Effect of activity level after a posterior-stabilized TKA on the relative bone mineral density measured on standard radiographs in periprosthetic tibial bone

Background: The aim of this study was to evaluate the effect of activity level after a posterior-stabilized total knee arthroplasty (TKA) on the relative bone mineral density (rBMD) measured on standard radiographs in periprosthetic tibial bone. Methods: A retrospective review identied 110 patients (110 knees (cid:0) 20 men/90 women) who underwent PS TKA with 5 years follow-up. Patients activity level was evaluated by University of California Los Angeles (UCLA) activity score, and the rBMD in periprosthetic tibial bone was measured on anteroposterior X-ray images. Clinical assessments included Western Ontario and McMaster Universities (WOMAC), Knee Society score (KSS) and visual analogue scale (VAS). Nonlinear regression analysis was used to assess the impact of activity levels on periprosthesis bone density. Results: During 5-year follow-up period, the bone density in the medial, lateral and distal areas decreased compared with that before surgery (p<0.0001). There was a U-shaped distribution between UCLA activity rating and rBMD loss, with the lowest rBMD loss when the UCLA activity score was between 6-8 at 1 and 3 years. The curve tting of UCLA activity level and rBMD% showed there was a parabolic relationship between UCLA activity level and rBMD% at 1 and 3 years after surgery (P<0.001, P=0.001), while there was no signicant relationship between UCLA activity level and rBMD% at 5 years after surgery (P=0.436). Conclusions: We found that physical activity had a signicant effect on radiographic measurements of BMD at 1 and 3 years but not at 5 years. Moderate activity may be associated with less proximal tibial BMD loss after TKA, therefore it may be the most appropriate activity intensity for patients with TKA.


Background
An increasing number of patients with end-stage osteoarthritis are receiving treatment with total knee arthroplasty (TKA), which is a successful procedure for alleviating pain, improving functional ability, and enhancing quality of life [1]. Bone mineral density (BMD) is an indicator of bone quality and re ects the material properties, bone metabolism and risk of fracture [2,3]. Postoperative changes in the periprosthetic bone density in the tibia are closely related to the outcomes of TKA [4,5]. Several studies [6][7][8][9] have reported a reduction in BMD in the proximal tibia after TKA, which can cause the subsidence of some components, especially of the tibial plateau, and increase the risk of prosthetic loosening and further revision.
Physical activity is a critical part of functional recovery of the knee joint after TKA [10]. In clinical practice, it is found that the gray value (X rays) of patients who actively engage in functional exercises is signi cantly brighter than that of patients who stay in bed for a long time or not take functional exercises, suggesting that the physical activity is related to the BMD around the prosthesis. Oktas et al [11]concluded that a rehabilitation program for strengthening the muscles around the hip and knee joints was quite important to the success of TKA. However, Kilgus, DJ et al [12] reported that a high level of physical activity was correlated with increased osteoporosis-related prosthetic loosening. Therefore, we hypothesized that the physical activity after TKA would in uence the bone density around the prosthesis. The aim of this study was to evaluate the effect of activity level after a posterior-stabilized TKA on the relative bone mineral density measured on standard radiographs in periprosthetic tibial bone.

Study design
This was a retrospective study based on data collected from consecutive patients undergoing primary TKA from January 2010 to December 2015. Postoperative assessments were conducted at 1 week, 3 months, 1 year, 3 years, and 5 years after surgery. This study was approved by the Medical Ethics Committee of The First A liated Hospital of Sun Yat-Sen University (code number [2011] 57), and all the procedures followed the principles of the Helsinki Declaration.

Patients enrollment
A total of 121 patients with a diagnosis of knee osteoarthritis (Kellgren-Lawrence classi cation III or IV) were enrolled in the research, 11 patients were excluded because of incomplete data. At last, 110 patient data were included in the study and analyzed. The mean age of the patients (90 females, 20 males) was 66.6±7.4. Patients were considered eligible if they met the following criteria: More than 50 years old; Reported the presence of knee pain greater than 6 months; diagnosed with knee arthritis by a surgeon; treated surgically with a KTA. Patients were excluded based on the following: varus deformity greater than 15° rheumatoid arthritis as the primary indication for surgery; drugs that affect bone mineral density were used; Body Mass Index (BMI) was greater than 30; Failure to complete long-term follow-up.

