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Changes of tibia bone properties after spinal cord injury: Effects of early intervention
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Changes of Tibia Bone Properties After Spinal Cord Injury: Effects of Early Intervention Eling D. de Bruin, MSc, Petra Frey-Rindova, MD, Roland E. Herzog, Msc, Volker Diet& MD, Maximilian A. Dambacher, MD, Edgar Stiissi, PhD ABSTRACT. de Bruin, ED, Frey-Rindova P, Herzog RE, Dietz V, Dambacher MA, Sttissi E. Changes of tibia bone properties after spinal cord injury: effects of early intervention. Arch Phys Med Rehabil 1999;80:214-20. Objective: To evaluate the effectiveness of an early intervention program for attenuating bone mineral density loss after acute spinal cord injury (SCI) and to estimate the usefulness of a multimodality approach in diagnosing osteoporosis in SCI. Design: A single-case, experimental, multiple-baseline design. Setting: An SC1center in a university hospital. Methods: Early loading intervention with weight-bearing by standing and treadmill walking. Patients: Nineteen patients with acute SCI. Outcome Measures: (1) Bone density by peripheral computed tomography and (2) flexural wave propagation velocity with a biomechanical testing method. Results: Analysis of the bone density data revealed a marked decrease of trabecular bone in the nonintervention subjects, whereas early mobilized subjects showed no or insignificant loss of trabecular bone. A significant change was observed in 3 of 10 subjects for maximal and minimal area moment of inertia. Measurements in 19 subjects 5 weeks postinjury revealed a significant correlation between the calculated bending stiffness of the tibia and the maximal and minimal area moment of inertia, respectively. Conclusion: A controlled, single-case, experimental design can contribute to an efficient tracing of the natural history of bone mineral density and can provide relevant information concerning the efficacy of early loading intervention in SCI. The combination of bone density and structural analysis could, in the long term, provide improved fracture risk prediction in patients with SC1 and a refined understanding of the bone remodeling processesduring initial immobilization after injury. 0 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation NE OF THE COMPLICATIONS of spinal cord injury (SCI) is the associated bone mass loss that occurs, mostly 0 below the pelvis. l-l1 Approximately 2 years after the accident that causes the injury, an equilibrium is reestablished between
From the Department of Material Sciences, Laboratoly for Biomechanics ETH (Mr. de Bruin, Mr. Herzog, Dr. Stiissi), and the Paraplegic Centre, University Hospital Balgrist (Drs. Frey-Rindova, Die& Dambacher), Zurich, Switzerland. Submitted for publication April 15,1998. Accepted in revised form June 23, 1998. Supported by the Swiss Paraplegic Foundation and by the “Schweizerische Bankgesellschaft” on behalf of a client of tbe bank. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Eling D. de Bruin, MSc, Laboratorium fur Biomechanik ETHZ, Wagistrasse 4, CH-8952 Schlieren, Switzerland. 0 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/99/8002-4973$3.00/O
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bone resorption and formation, but only after the patient has lost significant bone mineral. Immobilization due to neurologic diseases, where concomitant neurologic disturbances follow, leads to more severe bone loss than bone loss after bedrest.‘* It is unknown as to whether any intervention can sustain bone mass after SCI.13There is agreement, however, that remobilization will not repair mineral loss after the first 6 months of immobilization, ie, when the osteoporosis has become inactive and established.2 Several intervention studies aimed at influencing bone have been reported.i4-l* Thoumie and coworkers14 and NeedhamShropshire and associatesI studied the effects of walking training on bone. Both concluded that there was no effect of their training on bone. i4,i5 The effect of standing on bone has been reported in several other studies.16-18The results, however, seem to be contradictory. Kunkel and colleaguesi concluded that standing did not alter measured bone variables. Goemaere and associatesi reported that subjects regularly performing standing, starting 1 year after SCI, had better preserved bone mineral density than age- and sex-matched healthy controls. In patients with incomplete SCI, tilt-table exercises reportedly reduced hypercalciuria and resulted in a more positive calcium balance, particularly in an early group of patients.ls In conclusion, to prevent bone loss, it seems to be important to mobilize the subject with SC1 as soon as possible after injury, and to include the performance of “normal” muscle function and load bearing in the exercise regimen.2*8 Osteoporosis combines a medical cause with an osteopenia and mechanical incompetence of bone.i9 One of the clinical effects of osteoporosis in paraplegia is spontaneous fractures of long bones. These fractures occur in paraplegic patients with an incidence of 2% to 6%.20-22The usual history of trauma and the classical signs of fracture are absent in these patients. Frequently, minor trauma is the cause of fracture.23~~The diagnosis of osteoporosis based on bone mass measurement, however, is problematic. The reason for this is that bone mass measurements, although informative on material properties on the level of tissue, do not and cannot predict risk of fracture of bone as a whole. Bone strength depends on these material properties25,26 as well as on macroscopic structural propertiesz7 known as bone architecture on the level of the organ. Progress in clinical characterization of bone relies on developing means to clinically assess all the important determinants of bone quality, specifically the intrinsic material properties of a bone (stiffness and brittleness) versus the macroscopic structural properties.27 The mechanical properties of the tibia can be assessedby measuring the bending stiffness of the tibia using the phase velocity of flexural waves passing through it. In accordance with the Bernoulli-Euler model, the bending stiffness of a rotationally symmetrical long beam is proportional to the phase velocity of fourth-order flexural waves.** The validity of this relationship for the tibia has been confirmed in vitro. Bending stiffness for 21 tibias was measured using three-point bending tests, and was compared to calculated bending stiffness from phase velocity and area moment of inertia of tibia1 bone. This resulted in a very good correlation (r = .96). To define the
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relation between bending stiffness and fracture resistance of tibia1 bone, all 21 tibias were loaded until fracture. This gave an impression of maximum bending moment of the tibia bone. It was concluded that measurement of bending stiffness relates to fracture risk.2X Results from an in vivo assessment of the bending stiffness of human tibiae with a Bone Stiffness Measurement Device Swing (BSMD-Swing)” demonstrate that bone mineral measurements are not suitable predictors to evaluate changes in mechanical properties of long bones.29The BSMD-Swing was adapted under a European Space Agency contract to provide information about bone strength changes that could occur during long-term exposure to low gravity. After successful completion of its tasks on the Euromir ‘95 mission it was concluded that the BSMD-Swing might be used to determine changes in the bending stiffness of the bone due to the effects of long-term immobilization.30z31 Therefore, the question arose as to whether the BSMD-Swing is also able to provide additional clinically useful information about bone strength in patients with SCI. Do measurements on the organ level of bone provide additional information to measurements on the tissue level, eg, to measurement of bone mass? Additionally, could clinically relevant information reliably predict osteoporosis, or could it indicate the effectiveness of treatments aimed at the prevention or attenuation of osteopenia? This question, however, is difficult to answer without including information on the daily loading pattern to which the patients were subjected. In vivo, the phase velocity is calculated from eight accelerometers that have been pressed firmly against the tibia. The flexural wave is produced by mechanical impact to the head of the tibia, the strength of the impact being comparable to a patella-tendon reflex test. The basic methodology used in quantitative computed tomography (QCT) involves the computation of the cross-sectional distribution of x-ray attenuation in a body by back-projecting the x-ray transmission measurements acquired at many angles around the body until the spatial arrangement of the absorbing structures can be determined. 32 With the information available in QCT scans, it is possible to isolate densitometric and geometric changes in both cortical and trabecular compartments.33 Hence, the aim of the study was twofold: (1) to evaluate the effectiveness of an early loading intervention program in paraplegia on attenuating bone mineral density loss after acute SC1with a peripheral QCT (pQCT) scanner; and (2) to estimate the usefulness of simultaneously measuring bone material (tissue) composition and strength of bone as an organ. The bony organ chosen was the tibia. METHODS Subjects During 1% years, 19 SC1 subjects were enrolled in the study after receiving oral and written information. All participants signed a statement of informed consent approved by the Institutional Review Board of our center. All subjects had traumatic SCI, and were men. A summary of subject characteristics is given in table 1. The first 13 subjects had follow-up measurements for 25 weeks during the research period. Of these 13 subjects, six were selected for a combination of standing exercises and treadmill walking according to the in-house selection protocol, and seven patients were selected for the customary inpatient rehabilitation program with standing exercises only. The last six patients included in the study had bone measurements in week 5 after SCI. Since these subjects all entered the study in the last 3
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Table
1: Characteristics
Subject
Age at Injury MS)
of Subjects
Level of Lesion
ASIA Score
and the
Exercise
Program Time Between Injury and Intervention (Weeks)
Type of Intervention
I-400
53
C6
C
Walking
4
Z-405 3-406
32 24
T4/5 C4
C B
Immobilization Immobilization
* *
4-409 5-412
27 22
C6 T12
C D
Walking Walking
3 2
6-413 7-401
37
c4
C
c4 Tll
B A
Walking Immobilization
4 *
S-402
33 25
Standing
1
9-403 1 O-407 1 I-408
34 43 48
T9 T12 TIO
A A A
Standing Standing Standing
2 1 3
12-410 13-411
21 26
Ll T4/5
A B
Immobilization
*
Standing
3
14-415 15-417
26 26
C6 T6
6 A
-
16-418 17-419
59
TIO
A
1 S-420
32 40
T12 T6
D A
19-421
19
c5
B
-
* No-loading exercise within the 25week reached the desired level of 5 hours weekly.
