Strength training for osteoporosis prevention during early menopause (STOP-EM): a pilot study protocol for a single centre randomised waitlisted control trial in Canada

Abstract

Introduction

Women lose up to 10% of their bone mass around menopause and the decade following. There is a need for proactive approaches to preserve bone mass and quality around menopause. Existing work has found that high-intensity resistance and impact training (HiRIT) can improve bone and muscle measures in late postmenopausal women. However, this has not been investigated in perimenopausal and early postmenopausal women who are in the midst of the menopausal transition.

Methods and analysis

This study is a 9-month randomised controlled feasibility trial evaluating a HiRIT programme in perimenopausal and early postmenopausal women. The primary objective of this study is to determine the feasibility of HiRIT in 40 perimenopausal and early postmenopausal women (45–60 years). Participants will be randomised 1:1 into a supervised HiRIT exercise intervention and waitlisted control. The primary outcomes are recruitment, retention and adherence to the exercise intervention. Secondary outcomes include bone (bone mineral density, microarchitecture and strength), muscle (mass, strength and power), physical function (balance and aerobic fitness) and quality of life measures. Feasibility will be assessed based on a priori criterion for success and secondary outcomes will be assessed via multiple linear regressions. The study will be considered feasible if>50% of interested and eligible participants are recruited, if there is>60% adherence to the two times per week, 9-month exercise intervention and if at least 65% of the sample complete the final study visit. Feasibility outcomes will be used to inform a larger, future trial aimed at identifying the efficacy of the exercise intervention for improving various health outcomes, including bone density and muscle mass. Secondary exploratory outcomes will provide insight into the effect of exercise on muscle and bone in perimenopausal and early postmenopausal women.

Ethics and dissemination

This study has been approved by the Conjoint Health Research Ethics Board of the University of Calgary REB22-1632. The results of this study will be disseminated at national and international conferences and published in academic journals.

Trail registration number

ClinicalTrials.gov: NCT05961371. (Protocol V.1.2, 28 September 2023)

STRENGTHS AND LIMITATIONS OF THIS STUDY.

• Our inclusion criteria allow for perimenopausal women to participate in our study, therefore including a historically understudied population who are rarely included in exercise trials.

• Our exercise intervention is supervised which allows us to accurately track adherence.

• Due to the nature of the intervention, we are unable to blind participants to the intervention.

• Using a scheduled, supervised intervention narrows our population to women who can access the location and are available at the scheduled times.

Introduction

Background and rationale

During menopause and the decade following, women lose up to 10% of their bone mass¹ and half will sustain a fragility fracture after age 50.² Oestrogen prevents bone resorption and supports bone formation; thus, rapid bone loss occurs during menopause due to declines in oestrogen production.³ Although the majority of lifetime bone loss in women occurs around menopause,⁴ effective preventative strategies during this time are lacking. Further, although menopause represents a prime opportunity to prevent bone loss and future morbidity most osteoporosis clinical trials have excluded women within 5 years of menopause⁵ due to considerable intraindividual and interindividual variation in hormone levels. Therefore, there is a paucity of evidence regarding the efficacy of interventions for early postmenopausal women. In addition to losing bone during the menopausal transition, women also experience accelerated loss of muscle mass and strength.6,8 Declines in oestrogen production,⁹ along with reduced physical activity¹⁰ and insufficient protein intake,¹¹ are largely responsible for the accelerated loss of muscle during menopause. Therefore, there is a pressing need for proactive approaches to preserve bone and muscle mass and quality around the time of menopause.

Exercise interventions have the potential to slow bone loss, detrimental changes in bone microarchitecture and strength as well as muscle loss during early menopause. Exercises that benefit bone typically include dynamic, high-impact activities,¹² yet many interventions evaluated low-impact or non-weight-bearing exercise for preventing osteoporosis. Perceived risk of injury may explain why high-impact loading is less common in exercise interventions in adults¹³ and why interventions typically only demonstrate marginal bone gains.¹⁴ Further, the primary outcome of interest in most studies has been areal bone mineral density (aBMD) using dual X-ray absorptiometry (DXA). Although DXA is the clinical standard, it relies on areal (two-dimensional) BMD as a surrogate for bone strength. High-resolution peripheral quantitative CT (HR-pQCT), on the other hand, is a three-dimensional imaging device (resolution 61 µm; as fine as a human hair) capable of assessing cortical and trabecular bone compartments, volumetric BMD, microarchitecture¹⁵ and estimating bone strength.¹⁶ The excellent sensitivity of HR-pQCT is particularly relevant for assessing the efficacy of exercise interventions. While exercise only marginally improves aBMD (0.85% change at the lumbar spine, based on any exercise compared with control) by DXA,¹⁴ meta-analyses demonstrate more than a 60% relative reduction in fracture risk,¹⁷ indicating that exercise conveys benefits to bone health beyond that detected by DXA. To improve fracture prevention, we need to employ imaging approaches that accurately quantify not only bone mass but also trabecular and cortical bone microarchitecture and bone strength.

