How do combat-related injuries and their treatments affect bone health?

Combat-related injuries to bone are common in military personnel and can lead to pain and disability. Results from a new study in the Journal of Bone and Mineral Research suggest that amputations for such injuries may negatively affect bone mass.

In the study of 575 male adult UK military personnel with combat-related traumatic injuries and 562 without such injuries, veterans who sustained traumatic amputations often had low bone density in the hip region. Changes in bone health appeared to be mechanically driven rather than systemic and were only evident in those with lower limb amputations.

“We hope these results will drive further research into ways to reverse bone mineral density changes,” said co-author Group Captain Alex Bennett, Defence Professor of Rehabilitation, Defence Medical Rehabilitation Centre. “We need to investigate the role of prosthetics and exercise in reversing bone mineral density loss to reduce the longer-term risk of hip fracture. Because systemic treatments like bisphosphonates are not indicated in this young population with bone mineral density loss, it is important to understand other ways to reduce their hip fracture risk.”

Recent conflicts in Iraq and Afghanistan have resulted in large numbers of personnel exposed to combat related traumatic injury (CRTI) including 265 UK military personnel sustaining a total 416 amputations, most frequently of the lower limb.⁽¹⁾ The mean age at time of amputation was 22 years, an age at which osteoporosis is uncommon.⁽²⁾ In studies of amputees over 5 years following amputation disproportionate numbers (more than 50%) of amputees are diagnosed with osteoporosis and osteopenia.^(3–5) CRTI can induce systemic inflammation⁽⁶⁾ and hormonal changes,⁽⁷⁾ both of which have been shown to lead to osteoporosis. CRTI with traumatic amputation has the potential to lead to osteoporosis through not only systemic inflammation and hormonal changes but also altered loading. Although a documented long-term complication of lower limb amputation is osteoporosis, this is often observed in older less active subjects with comorbidities, thus it is unknown whether this is secondary to systemic changes or changes to the loading environment.^(3, 8, 9) A comparison of CRTI and traumatic amputation enables the differences between systemic effects and localized effects to be investigated due to the change in loading on the amputated limb.

The long-term consequences of osteopenia and osteoporosis include stress fractures, femoral neck and vertebral wedge fractures, with serious implications on loss of mobility, physical dependency, and morbidity, including compromising future prosthetic use. Although there is currently no direct evidence that amputation influences fracture risk, indirectly lower bone mineral density (BMD) would imply a greater risk. Current systemic treatments include hormone replacement therapy and use of bone-preserving medication such as bisphosphonates, but such treatments have been shown to have adverse effects elsewhere in the body.^(10, 11) It is therefore important to understand whether amputees suffer from systemically driven osteopenia/osteoporosis or whether it is a localized phenomenon similar to disuse osteopenia.

There is some evidence in the literature from studies in older groups, using X-ray data as a surrogate of BMD, few numbers of amputees, without control groups, and without controlling or accounting for differences in activity levels, smoking or body mass index (BMI), that amputee bone loss is commonly localized to the amputated limb.^(12–15) Thus it is postulated that BMD loss in amputees is a mechanical phenomenon, similar to disuse osteopenia, where altered, nonphysiological loading, post-amputation, drives progressive bone loss over the course of many remodeling cycles. Literature has suggested this might come from: offloading by the predominantly ischial tuberosity weight bearing prosthetic socket⁽¹³⁾ that would be worse for above knee amputees than below knee amputees, bedrest immediately postsurgery,⁽¹²⁾ reduced activity as ambulation becomes more challenging,^(16, 17) and significantly lowered muscle forces from extreme atrophy.⁽¹⁸⁾ Diagnosis discordance in measures of BMD can be used to investigate local versus systemic phenomena, where minor discordance is found when the scores at two different measurement sites are separated by one diagnostic class. Major discordance is when one site is considered osteoporotic and the other normal.⁽¹⁹⁾ The presence of discordance means that the BMD loss is localized and not systemic.

The aim of this study was to test the following hypotheses in a prospective military cohort:

1. BMD in the CRTI group is lower than the uninjured group;
2. BMD in the femoral neck of the amputated limb of lower limb amputees is lower than in the CRTI non-amputee or uninjured groups;
3. BMD loss is greater in above knee amputees than below knee amputees; and
4. BMD changes in the amputee population exhibit higher levels of diagnosis discordance than in the populations of CRTI non-amputee and uninjured groups.

