Impact of whole-body vibration exercise on physical performance and bone turnover in patients with monoclonal gammopathy of undetermined significance.

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Introduction

Monoclonal gammopathy of undetermined significance (MGUS) and the clinically more advanced smoldering myeloma are confirmed precursors of symptomatic multiple myeloma (MM) [1] . Both conditions are characterized by increased production of complete or incomplete monoclonal immunoglobulins and an increased plasma cell fraction in the bone marrow. Clinical symptoms such as hypercalcemia, renal insufficiency, anemia or osteolytic lesions indicate the progression to symptomatic MM [2] .

There is growing evidence that compromised structure, quality and metabolism of bone along with an increased fracture risk already occur in MGUS patients [3] , [4] , [5] , [6] , while reductions in bone mineral density are not unequivocally confirmed [7] . Accordingly, a comparative high-resolution peripheral quantitative computed tomography analysis revealed that MGUS patients exhibit altered trabecular microarchitecture, reduced trabecular and cortical thickness with increased endocortical area and cortically reduced volumetric bone mineral density [8] . Data of this investigation showed impaired bone formation accompanied by increased serum levels of the osteoblast inhibitor Dickkopf-1 (DKK-1) in MGUS patients [8] . Finite element analysis confirmed increased cortical porosity and a lower apparent modulus indicating reduced bone strength in MGUS patients [9] . Tibial and radial assessments in a current high-resolution peripheral quantitative computed tomography study revealed predominantly trabecular abnormalities in this condition [10] .

In case of progression to symptomatic MM, myeloma bone disease frequently occurs with lytic lesions and osteopenia due to increased resorptive osteoclast activity and suppressed osteoblast function [11] . Even though the underlying pathophysiology governing bone turnover in myeloma bone disease is not completely understood, established indicators include a high biologic activity of the receptor activator of nuclear factor-kappa B (RANK) pathway triggering osteoclast activity and recent data suggest a correlation between high levels of RANK ligand and an elevated RANK ligand and osteoprotegerin ratio with an increased risk of progression from MGUS to MM [12] . Concomitantly, increased expression of WNT signaling inhibitors such as secreted frizzled-related protein 3, sclerostin and DKK-1 is considered key to compromised bone formation and regeneration in myeloma bone disease. While only minor sclerostin expression is detected in primary MM cells from patients or MM cell lines, osteocytes seem to be the primary source for sclerostin in myeloma bone disease [11] , [13] . Conversely, substantially increased expression of DKK-1 by MM cells was demonstrated in MM patients and DKK-1 levels appear to correlate with the extent of bone disease [14] , [15] . In addition, DKK-1 apparently upregulates sclerostin expression by osteogenic precursors and osteocytes [16] . DKK-1 is therefore considered a MM cell-derived mediator of compromised bone remodeling in MM and potentially in MGUS [17] .

Patients newly diagnosed with MM report reduced physical function and quality of life already before initiation of treatment [18] . Exercise interventions enhance physical fitness in patients with malignant disorders and multiple organizations have issued exercise recommendations for patients living with cancer [19] , [20] . However, results are inconclusive, particularly regarding direct associations of distinct treatment objectives with defined types of activity, intensity, duration and frequency [19] , [20] . Unfortunately, evidence confirming direct exercise-induced bone health is scarce [21] , [22] , [23] , [24] , [25] , [26] . Inconsistent findings may result from insufficient application of exercise training principles, particularly the principles of specificity, progression and overload [27] , [28] . In this regard, a recent review on exercise interventions in patients with MM reports inconclusive effectiveness because of weak methodology [29] .

Whole-body vibration exercise (WBV) is an effective means of providing specific exercise intervention for patients not amenable to conventional neuromuscular exercise due to health issues, injury risk, time or motivational constraints and lacking exercise experience [30] . To ensure the quality of reporting WBV treatment trials biomechanical parameters such as frequency, peak-to-peak displacement or periodicity of the sessions have been defined [31] , [32] . Many findings confirm safety and feasibility as well as efficacy of low-magnitude high-frequency WBV for improving physical performance in healthy subjects as well as in adult patients with chronic diseases, chemotherapy-induced peripheral neuropathy as well as pediatric cancer patients [33] , [34] , [35] , [36] , [37] , [38] , [39] , [40] . More recently, favorable effects of WBV on quality of life, physical functioning, and fatigue were evidenced in patients with hematological malignancies [41] , [42] . Beyond the well-established neuromuscular adaption, further evidence implies positive responses of WBV on bone metabolism and bone mineral density in patients with osteoporosis [43] , [44] . Whether these alterations of bone structure and metabolism in osteoporotic patients are mainly caused by enhanced muscular function or rather a direct vibration-induced bone response through e.g. fluid-flow or sheer stress onto osteocytes warrants investigation.

Recent in-vitro studies suggest that mechanical stimulation ameliorates the inhibitory effect of the MM microenvironment on osteocyte growth and a previous animal model confirmed that low intensity vibration protects bone quantity and quality and mitigates progression in a murine model of MM [45] , [46] . In wistar rats mechanical vibration increases bone density dependent of the vibration stimulus frequencies [47] . Consequently, it can be speculated that WBV might be a promising stimulus to enhance physical performance and bone quality in patients with MM and its precursor condition MGUS, thereby improving quality of life, reducing fracture risk and potentially reinforcing resilience of the bone against osteolytic action. The aim of this study was the use of WBV exercise in patients with MGUS to investigate whether WBV improves physical performance of the lower extremities and elicits an adaptive response of bone turnover and consecutive adjustments of tibial bone structures.

Patients and methods

Study design and participants

To answer the research question a prospective, non-randomized, one-arm, single-center exploratory exercise intervention study was applied. The study duration for each participant lasted at least three months with an optional three months extension. All participants were recruited at regular follow-up consultations for their precursor condition. Key selection criteria were an age of ≥ 18 years with a pre-established diagnosis of MGUS or smoldering myeloma with no contraindications to WBV exercise (Supplement 1). For sample size calculation an average increase in bone density by vibration stimulation of 1% within three to six months was estimated. Based on study data on bone strength in tibia of postmenopausal women [48] , we assumed a standard deviation of the relative change in bone density of 1.25%. Based on these assumptions, fifteen patients in a one-group design were calculated to be required to significantly represent the increase in bone density with 80% power on a 0.05 significance level. All participants provided written informed consent before any study-related procedures. The investigation was conducted in accordance with the Declaration of Helsinki, and the protocol was approved by the Ethics Committee of the University of Würzburg (No. 178/17) and registered with the German Clinical Trial Register (DRKS 00014792).

