PARKINSON DISEASE IS associated with a significant increase

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1 ORIGINAL ARTICLE Type of Hip Fracture in Patients With Parkinson Disease is Associated With Femoral Bone Mineral Density Marco Di Monaco, MD, Fulvia Vallero, MD, Roberto Di Monaco, DPS, Rosa Tappero, MD, Alberto Cavanna, MD ABSTRACT. Di Monaco M, Vallero F, Di Monaco R, Tappero R, Cavanna A. Type of hip fracture in patients with Parkinson disease is associated with femoral bone mineral density. Arch Phys Med Rehabil 2008;89: Objective: To investigate the association between bone mineral density (BMD) and hip fracture type (cervical or trochanteric) in a sample of fallers with Parkinson disease (PD). Design: Observational study. Setting: Rehabilitation hospital in Italy. Patients: We investigated 1040 of 1120 white fallers consecutively admitted to a rehabilitation hospital for hip fracture. Thirty-eight (3.65%) of the 1040 patients suffered from PD secondarily. Thirty-eight controls matched for sex, age, and hip fracture type were found among the 1002 non-pd fallers. Interventions: Not applicable. Main Outcome Measures: BMD was assessed by dualenergy x-ray absorptiometry at a mean SD of days after fracture occurrence in the 38 PD patients and days after fracture occurrence in the 38 controls. Results: BMD assessed at total femur, trochanter, and intertrochanteric region was significantly lower in the 15 PD patients with trochanteric fractures than in the 23 with cervical fractures; the mean T score differences were 0.57 (95% confidence interval [CI], ; P.028), 0.66 (95% CI, ; P.037), and 0.63 (95% CI, ; P.019), respectively. A significant association between femoral BMD and hip fracture type was found at logistic regression after adjustment for several confounders. Results in the 38 controls were similar to those obtained in the 38 PD fallers. Conclusions: In a sample of PD fallers as in a control group of non-pd fallers, BMD levels assessed at 3 femoral sites were significantly lower in the patients who sustained trochanteric fractures than in those with cervical fractures of the hip. Key Words: Bone mineral density; Hip fractures; Osteoporosis; Parkinson disease; Rehabilitation by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation From the Osteoporosis Research Center (M. Di Monaco, Vallero, Cavanna) and the Division of Physical Medicine and Rehabilitation (Tappero), Presidio Sanitario San Camillo, and the Institute of Social and Economical Research S.R.F.- Società Ricerca e Formazione (R. Di Monaco), Torino, Italy. Supported in part by Regione Piemonte, Ricerca Sanitaria Finalizzata. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit on the authors or on any organization with which the authors are associated. Reprint requests to Marco Di Monaco, MD, Osteoporosis Research Center, Presidio Sanitario San Camillo, Strada Santa Margherita 136, 10131, Torino, Italy, medici@h-sancamillo.to.it, marco.di.monaco@alice.it /08/ $34.00/0 doi: /j.apmr PARKINSON DISEASE IS associated with a significant increase in fracture risk. 1-5 Among fracture sites, a relatively high proportion of hip fractures was observed. 1,4-6 PD more than doubled hip fracture risk over a 10-year follow up, 4 and, by 10 years after diagnosis, an estimated 27% of a PD cohort experienced a new hip fracture. 1 The increase in hip fracture risk in PD was attributed to a variety of factors including low BMD levels; increased incidence of falls caused by balance disturbances, bradykinesia, rigidity, and postural hypotension; absence of adequately directed arm movements in fallers; and tendency to fall backwards or to the side. 1,4,6-15 Hip fractures are usually classified as either cervical or trochanteric. Trochanteric fractures are associated with a more severe and generalized bone loss, especially of the trabecular component as shown by BMD measurement at the proximal femur and the spine 19 and ultrasound determinations at calcaneus. 16,20 Consistently, previous vertebral fractures are twice as common in women with trochanteric fracture, 21 and at histomorphometric evaluations the trabecular bone volume, trabecular surface density, and mean wall thickness are all lower in patients with trochanteric fracture. 