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Bone health in chronic neurological diseases: a focus on multiple sclerosis and parkinsonian syndromes
  1. Ruth Dobson1,
  2. Alison Yarnall2,
  3. Alastair John Noyce1,3,
  4. Gavin Giovannoni1
  1. 1Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University, London, UK
  2. 2Institute for Ageing and Health, Newcastle University, Newcastle, UK
  3. 3Reta Lila Weston Institute of Neurological Studies, UCL Institute of Neurology, London, UK
  1. Correspondence to Dr Ruth Dobson, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University, 4 Newark Street, London E1 2AT, UK; ruth.dobson{at}qmul.ac.uk

Abstract

The importance of bone health is increasingly recognised, and there is mounting evidence that neurological conditions are associated with a significantly increased risk of osteoporosis and fractures. This increase in risk is likely to be multifactorial. Multiple sclerosis and Parkinson's disease were identified in the Global Longitudinal Study of Osteoporosis in Women study as significantly associated with osteoporosis. Here, we discuss the literature on bone health, falls and fractures in MS and akinetic-rigid syndromes, and suggest strategies to investigate and manage bone health in the neurology clinic.

  • Multiple Sclerosis
  • Parkinson-S Disease
  • Quality Of Life

https://doi.org/10.1136/practneurol-2012-000435

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    Introduction

    The importance of bone health is increasingly being recognised. Osteoporosis is a major risk factor for fragility-related fractures, such as those at the neck of femur. Fragility fractures (see table 1 for definition) secondary to osteoporosis are a major cause of both morbidity and fatality. Hip fractures account for more mortality, disability and medical cost than all other osteoporosis-related fractures combined,1 and the 1-year death rate following fractured neck of femur is up to 30%.2 Both neurological conditions and treatments used in the neurology clinic (such as long-term corticosteroids and anticonvulsants) have been associated with osteoporosis; however, a bone health assessment is not always routine in the neurology clinic.

    View this table:
    Table 1

    Factors used in the FRAX and QFracture algorithms for assessing fracture risk in individuals

    While a discussion of the entire range of conditions and treatments that require the neurologist to consider bone health is beyond the scope of this review, many of the points raised, and approaches suggested here, can be extended to other conditions. The use of fracture risk tools (see below) should be incorporated into outpatient assessments where appropriate. Multiple sclerosis (MS) and Parkinson's disease (PD) were the two neurological conditions associated with a significantly increased risk of osteoporosis in the Global Longitudinal study of Osteoporosis in Women (GLOW) study,3 and so this review will be limited to MS and parkinsonian syndromes.

    Treatments for osteoporosis range from non-pharmacological lifestyle interventions, such as advice about smoking cessation, through to pharmacological interventions, including calcium and vitamin D supplementation, bisphosphonates, strontium, raloxifene, oestrogen and testosterone supplementation and, most recently, the RANKL inhibitor, denosumab. The use of these are covered by the current guidance from the UK's National Institute of Health and Clinical Excellence (NICE) on the diagnosis (CG146) and treatment of primary (TA160, TA204) and secondary (TA161, TA204) osteoporosis (see table 2). Many variables contribute to osteoporosis risk, including age, sex, weight, height, race, smoking status, vitamin D deficiency, alcohol intake and family history.

    View this table:
    Table 2

    NICE guidelines for the primary prevention of osteoporotic fragility fractures

    Vitamin D deficiency is associated with reduced bone mineral density, probably due to compensatory (or secondary) hyperparathyroidism with a chronic increase in bone resorption as a result. Vitamin D, either photosynthesised by ultraviolet-B radiation in the skin, or obtained from dietary sources, is converted in the liver to 25-hydroxyvitamin D (25-OH vD). It is then activated in the kidneys by 1-α-hydroxylase (1α-OHase) to its active form, 1,25-dihydroxyvitamin D (figure 1).

    Figure 1
    Figure 1

    Vitamin D formation and metabolism.

    A falls assessment is essential when assessing fracture risk: 5% of falls result in a fracture, but 20% of all falls require medical attention.4 Ninety percent of fractures are preceded by a fall.1 The WHO FRAX tool5 provides validated 10-year fracture risk estimates for individuals (see table 1 and figure 2). However, it does not take into account a number of risk factors for osteoporosis including falls risk, or the overall number of secondary causes for osteoporosis that an individual has; this arguably limits its usefulness in neurological conditions. The QFracture algorithm (see table 1 and figure 3) was developed from the UK General Practice database and uses variables included in the FRAX tool, in addition to other variables that affect risk of fracture, including falls, diabetes mellitus, cardiovascular disease and use of systemic corticosteroids and tricyclic antidepressants (table 1). QFracture has been recently updated to include additional variables, including PD, care home residence, anticonvulsant and other antidepressant use.6 An MS-specific fracture risk calculator has been designed,7 but is currently in the early stages of development.

