Osteoporosis is one of the most important healthcare concerns and results in osteoporotic fractures in elderly population.12 Osteoporotic fractures lead to the decreased mobility, activity and quality of life in these population.34

Bisphosphonates, one of potent anti-resorptive agents, have been recommended to treat osteoporosis and to prevent osteoporotic fractures.25

Recent studies have reported that long-term use of bisphosphonates was associated with the increased risk of atypical femoral fractures (AFFs).67 These fractures occur spontaneously or after minimal trauma at the subtrochanteric region or femoral shaft (ST/FS).89 They are often proceeded by a prodromal pain, and have radiographic features of an insufficiency fracture; lateral cortical thickening and transverse fracture pattern,10 and are associated with high rates of non-union and reoperation.111213141516

Based on several epidemiologic studies with large scale cohorts, the incidence rate of ST/FS fractures among bisphosphonate users varies from 76 to 310 per 100,000 person-years.171819202122 Most studies were conducted in western countries involving Caucasians.1718192021

In East Asia as elsewhere, osteoporosis and osteoporotic fractures are prevalent due to aging of population,2324 and the use of bisphosphonate to prevent and treat osteoporosis becomes increasing.2225262728 Accordingly, bisphosphonate associated AFF is a growing concern in that area. 92729

Previous studies, which were conducted in health care registry of western countries, evaluated ethnic differences of AFFs and reported that the AFF incidence was higher in Asian population than in Caucasian population.293031323334 However, a recent hospital-based study showed that the AFF incidence in Korean population was not higher than those in western population.35 Therefore, the exact incidence of AFF in East Asian countries remains to be revealed. Considering the rarity of AFFs, a large epidemiologic study based on nationwide database is necessary to reveal the AFF incidence with sufficient statistical power. However, there has been no such a study conducted in East Asia.

Several studies examined the risk of AFF in long-term users of bisphosphonates. In these studies, the use of bisphosphonates was not associated with a greater risk of ST/FS fractures.17182022 Even a decreasing risk was observed with increasing average daily dose of alendronate in a nationwide cohort study from Denmark.19

Therefore, the purpose of this study was to determine the risk of ST/FS fractures and the benefit of typical hip fractures prevention among bisphosphonate users from a database on National Health Insurance Service-National Sample Cohort (NHIS-NSC).

From the 551,556 eligible women, who were included in the Korean NHIS-NSC database from 2002 to 2013, we identified 46,420 bisphosphonate users who received prescriptions for at least one bisphosphonate. Among them, 36,529 people met the inclusion criteria (Fig. 1).

After calculating duration of bisphosphonate use, 14,689 users were selected as long-term users (≥ 1 year) and 21,840 people were defined as short-term users (< 1 year) (Fig. 1). Table 1 shows the baseline characteristics of long-term and short-term users.

During the study period, 61 of the long-term users had ST/FS fractures, while 36 of the short-term users had such fractures. The incidence rate of ST/FS fractures was 67.1/100,000 person-years (95% CI, 50.3–83.9) in the long-term users and 31.2/100,000 person-years (95% CI, 21.0–41.4) in the short-term users. The cumulative incidence of ST/FS fracture was higher in the long-term users than in the short-term users (P < 0.001) (Fig. 2).

The risk of ST/FS fractures was higher in long-term users than in short-term users (adjusted HR, 2.345; 95% CI, 1.541–3.569) (Table 2).

During the study period, 204 of the long-term users had FN/IT fractures, while 511 of the short-term users had such fractures. The incidence rate of FN/IT fractures was 225.5/100,000 person-years (95% CI, 194.6–256.5) in the long-term users and 448.6/100,000 person-years (95% CI, 409.7–487.5) in the short-term users. The cumulative incidence of FN/IT fractures was higher in the short-term users than in the long-term users (P < 0.001) (Fig. 3).

Using the short-term users as a reference, long-term use significantly reduced the risk of typical hip fracture (adjusted HR, 0.578; 95% CI, 0.490–0.682) (Table 3).

