Incidence of atypical femoral fractures in the treatment of bone metastasis: An alert report.

Introduction

Patients with bone metastasis are usually treated with bone-modifying agents (BMAs) such as zoledronate or denosumab to reduce the risk of skeletal-related events (e.g., pathological fracture and spinal cord compression), which require radiation therapy or orthopaedic surgery [1] , [2] , [3] , [4] , [5] . The life expectancy of cancer-bearing patients, even those with distant metastasis, has increased because of recent advances in cancer treatment [6] , and thus the frequency of treating cancer patients with bone metastasis is on the rise. These patients tend to receive long-term treatment with BMAs and are at risk of developing atypical femoral fracture (AFF) [7] , [8] , [9] , [10] .

AFFs are defined as diaphyseal femoral fractures with specific features, including the following major features: 1. association with low-energy trauma or no trauma; 2. transverse or oblique fractures originating from the lateral cortex; 3. complete fracture extending through both cortices or incomplete fracture involving only the lateral cortex; 4. noncomminuted or minimally comminuted; and 5. periosteal or endosteal thickening of the lateral cortex [11] . AFF is considered a multifactorial condition, and its pathogenesis is reported to involve certain drugs (e.g., bisphosphonates, denosumab, proton pump inhibitors, and glucocorticoids) [11] , [12] , [13] as well as certain diseases [14] , femoral morphology [15] , [16] , [17] , [18] , loading stress [17] , [18] , [19] , [20] , and bone fragility [21] , [22] . However, prolonged exposure to specific drugs including BMAs, which can suppress bone turnover, could be the most common etiology of AFF worldwide [12] , [13] , [23] , [24] , [25] , [26] .

Although higher and more frequent doses of BMAs are used in the treatment of bone metastasis in general compared with treatment of osteoporosis or osteopenia [1] , [2] , [3] , [4] , [5] , [27] , only a few studies have investigated the association between prolonged high-dose BMA use and AFF onset [28] , [29] , [30] . Also, there is inadequate clinical data on the risk of developing AFF in the treatment of bone metastasis using BMAs. In this study, we examined the incidence of AFF using a database for multidisciplinary treatment of bone metastasis in a single institution.

Patients and methods

Study design and setting

This study was conducted at a Japanese national university hospital with an established bone metastasis consultation system run by orthopaedic surgeons since April 2011. In this retrospective observational study, we reviewed the medical records of patients with bone metastasis who had been registered in the above consultation system from April 2011 through October 2019 at one high-volume multidisciplinary cancer research institute in Japan. This institute registers about 2600 new cancer patients annually.

Patient demographics

During the study period, 721 patients with bone metastasis (436 men, 285 women; age at registration, mean 65.7 ± standard deviation 12.4 years) were entered into the database. Primary cancer types are shown in Table 1 . Lung cancer ( n = 155, 21.5%) was the most common, followed by breast cancer ( n = 78, 10.8%) and prostate cancer ( n = 68, 9.4%). Others ( n = 31) were uterine cancer, uterine sarcoma, ovarian cancer, testicular cancer, adrenal cancer, malignant pleural mesothelioma, thymic carcinoma, thymic carcinoid, angiosarcoma, hemangiopericytoma, leiomyosarcoma, malignant insulinoma, duodenal cancer, and small intestinal cancer (each <1%). It should be noted that the bone metastasis consultation system in this study has no strict consultation criteria or protocol, and that patients are referred to the orthopaedic department at the discretion of the primary physician after a diagnosis of bone metastasis.

Bone-modifying agents

Using the pharmacy database at our institution, we examined the administration and type of BMAs used for all 721 registered patients during follow-up for bone metastasis. Receipt of zoledronate and/or denosumab for treatment of bone metastasis according to the judgement of the attending clinician was regarded as BMA use. The administration of these drugs for other purposes (e.g., osteoporosis) was excluded from BMA use.

