Conservative Treatment With Teriparatide for Symptomatic Incomplete Atypical Femoral Fractures: A Retrospective Observational Study

Abstract

Introduction

Prophylactic surgery for symptomatic incomplete atypical femoral fractures (SIAFFs) has demonstrated favorable outcomes. However, concerns remain regarding surgical intervention for a fracture that has not yet completed. This retrospective study aimed to evaluate the efficacy of conservative treatment using teriparatide (TPTD) as a conservative treatment for SIAFF.

Methods

This retrospective study reviewed 30 cases with SIAFF who underwent conservative treatment between November 2012 and September 2019. The diagnosis of SIAFF was based on the criteria established by the Task Force of the American Society for Bone and Mineral Research(ASBMR). The treatment protocol included (1) discontinuation of bisphosphonates, (2) use of 2 crutches or a four-point walker, (3) daily subcutaneous TPTD injection until pain subsided, and (4) monthly radiographic follow-up. Radiographs and bone scans were used to assess bone union, and follow-up continued for up to 2 years from protocol initiation. Comparisons between the successful and failed treatment groups were performed using the Student’s t-test for continuous variables and Fisher’s exact test for categorical variables.

Results

The mean age was 72.6 years (range, 55-87) and all patients were female. 13 cases involved the diaphyseal region and 17 involved the subtrochanteric region. The average duration of TPTD treatment was 6.5 months (range, 3-12), and the average follow-up was 45.5 months (range, 19-84) after the final injection. The mean SIAFF severity score was 9.5 (range, 7-11). Symptom-free bone union was achieved in 23 of 30 cases (76.7%). Five cases (4 with worsening pain, 1 with radiographic progression) underwent prophylactic intramedullary nailing, and 2 cases progressed to complete fracture and were treated with intramedullary nailing.

Conclusion

The result of this study suggests that the conservative treatment with teriparatide injection may be a potentially effective option for patients with SIAFF.

Introduction

Bisphosphonates (BPs) are widely used in the treatment of osteoporosis, as they increase bone density and significantly reduce the risk of fractures. ¹ However, long-term BP use has been associated with the development of atypical femoral fractures (AFFs), which are characterized as low-energy or non-traumatic fractures.^2,3 It is hypothesized that suppressed bone turnover resulting from prolonged BP use leads to accumulation of microdamage and delayed fracture healing, contributing to the pathogenesis of AFFs. ⁴

Teriparatide (TPTD), an anabolic agent that stimulates bone remodeling, has been reported to be beneficial in the treatment of AFFs.^5-9 It has been proposed as a safe therapeutic option for promoting fracture healing in AFF patients. ² Murphy et al ¹⁰ demonstrated in a rat model that TPTD could counteract BP-induced suppression of bone turnover, thereby providing a potential mechanism for its therapeutic effects. While several studies have explored TPTD as a conservative treatment for AFFs, most are retrospective or small-scale prospective studies, and very few have used TPTD consistently in all patients. ¹¹ Furthermore, the efficacy of anabolic agents in enhancing the healing of AFFs remains unclear.

Since the first report by Odvina et al in 2005, ¹² no definitive treatment guidelines have been established for the full spectrum of AFFs. One of the most debated issues is the optimal treatment of symptomatic incomplete atypical femoral fractures (SIAFFs), which are incomplete fractures with the potential to progress to complete fractures.^13,14 To predict this progression, Min et al ¹⁵ proposed a scoring system that has been utilized in clinical practice. The choice between prophylactic surgery and conservative treatment remains controversial. Although prophylactic intramedullary (IM) nailing has shown favorable outcomes,^13,16 concerns persist regarding the necessity and risk of surgically treating a fracture that has not yet completed.

Considering these concerns, some authors have explored the used of conservative treatment with TPTD in patients who refuse or are not candidates for prophylactic surgery. The purpose of this study is to evaluate the efficacy and safety of TPTD-based conservative treatment for SIAFFs.

