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. 2023 Apr 28;18:101682. doi: 10.1016/j.bonr.2023.101682

Bone density changes after five or more years of unilateral lower extremity osseointegration: Observational cohort study

Jason Shih Hoellwarth a,⁎, Atiya Oomatia b, Kevin Tetsworth c, Elisabeth Vrazas d, Munjed Al Muderis b
PMCID: PMC10189091  PMID: 37205925

Abstract

Context

Rehabilitation following lower extremity amputation presents multiple challenges, many related to the traditional prosthesis (TP) socket. Without skeletal loading, bone density also rapidly decreases. Transcutaneous osseointegration for amputees (TOFA) surgically implants a metal prosthesis attachment directly into the residual bone, facilitating direct skeletal loading. Quality of life and mobility are consistently reported to be significantly superior with TOFA than TP.

Objective

To investigate how femoral neck bone mineral density (BMD, g/cm2) changes for unilateral transfemoral and transtibial amputees at least five years following single-stage press-fit osseointegration.

Methods

Registry review was performed of five transfemoral and four transtibial unilateral amputees who had dual x-ray absorptiometry (DXA) performed preoperatively and after at least five years. The average BMD was compared using Student's t-test (significance p < .05). First, all nine Amputated versus Intact limbs. Second, the five patients with local disuse osteoporosis (ipsilateral femoral neck T-score < −2.5) versus the four whose T-score was greater than −2.5.

Results

The average Amputated Limb BMD was significantly less than the Intact Limb, both Before Osseointegration (0.658 ± 0.150 vs 0.929 ± 0.089, p < .001) and After Osseointegration (0.720 ± 0.096 vs 0.853 ± 0.116, p = .018). The Intact Limb BMD decreased significantly during the study period (0.929 ± 0.089 to 0.853 ± 0.116, p = .020), while the Amputated Limb BMD increased a not statistically significant amount (0.658 ± 0.150 to 0.720 ± 0.096, p = .347). By coincidence, all transfemoral amputees had local disuse osteoporosis (BMD 0.545 ± 0.066), and all transtibial patients did not (BMD 0.800 ± 0.081, p = .003). The local disuse osteoporosis cohort eventually had a greater average BMD (not statistically significant) than the cohort without local disuse osteoporosis (0.739 ± 0.100 vs 0.697 ± 0.101, p = .556).

Conclusions

Single-stage press-fit TOFA may facilitate significant BMD improvement to unilateral lower extremity amputees with local disuse osteoporosis.

Keywords: Osseointegration, Bone density, Transfemoral amputation, Above knee amputation, Transtibial amputation, Below knee amputation

Highlights

  • •

    Femoral neck bone density is lower for an amputated versus intact lower extremity.

  • •

    Bone density is worse in transfemoral than transtibial amputees.

  • •

    Osseointegration confers direct skeletal loading to an amputated extremity.

  • •

    Osseointegration often improves ipsilateral femoral neck bone density.

  • •

    Osseointegration significantly improves local disuse osteoporosis bone density.

1. Introduction

Patients face many challenges following limb loss, the most obvious of which is regaining function from the amputated limb. Currently, the most common rehabilitation solution is the socket-based traditional prosthesis (TP), with an estimated 86 % of lower extremity amputees attempting the use of at least one device (Leijendekkers et al., 2017; Dudek et al., 2005). Unfortunately, TPs have many shortcomings and difficulties which reduce patients' quality of life (QOL) and mobility; over 40% (Dudek et al., 2005; Meulenbelt et al., 2009) of patients experience substantial and frequent skin problems such as hyperhidrosis, dermatitis, ulcers, and difficulty maintaining a comfortable and stable fit (Dudek et al., 2005; Meulenbelt et al., 2009; Butler et al., 2014). These issues contribute to secondary health problems, including low bone density. Because the TP cannot directly load the skeleton through the terminal limb, amputees necessarily locally lose bone density and develop local disuse osteopenia or osteoporosis in the affected limb earlier than if they had not had limb loss (Sherk et al., 2008; Bemben et al., 2017). This localized bone loss can be substantial, and some patients and care providers express concern whether osteopenic or osteoporotic bone may irreparably fracture during surgery or during postoperative rehabilitation, rendering a patient more disabled instead of better abled.

