Abstract
Objective
To determine the feasibility and safety of implementing a 12-week rehabilitation program after mesenchymal stromal cell (MSC) transplantation augmented by vascularized bone grafting for idiopathic osteonecrosis (ION) of the femoral head.
Design
A prospective case series.
Setting
University clinical research laboratory.
Participants
Participants (N=10) with ION who received MSC transplantation augmented by vascularized bone grafting.
Intervention
A 12-week exercise program, which included range-of-motion (ROM) exercises, muscle-strengthening exercises, and aerobic training.
Main Outcome Measures
Measures of ROM, muscle strength, Timed Up and Go test, and Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36) were collected before surgery and again at 6 and 12 months after surgery.
Results
All participants completed the 12-week program. External rotation ROM as well as extensor and abductor muscle strength significantly improved 6 months after treatment compared with that before treatment (P<.05). Significant improvements were also seen in physical function, role physical, and bodily pain subgroup scores of the SF-36 (P<.05). No serious adverse events occurred.
Conclusions
This study demonstrates the feasibility and safety of a multiplex rehabilitation program after MSC transplantation and provides support for further study on the benefits of rehabilitation programs in regenerative medicine.
Keywords
List of abbreviations:
ION (idiopathic osteonecrosis), MSC (mesenchymal stromal cell), RM (repetition maximum), ROM (range of motion), SDIC (Specific Disease Investigation Committee), SF-36 (Medical Outcomes Study 36-Item Short-Form Health Survey), THA (total hip arthroplasty)Idiopathic osteonecrosis (ION) of the femoral head is a painful disorder that progresses to femoral head collapse and osteoarthritis of the hip joint.
1
, 2
This disease mainly affects individuals aged 30 to 40 years.3
The exact pathologic mechanism of ION remains unknown; however, obstruction of blood flow to the femoral head, which causes death of bone-forming cells, is a hallmark of this condition. Without bone-forming cells, bone tissue gradually loses its mechanical properties and eventually collapses, causing articular surface deformities.1
, 2
, 3
Recently, surgical treatment has become more common than nonsurgical treatment for ION in the United States.
4
Conservative treatment to offload forces by limiting weight-bearing, activity modification, and physical therapy is thought to have limited success in preventing disease progression.3
, 4
If the disease progresses, the patient eventually requires total hip arthroplasty (THA).1
, 2
, 3
Although the survival rate of THA has improved markedly, individuals with ION are typically young, and THA durability is limited; therefore, joint-preserving treatment is preferred. However, recent data indicate that joint-preserving procedures are performed less often than THA.3
Regenerative medicine using cell transplantation is a promising treatment for patients with refractory disease. Mesenchymal stromal cell (MSC) transplantation, for example, is a promising new treatment for joint preservation in ION. MSCs can differentiate into cells of osteogenic, chondrogenic, and adipogenic lineages in vitro.
5
, 6
, 7
During early-stage ION, treatment with MSCs in combination with core decompression surgery has resulted in significant delay and even prevention of femoral head collapse.8
, 9
, 10
, 11
, 12
However, in more advanced stages, the result of this procedure has not been satisfactory.12
, 13
, 14
Because bone marrow pressure is elevated in the early stage of ION,15
core decompression to reduce the pressure is required. However, in advanced-stage disease, when subchondral bone fractures occur, initial strengthening, instead of decompression, is needed to prevent collapse.16
We designed a protocol using a combination of MSCs and vascularized bone grafts for treating advanced stages of ION.
17
Because ION is caused by loss of blood supply and bone-forming cells as well as mechanical vulnerability, vascularized bone grafting is, theoretically, a reasonable treatment for this condition.16
, 17
Although MSC transplantation is a promising therapeutic strategy, rehabilitation interventions after surgery may have a significant effect on the ultimate treatment result. However, detailed information about rehabilitation programs after cell transplantation has not yet been reported.8
, 9
, 10
, 11
, 12
, 13
, 14
Moreover, the effect of rehabilitation alone on ION is controversial.18
, 19
This study aimed to determine the feasibility and safety of a rehabilitation program that was performed in a clinical trial of MSC transplantation augmented by vascularized bone grafting for ION.- Neumayr
LD, for the National Osteonecrosis Trial in Sickle Cell Anemia Study Group. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment.
J Bone Joint Surg Am. 2006; 88: 2573-2582
Methods
The current study was a prospective case series of subjects enrolled in a clinical trial. Details of this prospective, open-labeled, proof-of-concept clinical trial, conducted at Kyoto University Hospital, have been previously reported.
