Negative pharmacological effect on spine fusion: A narrative review of the literature of evidence-based treatment.

Spine fusion surgery is commonly performed for diverse indications, the most frequent one being degenerative spine diseases. Despite the growing importance of this surgery, there is limited evidence concerning the effects of drugs on the process of spine fusion and healing. While asymptomatic sometimes, nonunion of the spine can have tremendous repercussions on the patients' quality of life and the healthcare system rendering it an "expensive complication". This literature review identifies the role of some perioperative drugs in spine fusion and reveals their potential role in pseudarthrosis of the spine. This review also benefits spine surgeons looking for current evidence-based practices. We reviewed the data related to nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids, vancomycin, bisphosphonates, proton pump inhibitors (PPIs), pregabalin, and opioids. From the available experimental and clinical studies, we conclude that bisphosphonates might positively influence the process of spine fusion, while steroids and vancomycin have shown variable effects, and the remaining medications likely disturb healing and union of the spine. We recommend spine surgeons be cautious about the drugs they resort to in the critical perioperative period until further clinical studies prove which drugs are safe to be used.

Do Nonsteroidal Anti-Inflammatory or COX-2 Inhibitor Drugs Increase the Nonunion or Delayed Union Rates After Fracture Surgery?: A Propensity-Score-Matched Study.

BACKGROUND: The effects of nonsteroidal anti-inflammatory drugs (NSAIDs)/cyclooxygenase (COX)-2 inhibitors on postoperative fracture-healing are controversial. Thus, we investigated the association between NSAID/COX-2 inhibitor administration and postoperative nonunion or delayed union of fractures. We aimed to determine the effects of NSAID/COX-2 inhibitor administration on postoperative fracture-healing with use of a common data model. METHODS: Patients who underwent operative treatment of a fracture between 1998 and 2018 were included. To determine the effects of NSAID/COX-2 inhibitor administration on fracture-healing, postoperative NSAID/COX-2 inhibitor users were compared and 1:1 matched to nonusers, with 3,264 patients matched. The effect of each agent on bone-healing was determined on the basis of the primary outcome (nonunion/delayed union), defined as having a diagnosis code for nonunion or delayed union ≥6 months after surgery. The secondary outcome was reoperation for nonunion/delayed union. To examine the effect of NSAIDs/COX-2 inhibitors on bone union according to medication duration, a Kaplan-Meier survival analysis was performed. RESULTS: Of the 8,693 patients who were included in the analysis, 208 had nonunion (178 patients; 2.05%) or delayed union (30 patients; 0.35%). Sixty-four (30.8%) of those 208 patients had a reoperation for nonunion or delayed union. NSAID users showed a significantly lower hazard of nonunion compared with the matched cohort of nonusers (hazard ratio, 0.69 [95% confidence interval, 0.48 to 0.98]; p = 0.040) but did not show a significant difference in the other matched comparison for any other outcomes. Kaplan-Meier survival analysis revealed significantly lower and higher nonunion/delayed union rates when the medication durations were ≤3 and >3 weeks, respectively (p = 0.001). For COX-2 inhibitors, the survival curve according to the medication duration showed no significant difference among the groups (p = 0.9). CONCLUSIONS: Our study demonstrated no short-term impact of NSAIDs/COX-2 inhibitors on long-bone fracture-healing. However, continued use of these medications for a period of >3 weeks may be associated with higher rates of nonunion or delayed union. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Risk of Nonunion with Nonselective NSAIDs, COX-2 Inhibitors, and Opioids.

