The effects of different antihypertensive drugs on pain and joint space width of knee osteoarthritis – A comparative study with data from Osteoarthritis Initiative

Abstract Hypertension was one common comorbidity of knee osteoarthritis (KOA), but the effect of different types of antihypertensive drugs on pain and joint space width (JSW) was unclear and not compared. Four hundred ninety KOA patients using one of the beta‐blockers, ACE inhibitors, angiotensin receptor blockers, Calcium channel blockers (CCBs), or thiazide diuretics were followed for four years. The blood pressure, cumulative knee replacement rate, Womac pain, and JSW were compared among groups. All data were from the Osteoarthritis Initiative project. The CCBs group has the highest systolic blood pressure, replacement rate, and pain score at most visit timepoints. At baseline, the CCBs group was with significantly higher pain score than the beta‐blockers group (3.3 vs 1.3, p < .05), the angiotensin receptor blockers group (3.3 vs 1.4, p < .05), and the thiazide diuretics group (3.3 vs 1.6, p < .05) in male; the CCBs group was with significantly higher pain score than the beta‐blockers group (3.8 vs 2.0, p < .01), and the angiotensin receptor blockers group (3.8 vs 2.2, p < .05) in female. The results of females at 36 months were similar to the baseline. Among the common antihypertensive drugs, CCBs were associated with high replacement rates, high pain scores, and less JSW in KOA patients.


METHODS
In the Osteoarthritis Initiative project (OAI, https://nda.nih.gov/oai), were included. When both knees of one subject were qualified, only one knee was selected out randomly. Patients who changed the initial antihypertensive drugs in more than half the follow-up time were excluded. Finally, 133 patients using beta-blockers, 124 patients using ACE inhibitors, 79 patients using angiotensin receptor blockers, 76 patients using CCBs, and 78 patients using thiazide diuretics were included in this study ( Figure 1).

RESULTS
Among the five types of antihypertensive drug groups, the age distribution, mean BMI, mean CCI, KL grade distribution, and antihypertensive use frequency showed no significant difference. However, the percent of females varied from 50% in the ACE inhibitors group to 74% in the CCBs group (Table 2). Since the sex distribution was significantly different, the following analysis was stratified by sex to reduce the bias.

Blood pressure
At most timepoints, the mean systolic blood pressure in the CCBs group was highest ( Figure 2). In males, the value of the CCBs group was significantly higher than the beta-blockers group at 36-month (134.2 vs 122.9, p < .05) and 48-month (133.7 vs 123.2, p < .05). In females, the value of the CCBs group was significantly higher than the angiotensin receptor blockers group (134.6 vs 123.8, p < .05) at 36 months.

Replacement
In the KM curve, the CCBs group seemed to have a higher rate of knee replacement in a 9-year follow-up ( Figure 3). However, the Log-Rank test presented a p value of .77, suggesting the difference between the groups was not statistically significant. Due to the overall replacement number was small, stratified analysis by sex was not conducted.

Pain
In the 4-year follow-up, the CCBs group had the highest mean Womac pain score at most visit time points ( Figure 4A). In males, the mean Womac pain score in the CCBs group was significantly higher than the beta-blockers group (

JSW
In both males and females, the CCBs group had the narrowest medial minimal JSW in the five groups at the most visit period ( Figure 4B).
However, there was no significant difference among the five groups no matter in males or females.
In the CCBs group, patients were divided into dihydropyridine and non-dihydropyridine. No significant difference was detected between the two subgroups in systolic blood pressure, pain, and joint width at any time points (Supplementary 1).

