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Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee arthroplasty
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The Knee
Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee arthroplasty Yasutaka Murahashi a, Atsushi Teramoto a,⁎, Shunsuke Jimbo a, Yohei Okada a, Tomoaki Kamiya a, Rui Imamura b, Hiroyuki Takashima b, Kota Watanabe c, Satoshi Nagoya d, Toshihiko Yamashita a a
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan Division of Radiology and Nuclear Medicine, Sapporo Medical University Hospital, Sapporo, Hokkaido, Japan Department of Physical Therapy, Sapporo Medical University School of Health Sciences, Sapporo, Hokkaido, Japan d Department of Musculoskeletal Biomechanics and Surgical Development, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan b c
a r t i c l e
i n f o
Article history: Received 14 August 2019 Received in revised form 2 December 2019 Accepted 17 December 2019 Available online xxxx Keywords: Periprosthetic bone Bone mineral density Osteoporosis Total knee arthroplasty Denosumab Treatment
a b s t r a c t Background: Periprosthetic bone quality is one of the most important factors preventing early prosthesis migration and long-term failure. Although denosumab, which binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), has been linked with periprosthetic bone mineral density (BMD), the effectiveness of denosumab against bone loss remains unclear. We hypothesized that denosumab treatment after total knee arthroplasty (TKA) could prevent periprosthetic bone resorption. Methods: In this prospective cohort study, 28 patients with primary knee osteoarthritis were divided into two groups: denosumab (denosumab and vitamin D) and control (vitamin D only) groups. All patients underwent TKA with the same implant model and received medication after surgery. We used dual-energy X-ray absorptiometry to measure periprosthetic BMD after TKA. Results: In the control group, the BMD of the proximal medial tibia decreased drastically at 12 months after TKA (−19.7%). Denosumab treatment significantly preserved this BMD loss (0.7%). The linear regression analysis revealed that denosumab intervention had the highest significantly positive relationship with BMD. Conclusions: Our results indicate that denosumab treatment significantly reduces periprosthetic BMD loss, even at the early stages after TKA. This therapeutic strategy may facilitate early stable fixation of the prosthesis which, in turn, may help to prevent early implant migration and reduce the need for revision surgery. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Total knee arthroplasty (TKA) is one of the most widely performed procedures in orthopedic surgery. Although TKA provides excellent outcomes in terms of relieving pain and restoring joint function, over time, issues such as implant wear and loosening may result in the requirement for revision TKA. It is well recognized that the stability of the prosthesis is important for component survival and is dependent on multiple factors [1], including the quality of the proximal tibial bone [2–4]. Jaroma et al. previously reported that tibial metaphyseal periprosthetic bone is remodeled due to stress shielding after cemented TKA, as a form of me-
⁎ Corresponding author at: Department of Orthopaedic Surgery, Sapporo Medical Univ. School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Hokkaido, Japan. E-mail address: [email protected]. (A. Teramoto).
https://doi.org/10.1016/j.knee.2019.12.010 0968-0160/© 2020 Elsevier B.V. All rights reserved.
Please cite this article as: Y. Murahashi, A. Teramoto, S. Jimbo, et al., Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee ..., The Knee, https://doi.org/ 10.1016/j.knee.2019.12.010
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chanical axis correction [5]. Bone mineral density (BMD) continues to decrease considerably for as long as seven years after TKA [4]. Several studies have shown that bisphosphonates, which are most commonly used in the treatment of osteoporosis, can improve periprosthetic BMD after TKA [6–10], and reduce early migration of the prosthetic component [11]. Indeed, in an external population-based cohort study, bisphosphonate users had a 59% reduced risk of requiring revision surgery [8]. Denosumab is a human monoclonal immunoglobulin G2 (IgG2) antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL), preventing its osteoclastic bone resorptive activity. A previous animal study has suggested that antiRANKL agents are superior to bisphosphonates in the context of implant fixation or fracture healing [12]. In a recent clinical study, denosumab prevented BMD loss around the implant after total hip arthroplasty [13]. However, there is no evidence of the anti-resorptive effect of denosumab treatment on periprosthetic bone density after TKA. It is important to prevent periprosthetic bone density loss after TKA to maintain stable fixation of the prosthesis component, and to decrease the risk of prosthesis migration and the need for revision surgery. We hypothesized that denosumab treatment after TKA could prevent periprosthetic bone resorption, as measured using dual energy X-ray absorptiometry (DEXA). In this prospective study, we investigated the short-term changes in periprosthetic BMD across seven defined regions of interest (ROIs).
2. Materials & methods 2.1. Patients Primary TKA was performed in 102 patients (115 knees) who visited our hospital between March 2015 and November 2017 (Figure 1). To preserve homogeneity in the study, we included only patients with osteoporosis (diagnosed with a T score of −2.5 or below in the BMD of the femoral neck) and primary osteoarthritis of the knee who underwent TKA using the Vanguard posterior-stabilized (PS) knee cemented prostheses (Zimmer Biomet, Warsaw, IN, USA). We excluded patients who underwent TKA with another prosthesis, those undergoing revision surgery, and those who had previously taken anti-osteoporotic drugs or other medications known to influence bone mineral metabolism. The sample size (n = 27) was calculated based on similar studies to detect a mean difference of 15% in relative periprosthetic bone density, with a standard deviation of 20% (α = 0.05 and 80% power) [7,10,14]. Patients were divided into two groups: patients in the control group received 0.5 μg active vitamin D3 daily by oral administration (Alfacalcidol; Chugai Pharmaceutical Co., Tokyo, Japan), whereas those in the denosumab group received 0.5 μg vitamin D3 daily and 60 mg denosumab every six months by subcutaneous injection (Denosumab; Daiichi-Sankyo Co., Tokyo, Japan) from the day after surgery. All patients in the denosumab group were uniformly administered 60 mg of denosumab on the day after surgery, at six months postoperatively, and at 12 months postoperatively. Denosumab was discontinued at 12 months postoperatively. Patients who underwent surgery from March 2015 to March 2016 were enrolled in the denosumab group, while patients who underwent surgery from April 2016 to November 2017 were enrolled in the control group. Patients were advised to discontinue the medication and contact their physician if they experienced any adverse effects. Seven patients were lost to follow up (due to relocation). Three patients visited our hospital but were not able to be examined by DEXA because of machine problems. At the final analysis, the denosumab group comprised 13 patients and the control group comprised 15 patients (Figure 1). Both groups were administered with medications continuously throughout the study period.
Figure 1. Flowchart of inclusion. DEXA, dual energy X-ray absorptiometry; RA, rheumatoid arthritis; TKA, total knee arthroplasty.
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2.2. Surgery Surgery was performed by two experienced orthopedic surgeons using the Vanguard PS knee prosthesis with the cemented technique. The patella was resurfaced in all patients. A tourniquet was used for the entire operation. Full weight-bearing was allowed immediately after surgery for all patients.
2.3. Evaluation The BMD of the femoral neck, the total femur, and the periprosthetic proximal tibia was measured by fan-beam DEXA in anteroposterior (AP) projection using Hologic Apex, version 5.6.0.2 (Horizon A; Hologic, Ontario, Canada). All patients were examined in the supine position, and the ankle was fixed with hip positioner devices with the patella in the front position and the knee extended to obtain a repeatable position. Four measurements were taken; these measurements were made in the first week postoperatively (baseline), and at three, six, and 12 months postoperatively. We analyzed periprosthetic bone density across seven ROIs: three medial tibial regions (M1, M2, M3), three lateral tibial regions (L1, L2, L3), and the distal tibial region below the prosthetic stem (D) (Figure 2). An edge-detection algorithm was used to define the outlines of the bone, prosthesis, and cemented areas. The periprosthetic zones were classified based on previous studies [5,7,14,15]. To avoid measuring peripheral cement, the medial and lateral regions were initially placed automatically by Prosthetic Hip software (Hologic), and the technologist then manually positioned the ROI 1.0 cm distal to the prosthesis–bone interface, with the distal region located 0.5 cm below the prosthetic stem. After using this combined manual and automatic technique to position the ROIs for the first scan, the ‘compare’ facility in the software was used to copy the ROIs for the second scan. Although the ROIs used in the present study were relatively small, which may potentially decrease the repeatability of the results, a previous study using the same ROIs reported high reproducibility even with a small periprosthetic ROI [16]. The change in BMD at each ROI is shown as the value relative to the baseline. For BMD outcome data, Cohen's d effect size was applied to estimate the overall effect size of denosumab on BMD (b 0.2: not clinically relevant; N0.2: small; N0.5: moderate; N 0.8: large; N1.2: very large). Long standing radiographs were taken preoperatively to measure the femorotibial angle (FTA), which was used to indicate knee alignment, as previously described [17]. Kellgren–Lawrence (KL) grading (0–4) was used to evaluate osteoarthritis severity on preoperative radiographs [18], with grade 0 considered normal and grade 4 indicating the most severe deformity. The medical records of 10 patients in the control group and 10 patients in the denosumab group were reviewed at more than 12 months postoperatively to evaluate the risk of fracture after denosumab discontinuation; the mean (± standard deviation) follow-up periods were 20.3 ± 6.5 months in the control group and 29.0 ± 9.4 months in the denosumab group.
