone health in ambulatory individuals with multiple sclerosis: impact of physical activity, glucocorticoid use, and body composition. J Rehabil Res Dev. 2008;45(6):851–61.
Steffensen LH, Mellgren SI, Kampman MT. Predictors and prevalence of low bone mineral density in fully ambulatory persons with multiple sclerosis. J Neurol. 2010;257(3):410–8.
De Nijs RN. Glucocorticoid-induced osteoporosis: a review on pathophysiology and treatment options. Minerva Med. 2008;99(1):23–43.
Dovio A, et al. Immediate fall of bone formation and transient increase of bone resorption in the course of high-dose, short-term glucocorticoid therapy in young patients with multiple sclerosis. J Clin Endocrinol Metab. 2004;89(10):4923–8.
Tuzun S, et al. Bone status in multiple sclerosis: beyond corticosteroids. Mult Scler. 2003;9(6):600–4.
Schwid SR, et al. Sporadic corticosteroid pulses and osteoporosis in multiple sclerosis. Arch Neurol. 1996;53(8):753–7.
Olafsson E, Benedikz J, Hauser WA. Risk of epilepsy in patients with multiple sclerosis: a population-based study in Iceland. Epilepsia. 1999;40(6):745–7.
Ghezzi A, et al. Epilepsy in multiple sclerosis. Eur Neurol. 1990;30(4):218–23.
Petty SJ, et al. Effect of antiepileptic medication on bone mineral measures. Neurology. 2005;65(9):1358–65.
Lee RH, Lyles KW, Colon-Emeric C. A review of the effect of anticonvulsant medications on bone mineral density and fracture risk. Am J Geriatr Pharmacother. 2010;8(1):34–46.
Truini A, et al. A mechanism-based classification of pain in multiple sclerosis. J Neurol. 2013;260(2):351–67.
Solaro C, Trabucco E, Messmer Uccelli M. Pain and multiple sclerosis: pathophysiology and treatment. Curr Neurol Neurosci Rep. 2013;13(1):320.
Daniell HW. OPioid osteoporosis. Arch Internal Med. 2004;164(3):338.
Elhassan AM, et al. Methionine-enkephalin in bone and joint tissues. J Bone Miner Res. 1998;13(1):88–95.
Loskutova N, et al. Bone density and brain atrophy in early Alzheimer’s disease. J Alzheimers Dis. 2009;18(4):777–85.
Batista S, et al. Cognitive impairment is associated with reduced bone mass in multiple sclerosis. Mult Scler. 2012;18(10):1459–65.
Shuhaibar M, et al. Favorable effect of immunomodulator therapy on bone mineral density in multiple sclerosis. Ir J Med Sci. 2009;178(1):43–5.
Weinstock-Guttman B, et al. Interferon-beta modulates bone-associated cytokines and osteoclast precursor activity in multiple sclerosis patients. Mult Scler. 2006;12(5):541–50.
National Osteoporosis Foundation. NOF’s clinicians’ guide to the prevention and treatment of osteoporosis (http://nof.org/hcp/resources/913.
Ishii M, et al. Sphingosine-1-phosphate mobilizes osteoclast precursors and regulates bone homeostasis. Nature. 2009;458(7237):524–8.
Sato C, et al. Sphingosine 1-phosphate receptor activation enhances BMP-2-induced osteoblast differentiation. Biochem Biophys Res Commun. 2012;423(1):200–5.
Huang C, et al. Local delivery of FTY720 accelerates cranial allograft incorporation and bone formation. Cell Tissue Res. 2012;347(3):553–66.
Kanis JA, et al. FRAX and the assessment of fracture probability in men and women from the UK. Osteoporos Int. 2008;19(4):385–97.
Melton LJ 3rd, et al. Potential extensions of the US FRAX algorithm. J Osteoporos. 2012;2012:528790.
Dennison EM, et al. Effect of co-morbidities on fracture risk: findings from the global longitudinal study of osteoporosis in women (GLOW). Bone. 2012;50(6):1288–93.
Bazelier MT, et al. A simple score for estimating the long-term risk of fracture in patients with multiple sclerosis. Neurology. 2012;79(9):922–8.
Sundstrom P, Salzer J. Vitamin D and multiple sclerosis: timing of sampling, treatment and prevention. Biomark Med. 2013;7(2):193–5.
Myhr KM. Vitamin D treatment in multiple sclerosis. J Neurol Sci. 2009;286(1–2):104–8.
Weinstock-Guttman B, et al. Vitamin D and multiple sclerosis. Neurologist. 2012;18(4):179–83.
Ascherio A, et al. Vitamin D as an early predictor of multiple sclerosis activity and progression. JAMA Neurol. 2014;71(3):306–14.
Kmietowicz Z. NICE publishes osteoporosis guidance after more than six years of consultation. BMJ. 2008;337:a2397.
Compston J. NICE: its influence in treating osteoporosis in the UK and beyond. Ther Adv Musculoskelet Dis. 2009;1(2):63–6.
McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014; 370(5):412-20
Cummings SR, et al. Lasofoxifene in postmenopausal women with osteoporosis. N Engl J Med. 2010;362(8):686–96.
Trojano M, et al. The transition from relapsing-remitting MS to irreversible disability: clinical evaluation. Neurol Sci. 2003;24(Suppl 5):S268–70.
Lenart BA, Lorich DG, Lane JM. Atypical fractures of the femoral diaphysis in postmenopausal women taking alendronate. N Engl J Med. 2008;358(12):1304–6.
Black DM, et al. Bisphosphonates and fractures of the subtrochanteric or diaphyseal femur. N Engl J Med. 2010;362(19):1761–71.
Odvina CV, et al. Unusual mid-shaft fractures during long-term bisphosphonate therapy. Clin Endocrinol. 2010;72(2):161–8.
Shane E, et al. Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American society for bone and mineral research. J Bone Miner Res. 2014;29(1):1–23.
Formica CA, et al. Reduced bone mass and fat-free mass in women with multiple sclerosis: effects of ambulatory status and glucocorticoid use. Calcif Tissue Int. 1997;61(2):129–33.
Conflict of interest
B Weinstock-Guttman has participated in speaker’s bureaus and served as a consultant for Biogen Idec, Teva Neurosciences, EMD Serono, Pfizer, Novartis, Genzyme, Sanofi, Mylan, and Acorda. She has also received grant/research support from the agencies listed above as well as ITN, Questcor, and Shire. No other industry financial relationships exist.
Dr. Murali Ramanathan received research funding or consulting fees from EMD Serono, Biogen Idec, Pfizer, Novartis, Monsanto, the National Multiple Sclerosis Society, the Department of Defense, Jog for the Jake Foundation, and the National Institutes of Health and National Science Foundation. He received compensation for serving as an editor from the American Association of Pharmaceutical Scientists. These are unrelated to the research presented in this report.
Sahil Gupta has no disclosures.
Irfan Ahsan has no disclosures.
Naeem Mahfooz has no disclosures.
Noureldin Abdelhamid has no disclosures.
No funding was provided for preparing this manuscript.
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Gupta, S., Ahsan, I., Mahfooz, N. et al. Osteoporosis and Multiple Sclerosis: Risk Factors, Pathophysiology, and Therapeutic Interventions. CNS Drugs 28, 731–742 (2014). https://doi.org/10.1007/s40263-014-0173-3
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DOI: https://doi.org/10.1007/s40263-014-0173-3
Keywords
- Bone Mineral Density
- Osteoporosis
- Multiple Sclerosis
- Multiple Sclerosis Patient
- Denosumab