BACKGROUND: Cyclooxygenase-2 (COX-2) has been found to be important for fracture-healing in animal models, raising concerns about use of nonsteroidal anti-inflammatory drugs (NSAIDs) and selective COX-2 inhibitors after fractures. We evaluated associations of NSAIDs, COX-2 inhibitors, and opioids with nonunion after long-bone fracture. METHODS: Using private health insurance claims data from Optum's de-identified Clinformatics Data Mart database from January 1, 2000, to September 30, 2015, we identified adults with a single long-bone fracture or commonly paired long-bone fractures who had 1 year of available follow-up data. Using multivariable logistic regression models, we examined associations between NSAID, COX-2-inhibitor, or opioid prescription fills after the fracture and the risk of nonunion within 1 year, defined as a nonunion diagnosis with a procedure to treat the nonunion. RESULTS: A nonunion diagnosis with a procedure to treat the nonunion was identified after 2,996 (0.9%) of the 339,864 fracture episodes, with rates varying by fracture site. The risk of that outcome was greater in patients who had filled COX-2-inhibitor prescriptions (adjusted odds ratio = 1.84 [95% confidence interval = 1.38 to 2.46]) or opioid prescriptions (1.69 [1.53 to 1.86]), but not in patients who had filled nonselective-NSAID prescriptions (1.07 [0.93 to 1.23]) after the fracture. Results were similar when the outcome definition was changed to just a nonunion diagnosis. CONCLUSIONS: COX-2 inhibitors, but not nonselective NSAIDs, were associated with a greater risk of nonunion after fracture. Opioids were also associated with nonunion risk, although patients filling prescriptions for opioids may have had more severe fractures. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

The Effect of Postoperative Nonsteroidal Anti-inflammatory Drugs on Nonunion Rates in Long Bone Fractures.

The association of nonsteroidal anti-inflammatory drugs (NSAIDs) with non-union in long bone fractures has been controversial. The purpose of this study was to evaluate whether NSAID exposure results in increased risk of non-union in operatively treated long bone fractures. The authors used International Classification of Diseases and Current Procedural Terminology codes to identify patients under a single-payer private insurance with operatively treated humeral shaft, tibial shaft, and subtrochanteric femur fractures from a large database. Patients were divided into cohorts based on NSAID use in the immediate postoperative period, and nonunion rates were compared. A cost analysis and a multivariate analysis were performed. Between 2007 and 2016, a total of 5310 tibial shaft, 3947 humeral shaft, and 8432 subtrochanteric femur fractures underwent operative fixation. Patients used NSAIDs in the first 90 days postoperatively in 900 tibial shaft, 694 humeral shaft, and 967 subtrochanteric femur fractures. In these patients, nonunion rates were 18.8%, 17.4%, and 10.4%, respectively. When no NSAIDs were used, the rates were 11.4%, 10.1%, and 4.6% for each fracture type, respectively (P<.05). Among patients taking NSAIDs, subtrochanteric femur fractures had a 2.4 times higher risk of nonunion and humeral shaft and tibial shaft fractures both had a 1.7 times higher risk of nonunion (P<.05). Multivariate analysis showed NSAID use to be an independent risk factor in all 3 types. Cost analysis showed a great increase in economic burden (P<.05). This study indicated that NSAID exposure was associated with fracture nonunion. [Orthopedics. 2020;43(4):221-227.].

Opioid exposure is associated with nonunion risk in a traumatically injured population: An inception cohort study.

INTRODUCTION: Certain common medications are associated with an elevated risk of fracture and recent data suggests that medications can also increase nonunion risk. Medication use is a modifiable nonunion risk factor, but it is unknown whether risk accrues solely to chronic medication use or whether there is also risk inherent to acute use. METHODS: Multivariate logistic regression was used in an inception cohort to calculate odds ratios (OR) for fracture nonunion associated with medication use, in context with other risk factors demonstrated to influence nonunion. Patient-level health claims for medical and drug expenses were compiled from a payer database. Patients were included if they had a fracture coded in 2011, with continuous enrollment for 1 month prior to and 12 months after fracture. The database contained demographic descriptors, treatment procedures per CPT codes, co-morbidities per ICD-9 codes, and prescriptions per National Drug Codes. Chronic medication use was defined as ≥30 days of prescription prior to fracture with ≥1 day afterward; acute use was any other prescription. RESULTS: Most non-analgesic medications were safe in acute or chronic use, but risk of nonunion was elevated for a wide range of analgesics. Overall, 45,085 fractures (14.6% of fractures) affected patients using chronic opioids. Nonunion OR was elevated for acute and chronic use of Schedule 2 opioids including acetaminophen/oxycodone, hydromorphone, oxycodone, and acetaminophen/hydrocodone bitartrate, as well as Schedule 3-5 opioids including tramadol (all, p < 0.0001). The highest ORs were associated with chronic administration of Schedule 2 opioids. DISCUSSION: Most medications do not increase nonunion risk, but acute and chronic use of NSAIDs or opioids was associated with impaired fracture healing. There is particular risk in prescribing opioid analgesics for fracture, though literature suggests that roughly half of opioid-naïve patients receive such a prescription. CONCLUSIONS: Patients evaluated in this study were not a random sample of Americans; they may approximate a random sample of the Emergency Department population in the United States. Thus, trauma patients may represent a population enriched for nonunion risk factors. Opioids impair recovery from injury; if they also predispose to injury, the ongoing opioid epidemic could presage an increase in nonunion prevalence.