Subjects and Methods

Study design and participants

The Armed Services Trauma Rehabilitation Outcome (ADVANCE) study⁽²⁰⁾ is a prospective cohort study comprising 575 male adult UK military personnel (UK-Afghanistan War 2003 to 2014; 153 lower limb amputees of varying amputation type and level) with CRTI (mean of 8 years since injury) who were frequency-matched to 562 uninjured men by age, service, rank, regiment, deployment period, and role-in-theater. The adjusted recruitment response rates (excluding those who had died, had no known contact details or for whom no contact was attempted) were equivalent between groups at 58.0%. CRTI was defined as injury requiring aeromedical evacuation.⁽²¹⁾ Ethical approval was received from the Ministry of Defence Research Ethics Committee and all participants provided written consent prior to inclusion. All lower limb amputee subjects were below or above-knee amputees in at least one limb.

Variables

Dual-energy X-ray absorptiometry (DXA) scanning was used to measure BMD and T-score at both the lumbar spine and femoral neck. T-score was selected (as opposed to Z-score) because the patient population is young therefore comparison to a healthy 30-year-old is appropriate to age. Measurements presented from the femoral neck of CRTI non-amputee, bilateral amputees, and uninjured control participants represent an average of both right and left legs. In unilateral amputee participants, the data of one limb was used for analysis separately as opposed to either the amputated or non-amputated limb.

The following data were also collected to control for any factors that could account for differences in amputee and uninjured BMD:

1. Age;
2. Height, or preinjury height for bilateral amputees;
3. Adjusted body mass, to include the lost mass of the amputated limb(s)⁽²²⁾;
4. Adjusted BMI;
5. Smoking status (pack years), to account for the known adverse effects of smoking on bone turnover^(23, 24); and
6. Activity levels (using the International Physical Activity Questionnaire [IPAQ],⁽²⁵⁾ a validated patient-reported outcome measure where moderate activity is defined as “activities.… [that] make you breathe somewhat harder than normal” and vigorous activity as “activities that take hard physical effort and make you breathe much harder than normal”).

Statistical methods and sample size

Forty-three amputees are required to detect a clinically significant difference between T-score at the spine and femoral neck with 80% power and 1% level of significance^(16, 19); unilateral (as opposed to bilateral) amputees are required to detect a clinically significant difference between T-score in the femur of amputated and contralateral limbs.⁽¹⁵⁾ A clinically significant difference here is defined as a change from one diagnostic class to another.

Statistical analysis was carried out using Stata Version 16 (StataCorp, College Station, TX, USA). For comparisons between two groups (uninjured versus CRTI), independent t tests were used for normally distributed data, and Mann-Whitney U tests for non-normally distributed data. For comparisons between three or more groups (non-injured versus CRTI non-amputees versus amputees, subcategories of amputees), one-way ANOVAs were used for normally distributed data, whereas the Kruskal Wallis test was used for non-normally distributed data. Where significant differences were found, post-hoc pairwise comparisons with Bonferroni corrections were conducted.

Logistic binary regression with femoral neck pathology (T-score less than −1) as the outcome measure was performed to investigate the contribution of the following variables on femoral neck BMD pathology: amputee status, smoking history, total IPAQ walking minutes, total IPAQ activity minutes, and adjusted BMI. To assess discordance, Fisher’s exact test tests were performed for differences in magnitude and type (spine lower than hip or hip lower than spine) of discordance between controls, injured non-amputees, and amputees. A conservative threshold of p < 0.01 was set for statistical significance of all analyses due to the large sample size to reduce the chances of significant results for very small differences.

Results

The injured and uninjured groups are summarized in Table 1. Adjusted body mass and BMI were significantly higher in the injured compared to uninjured participants. There was no statistical difference in the T-score at the spine between the whole injured and non-injured groups (p = 0.959, Table 1). However, the whole injured group demonstrated a reduced femoral neck T-score compared to the uninjured group (p < 0.001, Table 1).Table 1. Participant Details of Uninjured, Injured, and Injured Subgroups (Non-amputees, Unilateral, and Bilateral Amputees)