Skeletal-related events

From the database of our bone metastasis consultation system, we evaluated patients who underwent orthopaedic surgery for skeletal-related events. To assess the occurrence of AFF, we categorized these surgeries into two: surgery involving the femur and others.

Among patients who required surgical intervention involving the femur, we extracted and investigated patients with AFF. The case definition of AFF was in accordance with the revised diagnostic criteria for AFF published by the American Society for Bone and Mineral Research Task Force in 2014 [11] . Then, we examined the clinical characteristics of patients with AFFs; primary cancer type, sites of bone metastasis, history of BMA use at AFF onset, fracture type using AO Foundation/Orthopaedic Trauma Association (AO/OTA) classification, fracture location, bilaterality, surgical procedure for AFF, and bone healing after surgery.

Results

Bone-modifying agents

Among the registered 721 patients with bone metastasis, 529 patients (73.4%) had received BMAs for treatment of bone metastasis ( Table 2 ). Zoledronate (intravenous; 4 mg) was administered to 199 (27.6%), denosumab (subcutaneous; 120 mg or 60 mg) was administered to 401 (55.6%), and both agents were administered to 71 (9.8%) patients. In most patients who had been exposed to both drugs, BMA use was switched from zoledronate to denosumab. No patient received zoledronate for purposes other than treatment of bone metastasis, and only 2 of all 721 patients received only a single dose of low-dose (60 mg) denosumab for other therapeutic indications, such as osteoporosis. In 401 patients who received denosumab for treatment of bone metastasis, high-dose (120 mg) denosumab was generally injected every 4 weeks.

Skeletal-related events

Among all 721 patients registered in our bone metastasis consultation system, orthopaedic surgery for skeletal-related events was performed in 36 patients (5.0%): femur, 13 (1.8%) and others, 23 (3.2%). Surgical sites other than the femur were the spine ( n = 17, 2.4%), humerus ( n = 4, 0.6%), and pelvis ( n = 2, 0.3%).

Incidence and clinical characteristics of AFF

Among 13 patients who underwent surgical intervention involving the femur, 5 patients (1 man and 4 women) had 8 AFFs ( Table 3 ). Primary cancer type was breast cancer in all 4 female patients, and prostate cancer in the 1 male patient. All 5 patients with AFF had a history of BMA use (>6 years, n = 3; 4.5 years, n = 1; 1.5 years, n = 1) for treatment of bone metastasis. In 192 patients who had not been exposed to BMAs in this survey, critical (surgically treated) AFF was not detected. Thus, the incidence of critical AFF was 0.9% in 529 patients who received BMAs for bone metastasis. Notably, the incidence was 6.6% in BMA-exposed patients with breast cancer (4 of 61). Surgical treatment using anterograde intramedullary nailing was required for all 8 AFFs (complete, 5; incomplete, 3) in the 5 patients ( Fig. 1 , Fig. 2 ). All 5 complete AFFs were definitively classified as simple fracture (AO/OTA classification 32A), and clinical bone union was achieved in all cases. No implant breakage was seen in any of the 8 AFFs during follow-up.

Discussion

In the treatment of patients with bone metastasis, especially those with longer life expectancy who are receiving BMAs, AFF can occur and the incidence cannot be ignored. In this study, we reviewed over 500 cancer patients with BMA use for bone metastasis treatment and demonstrated a high incidence of critical (surgically treated) AFF: 0.9%. The annual incidence rate (in 2012) of hip fracture in Japan was reported as 6.10 per 10,000 population [31] , and the incidence of AFF accounted for 0.5% of all hip fractures [32] . In the context of AFF in patients with bone metastasis, some reports have described varying incidence. Puhaindran et al. reviewed 327 patients with intravenous bisphosphonate use (>24 doses) for bone metastasis and reported the incidence of subtrochanteric AFF as 1.2% (4/327) [33] . Edwards et al. reported 23 AFF cases (clinical, 14; subclinical, 9) out of 10,587 patients who had been exposed to bisphosphonates for bone metastasis (total dosing period, 4482 years), and estimated the incidence as 0.05 per 100,000 person-years [34] . In recent years, several studies have focused on the association between denosumab use and AFF in patients with bone metastasis. A multi-center retrospective study conducted in Japan revealed 5 clinical AFF cases among 277 patients with denosumab use for bone metastasis (incidence, 1.8%) [28] . In that report, 4 of the patients with AFF had primary breast cancer and been exposed to zoledronate and subsequent denosumab (>45 doses) [28] . In a retrospective imaging review, the incidence of AFF associated with denosumab use for treatment of bone metastasis was reported as 0.4% (clinical, 1/253) and 4.5% (subclinical, 3/66) [29] . Although there was selection bias because of the retrospective analysis using available images in only 66 patients [29] , the high incidence of asymptomatic AFF (4.5%) suggests that more patients with subclinical AFF might be missed in daily practice for bone metastasis.

