Whole-Body Vibration as Antihypertensive Non-Pharmacological Treatment in Hypertensive Individuals with Knee Osteoarthritis: Randomized Cross-Over Trial

: (1) Background: Hypertension is a serious medical condition characterized by a persistent increase in blood pressure (BP), which is prevalent in individuals with knee osteoarthritis (KOA). Pharmacological interventions are normally used to treat both hypertension and KOA; however, a more sustainable form of treatment is desirable for these clinical conditions. Whole-body vibration (WBV) exercise has been proposed as a non-pharmacological therapy for reducing both BP and KOA symptomatology. This study aimed to evaluate the antihypertensive e ﬀ ect of WBV in hypertensive individuals with KOA. (2) Methods: Nineteen hypertensive individuals with KOA were randomly allocated to either a control (CG) (n = 9) or a WBV group (WBVG) (n = 10). Subjects in the WBVG were positioned sitting in a chair in front of a vibrating platform (VP) with the feet on the base (peak-to-peak displacement 2.5, 5.0 and 7.5 mm; frequencies 5 to 14 Hz). In the CG, subjects assumed the same position with the VP turned o ﬀ . The protocols in the CG and WBVG were performed 2 days / week for a total of 5 weeks. (3) Results: No baseline di ﬀ erences (age, anthropometrics, BP parameters and medications) between the groups were found ( p > 0.05). WBV exercise reduced systolic BP (SBP: 126.1 ± 2.7 versus 119.1 ± 3.2 mmHg; p = 0.001; post hoc: p = 0.02; F = 23.97) and mean BP (MBP: 82.6 ± 1.8 versus 78.7 ± 1.8, p = 0.001, post hoc: p = 0.02; F = 23.97), while no signiﬁcant changes were found in diastolic BP (DBP: 68.5 ± 2.2 versus 64.4 ± 2.3; p = 0.11; F = 2.68). (4) Conclusions: WBV might be considered a sustainable therapy for exerting an antihypertensive e ﬀ ect in medicated hypertensive individuals with KOA. This decline in BP might translate to a reduction in pharmacological need, although further studies are necessary to understand the mechanisms underlying the described e ﬀ ect.

KOA, considered a systemic disease, is connected with biomechanical factors and an important inflammatory component affecting articular and periarticular structures [6,7]. In addition, KOA is also linked with some cardiovascular risk factors, as MSyn [8], obesity [9], elevated prevalence of diabetes and a rise in BP [10]. Liu et al. showed the association of mortality risk in individuals with symptomatic KOA, including hypertension, as one of these factors [11]. The new classification for phenotyping KOA involves components of MSyn, such as increased BP associated with cardiovascular risk factors (i.e., "pre-hypertension or hypertension") [12]. Although many studies reported the association between KOA and hypertension [13][14][15]; to our knowledge, only a longitudinal investigation reported the incidence of hypertension in individuals with KOA. The authors of this investigation concluded that individuals with KOA are 13% more likely to develop hypertension than those without KOA [2].
Different mechanisms seem to influence the elevated risk of cardiovascular disease (CVD) among KOA individuals, including: (i) the presence of low-chronic grade inflammation (inflamm-aging) [16,17]; (ii) relevant changes in extracellular matrix (ECM) [18,19] and (iii) pain and disability that may result in physical inactivity (sedentary lifestyle) [20].
Since individuals with KOA are more likely to develop hypertension, monitoring and treating BP in these individuals is desirable. Therefore, in order to obtain long-term health benefits and prevent CVD, the close surveillance and better management of BP in this population is recommended [2].
The use of medications is indicated for the treatment of hypertension and for the reduction of symptoms related to KOA [21,22]. The presence of these two diseases leads to an increase in the consumption of medicines, increasing the cost for the individual. In addition, the administration of a greater number of medications can have greater adverse/side effects for the individual and for the environment. Green Chemistry and Green Engineering have worked on the development of safer materials and chemicals, assessing the toxicological risk for both the environment and consumers (Green Toxicology) [23]. However, in order to achieve a sustainable and safe production of new chemical products, this process requires important measures. In the case of pharmaceutical compounds, there may be limitations on obtaining ecological medicines that are safe and effective without increasing the final cost for the consumer [23]. In this context, a good strategy would be to investigate non-pharmacological and low-cost treatments in the health area. Ikeda et al. [24] reported that in some low-and middle-income countries, the use of medications for hypertension is reduced. This suggests that a comprehensive approach to the prevention and control of high BP has been investigated since medication is an expensive alternative and most people are hypertensive. Following these considerations, physical exercise has been prescribed to reduce both BP and symptoms related to KOA [22,25].
Among the various modalities of exercise proposed for KOA individuals, whole-body vibration (WBV) exercise has been suggested due to relevant responses related to the reduction of BP [26]. Moreover, WBV exercise promotes improvements in the quality of life, knee joint function (neuromuscular function, flexibility, muscle power and strength), bone mineral density, and decreases pain levels and number of falls [27][28][29][30]. WBV exercise has also been shown to have an important clinical application for subjects with cardiovascular risk [26,[31][32][33], particularly for individuals unable to perform regular physical exercise, such as KOA individuals. Moreover, the WBV intervention is a non-pharmacological treatment option that is economic and safe for individuals who cannot use or refuse medication. Thus, the current study aimed to evaluate the antihypertensive effects of WBV exercise in hypertensive individuals with KOA. The hypothesis is that a WBV exercise program (5 weeks) would improve BP in hypertensive individuals with KOA.