17
The study protocol was approved by the Ethics Committee of Kyoto University Graduate School and Faculty of Medicine and was conducted according to the Declaration of Helsinki. For this clinical trial, participants were recruited via the website page of Kyoto University Hospital and the University Hospital Medical Information Network (UMIN) Clinical Trials Registry.Assessment of necrotic lesion and radiographic stage
Necrotic lesion type and size were assessed using the radiographic classification proposed by the Specific Disease Investigation Committee (SDIC) in Japan (appendix 1).
20
Staging of ION proposed by the SDIC in Japan is a modified version of the system proposed by the Association Research Circulation Osseous Committee.20
Inclusion criteria
Patients aged 20 to 50 years with radiographic stage 3A or 3B, according to SDIC staging,
20
were eligible for enrollment. Written informed consent was obtained from all participants in the clinical trial.Exclusion criteria
Exclusion criteria were a history of transplantation on the affected part of the hip, heavy smoking (Brinkman index >600), current use of warfarin, diabetes mellitus (defined as hemoglobin A1c >9.0%), arteriosclerosis obliterans, pregnancy, malignant disease, myocardial infarction, brain infarction, rheumatoid arthritis, dialysis use, hematologic disease (leukemia, myeloproliferative disorder, myelodysplastic disorder), limited life expectancy, hepatitis B, hepatitis C, human immunodeficiency virus infection, syphilis, hypotension (systolic blood pressure <90mmHg), low body weight (<40kg), loss of marrow function (neutrophil count <1500/mm3, hemoglobin level <11.0g/dL [men] or <10.0g/dL [women], platelet count <100,000/mm3), change in medication (bisphosphonates or steroids) within 3 months of the study, and ineligibility determined by a doctor.
MSC transplantation augmented by vascularized bone grafting
Under general anesthesia, 100mL of bone marrow was obtained from the posterior iliac crest. Mononuclear cells containing MSCs were cultured for approximately 2 weeks under 20% partial pressure of oxygen (Po2) and 5% partial pressure of carbon dioxide (Pco2) conditions at 37°C.
MSC transplantation was augmented by vascularized bone grafting. Briefly, participants were placed on the table in the supine position. A curved skin incision (modified Smith-Peterson approach) was made from the iliac crest to the anterior aspect of the proximal thigh.
17
The rectus femoris was released, and the anterior aspect of the femoral neck was explored. Then, a cortical window (1.5×4cm) was prepared, through which a bony trough connecting the necrotic area was created under both fluoroscopic and endoscopic guidance. MSCs (0.5–1.5×108) premixed with β-tricalcium phosphate granules (Osferiona) were transplanted into the cavity created by curettage. Tricortical iliac crest bone was harvested with a vascular pedicle and grafted into the bone trough.16
Then, the joint capsule and rectus femoris were sutured.Rehabilitation program
Rehabilitation was performed at a hospital for 12 weeks. During the initial 4 weeks, rehabilitation was performed at an acute care hospital (table 1). Participants continued rehabilitation at a special rehabilitation hospital for 8 additional weeks. During the first 4 weeks, physical therapy was performed for 40 minutes at a time, once a day, 5 days a week. After the initial 4 weeks, it was performed for 60 minutes at a time, twice a day, 6 days a week. The entire rehabilitation program was supervised by skilled physiotherapists, and the specific therapy received was recorded in the participant's medical record.
Table 1Rehabilitation program
| Time Course After Treatment | Side | Day 1 | Day 3 | Week 1 | Week 2 | Week 3 | Week 4 | Week 5 | Week 6 | Week 8 | Week 10 | Week 12 | Discharge |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Rest level | Bed rest | Wheelchair | Walk on crutch | → | Walk on T-cane | ||||||||
| Weight-bearing | NWB | → | 1/3 WB | 1/2 WB | 2/3 WB | FWB | |||||||
| ROM exercise | Transplant | Passive F, E→ | |||||||||||
| Passive Ab→ | |||||||||||||
| Passive R→ | |||||||||||||
| Active F, E, Ab, R | |||||||||||||
| Nontransplant | Passive & active F, E, Ab, R→ | ||||||||||||
| Muscle strength exercise | Transplant | Isotonic (Straight leg raising, no weight)→ | |||||||||||
| Isotonic (Straight leg raising, 2-kg weight) | |||||||||||||
| Isokinetic F, E→ | |||||||||||||
| Isokinetic Ad→ | |||||||||||||
| Isokinetic R→ | |||||||||||||
| Isokinetic Ab | |||||||||||||
| Squat & heel raise | |||||||||||||
| Nontransplant | Isometric F, E, Ab, R | → | |||||||||||
| Isokinetic F, E, Ab, R | |||||||||||||
| Squat & heel raise | → | ||||||||||||
| Muscle strength exercise of upper limb→ | |||||||||||||
| Aerobic training | Aerobike→ | ||||||||||||
Abbreviations: Ab, abduction; Ad, adduction; E, extension; F, flexion; FWB, full weight-bearing; NWB, non–weight-bearing; R, rotation; WB, weight-bearing.