Assessments

A comprehensive evaluation including physical performance testing, bone density measurements by tibial peripheral quantitative computed tomography and laboratory analyses took place at baseline, after three and six months. Bone structure and quality of the left distal tibia was assessed with an XCT 2000 bone scanner (Stratec Medizintechnik, Pforzheim, Germany). A technician performed a 30 mm planar scout view of the talocrural joint (at a speed of 30 mm/s) and placed a reference line at the tibial endplate. Images were obtained at 4, 14 and 38% of distal tibial length. Voxel size was 0.5 mm, slice thickness was 2.5 mm. The readout parameters included: total volumetric bone mineral density (mg/cm 3 , at 4% of distal tibial length), trabecular bone mineral density (mg/cm 3 , at 4% of distal tibial length), cortical bone mineral density (mg/cm 3 , at 14% of distal tibial length), cortical cross-sectional area (mm 2 , at 14% of distal tibial length) and proportional cortical area (%, at 38% of distal tibial length).

A certified, automated clinical routine laboratory analyzer assessed the following blood variables: blood count, creatinine, calcium, immunoglobulin levels, light-chains (kappa and lambda) levels, M−Gradient of the specific immunoglobulins, alkaline phosphatase, N-terminal telopeptide of collagen type 1, osteocalcin, procollagen I N-terminal propeptide, tartrate resistant acid phosphatase 5b. DKK-1, sclerostin, bone-specific alkaline phosphatase, and myostatin were assessed by an external supplier (Immundiagnostik AG, Bensheim, Germany).

Assessment of physical performance involved the 6-minute walk test, handgrip strength in a seated position and the elbow flexed at 90 degrees employing a dynamometer (DynEx1, Akern srl, Florence, Italy), the short physical performance battery including chair rise test, usual gait speed and static balance [49] , timed up and go test and single-two leg jump performance (Leonardo, Novotec Medical, Pforzheim, Germany). Anthropometric evaluation comprised of body height and mass as well as the skeletal muscle index (skeletal muscle mass by height squared, kg/m 2 ) calculated from bioelectrical impedance analysis data (BIA 101 Anniversary, Akern srl, Florence, Italy) [50] .

Intervention

The intervention lasted three months with an optional extension of another three months. The 30-min training sessions were guided and scheduled twice per week with two participants exercising at the same time. All WBV exercises were predefined and performed on the side-alternating vibration platform (Galileo, Novotec Medical GmbH, Pforzheim/ Germany). The progression of intensity included increasing WBV frequency, amplitude with progressive difficulty of specific types of exercises. Details are provided in the supplements (Supplement 2). Briefly, the parameters used in this investigation were as follows: (1) frequency: 7–30 Hz, (2) amplitude 1.5–3 mm, and (3) exercise duration ranging from 30 to 180 sec. Adverse events such as muscle weakness, pain and fatigue were closely monitored.

Statistical analysis

Descriptive statistical analysis included absolute frequencies and corresponding proportions, and median analyses. Due to the small sample size with non-normal distribution of data, pairwise comparisons were employed with Wilcoxon signed-rank test. *P < 0.05 and **P < 0.01 were considered as significant. If not indicated otherwise, analyses are based on a per-protocol analysis. All statistical analyses were performed with SPSS version 25 statistical software package (SPSS Inc. Chicago IL) and all graphs with GraphPad PRISM Version 8.

Results

Details on recruitment are provided in the consolidated standards of reporting trials scheme ( Fig. 1 ). Fifteen participants (9 females) with a median age of 62.0 years (range 47–73) commenced the intervention program. Three patients were diagnosed with smoldering myeloma, twelve had MGUS. Baseline characteristics are summarized in Table 1 . The adherence to training sessions of the fifteen participants in the first three months ranged from 83 to 100% (mean 96%). While fifteen participants completed only three months of exercise, ten volunteered to extend the intervention for three months. Adherence to training sessions of the ten participants in the extension period was on average 97% (range 96–100%). All participants also including those who quit the guided exercise sessions after three months attended both the three- and six-month assessment. The six-month outcome data of the five patients who stopped the exercise intervention after three months were inhomogeneous due to some patients continuing various individual exercise programs and others ceasing completely. Since the results cannot be interpreted reliably their data were excluded here. None of the participants cancelled their involvement prematurely and no intervention-associated adverse events were observed. Fig. 1 Flow-chart of the patient recruitment process and follow-up. Table 1 Baseline characteristics of the participants. Variable Median (interquartile range) Minimum Maximum Age [y] 62.0 (13.0) 47.0 73.0 Height [cm] 165.0 (11.0) 158.0 180.0 Body mass [kg] 75.4 (17.1) 59.4 119.0 Bone mass index [kg/m 2 ] 26.4 (8.5) 23.0 37.0 Skeletal muscle index [kg/m 2 ] 9.3 (2.5) 6.5 11.3 Minimum: lowest value; Maximum: highest value.

Physical performance

Key variables related to physical performance improved with the WBV exercise intervention. Specifically, median distance covered in the 6-minute walk test increased progressively from 555 m to 582 m (p = 0.009) and 661.5 m (p = 0.005) after three and six months, respectively ( Table 2 ; Fig. 2 ). Chair rise test (p = 0.006 and p = 0.007) and timed up and go (p = 0.002 and p = 0.009) also improved after three and six months. Handgrip strength increased from 32.9 kg to 34.4 kg (p = 0.3) and 36.6 kg (p = 0.032) after three and six months. The short physical performance battery reflecting a comprehensive analysis of three individual tests (static balance; usual gait speed; chair rise test) also improved over time (data not shown). Table 2 Parameters of physical assessment at baseline, three and six months of WBV (Median (interquartile range)). Variable Baseline 3 Months Change in % p -Value Baseline 6 Months Change in % p -Value Number of participants 15 15 10 10 Handgrip Strength [kg] 32.9 (11.4) 34.4 (10.8) 4.6 0.300 33.9 (12.2) 36.6 (7.0) 8.0 0.032* Gait Speed [m/s] 1.5 (0.2) 1.5 (0.2) 0 0.041* 1.5 (0.2) 1.5 (0.2) 0 0.483 Time in chair rise test [s] 8.7 (2.3) 6.8 (1.9) −21.8 0.006** 8.6 2.7) 6.6 (2.5) –23.3 0.007** Time for timed up and go [s] 7.1 (1.3) 5.8 (1.5) −18.3 0.002** 6.7 (1.0) 5.7 (0.7) −14.9 0.009** Distance in 6-minute walk [m] 555.0 (84.0) 582.0 (1 2 8) 4.8 0.009** 565 (89.5) 661.5 (1.3) 17.1 0.005** Fig. 2 Distance covered during the 6-minute walk test (median, interquartile range) at baseline and after three (circles) and six (triangles) months of WBV exercise for each participant.