observation
period
that
months of the l%-year monitoring period, only their first measurement data were included in our analysis. Within 24 hours postinjury all patients received 2g Cortisol on the basis of a NASCIC II protocol.34 In all subjects heparinization (amount adapted to body weight) took place during the 8 weeks after injury. Other medications taken by the subjects were usually muscle relaxant and antispastic drugs, with some patients also taking urinary antibacterial agents, stool softeners, or medication to control hypertension. None of the pharmaceutical agents is known to directly influence bone metabolism. Protocol Extensive medical screening was performed for each subject to identify any contraindications to participating in one of the exercise programs. To exclude other illnesses, medical evaluations included blood analysis and urinanalysis, X-rays of the lower extremities and chest, and psychologic testing in the form of a conversation with a psychologist. Standardized neurologic examinations were performed according to the American Spinal Injury Association (ASIA) protocol.35 The ASIA motor (maximum 100 points) and sensory (maximum for both aesthesia and algesia 112 points) scores indicated the severity of the SC1 lesion, Only those subjects with medical clearance were allowed to participate in the study. No subjects were excluded based on these tests. Contraindications for participation in walking exercise include lower motor neuron involvement, previous lower extremity fracture, and medical and/or psychologic instability. Participation in the combined standing/walking program was decided on the following general inclusion/exclusion criteria: central (spinal) lesion, age older than 10 and younger than 60 years; no other lesions and/or infirmity; no circulatory disturbances during standing; and patient’s informed consent. If selected for the combined standing/walking program, the subjects started training as soon as possible after the injury, and performed half an hour of walking and standing for half an hour, 5 days per Arch
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week for half a year. Detailed electromyography (EMG) activity results have been reported.36-38The amount of unloading during the course of this training had a range of 20% to 80%, with a mean of 40%. For all subjects a precise protocol of all other physical activities that might influence the lower extremity bones was registered. The subjects allocated to the customary rehabilitation program trained in weight-bearing only by standing. The start of training was defined by medical clearance and was implemented as soon as possible after injury. The aim of the rehabilitation program was to have patients standing or standing/ walking for at least 1 hour daily, 5 days per week. To quantify the influence of the amount of loading exercise on the various bone parameters, the subjects were divided into three groups. Group 1 Individuals had 0 to 5 hours per week loading exercises (immobilization); group 2 had 5 or more hours of standing exercises per week (standing); and group 3 had 5 or more hours of combined standing and walking exercises per week (walking). The starting point of intervention was defined as the first week postinjury in which the minimal desired amount of exercise was reached (table 1). Subjects were randomly selected to participate in one of the intervention programs. Training Equipment Subjects with complete paraplegia allocated to the walking program and subjects with incomplete paraplegia at the beginning of training started stepping movements that could be induced on a treadmill moving at low speed (about 1.3km/h). Physiotherapists assisted the movement of the feet in complete paraplegic patients, especially at lift-off and heel-strike. Body weight was partially supported by suspending subjects over the treadmill on a parachute harness connected to a winch. The degree of support was provided by a scale on a winch (fig 1A). Standing was performed using a standing frame with a hip-suspension band necessary to maintain the patient in the upright position (fig 1B). Bone Measurements Bone density measurements were performed with a Densiscan 2000b on the left tibia, unless it had been fractured before the XI. Fractures, even those completely healed, yield spurious bone density values.2s Two stacks of CT scans were analyzed: one close to the ankle joint and one in the diaphysis.
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To ensure that the CT scanswere always made at the same angle relative to the bone axis, the extremity was measured in an anatomically formed radiolucent cast. A detailed description of the tibia examination protocol has been described elsewhere.25 Four parameters were derived and calculated for a general characterization of the measured bone: Trabeczdar bone. To determine this bone parameter, the inner core of the bone was assessed.The core area contains only trabecular bone. Compact bone (ie, cortical bone). This parameter represents the average bone density at the diaphyseal measuring site (bone mass divided by total cross-sectional area of the bone). The area moment of inertia of the tibia. The area moment of inertia (AMOI) with respect to the maximal (maxAMO1) and minimal AM01 (minAMO1) orthogonal directions at diaphysis was calculated numerically from the CT scans. All pQCT bone measurements were performed in weeks 5,9, 13, 17,21, and 25 after injury. Phase velocity propagation in the tibia was measured with an initial version of the BSMD-Swing” that has been described in detail elsewhere.2g,30,3g,40 For the measurements with the BSMDSwing, a standardized measurement protocol was followed. Measurements took place around week 5 and week 25 postinjury. Bending stiffness was calculated from the phase velocity values and anthropometric variables of the tibia in accordance with previously described procedures41 Reproducibility of Bone Measurements Reproducibility in routine patient measurements was determined earlier to vary between .2O% and .30% for the tibia with PQCT.~~Measurements on actual test subjects with the BSMDSwing have shown a receiver signal reproducibility within 22% (standard deviation).30 Research Design Because of the heterogeneity of the population involved, for part of the data analysis a controlled, single-case, experimental, multiple-baseline design was chosen. In traditional controlled group studies, treatments are contrasted by comparing groups of patients, each group being subjected to one intervention condition. Unless special statistical techniques are used, intersubject variability may well mask specific treatment effects. Controlled, single-case experimental design appears to provide
Fig 1. Schematic exercise set-up for early (A) walking on a treadmill and (B) standing exercises. Patients are suspended over the treadmill in a parachute harness. The harness is connected to a winch that allows for body weight support adjustment. During exercises the treadmill moves at a speed of about 1.3km/h. Standing is performed in a standing frame. To maintain the patient in upright position, a hip-suspension band is applied.
’ fine plate Arch
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a way to circumvent this problem, and previous rehabilitation research has shown that single-case methodology can be an appropriate means.42 The multiple baseline design with staggered lengths of A-phases controls for selection bias and contamination. Starting with a baseline phase may meet with ethical, rather then methodological problems. In this study this problem was “solved” on the basis of ability and/or motivation of patients to participate in the early rehabilitation program.
Table 2: Development, in Terms of Change From Initial Values, During the First 25 Weeks Postinjury for Immobilized Subjects
Statistical Analysis Both visual inspection and statistical analysis were used for the analysis of the data from the single-subject studies.42 Repeated-measures analysis of variance was used for the statistical analysis of the time series observations of the studied cases. Pearson correlations were used to evaluate the relationships between tibia bone parameters measured with pQCT and with BSMD-Swing, and to evaluate the influence of time postinjury on maxAM and minAMO1. Statistical analysis was performed with the SAS statistical package running on a PC. For all tests, a significance level of .05 was chosen unless otherwise indicated. The desired level of reliability in the assessmentof a patient’s phase velocity propagation was set at 35m/sec. Each patient was measured in weeks 4, 5, and 6 postinjury with a repetition of measurement on each occasion. Measurements were always performed by the same tester. This procedure was repeated in weeks 24, 25, and 26 postinjury. In such a design, a difference in phase velocity of 35m/sec or more within 20 weeks indicated a real difference, rather than a possible error.43
Phase
RESULTS Tibia Bone Changes During Early Intervention Exercise In the group of 13 patients who were monitored for 25 weeks, two subjects initially selected for the walking program were not able to reach an exercise level of 5 hours per week during the first 25 weeks postinjury. Subject 2 underwent a conservative treatment of a vertebral fracture, and was immobilized for 3 months postinjury. After this period he was only able to gradually reach the desired amount of exercise time. Subject 3 suffered from various medical complications during the 25week observation period, which caused major obstacles in his walking exercise rehabilitation. Two subjects selected for standing exercises were not able to comply with the goals of loading exercise. Subject 7 suffered from severe decubitus in the pelvic region and was for that reason immobilized for several weeks. Various complications after recovery from the decubitus caused major obstacles to his rehabilitation. Subject 12 had motivational problems and did not comply with the goals of the rehabilitation program of his own will. This led to a categorization of the participating subjects into one of two groups: (1) immobilization (n = 4), and (2) early intervention with standing only (n = 5) or combined standing and walking (n = 4). Visual inspection of the individual bone parameter development. The 13 subjects who entered the early intervention
exercise programs had two (n = l), three (n = 2), or five (n = 10) follow-up measurements. The difference in measured bone parameter between two measurements (week 5 and week 25) was calculated as a percent relative to the initial value of the two measurements. As can be seenin tables 2 through 4, various degrees of loss were observed. Strongest changes were observed in the trabecular bone parameter of the immobilized individuals. This change seems to depend on the amount of
Subject 2 Trabecular Compact MaxAMOl MinAMOl(%)
bone (%) bone (%) (%)
velocity
(mkec)
* Significance
level
3
7
12
-8.4 -1.1
-9.4 -1.6
-6.9 -0.7
-7.4 1 .a
-0.8 -0.5
-0.4 0.0
-0.6 -2.7”
0.4 -1.1
29
25
-7
-10
is p < .05.
loading exercise performed. In the patients with early mobilization, only a moderate loss or even a moderate increase could be observed. The type of exercise performed, standing only or standing and walking, did not cause an obvious difference in loss. Changes in compact bone were moderate, and did not differ for the individuals in the different groups. Marked differences between individuals can be observed in the percentage of change in maxAM and minAMO1. Statistical
comparison
of the bone parameter
development.
