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Bone Mineral Density and Serum Vitamin D Status in Parkinson's Disease: Are the Stage and Clinical Features of the Disease Important?
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.283755
Keywords: Bone mineral density, clinical characteristics, Hoehn and Yahr stage, Parkinson's disease, serum vitamin D
Parkinson's disease (PD) usually begins after the age of 50 years and is the second most common chronic, progressive, neurodegenerative disorder following Alzheimer's disease.[1] The prevalence of the disease is estimated at 0.3% in the general population, and it increases with age.[2] Approximately, 1%–2% of the population over 65 years suffers from PD, and this proportion increases to 3%–5% in people 85 years and older.[3] The incidence of PD is increasing in parallel with the increasingly aging population and the increase in life expectancy. The global number of people living with PD is 7–10 million and prevalence above the age of 50 is expected to double by 2030.[4] Therefore, from a socio-economic point of view, PD is one of the most significant chronic health issues at present, and it will probably continue to grow in the future. PD is known to adversely affect bone quality and bone mineral density (BMD).[5],[6],[7],[8],[9],[10],[11] In addition to low BMD, falls, especially recurrent falls due to underlying symptoms such as postural instability, gait and balance disorders, and freezing of gait are among the possible reasons for fractures in PD patients.[12] Recurrent falls and fracture, especially hip fractures due to falls, have a negative effect on the quality of life of patients. There is the undeniable importance of vitamin D in bone health, building and maintaining good bone quality when bone quality has come into question. Except for the impact on bone health, vitamin D also affects muscle strength, balance, and falling.[10],[13] Although previous studies indicate both BMD and serum vitamin D level were lower in PD patients compared to healthy controls,[10],[14],[15],[16] it is presently unclear at what stage of the disease these abnormalities develop. To the best of our knowledge, the present study is the first study in the literature focusing on the relationship between stage and clinical characteristics of the disease in PD and BMD values or serum vitamin D level.
Subjects and controls One hundred and ninety-eight consecutive PD patients recruited from Movement Disorders Outpatient Clinic of the University of Health Sciences, Diskapi Yildirim Beyazit Training and Research Hospital between March and October 2015 were evaluated in the present single-center, prospective study. All patients fulfilled diagnostic criteria for PD[17] and optimization of medical treatment performed by the same neurologist (BK). The control group was comprised of spouses and caregivers of patients. Eligibility criteria were: (a) age between 50 and 80 years; (b) ambulatory persons for both groups; and (c) Hoehn and Yahr (H and Y) stage ≤4 for patients with PD. Exclusion criteria included the previous diagnosis of osteoporosis; vitamin D supplementation in the last six months; history of metabolic bone disorders, renal dysfunction and failure, and severe cardiovascular and systemic diseases affecting the overall health of participants; previous fragility fracture history for both groups; and a history of deep brain stimulation surgery for PD patients. Demographic data (age, gender, weight, and body mass index [BMI, kg/m[2]]) of patients and control groups were collected. In PD patients, disease characteristics (daily levodopa dose, daily levodopa equivalent dose [LED],[18] and disease duration), disease severity (described by H and Y scale[19]), and disease symptoms (evaluated by Unified Parkinson's Disease Rating Scale [UPDRS][20]) were recorded. In addition to UPDRS part II (daily living activities) and part III (motor symptoms), UPDRS part III subscores (tremor, rigidity, bradykinesia, and postural instability and gait disorders) were also calculated. After recording demographic information of both groups and disease characteristics of the patients' group, participants' BMD and serum vitamin D level were measured. BMD measurements (g/cm[3]) were performed with DEXA using a Hologic QDR-4500A. Lumbar (lumbar total) and femoral (femoral neck, trochanter, intertrochanteric area, total proximal femur, and Ward's triangle) BMD values were recorded, T-scores were calculated. The serum 25(OH) D3 level was measured using a commercial ELISA kit (Immuno-Biological Laboratories, Minneapolis, USA). The study was performed in agreement with the principles of the Declaration of Helsinki. The study protocol was approved by the local ethics committee (Number 20.01.2014 13/04). All patients were informed of the purpose of the study, and informed consent was obtained from each participant. Statistical analysis Statistical analyses were performed using MedCalc for Windows, version 14.12 (MedCalc Software, Ostend, Belgium). The variables were investigated using visual (histograms, probability plots) and analytical methods (Kolmogorov-Smirnov test) to assess whether or not they are normally distributed. Descriptive analyses were presented as counts (percentage) or mean ± standard deviation. One-way ANOVA was used to compare normally distributed variables. Levene test was used to assess the homogeneity of the variances. An overall P value of less than 0.05 was considered to show a statistically significant result. When an overall significance was observed, pairwise post-hoc tests were performed using Tukey's test. Kruskal–Wallis test was conducted to compare not normally distributed variables. The Mann–Whitney U test was performed to test the significance of pairwise differences using a Bonferroni correction to adjust for multiple comparisons. An overall %5 type-I error level was used to infer statistical significance. Pearson or Spearman correlation coefficients were calculated between BMD and serum vitamin D level and clinical characteristics of PD. Statistical significance was based on a 5% level.
