Description of the condition
Spinal cord injury (SCI) is an insult to the spinal cord resulting in a change, either temporary or permanent, in its normal motor, sensory, or autonomic function (ASIA 2000). The main causes are road traffic injuries, falls, sport injuries and injuries related to violence (Lazo 2001).
Traumatic spinal cord injury has an incidence of 15 to 40 cases per million, with young men being four times more affected than woman. Worldwide prevalence is estimated at 700 to 900 million (Sekhon 2001). SCI often determines a profound and long-term disability, which is life-changing for the injured person and his or her family. These injuries also have an important social cost associated with expensive healthcare treatment, rehabilitation, and loss of productivity (Pickett 2006).
Osteoporosis is a condition characterised by low bone mass and deterioration of the skeletal micro-architecture. It is a known consequence of spinal cord injury and occurs in almost every person with SCI.
The mechanism underlying osteoporosis in people with SCI is a dramatic reduction in bone density and bone mineral content, explained through immobility, and several neuronal, vascular and hormonal changes (Jiang 2006). These changes in bone lead to a high resorption rate, which is evidenced in more erosion of surfaces and osteoclast activity. The levels of biochemical markers of resorption begin to increase within a few weeks of injury, reaching maximum levels between weeks 10 and 16. After one year, resorption markers remain high and bone formation markers low. Some studies show that a steady state is achieved around year two, but others note a continuous bone loss (Maïmoun 2006).
The significant decrease in bone mineral density that develops increases the risk of fracture, predominantly in the lower extremities (Jiang 2006). Some studies report a fracture risk of 34% in people with SCI (Lazo 2001), mostly due to low intensity trauma, such as transfer from a bed to a chair (Vestergaard 1998).
In people with SCI, fractures are associated with many other complications such as pressure ulcers, spasticity and deep venous thrombosis which further increase morbidity, mortality and healthcare costs (Lazo 2001; Maïmoun 2006).
Description of the intervention
Osteoporosis in people with spinal cord injury can be principally attributed to an alteration in the bone remodeling process with increased bone resorption, so the pharmacological therapy is mainly oriented to inhibit osteoclast function (Maïmoun 2006).
Antiresorptive therapies include five principal classes of agents: bisphosphonates, estrogens, selective estrogen receptor modulators (SERMs), calcitonin and monoclonal antibodies.
Combinations of antiresorptive agents may provide additional benefits in comparison to monotherapy. For instance, one study showed that hormone replacement therapy added to bisphosphonates or calcitonin provided an additional benefit (Wimalawansa 2000).
How the intervention might work
Antiresorptive agents decrease bone resorption through a variety of mechanisms, including physicochemical, cellular and biochemical processes, aimed to reduce or stop net bone loss.
Bisphosphonates constitute the most widely used antiresorptive agents. They are structural analogs of natural pyrophosphates and act through binding the mineral component of bone, interfering with the action of osteoclasts. Nitrogen-containing bisphosphonates act as inhibitors of farnesyl-pyrophosphate synthase, which leads to inhibition of the prenylation of many intracellular signaling proteins, resulting in inhibition of osteoclasts’ mediated resorption and remodeling process (Baron 2011; Recker 2011).
Estrogens exert their action through the blockade of cytokine signals that activate osteoclasts. Hormone replacement therapy can be considered in early postmenopause, however adverse effects associated with long-term use make them unsuitable as first-line therapy for osteoporosis (Chen 2011).
Raloxifene is the only selective modulator of estrogen receptor (SERM) approved for treatment and prevention of fractures in people with postmenopausal osteoporosis. It improves bone quality and inhibits bone resorption through the same mechanism as estrogens. However, postreceptor activity is limited to the skeleton, without the adverse effects of estrogens in breast and endometrial tissue.
Calcitonin inhibits bone resorption by binding osteoclasts in a high-affinity receptor, but the reduction in bone turnover is smaller than with other antiresorptive agents (Chen 2011).
