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- SUBJECTS AND METHODS
Cyclooxygenase-2 enzyme activity is required for fracture healing (1). Several animal studies have documented that high-dose nonselective nonsteroidal antiinflammatory drugs (NSAIDs), medications that inhibit cyclooxygenase, impair fracture healing (2–4). However, NSAIDs are widely used by trauma patients and there have been no consistent findings suggesting that these drugs inhibit fracture healing in humans (5, 6). Prior studies have been limited by small sample sizes, referral populations, dependence on self report for NSAID exposure, and inconsistent definitions of nonunion.
Important clinical controversy exists regarding the safety of NSAIDs in the setting of healing fractures. The goal of the present study was to examine the relationship between nonselective NSAIDs and nonunion of fractures in older adults. To ensure adequate numbers of nonunions and unbiased reporting of NSAID exposure, we studied this question using a large community-based population where information on health care and pharmacy claims can be linked.
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- SUBJECTS AND METHODS
We identified 9,995 patients with an index humerus fracture and 105 (1.1%) had procedures for nonunion (see Table 1). The majority of patients were women with a mean age of 77 years. Most patients in the study sample were white, approximately one-quarter had diabetes mellitus, 10% had a diagnosis of osteoporosis, and the average number of comorbid conditions was ∼2.0. Nursing home residency was less common among patients who experienced nonunions.
Table 1. Characteristics of study cohort
| ||Nonunion n = 105||Healed fracture n = 9,890||P*|
|Age, mean ± SD, years||78 ± 6.3||77 ± 6.5||0.29|
|Female sex, no. (%)||94 (89)||8691 (87)||0.60|
|Race, no. (%)|| || || |
| White||98 (93)||9,093 (91)||0.60|
| Other||7 (7)||797 (8)|| |
|History of diabetes mellitus, no. (%)||30 (28)||2,548 (25)||0.51|
|History of osteoporosis, no. (%)||10 (9)||1,297 (13)||0.27|
|Nursing home residency, no. (%)||9 (9)||1,704 (17)||0.02|
|Comorbidity score, mean ± SD||1.8 ± 1.7||1.8 ± 1.3||0.29|
NSAID use was common in the study cohort; 1,032 (10.3%) patients in both groups used NSAIDs within the 90 days after the index fracture. Many patients used NSAIDs in several of the 30-day periods immediately after their index humerus fracture (see Table 2). NSAID use in the 90 days after the index humeral fracture was more common in patients with nonunion than in patients with healed fractures.
Table 2. Patterns of prescription NSAID use*
| ||Nonunion||Healed fracture|
|Any NSAID use||33 (31)||999 (10)|
|0–30 days||1 (1)||157 (2)|
|31–60 days||1 (1)||131 (1)|
|61–90 days||8 (8)||205 (2)|
|0–60 days||2 (2)||105 (1)|
|0–30 and 61–90 days||0 (0)||21 (0.2)|
|31–90 days||10 (10)||195 (2)|
|0–90 days||11 (11)||185 (2)|
Patients using NSAIDs within the 90 days after fracture had an unadjusted relative risk (RR) of nonunion of 3.7 (95% confidence interval [95% CI] 2.4–5.6) (see Table 3). Exposure to NSAIDs within any of the 3 30-day exposure periods was associated with an increased unadjusted risk of nonunion. Exposure during the period 61–90 days had the highest risk (RR 5.2, 95% CI 3.4–8.0).
Table 3. Unadjusted relative risk of humeral shaft nonunion in subjects using prescription NSAIDs or opioids*
|Exposure after index humeral fracture||Relative risk (95% CI)|
|NSAID use within 1–90 days||3.7 (2.4–5.6)|
|NSAID period, days|| |
| 1–30||2.9 (1.6–5.1)|
| 31–60||4.0 (2.6–6.4)|
| 61–90||5.2 (3.4–8.0)|
|Opioid use within 1–90 days||1.6 (1.1–2.5)|
|Opioid period, days|| |
| 1–30||1.3 (0.8–2.1)|
| 31–60||1.7 (1.0–2.9)|
| 61–90||2.6 (1.6–4.2)|
To control for the independent contribution of each exposure period, all 3 exposure periods were entered into the same multivariate model. When NSAID use during each of the 3 30-day exposure periods was included in the same adjusted model, only NSAID use during the period 61–90 days postfracture proved to be significant: RR 3.9, 95% CI 2.0–6.2 (Figure 1). The RR of nonunion for NSAID exposure during the periods 1–30 days and 31–60 days after the index fracture were no longer significantly elevated.
Figure 1. Multivariate analysis of nonselective nonsteroidal antiinflammatory drugs (NSAIDs) and nonunion risk. Data are controlled for age, sex, nursing home status, diabetes, osteoporosis, and comorbidity index. Error bars represent 95% confidence intervals.
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To assess whether NSAID use in the period 61–90 days postfracture was aimed to treat the pain of nonunion, we investigated the pattern of opioid use in similar 30-day periods. Opioid use in the period 61–90 days postfracture was also significantly associated with nonunion: RR 2.7, 95% CI 1.5–5.2 (see Figure 2). The 2 earlier opioid exposure periods were not associated with nonunion.
