CNS Drugs (2014) 28:731–742 DOI 10.1007/s40263-014-0173-3
REVIEW ARTICLE
Osteoporosis and Multiple Sclerosis: Risk Factors, Pathophysiology, and Therapeutic Interventions Sahil Gupta • Irfan Ahsan • Naeem Mahfooz • Noureldin Abdelhamid • Murali Ramanathan • Bianca Weinstock-Guttman
Published online: 29 May 2014 Ó Springer International Publishing Switzerland 2014
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.
S. Gupta I. Ahsan N. Mahfooz N. Abdelhamid M. Ramanathan B. Weinstock-Guttman Department of Neurology, State University of New York, Buffalo, NY, USA M. Ramanathan Pharmaceutical Sciences, State University of New York, Buffalo, NY, USA B. Weinstock-Guttman (&) UBMD Neurology, Jacobs MS Center, 100 High Street, Buffalo, NY 14203, USA e-mail:
[email protected]
Key Points Multiple sclerosis is associated with an increased risk for osteoporosis. The cause for osteoporosis in multiple sclerosis is multifactorial. The disease-modifying therapies used for the treatment of multiple sclerosis may have beneficial impact on bone health.
1 Introduction Multiple sclerosis (MS) is a chronic inflammatory demyelinating disease of the central nervous system (CNS) affecting primarily young adults [1]. The demyelination, inflammation, and axonal damage that underlay the pathobiology of the disease is associated with subsequent disruption of neuronal impulses causing muscle weakness, sensory dysfunction, and vision and balance impairment [2]. MS is associated with an increased risk of osteoporosis and reduced bone mass, which when combined with the functional impairments of the disease, augments the possibility of fractures [3–9]. The development of osteoporosis in MS patients can be related to the cumulative effects of various factors. Physical inactivity and reduced mechanical load on the bones (offsetting gravity) is likely the major contributing factor for osteoporosis in MS [10]. Other possible factors leading to reduced bone mass are low vitamin D levels, use of medications such as glucocorticoids and anticonvulsants, and the role of the inflammatory processes of the disease [9]. Both males and females with MS have an increased risk of developing osteoporosis [3, 4]. A better understanding of
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the osteoporosis process and its impact on the MS population as well as the preventive and active therapeutic interventions that can limit and/or prevent this devastating comorbidity represent an important research venue.
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newly diagnosed MS and clinically isolated syndrome (CIS), patients who had no ambulatory deficits (i.e., a median EDDS score of 1.0). These data undoubtedly support the detrimental influence of an underlying inflammatory milieu in MS on the bone status that is independent from the known disability impact.
2 Prevalence of Osteoporosis in Multiple Sclerosis (MS) Patients Numerous studies indicate that the prevalence of osteoporosis in people with MS is far higher than in the general population [3–8]. Most of these studies use dual X-ray absorbance spectrometry (DXA) to assess the bone mineral density (BMD) of the different bone areas. The results are further interpreted in terms of standard deviation changes from a young population (T scores) or from an age-matched group (Z scores). Osteopenia is defined as a T score between -1 and -2.5, whereas osteoporosis is defined as a T score of -2.5 or lower [11]. Marrie et al. conducted a study using North American Research Committee on Multiple Sclerosis (NARCOMS) data and found that 27.2 % (2,501/9,029) of the patients reported low bone mass and 15.4 % reported osteoporosis [6]. Data from a large MS center found that 80 % of males with MS evaluated with DXA scan had reduced bone mass at the lumbar spine or femoral neck [3]. Reduced bone mass also translated into increased fracture rates as was shown by Cosman et al. [12]. In this study, 22 % of patients with MS suffered fractures as compared with only 2 % of age-matched controls. It has been shown that different types of MS affect BMD differently. Progressive forms of MS have a