关键词: 帕金森病, 骨折风险, 营养状况, 身体成分, 平衡量表

Abstract: Sex-specific Correlations of Fracture Risk with Nutritional Status，Body Composition and Balance Condition in Parkinson's Disease Patients
XU Xiaohui1，TIAN Junmei2，CAI Weiwei1，ZHAO Yongfei2，WANG Yupeng1，LIU Chao1，
DUAN Zhihui1*
1.Department of Neurology，Luoyang Central Hospital Affiliated to Zhengzhou University，Luoyang 471000，China
2.Department of Nutrition，Luoyang Central Hospital Affiliated to Zhengzhou University，Luoyang 471000，China
*Corresponding author：DUAN Zhihui，Chief physician；E-mail：duanzhihui76@126.com
【Abstract】 Background Sufficient attention has not been paid to malnutrition，one of the non-motor symptoms of Parkinson's disease （PD），for a long time. Malnutrition，sarcopenia and balance disorders increase fracture risk in PD patients. Currently，the research in this field is relatively rare in China. Objective To examine sex-specific correlations of nutritional status，bodycomposition and balance condition with fracture risk in PD patients.Methods A total of 68 PD patients （37 males and 31 females）treated in Luoyang Central Hospital Affiliated to Zhengzhou University from December 2018 to December 2020 were enrolled，and their general data were collected. Then，the 10-year risks for major osteoporotic fractures （MOF） and hip fractures （HF） were predicted using the Fracture Risk Assessment Tool. Motor and balance functions were assessed using the Unified Parkinson Disease Rating Scale-part Ⅲ （UPDRS Ⅲ ）. Nutrition status was assessed using the Mini-Nutritional Assessment （MNA）. Balance ability was measured by the Berg Balance Scale （BBS）. Balance confidence for performing activities was rated by the Activities-specific Balance Confidence（ABC） Scale. The T-score of femoral neck bone mineral density（BMD） was calculated and body composition was measured. The correlations of fracture risk with various factors were analyzed. And fracture risk and various factors were subjected to partial correlation analysis after controlling for age，gender and T-score of femoral neck BMD. Results Compared to women PD patients，men had lower the 10-year risk for MOF，UPDRS Ⅲ score，and body fat rate （BFR），as well as greater mean triceps skin fold thickness，but higher mean T-score of femoral neck BMD，mean trunk muscle mass，upper limb muscle mass，lower limb muscle mass and BBS score （P<0.05）. In men PD patients，the 10-year risks for MOF and HF were negatively correlated with the MNA score，lower limbs muscle mass，BBS score and ABC score （P<0.05），but were positively correlated with the UPDRS Ⅲ score （P<0.05）；the T-score of femoral neck BMD was positively correlated with lower limbs muscle mass （P<0.05），while negatively correlated with BFR （P<0.05）. In women PD patients，the 10-year risk for MOF was positively correlated with the UPDRS Ⅲ score and age，while negatively correlated with the MNA score，muscle mass of lower limbs，BBS score and ABC score （P<0.05）；the 10-year risk for HF was positively correlated with the UPDRS Ⅲ score，while negatively correlated with MNA score，muscle mass of upper limbs and lower limbs，BBS score and ABC score （P<0.05）. Besides，the T-score of femoral neck BMD was positively correlated with muscle mass of lower limbs （P<0.05），while negatively correlated with age and waist-to-hip ratio （P<0.05）. The results of partial correlation analysis revealed that the 10-year risks for MOF and HF had negative correlations with MNA score，muscle mass of lower limbs，BBS score and ABC score （P<0.05），and a positive association was found between the 10-year
risk for MOF and UPDRS Ⅲ score （P<0.05）. Conclusion The body composition and T-score of femoral neck BMD in males are different from those in females. Malnutrition，decreased muscle mass of lower limbs，reduced balance capacity and severity of PD are important predictors of the risk of MOF in PD patients. In view of this，to prevent and treat osteoporosis and fractures in PD patients，it is essential to pay attention to nutritional status and muscle mass of them，especially female patients.
