Joint Bone Spine 82 (2015) 406–410
Available online at
ScienceDirect www.sciencedirect.com
Review
Parkinson’s disease: A risk factor for osteoporosis Sandrine Malochet-Guinamand a,∗ , Franck Durif b , Thierry Thomas c a
Department of Rheumatology, Clermont-Ferrand University Hospital, 63003 Clermont-Ferrand cedex 1, France Department of Neurology, Clermont-Ferrand University Hospital, 63003 Clermont-Ferrand cedex 1, France c Inserm U1059, Rheumatology Department, University Hospital of Saint-Étienne, 42055 Saint-Étienne cedex 2, France b
a r t i c l e
i n f o
Article history: Accepted 11 March 2015 Available online 6 October 2015 Keywords: Parkinson’s disease Osteoporosis Fracture Risk factors
a b s t r a c t Parkinson’s disease is the most common neurodegenerative disease after Alzheimer’s disease. On the long term, it may be complicated by various musculoskeletal problems, such as osteoporotic fractures, that have significant socioeconomic consequences. Indeed, patients suffering from Parkinson’s disease have a higher fracture risk, particularly hip fracture risk, than other subjects of the same age because of both a higher risk of falls and lower bone mineral density. Bone loss in Parkinson’s disease may be associated with the severity and duration of the disease. We review here the different suspected mechanisms of accelerated bone loss in Parkinson’s disease, amongst which weight loss and reduced mobility appear to play key roles. Antiparkinsonian drugs, particularly levodopa, may also be associated with decreased bone mineral density as a result of hyperhomocysteinaemia. We discuss the role of other nutritional deficiencies, such as vitamin B12, folate or vitamin K. In conclusion, it seems necessary to screen for and treat osteoporosis in this at-risk population, while actions to prevent falls are still disappointing. A better understanding of the factors explaining bone loss in this population would help implementing preventive actions. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Parkinson’s disease (PD) is the most frequently-seen neurodegenerative disease after Alzheimer’s disease. It has an estimated prevalence of 1% in subjects over the age of 60, and due to population aging, the socioeconomic impact of PD is markedly growing [1]. PD generally begins around the age of 60, and is evidenced by bradykinesia, plastic rigidity and a resting tremor. It is caused by a severe decline in dopamine amount in the striatum secondary to a progressive loss of dopaminergic neurones in the pars compacta of the substantia nigra. Treatment is mainly symptomatic and based on the use of dopaminergic drugs, such as l-dopa dopaminergic agonists and inhibitors of the l-dopa/dopamine catabolic enzymes. The therapeutic arsenal also includes non-dopaminergic drugs, such as anticholinergics drugs and glutamatergic receptor inhibitors. In advanced PD forms, deep brain stimulation of the subthalamic nuclei can be proposed. PD is associated with many comorbidities, and musculoskeletal problems are among the most frequent ones. Indeed, a survey of PD patients revealed that they significantly suffer from musculoskeletal problems more than age- and gender-matched controls (66.3%
∗ Corresponding author. E-mail address: [email protected] (S. Malochet-Guinamand).
vs. 45.7%, P < 0.001) [2]. Age, female gender, and disease severity were associated with musculoskeletal problems in the PD patient group [2]. 2. Parkinson’s disease, fractures and falls Retrospective case-control studies have demonstrated that PD patients have a higher risk of fragility fractures than age-matched controls [3–5]. A meta-analysis of prospective cohort studies confirmed the higher risk of fracture in these patients (hazard ratio 2.66, 95% confidence interval CI = 2.10–3.36) [6]. In the multinational GLOW cohort, 52,960 participants were followed for two years and 3224 had a fracture. The PD appeared as the most closely associated with fracture comorbidity (age-adjusted hazard ratio 2.2; 95% CI = 1.6–3.1, P < 0.001) [7]. The most frequent site of fractures is the hip [3,4,8]. A retrospective study analysing the “Nationwide Inpatient Sample” cohort, which represents 20% of US hospital admissions from 1988 to 2007, demonstrated that 3.6% of patients hospitalised for a hip fracture had PD. The prevalence of PD in these hospitalised patients was actually four times higher than the prevalence expected in the general population after adjustments for gender and age [9]. Likewise, an analysis of a prospective database of the United Kingdom health insurance system showed an increase in the relative risk of hip fracture (i.e. 3.7; 95% CI = 2.6–5.3) in PD patients over the age of 60 compared to the
http://dx.doi.org/10.1016/j.jbspin.2015.03.009 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
rest of the population. This increased risk was present regardless of the gender and age group, except in subjects over the age of 85 years old [10], while the same analysis in a large German health insurance company database demonstrated a larger increase in hip fracture risk in women than in men [11]. The retrospective study of the General Practice Research Database in United Kingdom delivered very similar results, with a significant increase in hip fracture risk in Parkinsonian patients compared with the rest of the population (adjusted hazard ratio [AHR] 3.08; 95% CI = 2.43–3.89) [8]. Moreover a meta-analysis of second hip fracture risk factors showed that PD was also a major risk factor for subsequent hip fractures [12]. These fractures generate high treatment costs for PD patients [13]. In the British database analysis [10], time to discharge to home was longer in PD patients than in other patients, with less postoperative mobility. In their prospective cohort study following 920 hip fractures, Idjadi et al. also demonstrated that Parkinsonian patients experienced longer hospitalisations and were more frequently discharged to a skilled nursing facility as they were more dependent when performing activities of daily living [14]. While, 2 prospective studies conducted in patients after hip fracture did not reveal higher postoperative mortality after one [14] and 2 years [15] in PD patients, a retrospective observational analysis of a cohort of MEDICARE patients showed instead a higher mortality after hip or pelvic fracture in PD patients (HR 2.41, 95% CI = 2.37–2.46) [16]. The occurrence of falls is a major factor related to fracture risk in Parkinsonian patients [8,17,18]. In fact, the meta-analysis of six prospective studies assessing fall risk in PD demonstrated a fall risk of approximately 50% over a three-month follow-up period [19]. Over a longer eight-year follow-up period, 75% of PD patients reported at least one fall [20]. However the higher fall risk is not the only explanation for the increased risk of fracture in PD. Thus, in a retrospective cohort study conducted by Pouwels et al. [8], the fracture risk was higher in patients with a history of fracture, fall, low body mass index (BMI), kidney disease, antidepressant use and the use of high doses of antipsychotics. This study did not provide any bone mineral density (BMD) data. In a small prospective cohort study evaluating fracture risk in PD, the patients experiencing fractures had lower BMI, metacarpal BMD, ionised calcium and lower vitamin D levels, together with higher parathyroid hormone levels, compared to those who did not experience fractures. In addition, women with fractures tended to have a longer period since menopause [21]. A case-control study of Danish health registries demonstrated that the higher fracture risk in PD patients compared with age- and gender-matched controls (OR 2.2; 95% CI = 2.0–2.05) declined (OR 1.18; 95% CI = 1.01–1.37) after adjusting for different variables, such as corticosteroid use, lifestyle, number of bed days in hospital, number of contacts to general practitioner or specialist and intake of various treatments [22]. Beside the PD itself, l-dopa treatment was associated with an overall higher fracture risk and at high doses, a higher risk of hip fracture. Use of neuroleptics also was associated with a higher fracture risk at nearly all sites and at almost any dose [22]. There were no data on BMD in this study. In a prospective SOF cohort study of 6767 women over the age of 66 years old, PD was the most predictive factor of hip fracture in a multivariate analysis not taking BMD into consideration. In the multivariate analysis model integrating femoral neck BMD, PD remained strongly correlated with hip fracture risk, but the correlation was no more significant [23]. The authors suggested that this absence of significance was related to the limited number of PD subjects in the study (n = 32).
