This trial was funded by the National Center for Complementary and Alternative Medicine (NCCAM), National Institutes of Health. The Harvard Medical School (HMS) Osher Research Center was the organizational center for the study. All clinical work was performed in Boston, MA at the Beth Israel Deaconess Medical Center and the biomechanical sub-study was conducted at the Spaulding Rehabilitation Hospital. Tai Chi was administered in the community as described below. Institutional Review Boards representing all collaborating institutions approved this study. At the time of writing this manuscript, recruitment and enrollment have been completed but interventions and outcome assessments are ongoing.
This study is a pilot randomized controlled pragmatic trial assessing the effectiveness of Tai Chi for attenuating bone loss for post-menopausal osteopenic women. Participants have been randomized to either a group-based 9-month Tai Chi program plus standard care (n = 43) or to standard care only (n = 43). Our study has been designed to address three specific aims. Aim 1 is to assess the feasibility of conducting a randomized controlled trial of Tai Chi exercise for postmenopausal osteopenic women. Feasibility is evaluated with respect to our success in recruiting subjects, administering our interventions and outcome measurements, eliciting subject compliance, and retaining subjects in the trial. Aim 2 is to collect preliminary data on the effectiveness of Tai Chi in reducing rates of BMD loss in osteopenic women. Measurements at baseline, 3 months, and 9 months include markers of bone resorption (C-terminal cross linking telopeptide of type I collagen (CTX)), bone formation (osteocalcin (OSC)), and bone density of the lumbar spine and proximal femur (dual-energy X-ray absorptiometry (DXA) at baseline and 9 months only). Aim 3 is to collect preliminary data evaluating the biomechanical, physiological, and psychological mechanisms through which Tai Chi may reduce rates of decline in BMD and fracture risks associated with osteopenia. Measurements at baseline, 3 months, and 9 months on a subset of patients (n = 16) include kinetic and kinematic characterization of gait, standing, and rising from a chair. These data will be used to model skeletal mechanical loads and postural stability. Health-related quality-of-life, exercise behavior, and psychological well-being are also being assessed over time for all participants.
Study participants randomized to the control group are offered a 3-month course of Tai Chi as a courtesy at the end of the trial. Figure summarizes the overall study design and the flow of participants through the study.
Study population and enrollment procedures
Participants were recruited through Harvard Vanguard Medical Associates (HVMA), a large practice of 15 clinical sites serving approximately 300,000 members in the Boston Metropolitan area. To do this we utilized the HVMA Clarity and EpicCare databases to identify all women aged 45-70 who had a DXA scan during the prior two years at a HVMA facility, with BMD of the hip (femoral neck or trochanter) and/or spine falling within the T-score range of -1.0 and -2.5. For patients who initially met these eligibility criteria based on electronic screening of HVMA records, letters were sent through the HVMA electronic medical record to primary care physicians requesting permission to contact them. If permission was granted from physicians, an introductory letter was sent to patients that describes the study and invites participation. A toll free number was provided for those interested, as well as for those who opt-out. Following a phone screen, eligible and interested participants were then scheduled for an in-person meeting conducted at the BIDMC. At the enrollment meeting, eligibility criteria were reconfirmed, and subjects provided written informed consent to participate in two stages of the study. The first stage involved a DXA screen to confirm that subjects were osteopenic (i.e. T-scores of the hip and/or spine have remained between -1.0 to -2.5). If BMD T-scores fell within the eligible range, subjects were able to continue into stage 2--the intervention stage of the trial. These subjects then completed additional baseline testing and were randomized to either the Tai Chi or the control group. During this baseline visit, randomized subjects were also asked if they wished to participate in the biomotion sub-study. This process was continued until eight participants from each study arm volunteered. Sub-study participants were then given an appointment for another baseline biomotion testing visit at Spaulding Rehabilitation Hospital, which was scheduled within two weeks of enrollment.
Participant inclusion criteria were: 1) Women ages 45-70y; BMD T-scores of the hip (fermoral neck or trochanter) and/or spine between -1.0 and -2.5; 2) post-menopausal without menses for ≥ 12 months; 3) does not exercise more than 5 days a week on average for more than 60 minutes per day.