22 In the overall population of hip fracture patients, the association between more severe bone fragility and trochanteric fractures is established. Conversely, in PD patients, the role of BMD in the genesis of hip fracture type is unknown. We hypothesized that the association between femoral BMD levels and hip fracture type may be similar in the general population and in PD patients. To test this hypothesis, we investigated a sample of PD fallers with hip fracture and a control group of hip fracture fallers without PD matched for age, sex, and hip fracture type. METHODS We evaluated 1120 white patients consecutively admitted to our physical medicine and rehabilitation division because of their first hip fracture. We focused on white patients because few nonwhite elderly people live in Italy. Seventy-two of the 1120 patients were excluded from the study because their fractures resulted from major trauma or cancer affecting bone or because they occurred spontaneously. The remaining 1048 patients sustained fractures that resulted from a fall. Four of these 1048 patients were excluded from our study because they had arthroplasties at the unfractured hip, and we could not measure the hip BMD. The remaining 1044 patients were asked to undergo DXA assessment. Four of these 1044 patients refused to undergo DXA assessment and were excluded from the study. The final study sample included 1040 patients. BMD BMI CI DXA PD List of Abbreviations bone mineral density body mass index confidence interval dual-energy x-ray absorptiometry Parkinson disease 2297

2 2298 HIP FRACTURE IN PARKINSON DISEASE, Di Monaco Table 1: Descriptives in the 15 PD Patients With Trochanteric Fractures and the 23 With Cervical Fractures Variables Cervical Fractures (n 23) Trochanteric Fractures (n 15) Age (y) BMI (kg/m 2 ) L-DOPA dosage (mg) Duration of disease (y) Sex, men/women (%) 26/74 40/60.37 Hoehn and Yahr stage (median and interquartile range) 3; 2 to 4 3; 3 to 4.54 NOTE. Data are shown as mean SD unless otherwise stated. Thirty-eight (3.65%) of the 1040 patients were affected by PD (the diagnosis either was self-reported or derived from clinical records, and it was confirmed by a neurologist during the hospital stay). Twenty-six of the 38 PD patients were women (12 men), whereas 23 suffered from cervical fractures (15 suffered from trochanteric fractures). The mean age SD in the 38 patients was years (range, 60 98y). BMI was (mean SD). The number of years of PD and levodopa dosage were (mean SD) and mg, respectively. Hoehn and Yahr stage scale scores ranged from 1 to 4 (mean SD, ; median, 3; interquartile range, 2). Fourteen of the 38 patients had Parkinsonism variants. No current smokers were found among the 38 patients. Thirty-eight, nonsmoking controls matched for sex, age, and hip fracture type (cervical or trochanteric) were found among the 1002 non-pd patients. When we found multiple matched controls for a single PD patient, we randomly selected among them the single matched control who was included in the study. BMI in the 38 controls was (mean SD) kg/m 2. None of the controls was affected by neurologic diseases. BMD was assessed by DXA a (mean SD) days after fracture occurrence in the 38 PD patients ( d after fracture occurrence in the 38 controls). Four sites were assessed in each patient at the unfractured hip: total proximal femur, femoral neck, trochanter, and intertrochanteric area. Body weight and height were measured at the time of DXA assessment, and BMI was calculated as body weight/(body height) 2. None of the patients included in the study had begun specific treatment with drugs for osteoporosis after fracture occurrence before DXA assessment. Institutional review board approval was obtained for the study protocol. Data Analysis BMD values were expressed as a T score (BMD values were compared with the reference range of the young sex-matched population by using SD units). The reference population for T score calculation was derived from the Third National Health and Nutrition Examination Survey. Because BMD values were normally distributed, BMD comparison between PD patients with cervical or trochanteric fractures was performed by an unpaired t test. The same test was used to compare BMI, age, levodopa dosage, and number of years of PD between the 2 groups. A Mann-Whitney U test was used to compare Hoehn and Yahr stage and sex distribution between the 2 groups. To adjust data for potential confounders, we performed a binary logistic regression (dependent variable hip fracture type). At a preliminary step, we assessed the simple association between each potential confounder (age, BMI, Levodopa dosage, duration of disease, sex distribution, and Hohen and Yahr stage) P and hip fracture type. For 1 of the potential confounders (ie, age), we found a P value less than.30 (P.188). We included age as a covariate together with BMD in the binary logistic regression. Regression analysis was repeated adding as covariates all the variables listed previously as possible confounders, irrespective of the significance of their association with the hip fracture type. The same statistics performed in the 38 PD patients were performed in the 38 controls. The potential confounders evaluated in the controls were age, BMI, and sex. The statistic package used was SPSS, version 14. b RESULTS Descriptive statistics in the 2 groups of PD patients are shown in table 1. BMD values assessed at 4 femoral sites in the PD patients are shown in