Materials and Methods

Patients Selection

This retrospective study was approved by the Institutional Review Board of our institution. The requirement for informed consent was waived due to the retrospective nature of the study. We reviewed the medical records and radiological images of 30 cases diagnosed with SIAFFs who received conservative treatment at a single tertiary medical institution from November 2012 to November 2019. Inclusion criteria were patients diagnosed with SIAFFs during this period who were managed with TPTD. Exclusion criteria included patients with complete atypical femoral fractures, patients with a history of prior TPTD treatment, or those with insufficient follow-up (<12 months). Patients who were initially offered prophylactic surgery without an initial trial of conservative treatment were excluded from this study. The diagnosis of SIAFF was based on the criteria defined by the Task Force of the American Society for Bone and Mineral Research(ASBMR)^2,3: (1) fracture located along the diaphysis, from just distal to the lesser trochanter to just proximal to the supracondylar flare; (2) minimal or no trauma; (3) transverse fracture line or localized periosteal reaction involving only the lateral cortex; and (4) noncomminuted or minimally comminuted configuration. Additionally, clinical criteria included weight-bearing pain or localized tenderness and a corresponding hot uptake on bone scan. The mean interval from symptom onset to diagnosis was 5 weeks (range 1-10). Bone mineral density (BMD) was evaluated using Dual-energy X-ray absorptiometry (DXA) at the lumbar spine and total hip. The study protocol was approved by the Institutional Review Board (IRB).

Conservative Treatment Protocol

The standardized treatment protocol consisted of (1) immediate discontinuation of bisphosphonates, (2) strict use of a 2 crutches or a four-point walker, (3) daily subcutaneous injection of TPTD (Fosteo, Eli Lilly and Company, Indianapolis, IN, USA) at a dose of 20 μg/day until pain subsided, (4) monthly follow-up radiographs, and (5) a follow-up bone scan to evaluate lesion activity upon radiographic evidence of bone union. Adherence to conservative treatment protocol was confirmed through patient interviews at each monthly follow-up visit. Considering that many patients were elderly, we also provided thorough education to their caregivers who accompanied them to ensure strict compliance with the treatment protocol (Table 1).

Table 1.

Conservative Treatment Protocol

1	Immediate discontinuation of bisphosphonates
2	Continual use of 2 crutches or four-point walker
3	Teriparatide injections (forsteo, eli lilly and Co, Indianapolis, IN, USA) of 20mcg/d subcutaneously until pain relief was obtained
4	Monthly follow-up radiographs
5	Follow-up bone scans when bony union was radiographically identified

Clinical and Radiological Outcome Assessment

Clinical data were collected for each patient, including age, sex, height, weight, body mass index (BMI), follow-up duration, BP use and type, BP treatment duration, TPTD use, and TPTD treatment duration. Outpatient follow-up was conducted every 4 weeks. Clinical union was defined as the resolution of weight-bearing pain and localized tenderness.

Radiologic assessment was based on anteroposterior and lateral femoral radiographs. Fracture location (subtrochanteric or diaphyseal) and the presence of radiolucent lines were recorded. The risk of progression to complete fracture was evaluated using scoring system proposed by Min et al ¹⁵ Radiological union was defined as disappearance of the fracture line on serial radiographs, ⁶ and the resolution of increased uptake on follow-up bone scans. Two authors evaluated all radiographs and applied the scoring system. Inter- and intra-observer agreement showed near-perfect reliability, with 95% confidence intervals.

Conservative Treatment Outcome Analysis

Patients were stratified into 2 groups based on the outcome of conservative treatment with TPTD: a failed group, which included cases that progressed to complete fracture or required prophylactic surgical intervention, and a successful group, which achieved symptom-free bone union without the need for surgery. The primary outcome measures were radiological and clinical union, while secondary outcome measures included TPTD treatment duration and treatment failure, defined as progression to complete fracture or the need for prophylactic surgery. Clinical and radiological variables were compared between the 2 groups, including age, BMI, score, follow-up duration, bisphosphonate treatment duration, TPTD treatment duration, total hip and lumbar spine BMD T-scores, type of bisphosphonate, presence of radiolucent lines, and fracture location.

Statistical Analysis

All statistical analyses were performed using IBM SPSS Statistics version 22.0 (IBM Corp., Armonk, NY, USA). A P-value of <0.05 was considered statistically significant. Means and standard deviations are reported for normal continuous data. The Shapiro-Wilk test was used to test the data for normality. Comparisons between the groups were made using the two-tailed Student’s t-test for continuous variables and the Fisher’s exact test for categorical variables. No missing data were identified in the dataset.