Peripheral quantitative computed tomography measures

No statistical difference between time points was observed for total bone mineral density (p = 0.221 and p = 0.441 after three and six months; Table 3a ). Trabecular and cortical bone mineral density also showed no significant changes over time ( Table 3a ). Cortical area decreased after six months in the ten subjects participating in the extension period (p = 0.022; Table 3a ). An additional sub-group analysis revealed that in the more homogeneous cohort of female participants (n = 9) total bone mineral density continuously increased over time ( Table 3b ) with an increase of cortical bone mineral density after three months (p = 0.038). Table 3a Parameters of peripheral quantitative computed tomography at baseline, three and six months of WBV (Median (interquartile range)). Variable Baseline 3 Months Change in % p -Value Baseline 6 Months Change in % p -Value Number of participants 15 15 10 10 Total bone mineral density [mg/cm 3 ] 428.9 (118.9) 443.0 (113.5) 3.3 0.221 423.1 (126.1) 444.1 (80.8) 5.0 0.441 Trabecular bone mineral density [mg/cm 3 ] 107.2 (40.0) 105.7 (49.6) −1.4 0.279 119.0 (44.4) 110.6 (68.8) −7.1 1.000 Cortical bone mineral density [mg/cm 3 ] 1151.1 (58.2) 1157.8 (57.2) 0.6 0.118 1154.9 (34.4) 1154.0 (28.1) 0 0.721 Cortical cross-sectional area [mm 2 ] 267.8 (101.9) 265.8 (101.5) −0.8 0.950 273.4 (104.3) 269.3 (92.4) −1.5 0.022* Proportional cortical area [%] 35.2 (13.2) 35.5 (13.8) 0.9 0.112 35.0 (14.1) 33.6 (12.2) −4 0.169 Table 3b Parameters of peripheral quantitative computed tomography at baseline, three and six months of WBV for all female subjects (Median (interquartile range)). Variable Baseline 3 Months Change in % p -Value Baseline 6 Months Change in % p -Value Number of participants 9 9 5 5 Total bone mineral density [mg/cm 3 ] 415.3 (83.2) 428.1 (91.8) 3.0 0.093 415.3 ## (48.6) 444.1 ## (59.2) 6.9 0.465 ## Trabecular bone mineral density [mg/cm 3 ] 102.2 ### (27.6) 98.7 ### (33.2) −3.4 0.063 ### 112.0 #### 99.2 #### (92.6) −11.4 0.109 #### Cortical bone mineral density [mg/cm 3 ] 1151.1 (78.0) 1157.8 (80.4) 0.6 0.038* 1151.1 (33.5) 1172.3 (36.8) 1.8 0.138 Cortical cross-sectional area [mm 2 ] 218.8 (86.0) 218.8 (57.1) 0 0.326 218.8 (56.6) 213.5 (49) −2.4 0.225 Proportional cortical area [%] 34.7 (8.5) 32.9 (12.88) −5.2 0.110 34.7 (11.5) 32.8 (6.7) −5.5 0.500 # n = 8; ## n = 4; ### n = 7; #### n = 3.

Parameters of bone turnover and blood chemistry

Regarding bone turnover a decrease of total alkaline phosphatase was detected after three and six months of WBV (-15.2% and −13.8%; p = 0.048; p = 0.016, Table 4 ). Bone-specific alkaline phosphatase (−16.9% and −13.9%; p = 0.088; 0.721), procollagen I N-terminal propeptide (−8.4% and −13.2%; p = 0.100; p = 0.074) and osteocalcin (−11.4% and −11.9%; p = 0.345; p = 0.407) decreased not significantly over time. Tartrate resistant acid phosphatase 5b increased initially at three months and returned towards baseline levels at six months (40.7% and 15.1%; p = 0.096; p = 0.953). Levels of DKK-1 declined by 13.3% after six months of WBV (p = 0.093, Fig. 3 ) while DKK-1 levels reversed towards baseline levels in the participants quitting WBV exercise after three months (data not shown). In parallel, there was an increase in sclerostin levels by 2.6% over the six months timespan (p = 0.093, Fig. 3 ). Myostatin levels did not change over the course of the study (p = 0.865; p = 0.445 at three and six months). Further markers including calcium, creatinine, hemoglobin and M−protein levels revealed only minor changes over time with no consistent trend ( Table 4 ). Table 4 Blood chemistry at baseline, 3 and 6 months of WBV (Median (interquartile range)). Variable Baseline 3 Months Change in % p -Value Baseline 6 Months Change in % p -Value Number of participants 15 15 10 10 Alkaline phosphatase [U/l] 79.00 (27.5) 67.00 (25.0) −15.2 0.048* 79.50 (39.0) 68.50 (24.8) −13.8 0.016* Bone-specific alkaline phosphatase [U/l] 16.48 (9.0) 13.78 (8.6) −16.9 0.088 16.18 (8.8) 13.93 (8.0) −13.9 0.721 Osteocalcin [ng/ml] 13.10 (13.7) 11.60 (10.0) −11.4 0.345 11.75 (16.7) 10.35 (6.1) −11.9 0.407 Procollagen I N-terminal propeptide [µg/l] 45.50 (42.7) 41.70 (44.8) −8.4 0.100 44.50 (41.1) 38.60 (21.3) −13.2 0.074 Tartrate resistant acid phosphatase 5b [U/l] 1.62 (1.1) 2.28 (1.7) 40.7 0.096 1.72 1.24 1.98 (1.1) 15.1 0.953 DKK-1 [pmol/l] 55.19 (29.0) 51.28 (37.0) −7.1 0.156 50.48 (33.9) 43.76 (31.4) −13.3 0.093 Sclerostin [pmol/l] 42.70 (13.3) 45.46 (21.0) 6.5 0.125 45.28 (27.1) 46.46 (18.0) 2.6 0.093 Myostatin [ng/ml] 37.55 (12.0) 35.79 (6.8) −4.7 0.865 36.40 (12.7) 38.07 (9.2) 4.6 0.445 Calcium [mmol/l] 2.31 (0.3) 2.32 (0.1) 0.9 0.330 2.29 (0.2) 2.22 (0.2) −3.1 0.241 N-terminal telopeptide of collagen type 1 [nM BCE/l] 9.10 (6.4) 10.60 (3.1) 16.4 0.201 8.45 (7.0) 7.75 (6.4) −8.3 0.919 M−gradient [g/l] 5.3 (5.7) 4.5 (6.5) −15.1 0.507 4.1 (4.6) 4.8 (5.8) 17.1 0.178 Hemoglobin [g/dl] 13.8 (1.5) 13.7 (1.6) 0 0.527 13.7 (1.9) 13.3 (2.4) −0.03 0.046* Creatinine [mg/dl] 0.9 (0.3) 0.9 (0.4) 0 0.432 0.9 (0.4) 1.0 (0.4) 11 0.038* Fig. 3 Serum levels of DKK-1 and sclerostin (median, interquartile range) at baseline and after three and six months of WBV for each participant (circles, triangles).