Participant exclusion criteria were: 1) Osteoporotic (T-score < -2.5) at any site or a fracture in the past 2 years not caused by motor vehicle accident; 2) prior or current use of use of medication that increase risks of fracture (e.g. steroids, anti-convulsants, anticoagulants, lithium); 3) prior or current use of medications that modify bone metabolism (e.g. bisphosphonates, selective estrogen receptor modulators such as Raloxifene); 4) use of calcium supplements above levels suggested within the recommendations of standard care (i.e., above 1200-1500 mg); 5) current or prior year use of estrogen or calcitonin; 6) Malignancies other than skin cancer; 7) diagnosis of anorexia along with a BMI of < 17.5; 8) conditions that cause secondary osteoporosis (e.g. Cushing's syndrome, Marfan's syndrome); 9) tobacco use in past year; 10) physical or mental disabilities that will preclude informed consent or active study participation; 11) geographic or scheduling limitations that would preclude required participation in weekly Tai Chi classes and study procedures; 12) current regular practice of Tai Chi.
Randomization assignments were generated by a computer program using a permuted block design with a variable block size. The program created a permanent record of the treatment assignment associated with each study ID. Assignments were sealed in opaque envelopes, and opened by the study staff following informed consent procedures and baseline testing.
Participants randomized to both the Tai Chi intervention and the control group were encouraged to follow standard of care for osteopenic women as prescribed by their primary care physicians. These guidelines vary slightly depending on T-scores as follows. For T-scores between -1.0 and -2.0, recommendations include: daily calcium (1200-1500 mg) supplements; daily vitamin D (400-800 IU); and regular exercise including weight bearing, strengthening, and balance exercise. According to HVMA guidelines, pharmacologic treatment is not indicated for this group. For women with T-scores between -2.0 and -2.5, in addition to the same supplement and exercise recommendations above, pharmacologic treatment "may be added" depending on the patient's risk profile and individual preference. Participants receiving pharmacological treatment were excluded from our trial.
Tai Chi intervention
Participants in the Tai Chi group receive nine months of Tai Chi training in addition to standard care. Participants were told that they were required to attend a minimum of two classes per week for the first month of the intervention, and then a minimum of one class per week for eight months thereafter (minimum class duration of one hour). They were also required to practice an additional two times per week during the first month, and three times per week thereafter (minimum of 30 minutes per session). This additional practice could take place at home, or in additional classes offered within their Tai Chi program.
Registration and enrollment in classes was facilitated by the study staff. All Tai Chi interventions have been administered at selected, reputable and long-standing Tai Chi schools throughout the Greater Boston area that meet specific guidelines described below (Table ). A fee-for-service relationship was established between HMS and selected schools. Administering the intervention through already existing Tai Chi programs has a number of important practical and scientific advantages that increase the likelihood of success of this study. First, nine months of regular Tai Chi practice is a long and significant commitment. By allowing subjects to enroll in programs that are both located in a variety of places throughout the Greater Boston area (and thus close to homes and work places), and that offer the convenience of multiple entry-level classes per week, we hope to achieve high rates of subject recruitment, compliance, and retention. Additionally, this approach enables us to have a broad window for recruitment (i.e. rolling admission) and baseline/follow-up testing, as Tai Chi schools are eligible only if they offer ongoing enrollment or begin new entry-level courses at a minimum of every 3 months. Administering the intervention through traditional Tai Chi schools also affords a high level of ecological validity. Participants are involved in a number of traditional components of Tai Chi training that accompany the exercises themselves, including studying in traditional settings and interacting with fellow students within the school's community. These elements are often absent in fixed protocols provided in medical settings. Participation in these natural and convenient settings also make it more likely that subjects will continue studying Tai Chi once the trial is completed. This is relevant as post-study long-term adherence to Tai Chi is an outcome variable of interest in this study and will be assessed in a final audio taped exit interview. Finally, because of the inclusion of multiple Tai Chi styles and instructors, the results of this study will have good external validity--applying not only to a single protocol taught by one teacher, but to a range of approaches that share a common, well-defined set of criteria.