worse bone health outcome than relapsing-remitting MS (RRMS) [3, 6, 8]. It is still not known whether lumbar vertebrae or the femoral neck is more affected by MS. Mechanical factors related mostly to ambulation may suggest that hip involvement should overcome the lumbar bone loss. Nieves et al. [13] reported a Z score of -1.0 in the vertebrae and -1.6 in the hip13. On the other hand, in a study of 31 pre-menopausal female and male patients, a Z score of -0.98 and -0.67 was observed in the L2–L4 vertebrae and femoral neck, respectively [14] (Table 1). A study by Zorzon et al. [5] showed no significant difference in number of patients with osteoporosis; however, an increased percentage of osteopenia was observed. Achiron et al. [15] also reported no significant difference in cortical bone density measured with the help of an ultrasound machine. These results are mostly attributed to a low disability status as measured with the Expanded Disability Status Scale (EDSS) score (EDSS ranges 1.6–3.7) as compared with the previously mentioned studies (EDSS ranges 3.13–7.0). However, a recent study by Moen et al. [16] found low bone mass in
3 Clinically Relevant Physiological Mechanism of Osteoporosis in MS 3.1 Normal Pathophysiology of Bone Remodeling and Osteoporosis Bone tissue homeostasis is a continuous process involving osteoclasts, which resorb bone, and osteoblasts, which form bone. Osteoporosis results in bone mineral loss and occurs when osteoblastic activity cannot keep up with the osteoclastic bone resorption. This increase in osteoclastic activity leads to bone loss [17]. Various mechanisms are involved in regulating the balance between osteoblasts and osteoclasts. In bone matrix, transforming growth factor (TGF)-b1 and insulin-like growth factor (IGF)-1 are the main mediators of bone remodeling [18]. These factors are released in response to osteoclastic bone resorption and lead to migration of osteoblastic cells so that both processes, bone resorption and bone formation, are coupled. In addition, receptor activator of nuclear factor j B (RANK) ligands expressed on the osteoblastic cell surface bind to the RANK cell membrane receptor present on osteoclast progenitor cells to promote osteoclastogenesis [19]. A new mechanism of regulation has also been discovered by NegishiKoga et al. [20], which reveals that semaphorin 4D (sema4d) secreted from osteoclasts regulates osteoblastic differentiation by binding to plexin-B1 receptors on the osteoblasts, thus creating a negative feedback loop (Fig. 1). 3.2 Common Physiologic Mediators of MS and Osteoporosis MS is known to be a primarily T-helper (Th)-1 mediated disorder. Newer research findings have also revealed roles of Th17, B cells, CD8? T cells, and both CD8? and CD4? T regulatory cells to be contributory to the pathogenesis of inflammation associated with MS [21]. Cytokines derived from these cells, especially interleukin (IL)-1, tumor necrosis factor (TNF)-a, IL6, and IL11 are also known to mediate the pathogenesis of osteoporosis [22]. These cytokines have been shown to promote osteoclastogenesis, thereby causing bone resorption [23] (Fig. 2).
80
30
71
54
31
40 males
65
43
256
Nieves et al. [13]
Schwid [67]
Formica et al. [101]
Cosman et al. [12]
Ozgocmen et al. [14]
WeinstockGuttman [3]
Tuzun et al. [66]
Zorzon et al. [5]
Achiron et al. [15]
3.7 ± 2.5
Pts receiving steroids during relapses: 2.8 ± 2.1
Pts receiving steroids during relapses: 41.7 ± 10.3
44.3 ± 11.4
Pts receiving continuous steroid: 1.6 ± 1.3
3.5 ± 1.9
Male: 35.1 ± 5.5
Pts receiving continuous steroids: 43.3 ± 10.3
3.6 ± 2.3
5.8 ± 1.9
Female: 33.5 ± 5.3
51.2 ± 8.7
3.13 ± 2.03
Men: 46 ± 2.9
38.2 ± 10.1
6.3 7.0
Postmenopausal women: 55 ± 1.4
Significantly higher proportion of pts with T score [1 in MS group vs. control group (p = 0.001)
Correlation between EDSS and femoral BMD (r = -0.031, p \ 0.05)
Increased probability of MS pts to be osteopenic vs. healthy controls (OR 2.6, p = 0.016)
Correlation between disease duration and BMD (r = 0.507, p = 0.001)
BMD decreased in femoral and lumbar sites vs. controls (p \ 0.0001)
Correlation between number of cycles of steroid tx and BMD (r = -0.34, p = 0.039)