Discussion

We hypothesized that WBV exercise improves physical performance and bone turnover in patients with MGUS. To the best of our knowledge, this is the first exploratory study to investigate the effects of WBV exercise on sclerostin, DKK-1 and on bone mineral density in patients with MGUS. Over the time course of three to six months, peripheral quantitative computed tomography data indicates overall favorable adaptions specifically in total bone mineral density and cortical bone mineral density for the females, along with a reversal of transiently increased levels of tartrate resistant acid phosphatase 5b and N-terminal telopeptide of collagen type 1. Overall trabecular bone mineral density evidenced by peripheral quantitative computed tomography in connection with three- and six-months WBV remained statistically unaltered over the time course. This finding appears to be in line with current literature, reporting no structural adaptations of the tibial bone detectable by peripheral quantitative computed tomography in connection with WBV after three, six months and even after twelve months in osteoporotic individuals [51] , [52] . However, the external WBV-induced load, i.e. amount of WBV sessions per week, session duration, and intensity in previous studies may have been insufficient to induce structural bone adaptation since the participants of these studies did not show any functional improvement [51] , [52] . The progressive increase of total bone mineral density of 3.3% ( Table 3a ) observed along with the significant functional improvements in our investigation may imply a beneficial bone and functional response of our patients to WBV. Further studies with larger sample size and greater exercise stimulus, i.e. more and/or longer sessions per week or increased exercise intensity are warranted to verify this conclusion. A progressive increase in total bone mineral density was observed in the more homogeneous subgroup of female participants, also during the extension period of the intervention. More specifically, in the females, the cortical bone mineral density after three months increased significantly along with a non-significant decrease of the trabecular bone mineral density. In summary, these data may indicate a sufficient mechanical load by the WBV exposure to induce adaptive responses in a generally smaller and thinner female compared to male tibia. Accordingly, further large-scale studies need to investigate the influence of WBV-induced load in male patients.

Analysis of bone biomarkers support the finding of a WBV-induced adaptive response of the bone, revealing an increase in both tartrate resistant acid phosphatase 5b as a marker for osteoclast number as well as an transient increase in N-terminal telopeptide of collagen type 1 indicating enhanced bone resorptive activity, potentially matching the decline in trabecular bone mineral density and cortical cross-sectional area, with both markers returning towards baseline levels after six months. Conversely, alkaline phosphatase and bone alkaline phosphatase as well as osteocalcin and procollagen I N-terminal propeptide decreased after three months of WBV. In summary, the combination of reduced bone forming activity together with increased resorption actually would reflect a state of reduced WNT signaling in bone cells [53] . In line with this observation we detected an increase in sclerostin levels after three months. While literature regarding sclerostin expression with WBV intervention seems inconsistent with either decreased or unaltered levels, an increase has not been reported so far [51] , [54] . One explanation for the increased sclerostin expression might be the finding of an inverse decrease in DKK-1 levels, supposed to correlate with the extent of bone disease in MM patients [15] .

Both Sclerostin and DKK-1 are secreted WNT antagonists. DKK-1 binds a larger region on the receptors’ extracellular surface compared to sclerostin and blocks additional classes of WNT proteins [55] . Even though Sclerostin and DKK-1 are perceived as having somewhat redundant functions in WNT inhibition, the bone forming potential of DKK-1 inhibition appears limited [56] compared to the more effective sclerostin inhibition [57] . Furthermore, the sources of both factors are different in myeloma and its precursor conditions. While sclerostin is preferentially secreted by osteocytes, DKK-1 may preferentially stem from plasma cells in the bone marrow microenvironment [11] , [13] , [58] . Divergent developments of DKK-1 and sclerostin levels have been observed before and are commonly considered a consequence of compensatory regulation [55] . It has been demonstrated that sclerostin inhibition or deficiency of the SOST gene encoding sclerostin lead to a compensatory increase in DKK-1 [55] , since DKK-1 is a direct transcriptional target of the beta-catenin downstream WNT signaling [59] . Accordingly, it is tempting to speculate that DKK-1 engenders an increase in sclerostin. There is data suggesting that DKK-1 may stimulate SOST mRNA and sclerostin protein expression in myeloma bone disease [16] . Vice versa an increase in sclerostin may trigger a decrease in DKK-1. WBV exercise may cause an increase in sclerostin, potentially liberated from apoptotic osteocytes. As a result, WBV may trigger an initial response of preferentially trabecular bone resorption and reduced formation by inhibiting osteoblastic WNT signaling. This may get along with a preferentially cortical adaption and condensation leading to increased cortical and total bone mineral density. WBV-induced increase in sclerostin may elicit an inhibiting effect on myeloma cells, reflected in the observed decrease in plasma cell-derived DKK-1, analogously to what has been reported for a successful MM treatment response [17] .

The present work focused on investigating participants with the precursor conditions MGUS and smoldering myeloma to avoid a potential MM treatment-associated bias and to reduce the risk of intervention-related adverse events. WBV as intervention was selected for this type of patients because i) available data confirms this type of exercise to be safe [33] , ii) WBV is time efficient, iii) WBV allows employing established principles of exercise intervention in untrained elderly patients [27] and iv) evidence reveals that WBV vibration is a potent stimulus to induce favorable changes in bone metabolism and architecture [43] . There is clear evidence that exercise intervention and specifically WBV elicit improvements in neuro-muscular performance [35] , [41] . Accordingly, the comprehensive assessment of physical performance in the present investigation was an integral part of the outcome measures [60] . The plantar-induced vibration exercise (2x/week) improved functional tasks assessed by 6-minute walk test, chair rise test and timed up and go which largely depend on leg muscle strength and endurance. From this perspective it is not astonishing that handgrip strength exhibited only minor improvements [27] . Interestingly while endurance performance (6-minute walk test) improved progressively over six months, improvements in chair rise test and timed up and go associated with maximum power plateaued after three months. In general, improvements in muscle strength at the beginning of a period of strength training are considered to be more functional than morphological [61] and the present findings suggest that the extent of progression and overload could have been more pronounced during the second part of the intervention.