rBMD (calibrated grayscale value) measurements
Dual X-ray absorptiometry (DXA) is the golden standard used to evaluate BMD, but it is not used in routine examinations after TKA. Hernandez-Vaquero et al [13] reported a method based on digital X-rays images to evaluate BMD, and the consistency between the BMD measured by DXA and the relative BMD (rBMD )measured by this method was approximately 0.72 to 0.92. Therefore, this method was used to evaluate BMD in this study.
In order to ensure the comparability between the X images, all X-rays were taken on the same machine, and the patient's knee joint was controlled in a neutral position, so as to reduce the errors caused by the difference in the position of knee. Knee exion was minimized by xing the tibial tubercle at the lower end of the knee. Rotation was controlled by xing the heel and the rst and second toes. Ten regions of interest (ROIs) were chosen as the measured regions in tibia: four lateral regions (L1, L2, L3, L4), four medial regions (M1, M2, M3, M4), and two distal regions (D1, D2) (Fig 1). ImageJ, (version1.8, NIH, USA) was used to measure the mean grayscale value in the established regions of the radiographs. The measured grayscale value of each designated region was calibrated using the formula:, where G C,R is the calibrated grayscale value, also representing the rBMD in a given region, G R is the grayscale value within an ROI, G a is the value of air within the radiograph, and G f is the grayscale value of the femoral component.
The medial tibial rBMD was de ned as the mean values of M1, M2 and M3, the lateral tibial rBMD as the mean values of L1, L2 and L3, and the distal tibial plateau as the mean values of D1 and D2, and the tibial rBMD as the mean values of 10 ROIs.
Clinical data collection Data of gender, age, BMI, Operative Duration, Kellgren-Lawrence Classi cation, length of Stay were obtained through patient medical records. The hip-knee-ankle (HKA) angle was measured by X-ray. All patients were clinically evaluated with respect to knee function using the Knee Society Score (KSS) [14], the Western Ontario and McMaster University Osteoarthritis Index (WOMAC) [15] and visual analogue scale (VAS) score. The level of activity was evaluated using the University of California Los Angeles (UCLA) Activity Rating Scale [16,17].

Statistical analysis
All statistical analyses were performed using SPSS, Version 21.0. (SPSS Inc., Chicago, IL, USA). The Shapiro-Wilk test was used to con rm that the data were normally distributed. One-way ANOVA was used to compare clinical scores and rBMD at different time points. To verify the in uence of other factors on rBMD%, Pearson's chi-squared test was used to examine the association between sex, age, HKA angle, BMI and rBMD%. Curve tting and nonlinear regression were performed to clarify the relationship between the UCLA activity rating and rBMD% at different time point. Post hoc power analyses were performed after the study. Signi cance was de ned as P<0.05.

Results
At last, a total of 110 patients (20 men/90women) were included in the analysis. Post hoc power analysis suggested that our sample size was su cient. The mean age was 66 years. Details of the patients are shown in Table 1. A proportion of patients (9%) were excluded from the analysis due to lack of complete data. There no signi cant differences between the characteristics of the included and excluded patients.
Clinical outcome-WOMAC, KSS and VAS By the 5-year follow-up examination, the knee score and function score (WOMAC, KSS, VAS score) for each study participant had improved signi cantly over preoperative scores (P<0.001, Table 2).
Changes in tibial rBMD after TKA During 5-year follow-up period, the bone density in the medial, lateral and distal areas decreased compared with that before surgery (p<0.0001). As shown in Figure 2 and Table 3, compared with the baseline, rBMD of medial side, lateral side and distal side decreased by 3.0 %, 4.2 % and 1.4 % respectively at 3 months, decreased by 3.5%, 5.1% and 1.4% respectively at 1 year, decreased by 4.0%, 5.6% and 1.8% respectively at 3 years, and decreased by 6.7%, 9.7% and 3.3% respectively at 5 years.

Effect of activity level after TKA on rBMD in tibial
Pearson's chi-squared test showed that there were no signi cant association between them (Table 4). To verify the effect of postoperative activity level (UCLA activity scale) on rBMD%, a line graph of UCLA activity scale and rBMD% was drawn and the results showed that there was a U-shaped distribution between them with the lowest rBMD loss when the UCLA activity score was between 6-8 at 1 and 3 years (Fig 3, Table 5).
To nd relation between UCLA activity rating and rBMD%, the curve tting has been employed (Fig 4). The curve tting of UCLA activity rating and rBMD% showed there was a parabolic relationship between UCLA activity rating and rBMD% at 1 and 3 years after surgery (P<0.001, P=0.001), while there was no signi cant relationship between UCLA activity rating and rBMD% at 5 years after surgery (P=0.436).

