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Bone Health

Pharmacological Therapy: Prevention of Bone Loss (Within 12 Months of Injury)

Author Year; Country
Score
Research Design
Total Sample Size		 Methods Outcome

Bauman et al. 2005a; USA
PEDro=10
RCT
Level 1
N=14

Population: 14 participants (8 men, 3 women); age: 35 ± 12 years (range: 21–61); motor complete para (n=6) or tetraplegia (n=5); TPI: 44 ± 18 days (range: 22–65). AIS A.
Treatment: Pamidronate for 12 months. Participants randomized to 1. 60mg intravenous (n=6) or 2. Placebo (n=5)
Outcome measures: BMD by DXA, bone turnover markers at baseline, 1, 2, 3, 6, 9, 12-months post-SCI.
  1. There was no significant between-group difference in BMD decline at 1 year.
  2. The treatment group had significantly lower 24-hr urinary calcium at 1 month vs. placebo group (P<0.05) and there were no significant changes in markers of bone formation over the 12-month study.
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%CI) as calculated from pre- to post-intervention data and pre-intervention to retention/follow-up data

Minaire et al. 1981; France
PEDro=10
RCT
Level 1
N=21

Population: 17 men and 4 women; age: 29 years (range: 15-54); traumatic complete paraplegia; T1 – T12; TPI: 7.6 days (range: 5-29).
Treatment: Clodronate for 3.5 months. Participants randomized to 1. 400mg per day (n=7); 2.1,600 per day (n=7); or 3. Placebo (n=7).
Outcome measures: BMD by DPA, histomorphometry.
  1. No reported adverse effects on bone mineralization with intervention.
  2. Increase in serum and urine markers in the Placebo group (indicative of increased bone turnover).
  3. Effective for acute prevention of declining bone mass and maintenance of BMC of the femur and tibia in the treatment groups.
Effect Sizes:Forest plot of standardized mean differences (SMD ± 95%CI) as calculated from pre- to post-intervention data and pre-intervention to retention/follow-up data

Chappard et al. 1995; France
PEDro=9
RCT
Level 1
N=20

Population: 20 participants (14 men, 6 women), age: 28.0 + 6.4 years; traumatic injuries between C5-T12.
Treatment: Tiludronate for 3 months. Participants randomized to 1. 400 mg/day (n=7); 2. 200 mg/day (n=7); or 3. Placebo (n=6).
Outcome measures: histomorphometry.
  1. There was an increase in total bone volume in the treatment group 1(400mg/day) vs. treatment group 2 (200mg/day) and placebo groups.
  2. Increased bone resorption indicators in the placebo group vs. the treatment groups.
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%CI) as calculated from pre- and post-intervention data

Schnitzer et al. 2016; USA
PEDro=8
RCT
Level 1
N=16

Population: 16 participants (15 men, 1 women) with acute SCI; AIS-A/B, or AIS-C; and non-weight-bearing; age: 38.6 ± 16.2 years; 8 cervical, 8 thoracic; TPI: Placebo = 95.3 ± 50.0 days, Zoledronic acid: 35.1 ± 15.4 days.
Treatment: Infusion of zoledronic acid (5 mg) or placebo (dilutant only)
Outcome measures: BMD by DXA, bone turnover markers at baseline, 3, 6, 12-months post-treatment.
  1. Significant between-group difference at 6 months post-treatment in change of (mean±SD, zoledronic acid vs. placebo):
    Lumbar spine BMD: +2.4±1.8% vs. -2.5±2.2%
    Left total hip BMD: -3.7±1.0% vs. -12.3±6.9%
    Right total hip BMD: -2.2±3.4% vs. -8.6±3.5%
    Left femoral neck BMD: -1.1±3.5% vs. -11.1±7.4%
    Right femoral neck BMD: -5.1±6.5% vs. -20.0±6.4%
  2. Zoledronic acid group observed decreased BMD for left & right total hip and femoral neck but observed increased BMD for lumbar spine over 18-24 months post-treatment
  3. Elevated levels of serum CTX and P1NP at baseline, and are reduced at 3 months in both zoledronic acid and placebo groups
  4. Delayed zoledronic acid infusion in those with >10% BMD loss after 6 months of placebo resulted in stabilization in total hip, left femoral neck, and lumbar spine; however, BMD of left distal femur continued to decline
  5. No adverse effects other than temperature elevations (n=3)
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%CI) as calculated from pre- and post-intervention data
Pearson et al. 1997; Canada
PEDro=8
RCT
Level 1
N=13		 Population: 12 men and 1 woman; age: 22-57 years; injuries between C5-T12; AIS: A or D.
Treatment: Etidronate for 30 weeks. Participants randomized to 1.800mg daily (n=6; 5 men 1 woman; mean age: 35.6 years) or 2. Conventional rehab and calcium 1000mg/day (n=7; 7 men; mean age: 33.6 years).
Outcome measures: DXA and adverse event rate.
  1. BMD loss at the distal femur was 26% and 22% at the proximal tibia. The rate of decline in BMD was greatest amongst the AIS A individuals. BMD of lower extremity for the Etidronate-treated AIS D individuals was preserved.
  2. Oral Etidronate was safe and well-tolerated by participants.

