Alendronate Prevents Early Periprosthetic Bone Loss in Cementless Total Hip Arthroplasty Better Than Simvastatin

Abstract

Background and Objectives: Cementless total hip arthroplasty leads to an early periprosthetic bone loss, which can impair the osseointegration process and lead to a femoral implant migration during early weight-bearing. An altered osseointegration process can lead to aseptic loosening, which is the most frequent late complication in these surgical procedures. The objective of this study was to compare the effect of alendronate and simvastatin in the prevention of early periprosthetic bone loss found in osteoporotic patients. This can lead to earlier weight-bearing in patients, as well as reduce the rate of aseptic loosening. Materials and Methods: Forty-five patients undergoing cementless total hip arthroplasty were equally distributed into three groups: group I (alendronate), group II (simvastatin), and group III (control). The alendronate group received 5 mg of alendronate postoperatively, daily for 8 weeks, and the simvastatin group received 20 mg daily for 4 weeks postoperatively, followed by 40 mg daily for 4 weeks. We determined bone mineral density (BMD), as well as bone serum markers beta cross-laps (β-CTx) and alkaline phosphatase (ALPL) preoperatively, 4 weeks postoperatively, and 8 weeks postoperatively. All patients were not allowed to fully bear weight for 6 weeks postoperatively. Results: Alendronate statistically significantly increases the BMD at one month postoperatively compared to the control group in Gruen zones 5 and 6 (p = 0.042 and p = 0.039). Overall, the BMD was higher in the alendronate group compared to the control group at one month postoperatively (p = 0.043). Alendronate decreased β-CTx bone serum marker compared to control at one month and two months (p = 0.024 and p = 0.012). Moreover, alendronate showed a higher decrease in β-CTx compared to simvastatin at both timelines (p = 0.028 and p = 0.03, respectively). Conclusions: The study shows that alendronate administration following cementless total hip arthroplasty offers better protection against periprosthetic bone loss compared to simvastatin.

1. Introduction

Hip osteoarthritis is one of the most common musculoskeletal pathologies, affecting more than 1.5 billion people worldwide [1]. This pathology can lead to pain and functional impairment, which can severely alter patients’ quality of life [1]. The treatment of hip osteoarthritis includes both conservative treatments, such as weight loss, physiotherapy, non-steroidal anti-inflammatory drugs (NSAIDs), and surgical treatment, which is mostly represented by total hip arthroplasty.

This surgical procedure is one of the most frequently performed orthopedic surgical procedures worldwide. There are two types of total hip arthroplasties, depending on fixation, which are cemented and cementless. In contrast to cemented total hip arthroplasties, cementless total hip arthroplasties require bone ingrowth at the implant site for proper fixation of the component, a process called osseointegration. There is no consensus among orthopedic surgeons on whether or not to fully weight-bear the patients during the first 6 to 8 weeks postoperatively. Despite research papers supporting the safety of early total weight-bearing, some surgeons consider that the presence of early periprosthetic bone loss could produce an early femoral migration during total weight-bearing [2].

Most cementless total hip arthroplasty patients experience good functional results, and the implant survival is around 95% at 10 years postoperatively [3]. Nevertheless, late complications can occur, leading to important medical and socio-economic consequences [4]. The most common late complication of total hip arthroplasty is represented by aseptic loosening, meaning a mechanical failure at the bone–implant interface [4]. Aseptic loosening can lead to pain, which can alter all physical activities, including walking [4]. The treatment of aseptic loosening is represented by revision surgeries, which are complex and high-risk surgeries that result in lower patient satisfaction compared to the primary surgical procedure [4].

