Appendix 3. Detailed information of the included randomized clinical trials

Author; Year Groups BMD/BMC Biochemical markers Ca/ Vit. D

Studies of pharmacological treatment

Bauman,

2005a

Pamidronate

60mg IV

12 month

(N=6)

Leg BMD (g/cm2):

Baseline: 1.466 ± 0.139 1m: 1.481 ± 0.147 3m: 1.448 ± 0.168 6m: 1.403 ± 0.176 12m: 1.339 ± 0.172 18m: 1.245 ± 0.166 24m: 1.208 ± 0.180

Pelvis BMD (g/cm2):

Baseline: 1.237 ± 0.140 1m: 1.231 ± 0.127 3m: 1.191 ± 0.110 6m: 1.190 ± 0.151 12m: 1.135 ± 0.167 18m: 1.073 ± 0.134 24m: 1.043 ± 0.126

Distal femur BMD (g/cm2):

Baseline: 0.957 ± 0.167 1m: 0.988 ± 0.129 3m: 0.920 ± 0.132 6m: 0.889 ± 0.128 12m: 0.853 ± 0.068 18m: 0.772 ± 0.107 24m: 0.756 ± 0.060

Proximal Tibia BMD (g/cm2):

Baseline: 1.107 ± 0.253 1m: 1.073 ± 0.219

Urine NTx./Cr (nmol/mmol):

Baseline: 217 ± 268 1m: 113 ± 77 3m: 116 ± 82 6m: 129 ± 55 12m: 108 ± 60 18m: 85 ± 21 24m: 56 ± 36

Osteocalcin (ng/mL):

Baseline: 3.4 ± 3.5 1m: 4.8 ± 5.5 3m: 3.3 ± 2.1 6m: 4.4 ± 4.1 12m: 4.0 ± 3.0 18m: 2.9 ± 2.5 24m: 3.1 ± 2.9

PINP (ng/mL)

Baseline: 35 ± 26 1m: 53 ± 75 3m: 25 ± 23 6m: 52 ± 94 12m: 65 ± 80 18m: 58 ± 77 24m: 57 ± 73

Urine Ca (mg/dL)

Baseline: 285 ± 166 1m: 141 ± 87 3m: 203 ± 42 6m: 189 ± 94 12m: 205 ± 82 18m: 202 ± 9 24m: 172 ± 46

Serum Ca (mg/d)

Baseline: 9.2 ± 0.4 1m: 9.3 ± 0.8 3m: 9.3 ± 0.4 6m: 9.4 ± 0.6 12m: 9.4 ± 0.3 18m: 9.2 ± 0.3 24m: 9.4 ± 0.3

3m: 1.015 ± 0.166 6m: 0.924 ± 0.180 12m: 0.821 ± 0.203 18m: 0.665 ± 0.196 24m: 0.654 ± 0.21

Leg BMC (g):

Baseline: 1,408 ± 317 1m: 1,351 ± 271 3m: 1,351 ± 271 6m: 1,259 ± 281 12m: 1,179 ± 272 18m: 1,105 ± 249 24m: 1,067 ± 251

Placebo

(N=5)

Leg BMD (g/cm2):

Baseline: 1.514 ± 0.171 1m: 1.494 ± 0.116, P<0.05 3m: 1.423 ± 0.126 6m: 1.374 ± 0.111, P<0.05 12m: 1.328 ± 0.078 18m: 1.240 ± 0.085 24m: 1.223 ± 0.062

Pelvis BMD (g/cm2):

Baseline: 1.265 ± 0.107 1m: 1.215 ± 0.123 3m: 1.204 ± 0.091 6m: 1.171 ± 0.95 12m: 1.102 ± 0.061 18m: 1.075 ± 0.063 24m: 1.029 ± 0.058

Distal femur BMD (g/cm2):

Baseline: 1.071 ± 0.266 1m: 1.046 ± 0.235 3m: 0.988 ± 0.264 6m: 0.983 ± 0.263 12m: 0.915 ± 0.203 18m: 0.806 ± 0.073

Urine NTx./Cr (nmol/mmol):

Baseline: 289 ± 190 1m: 273 ± 123, P<0.05 3m: 213 ± 126 6m: 114 ± 30 12m: 96 ± 44 18m: 86 ± 41 24m: 80 ± 42

Osteocalcin (ng/mL):

Baseline: 3.5 ± 1.5 1m: 4.4 ± 1.4 3m: 6.2 ± 2.8 6m: 4.9 ± 3.3 12m: 4.1 ± 2.5 18m: 2.8 ± 1.6 24m: 3.3 ± 2.1