Participants were kept non–weight-bearing for 6 weeks after transplantation surgery, followed by one-third weight-bearing, one-half weight-bearing, and two-thirds weight-bearing, progressing at 2-week intervals (see table 1). Full weight-bearing was permitted 12 weeks after treatment.
Before performing range-of-motion (ROM) exercises, pain level was assessed using a numeric rating scale. Passive flexion and extension ROM exercises were initiated 2 weeks after treatment on the transplant side. Passive adduction was initiated 3 weeks after treatment, and passive rotation ROM exercise was initiated 6 weeks after treatment. Active ROM exercise in all directions was initiated 12 weeks after treatment (see table 1). Passive and active ROM exercises in all directions were initiated 3 days after treatment on the nontransplant side (see table 1).
For isotonic flexion muscle-strengthening exercise, straight leg raising with no weight was started 6 weeks after treatment on the transplant side (see table 1). Straight leg raising with 2-kg weight was started after 10 weeks. The intensity of exercise was defined by pain level. Each position was held for 5 seconds and performed 5 times. For isokinetic flexion and extension muscle-strengthening exercises, resistance training was started 6 weeks after treatment on the transplant side. The intensity of exercise was increased by increasing the load by 40% to 80% of 10-repetition maximum (RM). Isokinetic adduction exercise was added at 8 weeks, rotation exercise at 10 weeks, and adduction exercise at 12 weeks after treatment. Isokinetic rotation exercise was performed using Coxa Link.b Squat and heel raise exercises were performed 12 weeks after treatment. On the nontransplant side, isometric and isokinetic exercises were started 3 days after treatment. If muscle weakness was present, the intensity of exercise was increased by increasing the load by 70% to 100% of 10RM for muscular hypertrophy. If muscle weakness was not present, exercise loading was increased by 60% to 70% of 15RM for muscular endurance. Nontransplant side squat and heel raise exercises were started 6 weeks after treatment. Upper limb muscle-strengthening exercises were performed using Shoulder Linkb 1 week after treatment (see table 1).
Aerobic training was started 8 weeks after treatment. The intensity of exercise was defined as a target heart rate of 220×(age×0.6) by using an Aerobike Aic for 30 minutes. After discharge, participants continued home exercises and were assessed once a month. Patients were allowed to resume sports and work 6 months after confirmation of bone ossification (see table 1).
Assessment
All participants underwent assessment before treatment and 6 and 12 months after treatment. Passive hip flexion, extension, abduction, and external rotation angles were measured using universal goniometry. Hip flexor, extensor, and abductor strengths were measured using a handheld dynamometerd during isometric contraction for 3 seconds with manual resistance. Knee extensor and flexor strengths and lower limb load were assessed using the Iso Force GT-330.e Torque was expressed as a percentage of body weight (Nm/kg). Values of lower limb load force were normalized to body weight (N/kg). In the Timed Up and Go test, the time (in seconds) that a participant required to stand from an armless chair (chair seat height, 45cm), walk a distance of 3m, turn, walk back to the chair, and sit down was measured. Health-related quality of life was evaluated using the Medical Outcomes Study 36-Item Short-Form Health Survey (SF-36).
21
Adverse events
Compliance with the rehabilitation program and adverse events were recorded in each participant's medical record. Adverse events were monitored by the Department of Clinical Trial Design and Management Translational Research Center. Serious adverse events were assessed by the External Data Monitoring Committee.
Statistical analysis
ROM, muscle strength, and SF-36 score were presented as the median with 25% to 75% quartiles. For follow-up assessment of changes in each outcome over time, the Friedman test was used to identify overall significant differences at 3 different time points (before treatment and 6 and 12mo after treatment) for each variable. Post hoc Scheffe test was used to assess which time points showed significant differences. A P value of <.05 was considered statistically significant for all analyses.
Results
Between November 2007 and June 2009, 10 participants were recruited into the clinical trial. All participants were men with an average age of 31.7 years (range, 20–48y). A history of steroid treatment was found in 4 participants (table 2). The pretreatment radiographic stage was 3A in 6 hips and stage 3B in 4 hips (see table 2). During the rehabilitation period (6mo after surgery), there was no progression of disease. At 1 year after surgery, 6 hips with stage 3A and 2 hips with stage 3B did not progress, but 2 hips with stage 3B (cases 3 and 7) progressed to stage 4.