Correlation between EDSS and femoral BMD (r = -0.53, p = 0.001) Correlation between BMI and femoral BMD (r = 0.44, p = 0.005)
Multiple linear regression modeling retained EDSS (p = 0.0018) and BMI (p = 0.004) as significant variables
80 % of pts reduced bone mass, 42.5 % were osteopenic, 37.5 % osteoporotic
Correlation between steroid dose and BMD for femoral trochanter (r = -0.38, p = 0.03)
Decreased levels of 25(OH)D in MS pts vs. controls (p = 0.001)
Mean Z score in femoral trochanter is -0.67 vs. 0.2 in control group
Correlation found between EDSS and rate of bone loss (lumbar vertebra r = -0.40 p = 0.008, hip r = -0/38 p = 0.01) Mean Z score in MS pts in L2–L4 vertebra is -0.98 vs. -0.06 in control group
Increased bone loss in pts with decreased 25(OH)D levels. p \ 0.01
Fracture rates in MS pts vs. controls: 22 vs. 2 % (p \ 0.002)
BMD in MS pts at lumbar spine and FN decreased by 1 and 1–1.6 SD vs. age-matched healthy controls
Correlation between EDSS and TBBM (r = 0.33, p \ 0.01)
6.5
Lower TBBM vs. control group (p \ 0.004)
Ambulatory pts = 5.8 ± 0.2
After 6 months of pulse steroid tx, pts with EDSS B5 gained 2.9 % BMD whereas pts with EDSS C5.5 lost 1.6 % (p = 0.04)
Mean Z score of -0.87 at FN (p = 0.002)
Ambulatory pts had increased TBBM vs. non-ambulatory pts (p \ 0.02)
Z score of -0.98 at lumbar sites and -1.7 at FN
Results
Non-ambulatory pts = 7.8 ± 0.2
Not calculated
5.15 ± 1.22
Mean EDSS
Premenopausal women: 40 ± 1.4
45.6 ± 1.1
45 ± 10
44.24 ± 7.97
Mean age
BMD bone mineral density, BMI body mass index, EDSS expanded disability status scale, FN femoral neck, MS multiple sclerosis, OR odds ratio, pt(s) patient(s), SD standard deviation, TBBM total bone body mineral content, tx treatment, 25(OH)D 25-hydroxyvitamin D
Patients (n)
Study
Table 1 Studies investigating bone mineral density in patients with multiple sclerosis
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Fig. 1 Mechanism of maintenance of bone health. Bone resorption and bone formation are coupled through various levels of cellular communication. (1) In the bone matrix, TGF-beta1 and IGF are released in response to bone resorption. These factors subsequently lead to osteoblastic migration to the cell surface and thereby resulting in bone formation. (2) Sema4D released from osteoclast regulates
differentiation of the osteoblasts by binding to Plexin-B1. (3) RANKRANKL mediates communication to induce osteoclast progenitor differentiation. Increased osteoblastic RANKL induces osteoclastic production of Sema4D, therefore creating a negative feedback loop. IGF insulin-like growth factor, RANK receptor activator of nuclear factor j B, sema4D semaphorin 4D, TGF transforming growth factor
3.2.1 Common Immunomodulators of Bone and Central Nervous System (CNS)
37.5 % of those with low BMD had decreased vitamin D levels; the rest had normal vitamin D concentration. This advocates that there are more factors at play that regulate MS and osteoporosis [3]. Interferon (IFN), a well established treatment for MS, has also been shown to inhibit osteoclastogenesis. IFN-b binds to its biological receptor and initiates a signal transduction cascade through the classic JAK/STAT pathway, which ultimately leads to inhibition of c-fos protein production and osteoclast proliferation and differentiation [28]. IFN-b has also been shown to induce nitric oxide, which subsequently inhibits osteoclast formation. Molecular studies have also revealed that interaction of RANKRANKL induces osteoclastogenesis and leads to production of IFN-b, thus forming a negative feedback loop [29]. Interestingly, a recent study comparing the bone turnover markers (i.e., cross-linked N-terminal telopeptide of type 1 collagen [NTX], bone alkaline phosphatase [bALP]) in patients with CIS and an early MS cohort diagnosed with a lower bone density did not differ significantly from a healthy control group [30]. These findings suggest that the bone deficit in patients newly diagnosed with MS and CIS may not be caused by recent acceleration of bone loss, but related to the other etiological factors as detailed in this review.