A comparison of trabecular bone revealed a significant difference between immobilized subjects and subjects participating in early exercise programs. The subjects performing standing only and those doing standing combined with walking did not differ significantly from each other. The repeated-measures analysis of variance showed that there was no significant difference in change of compact bone between the individuals who were classified as immobilized and those participating in standing or walking exercises. Changes in AMOZ. The time series of maxAM and minAMO1 are plotted in figure 2 for the first 10 subjects who entered the study. Each of these subjects underwent five follow-up measurements. Pearsoncorrelations showed a significant change during the first 25 weeks postinjury in maxAM for three subjects and in minAMO1 for three subjects. Changes in phase velocity propagation. For this parameter patients were measured on three occasions around week 5 and week 25 postinjury, with one repetition of each measurement. None of the subjects had real changes in phase velocity propagation during the 25-week observation period. Correlations
between BSMD-Swing
andpQCTparameters.
No significant correlation was found between phase velocity propagation and density values of trabecular bone, density values of compact bone, maxAMO1, and minAMO1 in 19 individuals measured during week 5 postinjury. However, the calculated bending stiffness revealed a significant correlation with maxAM and minAMO1. Figure 3 shows the correlation of the calculated bending stiffness with maxAM and minAMOI. The calculated bending stiffness did not correlate with density values of trabecular or compact bone. Table During
3: Development, in Terms of Change From Initial Values, the First 25 Weeks Postinjury for Subjects Who Performed Standing Exercises Subject 8
Trabecular
bone
Compact bone MaxAMOl (%) MinAMOl(%) Phase velocity * Significance
(%)
0.6
(%)
-3.3 -6.8" -4.1" 20
(mkec) level
9
10
11
13
-1.0
-1.0
-1.4
0.3
0.4 -0.5 -0.6 30
-0.1 -6.P -3.4 21
-3.0 0.4 -4.4" -27
0.3 0.4 0.8 -6
is p < .Ol.
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4: Development, in Terms of Change From Initial Values, the First 25 Weeks Postinjury for Subjects Who Performed Walking Exercises
Trabecular Compact
bone (%) bone (%)
MaxAMOl MinAMOl Phase
-0.8” 0.0 (m/set)
Subject 4 missing software analysis. * Significant level
bone
6
-
-0.6 -0.1
-0.3 -0.7
-1.8 -1.2
-1.4 0.3
-1.9 -0.7
2
5
19
because
of failure
in pQCT
-0.3 -1.3
(%) (%)
velocity
5
4
-15 density
values
g
l3
”
Weeks post injury
21
25
104
z z.
102
J
100
;
96
8 c 5
96 94
9%
25
Fig 2. Change data are given time postinjury.
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--
8 5
1.50E-08
--
2 ti m =
l.OOE-08
--
5.OOE-09 -O.OOE+OO 7 0
50
100 Calculated
150 Bending
200
250
300
250
303
Stifhess(Nm~2)
is p < .05.
106
I
2.O;)E-08
*
DISCUSSION Biomedical research in the area of osteoporosis is concentrated on preventing both the condition and its traumatic effects, on assessing bone strength, and on treatment modalities. Biomechanics can contribute to research by investigating the relationships between bone mass, architecture, and strength to develop dependable diagnostic tools for bone strength in vivo.44 The aims of this study were (1) to evaluate with a special pQCT scanner the effectiveness of an early intervention program in paraplegic patients on attenuating bone mineral density loss after acute SCI, and (2) to explore the relationship between bone composition data measured with pQCT and bone physical properties measured with BSMD-Swing. The first 13 patients were monitored for 25 weeks, with continuous parameter assessment of every patient. In this group, for different reasons, four patients were immobilized for a longer period. In this way the assessment information was available on repeated occasions with and without treatment. Because several different cases were included in this study, history and maturation are not likely to interfere with drawing conclusions about the causal role of treatment. Threats to internal validity related to testing are handled largely by the assessmentover time.45 Changes occurring elsewhere and not in the baseline-only control series are more likely to have been
A 5
de Bruin
F
Subiect 1
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Rehabil
and (B) minAMOl for 10 subjects. The of initial value and are plotted against
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0.00EtOO B
-i 0
50
10 Calculated
Fig 3. (A) Correlation (n = 19) (R* = .2553), stiffness and minAMOl
150 Bending
200 Stiffness
(Nm*2)
of calculated bending stiffness and and (B) correlation of calculated (n = IS) (R* = .2574).
maxAM bending
produced by treatment. 46 The early intervention exercise training applied in this study obviously reduces the rate of bone loss in SC1 compared to the loss seen in immobilized patients. The subjects involved in early loading intervention exercise lost almost no bone mineral, whereas the immobilization subjects lost between -6.9% and -9.4% of trabecular bone. In patients with complete paraplegia, coordinated stepping movements can be induced on a moving treadmill. The pattern of leg muscle EMG activity in this form of exercise is similar to that seen in healthy subjects.36,37Furthermore, the locomotion pattern trained under conditions of reduced body weight can, in incomplete paraplegic patients, be subsequently executed on a static surface with full body weight bearing by the paralyzed limb.37,38In the literature it was hypothesized that early exercise training could prevent or retard bone mineral loss when bone loss was expected.2,8 In this study it was hypothesized that prevention or retardation of bone loss could be reached by standing exercisesor combined standing and treadmill walking. The results presented here suggest that an early exercise program where standing exercises are combined with walking seems to reduce the expected rate of loss of bone mineral after SCI. However, the hypothesis is at variance with the observation that there is no difference in effect between combined standing and walking exercises and early standing only. Therefore, the consequences in relation to functional strain of a limited amount of physical activity on the bones are still not yet well assessed,and further investigation is indicated. Pristine design and methodology of human exercise intervention trials should be an important goal, but it is clearly something difficult to achieve. However, the major difference between the intervention reported here and those of other studies14-18is the time since onset of the SCI. Based on our results, it seems that early mobilization intervention with weight bearing might play an important role in preventing or retarding bone mineral loss after SCI.
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No major differences could be observed during the 25-week observation period in the mineral content of compact bone at the diaphyseal measuring site. This is in line with the findings of another longitudinal study, in which the reduction of cortical bone appeared to be somewhat delayed compared to the primarily affected trabecular bone.8 This does not mean, however, that no changes occur in this region. Three of 10 subjects showed a significant decrease in the maxAMO1, and three of 10 showed a significant decrease in the minAMO1. In a study of the biomechanical properties of human tibia in long-term spinal cord injury it was suggested that tibia bone may undergo microstructural changes as well as structural adaptation after SCI, which may alter its mechanical properties.49 The findings of this study support the latter suggestion and show that these changes occur rapidly and take place in some of the patients immediately after the SCI. Clinical detection of changes in AM01 allow the division of SC1 patients into two groups: with and without changes in AMOI. In healthy subjects the area moment of inertia of the tibia is a predictor of stress fractures. 5o Changes in AM01 could have several implications. If, as in this study, the AM01 in the tibia of SC1 subjects changes, then this could help to explain mechanically the occurrence of trifle fractures in SCI. Secondly, it could show that bending forces are an important causal factor for trifle fractures in the tibia, and perhaps in the femur. Although osteoporosis results from a complex, incompletely understood set of physiologic and biochemical conditions, the symptom is purely mechanical: a bone spontaneously fractures without adequate trauma. The quality of a bone-its ability to resist such mechanical failure-is a biomechanical property.27 The bone’s ability to resist forces such as tension, compression, torsion, and bending depends, among other factors, on its geometry. The bending strength of a bone is a function of the AM01 about the axis of bending for the particular cross-section of bone studied.50 In this study a correlation between the maxAM and minAMO1 and the calculated bending stiffness was assessed. Results of this assessment lead to the conclusion that the BSMD-Swing used as a clinical tool has the potential to deliver clinically relevant information on the mechanical properties of tibia bone in patients with SCI. Specific bending rigidity, for example, is determined by geometrical properties and material properties. 51 It would be interesting to know whether a change in specific bone rigidity is due to an altered material or a change in geometrical properties. Before this question can be studied in more detail, however, the obtained correlation should be reproduced in another study. It is appropriate to take the R2 found here as serious only if we have a good-sized sample with a minimum of 30 subjects.52 The fact that in this study no reliable changes in the phase velocity propagation were observed, and, on the other hand, changes in maxAM and minAMO1 were detected, might be attributable to the different sensitivities of the systems used for the measurement of the different parameters.