【Key words】 Parkinson disease；Fracture risk；Nutritional status；Body composition；Balance scale
Patients with Parkinson's disease (PD) often experience weight loss and malnutrition, which may continue throughout the entire disease process, even prior to the onset of symptoms.However, compared with other non-motor symptoms, there have been few clinical studies on the nutritional status of PD patients. As reported in foreign studies, a remarkably higher risk of malnutrition is found in PD population than healthy individuals, while malnutrition is present in 0-24% of patients and those with malnutrition riskconstitute 3-60%[1] of all cases. Poor nutrition may cause reduction in muscle quantity and induce other diseases, and relevant fractures may result in disability or even death.There exist certain differences in body composition between females and males. At present, the research that investigates the relations betweenskeletal muscle index and osteoporotic fracture in postmenopausal females and elderly males has been reported in China [2-3], whereas there are few publications on the associations of nutritional status and body composition with fracture risk in PD patients.Fracture Risk Assessment Tool (FRAX) as an available means of screening the risk of osteoporotic fracture is commonly used in clinic, so as to prevent the occurrence of fracture[4].This study aimed to analyze the correlations between fracture risk predicted by FRAX and nutritional status score, body composition and balance scale score, thus providingnovel perspectives and references for the prevention and treatment of osteoporotic fracture in PD patients.
1 Subjects and Methods
1.1 Research subjectsPD patients treated in Luoyang Central Hospital Affiliated to Zhengzhou University from December 2018 to December 2020 were enrolled，and their general data were collected.Inclusion criteria were as follows: patients who met the diagnostic criteria for primary PD[5], those in stage 1-3 according to
Hoehn-Yahr(H-Y)staging, and those who signed the informed consent.Exclusion criteria involved: long-term bedridden patients, those who could not cooperate in questionnairesurvey, those with severe cardiovascular or cerebrovascular diseases, or those with severe osteoporosis.Finally, 68 patients were enrolled in this study, including 37 males and 31 females aged 62-78 years old, averagely (65.5±9.8) years old. This study was conducted by the medical ethics Committee of Luoyang Central Hospital affiliated to Zhengzhou UniversityApproval will be reviewed (Approval No: LWLL-2021-06-04).
1.2 Data collection （1）the general data, including age, gender, living alone or not, fracture history, and wearing-off, gait freezing and on-off phenomena or not, were gathered. （2）in terms of fracture risk, FRAX (http://www.shef.ac.uk/FRAX/) was utilized to predict the 10-year risks for major osteoporotic fracture (MOF) risk and hip fracture (HF), and the individuals who had HF risk ≥3% or MOF risk ≥20% were identified as patients at high risk of osteoporotic fracture.（3） the Unified Parkinson's Disease Rating Scale-motor score (UPDRS-III) with 16 items (0-4 points each, 56 points in total) was adopted, and the higher the score, the worse the motor and balance function[6]. In addition, the Mini Nutritional Assessment (MNA) scale (30 points in total) was used to measure the nutritional status of patients, MNA score ≥24 points indicated good nutritional status, MNA score ranged 17-23.5 points denoted malnutrition risk, and MNA score <17 points represented malnutrition[7].（4）femoral neckbone mineral density (BMD) T-value was tested using a Lexxos dual-energy X-ray bone densitometer purchased from DMS. In addition, body composition indexes including body fat ratio (BFR), body mass index (BMI), triceps skinfold thickness, arm circumference (AC), waist-to-hip ratio (WHR) and limb muscle quantity were measured using Inbody 720 (a body composition analyzer) under fasting state and 2-3 h after eating. （5） the balance scale score was evaluated bythe Berg Balance Scale (BBS) (0-4 points) with respect to the balance ability of patients from sitting to standing, and a lower score meant poorer balance control[8]. In addition, the Activities-specific Balance Confidence (ABC) scale was employed to assess the patients' confidence in their own balance ability during activities, with a total of 0-100
points, and the higher the score, the better the confidence in the balance ability[9].
1.3 Statistical analysisSPSS 23.0 software was adopted for statistical analysis. Normally-distributed measurement data were expressed by mean ± standard deviation (χ±s), and independent-samplest-test was used for comparison between groups. If the data did not conform to normal distribution, they were expressed as median (interquartile range) [M (P25, P75)], and non-parametric Mann-Whitney U test was utilized for comparison between groups. Enumeration data were expressed by ratio (%) and analyzed using χ2test. Pearson correlation analysis and Spearman rank correlation analysis were adopted to analyze correlations. Besides, after controlling age, gender and femoral neck BMD T-value, partial correlation analysis was employed to investigate the correlations between the main factors and fracture risk.p<0.05 represented statistically significant differences.