    View this table:
    Table 3

    useful definitions

    Figure 2
    Figure 2

    Screenshot from FRAX tool showing data entry portal and results page, accessed via http://www.shef.ac.uk/FRAX/.

    Figure 3
    Figure 3

    Screenshot from QFracture tool showing data entry portal and results page, accessed via http://www.qfracture.org/.

    Bone health and MS

    People with MS have multiple reasons to be at an increased risk of osteoporosis. Factors that influence MS risk before the onset of overt clinical disease, such as vitamin D deficiency8 and smoking,9 are also associated with osteoporosis. MS is more common in females, with a widening gender ratio over time.10 Following a diagnosis of MS, there are additional factors that may influence an individual's risk of osteopenia and osteoporosis. Physical activity enhances bone health, and the disability and physical fatigue associated with MS combine to adversely affect bone health. The use of high-dose corticosteroids during relapses, and the increased risk of epilepsy11 (and therefore anticonvulsant use) in people with MS may act to decrease bone mineral density.

    Although there is no proven causal link between vitamin D deficiency and MS, there is considerable circumstantial evidence. MS has a strong latitudinal gradient, and its prevalence mirrors ambient ultraviolet radiation.12 Individuals born in the spring (whose mothers have low vitamin D levels during winter pregnancy) have a significantly increased risk of MS,13 and those with serum vitamin D levels in the highest quintile have a relative risk of MS of 0.38 compared with those in the lowest quintile.8

    Falls are a common symptom in MS, with 60% of MS patients reporting single or recurrent falls in the previous 6 months, 60% of which resulted in injury.14 Side effects from medications, such as benzodiazepines, anticonvulsants and antidepressants15 further increase the falls risk.

    Several studies have examined self-reported osteoporosis and/or osteopenia in MS (see16 for review). Both osteopenia and osteoporosis are more common at the femoral neck than the lumbar spine in MS, possibly due to the pattern of immobility. It appears that bone mineral density loss starts early in MS: even ambulatory patients with MS have significantly lower bone mineral density than healthy controls.16

    Whether the treatments used in MS have any effect on bone mineral density remains controversial. There is no definitive answer as to whether short-term high-dose corticosteroids (such as those used to treat relapses) increase the fracture risk in MS: studies appear both to confirm17 and to refute18 this theory. Short course treatments of this type are not accounted for in the FRAX algorithm, which defines glucocorticoid exposure as ‘exposure for more than 3 months at a dose of greater than 5 mg prednisolone/day (or equivalent)’.5 In theory, at least, interferon-β preparations should protect against bone mineral loss in MS through induction of the tumour necrosis factor-related apoptosis-inducing ligand,19 but practical evidence is lacking.

    While some studies report no overall increase in fracture risk with MS,18 ,20 others report an increase in the risk of ‘any fracture’ of up to 1.99.17 ,21 Hip fracture rates are higher in people with MS, who have a HR of 1.9–4.08 (see online supplementary table S1 for a summary of the literature). This is in keeping with the GLOW study, where the HR of fracture in women with MS was 1.7 (95% CI 1.2 to 2.6).3 The predictive power of the FRAX algorithm is improved when MS is incorporated,3 and it seems likely that the FRAX algorithm underestimates the fracture risk in MS.

    To date, there are no papers examining primary prevention of osteoporosis or osteoporotic fractures in MS. There remains much work to be done on bone health in MS, including assessing the effect of both MS disease-modifying treatments and traditional osteoporosis prevention on fracture risk.

    Bone health, PD and atypical parkinsonism

    PD is a clinical diagnosis. The motor features are progressive in nature, and falls increase in frequency with longer disease duration. Falls are relatively unusual in early idiopathic PD and are considered a red/yellow flag for atypical parkinsonism, being more commonly encountered in progressive supranuclear palsy (PSP) and multiple system atrophy.22

    While symptomatic treatment for PD may ameliorate bradykinesia, rigidity and tremor with varying efficacy, dopamine replacement has far less effect on postural instability and falls. Physiotherapy may offer some benefit, but there are no high-quality studies to date. Deep brain stimulation of the subthalamic nucleus can worsen axial symptoms, but it does improve postural stability and reduces falls when the pedunculopontine nucleus is targeted.

