Effect of Intravenous Zoledronic Acid on Total Knee Replacement in Patients With Symptomatic Knee Osteoarthritis and Without Severe Joint Space Narrowing: A Prespecified Secondary Analysis of a Two‐Year, Multicenter, Double‐Blind, Placebo‐Controlled Clinical Trial

To determine the effect of zoledronic acid (ZA) on the risk of total knee replacement (TKR) in patients with symptomatic knee osteoarthritis and without severe joint space narrowing (JSN).

are dissatisfied with their postoperative outcome. 3,5,6Therefore, new treatments are needed to delay the progression of knee osteoarthritis.
Bisphosphonates are a first-line therapy for the prevention and treatment of osteoporosis. 7The role of bisphosphonates in reducing bone remodeling and osteoclastic pain has made them a potential treatment for osteoarthritis, another bone disease with abnormal bone remodeling and osteoclast activity. 8Populationbased observational studies suggested that bisphosphonate use was associated with greater pain reduction, 9,10 less structural progression, 11 and decreased use of pain medicine. 12Two registry-based large cohort studies observed a significantly lower risk of total knee replacement among bisphosphonate users, compared to nonusers. 12,13However, findings from randomized clinical trials were less consistent, [14][15][16][17][18][19][20] with a systematic review of randomized clinical trials indicating that bisphosphonates have no effect on symptomatic or structural progression of knee osteoarthritis. 21In a recent two-year multicenter randomized clinical trial, zoledronic acid, the most potent bisphosphonate, 22 had no effect on knee pain and magnetic resonance imaging (MRI)detected cartilage loss over two years, and surprisingly, more self-reported total knee replacements were recorded in participants receiving zoledronic acid than placebo (9% vs 2%). 20While total knee replacement is a common endpoint of knee osteoarthritis, currently no randomized clinical trials have examined the effect of bisphosphonates on total knee replacement.Because there is widespread use of bisphosphonates, especially in older adults, a prespecified secondary analysis was conducted using data from a multicenter randomized clinical trial of zoledronic acid, 20 with follow-up time extended and total knee replacement ascertained by linkage to data registry.This study aimed to assess the effect of two annual infusions with 5 mg of zoledronic acid on the risk of total knee replacement in participants with symptomatic knee osteoarthritis and without severe joint space narrowing (JSN).