The strength of the current work is the first demonstration of the highly significant improvement of physical performance in patients with MGUS and a trend in favorable bone turnover markers in female participants after six months of WBV.

Conclusions

This prospective, non-randomized single-center exploratory study involving progressive WBV exercise (2x/week for three months) improves variables related to muscle strength and endurance and seems to induce favorable bone turnover in the MM precursor conditions MGUS and smoldering myeloma. Further studies are warranted to specify the effect of WBV on bone turnover, bone mineral density and bone structure in myeloma bone disease.

Limitations

The limitations of the present setup include the overall small number of participants, the lack of a control group and a relevant intra-cohort heterogeneity. However, the small number of participants allowed to accurately control duration and intensity and execution of each movement during WBV exposure. Individual motivational problems commonly associated with exercise intervention studies were overcome by providing an attractive and guided exercise intervention reflected by the high adherence to training sessions (96–100%). Motivational factors may have been apparent during enrollment. Even though the present exercise intervention did not require previous exercise experience nor athletic ambitions, 26 out of 42 patients (62%) declined to participate. However, all participating individuals adhered for at least three months and two-third even completed a voluntary three-month extension period. The five subjects who quite after three months did so because of time constraints commuting to the exercise facility twice weekly.

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

References

1 Landgren O. Kyle R.A. Pfeiffer R.M. Katzmann J.A. Caporaso N.E. Hayes R.B. Dispenzieri A. Kumar S. Clark R.J. Baris D. Hoover R. Rajkumar S.V. Monoclonal gammopathy of undetermined significance (MGUS) consistently precedes multiple myeloma: a prospective study Blood 113 22 2009 5412 5417 19179464 10.1182/blood-2008-12-194241 PMC2689042

2 Rajkumar S.V. Dimopoulos M.A. Palumbo A. Blade J. Merlini G. Mateos M.V. Kumar S. Hillengass J. Kastritis E. Richardson P. Landgren O. Paiva B. Dispenzieri A. Weiss B. LeLeu X. Zweegman S. Lonial S. Rosinol L. Zamagni E. Jagannath S. Sezer O. Kristinsson S.Y. Caers J. Usmani S.Z. Lahuerta J.J. Johnsen H.E. Beksac M. Cavo M. Goldschmidt H. Terpos E. Kyle R.A. Anderson K.C. Durie B.G. Miguel J.F. International Myeloma Working Group updated criteria for the diagnosis of multiple myeloma Lancet Oncol. 15 12 2014 e538 e548 25439696 10.1016/S1470-2045(14)70442-5

3 Kristinsson S.Y. Tang M. Pfeiffer R.M. Bjorkholm M. Blimark C. Mellqvist U.H. Wahlin A. Turesson I. Landgren O. Monoclonal gammopathy of undetermined significance and risk of skeletal fractures: a population-based study Blood 116 15 2010 2651 2655 20610813 10.1182/blood-2010-04-282848 PMC3324256

4 Melton L.J. 3rd Rajkumar S.V. Khosla S. Achenbach S.J. Oberg A.L. Kyle R.A. Fracture risk in monoclonal gammopathy of undetermined significance J. Bone Miner. Res. 19 1 2004 25 30 14753733 10.1359/JBMR.0301212

5 Thorsteinsdottir S. Lund S.H. Lindqvist E.K. Thordardottir M. Sigurdsson G. Costello R. Burton D. Steingrimsdottir H. Gudnason V. Eiriksdottir G. Siggeirsdottir K. Harris T.B. Landgren O. Kristinsson S.Y. Bone disease in monoclonal gammopathy of undetermined significance: results from a screened population-based study Blood Adv. 1 27 2017 2790 2798 29296931 10.1182/bloodadvances.2017010454 PMC5745135

6 Drake M.T. unveiling skeletal fragility in patients diagnosed with MGUS: no longer a condition of undetermined significance? J. Bone Miner. Res. 29 12 2014 2529 2533 25319751 10.1002/jbmr.2387 PMC4268401

7 Veronese N. Luchini C. Solmi M. Sergi G. Manzato E. Stubbs B. Monoclonal gammopathy of undetermined significance and bone health outcomes: a systematic review and exploratory meta-analysis J. Bone Miner. Metab. 36 1 2018 128 132 28243796 10.1007/s00774-017-0817-8

8 Ng A.C. Khosla S. Charatcharoenwitthaya N. Kumar S.K. Achenbach S.J. Holets M.F. McCready L.K. Melton L.J. III Kyle R.A. Rajkumar S.V. Drake M.T. Bone microstructural changes revealed by high-resolution peripheral quantitative computed tomography imaging and elevated DKK1 and MIP-1α levels in patients with MGUS Blood 118 25 2011 6529 6534 22042700 10.1182/blood-2011-04-351437 PMC3242716

9 Farr J.N. Zhang W. Kumar S.K. Jacques R.M. Ng A.C. McCready L.K. Rajkumar S.V. Drake M.T. Altered cortical microarchitecture in patients with monoclonal gammopathy of undetermined significance Blood 123 5 2014 647 649 24227822 10.1182/blood-2013-05-505776 PMC3907752

10 Stein E.M. Dash A. Bucovsky M. Agarwal S. Fu J. Lentzsch S. Shane E. Disrupted radial and tibial microarchitecture in patients with monoclonal gammopathy of undetermined significance Osteoporos. Int. 30 3 2019 629 635 30488275 10.1007/s00198-018-4787-z PMC10081445

11 Terpos E. Christoulas D. Gavriatopoulou M. Biology and treatment of myeloma related bone disease Metabolism 80 2018 80 90 29175022 10.1016/j.metabol.2017.11.012

12 Lipe B. Kambhampati S. Veldhuizen P.V. Yacoub A. Aljitawi O. Mikhael J. Correlation between markers of bone metabolism and vitamin D levels in patients with monoclonal gammopathy of undetermined significance (MGUS) Blood Cancer J. 7 12 2017 646 29238066 10.1038/s41408-017-0015-x PMC5802504