Multiple factors can prevent aseptic loosening in total hip arthroplasties, such as implant characteristics, surgical technique, patient-related factors, and postoperative factors [4]. The postoperative factors have been the least studied, although they can provide an inexpensive and low-risk option to prevent aseptic loosening in total hip arthroplasty [5]. Two postoperative factors leading to an enhanced osseointegration process in the animal model are represented by bisphosphonates and statins [5]. Previous studies showed that both alendronate and simvastatin could limit the periprosthetic bone loss following cementless total hip arthroplasty [5]. Nevertheless, there has never been a direct comparison between these two drugs to decide which has the superior effect on the early periprosthetic bone loss following cementless total hip arthroplasty. The use of alendronate and simvastatin can also have side effects. Alendronate use can most commonly lead to abdominal pain, nausea, dyspepsia, constipation, diarrhea, musculoskeletal pain, and headache. On the other hand, the most common side effects of simvastatin are represented by gastrointestinal disorders, myalgia, and arthralgia.

The early bone formation process can be detected by examinations such as bone mineral density scan (DEXA) or bone serum markers [6]. The bone serum markers are represented by bone formation markers, such as alkaline phosphatase (ALPL), and bone resorption markers, such as beta cross-laps (β-CTx) [6].

This study aimed to test and compare the efficiency of alendronate and simvastatin in terms of the early bone formation process following cementless total hip arthroplasty. The study was performed on osteoporotic patients previously diagnosed using a DEXA scan. Moreover, the patients were not allowed full weight-bearing for the first 6 weeks postoperatively, as this was the standard postoperative protocol of the institution.

We consider that by limiting the periprosthetic bone loss, more patients will be allowed to fully weight-bear during the early postoperative period. Moreover, we consider that a better initial implant fixation can have a favorable effect on the implant’s survival.

2. Materials and Methods

The study received the Ethical Commission approval from the University of Medicine and Pharmacy Cluj-Napoca (no. 229/22/06/2020) and was performed in a single institution. The sample size was calculated using data from a similar study, an alpha type I/II error rate of 0.05, and a power of 80% [7].

The inclusion criteria were represented by age >18 years old, primary osteoarthritis, and cementless total hip replacement, while the exclusion criteria were represented by patients not willing to undergo the experiment, liver failure, allergy to simvastatin or its other compounds, allergy to alendronate or its other compounds, use of drugs contraindicated with the use of alendronate or simvastatin, as well as previous use of bisphosphonates and statins.

Once the patients were admitted to the hospital for the standard preoperative screening tests (including blood tests), informed consent was obtained. All patients included in the study underwent a preoperative DEXA scan to determine the bone mineral density (BMD) using a DEXA GE Prodigy Advance device. Osteoporosis was diagnosed when a T score of −2.5 or less was obtained. An additional spine protocol was also applied to the affected hip for further analysis, as is described.

Only patients with osteoporosis were further enrolled in the study. If the patients had hyperlipidemia diagnosed during the preoperative screening tests, they were allocated to group II (simvastatin) until a number of 15 patients was reached. The rest of the patients were randomly allocated to group I (alendronate) or group III (control) until a number of 15 patients was obtained in each group. When group II had reached 15 patients, the following patients with hyperlipidemia were randomly assigned to group I (alendronate) or group III (control) until a number of 15 patients were allocated within each group. We also collected the following data from each of the patients: sex, age, body mass index (BMI), history of smoking, history of diabetes, and hypertension.

Blood serum was harvested preoperatively and used for the determination of beta cross-laps (β-CTx) and alkaline phosphatase (ALPL) blood test analysis. Two Enzyme-linked immunosorbent assay (ELISA) kits were used for the determination of ALPL (Cat. No. E-EL-H2598) and B β-CTx (Cat. No. E-EL-H0960) levels in human serum (sau era Plasma). Both ELISA kits were purchased from Elabscience (Elabscience Biotechnology Inc., Huston, TX, USA. The plate absorbances were read at 450 nm using a TECAN SPARK10M (TECAN, Austria GmbH, Grodig, Austria), and the results were analyzed compared to the standard curve). The samples were handled according to the protocol, and the results were expressed as pg/mL of each molecule of interest.