Factors Associated with Increased Healing Time in Complete Femoral Fractures After Long-Term Bisphosphonate Therapy.

BACKGROUND: The purpose of this study was to analyze factors that affect healing time after operative treatment of complete femoral fractures associated with long-term use of bisphosphonates. In particular, we sought to determine surgically controllable factors related to fracture-healing time. METHODS: Ninety-nine consecutive patients (109 fractures) who had been surgically treated for a complete atypical femoral fracture were enrolled. All patients had a documented history of bisphosphonate therapy at the time of presentation, with an average duration of 7.4 ± 3.5 years (range, 3 to 20 years). Baseline demographic data, characteristics of the fracture and surgery, and radiographic findings including femoral neck-shaft angle, coronal and sagittal bowing of the femur, and thickness of the femoral cortex were examined. Univariate and multivariate logistic regression analyses were performed to identify predictive factors associated with delayed union or nonunion. RESULTS: Of the 109 fractures, 76 (69.7%) showed osseous union within 6 months after the index surgery and were assigned to the successful healing group. The remaining 33 fractures (30.3%), which showed delayed union or nonunion, were assigned to the problematic healing group. There were differences in body mass index (BMI), bisphosphonate therapy duration, and the rate of prodromal symptoms between the 2 groups. Supra-isthmic fracture location, femoral bowing of ≥10° in the coronal plane, and a lateral/medial cortical thickness ratio of ≥1.4 were predictive of problematic healing but were uncontrollable factors. Iatrogenic cortical breakage around the fracture site as well as a ratio of ≥0.2 between the remaining gap and the cortical thickness on the anterior and lateral sides of the fracture site were controllable predictive factors associated with problematic healing. CONCLUSIONS: Intramedullary nailing without cortical breakage around the fracture site and decreasing the anterior and lateral fracture gaps (avoidance of distraction) as much as possible are recommended to reduce healing time in complete femoral fractures associated with long-term use of bisphosphonates. LEVEL OF EVIDENCE: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Does bisphosphonate-based anti-osteoporosis medication affect osteoporotic spinal fracture healing?

UNLABELLED: Effects of bisphosphonate on fracture healing were prospectively investigated for osteoporotic spinal fracture. Although there were no significant differences in clinical outcomes, the presence of intravertebral cleft was related to the medication use. These results suggest that suspension of bisphosphonate use should be considered during the fracture healing period. INTRODUCTION: The purpose of this prospective study is to investigate whether bisphosphonate-based anti-osteoporosis medication affects fracture healing and clinical outcomes of conservatively treated osteoporotic spinal fractures (OSFs). METHODS: A total of 105 patients who were diagnosed with acute OSFs were prospectively enrolled. According to their previous medication history, the patients were allocated into group I (n = 39, no history of bisphosphonate use) or group II (n = 66, history of bisphosphonate use). Clinical outcomes were assessed using visual analogue scale (VAS), and Oswestry disability index (ODI). Radiographic parameters including changes in height loss and kyphotic angle at the index vertebra were measured, and radiographic findings suggesting impaired fracture healing such as the intravertebral cleft (IVC) sign and fracture instability were evaluated. Univariate and multivariate regression analyses were used to identify related factors. RESULTS: There were no significant differences in the last VAS and ODI between groups. There were also no significant differences in the radiographic parameters. Although the IVC sign was seen more commonly in group II (30.3 %) than in group I (20.5 %), fracture instability combined with IVC was noted in the same number of cases. On multiple regression analysis, medication history showed no significant relationship with the clinical parameters. However, the presence of the IVC sign was related to medication history (odds ratio 4.8; 95 % confidence interval [CI] 1.02-22.69). CONCLUSIONS: Bisphosphonate use does not significantly affect the clinical results during conservative treatment for OSFs. However, the occurrence of the IVC sign was related to medication history. Although further studies are needed to verify our findings, these results suggest that suspension of bisphosphonate use should be considered during the fracture healing period for acute OSFs.