Results

All patients were female, with a mean age of 72.6 years (range, 55-87) and a mean BMI of 24.3 kg/m² (range, 17.8-38.0). The mean spine BMD T-score at the time of diagnosis was −2.9 (range, −4.8-0.7), and the mean total hip BMD T-score was −1.9 (range, −3.5-0.2). There were 13 diaphyseal fractures and 17 subtrochanteric fractures. The mean duration of BP therapy was 5.3 years (range, 1-20) excluding one BP-naïve case. The most commonly used BPs were alendronate, followed by ibandronate, and risedronate. The mean follow-up duration was 45.5 months (range, 19-84).

All patients received TPTD, with a mean treatment duration of 6.5 months (range, 3-12). According to the scoring system proposed by Min et al, ¹⁵ the mean score was 9.4 (range, 7-11). Twenty-three cases achieved symptom-free recovery, and TPTD injections were subsequently discontinued. Two cases progressed to complete fractures—one located in the subtrochanteric region and the other in the diaphyseal region. Four cases with worsening weight-bearing pain and one case with radiographic progression discontinued conservative treatment and underwent prophylactic IM nailing. Overall, 23 of the 30 cases (76.7%) achieved symptom-free bone union after a minimum follow-up period of 18 months. One patient experienced symptom recurrence 5 years after initial union and subsequently underwent prophylactic IM nailing (Figure 1).

Figure 1.

Treatment Outcome of Symptomatic Incomplete Atypical Femoral Fractures

Comparison Between Failed and Successful TPTD Treatment Group

A total of seven cases required surgical treatment. The comparison of clinical and radiological variables between the failed and successful TPTD treatment group is summarized in Table 2. The mean age in the failed group was significantly higher than in the successful group (79.6 ± 5.6 vs 70.4 ± 7.0 years, P = 0.004). The duration of TPTD treatment was also significantly longer in the failed group compared to the successful group (8.6 ± 3.6 months vs 5.9 ± 2.2, P = 0.022). The mean total hip BMD T-score was significantly lower in the failed group (−2.8 ± 0.8) than in the successful group (−1.5 ± 1.0, P = 0.006). For all other variables, including BMI, Min score, lumbar spine T-score, and fracture location, there were no statistically significant differences between the 2 groups. All seven patients in the failed group had a visible radiolucent line on plain radiographs and a Min score greater than 8.

Table 2.

Comparison Between Failed TPTD Treatment Group and Successful TPTD Treatment Group

Variable	Failed TPTD treatment (N = 7)	Successful TPTD treatment (N = 23)	P value
Age	79.6 ± 5.66	70.4 ± 7.0	0.004 a
BMI	23.6 ± 4.3	24.5 ± 3.8	0.618 a
Score b	9.9 ± 0.9	9.2 ± 1.3	0.241 a
Follow-up duration(months)	42.3 ± 12.0	46.4 ± 15.7	0.528 a
BP treatment duration(months)	56.3 ± 38.6	65.2 ± 54.1	0.691 a
TPTD treatment duration(months)	8.6 ± 3.6	5.9 ± 2.2	0.022 a
Total hip BMD T-score	−2.8 ± 0.8	−1.5 ± 1.0	0.006 a
Lumbar BMD T-score	−3.4 ± 1.1	−2.7 ± 1.2	0.184 a
Type of BP
BP Naïve	0	1
Alendronate	3	12
Ibandronate	3	7	0.879 c
Risedronate	1	3
Radiolucent line (yes/no)	7/0	16/7	0.154 c
Scoring system (>8/≤8) b	7/0	14/9	0.071 c
Fracture location (subtrochanteric/diaphyseal)	4/3	13/10	1.000 c

^aStudent’s t-test.

^bMin et al.⁽¹⁵⁾They recommended prophylactic surgery if the score exceeds eight.

^cFisher’s exact test.

Discussion

This study aimed to evaluate the efficacy of conservative treatment with TPTD in patients with SIAFF. We found that symptom-free bone union was achieved in 76.7% of patients managed conservatively with TPTD, while 23.3% required surgical fixation. These findings suggest that TPTD-based conservative therapy may be an effective treatment option.