    Up to 50% of patients with PD report falling during a 3-month period.23 In a study of 100 patients with PD, 38 reported falls and 13 fell more than once per week.24 Thirteen patients reported fall-related fractures, of which four were femoral neck fractures. Risk factors included older age, disease duration, disease severity and clinical features including bradykinesia, rigidity, postural instability and inability to rise from a chair.24 The GLOW study reported that PD showed the strongest association with incident fractures above all other characteristics.3

    Contributory factors to the increased falls risk in PD include impaired cognition and autonomic dysfunction, including postural hypotension and urinary urgency. Dementia is an independent risk factor for both falls25 and fracture26 in PD. Hip fractures are the most common fragility-related fracture in PD, possibly due to the mechanism of falling.22 ,27 ,28 Online supplementary table S2 summarises the current literature on fracture risk in PD.

    An increased tendency to fall does not entirely explain the elevated fracture risk in PD; PD is also a secondary cause of reduced bone mineral density.29 PD patients have lower serum levels of vitamin D,30 and higher serum vitamin D was associated with a lower risk of developing PD in a longitudinal cohort study.31 Similar to that described in MS, there is a latitudinal gradient of PD prevalence, and there may be an excess risk of PD in those born in springtime;32 although the prevailing viewpoint remains that there is little geographic variation in the prevalence of sporadic PD. Additionally, immobility is associated with both PD and osteoporosis. Inadequate oral intake secondary to dysphagia, nausea and/or depression may lower the body mass index, a further risk factor for osteoporosis. Treatment with levodopa may also increase fracture risk.33

    A study from the Queen Square Brain Bank retrospectively reviewed the case notes of 782 patients with a pathologically confirmed parkinsonian disorder. The mean latency from disease onset to first fall was 12 months in PSP–Richardson syndrome, 42 months in multiple system atrophy, 47 months in PSP–parkinsonism and 108 months in idiopathic PD. Falls were documented in 97.5% of PSP patients (mean disease duration 8 years) and 73.3% of PD patients (mean duration 16 years).22 Early falls in PSP were associated with earlier fatality by 3.3 years.22 Hip fractures were less common in PSP than PD, whereas fractures of the upper limb, other than the wrist, were more common in PSP. Multiple fractures were significantly more common in PSP than in PD or multiple system atrophy.22 More recently, a small study explored falls frequency, fracture risk and subsequent osteoporosis treatment in PSP and multiple system atrophy.34 All subjects had fallen within the last year, with just under half falling monthly. A quarter had sustained a fracture, with hip and rib fracture most common.

    There is little evidence on treating and preventing osteoporosis in PD, and no trials in atypical parkinsonian syndromes. In one study, 86 community-dwelling PD subjects were randomised to either active treatment with an active form of vitamin D (1α-hydroxyvitamin D3) or placebo, and followed-up for 18 months.35 Bone mineral density declined in both groups, but less so in those on active treatment (1.2% vs 6.7%). There were significantly fewer non-vertebral fractures in the treatment group (OR 9.8). Further trials showed that vitamin D2 plus daily risedronate in men,36 and weekly risedronate in women,37 reduced the relative risk of hip fracture in the active group (0.33) versus placebo group (0.20). Daily alendronate with vitamin D2 produced a relative reduction in hip fracture of 0.29 in the active group,38 with a concomitant increase in bone mineral density by 3.8%.

    More recently, PD subjects were assigned to regular sunlight exposure (15 min outdoors on a clear day) or usual lifestyle (n=162 in each group). Vitamin D dietary intake was assessed before and during the study. At 2 years, those in the sunlight-exposed group had an increase in bone mineral density (+3.8% vs −2.6%), an increase in 25-OH vD from 27 nmol/l to 52 nmol/l, and fewer hip fractures (OR 2.4).39

    There are several caveats when interpreting these results. The studies were all undertaken by the same group in Asia, and therefore, may not be generalisable to a Caucasian population. They involved relatively small numbers of patients and have not been replicated. Computer x-ray densitometry, rather than dual-energy x-ray absorptiometry (DXA, the gold standard), was used to measure bone mineral density. Additionally, the doses of both alendronate and risedronate were lower than those used in the UK.

    Discussion

    Both MS and PD are significant risk factors for falls, osteopenia, osteoporosis and fractures. In MS, bone mineral density loss starts before clinical presentation. As discussed previously, reduced bone mineral density in neurological disorders is multifactorial, and requires an integrated and multifaceted approach. Active prevention of immobility and falls is important, as well as adopting other avenues of primary prevention.