Transcutaneous osseointegration for amputees (TOFA), recently reviewed (Hoellwarth et al., 2020a; Hoellwarth et al., 2022f), is a surgical reconstruction technique wherein an intramedullary metal implant is anchored directly to the skeleton and then attached to a standard external prosthetic limb via a permanent transcutaneous connector. Versus TP, TOFA improves prosthetic use and quality of life (Hagberg et al., 2008; Lundberg et al., 2011) without minimal associated risk of complications leading to proximal limb amputation or mortality (Hoellwarth et al., 2022a). Because TOFA implants are directly anchored to the terminal bone, patients load their residual limb and skeleton much more anatomically, allowing the more frequent limb loading (Kunutsor et al., 2018; Hebert et al., 2017) to also be more physiologic (Tranberg et al., 2011), which could lead to improved bone density in the limb (Simkin et al., 1987; Chahal et al., 2014). However, only three studies have investigated bone density in relation to osseointegration, all over less than three years' time (Hansen et al., 2019; Thomson et al., 2019a).

This study aims to enhance the understanding of direct bone loading for amputees by evaluating how femoral neck BMD changed over five or more years, the longest time studied for an osseointegrated population. The primary aim was to evaluate the changes in dual x-ray absorptiometry (DXA): g/cm2 (bone mineral density, BMD) and T-score for the entire cohort. The secondary aim was to compare the changes between patients who preoperatively met criteria for local disuse osteoporosis (Amputated Side femoral neck T-score ≤ −2.5) versus those who did not (Amputated Side femoral neck T-score > −2.5. The tertiary aim was to compare the bone density changes for transfemoral versus transtibial amputees.

2. Methods

This retrospective cohort study, conducted at a tertiary referral center specializing in osseointegration surgery for the reconstruction of amputated limbs, was approved by our institutional ethics board, and follows the STrengthening the Reporting of OBservational studies in Epidemiology (STROBE) reporting guideline for observational studies.

All patients were already existing amputees before seeking consultation for osseointegration, having attempted TP use to the extent they were willing, prior to seeking TOFA. The preoperative DXA did not rule out any patient from the opportunity for TOFA.

In this article, the term “bone density” indicates the general concept of bone health from a general structural integrity standpoint, and the term “bone mineral density (BMD)” specifically indicates the quantitative DXA measurement of the density of bone, in the units of g/cm2.

2.1. Patient selection

Retrospective chart review was performed of the institution's osseointegration registry to identify patients who met this study's inclusion criteria: unilateral lower extremity TOFA, performed at least five years prior to the start of this study (early 2022), with preoperative bilateral hip DXA. For a period, our practice routinely obtained DXA preoperatively for all patients prior to TOFA because there was concern whether lower bone density could be associated with fracture intraoperatively or postoperatively; this routine was discontinued after it seemed to us that there was no associated risk. Patients who did not have bilateral DXA prior to unilateral lower extremity TOFA, at least five years prior, were excluded. These criteria identified 48 unilateral lower limb patients, all treated during 2015–2016, previously reported on in separate studies (Thomson et al., 2019a; Thomson et al., 2019b). In 2022, attempts were made to arrange a repeat DXA at a location close to the patients' homes. 12 patients could not be contacted, 8 patients now live in places with no accessible DXA imaging, 17 patients could not get DXA studies due to persistent resource limitations related to COVID restrictions, and 2 patients had additional surgeries which confounded analysis (one had a total hip replacement on the osseointegrated side following index TOFA, the other had transfemoral amputation to manage total knee replacement infection above the transtibial TOFA). This yielded 9 patients with complete preoperative and current DXA data. Preoperative DXA were acquired at two imaging centers using a standardized protocol at both locations using a GE Lunar Prodigy (GE Healthcare, Chicago, IL). DXA was acquired with patients lying in a supine position with both lower limbs rotated internally at 15° and slightly abducted to a position such that the femoral neck was parallel to the table. Scans were taken of both femoral necks. Five-year DXA studies were performed at various locations, but with the same positioning instructions provided. The machines used for these follow-up studies were: GE Lunar Prodigy (patients 1, 2, 5, 6, and 9), Hologic Horizon Wi (Hologic, Inc., Marlborough, MA, USA) (patients 3, 4 and 8), and Medix DR (Medilink, France) (patient 7). No inter-system calibration was performed. The demographic information is summarized in Table 1; the body mass index (BMI) was estimated using the Amputee Coalition calculator (Wong and Wong, 2017) (https://www.amputee-coalition.org/content/amputee-bmi-calculator/index.html).