Bony non-union in a patient receiving androgen deprivation therapy for prostate cancer.

We present a case of a 76-year-old man who underwent a corrective femoral osteotomy for a varus deformity and stress fractures. The patient was on androgen deprivation therapy (ADT) for prostate cancer and the osteotomy failed to heal. At 13 months, the ADT was stopped and bony union was achieved in 3 months. Orthopaedic surgeons treating fractures in this patient population need to aware of the problems associated with ADT and closely liaise with oncologists and urologists to stop ADT or start alternative treatment until bony union has been achieved.

Bisphosphonates and their influence on fracture healing: a systematic review.

UNLABELLED: Bisphosphonates are commonly used in osteoporosis, but concerns have been raised about possible negative effects on fracture healing. We systematically reviewed the literature and found that bisphosphonates significantly prolong union times of distal radius fractures but not femoral fractures. The timing of bisphosphonate introduction does not affect fracture union time. INTRODUCTION: Bisphosphonates are the most commonly prescribed drugs in patients suffering from and at higher risk of developing osteoporosis. However, concerns have been raised as to whether these drugs have a negative effect on fracture healing. The aim of this systematic review is to explore further these concerns. METHODS: A literature review was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. All relevant articles found via MEDLINE, Cochrane, CINAHL, EMBASE and Google Scholar were screened. Studies with information on bisphosphonates' effect on fracture healing in humans were included and systematically reviewed. RESULTS: Patients with distal radius fractures on bisphosphonates had a significantly longer union time compared with controls, but not patients with femoral fractures. No correlation between timing of bisphosphonate introduction and union time for fractures was found. Although one study reported a higher humeral non-union associated with bisphosphonate introduction following the fracture, there was no evidence that bisphosphonate introduction, timing or dose resulted in a significant delay in union following other fractures. CONCLUSIONS: This systematic review has shown that bisphosphonates significantly prolong union times of distal radius fractures. Some clinical findings are in contrast with preclinical studies highlighting the need to develop better animal models to study osteoporosis, treatment and fracture healing. There is also a need for more well-constructed studies looking at the clinical effect of bisphosphonate on fracture healing in a large number of patients. These robust studies need to look at union time and non-union rates as a function of duration and dose of different bisphosphonates in different upper and lower limb fractures.

Indomethacin prophylaxis for heterotopic ossification after acetabular fracture surgery increases the risk for nonunion of the posterior wall.