Figure 2. Radiograph showing the regions of interest (ROIs) for the measurement of periprosthetic bone mineral density (BMD) with dual-energy X-ray absorptiometry (DEXA). The proximal medial tibial bone was divided into three medial regions (M1, M2 and M3). The proximal lateral tibial bone was also divided into three lateral regions (L1, L2 and L3). The ROI for the distal part of the prosthesis is indicated as ‘D’. Scale bar = 1 cm.
Please cite this article as: Y. Murahashi, A. Teramoto, S. Jimbo, et al., Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee ..., The Knee, https://doi.org/ 10.1016/j.knee.2019.12.010
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2.4. Statistical analysis Baseline characteristics of the groups were compared using independent samples t-tests and Chi-squared tests, as appropriate. For multiple comparisons, differences between groups with normality and homogeneity of variance were determined with oneway analysis of variance (ANOVA) followed by Dunnett's post hoc test. The relationship between periprosthetic tibial BMD and denosumab intervention was analyzed by univariate and multivariate linear regression models, with age, gender, body mass index (BMI), KL grade, and preoperative FTA as the independent variables; these factors may affect bone metabolism and are potential confounders. The unstandardized coefficient of regression, calculated through the multivariate analysis, was compared for an estimate of size confounding. The results are presented as the mean and standard deviation. P-values b0.05 were considered significant. All analyses were undertaken using JMP 13 (SAS Institute; Cary, NC, USA). 2.5. Ethics and registration This study was registered in the University Hospital Medical Information Network (UMIN ID: 000035653) and carried out in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The study was approved by the Institutional Review Board for Clinical Research at our hospital (reference number 262-112; approval date 11 December 2014), and informed consent was obtained from all study participants before study inclusion. 3. Results The preoperative characteristics did not significantly differ between the groups (Table 1). None of the patients needed to discontinue their medication due to adverse effects. In the region of the total femur, the BMD was decreased in the control group at all timepoints after TKA compared with baseline. In contrast, the BMD in the denosumab group was increased above the baseline levels for up to 12 months after TKA, with significant differences in the total femur BMD noted between the two groups (Table 2). In the periprosthetic region in the control group, the BMD of the medial tibial bone (M1, M2, M3) was markedly decreased compared with the BMD of the lateral tibial bone (L1, L2, L3). Denosumab intervention significantly prevented this BMD loss in the medial tibial bone. There was an early and marked decrease in the BMD at M1 in the control group over the first three months, reaching a 12.3% loss in BMD. However, this loss was not observed in the denosumab group, and the differences between the two groups were significant for up to 12 months after surgery. The responsiveness to denosumab was large in the M1 region at 12 months after surgery (effect size, 1.54; 95% confidence interval, 0.53–2.42). In all regions, the BMD was decreased at three months after TKA compared with baseline in the control group, but this BMD decrease was prevented by denosumab supplementation. Linear regression analysis was used to predict the confounding effects of age, gender, BMI, severity of osteoarthritis, preoperative and postoperative knee alignment, and denosumab intervention in the M1 region (Table 3). The effect of denosumab was significant, even after adjustments for other confounding factors. At more than 12 months postoperatively, no patients in the control group had fractures, while two patients in the denosumab group had single vertebral fractures. In these two patients with vertebral fractures, the fractures were observed at 12 and 16 months after denosumab discontinuation, respectively. There were no periprosthetic or other fractures in either group. 4. Discussion This prospective study revealed that the administration of denosumab with vitamin D3 after TKA prevented periprosthetic tibial bone atrophy for up to 12 months after surgery. Although the BMD in all of the periprosthetic tibial regions was decreased at three months after TKA compared with baseline in the control group, treatment with denosumab significantly prevented this early periprosthetic BMD loss. Table 1 General preoperative characteristics.
No. of patients Male/female Age (years) BMI (kg/m2) Kellgren–Lawrence grade Femorotibial angle (degrees) Total femur BMD (g/cm2) T-score Femoral neck BMD (g/cm2) T-score
Denosumab
Control
P value
13 1/12 76.9 (7.3) 26.2 (3.4) 3.6 (0.5) 180.1 (7.8) 0.72 (0.14) −1.38 (1.18) 0.71 (0.14) −2.01 (1.19)
15 1/14 75.3 (8.7) 25.6 (3.8) 3.8 (0.4) 186.4 (11.6) 0.66 (0.11) −1.91 (0.98) 0.65 (0.11) −2.25 (0.62)
0.69 0.60 0.61 0.31 0.10 0.21 0.22 0.26 0.53
Values are presented as mean (standard deviation). Welch's t-test was used for all comparisons except gender where Chi-squared was used. BMD, bone mineral density; BMI, body mass index.
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Table 2 Percentage change in bone mineral density (BMD) of total femur and periprosthetic tibial bone at each follow up interval. Percentage change in BMD ± SD (P)
Total femur M1 M2 M3 L1 L2 L3 D
Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group
Baseline
3 months
6 months
12 months
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
−0.45 ± 2.68 (0.963a, 0.067b) −2.64 ± 2.49 (0.080a) 5.15 ± 5.77 (0.254a, 0.002b) −12.30 ± 16.62 (0.070a) 5.17 ± 8.65 (0.278a, 0.010b) −6.21 ± 11.68 (0.320a) 5.56 ± 7.09 (0.086a, 0.004b) −4.26 ± 8.59 (0.439a) 5.07 ± 12.09 (0.456a, 0.181b) −3.77 ± 19.68 (0.906a) 3.72 ± 8.16 (0.532a, 0.121b) −3.58 ± 14.20 (0.796a) 3.30 ± 6.94 (0.392a, 0.026b) −6.15 ± 12.49 (0.282a) 2.36 ± 5.81 (0.554a, 0.010b) −6.58 ± 9.82 (0.171a)
1.39 ± 3.13 (0.441a, 0.009b) −2.56 ± 4.13 (0.086a) −2.04 ± 10.20 (0.849a, 0.016b) −17.06 ± 19.18 (0.006a) 3.82 ± 9.10 (0.500a, 0.015b) −8.30 ± 14.81 (0.117a) 3.90 ± 7.51 (0.283a, 0.020b) −5.25 ± 11.56 (0.261a) 5.71 ± 6.58 (0.343a, 0.251b) −1.17 ± 21.22 (0.996a) 5.56 ± 6.09 (0.205a, 0.065b) −3.03 ± 15.60 (0.857a) −0.20 ± 6.01 (1.000a, 0.140b) −5.60 ± 11.88 (0.341a) 0.02 ± 5.98 (1.000a, 0.138b) −5.39 ± 11.87 (0.299a)
1.52 ± 3.39 (0.409a, 0.180b) −0.90 ± 4.51 (0.826a) −0.72 ± 10.17 (0.992a, 0.002b) −19.65 ± 14.16 (0.004a) 5.95 ± 10.25 (0.182a, 0.003b) −9.94 ± 12.10 (0.075a) 4.35 ± 7.17 (0.222a, 0.052b) −3.80 ± 10.81 (0.579a) 9.04 ± 14.65 (0.075a, 0.889b) 7.82 ± 24.35 (0.586a) 12.14 ± 12.60 (0.001a, 0.108b) 2.19 ± 14.98 (0.950a) 2.78 ± 7.71 (0.527a, 0.292b) −2.10 ± 12.70 (0.926a) 2.04 ± 6.36 (0.656a, 0.135b) −4.40 ± 11.95 (0.526a)
SD, standard deviation. Bold values indicate statistical significance. a P-value within the groups (vs baseline); analysis of variance (ANOVA) followed by Dunnett's post hoc test. b P-value between the groups; Welch's t-test.