Table 1.

Demographic summary of included patients.

Patient number Age, sex, level, implanta Adjusted BMI Reason for amputation Years from amputation to osseointegration Years between DXAs Preoperative amputated g/cm2, (T-score) Postoperative amputated g/cm2, (T-score) Preoperative intact g/cm2, (T-score) Postoperative intact g/cm2, (T-score) Refashioning
1 53, M, f, ILP 32.3 Trauma 40 7.2 0.529 (−4.2) 0.826 (−1.9) 1.073 (0.0) 1.085 (0.1) 68 months –
2 61, M, f, ILP 19.9 Trauma 31 6.3 0.647 (−3.3) 0.755 (−2.4) 1.039 (−0.2) 0.961 (−0.8) – –
3 68, M, f, ILP 34.9 Infection 44 6.7 0.571 (−3.8) 0.694 (−1.7) 0.944 (−1.0) 0.790 (−1.0) – –
4 66, M, t, ILP 27.8 Trauma 2 6.3 0.758 (−2.4) 0.630 (−2.2) 0.826 (−1.9) 0.714 (−1.6) 9 months 78 months
5 59, F, f, ILP 28.7 Trauma 39 6.3 0.484 (−4.2) 0.590 (−3.4) 0.821 (−1.5) 0.790 (−1.8) – –
6 48, M, f, ILP 20.9 Trauma 6 6.5 0.496 (−4.4) 0.828 (−1.9) 0.869 (−1.5) 0.820 (−1.9) – –
7 50, F, t, ILP 32.0 Trauma 23 7.6 0.734 (−2.2) 0.607 (−2.7) 0.954 (−0.5) 0.871 (−1.7) 7 months –
8 50, M, t, ILP 21.9 Vascular 8 6.9 0.916 (−1.2) 0.721 (−1.5) 0.961 (−0.8) 0.744 (−1.4) – 70 months
9 67, M, t, OPL 33.9 Vascular 22 5.7 0.790 (−2.1) 0.829 (−1.9) 0.870 (−1.6) 0.902 (−1.3) – –
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a

The column data is presented in Age at surgery (years), Sex (M = male, F = female), Amputation Level (f = femur, t = tibia), and Implant Model (ILP=Integral Limb Prosthesis, OPL = Osseointegrated Prosthetic Limb).

2.2. General osseointegration evaluation criteria

The general indication criteria for patients considering TOFA are previously described (Al Muderis et al., 2017; Haque et al., 2020). Overall, patients considered for osseointegration are skeletally mature adults who either 1) report pain or mobility dissatisfaction with their TP; 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) are recent amputees preferring osseointegration to TP rehabilitation. Comorbidities such as diabetes mellitus (Jawazneh et al., 2017), peripheral vascular disease (Akhtar et al., 2021), and other comorbidities (Hoellwarth et al., 2021; Akhtar et al., 2022; Hoellwarth et al., 2022b; Hoellwarth et al., 2022c; Hoellwarth et al., 2022d) do not appear to necessitate contraindication. The only situations we consider particularly rigid contraindications to osseointegration are modifiable compromises to successful bone and/or wound healing, such as active infection or malignancy, though upon treatment of those modifiable compromises most patients can be suitable. No patients are excluded from TOFA based on bone density. All patients, regardless of bone density, are recommended to start supplementation with vitamin d3 (typically 1000 IU daily) and calcium (typically 600 mg daily) at the time of consultation and maintain daily intake through at least three months following osseointegration. The patient's compliance is not a criteria for surgery.

