icon-    folder.gif   Conference Reports for NATAP  
 
   
Back grey_arrow_rt.gif
 
 
 
Bispohosphonates Bone Therapy: duration of therapy; new study on atypical femoral fracture risk, commentary
 
 
  Download the PDF here

Download the PDF here

Bisphosphonates for Osteoporosis - Where Do We Go from Here?/Duration of Therapy - Perspective - (05/17/12)

Atypical Femoral Fracture Risk in Patients Treated With Bisphosphonates:
Comment on "Increasing Occurrence of Atypical Femoral Fractures Associated With Bisphosphonate Use"


Douglas C. Bauer, MD
Arch Intern Med. May 2012 ONLINE FIRST

"bisphosphonates are generally well tolerated; and atypical subtrochanteric and femoral shaft fractures may be more frequent after bisphosphonate therapy but are rare compared with typical osteoporotic fractures......The case-control study by Meier et al7 in this issue of the Archives adds further data suggesting that the association between bisphosphonate use and atypical femur fractures is causal..... 'Despite these results, the authors pointed out that "averaged over the 12 years of observation ... the incidence rate [for atypical fracture] is very low; there were 11 times more classic fractures during the same period," adding that bisphosphonate therapy still comes out ahead for reducing vertebral fractures by as much as 70% and wrist fractures by 50%.'

"clinicians should continue the current practice of using bisphosphonates as first-line therapy for individuals who are at high risk of fracture and should be sure to discuss with their patients the rare but apparently causal relationship between bisphosphonate use and atypical fractures. Finally, discontinuation of treatment with selected bisphosphonates after 3 to 5 years should be considered in lower-risk individuals, but the optimal duration without therapy and the utility of follow-up BMD assessment or other tests after discontinuation of treatment remain uncertain......Taken in aggregate, these and other high-quality studies lead to the following conclusions: bisphosphonate therapy can prevent spine and nonspine fractures among appropriately selected high-risk individuals (particularly those with previous hip or spine fractures and those with hip bone mineral density [BMD] T scores lower than -2.5); bisphosphonates are generally well tolerated; and atypical subtrochanteric and femoral shaft fractures may be more frequent after bisphosphonate therapy but are rare compared with typical osteoporotic fractures. If discontinuation of bisphosphonate therapy does indeed reduce the risk of atypical fractures (as suggested by the Swedish study), then a critical consideration is the antifracture efficacy of bisphosphonates with use beyond 3 to 5 years"

There is increasing evidence that the use of bisphosphonates to prevent osteoporotic fractures, particularly long-term use, is associated with an increased risk of unusual fractures of the proximal femur. Numerous case reports of these "atypical" fractures of the femur among bisphosphonate-treated women have appeared over the last 5 years or more.1 - 2 A case definition for atypical femur fractures has now been proposed3 that includes subtrochanteric (below the lesser trochanter) or diaphyseal (above the distal metaphysis) location, transverse or nearly transverse "chalklike" fracture line (as opposed to the more typical spiral or comminuted fractures), and paucity of trauma. Additional features may include the presence of prodromal thigh pain, bilateral involvement, cortical thickening, and the presence of other selected diseases (such as rheumatoid arthritis or diabetes) or medication use (such as corticosteroids or proton pump inhibitors). Some reports, but certainly not all, suggest marked suppression of bone turnover as assessed by bone turnover markers and iliac crest histomorphometry.1 Even if causally related, these atypical fractures must be quite rare among osteoporotic women treated with bisphosphonates, as a recent pooled analysis of 3 large clinical trials (FIT, FLEX, and HORIZON) with up to 10 years of follow-up4 found that all types of subtrochanteric and diaphyseal fractures were infrequent and similar among placebo- and bisphosphonate-treated women. Although these findings are reassuring, important limitations were that relatively few women received more than 5 years of bisphosphonate treatment, information on atypical features was not specifically collected, and only radiographic reports were reviewed. Clearly, because atypical subtrochanteric fractures occur infrequently, they are unlikely to be easily studied in randomized trials, and other study designs will be necessary.