A. Koh et al ¹³ conducted a systematic review of 834 atypical fractures, including 159 incomplete fractures managed conservatively and 119 treated with prophylactic surgery. In the surgical group, 97% of the 106 fractures achieved bone union. In contrast, among the conservative group, 45% healed spontaneously, 20% progressed to complete fracture, 27% required surgery due to intractable pain, and 8% failed to heal during follow-up. Based on these findings, the authors concluded that conservative treatment alone may not be a reliable approach for incomplete AFF, especially in cases accompanied by persistent pain. However, the conservative protocols varied across studies, and only 39 fractures in the review received TPTD therapy. Furthermore, Saleh et al ⁸ was the only study in which all patients received TPTD, though the sample size was limited to just 9 cases.

TPTD has been proposed as a conservative treatment for patients with SIAFF.^6-10,17 However, few clinical studies have used TPTD in SIAFF treatment. In 2020, Van de Laarschot et al ¹¹ published a systematic review that included 31 case reports, 9 retrospective studies, and 3 prospective studies involving TPTD treatment for AFFs. None of the studies were randomized controlled trials. Among the prospective studies, only 8 cases were conservatively managed SIAFFs. When data from all studies were combined, a total of 165 AFF cases received TPTD, with 96% being female. Of the 30 incomplete AFFs treated with TPTD, 17 (56%) achieved union, and 4 (13%) progressed to complete fracture.

Chiang et al ⁶ reported that TPTD increased bone remodeling and promoted healing in AFF patients in a prospective study. In their series, all 4 SIAFF patients treated with TPTD achieved pain relief and union. In a retrospective study by Lee et al. ⁹ 65 SIAFF cases were treated conservatively; 31 hips (47.7%) progressed to complete fracture or intractable pain requiring surgery. Among the 26 surgically treated patients, only 7 (26.9%) had received TPTD. The authors found no statistically significant correlation between TPTD use and a reduced need for surgical fixation.

Miyakoshi et al ⁷ reported on eight SIAFF patients treated conservatively, 5 of whom received TPTD. All eight cases achieved bone union. Saleh et al ⁸ investigated 14 SIAFFs, all treated with TPTD. Among the 5 fractures without a radiolucent fracture line, all these fractures achieved bone union. Among the 9 patients with a radiolucent fracture line, only 2 fractures were treated successfully with conservative treatment, while seven underwent prophylactic surgery after 3 months of conservative treatment. Their findings suggest that radiographic fracture penetration is a predictor of conservative treatment failure within 3 months.

Min et al ¹⁵ studied 46 SIAFFs and reported that 13 cases (28.3%) progressed to complete fracture within 6 months. They recommended prophylactic surgery for cases with a score greater than 8 points. Notably, TPTD was used in only 2 of the 46 cases. In contrast, our study included 30 SIAFFs, all treated conservatively with TPTD, with a mean score of 9.37 (range, 7-11). Despite the high scores, only 2 cases progressed to complete fracture, and 23 (76.7%) achieved asymptomatic union.

Although TPTD has been investigated for conservative treatment in SIAFF, most studies are limited by small sample sizes and inconsistent treatment protocols. Very few studies used TPTD uniformly in all patients. Furthermore, in studies recommending prophylactic surgery, the conservative treatment groups rarely used TPTD, making it difficult to isolate its effects.^9,11,13,18

Our study evaluated conservative TPTD treatment in 30 SIAFFs who declined prophylactic surgery. All patients followed a uniform protocol and were monitored using bone scans to assess healing. The mean treatment duration was 6.7 months (range, 3-12), and at a minimum follow-up of 18 months, 23 cases (76.7%) achieved asymptomatic union. These results are comparable to those of Saleh et al. ⁸⁾ who reported successful outcomes with conservative TPTD therapy over 3 months.

Moreover, our findings showed a higher union rate and lower complete fracture rate than previously reported conservative treatments, when patients strictly follow the protocol suggested by A. Koh et al ¹³ These outcomes suggest that conservative treatment with TPTD may be a viable option for patients unwilling or unfit to undergo prophylactic surgery.