2 Results
2.1 Comparison of general data between different genders of PD patients
No statistically significant differences were found in age, living alone, fracture history,wearing-off, gait freezing and on-off phenomena, the 10-year risks for HF, MNA score, BMI, AC, WHR and ABC score between different genders of PD patients(p>0.05).The 10-year risks for MOF, UPDRS-III score, BFR and triceps skinfold thickness were lower, while femoral neck BMD T-value, trunk muscle quantity, double upper and lower limb muscle quantity and BBS score were higher in males than those in females (p<0.05) (Table 1).
2.2 Analysis of correlations of fracture risk, femoral neck BMD T-value with other indexes in PD patients of different genders
In male PD patients,there were negative associations of MNA score, double lower limb muscle quantity, BBS score and ABC score with the 10-year risks for MOF and HF (p<0.05), positive relations between UPDRS-III score and the 10-year risks for MOF and HF (p<0.05) as well as between double lower limb muscle quantity and femoral neck BMD T-value (p<0.05), and negative correlations between BFR and femoral neck BMD T-value (p<0.05) (Table 2).In female PD patients, positive relations were found between UPDRS-III score and the 10-year risks for MOF and
HF(p<0.05), between age and the 10-year risks for MOF (p<0.05), and between double lower limb muscle quantity and femoral neck BMD T-value (p<0.05), while there were negative associations of MNA score, double lower limb muscle quantity, BBS score and ABC score with the 10-year risks for MOF (p<0.05), of MNA score, double upper and lower limb muscle quantity, BBS score and ABC score with the 10-year risks for HF (p<0.05), and of age and WHR with femoral neck BMD T-value (p<0.05) (Table 2).
2.3 Analysis of partial correlation of fracture risk with other indexes
After controlling gender, ageand femoral neck BMD T-value, partial correlation analysis revealed that MNA score, double lower limb muscle quantity, BBS score and ABC score were negatively associated with the 10-year risks for MOF and HF (p<0.05), and UPDRS-III score was positively correlated with the 10-year risks for MOF (p<0.05) (Table 3).
3 Discussion
PD patients tend to suffer from malnutrition and weight loss followed by aggravation of motor symptoms or even fractures.In this study, the results displayed the MNA score<24 points [7]in the majority of PD patients, lower than the good standard value, and MNA score was negatively associated with the 10-year risks for MOFand HF, confirming that malnutrition appears in PD patients, and is related to fracture risk. The following reasons are commonly implicated in malnutrition and weight loss in PD patients, i.e.poor appetite and nutrition intake reductionresulted from early hyposmia[10], levodopa-induced gastrointestinal symptoms[11], neuroendocrine abnormalities[12], energy metabolism disorder[13],and excessive energy consumption due to muscle rigidity and dyskinesia[14]. In addition, the excessive control of protein intake aiming to reduce the impact of levodopa drugs is also one of the reasons for malnutrition in some patients.In recent years, more attention has been paid to bodycomposition such as muscle loss and osteoporosis which may cause balance abilitydecline and increase the risk of falls and fragility fractures[15]. As reported in a multi-center study, for every 1 standard deviation increase in limb muscle quantity, the risk of osteoporosis declines by 37%, and BMD is positivelyrelated to muscle
quantity[16].Consistent with the above-mentioned conclusion, this study also revealed that in male and female PD patients,double lower limb muscle quantity was positively correlated with femoral neck BMD T-value[17-18].According to two other prospective studies, it can be seen that the reduction in muscle quantity is an independent risk factor for fractures. This study manifested thatin male and female PD patients, there were negative associations of double lower limb muscle quantity with the 10-year risks for MOF and HF. The findings demonstrated that the reduction in muscle quantity of the lower limbs increases the risk of osteoporotic fracture, which is consistent with foreign reports[19-20].The results of this study displayedthat double upper limb muscle quantity in female PD patients was also negatively associated with the 10-year risks for HF, and the reason is that the reduction in muscle quantity of the upper limbs may weakenupper limb strength and grip strength and influence physical function, indirectly increasing the risk of fracture.