Denosumab is a human monoclonal antibody that reduces bone resorption by inhibiting receptor activator of nuclear factor kappa-B ligand (RANKL), the molecule that signals differentiation of circulating osteoclast precursors into active osteoclasts, thereby inhibiting the development, activation, and survival of osteoclasts. It provides a new therapeutic target and its antifracture effect may be similar to that seen with bisphosphonates (Recker 2011; Baron 2011).
Why it is important to do this review
The efficacy of antiresorptive treatments in decreasing bone turnover, increasing bone mineral density (BMD), and reducing fracture risk in postmenopausical osteoporosis has been demonstrated in numerous clinical trials (Chen 2011). However, there is no clear evidence of their effects in people with osteoporosis and fractures after spinal cord injury.
To assess the effects of antiresorptive agents for the prevention of fractures in people with spinal cord injury.
Criteria for considering studies for this review
Types of studies
Randomised controlled trials (RCTs).
Types of participants
People with traumatic spinal cord injury resulting in some degree of transient or permanent loss of neurological functions.
Types of interventions
Any trial assessing antiresorptive agents as monotherapy or in combination with calcium and/or vitamin D, compared with placebo, no treatment or standard therapy, or to another pharmacological intervention.
We will include pharmacological agents from the following classes:
- Bisphosphonate: e.g. alendronate, etidronate, ibandronate, pamidronate, risedronate, tiludronate, zolendronic acid
- Selective estrogen receptor modulators (SERM): e.g. raloxifene
Types of outcome measures
- Symptomatic fractures, as defined by the studies.
- Asymptomatic fractures, as defined by the studies.
- Bone mineral density measured by any method.
- Adverse effects.
Assuming a conservative baseline risk of 25% (the upper limit of the range of reported baseline risks in an observational study Lazo 2001) and a plausible relative risk reduction (RRR) of 20% for symptomatic fractures (our primary outcome) the optimal information size, using standard alpha (0.05) and beta (0.10) values, is a total of 964 patients.
Search methods for identification of studies
We will not restrict our search by date, language or publication status.
The Cochrane Injuries Group Trials Search Co-ordinator will search the following:
- Cochrane Injuries Group Specialised Register (present version);
- Cochrane Central Register of Controlled Trials (CENTRAL) (all years to present);
- MEDLINE (OvidSP) (1946 to present);
- EMBASE Classic + EMBASE (OvidSP) (1947 to present);
- CINAHL Plus (EBSCO) (1939 to present);
- PEDro (Physiotherapy Evidence Database [www.pedro.org.au/]) (1929 to present);
- ISI Web of Science: Science Citation Index Expanded (SCI-EXPANDED) (1970 to present);
- ISI Web of Science: Conference Proceedings Citation Index- Science (CPCI-S) (1990 to present).
The electronic database searches will be based on the MEDLINE strategy (Appendix 1).
Searching other resources
We will search the reference lists of included studies and previously published reviews for additional study references. We will also contact authors and experts in the field to identify additional studies.
In order to find additional literature, we will run several Google Scholar searches using one term for a condition (spinal cord, paraplegia, quadriplegia) combined with terms describing antiresorptives agents. We will review the first five pages of each search.
We will search the online trials registers www.clinicaltrials.gov and www.controlled-trials.com, and the World Health Organization Clinical Trials Registry Platform (ICTRP) http://apps.who.int/trialsearch/.
Data collection and analysis
We will work with the Cochrane Injuries Group's Trials Search Co-ordinator to run the searches. She will collate the search results using bibliographic software, such as EndNote, and remove duplicates before two review authors (JG and CM) begin the screening process.
Selection of studies
Two review authors (JG and CM) will independently check the title and/or abstracts of each reference. We will obtain the full-text of all potentially eligible studies to evaluate whether each fulfils our inclusion criteria. If there is disagreement, another review author (GR) will help resolve discrepancies.
Data extraction and management
Two review authors (JG and CM) will independently extract data onto pre-designed data extraction and validity assessment forms. A third author (GR) will act as an arbiter in case of disagreement.