OBJECTIVES: To determine if indomethacin has a positive clinical effect for the prophylaxis of heterotopic ossification (HO) after acetabular fracture surgery. To determine whether indomethacin affects the union rate of acetabular fractures. DESIGN: Prospective randomized double-blinded trial. SETTING: Level 1 regional trauma center. PATIENTS: Skeletally mature patients treated operatively for an acute acetabular fracture through a Kocher-Langenbeck approach. INTERVENTION: Patients were randomly allocated to 1 of 4 groups comparing placebo (group 1) to 3 days (group 2), 1 week (group 3), and 6 weeks (group 4) of indomethacin treatment. MAIN OUTCOME MEASUREMENTS: Factors analyzed included the overall incidence, Brooker class and volume of HO, radiographic union of the acetabular fracture, and pain. Patients were followed clinically and radiographically at 6 weeks, 3 months, 6 months, and 1 year. Serum levels of indomethacin were drawn at 1 month to assess compliance. Computed tomographic scans were performed at 6 months to assess healing and volume of HO. RESULTS: Ninety-eight patients were enrolled into this study, 68 completed the follow-up and had the 6-month computed tomographic scan, and there was a 63% compliance rate with the treatment regimen. Overall incidence of HO was 67% for group 1, 29% for group 2 (P = 0.04), 29% for group 3 (P = 0.019), and 67% for group 4. The volume of HO formation was 17,900 mm for group 1, 33,800 mm for group 2, 6300 mm for group 3 (P = 0.005), and 11,100 mm for group 4. The incidence of radiographic nonunion was 19% for group 1, 35% for group 2, 24% for group 3, and 62% for group 4 (P = 0.012). Seventy-seven percent of the nonunions involved the posterior wall segment. Pain visual analog scores (VASs) were significantly higher for patients with radiographic nonunion (VAS 4 vs. VAS 1, P = 0.002). CONCLUSIONS: Treatment with 6 weeks of indomethacin does not appear to have a therapeutic effect for decreasing HO formation after acetabular fracture surgery and appears to increase the incidence of nonunion. Treatment with 1 week of indomethacin may be beneficial for decreasing the volume of HO formation without increasing the incidence of nonunion. LEVEL OF EVIDENCE: Therapeutic Level II. See Instructions for Authors for a complete description of levels of evidence.

Delayed/non-union of upper limb fractures with bisphosphonates: systematic review and recommendations.

BACKGROUND: Bisphosphonates (BPs) are widely used for the treatment of osteoporosis. Oversuppression of bone turnover with BPs may paradoxically limit the reserve capacity of bone to heal. The aim of this review was to study the predisposition of some patients to delayed/non-union of upper limb fractures associated with BPs and give recommendations on how they should be treated. METHODS: A systematic search of two electronic databases was conducted to identify relevant studies for inclusion. All relevant studies found were included and assessed through methodology criteria predetermined by two independent reviewers. RESULTS: Six papers comprising of three case reports, one nested case control study, one restrospective review and one randomized clinical trial were used. In comparative studies of pre-fracture BP use, a 6-day delay in average healing times was reported among BP users. There was no elevation in risk of non-union. Post-fracture BP use was associated with an approximate doubling of the risk of non-union. Timing of BP therapy initiation following a fracture was not associated with a difference in healing times. An atypical ulna fracture treated conservatively resulted in non-union, there was no effect of type of surgical treatment on distal radius fracture healing and there was insufficient evidence to comment on humeral fracture treatment. CONCLUSIONS: Differences in union time between BP users and non-users are not significant enough to change current practice patterns and do not outweigh the benefits of BP therapy. There is no evidence to encourage early surgical management of BP-related upper limb fractures.

Nonsteroidal anti-inflammatory drugs' impact on nonunion and infection rates in long-bone fractures.

BACKGROUND: There is a dearth of clinical data regarding the effect of nonsteroidal anti-inflammatory drugs (NSAIDs) on long-bone fracture (LBF) healing in the acute trauma setting. The orthopedic community believes that the use of NSAIDs in the postoperative period will result in poor healing and increased infectious complications. We hypothesized that, first, NSAID use would not increase nonunion/malunion and infection rates after LBF. Second, we hypothesized that tobacco use would cause higher rates of these complications. METHODS: A retrospective study of all patients with femur, tibia, and/or humerus fractures between October 2009 and September 2011 at a Level 1 academic trauma center was performed . In addition to nonunion/malunion and infection rates, patient records were reviewed for demographic data, mechanism of fracture, type of fracture, tobacco use, Injury Severity Score (ISS), comorbidities, and medications given. RESULTS: During the 24-month period, 1,901 patients experienced LBF; 231 (12.1%) received NSAIDs; and 351 (18.4%) were smokers. The overall complication rate including nonunion/malunion and infection was 3.2% (60 patients). Logistic regression analysis with adjusted odds ratios were calculated on the risk of complications given NSAID use and/or smoking, and we found that a patient is significantly more likely to have a complication if he or she received an NSAID (odds ratio, 2.17; 95% confidence interval, 1.15-4.10; p < 0.016) in the inpatient postoperative setting. Likewise, smokers are significantly more likely to have complications (odds ratio, 3.19; 95% confidence interval, 1.84-5.53; p < 0.001). CONCLUSION: LBF patients who received NSAIDs in the postoperative period were twice as likely and smokers more than three times likely to suffer complications such as nonunion/malunion or infection. We recommend avoiding NSAID in traumatic LBF. LEVEL OF EVIDENCE: Epidemiologic & therapeutic study; level II.