3. Parkinson’s disease and bone loss A meta-analysis concluded that PD patients were at higher risk of osteoporosis than healthy control subjects (OR 1.18, 95%
407
CI = 1.09–1.27). The risk was more marked in male PD subjects than in healthy controls with an odds ratio of 2.44 versus male control subjects (95% CI = 1.37–4.34) [24]. A recent second meta-analysis provided consistent results, with Parkinsonian patients having a higher risk of being osteoporotic than healthy controls (OR 2.61, 95% CI = 1.69–4.03) [25] and a lower risk of osteoporosis or osteopenia in men than in women (OR 0.45; 95% CI 0.29–0.68). Longitudinal prospective studies demonstrated more rapid bone loss in Parkinsonian patients than in controls. For example, in the Mr OS cohort study of 5937 men over the age of 65 who were followed for a mean of 4.6 years (± 0.4 SD), annual aged-adjusted hip bone loss was significantly faster in PD men than in controls (−1.08% vs. −0.36%, P < 0.001) [26]. Likewise in the SOF cohort study, PD women aged 65 or older with a mean follow-up period of 3.6 years had a hip bone loss of 1.3% compared to 0.6% in controls (P = 0.01) [27]. While Lorefält et al. found in a small longitudinal case-control study, an annual hip bone loss of 3.9% in patients having PD for approximately 4.6 years, versus 0.4% in the control group [28], Lee et al. reported in the placebo arm of a small controlled study conducted in PD patients whose disease had been present for an average of 36 months, a rate of bone loss of 1.2% per year at the spine and 2.5% per year at the hip [29]. While these studies do not infer that BMD alteration might be related to the duration of the disease, other studies suggest that the relationship between PD and low bone density is related to the severity of the disease, as measured by Hoen and Yahr scale stages, and to the duration of disease evolution [30–33]. However, most of these studies do not eliminate potential confounding factors such as age or weight by multivariate analysis or adjustments. Therefore it remains difficult to determine whether there is a real interaction between disease severity or duration and bone loss. In addition, some authors do not confirm this association [28,34,35]. These discrepancies could be due to different inclusion criteria in the study populations, whereas in prospective cohort studies, the influence of the PD characteristics could not be reliably evaluated because PD diagnosis was only declarative [7,26,27].
4. Pathophysiology of Parkinson’s disease-related bone loss 4.1. Weight loss Several mechanisms may contribute to this PD-related bone loss. Weight and body mass index (BMI) strongly correlate with bone mass. After adjustment for age, the women of the SOF cohort study with PD had a 7.3% lower BMD than other women (P < 0.01). A multivariate analysis demonstrated that PD women had a BMD 2.1% lower than the other women after adjustment for weight, age, neuromuscular function, calcium and vitamin D intake, but the difference was no more significant (P = 0.41). In the multivariate analysis, body weight explained 72% of the BMD difference between the PD group and the control group [27]. Weight and BMI also emerged as factors associated with BMD in PD for other authors [28,29,35]. Weight loss and malnutrition are definitely observed in PD and the severity of the malnutrition is partly related to the severity of the disease [36]. In their meta-analysis, Van der Mark et al. demonstrated that PD patients had a lower BMI than controls (overall effect 1.73, 95% CI = 1.11–2.35 P < 0.00) [37]. This weight loss was greater in patients with more severe disease (Hoehn and Yahr stage 3 versus 2) but was not related to the duration of the disease [37]. Weight loss may even occur in the early stages of the disease, and contrary to what is observed in other diseases, there seems to be a more marked loss of fat mass [38]. Different hypotheses were put forward to explain this weight loss, such as a decrease in food intake, although this has not been demonstrated. There is also an
408
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
increase in energy expenditure, which seems to return to normal after subthalamic stimulation [39]. Finally, some data suggest that hypothalamic dysfunction may be responsible for disturbance in appetite regulation and weight loss in Parkinsonian patients [38]. 4.2. Mobility, muscle strength Bone is a tissue that is sensitive to mechanical loading. Immobilization or hypokinesia lead to a decrease in bone density, while mechanical loading through physical exercise improves bone density [40]. Low levels of physical exercise can be correlated with low bone density in Parkinson’s disease [28]. According to Van den Bos et al. [35] the level of physical activity was one of the determinants of BMD in Parkinsonian patients, although the association was lost after adjusting for age, gender, weight and height. For other authors, a decrease in physical performance [27] or a decrease in muscle strength [41,42] was associated with a low BMD. In a case-control study conducted by Pang MY et al., PD patients had significantly lower walking velocity, walking endurance and leg muscle strength than matched control subjects. Leg muscle strength alone explained 8.8 to 10.6% of the variance in hip BMD in PD patients after controlling for BMI, time since menopause, Hoehn and Yahr stage and postural stability (P < 0.05) [41]. Another study by the same authors demonstrated that PD patients had significantly lower trunk muscle strength compared with controls, but had more trunk rigidity. After adjustment, trunk muscle strength but not rigidity was independently related to spine BMD, explaining 10% of the variance [42]. 4.3. Parkinson’s disease and vitamin D Several authors have suggested a link between vitamin D levels and Parkinson’s disease. In fact, animal studies demonstrated that vitamin D could provide protection from toxic aggressions that can damage dopaminergic cells [43,44]. The 1,25-dihydroxyvitamin D receptor (VDR) and 1␣-hydroxylase, the enzyme responsible for the formation of the active form of vitamin D are present in the substantia nigra and it has been suggested that vitamin D insufficiency may lead to degeneration and death of dopaminergic neurons [44]. Vitamin D could also have an effect on the development and severity of PD, but the only interventional study performed so far to improve PD symptoms had demonstrated negative results [45]. PD patients have lower vitamin D levels than healthy controls [45] and patients with Alzheimer disease [46]. However, it is difficult to know if this observation is a cause or a consequence of the PD. It may be just that the loss in mobility related to the disease is responsible for a decrease in vitamin D levels due to a decrease in sun exposure. Furthermore, low vitamin D levels seem to be associated with an increased fall risk in elderly subjects. Likewise, low vitamin D levels are associated with bone loss and an increased non-vertebral and hip fracture risk in elderly subjects [47]. For Van den Bos et al., vitamin D levels was one of the factors that significantly correlated with a low BMD in PD patients and this association remained significant after multivariate analysis [35]. 4.4. Parkinson’s disease treatments PD treatments may also have a detrimental effect on bone mineral density. Several data suggest a correlation between l-dopa therapy and increased fracture risk [22,48]. In addition, it has been demonstrated that higher doses of l-dopa were associated with lower BMD values at some sites [34]. This adverse effect of l-dopa could be secondary to the increase in homocysteine levels. Indeed, in the presence of dopa decarboxylase, l-dopa metabolism leads to homocysteine production. A meta-analysis demonstrated that homocysteine levels were significantly higher in patients suffering