CONCLUSIONS The application of a controlled, single-case, experimental design contributed toward an efficient tracing of the natural history of bone mineral density after SCI. This form of analysis contributed with relevant information concerning the efficacy of early loading intervention in SCI. The case study used provides a strong basis for drawing valid inferences about the impact of early intervention. The combination of bone density and structural analysis could, in the long term, provide an improved prediction of fracture risk in patients with SCI. Furthermore, it may contribute to a refined understanding of the
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bone remodeling processes during the initial immobilization after SCI. The long-term goal is to provide a biomechanical test that can be applied along with other modalities, such as bone densitometry, to the clinical evaluation of the bone fractures in patients with SCI. Acknowledgments: The authors thank all subjects for participating in the study and acknowledge the contribution of I. Hardegger and Th. Emi in data collection and analysis. References 1. Griffiths HJ, Bushueff B, Zimmerman RE. Investigation of the loss of bone mineral in patients with spinal cord injury. Paraplegia 1976;14:207-12. 2. Elias AN, Gwinup G. Immobilization osteoporosis in paraplegia. J Am Paraplegia Sot 1992;15:163-70. 3. Uebelhart D, Demiaux-Domenech B, Roth M, Chantraine A. Bone metabolism in spinal cord injured individuals and in others who have prolonged immobilization. A review. Paraplegia 1995;33: 669-73. 4. Chantraine A, Nusgens B, Lapiere CM. Bone remodelling during the development of osteoporosis in paraplegia. Calcif Tissue Int 1986;38:323-7. 5. Finsen V, Indredavik B: Fougner KJ. Bone mineral and hormone status in paraplegics. Paraplegia 1992;30:343-7. 6. Garland DE, Stewart CA, Adkins RH, Hu SS, Rosen C, Liotta FJ, et al. Osteoporosis after spinal cord injury. J Orthop Res 1992;lO: 371-8. 7. Biering-Qrensen F, Bohr H, Schaadt 0. Bone mineral content of the lumbar spine and lower extremities years after spinal cord lesion. Paraplegia 1988;26:293-301. 8. Biering-S@rensen F, Bohr HH, Schaadt OP. Longitudinal study of bone mineral content in the lumbar spine, the forearm and the lower extremities after spinal cord injury. Eur J Clin Invest 1990;20:330-5. 9. Bergmann P, Heilpom A, Schoutens A, Patemot J, Tricot A. Longitudinal study of calcium and bone metabolism in paraplegic patients. Paraplegia 1977-78;15:147-59. 10. Szollar SM, Martin EME, Parthemore JG, Sartoris DJ, Deftos LJ. Demineralization in tetraplegic and paraplegic man over time. Spinal Cord 1997135:223-g. 11. Wilmet E, Ismail AA, Heilpom A, Welraeds D, Bergmann P. Longitudinal study of the bone mineral content and of soft tissue composition after spinal cord section. Paraplegia 1995;33:674-7. 12. van der Wiel HE. The influence of mechanical factors on the skeleton [dissertation]. Amsterdam: Vrije Universiteit; 1993. 13. Ragnarsson KT, Pollack SF, Twist D. Lower limb endurance exercise after spinal cord injury: implications for health and functional ambulation. J Neural Rehabil 1991;5:37-48. 14. Thoumie P, Le Claire G, Beillot J, Dassonville J, Chevalier T, Perrouin-Verbe B, et al. Restoration of functional gait in paraplegic patients with the RGO-II hybrid orthosis. A multicenter controlled study. II: Physiological evaluation. Paraplegia 1995;33:654-9. 15. Needham-Shropshire BM, Broton JG, Klose KJ, Lebwohl N; Guest RS, Jacobs PL. Evaluation of a training program for persons with SC1 paraplegia using the Parastep@l ambulation system: Part 3. lack of effect on bone mineral density. Arch Phys Med Rehabil 1997;78:799-803. 16. Kunkel CF, Scremin AME, Eisenberg B, Garcia JF, Roberts S, Martinez S. Effect of “standing” on spa&city, contracture, and osteoporosis in paralyzed males. Arch Phys Med Rehabil 1993;74: 73-8. 17. Goemaere S, Van Laere M, De Neve P, Kaufman JM. Bone mineral status in paraplegic patients who do or do not perform standing. Osteoporos Int 1994;4:138-43. 18. Kaplan PE, Roden W, Gilbert E, Richards L, Goldschmidt JW. Reduction of hypercalciuria in tetraplegia after weight-bearing and strengthening exercises. Paraplegia 1981;19:289-93. 19. Frost H. Perspectives; the role of changes in mechanical usage set points in the pathogenesis of osteoporosis. J Bone Miner Res 1992;7:253-61. Arch
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20. Comarr AE, Hutchinson RH, Bors E. Extremity fractures of patients with spinal cord injuries. Am J Surg 1962;103:732-9. 21. Eichenholtz SN. Management of long-bone fractures in paraplegic patients. J Bone Joint Surg 1963;45-A:299-310, 22. Ragnarsson KT, Heiner Sell G. Lower extremity fractures after spinal cord injury: a retrospective study. Arch Phys Med Rehabil 1981;62:418-23. 23. Keating JF, Kerr M, Delargy M. Minimal trauma causing fractures in oatients with soinal cord iniurv. Disabil Rehabil 1992:14:108-9. 24. Friehafer AA, Mast WA. Lower extremity fractures in patients with spinal-cord injury. J Bone Joint Surg 1965;47-A:683-94. 25. Rtiegsegger P. The use of peripheral QCT in the evaluation of bone remodelling. Endocrinologist 1994;4:167-76. 26. Dequeker J. Assessment of quality of bone in osteoporosisBIOMED I: fundamental study of relevant bone. Clin Rheumatol 1994;13 Suppl 1:7-12. 21. Brandenburger GH. Clinical determination of bone quality: is ultrasound an answer? Calcif Tissue Int 1993;53 Suppl l:S151-6. 28. Bischof H. Schallwellen in langen Rohrenknochen: Eine Methode zur Bestimmung von Biegesteifigkeit und maximaler Bruchkraft [dissertation]. Zurich: University Zurich; 1993. 29. Sttissi E. Entwicklung und Anpassung der Biegesteifigkeit des Extremitatenskelettes durch Training am Beispiel der Tibia (Development and adaptation of bending stiffness of the skeleton of the extremities as exemplified by the human tibia through exercise). Sportverl Sportschad 1994;8:103-10. 30. Sttissi E, Lawson R. The flight of a bone stiffness measurement device on Euromir ‘95 and future applications. Microgravity News 1996;9: 1-4. 31. Herzog R, Ring H, Ehwald J, Sttissi E. Comparison of changes in bone stiffness due to space flight with normal age related changes [abstract]. J Biomech 1998;31 Suppl 1:54. 32. Stytz MR, Frieder 0. Three-dimensional medical imaging modalities: an overview. Biomed Eng 1990; 18: l-25. 33. Hayes WC, Bouxsein ML. Biomechanics of cortical and trabecular bone: implications for assessment of fracture risk. In: Mow VC, Hayes WC, editors. Basic orthopaedic biomechanics. 2nd ed. Philadeluhia (PA’): Linoincott-Raven Publishers: 1997. u. 69-111. 34. BrackenLMB,‘ ShephG MJ, Collins WF, Molford TR, Young W, Bastem DS, et al. Arandomized, controlled trial of methylprednisolone or naxolone in the treatment of spinal cord injury. N Engl J Med 1990;322:1405-11. 35. Ditunno JF, Young W, Donovan WH, Creasey G. The International Standards booklet for neurological and functional classification of spinal cord injury. Paraplegia i994;32:70-80. 36. Dietz V. Colombo G. Jensen L. Locomotor activitv, in sninal man. I Lancet 1994;344:1260-3. 37. Dietz V, Colombo G, Jensen L, Baumgartner L. Locomotor capacity of spinal cord in paraplegic patients. Ann Neurol 1995;37: 574-82.
