Incidence of Atypical Femur Fractures in Cancer Patients: The MD Anderson Cancer Center Experience

Introduction

Bisphosphonates (BPs) significantly reduce skeletal-related events (SREs), delay the time to first SRE in patients with bony metastatic disease, and reduce the risk of fractures, radiotherapy, and hypercalcemia.1-3 However, there has been some concern over the sporadic occurrence of atypical femoral fractures (AFFs).4 In the 2010 American Society of Bone and Mineral Research (ASBMR) task force report, AFFs were defined as atraumatic or low-trauma fractures located in the subtrochanteric region or femoral shaft.5 Other radiographic features (Fig. 1) include a transverse fracture line at the point of origination in the lateral cortex. As the fracture propagates across the diaphysis to the medial cortex, the orientation may become more oblique and when it becomes complete a prominent medial “spike” may be present. There may be a focal or diffuse periosteal reaction of the lateral cortex surrounding the region where the fracture initiated. This reaction may appear as cortical “beaking” or “flaring” adjacent to a discrete transverse lucent fracture line,6-8 or as focal thickening of the lateral cortex.4, 5

AFFs have been well documented in patients with osteoporosis; however, only isolated cases have been identified in the cancer literature. Eight cases of AFF were reported in myeloma and metastatic breast cancer on prolonged intravenous BP therapy, and one case in nonmetastatic prostate cancer.9-12 Zoledronic acid (ZOL) has been shown to decrease skeletal-relevant events in prostate cancer, breast and renal cell carcinoma patients, and also recommended as a means to prevent further fractures or skeletal-relevant events because of its efficacy for treatment of bone metastases, regardless of osteolytic or osteoblastic lesions13 of the bone.

The postulated etiology of AFFs has included the presence of comorbidities and drugs that affect bone metabolism, such as diabetes or corticosteroid use, which are fairly prevalent in cancer patients. Diabetes causes accumulation of advanced glycation end products, increasing bone brittleness and fractures.14-16 Corticosteroids suppress bone formation and upregulate bone resorption, also increasing fracture risk.17-19 Prolonged use of BPs may result in less tissue heterogeneity in terms of mineralization crystal size and perfection, particularly affecting cortical bone.20, 21 Accumulation of skeletal microdamage and osteoblast suppression from BP use have also been considered.22-25 BP use has been associated with reduced bone toughness.26 BPs increase mean tissue age and mineralization, resulting in an increased propensity for microcracks and reduced bone resilience that collectively increase the fracture risk.27 Furthermore, the mineral content (mineral/matrix ratio) of cortical bone but not cancellous bone has been shown to be increased by BP treatment.28 The aim of this study is to assess the incidence and risk factors for AFF in a large cancer center.

Materials and Methods

This case control study was conducted at the University of Texas MD Anderson Cancer Center from January 2004 through December 2013. This study was conducted after AFFs had been described and imaging features characterized in the published literature.4, 5 AFFs were identified and a single radiologist with a 40-year career practicing musculoskeletal radiology validated every case. We did not determine the denominator including every femoral fracture in the cancer center.

Data abstraction from medical records was conducted onto a standardized case report form; data items included demographics and clinical characteristics. For oral medications, we reviewed the medical records at each visit because nurses review and update the medication list on a regular basis. Thus the presence of oral BPs reflected current usage. The Department of Pharmacy Medication Management and Analytics provided us with the January 1, 2004 through June 30, 2013 list of BP recipients. Data provided included demographics, number of doses, route of administration, dosing frequency, and last dose received. The total duration of BP use for the recipients was calculated. The control group included patients on BPs (January 1, 1990 through April 1, 2013) who remained fracture-free, matched for age (± 1 year), and gender matching with two or three controls. Cases and controls were reviewed for the presence of diseases and drugs affecting bone metabolism, the presence of vitamin D deficiency, clinical management, and outcome. Corticosteroid dosing was converted to dexamethasone dose equivalent.

Regulatory agency databases such as the U.S. Food and Drug Administration Adverse Event Reporting System (FAERS), the European Medicine Agency (EMA), and Canada Health were searched for the terms bisphosphonates, atypical femoral fractures, and cancer. The medical subject headings (MeSH) search included bisphosphonates, alendronate (ALN), ZOL, and pamidronate (PAM) among other BPs, oncology, and cancer therapy. This was followed by an assessment of the pathophysiology surrounding the adverse event, assessing for biologic plausibility.