from idiopathic Parkinson’s disease treated by l-dopa compared to PD patients not being treated with l-dopa or treatment naive PD patients and compared to healthy control subjects [49]. Hyperhomocysteinaemia seems to be associated with low BMD and increased fracture risk in the general population although some results are inconsistent [50]. It may have a deleterious effect on bone through an effect on bone remodelling, reducing bone formation and increasing osteoclastic bone resorption activity as a result of increased intracellular oxidative stress. Hyperhomocysteinemia may also have a direct deleterious action on the bone matrix [51]. 4.5. Dietary deficiencies Eating disorders associated with Parkinson’s disease could promote folate and vitamin B12 deficiencies, and thus be another source of increased plasma homocysteine levels. In fact, Lee et al. showed that vitamin B12 and folate supplementation in PD patients treated with l-dopa could prevent hyperhomocysteinaemia and bone loss [29]. Other nutritional factors, such as vitamin K, could also be implicated. Vitamin K is involved in the carboxylation of some proteins containing the GLA residue, such as bone proteins like osteocalcin. Epidemiological studies in the general population demonstrated that low vitamin K levels are correlated with a lower BMD and an increased fracture risk [52]. A case-control study conducted by Sato et al. demonstrated that vitamin K level was independently correlated with bone density in PD patients with severe functional disabilities (Hoehn and Yahr stage 3 to 5) [53]. They also showed in a small controlled study that vitamin K supplementation could improve metacarpal BMD of patients aged 65 and older being followed for PD for a mean duration of 5 years [54]. 5. Parkinson’s disease and osteoporosis treatment The efficacy of osteoporosis treatments in reducing fracture rate has been clearly demonstrated in postmenopausal women. There are fewer studies in men, and their results rely mostly on their effectiveness evaluated by bone mineral density changes. Results in terms of fracture prevention are less consistent due to the heterogeneity of the disease in men and a lack of power related to insufficient subject numbers. Only rare data are available on the effectiveness of osteoporosis treatments in Parkinsonian patients. A small, double-blind, randomised study of 288 elderly women with PD treated either with alendronate and vitamin D or placebo and vitamin D for two years demonstrated a significant decrease in hip fracture risk in the alendronate treatment arm (relative risk 0.29; 95% CI = 0.10–0.85) [55]. The same authors found similar results with another bisphosphonate, risedronate, in elderly women suffering from PD with a relative risk of hip fracture of 0.2 at two years in treated women compared to the placebo group (95% CI = 0.06–0.66) [56]. Finally, the authors also conducted a study on 272 elderly men with PD. They observed an insignificant decrease in the number of hip fractures in the risedronate plus vitamin D arm compared with the placebo plus vitamin D arm (3 vs. 9). However, bone density significantly increased in the treatment group after two years while it decreased in the placebo group. The authors also observed a significant decrease in bone resorption markers in the risedronate group compared with the placebo group [57]. The facts that these studies all come from the same team have small study populations and were over a short duration limit the strength of their conclusion. There are no specific data on zoledronic acid efficacy in this population, although it has demonstrated its effectiveness in preventing vertebral, non-vertebral and hip fractures in postmenopausal women [58]. Zoledronic acid was also associated with
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
a reduction in the rate of new clinical fractures in elderly male and female after hip fracture [59]. Because it is administrated intravenously once a year, it would seem to be a treatment of choice for osteoporosis in these patients who are taking multiple medications and are often prone to swallowing problems. The use of denosumab, an anti-RANK-ligand antibody is also an interesting alternative in this situation as it has demonstrated a comparable effectiveness in reducing fracture risk in postmenopausal osteoporosis with a simple route of administration (i.e. a subcutaneous injection every six months) [60]. 6. Conclusion It has been clearly demonstrated that PD patients have an increased risk of fracture, particularly at the hip, as a result of an increased risk of falls and other risk factors, particularly lower BMD. The consequences of these fractures are even more serious in this population, particularly in terms of morbidity. There are no data on radiological vertebral fracture prevalence in this population, although it is likely to be high. These results strongly support recommendations of a regular assessment of bone density and risk factors for fracture in PD patients. Even though the fall risk factors have been identified in PD, no specific preventive management has yet been proven [61]. Therefore in cases of densitometric osteoporosis or after the occurrence of a low energy fracture it is mandatory to follow the current guidelines for the management of postmenopausal osteoporosis, even though they are not specifically dedicated to PD patients. A better understanding of the mechanisms of bone loss in PD, some of which are modifiable, could lead to early preventive measures that may reduce fracture risk through improved nutrition and physical activity. It is also important to correctly assess the impact of PD treatments in this context. Further studies, conducted in a prospective manner in large populations, are required to better clarify the respective role of different factors responsible for bone fragility related to PD. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol 2006;5:525–35. [2] Kim YE, Lee WW, Yun JY, et al. Musculoskeletal problems in Parkinson’s disease: neglected issues. Parkinsonism Relat Disord 2013;19:666–9. [3] Johnell O, Melton 3rd LJ, Atkinson EJ, et al. Fracture risk in patients with parkinsonism: a population-based study in Olmsted County, Minnesota. Age Ageing 1992;21:32–8. [4] Genever RW, Downes TW, Medcalf P. Fracture rates in Parkinson’s disease compared with age- and gender-matched controls: a retrospective cohort study. Age Ageing 2005;34:21–4. [5] Chen YY, Cheng PY, Wu SL, et al. Parkinson’s disease and risk of hip fracture: an 8-year follow-up study in Taiwan. Parkinsonism Relat Disord 2012;18:506–9. [6] Tan L, Wang Y, Zhou L, et al. Parkinson’s disease and risk of fracture: a metaanalysis of prospective cohort studies. PLoS One 2014;9:e94379. [7] Dennison EM, Compston JE, Flahive J, et al. Effect of co-morbidities on fracture risk: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Bone 2012;50:1288–93. [8] Pouwels S, Bazelier MT, de Boer A, et al. Risk of fracture in patients with Parkinson’s disease. Osteoporos Int 2013;24:2283–90. [9] Bhattacharya RK, Dubinsky RM, Lai SM, et al. Is there an increased risk of hip fracture in Parkinson’s disease? A nationwide inpatient sample. Mov Disord 2012;27:1440–3. [10] Walker RW, Chaplin A, Hancock RL, et al. Hip fractures in people with idiopathic Parkinson’s disease: incidence and outcomes. Mov Disord 2013;28:334–40. [11] Benzinger P, Rapp K, Maetzler W, et al. Risk for femoral fractures in Parkinson’s disease patients with and without severe functional impairment. PLoS One 2014;9:e97073. [12] Zhu Y, Chen W, Sun T, et al. Meta-analysis of risk factors for the second hip fracture (SHF) in elderly patients. Arch Gerontol Geriatr 2014;59:1–6.