Large observational studies have also examined the relationship between bisphosphonate use and subtrochanteric or diaphyseal fractures. For example, Abrahamsen et al5 used Danish administrative data to examine the relationship between bisphosphonate use and subtrochanteric or diaphyseal femur fractures among 39 567 alendronate users and 158 268 nonusers. As would be expected because of their higher pretreatment risk, alendronate users were more likely to suffer classic hip fractures than nonusers (hazard ratio, 1.5; 95% CI, 1.4-1.5), and a similar increase was observed for subtrochanteric and diaphyseal femur fractures (hazard ratio, 2.0; CI, 1.8-2.3). The observation that subtrochanteric and diaphyseal fracture risks were similar among individuals receiving short-term (several months) and long-term (5-10 years) alendronate treatment was somewhat reassuring, but the study was unable to specifically identify which of the fractures included were atypical. Contrary to the results of Abrahamsen and colleagues, a large retrospective cohort study from a California Health Maintenance Organization linking pharmacy and radiographic data6 found that among 15 000 femur fractures identified between 2007 and 2009, radiographic review identified 135 subtrochanteric and diaphyseal fractures with atypical features. Nearly all of the individuals with atypical femoral fractures had taken bisphosphonates (97%), and longer duration of use further increased the risk. Although only presented in abstract form and not yet published, these preliminary data appear to support a causal relationship between bisphosphonate use and atypical femoral fractures.

The case-control study by Meier et al7 in this issue of the Archives adds further data suggesting that the association between bisphosphonate use and atypical femur fractures is causal. These Swiss investigators reviewed radiographs from 477 individuals with subtrochanteric or proximal femoral shaft fractures collected between 1999 and 2010 at a single center and identified 39 with atypical features (0.7% of all femur fractures). For comparison, the investigators used 2 groups: individuals with typical femur fractures and a completely separate group of individuals without fractures. Of the individuals with atypical fractures, 82% reported bisphosphonate use compared with only 6% in the typical fracture group and 12% in the group without fractures. Furthermore, Meier and colleagues found that longer use of bisphosphonates (5-9 years) was associated with a greater risk of atypical fractures (odds ratio, 117; 95% CI, 34-402) compared with shorter use (<2 years) (odds ratio, 35; 95% CI, 10-124). Although Meier and coauthors did not address the issue, a Swedish observational study8 found that the risk of atypical fractures attenuated quickly after discontinuation of long-term bisphosphonate use.

Taken in aggregate, these and other high-quality studies lead to the following conclusions: bisphosphonate therapy can prevent spine and nonspine fractures among appropriately selected high-risk individuals (particularly those with previous hip or spine fractures and those with hip bone mineral density [BMD] T scores lower than -2.5); bisphosphonates are generally well tolerated; and atypical subtrochanteric and femoral shaft fractures may be more frequent after bisphosphonate therapy but are rare compared with typical osteoporotic fractures. If discontinuation of bisphosphonate therapy does indeed reduce the risk of atypical fractures (as suggested by the Swedish study), then a critical consideration is the antifracture efficacy of bisphosphonates with use beyond 3 to 5 years.

As recently summarized at a hearing of the Food and Drug Administration,9 the evidence supporting the efficacy of bisphosphonate use beyond 3 to 5 years is not robust. Only 2 trials, 1 of daily oral alendronate therapy and 1 of yearly intravenous zoledronic acid therapy, randomized postmenopausal women who were previously treated with bisphosphonates for 3 years (zoledronic acid) or 5 years (alendronate) either to continue active treatment or to discontinue treatment.10 - 11 Both studies were designed to assess changes in bone mass over several years as the primary outcome, but both adjudicated spine and nonspine facture outcomes, and the results were surprisingly consistent: compared with the patients who continued bisphosphonate therapy, those who discontinued treatment gradually lost bone mass, but nonspine fracture risk did not differ significantly. Interestingly, both studies found that the risk of spine fractures was higher among those who discontinued use than among those who continued use. Therefore, the best data to date suggest that after 3 years of zoledronic acid therapy or 5 years of alendronate therapy, many older women can consider stopping treatment for 3 to 5 years and perhaps longer. A potential but unproven benefit of this approach is fewer atypical fractures, but at the cost of additional vertebral fractures. Operationally, individuals without previous hip or spine fractures and those with hip BMD T scores higher than -2.5 after 3 to 5 years of treatment might be the best candidates for discontinuation of bisphosphonate therapy. Because the skeletal retention and other properties of various bisphosphonates differ, it is risky to assume that all bisphosphonates provide similar persistent antifracture benefits when their use is discontinued after 3 to 5 years.

