Risk of atypical femoral fracture during and after bisphosphonate use

Figures & data

Figure 1. Identification of atypical femoral fractures in the study population. Patients from 2008 were women only. ^a Mechanically altered femurs include patients with knee and hip prostheses, retained plates, screws, intramedullary nails, joint arthrodeses, and other conditions.

Table 2. Age-adjusted relative risk (RR) and absolute risk (AR), with 95% confidence intervals (95% CIs), of atypical femoral fracture associated with use of bisphosphonate in women and men 55 years of age or older, during the 3-year period 2008–2010

Bisphosphonate use	No. of atypical fractures	Crude incidence n/10,000 patient-years	Age-adjusted RR (95% CI)	Age-adjusted AR (95% CI)
Women
Never use	30	0.08	Reference	Reference
Any type of bisphosphonate	130	5.0	55 (39–79)	0.0005 (0.0004–0.0006)
Alendronate	117	5.9	63 (41–97)	0.0006 (0.0005–0.0007)
Risedronate	15	5.4	35 (19–66)	0.0003 (0.0001–0.0006)
Men
Never use	8	0.03	Reference	Reference
Any type of bisphosphonate	4	1.6	54 (15–192)	0.0002 (0.0000–0.0003)
Women compared to men ^a
Men, users of bisphosphonate	4	1.6	Reference	Reference
Women, users of bisphosphonate	86	5.0	3.1 (1.1–8.4)	0.0003 (0.0001–0.0005)
Men, non-users	8	0.030	Reference	Reference
Women, non-users	21	0.072	2.3 (1.0–5.3)	< 0.000001

^a Based on data from 2009 and 2010.

Figure 2. Age-adjusted relative risk of atypical femoral fracture in women, by duration of use compared to non-use. Relative risk estimates (dots) with error bars representing 95% CIs.

Table 3. Characteristics of stress fracture cases and controls with ordinary femoral shaft fractures

	Cases (n = 172) Bisphosphonate		Controls (n = 952) Bisphosphonate
	users	non-users	users	non-users
	n = 134	n = 38	n = 110	n = 842
Age ^a	77 (7.8)	75 (9.3)	81 (8.5)	82 (9.8)
Women ^b	130 (97)	30 (79)	104 (95)	670 (80)
Men ^b	4 (3)	8 (21)	6 (5)	172 (20)
Drug use ^b
Cortisone	48 (36)	5 (13)	35 (32)	116 (14)
Estrogen	43 (32)	7 (18)	34 (31)	141 (17)
SERM	1 (1)	0	2 (2)	1 (0)
Antidepressives	28 (21)	8 (21)	41 (37)	283 (34)
Antiepileptics	8 (6)	3 (8)	6 (5)	76 (9)
Proton-pump inhibitors	56 (42)	9 (24)	37 (34)	251 (30)
Previous diseases ^b
Any fracture ^c	59 (44)	17 (45)	57 (52)	341 (41)
Osteoporotic fracture ^d	42 (31)	10 (26)	50 (45)	291 (35)
Hip fracture	11 (8)	5 (13)	18 (16)	106 (13)
Musculoskeletal disease	86 (64)	18 (47)	73 (66)	321 (38)
Inflammatory joint disease	6 (4)	0 (0)	6 (5)	15 (2)
Osteoporosis	21 (16)	0 (0)	16 (14)	18 (2)
Cardiovascular disease	65 (49)	14 (37)	74 (67)	493 (59)
Ischemic heart disease	27 (20)	6 (16)	22 (20)	179 (21)
Stroke	5 (4)	0 (0)	12 (11)	107 (13)
Endocrine disorder	24 (18)	9 (24)	33 (30)	261 (31)
Diabetes mellitus	5 (4)	2 (4)	15 (14)	136 (16)
Malignancy	18 (13)	6 (16)	19 (17)	160 (19)
Neurological disorder	13 (10)	1 (3)	21 (19)	205 (24)
Psychiatric disease	9 (7)	3 (8)	26 (24)	201 (24)
Kidney or urinary disease	43 (32)	10 (26)	53 (48)	318 (38)
Gastrointestinal disease	42 (31)	15 (40)	46 (42)	283 (34)
Respiratory disease	32 (24)	8 (21)	19 (17)	199 (24)

^a mean (SD)

^b n (%)

^c Including ICD-10 codes: S12, S22, S32, S42, S52, S62, S72, S82, S92.

^d Including ICD-10 codes: hip S720, S721, S722; proximal humerus S422; distal forearm: S524, S525, S526; spine S220, S320.

Table 4. Odds ratios (ORs), with 95% confidence intervals (CIs), for femoral stress fractures associated with bisphosphonate use

Bisphosphonate use	Cases Controls		Age- and sex-adjusted OR (CI)	Multi variable-adjusted ^a OR (CI)
Never use	38	842	1.0 (reference)	1.0 (rreference)
Ever use	134	110	26 (20–34)	26 (18–38)
		(78%)	(12%)
Alendronate use	120	73	36 (29–44)	36 (28–46)
Any other oral bisphosphonate	18	39	7.8 (4.1–15)	8.0 (4.0–16)
Risedronate use	16	26	12 (6.5–21)	13 (6.1–26)
Etidronate use	0	13	NA	NA
Ibandronate use	2	0	NA	NA
Zoledronate use	0	2	NA	NA
Per year since last use			0.31 (0.28–0.36)	0.31 (0.27–0.35)
Per year of use			2.6 (2.1–3.2)	2.5 (2.0–3.1)
Current use (within the last year)	129	79	34 (26–46)	35 (23–51)
Years of use ^b in current users
0–1	1	10	1.3 (0.1–16)	1.7 (0.2–19)
1–2	5	11	8.4 (2.5–28)	8.2 (2.5–27)
2–3	17	11	27 (25–30)	29 (26–32)
3–4	12	5	47 (22–99)	40 (17–91)
4–5	13	3	81 (40–164)	116 (58–234)
> 5	11	5	85 (66–111)	93 (66–132)
Women
Never use	30	670	1.0 (reference)	1.0 (reference)
Ever use	130	104	26 (21–33)	29 (21–41)
		(81%)	(13%)
Per year of use			2.6 (2.2–3.2)	2.6 (2.1–3.3)
Per year since last use			0.30 (0.28–0.33)	0.29 (0.26–0.32)
Men
Never use	8	172	1.0 (reference)	1.0 (reference)
Ever use	4	6	19.1 (8.0–46.0)	19.0 (9.9–36.6)
		(33%)	(3%)
Per year of use			2.1 (1.3–3.3)	2.4 (2.1–2.7)
Per year since last use			0.37 (0.28–0.50)	0.37 (0.30–0.47)

^a Adjusted by age (continuous), sex, cortisone use (yes/no), and Charlson’s co-morbidity index (continuous).

^b First use after October 1, 2005 to ascertain non-use in the period July through September 2005. The national Swedish Prescription Register started on July 1, 2005, and provides complete national data on individuals exposed to dispensed drugs in the Swedish population; the drugs are normally dispensed every third month.

NA: not applicable.

Figure 3. Schematic graph of risk over time, with arbitrary units. Blue curve: risk of fragility fracture; red curve: total fracture risk; dashed red line: projected total risk without cessation. The curves are based on the assumption that the protective effect against ordinary (non-atypical) fractures has a longer half-life than the risk of atypical fracture.