409
[13] Pressley JC, Louis ED, Tang MX, et al. The impact of comorbid disease and injuries on resource use and expenditures in parkinsonism. Neurology 2003;6:87–93. [14] Idjadi JA, Aharonoff GB, Su H, et al. Hip fracture outcomes in patients with Parkinson’s disease. Am J Orthop 2005;34:341–6. [15] Londos E, Nilsson LT, Strömqvist B. Internal fixation of femoral neck fractures in Parkinson’s disease. 32 patients followed for 2 years. Acta Orthop Scand 1989;60:682–5. [16] Harris-Hayes M, Willis AW, Klein SE, et al. Relative mortality in U.S. Medicare beneficiaries with Parkinson disease and hip and pelvic fractures. J Bone Joint Surg Am 2014;96:e27. [17] Shribman S, Torsney KM, Noyce AJ, et al. A service development study of the assessment and management of fracture risk in Parkinson’s disease. J Neurol 2014;261:1153–9. [18] Cheng KY, Lin WC, Chang WN, et al. Factors associated with fall-related fractures in Parkinson’s disease. Parkinsonism Relat Disord 2014;20:88–92. [19] Pickering RM, Grimbergen YA, Rigney U, et al. A meta-analysis of six prospective studies of falling in Parkinson’s disease. Mov Disord 2007;22:1892–900. [20] Hiorth YH, Larsen JP, Lode K, et al. Natural history of falls in a populationbased cohort of patients with Parkinson’s disease: an 8-year prospective study. Parkinsonism Relat Disord 2014;20:1059–64. [21] Sato Y, Kaji M, Tsuru T, et al. Risk factors for hip fracture among elderly patients with Parkinson’s disease. J Neurol Sci 2001;182:89–93. [22] Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with parkinsonism and anti-Parkinson drugs. Calcif Tissue Int 2007;81:153–61. [23] Taylor BC, Schreiner PJ, Stone KL, et al. Long-term prediction of incident hip fracture risk in elderly white women: study of osteoporotic fractures. J Am Geriatr Soc 2004;52:1479–86. [24] Zhao Y, Shen L, Ji HF. Osteoporosis risk and bone mineral density levels in patients with Parkinson’s disease: a meta-analysis. Bone 2013;52:498–505. [25] Torsney KM, Noyce AJ, Doherty KM, et al. Bone health in Parkinson’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2014;85:1159–66. [26] Fink HA, Kuskowski MA, Taylor BC, et al. Association of Parkinson’s disease with accelerated bone loss, fractures and mortality in older men: the Osteoporotic Fractures in Men (MrOS) study. Osteoporos Int 2008;19:1277–82. [27] Schneider JL, Fink HA, Ewing SK, et al. The association of Parkinson’s disease with bone mineral density and fracture in older women. Osteoporos Int 2008;19:1093–7. [28] Lorefält B, Toss G, Granérus A-K. Bone mass in elderly patients with Parkinson’s disease. Acta Neurol Scand 2007;116:248–54. [29] Lee SH, Kim MJ, Kim BJ, et al. Homocysteine-lowering therapy or antioxidant therapy for bone loss in Parkinson’s disease. Mov Disord 2010;25:332–40. [30] Abou-Raya S, Helmii M, Abou-Raya A. Bone and mineral metabolism in older adults with Parkinson’s disease. Age Ageing 2009;38:675–80. [31] Bezza A, Ouzzif Z, Naji H, et al. Prevalence and risk factors of osteoporosis in patients with Parkinson’s disease. Rheumatol Int 2008;28:1205–9. [32] Kamanli A, Ardicoglu O, Ozgocmen S, et al. Bone mineral density in patients with Parkinson’s disease. Aging Clin Exp Res 2008;20:277–9. [33] Song IU, Kim JS, Lee SB, et al. The relationship between low bone mineral density and Parkinson’s disease in a Korean population. Clin Neurosci 2009;16:807–9. [34] Lee SH, Kim MJ, Kim BJ, et al. Hyperhomocysteinemia due to levodopa treatment as a risk factor for osteoporosis in patients with Parkinson’s disease. Calcif Tissue Int 2010;86:132–41. [35] Van den Bos F, Speelman AD, van Nimwegen M, et al. Bone mineral density and vitamin D status in Parkinson’s disease patients. J Neurol 2013;260:754–60. [36] Sheard JM, Ash S, Mellick GD, et al. Markers of disease severity are associated with malnutrition in Parkinson’s disease. PLoS One 2013;8:e57986. [37] Van der Marck MA, Dicke HC, Uc EY, et al. Body mass index in Parkinson’s disease: a meta-analysis. Parkinsonism Relat Disord 2012;18:263–7. [38] Rieu I, Boirie Y, Morio B, et al. The idiopathic Parkinson’s disease: a metabolic disease? Rev Neurol (Paris) 2010;166:822–8. [39] Montaurier C, Morio B, Bannier S, et al. Mechanisms of body weight gain in patients with Parkinson’s disease after subthalamic stimulation. Brain 2007;130:1808–18. [40] Howe TE, Shea B, Dawson LJ, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev 2011, http://dx.doi.org/10.1002/14651858 [CD000333]. [41] Pang MY, Mak MK. Muscle strength is significantly associated with hip bone mineral density in women with Parkinson’s disease: a cross-sectional study. J Rehabil Med 2009;41:223–30. [42] Pang MY, Mak MK. Trunk muscle strength, but not trunk rigidity, is independently associated with bone mineral density of the lumbar spine in patients with Parkinson’s disease. Mov Disord 2009;24:1176–82. [43] Peterson AL. A review of vitamin D and Parkinson’s disease. Maturitas 2014;78:40–4. [44] Newmark HL1, Newmark J. Vitamin D and Parkinson’s disease – a hypothesis. Mov Disord 2007;22:461–8. [45] Lv Z, Qi H, Wang L, et al. Vitamin D status and Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci 2014;35:1723–30. [46] Evatt ML, DeLong MR, Khazai N, et al. Prevalence of vitamin D insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 2008;65:1348–52. [47] Rizzoli R, Boonen S, Brandi ML, et al. Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Curr Med Res Opin 2013;29:305–13.
410
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
[48] Arbouw ME, Movig KL, van Staa TP, et al. Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study. Osteoporos Int 2011;22:2197–204. [49] Hu XW, Qin SM, Li D, et al. Elevated homocysteine levels in levodopatreated idiopathic Parkinson’s disease: a meta-analysis. Acta Neurol Scand 2013;128:73–82. [50] Nieves JW. Skeletal effects of nutrients and nutraceuticals, beyond calcium and vitamin D. Osteoporos Int 2013;24:771–86. [51] Vacek TP, Kalani A, Voor MJ, et al. The role of homocysteine in bone remodeling. Clin Chem Lab Med 2013;51:579–90. [52] Knapen MH, Drummen NE, Smit E, et al. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int 2013;24:2499–507. [53] Sato Y, Kaji M, Tsuru T, et al. Vitamin K deficiency and osteopenia in vitamin D-deficient elderly women with Parkinson’s disease. Arch Phys Med Rehabil 2002;83:86–91. [54] Sato Y, Honda Y, Kaji M, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency. Bone 2002;31:114–8.
[55] Sato Y, Iwamoto J, Kanoko T, et al. Alendronate and vitamin D2 for prevention of hip fracture in Parkinson’s disease: a randomized controlled trial. Mov Disord 2006;21:924–9. [56] Sato Y, Iwamoto J, Honda Y. Once-weekly risedronate for prevention of hip fracture in women with Parkinson’s disease: a randomised controlled trial. J Neurol Neurosurg Psychiatry 2011;82:1390–3. [57] Sato Y, Honda Y, Iwamoto J. Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease. Neurology 2007;68:911–5. [58] Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809–22. [59] Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799–809. [60] Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65. [61] Allen NE, Schwarzel AK, Canning CG. Recurrent falls in Parkinson’s disease: a systematic review. Parkinsons Dis 2013, http://dx.doi.org/10.1155/ 2013/906274.