Over the past decade, several studies have reported that alendronate, a well-studied bisphosphonate, attenuates BMD loss after TKA [6,7,10]. However, alendronate improves periprosthetic BMD only after six months, not as early as three months after TKA, as shown with denosumab in the present study [6,10]. This may result from a lower reduction in the biochemical markers of bone turnover with alendronate at one to three months compared with that at six months [19]. In clinical trials, denosumab treatment significantly increased the BMD of the lumbar spine and hip at one to three months, as determined using DEXA [20,21]. Thus, denosumab intervention after TKA may prevent periprosthetic bone atrophy that would otherwise occur due to mechanical axis correction, stress-shielding, and immobilization in the early phase after surgery. Several large clinical trials have shown the advantages of denosumab compared with bisphosphonates in postmenopausal women [19,22,23]. Robust effects of denosumab are observed in patients who switch from bisphosphonate therapy to denosumab treatment [19]. Ledin et al. showed that denosumab reduced the early migration of the tibial component in TKA, as determined using radiostereometric analysis [24]. However, the anti-resorptive effect of denosumab on periprosthetic bone has remained unclear. The current study found that denosumab adjuvant therapy reduced bone atrophy and increased BMD in the periprosthetic medial tibia for up to 12 months after TKA. As several previous studies have shown an association between early migration of the tibial component and the need for late revision due to loosening [3,25], the periprosthetic tibial bone was evaluated in detail in the present study, while the femoral side was not evaluated. The distal tibial region below the prosthetic stem (D) may be associated with the overall axial load, and the BMD loss of the control group in this region after surgery may have been secondary to a temporary decrease in activity due to postoperative pain rather than a mechanical change. The BMD of the D region decreased after surgery in the control group, while denosumab prevented this BMD loss. In the region of the total femur, the denosumab group had significantly greater BMD compared with the control group at six months postoperatively. This means that denosumab affected the systemic bone in patients with osteoporosis. However, there were no statistically significant differences between the two groups in the BMD at both three and 12 months after surgery. The present study assessed the changes in BMD at unusual timepoints such as the postoperative phase, in which there was a temporary decline in activity, and this unique condition may have affected the response to denosumab. Furthermore, the use of a small ROI in the periprosthetic tibial bone may have led to substantial variability Table 3 Univariable and multivariable linear regression of bone mineral density (BMD) in M1 region at 12 months from age, gender, body mass index (BMI), Kellgren–Lawrence (KL) grading score, preoperative knee alignment (femorotibial angle (FTA)) and denosumab intervention. Univariable analysis
Age Gender BMI KL grade Preoperative FTA Denosumab intervention
Multivariable analysis
Coefficients (95% CI)
P
Standardized coefficients
0.78 (−0.02, 1.59) 18.87 (−13.76, 51.50) −0.41 (−2.67, 1.85) −1.18 (−17.97, 15.61) −0.86 (−1.45, −0.26) 18.93 (7.96, 29.90)
0.057 0.41 0.242 0.26 0.711 −0.08 0.885 −0.03 0.007 −0.56 0.002 0.63
R2
Coefficients (95% CI)
P
0.17 0.07 0.007 0.001 0.31 0.39
0.77 (0.28, 1.26) −1.29 (−20.88, 18.31) −1.18 (−2.42, 0.05) 2.97 (−6.27, 12.20) −0.89 (−1.33, −0.44) 17.68 (9.65, 25.70)
0.004 0.41 0.890 −0.02 0.059 −0.24 0.502 0.08 b0.001 −0.58 b0.001 0.59
Standardized coefficients
R2 0.83
CI, confidence interval. Bold values indicate statistical significance.
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and reduced the ability to detect a significant difference in the periprosthetic BMD between the two groups at 12 months postoperatively. Several studies report that denosumab discontinuation without alternative antiresorptive treatment increases the incidence of vertebral fracture, known as rebound-associated vertebral fracture (RAVF) [26–29]. A large clinical trial reported that the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1 per 100 participant-years after denosumab discontinuation [29]. Furthermore, Anastasilakis et al. showed that all fractures occurred eight to 16 months after the last denosumab injection [27]. In the current study, two patients developed spontaneous vertebral fractures at 12 and 16 months after denosumab discontinuation without alternative antiresorptive treatment, respectively. Therefore, the current therapy needs to be monitored and appropriately managed in these patients to reduce the risk of RAVFs. There were several limitations in this study. First, there was a high rate of loss to follow up, presumably due to the regional nature of our institution and the older age of the study population. Furthermore, the present results may have been affected by the small sample size, even before the losses to follow up. Second, only patients with primary osteoarthritis with osteoporosis were evaluated in the current study. As osteoarthritis is more common in persons without severe osteoporosis, the present results may not be generalizable to all patients with osteoarthritis [30]. Third, the present study could not be randomized due to the small number of personnel at our facility; thus, the denosumab group was evaluated first, and it became a quasi-randomized study, which could potentially have introduced some bias. The present results require confirmation in further double-blind randomized trials. Fourth, the reproducibility of the periprosthetic BMD measurements was not evaluated. However, although small ROIs in DEXA generally generate large variability and may lead to low reproducibility, a similar previous study reported high reproducibility values, even with a small periprosthetic ROI similar to the one used in the present study [26]. Furthermore, the BMD in the L1 and L2 regions included the fibula. Although the region was re-scanned at each measurement and analyzed so that positioning was the same as for the previous measurement, variations in positioning may have impacted the BMD values. Fifth, the periprosthetic ROIs were decided with a combined manual and automatic technique to avoid measuring the peripheral cement and implant surface. This combination method may have led to further variability. Sixth, the periprosthetic BMD was not measured before the surgery because the ROI was set using the implant as an index. However, we consider that the BMD results obtained immediately after surgery would be almost the same as those before surgery, and thus can be applied as standard values. Finally, the anti-resorptive effect of denosumab was not compared with the effects of other anti-resorptive drugs, including bisphosphonates. Despite these limitations, the present results show that denosumab significantly prevented bone resorption, even in the early phase after TKA. Proximal tibial bone resorption in the early phase after TKA may lead to migration, instability and aseptic loosening of the prosthesis [2–4,8,11,31]. Denosumab prevented periprosthetic tibial bone resorption and this, in turn, may reduce the rate of early component migration and improve prosthesis survival. In conclusion, denosumab may be a beneficial treatment option to prevent periprosthetic bone resorption and therefore prevent early implant migration and reduce the need for revision surgery after TKA. The beneficial effect of denosumab requires confirmation in further double-blind randomized trials. Clinicians should be aware of the risk of RAVFs and the need to appropriately manage the denosumab treatment. Authors' contributions Y.M., A.T., H.T., K.W., S.N. and T.Y. designed the research; Y.M., A.T., S.J., R.I., and H.T. performed the research; Y.M., A.T., Y.O., T.K., R.I., and H.T. analyzed the data; Y.M. and A.T. wrote the manuscript. Declaration of competing interest The authors have no competing interests. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgments We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. References [1] Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C. Aseptic loosening, not only a question of wear: a review of different theories. Acta Orthop 2006;77: 177–97. https://doi.org/10.1080/17453670610045902. [2] Andersen MR, Winther NS, Lind T, Schrøder HM, Flivik G, Petersen MM. Low preoperative BMD is related to high migration of tibia components in uncemented TKA-92 patients in a combined DEXA and RSA study with 2-year follow-up. J Arthroplasty 2017;32:2141–6. https://doi.org/10.1016/j.arth.2017.02.032. [3] Petersen MM, Nielsen PT, Lebech A, Toksvig-Larsen S, Lund B. Preoperative bone mineral density of the proximal tibia and migration of the tibial component after uncemented total knee arthroplasty. J Arthroplasty 1999;14:77–81. https://doi.org/10.1016/S0883-5403(99)90206-1. [4] Li MG, Nilsson KG. The effect of the preoperative bone quality on the fixation of the tibial component in total knee arthroplasty. J Arthroplasty 2000;15:744–53. https://doi.org/10.1054/arth.2000.6617. [5] Jaroma A, Soininvaara T, Kröger H. Periprosthetic tibial bone mineral density changes after total knee arthroplasty. Acta Orthop 2016;87:268–73. https://doi.org/ 10.3109/17453674.2016.1173982. [6] Soininvaara TA, Jurvelin JS, Miettinen HJ, Suomalainen OT, Alhava EM, Kroger PJ. Effect of alendronate on periprosthetic bone loss after total knee arthroplasty: a one-year, randomized, controlled trial of 19 patients. Calcif Tissue Int 2002;71:472–7. https://doi.org/10.1007/s00223-002-1022-9.