A number of different immunomodulators are also common in the pathophysiological pathways of MS and osteoporosis. Osteopontin is an extracellular matrix protein with chemokine, integrin, and cytokine properties. It is biosynthesized by a variety of cells, including macrophages and T lymphocytes [24]. Osteopontin acts as a proinflammatory cytokine, and increased levels of osteopontin are shown in plasma and cerebrospinal fluid (CSF) of MS patients as compared with healthy controls [25]. Osteopontin levels have also been shown to be positively correlated with bone density of the femur neck [24]. This correlation suggests osteopontin to be involved in a pathway common to the development of both MS and osteoporosis. Vitamin D also tends to exert an immunomodulatory response on the immune system. It has been observed that areas with high sunlight exposure, a major inducer of vitamin D synthesis, have significantly lower rates of MS [26]. Similarly high circulating levels of vitamin D are associated with a lower risk of MS [27]. Although the role of vitamin D in calcium homeostasis is well established, a recent cross-sectional study of 40 patients showed that only
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Fig. 2 Simplified diagram of bone formation and bone resorption and the factors affecting it. Red decreases bone mineral density, green increases bone mineral density. IGF insulin-like growth factor, IL
interleukin, NS nervous system, RANK receptor activator of nuclear factor j B, SEMA4D semaphorin 4D, TGF transforming growth factor, TNF tumor necrosis factor
3.2.2 Role of CNS in Bone Maintenance
correlation between leptin levels and BMD [37, 38]. But due to the pro-inflammatory effects of leptin, it may nullify the effect of mechanical loading on the bone with further deterioration of the bone [39]. Various studies have established a link between metabolic factors and the immune system. Leptin activates the JAK-STAT pathway and promotes phagocytosis and secretion of pro-inflammatory cytokines [40, 41]. Leptin-deficient mice showed various immune abnormalities, including decreased IL2, IL8, and TNF production, abnormal CD4? T-cell function, and impaired T-cell immunity. These mice were shown to be resistant to actively and passively induced experimental autoimmune encephalitis (EAE) [42]. However, leptin administration converted the resistance to susceptibility by restoration of the immune function, as was shown by Matarese et al. [43]. Neuromedin U (NmU) is a neuropeptide that is produced in the brain, spinal cord, and the gastrointestinal tract and that helps inhibit food intake [44]. Sato et al. [45] demonstrated increased bone mass in NmU-deficient mice. NmU-receptor agonist treatment decreased bone mass in wild-type mice45. Neuromedin is also considered to be a proinflammatory neuropeptide as it induces the production of IL4, IL5, IL6, IL10, and IL13. Neuropeptide Y (NPY) in bone acts consistently to repress osteoblastic activity. It exerts its effect through the
CNS influences bone health through various neuronal factors. The most prominent neuronal factors affecting bone physiology are leptin, neuromedin U, neuropeptide Y, and serotonin. Leptin, a peptide hormone, has been found to influence bone mass in both animal models and human subjects. In vitro models have shown leptin to increase the osteoblast differentiation and proliferation [31, 32]. However, in animal models, the results were contrary to the in vitro findings. Ducy et al. [33] observed increased trabecular bone mass in ob/ob (leptin-deficient) and db/db (leptinreceptor deficient) mice due to high osteoblastic activity. Elefteriou et al. [34] demonstrated a relationship between leptin and bone mass in transgenic mice. They observed that reducing the serum-free leptin level by overexpressing a soluble receptor for leptin increased bone mass and vice versa. Similar results were found in an epidemiological study by Ruhl et al. [35], which revealed an inverse relationship between leptin and bone mass. It has been found that plasma leptin levels increase with increase in body weight [36]. As increase in body weight would also lead to increased mechanical loading of the bone, which subsequently results in osteoblastic differentiation and improved BMD, it might be assumed that there might be a positive
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central Y2 receptor and osteoblastic Y1 receptor and inhibits bone formation. On the other hand, loss of NPY expression or receptor signaling induces increased osteoblast activity and bone mass [46, 47]. Serotonin may also have regulatory effects on the bone. Preliminary data suggest that it might increase bone resorption through increased osteoclast differentiation, which may be regulated by lipoprotein receptorrelated protein 5 [48, 49]. Serotonin-reuptake inhibitors have been found to have improved outcomes and attenuate disease in EAE models, thus suggesting a common physiological role of serotonin in MS and bone health [50]. Sympathetic nervous system signaling through b2 adrenergic receptors present on osteoblasts controls bone formation. Leptin-regulated neural pathways promote osteoclastogenesis through sympathetic signaling and therefore cause decreased BMD [51]. On the other hand, the parasympathetic nervous system, through muscarinic 3 receptors on the locus cereleus, may mitigate the effect of sympathetic signaling and inhibit bone resorption [52].