PINP (ng/mL)

Baseline: 13 ± 3 1m: 20 ± 15 3m: 36 ± 42 6m: 16 ± 14 12m: 42 ± 49 18m: 41 ± 46

Urine Ca (mg/dL)

Baseline: 337 ± 93 1m: 337 ± 143, P<0.05 3m: 268 ± 120 6m: 249 ± 68 12m: 157 ± 44 18m: 167 ± 51 24m: 144 ± 15

Serum Ca (mg/d)

Baseline: 9.1 ± 0.6 1m: 9.2 ± 0.1 3m: 9.3 ± 0.5 6m: 9.3 ± 0.5 12m: 9.1 ± 0.9 18m: 9.2 ± 0.2 24m: 9.7 ± 0.5

24m: 0.754 ± 0.098Proximal Tibia BMD (g/cm2):

Baseline: 1.089 ± 0.205 1m: 1.060 ± 0.196 3m: 0.995 ± 0.203 6m: 0.892 ± 0.178 12m: 0.771 ± 0.162 18m: 0.651 ± 0.102 24m: 0.619 ± 0.111

Leg BMC (g):

Baseline: 1,275 ± 148 1m: 1,267 ± 152 3m: 1,191 ± 217 6m: 1,161 ± 190 12m: 1,114 ± 175 18m: 1,001 ± 127 24m: 980 ± 110

24m: 21 ± 24

Bauman,

2005b

Ca 1300 mg/d + Vit D 800 IU daily + 1-α vitamin D2 4 μg daily

24 mo

(N = 19).

Leg BMD (g/cm2):

Baseline: 1.018 ± 0.240 6m: 1.031 ± 0.243 12m: 1.039 ± 0.244 18m: 1.041 ± 0.247 24m: 1.040 ± 0.244

Urine NTx./Cr (nmol/mmol):

Baseline: 30 ± 27 6m: 17 ± 8 12m: 17 ± 15 18m: 19 ± 9 24m: 20 ± 13

Osteocalcin (ng/mL):

Baseline: 5.1 ± 4.3 6m: 5.1 ± 3.9 12m: 4.5 ± 2.4 18m: 5.4 ± 4.1 24m: 5.4 ± 3.5

PINP (ng/mL)

Baseline: 25.3 ± 16.7 6m: 34.5 ± 29.3 12m: 26.0 ± 12.8

Urine Ca (mg/dL)

Baseline: 166 ± 108 6m: 250 ± 147 12m: 220 ± 98 18m: 217 ± 114 24m: 221 ± 102

Total Ca (mg/dL)

Baseline: 9.0 ± 0.5 6m: 9.4 ± 0.4 12m: 9.6 ± 0.4 18m: 9.4 ± 0.52 24m: 9.5 ± 0.5

25 OH Vit D (ng/mL)

Baseline: 11.2 ± 8.4 12m: 22.9 ± 7.1

18m: 32.5 ± 21.9 24m: 32.5 ± 21.9

Ca 1300 mg daily + Vit D 800 IU daily + placebo

24 mo

(N=21)

Leg BMD (g/cm2):

Baseline: 1.045 ± 0.166 6m: 1.040 ± 0.166 12m: 1.033 ± 0.158, P<0.01 18m: 1.033 ± 0.149, P<0.01 24m: 1.033 ± 0.149, P<0.01

Urine NTx./Cr (nmol/mmol):

Baseline: 25 ± 16 6m: 25 ± 23, P<0.01 12m: 21 ± 10, P<0.01 18m: 22 ± 14, P<0.01 24m: 27 ± 18, P<0.01

Osteocalcin (ng/mL):

Baseline: 5.3 ± 3.2 6m: 5.5 ± 3.6 12m: 5.3 ± 3.1 18m: 4.9 ± 2.4 24m: 5.9 ± 3.0

PINP (ng/mL)

Baseline: 29.1 ± 20.3 6m: 29.0 ± 19.6 12m: 30.0 ± 18.8 18m: 26.8 ± 13.1 24m: 38.0 ± 19.6

Urine Ca (mg/dL)

Baseline: 177 ± 109 6m: 183 ± 92 12m: 215 ± 88 18m: 203 ± 87 24m: 178 ± 78

Total Ca (mg/dL)