    Because most fractures result from falls, falls prevention is important. A recent meta-analysis of six prospective studies of falling in PD found that the strongest predictor of falling was a previous fall in the last year.40 While there is no evidence regarding falls reduction in neurological disorders, falls in the elderly population can be reduced by single or multifactorial interventions. Exercise programmes targeting multiple components (strength, balance, flexibility and endurance) reduce falls rate and risk in community-dwelling elderly people.41 Medication review (withdrawal of psychotropic medications), occupational therapy home assessment, visual assessment and treatment, falls education and management of untreated medical problems reduce the rate but not the risk of falling.41

    We do not have rigorous, evidence-based guidelines to assess and treat low bone mineral density in neurological conditions. Without disease-specific guidelines at present, we suggest that interventions to optimise bone health should follow a logical pattern based on available evidence, and extrapolated to neurological diseases, as outlined in figure 4. Clinicians should actively enquire about risk factors for osteoporosis, and addressing these where needed.

    Figure 4
    Figure 4

    Recommendations for bone health management in multiple sclerosis (MS) and parkinsonian syndromes. (1) There are no falls risk assessment tools that have been validated for use in MS. The best assessed in other conditions is the Activities Balance Confidence scale, ABC, a patient-reported scale. Further research is needed in this area. (2) Given the prevalence of vitamin D deficiency in neurological diseases, patients should have vitamin D status checked at least at baseline, and, if deficient, this should be treated with supplementation. The response to treatment should be monitored. (3) Thyroid function should be checked at least at baseline, given the potentially non-specific symptoms of thyroid dysfunction, which may mimic symptoms associated with neurological diseases. There is currently no indication for regular monitoring unless a clinical suspicion of thyroid dysfunction arises (UK Guidelines for the Use of Thyroid Function Tests; published by the British Thyroid Society 2006).

    We advocate testing vitamin D levels in all patients with MS, and in those PD patients with additional risk factors for osteoporosis. However, the latest guidelines for the general population from the UK National Osteoporosis Society suggest that serum 25-OH vD should only be routinely measured in those with bone diseases (namely osteoporosis and osteomalacia) and those with musculoskeletal symptoms attributable to vitamin D deficiency.42 Having said this, the cause of musculoskeletal symptoms may be difficult to determine in patients with MS, due to the overlap with MS symptoms. Where there is vitamin D deficiency it should be treated; recent European guidelines state that a daily vitamin D dose of 250 µg/day (10 000 IU) gave rise to no adverse effects, and recommend a daily intake of 100 µg/day (4000 IU). Currently, in line with UK Department of Health guidance, the National Osteoporosis Society suggest that people aged 65 years and over, and people who are not exposed to much sunlight should take a daily supplement containing 10 μg (400 IU) of vitamin D; however, it cannot be long before the UK Department of Health catches up with the rest of Europe.

    Higher doses of vitamin D supplementation (>400 IU) are generally only licensed for use in those patients with biochemically demonstrated vitamin D deficiency, meaning that ‘blind’ prescribing of high-dose vitamin D is not possible; patients should have a baseline vitamin D level checked. In patients taking anticonvulsants there are no evidence-based guidelines to guide the dose of vitamin D used for supplementation; however, with the recent increase in the recommended daily intake, clinicians should feel reassured in using high-dose supplementation. Such doses of vitamin D are generally only available without additional calcium, and in the absence of dietary deficiency there is no evidence supporting additional calcium supplementation. Clinicians should take care as vitamin D supplementation can unmask undiagnosed hyperparathyroidism; recent draft guidelines recommend checking adjusted serum calcium 1 month after starting vitamin D.42

    There is an increasing literature in MS supporting the assertion that for optimal immunological function, the level of supplementation should be 4000–5000 IU/day, and recent trials have used doses as high as 20 000 IU per week. In view of the lack of specific guidance and literature in PD, we propose that the European guidance to the general population should be extrapolated to this patient group.

    Thyroid function should also be checked, as the non-specific symptoms of hypothyroidism overlap with those commonly experienced by people with both MS and PD. NICE guidelines (TA204) recommend assessing fracture risk in women aged under 65 years and men under 75 years who have ‘secondary causes of osteoporosis’, one of which is immobility. As discussed above, the FRAX tool is likely to underestimate the risk of fracture. However, we recommend using either this or QFracture to identify those patients requiring DXA imaging regardless of their neurological comorbidity. If disease-specific fracture risk calculators become validated then we would recommend their use.7

    There is no consensus as to the magnitude of 5- or 10-year fracture risk at which to perform a DXA scan. The UK National Osteoporosis Guideline Group recommends an age-dependent intervention threshold, ranging from 7.5% to 30% 10-year fracture risk. It would therefore seem appropriate to suggest DXA to patients with an estimated fracture of risk 5–25%, depending on age (see http://www.shef.ac.uk/NOGG/downloads.html for guidance tables). Those patients who have sustained a fragility fracture and are aged under 75 years should have DXA scanning regardless of their calculated 10-year fracture risk.