Available online at
ScienceDirect www.sciencedirect.com
Review
Parkinson’s disease: A risk factor for osteoporosis Sandrine Malochet-Guinamand a,∗ , Franck Durif b , Thierry Thomas c a
Department of Rheumatology, Clermont-Ferrand University Hospital, 63003 Clermont-Ferrand cedex 1, France Department of Neurology, Clermont-Ferrand University Hospital, 63003 Clermont-Ferrand cedex 1, France c Inserm U1059, Rheumatology Department, University Hospital of Saint-Étienne, 42055 Saint-Étienne cedex 2, France b
a r t i c l e
i n f o
Article history: Accepted 11 March 2015 Available online 6 October 2015 Keywords: Parkinson’s disease Osteoporosis Fracture Risk factors
a b s t r a c t Parkinson’s disease is the most common neurodegenerative disease after Alzheimer’s disease. On the long term, it may be complicated by various musculoskeletal problems, such as osteoporotic fractures, that have significant socioeconomic consequences. Indeed, patients suffering from Parkinson’s disease have a higher fracture risk, particularly hip fracture risk, than other subjects of the same age because of both a higher risk of falls and lower bone mineral density. Bone loss in Parkinson’s disease may be associated with the severity and duration of the disease. We review here the different suspected mechanisms of accelerated bone loss in Parkinson’s disease, amongst which weight loss and reduced mobility appear to play key roles. Antiparkinsonian drugs, particularly levodopa, may also be associated with decreased bone mineral density as a result of hyperhomocysteinaemia. We discuss the role of other nutritional deficiencies, such as vitamin B12, folate or vitamin K. In conclusion, it seems necessary to screen for and treat osteoporosis in this at-risk population, while actions to prevent falls are still disappointing. A better understanding of the factors explaining bone loss in this population would help implementing preventive actions. © 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
1. Introduction Parkinson’s disease (PD) is the most frequently-seen neurodegenerative disease after Alzheimer’s disease. It has an estimated prevalence of 1% in subjects over the age of 60, and due to population aging, the socioeconomic impact of PD is markedly growing [1]. PD generally begins around the age of 60, and is evidenced by bradykinesia, plastic rigidity and a resting tremor. It is caused by a severe decline in dopamine amount in the striatum secondary to a progressive loss of dopaminergic neurones in the pars compacta of the substantia nigra. Treatment is mainly symptomatic and based on the use of dopaminergic drugs, such as l-dopa dopaminergic agonists and inhibitors of the l-dopa/dopamine catabolic enzymes. The therapeutic arsenal also includes non-dopaminergic drugs, such as anticholinergics drugs and glutamatergic receptor inhibitors. In advanced PD forms, deep brain stimulation of the subthalamic nuclei can be proposed. PD is associated with many comorbidities, and musculoskeletal problems are among the most frequent ones. Indeed, a survey of PD patients revealed that they significantly suffer from musculoskeletal problems more than age- and gender-matched controls (66.3%
∗ Corresponding author. E-mail address: [email protected] (S. Malochet-Guinamand).
vs. 45.7%, P < 0.001) [2]. Age, female gender, and disease severity were associated with musculoskeletal problems in the PD patient group [2]. 2. Parkinson’s disease, fractures and falls Retrospective case-control studies have demonstrated that PD patients have a higher risk of fragility fractures than age-matched controls [3–5]. A meta-analysis of prospective cohort studies confirmed the higher risk of fracture in these patients (hazard ratio 2.66, 95% confidence interval CI = 2.10–3.36) [6]. In the multinational GLOW cohort, 52,960 participants were followed for two years and 3224 had a fracture. The PD appeared as the most closely associated with fracture comorbidity (age-adjusted hazard ratio 2.2; 95% CI = 1.6–3.1, P < 0.001) [7]. The most frequent site of fractures is the hip [3,4,8]. A retrospective study analysing the “Nationwide Inpatient Sample” cohort, which represents 20% of US hospital admissions from 1988 to 2007, demonstrated that 3.6% of patients hospitalised for a hip fracture had PD. The prevalence of PD in these hospitalised patients was actually four times higher than the prevalence expected in the general population after adjustments for gender and age [9]. Likewise, an analysis of a prospective database of the United Kingdom health insurance system showed an increase in the relative risk of hip fracture (i.e. 3.7; 95% CI = 2.6–5.3) in PD patients over the age of 60 compared to the
http://dx.doi.org/10.1016/j.jbspin.2015.03.009 1297-319X/© 2015 Société franc¸aise de rhumatologie. Published by Elsevier Masson SAS. All rights reserved.
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
rest of the population. This increased risk was present regardless of the gender and age group, except in subjects over the age of 85 years old [10], while the same analysis in a large German health insurance company database demonstrated a larger increase in hip fracture risk in women than in men [11]. The retrospective study of the General Practice Research Database in United Kingdom delivered very similar results, with a significant increase in hip fracture risk in Parkinsonian patients compared with the rest of the population (adjusted hazard ratio [AHR] 3.08; 95% CI = 2.43–3.89) [8]. Moreover a meta-analysis of second hip fracture risk factors showed that PD was also a major risk factor for subsequent hip fractures [12]. These fractures generate high treatment costs for PD patients [13]. In the British database analysis [10], time to discharge to home was longer in PD patients than in other patients, with less postoperative mobility. In their prospective cohort study following 920 hip fractures, Idjadi et al. also demonstrated that Parkinsonian patients experienced longer hospitalisations and were more frequently discharged to a skilled nursing facility as they were more dependent when performing activities of daily living [14]. While, 2 prospective studies conducted in patients after hip fracture did not reveal higher postoperative mortality after one [14] and 2 years [15] in PD patients, a retrospective observational analysis of a cohort of MEDICARE patients showed instead a higher mortality after hip or pelvic fracture in PD patients (HR 2.41, 95% CI = 2.37–2.46) [16]. The occurrence of falls is a major factor related to fracture risk in Parkinsonian patients [8,17,18]. In fact, the meta-analysis of six prospective studies assessing fall risk in PD demonstrated a fall risk of approximately 50% over a three-month follow-up period [19]. Over a longer eight-year follow-up period, 75% of PD patients reported at least one fall [20]. However the higher fall risk is not the only explanation for the increased risk of fracture in PD. Thus, in a retrospective cohort study conducted by Pouwels et al. [8], the fracture risk was higher in patients with a history of fracture, fall, low body mass index (BMI), kidney disease, antidepressant use and the use of high doses of antipsychotics. This study did not provide any bone mineral density (BMD) data. In a small prospective cohort study evaluating fracture risk in PD, the patients experiencing fractures had lower BMI, metacarpal BMD, ionised calcium and lower vitamin D levels, together with higher parathyroid hormone levels, compared to those who did not experience fractures. In addition, women with fractures tended to have a longer period since menopause [21]. A case-control study of Danish health registries demonstrated that the higher fracture risk in PD patients compared with age- and gender-matched controls (OR 2.2; 95% CI = 2.0–2.05) declined (OR 1.18; 95% CI = 1.01–1.37) after adjusting for different variables, such as corticosteroid use, lifestyle, number of bed days in hospital, number of contacts to general practitioner or specialist and intake of various treatments [22]. Beside the PD itself, l-dopa treatment was associated with an overall higher fracture risk and at high doses, a higher risk of hip fracture. Use of neuroleptics also was associated with a higher fracture risk at nearly all sites and at almost any dose [22]. There were no data on BMD in this study. In a prospective SOF cohort study of 6767 women over the age of 66 years old, PD was the most predictive factor of hip fracture in a multivariate analysis not taking BMD into consideration. In the multivariate analysis model integrating femoral neck BMD, PD remained strongly correlated with hip fracture risk, but the correlation was no more significant [23]. The authors suggested that this absence of significance was related to the limited number of PD subjects in the study (n = 32).