In summary, atypical femur fractures are uncommon but do appear to be more frequent among individuals who are being treated with oral and intravenous bisphosphonates, and longer duration of use further increases the risk. Additional studies of atypical fractures are needed to clarify the mechanism and other key risk factors as well as to confirm that discontinuation of treatment after long-term use substantially lowers the risk. In the meantime, clinicians should continue the current practice of using bisphosphonates as first-line therapy for individuals who are at high risk of fracture and should be sure to discuss with their patients the rare but apparently causal relationship between bisphosphonate use and atypical fractures. Finally, discontinuation of treatment with selected bisphosphonates after 3 to 5 years should be considered in lower-risk individuals, but the optimal duration without therapy and the utility of follow-up BMD assessment or other tests after discontinuation of treatment remain uncertain.

------------------------------

Bone Drug Link to Uncommon Breaks Confirmed - full text, commentary, pdfs below

By Shalmali Pal, Contributing Editor, MedPage Today

Published: May 21, 2012

Action Points

· This Swiss study found that patients with atypical femoral fractures were far more likely to be taking bisphosphonates and for a longer duration than those with classic femoral fractures or no fracture.

· Note that atypical femoral fractures were still quite rare.

Bisphosphonate therapy appears to be associated with an increased risk of atypical fractures of the femur, and may be driven by the duration of treatment, according to new research.

Of 477 patients hospitalized at one center, 39 had atypical fractures and 438 had common fractures. Among those with atypical fractures, 82.1% had been taking bisphosphonates compared with just 6.4% of those with common fractures, Raphael P.H. Meier, MD, from University Hospitals of Geneva, and colleagues reported online in the Archives of Internal Medicine.

They also noted that the atypical-fracture group had a longer treatment period on bisphosphonates -- including alendronate (Fosamax), risedronate (Actonel), pamidronate (Aredia), and ibandronate (Boniva) -- than the classic-fracture group, at a mean of 5.1 years versus 3.3 years (P=0.02).

Nonetheless, compared with a 200-patient fracture-free control group, use of bisphosphonates was associated with a 47% reduction in the risk of common fractures (OR 0.5, 95% CI 0.3 to 0.9), making the absolute risk:benefit ratio of bisphosphonates a positive one, they added.

The current evidence on bisphosphonate use and atypical fractures is conflicting. A recent meta-analysis of randomized trials found no association. But a registry-based study suggested that the risk of atypical fracture was more than doubled when bisphosphonates were taken for longer than 5 years (JAMA 2011; 305: 783-789).

In 2010, the FDA confirmed that bisphosphonate drugs for osteoporosis carried a small but meaningful risk of femoral fractures and ordered an update to product labels.

To add to the data on the subject, Meier's group identified patients admitted to their level I trauma center with a fracture of the subtrochanteric femoral shaft area between 1999 and 2010 and divided them into two groups.

One arm consisted of patients with atypical fractures, defined as "a transverse or short oblique fracture line originating at the lateral femoral cortex between the lesser trochanter and the distal metaphysis."

Another arm was made up of patients with common or classic fractures that were in the same location as atypical fractures, but with spiral, wedge, segmental, or complex irregular appearance.

They also established a control group of people who did not have a history of femoral fracture.