2.3. Implants, surgical technique, and rehabilitation

The implants (Hoellwarth et al., 2020b) and surgical technique (Hoellwarth et al., 2022e; Geiger et al., 2022) are detailed elsewhere, and summarized as follows. The initial implant utilized was the Integral Limb Prosthesis (ILP, Orthodynamic, Lubeck, Germany) before transitioning to the Osseointegrated Prosthetic Limb (OPL, Permedica Medical Manufacturing, Lecco, Italy). Both these implant systems are specifically designed for press-fit fixation and consist of two components inserted in a single surgical procedure: an intramedullary stemmed component that achieves skeletal integration, and a dual cone adapter that mates with the intramedullary component and is passed through a permanent transcutaneous portal to connect with the external prosthetic limb (Fig. 1). The key surgical steps include primary or revision amputation to an optimal length to ensure the external prosthesis's knee or ankle joint is near the level of patient's contralateral joint, intramedullary canal preparation, implant insertion, soft tissue contouring (Marano et al., 2020), and closure around the transcutaneous implant. The recommendation is for this all to be performed in a single surgical event. Patients progress through the postoperative care and rehabilitation protocol, summarized as (1) progressively increasing static axial-only loading directly on the prosthesis abutment within 3 days after TOFA surgery; (2) after half body weight loading has been achieved (around 2–3 weeks), increase axial-only loading using a temporary light-weight prosthesis; then (3) full-weight axial loading with a personalized prosthesis at 4 to 6 weeks postoperatively, with independent ambulation without walking aides at around 12 weeks. No casts or splints are used. Surgeon follow-up evaluations are scheduled at 3 weeks, 6 weeks, 3 months, 6 months, and annually, or as needed.

Fig. 1.

Fig. 1

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Osseointegration technology. (A) Integral Limb Prosthesis (ILP) system componentry. 1, proximal cap screw; 2, ILP body with main portion textured, distal flare untextured, abutment highly polished with titanium niobium oxynitride ceramic surface; 3, dual cone abutment adapter; 4, safety screw; 5, taper sleeve; 6, distal bushing; 7, permanent locking propeller screw; and 8, temporary cover screw. Adapted by permission from Springer Nature: Springer Nature, Operative Orthopädie und Traumatologie. Aschoff HH, Clausen A, Tsoumpris K, Hoffmeister T. Implantation der Endo-Exo-Femurprothese zur Verbesserung der Mobilität amputierter Patienten. Oper Orthop Traumatol. 2011 Dec;23[5]:462-72. The zoom-in box of surface texture in Fig. 2A is adapted, by permission, from Springer Nature: Springer Nature, Der Orthopäde. Juhnke DL, Aschoff HH. Endo-Exo-Prothesen nach Gliedmaßenamputation. Der Orthopäde. 2015 Jun; 44[6]:419-25. Epub 2015 May 14. Copyright 2015. (B) Osseointegrated Prosthetic Limb (OPL) system componentry in approximately the proximal-distal levels in which they would be once assembled and implanted in a patient who had undergone a femoral amputation. 1, proximal cap screw; 2, OPL body; 3, safety screw; 4, dual cone abutment adapter; 5, permanent locking propeller screw; 6, proximal connector; and 7, prosthetic connector. (C) Anterior-posterior radiograph of an OPL in a transfemoral amputee. (D) shows a transfemoral amputee in the process of donning the prosthesis. (E) Shows a transtibial amputee jogging on the prosthetic leg.

2.4. Study outcomes, data collection, and analysis

The DXA data of interest were bone mineral density (BMD, g/cm2) and T-score. Adverse events related to the surgery or patient's status as an osseointegrated amputee were recorded. Specifically, these included postoperative systemic complications (such as cardiovascular, circulatory, or pulmonary events), more proximal amputation, death, or other operative intervention to manage complications such as infection or refashioning (a soft tissue debulking procedure akin to tissue tightening or redraping, removing skin and excess fat to stabilize the tissue overlying the muscles which form the residual limb).