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[7] Wang CJ, Wang JW, Ko JY, Weng LH, Huang CC. Three-year changes in bone mineral density around the knee after a six-month course of oral alendronate following total knee arthroplasty. A prospective, randomized study. J Bone Joint Surg Am 2006;88:267–72. https://doi.org/10.2106/JBJS.E.00051. [8] Prieto-Alhambra D, Lalmohamed A, Abrahamsen B, Arden NK, de Boer A, Vestergaard P, et al. Oral bisphosphonate use and total knee/hip implant survival: validation of results in an external population-based cohort. Arthritis Rheumatol 2014;6:3233–40. https://doi.org/10.1002/art.38789. [9] Namba RS, Inacio MC, Cheetham TC, Dell RM, Paxton EW, Khatod MX. Lower total knee arthroplasty revision risk associated with bisphosphonate use, even in patients with normal bone density. J Arthroplasty 2016;31:537–41. https://doi.org/10.1016/j.arth.2015.09.005. [10] Jaroma AV, Soininvaara TA, Kröger H. Effect of one-year post-operative alendronate treatment on periprosthetic bone after total knee arthroplasty. A seven-year randomised controlled trial of 26 patients. Bone Joint J 2015;97-B:337–45. https://doi.org/10.1302/0301-620X.97B3.33643. [11] Hilding M, Aspenberg P. Postoperative clodronate decreases prosthetic migration: 4-year follow-up of a randomized radiostereometric study of 50 total knee patients. Acta Orthop 2006;77:912–6. https://doi.org/10.1080/17453670610013213. [12] Bernhardsson M, Sandberg O, Aspenberg P. Anti-RANKL treatment improves screw fixation in cancellous bone in rats. Injury 2015;46:990–5. https://doi.org/10. 1016/j.injury.2015.02.011. [13] Nagoya S, Tateda K, Okazaki S, Kosukegawa I, Shimizu J, Yamashita T. Restoration of proximal periprosthetic bone loss by denosumab in cementless total hip arthroplasty. Eur J Orthop Surg Traumatol 2018;28:1601–7. https://doi.org/10.1007/s00590-018-2223-x. [14] Windisch C, Windisch B, Kolb W, Kolb K, Grützner P, Roth A. Osteodensitometry measurements of periprosthetic bone using dual energy X-ray absorptiometry following total knee arthroplasty. Arch Orthop Trauma Surg 2012;132:1595–601. https://doi.org/10.1007/s00402-012-1601-9. [15] Ritter MA, Davis KE, Small SR, Merchun JG, Farris A. Trabecular bone density of the proximal tibia as it relates to failure of a total knee replacement. Bone Joint J 2014;9:1503–9. https://doi.org/10.1302/0301-620X.96B11.33465. [16] Small SR, Ritter MA, Merchun JG, Davis KE, Rogge RD. Changes in tibial bone density measured from standard radiographs in cemented and uncemented total knee replacements after ten years' follow-up. Bone Joint J 2013;95:911–6. https://doi.org/10.1302/0301-620X.95B7.30537. [17] Moreland JR, Bassett LW, Hanker GJ. Radiographic analysis of the axial alignment of the lower extremity. J Bone Joint Surg Am 1987;69:745–9. https://doi.org/10. 2106/00004623-198769050-00016. [18] Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494–502. https://doi.org/10.1136/ard.16.4.494. [19] Kendler DL, Roux C, Benhamou CL, Brown JP, Lillestol M, Siddhanti S, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res 2010;25:72–81. https://doi.org/10.1359/jbmr.090716. [20] Bolognese MA, Teglbjærg CS, Zanchetta JR, Lippuner K, McClung MR, Brandi ML, et al. Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. J Clin Densitom 2013;16:147–53. https://doi.org/10.1016/j.jocd.2012.02.006. [21] McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821–31. https://doi.org/10.1056/NEJMoa044459. [22] Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24:153–61. https://doi.org/10.1359/ jbmr.0809010. [23] Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, et al. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab 2016;101:3163–70. https://doi.org/10.1210/jc.2016-1801. [24] Ledin H, Good L, Aspenberg P. Denosumab reduces early migration in total knee replacement. Acta Orthop 2017;88:255–8. https://doi.org/10.1080/17453674. 2017.1300746. [25] Pijls BG, Valstar ER, Nouta KA, Plevier JW, Fiocco M, Middeldorp S, et al. Early migration of tibial components is associated with late revision: a systematic review and meta-analysis of 21,000 knee arthroplasties. Acta Orthop 2012;83:614–24. https://doi.org/10.3109/17453674.2012.747052. [26] Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report. J Clin Endocrinol Metab 2017;102:354–8. https://doi.org/10.1210/jc.2016-3170. [27] Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res 2017;32:1291–6. https://doi.org/10.1002/jbmr.3110. [28] Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics. Osteoporos Int 2016; 27:1917–21. https://doi.org/10.1007/s00198-015-3458-6. [29] Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018;33:190–8. https://doi.org/10.1002/jbmr.3337. [30] Dequeker J, Boonen S, Aerssens J, Westhovens R. Inverse relationship osteoarthritis-osteoporosis: what is the evidence? What are the consequences? Br J Rheumatol 1996;35:813–8. https://doi.org/10.1093/rheumatology/35.9.813. [31] Nilsson KG, Kärrholm J, Ekelund L, Magnusson P. Evaluation of micromotion in cemented vs uncemented knee arthroplasty in osteoarthrosis and rheumatoid arthritis. Randomized study using roentgen stereophotogrammetric analysis. J Arthroplasty 1991;6:265–78. https://doi.org/10.1016/S0883-5403(06)80174-9.
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The Knee
Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee arthroplasty Yasutaka Murahashi a, Atsushi Teramoto a,⁎, Shunsuke Jimbo a, Yohei Okada a, Tomoaki Kamiya a, Rui Imamura b, Hiroyuki Takashima b, Kota Watanabe c, Satoshi Nagoya d, Toshihiko Yamashita a a
Department of Orthopaedic Surgery, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan Division of Radiology and Nuclear Medicine, Sapporo Medical University Hospital, Sapporo, Hokkaido, Japan Department of Physical Therapy, Sapporo Medical University School of Health Sciences, Sapporo, Hokkaido, Japan d Department of Musculoskeletal Biomechanics and Surgical Development, Sapporo Medical University School of Medicine, Sapporo, Hokkaido, Japan b c
a r t i c l e
i n f o
Article history: Received 14 August 2019 Received in revised form 2 December 2019 Accepted 17 December 2019 Available online xxxx Keywords: Periprosthetic bone Bone mineral density Osteoporosis Total knee arthroplasty Denosumab Treatment
a b s t r a c t Background: Periprosthetic bone quality is one of the most important factors preventing early prosthesis migration and long-term failure. Although denosumab, which binds to the receptor activator of nuclear factor kappa-B ligand (RANKL), has been linked with periprosthetic bone mineral density (BMD), the effectiveness of denosumab against bone loss remains unclear. We hypothesized that denosumab treatment after total knee arthroplasty (TKA) could prevent periprosthetic bone resorption. Methods: In this prospective cohort study, 28 patients with primary knee osteoarthritis were divided into two groups: denosumab (denosumab and vitamin D) and control (vitamin D only) groups. All patients underwent TKA with the same implant model and received medication after surgery. We used dual-energy X-ray absorptiometry to measure periprosthetic BMD after TKA. Results: In the control group, the BMD of the proximal medial tibia decreased drastically at 12 months after TKA (−19.7%). Denosumab treatment significantly preserved this BMD loss (0.7%). The linear regression analysis revealed that denosumab intervention had the highest significantly positive relationship with BMD. Conclusions: Our results indicate that denosumab treatment significantly reduces periprosthetic BMD loss, even at the early stages after TKA. This therapeutic strategy may facilitate early stable fixation of the prosthesis which, in turn, may help to prevent early implant migration and reduce the need for revision surgery. © 2020 Elsevier B.V. All rights reserved.