Eligibility criteria for Tai Chi schools
Overview of outcome measurements
All outcome measures are assessed by study staff blind to treatment assignment. Our primary outcomes are biochemical measures of bone resorption (C-terminal cross linking telopeptide of type I collagen (CTX)), bone formation (osteocalcin (OSC)), and BMD assessed using DXA assessed at baseline and then nine months later. Secondary outcomes include measures of bone resorption and formation assessed at three months, and health-related quality of life (HRQOL), balance confidence, and exercise behavior assessed at three and nine months. Biomotion substudy participants were also evaluated to assess postural and biomechanics during activities of daily living. Table provides a summary and schedule of all outcome measures.
Summary and schedule of outcome variables
Bone turnover markers
To study the sequence of bone remodeling activity that occurs in response to Tai Chi, we measure two bone turnover markers that reflect activity of osteoclastic resorption and osteoblastic bone formation. Type I collagen is a major component of bone, accounting for more than 90% of the organic matrix. C-terminal cross-linking telopeptide of type 1 collagen (CTX) is a breakdown product of type 1 collagen [69
]. Serum levels of CTX have been shown to be sensitive and specific markers of bone resorption, and when compared with alternative resorption markers, superior [70
]. Relatively short-term changes in CTX levels (e.g. 3 month) have predicted longer-term changes in BMD in pharmaceutical interventions [69
]. We also measure serum osteocalcin (OSC), a calcium binding protein which is a major component of the non-collagenous bone matrix. During bone formation, osteoblasts synthesize OSC, which is incorporated into the extracellular bone matrix and a small fraction is released into circulation [72
]. Serum OSC has demonstrated clinical utility as a biomarker for bone formation both in response to exercise [74
] and pharmacological interventions [75
]. We hypothesize that Tai Chi will have antiresorptive effects. Thus we expect to see decreases in markers of resorption and formation, since bone resorption is tightly coupled with bone formation. If Tai Chi has any anabolic potential on bone, we would expect to observe increases in both markers. By obtaining all specimens in the morning and following a 12 hour fast, diurnal variability is minimized. Processed samples of blood are stored in -80 C freezers. All specimens will thawed only once and will be analyzed as one batch at the end of the trial.
DXA measures of BMD
BMD of the hip and spine are measured by DXA using a QDR 4500 Discovery densitometer (Hologic, Inc., Waltham, MA) in the array (fan beam) mode. In this short trial, hip BMD is not expected to show statistically significant changes, but is being measured at baseline for eligibility determination, and at 9 months to estimate an effect size for a future study. At the screening visit, subjects undergo a single measurement of the left hip and spine. Nine-month follow-up measurements are analyzed using the "comparison" feature of the standard Hologic APEX 2.3 analysis program. The densitometry technician matches identical regions of interest (ROI) for the duplicate and follow-up examinations. Short-term in vivo estimates of the coefficients of variation for replicate baseline measurements for the total hip and lumbar spine measurements in women are expected to be about 1.5% [76
]. DXA has good precision (1%) and low radiation dose (10-40 uSv) [77
]. Longitudinal machine performance is monitored for drift using the manufacturer's phantom as is routinely done in clinical trials. The director of the DXA lab (DK) reviews all DXA analyses.
Health-related quality of life
As a holistic intervention, Tai Chi may simultaneously impact many components of health. Prior studies of Tai Chi have reported improvements in mood, decreased anxiety and enhancement of vigor [80
], and some studies have reported correlations between Tai Chi-induced reduction in fall anxiety and subsequent fall probability [84
Health-related quality-of-life (HRQOL) is a multidimensional concept that includes physical, mental, psychosocial functioning, as well as perceptions of overall health. Previous studies suggest that patients who participate in Tai Chi report significant improvements in HRQOL [38
]. To capture health-related QOL, we are using the Medical Outcomes Survey Form (SF-36) health status survey [86
]. The SF-36 has been validated for use in patients with diverse medical problems. Reported test-retest reliability coefficients range from 0.72-0.93. Fear of falling will be assessed using the Activity-specific Balance Confidence Scale (ABC Scale), which has been validated in numerous study populations [87
]. We are also evaluating menopausal symptoms using the Menopause Quality of Life instrument [90
]. One published study suggests Tai Chi can favorably manage menopausal symptoms in addition to reduced BMD [74
]. Finally, a three question expectancy scale [91
] to quantify participant's beliefs regarding Tai Chi is included because such beliefs have been shown to impact responses within clinical trials to other CAM modalities such as acupuncture [92
Tai Chi class attendance and home practice compliance
Attendance in Tai Chi classes is recorded by having participants ask Tai Chi instructors to initial and date a wallet-size attendance card at the end of each class. Home practice is recorded using a simple practice log indicating the frequency and duration of home Tai Chi practice each week. Prepaid envelopes are provided and participants are asked to mail both class attendance cards and home practice logs at the end of each month. If attendance and/or practice logs are not submitted on time, or a participant is absent from class 3 times in a row or non-compliant with the home practice protocol (i.e. < 70% recommended), the study coordinator immediately contacts the participant, and works with them to identify and overcome any barriers related to their participation.