4 Risk Factors for Osteoporosis in MS Osteoporosis is a widespread epidemic and affects a huge percentage of the population worldwide. Various risk factors that predispose a person to osteoporosis have been recognized (Fig. 3). Early identification of these risk factors and subsequent intervention would help in preventing or delaying the incidence of the disease. Furthermore, three risk factors important in the MS population are smoking, physical inactivity due to disease-related disability or fatigue, and glucocorticoid treatment.
Fig. 3 Osteoporosis risk factors. Adapted from Sambrook and Cooper. Osteoporosis. Lancet. 2006;367(9527):2010–2018. GnRH gonadotropic-releasing hormone
4.1 Smoking and its Effects on Bone and MS Smoking can result in disease progression in both MS and osteoporosis. Pro-inflammatory effects of cigarette smoking have been extensively studied. It has been shown to increase the leukocyte count [53]. Smoking also elevates C-reactive protein and IL6 and causes abnormalities in T-cell function [54]. Smoking has been associated with worsening of MS symptoms [55–57]. A prospective study comprising more than 200,000 women showed a significant increase in MS risk among current smokers. It also showed increased incidence of MS with increased cumulative exposure to smoking [58]. Smoking contributes to osteoporosis by significantly decreasing levels of 25-hydroxyvitamin D (25(OH)D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D),and also has a damaging effect on osteoblastic differentiation [59, 60]. 4.2 Physical Inactivity Physical activity regulates bone health by stimulating bone formation as well as strengthening muscles, improving balance and thus reducing overall risk of falls [61]. MS patients with compromised ambulation are at higher risk of osteoporosis. It is well established that increase in body mass index (BMI) is positively correlated with increase in BMD, especially in the femur [62]. A study in 40 male MS patients found that 58 % of MS patients with EDSS \5.5 were osteopenic or osteoporotic [3]. A study by Steffensen et al. [63] also showed that 25 % of fully ambulatory MS patients had low BMD levels. These results prove that decreases in osteoporosis in MS results from an interplay of various factors rather than decreased mechanical load on the bones.
Risk Factors for Osteoporosis
Congenital Factors • Age • Family history • Chronic Disease • Caucasian Race • Female Gender
Acquired Factors • Visual Impairment • Dementia • Low Body Weight • Recurrent Falls • Early menopause • Hypothyroidism& Hyperthyroidism
Lifestyle • Low Ca • Alcoholism • Vitamin D deficiency • Inactivity • Smoker
Iatrogenic Factors • Glucocorticoids • Cyclosporine • Anticonvulsant • Thyroxin • Aluminum • GnRH agonist • Lithium • Aromatase inhibitor
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4.3 Glucocorticoid Use in MS
6 Effects of MS Therapies on Bone Health
Steroids are used in MS, usually during relapses. The adverse effects of steroid therapy on bone are well known. Glucocorticoid therapy leads to inhibition of osteoblast differentiation and migration as well as increased bone resorption through induced hyperparathyroidism and impaired calcium absorption [64]. But due to the transient nature of the use of high-dose steroids in MS, the adverse effects on bone are not long-term [5, 65–67]. A study by Zorzon et al. [5] found that neither pulsed nor continuous steroid therapy in MS patients had a significant effect on BMD. The primary negative influence on bone status identified in this paper was disability, whereas the use of repeated intravenous steroids that prevented disability was associated with better bone status outcomes.