Recent trials in postmenopausal women and older men with low bone mass highlighted the safety, feasibility and efficacy of high-intensity resistance and impact training (HiRIT) for improving bone mass (via DXA).^{18 19} Systematic reviews also demonstrate that high-intensity exercise tends to be more effective for bone than low or moderate-intensity exercise in postmenopausal women.^{20 21} It is currently unknown whether HiRIT is an effective bone and muscle loss prevention strategy during perimenopause and early postmenopause and how HiRIT affects bone microarchitecture and strength as well as muscle mass, strength and power. This 9-month randomised controlled feasibility trial will evaluate the feasibility of HiRIT in perimenopausal and early postmenopausal women to inform a larger, longer-term clinical trial evaluating the effects of HiRIT on bone and muscle health. The purpose of the feasibility study prior to an efficacy trial is twofold. First, although previous work demonstrated the feasibility and efficacy of HiRIT in late postmenopausal women,^{13 19} it is necessary to understand whether perimenopausal and early postmenopausal women, who may have more constraints on their time (eg, employment and caregiving), are interested in and able to attend two times per week in-person exercise sessions. Second, it is essential for our team to pilot the study protocol and logistics, including securing appropriate training locations and parking. The future trial will be similar to this feasibility study with single-site recruitment, a 9-month intervention and a waitlisted control. The primary outcomes of the future trial will be bone microarchitecture and strength (via HR-pQCT).

Objectives

The primary objective of this trial is to assess the feasibility (ie, recruitment capacity, attrition and protocol adherence) of a 9-month HiRIT programme in perimenopausal and early postmenopausal women. Secondary objectives include exploratory analyses assessing whether the intervention improves musculoskeletal health outcomes. We will examine changes in bone microarchitecture, density, strength and biomarkers of bone turnover. We will also assess changes in lean body mass, muscle strength and power, menopausal symptoms, physical function and quality of life. We hypothesise that HiRIT is feasible in perimenopausal and early postmenopausal women and that exploratory analyses will find that women in the HiRIT intervention will lose less bone and muscle over the 9-month period than those in the control group.

Methods

Trial design

This is a single-blinded, randomised, waitlisted control exercise intervention in perimenopausal and early postmenopausal women (n=40) conducted at the University of Calgary, Calgary, Canada. This study is registered with ClinicalTrials.gov (ID: NCT05961371). Recruitment will begin in September 2023 with the study starting in January 2024 and ending in December 2025. Participants will be recruited from the general population via posters, emails and public media outlets. Interested participants will be initially screened via a survey (Qualtrics) for sex, age, estimated menopausal status via last known menses and current activity level. Those meeting initial screening criteria will be contacted by the research coordinator to determine availability for training and confirm they meet eligibility criteria. Eligible women will be randomly assigned to a 9-month supervised exercise intervention or the waitlist control group, with an allocation ratio of 1:1, stratified by hormone replacement therapy (HRT) use (yes vs no) and menopausal status (peri vs early). The waitlist group will serve as a control for normal bone changes during perimenopause and early postmenopause.

Eligibility criteria

To be eligible for this study participants must meet the following inclusion criteria: (1) women between 45 and 60 years of age and (2) perimenopausal or early postmenopausal: −2 or −1 of the stages for reproductive ageing 10+ staging system²² or within 5 years of menopause. Perimenopause is defined as: a variable cycle length, ≥7-day difference between consecutive cycles or has had a menstrual cycle in the last 12 months but not the last 60 days. Early postmenopausal is defined as: within the first 5 years after menopause, with menopause defined retrospectively as 1 year after cessation of the menstrual cycle.

Exclusion criteria are:

• Pregnancy or a planned pregnancy within the next year.

• Orthopaedic conditions that may worsen with exercise.

• Low back pain, type 1 diabetes, unmanaged hypertension, lipidaemia or cardiovascular disease.

• A history of metabolic bone disease.

• Occurrence of a low trauma fracture within the last 5 years.

• Previous treatment with osteoporosis pharmacotherapy.

• Active glucocorticoid use.

• Low serum vitamin D (25-hydroxyvitamin D (25(OHD))<30 nmol/L or serum calcium<2.10 mmol/L.

• Current or recent (within the past 6 months) participation in progressive resistance training (ie, any programme or training regime that systematically increases load).

Our screening tool will ask participants if they are participating or recently participated in progressive resistance training. If they answer yes to this question, they will be contacted by a Canadian Society for Exercise Physiology certified exercise physiologist (CSEP-CEP) to determine whether their training meets our definition of progressive resistance training. Participants meeting the above eligibility criteria will be further assessed using the CSEP Get Active Questionnaire to assess the safety of exercise. If participants answer ‘yes’ to any questions indicating it may be unsafe to exercise they must be cleared to exercise by a healthcare professional before they are enrolled in the study. Participants will have their heart rate and blood pressure taken during baseline testing to ensure they are within recommendations for exercise. If potential participants have a resting heart rate>100 bpm, systolic blood pressure>160 mm Hg or diastolic blood pressure>90 mm Hg, they will be asked to see their physician. The participant will not be able to complete the physical tests or participate in the trial unless cleared by a health professional.