Subjects
Nineteen outpatients from the Orthopedics Department of the Hospital Universitário Pedro Ernesto, Universidade do Estado do Rio de Janeiro (HUPE-UERJ) with KOA diagnostic according to the criteria of the Ahlbäck [34] participated in the current study. Subjects were recruited between March 2014 and July 2017. This investigation with hypertensive KOA individuals is included in a general project about the clinical intervention of WBV exercise in a KOA population, which was approved by the Ethics Committee in Research of the HUPE-UERJ. All the interventions are in accordance with the Declaration of Helsinki and have a clinical trial registration (CAAE-19826413.8.0000.5259 and RBR-7dfwct, respectively).

Inclusion Criteria
Participants had a clinical diagnosis of KOA with Ahlbäck degree 2 and 3, were over 50 years of age, and had low functional capacity (International Knee Documentation Committee (IKDC) score between 20 and 50) [35]. All participants self-declared the continuous use of antihypertensive drugs prescribed by their doctors and were unaware of their hypertension level.

Exclusion Criteria
Participants with joint prosthesis or total knee replacement, other musculoskeletal disorders, neurological diseases or hypertension without treatment, and those that refused to sign the informed consent were excluded.

Study Design
The study was a two step crossover trial [36] with a washout period for the total elimination of the mechanical vibration effect, which is in accordance with a previous investigation [37] (Figure 1). Following an initial screening that included medical history, anthropometric (age, stature, body mass and body mass index (BMI)) and BP measurements, eligible participants were randomly assigned by arrival order to either a WBV group (WBVG) or a control group (CG). In WBVG, the individuals were exposed to mechanical vibration and in the CG, the individuals participated in the same protocol as the WBVG, but with the vibrating platform (VP) turned off. Following the initial intervention and an 8-week washout period, the groups were switched to the second intervention step. Data were collected at baseline (before starting the protocol) and at the end of the protocol (after 5 weeks) always at the same time (±1 h), in the morning.
Participants were instructed to maintain the antihypertensive drugs prescribed by their doctors and not to modify their lifestyle habits (diet, exercise) during the study.

