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Association Between Osseointegration of Lower Extremity Amputation and Mortality Among Adults

Key Points Question What are the causes and potential factors associated with death after lower extremity osseointegration? Findings In this cohort study of 485 patients who underwent transcutaneous osseointegration post amputation and were followed up for as long as 10 years, 19 patients (4%) died, including 17 who died of causes unrelated to osseointegration and 2 who died of osseointegration-related causes. Risk factors for mortality included increased age at osseointegration and the indication for amputation being either for vascular or infectious etiology; factors not associated with mortality risk included postosseointegration infection and sex. Meaning These findings suggest that patients considering osseointegration to improve their mobility and quality of life have a minimal risk of mortality.


Introduction
Transcutaneous osseointegration post amputation (TOPA), 1 a procedure that creates a direct linkage between residual bone and an external prosthetic limb, continues to gain momentum as a viable rehabilitation alternative to traditional compression and suction prostheses. Osseointegration provides improved mobility and quality of life compared with traditional prostheses for most patients with lower extremity amputation. 2,3 As with any major elective orthopedic surgical procedure, there are inherent risks to balance against the potential benefits, 4,5 with 1 potential risk being associated mortality. It is therefore imperative to investigate this risk so that clinicians may provide better information and patients may make better-informed decisions regarding this method of surgical reconstruction.
A 2018 systematic review of osseointegration complications 6 found that mortality has never been the focus of investigation. Our own searches of subsequent literature identified no studies that focused on mortality after osseointegration. Deaths reported in literature evaluating other aspects of osseointegration are rare, perhaps owing to careful patient selection that prioritizes healthy patients, 7,8 relatively short follow-up, or underreporting given that death was never the primary outcome of investigation. It is important to understand to what extent patient mortality may be associated with preoperatively modifiable risk factors or avoidable or unavoidable postoperative complications or whether mortality may be completely unrelated to this surgical procedure. To address this knowledge gap, we evaluated the incidence, causes of, and factors potentially associated with mortality among patients who have undergone TOPA.

Methods
The Macquarie University ethical committee approved this cohort study and waived the need for informed consent for record review based on the combination of 3 situations: first, the patients of specific interest were deceased; second, the only expected potential harm to living patients being a breach of confidentiality; and third, the number of patients to consent. The study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Study Design
All patients in our prospectively maintained osseointegration registry were included in the evaluation. Patients from several continents had index osseointegration between November 1, 2010, and October 31, 2021, and were followed up for as long as 10 years. Indication criteria for patients considering osseointegration surgery have been described previously 8,9 and are summarized as follows. Generally, patients considered for osseointegration (Figure 1) are skeletally mature adults who (1) report pain or mobility dissatisfaction with their traditional compression and suction prostheses; (2) have an intact limb with incapacitating pain, complex deformity, or profound distal weakness whose functional capacity is considered likely to be improved by amputation; or (3)  patients overall [0.4%]) were related to osseointegration-both of which were due to infectious complications, and 1 of which (0.2%) was coclassified as a preexisting health probem that was exacerbated by the procedure (myocardial infarction after subsequent surgery to manage infection).
No deaths occurred after periprosthetic fracture or intraoperatively or were associated with inpatient recuperation or short-term perioperative complications after index osseointegration, cardiopulmonary or circulatory complications (eg, fat embolism or respiratory distress, pulmonary embolism), or operation-associated infections (eg, urinary, respiratory, or line-associated infection).
The remaining 17 patient deaths were considered unrelated to osseointegration. The most common cause of death consisted of cardiac issues that occurred after and were unrelated to The survival analysis was performed using Kaplan-Meier survival modeling and presented as cumulative incidence.  Patient weight and the interval from amputation to osseointegration were not significant risks.

Discussion
The most important finding of this cohort study is that our data suggest that mortality due to osseointegration-related complications after TOPA is rare. Only 2 of 485 patients (0.4%) died of osseointegration-related complications, and only 19 (3.9%) died of any cause during follow-up after osseointegration. Regression modeling and Kaplan-Meier survival analysis with log-rank pairwise comparison revealed that patients with amputations performed to manage vascular problems or infection have increased mortality vs those whose amputations were performed for other reasons, significantly greater than patients who underwent amputation for oncologic and traumatic causes.
As might be expected, increasing patient age was a risk factor for mortality, but not owing to osseointegration-related issues. Because this study is the first, to our knowledge, to focus on postosseointegration mortality, there is no direct literature providing any context. Therefore, this discussion regarding mortality among patients who underwent osseointegration focuses on 3 topics.   The graph's vertical axis (cumulative incidence of mortality) is truncated to improve the visibility of the data. For infection vs no infection, log-rank P = .82; for femur vs tibia, log-rank P = .31.   The graph's vertical axis (cumulative incidence of mortality) is truncated to improve the visibility of the data. The log-rank comparisons are presented for each pairwise test. years among 149 patients. Our cohort was decidedly heterogeneous regarding indications for primary amputation and timing of osseointegration in relation to the original amputation, so unfortunately this study was not designed to directly compare against studies following a single indication for amputation.