Sample size

Consolidated Standards of Reporting Trials (CONSORT) guidelines²³ do not recommend hypothesis testing of efficacy outcomes for pilot and feasibility studies, so we have justified sample size based on feasibility outcomes (recruitment rates, attrition and protocol adherence) and an adopted traffic light system (Stop, Modify, Continue) based on the framework by Lewis et al.²⁴ Hypothesis testing of feasibility outcomes incorporates a 1-sided alpha=5% and power of 80% and a normal approximation.

For recruitment, progression criteria include>50% (continue zone) and<35% (stop zone), thus we will require n=68 total screened participants. For participant retention, progression criteria require>85% (continue zone) and<65% (stop zone); thus, we require n=34 (n=17 in each arm). For protocol adherence (sessions attended), progression criteria require>80% (continue zone) and<60% (stop zone); thus, we require n=38 (n=19 in each arm) and will use a sample size of n=40.

Randomisation

Participants meeting inclusion criteria will be randomly assigned using the REDCap (Research Electronic Data Capture) randomisation module to either the intervention group or a waitlisted control group, stratified by HRT use (yes vs no) and menopausal status (peri vs early). The computer-generated randomisation table will be uploaded to REDCap and only visible to the database developers and the research coordinator. Study staff (except for the research coordinator) will be blinded to the allocation of study participants. The study staff will only know the study arms as A and B. The research coordinator will generate the randomisation allocations using REDCap, will inform participants of their assignments and enrol participants in the study. There should be no need to unblind the allocated treatment. If a contraindication to the exercise intervention develops, the intervention will be stopped and all usual standards of care given.

Intervention

Supervised exercise intervention

The intervention consists of a 9-month supervised, progressive resistance training programme that was developed in partnership with a CSEP-CEP. Participants will attend two supervised sessions per week led by an instructor who will be either a CEP or personal trainer (CSEP-CEP or CSEP personal trainer). The lead CEP trainer will lead most of the sessions and will be responsible for training other CSEP-CEPs or CSEP personal trainers involved in the study. The exercise programme consists of 5 phases: the foundation phase (1 month), the building phase (2 months) and three strength phases (2 months each; 6 months total). Fidelity will be evaluated by having a third party assess the extent to which instructors are following the protocol using a checklist of all exercises that should be completed by participants within a session. Participants allocated to the intervention group will be asked to maintain their current lifestyle (ie, physical activity levels and nutrition), aside from the addition of the exercise intervention. Participants will be provided with a questionnaire after the intervention is completed to assess whether they changed their physical activity outside of the intervention.

Exercise phases

The foundation phase consists of postural and joint integrity exercises to ensure participants have full range of motion and control, followed by movement patterning to limit the risk of injury.

The building phase introduces loading to the movements learnt in the foundation cycle via dumbbells, kettlebells and barbells. During this phase, intensity will increase by 5% per week for 6 weeks. After 6 weeks, there will be a week of lower intensity (60% of one-repetition maximum (1RM) or 6 out of 10 on the rated perceived exertion (RPE) scale) followed by a week of maximal testing to adequately prescribe intensity in the subsequent phases.

The remainder of the protocol will consist of three, 8-week strength cycles. These strength cycles will consist of two similar workouts each week, with slightly varied exercises between the two sessions (table 1). Each exercise will be 5 sets of 5 repetitions performed between 80% and 85% of the participant’s 1RM or an 8–9 rating of RPE. Participants will increase the load by 5% once they are able to complete all 5 sets of 5 repetitions at an RPE of 8–8.5. This will ensure the participant is staying between 80% and 85% of their 1RM with increases in strength. Finally, each workout will finish with drop landings, balance and core exercises. The drop landings will be performed from a box height that the participant is comfortable with and will increase in height as the programme progresses. If a participant is unable to complete an exercise due to mobility restrictions, past injuries, etc, they will perform a modification that will target the same muscle group.

Table 1. Strength phase workouts detailed by day.

Exercises	Modify/progress/other
Day 1: Resistance exercises at 80% to 85% of 1RM (5 sets of 5 repetitions)
Deadlift/rack pull below knees
Barbell chest press	If barbell is too heavy: dumbbell chest press
Barbell back squat to box	Use box height to ensure each participant is squatting in the same position
Dumbbell single arm bent over row
Day 2: Resistance exercises at 80% to 85% of 1RM (5 sets of 5 repetitions)
Deadlift/rack pull below the knees
Barbell shoulder press	If barbell is too heavy: dumbbell overhead press
Back squat to box	Use box height to ensure each participant is squatting in the same position
Pull-up	Start banded with feet supported, progress to less supported
Days 1 and 2
Drop landings from a box (3 sets of 10 repetitions)	Increase box height
Balance exercise (3 sets of 10 or 20s)	One of the following each day:  ‘Tight rope walking’ with or without load  Farmer’s carry  Single arm farmer’s carry  Backwards farmer’s carry  Overhead dumbbell walk  Single arm dumbbell walk  T-balance  Airplanes
Core exercise (1 set of 10 or 20s)	One of the following each day:  Posterior—glute bridge on foam roller, superman hold, single leg glute bridge and supermans  Anterior—Hollow hold/hollow rockers, deadbug and primal position bird dog  Lateral—Side plank/hip abducted and modified side plank  Rotation—Half kneeling Hay Bailer and half kneeling cable core rotations  Anti-rotation—Pallof press  Plank with shoulder tap