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38. Wernig A, Mtiller S. Laufband locomotion with body weight support improved walking in persons with severe spinal cord injuries. Paraplegia 1992;30:229-38. velocity measurement of flexural waves in 39. F& D, St&E.-Phase human tibia. J Biomech 1988:21:975-83. 40. Sttissi E, Fah D. Assessment of bone mineral content by in vivo measurement of flexural wave velocities. Med Biol Eng Comput 1988;26:349-54. 41. Bischof H. Schalwellen in langen Rohrenknochen: Eine Methode zur Bestimmung von Biegesteifigkeit und maximaler Bruchkraft; Laboratorium ftir Biomechanik ETHZ. [dissertation]. Zurich: University of Zurich; 1993. 42. Wagenaar RC, Meijer OG, van Wieringen PCW, Kuik DJ, Hazenberg GJ, Lindeboom J, et al. The functional recovery of stroke: a comparison between neuro-developmental treatment and the Brunnstrom-method. Stand J Rehabil Med 1990;22: 1-7. 43. de Bruin ED, Rozendal RH, Sttissi E. Reliability of phase velocity measurements of tibia1 bone. Phys Ther 1998;78:1166-74. 44. Huiskes R. Biomechanics and osteoporosis. Key lecture at: XVIth Congress of the International Society of Biomechanics. Tokyo: International Society of Biomechanics; 1997. Abstract S9. 45. Kazdin AE. Drawing valid inferences from case studies. J Consult Clin Psycho1 1981;49:183-92. 46. Hayes SC. Single case experimental design and empirical practice. J Consult ClinPsychol 1981;49:193-211: ^ 47. Deaueker J. Reeve J. Pearson J. COMAC-BME Ouantitative Asskssment ‘of Osteoporosis Study Group. Multicentre European COMAC-BME study on the standardisation of bone densitometry procedures. Technol Health Care 1993;1:127-31. 48. Dequeker J. Quality control for bone mineral measurements by QCT, DXA and SPA: a concerted European research action. Pellenberg, Belgium: Arthritis and Metabolic Bone Disease Research Unit, K.U. Leuven; 1993. 49. Lee TQ, Shapiro TA, Bell DM. Biomechanical properties of human tibias in long-term spinal cord injury. J Rehabil Res Dev 1997;34:295-302. 50. Milgrom C, Giladi M, Simkin A, Rand N, Kedem R, Kashtan H, et al. The area moment of inertia of the tibia: a risk factor for stress fractures. J Biomech 1989;22:1243-8. 51. Van der Perre G, Lowet G. Vibration, sonic and ultrasonic wave propagation analysis for the detection of osteoporosis. Clin Rheumatol 1994;13 Suppl 1:45-53. 52. Graziano AM, Raulin ML. Research methods; a process of inquiry. New York Harper Collins Publishers; 1989. Suppliers a. Laboratory for Biomechanics ETHZ, Wagistrasse 4, CH-8952 Schlieren, Switzerland. b. Scanco Medical, Auenring 8, CH-8303 Bassersdorf, Switzerland.
Changes of Tibia Bone Properties After Spinal Cord Injury: Effects of Early Intervention Eling D. de Bruin, MSc, Petra Frey-Rindova, MD, Roland E. Herzog, Msc, Volker Diet& MD, Maximilian A. Dambacher, MD, Edgar Stiissi, PhD ABSTRACT. de Bruin, ED, Frey-Rindova P, Herzog RE, Dietz V, Dambacher MA, Sttissi E. Changes of tibia bone properties after spinal cord injury: effects of early intervention. Arch Phys Med Rehabil 1999;80:214-20. Objective: To evaluate the effectiveness of an early intervention program for attenuating bone mineral density loss after acute spinal cord injury (SCI) and to estimate the usefulness of a multimodality approach in diagnosing osteoporosis in SCI. Design: A single-case, experimental, multiple-baseline design. Setting: An SC1center in a university hospital. Methods: Early loading intervention with weight-bearing by standing and treadmill walking. Patients: Nineteen patients with acute SCI. Outcome Measures: (1) Bone density by peripheral computed tomography and (2) flexural wave propagation velocity with a biomechanical testing method. Results: Analysis of the bone density data revealed a marked decrease of trabecular bone in the nonintervention subjects, whereas early mobilized subjects showed no or insignificant loss of trabecular bone. A significant change was observed in 3 of 10 subjects for maximal and minimal area moment of inertia. Measurements in 19 subjects 5 weeks postinjury revealed a significant correlation between the calculated bending stiffness of the tibia and the maximal and minimal area moment of inertia, respectively. Conclusion: A controlled, single-case, experimental design can contribute to an efficient tracing of the natural history of bone mineral density and can provide relevant information concerning the efficacy of early loading intervention in SCI. The combination of bone density and structural analysis could, in the long term, provide improved fracture risk prediction in patients with SC1 and a refined understanding of the bone remodeling processesduring initial immobilization after injury. 0 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation NE OF THE COMPLICATIONS of spinal cord injury (SCI) is the associated bone mass loss that occurs, mostly 0 below the pelvis. l-l1 Approximately 2 years after the accident that causes the injury, an equilibrium is reestablished between
From the Department of Material Sciences, Laboratoly for Biomechanics ETH (Mr. de Bruin, Mr. Herzog, Dr. Stiissi), and the Paraplegic Centre, University Hospital Balgrist (Drs. Frey-Rindova, Die& Dambacher), Zurich, Switzerland. Submitted for publication April 15,1998. Accepted in revised form June 23, 1998. Supported by the Swiss Paraplegic Foundation and by the “Schweizerische Bankgesellschaft” on behalf of a client of tbe bank. No commercial party having a direct financial interest in the results of the research supporting this article has or will confer a benefit upon the authors or upon any organization with which the authors are associated. Reprint requests to Eling D. de Bruin, MSc, Laboratorium fur Biomechanik ETHZ, Wagistrasse 4, CH-8952 Schlieren, Switzerland. 0 1999 by the American Congress of Rehabilitation Medicine and the American Academy of Physical Medicine and Rehabilitation 0003-9993/99/8002-4973$3.00/O
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bone resorption and formation, but only after the patient has lost significant bone mineral. Immobilization due to neurologic diseases, where concomitant neurologic disturbances follow, leads to more severe bone loss than bone loss after bedrest.‘* It is unknown as to whether any intervention can sustain bone mass after SCI.13There is agreement, however, that remobilization will not repair mineral loss after the first 6 months of immobilization, ie, when the osteoporosis has become inactive and established.2 Several intervention studies aimed at influencing bone have been reported.i4-l* Thoumie and coworkers14 and NeedhamShropshire and associatesI studied the effects of walking training on bone. Both concluded that there was no effect of their training on bone. i4,i5 The effect of standing on bone has been reported in several other studies.16-18The results, however, seem to be contradictory. Kunkel and colleaguesi concluded that standing did not alter measured bone variables. Goemaere and associatesi reported that subjects regularly performing standing, starting 1 year after SCI, had better preserved bone mineral density than age- and sex-matched healthy controls. In patients with incomplete SCI, tilt-table exercises reportedly reduced hypercalciuria and resulted in a more positive calcium balance, particularly in an early group of patients.ls In conclusion, to prevent bone loss, it seems to be important to mobilize the subject with SC1 as soon as possible after injury, and to include the performance of “normal” muscle function and load bearing in the exercise regimen.2*8 Osteoporosis combines a medical cause with an osteopenia and mechanical incompetence of bone.i9 One of the clinical effects of osteoporosis in paraplegia is spontaneous fractures of long bones. These fractures occur in paraplegic patients with an incidence of 2% to 6%.20-22The usual history of trauma and the classical signs of fracture are absent in these patients. Frequently, minor trauma is the cause of fracture.23~~The diagnosis of osteoporosis based on bone mass measurement, however, is problematic. The reason for this is that bone mass measurements, although informative on material properties on the level of tissue, do not and cannot predict risk of fracture of bone as a whole. Bone strength depends on these material properties25,26 as well as on macroscopic structural propertiesz7 known as bone architecture on the level of the organ. Progress in clinical characterization of bone relies on developing means to clinically assess all the important determinants of bone quality, specifically the intrinsic material properties of a bone (stiffness and brittleness) versus the macroscopic structural properties.27 The mechanical properties of the tibia can be assessedby measuring the bending stiffness of the tibia using the phase velocity of flexural waves passing through it. In accordance with the Bernoulli-Euler model, the bending stiffness of a rotationally symmetrical long beam is proportional to the phase velocity of fourth-order flexural waves.** The validity of this relationship for the tibia has been confirmed in vitro. Bending stiffness for 21 tibias was measured using three-point bending tests, and was compared to calculated bending stiffness from phase velocity and area moment of inertia of tibia1 bone. This resulted in a very good correlation (r = .96). To define the
CHANGES
OF TIBIA