All of the surgeries were performed in the same center, by the same surgeon, using the lateral approach and the same implants (Zimmer Biomet, Warsaw, IN, USA). Tranexamic acid was administered postoperatively, as previously described [8]. Moreover, all of the patients followed the same postoperative protocol in terms of anticoagulants, painkillers, antibiotic prophylaxis, and physical therapy exercises. In terms of weight-bearing, the patients were not allowed to bear full weight for 6 weeks postoperatively. In addition, patients in group 1 (alendronate) received 5 mg of alendronate orally daily for 8 weeks, starting on day 1 postoperatively, while group 2 (simvastatin) received 20 mg of simvastatin orally daily for 4 weeks, starting on the first postoperative day, followed by 40 mg daily for 4 weeks.

DEXA scans were performed postoperatively at 4 and 8 weeks postoperatively, and the regions were scanned according to Gruen zones (1–7), as previously described [9]. An example of Gruen zone calculation is seen in Figure 1. We used the spine protocol for a better analysis.

By using the preoperative DEXA scan, we also calculated the BMD in the modified Gruen zones (1, 2, 3, 5, 6, 7) using the spine protocol, as seen in Figure 2. For the modified Gruen zones, we used a template from the postoperative DEXA scan and applied it to the preoperative DEXA scan, as seen in Figure 2. We then analyzed the BMD surrounding the template according to the Gruen zones to identify the same zones as the ones in the postoperative DEXA scan. All of the DEXA scan measurements were performed by the same operator.

Moreover, beta cross-laps (β-CTx) and alkaline phosphatase (ALPL) blood test analysis (Elabsicence Houston, TX, USA) were performed at 4 and 8 weeks postoperatively.

The patients were instructed to report any side effects related to alendronate or simvastatin throughout the study.

The statistical analysis was performed using SPSS 16.0 and Microsoft Office Excel 16.41. The normal distribution was determined using the Shapiro–Wilk test. We calculated means, standard deviations, correlations, and Student’s t-test for equal variances. The results were considered statistically significant if the p-value was less than 0.05.

3. Results

3.1. Clinical Data

A total of 183 patients were screened during the study for the inclusion and exclusion criteria. Finally, the study included 15 patients in each group. The comparison of the clinical parameters is available in

Table 1. Clinical data of patients according to group distribution.

Parameter	Group I (Alendronate)	Group II (Simvastatin)	Group III (Control)
Sex
Male	2	8	11
Female	13	6	4
Age (years)	67.5 ± 3.2	68.9 ± 4.8	65.6 ± 5.3
BMI	22.5 ± 1.2	24.3 ± 0.7	21.3 ± 1.1
Hypertension	9	7	11
Diabetes	3	3	2
Smoking	2	1	1
Hyperlipidemia	4	15	3

. No statistically significant differences were observed within the groups in terms of age and BMI.

3.2. Bone Density Scan (DEXA)

All patients included in the study performed the DEXA scans preoperatively and 4 weeks postoperatively. From the total of 45 patients, eleven patients did not undergo the second postoperative DEXA scan at 8 weeks (five patients in Group I, three patients in Group II, and three patients in Group III).

The preoperative values of the DEXA scan according to modified Gruen zones are available in Figure 3a. The highest BMD values in all of the three groups were found in G3 and G5 zones. No statistically significant differences were observed between groups in any Gruen zone.

The postoperative DEXA scan at one month of the affected hip according to Gruen zones is available in Figure 3b. The alendronate group had the highest bone mineral density values at G2, G3, G4, G5, G6, and G7. Simvastatin showed higher values compared to control at G1, G2, G5, and G6. The only statistically significant differences were between alendronate and control at G5 and G6 (p = 0.042; p = 0.039).

The postoperative DEXA scan at two months of the affected hip according to Gruen zones is available in Figure 3c. The only statistically significant differences were between alendronate and simvastatin at G6 (p = 0.032).

The overall bone mineral density data are available in Figure 4. Alendronate showed an increase of 1.5% in bone mineral density at one month postoperatively, while simvastatin and the control group showed a decrease (12.8% and 11.6%, respectively). The only statistically significant result was between alendronate and control at one month postoperatively (p = 0.043).