1RMone-repetition maximum

Our HiRIT intervention differs from previous HiRIT trials^{13 19} in several ways. First, our foundation phase is 1 month longer. This month was added to ensure that all participants will have adequate joint mobility and stability and will have learnt proper movement patterns and posture before adding load. Further, our sessions will be an hour long instead of 30 min to allow for a warm-up period before each loaded session begins. Other differences include exercise selection, to ensure that all muscle groups are targeted by our exercise intervention, helping avoid potential injury and eliminating any potential compensation in movement patterns and posture. These changes include adding posterior chain exercises (dumbbell row and pull-ups) as well as chest presses. Finally, we chose to use boxes for the drop landings instead of jumping chin-ups/drop landings so we could standardise the height and progressively increase the height of the drop landings throughout the intervention.

1RM testing

1RM testing consists of three warm-up sets: the first warm-up set is 10 repetitions at 50% of the participant’s predicted 1RM and an RPE measure of 5–6. Participants will rest for 2 min and then complete the second warm-up set of 5 repetitions between 65% and 70% of their predicted 1RM and an RPE rating of 6–7. The third warm-up set is two repetitions at the weight the participants used in week 6 of that mesocycle (ie, building, strength 1, strength 2, strength 3). Following the warm-up, participants rest for 2 min before their first trial. The first trial will be a 2.5–5% increase in weight from the last warm-up set. Participants will continue to increase in 2.5–5% increments per trial until they fail to complete the lift with the correct form or rate the lift as a 9 or 10 on the RPE scale—acknowledging that another attempt could not be completed. Between each trial, participants will rest for 3 min. The objective is to have the participants reach their 1RM in five attempts or less.

Modifications to intervention

Changes in the protocol will include exercise selection and intensity (load) of the exercise. If a participant is injured or unable to perform an exercise with good form, resulting in a concern for the safety of the participant, a suitable modification will be substituted. This might include reducing the load for the exercise or changing the exercise selection so that the exercise is pain-free yet challenging. If that modification is still performed with incorrect form or is painful for the participant, the instructor will modify the exercise until the participant can execute the exercise with proper technique. If the instructor cannot find a modification that the participant can perform without pain that exercise will be removed for that day. Further, if a participant is uncomfortable performing an exercise they will be provided with modifications or will skip that exercise for the day. The modification of an exercise will only be approved by the lead instructor who will record any exercise modifications in the training log. The percentage of participants requiring exercise modifications will be assessed, along with a description of the most common required modifications. Instructors will track for each participant and each session whether participants completed 80% of the exercises (yes or no).

Waitlist control group

Participants in the waitlisted control group will be asked to maintain their current lifestyle and refrain from any progressive resistance training. Before and after the waitlist period, all participants will self-report physical activity levels and wear accelerometers. Further, all participants will self-report whether their physical activity, including resistance training habits, changed since the previous visit. To minimise dropout, participants in the waitlisted control group will be offered the exercise intervention after the initial 9-month period.

Discontinuation of the intervention

Participants may discontinue their participation in the study at any time, without consequence. Data collected from the participant up until the time of drop-out will be used in analyses, but no new data will be collected from that participant. Participants will not be replaced after they discontinue their participation. The clinical investigator will follow-up with participants who have withdrawn to inquire about reasons for withdrawal (exit survey). Participants will be removed from the study if an illness or injury will prevent them from completing the exercises safely, if they begin taking any medication that may influence their bone health or if they develop any other exclusion criteria. Participants may also be removed if they refuse to follow the safety guidelines and guidance of the research team.

Data collection and management

The consent form can be found in the online supplemental material. The study schedule and planned outcome analyses are presented in tables2 3, respectively. The research coordinator will be responsible for obtaining consent, enrolment and assessing recruitment and retention rates. The lead instructor running each exercise session will track adherence, safety issues and any injuries using log sheets at each session. Secondary outcomes will be assessed by trained study personnel (table 2) who will be blinded to group allocation.

Table 2. Schedule of enrolments, interventions and assessments.