Anthropometry and BP
BP and anthropometric parameters were measured in a silent temperature-controlled room (22-25 °C). A digital scale (WelmyTM, São Paulo, SP, Brazil) was used to measure the body mass (kg) and a wall mounted stadiometer (American Medical do Brazil, São Paulo, SP, Brazil) was utilized to measure height (cm).
Before the start of the protocol (first session) the systolic BP (SBP) and the diastolic BP (DBP) were measured in a left arm, in the seated position, using an automatic device (Omron 705IT device; OmronTM Healthcare Co., Kyoto, Japan) after 10 min of rest. The SBP and DBP were also measured immediately after the last session. Three measurements at 1-min intervals were collected and the mean of the three values was used for comparison. The mean of BP (MBP) was calculated using the equation MBP = (DBP.2) SBP/3 [38]. A difference after and before the intervention (∆ = post -pre) was calculated in each BP parameter (SBP, DBP and MBP).

Whole-Body Vibration Intervention
The WBV protocol was performed for 5 weeks, two days per week (10 sessions) with an interval of at least 2 days between sessions. The position of the subjects during the WBV session was in accordance with previous studies [39][40][41][42]: (i) participant sitting in an ancillary chair in front of the VP, (ii) feet on VP base (barefoot), (iii) knee with a comfortable flexion between 100-120° (measured by manual goniometer), (iv) the hands on the knees to facilitate the transmission of the mechanical vibration for the whole body of the individual. The VP used was a side alternated movement of the base (Novaplate Fitness Evolution, DAF Produtos Hospitalares LTDA, São Paulo, Brazil). The participants were instructed to maintain this position with feet in each peak-to-peak displacement (2.5, 5.0 and 7.5 mm) indicated on the base of the VP for 3 min, resting 1 min after each bout. The frequency was increased in each session from 5 Hz (first session) up to 14 Hz (last session), corresponding to peak acceleration (aPeak) from 0.12 to 2.95 g [39][40][41][42]. The CG followed the same protocol as the WBVG, but with the VP turned off (no vibration). Data were collected at baseline (before starting the protocol) and at the end of the protocol (after 5 weeks) always at the same time (±1 h), in the morning.
Participants were instructed to maintain the antihypertensive drugs prescribed by their doctors and not to modify their lifestyle habits (diet, exercise) during the study.

Anthropometry and BP
BP and anthropometric parameters were measured in a silent temperature-controlled room (22-25 • C). A digital scale (WelmyTM, São Paulo, SP, Brazil) was used to measure the body mass (kg) and a wall mounted stadiometer (American Medical do Brazil, São Paulo, SP, Brazil) was utilized to measure height (cm).
Before the start of the protocol (first session) the systolic BP (SBP) and the diastolic BP (DBP) were measured in a left arm, in the seated position, using an automatic device (Omron 705IT device; OmronTM Healthcare Co., Kyoto, Japan) after 10 min of rest. The SBP and DBP were also measured immediately after the last session. Three measurements at 1-min intervals were collected and the mean of the three values was used for comparison. The mean of BP (MBP) was calculated using the equation MBP = (DBP.2) SBP/3 [38]. A difference after and before the intervention (∆ = post -pre) was calculated in each BP parameter (SBP, DBP and MBP).

Whole-Body Vibration Intervention
The WBV protocol was performed for 5 weeks, two days per week (10 sessions) with an interval of at least 2 days between sessions. The position of the subjects during the WBV session was in accordance with previous studies [39][40][41][42]: (i) participant sitting in an ancillary chair in front of the VP, (ii) feet on VP base (barefoot), (iii) knee with a comfortable flexion between 100-120 • (measured by manual goniometer), (iv) the hands on the knees to facilitate the transmission of the mechanical vibration for the whole body of the individual. The VP used was a side alternated movement of the base (Novaplate Fitness Evolution, DAF Produtos Hospitalares LTDA, São Paulo, Brazil). The participants were instructed to maintain this position with feet in each peak-to-peak displacement (2.5, 5.0 and 7.5 mm) indicated on the base of the VP for 3 min, resting 1 min after each bout. The frequency was increased in each session from 5 Hz (first session) up to 14 Hz (last session), corresponding to peak acceleration (a Peak ) from Sustainability 2020, 12, 8944 5 of 13 0.12 to 2.95 g [39][40][41][42]. The CG followed the same protocol as the WBVG, but with the VP turned off (no vibration).