Non-Tai Chi exercise and physical activity
The goal of this study is to compare Tai Chi in addition to standard care for osteopenia--which already includes the suggestion of regular exercise--to standard care alone. Although our eligibility criteria exclude participants who state they exercise more than 5 days a week on average for more than 60 minutes per day, we actively track physical activity (other than Tai Chi) for subjects in both groups.
To measure physical activity, we employ the Seven-Day Physical Activity Recall (PAR) [93
], recently modified to include recall of strength and flexibility activities [95
]. The PAR is a general-purpose measure of physical activity widely used in clinical, epidemiological, and behavior change studies including studies of osteopenic women [96
], and tested for validity and reliability in many populations [93
]. The PAR estimates total energy expenditure (kcal/kg/d) using patient's recall of time spent during the previous 7 days conducting a range of activities.
Qualitative exit interviews
As part of the 9
-month follow-up, participants in the Tai Chi group participate in semi-structured qualitative exit interviews to further explore areas not captured in our standardized quantitative instruments. Six broad questions used in prior Tai Chi studies [39
] that are being used to structure interviews include: 1) Has participation in this program had any noticeable effect on your life?; 2) Has participation in the program affected your activities of daily living in any way?; 3) Do you feel like you benefited from this program?; 4) Did you find the program enjoyable?; 5) Would you recommend Tai Chi to other women with low bone density?; 6) Do you plan to continue practice of Tai Chi? Each interview session lasts approximately 15 minutes and is audiorecorded. Tapes are then transcribed verbatim and checked against audio recordings prior to analysis. Transcribed text will be coded using the Atlas ti program (Scientific Software Development, Berlin, Germany). Interviews will be evaluated for emerging themes using a grounded theory approach [99
Specific aims of the substudy are to evaluate whether, following Tai Chi training, individuals exhibit: 1) improved balance control during quiet standing, rising from a chair, and level walking; 2) changes in joint kinetics (moment and power trajectories) during rising from a chair and level walking; and 3) improved performance on clinical tests of balance, rising from a chair, and level walking. All biomotion studies are done in the Motion Analysis Laboratory (MAL) of Spaulding Rehabilitation Hospital. All tests are performed barefoot and completed in one session of approximately 3 hours. The instrumentation in the MAL includes an eight-camera motion analysis system (VICON, Oxford, UK) and a walkway with two embedded force platforms (AMTI, Watertown, MA). For all biomechanical tests, spherical reflective markers are attached to anatomical landmarks of the feet, legs, pelvis, trunk, arms and head. The trajectories of these markers are captured by the motion analysis system and used to calculate kinematics (joint angles) and center of mass (CoM) position. The force platforms embedded in the walkway are used to collect ground reaction forces, from which we estimate center of pressure (CoP) data. CoP data are used to characterize balance control. Force platform data are used to quantify joint kinetics (moment and power trajectories) during rising from a chair and during level walking.
Assessment of balance control during quiet standing
We conduct tests of quiet standing balance during which subjects are asked to stand on a force platform for 40 s with arms by their side, feet shoulder-width apart and their eyes closed. The CoP trajectory is captured during each of 10 trials. After 5 trials, the subject is allowed to take a short break and sit down.
