Bone Marrow-Derived Cell Therapies to Heal Long-Bone Nonunions: A Systematic Review and Meta-Analysis—Which Is the Best Available Treatment?

Table 1

Studies selected based on inclusion and exclusion criteria. Fracture grading is reporting based either on Gustilo and Anderson (G) or on AO-OTA (OTA) classification scale.

Treatment

subjects; Age range (years)

Site of fracture

Type of fracture

Type of nonunion

Duration of nonunion

Frequency of radiographic follow-up

Healing rate at 6 months (healed/total)

Healing rate at 12 months (healed/total)

Failure rate at last follow-up; Failure reason(s)

Type of study

Record bias

Reporting bias

Relevant confounding factor bias

Outcome reporting bias

Ref.

BMAC

10 subjects; 18-82

10 tibias

1 closed; 6 GII; 3 GIII

n.d.

7-36 months

n.d.

7/10

9/10

10%; n.d.

Prospective

No

Yes

Yes

—

[15]

BMAC

20 subjects; 18-65

15 tibias; 3 humeri; 2 ulnae

10 closed; 6 GI; 2 GII; 2 GIII

n.d.

6-18 months

Monthly

15/20

17/20

15%; Fractures with bone loss and ulnar fracture

Prospective

No

Yes

Yes

No

[16]

BMAC

1 subject; 44

1 tibia

1 GIII

n.d.

6 months

Every 6 weeks (until 6 months)

1/1

n.d.

0%

Case study

Yes

Yes

No

No

[17]

BMAC

19 subjects; 24-60

19 tibias

n.d.

9 atrophic; 10 hypertrophic

6-36 months

Every 4-6 weeks (until 6 months)

15/19

n.d.

21%; n.d.

Prospective

No

No

Yes

No

[18]

BMAC

17 subjects; 25-66

5 femurs; 10 tibias; 2 ulnae

17 closed

n.d.

6-24 months

Monthly (until 6 months)

16/17

n.d.

6%; Improper osteosynthesis

Prospective

No

Yes

Yes

No

[19]

BMAC

7 subjects; 25-66

2 femurs; 2 humeri; 5 ulnae

7 closed

7 atrophic

7-53 months

n.d. (until 6 months)

6/7

n.d.

10%; Alcoholism

Retrospective

Yes

No

Yes

—

[20]

BMAC

16 subjects; 19-59

16 femurs

12 closed; 3 GI; 1 GII

7 atrophic; 9 oligotrophic

9-97 months

1.5, 4, 6, and 12 months

7/16

8/16

10%; Alcoholism

Prospective

No

No

Yes

No

[21]

BMAC

17 subjects; 22-80

10 femurs; 5 tibias; 1 ulna; 1 humerus

12 closed; 5 open

17 atrophic

9-79 months

1, 2, 3, 6, 9, and 12 months

11/17

13/17

23.5%; n.d.

Retrospective

Yes

No

Yes

No

[22]

BMAC

54 subjects; 22-64

54 tibias

54 closed

n.d.

n.d.

n.d.

n.d.

49/54

9.25%; n.d.

Retrospective

Yes

Yes

Yes

—

[23]

BMAC/Scaffold (porous ceramic mixed with collagen)

3 subjects; 26-60

1 femur; 1 tibia; 1 ulna

n.d.

n.d.

7-12 months

1.5, 3, 6, and 12 months

1/3

2/3.

0%

Prospective

Yes

Yes

Yes

Yes

[24]

BMAC/Scaffold (DBM)

15 subjects; 22-87

3 femurs; 10 tibias; 2 humeri

n.d.

n.d.

n.d.

n.d.

n.d.

n.d.

40%; n.d.

Prospective

Yes

Yes

Yes

—

[25]

BMAC/Scaffold (allogeneic bone graft)

12 subjects; 19-68

12 tibias

2 closed; 1 GI; 3 GII; 6 GIII

n.d.

>6 months

n.d.

10/12

11/12

8.33%; n.d.

Prospective

No

Yes

Yes

—

[26]

BMAC/Scaffold (frozen cancellous bone)

2 subjects; 22 and 38

2 humeri

n.d.

n.d.

>6 months

n.d.