Baseline: 9.3 ± 0.4 6m: 9.4 ± 0.4 12m: 9.4 ± 0.4 18m: 9.3 ± 0.4 24m: 9.5 ± 0.5

25 OH Vit D (ng/mL)

Baseline: 10.3 ± 5.9 12m: 22.1 ± 8.0,

P<0.0001

Bubbear, 2011 Zoledronic acid (Single dose IV) 4mg

(N=7)

Lumbar spine BMD change from baseline (%):

12m: +3.5±3.9Total hip BMD change from baseline (%):

12m: −3.4±3.0Trochanter BMD change from baseline (%):

12m: −4.5±5.7Femoral neck BMD change from baseline (%):

12m: 9.8±10.0

PINP (ng/mL)

Baseline: 126 ±41.5 6w: 98 ±44.5 3m: 66 ±17.4 6m: 55 ±18.8 12m: 47 ±16.2

CTx (ng/mL)

Baseline: 1.2 ±0.3 6w: 0.4 ±0.2 3m: 0.3 ±0.2 6m: 0.3 ±0.1 12m: 0.3 ±0.1

-

Urine NTx/Cr (nmol/mmol)

Baseline: 175 ±39) 6w: 77 ±45 3m: 65 ±17 6m: 81 ±49 12m: 68 ±34

Standard nursing/ medical care

(N=7)

Lumbar spine BMD change from baseline (%):

12m: +0.8±4.9, P=0.033Total hip BMD change from baseline (%):

12m: −15.8±8.9, P=0.005Trochanter BMD change from baseline (%):

12m: −17.9±9.4, P=0.028Femoral neck BMD change from baseline (%):

12m: 14.6±7.0, P=0.741, NS

PINP (ng/mL)

Baseline: 133 ±68.6 6w: 143 ±34.5 3m: 151 ±38.2 6m: 115 ±49.5 12m: 74 ±39.0, P=0.514,

NSCTx (ng/mL)

Baseline: 1.1 ±0.9 6w: 1.2 ±0.4 3m: 0.8 ±0.4 6m: 0.7 ±0.3 12m: 0.6 ±0.2, P=0.047

Urine NTx/Cr (nmol/mmol)

Baseline: 196 ±80 6w: 131 ±66 3m: 148 ±88 6m: 104 ±60 12m: 68 ±31, P=0.469, NS

-

Chappard,

1995

Tiludronate:

1) 400 mg/d (N=7)

2) 200 mg/d (N=7)

3 month

- Bone volume (to total volume in %)

Baseline: 24.6 ± 6.4 3m: 23.7 ± 6.9

Eroded surfaces (to bone surface in %)

-

Baseline: 7.5 ± 2.5 3m: 11.3 ± 4.3

Osteoclast count (n/mm2)

Baseline: 10.5 ± 1.4 3m: 8.9 ± 3.5

Placebo (N=6) - Bone volume (to total volume in %)

Baseline: 22.9 ± 10.0 3m: 18.4 ± 4.9

Eroded surfaces (to bone surface in %)

Baseline: 9.3 ± 7.3 3m: 14.6 ± 3.7

Osteoclast count (n/mm2)

Baseline: 11.9 ± 7.6 3m: 26.5 ± 16.7, P<0.02

-

Gilchrist, 2007 Alendronate (oral) 70 mg weekly

12 months

(N=16)

Lumbar spine BMD (g/cm2):

Baseline: 1.196 ± 0.050 3m: 1.217 ± 0.052 6m: 1.231 ± 0.054 12m: 1.250 ± 0.056 18m: 1.265 ± 0.056

Total hip BMD (g/cm2):

Baseline: 1.108 ± 0.254 3m: 1.106 ± 0.058 6m: 1.078 ± 0.061 12m: 1.075 ± 0.054 18m: 1.028 ± 0.051

CTx (nmol/g)

Baseline: 0.89 ± 0.15 3m: 0.50 ±0.12

ALP (IU/L):

Baseline: 135.6 ± 21.8 12m: 66.7 ± 8

Serum Ca (nmol/liter)

Baseline: 2.27 ± 0.037 12m: 2.28 ± 0.03

Urine Ca (nmol/liter)

Baseline: 6.79 ± 0.9 3m: 2.66 ± 1.032 18m: 2.89 ± 0.074

Femoral neck BMD (g/cm2):

Baseline: 1. 090 ± 0.055 3m: 1.092 ± 0.059 6m: 1.076 ± 0.060 12m: 1.089 ± 0.052 18m: 1.049 ± 0.052

