The combined effect of Parathyroid hormone (1-34) and whole-body Vibration exercise in the treatment of OSteoporosis (PaVOS)- study protocol for a randomized controlled trial

Change in areal BMD of total hip and lumbar spine is measured by DXA from baseline until 6, 18, and 24 months (Table 2).

Images from high-resolution peripheral quantitative computed tomography (HR-pQCT) (Xtreme CT, Scanco Medical, AG, Brüttisellen, Switzerland), of the non-dominant distal radius and distal tibia (the opposite limb in the presence of a previous fracture) will be obtained to measure bone geometry, cortical morphology, trabecular morphology, and overall biomechanical competence. In in-vitro studies estimated bone strength of the radius using finite element analysis [22, 23] which has been shown to be more closely correlated to observed radius bone strength than areal BMD by DXA [22]. PTH 1-34 treatment has been shown to be associated with an increase in vertebral estimated bone strength [24] and preservation of the estimated bone strength of the radius and hip [25, 26]. The images are obtained at baseline, 6, 12, 18, and 24 months (Table 2). The reported outcomes will be total BMD, cortical thickness, cortical porosity, bone volume per trabecular volume (BV/TV), trabecular number, trabecular thickness, and finite element failure load. The scanning protocol and the image acquisition have previously been described in detail [22, 23].

Markers of bone formation (procollagen type-1 amino-terminal propeptide (P1NP)) and bone resorption (carboxy-terminal type-1 collagen crosslinks (CTX-1) will be measured by the method of chemiluminescence (iSYS, Immunodiagnostic Systems Ltd., Boldon, England). Sclerostin is analyzed using TECOmedical Human Sclerostin HS ELISA (TECOmedical group, Sissach, Switzerland). Bone turnover is affected by treatment with PTH 1-34, and studies have shown that a rise in the marker of bone formation, P1NP, during PTH 1-34 treatment is a predictor of the increase in BMD [27]. The assessment of bone biomarkers will allow exploration of mechanisms of action of WBV in augmenting PTH 1-34 treatment on bone turnover. The blood samples are taken at baseline, 3, 6, 12, 18, and 24 months (Table 2) after an overnight fast and stored at − 70 °C until analyzed in a central laboratory.

Functional biomarkers including measurements of muscle strength, function and balance is measured by: (1) Timed Up and Go (TUG), (2) Short Physical Performance Battery (SPPB), (3) leg extensor power (Nottingham power rig), and (4) grip strength (Smedley dynamometer, TTM, Tokyo, Japan).

Fragility fractures are most often associated with falls [21, 28]. The measurement of lower extremity function and mobility will indicate if WBV has the potential to reduce the risk of falls in osteoporotic patients, which is another important determinant of the risk of fracture, independent on the effects on bone [21]. The TUG is the measurement of functional mobility and is a simple and reliable clinical test used to screen for fall risk in community-dwelling older persons [29]. Lower-extremity function and balance can also be assessed by the SPPB which is a validated test in older adults [30].

Leg extension power is assessed using a leg extensor power rig, (Medical Engineering Unit, School of Biomedical Sciences, University of Nottingham Medical School, Nottingham, UK) reported to have good reliability with no significant differences found between two tests performed 1 week apart (r = 0.97; coefficient of variation = 9%) [31]. At each visit the same leg is tested with a series of five measurements from the same starting position. The leg is selected randomly at the first visit. The SPPB and the TUG are described in detail by others [30, 32]. Reduced grip strength is a predictor of fragility fractures independent of BMD [33]. A reliable and valid method is by using a Smedley dynamometer (TTM, Tokyo, Japan). The measurements are done twice with each hand using a protocol described by others [34].

The functional tests will be performed by technicians, who all have been trained by a physiotherapist and all tests are conducted by standardized protocols. The TUG, SPPB, grip strength and leg extension power tests will be performed at baseline, 3, 6, 12, 18, and 24 months (Table 2).

Full-body DXA (Hologic Discovery, Waltham, MA, USA) is performed at baseline, 12, and 24 months to assess muscle mass (Fig. 2).

Sarcopenia is a condition with low skeletal muscle mass leading to decreased muscle strength, and impaired physical function, associated with an increased risk of falls [35]. Sarcopenia is proposed to be assessed by a variety of measurements of muscle mass and function including but not limited to full-body DXA, SPPB, grip strength, and gait speed [36, 37].

The participants’ physical activity will be measured by a validated questionnaire, the International Physical Activity Questionnaire (IPAQ). The participants’ multiples of the resting metabolic rate will be generated (MET-min/week) [38].

Vertebral fractures have been shown to decrease quality of life [3] and the EuroQol 5-dimension, 5-level questionnaire (EQ-5D) is a well-validated measure of quality of life [39, 40].

The patients’ own fear of falling is associated with the risk of falls [41] and the the Falls Efficacy Scale International (FES-I) questionnaire, which is a reliable and validated questionnaire to measure the fear of falling in an older population [42].

The questionnaires IPAQ, EQ-5D, and FES-I will be distributed in paper versions to the participants at baseline, 12, and 24 months.

Adherence to WBV is ascertained using self-reported adherence in a log book. Dropouts and the reasons for this will be noted. The adherence to the PTH 1-34 treatment is ascertained by asking the patients and by using the prescription database.

Information on symptoms of dizziness, pain, and falls will be collected. The participants will be handed a calendar to note fall events, defining a fall as “an unexpected event in which the participants come to rest on the ground, floor, or lower level” [43]. Pain will be assessed by the Numeric Rank Score (0 being no pain, and 10 being unbearable pain) and the question about how many days they have felt dizzy during the last week, and falls will be assessed by monthly telephone calls during the first year and then every 3 months for the rest of the trial.

Demographic data, including data on risks factors associated with osteoporosis and fragility factures, will be collected at baseline and thus before randomization.

These factors include Body Mass Index, current and previous height, age, comorbidity, fall history, previous fractures, vitamin D and calcium intake, current, and previous history of medication.