1. Introduction Total knee arthroplasty (TKA) is one of the most widely performed procedures in orthopedic surgery. Although TKA provides excellent outcomes in terms of relieving pain and restoring joint function, over time, issues such as implant wear and loosening may result in the requirement for revision TKA. It is well recognized that the stability of the prosthesis is important for component survival and is dependent on multiple factors [1], including the quality of the proximal tibial bone [2–4]. Jaroma et al. previously reported that tibial metaphyseal periprosthetic bone is remodeled due to stress shielding after cemented TKA, as a form of me-
⁎ Corresponding author at: Department of Orthopaedic Surgery, Sapporo Medical Univ. School of Medicine, S-1, W-16, Chuo-ku, Sapporo, 060-8543, Hokkaido, Japan. E-mail address: [email protected]. (A. Teramoto).
https://doi.org/10.1016/j.knee.2019.12.010 0968-0160/© 2020 Elsevier B.V. All rights reserved.
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chanical axis correction [5]. Bone mineral density (BMD) continues to decrease considerably for as long as seven years after TKA [4]. Several studies have shown that bisphosphonates, which are most commonly used in the treatment of osteoporosis, can improve periprosthetic BMD after TKA [6–10], and reduce early migration of the prosthetic component [11]. Indeed, in an external population-based cohort study, bisphosphonate users had a 59% reduced risk of requiring revision surgery [8]. Denosumab is a human monoclonal immunoglobulin G2 (IgG2) antibody that binds to receptor activator of nuclear factor kappa-B ligand (RANKL), preventing its osteoclastic bone resorptive activity. A previous animal study has suggested that antiRANKL agents are superior to bisphosphonates in the context of implant fixation or fracture healing [12]. In a recent clinical study, denosumab prevented BMD loss around the implant after total hip arthroplasty [13]. However, there is no evidence of the anti-resorptive effect of denosumab treatment on periprosthetic bone density after TKA. It is important to prevent periprosthetic bone density loss after TKA to maintain stable fixation of the prosthesis component, and to decrease the risk of prosthesis migration and the need for revision surgery. We hypothesized that denosumab treatment after TKA could prevent periprosthetic bone resorption, as measured using dual energy X-ray absorptiometry (DEXA). In this prospective study, we investigated the short-term changes in periprosthetic BMD across seven defined regions of interest (ROIs).
2. Materials & methods 2.1. Patients Primary TKA was performed in 102 patients (115 knees) who visited our hospital between March 2015 and November 2017 (Figure 1). To preserve homogeneity in the study, we included only patients with osteoporosis (diagnosed with a T score of −2.5 or below in the BMD of the femoral neck) and primary osteoarthritis of the knee who underwent TKA using the Vanguard posterior-stabilized (PS) knee cemented prostheses (Zimmer Biomet, Warsaw, IN, USA). We excluded patients who underwent TKA with another prosthesis, those undergoing revision surgery, and those who had previously taken anti-osteoporotic drugs or other medications known to influence bone mineral metabolism. The sample size (n = 27) was calculated based on similar studies to detect a mean difference of 15% in relative periprosthetic bone density, with a standard deviation of 20% (α = 0.05 and 80% power) [7,10,14]. Patients were divided into two groups: patients in the control group received 0.5 μg active vitamin D3 daily by oral administration (Alfacalcidol; Chugai Pharmaceutical Co., Tokyo, Japan), whereas those in the denosumab group received 0.5 μg vitamin D3 daily and 60 mg denosumab every six months by subcutaneous injection (Denosumab; Daiichi-Sankyo Co., Tokyo, Japan) from the day after surgery. All patients in the denosumab group were uniformly administered 60 mg of denosumab on the day after surgery, at six months postoperatively, and at 12 months postoperatively. Denosumab was discontinued at 12 months postoperatively. Patients who underwent surgery from March 2015 to March 2016 were enrolled in the denosumab group, while patients who underwent surgery from April 2016 to November 2017 were enrolled in the control group. Patients were advised to discontinue the medication and contact their physician if they experienced any adverse effects. Seven patients were lost to follow up (due to relocation). Three patients visited our hospital but were not able to be examined by DEXA because of machine problems. At the final analysis, the denosumab group comprised 13 patients and the control group comprised 15 patients (Figure 1). Both groups were administered with medications continuously throughout the study period.
Figure 1. Flowchart of inclusion. DEXA, dual energy X-ray absorptiometry; RA, rheumatoid arthritis; TKA, total knee arthroplasty.
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2.2. Surgery Surgery was performed by two experienced orthopedic surgeons using the Vanguard PS knee prosthesis with the cemented technique. The patella was resurfaced in all patients. A tourniquet was used for the entire operation. Full weight-bearing was allowed immediately after surgery for all patients.
2.3. Evaluation The BMD of the femoral neck, the total femur, and the periprosthetic proximal tibia was measured by fan-beam DEXA in anteroposterior (AP) projection using Hologic Apex, version 5.6.0.2 (Horizon A; Hologic, Ontario, Canada). All patients were examined in the supine position, and the ankle was fixed with hip positioner devices with the patella in the front position and the knee extended to obtain a repeatable position. Four measurements were taken; these measurements were made in the first week postoperatively (baseline), and at three, six, and 12 months postoperatively. We analyzed periprosthetic bone density across seven ROIs: three medial tibial regions (M1, M2, M3), three lateral tibial regions (L1, L2, L3), and the distal tibial region below the prosthetic stem (D) (Figure 2). An edge-detection algorithm was used to define the outlines of the bone, prosthesis, and cemented areas. The periprosthetic zones were classified based on previous studies [5,7,14,15]. To avoid measuring peripheral cement, the medial and lateral regions were initially placed automatically by Prosthetic Hip software (Hologic), and the technologist then manually positioned the ROI 1.0 cm distal to the prosthesis–bone interface, with the distal region located 0.5 cm below the prosthetic stem. After using this combined manual and automatic technique to position the ROIs for the first scan, the ‘compare’ facility in the software was used to copy the ROIs for the second scan. Although the ROIs used in the present study were relatively small, which may potentially decrease the repeatability of the results, a previous study using the same ROIs reported high reproducibility even with a small periprosthetic ROI [16]. The change in BMD at each ROI is shown as the value relative to the baseline. For BMD outcome data, Cohen's d effect size was applied to estimate the overall effect size of denosumab on BMD (b 0.2: not clinically relevant; N0.2: small; N0.5: moderate; N 0.8: large; N1.2: very large). Long standing radiographs were taken preoperatively to measure the femorotibial angle (FTA), which was used to indicate knee alignment, as previously described [17]. Kellgren–Lawrence (KL) grading (0–4) was used to evaluate osteoarthritis severity on preoperative radiographs [18], with grade 0 considered normal and grade 4 indicating the most severe deformity. The medical records of 10 patients in the control group and 10 patients in the denosumab group were reviewed at more than 12 months postoperatively to evaluate the risk of fracture after denosumab discontinuation; the mean (± standard deviation) follow-up periods were 20.3 ± 6.5 months in the control group and 29.0 ± 9.4 months in the denosumab group.