3. Parkinson’s disease and bone loss A meta-analysis concluded that PD patients were at higher risk of osteoporosis than healthy control subjects (OR 1.18, 95%
407
CI = 1.09–1.27). The risk was more marked in male PD subjects than in healthy controls with an odds ratio of 2.44 versus male control subjects (95% CI = 1.37–4.34) [24]. A recent second meta-analysis provided consistent results, with Parkinsonian patients having a higher risk of being osteoporotic than healthy controls (OR 2.61, 95% CI = 1.69–4.03) [25] and a lower risk of osteoporosis or osteopenia in men than in women (OR 0.45; 95% CI 0.29–0.68). Longitudinal prospective studies demonstrated more rapid bone loss in Parkinsonian patients than in controls. For example, in the Mr OS cohort study of 5937 men over the age of 65 who were followed for a mean of 4.6 years (± 0.4 SD), annual aged-adjusted hip bone loss was significantly faster in PD men than in controls (−1.08% vs. −0.36%, P < 0.001) [26]. Likewise in the SOF cohort study, PD women aged 65 or older with a mean follow-up period of 3.6 years had a hip bone loss of 1.3% compared to 0.6% in controls (P = 0.01) [27]. While Lorefält et al. found in a small longitudinal case-control study, an annual hip bone loss of 3.9% in patients having PD for approximately 4.6 years, versus 0.4% in the control group [28], Lee et al. reported in the placebo arm of a small controlled study conducted in PD patients whose disease had been present for an average of 36 months, a rate of bone loss of 1.2% per year at the spine and 2.5% per year at the hip [29]. While these studies do not infer that BMD alteration might be related to the duration of the disease, other studies suggest that the relationship between PD and low bone density is related to the severity of the disease, as measured by Hoen and Yahr scale stages, and to the duration of disease evolution [30–33]. However, most of these studies do not eliminate potential confounding factors such as age or weight by multivariate analysis or adjustments. Therefore it remains difficult to determine whether there is a real interaction between disease severity or duration and bone loss. In addition, some authors do not confirm this association [28,34,35]. These discrepancies could be due to different inclusion criteria in the study populations, whereas in prospective cohort studies, the influence of the PD characteristics could not be reliably evaluated because PD diagnosis was only declarative [7,26,27].
4. Pathophysiology of Parkinson’s disease-related bone loss 4.1. Weight loss Several mechanisms may contribute to this PD-related bone loss. Weight and body mass index (BMI) strongly correlate with bone mass. After adjustment for age, the women of the SOF cohort study with PD had a 7.3% lower BMD than other women (P < 0.01). A multivariate analysis demonstrated that PD women had a BMD 2.1% lower than the other women after adjustment for weight, age, neuromuscular function, calcium and vitamin D intake, but the difference was no more significant (P = 0.41). In the multivariate analysis, body weight explained 72% of the BMD difference between the PD group and the control group [27]. Weight and BMI also emerged as factors associated with BMD in PD for other authors [28,29,35]. Weight loss and malnutrition are definitely observed in PD and the severity of the malnutrition is partly related to the severity of the disease [36]. In their meta-analysis, Van der Mark et al. demonstrated that PD patients had a lower BMI than controls (overall effect 1.73, 95% CI = 1.11–2.35 P < 0.00) [37]. This weight loss was greater in patients with more severe disease (Hoehn and Yahr stage 3 versus 2) but was not related to the duration of the disease [37]. Weight loss may even occur in the early stages of the disease, and contrary to what is observed in other diseases, there seems to be a more marked loss of fat mass [38]. Different hypotheses were put forward to explain this weight loss, such as a decrease in food intake, although this has not been demonstrated. There is also an
408
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
increase in energy expenditure, which seems to return to normal after subthalamic stimulation [39]. Finally, some data suggest that hypothalamic dysfunction may be responsible for disturbance in appetite regulation and weight loss in Parkinsonian patients [38]. 4.2. Mobility, muscle strength Bone is a tissue that is sensitive to mechanical loading. Immobilization or hypokinesia lead to a decrease in bone density, while mechanical loading through physical exercise improves bone density [40]. Low levels of physical exercise can be correlated with low bone density in Parkinson’s disease [28]. According to Van den Bos et al. [35] the level of physical activity was one of the determinants of BMD in Parkinsonian patients, although the association was lost after adjusting for age, gender, weight and height. For other authors, a decrease in physical performance [27] or a decrease in muscle strength [41,42] was associated with a low BMD. In a case-control study conducted by Pang MY et al., PD patients had significantly lower walking velocity, walking endurance and leg muscle strength than matched control subjects. Leg muscle strength alone explained 8.8 to 10.6% of the variance in hip BMD in PD patients after controlling for BMI, time since menopause, Hoehn and Yahr stage and postural stability (P < 0.05) [41]. Another study by the same authors demonstrated that PD patients had significantly lower trunk muscle strength compared with controls, but had more trunk rigidity. After adjustment, trunk muscle strength but not rigidity was independently related to spine BMD, explaining 10% of the variance [42]. 4.3. Parkinson’s disease and vitamin D Several authors have suggested a link between vitamin D levels and Parkinson’s disease. In fact, animal studies demonstrated that vitamin D could provide protection from toxic aggressions that can damage dopaminergic cells [43,44]. The 1,25-dihydroxyvitamin D receptor (VDR) and 1␣-hydroxylase, the enzyme responsible for the formation of the active form of vitamin D are present in the substantia nigra and it has been suggested that vitamin D insufficiency may lead to degeneration and death of dopaminergic neurons [44]. Vitamin D could also have an effect on the development and severity of PD, but the only interventional study performed so far to improve PD symptoms had demonstrated negative results [45]. PD patients have lower vitamin D levels than healthy controls [45] and patients with Alzheimer disease [46]. However, it is difficult to know if this observation is a cause or a consequence of the PD. It may be just that the loss in mobility related to the disease is responsible for a decrease in vitamin D levels due to a decrease in sun exposure. Furthermore, low vitamin D levels seem to be associated with an increased fall risk in elderly subjects. Likewise, low vitamin D levels are associated with bone loss and an increased non-vertebral and hip fracture risk in elderly subjects [47]. For Van den Bos et al., vitamin D levels was one of the factors that significantly correlated with a low BMD in PD patients and this association remained significant after multivariate analysis [35]. 4.4. Parkinson’s disease treatments PD treatments may also have a detrimental effect on bone mineral density. Several data suggest a correlation between l-dopa therapy and increased fracture risk [22,48]. In addition, it has been demonstrated that higher doses of l-dopa were associated with lower BMD values at some sites [34]. This adverse effect of l-dopa could be secondary to the increase in homocysteine levels. Indeed, in the presence of dopa decarboxylase, l-dopa metabolism leads to homocysteine production. A meta-analysis demonstrated that homocysteine levels were significantly higher in patients suffering