A scatter plot of the anteroposterior (AP) and mediolateral (ML) displacement of the CoP, called stabilogram, is analyzed for each trial. Balance control during the quiet standing trials is characterized via both traditional and random-walk sway parameters [100
We compute the following traditional sway parameters, which describe geometric features of the stabilogram: the mean stabilogram radius (measured in millimeters - mm), the area swept by the stabilogram (mm2
), the maximum radius of sway (mm), and the range of the AP and ML excursions (mm). We hypothesize that we will observe a reduction in postural sway, as reflected by a decrease in traditional sway parameter values thus indicating a tighter control of balance following Tai Chi training [6
We also estimate three random-walk sway parameters: the critical mean square displacement
(measured in square millimeters - mm2
), the effective long-term diffusion coefficient Drl
/s), and the long-term scaling exponential Hrl
. The conceptual framework underlying this analysis is based on the assumption that, during quiet standing, the postural control system uses open-loop and closed-loop control schemes over short-term and long-term intervals respectively [102
]. Over short-term intervals, the body tends to drift away from a relative equilibrium point. Over long-term intervals, the body tends to return to a relative equilibrium point. The critical mean square displacement characterizes the threshold at which the postural control system switches from one control strategy to the other. The effective long-term diffusion coefficient and the long-term scaling exponential characterize the behavior of the postural control system in the open-loop and closed-loop control conditions respectively. We hypothesize that a decrease in all three random-walk sway parameters will be observed following Tai Chi training indicating a more tightly regulated system [101
Changes in joint kinetics and dynamic balance control during chair rise
We test participants' ability to rise from sitting on a chair to a standing position. Subjects sit on a chair with their feet positioned about shoulder-width apart on a force platform. Subjects are asked to rise to a standing position and remain standing for about 5 s. They are allowed to rest their hands on their thighs while standing but are not allowed to use their arms to push off from the chair. Subjects are asked to perform this task 10 times and are given a break after 5 trials. The kinematics of upper and lower body movement is characterized by joint angles. The kinetics is described by joint moment and power trajectories. We assess the dynamic control of balance of each subject during the chair rise using parameters describing the relative trajectories of the CoM and CoP. We hypothesize that we will observe changes in joint kinetics and a more tightly control displacement between CoM and CoP after Tai Chi training.
Changes in joint kinetics and dynamic balance control during gait
The comfortable walking speed of each subject while walking barefoot is first determined during the baseline assessment. Subjects are asked to walk at this speed (± 10%) during the gait assessments at the baseline, 3-month and 9-month follow-up sessions. This will allow longitudinal within-subject comparisons of changes in gait kinematics and kinetics for the duration of each subject's participation in the trial. We collect up to 20 walking trials with good foot contacts on the force platforms. During each gait cycle, joint kinematics and kinetics will be characterized by deriving joint angle parameters and joint moment and power trajectories respectively. We will also assess dynamic stability during the walking trials by analyzing the path of the body CoM. We expect Tai Chi-induced adaptations in joint kinematics and kinetics to be associated with improved BMD [103
]. Furthermore, we anticipate that a more tightly controlled CoM trajectory [105
] will be observed following Tai Chi training [61
Subjects are asked to perform 5 clinical tests. The timed tandem walk [106
], the Timed Up and Go test (TUG) [107
], the Berg Balance Scale (BBS) [109
], the timed one-legged stance test [110
], and the timed chair rise test [112
]. These tests have been shown to discriminate balance ability, to be predictive of falls, and to be related to muscle strength [109
]. They represent a good range of subjective and objective clinical tests with a variety of balance-related tasks - walking, turning, and reaching - and both timed (continuous) and scored (discrete) measures. Subjects are given rest breaks between each test and trials of a test. We hypothesize that improvements in all the clinical test results will be observed following Tai Chi training [113
Adverse events are monitored through reports from the school instructors, reports from participants, and through systematic monthly safety calls to participants conducted by study staff. Each school was presented a safety and adverse event policy along with forms to report events that occurred in class or that were otherwise reported by participants. All study participants were informed of the study's safety policy and given adverse event forms at baseline. Study staff called participants in both the Tai Chi and control group twice during the first month and monthly for the remaining 8 months to ask if they had any questions or had any safety issues related to their participation in the study.