Statistical analysis was performed using Google Sheets (Google LLC, Mountain View, California, USA). Means were compared using Student's t-test (paired when comparing pre-post averages of the same side; unpaired when comparing contralateral sides, osteoporotic situation, and amputation level). Statistical significance was set as p ≤ .05. Charts were prepared using Chart Studio Cloud (Plotly, Montreal, Quebec, Canada).

3. Results

Table 1 presents the demographic data, BMD, and T-scores. There were 9 patients (7 males and 2 females, 5 transfemoral and 4 transtibial). The overall average age was 58.0 ± 8.0 years: 57.8 ± 7.7 transfemoral vs 58.3 ± 9.5 transtibial (t-test p = .942). Males represented 7/9 = 78 %, 5/9 = 56 % were transfemoral, and 8/9 = 89 % had an ILP implant. The overall average amputee-adjusted BMI was 28.0 ± 5.8 kg/m2, 27.3 ± 6.7 kg/m2 transfemoral vs 28.9 ± 5.3 kg/m2 transtibial (t-test p = .709). The overall average years from amputation to osseointegration was 23.9 ± 15.9, 32.0 ± 15.3 transfemoral versus 13.8 ± 12.7 transtibial (p = .072). The overall average years between the pre-TOFA and current DXA was 6.6 ± 0.6, 6.6 ± 0.4 transfemoral vs 6.6 ± 0.8 transtibial (p = .919).

The primary aim of this study was to evaluate the changes in BMD (g/cm2) with specific respect to the Amputated vs Intact Limb's changes. These data are graphically shown in Fig. 2. The Amputated Limb's BMD was significantly less than the Intact Limbs, both Before Osseointegration (0.658 ± 0.150 vs 0.929 ± 0.089, p < .001) and After Osseointegration (0.720 ± 0.096 vs 0.853 ± 0.116, p = .018). However, it is important to note that whereas the Intact Limb's BMD decreased significantly during the study period (0.929 ± 0.089 to 0.853 ± 0.116, p = .020), the Amputated Limb's BMD actually increased though not a statistically significant amount (0.658 ± 0.150 to 0.720 ± 0.096, p = .347).

Fig. 2.

Fig. 2

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Graphical depiction of the entire cohort bone density values Before and After TOFA. Both the Amputated and Intact limbs are evaluated. Boxplots portray the median and quartiles (solid line and box), average and standard deviation (dotted horizontal line and diamond), range (whiskers), and each data point (solid dot) of the cohort. Each patient's path from Before to After is shown by the lines connecting the dots, with color identification consistent among all figures. Short dots represent the Amputated Limb and dashes represent the Intact Limb. Amputated limbs had significantly lower average BMD than Intact limbs preoperatively (p < .001). The Intact limbs decreased significantly during the study period (p = .020) whereas the Amputated limbs increased (but not significantly, p = .347), such that the average Amputated BMD remained significantly less than the average Intact BMD (p = .018).

The secondary aim was to compare the changes between patients who preoperatively had local disuse osteoporosis in the amputated extremity (amputated side femoral neck T-score ≤ −2.5) versus patients whose amputated limb's femoral neck T-score was greater than −2.5. These data are shown in Table 2 and graphically depicted in Fig. 3. Five patients had preoperative local disuse osteoporosis in the Amputated Limb, four did not. Coincidentally, all of the patients with local disuse osteoporosis were transfemoral amputees (also, all the transfemoral amputees had local disuse osteoporosis), and all the patients without local disuse osteoporosis were transtibial amputees (also, all the transtibial patients were non-osteoporotic). By design, the local disuse osteoporosis cohort had significantly lower average BMD than the cohort without local disuse osteoporosis Before osseointegration (0.545 ± 0.066 vs 0.800 ± 0.081, p = .003). The local disuse osteoporosis cohort increased BMD significantly Before vs After (0.545 ± 0.066 vs 0.739 ± 0.100, p = .018), whereas the cohort without local disuse osteoporosis decreased BMD but not to a significant degree (0.800 ± 0.081 vs 0.697 ± 0.101, p = .131). It is notable that the cohort with preoperative local disuse osteoporosis eventually had a greater average BMD (though not statistically significant) than the cohort that did not have preoperative local disuse osteoporosis (0.739 ± 0.100 vs 0.697 ± 0.101, p = .556).