17
Table 2Baseline data of patients
| Case | Age (y) | Sex | Height (cm) | Weight (kg) | Affected Side | Steroid Use | Class | Stage | History |
|---|---|---|---|---|---|---|---|---|---|
| 1 | 27 | M | 170.9 | 66.5 | R | Y | C2 | 3B | Nephritis |
| 2 | 23 | M | 171.0 | 56.6 | L | Y | C2 | 3A | Cushing syndrome |
| 3 | 48 | M | 174.7 | 87.5 | R | N | C2 | 3B | Meningioma |
| 4 | 20 | M | 174.2 | 76.8 | R | Y | C1 | 3A | Hepatitis |
| 5 | 35 | M | 178.8 | 70.0 | L | N | C2 | 3A | None |
| 6 | 28 | M | 169.2 | 58.3 | R | N | C2 | 3A | None |
| 7 | 39 | M | 183.1 | 85.2 | R | Y | C2 | 3B | Leukemia |
| 8 | 26 | M | 175.1 | 66.4 | R | N | C2 | 3B | None |
| 9 | 33 | M | 174.2 | 61.0 | R | N | C2 | 3A | None |
| 10 | 38 | M | 166.7 | 52.9 | R | N | C2 | 3A | None |
Abbreviations: L, left; M, male; N, no; R, right; Y, yes.
∗ Radiographic clinical classification proposed by Japanese Investigation Committee.
† Radiographic staging score by Japanese Investigation Committee.
Hip ROM
While nearly all ROM measures improved after treatment, the only significant improvements were transplant-side external rotation at 6 months (P<.05) and nontransplant-side flexion at 12 months (P<.01) (table 3).
Table 3Comparison of hip ROM between pretreatment, 6 months after treatment, and 12 months after treatment (N=10)
| Hip ROM | Pretreatment | 6mo After Treatment | Effect Size (Pre/6mo) | 12mo After Treatment | Effect Size (Pre/12mo) | P at 3 Time Points (Pre/6mo/12mo) |
|---|---|---|---|---|---|---|
| Flexion (deg) | ||||||
| Transplant side | 97.5 (95.0–107.5) | 107.5 (96.3–110.0) | .58 | 107.5 (100–113.8) | .74 | .19 |
| Nontransplant side | 101.0 (100.0–110.0) | 112.5 (100.0–113.8) | .31 | 112.5 (101.3–120.0) | .47 | <.01 |
| Extension (deg) | ||||||
| Transplant side | 20.0 (15.0–20.0) | 20 (16.3–20.0) | .12 | 15.0 (15.0–18.8) | .47 | .34 |
| Nontransplant side | 20.0 (16.3–20.0) | 20.0 (15.0–20.0) | .01 | 17.5 (15.0–20.0) | 0 | .92 |
| Abduction (deg) | ||||||
| Transplant side | 30.0 (21.3–35.0) | 35.0 (30.0–40.0) | .52 | 35.0 (30.0–38.8) | .38 | .24 |
| Nontransplant side | 35.0 (31.3–38.8) | 37.5 (31.3–40.0) | .23 | 35.0 (35.0–35.0) | .11 | .53 |
| External rotation (deg) | ||||||
| Transplant side | 45.0 (37.5–53.8) | 50.0 (41.3–60.0) | .43 | 50.0 (42.5–53.8) | .31 | .09 |
| Nontransplant side | 40.0 (37.5–53.8) | 50.0 (45.0–60.0) | .46 | 50.0 (45.0–60.0) | .42 | .38 |
NOTE. Values are median (25%–75% quartiles) or as otherwise indicated. P values at 3 time points were calculated by Friedman test. Multiple comparison test was performed by Scheffe test.
∗ P<.01.
† P<.05 as calculated by comparison with pretreatment.
Muscle strength and function
While nearly all muscle strength measures improved after treatment, the only significant improvements were transplant-side extensor and abductor strength at 12 months after treatment (P<.05) (table 4).