Figure 2. Radiograph showing the regions of interest (ROIs) for the measurement of periprosthetic bone mineral density (BMD) with dual-energy X-ray absorptiometry (DEXA). The proximal medial tibial bone was divided into three medial regions (M1, M2 and M3). The proximal lateral tibial bone was also divided into three lateral regions (L1, L2 and L3). The ROI for the distal part of the prosthesis is indicated as ‘D’. Scale bar = 1 cm.
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2.4. Statistical analysis Baseline characteristics of the groups were compared using independent samples t-tests and Chi-squared tests, as appropriate. For multiple comparisons, differences between groups with normality and homogeneity of variance were determined with oneway analysis of variance (ANOVA) followed by Dunnett's post hoc test. The relationship between periprosthetic tibial BMD and denosumab intervention was analyzed by univariate and multivariate linear regression models, with age, gender, body mass index (BMI), KL grade, and preoperative FTA as the independent variables; these factors may affect bone metabolism and are potential confounders. The unstandardized coefficient of regression, calculated through the multivariate analysis, was compared for an estimate of size confounding. The results are presented as the mean and standard deviation. P-values b0.05 were considered significant. All analyses were undertaken using JMP 13 (SAS Institute; Cary, NC, USA). 2.5. Ethics and registration This study was registered in the University Hospital Medical Information Network (UMIN ID: 000035653) and carried out in accordance with the principles of the Declaration of Helsinki and Good Clinical Practice guidelines. The study was approved by the Institutional Review Board for Clinical Research at our hospital (reference number 262-112; approval date 11 December 2014), and informed consent was obtained from all study participants before study inclusion. 3. Results The preoperative characteristics did not significantly differ between the groups (Table 1). None of the patients needed to discontinue their medication due to adverse effects. In the region of the total femur, the BMD was decreased in the control group at all timepoints after TKA compared with baseline. In contrast, the BMD in the denosumab group was increased above the baseline levels for up to 12 months after TKA, with significant differences in the total femur BMD noted between the two groups (Table 2). In the periprosthetic region in the control group, the BMD of the medial tibial bone (M1, M2, M3) was markedly decreased compared with the BMD of the lateral tibial bone (L1, L2, L3). Denosumab intervention significantly prevented this BMD loss in the medial tibial bone. There was an early and marked decrease in the BMD at M1 in the control group over the first three months, reaching a 12.3% loss in BMD. However, this loss was not observed in the denosumab group, and the differences between the two groups were significant for up to 12 months after surgery. The responsiveness to denosumab was large in the M1 region at 12 months after surgery (effect size, 1.54; 95% confidence interval, 0.53–2.42). In all regions, the BMD was decreased at three months after TKA compared with baseline in the control group, but this BMD decrease was prevented by denosumab supplementation. Linear regression analysis was used to predict the confounding effects of age, gender, BMI, severity of osteoarthritis, preoperative and postoperative knee alignment, and denosumab intervention in the M1 region (Table 3). The effect of denosumab was significant, even after adjustments for other confounding factors. At more than 12 months postoperatively, no patients in the control group had fractures, while two patients in the denosumab group had single vertebral fractures. In these two patients with vertebral fractures, the fractures were observed at 12 and 16 months after denosumab discontinuation, respectively. There were no periprosthetic or other fractures in either group. 4. Discussion This prospective study revealed that the administration of denosumab with vitamin D3 after TKA prevented periprosthetic tibial bone atrophy for up to 12 months after surgery. Although the BMD in all of the periprosthetic tibial regions was decreased at three months after TKA compared with baseline in the control group, treatment with denosumab significantly prevented this early periprosthetic BMD loss. Table 1 General preoperative characteristics.
No. of patients Male/female Age (years) BMI (kg/m2) Kellgren–Lawrence grade Femorotibial angle (degrees) Total femur BMD (g/cm2) T-score Femoral neck BMD (g/cm2) T-score
Denosumab
Control
P value
13 1/12 76.9 (7.3) 26.2 (3.4) 3.6 (0.5) 180.1 (7.8) 0.72 (0.14) −1.38 (1.18) 0.71 (0.14) −2.01 (1.19)
15 1/14 75.3 (8.7) 25.6 (3.8) 3.8 (0.4) 186.4 (11.6) 0.66 (0.11) −1.91 (0.98) 0.65 (0.11) −2.25 (0.62)
0.69 0.60 0.61 0.31 0.10 0.21 0.22 0.26 0.53
Values are presented as mean (standard deviation). Welch's t-test was used for all comparisons except gender where Chi-squared was used. BMD, bone mineral density; BMI, body mass index.
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Table 2 Percentage change in bone mineral density (BMD) of total femur and periprosthetic tibial bone at each follow up interval. Percentage change in BMD ± SD (P)
Total femur M1 M2 M3 L1 L2 L3 D
Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group Denosumab group Control group
Baseline
3 months
6 months
12 months
0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0
−0.45 ± 2.68 (0.963a, 0.067b) −2.64 ± 2.49 (0.080a) 5.15 ± 5.77 (0.254a, 0.002b) −12.30 ± 16.62 (0.070a) 5.17 ± 8.65 (0.278a, 0.010b) −6.21 ± 11.68 (0.320a) 5.56 ± 7.09 (0.086a, 0.004b) −4.26 ± 8.59 (0.439a) 5.07 ± 12.09 (0.456a, 0.181b) −3.77 ± 19.68 (0.906a) 3.72 ± 8.16 (0.532a, 0.121b) −3.58 ± 14.20 (0.796a) 3.30 ± 6.94 (0.392a, 0.026b) −6.15 ± 12.49 (0.282a) 2.36 ± 5.81 (0.554a, 0.010b) −6.58 ± 9.82 (0.171a)
1.39 ± 3.13 (0.441a, 0.009b) −2.56 ± 4.13 (0.086a) −2.04 ± 10.20 (0.849a, 0.016b) −17.06 ± 19.18 (0.006a) 3.82 ± 9.10 (0.500a, 0.015b) −8.30 ± 14.81 (0.117a) 3.90 ± 7.51 (0.283a, 0.020b) −5.25 ± 11.56 (0.261a) 5.71 ± 6.58 (0.343a, 0.251b) −1.17 ± 21.22 (0.996a) 5.56 ± 6.09 (0.205a, 0.065b) −3.03 ± 15.60 (0.857a) −0.20 ± 6.01 (1.000a, 0.140b) −5.60 ± 11.88 (0.341a) 0.02 ± 5.98 (1.000a, 0.138b) −5.39 ± 11.87 (0.299a)
1.52 ± 3.39 (0.409a, 0.180b) −0.90 ± 4.51 (0.826a) −0.72 ± 10.17 (0.992a, 0.002b) −19.65 ± 14.16 (0.004a) 5.95 ± 10.25 (0.182a, 0.003b) −9.94 ± 12.10 (0.075a) 4.35 ± 7.17 (0.222a, 0.052b) −3.80 ± 10.81 (0.579a) 9.04 ± 14.65 (0.075a, 0.889b) 7.82 ± 24.35 (0.586a) 12.14 ± 12.60 (0.001a, 0.108b) 2.19 ± 14.98 (0.950a) 2.78 ± 7.71 (0.527a, 0.292b) −2.10 ± 12.70 (0.926a) 2.04 ± 6.36 (0.656a, 0.135b) −4.40 ± 11.95 (0.526a)
SD, standard deviation. Bold values indicate statistical significance. a P-value within the groups (vs baseline); analysis of variance (ANOVA) followed by Dunnett's post hoc test. b P-value between the groups; Welch's t-test.