In addition to more atypical fractures among the group taking bisphosphonates, 28.2% of the atypical group had a contralateral fracture compared with 0.9% in the classic-fracture group.

In the atypical group, all of the complete and incomplete fractures were in patients taking bisphosphonates.

Recurrent fracture was also more common in the atypical-fracture group compared with the classic-fracture group (OR 42.6, 95% CI 12.8-142.2).

After adjustment for potential risk factors, including vitamin D status, corticosteroids, proton pump inhibitor use, sex, and age, the authors found that any bisphosphonate use was associated with an OR of 69.1 (95% CI 22.8-200.5) for an atypical fracture versus a classic fracture.

When categorized by duration of treatment compared with no treatment, the OR for an atypical fracture compared with a classic fracture was:

· OR 35.1 for less than 2 years of treatment

· OR 46.9 for 2 to 5 years

· OR 117.1 for 5 to 9 years

· OR 175.7 for more than 9 years

When comparing the atypical-fracture group with the control group, the authors reported that bisphosphonate treatment was associated with an OR of 35.2 (95% CI 15.9-155.9, P<0.001).

Despite these results, the authors pointed out that "averaged over the 12 years of observation ... the incidence rate [for atypical fracture] is very low; there were 11 times more classic fractures during the same period," adding that bisphosphonate therapy still comes out ahead for reducing vertebral fractures by as much as 70% and wrist fractures by 50%.

And they cautioned that their retrospective design does not allow for definitive conclusions on causality.

But the study "adds further data suggesting that the association between bisphosphonate use and atypical fractures is causal," said Douglas Bauer, MD, of the University of California San Francisco, in an accompanying commentary.

"These and other high-quality studies lead to the following conclusions: bisphosphonate therapy can prevent spine and nonspine fractures among appropriately selected high-risk individuals ... and atypical subtrochanteric and femoral shaft fractures may be more frequent after bisphosphonate therapy but are rare compared with typical osteoporotic fractures," wrote Bauer.

The current data also draw attention to the idea that the antifracture efficacy of bisphosphonates may not last beyond a certain number of years. Bauer suggested that some older women could consider stopping therapy after 3 to 5 years, which may mean less atypical fractures but at the cost of additional vertebral fractures.

Meier's group, which acknowledged that they lacked sufficient information on confounding factors such as bone density, use of other medications, body mass index, smoking history, and exercise history, called for more research to determine why so few patients taking bisphosphonates have atypical fractures, and why these fractures also occur in people without any history of bisphosphonate use.

--------------------

ONLINE FIRST

Increasing Occurrence of Atypical Femoral Fractures Associated With Bisphosphonate Use

Raphael P. H. Meier, MD; Thomas V. Perneger, MD; Richard Stern, MD; René Rizzoli, MD; Robin E. Peter, MD

Arch Intern Med. May 2012

ABSTRACT

Background
Current evidence suggests that there is an association between bisphosphonate therapy and atypical femoral fractures, but the extent of this risk remains unclear.

Methods Between 1999 and 2010, a total of 477 patients 50 years and older were hospitalized with a subtrochanteric or femoral shaft fracture at a single university medical center. Admission radiographs and medical and treatment records were examined, and patients were classified as having atypical or classic femoral fractures. A random sample of 200 healthy individuals without femoral fracture were also identified. Multivariate logistic regression was used to assess the association of bisphosphonate use and atypical femoral fracture, and the incidence rates of each type of fracture over time were calculated.

