The limitations of today’s clinical guidance: Atypical femoral fracture and long-term bone-modifying agents in the oncology setting

Abstract

<jats:p> While bone-modifying agents such as bisphosphonates and denosumab are crucial to preventing skeletal-related events in patients with bone metastases, the optimal duration remains undefined. Extended duration may be associated with adverse effects such as osteonecrosis of the jaw and atypical femoral fracture. Although uncommon, atypical femoral fracture represents a serious consequence of prolonged bone-modifying agent use and are characterized by a prodrome and distinct radiographic findings. The oncology setting encompasses a unique set of atypical femoral fracture risk factors and considerations, with hormonal therapy in early stage disease, bone metastases in the advanced setting, and new targeted agents that may affect bone homeostasis. As outcomes in cancer treatment continue to improve, the questions of risks versus benefits of long-term bone-modifying agents and how to mitigate atypical femoral fracture risk become increasingly pertinent. </jats:p>

What enlightenment has the development of lung cancer bone metastasis brought in the last 22 years

“…Moreover, although adjuvant treatments, such as denosumab and zoledronic acid, can induce serious side effects, including hypocalcaemia, femoral fractures and osteonecrosis of the jaw, a large body of data suggests that they can play a significant role in prolonging the overall survival of LCBM patients and reducing the occurrence of a range of skeletal complications[ 14 , 15 , 44 ]. Therefore, it is not surprising that these treatments are major hot topics in LCBM research.…”

How has the field of metastatic breast cancer in bones evolved over the past 22 years?

“…Adjuvant chemotherapy, surgery, and targeted therapy with phosphonates also achieve better therapeutic results [49] , [50] , [51] , [52] , [53] . However, there are also serious side effects that affect the quality of life of patients, such as osteonecrosis of the jaw and heart damage [54] , [55] , [56] .…”

“…Others have mentioned that the use of denosumab is effective in reducing the probability of skeletal-related events, including disability and bone pain [52] , [53] . However, as with the use of phosphonates, adverse outcomes, such as atypical femur fractures, hypocalcemia, and osteonecrosis of the jaw, should be kept in mind in clinical practice [55] , [56] . Fulvestrant, pyrotinib, lapatinib, and trastuzumab all target estrogen receptors (ERs), which can provide significant relief in patients with certain types of MBCB [59] , [60] .…”

High doses of zoledronic acid induce differential effects on femur and jawbone microstructure

“…These patients may remain on bisphosphonate treatment for extended periods (Lockwood et al, 2019 ). In children and adolescents, bisphosphonates are used in the treatment of osteogenesis imperfecta (Malmgren et al, 2020 ) and a variety of diseases that result in bone density decrease and malignancies (Cheung & Borno, 2020 ).…”

“…Uncommon late site‐specific side effects, such as atypical fracture of the femur and osteonecrosis of the jaw, have been related to long‐term therapies with high‐dose bisphosphonates in adults (Ruggiero et al, 2014 ). Although their pathogenesis remains largely unknown, preclinical and clinical investigations lead to several proposed mechanisms, including remodeling oversuppression (Cheung & Borno, 2020 ; Ruggiero et al, 2014 ), microdamage accumulation (Cho et al, 2018 ; Hoefert et al, 2010 ; Lockwood et al, 2019 ), decreased bone vascularization (Soares et al, 2018 ), and impaired local trauma repair (Jabbour et al, 2014 ; Shane et al, 2010 ).…”