Atypical femoral fractures after anti-osteoporotic medication: a Korean multicenter study.

PURPOSE: Increasing numbers of atypical femoral fractures have been reported among long-term bisphosphonate users. We evaluated clinical characteristics of atypical femoral fractures throughout Korean multicenter studies. METHODS: We retrospectively analysed the bone mineral density, prodromal symptoms before femoral fracture, and medication history of osteoporosis in 76 cases of atypical femoral fracture. RESULTS: The mean age of cases was 71.4 ± 8.8 (range, 43-89) years old. The mean follow-up period after the fracture operation was 24.5 ± 12.9 (range, 12-79) months. BMI was 23.2 ± 3.0 on average. The mean BMD of femur was -1.9 ± 1.4 (range, -4.8 to 1.3). Prodromal symptoms including thigh pain before femoral fracture appeared in 22 (28.9 %) of 76 patients. All patients included in the study used bisphosphonate. The duration of taking bisphosphonate before fracture was 36.8 ± 50.8 (one-204 months) months. Fifty-seven (75 %) of 76 patients were taking the medication for more than three years. Delayed union occurred in 43 (56.5 %) of 76 patients. Delayed union was defined as a fractured bone that did not completely heal within six months of injury. The group of having taken anti-osteoporotic medication for more than three years showed relatively longer union period compared to that for a shorter period medication group (4.8 ± 2.5 months vs 9.3 ± 3.7 months, p = 0.017). The delayed union developed in 43 (56.5 %) of 76 patients and showed a significantly higher incidence in the group with long-term therapy (five/43 vs 38/43, p = 0.021). The bilateral femoral fractures developed in 23 (30.2 %) of 76 patients and showed a high incidence in the group medicated more than three years (two/23 vs 21/23, p = 0.039). CONCLUSIONS: The longer bisphosphonates are used, the more the cases of delayed union and the more frequent the development of bilateral fractures following unilateral fractures. With regard to the delayed union, the methods of the acceleration of fracture healing may be beneficial in atypical femoral fracture patients who had been receiving long-term bisphosphonates therapy. Careful observation is required for contra-lateral femurs due to a high incidence of bilateral atypical femoral fractures.

Association between timing of zoledronic acid infusion and hip fracture healing.

UNLABELLED: Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period. INTRODUCTION: Intravenous zoledronic acid 5 mg (ZOL) given after a hip fracture reduces secondary fracture rates and mortality. It has been postulated that bisphosphonates may affect healing if given soon after a fracture. We sought to determine whether the timing of ZOL infusion affected the risk of delayed hip fracture healing. METHODS: In the HORIZON Recurrent Fracture Trial, patients were randomized within 90 days of a low-trauma hip fracture to receive either once-yearly ZOL (n = 1,065) or placebo (n = 1,062). Clinical symptoms of delayed hip fracture healing were sought at randomization, 6 months and 12 months after fracture; if present, a central adjudication committee blinded to treatment assignment reviewed radiographs and clinical records. Median follow-up was 1.9 years. RESULTS: The overall incidence of delayed healing was 3.2% (ZOL) and 2.7% (placebo; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.72-1.90; p = 0.61). Logistic regression models revealed no association between ZOL and delayed healing even after adjusting for other risk factors (OR, 1.21; 95% CI, 0.74-1.99; p = 0.44). There was no interaction by timing of infusion, and nonunion rates were similar even when ZOL was given within 2 weeks of hip fracture repair. NSAID use was significantly associated with delayed fracture healing (OR, 2.55; 95% CI, 1.49-4.39; p < 0.001). CONCLUSIONS: ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period.