Results Thirty-nine patients with atypical fractures and 438 patients with classic fractures were identified. Of the patients with atypical fractures, 32 (82.1%) had been treated with bisphosphonates compared with 28 (6.4%) in the classic fractures group (odds ratios [OR], 66.9; 95% CI, 27.1-165.1) and 11.5% in the group without fracture (OR, 35.2; 95% CI, 13.9-88.8). Bisphosphonate use was associated with a 47% reduction in risk of classic fracture (OR, 0.5; 95% CI, 0.3-0.9). Considering the duration of use, the ORs (95% CIs) for atypical fractures were 35.1 (10.0-123.6) for less than 2 years, 46.9 (14.2-154.4) for 2 to 5 years, 117.1 (34.2-401.7) for 5 to 9 years, and 175.7 (30.0-1027.6) for more than 9 years compared with no use. A contralateral fracture occurred in 28.2% of atypical cases and in 0.9% of classic cases (OR, 42.6; 95% CI, 12.8-142.4). The incidence rate of atypical fractures was low (32 cases per million person-years) and increased by 10.7% per year on average.

Conclusions Atypical femoral fractures were associated with bisphosphonate use; longer duration of treatment resulted in augmented risk. The incidence of atypical fractures increased over a 12-year period, but the absolute number of such fractures is very small.

The use of bisphosphonates has been shown to increase bone mineral density and to reduce vertebral and proximal femur fracture risk in patients with osteoporosis.1 - 6 However, these drugs have a biological half-life that exceeds 10 years7 and may induce long-lasting inhibition of bone remodeling,8 which could affect the healing of "physiologic microcracks,"9 - 12 causing clinically apparent stress fractures in areas with high mechanical stress loads, such as the outer cortex of the femoral shaft.13

Consistent with this hypothesis, several recent publications have reported the emergence of a new type of subtrochanteric and femoral shaft stress fractures, defined as atypical fractures,14 occurring in patients who are receiving bisphosphonate treatment.15 - 22 The radiographic features include a transverse fracture line originating at an abnormal thickening of the lateral cortex of the femoral shaft.14 A sudden fracture with minimal or no trauma is often preceded by prodromal thigh pain for some weeks.14 ,23

Currently, there is conflicting evidence regarding the association between bisphosphonate treatment and atypical femoral fractures. A meta-analysis of randomized intervention trials24 and several registry studies25 - 26 found no association between atypical fractures and this class of compounds. In contrast, a recent large registry-based case-control study suggested that the risk of atypical hip fracture was more than doubled when the medication was taken for longer than 5 years as compared with transient use.27 However, radiographs were not examined, and both cases and controls had received bisphosphonates. Another retrospective study reported an adjusted odds ratio (OR) of 33 for atypical fractures associated with bisphosphonate use.28 However, that study focused only on the year 2008 and provided limited information concerning treatment duration. Accordingly, some questions remain unanswered, such as the magnitude of the association, whether there is a correlation with treatment duration, and whether the risk of atypical fracture is changing over time.

We conducted a case-control study of patients who sustained subtrochanteric or femoral shaft fractures over a 12-year period. We compared the characteristics of patients with atypical fractures with those of patients with classic fractures of the subtrochanteric or femoral shaft area (hereafter known as classic fractures) and individuals without femoral fractures. The objective of the study was to evaluate the association between fracture pattern and bisphosphonate treatment. Also, we examined incidence trends of classic and atypical femur fractures between January 1999 and December 2010.

RESULTS

Between 1999 and 2010, a total of 477 eligible patients were admitted with a first subtrochanteric or femoral shaft fracture (Figure 1). Based on a systematic review of standard admission radiographs, we identified 39 patients with an atypical fracture (atypical group) and 438 patients with a classic fracture (classic group). The interobserver agreement for fracture categorization was excellent30 : K, 0.96 (95% CI, 0.91-1.00).

A contralateral fracture occurred in 11 patients in the atypical group (28.2%) and 4 patients in the classic group (0.9%). The contralateral fracture was of the same type as the first fracture in all 15 patients. In the atypical group, there were 8 complete and 3 incomplete contralateral fractures, all in patients treated with bisphosphonates. The OR for recurrence in patients with atypical fractures was 42.6 (95% CI, 12.8-142.4) when compared with patients with classic fractures.