Trochanter BMD (g/cm2):

Baseline: 0. 930 ± 0.051 3m: 0.923 ± 0.055 6m: 0.858 ± 0.059 12m: 0.891 ± 0.051 18m: 0.837 ± 0.050

Femoral shaft BMD (g/cm2):

Baseline: 1. 307 ± 0.065 3m: 1.303 ± 0.068 6m: 1.276 ± 0.071 12m: 1.262 ± 0.068 18m: 1.214 ± 0.062

Legs BMD (g/cm2):

Baseline: 1. 364 ± 0.053 3m: 1.351 ± 0.058 6m: 1.327 ± 0.053 12m: 1.291 ± 0.056 18m: 1.250 ± 0.055

Arms BMD (g/cm2):

Baseline: 0. 975 ± 0.046 3m: 1.014 ± 0.046 6m: 1.010 ± 0.047 12m: 1.018 ± 0.045 18m: 1.077 ± 0.074

Total body BMD (g/cm2):

Baseline: 1.271 ± 0.038 3m: 1.271 ± 0.040 6m: 1.272 ± 0.041

12m: 1.267 ± 0.039 18m: 1.262 ± 0.042

Placebo

(N=15)

Lumbar spine BMD (g/cm2):

Baseline: 1.118 ± 0.048 3m: 1.172 ± 0.050 6m: 1.157 ± 0.052 12m: 1.173 ± 0.054, P=0.096, NS 18m: 1.170 ± 0.054

Total hip BMD (g/cm2):

Baseline: 1.154 ± 0.050 3m: 1.081 ± 0.054 6m: 0.997 ± 0.056 12m: 0.919 ± 0.050, P<0.001 18m: 0.881 ± 0.047

Femoral neck BMD (g/cm2):

Baseline: 1. 143 ± 0.051 3m: 1.091 ± 0.054 6m: 1.049 ± 0.056 12m: 0.985 ± 0.048, P<0.001 18m: 0.934 ± 0.048

Trochanter BMD (g/cm2):

Baseline: 0. 977 ± 0.047 3m: 0.893 ± 0.051 6m: 0.808 ± 0.055 12m: 0.728 ± 0.047, P<0.001 18m: 0.702 ± 0.046

Femoral shaft BMD (g/cm2):

Baseline: 1. 335 ± 0.060 3m: 1.260 ± 0.063 6m: 1.155 ± 0.066 12m: 1.088 ± 0.063, P<0.001 18m: 1.032 ± 0.058

Legs BMD (g/cm2):

Baseline: 1. 408 ± 0.049

CTx (nmol/g)

Baseline:1.07 ± 0.14 3m: 1.02 ± 0.11, P<0.001

ALP (IU/L):

Baseline: 143.5 ± 20.22 12m: 79.1 ± 7.4, NS

Serum Ca (nmol/liter)

Baseline: 2.26 ± 0.034 12m: 2.30 ± 0.032, NS

Urine Ca (nmol/liter)

Baseline: 8.78 ± 0.8 3m: 9.13 ± 0.91, P<0.001 18m: 3.9 ± 0.65, P<0.001

3m: 1.365 ± 0.054 6m: 1.300 ± 0.050 12m: 1.227 ± 0.051, P<0.001 18m: 1.177 ± 0.051

Arms BMD (g/cm2):

Baseline: 1.017 ± 0.043 3m: 0.987 ± 0.042 6m: 0.986 ± 0.044 12m: 0.995 ± 0.041, P=0.197, NS 18m: 0.981 ± 0.069

Total body BMD (g/cm2):

Baseline: 1.269 ± 0.036 3m: 1.244 ± 0.037 6m: 1.226 ± 0.038 12m: 1.196 ± 0.036, P<0.001 18m: 1.185 ± 0.038

Minaire, 1981 1.Clodronate

400 mg /d (N=7)

100 days

Right tibia BMD (g/cm2):

Baseline: 2.00 ± 0.04 3m: 1.92 ± 0.03 6m: 2.02± 0.06

Trabecular bone volume (%)

Baseline: 23.8 ± 3.8 100d: 17.5 ± 0.6

Total resorption surface (%)

Baseline: 6.4 ± 1.0 100d: 9.9 ± 1.2

Osteoclast count (n/mm2)

Baseline: 0.29 ± 0.05 100d: 0.34 ± 0.04

ALP (Bodansky Units):

Baseline: 4.2 ±0.1 1m: 4.2 ±0.1 2m: 6.2 ±1.1 3m: 5.3 ± 1.4 4m: 4.8 ± 1.3 5m: 5.25±2.2