DISCUSSION
The effect of different types of antihypertensive drugs on KOA pain and structural change was unclear and not compared. We analyzed the blood pressure, knee replacement rate, Womac pain, and JSW in patients with beta-blockers, ACE inhibitors, angiotensin receptor blockers, CCBs, and thiazide diuretics. CCBs were associated with higher joint replacement rate, more pain, and narrower JSW in KOA patients in the 4-year follow-up.
The blood pressure control results were quite unexpected because previous studies demonstrated that the interaction between NSAIDs and CCBs was less than the interaction between NSAIDs and other antihypertensive drugs. The interaction between NSAIDs and antihypertensive drugs mainly depends on the role that prostaglandins play in the antihypertensive mechanism, 18,19 while the antihypertensive effect of CCBs is not dependent on the action of prostaglandins. 20 Theoretically, CCBs should be less affected by NSAIDs, and previous researches also supported this. 21 31 Second, the vasodilating effects of CCBs might be impaired by NSAIDs. Pavlicević and colleagues found that NSAIDs did not significantly change body weight, urinary output, serum creatinine, or serum/urinary electrolyte profile, and they concluded that NSAID's pro-hypertensive effects seem mainly due to vasoconstriction rather than volume expansion. 32 The antagonistic action on the vessel between CCBs and NSAIDs might lead to poorly controlled hypertension, and therefore KOA patients using CCBs experienced more progression. Third, skeletal muscle might be the mediator between CCBs and KOA progression. Although skeletal muscle does not depend on extracellular calcium for muscle contraction, the CCBs also exert pharmacological effects on the skeletal muscle, such as glucose transport. 33 Considering that skeletal muscle may play an essential role in OA pathogenesis through its function, tissue, and molecular mechanisms, 34 researches about skeletal muscle and CCBs in KOA patients were necessary.
In our results, beta-blockers have favorable performance in KOA patients with relatively low pain scores. The beta-adrenergic receptor (b-AR) system has been recently targeted in pain management and drug development. 35,36 Specific beta-adrenergic receptors are located on peripheral nociceptors, superficial dorsal horn, and dorsal root ganglia, resulting in hyperalgesia. 37 Martin et al. reported that bupranolol, a beta-blocker, had good antinociceptive efficacy and safety in mouse models of chronic pain. 35 Valdes and colleagues supported that beta- with non-beta-blocker users as a control. 12 Nakafero and colleagues also reported a reduced cumulative risk of knee pain in the betablockers users than non-users. 38 Our results revealed the benefit of beta-blockers in pain management of KOA, and more importantly, the main difference between this study and previous studies was that we directly compared different types of antihypertensive drugs. Zhou and associates took all of the non-beta-blockers antihypertensive drugs as a control, and they detected no evidence of beta-blockers use in reducing knee pain. 13 This study classified antihypertensive drugs into five types and found significant difference between beta-blocker and CCBs.
However, there are several limitations. First, the OAI project did not collect the dosage of antihypertensive drugs, and different dosages might cause potential bias in this study. Futural high-quality RCTs were required to verify our results. Second, one type of drug was integrated as one group in the analysis, which might cause some heterogeneity.
For example, β1/β2 adrenoreceptor selectivity was not specially considered in the beta-blockers group. Although grouping patients with a single drug would be more convincing, it was difficult to collect enough eligible participants. Third, we could not clarify the causal relationship between the higher pain and higher blood pressure in the CCBs group. Further researches were still necessary to reveal the original trigger factor. Fourth, although we used prospective data of OAI, no randomization was applied for our study purpose, and confounding fac-tors might still exist. Fifth, the sample size of this study was not large.
Nation-wide database analysis in the future might provide extra solid evidence.

CONCLUSION
In the KOA patients using common antihypertensive drugs, high replacement rate, high pain score, and less JSW were observed in subjects with CCBs. More high quality RCTs are necessary to clarify the exact effect of CCBs in KOA.

ACKNOWLEDGMENTS
We would like to thank the OAI participants and Coordinating Center for their work in generating the clinical and radiological data of the OAI cohort and for making them publicly available.

ETHICAL APPROVAL STATEMENT
All procedures performed in studies involving human participants were in accordance with the ethical standards declaration and its later amendments or comparable ethical standards. OAI project was approved by the institutional review boards at different sites.