Results

We identified 10,587 unique cases that had received BPs from January 1, 2004 to December 31, 2013, for a total duration of BP of 4482 years. Twenty-three cases were identified; the estimated incidence of AFF in BP users was 0.05 per 100,000 person-years. Cases were matched for age (± 1 year) and gender with two or three controls; these and the matched 51 controls were included in the analysis. Clinical characteristics of cases are presented in Table 1. The type of cancer and extent of disease were similar in cases and controls. The median age of AFF in cancer cases was 58 years of age (range 39 to 69 years). Female/male ratio was 17:6. For oral medications, we reviewed the clinical notes in our electronic medical records (EMRs); at each visit medications were reviewed by the nurses, with an update on whether medicines had been stopped or new ones initiated. Thus the presence of oral BPs on the medical record reflected current use. However, we did not contact the pharmacies to obtain the mean possession ratio (MPR) or the medication persistence. Median time of BP use included ZOL (n = 13; 5 months), PAM (n = 3; 14 months), ALN (n = 6; 84 months), and IBN (n = 2; 36 months). Patients on IBN were receiving it for osteoporosis (ie, the dosing was 3 mg i.v. on a quarterly basis, as approved for osteoporosis, as opposed to 6 mg i.v. every 3 to 4 weeks for skeletal metastasis). IBN is not approved for skeletal metastasis in the United States.

Most cases had breast cancer (n = 15); multiple myeloma (n = 5); leukemia (n = 2); lymphoma, monoclonal gammopathy, enchondroma, and skin cancer (n = 1); in 7 cases the cancer was metastatic. Smoking, presence of diabetes, osteoporosis, and other comorbidities were similar in cases and controls. There were 2 cases of osteonecrosis of the jaw 1 to 2 years before AFF occurrence.

Between January 1, 2004 and December 31, 2013 there were 2 cases of AFF in 300,553 non-BP users. The odds ratio (OR) for AFF in BP users was 355.58 (95% CI, 84.1 to 1501.4, p < 0.0001). A case of AFF is seen in Fig. 1, progressing from prodromal symptoms through complete fracture, and healing after open reduction and internal fixation. Univariate analysis is presented in Table 2. The OR of having AFF among those on ZOL was 0.34 (95% CI, 0.12 to 0.97, p = 0.04). The OR of having AFF in ALN users was 5.54 times greater (95% CI, 1.60 to 19.11, p = 0.007) than the odds of having AFF among other BP users. Patients who received ALN for more than 3 years had a higher risk of having AFF than those who were on ALN for less than 3 years (OR 6.3 [95% CI, 1.49 to 26.72, p = 0.013]). We identified that 12 out of 30 patients with vitamin D deficiency had AFF, whereas 15 out of 51 patients without vitamin D deficiency had AFF. OR was 1.82 (95% CI, 0.71 to 4.66, p = 0.21) for AFF with vitamin D deficiency versus AFF without vitamin D deficiency.

Surgical intervention was performed in 14 patients with intramedullary rod placement in one or both femurs to treat a complete fracture (9 patients) or to prophylactically prevent a complete fracture (5 patients). All patients undergoing surgery experienced some degree of local pain. The remaining 9 patients had incomplete fractures. Table 1 includes the surgical description for reported cases. These remaining incomplete fractures were managed with conservative measures such as making them non–weight bearing, an intervention that has proven effective in other institutions.31 Prophylactic rodding was not performed at MD Anderson.

Discussion

This is one of the first case series describing AFFs in cancer cases. AFFs occurred in metastatic cancer cases on intravenous BPs and in cancer cases with a prior diagnosis of low bone mass or osteoporosis on long-term oral BPs used for osteoporosis therapy such as ALN, RIS, and IBN, and for the osteoporosis dose of ZOL. Consequently, recent ASBMR guidelines for management of long-term use of BPs have focused on use for osteoporosis.32 Our findings suggest that AFFs may affect cancer patients, although the incidence rates appear considerably lower than those observed in osteoporosis.

BP use in metastatic cancer is distinct from that in noncancer cases because BPs are likely to be more concentrated in an area of high resorption such as skeletal metastasis.33 BPs require more frequent and higher dosing in order to maintain an antiresorptive activity as measured by bone turnover markers. As an example, one dose of ZOL for hypercalcemia of malignancy resulted in persistent antiresorptive action for 5 weeks.33 A single dose of ZOL ranging from 4 to16 mg suppressed bone turnover markers in patients with skeletal metastasis for up to 8 weeks.34 This markedly contrasts with ZOL use for osteoporosis, where one dose of ZOL may show continued antiresorptive action for up to 3 years.35 Furthermore, it has been reported that 62% of ZOL is retained in the skeleton in breast cancer and in myeloma independently of the duration of ZOL therapy.36 We hypothesize that the likelihood of developing AFFs with ZOL use for metastatic cancer is low because most of the drug is consumed by active areas of skeletal metastasis, thus leaving a reduced amount of ZOL to affect other skeletal sites. This would stand in contrast to BPs used for osteoporosis, where available BPs may continue to affect other skeletal sites. Future investigations on the pathophysiology of ZOL-related AFFs are needed. Osteonecrosis of the jaw preceded the AFFs in 2 cases. This association has been previously described,37 and such findings lend credence to the notion that systemic skeletal abnormalities may be shared by osteonecrosis of the jaw and AFFs. It has been hypothesized that suppression of bone turnover or altered immune status may contribute to these conditions.38