Table 4Comparison of physical function between pretreatment, 6 months after treatment, and 12 months after treatment (N=10)
| Measure | Pretreatment | 6mo After Treatment | Effect Size (Pre/6mo) | 12mo After Treatment | Effect Size (Pre/12mo) | P at 3 Time Points (Pre/6mo/12mo) |
|---|---|---|---|---|---|---|
| Hip flexor strength (Nm/kg) | ||||||
| Transplant side | 1.39 (1.01–1.65) | 1.49 (1.35–1.86) | 0.74 | 1.79 (1.58–1.91) | 0.70 | .12 |
| Nontransplant side | 1.30 (1.05–1.50) | 1.82 (1.38–1.96) | 1.14 | 1.73 (1.68–2.03) | 1.12 | .08 |
| Hip extensor strength (Nm/kg) | ||||||
| Transplant side | 0.56 (0.43–0.78) | 1.48 (0.84–1.56) | 0.98 | 1.28 (0.86–1.69) | 1.00 | <.05 |
| Nontransplant side | 0.64 (0.37–0.80) | 1.13 (0.82–1.49) | 1.18 | 1.61 (0.96–1.77) | 1.62 | .08 |
| Hip abductor strength (Nm/kg) | ||||||
| Transplant side | 0.67 (0.51–1.29) | 1.20 (0.81–1.43) | 0.58 | 1.28 (1.05–1.78) | 0.86 | <.05 |
| Nontransplant side | 0.66 (0.52–1.37) | 1.21 (0.88–1.66) | 0.53 | 1.28 (1.21–1.85) | 0.71 | .20 |
| Knee flexor strength (Nm/kg) | ||||||
| Transplant side | 1.36 (1.18–1.79) | 1.55 (1.32–1.81) | 0.38 | 1.63 (1.37–1.71) | 0.47 | .15 |
| Nontransplant side | 1.36 (1.11–1.70) | 1.50 (1.12–1.66) | 0.29 | 1.55 (1.27–1.58) | 0.37 | .07 |
| Knee extensor strength (Nm/kg) | ||||||
| Transplant side | 2.77 (2.24–3.37) | 2.97 (2.42–4.09) | 0.46 | 3.22 (2.93–3.69) | 0.56 | .10 |
| Nontransplant side | 2.71 (2.50–4.00) | 3.38 (2.98–3.83) | 0.49 | 3.51 (2.72–4.10) | 0.36 | .19 |
| Lower limb load (N/kg) | ||||||
| Transplant side | 10.61 (8.01–14.58) | 15.78 (9.16–20.02) | 0.99 | 15.34 (12.04–19.74) | 0.98 | .06 |
| Nontransplant side | 14.16 (10.36–20.65) | 17.61 (12.49–21.72) | 0.47 | 18.04 (14.12–23.50) | 0.70 | <.05 |
| Timed Up and Go test (s) | 7.06(5.82–7.31) | 6.11 (4.96–7.00) | 0.51 | 5.40 (5.00–6.50) | 0.77 | .15 |
NOTE. Values are median (25%–75% quartiles) or as otherwise indicated. P values at 3 time points were calculated by Friedman test. Multiple comparison test was performed by Scheffe test.
∗ P<.05, as calculated by comparison with pretreatment.
On the nontransplant side, there was significant improvement in lower limb load strength (P<.05) (see table 4). The remaining subgroup scores showed posttreatment improvements that did not reach statistical significance.
SF-36 subgroup score
There were significant improvements in physical function, role physical, and bodily pain subgroup scores between the 3 time points (before treatment and 6 and 12mo after treatment) (P<.05) (table 5). There was also a significant difference in each score between values before and 12 months after treatment (P<.05).
Table 5Comparison of SF-36 subgroups scores between pretreatment, 6 months after treatment, and 12 months after treatment (N=6)
| SF-36 Subgroups | Pretreatment | 6mo After Treatment | Effect Size (Pre/6mo) | 12mo After Treatment | Effect Size (Pre/12mo | P at 3 Time Points (Pre/6mo/12mo) |
|---|---|---|---|---|---|---|
| Physical function | 45 (36.3–65) | 90 (78.8–95) | 1.54 | 92.5 (78.8–95) | 1.58 | <.05 |
| Role-physical | 40.6 (36.3–78.1) | 68.8 (57.8–93.8) | 0.71 | 96.9 (93.8–100) | 1.63 | <.05 |
| Bodily pain | 52 (51.3–52) | 72 (64.5–72) | 2.83 | 73 (64.5–81.5) | 3.18 | <.05 |
| General health | 59.5 (49.5–77) | 77 (61.8–90.8) | 0.66 | 79.5 (62–88) | 0.72 | .31 |
| Vitality | 71.9 (54.7–84.4) | 68.8 (62.5–84.4) | 0.22 | 71.9 (62.5–85.9) | 0.11 | .58 |
| Social function | 31.3 (25–84.4) | 100 (71.9–100) | 0.90 | 93.8 (78.2–100) | 1.00 | .21 |
| Role-emotion | 50 (37.5–87.5) | 100 (100–100) | 0.89 | 100 (100–100) | 1.15 | .13 |
| Mental health | 80 (71.2–88.8) | 90 (82.5–90) | 0.52 | 80 (80–83.4) | 0.44 | .27 |
NOTE. Values are median (25%–75% quartiles) or as otherwise indicated. P values at 3 time points were calculated by Friedman test. Multiple comparison test was performed by Scheffe test.
∗ P<.05 as calculated by comparison with pretreatment.