Gilchrist et al. 2007; New Zealand
PEDro=7
RCT
Level 1
N=31

Population: 31 participants (22 men, 9 women) age: 17-55 years; 10 AIS A, 1 AIS B, and 3 AIS C.
Treatment: Alendronate (oral) for 12 months within 10 days of acute injury. Participants randomized to 1. 70 mg once weekly (n=15; 10 men and 5 women); or 2. Placebo (n=16; 12 men and 4 women).
Outcome Measures: BMD and body composition by DXA, ultrasound, bone turnover markers.
  1. BMD at the femoral neck was maintained in the treatment group, and there was less BMD loss at other hip sites compared with the placebo group.
  2. BMD at the hip in the Placebo group declined steadily over the 18 months follow-up.
  3. At 12 months, there was a 5.3% difference in total body BMD and a 17.6% difference in the percent change in total hip BMD between the two groups.
  4. Alendronate compared with placebo-induced reductions in urinary calcium excretion and serum CTX at 3 months only.
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%CI) as calculated from pre- to post-intervention data and pre-intervention to retention/follow-up data

Shapiro et al. 2007; USA
PEDro=7
RCT
Level 1
N=18

Population:14 men and 4 women with traumatic SCI; age: 18-60 years (Placebo: 28.4 ± 9.4; Treatment: 30.1 ± 14.2); tetraplegia (n=5) or paraplegia (n=13); AIS A (n=14) or AIS B (n=4).
Treatment: Zoledronic acid. Participants randomized to 1. Single-dose intravenous solution either 4mg (n=4) or 5mg (n=4) (Total n=8), or 2. Placebo group received 50ml of normal saline over 15 minutes (n=10) Participants with low serum 25-hydroxyvitamin D received oral supplementation.
Outcome Measures: bone turnover markers, BMD by DXA
  1. Treatment group:
    Six months after zoledronic acid, BMD, bone cross-sectional area, and sectional modulus increased at the hip and buckling ratio decreased consistently with improved bone outcomes.
    At 12 months, narrow-neck femur values declined, and intertrochanteric and femoral shaft BMD was maintained.
  2. Placebo group: decrease in bone outcomes and an increase in buckling ratio at the hip at 6 and 12 months.
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%CI) as calculated from pre- and post-intervention data
Minaire et al. 1987; France
PEDro=7
RCT
Level 1
N=21		 Population: 21 men and women; age: 15-54 years, complete paraplegia.
Treatment: Clodronate for 100 days. Participants randomized to 1.400mg per day (n=7); 2. 1,600 per day (n=7); or 3. Placebo (n=7).
Outcome measures: DXA, histomorphometry, bone turnover markers.
  1. There was a greater increase in bone removal markers in Placebo group (48%), compared with treatment groups (17-27%).
  2. BMD was maintained in treatment groups with a ↓ in placebo group.
  3. Lower bone turnover markers in treatment groups.

Bubbear et al. 2011; UK
PEDro=6
RCT
Level 1
N = 14

Population: 14 acute SCI participants (Control: 5 men, 2 women; mean age 27 ± 14.4; Treatment: 4 men, 3 women; mean age 31.6 ± 7.1)
Treatment: 4 mg intravenous zoledronic acid (active treatment group) or standard nursing/medical care (control group)
Outcome Measures: BMD using DXA at baseline, 3, 6, 12 months for lumbar spine (L1-4) and hip (total, femoral neck, trochanter); Bone turnover markers (serum CTX and P1NP) and urinary N-terminal telopeptide/creatine ratio).
  1. Significant difference between control and treatment groups over 12 months at lumbar spine (+0.8±4.9% vs. +3.5±3.9%, p = 0.033), total hip (-15.8±8.9% vs. -3.4±3.0%, p=0.005), trochanter (-17.9±9.4% vs. -4.5±5.7%, p=0.028)
  2. No significant difference between groups with femoral neck BMD or with creatine markers.
  3. Bone turnover markers normalized within 6 weeks to 3 months in treatment group vs to up to 12 months in control group
  4. 5 of 7 participants in zoledronic group had flu-like symptoms over 24 hours
Effect Sizes: Forest plot of standardized mean differences (SMD ± 95%CI) as calculated from pre- and post-intervention data
Nance et al. 1999; Canada
Prospective Controlled trial (nonrandomized)
Level 2
N=24		 Population: 22 men and 2 women, ages 25-57, injuries between C5-T12, AIS A-D.
Treatment: Pamidronate for 6 months. Participants randomized to 30 mg intravenous every 4 weeks x 6 doses (total 180 mg/participant) [n=14; 30.8 ± 8.3 years (range 20 – 45)] or conventional rehab [n=10; 35.1 ± 10 years (range 25 – 57)].
Outcome measures: BMD by DXA, urine biochemical bone markers.
  1. There was a lower % decline in BMD in treatment vs. control group. The mean overall BMD decline was 8.1% in the placebo group but only 2.7% in the treatment group (p=0.02). The average loss of BMD was 3.1% in the AIS D group and 7.7% in the AIS A group.
* All data expressed as mean±SD, unless expressed otherwise.