relation between bending stiffness and fracture resistance of tibia1 bone, all 21 tibias were loaded until fracture. This gave an impression of maximum bending moment of the tibia bone. It was concluded that measurement of bending stiffness relates to fracture risk.2X Results from an in vivo assessment of the bending stiffness of human tibiae with a Bone Stiffness Measurement Device Swing (BSMD-Swing)” demonstrate that bone mineral measurements are not suitable predictors to evaluate changes in mechanical properties of long bones.29The BSMD-Swing was adapted under a European Space Agency contract to provide information about bone strength changes that could occur during long-term exposure to low gravity. After successful completion of its tasks on the Euromir ‘95 mission it was concluded that the BSMD-Swing might be used to determine changes in the bending stiffness of the bone due to the effects of long-term immobilization.30z31 Therefore, the question arose as to whether the BSMD-Swing is also able to provide additional clinically useful information about bone strength in patients with SCI. Do measurements on the organ level of bone provide additional information to measurements on the tissue level, eg, to measurement of bone mass? Additionally, could clinically relevant information reliably predict osteoporosis, or could it indicate the effectiveness of treatments aimed at the prevention or attenuation of osteopenia? This question, however, is difficult to answer without including information on the daily loading pattern to which the patients were subjected. In vivo, the phase velocity is calculated from eight accelerometers that have been pressed firmly against the tibia. The flexural wave is produced by mechanical impact to the head of the tibia, the strength of the impact being comparable to a patella-tendon reflex test. The basic methodology used in quantitative computed tomography (QCT) involves the computation of the cross-sectional distribution of x-ray attenuation in a body by back-projecting the x-ray transmission measurements acquired at many angles around the body until the spatial arrangement of the absorbing structures can be determined. 32 With the information available in QCT scans, it is possible to isolate densitometric and geometric changes in both cortical and trabecular compartments.33 Hence, the aim of the study was twofold: (1) to evaluate the effectiveness of an early loading intervention program in paraplegia on attenuating bone mineral density loss after acute SC1with a peripheral QCT (pQCT) scanner; and (2) to estimate the usefulness of simultaneously measuring bone material (tissue) composition and strength of bone as an organ. The bony organ chosen was the tibia. METHODS Subjects During 1% years, 19 SC1 subjects were enrolled in the study after receiving oral and written information. All participants signed a statement of informed consent approved by the Institutional Review Board of our center. All subjects had traumatic SCI, and were men. A summary of subject characteristics is given in table 1. The first 13 subjects had follow-up measurements for 25 weeks during the research period. Of these 13 subjects, six were selected for a combination of standing exercises and treadmill walking according to the in-house selection protocol, and seven patients were selected for the customary inpatient rehabilitation program with standing exercises only. The last six patients included in the study had bone measurements in week 5 after SCI. Since these subjects all entered the study in the last 3
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Table
1: Characteristics
Subject
Age at Injury MS)
of Subjects
Level of Lesion
ASIA Score
and the
Exercise
Program Time Between Injury and Intervention (Weeks)
Type of Intervention
I-400
53
C6
C
Walking
4
Z-405 3-406
32 24
T4/5 C4
C B
Immobilization Immobilization
* *
4-409 5-412
27 22
C6 T12
C D
Walking Walking
3 2
6-413 7-401
37
c4
C
c4 Tll
B A
Walking Immobilization
4 *
S-402
33 25
Standing
1
9-403 1 O-407 1 I-408
34 43 48
T9 T12 TIO
A A A
Standing Standing Standing
2 1 3
12-410 13-411
21 26
Ll T4/5
A B
Immobilization
*
Standing
3
14-415 15-417
26 26
C6 T6
6 A
-
16-418 17-419
59
TIO
A
1 S-420
32 40
T12 T6
D A
19-421
19
c5
B
-
* No-loading exercise within the 25week reached the desired level of 5 hours weekly.
observation
period
that
months of the l%-year monitoring period, only their first measurement data were included in our analysis. Within 24 hours postinjury all patients received 2g Cortisol on the basis of a NASCIC II protocol.34 In all subjects heparinization (amount adapted to body weight) took place during the 8 weeks after injury. Other medications taken by the subjects were usually muscle relaxant and antispastic drugs, with some patients also taking urinary antibacterial agents, stool softeners, or medication to control hypertension. None of the pharmaceutical agents is known to directly influence bone metabolism. Protocol Extensive medical screening was performed for each subject to identify any contraindications to participating in one of the exercise programs. To exclude other illnesses, medical evaluations included blood analysis and urinanalysis, X-rays of the lower extremities and chest, and psychologic testing in the form of a conversation with a psychologist. Standardized neurologic examinations were performed according to the American Spinal Injury Association (ASIA) protocol.35 The ASIA motor (maximum 100 points) and sensory (maximum for both aesthesia and algesia 112 points) scores indicated the severity of the SC1 lesion, Only those subjects with medical clearance were allowed to participate in the study. No subjects were excluded based on these tests. Contraindications for participation in walking exercise include lower motor neuron involvement, previous lower extremity fracture, and medical and/or psychologic instability. Participation in the combined standing/walking program was decided on the following general inclusion/exclusion criteria: central (spinal) lesion, age older than 10 and younger than 60 years; no other lesions and/or infirmity; no circulatory disturbances during standing; and patient’s informed consent. If selected for the combined standing/walking program, the subjects started training as soon as possible after the injury, and performed half an hour of walking and standing for half an hour, 5 days per Arch
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week for half a year. Detailed electromyography (EMG) activity results have been reported.36-38The amount of unloading during the course of this training had a range of 20% to 80%, with a mean of 40%. For all subjects a precise protocol of all other physical activities that might influence the lower extremity bones was registered. The subjects allocated to the customary rehabilitation program trained in weight-bearing only by standing. The start of training was defined by medical clearance and was implemented as soon as possible after injury. The aim of the rehabilitation program was to have patients standing or standing/ walking for at least 1 hour daily, 5 days per week. To quantify the influence of the amount of loading exercise on the various bone parameters, the subjects were divided into three groups. Group 1 Individuals had 0 to 5 hours per week loading exercises (immobilization); group 2 had 5 or more hours of standing exercises per week (standing); and group 3 had 5 or more hours of combined standing and walking exercises per week (walking). The starting point of intervention was defined as the first week postinjury in which the minimal desired amount of exercise was reached (table 1). Subjects were randomly selected to participate in one of the intervention programs. Training Equipment Subjects with complete paraplegia allocated to the walking program and subjects with incomplete paraplegia at the beginning of training started stepping movements that could be induced on a treadmill moving at low speed (about 1.3km/h). Physiotherapists assisted the movement of the feet in complete paraplegic patients, especially at lift-off and heel-strike. Body weight was partially supported by suspending subjects over the treadmill on a parachute harness connected to a winch. The degree of support was provided by a scale on a winch (fig 1A). Standing was performed using a standing frame with a hip-suspension band necessary to maintain the patient in the upright position (fig 1B). Bone Measurements Bone density measurements were performed with a Densiscan 2000b on the left tibia, unless it had been fractured before the XI. Fractures, even those completely healed, yield spurious bone density values.2s Two stacks of CT scans were analyzed: one close to the ankle joint and one in the diaphysis.
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To ensure that the CT scanswere always made at the same angle relative to the bone axis, the extremity was measured in an anatomically formed radiolucent cast. A detailed description of the tibia examination protocol has been described elsewhere.25 Four parameters were derived and calculated for a general characterization of the measured bone: Trabeczdar bone. To determine this bone parameter, the inner core of the bone was assessed.The core area contains only trabecular bone. Compact bone (ie, cortical bone). This parameter represents the average bone density at the diaphyseal measuring site (bone mass divided by total cross-sectional area of the bone). The area moment of inertia of the tibia. The area moment of inertia (AMOI) with respect to the maximal (maxAMO1) and minimal AM01 (minAMO1) orthogonal directions at diaphysis was calculated numerically from the CT scans. All pQCT bone measurements were performed in weeks 5,9, 13, 17,21, and 25 after injury. Phase velocity propagation in the tibia was measured with an initial version of the BSMD-Swing” that has been described in detail elsewhere.2g,30,3g,40 For the measurements with the BSMDSwing, a standardized measurement protocol was followed. Measurements took place around week 5 and week 25 postinjury. Bending stiffness was calculated from the phase velocity values and anthropometric variables of the tibia in accordance with previously described procedures41 Reproducibility of Bone Measurements Reproducibility in routine patient measurements was determined earlier to vary between .2O% and .30% for the tibia with PQCT.~~Measurements on actual test subjects with the BSMDSwing have shown a receiver signal reproducibility within 22% (standard deviation).30 Research Design Because of the heterogeneity of the population involved, for part of the data analysis a controlled, single-case, experimental, multiple-baseline design was chosen. In traditional controlled group studies, treatments are contrasted by comparing groups of patients, each group being subjected to one intervention condition. Unless special statistical techniques are used, intersubject variability may well mask specific treatment effects. Controlled, single-case experimental design appears to provide
Fig 1. Schematic exercise set-up for early (A) walking on a treadmill and (B) standing exercises. Patients are suspended over the treadmill in a parachute harness. The harness is connected to a winch that allows for body weight support adjustment. During exercises the treadmill moves at a speed of about 1.3km/h. Standing is performed in a standing frame. To maintain the patient in upright position, a hip-suspension band is applied.