Statistical Analysis
The Kolmogorov-Smirnov test was used to test data normality. Mauchly's and Levene's tests were used to verify the sphericity and homogeneity of data and when necessary, the Greenhouse-Geisser correction was applied.
Student-t test was performed for calculation of possible baseline differences between the two groups. A 2-way ANOVA (group (G and WBVG) X time (pre and post treatments)) was performed to establish the intervention effects over time. In case of significant F ratio, the Bonferroni post-hoc test was applied. Data are expressed as mean ± standard error (SEM). The software SPSS 20.0 (SPSS IncTM, Chicago, IL, USA) was used for the statistical calculations and p ≤ 0.05 was considered as probability level for statistical significance.
Based on previous study [31], the software G*Power 3.1.5 (Universitat Dusseldorf, Dusseldorf, Germany) performed a sample size taking into consideration a α error probability = 0.05; β error probability = 0.80; effect size f = 0.25; correlation among repeated measures = 0.5; nonsphericity correction ε = 1. A statistical power of 0.82 was estimated and after calculations, it was determined to be a total of n = 24 (12 participants per group).

Results
Nineteen individuals with KOA were randomly allocated in CG (n = 9) and WBVG (n = 10). Five individuals from the WBVG returned to perform the second step of the treatment (CG) and four individuals from the CG returned to the WBVG totaling fourteen people in each group (2 males and 12 females) ( Figure 1). Therefore, 14 individuals in CG and 14 individuals in WBVG concluded all the protocols proposed which were similar to previous studies [31,43,44]. Table 1 shows that anthropometric and BP parameters collected before the interventions and the medications used by participants were not significantly different in the two groups (p > 0.05). Although all individuals were taking antihypertensive drugs, the SBP levels of both groups were compatible with prehypertension (n = 11) and hypertension (n = 3) [45].  Figure 4A). In addition, significant differences were found between post-conditions (WBVG versus CG) for SBP (119.1 ± 3.2 versus 126.1 ± 2.7 mmHg; ∆-9.6 mmHg; post hoc: p = 0.02), as shown in Figure 2B, and MBP (78.7 ± 1.8 versus 82.6 ± 1.8; ∆-5.0 mmHg; p = 0.04), as reported in Figure 3B, but not for DBP (64.4 ± 2.3 versus 68.5 ± 2.2; ∆-4.1 mmHg, p = 0.2) ( Figure 4B).

Discussion
The association of KOA with cardiovascular risk factors has been discussed in several studies [10][11][12]. As far as we know, the current work is the first which aimed to evaluate the WBV exercise effects on the BP levels in individuals who suffer with KOA. It is important to report that the washout period of 8 weeks [37] was sufficient for a total elimination of the mechanical vibration effect, because the comparison of the baseline in both groups was similar (SBP -p = 0.87; DBP -p = 0.881 and MBPp = 0.943). Although previous studies have used longer protocols (between 6 and 12 weeks) in non-KOA populations [31,[43][44][45][46][47], we showed that an even shorter duration protocol (5 weeks) provides promising outcomes for hypertensive KOA individuals. This encourages further short studies in this population.

Blood Pressure and Whole-Body Vibration
The most relevant results of the present investigation are that SBP and MBP had a significant reduction after 5 weeks of WBV intervention in individuals with KOA compared with CG. These findings are in line with several authors that have previously demonstrated that resting BP decreases

Discussion
The association of KOA with cardiovascular risk factors has been discussed in several studies [10][11][12]. As far as we know, the current work is the first which aimed to evaluate the WBV exercise effects on the BP levels in individuals who suffer with KOA. It is important to report that the washout period of 8 weeks [37] was sufficient for a total elimination of the mechanical vibration effect, because the comparison of the baseline in both groups was similar (SBP -p = 0.87; DBP -p = 0.881 and MBPp = 0.943). Although previous studies have used longer protocols (between 6 and 12 weeks) in non-KOA populations [31,[43][44][45][46][47], we showed that an even shorter duration protocol (5 weeks) provides promising outcomes for hypertensive KOA individuals. This encourages further short studies in this population.

