Basal elevated serum calcium phosphate product as an independent risk factor for mortality in patients with fractures of the proximal femur—A 20 year observation study

Injury, Int. J. Care Injured 47 (2016) 728–732

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Basal elevated serum calcium phosphate product as an independent risk factor for mortality in patients with fractures of the proximal femur—A 20 year observation study Florian M. Kovar a,*, Georg Endler b,c, Oswald F. Wagner b, Andreas Wippel a, Manuela Jaindl a a

Department of Trauma Surgery, General Hospital Vienna, Medical University Vienna, Austria Institute of Central Laboratory, General Hospital Vienna, Medical University Vienna, Austria c Labors.at, Vienna, Austria b

A R T I C L E I N F O

A B S T R A C T

Article history: Accepted 22 November 2015

Introduction: Fractures of the proximal femur are a significant cause of mortality and morbidity in the elderly population. Yet predictive marker of unfavourable prognosis are still lacking. Calcium phosphate product is a marker of osteo-renal dysregulation. This study investigated the role of serum calcium phosphate product (SCPP) levels as a prognostic parameter for outcome in those patients. Patients and methods: A total of 3577 consecutive patients with diagnosed fractures of the proximal femur were included in our study (72.5% females). SCPP was divided into tertiles: <1.92 mmol2/l2, 1.93– 2.38 mmol2/l2 and >2.39 mmol2/l2. Data collection was performed prospectively and statistical evaluation was performed retrospectively. Results: Mean follow up in our study group was 11.0  0.3 months. The mean age of our study group was 79.0 years (SEM 14 years). To facilitate analysis, patients were divided in two groups: 84 years (64.4%) and 85 years (35.6%), and mortality <12 months was 12.4% (n = 445). In our study population higher SCPP levels ad admission were associated with a markedly elevated mortality. In a multivariate logistic regression model adjusted for age and sex, plasma creatinine and haemoglobin at admission caused a 1.3 (CI: 1.01–1.6) for SCPP 1.93–2.38 mmol2/l2, and a 1.6 (CI: 1.2–2.0) for SPP >2.39 mmol2/l2 fold increase in overall mortality compared to patients with baseline SCPP levels (<1.92 mmol2/l2) as reference category. Conclusion: Those findings in our study population with 3577 patients over a period of 20 years proved to be, that serum Ca levels may be a good predictor for mortality in patients with fracture of the proximal femur. Further studies are required to evaluate whether these high risk patients might benefit from specific therapeutic measurements. This prognostic factor may help to increase the outcome of elderly patients with a fracture of the proximal femur. ß 2015 Elsevier Ltd. All rights reserved.

Keywords: Fracture of the proximal femur Mortality Elderly patients Serum phosphate product Gender Plasma creatinine Haemoglobin levels

Introduction Fractures of the proximal femur are a worldwide health problem, with several studies addressing the rates and risk factors that result in mortality following this injury [1–8]. The rising annual incidence of fractures of the proximal femur has made it

* Corresponding author at: Department of Trauma Surgery, General Hospital Vienna, Medical University Vienna, Waehringerguer 18-20, A-1090 Vienna, Austria. Tel.: +43 1 40400/59020; fax: +43 1 40400/59490. E-mail address: fl[email protected] (F.M. Kovar). http://dx.doi.org/10.1016/j.injury.2015.11.033 0020–1383/ß 2015 Elsevier Ltd. All rights reserved.

one of the most common and expensive causes for admission following trauma [9–12]. The mean age of patients with fracture of the proximal femur is high, often over 80 years, and comorbidity in this patient group is therefore frequent [13–15]. Women make up at least 70% of all patients with a proximal femoral fracture according to literature [16,17]. Many studies have identified predisposing factors for fracture of the proximal femur, but little is known about independent risk factors for mortality in this selected patients group [8,12,18–23]. A possible association between mortality after fracture of the proximal femur and reduced haemoglobin levels at admission has already been reported in recent findings [19].