NSAID exposure and risk of nonunion: a meta-analysis of case-control and cohort studies.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are frequently used for postoperative pain control. However, concerns regarding the potential deleterious effects of NSAIDs on bone healing have compelled many physicians to avoid NSAIDs in patients with healing fractures, osteotomies, and fusions. We systematically reviewed and analyzed the best clinical evidence regarding the effects of NSAID exposure on bone healing. Medline, Embase, and Cochrane electronic databases were searched for prospective and retrospective clinical studies of fracture, osteotomy, and fusion studies of patients with NSAID exposure and nonunion as an outcome. Study quality was assessed using the Newcastle-Ottawa Scale. Data on study design, patient characteristics, and risk estimates were extracted. Pooled effect estimates were calculated. Subanalyses were performed by bone type and by NSAID dose, duration, and route of administration. In the initial analysis of 11 cohort and case-control studies, the pooled odds ratio for nonunion with NSAID exposure was 3.0 (95% confidence interval 1.6-5.6). A significant association between lower-quality studies and higher reported odds ratios for nonunion was observed. When only higher-quality studies were considered, seven spine fusion studies were analyzed, and no statistically significant association between NSAID exposure and nonunion was identified (odds ratio = 2.2, 95% confidence interval 0.8-6.3). There was no increased risk of nonunion with NSAID exposure when only the highest-quality studies were assessed. Randomized controlled trials assessing NSAID exposure in fracture, fusion, and osteotomy populations are warranted to confirm or refute the findings of this meta-analysis of observational studies.

Femoral cortical stress lesions in long-term bisphosphonate therapy: a herald of impending fracture?

OBJECTIVE: Lateral cortical stress reactions have been documented to precede femoral insufficiency fractures after long-term bisphosphonate therapy. We studied the natural history of femoral stress lesions associated with long-term bisphosphonate therapy. DESIGN AND SETTING: A retrospective clinical and radiologic review of all patients with radiologically documented femoral stress lesions associated with bisphosphonate therapy was carried out in a tertiary center involved with geriatric trauma care. PATIENTS: Of 1463 geriatric hip fractures occurring from May 1, 2004, to July 31, 2008, 33 were of a distinct metaphyseal-diaphyseal configuration. Thirty-two were on prior bisphosphonate therapy. Sixteen femurs showed a lateral cortical thickening either on prefracture radiographs (four femurs) or on radiographs of the contralateral femur (12 femurs). MAIN OUTCOME MEASURES: Features that predispose to complete stress fractures were determined. The intact femurs were followed up for symptomatic and radiologic progression and occurrence of new lesions. RESULTS: All four cases that fractured had a "dreaded black line" in the lesion, whereas only 1 of 12 patients had this fracture in femurs which remained intact (100% versus 8.3%, P = 0.003). All patients who fractured reported thigh discomfort over 1 month (range, 0.1-9.0 months; standard deviation, 4.0 months), whereas three of 12 patients who did not fracture reported thigh discomfort (100% versus 25%, P = 0.019). In the remaining patients, eight patients were asymptomatic, two patients had reduced symptoms, and one patient had persistent thigh pain at 23.0 months (range, 5-35 months; standard deviation, 10.2 months). One patient was too demented for symptomatic assessment. No patient developed a new lesion. Radiologic stabilization of the lateral cortical thickening was evident on follow-up radiographs. CONCLUSION: Cortical stress reactions associated with prolonged antiresorptive therapy, in the presence of pain and the "dreaded black line," have an increased risk for complete stress fractures.

The relation between bisphosphonate use and non-union of fractures of the humerus in older adults.