Table 2.

Femoral neck bone density values of the Amputated side, grouped by Before vs After, and with preoperative local disuse osteoporosis (T-score < −2.5) vs without preoperative local disuse osteoporosis.

Amputated Side Only BMD
Before After p=
Local disuse osteoporosis (n = 5) 0.545 ± 0.066 (0.484 to 0.647) 0.739 ± 0.100 (0.590 to 0.828) 0.018
No local disuse osteoporosis (n = 4) 0.800 ± 0.081 (0.734 to 0.916) 0.697 ± 0.101 (0.607 to 0.829) 0.131
p= 0.003 0.556
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Values are presented as Mean ± SD (range). Five patients met criteria for osteoporosis in the hip on the amputated side (preoperative DXA T-score ≤ −2.5), four did not. Statistical comparison was Student's t-test (paired samples for Before vs After subgroup comparisons, unpaired samples for osteoporosis-nonosteoporosis comparisons).

Fig. 3.

Fig. 3

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Graphical depiction of the bone density values Before and After TOFA, based on the Amputated Limb's preoperative osteoporosis status. Boxplots portray the median and quartiles (solid line and box), average and standard deviation (dotted horizontal line and diamond), range (whiskers), and each data point (solid dot) of the cohort. Only the Amputated Limb is evaluated. Each patient's path from Before to After is shown by the lines connecting the dots, with color identification consistent among all figures. Dotted lines represent the Osteoporotic patients and solid lines represent the Nonosteoporotic patients. The average BMD was lower in the Osteoporotic patients than the Non-Osteoporotic patients (p = .003). The Non-Osteoporotic patients BMD decreased but not significantly (p = .131), whereas the Osteoporotic patients BMD improved significantly (p = .018) and actually achieved a greater average BMD than the Non-Osteoporotic patients (but not significant, p = .556).

Adverse events were likely of minimal impact to the outcomes of this study. No patients had systemic postoperative complications. No patients sustained a fracture. No patients required implant removal. Three patients had soft tissue refashioning to address irritating sagging tissue (patient 1 at 68 months, patient 4 at 9 months, patient 7 at 7 months). Two patients had debridement with implant retention to address soft tissue infection (patient 4 at 78 months, patient 8 at 70 months).

4. Discussion

This study aimed to understand changes in BMD and T-score after at least five years following unilateral lower extremity. Outcomes focused on the Amputated Side femoral neck vs Intact Side femoral neck, patients who had preoperative local disuse osteoporosis vs patients who did not, and transfemoral vs transtibial amputees. The most important finding is that press-fit TOFA consistently facilitated improvements in amputated limb bone density over this time period. There was a clear difference of bone density impact based on level of amputation: all five transfemoral patients had local disuse osteoporosis preoperatively, and all improved BMD during the five years such that only 1/5 = 20 % was such postoperatively. Conversely, none of the transtibial patients had local disuse osteoporosis preoperatively, and 3/4 = 75 % decreased bone density during the study period. The uniform association of transfemoral amputation with local disuse osteoporosis, and transtibial amputation without local disuse osteoporosis, was not planned, was not anticipated, and is remarkable. This situation meant that the tertiary aim (comparison of BMD in transfemoral versus transtibial amputees) ends up being exactly the same as the secondary aim. To emphasize, this was not by design or selection, but by coincidence. No patients required an implant removal. It is also important to emphasize that no patients sustained a periprosthetic fracture.