Various disease-modifying therapies are available for treatment of MS. These treatments are used to slow the progression of the disease. The outcomes of these treatments may directly influence bone health [78]. Nevertheless, there are only limited data supporting a direct bone effect. IFN has been shown to inhibit osteoclastogenesis and osteoclast differentiation through the JAK/STAT pathway as discussed earlier. In a study by Weinstock-Guttman et al. [79], IFN was shown to modulate RANKL and osteoprotegerin in a time-dependent manner. The effect on bone health of glatiramer acetate, another first-line therapy for MS, is still unknown as not enough research has been conducted in that area. However, one such ongoing study is comparing the effect of IFN and glatiramer acetate on bone in MS patients; final results are not yet available [80]. Fingolimod is a sphingosine-1-phosphate (S1P) analog that has recently been approved for treatment of MS. A study by Ishii et al. [81] reported that S1P regulates the migration of osteoclast precursors and contributes to the dynamic control of bone homeostasis in mice81. It was also shown that S1P enhances bone morphogenic protein-2induced osteoblast differentiation [82]. Huang et al. [83] reported that local delivery of fingolimod accelerated bone formation in mice. The rate of acceleration in bone formation persisted until week 4, but by week 8 the increase in bone formation was not statistically significant. Further research is warranted to investigate the effect of other MS therapies such as natalizumab, teriflunomide, dimethyl fumarate, and alemtuzumab on BMD.
4.4 Other Iatrogenic Risk Factors in MS Multiple sclerosis is an important risk factor for developing epilepsy [68, 69]. Patients with MS have a threefold increase in risk of having seizures as compared with the general population [68]. Various studies have proven the detrimental effect of anti-epileptic drugs on bone density [70]. Anti-epileptic drugs (i.e., phenytoin, phenobarbital, carbamazepine) predispose patients to fracture risk [71]. Pain is also a very common complaint is MS patients [72]. Chronic opioid therapy is used in these patients to alleviate pain and pain-related symptoms [73]. Chronic opioid treatment causes hypogonadism, which subsequently leads to decreased bone mass [74]. Opioid treatment also decreases the BMD by directly inhibiting the growth of human osteoblastic tissue [75].
5 Effect of Cognitive Dysfunction on Bone Health in MS Ever since the discovery of the role of neuronal signaling in bone homeostasis, the disciplines of neurosciences and bone physiology have been consistently converging. In recent studies in patients with Alzheimer’s disease by Loskutova et al. [76], the authors revealed BMD to be in direct correlation with cognitive performance. Thereafter, Batista et al. [77] investigated the relationship between BMD and cognitive performance in MS patients. Their study revealed a prevalence of osteopenia or osteoporosis in 59.3 % of cognitively impaired MS patients compared with 24.1 % of the non-cognitively impaired group (odds ratio 4.57, p = 0.008). The association of cognitive impairment with reduced BMD in MS patients advocates direct involvement of central neuroinflammatory and neurodegenerative processes in bone homeostasis [77].