In subgroup analyses, patients were stratified into a failed TPTD treatment group, which included those who progressed to complete fracture or required surgical intervention, and a successful TPTD treatment group, which consisted of patients who achieved bone union without surgery. All patients in the failed group exhibited radiolucent lines and Min scores greater than 8, supporting previous findings that these are significant risk factors.^8,15 When comparing the presence of a radiolucent line alone, no statistically significant difference was observed between the 2 groups. However, when using Min’s scoring system—which incorporates radiolucent line along with other parameters including subtrochanteric involvement, severity of pain, status of the contralateral femur, and the extent of the radiolucent line—a borderline significance (P = 0.071) was noted. Min et al also reported that combining these variables yielded the highest area under the curve of the ROC curve compared with any single variable. Therefore, a Min’s score of 8 or less may indicate suitable candidates for conservative treatment with TPTD.

Additionally, failed group showed lower total hip BMD T-scores than successful group. Watts et al ¹⁹ found that while lumbar spine BMD improved after 12 and 24 months of TPTD, total hip BMD showed no meaningful improvement, suggesting that TPTD may be less effective in improving femoral BMD. This highlights the need for caution in patients with initially low total hip BMD. Interestingly, successful group had shorter TPTD treatment durations than failed group, indicating that a more rapid response to TPTD may improve the outcomes and reduce the treatment periods. Advanced age was also correlated with failed TPTD treatment, emphasizing the need for careful monitoring and timely decision-making in elderly patients.

Ramchand et al ²⁰ reported a case of recurrent bilateral AFF in a patient who had achieved bone union with TPTD but later developed new fractures after 6 months of denosumab therapy. Similarly, our study documented one case of SIAFF recurrence 5 years after initial bone union, requiring prophylactic surgery. These findings underscore the potential for late recurrence, warranting continued long-term follow-up.

All our patients were female, which may be attributed to the fact that osteoporosis is one of the female-dominant disease with a 96% (92.9-100%) female predominance in other AFF studies, ⁸ reflecting the epidemiological characteristics of AFF.

This study has several limitations. First, as a retrospective study, it relied on medical records, which may introduce selection or reporting bias. In addition, due to the observational nature of this study and absence of a control group, causality cannot be established. However, SIAFF is a rare condition, no randomized controlled trials have yet been conducted, and it is challenging to perform a prospective study with an adequately large sample size. Therefore, in this study, we included all eligible patients identified at our single institution to minimize the risk of missing cases. Second, no follow-up assessments of bone turnover markers or BMD were performed during treatment due to insurance restrictions in Korea, which only allow BMD once annually. Third, all patients in this study were Asian women, which represents a major limitation as it restricts the generalizability of our findings to other populations. However, previous studies have reported that Asian women, particularly those with lateral femoral bowing, have a substantially higher risk of atypical femoral fractures.^16,21,22 Lo et al demonstrated that the rate of AFF was eightfold higher among Asian women than among White women (64.2 vs 7.6 per 100 000 person-years). Although the absolute incidence remains low, the relatively higher risk among Asian women allows for the accumulation of larger cohorts within this demographic. Accordingly, this study represents one of the largest cohorts of SIAFF patients uniformly treated with TPTD and provides meaningful insight into the potential efficacy of conservative management in this rare patient population. Nevertheless, despite being one of the largest cohorts reported to date, the overall sample size remains limited. Therefore, further large-scale, multicenter studies are required to confirm and generalize our findings.

In Korea, the use of teriparatide is subject to strict reimbursement criteria under the National Health Insurance system, and most patients are required to pay the full cost out-of-pocket. Given its high cost and limited accessibility, the clinical application of teriparatide should take into account not only its potential efficacy but also socioeconomic feasibility. Broader insurance coverage and cost reduction would be needed to facilitate its use as a conservative treatment option for atypical femoral fractures.

Conclusion

This study suggests that conservative treatment with teriparatide injections may be an effective therapeutic option for patients with symptomatic incomplete atypical femoral fractures. When patients strictly adhere to the treatment protocol, the risk of progression to a complete fracture appears to be lower than previously reported. Prophylactic intramedullary nailing may be reserved for patients who are unable to complete to this conservative treatment strategy.