Activity	Study personnel	Time point in study schedule
		T-1 (recruitment and enrolment)	T0 (study visit 1)	T1-T9	T10 (study visit 2)
Recruitment and screening
Initial interest survey with inclusion/exclusion criteria	Participant	X
Inclusion/exclusion criteria screening	Staff unblinded	X
Screening for availability to attend intervention	Staff unblinded*	X
Consent	Staff unblinded*	X
Assessments
Randomisation	Staff unblinded*		X
Demographic questionnaire	Participant		X		X
CSEP Get Active Questionnaire	Participant		X
CSEP PASB-Q	Participant		X		X
BPAQ	Participant		X
SF-36v2 Health Survey	Participant		X		X
MENQ	Participant		X		X
Fasted blood draw	Alberta Precision Laboratories		X		X
Height and weight	Staff blinded*		X		X
Imaging (HR-pQCT and DXA) acquired	Radiation technologist, staff blinded*		X		X
Blood pressure and heart rate	Staff blinded*		X		X
6-minute walk test	Staff blinded*		X		X
Jump mechanography (counter-movement jump)	Staff blinded*		X		X
Hand grip dynamometer	Staff blinded*		X		X
Four-square-step test	Staff blinded*		X		X
Physical activity levels using accelerometer	Staff blinded*		X		X
Intervention/comparator intervention
For intervention group
Deliver exercise intervention	Staff unblinded*			X
Track exercise intervention attendance	Staff unblinded*			X

^*Staff refers to research coordinator, research assistant, or graduate student.

BPAQ, Bone-Specific Physical Activity Questionnaire; CSEP PASB-QCanadian Society for Exercise Physiology: Physical Activity and Sedentary Behaviour QuestionnaireDXAdual X-ray absorptiometryHR-pQCThigh-resolution peripheral quantitative CTMENQ, Menopause-Specific Quality of Life Questionnaire; SF-36v2, Quality of Life Questionnaire

Table 3. Outcomes of the STOP-EM study.

Variable/outcome	Outcome measures	Metrics of analysis
Primary outcomes
Recruitment	Percentage of eligible participants recruited	Did we recruit 50% of eligible participants to meet our a priori criterion for success
Protocol adherence	Percentage of supervised exercise sessions attended by participants	Did participants attend an average of 60% of exercise sessions to meet our a priori criterion for success
Retention	Percentage of participants randomly allocated to the intervention who complete the final study visit	Did 65% of participants complete the final study visit to meet our a priori criterion for success
Secondary outcomes
Bone outcomes	TbTh, TbN, CtTh, CtPo and total, trabecular and cortical vBMD via HR-pQCT aBMD at the left hip (total hip and femoral neck), lumbar spine and total body via DXA	Difference in change from baseline between the intervention and control groups
Muscle strength and power	Max voluntary contraction of the knee Hand grip strength Peak power from countermovement jump	Difference in change from baseline between the intervention and control groups
Functional tests (dynamic balance and aerobic fitness)	Time to complete the four-square-step test Predicted VO2max based on distance from the 6-minute walk test	Difference in change from baseline between the intervention and control groups
Physical activity levels	Moderate-to-vigorous and sedentary activity via waist-worn accelerometer CSEP PASB-Q for adults	Difference in change from baseline between the intervention and control groups
Quality of life and menopausal symptoms	MENQ—change in mean score in all domains of the questionnaire: vasomotor, psychosocial, physical and sexual domains of the questionnaire SF-36v2 Health Survey—change in mean score in all domains of the questionnaire: physical functioning, role-physical, bodily pain, general health, vitality, social functioning, role-emotional and mental health	Difference in change from baseline between the intervention and control groups
Biomarkers	Oestradiol, FSH, plasma 25-hydroxyvitamin D, plasma calcium, plasma creatinine CTx and P1NP	Difference in change from baseline between the intervention and control groups
Sensitivity and subgroup analysis
Hormone replacement therapy use yes versus no	All secondary outcomes	Include as covariate in relevant statistical analyses
Menopausal status peri- versus early	All secondary outcomes	Include as covariate in relevant statistical analyses
≥80% adherence to exercise intervention	All secondary outcomes

aBMD, areal bone mineral density; BPAQ, bone-specific physical activity questionnaire; CSEP PASB-QCanadian Society for Exercise Physiology: Physical Activity and Sedentary Behaviour QuestionnaireCtPo, cortical porosity; CtTh, cortical thickness; CTx, c-terminal telopeptide; DXA, dual-energy x-ray absorptiometry; FSH, follicle-stimulating hormoneHR-pQCT, high-resolution peripheral quantitative CT; MENQ, Menopause-Specific Quality of Life Questionnaire; P1NP, plasma procollagen 1 intact N-terminal propeptide; SF-36v2, Quality of Life Questionnaire; STOP-EMstrength training for osteoporosis prevention during early menopauseTbN, trabecular number; TbTh, trabecular thickness; vBMD, volumetric bone mineral densityVO_2maxmaximum rate of oxygen consumption

Assessments will be performed at:

• T₀: Baseline testing (preintervention).

• T₁₀ (Exercise intervention takes place from T₁–T₉, with baseline testing at T₀ and postintervention testing at T₁₀.): 9 months after baseline testing: post-exercise intervention for those in the exercise intervention group and 9 months after baseline assessment for those in the waitlisted control group.