13 Delgado-Calle J. Bellido T. Roodman G.D. Role of osteocytes in multiple myeloma bone disease Curr. Opin. Support Palliat. Care 8 4 2014 407 413 25289928 10.1097/SPC.0000000000000090 PMC4278961

14 Kristensen I.B. Christensen J.H. Lyng M.B. Moller M.B. Pedersen L. Rasmussen L.M. Ditzel H.J. Abildgaard N. Expression of osteoblast and osteoclast regulatory genes in the bone marrow microenvironment in multiple myeloma: only up-regulation of Wnt inhibitors SFRP3 and DKK1 is associated with lytic bone disease Leuk. Lymphoma 55 4 2014 911 919 23915193 10.3109/10428194.2013.820288

15 Kaiser M. Mieth M. Liebisch P. Oberlander R. Rademacher J. Jakob C. Kleeberg L. Fleissner C. Braendle E. Peters M. Stover D. Sezer O. Heider U. Serum concentrations of DKK-1 correlate with the extent of bone disease in patients with multiple myeloma Eur. J. Haematol. 80 6 2008 490 494 18331598 10.1111/j.1600-0609.2008.01065.x

16 Eda H. Santo L. Wein M.N. Hu D.Z. Cirstea D.D. Nemani N. Tai Y.T. Raines S.E. Kuhstoss S.A. Munshi N.C. Kronenberg H.M. Raje N.S. Regulation of Sclerostin Expression in Multiple Myeloma by Dkk-1: A Potential Therapeutic Strategy for Myeloma Bone Disease J. Bone Miner. Res. 31 6 2016 1225 1234 26763740 10.1002/jbmr.2789 PMC5002355

17 Heider U. Kaiser M. Mieth M. Lamottke B. Rademacher J. Jakob C. Braendle E. Stover D. Sezer O. Serum concentrations of DKK-1 decrease in patients with multiple myeloma responding to anti-myeloma treatment Eur. J. Haematol. 82 1 2009 31 38 19067746 10.1111/j.1600-0609.2008.01164.x

18 Larsen R.F. Jarden M. Minet L.R. Frolund U.C. Moller S. Abildgaard N. Physical function in patients newly diagnosed with multiple myeloma; a Danish cohort study BMC Cancer 20 1 2020 169 32126972 10.1186/s12885-020-6637-6 PMC7055017

19 Campbell K.L. Winters-Stone K.M. Wiskemann J. May A.M. Schwartz A.L. Courneya K.S. Zucker D.S. Matthews C.E. Ligibel J.A. Gerber L.H. Morris G.S. Patel A.V. Hue T.F. Perna F.M. Schmitz K.H. Exercise Guidelines for Cancer Survivors: Consensus Statement from International Multidisciplinary Roundtable Med. Sci. Sports Exerc. 51 11 2019 2375 2390 31626055 10.1249/MSS.0000000000002116 PMC8576825

20 Schmitz K.H. Campbell A.M. Stuiver M.M. Pinto B.M. Schwartz A.L. Morris G.S. Ligibel J.A. Cheville A. Galvão D.A. Alfano C.M. Patel A.V. Hue T. Gerber L.H. Sallis R. Gusani N.J. Stout N.L. Chan L. Flowers F. Doyle C. Helmrich S. Bain W. Sokolof J. Winters-Stone K.M. Campbell K.L. Matthews C.E. Exercise is medicine in oncology: Engaging clinicians to help patients move through cancer CA Cancer J. Clin. 69 6 2019 468 484 31617590 10.3322/caac.21579 PMC7896280

21 Swolin-Eide D. Magnusson P. Does Whole-Body Vibration Treatment Make Children's Bones Stronger? Curr Osteoporos Rep 2020 10.1007/s11914-020-00608-0 PMC7532958 32696294

22 Duran I. Martakis K. Stark C. Schafmeyer L. Rehberg M. Schoenau E. Effect of an interval rehabilitation program with home-based, vibration-assisted training on the development of muscle and bone in children with cerebral palsy - an observational study J. Pediatr. Endocrinol. Metab. 2020 10.1515/jpem-2020-0080 32653878

23 Perez-Gomez J. Adsuar J.C. Garcia-Gordillo M.A. Munoz P. Romo L. Maynar M. Gusi N. C.R. P Twelve Weeks of Whole Body Vibration Training Improve Regucalcin, Body Composition and Physical Fitness in Postmenopausal Women: A Pilot Study Int. J. Environ. Res. Public Health 17 11 2020 10.3390/ijerph17113940 PMC7312189 32498351

24 Vesey R.M. Hofman P.L. Derraik J.G. Colle P. Biggs J.B. Munns C.F. Cutfield W.S. Gusso S. Safety, feasibility and efficacy of side-alternating vibration therapy on bone and muscle health in children and adolescents with musculoskeletal disorders: A pilot trial J. Paediatr. Child Health 56 8 2020 1257 1262 32436612 10.1111/jpc.14913

25 S. Gusso, R.M. Vesey, J.G.B. Derraik, C.F. Munns, P. Colle, J.B. Biggs, P.L. Hofman, The Effects of 20 Weeks of Side-Alternating Vibration Therapy on Physical Function, Bone and Muscle Health in Adolescents with Down Syndrome, Phys Occup Ther Pediatr (2020) 1-12. 10.1080/01942638.2020.1758983 32345083

26 Marin-Puyalto J. Gomez-Cabello A. Gonzalez-Aguero A. Matute-Llorente A. Gomez-Bruton A. Jurimae J. Casajus J.A. Vicente-Rodriguez G. Effects of whole-body vibration training on bone density and turnover markers in adolescent swimmers J. Pediatr. Endocrinol. Metab. 33 5 2020 623 630 32229668 10.1515/jpem-2019-0400

27 Winters-Stone K.M. Neil S.E. Campbell K.L. Attention to principles of exercise training: a review of exercise studies for survivors of cancers other than breast Br. J. Sports Med. 48 12 2014 987 995 23293010 10.1136/bjsports-2012-091732

28 Persoon S. Chin A.M.J.M. Buffart L.M. Liu R.D.K. Wijermans P. Koene H.R. Minnema M.C. Lugtenburg P.J. Marijt E.W.A. Brug J. Nollet F. Kersten M.J. Randomized controlled trial on the effects of a supervised high intensity exercise program in patients with a hematologic malignancy treated with autologous stem cell transplantation: Results from the EXIST study PLoS ONE 12 7 2017 e0181313 10.1371/journal.pone.0181313 PMC5519072 28727771

