Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review

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Abstract

Background

While denosumab has been shown to prevent skeletal-related events in patients with bone metastasis, there is a concern that it may cause atypical femoral fracture (AFF). While AFF has been reported in patients with osteoporosis receiving denosumab, data are scarce in the context of AFF occurring in patients with bone metastasis receiving monthly denosumab therapy.

Methods

To analyze the incidence of AFF in patients with bone metastasis, we reviewed the medical records of patients who had received monthly denosumab (120 mg) treatment from May 2012 to June 2017 at any of the three participant institutions.

Results

The study population consisted of 277 patients who had received a median of 10 doses (range, 1–79) of denosumab. Five patients were diagnosed as having AFF or symptomatic atypical femoral stress reaction (AFSR) needing surgical intervention, representing an incidence rate of 1.8% (95% confidence interval, 0.77–4.2). These patients had received 15, 45, 45, 46 or 47 doses of denosumab, respectively. Four of the patients had received prior zoledronic acid treatment. The results of our analysis suggested that long-term use of denosumab, especially for more than 3.5 years, and prior use of zoledronic acid were risk factors for the development of AFF.

Conclusions

We found the AFF events in 5 patients (1.8%) among 277 cancer patients who had received monthly denosumab (120 mg) treatment. Long-term denosumab treatment and prior zoledronic acid treatment were identified as risk factors for the development of AFF.

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Most cited references 23

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Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research.

Elizabeth Shane, David Burr, Bo Abrahamsen … (2014)

Bisphosphonates (BPs) and denosumab reduce the risk of spine and nonspine fractures. Atypical femur fractures (AFFs) located in the subtrochanteric region and diaphysis of the femur have been reported in patients taking BPs and in patients on denosumab, but they also occur in patients with no exposure to these drugs. In this report, we review studies on the epidemiology, pathogenesis, and medical management of AFFs, published since 2010. This newer evidence suggests that AFFs are stress or insufficiency fractures. The original case definition was revised to highlight radiographic features that distinguish AFFs from ordinary osteoporotic femoral diaphyseal fractures and to provide guidance on the importance of their transverse orientation. The requirement that fractures be noncomminuted was relaxed to include minimal comminution. The periosteal stress reaction at the fracture site was changed from a minor to a major feature. The association with specific diseases and drug exposures was removed from the minor features, because it was considered that these associations should be sought rather than be included in the case definition. Studies with radiographic review consistently report significant associations between AFFs and BP use, although the strength of associations and magnitude of effect vary. Although the relative risk of patients with AFFs taking BPs is high, the absolute risk of AFFs in patients on BPs is low, ranging from 3.2 to 50 cases per 100,000 person-years. However, long-term use may be associated with higher risk (∼100 per 100,000 person-years). BPs localize in areas that are developing stress fractures; suppression of targeted intracortical remodeling at the site of an AFF could impair the processes by which stress fractures normally heal. When BPs are stopped, risk of an AFF may decline. Lower limb geometry and Asian ethnicity may contribute to the risk of AFFs. There is inconsistent evidence that teriparatide may advance healing of AFFs.

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Severely suppressed bone turnover: a potential complication of alendronate therapy.

Clarita V Odvina, Joseph Zerwekh, D Sudhaker Rao … (2005)

Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.

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Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.

Lara Lipton, Shu-Huei Wang, Sara Henry … (2012)