• T₁₉: 18 months after the beginning of the trial: post-exercise intervention only for those in the waitlisted control group who chose to complete the intervention after the initial 9-month control period.

Each participant will receive a unique study ID. Data will be collected and stored in REDCap. Source data to be recorded directly in case report forms includes: participant name, phone number, email address, mailing address, date of birth and age. Case report forms will be in digital format with study data recorded by the research coordinator directly into REDCap. Apart from the case report form, data collected are de-identified and identified by the Study ID number.

Monitoring will be conducted on-site; data will be verified and accounted for by the study coordinator periodically. REDCap entries will be directly verified against the source documents. All source documents and lab reports will be reviewed after enrolment by the study coordinator, who will check for accuracy and completion. Participants will be automatically contacted via REDCap to complete any missing questionnaire data. Missing data will be noted in the analysis.

Primary outcome: feasibility

The feasibility of this study will be assessed by assessing recruitment rates, protocol adherence and attrition throughout the 9-month intervention. Recruitment rates will be measured based on the number of participants recruited each month and the number of eligible participants who consented to participate in the study, protocol adherence as the percentage of the exercise sessions attended by participants and retention based on the percentage of randomised participants with valid outcome data at the end of the study. All data will be stored in REDCap. Study staff will follow-up with participants who have missed two consecutive sessions or more to inquire about injuries or illness.

A priori criteria for success

1. Recruitment rates: the study will be considered feasible if>50% of interested and eligible participants are recruited.

2. Adherence: the study will be considered feasible if there is>60% adherence to the two times per week, 9-month exercise intervention. Previous work has shown positive outcomes in exercise interventions with approximately 60%.²⁵

3. Retention rates: the study will be considered feasible if at least 65% of the sample completes the final study visit. Other HiRIT studies in late postmenopausal women have demonstrated higher retention (eg, 85%).¹⁹ It is conceivable that retention may be lower in perimenopausal and early postmenopausal women; thus, we selected a lower value, although our continue criteria with no modifications is set at 85%.

Secondary outcomes

All secondary outcomes will be measured preintervention and postintervention. If participants assigned to the waitlisted control group choose to participate in the exercise intervention after the 9-month control period, outcomes will be assessed for a third time post-exercise intervention. However, results from the control group post-exercise intervention will be exploratory and will not be analysed alongside secondary group outcomes.

Anthropometrics

Height and weight will be measured using a stadiometer (SECA model 222, Hamburg, Germany) and a scale (SECA model 860, Hamburg, Germany). DXA (GE lunar iDXA healthcare, Chicago, Illinois, USA) scans of the total body will be used to assess lean body mass and fat mass.

Sociodemographic information

A demographic questionnaire will be used to identify ethnicity, gender identity, level of education, socioeconomic status, social capital, marital status and disability as per the Cochrane Methods Equity PROGRESS-Plus framework.²⁶

Bone outcomes

Changes in bone outcomes will be assessed using HR-pQCT (XtremeCT II, Scanco Medical, Switzerland) and DXA (GE lunar iDXA healthcare, Chicago, Illinois, USA). HR-pQCT will be used to assess the metaphysis of the non-dominant distal radius and left tibia. Scans will be acquired using the fixed standard size of 22.5 mm and 9.5 mm proximal from the reference line, for the tibia and radius, respectively. In the case of a previous fracture, the contralateral limb will be scanned. Outcomes at both sites include bone microarchitecture (trabecular thickness and number and cortical thickness and porosity) and total, trabecular and cortical volumetric BMD. HR-pQCT images will also be used to estimate bone strength via finite element (FE) analysis. FE models will simulate axial compression up to 1% strain using a single homogenous tissue modulus of 8748 MPa and a Poisson ratio of 0.3.¹⁶ Failure load will be estimated using the Pistoia criterion; the force required for 2% of the bone tissue in the model to exceed 0.7% strain.²⁷ Image registration will be used to align HR-pQCT scans from the second time point to the first to ensure the same region of bone is being assessed.²⁸ DXA will be used to measure aBMD at the left hip (total hip and femoral neck), lumbar spine and the total body.

Muscle strength and power

Muscle strength testing will include maximal isometric voluntary contractions of the knee extensors using a Biodex System 4 Pro isometric dynamometer (Biodex Medical Systems, Shirley, New York, USA). Participants will perform two sets of three repetitions. The first set is a familiarisation set where participants will be instructed to extend their leg, positioned at a 90° angle, at their perceived 50% maximum exertion. For the second set participants will be instructed to extend at their perceived 100% maximum exertion. Each repetition will last 5 s and there will be 1 min rest periods between each repetition. The participant’s maximum attempt in N•kg will be analysed.²⁹ Hand grip strength of both hands will be measured using a hydraulic hand dynamometer (Jamar) while seated with the elbow flexed at 90°.³⁰ Participants will have one practice attempt and two recorded attempts per hand. For each attempt, participants will be instructed to squeeze the dynamometer as hard as they can for 3 s. They will have a 15 s break between each attempt. Their maximum attempt in kg for each hand will be analysed. Muscle power will be assessed using a countermovement jump on a Leonardo Mechanograph force plate (Novotec Medical GmbH, Baden-Württemberg, Germany).³¹ Participants will have three practice jumps and three recorded jumps. The recorded jump with the highest maximal absolute power (W) will be used for analysis. To properly perform the jump, participants will stand on the force plate with their feet about hip-width apart with their hands on their hips. Participants will initiate their jump after a 5 s delay of standing on the force plate.