PATIENTS AND METHODS
Study settings.The Zoledronic Acid for Osteoarthritis Knee Pain (ZAP2) study was a two-year multicenter, double-blind, placebo-controlled clinical trial conducted in 223 participants with symptomatic knee osteoarthritis at four study sites in Australia (Hobart, Melbourne, Adelaide, and Sydney) between November 2013 and October 2017. 20This study is a secondary analysis of the ZAP2 trial as prespecified in the published study protocol, in which the details of the trial design have been described (Australian New Zealand Clinical Trials Registry: ACTRN12613000039785). 23 This study followed the Consolidated Standards of Reporting Trials reporting guideline. 24Ethics approvals were granted by ethics committees at each site.All participants provided written informed consent.
Participants and intervention.The inclusion and exclusion criteria of ZAP2 are detailed elsewhere. 23Participants were eligible if they were 50 years or older, had significant knee pain (defined as a pain score of ≥40 mm on a 100-mm visual analog scale) on most days during the last month, met the American College of Rheumatology criteria for symptomatic knee osteoarthritis, 25 26 had surgery in the study knee during the last 12 months, cancer, or contraindications to MRI.If both knees met the inclusion criteria, the study knee was defined as the one with worse knee pain and milder JSN as graded by a rheumatologist.Eligible participants were randomized in a 1:1 ratio to receive annual infusions of either 5 mg of zoledronic acid in 100 mL saline (n = 113) or placebo (n = 110) at baseline and 12 months and were followed up until 24 months.
Total knee replacement.Total knee replacement of the study knee and the contralateral knee were identified by linking the ZAP2 records to the Australian Orthopaedic Association National Joint Replacement Registry (AOANJRR), as prespecified in the published protocol, 23 for total knee replacement performed between the baseline of ZAP2 (November 2013 -September 2015) and February 22, 2022.The AOANJRR collects data on joint replacements from both public and private hospitals.Data validation is a sequential multilevel matching process against health department unit record data. 27Data obtained included the date and side of a total knee replacement, primary or revision total knee replacement, and the reason for the procedure (eg, osteoarthritis, inflammatory arthritis, and osteonecrosis).The outcome of interest was primary total knee replacement due to knee osteoarthritis; therefore, revision total knee replacement and total knee replacement procedures not due to knee osteoarthritis were excluded from the data analysis.The present study included 222 participants (113 received zoledronic acid and 109 received placebo) from the ZAP2 trial, with one participant being excluded because the participant underwent bilateral total knee replacement due to rheumatoid arthritis (Figure 1).For the analysis of total knee replacement in any knee, the contralateral knee with a history of total knee replacement before ZAP2 was excluded.The date of death was not obtained in this study.
Selection and assessment of covariates.Covariates in this study were selected based on their relevance to knee osteoarthritis and between-group imbalances at baseline.They included age, sex, knee pain and JSN of the study knee, study site, and deciles of socioeconomic status.Knee pain was assessed using a 100-mm visual analog scale over the past seven days, with a higher score indicating more severe pain.JSN on the radiograph was graded as 0, 1, and 2 according to the OARSI atlas. 26Socioeconomic status was determined using the Socio-Economic Indexes for Areas developed by the Australian Bureau of Statistics in 2001. 28atistical analysis.Mean (SD) and n (%) were used to describe baseline characteristics, split by treatment group.The person-time was calculated from the date of the first infusion (either zoledronic acid or placebo) to the date of total knee replacement or the end of follow-up (February 22, 2022) if no total knee replacement was performed (ie, right censored).Cox proportional hazard regression models were used to evaluate the effect of zoledronic acid on the risk of total knee replacement in any knee and the study knee, respectively.The proportional hazards assumption was tested using the Schoenfeld's method. 29ecause the treatment effect failed the proportional hazards assumption, a time-varying coefficients analysis for treatment was conducted by splitting the study into two periods (ie, period 1: during the trial, and period 2: after two years of randomization), because two years was set as the length of follow-up for the ZAP2 trial.As well as univariable analyses, multivariable analyses were performed with adjustment for age, sex, knee pain, JSN, study center, and deciles of socioeconomic status at baseline.Hazard ratios (HRs) with 95% confidence intervals (CIs) were used to describe the effect of zoledronic acid on the risk of total knee replacement compared to placebo.The proportions of participants who had improved, stable, and worse knee pain scores at each follow-up visit (ie, 3, 6, 12, 18, and 24 months) were described, where the cut-off point for change in knee pain scores was set at 15 mm (ie, the minimum clinically important difference) in a 0 to 100 mm visual analog scale. 30Data analyses were conducted with Stata/SE version 16.1 (StataCorp).A two-sided P < 0.05 was considered statistically significant.