Discussion
This retrospective study revealed that the bone density in periprosthetic tibial decreased after TKA, with the largest decrease at 1 year after surgery, and gradually stabilized in the future; Physical Activity was an important factor that affects bone mineral density; The effect of physical activity on bone density in periprosthetic tibial was time-dependent.
This research demonstrated a decrease in BMD in the proximal tibia after TKA. The decline was most pronounced in the rst year. Li and Nilsson [18] reported that bone density temporarily dropped by 13 percent in the rst three months after TKA. Hvid et al. [19]found an 11 % decrease in BMD at two years, whereas Petersen et al. [9]reported a 22% decrease in BMD after three years of TKA. In clinical practice, bone resorption and osteoporosis were observed around the prosthesis after TKA, and osteoporosis was obviously observed during revision surgery.
In fact, the decrease in BMD after TKA had been reported and was generally believed to be the result of a biomechanical response to stress shielding of the tibial component [20][21][22][23]. TKA surgery altered the intraarticular environment and osteotomies exposed cancellous bone directly to the environment, making the distal tibia more susceptible to environmental change. Prosthesis implantation produced stress shielding effect on bone, so the stress load on bone was reduced, which leaded to increased bone absorption, decreased bone mass, and decreased bone density. On the other hand long-term interaction between the prosthesis and bone resulted in wear particles, which in turn leaded to aseptic in ammation and aggravated osteolysis.
It was found that the activity level had a bidirectional effect on the bone density around the prosthesis. A nonlinear (parabolic) relationship between the UCLA activity level and rBMD% in the proximal tibia suggested that moderate physical activity was bene cial to maintain bone mass, while insu cient or excessive functional exercise aggravated bone loss. This phenomenon is consistent with Wolff's law [24], which indicates that mechanical stress stimulates bone formation, while disuse leads to bone loss.
Petersen et al [9] revealed that a decreased load led to rapid bone loss, while an increased load led to a small increase in BMD in the tibial condyles. Gallo, J et al. [25] reported that for man, high levels of physical activity, and a high historical level of physical activity were associated with a higher risk of reoperation; for women, the early reoperation was associated with lower physical activity.
The effect of activity level on bone mineral density was correlated with time. The results showed that the activity level had a signi cant effect on bone density at 1 year and 3 years after surgery, but no signi cant at 5 years. The signi cant in uence of activity level on rBMD at 1 and 3 years could be attributed to adaptive bone remodeling and stress shielding effect, as Jaroma, A et al. reported that tibial metaphyseal periprosthetic bone was remodeled after TKA due to mechanical axis correction [8]. Seitz et al [26] found that there was a reparation phase and a stabilization phase during bone remodeling period after TKA and no signi cant BMD change was observed during the stabilization phase. After long-term interaction between bone and prosthesis, a stable state was formed, which was manifested as a close bond between bone and prosthesis and a fusion of bone and prosthesis interface. In such a stable state, bone mineral density was less or even not affected by external environment. This study showed that 5 years after TKA, the bone mineral density in proximal tibial tended to be stable, and activity level had no signi cant effect on bone mineral density.
Our results revealed 3 important ndings First, the bone density in periprosthetic tibial decreased after TKA; Second, physical activity was an important factor affecting bone density in periprosthetic tibial; Third, the in uence of physical activity on bone density was bidirectional and time-dependent. Clinically, prosthesis instability, periprosthetic fractures, and proximal tibial osteoporosis are closely related to periprosthetic bone density decrease after TKA. Therefore, according to the changes of bone density after TKA, appropriate intervention therapy should be conducted to guide postoperative rehabilitation, so as to reduce bone loss in proximal tibial and improve clinical e cacy. Firstly, in view of the decrease of bone density in periprosthetic tibial after TKA, interventions that can improve bone mineral density should be taken in postoperative rehabilitation period, such as body weight control, oral drugs to improve bone mineral density, and proper functional exercises. Secondly, because activity level had an impact on bone mineral density, and appropriate activity level could reduce bone density loss, moderate level of functional exercise should be conducted after TKA. Thirdly, the effect of activities on bone mineral density was time-dependent, so patients should have appropriate functional exercise activities in the early postoperative period.
There are some limitations in our study. First this was a retrospective study, with selective bias and confounders bias, and the number of participants in the study was limited. Second, no control group was established in this study. Third, the sex distribution was atypical with 82% females. However, according to relevant statistics, the ratio of male to female knee osteoarthritis is about 1:7, so female subjects are the majority. Forth, the BMD measured on standard X-ray images is a relative value. Although the rBMD measured on standard X-ray images is not the true BMD, Hernandez-Vaquero et al [13] have proven that the relationship between the rBMD measured on standard X-ray images and the true BMD measured by DXA is linear, therefore, rBMD could serve as an alternative to BMD.

Conclusion
In this retrospective study, we found that the bone density in periprosthetic tibial decreased after TKA and physical activity had a signi cant effect on radiographic measurements of BMD at 1 and 3 years but not at 5 years. Moderate activity may be associated with less proximal tibial BMD loss after TKA, therefore it may be the most appropriate activity intensity for patients with TKA. The datasets used and/or analysed during the current study are available from the corresponding author on reasonable request.

Competing interests
The authors declare that they have no competing interests   Note: Values are the mean ± SD. P value is compared between 5 years after surgery and preoperative by t test.  Note: Pearson's chi-squared test was used to examine the association between sex, age, hip-knee-ankle (HKA) angle, BMI and rBMD%, the results showed that there were no signi cant association between them.