JAMA Network Open | Physical Medicine and Rehabilitation
Mortality after total hip (THA) and knee (TKA) arthroplasty has been studied more frequently.
Although total joint replacement is substantially different from osseointegration, we consider comparison with these patient groups purposeful because both osseointegration and joint replacement are performed to improve patient mobility and quality of life, usually electively, and feature relatively large, permanent implants in extremities. Studies investigating standardized mortality ratios identify that historically, the 90-day period after THA or TKA was associated with worse standardized mortality ratios. 17 However, during the last 20 years, patients who underwent THA and TKA tended to have similar or better standardized mortality ratios vs the average population, 18 with the benefit persisting for approximately 1 decade after surgery. 19 The acute improvement in survival is attributed to continuously enhanced anesthesia and postoperative protocols, with the longer-term survival attributed to patient selection and preoperative medical optimization. 20 Other studies 21,22 have reported 90-day THA and TKA mortality as ranging from 0.4% to 0.6%; in our cohort, TOPA-related mortality was 0.2%. A systematic review 23 identified cardiac complications as the most common cause of death (0.1%-0.3%), followed by pulmonary emboli (0.1%). 22 Long-term studies 19,24 identify cardiac, vascular, cancer, and cerebrovascular events as the most frequent causes of death. Our cohort's leading causes of death were cancer, pulmonary issues, and cardiac issues, consistent with those studies, but suicide was a leading cause of death in our cohort that was not identified in the THA and TKA studies. Beyond joint replacement orthopedic surgery, mortality after noncervical spine surgery has an estimated short-term mortality of 0.4% to 0.7%, 25,26 and even total shoulder 27 and total ankle arthroplasty 28 have nonnegligible short-term mortality rates. These studies emphasize how and why understanding the rates and causes of mortality after surgery is important to properly counsel patients.
Infection remains the paramount concern for TOPA, but its association with mortality has not been previously evaluated. Of our 485 patients with TOPA of the lower extremity, 59 (12.2%) required at least 1 subsequent operative intervention for infection, and both patients in this study who died of osseointegration-related complications had infection originating from the stoma site.
Preventing stoma infection is a complex issue not only for transcutaneous extremity osseointegration but for any situation involving long-term transcutaneous bone implants. The most common such situation, and the most studied, is for external fixation. External fixator pin site infection is estimated to occur in 4% of patients who have undergone nonacute trauma deformity correction. 29 Approximately 28% of patients with external fixation applied as part of acute trauma care develop infection, 30 and 2.5% of pins become clinically loose, necessitating their removal. 31 Repetitive microtrauma to the pin site leading to local inflammation and bacterial ingress is believed to increase the susceptibility to infection. 29  Three patients in this cohort committed suicide, the third-largest cause of mortality for our patients. Although these suicides seem unlikely to be directly related to TOPA, they are arguably preventable and are certainly a devastating event for the patient's family and for the physician. Suicide in relation to osseointegration has not been previously investigated, but individuals who have undergone amputation have long been recognized as a population at risk for mental health issues, including suicide. Pierce et al 34 highlighted several associated risks among individuals who have   undergone amputation: unemployment, substance abuse, additional surgical procedures, chronic pain, and mobility problems associated with prosthesis sockets. The rate of suicidal ideation among these patients varies and depends on many factors, but it has been estimated to be at 15% to 30%. 35,36 A full discussion of mental health and suicidal ideation among this population far exceeds the scope of this article, but some points are common and noteworthy. Individuals who have undergone amputation rely on caregivers, particularly in the immediate postoperative and early rehabilitation periods. The spouse or other family member is often the caretaker, and this arrangement can stress relationships and lead to depressive symptoms. 37 Depressive symptoms may be the most reliable factor associated with suicidal ideation, 38 and improved independence 35 and rehabilitation appear to be protective against depressive symptoms and suicidality. 39 Given that most patients improve their quality of life and mobility after TOPA, 2 and the recent investigation by

JAMA Network Open | Physical Medicine and Rehabilitation
Reif et al 14 also identifies improved mental health, it seems reasonable to offer this reconstruction to appropriately selected patients.
Our preoperative evaluation includes several components that have been identified as protective against suicide risk: an integrated care team including a physiatrist, physiotherapist, prosthetist, and internist; separate formal consultation with a clinical psychologist; and formal inquiries regarding patients' mental health, with both preoperative and postoperative questionnaires. 35 The 3 patients who committed suicide had preexisting mental health conditions (bipolar disorder, posttraumatic stress disorder, and/or depression) but were assessed as stable and well supported before surgery. Why, then, might they have committed suicide? Notably, these patients also had phantom pain and neuroma pain that was incompletely improved after TOPA. It is possible that the lack of this specific pain relief could have been a factor behind their suicide. There is optimism that providing targeted muscle reinnervation (TMR) and regenerative peripheral nerve interface (RPNI) surgery, techniques recently identified to improve nerve-related pain among patients who have undergone amputation, may provide better pain improvement for all patients and possibly reduce this specific risk of suicide in those who are at risk. 40

Strengths and Limitations
The main strengths of this study include the relatively large cohort size (485 patients) and the high rate of recent follow-up (93.8% contact within the prior 2 years). Furthermore, the cause of death was known for all but 1 patient. The influence of several major factors (sex, age, weight, and time since amputation) were assessed, and the rates of mortality were compared for several relevant variables (age, sex, level of amputation, postoperative infection, and amputation etiology).
The major limitations of this study are those inherent in any longitudinal cohort study, including selection bias and reporting bias. In addition, a greater rate of procedures was performed each year, so longer-term follow-up has lower relative representation. In addition, the mortality rates may be influenced by the relatively strict patient selection criteria used in our group's early experience with osseointegration: young and healthy patients were generally considered more suitable candidates for osseointegration initially. The indications were gradually expanded as procedural familiarity and generally positive outcomes guided counseling for patients considered to be potentially at greater risk. Generalizability of the results is likely most contingent on the health of patients or cohorts.

Conclusions
The findings of this cohort study suggest that patients who have had osseointegration rarely die of complications associated with the procedure. Infection remains the most common complication associated with osseointegration and is the only osseointegration-related cause of death in our cohort. As with any population of individuals who have undergone amputation, clinicians should