In this study, we identified critical (surgically treated) AFF in 4 of 61 patients with breast cancer who received BMAs (incidence of critical AFF, 6.6%). Previous reports indicated that most patients with AFF had breast cancer; followed by prostate cancer, myeloma, and other cancer [28] , [29] , [33] , [34] , consistent with our results. In contrast, none of the 155 patients with lung cancer, the most common cancer type in this study, developed AFF. Although AFF has been reported in 2 patients with non-small cell lung carcinoma, both were cases of double cancers, namely, breast cancer and non-small cell lung carcinoma; one had a prior history of bisphosphonate use for osteoporosis and the other had bone metastasis from primary breast cancer [29] , [35] . Thus, to our knowledge, there has been no report of AFF in patients with single primary lung cancer. A population-based registry of cancer statistics in Japan reports the 5-year survival rate (initial diagnosis, 2006–2008) of lung cancer to be 31.9%, whereas that of breast and prostate cancer was 91.1% and 97.5%, respectively [6] . Furthermore, when limited to patients with distant metastasis, the 5-year survival rate of lung cancer was 4.9%, whereas that of breast and prostate cancer was 33.7% and 49.1%, respectively [6] . These data demonstrate that patients with breast or prostate cancer tend to have longer life expectancy, and thus more prolonged exposure to BMAs, than those with lung cancer. This might result in higher incidence of AFF in patients with breast or prostate cancer. However, because the 5-year survival rate in almost all cancer types including lung cancer is gradually improving in recent years [6] , it might be necessary to pay more attention to the development of AFF in patients with other cancer previously regarded as low risk. Thus, routine radiographic screening for the development of AFF might be necessary in patients with long-term (e.g., >2–3 years) exposure to BMAs for bone metastasis, even if asymptomatic.

AFF in patients with bone metastasis may not be complicated by nonunion. AFF is often reported to be at high risk of delayed bone healing [11] , [36] , [37] , [38] , [39] , [40] , [41] , especially in cases with subtrochanteric AFF associated with bone turnover suppression due to specific drugs (e.g., bisphosphonates) [42] . Meanwhile, this report has some discrepancies compared with previous knowledge, including multiple sites in both the subtrochanteric and mid-shaft regions; and non-suppressed biological activity, which induced early clinical bone healing without implant failure via breakage. Although these clinical pictures might be due to the patients’ peculiar bone metabolism or oncologic use of BMAs, this issue requires further investigation.