figure 1. BMD assessed at total femur was significantly lower in the 15 patients with trochanteric fractures than in the 23 with cervical fractures; the mean T score difference was 0.57 (95% CI, ; P.028). We found similar results when BMD was assessed at trochanter (mean difference 0.66; 95% CI, ; P.037) and at intertrochanteric region (mean difference 0.63; 95% CI, ; P.019). The difference between the 2 groups did not reach statistical significance when BMD was assessed at the femoral neck; the mean difference was 0.42 (95% CI, 0.05 to 0.89; P.075). Binary logistic regression is shown in table 2; after adjustment for age, a significant association was found between BMD assessed at the total femur, trochanter, or intertrochanteric region and hip fracture type in the 38 patients with PD. The inclusion in the regression models of all the variables listed in table 1 (covariates) did not materially change the significant association between BMD and fracture type (data not shown). BMD values assessed at 4 femoral sites in the 38 controls are shown in figure 2. BMD assessed at the total femur was significantly lower in the 15 controls with trochanteric fractures than in the 23 with cervical fractures; the mean T score difference was 0.80 (95% CI, ; P.005). We found similar results when BMD was assessed at the trochanter (mean difference 0.87; 95% CI, ; P.002) and intertrochanteric regions (mean difference 0.56; 95% CI, ; P.043). Difference between the 2 groups did not reach statistical significance when BMD was assessed at the femoral neck; the mean difference was 0.56 (95% CI, 0.02 to 1.13; Fig 1. Femoral bone mineral density at the 4 sites assessed (total proximal femur, femoral neck, trochanter, intertrochanteric region) in the 38 hip fracture fallers with PD. The bars indicate the mean BMD value (T score), and the lines indicate the SD. White bars, patients with cervical fracture (n 23); gray bars, patients with trochanteric fracture (n 15).

3 HIP FRACTURE IN PARKINSON DISEASE, Di Monaco 2299 Table 2: Binary Logistic Regression Models BMD (total femur) ( ).034 Age ( ).089 BMD (femoral neck) ( ).089 Age ( ).190 BMD (trochanter) ( ).034 Age ( ).072 BMD (intertrochanteric area) ( ).022 Age ( ).060 NOTE. The dependent variable was the hip fracture type (cervical or trochanteric). Covariates were BMD (assessed at 1 of the 4 femoral sites) and age. P.059). At binary logistic regression, we found a significant association between BMD assessed at the total femur, trochanter, or intertrochanteric region and hip fracture type in the 38 controls after the adjustment for age (data not shown). The inclusion in the regression models of BMI and sex as covariates did not materially change the results (data not shown). DISCUSSION The Prevalence of PD Among Hip-Fracture Patients In 1 sample of elderly fallers with hip fracture, 38 (3.65%) of 1040 suffered from PD. In previous reports, the prevalence of PD among hip fracture patients ranged from 3.37% to 5.4%, 13,23-25 which is consistent with our data. Overall, the prevalence of PD among hip fracture patients appears to be higher than that observed in the general population, 26 which is in agreement with the known increase in hip fracture risk resulting from PD. 1-5 The Association Between BMD and Hip Fracture Type in PD Patients: Meaning of the Study BMD levels assessed at the 3 femoral sites were significantly lower in PD fallers with trochanteric fractures than in those with cervical fractures. To our knowledge, no previous studies investigated the relationship between BMD and hip fracture type in PD patients. In the general population of older persons who sustained a hip fracture, several reports showed that trochanteric fractures were significantly associated with a more severe osteoporosis than cervical fractures Data in our control group of non-pd fallers are in agreement with these reports. Because our findings in PD patients and controls were similar, a key role of BMD in affecting hip fracture type in PD fallers so as in the overall population of elderly fallers is suggested. Interestingly, a recent report showed that hip fractures occurred at a similar absolute level of femoral BMD in PD and non-pd fallers. 13 Our current data confirm this result because femoral BMD levels expressed as a T score were quite similar between PD patients and controls. Altogether, data from DXA scans in hip fracture patients suggests that BMD affects both hip fracture risk and type in a similar way in PD and non-pd fallers. In the general population, BMD assessment plays a crucial role in case finding strategies for hip fracture prevention. Our data suggest that BMD assessment may likewise play a crucial role to find subjects at high risk for hip fracture among PD patients. In the overall population of elderly subjects, osteoporosis treatment plays a pivotal role in hip fracture prevention. 