Blood Pressure and Whole-Body Vibration
The most relevant results of the present investigation are that SBP and MBP had a significant reduction after 5 weeks of WBV intervention in individuals with KOA compared with CG. These findings are in line with several authors that have previously demonstrated that resting BP decreases after WBV in different populations. Alvarez-Alvarado et al. [32] and Figueroa et al. [26] reported reductions at resting SBP (−5 mmHg) without changes in DBP in young women (overweight/obese) and normotensive (Baseline: SBP/DBP < 120/80 mmHg) after 6 weeks of a WBV program. Furthermore, authors observed SBP and MBP reduction after a WBV program versus a control group (6-12 weeks) in obese postmenopausal women with both elevated BP and hypertension [31,[43][44][45][46][47]. Other investigations indicated a greater decrease in blood pressure between WBV intervention versus control group, when the baseline BP is high (>120/80 mmHg). Figueroa et al. [31] reported a decrease in SBP (~9 mmHg) in obese postmenopausal women with high BP. Figueroa et al. [44] showed a reduction of the SBP (~10 mmHg), DBP (~5 mmHg) and MBP (~6 mmHg) in postmenopausal women with hypertension. Wang et al. [47] found a decrease in SBP (~8 mmHg) and DBP (−3 mmHg) in obese hypertensive postmenopausal women. In the current study, we found significant reductions in SBP and MBP between intervention and control groups (~9.0 and 5.0 mmHg respectively). However, we note that three subjects that began the study with SBP levels above 140 mmHg (143, 144 and 148 mmHg) had a major reduction in SBP (~15 mmHg) after the WBV protocol. This find is similar to other studies [31,44,47], in which greater reductions in BP can be achieved in individuals who begin the WBV exercise with higher BP. Further studies are needed to confirm this suggestion.
Considering that the local vascular resistance was modulated by the high production of metabolites after several muscle contractions during physical exercise [48], chronic reductions in BP after WBV have been attributed to arterial vasodilation in the exercised limbs [31,44]. In the present study, reductions in SBP and MBP would be elicited by means of WBV without voluntary contraction of the musculature, due to the position of the individuals on the VP (sitting in an ancillary chair in front of the VP with the feet supported on its base). This decrease is compatible with another study that showed a decrease in SBP (−12 mmHg) and MBP (−9 mmHg) after WBV in obese postmenopausal women [44]. Despite this study not showing any significant changes in DBP, Manimmanakorn et al. reported that 12 weeks of WBV improved resting DBP pressure in type II diabetic patients [49]. Beijer et al. compared a resistance exercise with and without vibration performed by healthy males during 6 weeks of intervention. They found a positive effect of vibratory stimulus in decreasing DBP [50]. No modification in the antihypertensive treatment was detected in both groups during the study.