Functional tests

The four-square-step test will be used to assess dynamic balance. Participants will have one practice attempt and two recorded attempts with a 15 s break after each attempt. They will be instructed to perform the sequence as quickly as possible without running, jumping or jogging. They must also ensure both feet are in each square before moving to the next square and must avoid touching the sticks. The sequence is as follows: step from square one forward into square two, then sideways into square three, backwards into square four, sideways into square one, sideways back into square four, forward into square three, sideways into square two and finally backwards into square one. Their fastest attempt in seconds will be analysed.^{32 33} The 6-min walk test will measure predicted aerobic fitness. To perform this test, participants will walk back and forth as fast as they can around cones set 25 metres apart. Each time they pass a cone, the outcome assessor will count a lap. At the end of the 6 min, participants will stop where they are and the total distance travelled will be measured. Predicted VO_2max (mL/kg/min), will be calculated using the equation proposed by Mänttäri et al.³⁴

Physical activity

Physical activity will be assessed using an ActiGraph GT9X (ActiGraph, Pensacola, Florida, USA) accelerometer for 7 days. Minimum wear time requirements are 3 days of 8 hours of wear time, including 1 weekend day. Non-wear periods are defined as 60 min of consecutive zeros, while epoch length is set at 1 s. We will use Freedson’s VM3 adult cutpoints to define intensity thresholds.³⁵ The Bone Specific Physical Activity Questionnaire^{36 37} and the CSEP Physical Activity and Sedentary Behaviour Questionnaire for Adults³⁸ will also be completed to assess past and current physical activity levels.

Menopausal symptoms and quality of life

Menopausal symptoms and quality of life will be evaluated through a reproductive health questionnaire, the Menopause-Specific Quality of Life Questionnaire (MENQ),^{39 40} a quality-of-life questionnaire (SF-36v2 Health Survey),⁴¹ self-compassion,⁴² stress,^{43 44} physical activity motivation,45,47 and perceptions about the exercise intervention.^{48 49}

Biomarkers

A fasted serum sample will be collected for biomarker profiling and sent to Alberta Precision Laboratories for immediate processing to analyse oestradiol, follicle-stimulating hormone, 25(OHD), calcium, creatinine and c-terminal telopeptide. Procollagen 1 intact N-terminal propeptide will be profiled by Dynacare.

Adverse events

Any adverse events, injuries and/or illnesses will be reported to study personnel at the beginning of each exercise session. Study personnel will record the type of event, how the event occurred (if necessary), the date of the event, how many days it affected the participant’s day-to-day activities and how many sessions were compromised due to the event. A member of the study staff will call participants who have missed two or more consecutive sessions without notice to inquire about injuries or illnesses. Adverse events will be reported to the principal investigator (PI) for assessment and recording in the adverse events log. We will report all serious and non-serious adverse events (SAEs), related or not related to the intervention.

Local SAEs are adverse events experienced by research participants at the site(s) under the jurisdiction of the University of Calgary Conjoint Health Research Ethics Board (CHREB). A local SAE will be reported if the PI believes it is an unanticipated problem, that is, it is unexpected, related or possibly related to the research and places research participants or others at a greater risk of harm. The PI will complete the local SAE report when the local SAE meets the definition of an unanticipated problem. Local SAEs that are fatal or life-threatening will be reported to the CHREB within 7 calendar days of the PI becoming aware of them. All other local SAEs will be reported to the CHREB within 15 calendar days of the PI becoming aware of them. Study staff will inform the sponsor of adverse events through the university’s IRISS (Institutional Research Information Services Solution) portal. Participants with soft tissue injuries will be referred to the University of Calgary Sports Medicine Clinic.