The following data will be extracted where possible:
- Method of randomisation;
- Criteria for participant inclusion and exclusion;
- Details of the intervention including dose, route of administration, duration;
- Details of any co-intervention;
- Details of post-intervention treatment;
- Participant characteristics, including age, duration of spinal cord injury, neurological level (paraplegic versus tetraplegic), type of injury (complete versus incomplete);
- Any measure of the severity of osteoporosis;
- Number of participants assigned to each treatment group;
- Number of participants with co-morbidity per treatment group;
- Number of participants per treatment group with the outcomes of interest;
- Blinding of the outcome assessor, participants and carers;
- Drop-outs, with reasons.
We will contact study authors for further information whenever necessary.
Assessment of risk of bias in included studies
We will assess the risk of bias in included studies according to the 'Risk of bias' table which is the tool recommended by the Cochrane Collaboration, as described in Chapter 8 of the Cochrane Handbook (Higgins 2011). We will provide a description and judgement about the following domains for each study: adequacy of sequence generation, allocation concealment, blinding (of personnel, participants and outcome assessors), addressing incomplete outcome data, likelihood of selective outcome reporting and other potential sources of bias (e.g. if co-interventions are present).
One author will complete the 'Risk of bias' tables and a second author will check the information included for accuracy.
Measures of treatment effect
We will report pooled outcomes as risk ratios (RRs) with 95% confidence intervals (CIs) for dichotomous outcomes, and as mean differences (MDs) with 95% CI for continuous outcomes. If different measures are used for continuous outcomes (for example, different measures of bone mineral density) we will pool outcomes as standardised mean differences (SMDs) with 95% CIs.
Unit of analysis issues
The unit of analysis will be the person with a spinal cord injury. Considering the type of intervention, it is likely that only parallel RCTs will be included, so each person will have received only one intervention. In studies where more than two interventions have been compared (intervention 1 versus intervention 2 versus placebo), we will take extra care to avoid double-counting of people and outcomes in the meta-analysis.
Dealing with missing data
We will contact authors of studies not reporting data on the primary outcome. If a response is not received, and sufficient data exist to analyse secondary outcomes, then we will analyse the available data. We will address the potential impact of missing data on the findings of the review in the Discussion section using a 'worst-case' and 'best-case' scenario. If authors did not report an intention-to-treat analysis (ITT), or report a modified ITT analysis, we will re-analyse data following the principle of ITT when possible. If analysing data according to ITT is not possible, then we will address the issue in the Discussion section.
Assessment of heterogeneity
We will assess heterogeneity quantitatively with a formal statistical test (Q statistic) and the I² statistic. Statistically significant heterogeneity will be defined as at least one positive test (either P < 0.10 using the Mantel-Haenszel Chi² test, or > 50% using the I² statistic) (Higgins 2003).
Assessment of reporting biases
We will investigate the presence of publication bias with the use of funnel plots, provided that 10 or more studies are included in an analysis. We will base evidence of asymmetry on P < 0.10, and present intercepts with 90% CIs. We will evaluate other reporting biases, including outcome reporting bias, through discrepancies between the registered protocol and the final publication. If we can not find the record of a study in the WHO International Clinical Trials Registry Platform, we will contact the authors directly for information.
We will perform statistical analyses in accordance with the guidelines in the Cochrane Handbook (Higgins 2011). We will use a fixed-effect model for all the analyses.
Subgroup analysis and investigation of heterogeneity
The influence of the following factors on the outcomes will be assessed by subgroup analyses:
- Duration of spinal cord injury (less than one year versus one year or more);
- Neurological level (paraplegic versus tetraplegic);
- Type of injury (complete versus incomplete)
We will perform sensitivity analyses to address the impact of allocation concealment.
Appendix 1. Search strategies
1.exp Spinal Cord Injuries/
2.exp Spinal Cord Ischemia/
3.exp Central Cord Syndrome/
4.(myelopathy adj3 (traumatic or post-traumatic)).ab,ti.