7 Approach to Management of Osteoporosis in MS Patients Osteoporosis and fractures represent important co-morbidities identified in MS patients. Unfortunately, no uniform guidelines have been established to treat bone-reduced BMD in this specific patient population. The World Health Organization provides the FRAXÒ tool to predict 10-year probability of hip fracture or osteoporotic fracture in patients [84]. The factors that the FRAX tool takes into consideration while estimating the fracture risk are as follows: age, sex, BMI, history of fracture, parental history of fracture, smoking, use of glucocorticoids, history of rheumatoid arthritis, secondary osteoporosis, and high alcohol consumption [84] (Box 1). The FRAX tool uses data from nine cohorts around the world and provides fracture risk customized to the epidemiology of different countries [84, 85]. Additional comorbidities, such as Parkinson disease, chronic obstructive pulmonary disease (COPD),
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Table 2 Pharmacological therapies for osteoporosis in multiple sclerosis Treatments Bisphosphonates
Drugs
Efficacy
Adverse effects
Contraindications
Alendronate (oral)
Prevents vertebral, hip, non-vertebral fractures
Upper GI intolerance (oral)
Dysphagia (oral)
Risedronate (oral)
eGFR \35 ml/min
Flu-like symptoms (IV)
Zoledronate (IV) Selective ER modulator
Raloxifene Bazedoxifene
Reduces vertebral fractures
Hot flashes, thromboembolism
Pregnant women Past history of thromboembolic events
RANK ligand monoclonal antibody
Denosumab
Reduces vertebral, hip, non-vertebral fractures in post-menopausal women
UTI and respiratory tract infections
Hypocalcemia
Anabolic therapy
PTH peptide: e.g. teriparatide
Protects against vertebral, non-vertebral fractures
Dizziness
Malignancy, metabolic bone disease
Strontium ranelate
Prevents hip, vertebral, non-vertebral fractures
Diarrhea, rashes, thromboembolism
Anabolic and antiresorptive therapy
Hypercalcemia
eGFR \30 ml/min
eGFR estimated glomerular filtration rate, ER estrogen receptor, GI gastrointestinal, IV intravenous, PTH parathyroid hormone, RANK receptor activator of nuclear factor j B, UTI urinary tract infection
osteoarthritis, and heart disease could be also associated with a high risk of fracture [86]. Although the FRAX tool provides some consistency in assessing the fracture risk of patients in the general population, it doesn’t account for the risk factors found specifically in the MS population. To meet this requirement, Bazelier et al. [87] designed a riskscoring system to evaluate the risk of osteoporosis and fracture in MS patients. This scoring system contains several new risk factors, including the use of antidepressants, the use of anticonvulsants, a history of falling related to MS neurological deficits, and a history of fatigue. Osteoporotic bone disease should be treated with a multi-pronged approach that includes lifestyle changes such as smoking cessation, reducing alcohol intake, increasing physical activity, and drug treatments like optimizing vitamin D levels, calcium intake of 1,000 mg/day (up to 1,200 for women over 50 years), and anti-resorptive therapy. Resistance training is also a useful intervention that would help increase bone strength and muscle power and reduce the risk of falling by improving balance. Vitamin D deficiency should also be corrected by encouraging patients to obtain enough sunlight exposure and by prescribing vitamin D at a dose of 600 IU/day for those aged \70 years and 800 IU/day for those aged [70 years until serum 25(OH)D levels reach at least 50 nmol/L [88, 89]. Recent recommendations specific for MS patients suggest an even higher intake of up to 4,000 IU, with repeated testing of vitamin D levels to reach 30–40 ng/ml, mostly based on the beneficial effect of vitamin D related to its immune-modulatory effects and not only its influence on bone status [90, 91].