CASE-CONTROL ANALYSIS

Among the 39 patients who had atypical fractures, 32 (82.1%) had been treated with bisphosphonates. In the classic fracture group, 28 (6.4%) had received bisphosphonates (Table 1). The crude OR was 66.9 (95% CI, 27.1-165.1). Taken separately, treatment with alendronate, risedronate, pamidronate, and ibandronate was associated with augmented ORs for atypical fractures. Other univariate risk factors for atypical fractures included female sex, younger age, and use of vitamin D or corticosteroids. The OR of 1.9 (95%, CI 1.0-3.7) with proton pump inhibitor use was not statistically significant.

After adjustment for potential risk factors (vitamin D, corticosteroids, proton pump inhibitor, sex, and age), use of bisphosphonates (any vs none) was associated with an OR of 69.1 (95% CI, 22.8-209.5) for an atypical fracture compared with the classic fracture group. Of note, none of the potential confounders was statistically significant in the multivariate model except for the following age groups: 50 through 69 years and 70 through 79 years (Table 1). The Hosmer-Lemeshow test result was not significant (P = .48).

The characteristics of the patients with atypical and classic fractures among bisphosphonate users and nonusers are shown in Table 2. Among the patients who received bisphosphonates, the atypical fracture group had a longer treatment period than the classic fracture group (mean [SD], 5.1 [3.1] years vs 3.3 [2.6] years; P = .02). Once categorized by duration of treatment, the ORs (95% CIs) for an atypical fracture vs a classic fracture were 35.1 (10.0-123.6) for less than 2 years, 46.9 (14.2-154.4) for 2 to 5 years, 117.1 (34.2-401.7) for 5 to 9 years, and 175.7 (30.0-1027.6) for 9 years or more compared with no use.

The 200 patients without femoral fractures were aged 63 to 67 years (mean age, 65 years), and 157 (78.5%) were women. Twenty-three (11.5%) were bisphosphonate users; 71 (35.5%) had been treated with vitamin D; and 6 (3.0%) had been treated with corticosteroids. Comparing the atypical fracture group with the nonfracture controls, bisphosphonate treatment was associated with an OR of 35.2 (95% CI, 13.9-88.8; P < .001) for atypical fracture. The ORs were 1.7 (95% CI, 0.9-3.4; P = .12) for vitamin D use, 7.1 (95% CI, 2.2-22.4; P = .001) for corticosteroid use, and 3.3 (95% CI, 1.0-11.2; P = .06) for female sex. After adjustment for these potential risk factors, the use of bisphosphonates was associated with an OR of 49.7 (95% CI 15.9-155.1; P < .001) for an atypical fracture. The adjusted ORs were 0.3 (95% CI, 0.1-1.0; P = .05) for vitamin D use, 5.9 (95% CI, 1.1-30.4; P = .03) for corticosteroid use, and 1.7 (95% CI, 0.3-10.6; P = .59) for female sex. The OR was 0.5 (95% CI, 0.3-0.9; P = .03) for bisphosphonate use when patients with classic fractures were compared with individuals without fractures, indicating that bisphosphonate therapy was associated with a 47% reduction in fracture risk.

INCIDENCE RATES AND TEMPORAL TREND

Averaged over the 12 years of observation, the incidence rates were 357 cases per million person-years for classic fractures and 32 cases per million person-years for atypical fractures. Between 1999 and 2010, the overall incidence rate of classic fractures remained stable, while the incidence of atypical fractures increased (Figure 2). In Poisson regression models, the mean annual change in incidence was +0.4% (95% CI, -2.3% to +3.1%; P = .78) for classic fractures and +10.7% (95% CI, +1.2% to +20.3%; P = .03) for atypical femoral fractures. The temporal trend of atypical fractures differed significantly from the temporal trend of classic fractures (difference, +10.3% per year; 95% CI, +0.4% to +20.3%; P = .04). Between 1999 and 2010, the prevalence of bisphosphonate users (mean [SD], 19.8% [7.5%]) remained stable in our study population, and the mean annual change was -1.5% (95% CI, -5.2% to +2.2%; P = .43).