Adverse events
All participants completed the 12-week rehabilitation program. There were 5 cases of muscle pain, 2 cases of muscle stiffness, and 1 case of ankle pain on initiation of load bearing, but no serious adverse events were associated with rehabilitation. Radiography showed no evidence of progression in femoral head collapse during the rehabilitation period.
Discussion
In the current study, we designed a rehabilitation program that focused on 3 aspects: (1) improving hip joint function, (2) avoiding collapse of the femoral head, and (3) promoting bone formation from transplanted cells by using a physical therapy protocol.
In the field of rehabilitation, the relationship between pursuing functional improvement and risk reduction becomes a trade-off in some cases, but compatibility between them is important. To accomplish this trade-off, it is helpful to simultaneously assess the etiologic factors and radiologic findings of these patients in order to treat ION.
22
, 23
Further, lesion size, lesion location, and radiographic staging can help determine the natural course of ION.22
In our patients, necrotic lesion size was broad, and radiographic stage had progressed (see table 2). The prognosis for steroid-induced ION is better than that for ION associated with sickle cell anemia.22
In our study, among the 10 participants, 4 had a history of steroid use, while the other 6 had idiopathic ION (see table 2). The rehabilitation program in patients with ION should consider these aspects and should be planned carefully to avoid collapse of the femoral head.Weight-bearing was prohibited until 6 weeks after treatment (see table 1), and full-weight sitting-to-standing actions were prohibited until 12 weeks after treatment because of the high pressure placed on the top of the femoral head.
24
, 25
, 26
Not only weight-bearing, but also muscle activity increases the acetabular contact pressure. Isometric hip extension and active hip flexion generate high pressure on the femoral head, equal to weight-bearing and walking.25
, 26
By comparison, the pressure generated by isotonic and isokinetic exercises is much less.25
, 26
Such joint-preserving, muscle-strengthening exercise has been reported in physical therapy for osteoarthritis.27
, 28
We designed the rehabilitation program so that isotonic and isokinetic exercises could be performed on the transplant side before isometric exercises (see table 1). All participants completed the 12-week rehabilitation program without excessive pain. Functional improvement was observed, and there were no serious adverse events associated with rehabilitation. These results suggest that the first 2 aims of our study were achieved.Although we could not show clear evidence that the current rehabilitation program promotes bone formation, mechanical stimulation may be important for bone formation of transplanted cells. Lack of mechanical loading causes bone loss and fractures in the elderly.
29
During physical activity, mechanical forces are placed on the bones through ground reaction forces and the contractile activity of muscles.30
, 31
Adapting physical forces to bone structure results in maintenance and prevention of fractures in the elderly.30
Fluid flow, strain, and hydrostatic pressure are mechanotransducers of physical force to osteocytes.29
, 31
, 32
Stimulated mechanoreceptors on osteocytes activate the prostaglandin and Wnt pathways.33
Mechanical loading stimulates not only osteocytes but also osteoblasts34
, 35
and MSCs.36
, 37
Oscillatory fluid flow promotes the proliferation and differentiation of marrow MSCs.37
Furthermore, mechanical signals inhibit adipogenesis and promote the anabolism of osteogenesis.36
A report by Ambrosio et al38
reveals important information about this issue. Treadmill running has a synergistic effect on healing injured skeletal muscle after muscle-derived stem cell transplantation,38
in addition to the positive effects of improved weight management, cardiovascular health, and metabolic profile.39
Our previous report40
suggested that adequate exercise promotes muscle remodeling after bilateral broad necrosis of the soleus muscles. It is hypothesized that suitable mechanical stimulation drives the differentiation of MSCs, while the beneficial paracrine effect may induce a synergistic effect between MSC transplantation and rehabilitation. However, further basic and clinical research is required to prove this hypothesis.Evaluation of the effect of nonsurgical procedures on ION is important. Mont et al
18
compared the effect of core decompression surgery with nonsurgical management of ION and reported a 63.5% satisfactory clinical result with core decompression, but only 22.7% with nonsurgical management. However, this study was not an adjusted case-control study but was a literature review. Therefore, etiologic factors and radiographic findings were not fully assessed.18
In multicenter, randomized controlled studies, physical therapy has similar effects in ION patients with sickle cell disease as does core decompression surgery with physical therapy.19
, - Neumayr
LD, for the National Osteonecrosis Trial in Sickle Cell Anemia Study Group. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment.
J Bone Joint Surg Am. 2006; 88: 2573-2582
41
Basic studies to design the rehabilitation protocol and further clinical studies are needed, but the information provided from the current study may aid in the development of rehabilitation protocols after cell transplantation for the treatment of ION.Study limitations
The current study has several major limitations. This was a small-scale, single-group, pre-post preliminary study. Case-control and large-scale studies are needed to demonstrate the efficacy of the rehabilitation protocol. The current study was based on the original clinical trial, so it is not an individual study. The population size of the clinical trial itself was limited because it was a feasibility study.