The main pharmacological interventions for the treatment of osteoporosis are bisphosphonates, denosumab, parathyroid hormone (PTH; PTH1-34, PTH1-94), raloxifene, and strontium ranelate. The UK National Institute for Health and Care Excellence (NICE) provides guidelines for osteoporotic fragility fractures [92, 93]. These recommendations by NICE can also be used for MS patients, as no treatment guidelines have been customized for osteoporosis in MS patients. NICE guidelines recommend alendronate as the first-line treatment for osteoporosis. Risedronate and etidronate are recommended as second-line, and strontium ranelate makes up the third-line option. However, the EU Pharmacovigilance Risk Assessment Committee (PRAC) recommended that strontium should no longer be used to treat osteoporosis to reduce the risk of any cardiovascular problems. This matter was subsequently taken up by the Committee for Medicinal Products for Human use (CHMP) and was discussed in the meeting held in February 2014. Following the meeting, the CHMP recommended that patients who have no alternative treatment should be regularly screened and monitored to exclude any cardiovascular disease. The patients with no cardiovascular problems can continue to have access to strontium ranelate. CHMP also recommended that strontium ranelate is strongly contraindicated in patients with established, current or past history of ischaemic heart disease, peripheral arterial disease and/or cerebrovascular disease or uncontrolled hypertension. Raloxifene is not recommended as a treatment option for primary prevention of osteoporotic fragility fractures in postmenopausal women (Table 2). New drugs like romosozumab look promising for the treatment of post-menopausal women with low BMD [94]. A new selective
Osteoporosis and Multiple Sclerosis Fig. 4 Algorithm for management of bone health in multiple sclerosis patients. DXA dual X-ray absorbance spectrometry, EDSS Expanded Disability Status Scale, IV intravenous, MS multiple sclerosis, NOF National Osteoporosis Foundation, PTH parathyroid hormone, SERM selective estrogen-receptor modulator
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Post-menopausal MS woman and men over 40 or patients with disability ( EDSS 5)
Patients with EDSS 5
Assess Vitamin D levels and Calcium intake. Optimize if required
Assess Vitamin D levels and Calcium intake. Optimize if required
DXA Scan
Patients with increased risks: 1. Recent fracture 2. Prolonged steroid therapy 3. Anticonvulsant medication 4. History of frequent falls (see Fig 3)
yes
FRAX algorithm & NOF
no Treatment
Oral Bisphosphonates
No Treatment
yes Dysphagia?
Other Drugs: • Bisphosphonates (IV) • Denosumab • PTH • SERMs
Lifestyle Modification: • Smoking Cessation • Resistance Training • Physical Activity
No
estrogen-receptor modulator (SERM) also recently became available. Bazedoxifene/conjugated estrogens (trade name Duavee in the USA) is a fixed-dose combination drug containing the selective estrogen-receptor modulator bazedoxifene and conjugated estrogens and is approved by FDA for the treatment of menopause symptoms and postmenopausal osteoporosis. Lasofoxifene, another new SERM (similar to tamoxifene) still under investigation, showed reduced risks of non-vertebral and vertebral fractures, estrogen receptorpositive breast cancer, coronary heart disease, and stroke, but an increased risk of venous thromboembolic events [95]. The National Osteoporosis Foundation (NOF) algorithm was updated in 2013 [80]. An important updated caveat is that none of the recommended osteoporosis therapies should be continued indefinitely, and a risk-benefit reassessment should be performed after 3–5 years of therapy. As no uniform guidelines are established, we would like to propose an algorithm for management of osteoporosis in MS patients (Fig. 4). All MS patients supposed to be at risk of osteoporosis should be checked for vitamin D and calcium levels. Serum 25(OH)D levels should be optimized if found deficient; vitamin D 2,000–4,000 IU and calcium 600–1,200 mg/day supplementation is recommended [90]. Patients who cannot ambulate without assistance (EDSS C5), post-menopausal women, and men aged over 40 years should receive a DXA scan to evaluate the BMD. EDSS C5 is an appropriate cut-off as it has been shown to signify irreversible disease progression [96]. Patients with EDSS B5 with presence of other risk factors like recent
fractures, recurrent falls, use of anti-convulsants or steroids, or cognitive dysfunction should also be tested with a DXA scan. Subsequently, the FRAX algorithm should be used to determine whether a patient is suitable for anti-resorptive therapy. Alendronate is the first-line option for treatment of osteoporosis in such patients. Other bisphosphonates, denosumab and strontium ranelate, are the other therapies available. Long-term treatment with anti-resorptive therapies (over 3–5 years) should be re-evaluated given the risk for atypical femoral fracture [97–100]. All at-risk MS patients should also receive counseling to help them alleviate the lifestyle risk factors like cigarette smoking and should be encouraged to perform resistance training and increased specific oriented physical therapy.
8 Conclusion Osteoporosis and fractures are a major cause of morbidity in MS patients. Heightened clinical vigilance to identify risk factors that predispose an MS patient to fractures is warranted because early intervention can improve bone health and decrease fracture risk. A uniform set of guidelines for assessment of fracture risk is necessary. An important facet of this research is required to better understand the effect of specific MS disease-modifying therapies on bone health. More studies should be conducted to provide better treatment plans customized for the requirements of this unique group of patients.
740 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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