5.((spine or spinal) adj3 (fracture* or wound* or trauma* or injur* or damag*)).ab,ti.
6.(spinal cord adj3 (contusion or laceration or transaction or trauma or ischemia)).ab,ti.
7.central cord injury syndrome.ab,ti.
8.central spinal cord syndrome.ab,ti.
9.exp Cervical Vertebrae/in [Injuries]
10.exp Spinal Cord/
14.(paraplegia* or quadriplegia* or tetraplegia*).ab,ti.
17.exp Bone Density/
18.exp Osteoporotic Fractures/
19.exp Absorptiometry, Photon/
21.exp Fracture Fixation/
23.(Osteoporo* or Absorptiometry or Densitometry).ab,ti.
24.(Bone* adj3 (break* or broke* or density or "mineral content")).ab,ti.
26. exp Bone Density Conservation Agents/
27. exp Diphosphonates/
28. exp Estrogen Receptor Modulators/
29. exp raloxifene/
30. exp Calcitonin/
31. (antiresorptive agent* or bisphosphonate* or zolendronic acid* or alendronate or etidronate or ibandronate or pamidronate or risedronate or tiludronate or calcitonin* or raloxifen or denosumab).ab,ti.
34.randomized controlled trial.pt.
35.controlled clinical trial.pt.
37.clinical trials as topic.sh.
41.(animals not (humans and animals)).sh.
42.40 not 41
37.15 and 25 and 32 and 42
EMBASE Classic + EMBASE (OvidSP)
1. exp Spinal Cord Injuries/
2. exp Spinal Cord Ischemia/
3. exp Central Cord Syndrome/
4. (myelopathy adj3 (traumatic or post-traumatic)).ti,ab.
5. ((spine or spinal) adj3 (fracture* or wound*or trauma* or injur* or damag*)).ti,ab.
6. (spinal cord adj3 (contusion or laceration or transaction or trauma or ischemia)).ti,ab.
7. central cord injury syndrome.ti,ab.
8. central spinal cord syndrome.ti,ab.
9. exp cervical spine/
11. 9 and 10
12. exp SPINAL CORD/
14. exp PARAPLEGIA/
15. exp Quadriplegia/
16. (paraplegia* or quadriplegia* or tetraplegia*).ti,ab.
17. 1 or 2 or 3 or 4 or 5 or 6 or 7 or 8 or 11 or 12 or 13 or 14 or 15 or 16
18. exp Osteoporosis/
19. exp Bone Density/
20. exp Osteoporotic Fractures/
21. exp Absorptiometry, Photon/
22. exp Densitometry/
23. exp Fracture Fixation/
24. (Osteoporo* or Bone Density or Fracture Risk or Absorptiometry or Densitometry or fracture fixation).ti,ab.
25. 18 or 19 or 20 or 21 or 22 or 23 or 24
26. 17 and 25
27. exp Diphosphonates/
29. exp Bone Density Conservation Agents/
30. exp Estrogen Receptor Modulators/
29. exp raloxifene/
30. exp Calcitonin/
31. (antiresorptive agent* or bisphosphonate* or zolendronic acid* or alendronate or etidronate or ibandronate or pamidronate or risedronate or tiludronate or calcitonin* or raloxifen or denosumab).ti,ab.
32. 27 or 28 or 29 or 30 or 31
34. randomized controlled trial.pt.
35. controlled clinical trial.pt.
37. exp "clinical trial (topic)"/
40. 33 or 34 or 35 or 36 or 37 or 38 or 39
41. (animals not (humans and animals)).sh.
42. 40 not 41
43. 26 and 32 and 42
Contributions of authors
All authors contributed to the protocol.
Declarations of interest
Sources of support
- Hospital Clínico Mutual de Seguridad, Chile.The hospital did not provide specific support for the development of the review, but Claudio Soto receives a fixed salary from the institution.
- Pontificia Universidad Católica de Chile, Chile.The University did not provide specific support for the development of the review, but Gabriel Rada receives a fixed salary from the institution.
- No sources of support supplied