The changes in BMD for each Gruen zone at 1 month postoperatively compared to preoperatively are available in Figure 5. The highest periprosthetic bone loss was in Gruen zone 7 (an average of 54% for all groups), followed by zone 1 (an average of 38% for all groups) and zone 6 (an average of 34% for all groups). On the other hand, the least periprosthetic bone loss was found in zone 2 (an average of 4% for all groups) and zone 3 (an average of 8% for all groups).

3.3. Blood Serum Analysis

All patients included in the study performed the preoperative and 4 weeks postoperative blood serum analysis of β-CTx and ALPL. Eleven patients did not undergo the second postoperative determination at 8 weeks (four in Group I, three in Group II, and four in Group III).

The β-CTx levels can be seen in Figure 6. There is a decrease in β-CTx level in each group at one month postoperatively. The β-CTx levels continued to decrease in alendronate and simvastatin groups, while they increased in the control group. No statistically significant differences were found between groups.

The ALPL levels are available in Figure 6. There is an increase in ALPL level in each group at one month postoperatively. The ALPL levels continued to increase in alendronate and control groups, while they slightly decreased in the simvastatin group. No statistically significant differences were found between groups.

Alendronate showed the highest decrease in β-CTx compared to baseline at one and two months postoperatively (Figure 7). The difference was statistically significant between alendronate and control at both one month and two months postoperatively (p = 0.024 and p = 0.012, respectively). Alendronate also showed a higher decrease in β-CTx compared to simvastatin at both timelines (p = 0.028 and p = 0.03, respectively).

ALPL levels had a statistically significant greater increase at one month compared to alendronate and simvastatin (p = 0.027 and p = 0.022, respectively) (Figure 7). Alendronate showed a higher increase at two months postoperatively, but no statistically significant differences were obtained.

None of the patients reported side effects regarding alendronate and simvastatin administration.

4. Discussion

To our knowledge, this is the first study in the literature to test and compare alendronate and simvastatin in terms of early periprosthetic bone loss following cementless total hip arthroplasty.

Despite other studies in the literature using a minimum of 6 months postoperatively for evaluation, we decided to perform the DEXA and serum marker examinations at one and two months postoperatively because the study aims to decide whether or not alendronate and simvastatin can prevent early periprosthetic bone loss.

None of the patients were allowed full weight-bearing because this was the standard postoperative protocol used within the institution. Although numerous research articles showed that immediate full weight-bearing postoperatively is safe, there are many orthopedic surgeons who avoid full weight-bearing [10,11,12,13]. Before we began the study, we asked 23 orthopedic surgeons in our region who perform a cementless total hip replacement, and only 13% (n = 3) of them allowed immediate full weight-bearing postoperatively.

In order to compare the same zones both preoperatively and postoperatively, we had to modify the technique described by Gruen. Therefore, we used a template of the femoral implant from the postoperative DEXA scan, and thus we could detect the same Gruen zones as the ones in the postoperative setting. The only exception is Gruen zone 4, which is located beneath the distal pole of the femoral implant. This zone was not possible for us to calculate because the standard preoperative DEXA scans did not extend distally enough to contain Gruen zone 4.

The preoperative values of the DEXA scan, which show higher values in the Gruen zones 3 and 5, are similar to other results reported in the literature [14]. The periprosthetic bone loss postoperatively, as found in our studies, is also supported by other studies in the literature [14].

Alendronate administration limited the periprosthetic bone loss at one month postoperatively compared to the control group in all of the Gruen zones, but due to the limited number of patients, the only significant results were in zones 5 and 6. There is no previous study on the early rate of periprosthetic bone loss after alendronate administration. The earliest interval of DEXA examination after alendronate administrations in previous studies is 6 months; therefore, a comparison with our study’s results cannot be performed [15,16]. The explanation for a later DEXA scan is that previous studies focus on the risk of aseptic loosening, which is the late complication in the case of total hip arthroplasty, while our study focuses on early complications.

