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

A 12-month, superiority multi-centre randomized active comparator trial (RCT) with two parallel arms investigating the effect on bone parameters of combined WBV and teriparatide treatment compared to teriparatide treatment alone was conducted from November 2015 to November 2018. All participants were treated with teriparatide due to their severe osteoporosis. It was considered unethical to include a group with no pharmacological treatment due to the high fracture risk in the population participating in the study.

All participants received subcutaneous teriparatide treatment (20 μg/day) and were all advised to take supplements with calcium and vitamin D according to current Danish osteoporosis treatment guidelines. A computer-generated web-based block-randomization scheme with block size of 4–6 with no stratification and a 1:1 allocation was used to assign eligible participants to the intervention group (WBV and teriparatide) or active comparator group (teriparatide alone). Web-based randomization was conducted after inclusion, and baseline measurements were obtained. Demographic data were collected at baseline, and T-scores were calculated using reference values from the NHANES III database for the total hip and a Hologic reference material for lumbar spine provided by the manufacturer. Technicians performing bone measurements were blinded to group allocation, but sham WBV was not utilized.

Recruitment was performed in the following five Danish outpatient clinics: the Osteoporosis Clinics at Odense University Hospital (Odense and Svendborg), the Department of Geriatrics at Odense University Hospital, the Department of Endocrinology at Hospital South West Jutland, the Department of Endocrinology at Hospital Lillebaelt and the Department of Endocrinology and Internal Medicine, Aarhus University Hospital. The inclusion criteria were as follows: postmenopausal women ≥ 50 years of age, with either one vertebral fracture within the last 3 years with > 25% reduction in vertebral height and T-score < − 3 at the lumbar spine or total hip, or at least two vertebral fractures with > 25% reduction in vertebral height, with no additional requirements for low BMD, planned to start treatment with teriparatide. Exclusion criteria were ongoing oral glucocorticoid treatment, inability to tolerate WBV for 1 min at screening or contraindications to WBV, such as the presence of pacemakers or joint replacements. All participants gave informed consent, and the study was approved by the Ethical Scientific Committee of Southern Denmark.

The WBV was conducted using Power Plate My5 (Power Plate®, UK), with a frequency of 30 Hz and amplitude of 1 mm (low displacement) and peak acceleration of 35.53 m s⁻² root-mean-square (3.6 g). The training was conducted at the participants’ own homes. The protocol and monitoring by attendance log has previously been described in detail in a protocol paper [32]. The WBV training protocol consisted of twelve minutes training with the WBV:rest ratio 1:1 min, including six minutes of vibration, three days a week with one day pause in between. The WBV protocol has previously been shown to be safe, feasible and anabolic to bone in an older population [18]. The WBV intervention was conducted with the knees slightly bent (at approximately 20°) to prevent vibrations causing side effects such as dizziness from the vibration transmitted to the head. Others have shown that 9–28% of the vibration transmit to the spine measure at L3 with flexed knees using high-magnitude WBV [33]. The training gradually progressed up to the six minutes during the first eight weeks to ensure that participants could tolerate the training. We measured adherence by calculating the percentage of total conducted vibration sessions in relation to the total sessions in the training protocol, with high adherence being defined as completing ≥ 75% of the WBV sessions. Falls were assessed with calendars, and monthly telephone contact was used to ensure adherence and to collect data on pain, dizziness, falls and adverse events.

Demographic data was obtained at baseline before randomization, and physical activity was assessed using the international physical activity questionnaire (IPAQ) with the participants reporting a full week’s physical activity.

Adherence to the teriparatide treatment was calculated as percentage of participants collected ≥ 80% of prescriptions in the twelve months using the Danish national electronic prescription database which stores data on prescriptions handled in all pharmacies in Denmark.

Areal BMD of lumbar spine (L1–L4) and the total hip was measured by dual-energy X-ray absorptiometry (DXA) (Hologic Discovery, Waltham, MA, USA) at baseline and after six and twelve months of follow-up. Trained technicians acquired and analyzed all DXA scans on the same scanner according to standard Hologic protocols and performed daily quality control procedures. The coefficient of variation (CV) of the BMD measurements at the lumbar spine and total hip was 1.5% at both sites at the research unit conducting the scans.