Serum Ca (nmol/liter)

Significant increase in serum ca at 1 and 2m in group 1

Urine Ca (nmol/liter)

Significant increase in urine ca at 1, 2 and 3m in group 1

2.Clodronate 1600 mg/d (N=7)

100 days

Right tibia BMD (g/cm2):

Baseline: 1.98 ± 0.05 3m: 1.93 ± 0.04 6m: 1.97 ± 0.05

Total resorption surface (%)

Baseline: 5.5 ± 1.3 100d: 9.4 ± 2.9

Osteoclast count (n/mm2)

Trabecular bone volume (%)

Baseline: 23.0 ± 5.2 100d: 18.7 ± 2.0

Baseline: 0.32 ± 0.05 100d: 0.44 ± 0.14

ALP (Bodansky Units):

Baseline: 4.5 ± 0.8 1m: 5.4 ± 0.9 2m: 5.5 ± 1.2 3m: 5.5 ±0.6 4m: 4.6 ± 1.1 5m: 4.5 ± 1.6

3.Placebo (N=7) Right tibia BMD (g/cm2):

Baseline: 1.99 ± 0.01 3m: 1.87 ± 0.02 6m: 1.85 ± 0.04, P<0.05 (between

group 1 & 3) Trabecular bone volume (%)

Baseline: 21.0 ± 1.1 100d: 15.7 ± 2.0

Total resorption surface (%)

Baseline: 8.5 ± 1.0 100d: 9.2 ± 0.9

Osteoclast count (n/mm2)

Baseline: 0.46 ± 0.14 100d: 0.68 ± 0.17

ALP (Bodansky Units):

Baseline: 4.9 ± 0.5 1m: 4.9 ± 0.5 2m: 5.5 ± 0.7 3m: 4.0 ± 0.7 4m: 4.3 ± 0.8 5m: 4.7 ± 0.5

Moran de

Brito,

2005

Alendronate 10mg

+ Ca 1000 mg bid

6 months

(N=10)

Trunk BMD (g/cm2):

Baseline: 0. 94 ± 0.11 6m: 0. 96 ± 0.11

Lower extremities BMD (g/cm2):

Baseline: 1.07 ± 0.20 6m: 1.06 ± 0.18

Upper extremities BMD (g/cm2):

- -

Baseline: 0. 97 ± 0.14 6m: 0. 94 ± 0.09

Total BMD (g/cm2):

Baseline: 1.12 ± 0.11 6m: 1.11 ± 0.10

Ca 1000 mg bid

(N=9)

Trunk BMD (g/cm2):

Baseline: 0. 94 ± 0.09 6m: 0. 93 ± 0.07, P=0.54, NS

Lower extremities BMD (g/cm2):

Baseline: 1.02 ± 0.17 6m: 1.01 ± 0.15, P=0.73, NS

Upper extremities BMD (g/cm2):

Baseline: 0. 96 ± 0.07 6m: 0. 99 ± 0.08, P=0.14, NS

Total BMD (g/cm2):

Baseline: 1.10 ± 0.09 6m: 1.11 ± 0.08, P=0.04

- -

Pearson, 1997 Etidronate 800 mg/d

30 week & Ca 1000

mg/d (N=6)

Bone density of the Etidronate-treated walking patients was preserved over time, whereas the Etidronate-treated wheelchair-dependent patients lost bone density, as did the control patients regardless of ambulatory status.

Although all patients lost BMD at the femoral neck, the density of distal femoral and proximal tibial epiphyses in Etidronate-treated ambulatory patients, increased from the

- -

Conventional rehab &

Ca 1000mg/d (N=7)

baseline values by an average of 14.3%.

Schnitzer,

2015

Zoledronic Acid (Single dose, IV) 5mg/d +

Vit D 1000 IU/d + Ca 500 mg/d

(N=7)

Total hip BMD change from baseline (%):

- Right: 6m: -2.2 ± 3.4 12m: -3.1 ± 2.7 18m: -13.1 ± 2.4 24m: -

- Left: 6m: -3.7 ± 1.0 12m: -4.8 ± 1.1 18m: -6.2 ± 2.6 24m: -12.4 ± 0.8

Femoral neck BMD change from baseline (%):