On the other hand, simvastatin administration only limited the bone loss in zones 1, 2, 5, and 6, but the results did not prove to be statistically significant. Like in the case of alendronate, we did not find any previous research in the literature to study the simvastatin effect at one month postoperatively.

At two months postoperatively, alendronate and simvastatin did not show to protect against the periprosthetic bone loss compared to the control group. Alendronate showed a better bone loss prevention compared to simvastatin in Gruen zones 6 and 7, which is the most important due to the presence of the calcar area and provides good implant stability. We do not have a clear explanation for these findings, and since no previous studies were found, we cannot compare our study to other results.

Overall, at one month postoperatively, alendronate administration showed a 1.58% gain in bone mineral density, while simvastatin and the control group had a similar loss in bone mineral density (11.6% and 12.8%, respectively). This result shows that alendronate is better compared to simvastatin for the prevention of early bone loss postoperatively.

The favorable effect of alendronate on periprosthetic bone loss is supported by other studies in the literature [15,16,17]. Yukizawa et al. showed an average of 17% increase in the BMD levels at one year at the level of the calcar are, compared to the control group [17]. Moreover, Iwamoto et al. proved that alendronate prevents the periprosthetic BMD loss and lumber spine at one year postoperatively [18]. Tapanien et al. nevertheless showed that the protective effect of alendronate is not maintained at 5 years postoperatively [16]. Regarding simvastatin, there are limited data on its use following total hip arthroplasty. Zhang et al. showed that simvastatin, when administered one year postoperatively, can prevent BMD loss in ROI 1, 2, 6, and 7 [19]. Regarding the osseointegration process, simvastatin could improve the osseointegration process of the femoral component, as shown in an animal mode [20].

Regarding bone serum markers, we opted for both a bone formation marker (alkaline phosphatase) and a bone resorption marker (β-CTx). These markers are one of the most commonly used for the characterization of bone metabolism. During the three determinations, the beta cross-laps (β-CTx) marker decreased in the alendronate group; it remained at a similar level in the simvastatin group while increasing in the control group. This result shows that the bone resorption process is the lowest in the alendronate group, while simvastatin also proved improved results compared to the control group.

Regarding alkaline phosphatase (ALPL) marker, simvastatin showed the greatest increase at 1 month postoperatively, while alendronate showed the greatest increase at 2 months postoperatively.

From the bone serum marker point of view, alendronate can prevent excessive periprosthetic bone loss at one month postoperatively. Moreover, simvastatin also protects against periprosthetic bone loss, but the results were not statistically significant. The lack of side effects related to alendronate and simvastatin in our patients shows that the treatment is safe for patients to use. The lack of side effects can also be explained by the short-term treatment administration.

Because the patients were not allowed full weight-bearing postoperatively, these results may not apply to those cases where the patients are allowed immediate full weight-bearing. The reason is that full weight-bearing might limit the bone resorption process postoperatively, thus reducing the effect of alendronate and simvastatin on the periprosthetic bone. We found no studies to sustain the mention above, but the extra loading should only prove beneficial in limiting the periprosthetic bone loss, according to Wolff’s Law [21]. Regarding the osseointegration process, this is difficult to quantify with standard imaging techniques, and no studies are available to compare the osseointegration process in the partial and full weight-bearing postoperative protocol.

Limitations of this study include a low number of patients, lack of patient randomization, lack of non-osteoporotic patients, the short time follow-up, lack of functional scores, and lack of aseptic loosening rate. Moreover, the groups were not comparable in terms of hyperlipidemia, which also represents a limitation of our study.

As this is the first study to compare alendronate and simvastatin in the early postoperative setting, further studies are needed to confirm our result before alendronate can be widely used for the prevention of femoral stem migration when early full weight-bearing is permitted.

5. Conclusions

The study shows that alendronate administration following cementless total hip arthroplasty offers better protection against periprosthetic bone loss compared to simvastatin when immediate full weight-bearing is not permitted.