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Calcium phosphate product is a clinically relevant tool to estimate the cardiovascular risk of patients with renal failure [24] and an early marker of osteo-renal dysregulation. SCPP levels are positively associated with unfavourable outcome in patients with chronic kidney disease, but there are also a few data related to chronic heart failure [25,26] and stroke [27]. Despite those findings, evidence that SCPP is an independent risk factor for mortality and morbidity is questioned by some authors [28]. However, up to now, little is known about the independent risk factor SCPP in patients with a fracture of the proximal femur. Although a study group around Rostami et al. investigated the correlation between SCPP and quality of life and hospitalisation, clear data on patients with fracture of the proximal femur are still missing [29]. The purpose of our study was to assess the relationship between serum calcium phosphate product (SCPP) levels at admission and morbidity and mortality in elderly patients with fractures of the proximal femur. Patients and methods A total of 3775 consecutive patients with a proximal femur fracture, admitted to our Department, from 1992 to 2012 have been considered for inclusion. Inclusion criteria included: proximal femur fracture, surgical treatment and availability of laboratory results. One hundred seventy eight individuals had to be excluded due to missing data resulting in 3577 individuals that were included in our analysis. Data collection was performed prospectively and statistical evaluation was performed retrospectively, approved by local IRB (EK 814/2010). Patients were identified from surgical records and hospital in-patient enquiry system. Patients’ clinical and demographic data were retrieved from our database. Laboratory findings at admission were retrieved from the database of Institute of Central Laboratory, General Hospital Vienna. Patients were classified in femoral neck and intertrochanteric fractures, with a total number of 101 unclassified fractures, due to the fact that a clear disposition in one of the two groups was not possible. Study population was divided into the following sub-groups: SCPP was divided into tertiles to facilitate analysis. The lowest group with SCPP level at admission <1.92 mmol2/l2 served as reference group, followed by the second (1.93–2.38 mmol2/l2) and third tertile (>2.39 mmol2/l2). Patients not managed operatively were excluded from the study. Other exclusion criteria were pathological fractures and those patients who did not have a full blood count undertaken at admission. After discharge from hospital, patients were followed-up in a hip-fracture clinic. The primary outcome measured was the SCPP associated mortality. Plasma creatinine and haemoglobin levels were also observed. We were able to trace the outcomes of all patients by a data adjustment with the Austrian Death Register. Statistical methods For statistical analyses we used the SPSS 16.0 software package (SPSS, Chicago, IL, USA). Mean values and standard error of the mean were given unless otherwise indicated for continuous variables. Discrete data are presented as counts and percentages. A two-tailed values less than p 0.05 was considered statistically significant. p-Value was calculated to reference category with normal SCPP levels <1.92 mmol2/l2. To assess the value of SCPP levels as an independent risk factor for mortality we performed a multivariate logistic regression analysis adjusted for age and sex. Hazard ratios and 95% confidence intervals were calculated within our patients.

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Results We enrolled 3577 patients with a mean age of 79 years (range 65–93). 72.5% were females, and 27.5% were male. Follow up was 11  0.3 months and approximately two thirds of the individuals were 84 years (64.4%) and around one third 85 years (35.6%). Gender distribution showed an overrepresentation of males in the reference group with SCPP level at admission <1.92 mmol2/l2 (n = 1.209, m 34.6%; f 65.4%) compared to the second group 1.932.38 mmol2/l2 (n = 1.214, m 23.1%; f 76.9%) and severe elevated >2.39 mmol2/l2 (n = 1.154, m 27.5%; f 72.5%). A total number of 390 patients (10.9%) died within 3 months. Mortality <6 months was observed in 416 cases (11.6%), and mortality <12 months was detected in 445 patients (12.4%). Overall mortality within follow up time was n = 545 (15.2%). Table 1 details the characteristics of the study population and the group disposition. Mortality hazard ratio compared to reference category is described in detail in Fig. 1. Elevated SCPP levels and admission were associated with statistical significant higher mortality. Even slightly elevated SCPP levels at admission caused a 1.3 (CI: 1.01– 1.6) fold increase in mortality, and severe elevated SCPP levels caused a 1.6 (CI: 1.2–2.0) increase in overall mortality (all values at p < 0.01). Our results have been adjusted according to age, gender, plasma creatinine and Hb levels to exclude possible bias.