29 Gan J.H. Sim C.Y. Santorelli L.A. The effectiveness of exercise programmes in patients with multiple myeloma: A literature review Crit. Rev. Oncol. Hematol. 98 2016 275 289 26633247 10.1016/j.critrevonc.2015.11.005

30 Kemmler W. von Stengel S. Alternative Exercise Technologies to Fight against Sarcopenia at Old Age: A Series of Studies and Review J Aging Res 2012 2012 109013 10.1155/2012/109013 PMC3303675 22500224

31 Rauch F. Sievanen H. Boonen S. Cardinale M. Degens H. Felsenberg D. Roth J. Schoenau E. Verschueren S. Rittweger J. M International Society of, I. Neuronal, Reporting whole-body vibration intervention studies: recommendations of the International Society of Musculoskeletal and Neuronal Interactions J. Musculoskelet. Neuronal Interact. 10 3 2010 193 198 20811143

32 Wuestefeld A. Fuermaier A.B.M. Bernardo-Filho M. da Cunha D. de Sa-Caputo J. Rittweger E. Schoenau C. Stark P.J. Marin A. Seixas S. Judex R. Taiar C. van der Nyakas E.A. van Zee M.J.G. Heuvelen O. Tucha Towards reporting guidelines of research using whole-body vibration as training or treatment regimen in human subjects-A Delphi consensus study PLoS ONE 15 7 2020 e0235905 10.1371/journal.pone.0235905 PMC7375612 32697809

33 Li G. Zhang G. Wang Y. Wang X. Zhou H. Li H. Chen L. The effect of whole body vibration on health-related quality of life in patients with chronic conditions: a systematic review Qual. Life Res. 28 11 2019 2859 2870 31471814 10.1007/s11136-019-02274-x

34 Seefried L. Genest F. Luksche N. Schneider M. Fazeli G. Brandl M. Bahner U. A.H. A Efficacy and safety of whole body vibration in maintenance hemodialysis patients - A pilot study J. Musculoskelet. Neuronal Interact. 17 4 2017 268 274 29199185 PMC5749032

35 Lai C.C. Tu Y.K. Wang T.G. Huang Y.T. Chien K.L. Effects of resistance training, endurance training and whole-body vibration on lean body mass, muscle strength and physical performance in older people: a systematic review and network meta-analysis Age Ageing 47 3 2018 367 373 29471456 10.1093/ageing/afy009

36 Schonsteiner S.S. Bauder Missbach H. Benner A. Mack S. Hamel T. Orth M. Landwehrmeyer B. Sussmuth S.D. Geitner C. Mayer-Steinacker R. Riester A. Prokein A. Erhardt E. Kunecki J. Eisenschink A.M. Rawer R. Dohner H. Kirchner E. Schlenk R.F. A randomized exploratory phase 2 study in patients with chemotherapy-related peripheral neuropathy evaluating whole-body vibration training as adjunct to an integrated program including massage, passive mobilization and physical exercises, Exp Hematol. Oncol. 6 2017 5 10.1186/s40164-017-0065-6 PMC5297221 28194306

37 Streckmann F. Lehmann H.C. Balke M. Schenk A. Oberste M. Heller A. Schurhorster A. Elter T. Bloch W. Baumann F.T. Sensorimotor training and whole-body vibration training have the potential to reduce motor and sensory symptoms of chemotherapy-induced peripheral neuropathy-a randomized controlled pilot trial Support. Care Cancer 27 7 2019 2471 2478 30382392 10.1007/s00520-018-4531-4

38 Rustler V. Prokop A. Baumann F.T. Streckmann F. Bloch W. Daeggelmann J. Whole-Body Vibration Training Designed to Improve Functional Impairments After Pediatric Inpatient Anticancer Therapy: A Pilot Study Pediatr Phys Ther 30 4 2018 341 349 30277971 10.1097/PEP.0000000000000536

39 H.K. Fuzari, A. Dornelas de Andrade, A.R. M, I.M. A, F.P. M, A.M. Lima, M.S. Cerqueira, P.E. Marinho, Whole body vibration improves maximum voluntary isometric contraction of knee extensors in patients with chronic kidney disease: A randomized controlled trial, Physiother Theory Pract 35(5) (2019) 409-418. 10.1080/09593985.2018.1443537 29482412

40 Guedes-Aguiar E.O. de Sa-Caputo D.D.C. Moreira-Marconi E. de Macedo Uchoa S.M. de Barros P.Z. Valentin E.K. Bergmann A. Taiar R. Bernardo-Filho M. Effect of whole-body vibration exercise in the pelvic floor muscles of healthy and unhealthy individuals: a narrative review Transl. Androl. Urol. 8 4 2019 395 404 31555564 10.21037/tau.2019.06.14 PMC6732087

41 Pahl A. Wehrle A. Kneis S. Gollhofer A. Bertz H. Whole body vibration training during allogeneic hematopoietic cell transplantation-the effects on patients' physical capacity Ann. Hematol. 99 3 2020 635 648 31970448 10.1007/s00277-020-03921-x PMC7060160

42 Pahl A. Wehrle A. Kneis S. Gollhofer A. Bertz H. Feasibility of whole body vibration during intensive chemotherapy in patients with hematological malignancies - a randomized controlled pilot study BMC Cancer 18 1 2018 920 30253746 10.1186/s12885-018-4813-8 PMC6156963

43 Sen E.I. Esmaeilzadeh S. Eskiyurt N. Effects of whole-body vibration and high impact exercises on the bone metabolism and functional mobility in postmenopausal women J. Bone Miner. Metab. 2020 10.1007/s00774-019-01072-2 31897748

44 Marin-Puyalto J. Gomez-Cabello A. Gonzalez-Aguero A. Gomez-Bruton A. Matute-Llorente A. Casajus J.A. Vicente-Rodriguez G. Is Vibration Training Good for Your Bones? An Overview of Systematic Rev., Biom. Res. Int. 2018 2018 5178284 10.1155/2018/5178284 PMC6241242 30519579

45 Pagnotti G.M. Chan M.E. Adler B.J. Shroyer K.R. Rubin J. Bain S.D. Rubin C.T. Low intensity vibration mitigates tumor progression and protects bone quantity and quality in a murine model of myeloma Bone 90 2016 69 79 27262776 10.1016/j.bone.2016.05.014 PMC4970889