VANDER MARCKet al[21]. reported that weight loss in PD patients is mainly attributed to adipose tissue reduction, while the reduction of muscle is notapparent.However, this study exhibited that the lower limb muscle quantity was lower than reference range in most PD patients, and 1 patient had an extremely low muscle quantity of the lower limbs and presented with obvious fatigue. Theresults of this study denoted male PD patients showed greater trunk muscle quantity, doubleupper and lower limb muscle quantity than female PD patients[22]. However, foreign studies have indicated that the detection rate of skeletal muscle reduction is remarkably higher in male PD patients than that in females and scholars consider that male testosterone has a significant influence on muscle quantity than female estrogen[23-24].Wang et al[25]. reported that increasing the testosterone level in young male patients with a low level of sex hormone contributes to musclequantity elevated by 20-60%. In this study, all male PD patients enrolled were elderly individuals, while the enhancement effect of testosterone on the muscle quantity is weaker in elderly males than that in young males[26]. Moreover, the female PD patients enrolled in this study were postmenopausal elderly women with obviously reduced estrogen levels. Consequently, the results appeared to be different.
In the present study, two scales were used for balance scale scoring, of which BBS is capable of evaluating the fall risk of PD patients, from static state to dynamic state, during posture changes, and ABC is able to assess the confidence of PD patients in their own balance ability during activities.The combination of the two scales can better reflect PD patients' balance conditions. In addition, the correlation analysis manifested that BBS score and ABC score in male and female PD patients were negatively related tothe 10-year risks for MOF and HF, indicating the reduction of balance ability and the increased risk of fracture. Thus, it is necessary to focus on the balance ability training in PD patients. UPDRS-III score in both male and female PD patients was positively correlated with the 10-year risks for MOF and HF, suggesting the relations between PDseverity and fracture risk. Positive correlations between age and the 10-year risks for MOF among females PD patients indicated the associations between age and osteoporotic fracture risk in female PD patients, which was similar to previous research[27]. PD mostly occurs in elderly people, leading to the gradual reduction in vitamin D and blood calcium levels, and postmenopausal women will have reduced estrogenlevels, which may cause bone loss and osteoporosis, increasing the risk of fracture.
To further explore the correlations of balance, nutritional status and body composition with fracture risk, partial correlation analysis following controlling gender, age and femoral neck BMD T-value was conducted, and the results revealed that the 10-year risks for MOF and HF were negatively associated with BBS score, ABC score, MNA score and double lower limb muscle quantity. Positive relations between the 10-year risks for MOF and UPDRS-III score further verified that the low muscle quantity of the lower limbs, poor balance function, poor nutritional status and severe PD are risk factors for osteoporotic fracture, significantlyincreasing the risk of fracture.In addition to nutritional assessment, balance evaluation and bone mineral density measurement, body composition also can be detected to measure limb muscle quantity in PD patients, especially the nutritional status and muscle quantity of elderly female PD patients, so as to recognize the patients at high risk of fracture in advance and provide corresponding nutritional interventions. Then through comprehensive
analysis on the body balance abilities in patients of different genders, personalized treatment protocols are administered to reduce the risk of falls and osteoporotic fractures in PD patients. In this study, manual questionnaire and instrument measurement may cause subjective or objective errors due to small sample sizes. Thus, it is of necessity to expand the sample size and further investigate relevant risk factors for fracture in PD patients.

Table 1 Comparison of general characteristics of PD patients by sex 

Note: arepresents Z value, brepresents χ 2 value, and the residual test statistic value represents t value. MOF= Major osteoporotic fractures, HF= Hip fractures, UPDRS III= Parkinson's Disease Unified Assessment Scale Part III Exercise, MNA= Simplified Nutrition Assessment Scale, BFR= Body Fat percentage, BMI= body Index, AC= Upper arm Circumference, WHR= Waist-to-hip fat ratio, BBS=Berg Balance Scale, ABC= Activity balance confidence Scale.

Table 2 Correlation analysis of fracture risk and T-score of femoral neck bone mineral density with other indicators in PD patients by sex

Key words: Parkinson disease, Fracture risk, Nutritional status, Body composition, Balance scale