Absolute risk increase for ST/FS was 0.0025 (61/14,689–36/21,840) and the NNH for ST/FS was 400, which mean that one ST/FS will occur if 400 patients were treated with long-term use of bisphosphonate. Absolute risk reduction for typical hip fracture was 0.0095 (511-21,840 - 204/14,689) and the NNT for typical hip fracture was 105, which mean that 105 patients would have to be treated with long-term bisphosphonate to avoid one typical hip fracture.

In this population-based cohort study using diagnostic and procedure codes, we found out the association between the long-term use of bisphosphonate and the risk of ST/FS fractures. However, our results showed that the long-term use of bisphosphonate (≥ 1 year) was associated with the reduced risk of FN/IT fractures.

The incidence rate of ST/FS fractures was 67.1/100,000 person-years, which was comparable with or lower than reportedly known rates in western countries (Table 4).172022

The estimated incidence rate might be overestimated in our study because we could not exclude high energy fractures by using ICD-10 codes. Nevertheless, we observed a much lower incidence rate of ST/FS fractures in Korea than those of western countries (Table 4).172022

Our results were not consistent with those of previous studies, which reported that the occurrence of ST/FS fractures was higher in Asian than Caucasian.293031323334

Several studies reported that the use of bisphosphonate was not associated with an increased risk of AFFs,1718192022 while other studies have demonstrated that the occurrence of those fractures was significantly associated with the long-term use of bisphosphonate.717202122294142 Our study showed that the long-term use of bisphosphonate (≥ 1 year) was a potential risk factor of ST/FS fractures.

On the other hand, many clinical trials and registry-based cohort studies have reported that bisphosphonate use provides benefits of hip fracture prevention.2643 Several guidelines on osteoporosis treatment have recommended use of bisphosphonate to prevent osteoporotic fractures.44454647 Our results supported these guidelines and those studies on benefits of bisphosphonate on fracture prevention.

Our results, the difference between NNH (400) for ST/FS and NNT (105) for typical hip fracture, mean that just one ST/FS could occur, while 4 typical hip fractures would be prevented, if 400 patient was treated with long-term bisphosphonate. Our findings showed that the benefit of long-term use of bisphosphonate for prevention of typical hip fracture was larger than the risk for ST/FS.

Our study has several strengths. First, our cohort was one of the largest from Asian, allowing us to investigate even rare events such as AFFs. Second, we conducted population-based study design using a nationwide claims database containing drug prescriptions.

There were several limitations in this study. First, although we used a very large cohort, our cohort was a sampled one and might not have represented the entire female population in Korea. However, the Korean government provided a standardized cohort by using stratification according to the age, gender, and level of socioeconomic status. Second, we could not evaluate radiographs to confirm the atypical features of ST/FS fractures. This study might have a potential bias due to inaccurate coding and incomplete medical records.48 However, previous several studies on the epidemiology of AFFs have used the same coding system.171819202122 A evaluation for the validity of discharged diagnosis showed that the overall positive predictive value of the diagnoses was 83.4% in patients, who were admitted to hospital.49 Third, we could not analyze possible confounding factors such as menopausal status, bone turnover status, and bone mineral density, because the claim database did not include these. Fourth, fracture due to high-energy injury might be included in this study, because the ICD-10 coding system did not distinguish between high and low-energy fractures. However, we did not need an additional operational definition to exclude high energy trauma, because the NHIS database does not include high-energy injuries such as those from traffic accidents and industrial injury.50

Despite these limitations, our results showed that bisphosphonates may be playing a differential role between FN/IT fracture and ST/FS fracture. The longer use of bisphosphonate was associated with the lower risk of typical hip fracture, while it was associated with the higher risk of occurrence of ST/FS fractures in Korean women. Our study suggested that the raised concerns about bisphosphonate-associated ST/FS fractures in East Asia may be overestimated than the reality, considering the longer use of bisphosphonate was associated with the lower risk of FN/IT fractures.