RESULTS
The study flowchart appears in Figure 1.A total of 222 participants (mean age 62 years, 52% female) were included.Only a single participant included in the study had any history of bisphosphonate treatment (prior use of oral bisphosphonates for one year but stopped treatment more than two years ago) and was allocated to the placebo group.The baseline characteristics of the two groups were similar, except that those in the zoledronic acid group had milder knee pain and were more likely to be men (Table 1).Compared to the placebo group, a slightly higher proportion (10%-14% vs 7%-10%) of participants in the zoledronic acid group experienced worsening knee pain, and a lower proportion (38%-44% vs 49%-55%) of participants experienced improvement of knee pain at each follow-up visit (Figure 2).
During the median follow-up of 7.0 years (range 0.3-8.2years), 44 (39%) participants in the zoledronic acid group and 33 (30%) participants in the placebo group had a total knee replacement, of whom 32 (28%) and 20 (18%) had a total knee replacement in the study knee, respectively.When stratified by period a Five participants have missing data for joint space narrowing (two in the placebo group and three in the zoledronic acid group).a Eight total knee replacements in the contralateral knee were conducted before the ZAP2 trial (two in the placebo group and six in the zoledronic acid group).
(during period 1 or after two years of randomization [period 2]), 13 (12%) participants in the zoledronic acid group and 3 (3%) participants in the placebo group had a total knee replacement in any knee in period 1, and 31 (27%) and 30 (28%) had a total knee replacement in period 2, respectively.More total knee replacements were conducted in knees with grade 1 and 2 JSN, compared to knees with grade 0 JSN.For the study knee, the risk of total knee replacement in knees with grade 1 and 2 JSN was numerically higher in the zoledronic acid group than the placebo group.For the contralateral knee, the risk of total knee replacement was comparable in the two groups (Table 2).
The effect of zoledronic acid on the risk of total knee replacement is shown in Table 3 and Figure 3.In period 1, treatment with zoledronic acid, compared to placebo, was statistically significantly associated with a higher risk of total knee replacement in any knee (HR 4.2, 95% CI 1.2-14.7),and the risk was large in the study knee (HR 6.8, 95% CI 0.9-53.9),albeit with wide CIs and not statistically significant.In period 2, the risk of total knee replacement in any knee (HR 1.2, 95% CI 0.5-1.8)or in the study knee (HR 1.4, 95% CI 0.5-2.2) was not statistically significantly different between the zoledronic acid and placebo groups.

DISCUSSION
In this prespecified secondary analysis of a randomized clinical trial, participants with symptomatic knee osteoarthritis who received zoledronic acid did not have a reduction in the risk of total knee replacement over seven years, and they were more likely to have an increased risk of total knee replacement during the study period (ie, first two years of randomization), compared to those who received placebo.Our findings do not support the use of zoledronic acid for reducing the risk of total knee replacement in patients with symptomatic knee osteoarthritis and without severe JSN.
The cumulative incidence of total knee replacement in this study was comparable to a recent study with a median followup of 5.6 years conducted in nearly 1 million US patients with knee osteoarthritis (34.7% vs 33.1%). 31We did not find a reduced risk of total knee replacement over a median follow-up period of 7.0 years in participants receiving zoledronic acid, compared to those who received placebo.This is consistent with two previous randomized clinical trials, 14,16 showing that bisphosphonates had no effect on the risk of total joint replacement over one to two years but contrasts with two previous cohort studies showing that bisphosphonates reduced the risk of total knee replacement over 2.5 and 3 years, respectively. 12,13he inconsistency could be explained by "confounding by indication," 32 especially given the modest follow-up period in previous observational studies. 12,13For example, in cohort studies, patients who are prescribed these medications are likely to have or be at a higher risk of low bone mineral density (BMD). 7ur previous study showed that BMD was positively associated  with an increased risk of osteoarthritis-related knee and hip replacements. 33Moreover, patients who received zoledronic acid may have increased BMD and bone rigidity because of the medication, and in turn this may have accelerated the progression of osteoarthritis.Therefore, the protective effect of bisphosphonates on total knee replacement as observed in the observational studies may have been biased, at least in part, by the relatively low BMD in bisphosphonate users, although one of the two observational studies adjusted for comorbidities of osteoporosis, osteopenia, and fractures. 13nee pain and structural destruction are core indications for total knee replacement due to knee osteoarthritis.In the scenario of population-based observational studies, bisphosphonates appeared to be beneficial for both symptomatic and structural progression of knee osteoarthritis.In the Osteoarthritis Initiative, bisphosphonate use was associated with a reduction in knee pain and milder radiographic progression of knee osteoarthritis, 10 especially in early-stage patients (Kellgren-Lawrence grade <2). 11t is therefore not surprising that a reduced risk of total knee replacement with bisphosphonate use was seen in observational studies. 12,13However, this association could be affected by confounding given the evidence from randomized clinical trials shows that bisphosphonates have no effect on symptomatic and structural progression of knee osteoarthritis. 20,21Altogether, it remains unlikely that bisphosphonates reduce the need for total knee replacement in patients with knee osteoarthritis.
Our finding that zoledronic acid increased the risk of total knee replacement during treatment is unexpected.This finding is consistent with the adverse event reports in the main ZAP2 trial, in which we saw that more total knee replacement surgeries were conducted in zoledronic acid receivers at the two-year followup. 20However, this finding, being from a secondary analysis, must be interpreted cautiously.Although zoledronic acid may have increased BMD and bone rigidity and thus accelerate the progression of osteoarthritis, as discussed above, the effect of zoledronic acid on the risk of total knee replacement needs further investigation.
This study has several limitations.First, the sample size was modest, and it is possible the results of this study are due to chance.However, total knee replacements were retrieved from a national registry, and a large percentage (34.7%) of patients had total knee replacement conducted during the follow-up.Therefore, there was no missing data on total knee replacement and statistically significant between-group differences in the risk of total knee replacement were found.Second, this was a secondary analysis of a randomized clinical trial.Although participants were informed of their treatment group after the ZAP2 trial ended, there was no direct follow-up with patients thereafter.A separate trial evaluating the effect of bisphosphonates on the risk of total knee replacement is unlikely to ever be conducted, given the ethical concerns of randomization to an intervention that is not efficacious and which is associated with adverse events. 21,34Future work could explore other long-term trials of bisphosphonates for osteoporosis to see if our results can be replicated.Third, we did not obtain the date of death, which may have a competing effect on the risk of total knee replacement.However, the mean age of the study participants was 62 years, so mortality rates are unlikely to materially change our findings.Fourth, the ZAP2 trial excluded patients who had severe radiographic knee osteoarthritis, an important factor that predicts total knee replacement.Therefore, we cannot be sure whether zoledronic acid plays a role in the risk of total knee replacement among patients with severe radiographic knee osteoarthritis.In conclusion, these results suggest that zoledronic acid is not protective against total knee replacement in patients with symptomatic knee osteoarthritis and without severe JSN.