A total of 74 PD patients were excluded from the study; 19 had a history of bisphosphonate use, 23 had a history of some vitamin D supplement, 14 had a history of prior lumbar surgery, 10 had prior primary total hip replacement surgeries, and 8 had H and Y stage 5. Of the 124 patients deemed suitable for the study, 54 were male (43.5%), and 70 were female (56.5%). The mean age of patients in the PD was 68.1 ± 8.4 years, and mean disease duration was 64.0 ± 54.6 months, mean levodopa dose was 385.7 ± 308.6 mg/day, mean LED was 765.0 ± 466.2 mg/day, and mean H and Y stage was 2.4 ± 1.0. The mean UPDRS II score was 11.4 ± 7.3, and UPDRS III score was 27.4 ± 13.7. The mean UPDRS III tremor subscore was 5.1 ± 4.0, rigidity subscore was 5.4 ± 3.1, bradykinesia subscore was 11.8 ± 6.9, and PIGD subscore was 3.3 ± 3.1. The control group was comprised of 47 males (40.5%) and 69 females (59.5%), making a total of 116 individuals. The mean age of controls was 67.1 ± 6.3 years. The demographic variables, BMD values, and serum vitamin D level of both groups was presented in [Table 1]. Lumbar total and all femoral BMD values and T-scores, and serum vitamin D level were significantly lower in PD patients compared with controls (P < 0.001, for all).
After patients with PD were divided into four groups according to H and Y stage, the group I (H and Y stages 1 and 1.5) comprised of 38 patients, group II (H and Y stages 2 and 2.5) consisted of 39 patients, group III (H and Y stage 3) comprised of 24 patients, and group IV (H and Y stage 4) comprised of 23 patients. The demographic and clinical characteristics of the four PD groups (groups I, II, III, and IV) and controls (group C) are shown in [Table 2].
While a difference was not present between 5 groups regarding age and sex, statistically significant weight and BMI difference were present between groups (P < 0.001, for both). When compared the clinical characteristics of the disease among patients in the four PD groups, although a difference was not established with disease duration (P = 0.065) and tremor subscores (P = 0.214), a statistically significant difference was found with daily levodopa dose (P < 0.001), daily LED (P < 0.001), and UPDRS II and III scores (P < 0.001, for both) as well rigidity, bradykinesia, and postural instability and gait disorder subscores (P < 0.001, for all), and this manifested a positive relationship with the disease stage. BMD values, T-scores, and vitamin D level of five groups are given in [Table 3]. BMD values showed a statistically significant difference between the groups in all six regions (P < 0.001, for all). In addition, when compared with the controls, lumbar total (P < 0.001), femoral neck (P = 0.023), total proximal femur (P = 0.042), and ward's triangle (P = 0.039) BMD values were significantly lower even in early PD patients (group I; H and Y stage 1 and 1.5). When compared the five groups regarding T-scores, a difference was established between the groups in both lumbar and all femoral regions (P < 0.001, for all). Serum vitamin D level demonstrated a statistically significant difference between the groups (P < 0.001, for all) and is significantly lower in patients with early PD than in controls (P = 0.038).