SUMMARY: While nitrogen-containing bisphosphonates have been shown to reduce fracture risk in postmenopausal women and men, their safety in the period after a fracture is unclear. In fully adjusted multivariable regression models, bisphosphonate use in the post-fracture period was associated with an increased probability of non-union [odds ratio (OR) 2.37, 95% confidence interval (CI) 1.13-4.96]. Clinicians might consider waiting for several months before introduction of a bisphosphonate after a fracture. INTRODUCTION: While nitrogen-containing bisphosphonates have been shown to reduce fracture risk in postmenopausal women and men, their safety in the period after a fracture is unclear. We examined the risk of non-union associated with post-fracture bisphosphonate use among a group of older adults who had experienced a humerus fracture. METHODS: We conducted a nested case-control study among subjects who had experienced a humerus fracture. From this cohort, cases of non-union were defined as those with an orthopedic procedure related to non-union 91-365 days after the initial humerus fracture. Bisphosphonate exposure was assessed during the 365 days prior to the non-union among cases or the matched date for controls. Multivariable logistic regression models were examined to calculate the OR and 95% CI for the association of post-fracture bisphosphonate use with non-union. RESULTS: From the cohort of 19,731 patients with humerus fractures, 81 (0.4%) experienced a non-union. Among the 81 cases, 13 (16.0%) were exposed to bisphosphonates post-fracture, while 69 of the 810 controls (8.5%) were exposed in the post-fracture interval. In fully adjusted multivariable regression models, bisphosphonate use in the post-fracture period was associated with an increased odds of non-union (OR 2.37, 95% CI 1.13-4.96). Albeit limited by small sample sizes, the increased risk associated with bisphosphonate use persisted in the subgroup of patients without a history of osteoporosis or prior fractures (OR 1.91, 95% CI 0.75-4.83). CONCLUSIONS: In this study of older adults, non-union after a humerus fracture was rare. Bisphosphonate use after the fracture was associated with an approximate doubling of the risk of non-union.

Best evidence topic report. Do non-steroidal anti-inflammatory drugs cause a delay in fracture healing?

A short cut review was carried out to establish whether there is any evidence that non-steroidal anti-inflammatory drugs (NSAIDs) might delay fracture healing. A total of 514 papers were found using the reported search, of which three represent the best evidence to answer the clinical question. The author, date and country of publication, patient group studied, study type, relevant outcomes, results, and study weaknesses of these best papers are tabulated. At present, although there are theoretical concerns about the adverse effects of NSAIDs on fracture healing, there is not enough clinical evidence to deny patients with simple fractures their analgesic benefits.

Nonsteroidal antiinflammatory drugs and nonunion of humeral shaft fractures.

OBJECTIVE: To analyze the relationship between nonunion of humeral shaft fractures and nonsteroidal antiinflammatory drug (NSAID) exposure in older adults. METHODS: A cohort of 9,995 patients with humeral shaft fractures was identified using diagnosis and procedure codes from a Medicare database of >500,000 patients. Prescription NSAID as well as prescription opioid use was assessed from pharmacy claims data for 3 30-day periods immediately after the initial fracture. Nonunion was defined by the presence of procedure codes for repair of nonunion 90-365 days after the index fracture. We examined the association between NSAIDs and nonunion using multivariate Cox proportional hazards models. RESULTS: Of the 9,995 humeral shaft fractures, 105 patients developed nonunions (1.1%), and 1,032 (10.3%) were exposed to NSAIDs in the 90 days after fracture. NSAID exposure within the first 90 days was significantly associated with nonunion (relative risk [RR] 3.7, 95% confidence interval [95% CI] 2.4-5.6). When indicators for exposure to NSAIDs during each of the 3 30-day windows were placed into the same multivariate model, only the period 61-90 days post-fracture was significantly associated with nonunion (RR 3.9, 95% CI 2.0-6.2). We observed a similar association between opioids and nonunion, with exposure to opioids between 61 and 90 days associated with nonunion (RR 2.7, 95% CI 1.5-5.2), but exposure to opioids during neither of the 2 earlier 30-day periods significantly associated with nonunion. CONCLUSION: We found that exposure to nonselective NSAIDs or opioids in the period 61-90 days after a humeral shaft fracture was associated with nonunion. Although these associations may be causal, they are more likely to reflect the use of analgesics by patients with painful nonhealing fractures.