46 Wang X. He Y. Tian S. Zhu F. Huang B. Zhang J. Chen Z. Wang H. Fluid Shear Stress Increases Osteocyte and Inhibits Osteoclasts via Downregulating Receptor-Activator of Nuclear Factor kappaB (RANK)/Osteoprotegerin Expression in Myeloma Microenvironment Med. Sci. Monit. 25 2019 5961 5968 31400110 10.12659/MSM.915986 PMC6699202

47 Cardoso A.L. Frederico E.H. Guimaraes C.A. Guedes-Aguiar E.O. Moreira-Marconi E. Paineiras-Domingos L.L. Sa-Caputo D.C. Bernardo-Filho M. Asad N.R. Long-term Effects of Mechanical Vibration Stimulus on the Bone Formation of Wistar Rats: An Assessment Method Based on X-rays Images Acad. Radiol. 2020 10.1016/j.acra.2020.05.035 32624402

48 Cheung A.M. Majumdar S. Brixen K. Chapurlat R. Fuerst T. Engelke K. Dardzinski B. Cabal A. Verbruggen N. Ather S. Rosenberg E. de Papp A.E. Effects of odanacatib on the radius and tibia of postmenopausal women: improvements in bone geometry, microarchitecture, and estimated bone strength J. Bone Miner. Res. 29 8 2014 1786 1794 24643905 10.1002/jbmr.2194

49 Guralnik J.M. Simonsick E.M. Ferrucci L. Glynn R.J. Berkman L.F. Blazer D.G. Scherr P.A. Wallace R.B. A short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission J. Gerontol. 49 2 1994 M85 M94 8126356 10.1093/geronj/49.2.m85

50 Janssen I. Heymsfield S.B. Baumgartner R.N. Ross R. Estimation of skeletal muscle mass by bioelectrical impedance analysis J. Appl. Physiol. 89 2 2000 465 471 10926627 10.1152/jappl.2000.89.2.465

51 Jepsen D.B. Ryg J. Hansen S. Jorgensen N.R. Gram J. Masud T. The combined effect of Parathyroid hormone (1–34) and whole-body Vibration exercise in the treatment of postmenopausal OSteoporosis (PaVOS study): a randomized controlled trial Osteoporos. Int. 30 9 2019 1827 1836 31309239 10.1007/s00198-019-05029-z PMC6717187

52 Liphardt A.M. Schipilow J. Hanley D.A. Boyd S.K. Bone quality in osteopenic postmenopausal women is not improved after 12 months of whole-body vibration training Osteoporos. Int. 26 3 2015 911 920 25567775 10.1007/s00198-014-2995-8

53 Baron R. Kneissel M. WNT signaling in bone homeostasis and disease: from human mutations to treatments Nat. Med. 19 2 2013 179 192 23389618 10.1038/nm.3074

54 Tubic B. Zeijlon R. Wennergren G. Obermayer-Pietsch B. Marild S. Dahlgren J. Magnusson P. Swolin-Eide D. Randomised study of children with obesity showed that whole body vibration reduced sclerostin Acta Paediatr. 108 3 2019 502 513 30071142 10.1111/apa.14531

55 Florio M. Gunasekaran K. Stolina M. Li X. Liu L. Tipton B. Salimi-Moosavi H. Asuncion F.J. Li C. Sun B. Tan H.L. Zhang L. Han C.Y. Case R. Duguay A.N. Grisanti M. Stevens J. Pretorius J.K. Pacheco E. Jones H. Chen Q. Soriano B.D. Wen J. Heron B. Jacobsen F.W. Brisan E. Richards W.G. Ke H.Z. Ominsky M.S. A bispecific antibody targeting sclerostin and DKK-1 promotes bone mass accrual and fracture repair Nat. Commun. 7 2016 11505 27230681 10.1038/ncomms11505 PMC4894982

56 Li X. Grisanti M. Fan W. Asuncion F.J. Tan H.L. Dwyer D. Han C.Y. Yu L. Lee J. Lee E. Barrero M. Kurimoto P. Niu Q.T. Geng Z. Winters A. Horan T. Steavenson S. Jacobsen F. Chen Q. Haldankar R. Lavallee J. Tipton B. Daris M. Sheng J. Lu H.S. Daris K. Deshpande R. Valente E.G. Salimi-Moosavi H. Kostenuik P.J. Li J. Liu M. Li C. Lacey D.L. Simonet W.S. Ke H.Z. Babij P. Stolina M. Ominsky M.S. Richards W.G. Dickkopf-1 regulates bone formation in young growing rodents and upon traumatic injury J. Bone Miner. Res. 26 11 2011 2610 2621 21773994 10.1002/jbmr.472

57 Atkinson E.G. Delgado-Calle J. The Emerging Role of Osteocytes in Cancer in Bone JBMR Plus 3 3 2019 e10186 10.1002/jbm4.10186 PMC6419608 30918922

58 Politou M.C. Heath D.J. Rahemtulla A. Szydlo R. Anagnostopoulos A. Dimopoulos M.A. Croucher P.I. Terpos E. Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation Int. J. Cancer 119 7 2006 1728 1731 16646053 10.1002/ijc.22033

59 Chamorro M.N. Schwartz D.R. Vonica A. Brivanlou A.H. Cho K.R. Varmus H.E. FGF-20 and DKK1 are transcriptional targets of beta-catenin and FGF-20 is implicated in cancer and development EMBO J. 24 1 2005 73 84 15592430 10.1038/sj.emboj.7600460 PMC544900

60 Luo X. Zhang J. Zhang C. He C. Wang P. The effect of whole-body vibration therapy on bone metabolism, motor function, and anthropometric parameters in women with postmenopausal osteoporosis Disabil. Rehabil. 39 22 2017 2315 2323 27718643 10.1080/09638288.2016.1226417

61 Cook C.J. Kilduff L.P. Beaven C.M. Improving strength and power in trained athletes with 3 weeks of occlusion training Int J Sports Physiol Perform 9 1 2014 166 172 23628627 10.1123/ijspp.2013-0018

Supplementary data

The following are the Supplementary data to this article: Supplementary data 1

Supplementary data 2

Acknowledgement

Analysis of bone turnover markers was financially supported by the 10.13039/100008308 Comprehensive Cancer Center Mainfranken Würzburg, Germany.

Supplementary data to this article can be found online at https://doi.org/10.1016/j.jbo.2020.100323 .