from idiopathic Parkinson’s disease treated by l-dopa compared to PD patients not being treated with l-dopa or treatment naive PD patients and compared to healthy control subjects [49]. Hyperhomocysteinaemia seems to be associated with low BMD and increased fracture risk in the general population although some results are inconsistent [50]. It may have a deleterious effect on bone through an effect on bone remodelling, reducing bone formation and increasing osteoclastic bone resorption activity as a result of increased intracellular oxidative stress. Hyperhomocysteinemia may also have a direct deleterious action on the bone matrix [51]. 4.5. Dietary deficiencies Eating disorders associated with Parkinson’s disease could promote folate and vitamin B12 deficiencies, and thus be another source of increased plasma homocysteine levels. In fact, Lee et al. showed that vitamin B12 and folate supplementation in PD patients treated with l-dopa could prevent hyperhomocysteinaemia and bone loss [29]. Other nutritional factors, such as vitamin K, could also be implicated. Vitamin K is involved in the carboxylation of some proteins containing the GLA residue, such as bone proteins like osteocalcin. Epidemiological studies in the general population demonstrated that low vitamin K levels are correlated with a lower BMD and an increased fracture risk [52]. A case-control study conducted by Sato et al. demonstrated that vitamin K level was independently correlated with bone density in PD patients with severe functional disabilities (Hoehn and Yahr stage 3 to 5) [53]. They also showed in a small controlled study that vitamin K supplementation could improve metacarpal BMD of patients aged 65 and older being followed for PD for a mean duration of 5 years [54]. 5. Parkinson’s disease and osteoporosis treatment The efficacy of osteoporosis treatments in reducing fracture rate has been clearly demonstrated in postmenopausal women. There are fewer studies in men, and their results rely mostly on their effectiveness evaluated by bone mineral density changes. Results in terms of fracture prevention are less consistent due to the heterogeneity of the disease in men and a lack of power related to insufficient subject numbers. Only rare data are available on the effectiveness of osteoporosis treatments in Parkinsonian patients. A small, double-blind, randomised study of 288 elderly women with PD treated either with alendronate and vitamin D or placebo and vitamin D for two years demonstrated a significant decrease in hip fracture risk in the alendronate treatment arm (relative risk 0.29; 95% CI = 0.10–0.85) [55]. The same authors found similar results with another bisphosphonate, risedronate, in elderly women suffering from PD with a relative risk of hip fracture of 0.2 at two years in treated women compared to the placebo group (95% CI = 0.06–0.66) [56]. Finally, the authors also conducted a study on 272 elderly men with PD. They observed an insignificant decrease in the number of hip fractures in the risedronate plus vitamin D arm compared with the placebo plus vitamin D arm (3 vs. 9). However, bone density significantly increased in the treatment group after two years while it decreased in the placebo group. The authors also observed a significant decrease in bone resorption markers in the risedronate group compared with the placebo group [57]. The facts that these studies all come from the same team have small study populations and were over a short duration limit the strength of their conclusion. There are no specific data on zoledronic acid efficacy in this population, although it has demonstrated its effectiveness in preventing vertebral, non-vertebral and hip fractures in postmenopausal women [58]. Zoledronic acid was also associated with
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
a reduction in the rate of new clinical fractures in elderly male and female after hip fracture [59]. Because it is administrated intravenously once a year, it would seem to be a treatment of choice for osteoporosis in these patients who are taking multiple medications and are often prone to swallowing problems. The use of denosumab, an anti-RANK-ligand antibody is also an interesting alternative in this situation as it has demonstrated a comparable effectiveness in reducing fracture risk in postmenopausal osteoporosis with a simple route of administration (i.e. a subcutaneous injection every six months) [60]. 6. Conclusion It has been clearly demonstrated that PD patients have an increased risk of fracture, particularly at the hip, as a result of an increased risk of falls and other risk factors, particularly lower BMD. The consequences of these fractures are even more serious in this population, particularly in terms of morbidity. There are no data on radiological vertebral fracture prevalence in this population, although it is likely to be high. These results strongly support recommendations of a regular assessment of bone density and risk factors for fracture in PD patients. Even though the fall risk factors have been identified in PD, no specific preventive management has yet been proven [61]. Therefore in cases of densitometric osteoporosis or after the occurrence of a low energy fracture it is mandatory to follow the current guidelines for the management of postmenopausal osteoporosis, even though they are not specifically dedicated to PD patients. A better understanding of the mechanisms of bone loss in PD, some of which are modifiable, could lead to early preventive measures that may reduce fracture risk through improved nutrition and physical activity. It is also important to correctly assess the impact of PD treatments in this context. Further studies, conducted in a prospective manner in large populations, are required to better clarify the respective role of different factors responsible for bone fragility related to PD. Disclosure of interest The authors declare that they have no conflicts of interest concerning this article. References [1] de Lau LM, Breteler MM. Epidemiology of Parkinson’s disease. Lancet Neurol 2006;5:525–35. [2] Kim YE, Lee WW, Yun JY, et al. Musculoskeletal problems in Parkinson’s disease: neglected issues. Parkinsonism Relat Disord 2013;19:666–9. [3] Johnell O, Melton 3rd LJ, Atkinson EJ, et al. Fracture risk in patients with parkinsonism: a population-based study in Olmsted County, Minnesota. Age Ageing 1992;21:32–8. [4] Genever RW, Downes TW, Medcalf P. Fracture rates in Parkinson’s disease compared with age- and gender-matched controls: a retrospective cohort study. Age Ageing 2005;34:21–4. [5] Chen YY, Cheng PY, Wu SL, et al. Parkinson’s disease and risk of hip fracture: an 8-year follow-up study in Taiwan. Parkinsonism Relat Disord 2012;18:506–9. [6] Tan L, Wang Y, Zhou L, et al. Parkinson’s disease and risk of fracture: a metaanalysis of prospective cohort studies. PLoS One 2014;9:e94379. [7] Dennison EM, Compston JE, Flahive J, et al. Effect of co-morbidities on fracture risk: findings from the Global Longitudinal Study of Osteoporosis in Women (GLOW). Bone 2012;50:1288–93. [8] Pouwels S, Bazelier MT, de Boer A, et al. Risk of fracture in patients with Parkinson’s disease. Osteoporos Int 2013;24:2283–90. [9] Bhattacharya RK, Dubinsky RM, Lai SM, et al. Is there an increased risk of hip fracture in Parkinson’s disease? A nationwide inpatient sample. Mov Disord 2012;27:1440–3. [10] Walker RW, Chaplin A, Hancock RL, et al. Hip fractures in people with idiopathic Parkinson’s disease: incidence and outcomes. Mov Disord 2013;28:334–40. [11] Benzinger P, Rapp K, Maetzler W, et al. Risk for femoral fractures in Parkinson’s disease patients with and without severe functional impairment. PLoS One 2014;9:e97073. [12] Zhu Y, Chen W, Sun T, et al. Meta-analysis of risk factors for the second hip fracture (SHF) in elderly patients. Arch Gerontol Geriatr 2014;59:1–6.