COMMENT

The primary objective of our study was, first, to evaluate the association between bisphosphonate treatment and atypical femoral fractures and, second, to compare incidence trends of these fractures over the last decade. The key findings were (1) a significantly elevated risk of atypical femoral fracture among bisphosphonate users; (2) an increasing risk of atypical fracture with longer duration of use and no evidence of a threshold or a plateau; and (3) an increasing incidence of such fractures over the last decade. Our results are in agreement with those of others27 - 28 ,31 but contradict recent studies suggesting that the use of bisphosphonates does not increase the risk of atypical fractures.24 - 26

It is interesting to note that bilateral fractures were frequent in patients with atypical fractures. This finding strongly supports the need for radiographic examination of the contralateral femur in all patients presenting with an atypical fracture, whether or not symptomatic, to decide about treatment, including perhaps possible prophylactic internal fixation if a stress fracture pattern is detected.

We observed an incidence rate of 32 atypical cases per million person-years and noted an increasing occurrence of such cases over time. This incidence rate is very low; there were 11 times more classic fractures during the same period. Furthermore, if we consider a 50% reduction of proximal femur and classic fractures (supported by our results and by literature1 ,6 ) and a prescription rate of approximately 10% in the population at risk,28 the absolute benefit to risk ratio of bisphosphonate treatment would remain clearly favorable, notably keeping in mind that the use of bisphosphonates would also reduce vertebral fractures by 40% to 70% and wrist fractures by 50%.1 ,6

The strengths of our study include (1) the large number of patients; (2) the fact that patients were treated at the same institution over a 12-year period; (3) an accurate radiographic evaluation of all subtrochanteric and femoral shaft fractures; and (4) detailed information on temporal trends, duration of treatment, and bilateral fractures. However, we must acknowledge some limitations. First, a retrospective design does not allow definitive conclusions on causality. Second, although we adjusted for several available cofactors, other confounding or bias cannot be excluded. In particular, we did not have sufficient information concerning bone density, bone turnover, use of other medications, smoking history, body mass index, and exercise history to include into the analyses. Third, although associations and trends were statistically significant in our study, the small number of atypical fractures resulted in large CIs in the computation of ORs and year-to-year variability in the temporal trend of atypical fractures.

Another point that was not directly addressed in this study concerns the pathogenetic mechanism of atypical fractures. A mechanistic hypothesis based on the work of Perren32 - 33 might be proposed. He described interfragmentary strain at a fracture site as a variable defined as the displacement divided by the interfragmentary distance (Strain = Motion/Gap). Ideally, the interfragmentary strain should remain within limits of 1% to 2% to allow local osteoblast proliferation and repair of the crack. In the hypothetical situation of constant interfragmentary motion, the healing process of physiologic microcracks requires a widening of the interfragmentary distance to bring local strain within these narrow limits of 1% to 2%. This task is performed by osteoclasts. In cases of osteoclast dysfunction,34 the interfragmentary distance remains too small and the strain excessively high, thus failing to allow the physiologic repair process to take place. The perpetuation of this dysfunction may therefore lead to a clinically apparent stress fracture.

Nevertheless, important issues still require clarification. For instance, why do only a few patients who are being treated with bisphosphonates present with atypical fractures? And why do some others present with atypical fractures without any history of bisphosphonate use?35 - 36 Accordingly, a search for other potential cofactors should be a priority. Identification of patients who are at high risk for bisphosphonate-associated fractures would allow a targeted prescription of this class of drugs and a reduction or avoidance of atypical fractures in the future. A multifactorial model of atypical fractures also opens the door to the possibility of pathogenetic mechanisms not involving bisphosphonates.

In conclusion, we have demonstrated that the association between bisphosphonate treatment and the occurrence of atypical fractures of the femur is highly likely and that the duration of such treatment significantly correlates with augmented risk. However, the incidence rate was very low, and the absolute benefit to risk ratio of bisphosphonate use remains positive. The identification of patients who are at risk seems to be of crucial importance to reduce this complication in the future.