1/2

2/2

0%

Retrospective

Yes

Yes

Yes

—

[27]

BMAC/Scaffold (cancellous bone)

7 subjects; 26-70

3 femurs; 3 tibias; 1 ulna

n.d.

n.d.

>6 months

Monthly up to 12 months; Yearly afterwards

5/7

7/7

0%

Prospective

No

Yes

Yes

No

[28]

BMAC/Scaffold (autologous bone chips)

14 subjects; 33-92

14 femurs

9 OTA32-A2-1; 3 OTA32-B3-1; 2 OTA31-A2-3

14 atrophic

16-48 months

1.5, 3, 4, 5, 6, 8, 12, and 18 months or until union

7/14

14/14

0%

Retrospective

Yes

No

Yes

No

[29]

BMAC/Scaffold (DBM)

19 subjects; 20-73

1 femur; 8 tibias; 3 humeri; 3 radii; 2 ulnae; 2 metatarsi

n.d.

19 atrophic

>9 months

n.d.

n.d.

n.d.

21%; n.d.

Prospective

No

No

Yes

—

[30]

BMAC/Scaffold (autologous bone chips+PRP)

50 subjects; 18-76.7

n.d. femur; n.d. tibia

n.d.

39 atrophic; 11 hypertrophic

>6-9 months

1.5, 3,6, 12, and 24 months

23/50

42/50

4.88%; Bone loss and failure of fixation device

Retrospective; Controlled

Yes

Yes

Yes

No

[31]

BMAC/Scaffold (allogeneic cancellous bone)

18 subjects; 19-81

18 femurs

17 closed; 1 GIII

n.d.

6 months

Monthly

15/18

15/18

16.7%; Impaired bone vascularity

Prospective

No

Yes

Yes

No

[32]

BMAC/Scaffold (DBM)

11 subjects; 55-79

11 femurs

n.d.

n.d.

>6 months

0.5, 1.5, 3, 6, 9, and 12 months

11/11

11/11

0%

Retrospective

Yes

Yes

Yes

No

[33]

BMSC

6 subjects; 18-73

3 humeri; 1 ulna; 1 radius; 1 ulna and radius

1 OTA12-A1; 1 OTA12-B3; 1 OTA12-C1; 1 OTA22-A1; 1 OTA22-A2; 1 OTA22-C3

6 atrophic

n.d.

n.d.

6/6

6/6

0%

Retrospective

Yes

No

Yes

—

[34]

BMSC

3 subjects; 19-44

1 femur; 1 humerus; 1 forearm

n.d.

n.d.

19-39 months

3, 6, and 12 months

n.d.

3/3

0%

Retrospective

Yes

Yes

Yes

Yes

[35]

BMSC

1 subject; 47

1 ulna

1 OTA22-A1-1

1 atrophic

6 months

n.d.

0/1

1/1

0%

Case study

Yes

No

No

—

[36]

BMSC

7 subjects; 26-61

4 femurs; 3 tibias

3 closed; 4 open

7 atrophic

8-96 months

1, 3, 6, and 12 months

3/7

4/7

42.8%; n.d.

Prospective

No

No

Yes

No

[37]

BMSC

5 subjects; 23-55

3 femurs; 2 tibias

5 closed

5 atrophic

7-72 months

1, 3, 6, and 12 months

2/5

3/5

40%; n.d.

Prospective

No

No

Yes

No

[38]

BMSC/Scaffold (CaSO4 pellets)

1 subject; 34

1 tibia

1 closed

1 hypertrophic

9 years

n.d.

1/1

1/1

0%

Case study

Yes

No

No

—

[39]

BMSC/Scaffold (collagen microspheres)

3 subjects; 27-81

1 femur; 2 tibias

n.d.

3 atrophic

12-24 months

n.d.

n.d.

3/3

0%

Case reports

Yes

No

Yes

—

[40]

BMSC/Scaffold (HA granules)

5 subjects; 18-37

3 femurs; 1 tibia; 1 humerus

n.d.

5 atrophic

37.2 months

Monthly up to 12 months

0/5

5/5

0%

Prospective; Controlled

No

No

Yes

No

[41]

n.d.: nondescribed.