Figure 2. Multivariate analysis of opioid use and nonunion risk. Data are controlled for age, sex, nursing home status, diabetes, osteoporosis, and comorbidity index. Error bars represent 95% confidence intervals.
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- SUBJECTS AND METHODS
Because nonunion after fractures is a rare event, our study was designed to use a large health care claims database to investigate the relationship between NSAID use and nonunion. Because nonunion is defined as the absence of healing after a set duration, it is difficult to determine exactly when a nonunion began. This problem exists in our health care claims database as well as in the medical records. Moreover, clinical datasets that may be able to date nonunions more precisely are not large enough to study this rare outcome. This ambiguity with “dating” the endpoint makes estimating the association between a drug exposure and nonunion problematic.
In this study of older adults, we found no relationship between nonselective NSAID use in the first 60 days after humerus fracture and nonunion. The use of NSAIDs 61–90 days after fracture was associated with an increased risk of nonunion, and the increased risk was also observed for patients exposed to opioid analgesics in the same period 61–90 days after humerus fracture.
We doubt that this association between late use of NSAIDs and nonunion is causal. First, this effect is inconsistent with what is known about the biology of fracture healing. Cyclooxygenase activity is strongly upregulated in the first 14 days postfracture, and by 21 days returns to normal; even animals treated with high-dose NSAIDs will have fracture healing by 35 days (3). Second, there are no data suggesting that opioids retard fracture healing. For these 2 reasons, we strongly believe that the associations that we have described are due to protopathic bias (9), where NSAID and opioid analgesic use are markers for patients in pain from unstable fractures. Protopathic bias is essentially confusing the cause and effect, such that the drug-outcome relationship is reversed. In our example, a nonhealing fracture may prompt analgesia with an NSAID or an opioid and subsequently the patient undergoes a procedure to stabilize the nonunion. In our claims database, we cannot date the onset of the nonunion and thus late analgesic use might appear as the “cause” of nonunion.
Few human studies have investigated the relationship between NSAIDs and nonunions. Giannoudis et al retrospectively reviewed the medical records of 377 patients with femur fractures (5). Twenty of 32 patients with nonunion took NSAIDs at some point in their postoperative course (odds ratio 10.7). However the time course and dose of NSAID were not reported. It is possible that patients with nonunions experienced greater pain and may have been using NSAIDs to treat nonunions after they were beginning to develop. Bhandari and colleagues investigated the predictors of reoperation after tibia fractures and found that NSAIDs did not prove to be a significant risk factor for nonunion in the multivariate analysis (6). In a recent prospective randomized study of heterotopic ossification after acetabulum fractures, Burd and colleagues noted that the group receiving high-dose indomethacin for 6 weeks had an increased rate of long bone nonunion (10). However, this study was limited to patients at risk for heterotopic ossification and examined only one NSAID, high-dose indomethacin. Moreover, the previous clinical literature did not address the time course of NSAID use; thus, prior findings may be documenting the same phenomenon: NSAIDs are being used for the pain of nonhealing fractures, not that NSAIDs cause nonunions.
As noted by Einhorn, although the laboratory evidence of inhibition of fracture healing is strong, the widespread use of NSAIDs by patients with fractures has not manifested a clinical problem with nonunion (11). This may be due to differences in the biology of human fractures, or due to the relative doses of NSAIDs used in animals as compared with normal prescription doses. Because nonunion is a rare event (∼1%) with modern treatment regimens, adequately powered studies must be very large. We present the largest series to date with the greatest number of nonunions.
Our study has several limitations. First, we do not have detailed clinical data on the patients, such as fracture configuration or pain intensity. However, clinical databases that may contain such information usually rely on patient report to determine drug utilization. Because patient self report of medication use is unreliable, this poses its own set of problems. Second, we can only document prescription NSAID use. In low-income elderly patients with full drug benefits, prescription NSAID use (versus over-the-counter) is the presumption. However, if control patients were using over-the-counter NSAIDs, this would tend to bias the data toward the null. Third, our data do not allow us to know that patients actually took the medications, only that they filled a prescription. Fourth, there is little data on the biology of established nonunions. It may be that nonselective NSAID use 61–90 days postfracture does indeed have a strong detrimental effect on established nonunions. Finally, it may be that both NSAIDs and opioids are inhibitors of fracture healing through pain reduction and enhanced movement of the affected limb. Movement of a fractured humerus may potentiate nonunions. We cannot rule this out as a possible explanation of our findings.
In summary, the association between NSAIDs and nonunions is complex. Although crude analyses suggest that NSAID exposure is associated with nonunions, analysis of the time course suggests that it is use of NSAIDs late in fracture healing that is most strongly associated with nonunion. Because a similar association is observed with opioids, a drug category without any known effects on fracture healing, it is probable that NSAIDs are being used to treat painful impending nonunions, rather than the NSAIDs causing nonunions.