Over the past decade, several studies have reported that alendronate, a well-studied bisphosphonate, attenuates BMD loss after TKA [6,7,10]. However, alendronate improves periprosthetic BMD only after six months, not as early as three months after TKA, as shown with denosumab in the present study [6,10]. This may result from a lower reduction in the biochemical markers of bone turnover with alendronate at one to three months compared with that at six months [19]. In clinical trials, denosumab treatment significantly increased the BMD of the lumbar spine and hip at one to three months, as determined using DEXA [20,21]. Thus, denosumab intervention after TKA may prevent periprosthetic bone atrophy that would otherwise occur due to mechanical axis correction, stress-shielding, and immobilization in the early phase after surgery. Several large clinical trials have shown the advantages of denosumab compared with bisphosphonates in postmenopausal women [19,22,23]. Robust effects of denosumab are observed in patients who switch from bisphosphonate therapy to denosumab treatment [19]. Ledin et al. showed that denosumab reduced the early migration of the tibial component in TKA, as determined using radiostereometric analysis [24]. However, the anti-resorptive effect of denosumab on periprosthetic bone has remained unclear. The current study found that denosumab adjuvant therapy reduced bone atrophy and increased BMD in the periprosthetic medial tibia for up to 12 months after TKA. As several previous studies have shown an association between early migration of the tibial component and the need for late revision due to loosening [3,25], the periprosthetic tibial bone was evaluated in detail in the present study, while the femoral side was not evaluated. The distal tibial region below the prosthetic stem (D) may be associated with the overall axial load, and the BMD loss of the control group in this region after surgery may have been secondary to a temporary decrease in activity due to postoperative pain rather than a mechanical change. The BMD of the D region decreased after surgery in the control group, while denosumab prevented this BMD loss. In the region of the total femur, the denosumab group had significantly greater BMD compared with the control group at six months postoperatively. This means that denosumab affected the systemic bone in patients with osteoporosis. However, there were no statistically significant differences between the two groups in the BMD at both three and 12 months after surgery. The present study assessed the changes in BMD at unusual timepoints such as the postoperative phase, in which there was a temporary decline in activity, and this unique condition may have affected the response to denosumab. Furthermore, the use of a small ROI in the periprosthetic tibial bone may have led to substantial variability Table 3 Univariable and multivariable linear regression of bone mineral density (BMD) in M1 region at 12 months from age, gender, body mass index (BMI), Kellgren–Lawrence (KL) grading score, preoperative knee alignment (femorotibial angle (FTA)) and denosumab intervention. Univariable analysis
Age Gender BMI KL grade Preoperative FTA Denosumab intervention
Multivariable analysis
Coefficients (95% CI)
P
Standardized coefficients
0.78 (−0.02, 1.59) 18.87 (−13.76, 51.50) −0.41 (−2.67, 1.85) −1.18 (−17.97, 15.61) −0.86 (−1.45, −0.26) 18.93 (7.96, 29.90)
0.057 0.41 0.242 0.26 0.711 −0.08 0.885 −0.03 0.007 −0.56 0.002 0.63
R2
Coefficients (95% CI)
P
0.17 0.07 0.007 0.001 0.31 0.39
0.77 (0.28, 1.26) −1.29 (−20.88, 18.31) −1.18 (−2.42, 0.05) 2.97 (−6.27, 12.20) −0.89 (−1.33, −0.44) 17.68 (9.65, 25.70)
0.004 0.41 0.890 −0.02 0.059 −0.24 0.502 0.08 b0.001 −0.58 b0.001 0.59
Standardized coefficients
R2 0.83
CI, confidence interval. Bold values indicate statistical significance.
Please cite this article as: Y. Murahashi, A. Teramoto, S. Jimbo, et al., Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee ..., The Knee, https://doi.org/ 10.1016/j.knee.2019.12.010
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and reduced the ability to detect a significant difference in the periprosthetic BMD between the two groups at 12 months postoperatively. Several studies report that denosumab discontinuation without alternative antiresorptive treatment increases the incidence of vertebral fracture, known as rebound-associated vertebral fracture (RAVF) [26–29]. A large clinical trial reported that the vertebral fracture rate increased from 1.2 per 100 participant-years during the on-treatment period to 7.1 per 100 participant-years after denosumab discontinuation [29]. Furthermore, Anastasilakis et al. showed that all fractures occurred eight to 16 months after the last denosumab injection [27]. In the current study, two patients developed spontaneous vertebral fractures at 12 and 16 months after denosumab discontinuation without alternative antiresorptive treatment, respectively. Therefore, the current therapy needs to be monitored and appropriately managed in these patients to reduce the risk of RAVFs. There were several limitations in this study. First, there was a high rate of loss to follow up, presumably due to the regional nature of our institution and the older age of the study population. Furthermore, the present results may have been affected by the small sample size, even before the losses to follow up. Second, only patients with primary osteoarthritis with osteoporosis were evaluated in the current study. As osteoarthritis is more common in persons without severe osteoporosis, the present results may not be generalizable to all patients with osteoarthritis [30]. Third, the present study could not be randomized due to the small number of personnel at our facility; thus, the denosumab group was evaluated first, and it became a quasi-randomized study, which could potentially have introduced some bias. The present results require confirmation in further double-blind randomized trials. Fourth, the reproducibility of the periprosthetic BMD measurements was not evaluated. However, although small ROIs in DEXA generally generate large variability and may lead to low reproducibility, a similar previous study reported high reproducibility values, even with a small periprosthetic ROI similar to the one used in the present study [26]. Furthermore, the BMD in the L1 and L2 regions included the fibula. Although the region was re-scanned at each measurement and analyzed so that positioning was the same as for the previous measurement, variations in positioning may have impacted the BMD values. Fifth, the periprosthetic ROIs were decided with a combined manual and automatic technique to avoid measuring the peripheral cement and implant surface. This combination method may have led to further variability. Sixth, the periprosthetic BMD was not measured before the surgery because the ROI was set using the implant as an index. However, we consider that the BMD results obtained immediately after surgery would be almost the same as those before surgery, and thus can be applied as standard values. Finally, the anti-resorptive effect of denosumab was not compared with the effects of other anti-resorptive drugs, including bisphosphonates. Despite these limitations, the present results show that denosumab significantly prevented bone resorption, even in the early phase after TKA. Proximal tibial bone resorption in the early phase after TKA may lead to migration, instability and aseptic loosening of the prosthesis [2–4,8,11,31]. Denosumab prevented periprosthetic tibial bone resorption and this, in turn, may reduce the rate of early component migration and improve prosthesis survival. In conclusion, denosumab may be a beneficial treatment option to prevent periprosthetic bone resorption and therefore prevent early implant migration and reduce the need for revision surgery after TKA. The beneficial effect of denosumab requires confirmation in further double-blind randomized trials. Clinicians should be aware of the risk of RAVFs and the need to appropriately manage the denosumab treatment. Authors' contributions Y.M., A.T., H.T., K.W., S.N. and T.Y. designed the research; Y.M., A.T., S.J., R.I., and H.T. performed the research; Y.M., A.T., Y.O., T.K., R.I., and H.T. analyzed the data; Y.M. and A.T. wrote the manuscript. Declaration of competing interest The authors have no competing interests. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Acknowledgments We thank Edanz Group (www.edanzediting.com/ac) for editing a draft of this manuscript. References [1] Sundfeldt M, Carlsson LV, Johansson CB, Thomsen P, Gretzer C. Aseptic loosening, not only a question of wear: a review of different theories. Acta Orthop 2006;77: 177–97. https://doi.org/10.1080/17453670610045902. [2] Andersen MR, Winther NS, Lind T, Schrøder HM, Flivik G, Petersen MM. Low preoperative BMD is related to high migration of tibia components in uncemented TKA-92 patients in a combined DEXA and RSA study with 2-year follow-up. J Arthroplasty 2017;32:2141–6. https://doi.org/10.1016/j.arth.2017.02.032. [3] Petersen MM, Nielsen PT, Lebech A, Toksvig-Larsen S, Lund B. Preoperative bone mineral density of the proximal tibia and migration of the tibial component after uncemented total knee arthroplasty. J Arthroplasty 1999;14:77–81. https://doi.org/10.1016/S0883-5403(99)90206-1. [4] Li MG, Nilsson KG. The effect of the preoperative bone quality on the fixation of the tibial component in total knee arthroplasty. J Arthroplasty 2000;15:744–53. https://doi.org/10.1054/arth.2000.6617. [5] Jaroma A, Soininvaara T, Kröger H. Periprosthetic tibial bone mineral density changes after total knee arthroplasty. Acta Orthop 2016;87:268–73. https://doi.org/ 10.3109/17453674.2016.1173982. [6] Soininvaara TA, Jurvelin JS, Miettinen HJ, Suomalainen OT, Alhava EM, Kroger PJ. Effect of alendronate on periprosthetic bone loss after total knee arthroplasty: a one-year, randomized, controlled trial of 19 patients. Calcif Tissue Int 2002;71:472–7. https://doi.org/10.1007/s00223-002-1022-9.