409
[13] Pressley JC, Louis ED, Tang MX, et al. The impact of comorbid disease and injuries on resource use and expenditures in parkinsonism. Neurology 2003;6:87–93. [14] Idjadi JA, Aharonoff GB, Su H, et al. Hip fracture outcomes in patients with Parkinson’s disease. Am J Orthop 2005;34:341–6. [15] Londos E, Nilsson LT, Strömqvist B. Internal fixation of femoral neck fractures in Parkinson’s disease. 32 patients followed for 2 years. Acta Orthop Scand 1989;60:682–5. [16] Harris-Hayes M, Willis AW, Klein SE, et al. Relative mortality in U.S. Medicare beneficiaries with Parkinson disease and hip and pelvic fractures. J Bone Joint Surg Am 2014;96:e27. [17] Shribman S, Torsney KM, Noyce AJ, et al. A service development study of the assessment and management of fracture risk in Parkinson’s disease. J Neurol 2014;261:1153–9. [18] Cheng KY, Lin WC, Chang WN, et al. Factors associated with fall-related fractures in Parkinson’s disease. Parkinsonism Relat Disord 2014;20:88–92. [19] Pickering RM, Grimbergen YA, Rigney U, et al. A meta-analysis of six prospective studies of falling in Parkinson’s disease. Mov Disord 2007;22:1892–900. [20] Hiorth YH, Larsen JP, Lode K, et al. Natural history of falls in a populationbased cohort of patients with Parkinson’s disease: an 8-year prospective study. Parkinsonism Relat Disord 2014;20:1059–64. [21] Sato Y, Kaji M, Tsuru T, et al. Risk factors for hip fracture among elderly patients with Parkinson’s disease. J Neurol Sci 2001;182:89–93. [22] Vestergaard P, Rejnmark L, Mosekilde L. Fracture risk associated with parkinsonism and anti-Parkinson drugs. Calcif Tissue Int 2007;81:153–61. [23] Taylor BC, Schreiner PJ, Stone KL, et al. Long-term prediction of incident hip fracture risk in elderly white women: study of osteoporotic fractures. J Am Geriatr Soc 2004;52:1479–86. [24] Zhao Y, Shen L, Ji HF. Osteoporosis risk and bone mineral density levels in patients with Parkinson’s disease: a meta-analysis. Bone 2013;52:498–505. [25] Torsney KM, Noyce AJ, Doherty KM, et al. Bone health in Parkinson’s disease: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2014;85:1159–66. [26] Fink HA, Kuskowski MA, Taylor BC, et al. Association of Parkinson’s disease with accelerated bone loss, fractures and mortality in older men: the Osteoporotic Fractures in Men (MrOS) study. Osteoporos Int 2008;19:1277–82. [27] Schneider JL, Fink HA, Ewing SK, et al. The association of Parkinson’s disease with bone mineral density and fracture in older women. Osteoporos Int 2008;19:1093–7. [28] Lorefält B, Toss G, Granérus A-K. Bone mass in elderly patients with Parkinson’s disease. Acta Neurol Scand 2007;116:248–54. [29] Lee SH, Kim MJ, Kim BJ, et al. Homocysteine-lowering therapy or antioxidant therapy for bone loss in Parkinson’s disease. Mov Disord 2010;25:332–40. [30] Abou-Raya S, Helmii M, Abou-Raya A. Bone and mineral metabolism in older adults with Parkinson’s disease. Age Ageing 2009;38:675–80. [31] Bezza A, Ouzzif Z, Naji H, et al. Prevalence and risk factors of osteoporosis in patients with Parkinson’s disease. Rheumatol Int 2008;28:1205–9. [32] Kamanli A, Ardicoglu O, Ozgocmen S, et al. Bone mineral density in patients with Parkinson’s disease. Aging Clin Exp Res 2008;20:277–9. [33] Song IU, Kim JS, Lee SB, et al. The relationship between low bone mineral density and Parkinson’s disease in a Korean population. Clin Neurosci 2009;16:807–9. [34] Lee SH, Kim MJ, Kim BJ, et al. Hyperhomocysteinemia due to levodopa treatment as a risk factor for osteoporosis in patients with Parkinson’s disease. Calcif Tissue Int 2010;86:132–41. [35] Van den Bos F, Speelman AD, van Nimwegen M, et al. Bone mineral density and vitamin D status in Parkinson’s disease patients. J Neurol 2013;260:754–60. [36] Sheard JM, Ash S, Mellick GD, et al. Markers of disease severity are associated with malnutrition in Parkinson’s disease. PLoS One 2013;8:e57986. [37] Van der Marck MA, Dicke HC, Uc EY, et al. Body mass index in Parkinson’s disease: a meta-analysis. Parkinsonism Relat Disord 2012;18:263–7. [38] Rieu I, Boirie Y, Morio B, et al. The idiopathic Parkinson’s disease: a metabolic disease? Rev Neurol (Paris) 2010;166:822–8. [39] Montaurier C, Morio B, Bannier S, et al. Mechanisms of body weight gain in patients with Parkinson’s disease after subthalamic stimulation. Brain 2007;130:1808–18. [40] Howe TE, Shea B, Dawson LJ, et al. Exercise for preventing and treating osteoporosis in postmenopausal women. Cochrane Database Syst Rev 2011, http://dx.doi.org/10.1002/14651858 [CD000333]. [41] Pang MY, Mak MK. Muscle strength is significantly associated with hip bone mineral density in women with Parkinson’s disease: a cross-sectional study. J Rehabil Med 2009;41:223–30. [42] Pang MY, Mak MK. Trunk muscle strength, but not trunk rigidity, is independently associated with bone mineral density of the lumbar spine in patients with Parkinson’s disease. Mov Disord 2009;24:1176–82. [43] Peterson AL. A review of vitamin D and Parkinson’s disease. Maturitas 2014;78:40–4. [44] Newmark HL1, Newmark J. Vitamin D and Parkinson’s disease – a hypothesis. Mov Disord 2007;22:461–8. [45] Lv Z, Qi H, Wang L, et al. Vitamin D status and Parkinson’s disease: a systematic review and meta-analysis. Neurol Sci 2014;35:1723–30. [46] Evatt ML, DeLong MR, Khazai N, et al. Prevalence of vitamin D insufficiency in patients with Parkinson disease and Alzheimer disease. Arch Neurol 2008;65:1348–52. [47] Rizzoli R, Boonen S, Brandi ML, et al. Vitamin D supplementation in elderly or postmenopausal women: a 2013 update of the 2008 recommendations from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Curr Med Res Opin 2013;29:305–13.
410
S. Malochet-Guinamand et al. / Joint Bone Spine 82 (2015) 406–410
[48] Arbouw ME, Movig KL, van Staa TP, et al. Dopaminergic drugs and the risk of hip or femur fracture: a population-based case-control study. Osteoporos Int 2011;22:2197–204. [49] Hu XW, Qin SM, Li D, et al. Elevated homocysteine levels in levodopatreated idiopathic Parkinson’s disease: a meta-analysis. Acta Neurol Scand 2013;128:73–82. [50] Nieves JW. Skeletal effects of nutrients and nutraceuticals, beyond calcium and vitamin D. Osteoporos Int 2013;24:771–86. [51] Vacek TP, Kalani A, Voor MJ, et al. The role of homocysteine in bone remodeling. Clin Chem Lab Med 2013;51:579–90. [52] Knapen MH, Drummen NE, Smit E, et al. Three-year low-dose menaquinone-7 supplementation helps decrease bone loss in healthy postmenopausal women. Osteoporos Int 2013;24:2499–507. [53] Sato Y, Kaji M, Tsuru T, et al. Vitamin K deficiency and osteopenia in vitamin D-deficient elderly women with Parkinson’s disease. Arch Phys Med Rehabil 2002;83:86–91. [54] Sato Y, Honda Y, Kaji M, et al. Amelioration of osteoporosis by menatetrenone in elderly female Parkinson’s disease patients with vitamin D deficiency. Bone 2002;31:114–8.
[55] Sato Y, Iwamoto J, Kanoko T, et al. Alendronate and vitamin D2 for prevention of hip fracture in Parkinson’s disease: a randomized controlled trial. Mov Disord 2006;21:924–9. [56] Sato Y, Iwamoto J, Honda Y. Once-weekly risedronate for prevention of hip fracture in women with Parkinson’s disease: a randomised controlled trial. J Neurol Neurosurg Psychiatry 2011;82:1390–3. [57] Sato Y, Honda Y, Iwamoto J. Risedronate and ergocalciferol prevent hip fracture in elderly men with Parkinson disease. Neurology 2007;68:911–5. [58] Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med 2007;356:1809–22. [59] Lyles KW, Colón-Emeric CS, Magaziner JS, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med 2007;357:1799–809. [60] Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;361:756–65. [61] Allen NE, Schwarzel AK, Canning CG. Recurrent falls in Parkinson’s disease: a systematic review. Parkinsons Dis 2013, http://dx.doi.org/10.1155/ 2013/906274.
