Clinical trial NCT04275011: Bone Response to Exercise in Women on Antiresorptive Medications
Official title: Bone Response to Resistance and Impact Exercise (BRRIE) in Women on Antiresorptive Medications: A Randomized Controlled Trial
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: NA
Conditions: Osteoporosis
Bone Loss
Keywords: Exercise
Progressive Resistance Training
Impact Exercise
Anti-resorptive medication
Lead sponsor: University of Waterloo
Sponsor class: OTHER
First posted: 2020-02-19
Enrollment: 26
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: This is a single-blinded RCT comparing moderate-high progressive resistance training and impact exercise to an attention control who will be performing static posture and balance exercises.
Primary purpose: OTHER

Brief summary: Performing resistance training and impact exercise at a moderate to high intensity may help prevent bone loss. However, medications used to treat bone diseases such as osteoporosis reduce the activity of bone cells. The investigators are unsure whether bone cells will still respond to exercise in people on osteoporosis medications. Therefore, investigators have designed a study to compare bone response to moderate-high intensity exercise that involves resistance training and impact exercise versus posture and low intensity balance exercises. Women taking osteoporosis medication will be equally and randomly assigned to one of the exercise groups. There will be 23 participants per group and both exercise programs will be performed over a span of 6 months, twice weekly, for approximately 30-45 minutes per session. Investigators will measure sclerostin, a bone-related protein found in the blood, to see if there are any changes after 3 months of training. Higher levels of sclerostin may result in greater bone breakdown. It is expected that the moderate-high intensity exercise program will decrease sclerostin levels more than low intensity training. Further, changes in sclerostin levels during the 6-month exercise intervention will be explored. The effects of the exercise program on other bone markers in the blood, physical ability, and quality of life will be reported. The willingness of the participants to perform the exercise program and the safety of the exercises provided will also be assessed.

Detailed description: Pharmacological and exercise interventions aimed to treat osteoporosis are typically examined separately. A common pharmacological treatment for osteoporosis involves antiresorptive medications, which has been previously shown to blunt the bone response to exercise. Many studies have shown that moderate-high intensity progressive resistance training (PRT) and impact exercise is required to stimulate bone. There are only two RCT studies that examined the effect of progressive resistance training or impact exercise on bone response in participants taking antiresorptive medications. One study showed that the combination of antiresorptive medications and resistance training did not increase bone mineral density (BMD) to a greater extent than medications alone in postmenopausal women. Another study demonstrated no additive effect of antiresorptive medications and progressive impact exercise on reducing bone turn over markers (BTMs) in postmenopausal women. However, there are currently no available studies that examine the effect of both progressive resistance training along with impact exercise on the bone response in women taking antiresorptive medications. Most exercise studies exclude people taking medications that affect bone, or are heterogeneous with respect to antiresorptive medication use. Further, there is little data on the safety of moderate-high intensity PRT and impact exercise in individuals at moderate or high risk for fracture.

The bone response to medications and exercise can be measured via the assessment of bone biomarkers present in the blood. For instance, sclerostin is a protein secreted by osteocytes and it can influence the bone remodeling process by inhibiting bone formation. Human genetic disorders deficient in sclerostin, such as sclerosteosis and Van Buchem's disease, have been associated with significant increases in bone mass. Therefore, decreasing sclerostin levels may be a potential treatment for people with low bone mass conditions. A case-control study demonstrated that postmenopausal women who adequately responded to bisphosphonates (e.g., did not experience a fracture while on treatment) had significantly lower serum sclerostin concentrations than those who experienced a fracture while taking bisphosphonates. There is also a link between sclerostin and exercise as a previous cross-sectional study reported an association between low serum sclerostin levels and increased physical activity duration. In addition, PRT and high impact exercise interventions have been shown to decrease sclerostin levels in healthy pre-menopausal women and thus may eventually increase bone mass or prevent bone loss. Therefore, changes in serum sclerostin levels can be used to provide insight regarding the bone response to antiresorptive medications as well as exercise.

Investigators plan to conduct a single-blinded parallel-group randomized controlled trial (RCT) with 1:1 allocation ratio to determine whether participants with low bone mass are able to adhere and safely perform PRT and impact exercises at an intensity that is hypothesized to stimulate bone. Specifically, the primary aim will be to determine the effects of moderate-high PRT and impact training on sclerostin in women on antiresorptive medication. The secondary aims are: a) to explore the effects of moderate-high PRT and impact training on BTMs \[serum N-terminal procollagen of type I collagen (P1NP), C-terminal cross-linked of type I collagen (CTX), parathyroid hormone (PTH), Vitamin D and serum calcium\], physical function and quality of life and body composition; b) to determine the feasibility of the intervention by assessing adherence, participant satisfaction with the intervention, and the acceptability of the attention control group; and c) to determine if there are any adverse events, including falls, fractures, or other adverse health outcomes attributable to the exercise intervention.

Investigators hypothesize that a moderate-to high PRT and impact exercise program will decrease sclerostin levels to a greater extent than the posture and balance exercise program. Further, it is hypothesized that PRT and impact exercise will result in more favourable improvements in other bone biomarkers, physical function, mobility, quality of life and body composition than the control group. Investigators hypothesize a low drop-out rate since both groups will be receiving the same level of attention throughout the study. Further, no adverse events attributable to exercise are expected. Kinesiologists who are Certified Exercise Physiologists will provide coaching on proper form, and will use appropriate progression of exercise intensity and volume.