- Right: 6m: -5.1 ± 6.5 12m: -2.6 ± 4.1 18m: -7.8 ± 7.5 24m: -15.5, single case

- Left: 6m: -1.1 ± 3.5 12m: -0.7 ± 4.2 18m: -1.5 ± 2.5 24m: -4.1 ± 2.7

CTX (ng/mL):

Baseline:1.11 3m: 0.25 ≥6m: remained in this range

for the duration of the 24 months

P1NP (ng/mL):

Baseline:130.97 3m: 58.48 ≥6m: remained in this range

for the duration of the 24 months

-

Placebo +

Vit D 1000 IU/d + Ca 500 mg/d

(N=9)

Total hip BMD change from baseline (%):

- Right: 6m: -8.6 ± 3.5, P= 0.03

- Left: 6m: -12.3 ± 6.9, P= 0.03

Femoral neck BMD change from baseline (%):

- Right: 6m: -20.0 ± 6.4, P= 0.01

- Left: 6m: -11.1 ± 7.4, P= 0.02

CTX (ng/mL):

Baseline:1.13 3m: 0.97 6m: 0.68

P1NP (ng/mL):

Baseline:139.52 6m: 87.00

-

Shapiro, 2007 Zoledronic acid (Single dose IV) 1)4mg (N=4)

2)5mg (N=4)

In Both groups: Oral Vit D if serum 25-OH D3 was low

Femoral neck BMD change from baseline (%):

6m: positive changeIntertrochanteric BMD change from baseline (%):

6m: positive changeFemoral shaft BND change from baseline (%):

6m: positive changeLumbar BMD (gm/cm2):

Baseline: 1.08 12m: 1.165

Urine NTx/cr (nmol/mmol):

Baseline: 224.4 ± 103 12m: 76

Bone specific ALP (µg/L):

Baseline: 13.7 6m: 18.5 12m: 15.6

Baseline serum Ca values were normal at baseline in the placebo and treatment groups and remained normal at 3, 6, and 12 m.

Placebo

(50ml of normal saline over 15 minutes)

(N=10)

Femoral neck BMD change from baseline (%):

6m: negative change, P<0.05Intertrochanteric BMD change from baseline (%):

6m: negative change, P<0.05Femoral shaft BND change from baseline (%):

6m: negative changeLumbar BMD (gm/cm2):

Baseline: 1.07 12m: 1.18, P>0.05, NS

Urine NTx/cr (nmol/mmol):

Baseline: 181.5 ± 71 12m: 100, P>0.05, NS

Bone specific ALP (µg/L):

Baseline: 15.6 6m: 17.0 12m: 13.2, NS

Zehnder, 2004 Alendronate 1.10 mg/d + Ca 500 mg/d

24 months

(N=33)

Tibial epiphysis BMD (g/cm2):

Baseline: 0.495. ± 0.040 6m: 0.490 ± 0.030 12m: 0.480 ± 0.028 18m: 0.469 ± 0.028 24m: 0.463 ± 0.025

D-Pyr/Cr (pmol/mmol)

Baseline: 30.8 ± 5.4 24m: 19.0 ± 2.6

Osteocalcin (ng/ml):

Baseline: 24.1 ± 1.9

-

24m, change from baseline (%): -2.0 ± 2.9

Tibial diaphysis BMD (g/cm2):

Baseline: 1.152 ± 0.046 6m: 1.156 ± 0.044 12m: 1.144 ± 0.042 18m: 1.147 ± 0.043 24m: 1.137 ± 0.040 24m, change from baseline (%): -0.7 ±

1.0Distal forearm (ultra-distal part) BMD change from baseline (%):

24m: -0.04 ± 0.51Distal forearm (1/3 distal part) BMD change from baseline (%):

24m: -0.19 ± 0.38Hip BMD (g/cm2):

Baseline: 0.732. ± 0.037 6m: 0.738 ± 0.037 12m: 0.733 ± 0.036 18m: 0.730 ± 0.034 24m: 0.731 ± 0.034 24m, change from baseline (%): +0.43

± 1.2Lumbar spine BMD (g/cm2):

Baseline: 1.139 ± 0.037 6m: 1.167 ± 0.038 12m: 1.178 ± 0.038 18m: 1.196 ± 0.038 24m: 1.190 ± 0.040 24m, change from baseline (%): +5.1 ±

0.6

24m: 13.6 ± 0.7ALP change from baseline (%)

24m: -25.1 ± 4.0%

Ca 500 mg/d Tibial epiphysis BMD (g/cm2): D-Pyr/Cr (pmol/mmol) -

24 months

(N=32)