’ fine plate Arch
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a way to circumvent this problem, and previous rehabilitation research has shown that single-case methodology can be an appropriate means.42 The multiple baseline design with staggered lengths of A-phases controls for selection bias and contamination. Starting with a baseline phase may meet with ethical, rather then methodological problems. In this study this problem was “solved” on the basis of ability and/or motivation of patients to participate in the early rehabilitation program.
Table 2: Development, in Terms of Change From Initial Values, During the First 25 Weeks Postinjury for Immobilized Subjects
Statistical Analysis Both visual inspection and statistical analysis were used for the analysis of the data from the single-subject studies.42 Repeated-measures analysis of variance was used for the statistical analysis of the time series observations of the studied cases. Pearson correlations were used to evaluate the relationships between tibia bone parameters measured with pQCT and with BSMD-Swing, and to evaluate the influence of time postinjury on maxAM and minAMO1. Statistical analysis was performed with the SAS statistical package running on a PC. For all tests, a significance level of .05 was chosen unless otherwise indicated. The desired level of reliability in the assessmentof a patient’s phase velocity propagation was set at 35m/sec. Each patient was measured in weeks 4, 5, and 6 postinjury with a repetition of measurement on each occasion. Measurements were always performed by the same tester. This procedure was repeated in weeks 24, 25, and 26 postinjury. In such a design, a difference in phase velocity of 35m/sec or more within 20 weeks indicated a real difference, rather than a possible error.43
Phase
RESULTS Tibia Bone Changes During Early Intervention Exercise In the group of 13 patients who were monitored for 25 weeks, two subjects initially selected for the walking program were not able to reach an exercise level of 5 hours per week during the first 25 weeks postinjury. Subject 2 underwent a conservative treatment of a vertebral fracture, and was immobilized for 3 months postinjury. After this period he was only able to gradually reach the desired amount of exercise time. Subject 3 suffered from various medical complications during the 25week observation period, which caused major obstacles in his walking exercise rehabilitation. Two subjects selected for standing exercises were not able to comply with the goals of loading exercise. Subject 7 suffered from severe decubitus in the pelvic region and was for that reason immobilized for several weeks. Various complications after recovery from the decubitus caused major obstacles to his rehabilitation. Subject 12 had motivational problems and did not comply with the goals of the rehabilitation program of his own will. This led to a categorization of the participating subjects into one of two groups: (1) immobilization (n = 4), and (2) early intervention with standing only (n = 5) or combined standing and walking (n = 4). Visual inspection of the individual bone parameter development. The 13 subjects who entered the early intervention
exercise programs had two (n = l), three (n = 2), or five (n = 10) follow-up measurements. The difference in measured bone parameter between two measurements (week 5 and week 25) was calculated as a percent relative to the initial value of the two measurements. As can be seenin tables 2 through 4, various degrees of loss were observed. Strongest changes were observed in the trabecular bone parameter of the immobilized individuals. This change seems to depend on the amount of
Subject 2 Trabecular Compact MaxAMOl MinAMOl(%)
bone (%) bone (%) (%)
velocity
(mkec)
* Significance
level
3
7
12
-8.4 -1.1
-9.4 -1.6
-6.9 -0.7
-7.4 1 .a
-0.8 -0.5
-0.4 0.0
-0.6 -2.7”
0.4 -1.1
29
25
-7
-10
is p < .05.
loading exercise performed. In the patients with early mobilization, only a moderate loss or even a moderate increase could be observed. The type of exercise performed, standing only or standing and walking, did not cause an obvious difference in loss. Changes in compact bone were moderate, and did not differ for the individuals in the different groups. Marked differences between individuals can be observed in the percentage of change in maxAM and minAMO1. Statistical
comparison
of the bone parameter
development.
A comparison of trabecular bone revealed a significant difference between immobilized subjects and subjects participating in early exercise programs. The subjects performing standing only and those doing standing combined with walking did not differ significantly from each other. The repeated-measures analysis of variance showed that there was no significant difference in change of compact bone between the individuals who were classified as immobilized and those participating in standing or walking exercises. Changes in AMOZ. The time series of maxAM and minAMO1 are plotted in figure 2 for the first 10 subjects who entered the study. Each of these subjects underwent five follow-up measurements. Pearsoncorrelations showed a significant change during the first 25 weeks postinjury in maxAM for three subjects and in minAMO1 for three subjects. Changes in phase velocity propagation. For this parameter patients were measured on three occasions around week 5 and week 25 postinjury, with one repetition of each measurement. None of the subjects had real changes in phase velocity propagation during the 25-week observation period. Correlations
between BSMD-Swing
andpQCTparameters.
No significant correlation was found between phase velocity propagation and density values of trabecular bone, density values of compact bone, maxAMO1, and minAMO1 in 19 individuals measured during week 5 postinjury. However, the calculated bending stiffness revealed a significant correlation with maxAM and minAMO1. Figure 3 shows the correlation of the calculated bending stiffness with maxAM and minAMOI. The calculated bending stiffness did not correlate with density values of trabecular or compact bone. Table During
3: Development, in Terms of Change From Initial Values, the First 25 Weeks Postinjury for Subjects Who Performed Standing Exercises Subject 8
Trabecular
bone
Compact bone MaxAMOl (%) MinAMOl(%) Phase velocity * Significance
(%)
0.6
(%)
-3.3 -6.8" -4.1" 20
(mkec) level
9
10
11
13
-1.0
-1.0
-1.4
0.3
0.4 -0.5 -0.6 30
-0.1 -6.P -3.4 21
-3.0 0.4 -4.4" -27
0.3 0.4 0.8 -6
is p < .Ol.
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4: Development, in Terms of Change From Initial Values, the First 25 Weeks Postinjury for Subjects Who Performed Walking Exercises
Trabecular Compact
bone (%) bone (%)
MaxAMOl MinAMOl Phase
-0.8” 0.0 (m/set)
Subject 4 missing software analysis. * Significant level
bone
6
-
-0.6 -0.1
-0.3 -0.7
-1.8 -1.2
-1.4 0.3
-1.9 -0.7
2
5
19
because
of failure
in pQCT
-0.3 -1.3
(%) (%)
velocity
5
4
-15 density
values
g
l3
”
Weeks post injury
21
25
104
z z.
102
J
100
;
96
8 c 5
96 94
9%
25
Fig 2. Change data are given time postinjury.
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--
8 5
1.50E-08
--
2 ti m =
l.OOE-08
--
5.OOE-09 -O.OOE+OO 7 0
50
100 Calculated
150 Bending
200
250
300
250
303
Stifhess(Nm~2)
is p < .05.
106
I
2.O;)E-08
*
DISCUSSION Biomedical research in the area of osteoporosis is concentrated on preventing both the condition and its traumatic effects, on assessing bone strength, and on treatment modalities. Biomechanics can contribute to research by investigating the relationships between bone mass, architecture, and strength to develop dependable diagnostic tools for bone strength in vivo.44 The aims of this study were (1) to evaluate with a special pQCT scanner the effectiveness of an early intervention program in paraplegic patients on attenuating bone mineral density loss after acute SCI, and (2) to explore the relationship between bone composition data measured with pQCT and bone physical properties measured with BSMD-Swing. The first 13 patients were monitored for 25 weeks, with continuous parameter assessment of every patient. In this group, for different reasons, four patients were immobilized for a longer period. In this way the assessment information was available on repeated occasions with and without treatment. Because several different cases were included in this study, history and maturation are not likely to interfere with drawing conclusions about the causal role of treatment. Threats to internal validity related to testing are handled largely by the assessmentover time.45 Changes occurring elsewhere and not in the baseline-only control series are more likely to have been
A 5
de Bruin
F
Subiect 1
SCI,
in (A) maxAM as percentage
Rehabil
and (B) minAMOl for 10 subjects. The of initial value and are plotted against
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0.00EtOO B
-i 0
50
10 Calculated
Fig 3. (A) Correlation (n = 19) (R* = .2553), stiffness and minAMOl
150 Bending
200 Stiffness
(Nm*2)
of calculated bending stiffness and and (B) correlation of calculated (n = IS) (R* = .2574).