Lower extremity amputation negatively impacts bone density in many ways that are difficult to remediate. Mechanically loaded bone is prioritized for metabolic support whereas unloaded bone is gradually reabsorbed (Ruff et al., 2006). Therefore, many lower extremity amputees experience significant bone density loss (Ramírez et al., 2011). Bone loss is worse for patients with more proximal amputation (Sherk et al., 2008). Sometimes bone loss mainly occurs on the amputated side (Rush et al., 1994) but other times substantial loss occurs on both the amputated and intact sides (Flint et al., 2014). Patients who are more active in their socket prosthesis may slightly mitigate bone loss versus less active patients (Leclercq et al., 2003). Activity which loads the lower extremity improves bone density (Allison et al., 2015), but may not be achievable for socket prosthesis users because greater use often exacerbates skin ulceration and perspiration, and problems including fit trouble and poor perceived balance reduce prosthesis use (Koc et al., 2008; Meulenbelt et al., 2011; Yiğiter et al., 2002; Sahay et al., 2014; Sanders and Fatone, 2011). Because TOFA eliminates the socket, patients often achieve increased prosthesis wear time (Kunutsor et al., 2018; Hebert et al., 2017). Further, the osseointegrated implant directly loads the skeleton (Prochor and Sajewicz, 2018; Tomaszewski et al., 2010) rather than pushing the skin as a socket does. Such situations may better load the proximal bone and result in improved bone density.

However, despite TOFA being used clinically to reconstruct lower extremity amputees for over 30 years (Hoellwarth et al., 2022f; Hoellwarth et al., 2020b), only two human in vivo studies were identified reporting the effect on proximal femur bone density, both published in 2019. Hansen reported on 19 transfemoral amputees followed up to 30 months (Hansen et al., 2019). Those patients were reconstructed with a screw-type implant (different from the press-fit styles used in this study), which featured two surgical episodes at least six months apart during which patients were non-weight bearing. The study found that average Amputated Side proximal femur BMD started significantly worse than the Intact Side, then decreased 9 % between the two surgical episodes, and never recovered, eventually becoming significantly worse during the 30-month study period. The Intact Side did not significantly change BMD. This is notably different from our data, which found that the average intact side decreased BMD significantly whereas the Amputated Side increased, with the transfemoral level increasing significantly. That our patients' intact limb's BMD decreased whereas Hansen's patients' intact limb BMD remained similar may be related to an older average age in our cohort (58.0 ± 8.0 years: 57.8 ± 7.7 transfemoral vs 58.3 ± 9.5 transtibial) than theirs (47 ± 11.2, all transfemoral). Another difference was that 8/19 = 42 % of Hansen's patients had implant removal, whereas none of ours did, which could indicate less load transmission to those patients or less loading activity to begin with. One other study to investigate bone density was performed by Thomson, who evaluated the Z-score on Amputated and Intact sides of 48 patients treated with press-fit osseointegration (33 femur, 15 tibia) and followed up to three years. The current study includes some of those patients. Thomson found that Z-scores improved significantly for femur patients (though a femoral neck screw reduced the benefit) (Thomson et al., 2019a) whereas transtibial amputees' Z-scores did not significantly change. The Intact limb Z-scores did not significantly change.

What, then, may be the role of DXA in osseointegration screening or surveillance? At the moment, this seems hard to specify, given that there seems not to be a contraindication for TOFA based on BMD, and substantial limitations in data integrity following TOFA. Given the myriad difficulties and limitations of two-dimensional imaging to assess bone density, particularly in the context of limbs with atypical anatomy (amputees) and implants, quantitative computed tomography (QCT) may be necessary to discern reliable data (Whitmarsh et al., 2017). While QCT certainly exposes patients to more radiation, benefits include the ability to control for patient position by matching generated three dimensional models, the ability to measure cortical thickness along with cortical density, and the ability to assess both density and thickness at far greater granularity than with two-dimensional studies (Poole et al., 2012). Better calibration also overcomes the impact of patient clothing.