Discussion The rate of mortality in our cohort at the various time intervals was similar to that which has been previously reported [5,8,19,30–33]. Not all studies agree on the effect of age, and male gender in independently predicting mortality [2,8,34– 41]. Although early mortality rates after fracture of the proximal femur are well reported, the cause of this mortality is less clear [34]. Despite the advances in the surgical and medical management of fractures of the proximal femur, data on recent trends are scarce [8,19,23,34]. It is well known that a higher serum alkaline phosphatase (ALP) is associated with increased risks of all-cause and cardiovascular mortalities in haemodialysis and non-dialyzed patients [21,41,42]. In a study by Maruyama et al. a higher ALP was associated with an increased risk of both all-cause and cardiovascular mortalities in patients with fracture of the proximal femur [21]. In another study, Zoledronic acid proved to reduce the risk of death by 28% after fracture of the proximal femur, suggesting an even greater influence on cardiovascular events and pneumonia than on simply reducing secondary fractures [22]. Those findings together with other mentioned studies provide a possible strong correlation amongst vitamin D, calcium and phosphate metabolism as independent predictor for mortality [29,43–46]. The role of calcium phosphate product as an independent risk factor for mortality and morbidity is discussed controversial [28]. Despite that fact, there are abundant epidemiologic data showing correlations between SCPP and cardiovascular outcomes or mortality [28]. In a large cross-sectional study, both serum Ca and serum P concentrations were strongly associated with coronary calcification but SCPP was not analysed [28,47]. High concentrations of SCPP are also associated with an increased risk for allograft loss in kidney transplanted recipients [48]. Our results demonstrate lower mortality in patients with normal SCPP levels (reference group) compared to higher mortality rates in elevated SCPP levels (slightly and severe elevated group). Those findings suggest further substance to the thought that higher SCPP levels, may lead to higher mortality in elderly patients with fracture of the proximal femur.

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730 Table 1 Illustration of calcium phosphate product.

Total patients Gender Male Female Age Mean in years 84 85 Follow up in months Mean (SEM) Type of fracturea Femoral neck Intertrochanteric Mortality <3 months <6 months <12 months Over all Other parameters Plasma creatinine (mg/dL) Hb levels (g/dL) * a

<1.92 mmol2/l2 Calcium phosphate product

1.93–2.38 mmol2/l2 Calcium phosphate product

N

n

%

1209

%

1214

>2.39 mmol2/l2 Calcium phosphate product

Total calcium phosphate product

n

n

%

1154

p

%

3577 <0.01

418 791

34.6 65.4

280 934

23.1 76.9

284 870

24.6 75.4

982 2595

27.5 72.5

79  0.4 787 422

65.1 34.9

80  0.4 732 482

60.3 39.7

77  0.5 784 370

67.9 32.1

79  0.2 2303 1274

64.4 35.6

11  0.6

11  0.5

12  0.6

<0.01

ns*

11  0.3

<0.01 485 595

106 112 121 137

1.01  0.01 12.7  0.1

49.6 50.4

8.8 9.3 10.0 11.4

536 649

45.2 54.8

124 133 140 172

10.2 11.0 11.5 14.2

1.02  0.01 12.4  0.1

455 656

160 171 184 236

1.26  0.02 12.1  0.1

41.0 59

13.9 14.8 15.9 20.5

1576 1900

390 416 445 545

1.09  0.03 12.4  0.01

45.3 54.7

10.9 11.6 12.4 15.2

<0.01 <0.01 <0.01 <0.01

<0.01 <0.01

Not significant. Not all fractures have been classified in our study population according the groups.

Limitations of the study Our study may have been emasculated by the fact that it was a prospective data collection and retrospective data evaluation study, performed at only one level I Trauma Centre. We only

evaluated predominantly Caucasian, Austrian patients, a study population that might not be comparable to other regions in the world. However there is no evidence that our findings might be biased by local environmental or population specific factors. In contrast due to the large sample size of 3577 consecutive patients

Fig. 1. Overall survival in individuals after hip fracture according to SCPP. Survival curves were calculated in a multivariate cox regression adjusted for gender, age basal Hb and creatinine.

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