Conclusions
The present study demonstrated the feasibility and safety of an intensive multiplex rehabilitation program after MSC transplantation in individuals with ION. Despite this, future studies should investigate dosing and timing parameters, as well as the mechanistic basis for improvements in outcomes when a combination therapy is used.
Suppliers
- a.Olympus Terumo Biomaterials Co.
- b.Senoh Co.
- c.KONAMI Co.
- d.Nihon Medix Co Ltd.
- e.OG Giken Co Ltd.
Acknowledgments
We thank Kei-ichiro Kawanabe, MD, PhD, and Haruhiko Akiyama, MD, PhD, (Graduate School of Medicine, Kyoto University, Kyoto) for their technical advice on ION; Taira Maekawa, MD, PhD, Yasunari Kasai, BSc, Satoshi Teramukai, PhD, Harue Tada, PhD, Kazumi Miura, BA, Tatsuya Ito, PhD, Akira Shimizu, MD, PhD, and Ryota Asada, PhD, (Kyoto University Hospital, Kyoto) for promoting the clinical study; and Moritoshi Furu, MD, Akira Nasu, MD, Kenichi Fukiage, MD, Seiji Otsuka, MD, Takashi Kasahara, MD, Tatsuya Sueyoshi, MD, Kinya Ito, MD, Yonghui Jin, MD, Hiroto Mitsui, MD, and Michiko Ueda, BA, (Institute for Frontier Medical Sciences, Kyoto University, Kyoto) for their assistance with data collection.
Appendix 1. Assessment of Necrotic Lesions and Stages
Radiographic classification proposed by the SDIC in Japan
20
:- •Type A lesions occupied the medial one third or less of the weight-bearing portion.
- •Type B lesions occupied the medial two thirds or less of the weight-bearing portion.
- •Both types C1 and C2 lesions occupied more than the medial two thirds of the weight-bearing portion.
- •Type C2 lesions extended laterally to the acetabular edge, but type C1 lesions did not.
The ION staging proposed by the SDIC used in Japan is a modified version of the system proposed by the Association Research Circulation Osseous Committee.
20
- •Stage 1: Specific findings of osteonecrosis are not observed on magnetic resonance imaging, bone scintigram, histology, or radiographs.
- •Stage 2: Demarcating sclerosis is seen without collapse of the femoral head.
- •Stage 3: Collapse of the femoral head, including the crescent sign, is seen without joint-space narrowing. Mild osteophyte formation of the femoral head or acetabulum may be seen.
- •Stage 3A: Collapse of the femoral head <3mm
- •Stage 3B: Collapse of the femoral head ≥3mm
- •
- •Stage 4: Osteoarthritic changes are seen.
References
- Nontraumatic necrosis of bone (osteonecrosis).N Engl J Med. 1992; 326: 1473-1479
- Osteonecrosis of the femoral head: etiology, imaging and treatment.Eur J Radiol. 2007; 63: 16-28
- Osteonecrosis of the femoral head: an update in year 2012.World J Orthop. 2012; 3: 49-57
- Treatment of femoral head osteonecrosis in the United States: 16-year analysis of the Nationwide Inpatient Sample.Clin Orthop Relat Res. 2014; 472: 617-623
- Review: mesenchymal stem cells: cell-based reconstructive therapy in orthopedics.Tissue Eng. 2005; 11: 1198-1211
- Concise review: the clinical application of mesenchymal stem cells for musculoskeletal regeneration: current status and perspectives.Stem Cells Transl Med. 2012; 1: 237-247
- Multilineage potential of adult human mesenchymal stem cells.Science. 1999; 284: 143-147
- Treatment of osteonecrosis with autologous bone marrow grafting.Clin Orthop Relat Res. 2002; 405: 14-23
- Treatment of osteonecrosis of the femoral head with implantation of autologous bone-marrow cells. A pilot study.J Bone Joint Surg Am. 2004; 86: 1153-1160
- Autologous bone marrow cell implantation in the treatment of non-traumatic osteonecrosis of the femoral head: five year follow-up of a prospective controlled study.Bone. 2011; 49: 1005-1009
- Treatment of early stage osteonecrosis of the femoral head with autologous implantation of bone marrow-derived and cultured mesenchymal stem cells.Bone. 2012; 50: 325-330
- Use of concentrated bone marrow aspirate and platelet rich plasma during minimally invasive decompression of the femoral head in the treatment of osteonecrosis.Croat Med J. 2013; 54: 219-224
- Intralesional autologous mesenchymal stem cells in management of osteonecrosis of femur: a preliminary study.Musculoskelet Surg. 2013; 97: 223-228
- Treatment of osteonecrosis of the femoral head with thorough debridement, bone grafting and bone-marrow mononuclear cells implantation.Eur J Orthop Surg Traumatol. 2014; 24: 197-202