Baseline: 0.534. ± 0.030 6m: 0.515 ± 0.030 12m: 0.486 ± 0.025 18m: 0.479 ± 0.025 24m: 0.464 ± 0.022 24m, change from baseline (%): -10.8 ±

2.7, P= 0.017Tibial diaphysis BMD (g/cm2):

Baseline: 1.210 ± 0.031 6m: 1.196 ± 0.031 12m: 1.183 ± 0.032 18m: 1.177 ± 0.031 24m: 1.161 ± 0.029 24m, change from baseline: -3.9 ± 0.8,

P= 0.019Distal forearm (ultra-distal part) BMD change from baseline (%):

24m: +0.15 ± 0.67, NSDistal forearm (1/3 distal part) BMD change from baseline (%):

24m: -0.82 ± 0.56, NSHip BMD (g/cm2):

Baseline: 0.693. ± 0.017 6m: 0.681 ± 0.016 12m: 0.672 ± 0.014 18m: 0.665 ± 0.013 24m: 0.660 ± 0.014 24m, change from baseline (%): -4.1 ±

1.6Lumbar spine BMD (g/cm2):

Baseline: 1.107 ± 0.028 6m: 1.126 ± 0.030 12m: 1.122 ± 0.031 18m: 1.128 ± 0.030 24m: 1.138 ± 0.030

Baseline: 30.7 ± 8.6 24m: 22.4 ± 4.1, P= 0.022

Osteocalcin (ng/ml):

Baseline: 23.2 ± 1.9 24m: 17.4 ± 1.3, P= 0.005

ALP change from baseline (%)

24m: -5.2 ± 3.8, P= 0.034

24m, change from baseline (%): +2.3 ± 0.9, P=0.023

Studies of rehabilitative treatment

Ben, 2005 Tilt-table standing in one leg.

12 weeks

Proximal femur BMD (g/cm2):

Baseline: 0.913 ± 0.140 12w: 0.857 ± 0.131

- -

Control leg was not loaded in standing

Proximal femur BMD (g/cm2):

Baseline: 0.909 ± 0.158 12w: 0.848 ± 0.142, (CI: –0.015 to

0.025)

- -

de Bruin,

1999

1. >5 hrs per week standing exercises (N=5)

Tibia (trabecular bone) BMD change from baseline (%):

25w: 0.6, -1.0, -1.0, -1.4, 0.3Tibia (compact bone) BMD change from baseline (%):

25w: -3.3, 0.4, -0.1, -3.0, 0.3

- -

2. >5 hrs per week of combined standing ± walking exercises (N=4)

Tibia (trabecular bone) BMD change from baseline (%):

25w: 0-0.3, -, -0.6, -0.3Tibia (compact bone) BMD change from baseline (%):

25w: -1.3, -, -0.1, -0.7

- -

3. 0-5 hrs per week loading exercises (immobilization)

(N=4)

Tibia (trabecular bone) BMD change from baseline (%):

25w: -8.4, -9.4, -6.9, -7.4, P<0.05 (between intervention groups 1-2 and the control group 3)

Tibia (compact bone) BMD change from baseline (%):

25w: -1.1, -1.6, -0.7, 1.0, NS

- -

Groah,

2010

Usual inpatient SCI care + ES (bilateral quadriceps) 1 hour/d, 5x/week, 6 weeks

(N=16)

Lumbar BMD (g/cm2):

Baseline: 1.315 ± 0.16 ≈6w: 1.331 ± 0.23 ≈4.5m: 1.298 ± 0.15

Hip BMD (g/cm2):

Baseline: 1.185 ± 0.15 ≈6w: 1.168 ± 0.16 ≈4.5m: 1.018 ± 0.13

Femur BMD (g/cm2):

Baseline: 1.107 ± 0.19 ≈6w: 1.063 ± 0.20 ≈4.5m: 1.025 ± 0.22

Tibia BMD (g/cm2):

Baseline: 1.035 ± 0.17 ≈6w: 1.026 ± 0.15 ≈4.5m: 0.916 ± 0.26

Osteocalcin (µg/mL):

Baseline: 13.89 ± 7.364 ≈6w: 11.86 ± 6.77 ≈4.5m: 14.80 ± 12.91

Urine NTx (IU/L):

Baseline: 160.56 ± 140.06 ≈6w: 216.71 ± 128.40 ≈4.5m: 154.76 ± 69.12

-

Usual inpatient SCI care

(N=10)

Lumbar BMD (g/cm2):