    Should we be more proactive with our patients? Fragility fractures are a major source of morbidity and fatality, and there is considerable mobility loss associated with hip fractures in those with neurological diseases. Although there are no trials to support aggressive bone health monitoring, we argue that people with MS and PD should have fracture risk assessments and bone mineral density measurements performed proactively, identifying early, those with a significantly increased fracture risk. Also, those with MS who are suffering from frequent relapses and/or rapidly progressive disability should be offered repeat DXA screening, as recent relapse has been shown to affect overall fracture risk, possibly as a surrogate marker for a recent increase in disability.7 There is no evidence to guide the frequency of repeat DXA scanning, although a frequency of 3–5 years has been suggested in MS. A similar approach should be considered in patients with other chronic neurological disorders.

    The treatment of osteoporosis should follow locally agreed guidelines. Risk factor modification, such as smoking cessation advice and correcting low vitamin D should be routine in all patients, as discussed above. Combined calcium and vitamin D supplementation reduces fractures only in the institutionalised elderly,44 but in practice it forms the mainstay of primary osteoporosis prevention. The treatment of low bone mineral density demonstrated on DXA scanning is covered by NICE guidance on the treatment of primary (TA160, TA204) and secondary (TA161, TA204) osteoporosis (see table 2). Bisphosphonate use in neurological disease is complicated by side effects; the main side effect of strontium is nausea—a common non-motor symptom in PD. Intravenous bisphosphonates or subcutaneous denosumab may be suitable alternatives where bisphosphonates are not tolerated, or in those with neurological dysphagia, However, NICE guidelines preclude their use as a first-line therapy (see table 2). In atypical parkinsonian syndromes, as mean life expectancy is reduced, quality of life and reduction in morbidity are important considerations. In complex cases, or where first-line treatments are not tolerated, patients may require referral for a specialist opinion, either to a metabolic bone clinic or according to local pathways.

    It is clear that we need further trials in neurological diseases to better understand the magnitude of the problem; we need a suitable strategy for screening programmes in our patients, and we need effective strategies to treat reduced bone mineral density before patients suffer from fragility fractures.

    Key points

    • Think about factors affecting bone health in all neurology patients.

    • Both falls and reduced bone mineral density contribute to fracture risk, and so both aspects must be addressed.

    • Patients with MS and PD are likely to be deficient in vitamin D: remember to check and supplement where needed.

    • While fracture risk calculators are not perfect, they provide an indication as to who may need a DXA scan, and should be used routinely.

    Acknowledgments

    We thank Dr Terry J Aspray, Honorary Clinical Senior Lecturer and Consultant in Metabolic Bone Disease at the Freeman Hospital, Newcastle upon Tyne, for comments on the manuscript. In addition, we would like to thank Dr Sam Jackson for figure 3.

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    Supplementary materials

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    Footnotes

    • Contributors RD and GG conceived the idea of this review. RD, AY and AJN performed the literature search and wrote the initial draft of the manuscript. All authors contributed to the final development of the manuscript. GG is acting as guarantor of the manuscript.

    • Funding RD is funded by an Association of British Neurologists/MS Society of Great Britain Clinical Research Fellowship (grant number 940/10). AJY is supported by grants from the Newcastle University Lockhart Parkinson's Disease Fund and the MJ Fox Foundation. AJN is supported by Parkinson's UK Career Development Award (doctoral level). GG receives grant support from the MRC, National MS Society, MS Society of Great Britain and Northern Ireland, AIMS2CURE and the Roan Charitable Trust.

    • Competing interests AJY has received funds from Teva–Lundbeck and UCB for attending conferences. AJN has received funds from the National Institute of Health Research for attending conferences and has provided consulting to Élan Pharmaceuticals. GG has received research grant support from Bayer–Schering Healthcare, Biogen–Idec, GW Pharma, Merck Serono, Merz, Novartis, Teva and Sanofi–Aventis. GG has received personal compensation for participating on Advisory Boards in relation to clinical trial design, trial steering committees and data and safety monitoring committees from: Bayer–Schering Healthcare, Biogen–Idec, Eisai, Elan, Fiveprime, Genzyme, Genentech, GSK, Ironwood, Merck–Serono, Novartis, Pfizer, Roche, Sanofi–Aventis, Synthon BV, Teva, UCB Pharma and Vertex Pharmaceuticals.

    • Provenance and peer review Commissioned; externally peer reviewed. This paper was reviewed by Anthony Johannsen, Cardiff, UK.

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