The role of pharmacologic optimization of bone density for osseointegration patients remains uncertain. Fundamental nutritional interventions such as a diet rich in protein, calcium, and vitamin D seem unlikely to pose a risk. A major question is whether to provide metabolic bone therapeutics to patients in the perioperative period. One potential benefit of bisphosphonates would be to prevent periprosthetic fracture. All reported periprosthetic osseointegration fractures have occurred as a result of traumatic injury and not spontaneously with routine loading or activity (Ranker et al., 2020; Hoellwarth and Rozbruch, 2022; Hoellwarth et al., 2020c), so as of yet no patient has had such low bone density as to result in atraumatic fracture, meaning this may not be a clinically relevant problem that needs remediation. A pre- or perioperative bisphosphonate would likely improve BMD at the femoral neck and possibly surrounding the implant. However, could reducing osteoclast function impair remodeling and bone-implant integration and lead to early failure to integrate or long term implant loosening? Bisphosphonate therapy has been demonstrated to not impair cementless total hip replacement stability (Aro et al., 2018), and may reduce overall revision rates following cementless hip and knee arthroplasty (Ro et al., 2019; Anderson et al., 2020). But arthroplasty results may not be directly translatable to TOFA, as biomechanics and biome are very different. For example, there is minimal tension pulling hip components out of bone whereas a prosthetic leg does exert a pullout force through the osseointegrated implant, which may explain the complete inappropriateness of bone cement for TOFA (Hoellwarth et al., 2020d) versus its general suitability for arthroplasty. Systemic bisphosphonates can also cause non-trivial side effects such as jaw osteonecrosis, so locally administered bisphosphonates may be another option to rapidly improve peri-implant bone density (Guimarães et al., 2017). Anabolic therapeutics such as parathyroid hormone analogs do improve microarchitecture, but there is a temporary period of increased porosity (Chen et al., 2007; Tsai et al., 2016), so if it is used it may be best to delay surgery until this period has passed. Limited studies of teriparatide and cementless arthroplasty suggest reduced subsidence without an increase of adverse events (Huang et al., 2016; Kaneko et al., 2016). Pharmacologic bone metabolism medication may indeed eventually prove valuable in the preoperative, perioperative, and/or long term postoperative period, if it can improve resilience against trauma-related fracture. Before experimenting with metabolic bone medication, it may be most responsible to better understand bone remodeling in the context of osseointegration with better designed in vivo human studies.

This study has limitations to recognize. The evaluated cohort was relatively small, at nine patients. This was substantially impacted by the restrictions on non-essential travel and medical resources in our country and others during and following COVID, which also impacted the ability for patients to access the same DXA machines. Further, both men and women were considered together, although the ages were relatively similar. The women's menopausal status was not known, though based on their ages it would be expected they are post-menopausal. A primary strength of this study is the relatively long follow-up of the patients, all with a minimum of five years post-TOFA, which is the longest for any TOFA study evaluating bone density. Another strength is the elucidation of the significant difference in local disuse osteoporosis among transfemoral vs transtibial amputees, and the related postoperative changes in bone density.

5. Conclusions

Over a period of at least five years, direct skeletal loading of amputated lower extremities via single-stage press-fit osseointegration results in significant improvements of bone density for patients with preoperative local disuse osteoporosis (which may be most transfemoral amputees), and non-significant improvements patients without local disuse osteoporosis (which may be most transtibial amputees). There does not appear to be a minimum BMD below which osseointegration should be contraindicated. The clinical utility of DXA in osseointegration remains uncertain. The most appropriate next steps prompted by this study may be to organize well designed long term investigations utilizing QCT to produce data with greater reliability for osseointegrated patients, who are relatively challenging to evaluate with traditional methods.

Grants or other financial support of this paper

None.

CRediT authorship contribution statement

Jason Shih Hoellwarth: Formal analysis, writing - original draft, writing - review and editing, submission approval, supervision, project administration.

Atiya Oomatia - investigation, writing - review and editing, submission approval.

Kevin Tetsworth - conceptualization, writing - original draft, writing - review and editing, submission approval.

Elisabeth Vrazas - conceptualization, investigation, writing - review and editing, submission approval.

Munjed Al Muderis - conceptualization, investigation, writing - review and editing, submission approval.

Declaration of competing interest

Munjed Al Muderis owns the rights and patents to the OPL implant system worldwide. No other authors have any relevant disclosures.

Acknowledgments

None.

Data availability

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Data Availability Statement

Some or all datasets generated during and/or analyzed during the current study are not publicly available but are available from the corresponding author on reasonable request.

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