HR-pQCT (XtremeCT; Scanco Medical, Zurich, Switzerland) was used to obtain images of the non-dominant distal radius and tibia (or the dominant side in case of previous fracture at the desired site). The standard patient protocol for image acquisition was applied as described previously [34]. In brief, a 2D radiograph was obtained, and the scan region of interest was positioned with a 9.5 and 22.5 mm offset from the radius and tibia endplate, respectively, and extended 9.02 mm proximally. Each image comprised of 110 slices with an isotropic 82-μm voxel size. The operator immediately viewed the most distal slice for motion artefacts (e.g., blurring or cortical discontinuities), and up to two repeat acquisitions at each site were performed in case of visible motion artefacts. After reconstruction, image quality was graded by one author (DBJ) using a five-step scale as suggested by the manufacturer (1 = best, 5 = worst) and images with grade > 3 were disregarded [35]. Cortical and trabecular bone evaluation was performed using the manufacturer’s default method, where trabecular bone volume per tissue volume (BV/TV) was calculated from trabecular volumetric BMD (vBMD) assuming a mineral density of fully mineralized bone of 1.2 mg hydroxyapatite/mg³ [36]. Trabecular number (Tb·N) was extracted using a distance transformation method, whereas trabecular thickness (Tb·Th) was derived from BV/TV and Tb·N. In our unit, the CV for geometry, vBMD, and microarchitecture measures at the radius and tibia range from 0.3 to 7.0%.

Morning blood samples were collected in EDTA plasma tubes at baseline and three and six months under standardized conditions after a minimum five minutes rest from an antecubital vein after an overnight fast. The blood was rapidly centrifuged for ten minutes, and plasma was collected and frozen. For each assay, the sample aliquots were kept frozen at − 70 °C until the day of analysis. All samples were analyzed using one single batch of each assay. Assay performance was verified using the manufacturers’ control specimens. Subsequently, the plasma was analyzed for carboxy-terminal type 1 collagen crosslinks (CTX) and P1NP using Chemiluminescence (iSYS, Immunodiagnostic Systems Ltd., Boldon, England) and sclerostin using the TECOmedical Human Sclerostin HS ELISA assay (TECOmedical group, Sissach, Switzerland) at the scientific laboratory at the Department of Clinical Biochemistry, Rigshospitalet, Glostrup, Denmark. The CV for CTX, P1NP, and sclerostin ranged from 4.58 to 8.76%, 2.40 to 5.69% and 6.28 to 6.52%, respectively.

The sample size was calculated from expected changes in the primary outcome lumbar spine BMD. The inclusion of 32 participants (16 in each group) would give the study 80% power to detect an additional increase of 22% in BMD with WBV assuming a 9% increase of BMD in the active comparator group and 11% increase in the intervention group, and assuming a SD of the BMD increase of 2% with a level of significance of 0.05 [10]. Allowing for 20% drop out rate, the inclusion of 40 participants was planned.

All statistical analyses were performed using the Statistical Package STATA (version 14 and 15, Stata Corp., College Station, TX, USA). Between-group differences in baseline characteristics and study adverse events were assessed using the Student’s T-test, Wilcoxon rank-sum or the chi-squared test according to continues outcomes, normal or non-normal distributions or categorical outcomes, respectively. Because data represent repeated measures in individuals, we evaluated the differences in BMD over time as percent change from baseline between those treated with WBV + teriparatide and teriparatide using pre-planned multi-level mixed-effects linear regression models adjusted for baseline BMD (ANCOVA) [32]. Models included a group variable (WBV + teriparatide or teriparatide) and a time variable to assess if the overall level of the parameters differed between groups and whether the parameters changed over time. Longitudinal absolute changes in microarchitecture were compared using a linear mixed-effect model with fixed effect for treatment group, time and a time and treatment interaction term, with adjustment for baseline values. Biochemical markers of bone turnover and sclerostin had a non-normal distribution and unequal variation in the residuals and were analyzed using linear regression with a robust cluster estimation in order to accommodate for possible correlations between different measurements within one individual. Model assumptions were checked using histograms, plots of the residuals against fitted values and normal probability plots of the residuals. A significance level of 0.05 was chosen. For missing data, multiple imputations were planned when appropriate depending on amount and causation [37]. We did not apply correction for multiple testing. ITT analyses was performed primarily, and a secondary per protocol (PP) analysis was conducted to investigate if WBV adherence (> 75%) affected the results. Intention-to-treat analysis (ITT) was used as pre-specified in the published study protocol [32].