Statistical Analysis, Sample Size and Power
Specific Aim 1: To assess the feasibility of conducting a trial of Tai Chi in osteopenic women, we are using screening logs to determine the proportion of screened women who are eligible and the proportion of eligible women who enroll in the study. We track factors that make subjects ineligible, and for unwilling eligible subjects, reasons for not participating. We measure compliance through attendance at Tai Chi classes and self-reported home exercise logs. Participants who attend at least 80% of target number of classes and comply with 70% of prescribed home Tai Chi practice are considered compliant. Levels of exercise compliance will also be used as covariates in post-hoc analyses of all outcome variables (see below). We also track the proportion of participants in each group who complete each of the follow-up visits. Overall, we will consider further study feasible if at least 75% of intervention participants are compliant and at least 80% of participants in each group complete all study evaluations (i.e., baseline, 3-month and 9-month).
Specific Aim 2. The primary clinical outcomes are changes from baseline in CTX and osteocalcin (3 and 9 months), and BMD (9 months) assessed with DXA. Each outcome will be measured as the percentage change from the baseline value. Between-group comparisons will be tested using Wilcoxon rank sum tests. We will examine the distributions of the outcomes to determine whether parametric tests can be used in a definitive phase III trial. We will conduct all primary analyses according to the intention to treat paradigm. Exploratory analyses will include fitting ordinary least squares regression models to evaluate the association between the primary outcomes and a variety of possible predictors (e.g., baseline T-scores, use of calcium and vitamin D supplements, activity level, Tai Chi compliance, exposure to specific types of Tai Chi exercises, etc.). The goals are to identify factors that need to be included in the design of a definitive study (i.e., stratification factors) and to identify interesting associations for further investigation (i.e., hypothesis generation).
Specific Aim 3. To collect preliminary data evaluating the biomechanical and physiological mechanisms through which Tai Chi may impact bone turnover and fracture risks associated with osteopenia. Changes between baseline and 3 and 9 months in biomechanical parameters associated balance control during quiet standing, and joint kinetics and dynamic balance during chair rise and gait will be compared using signed rank tests. Similar analyses will be employed for clinical balance and function tests, as well as HRQOL and fear of falling. We will calculate Spearman correlations between measures of biomechanical parameters and measures of BMD changes (CTX, OSC, BMD) to evaluate the relationships between these domains. Based on these analyses, we will conduct exploratory regression analyses to explore mechanistic pathways to generate hypotheses for future validation.
Sample size and statistical power
There were no studies of osteopenic women that employed a 9 month Tai Chi intervention that we could use to estimate sample size and statistical power for the outcomes of interest. The closest approximation we found was the study by Yamazaki [53
] which: a) specifically targeted osteopenic women; b) included short-term measures of bone turnover rates (CTX at 3, 6, and 12 months) and BMD (6 and 12 month); and c) was a based on a relatively low impact weight bearing exercise like Tai Chi (i.e. walking). In this study, Yamazaki observed a mean reduction in CTX at 6 months of 21% with a standard deviation of approximately 35% in the exercise group and a mean change of 0% with a standard deviation of approximately 20% in the control group. Assuming the same standard deviations, a sample size of 34 per group would be required to provide power of 0.80 to detect a 20% difference between groups (e.g., 0% change in control vs. 20% change for Tai Chi), with a parametric test. For at least some of the outcomes we expect data to be skewed. Therefore, to be conservative we will use non-parametric tests, which will result in a loss of efficiency that we estimate to be 5%. Allowing for 15% of participants to fail to complete the 9-month evaluation (based on our prior experience), we require 43 participants per group to ensure adequate power.
Yamazaki also measured percent change in lumbar BMD from baseline to 6 and 12 months [53
]. At six months they observed changes of 0.47% ± 1.09% in the exercise group and -0.45% ± 1.20% in the control group. At 12 months, these changes were 1.71% ± 4.42% in the exercise group and -1.92% ± 2.94% in the control group. Using the same assumptions as above, our sample will provide power of 0.60 to detect a difference between groups of 0.90% at 9 months.