Although long-term BMA use might lead to AFF in patients with bone metastasis, BMAs do have benefits in reducing the risk of serious skeletal-related events [1] , [2] , [3] , [4] , [5] . A randomized controlled trial in Japanese female patients with bone metastases from breast cancer indicated that zoledronate could reduce the rate of skeletal-related events by 39% [2] . Furthermore, Martin et al. [3] and Henry et al. [5] reported that, compared with zoledronate, denosumab had significantly greater therapeutic effects on skeletal-related events in patients with bone metastases. In addition, regarding bisphosphonate use in the treatment of osteoporosis, the benefits of preventing fragility hip fractures far outweigh the risk of developing AFF [43] . Although bisphosphonates are predominantly used at higher doses for the treatment of bone metastasis than that for the treatment of osteoporosis, Puhaindran et al. demonstrated no significant difference in drug dose or duration between cancer patients who had subtrochanteric AFFs and those who did not [33] . However, the unexpected onset of complete AFF undoubtedly causes drastically diminished activities of daily living (ADL). In this study, case 4 involved impending AFF with an ideal surgical intervention by the orthopaedic surgeon, which contributed to maintaining ADL and quality of life (QOL) in this patient. Further analyses with a larger number of patients is required in order to devise a protocol for monitoring and detecting asymptomatic incomplete AFF in the early stage and for determining the optimal surgical treatment to prevent complete AFF in multidisciplinary treatment of bone metastasis.

This study has several limitations. First, this is a retrospective study and the regimen of BMAs for treatment of bone metastasis was not standardized. There was also selection bias at registration in this bone metastasis consultation system. Not all cancer patients with bone metastasis were registered throughout the study period. Second, we were unable to carry out a detailed review of the duration and timing of BMA use. Also, we were unable to investigate the administration of other bisphosphonates (for purposes other than treatment of bone metastasis) except zoledronate. Third, we could not review the follow-up period of registered patients, so we did not investigate differences in life expectancy for each primary cancer. Fourth, we were able to extract only those patients who underwent orthopaedic surgery at our hospital and it is possible that asymptomatic AFF cases could have been missed or that some patients might have undergone internal fixation for AFF at local hospitals other than our institution.

Conclusions

In this study, we demonstrated the credible incidence of critical (surgically treated) AFF in the context of a multidisciplinary bone metastasis consultation system in a Japanese national university hospital, and this frequency cannot be ignored. The current prolonged life expectancy of cancer patients is associated with a marked increase of BMA use. AFF should be recognized as a side effect of BMA use, and more attention should be paid to the risk of developing AFF especially in BMA-exposed patients with breast cancer. Early diagnosis and surgical treatment of AFF is important for preventing diminished ADL and QOL. Therefore, routine radiographic screening for the development of AFF should be considered in patients with long-term exposure to BMAs for bone metastasis, even if asymptomatic.

Ethics

This study was approved by the institutional review board, and opt-out consent was obtained from patients involved in this study. All procedures involving human participants were performed in accordance with the ethical standards of the relevant institutional and/or national research committees and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards. The data were fully anonymized, thereby protecting the patients’ privacy and dignity.

Conflicts of interest

The department to which the corresponding (YO) and fourth author (HK) belong has received funding for operating costs from Saku Central Hospital of the Nagano Prefectural Federation of Agricultural Cooperatives for Health and Welfare, Suwa Central Hospital, Doujin Hospital, Medtronic Sofamor Danek Co., Ltd., Stryker Japan Co. Ltd., and HOYA Technosurgical Co., Ltd. The other authors declare that they have no conflicts of interest.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Takumi Kaku: Conceptualization, Data curation, Formal analysis, Investigation, Visualization, Writing - original draft, Writing - review & editing. Yoto Oh: Conceptualization, Data curation, Investigation, Methodology, Project administration, Validation, Visualization, Writing - original draft, Writing - review & editing. Shingo Sato: Conceptualization, Data curation, Investigation, Methodology, Project administration, Writing - original draft, Writing - review & editing. Hirotaka Koyanagi: Conceptualization, Data curation, Investigation, Writing - review & editing. Takashi Hirai: Conceptualization, Investigation, Writing - review & editing. Masato Yuasa: Conceptualization, Investigation, Writing - review & editing. Toshitaka Yoshii: Conceptualization, Supervision, Writing - review & editing. Tsuyoshi Nakagawa: Conceptualization, Investigation, Resources. Satoshi Miyake: Conceptualization, Project administration, Resources, Supervision. Atsushi Okawa: Conceptualization, Methodology, Project administration, Resources, Supervision, Writing - review & editing.

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