The recruitment centres informed 93 eligible women who were starting teriparatide treatment about potential participation in the study (Fig. 1; consort flow chart). Thirty-five postmenopausal women with a mean age (± SD) of 69 ± 7 (range 53–81) years were recruited. Baseline characteristics of the study population are shown in Table 1. There were no significant differences in age, BMI, BMD or other demographic factors between the two groups. Of the 35 included participants, 32 (91.4%) completed 6 months BMD measurements and 33 (95%) completed 12 months BMD measurements. Due to a low number of missing observations, no imputation was applied to BMD measurements. In the intervention group, one participant never started teriparatide and was lost to follow-up after baseline measurements, another participant was lost to follow-up after three months and two participants discontinued the WBV at three months but attended the follow-up visits. Due to technical failure of the HR-pQCT scanner in two separate periods, a total of twelve measurements were missing and exchanged by multiple imputations. One participant had no baseline radius scan due to prior fractures and no imputations were applied. In the active comparator group, three participants had missing values in the bone turnover markers and one participant did not have BMD measurements at the six-month visit. Furthermore, one participant was non-fasting and, therefore, was not included in the CTX analyses, and P1NP measurements were excluded once in two participants following an acute fracture. Missing values were exchanged by multiple imputations. One set of measurements was completely missing at random, and no values for this set were imputed.

Lumbar spine BMD increased significantly in both groups at six and twelve months. Mean percent change in the WBV + teriparatide group at six months and twelve months was 6.47% ± 3.40 and 8.90% ± 5.48 compared to 3.48% ± 4.39 and 6.65% ± 5.57 in the teriparatide group, respectively (Table 2). The predefined primary adjusted mixed-effect model found a significant overall difference in treatment effect between groups of 2.95% [95% CI (0.14–5.77), P = 0.04].

There was no significant change in total hip BMD in the two groups or when comparing treatment effects between groups at six or twelve months (Table 2). In PP analysis with adherence > 75%, both groups increased significantly in lumbar spine BMD with no significant treatment effect although a positive trend was seen in favor of the intervention (P = 0.077) (n = 13). There were no changes in the results from total hip when applying the PP analysis (Supplementary material table 1).

Table 3 shows the microarchitecture parameters for the two groups. There were no significant changes from baseline in total vBMD, cortical thickness, BV/TV, trabecular number or trabecular thickness in either group, and no significant differences between groups. Moreover, there were no significant changes in microarchitecture parameters when applying the PP analysis (adherence > 75%) (Supplementary material table 2).

CTX and P1NP increased significantly in both groups after three and six months of follow-up. There were no significant differences between groups (Table 4). Sclerostin levels showed no significant change within or between groups. There were no significant changes in results from the bone turnover markers when applying the PP analysis (adherence > 75%) (Supplementary material table 3).

A total of 13 participants in the intervention group reported > 75% training adherence with the WBV (76% of the participants). Two participants reported pain in the lower extremities, and one stopped the WBV.

A total of 33 participants (94%) had an adherence of > 80% to teriparatide based on the number of collected prescriptions (of planned thirteen a year). Due to mild hypercalcemia, a short period off teriparatide treatment was necessary in one patient. There were no significant differences between groups in adherence to teriparatide.

A few serious adverse events (AE) were reported, which are as follows: five hospital admissions (four in the active comparator and one in the intervention group), one distal femur fracture (intervention group), and one vertebral fracture (intervention group). No serious adverse events were believed to be related to WBV. In the twelve-month intervention period, two participants in the active comparator group reported falls and five participants in the intervention group, none in relation to WBV sessions. There were no significant differences in falls between the two groups. There were no significant changes in reported pain or dizziness within the groups or between groups during the twelve months.