maxAM bending
produced by treatment. 46 The early intervention exercise training applied in this study obviously reduces the rate of bone loss in SC1 compared to the loss seen in immobilized patients. The subjects involved in early loading intervention exercise lost almost no bone mineral, whereas the immobilization subjects lost between -6.9% and -9.4% of trabecular bone. In patients with complete paraplegia, coordinated stepping movements can be induced on a moving treadmill. The pattern of leg muscle EMG activity in this form of exercise is similar to that seen in healthy subjects.36,37Furthermore, the locomotion pattern trained under conditions of reduced body weight can, in incomplete paraplegic patients, be subsequently executed on a static surface with full body weight bearing by the paralyzed limb.37,38In the literature it was hypothesized that early exercise training could prevent or retard bone mineral loss when bone loss was expected.2,8 In this study it was hypothesized that prevention or retardation of bone loss could be reached by standing exercisesor combined standing and treadmill walking. The results presented here suggest that an early exercise program where standing exercises are combined with walking seems to reduce the expected rate of loss of bone mineral after SCI. However, the hypothesis is at variance with the observation that there is no difference in effect between combined standing and walking exercises and early standing only. Therefore, the consequences in relation to functional strain of a limited amount of physical activity on the bones are still not yet well assessed,and further investigation is indicated. Pristine design and methodology of human exercise intervention trials should be an important goal, but it is clearly something difficult to achieve. However, the major difference between the intervention reported here and those of other studies14-18is the time since onset of the SCI. Based on our results, it seems that early mobilization intervention with weight bearing might play an important role in preventing or retarding bone mineral loss after SCI.
CHANGES
OF TIBIA
No major differences could be observed during the 25-week observation period in the mineral content of compact bone at the diaphyseal measuring site. This is in line with the findings of another longitudinal study, in which the reduction of cortical bone appeared to be somewhat delayed compared to the primarily affected trabecular bone.8 This does not mean, however, that no changes occur in this region. Three of 10 subjects showed a significant decrease in the maxAMO1, and three of 10 showed a significant decrease in the minAMO1. In a study of the biomechanical properties of human tibia in long-term spinal cord injury it was suggested that tibia bone may undergo microstructural changes as well as structural adaptation after SCI, which may alter its mechanical properties.49 The findings of this study support the latter suggestion and show that these changes occur rapidly and take place in some of the patients immediately after the SCI. Clinical detection of changes in AM01 allow the division of SC1 patients into two groups: with and without changes in AMOI. In healthy subjects the area moment of inertia of the tibia is a predictor of stress fractures. 5o Changes in AM01 could have several implications. If, as in this study, the AM01 in the tibia of SC1 subjects changes, then this could help to explain mechanically the occurrence of trifle fractures in SCI. Secondly, it could show that bending forces are an important causal factor for trifle fractures in the tibia, and perhaps in the femur. Although osteoporosis results from a complex, incompletely understood set of physiologic and biochemical conditions, the symptom is purely mechanical: a bone spontaneously fractures without adequate trauma. The quality of a bone-its ability to resist such mechanical failure-is a biomechanical property.27 The bone’s ability to resist forces such as tension, compression, torsion, and bending depends, among other factors, on its geometry. The bending strength of a bone is a function of the AM01 about the axis of bending for the particular cross-section of bone studied.50 In this study a correlation between the maxAM and minAMO1 and the calculated bending stiffness was assessed. Results of this assessment lead to the conclusion that the BSMD-Swing used as a clinical tool has the potential to deliver clinically relevant information on the mechanical properties of tibia bone in patients with SCI. Specific bending rigidity, for example, is determined by geometrical properties and material properties. 51 It would be interesting to know whether a change in specific bone rigidity is due to an altered material or a change in geometrical properties. Before this question can be studied in more detail, however, the obtained correlation should be reproduced in another study. It is appropriate to take the R2 found here as serious only if we have a good-sized sample with a minimum of 30 subjects.52 The fact that in this study no reliable changes in the phase velocity propagation were observed, and, on the other hand, changes in maxAM and minAMO1 were detected, might be attributable to the different sensitivities of the systems used for the measurement of the different parameters.
CONCLUSIONS The application of a controlled, single-case, experimental design contributed toward an efficient tracing of the natural history of bone mineral density after SCI. This form of analysis contributed with relevant information concerning the efficacy of early loading intervention in SCI. The case study used provides a strong basis for drawing valid inferences about the impact of early intervention. The combination of bone density and structural analysis could, in the long term, provide an improved prediction of fracture risk in patients with SCI. Furthermore, it may contribute to a refined understanding of the
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bone remodeling processes during the initial immobilization after SCI. The long-term goal is to provide a biomechanical test that can be applied along with other modalities, such as bone densitometry, to the clinical evaluation of the bone fractures in patients with SCI. Acknowledgments: The authors thank all subjects for participating in the study and acknowledge the contribution of I. Hardegger and Th. Emi in data collection and analysis. References 1. Griffiths HJ, Bushueff B, Zimmerman RE. Investigation of the loss of bone mineral in patients with spinal cord injury. Paraplegia 1976;14:207-12. 2. Elias AN, Gwinup G. Immobilization osteoporosis in paraplegia. J Am Paraplegia Sot 1992;15:163-70. 3. Uebelhart D, Demiaux-Domenech B, Roth M, Chantraine A. Bone metabolism in spinal cord injured individuals and in others who have prolonged immobilization. A review. Paraplegia 1995;33: 669-73. 4. Chantraine A, Nusgens B, Lapiere CM. Bone remodelling during the development of osteoporosis in paraplegia. Calcif Tissue Int 1986;38:323-7. 5. Finsen V, Indredavik B: Fougner KJ. Bone mineral and hormone status in paraplegics. Paraplegia 1992;30:343-7. 6. Garland DE, Stewart CA, Adkins RH, Hu SS, Rosen C, Liotta FJ, et al. Osteoporosis after spinal cord injury. J Orthop Res 1992;lO: 371-8. 7. Biering-Qrensen F, Bohr H, Schaadt 0. Bone mineral content of the lumbar spine and lower extremities years after spinal cord lesion. Paraplegia 1988;26:293-301. 8. Biering-S@rensen F, Bohr HH, Schaadt OP. Longitudinal study of bone mineral content in the lumbar spine, the forearm and the lower extremities after spinal cord injury. Eur J Clin Invest 1990;20:330-5. 9. Bergmann P, Heilpom A, Schoutens A, Patemot J, Tricot A. Longitudinal study of calcium and bone metabolism in paraplegic patients. Paraplegia 1977-78;15:147-59. 10. Szollar SM, Martin EME, Parthemore JG, Sartoris DJ, Deftos LJ. Demineralization in tetraplegic and paraplegic man over time. Spinal Cord 1997135:223-g. 11. Wilmet E, Ismail AA, Heilpom A, Welraeds D, Bergmann P. Longitudinal study of the bone mineral content and of soft tissue composition after spinal cord section. Paraplegia 1995;33:674-7. 12. van der Wiel HE. The influence of mechanical factors on the skeleton [dissertation]. Amsterdam: Vrije Universiteit; 1993. 13. Ragnarsson KT, Pollack SF, Twist D. Lower limb endurance exercise after spinal cord injury: implications for health and functional ambulation. J Neural Rehabil 1991;5:37-48. 14. Thoumie P, Le Claire G, Beillot J, Dassonville J, Chevalier T, Perrouin-Verbe B, et al. Restoration of functional gait in paraplegic patients with the RGO-II hybrid orthosis. A multicenter controlled study. II: Physiological evaluation. Paraplegia 1995;33:654-9. 15. Needham-Shropshire BM, Broton JG, Klose KJ, Lebwohl N; Guest RS, Jacobs PL. Evaluation of a training program for persons with SC1 paraplegia using the Parastep@l ambulation system: Part 3. lack of effect on bone mineral density. Arch Phys Med Rehabil 1997;78:799-803. 16. Kunkel CF, Scremin AME, Eisenberg B, Garcia JF, Roberts S, Martinez S. Effect of “standing” on spa&city, contracture, and osteoporosis in paralyzed males. Arch Phys Med Rehabil 1993;74: 73-8. 17. Goemaere S, Van Laere M, De Neve P, Kaufman JM. Bone mineral status in paraplegic patients who do or do not perform standing. Osteoporos Int 1994;4:138-43. 18. Kaplan PE, Roden W, Gilbert E, Richards L, Goldschmidt JW. Reduction of hypercalciuria in tetraplegia after weight-bearing and strengthening exercises. Paraplegia 1981;19:289-93. 19. Frost H. Perspectives; the role of changes in mechanical usage set points in the pathogenesis of osteoporosis. J Bone Miner Res 1992;7:253-61. Arch
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