Statistical methods

Analyses will be consistent with what is recommended in the CONSORT guidelines for reporting of pilot and feasibility studies.²³ We will estimate percentages for feasibility outcomes (ie, recruitment rates, attrition and exercise attendance); percentages will be described using descriptive statistics (ie, mean and SD). A significance level of 0.05 will be used for all secondary outcomes. This feasibility study is powered to investigate the feasibility of this intervention, so all analyses of secondary outcomes will be exploratory. We will compare group differences in secondary bone, biomarker, muscle and physical function and quality of life outcomes using linear regression for continuous variables adjusting for baseline variables (ie, lean mass and BMD) and χ² tests for frequency variables. Analyses will examine the moderation of stratifying variables of HRT use and menopausal status. To understand if individuals with greater levels of bone resorption markers or lower levels of reproductive hormones experience greater benefits of the intervention, we will fit secondary linear regressions that include biomarkers as covariates. All participants will be considered in the analysis. Intention to treat and exploratory per-protocol (>80% protocol adherence) analyses will be performed to determine if those with greater participation derived greater benefits. We will perform sensitivity analyses for per-protocol analyses and adjust for potential imbalances in baseline characteristics. Secondary linear regression analyses will examine whether changes in bone outcomes are associated with baseline or changes in biomarkers of bone turnover and hormonal status. Since secondary outcomes are exploratory, we will not adjust for multiple testing. Missing data will be handled using multiple imputations.

Data monitoring

The study will be monitored by the study investigators. Two investigators, including a clinical investigator, will comprise the internal data safety monitoring board. Ongoing review of data will occur actively during recruitment. The research team will use a procedure manual and standard operating procedures. All staff will have the required training to fulfil their roles in the study. Team member roles will be logged and signed off by the PI once training has occurred in the study task delegation log. Analyses of the baseline data will be conducted to explore whether there are differences between perimenopausal and early postmenopausal women for all secondary outcomes. There are no interim analyses planned nor are there stopping guidelines for this feasibility trial. The investigators will permit trial-related monitoring, audits, CHREB review and regulatory inspections, providing direct access to source data/documents. The study trial coordinator will be present to give access to source data and documents as required for monitoring and inspections.

Patient and public involvement

The development of this study was informed by a patient partner and knowledge user—a woman currently in perimenopause and another employed as a CEP working with this population. Partners helped inform study design (eg, the exercise intervention), recruitment and burden of assessments.

Ethics

This study has been approved by the University of Calgary Conjoint Health Research Ethics Board REB22-1632. Any amendments to the protocol will be submitted to the University of Calgary CHREB for review and approval prior to conduct. Any deviations from the original statistical plan will be described and justified in the final report.

All participants will be provided a consent form describing this study and providing sufficient information for participants to make informed decisions about their participation. The formal consent of a participant, using the CHREB-approved consent form, will be obtained before the participant partakes in any study procedure. The consent form must be signed by the participant or legally acceptable surrogate/third party and the investigator-designated research professional must obtain the consent before study participation.

The PI will discuss data confidentiality with all personnel working on this research project. The master list linking Study ID to participant name and personal information will be stored on a secure server in a password-protected file only accessible to the research coordinator. Any study data not stored on REDCap are stored in a locked room. The data collected are anonymous and identified by Study ID and initials. There will not be any disposal of participant data. Any publication resulting from this study will not identify participants in any way. The results will be presented as aggregated data so that no individual participant identification will be possible. Therefore, publication or release of the data will not affect participant confidentiality. Following study completion source documents will be sent to an approved designated offsite storage facility. Source data will be retained and maintained for a total of 5 years after study closure prior to disposal. The complete data set will reside within REDCap, with access being approved by the PI. The investigators have no relevant financial or competing interests.

Dissemination and anticipated impact

Study results will be presented at national and international conferences and published in academic journals. Participants will be given reports detailing changes in select bone and muscle outcomes from baseline to follow-up, along with summaries of study findings.

Currently, there is a lack of evidence-based strategies to prevent loss of bone and muscle mass and quality during the menopausal transition. HiRIT could potentially slow down the bone and muscle loss experienced during this transition but has not been studied in perimenopausal and early postmenopausal women. Therefore, this study will determine whether a 9-month HiRIT programme focused on the maintenance of bone and muscle health is feasible in this population. Our findings will inform the design of a larger study to evaluate the efficacy of HiRIT for preventing bone and muscle loss in women during the menopausal transition.

Additionally, our trial may help narrow the knowledge gap on how bone and muscle change during the menopausal transition. Our study population of perimenopausal and early postmenopausal women is chronically understudied and the longitudinal data we collect may help develop our understanding of how bone and muscle loss progress over time. Exploratory results may also inform the outcomes assessed in future trials.

We acknowledge that our study is not without limitations. Due to the nature of the intervention, we are unable to blind participants to their group allocation (intervention or control). Therefore, any changes that occur between baseline and follow-up in the intervention group could be affected by their knowledge that they have received the exercise intervention. Furthermore, although providing a supervised intervention enables us to accurately track adherence, it also narrows our study population to women who can access the location it is offered at and are available at the scheduled times. The 9-month length of the trial may also limit our ability to identify clinically significant changes in BMD. However, this length of time was chosen as a compromise between the length of a bone remodelling cycle⁵⁰ and maintaining high adherence to the intervention.

Ultimately, our goal is to develop proactive approaches for preventing osteoporosis, instead of treating it once osteoporosis has already developed. This feasibility study will provide important information to determine whether a HiRIT intervention is feasible in perimenopausal and early menopausal women so that we can design a larger definitive trial to determine whether it is an effective strategy to prevent bone and muscle loss.