Baseline: 1.274 ± 0.15 ≈6w: 1.182 ± 1.18 ≈4.5m: 1.25 ± 0.21, NS

Osteocalcin (µg/mL):

Baseline: 12.90 ± 7.30 ≈6w: 24.00 ± 4.29 ≈4.5m: 6.40 ± 7.28, NS

-

Hip BMD (g/cm2):

Baseline: 1.192 ± 0.14 ≈6w: 1.043 ± 0.14 ≈4.5m: 1.046 ± 0.10, NS

Femur BMD (g/cm2):

Baseline: 0.964 ± 0.21 ≈6w: 0.930 ± 0.27 ≈4.5m: 0.818 ± 0.26, NS

Tibia BMD (g/cm2):

Baseline: 0.855 ± 0.17 ≈6w: 0.844 ± 0.22 ≈4.5m: 0.731 ± 0.26, NS

Urine NTx (IU/L):

Baseline: 115.00 ± 34.10 ≈6w: 154.86 ± 70.41 ≈4.5m: 171.33 ± 75.8, NS

Johnstone,

2015

FES CE, 20 rpm (low-CAD), 1 hour/d, 3x/week, 6 months

Ca 1200 mg/d + Vit D 2000 IU/d if baseline Vit D <30 ng/ml

(N=9)

Distal femur areal BMD (cm2):

Baseline: 0.67 ± 0.37 6m: 0.63 ± 0.32

Apparent trabecular bone volume to total volume:

Baseline: 0.192 ± 0.080 6m: 0.198 ± 0.068

Cortical Volume (mm3):

Baseline: 50.5 ± 20.1 6m: 50.1 ± 20.0

Bone specific ALP (μg/L):

Baseline: 12.9 ± 3.6 6m: 10.8 ± 3.2

Urine NTx (mg/dL):

Baseline: 53.4 ± 25.3 6m: 35.0 ± 14.5

25-(OH) D (ng/mL):

Baseline: 44.5 ± 18.8 6m: 36.2 ± 10.0

PTH (pg/mL)

Baseline: 27.3 ± 11.3 6m: 27.9 ± 5.8

FES CE, 50 rpm (high-CAD), 1 hour/d, 3x/week, 6 months

Distal femur areal BMD (cm2):

Baseline: 0.80 ± 0.20 6m: 0.70 ± 0.20, P=0.86, NS

Apparent trabecular bone volume to total volume:

Bone specific ALP (μg/L):

Baseline: 13.4 ± 4.9 6m: 14.7 ± 6.1, P=0.03

Urine NTx (mg/dL):

Baseline: 52 ± 39.7 6m: 43.3 ± 21.4, P=0.15,

25-(OH) D (ng/mL):

Baseline: 35.7 ± 3.4 6m: 31.2 ± 6.1, P=0.72,

NSPTH (pg/mL)

Baseline: 23.6 ± 8.9

Ca 1200 mg/d + Vit D 2000 IU/d if baseline Vit D <30 ng/ml

(N=8)

Baseline: 0.211 ± 0.048 6m: 0.205 ± 0.052, P=0.27, NS

Cortical Volume (mm3):

Baseline: 50.7 ± 15.2 6m: 49.0 ± 14.0, P=0.34, NS

NS 6m: 16.7 ± 5.0, P=0.15, NS

Warden,

2001

Unilateral calcaneus pulsed therapeutic ultrasound (Active), 20 min/d, 5x/week,

6 week

Calcaneal BMC (g):

Baseline: 1.76 ± 0.26 6w: 1.62 ± 0.26

- -

Contralateral calcaneus pulsed therapeutic ultrasound (Passive), 20 min/d, 5x/week,

6 week

Calcaneal BMC (g):

Baseline: 1.74 ± 0.22 6w: 1.61 ± 0.2, NS

- -

ALP: alkaline phosphatase; BMD: bone mineral density; BMC: bone mineral composition; BT: bone turnover; Ca: calcium; CE: cycle ergometer; CI: confidence

interval; d:day; DEXA: dual energy X-ray absorptiometry; EMS: electrical muscular stimulation; ES: electrical stimulator; FES: functional electrical stimulation; hr:

hour; m: month(s); NS: not significant; Rehab: rehabilitative; SCI: spinal cord injury; Tx: treatment; Vit.: vitamin; w: week(s);

a Bauman, 2005 (J Rehabil Res Dev, 42(3)); b Bauman, 2005 (J Rehabil Res Dev, 42(5));