Association between Hypertension and Knee Osteoarthritis
Some symptoms of KOA may be related to hypertension; these include pain [51,52], physical inactivity [53] and inflammatory factor [54,55]. Furthermore, the use of some analgesics can affect BP and can interfere in the effects of antihypertensive therapy [56]. Authors have shown that WBV exercise might produce several benefits on the management of individuals with KOA such as a decrease in pain levels [29,57,58], improvement of functional capacity [29,[57][58][59] and the concentration of inflammatory biomarkers [58]. Wang et al. found a decrease in the level of pain, joint stiffness (knee) and an improvement of functional capacity in individuals with KOA after 12 weeks of WBV [29]. Zafar et al. showed in a systematic review and meta-analysis that WBV reduces the level of pain and improves the functional capacity in individuals with KOA [57]. Similarly, Wang et al. showed that WBV programs of 8 and 12 weeks were beneficial for improving functional capacity in the same population; it is suggested that WBV could be included in rehabilitation programs [59]. Simão et al. suggested that 12 weeks of WBV would improve the self-perception of pain level, functional capacity (balance and gait quality) and inflammatory markers (reductions in the concentrations of soluble tumor necrosis factor receptor -sTNFR1 and sTNFR2) in elderly subjects with KOA [58]. These studies could justify our findings about the BP reduction in this population after a WBV program.
In addition, symptoms related to KOA can impair the maintenance of squat positioning which is usually performed in studies with hypertensive patients without KOA [26,31,32,43,44,46,47]. The current work uses a protocol in which the KOA individuals are exposed to WBV exercise in a comfortable and safe position [39][40][41][42]. The seated position in an ancillary chair allows patients to perform the WBV protocol without increasing the load on their knee joints. Naturally, it is relevant to highlight that this positioning could benefit other hypertensive individuals who have other clinical limitations, such as obesity, wheelchair use or diseases that prevent the squat posture. Further studies using the same protocol with hypertensive individuals without KOA but with other physical disabilities are suggested.

Possible Mechanisms of the Whole-Body Vibration to Reduce Blood Pressure
Considering the WBV intervention, BP reductions could be associated with vasodilation of the muscular arteries [60]. Some authors have shown WBV to acutely improve arterial function such as leg's skin blood flow in healthy persons [60][61][62]. Additionally, these studies indicated that vibratory stimulus could produce local vasodilation of peripheral arteries, decreasing the BP and reducing cardiovascular strain. Indeed, it has been shown that WBV intervention increases blood flow [63] and decreases arterial stiffness [60] as well as wave reflection [62] in the exposed limbs.
The same mechanisms that cause vascular improvements through vasodilation might justify declines in resting BP after our WBV intervention. Another possibility for the significant BP reduction after WBV intervention would be the increase in concentration of nitric oxide (NO) and endothelial NO synthase activity [46,63]. Furthermore to NO, the reduction of endothelin-1 (a vasoconstrictor) could be another endothelial factor involved with vasodilatory response to vibratory stimulus [64]. Another potential mechanism may be an improvement in autonomic nervous system activity. Joyner et al. [65] reported that the autonomic nervous system and its sympathetic pathway performs a great function in BP regulation. Furthermore, decreased parasympathetic and increased sympathetic activities modify sympathovagal balance and it would be the main mechanism to establish hypertension and pre-hypertension [66]. Previous research reported concomitant decreases in both resting BP and sympathovagal balance after WBV intervention in overweight/obese women [26,47].

Limitations of Study
Some limitations of this work include that there was no separate osteoarthritis classification by Ahlbäck criteria. Moreover, vasoactive substances and sympathetic activity were not measured, which would have helped in the explanation of the current findings. We also did not control for some covariates, like Na+ intake, K+ intake, serum Na+, K+ levels, diuresis, sleep, and daily physical activity and this may interfere in some responses to the investigation.

Strength of Study
The strength of this work is that it shows the effectiveness of a non-pharmacological and low-cost intervention for the treatment of hypertensive individuals with KOA. It offers a more sustainable treatment option, as this population could reduce the consumption of medications, reducing adverse/side effects, improving not only health but helping to preserve the environment (Green Toxicology) [23].

Conclusions
The current study showed that WBV exercise was able to produce antihypertensive effect on SBP and MBP in medicated hypertensive KOA individuals. Thus, WBV exercise might be considered a sustainable tool to decrease BP. Of importance, no participant increased the use of medications or left the research due to BP related issues during the interventions. This suggests that further research should be carried out to investigate the association between the use of WBV intervention and the reduction of the consumption of antihypertensive medications.