It has been proposed that early diagnosis of AFFs may occur by incorporating an extended image at the time of dual-energy X-ray absorptiometry (DXA).39, 40 This has been tested in patients older than aged 50 years on oral BP therapy for more than 5 years. In a cohort study of 257 participants with osteoporosis, abnormal DXA images were suggested in 19 patients (7.4%). On radiographs, 7 patients (2.7%) showed evidence of AFFs; 5 patients had a periosteal flare and 2 patients had a visible fracture line, both of which needed insertion of an intramedullary nail. It was thus shown that early detection of incomplete AFFs was possible using extended femur-length imaging with a prevalence of 2.7% in an osteoporosis cohort.39, 40 Whether or not it would be cost-effective to monitor cancer patients on prolonged intravenous BPs using this technique remains to be determined.

Management of AFFs was similar to that of noncancer AFF cases. In this case series, several cases presented incomplete fractures, and a period of conservative therapy was successful in the majority.21, 39, 41 Teriparatide use, often utilized in osteoporosis-related AFF, was avoided in cancer patients with prior skeletal radiation. Prophylactic intramedullary nail fixation was effective,42 although healing was prolonged, with a mean duration of 8 months,43 and in 3 cases there was fracture nonunion after 3 years.21, 39 Cases with incomplete fractures were managed with conservative measures such as non–weight-bearing status, whereas surgery with intramedullary rodding was performed in the cases with complete fractures. Although prophylactic surgery has been reported as resulting in improved healing rates in some cancer cases, preventing fracture completion,42, 44 prophylactic surgery was not performed in our institution.42, 44 In only 2 cases was delayed healing evident after 24 months.

There are no guidelines for surveillance in cancer patients on BPs. The FDA initially posted in 2010 that AFFs seen in cases of osteoporosis were uncommon, accounting for less than 1% of femur fractures overall.45 These unusual femur fractures have been predominantly reported in patients taking BPs approved to treat osteoporosis, including ALN, risedronate, IBN, and the osteoporosis dose of ZOL; however, these warnings did not affect etidronate (Didronel), ZOL (Zometa), PAM, and their generic products.46 By January 2011, an update on BP safety included the 4-mg dose of ZOL as a BP that could produce AFFs, although at that time no cancer cases had been reported.47 In March 2012, the FDA updated the safety information on postmarketing experience of ZOL, reporting that atypical subtrochanteric and diaphyseal femoral fractures had been reported with BP therapy including ZOL (Zometa).48 The Committee for Medicinal Human Products of the EMA confirmed that the benefits of BPs greatly outweighed the risks, but that a warning of the risk of AFFs should be added to the prescribing information for all BP-containing medicines in the European Union.49 Canada Health and the Therapeutic Goods Administration (TGA) in Australia have issued a safety warning for AFFs and cite BPs used for osteoporosis alone.50

Limitations of this study include the retrospective nature of analysis and no assurance to detect all cases of AFF, but only most of the symptomatic cases. Thus we were not able to calculate absolute risk. Possible recall bias has been minimized because data were collected before study initiation and controls were randomly selected.51 There may be some degree of selection bias, however, in that these findings may be representative of a cancer population seen in a referral comprehensive cancer center. A challenge of being a referral center is that patients arrive for a second opinion (ie, they may have received treatment―including BPs―at their original oncology centers). Although we carefully reviewed the medical records, because we did not have pharmacy information such as MPR, the results may be limited by the available information in the database, which does not allow reconstruction of the clinical histories of all BP users and utilization of their records for assessing the overall risk of each medication. We only counted duration of BP use from the time they arrived at MD Anderson; their prior drug use was not considered when conducting our analysis. In most cases, AFFs occurred within 6 months of the first dose reported at MD Anderson. Finally, although this study is able to identify an association with specific risk factors, determination of causality was not within the scope of this work.52

AFFs in cancer were seen in patients who received ZOL and ALN; the incidence of this adverse event in cancer patients on BPs was low, at 0.05 cases per 100,000 person-years. Patients who were on ZOL had lower odds of developing AFF, compared with other BP users in this matched case control study. Oncologists must be aware that patients with prior low bone mass or osteoporosis may have received oral BPs for several years. In such cases, a consultation with a bone health specialist would be advisable. Although relatively rare in oncology, a greater awareness of AFFs is needed in the oncology community for incorporation of early diagnosis and management of such fractures. Early detection and preventive management of incomplete fractures may prevent progression to a complete atypical fracture and avert adverse consequences.

Conclusions

AFFs occur in cancer patients who receive BP therapy. Although the incidence appears lower than in osteoporosis, caution must be exercised with patients on BP therapy whether therapy is for preexisting osteoporosis or for metastatic cancer.

Disclosures

All authors state that they have no conflicts of interest.