Epidemiology, radiology and histology of atypical femoral fractures

Figures & data

Figure 1. Different osteoclasts. A: Giant osteoclast, detached from the bone, in a resorption cavity close to the fracture line of an atypical femoral fracture. B: Normal osteoclast in a healthy individual with tibial stress fracture.

Figure 2. Bisphosphonate-associated shaft fractures show radiographic signs of stress fractures. Note the fracture line running perpendicular to the long axis of the femur and its origin at the tensional side of the bone. Black arrow: endosteal callus reaction. Horizontal white arrow: periosteal callus reaction. Oblique white arrow: medial spike.

Figure 3. Upper part: Identification of atypical fractures in Paper I. Lower part: Further selection of cases and controls for Paper II.

Table 1. Age-adjusted relative risk (RR) and absolute risk (AR), with 95% confidence intervals (95% CI), of atypical femoral fracture associated with the use of bisphosphonate during the 3 years (2005–2008) preceding the fracture

Bisphosphonate use	No. of bisphosphonate users at risk	Number of atypical fractures ^a	Age-adjusted RR (95% CI)	Age-adjusted AR (95% CI)
Never use	1,437,820	13 (0.09)	1.0 (Reference)
Ever use	83,311	46 (5.5)	47.3 (25.6–87.3)	0.0005 (0.0004–0.0007)
Duration of use (years)
<1	15,672	3 (1.9)	18.4 (5.3–64.3)	0.0002 (0.0000–0.0004)
1–1.9	21,406	4 (1.9)	17.0 (5.7–50.7)	0.0002 (0.0000–0.0004)
2 or more	46,233	39 (8.4)	67.0 (35.8–125.8)	0.0008 (0.0006–0.0011)
Time since last use (years)
< 1	83,311	42 (5.0)	42.9 (22.9–80.4)	0.0005 (0.0004–0.0007)
1–1.9	70,036	1 (0.1)	3.5 (1.0–11.9)	0.0000 (0.0000–0.0000)
2 or more	75,583	3 (0.4)	3.2 (1.0–10.1)	0.0000 (0.0000–0.0001)

^a Crude incidence proportion per 10,000 women and year

Table 2. Odds ratios (OR), with 95% confidence intervals (95% CI), for atypical femoral fractures associated with bisphosphonate use

Bisphosphonate use	Cases N = 59	Controls N = 263	Age-adjusted OR (95% CI)	Multivariable-adjusted ^a OR (95% CI)
Never use	13	237	1.0 (Reference)	1.0 (Reference)
Ever use	46	26	27.2 (12.8–58.1)	33.3 (14.3–77.8)
Alendronate use	38	18	34.1 (15.2–76.6)	38.8 (15.9–94.6)
Risedronate use	6	4	19.7 (4.7–83.0)	41.2 (6.9–247.7)
Etidronate use	0	5	NA	NA
Ibandronate use	2	0	NA	NA
Per 100 DDDs among ever users	NA	NA	1.4 (1.2–1.6)	1.3 (1.1–1.6)
Duration of use (years)
Less than 1	3	7	6.8 (1.5–31.4)	9.8 (1.9–49.9)
1–1.9	4	6	7.1 (1.6–30.7)	9.5 (2.1–43.3)
2 or more	39	13	49.3 (20.6–118.0)	51.1 (20.3–128.2)
Time since last use (years)
< 1	42	16	44.0 (19.0–102.0)	47.5 (19.2–117.6)
1–1.9	1	4	2.4 (0.2–24.7)	3.7 (0.3–41.6)
2 or more	3	6	6.4 (1.3–31.9)	9.0 (1.8–45.8)
Per year since last use	NA	NA	0.29 (0.22–0.38)	0.28 (0.21–0.38)

^a Adjusted for age (as a continuous variable), use or nonuse of a glucocorticoid, and Charlson index.

Table 3. ASBMR Task force criteria for atypical femoral fractures from the first report in 2010 (left column) and revised after the second report in 2013 (right column). Bold font according to ASBMR´s original

2010	2013
Major features
Located anywhere along the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare Associated with no trauma or minimal trauma, as in a fall from a standing height or less Transverse or short oblique configuration Noncomminuted Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex.	The fracture is associated with minimal or no trauma, as in a fall from a standing height or less The fracture line originates at the lateral cortex and is substantially transverse in its orientation, although it may become oblique as it progresses medially across the femur Complete fractures extend through both cortices and may be associated with a medial spike; incomplete fractures involve only the lateral cortex The fracture is non-comminuted or minimally comminuted Localized periosteal or endosteal thickening of the lateral cortex is present at the fracture site (“beaking” or “flaring”)
Minor features
Localized periosteal reaction of the lateral cortex Generalized increase in cortical thickness of the diaphysis Prodromal symptoms such as dull or aching pain in the groin or thigh Bilateral fractures and symptoms Delayed healing Comorbid conditions (eg, vitamin D deficiency, RA, hypophosphatasia) Use of pharmaceutical agents (eg, BPs, GCs, PPIs)	Generalized increase in cortical thickness of the femoral diaphyses Unilateral or bilateral prodromal symptoms such as dull or aching pain in the groin or thigh Bilateral incomplete or complete femoral diaphysis fractures Delayed fracture healing

Figure 4. Measurement of fracture angle. A: atypical femoral fracture with a fracture angle close to 90 degrees measured on the proximal shaft fragment. B: fracture with an angle of about 30 degrees.

Figure 5. Frequency distribution of fracture angles. Fracture angles occurred in three different peaks. The peak in the middle represents a distinct subpopulation with fracture lines running close to perpendicular to the lateral cortex of the femoral shaft, i.e. 89 degrees, SD 10.

Table 4. Specificity and sensitivity of radiographic features to detect bisphosphonate treatment with 95% Confidence Intervals (CI)

	Specificity (95% CI)	Sensitivity (95% CI)
Fracture angle	0.93 (0.88–0.96)	0.61 (0.48–0.72)
Callus	0.96 (0.92–0.98)	0.55 (0.43–0.67)
Medial Spike	0.93 (0.88–0.96)	0.54 (0.41–0.66)
Number of fragments	0.48 (0.41–0.55)	0.78 (0.67–0.87)

Figure 6. A: Fracture line in the operating field surrounded by callus formation seen as a slight elevation of the surface. B: Bone biopsy including the fracture line.

Figure 7. Incomplete fracture. A: conventional radiograph. B: Cortical defect after taking a biopsy. C: Microradiography of the bone biopsy. Note the fracture line.

Figure 8. Incomplete fracture. g fracture gap, a amorphous material, r resorption cavity.

Figure 9. Incomplete fracture. g fracture gap. b bone fragments about to break off. d cellular remnants. r resorption cavity almost reaching into the fracture gap.

Figure 10. Incomplete atypical fracture, 18 months after cessation of bisphosphonate treatment. C periosteal callus. Dashed lines: fracture gap. White arrows: Remodeling within the fracture gap.

Figure 11. Hypothesis on the series of events leading to atypical femoral fracture.