Question:
In postmenopausal women who have been receiving long-term treatment with bisphosphonates, is there an increased risk for subtrochanteric or femoral shaft fractures?
Design:
Population-based nested case-control study with 7-year follow-up.
Setting:
Ontario, Canada.
Patients:
Cases were patients hospitalized with a subtrochanteric or femoral shaft fracture. The cases were drawn from a cohort of 205,466 women who were ≥68 years of age from Ontario, Canada, who initiated treatment with an oral bisphosphonate (alendronate, risedronate, or etidronate) between April 1, 2002, and March 31, 2008. Cases were matched to as many as 5 controls with no such fracture. Control patients were matched to case patients according to age and cohort entry period. Study participants were followed up to March 31, 2009. Exclusion criteria were any history of cancer in the preceding ten years; conditions associated with altered bone integrity, such as osteomalacia, osteopetrosis, hyperparathyroidism, hypercalcemia, epilepsy, celiac disease, Paget disease, renal osteodystrophy, or gastric bypass in the previous five years; or treatment with raloxifene, calcitonin, sodium fluoride, clodronate, pamidronate, or zoledronic acid in the preceding year.
Risk factors:
Participants were categorized as long-term users (≥5 years of therapy), intermediate users (three to five years of therapy), or short-term users (100 days to three years of therapy) of bisphosphonates. These exposure groups were compared with a reference group of transient (<100 days in total) users.
Main outcome measures:
The primary outcome was the association between hospitalization for a subtrochanteric or femoral shaft fracture and cumulative duration of bisphosphonate use for >5 years. The association of cumulative doses of three to five years and 100 days to three years was also examined. A secondary analysis examined the association between bisphosphonate use and typical femoral neck or intertrochanteric hip fracture associated with osteoporosis.
Main results:
Over the 7-year study period, 716 women (0.35%) treated with bisphosphonates had a subtrochanteric or femoral shaft fracture. Use of bisphosphonates for ≥5 years was associated with an increased risk for hospitalization for a subtrochanteric or femoral shaft fracture compared with transient use of bisphosphonates (Table). Intermediate or short-term use was not associated with increased risk (Table). In the secondary analysis, 9723 women had an intertrochanteric or femoral neck fracture. Prolonged bisphosphonate use was associated with reduced overall risk for these fractures (adjusted odds ratio, 0.76; 95% confidence interval, 0.63-0.93). Intermediate bisphosphonate use was associated with a borderline reduced risk for fracture associated with osteoporosis and short-term use was associated with a nonsignificant reduction (Table).
Conclusion:
Postmenopausal women who have been receiving bisphosphonate therapy for ≥5 years had an increased risk for subtrochanteric or femoral shaft fractures.
This study by Park-Wyllie and colleagues addresses the safety of long-term bisphosphonate therapy as related to the occurrence of subtrochanteric and diaphyseal femoral fractures.
Bisphosphonates for the treatment of osteoporosis have shown in randomized trials an approximate decline of 70% in vertebral compression fractures, 40% in hip fractures, and 25% in nonvertebral fractures across the bisphosphonate drug class. In the past decade, however, unique atypical subtrochanteric or femoral shaft fractures have been reported in patients with long-term bisphosphonate use. Controversies arose over association and causality. A return to the trial data could not identify a higher rate of these fractures. Unfortunately, those trials had no more than a three-year follow-up and there were too few patients to resolve the question. The American Society for Bone and Mineral Research formed a task force to examine the question and found sufficient evidence to support an association but not clear causality. The task force called for better data, clearer coding, and continued research1.
The study by Park-Wyllie carefully analyzed a well-monitored captive health population on bisphosphonate therapy and has three key messages. First, continued bisphosphonate therapy significantly decreases the risk for femoral neck and intertrochanteric fractures. Second, only in patients taking ≥5 years of bisphosphonates do atypical fractures substantially increase. In the two years following five years of treatment with bisphosphonates, the data suggest that one in 500 may sustain such a fracture. Third, atypical fractures are uncommon events and the balance of patient efficacy and safety favors bisphosphonate therapy. The U.S. Food and Drug Administration has recently warned that long-term bisphosphonate users with thigh pain should be evaluated for atypical fractures.
Reference
Shane
E;
Burr
D;
Ebeling
PR;
Abrahamsen
B;
Adler
RA;
Brown
TD;
Cheung
AM;
Cosman
F;
Curtis
JR;
Dell
R;
Dempster
D;
Einhorn
TA;
Genant
HK;
Geusens
P;
Klaushofer
K;
Koval
K;
Lane
JM;
McKiernan
F;
McKinney
R;
Ng
A;
Nieves
J;
O'Keefe
R;
Papapoulos
S;
Sen
HT;
van der Meulen
MC;
Weinstein
RS;
Whyte
M; American Society for Bone and Mineral Research. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res.
2010;25:2267-94.