- Idiopathic bone necrosis of the femoral head. Early diagnosis and treatment.J Bone Joint Surg Br. 1985; 67: 3-9
- Vascularized iliac bone graft for avascular necrosis of the femoral head.Clin Orthop Relat Res. 1997; 337: 140-148
- An exploratory clinical trial for idiopathic osteonecrosis of femoral head by cultured autologous multipotent mesenchymal stromal cells augmented with vascularized bone grafts.Tissue Eng Part B Rev. 2014; 20: 233-242
- Core decompression versus nonoperative management for osteonecrosis of the hip.Clin Orthop Relat Res. 1996; 324: 169-178
- LD, for the National Osteonecrosis Trial in Sickle Cell Anemia Study Group. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment.J Bone Joint Surg Am. 2006; 88: 2573-2582
- The 2001 revised criteria for diagnosis, classification, and staging of idiopathic osteonecrosis of the femoral head.J Orthop Sci. 2002; 7: 601-605
- The MOS 36-Item Short-Form Health Survey (SF-36). I. Conceptual framework and item selection.Med Care. 1992; 30: 473-483
- The natural history of untreated asymptomatic osteonecrosis of the femoral head: a systematic literature review.J Bone Joint Surg Am. 2010; 92: 2165-2170
- Longitudinal quantitative evaluation of lesion size change in femoral head osteonecrosis using three-dimensional magnetic resonance imaging and image registration.J Orthop Res. 2006; 24: 1231-1239
- Contact pressures in the human hip joint measured in vivo.Proc Natl Acad Sci U S A. 1986; 83: 2879-2883
- In vivo acetabular contact pressures during rehabilitation, part I: acute phase.Phys Ther. 1992; 72: 691-699
- Exercise and gait effects on in vivo hip contact pressures.Phys Ther. 1991; 71: 301-309
- Quadriceps strength, quadriceps power, and gait speed in older U.S. adults with diabetes mellitus: results from the National Health and Nutrition Examination Survey, 1999-2002.J Am Geriatr Soc. 2013; 61: 769-775
- A feasibility study of the effect of intra-articular corticosteroid injection on isokinetic muscle strength in children with juvenile idiopathic arthritis.Pediatr Exerc Sci. 2013; 25: 221-237
- Fluid and solute transport in bone: flow-induced mechanotransduction.Annu Rev Fluid Mech. 2009; 41: 347-374
- Mechanical loading and how it affects bone cells: the role of the osteocyte cytoskeleton in maintaining our skeleton.Eur Cell Mater. 2012; 24: 278-291
- Measurement of mechanical strain on mandibular surface with mastication robot: influence of muscle loading direction and magnitude.Orthod Craniofac Res. 2003; 6: 163-167
- Sensitivity of osteocytes to biomechanical stress in vitro.FASEB J. 1995; 9: 441-445
- Regulation of Wnt/β-catenin signaling within and from osteocytes.Bone. 2013; 54: 244-249
- Small oscillatory accelerations, independent of matrix deformations, increase osteoblast activity and enhance bone morphology.PLoS One. 2007; 2: e653
- Anabolism. Low mechanical signals strengthen long bones.Nature. 2001; 412: 603-604
- Mechanical signal influence on mesenchymal stem cell fate is enhanced by incorporation of refractory periods into the loading regimen.J Biomech. 2011; 44: 593-599
- Oscillatory fluid flow affects human marrow stromal cell proliferation and differentiation.J Orthop Res. 2004; 22: 1283-1289
- The synergistic effect of treadmill running on stem-cell transplantation to heal injured skeletal muscle.Tissue Eng Part A. 2010; 16: 839-849
- Biological basis of exercise-based treatments for musculoskeletal conditions.PM R. 2011; 3: S59-63
- Bilateral phlegmasia dolens associated with Trousseau’s syndrome: a case report.Arch Phys Med Rehabil. 2008; 89: 1187-1190
- Treatment for avascular necrosis of bone in people with sickle cell disease.Cochrane Database Syst Rev. 2012; 5: CD004344
Article info
Publication history
Published online: October 30, 2014
Footnotes
Current affiliation for Nakamura: Department of Orthopaedic Surgery, National Hospital Organization Kyoto Center, Kyoto, Japan.
Supported by the Japan Society for the Promotion of Science (grant nos. 23300199 and 26282154).
Disclosures: none.
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© 2015 American Congress of Rehabilitation Medicine. Published by Elsevier Inc.
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