A significant correlation was established between all 6 BMD regions and vitamin D. Disease duration (only femoral neck and ward's triangle), levodopa (only femoral neck, ward's triangle, and vitamin D), LED (only ward's triangle and vitamin D), H and Y (all region and vitamin D), UPDRS II (all region and vitamin D), UPDRS III (all-region and vitamin D), and tremor subscore (all-region except trochanter and vitamin D), rigidity subscore (all regio1n and vitamin D), bradykinesia subscore (all-region and vitamin D), and PIGD score (all region except lumbar total and vitamin D) [Table 4].
Parkinson's disease is an age-related, complex, and multisystem disorder. Musculoskeletal problems such as shoulder problems, low back pain, postural or striatal deformities, arthritis, osteoporosis, and fractures are common in patients with PD.[21] Among these problems, fractures related to low BMD and recurrent falls can lead to significant morbidity and mortality for patients. Although previous studies showed that the relationship between PD and BMD or vitamin D, it is unclear whether the stage of PD is related to BMD levels or serum vitamin D level. Therefore, the present study is focused on BMD and serum vitamin D levels in different stages of PD. There are three main results of this study: (1) patients with PD have lower BMD levels, T-scores, and serum vitamin D level compared to healthy controls, and this result is consistent with the literature; (2) the decrease in BMD levels, T-scores, and serum vitamin D level begin in the early stages of the disease (as early as H and Y stage 1 and 1.5), and they are marked by the progression of the PD; and (3) BMD levels, T-scores, and serum vitamin D level are closely associated with clinical features of the disease, such as UPDRS part II (activities of daily living) and III (motor symptoms), and UPDRS part III subscores in PD patients. PD is defined by a gradual loss of dopaminergic cells in the substantia nigra pars compacta and a consequent loss of striatal dopamine.[22] The motor symptoms occur when at least 60% of dopaminergic neurons are lost, and 80–85% of dopamine content in the striatum is empty.[23],[24] This occurs following approximately 4–6 years prodromal/preclinical period.[25] Different molecular mechanisms of neuronal death in PD pathogenesis have been described, including mitochondrial dysfunction, impairment of protein quality pathways, oxidative/nitrative stress, and microglia activation and inflammation.[26] The present study demonstrated that the lumbar and femoral BMD levels were lower not only in the advanced stages but also even in the early stages of PD, including H and Y stage 1–1,5. It is rational to infer that bone mass might be affected prior to the appearance of motor symptoms, namely, during the prodromal period of PD. Therefore, different molecular mechanisms affecting both the nervous and musculoskeletal system may be involved in the pathogenesis of PD. Moreover, it can be suggested that PD is not only a chronic, neurodegenerative disorder but also a systemic, catabolic process affecting the musculoskeletal system. In this study, there was a negative correlation between BMD and scores of activities of daily living or motor symptoms (except tremor). In Parkinson's disease, different mechanisms associated with the clinical appearance of Parkinson's disease may explain low BMD and T-scores related to BMD. With the progress of Parkinson's disease, the physical activity levels of the patients gradually decrease, and as a result, they become increasingly dependent on daily living activities. This results in a decrease in the quality of life of the patients and an increased risk of immobilization. Immobility may be an important factor explaining the negative relationship between BMD and the progression of Parkinson's disease. Previous studies have reported an association between low spine BMD with reduced axial mobility in the PD, and a similar relationship exists between reduced hip joint mobility and low femoral neck BMD.[5],[8],[27] Also, trunk muscle strength is closely related to the lumbar region BMD in PD, and there is an independent correlation between leg muscle strength hip BMD in female patients with PD.[28],[29] In addition to the reduction of axial mobility, postural changes, such as anteflexion due to increased abdominal rigidity with the progression of the disease not only lead to festination but also reduce the axial loading on the lumbar spine because of the forward displacement of the center of gravity.[30],[31] The decrease in axial loading on lumbar vertebrae in erect posture may also contribute to a low lumbar spine BMD by reducing mechanical load on vertebrae. This may be among the reasons explaining the negative correlation between the progress in the disease stage and spine BMD. In PD patients, gait disturbances, such as reduced stride length, decreased cadence (steps per minute), an increased proportion of the gait cycle spent in the double-limb support phase of stance, cause hip joints to participate in walking with a lower range of motion compared to the normal gait cycle.