Please cite this article as: Y. Murahashi, A. Teramoto, S. Jimbo, et al., Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee ..., The Knee, https://doi.org/ 10.1016/j.knee.2019.12.010
Y. Murahashi et al. / The Knee xxx (xxxx) xxx
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[7] Wang CJ, Wang JW, Ko JY, Weng LH, Huang CC. Three-year changes in bone mineral density around the knee after a six-month course of oral alendronate following total knee arthroplasty. A prospective, randomized study. J Bone Joint Surg Am 2006;88:267–72. https://doi.org/10.2106/JBJS.E.00051. [8] Prieto-Alhambra D, Lalmohamed A, Abrahamsen B, Arden NK, de Boer A, Vestergaard P, et al. Oral bisphosphonate use and total knee/hip implant survival: validation of results in an external population-based cohort. Arthritis Rheumatol 2014;6:3233–40. https://doi.org/10.1002/art.38789. [9] Namba RS, Inacio MC, Cheetham TC, Dell RM, Paxton EW, Khatod MX. Lower total knee arthroplasty revision risk associated with bisphosphonate use, even in patients with normal bone density. J Arthroplasty 2016;31:537–41. https://doi.org/10.1016/j.arth.2015.09.005. [10] Jaroma AV, Soininvaara TA, Kröger H. Effect of one-year post-operative alendronate treatment on periprosthetic bone after total knee arthroplasty. A seven-year randomised controlled trial of 26 patients. Bone Joint J 2015;97-B:337–45. https://doi.org/10.1302/0301-620X.97B3.33643. [11] Hilding M, Aspenberg P. Postoperative clodronate decreases prosthetic migration: 4-year follow-up of a randomized radiostereometric study of 50 total knee patients. Acta Orthop 2006;77:912–6. https://doi.org/10.1080/17453670610013213. [12] Bernhardsson M, Sandberg O, Aspenberg P. Anti-RANKL treatment improves screw fixation in cancellous bone in rats. Injury 2015;46:990–5. https://doi.org/10. 1016/j.injury.2015.02.011. [13] Nagoya S, Tateda K, Okazaki S, Kosukegawa I, Shimizu J, Yamashita T. Restoration of proximal periprosthetic bone loss by denosumab in cementless total hip arthroplasty. Eur J Orthop Surg Traumatol 2018;28:1601–7. https://doi.org/10.1007/s00590-018-2223-x. [14] Windisch C, Windisch B, Kolb W, Kolb K, Grützner P, Roth A. Osteodensitometry measurements of periprosthetic bone using dual energy X-ray absorptiometry following total knee arthroplasty. Arch Orthop Trauma Surg 2012;132:1595–601. https://doi.org/10.1007/s00402-012-1601-9. [15] Ritter MA, Davis KE, Small SR, Merchun JG, Farris A. Trabecular bone density of the proximal tibia as it relates to failure of a total knee replacement. Bone Joint J 2014;9:1503–9. https://doi.org/10.1302/0301-620X.96B11.33465. [16] Small SR, Ritter MA, Merchun JG, Davis KE, Rogge RD. Changes in tibial bone density measured from standard radiographs in cemented and uncemented total knee replacements after ten years' follow-up. Bone Joint J 2013;95:911–6. https://doi.org/10.1302/0301-620X.95B7.30537. [17] Moreland JR, Bassett LW, Hanker GJ. Radiographic analysis of the axial alignment of the lower extremity. J Bone Joint Surg Am 1987;69:745–9. https://doi.org/10. 2106/00004623-198769050-00016. [18] Kellgren JH, Lawrence JS. Radiological assessment of osteo-arthrosis. Ann Rheum Dis 1957;16:494–502. https://doi.org/10.1136/ard.16.4.494. [19] Kendler DL, Roux C, Benhamou CL, Brown JP, Lillestol M, Siddhanti S, et al. Effects of denosumab on bone mineral density and bone turnover in postmenopausal women transitioning from alendronate therapy. J Bone Miner Res 2010;25:72–81. https://doi.org/10.1359/jbmr.090716. [20] Bolognese MA, Teglbjærg CS, Zanchetta JR, Lippuner K, McClung MR, Brandi ML, et al. Denosumab significantly increases DXA BMD at both trabecular and cortical sites: results from the FREEDOM study. J Clin Densitom 2013;16:147–53. https://doi.org/10.1016/j.jocd.2012.02.006. [21] McClung MR, Lewiecki EM, Cohen SB, Bolognese MA, Woodson GC, Moffett AH, et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 2006;354:821–31. https://doi.org/10.1056/NEJMoa044459. [22] Brown JP, Prince RL, Deal C, Recker RR, Kiel DP, de Gregorio LH, et al. Comparison of the effect of denosumab and alendronate on BMD and biochemical markers of bone turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 trial. J Bone Miner Res 2009;24:153–61. https://doi.org/10.1359/ jbmr.0809010. [23] Miller PD, Pannacciulli N, Brown JP, Czerwinski E, Nedergaard BS, Bolognese MA, et al. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab 2016;101:3163–70. https://doi.org/10.1210/jc.2016-1801. [24] Ledin H, Good L, Aspenberg P. Denosumab reduces early migration in total knee replacement. Acta Orthop 2017;88:255–8. https://doi.org/10.1080/17453674. 2017.1300746. [25] Pijls BG, Valstar ER, Nouta KA, Plevier JW, Fiocco M, Middeldorp S, et al. Early migration of tibial components is associated with late revision: a systematic review and meta-analysis of 21,000 knee arthroplasties. Acta Orthop 2012;83:614–24. https://doi.org/10.3109/17453674.2012.747052. [26] Lamy O, Gonzalez-Rodriguez E, Stoll D, Hans D, Aubry-Rozier B. Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report. J Clin Endocrinol Metab 2017;102:354–8. https://doi.org/10.1210/jc.2016-3170. [27] Anastasilakis AD, Polyzos SA, Makras P, Aubry-Rozier B, Kaouri S, Lamy O. Clinical features of 24 patients with rebound-associated vertebral fractures after denosumab discontinuation: systematic review and additional cases. J Bone Miner Res 2017;32:1291–6. https://doi.org/10.1002/jbmr.3110. [28] Popp AW, Zysset PK, Lippuner K. Rebound-associated vertebral fractures after discontinuation of denosumab-from clinic and biomechanics. Osteoporos Int 2016; 27:1917–21. https://doi.org/10.1007/s00198-015-3458-6. [29] Cummings SR, Ferrari S, Eastell R, Gilchrist N, Jensen JB, McClung M, et al. Vertebral fractures after discontinuation of denosumab: a post hoc analysis of the randomized placebo-controlled FREEDOM trial and its extension. J Bone Miner Res 2018;33:190–8. https://doi.org/10.1002/jbmr.3337. [30] Dequeker J, Boonen S, Aerssens J, Westhovens R. Inverse relationship osteoarthritis-osteoporosis: what is the evidence? What are the consequences? Br J Rheumatol 1996;35:813–8. https://doi.org/10.1093/rheumatology/35.9.813. [31] Nilsson KG, Kärrholm J, Ekelund L, Magnusson P. Evaluation of micromotion in cemented vs uncemented knee arthroplasty in osteoarthrosis and rheumatoid arthritis. Randomized study using roentgen stereophotogrammetric analysis. J Arthroplasty 1991;6:265–78. https://doi.org/10.1016/S0883-5403(06)80174-9.
Please cite this article as: Y. Murahashi, A. Teramoto, S. Jimbo, et al., Denosumab prevents periprosthetic bone mineral density loss in the tibial metaphysis in total knee ..., The Knee, https://doi.org/ 10.1016/j.knee.2019.12.010