Discussion

Evidence for pharmacological prevention of SCI BMD decline includes 9 RCTs (n=168 participants) and 1 non-RCT (n=24) (Table 9). These studies were difficult to interpret as a group due to the variability in selection of the pharmacological treatment, primary outcome measure, relatively short duration of follow-up, small sample sizes, and the lack of stratification based on impairment level. Preventing BMD decline immediately following SCI is challenging given the rapid bone resorption especially in AIS A patients. The majority of studies found bisphosphonates resulted in a reduction of BMD decline compared with a control group. The two studies which report that first generation bisphosphonates (Clodronate) can maintain bone were short in duration (3 months intervention) and participants had less severe injury (paraplegia, incomplete SCI) (Minaire et al. 1981, 1987). In the studies by Pearson and colleagues (1997) and Nance and colleagues (1999), both groups continued to lose bone, except AIS D participants who had bone density preservation in the lower extremity with bisphosphonates while participants with AIS A had the greatest decline in both studies. A recent study which used a second-generation version of the bisphosphonate, Pamidronate, and a longer intervention period found no significant differences between groups for BMD decline after 1 year (Bauman 2005a). Gilchrist and colleagues (2007) noted a significant difference in BMD at the hip with once weekly Alendronate. Shapiro and colleagues (2007) tested the effect of once-yearly intravenous Zoledronate with significant improvement in BMD at the hip at 6 months that returned to baseline values at 12 months; the control group on the placebo treatment lost bone over the 12 months. Bubbear and colleagues (2011) also showed that once-yearly intravenous Zoledronate resulted in less BMD decline at the spine and hip over 12 months. The investigators also highlighted the added benefits of a once-yearly intravenous administration of bisphosphonate, as this eliminates issues surrounding poor patient adherence and the adverse gastrointestinal effects associated with alternate oral therapies. Schnitzer et al. (2016) compared the BMD of people with SCI before and after 12 months of zoledronic acid infusion (5 mg) and only showed increases in lumbar spine BMD. Although there is evidence that bisphosphonates may reduce bone resorption, current medications do not prevent BMD decline. Nonetheless, there is a window of opportunity soon after injury where SLOP prevention may be effective, and there is sufficient evidence of moderate prevention efficacy that patients should be counselled on the available therapies and allowed to ­­make their own decision regarding treatment.

Conclusion

There is level 1 evidence (from 3 RCTs: Minaire et al. 1981, 1987; Chappard et al. 1995) that oral Tiludronate and Clodronate prevent a decrease in BMD of the hip and knee region with no adverse effects on bone mineralization in men with paraplegia.

There is level 1 evidence (from 1 RCT: Pearson et al. 1997) that oral Etidronate prevents a decrease in BMD of the hip and knee region in people with incomplete paraplegia or tetraplegia (AIS D impairment) who return to walking within 3 months of the SCI.

There is level 1 evidence (from 1 RCT: Gilchrist et al. 2007) that once weekly oral Alendronate maintains hip region BMD.

There is level 1 evidence (from 2 RCTs: Shapiro et al. 2007; Bubbear et al. 2011) that a one-time IV infusion of Zoledronate may reduce bone loss in the hip region during the 12 months following administration.

There is level 1 evidence (from 1 RCT: Bauman et al. 2005a) that Pamidronate 60mg IV seven times per year and level 2 evidence (from 1 non-randomized prospective controlled trial) (Nance et al. 1999) that Pamidronate 30 mg IV six times per year is not effective for the prevention of BMD loss at the hip and knee region early after SCI in men and women who have motor complete paraplegia or tetraplegia.

Bone health management should begin early following SCI, given the significant declines in hip and knee region bone mass in the first year and the associated lifetime increased fracture risk.

The efficacy of drug interventions appears to be greater when medications are administered early after SCI onset.

Oral tiludronate and clodronate prevent a decrease in BMD of the hip and knee region with no adverse effects on bone mineralization in men with paraplegia.

Oral etidronate prevents a decrease in BMD of the hip and knee region in people with incomplete paraplegia or tetraplegia who return to walking.

Oral alendronate once weekly maintains BMD at the hip.

Once yearly IV infusion zoledronate may reduce bone loss at the hip during the 12 months following administration.

Pamidronate 30 mg IV or 60 mg IV 4x/year is not effective for the prevention of BMD loss at the hip and knee region early after SCI in people with motor complete paraplegia or tetraplegia.

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