[32] Also, anteflexion posture leads to semiflexion in the hip joint and reduces the load on the proximal femur. All of these factors can help clarify the BMDs are lower than controls in the entire proximal femur region of interest. Since gait disorders increase with the progression of the disease, the adverse effect of the disease progression on the BMD can be explained. There is also a negative effect of levodopa on BMD. It has been shown that high levodopa doses negatively affect BMD by causing an increase in high serum homocysteine concentration (hyperhomocysteinemia). High serum homocysteine levels may cause both poor bone quality and lower bone mass in several different ways: (1) it may interfere with collagen cross-linking, and (2) it can stimulate the differentiation of osteoclasts and the apoptosis of osteoblasts via increased intracellular reactive oxygen species.[33] In this study, there was a positive relationship between levodopa doses and disease progression. The increase in serum levodopa levels, which is parallel to the progression of the disease, maybe another reason for the decrease in BMD. There is no clear information about other dopaminergic drugs except levodopa.Vitamin D has a critical role in bone metabolism, and vitamin D deficiency is correlated with an increased risk of falls and fractures.[34] Low vitamin D levels are known to be an independent risk factor for low BMD values in PD patients[10] as well as the general population. Thus, we think that low vitamin D levels have negative effects on BMD from the early stages of the PD. The previous studies reported that vitamin D levels were low regardless of the stage of the disease.[10],[14],[15],[16] Unlike most other studies, we have shown that low vitamin D levels have been found even in the early stages of the PD, such as H and Y grade 1–1,5. Despite that, there is a dilemma in the relationship between PD and vitamin D. The reason for the dilemma is a continuous inadequate intake of vitamin D leads to a chronic loss of dopaminergic neurons in the brain. Knekt et al. decided that a low vitamin D status predicted the development of PD.[16] Also, vitamin D deficiency (10–20 ng/dL) and insufficiency (<10 ng/dL) is a risk factor for the occurrence of PD and increase the risk of PD 1.5 and 2.2 times, respectively.[35] It is, therefore, difficult at this stage to speculate whether low vitamin D levels are related to the presence of PD or whether it triggers the development of PD. Vitamin D has an important effect on BMD, and it would be necessary to discuss the issues caused by vitamin D deficiency in PD. Vitamin D deficiency is among quite important factors that contribute to a functional capacity decrease in the elderly by causing proximal muscle weakness, generalized muscle pain, gait disorder, increase in body sway, and fall risk. Observational studies that include large numbers of patients have shown that high 25 (OH) D3 levels are associated with better lower extremity functions, reduced risk of functional decline and falling, decreased community health service use and delay nursing care facility admission in elderly adults.[36],[37],[38],[39] These effects of vitamin D may be directly related to bone mass. The results of the present study also documented that low serum vitamin D level closely associated with both the stage and clinical features of the disease. Gradually increasing immobilization may exacerbate the decrease in vitamin D. Other reasons such as malnutrition, less exposure to sunlight due to social isolation, and decreased physical activities are among the factors that can lead to a low level of vitamin D.[40],[41],[42]
There are some limitations to this study. Since patients diagnosed previously with osteoporosis, or patients with a history of fracture, patients with immobility due to PD and or chronic disease, and H and Y stage 5 patients were not included in this study, the effect of PD on BMD may be lower compared to values established in this study. In addition, patients with DBS were excluded from the study. Since DBS has a positive effect on mobility, and because these patients were excluded from the study, BMD values established in patients with PD may be lower compared to the already established ones due to mobility having a positive impact on BMD.
In the present study, we found that BMD and vitamin D levels are decreased at early stages of PD, and they have been adversely affected by the progression of the disease. In addition to low BMD and vitamin D levels, predisposing to postural instability, impairment of balance, recurrent falls, and finally, the risk of fracture in PD, especially with H and Y stage 3 or above, patients should be assessed in these terms following the diagnosis of PD and necessary precautions should be taken from early stages. The fact that bone mass decreases in an accelerating manner with the advancement of disease stages necessitates a strong follow-up of patients. Due to low BMD and vitamin D levels proportionate to the stage in all stages of PD observed in this study group, implementation of protective recommendations such as patient information at early stages, exercise, nutrition, sunbathing, rehabilitation programs to prevent immobilization, and analyses of BMD and vitamin D levels may prove to be beneficial in preventing the risk of fracture that is an important cause of age-related morbidity and mortality. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3], [Table 4]
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