Sample Size Estimation:

The sample size estimation was determined using data from a cross-sectional study that reported an association between low physical activity duration and high serum sclerostin levels. Women who engaged in less than 30 minutes of exercise per week had statistically significantly higher serum sclerostin levels than women who engaged in 60-120 minutes of physical activity per week (27.84 +/- 4.98 pmol/L vs. 21.64 +/- 6.21 pmol/L; p\<0.0001, respectively). The study described used a manual ELISA® kit to assess sclerostin which is consistent with the current study protocol. Based on the study findings, to detect a difference in serum sclerostin of 6.2 pmol/L with a standard deviation of 1.23 pmol/L investigators will need 38 participants using an alpha level of 0.05 and a power of 90%. Investigators assumed a 20% attrition rate for the current study therefore the estimated sample size was increased to 46 participants.

Analyses:

The study protocol was prepared according to the Standard Protocol Items: Recommendations for Interventional Trial (SPIRIT) guidelines. Reporting will be consistent with Consolidated Standards of Reporting Trials (CONSORT) non-pharmacological trials extension. The proposed study protocol is summarized. Participant characteristics and outcomes that are considered continuous variables will be reported as mean +/- standard deviation or median and interquartile range. Categorical data will be reported as number (%). Analyses of the feasibility and safety of the exercise intervention will be descriptive. A participant flow diagram will be used to demonstrate the number of participants who were randomly assigned to each group, who completed the exercise training program and who were analyzed for each outcome. For each group, losses or exclusions after randomization will be recorded along with reasons. Intention-to-treat analysis will be performed and thus all participants will be included in the analysis and analysed according to the group to which they were randomized. Differences in outcome measures will be assessed using analysis of covariance (ANCOVA) while adjusting for baseline demographic and clinical characteristics (e.g., age, smoking status, physical activity level, dietary intake). Investigators will also perform sensitivity analysis to determine if participants with ≥80% adherence criteria to the exercise intervention experience greater benefits. At the end of the study, investigators will assess whether allocation concealment was maintained among the blinded research staff and whether participants were aware of the study hypothesis. Statistical significance will be set at p \< or equal to 0.05. All data analysis will be conducted using the IBM Corporation Statistical Package for the Social Sciences (SPSS) version 24.

Eligibility criteria: Inclusion Criteria:

* Women over 18 years of age AND
* Taking anti-resorptive medications for at least 12 months eg. risedronate (Actonel), alendronate (Fosamax, Fosavance), etidronate (Didronel, Didrocal), zoledronic acid (Aclasta, Reclast, Zometa), pamidronate (Aredia) and denosumab (Prolia, Xgeva).

Exclusion Criteria:

* Not able to communicate in English
* Already participating in structured progressive resistance exercise or impact training exercise program; presence of any progressive neurological disorders that can possibly prevent study completion; unable to stand or walk 10 m with or without gait aid; does not have the mental capacity to provide informed consent; have any contraindications to exercise as determined by a physician.
* Individuals that have had a fracture in the last 6 months need to have completed any immobilization (eg. casting) and post-fracture rehabilitation, and will need physician consent to participate in the study. Individuals with previous fractures (\> 6 months ago) will not be excluded.

Primary outcomes:
measure: Change from baseline Serum Sclerostin at 3 months and 6 months.
timeFrame: Baseline, 3-month and 6-month follow up.
Secondary outcomes:
measure: Descriptive Data - Demographic information
timeFrame: Baseline
measure: Descriptive Data - Medical History
timeFrame: Baseline
measure: Descriptive Data - Physical Activity
timeFrame: Baseline
measure: Descriptive Data - Dietary Intake
timeFrame: Baseline, 3-months, and 6-months
measure: Other bone biomarkers - Serum P1NP
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Other bone biomarkers - CTX
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Other bone biomarkers - Parathyroid Hormone
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Other bone biomarkers - Vitamin D
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Other bone biomarkers - Calcium
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Physical function and mobility - 40 metre Fast-paced Walk
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Physical function and mobility - 30-second Sit-to-Stand Test
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Physical function and mobility - 4-square Step Test
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Physical function and mobility - Stair Climb Test
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Quality of Life - EQ-5D
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Quality of Life - QUALEFFO-41
timeFrame: Baseline, 3-month and 6-month follow up.
measure: Bone Mineral Density
timeFrame: Baseline and 6 months.
measure: Body Composition
timeFrame: Baseline and 6 months.
measure: Feasibility (Number of participants retained)
timeFrame: 6 months.
measure: Feasibility (Adherence)
timeFrame: Through study, 6 months.
measure: Feasibility (Acceptability)
timeFrame: 6 months.
measure: Falls
timeFrame: Through study, up to 6 months
measure: Fractures
timeFrame: Through study, up to 6 months
measure: Adverse Events
timeFrame: Through study, up to 6 months.
Other outcomes:
Locations:
city: Waterloo
country: Canada
facility: University of Waterloo
state: Ontario
Study officials:
affiliation: University of Waterloo, Schlegel-UW Research Institute for Aging
name: Lora M Giangregorio, PhD
role: PRINCIPAL_INVESTIGATOR
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