Figure 1 .
Figure 1.CONSORT diagram of study enrollment and randomization.a One participant allocated to the placebo group incorrectly received zoledronic acid at both baseline and 12 months.b Participants who had major surgery (eg, heart surgery, hip replacement, back surgery) or wished to have an antiresorptive treatment (denosumab).c Participants who did not receive the second infusion but continued with the study visits and assessments.ACR, American College of Radiology; MRI, magnetic resonance imaging.

Figure 2 .
Figure 2. The percentages of participants with change in visual analog scale knee pain score (0-100 mm) from baseline.Improved: knee pain score decreased by ≥15 mm; stable: change in knee pain score of <15 mm; worse: knee pain score increased by ≥15 mm.No statistically significant between-group differences in change in knee pain were found for any visit (all P > 0.05).PBO, placebo; ZA, zoledronic acid.Color figure can be viewed in the online issue, which is available at http://onlinelibrary.wiley.com/doi/10.1002/art.42831/abstract.

Figure 3 .
Figure 3. Cumulative incidence of TKR in (A) any knee and (B) the study knee by treatment group.TKR, total knee replacement.

Table 1 .
Baseline characteristics of study participants

Table 2 .
Number and percentage of total knee replacement by treatment group* * Results are shown as n (%) or n/N (%).JSN was assessed according to the OARSI atlas (two participants with missing data in the placebo group and three in the zoledronic acid group).JSN, joint space narrowing; OARSI, Osteoarthritis Research Society International; ZAP2, Zoledronic Acid for Osteoarthritis Knee Pain.

Table 3 .
The effect of zoledronic acid on the risk of total knee replacement*