Denosumab, a fully human anti-RANKL monoclonal antibody, reduces the incidence of skeletal-related events in patients with bone metastases from solid tumors. We present survival data for the subset of patients with lung cancer, participating in the phase 3 trial of denosumab versus zoledronic acid (ZA) in the treatment of bone metastases from solid tumors (except breast or prostate) or multiple myeloma. Patients were randomized 1:1 to receive monthly subcutaneous denosumab 120 mg or intravenous ZA 4 mg. An exploratory analysis, using Kaplan-Meier estimates and proportional hazards models, was performed for overall survival among patients with non-small-cell lung cancer (NSCLC) and SCLC. Denosumab was associated with improved median overall survival versus ZA in 811 patients with any lung cancer (8.9 versus 7.7 months; hazard ratio [HR] 0.80) and in 702 patients with NSCLC (9.5 versus 8.0 months; HR 0.78) (p = 0.01, each comparison). Further analysis of NSCLC by histological type showed a median survival of 8.6 months for denosumab versus 6.4 months for ZA in patients with squamous cell carcinoma (HR 0.68; p = 0.035). Incidence of overall adverse events was balanced between treatment groups; serious adverse events occurred in 66.0% of denosumab-treated patients and 72.9% of ZA-treated patients. Cumulative incidence of osteonecrosis of the jaw was similar between groups (0.7% denosumab versus 0.8% ZA). Hypocalcemia rates were 8.6% with denosumab and 3.8% with ZA. In this exploratory analysis, denosumab was associated with improved overall survival compared with ZA, in patients with metastatic lung cancer.

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Author and article information

Contributors

Yukinori Ozaki:

ORCID: http://orcid.org/0000-0002-8064-648X

+81 3 3588 1111 , 1755ozaki@toranomon.gr.jp

Journal

Journal ID (nlm-ta): BMC Cancer

Journal ID (iso-abbrev): BMC Cancer

Title: BMC Cancer

Publisher: BioMed Central (London )

ISSN (Electronic): 1471-2407

Publication date (Electronic): 22 October 2019

Publication date PMC-release: 22 October 2019

Publication date Collection: 2019

Volume: 19

Electronic Location Identifier: 980

Affiliations

[1 ]ISNI 0000 0001 1014 9130, GRID grid.265073.5, Department of Palliative Care, , Tokyo Medical and Dental University, ; Tokyo, Japan

[2 ]ISNI 0000 0004 1764 6940, GRID grid.410813.f, Department of Medical Oncology, , Toranomon Hospital, ; 2-2-2 Toranomon, Minato-ku, Tokyo, 105-8470 Japan

[3 ]ISNI 0000 0001 2151 536X, GRID grid.26999.3d, Department of Biostatistics and Bioinformatics, Graduate School of Medicine, , The University of Tokyo, ; Tokyo, Japan

[4 ]ISNI 0000 0004 1764 6940, GRID grid.410813.f, Department of Pathology, , Toranomon Hospital, ; Tokyo, Japan

[5 ]Department of Orthopedic Surgery, Saiseikai Yokohama-shi Tobu Hospital, Tokyo, Kanagawa Japan

[6 ]ISNI 0000 0004 1764 6940, GRID grid.410813.f, Department of Breast and Endocrine Surgery, , Toranomon Hospital, ; Tokyo, Japan

[7 ]Department of Breast Oncology, Tokyo Kyosai Hospital, Tokyo, Japan

[8 ]Department of Medical Oncology, Sasebo Kyosai Hospital, Nagasaki, Japan

Author information

Yukinori Ozaki http://orcid.org/0000-0002-8064-648X

Article

Publisher ID: 6236

DOI: 10.1186/s12885-019-6236-6

PMC ID: 6805596

PubMed ID: 31640606

SO-VID: edbfde18-9830-48df-9b8f-b58046a04ec1

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

History

Date received : 12 May 2019

Date accepted : 3 October 2019

Funding

Funded by: Research fund from Mutual Aid Medical Society

Award ID: 469

Award Recipient : Yukinori Ozaki

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ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: femoral fractures,denosumab,bone metastasis,retrospective studiess,systematic review

Data availability:

ScienceOpen disciplines: Oncology & Radiotherapy

Keywords: femoral fractures, denosumab, bone metastasis, retrospective studiess, systematic review

Atypical femoral fracture in patients with bone metastasis receiving denosumab therapy: a retrospective study and systematic review

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Most cited references 23

Atypical subtrochanteric and diaphyseal femoral fractures: second report of a task force of the American Society for Bone and Mineral Research.

Severely suppressed bone turnover: a potential complication of alendronate therapy.

Overall survival improvement in patients with lung cancer and bone metastases treated with denosumab versus zoledronic acid: subgroup analysis from a randomized phase 3 study.

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