27 Similarly, it is expected to play a pivotal role in hip fracture prevention in PD patients. In agreement with this hypothesis, 1 randomized controlled trial recently showed that the administration of both oral alendronate and vitamin D actually reduced hip fracture incidence in PD patients over a 2-year followup. 28 Another randomized controlled trial in PD patients showed a trend toward a reduction in hip fracture risk because of treatment with oral risedronate and vitamin D, although statistic significance was not achieved. 29 Vitamin D supplementation possibly reduced fracture incidence independently of its actions on bone because vitamin-d deficiency is common in PD, 30 vitamin-d exerts extraskeletal effects that reduce fall risk and ameliorate ability to function, and it may even be involved in the pathogenesis of the selective loss of dopaminergic neurons in the substantia nigra. 34 However, in the 2 randomized controlled trials, 28,29 vitamin D was administered to both patients treated with bisphosphonates and controls. So, the observed reduction in the risk of hip fracture should be attributed to the bonestrengthening action exerted by bisphosphonates, at least in subjects who were vitamin D repleted by a specific supplementation. Most of the previous studies in the overall population of elderly persons who sustained a hip fracture showed that trochanteric fractures were significantly associated with older age and lower BMI than cervical fractures. In PD patients with trochanteric fractures, we show a nonsignificant trend toward an older age and a lower BMI than in PD patients with cervical fractures. Given the relatively small number of subjects included in this study, we cannot derive definitive conclusions on differences in age and anthropometric variables between the 2 groups of PD patients; the absence of statistical significance may be caused by the inadequate statistic power in this study. Study Limitations This study has several limitations. BMD values are influenced by race, 35 and our study included white patients only. As a consequence, our results are not generalizable to the overall population of patients who sustain hip fractures. Although hip BMD is a strong predictor of hip fracture risk, bone strength and fracture risk are also influenced by BMD-independent factors, including hip geometry; we did not assess this. 36 In PD patients, high homocysteine concentrations enhanced the risk for hip fracture independently of age-adjusted BMD levels, likely Fig 2. Femoral bone mineral density at the 4 sites assessed (total proximal femur, femoral neck, trochanter, intertrochanteric region) in the 38 hip fracture fallers without PD. The bars indicate the mean BMD value (T score), and the lines indicate the SD. White bars, patients with cervical fracture (n 23); gray bars, patients with trochanteric fracture (n 15).

4 2300 HIP FRACTURE IN PARKINSON DISEASE, Di Monaco because of homocysteine interference with collagen crosslinking. 37 Levodopa treatment induces hyperomocystinemia and may contribute to the high incidence of hip fracture by a BMD-independent mechanism. 37 We showed no significant associations between levodopa dosage and hip fracture type in our patients, but we did not evaluate homocysteinemia, which could affect fracture risk independently of BMD. We performed DXA assessment after hip fracture. The time between fracture occurrence and DXA assessment may be a confounding variable in our study because relevant changes in body composition, including a decrease in BMD, have been shown after hip fracture We performed DXA assessment about 3 weeks after fracture occurrence. A shorter time (ie, a few days) may be better to minimize the changes in BMD, but many patients cannot undergo DXA assessment a few days after fracture occurrence. Anyway, time between fracture occurrence and DXA assessment was quite similar in the patients with cervical or trochanteric fractures. We investigated the role of several potential confounders. However, other confounders may be relevant. The role of smoking habit in influencing fracture risk was ruled out because all patients and controls were nonsmokers. We did not evaluate other risk factors for hip fracture, including familiarity, previous fragility fractures, and fall characteristics. Finally, differences in soft-tissue body composition, which we did not investigate, may selectively impact on the risk of trochanteric or cervical fractures. 41 CONCLUSIONS In a sample of PD fallers, BMD levels assessed at 3 femoral sites were significantly lower in the patients who sustained trochanteric fractures than in those with cervical fractures of the hip. The results were similar to those obtained in a control group of non-pd fallers matched for sex, age, and hip fracture type. References 1. 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