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Fractures In Aging >50 Yrs Old: associated with antiepileptic drugs, comorbidities, hypertension osteoprotective - pdf attached
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"With expected increases in the incidence of osteoporosis owing to the aging population, we embarked on a population-based, pharmaco-epidemiological, matched cohort study to explore the relationship between AED (antiepileptic drug) use and nontraumatic fractures in those older than 50 years......In conclusion, our study showed that most AEDs except for valproic acid are associated with an increased likelihood of nontraumatic fracture in individuals aged 50 years or older. Future prospective studies of AEDs in newly treated drug-naive patients are needed to better examine the individual effects of AEDs on bone health. Second, the benefits of screening with bone densitometry also need to be studied before any recommendations can be made regarding the timing and frequency of bone densitometry screening in those on AEDs. Finally, randomized controlled trials assessing the effects of vitamin D and calcium prophylaxis as well as other osteoprotective medications in individuals who are receiving AEDs are also warranted.......It is interesting that those with fractures were less likely to have hypertension compared with those without fractures, suggesting a possible osteoprotective benefit from hypertension. This is consistent with prior studies suggesting higher bone mineral density in those with hypertension (possibly mediated through associations with overweight and obesity)25-27 but contrary to other studies reporting that hypertension is associated with fractures28-29 and bone density loss.30 Antihypertensives have been found to be osteoprotective by reducing blood pressure, which can lead to decreased urinary calcium loss and subsequent decreased fracture risk or increased bone mineral density.31-35
A significant increase in fracture risk was found for most individual AEDs studied (except for valproic acid) in this large population-based pharmaco-epidemiologic study of older adults. This increased risk persisted after adjusting for sociodemographic variables, comorbidities, and use of home care services. Our study is consistent with other population-based studies, demonstrating an increased risk of fractures in individuals receiving AEDs. our study found an association between phenytoin and the risk of fracture, while the study by Vestergaard et al13 did not report such an association. This is surprising considering that phenytoin has been associated with bone loss. the study by Vestergaard et al,13 contrary to our study, reported an association between valproic acid and fractures. In our study, valproic acid was significantly associated with the odds of fracture in a model only adjusted for sociodemographic variables but, after adjusting for home care use and the presence of comorbid conditions, this association was no longer statistically significant
The OR of sustaining a fracture decreased in magnitude when we added markers of frailty (eg, home care use) and comorbidity measures, suggesting a common mechanism to promote fracture risk in this population that may not be specifically AED related. Some of these mechanisms may be related to underlying health issues such as deconditioning, lack of antigravity activity, lack of sun exposure, low calcium intake, and overall poor vitamin D intake.8 Unfortunately, we did not have the ability to specifically adjust for these in our study, although adjustment for home care use was chosen as a surrogate marker for lack of antigravity activity and deconditioning.....There are other confounding factors that could contribute to bone loss in our population besides the ones for which we were able to adjust. For example, psychotropic drugs, in particular selective serotonin reuptake inhibitors, have been associated with bone density loss and fracture risk.36-37 There is often overlap between antidepressant and antiepileptic drug use. However, to minimize confounding from psychotropic agents, we adjusted for depression as a surrogate marker for psychotropic drug use."
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Medpagetoday comments
In the retrospective matched cohort study of over 63,000 people, an adjusted analysis found that odds ratios for fracture ranged from 1.24 (95% CI 1.05 to 1.47) among patients taking clonazepam to 1.91 (95% CI 1.58 to 2.30) for those using phenytoin, according to Nathalie Jettˇ, MD, of the University of Calgary, and colleagues.
The wrist was the most common site of fractures, seen in 52% of patients; fractures of the hip were found in 26.2% of patients and vertebral fractures in 21.7%.
Fractures were more likely among those living in urban settings, with low incomes, and using in-home care services.
Comorbidities associated with fracture included:
* Epilepsy, OR 2.89 (95% CI 2.12 to 3.94)
* Arthritis, OR 1.29 (95% CI 1.13 to 1.48)
* Chronic obstructive pulmonary disease, OR 1.13 (95% CI 1.08 to 1.19)
* Substance abuse, OR 2.19 (95% CI 1.95 to 2.45)
* Depression, OR 1.47 (95% CI 1.38 to 1.56)
* Schizophrenia, OR 2.17 (95% CI 1.75 to 2.69)
* Dementia, OR 1.96 (95% CI 1.81 to 2.13)
A possible explanation for this is that the drug is often used for chronic pain, which may predispose patients to mobility limitations and bone loss, Jettˇ and co-authors wrote.
The researchers noted that they were unable to adjust for all potential confounders including inadequate sun exposure and vitamin D intake.
Strengths of the study included the population-based design and large sample size, while limitations included the investigators' inability to adjust for sun exposure (relating to manufacture of vitamin D in skin cells), vitamin D intake, and physical activity.
The investigators also noted that they lacked bone mineral density measurements for the cohort, and administrative databases only captured those fractures for which medical attention was sought.
As well, they pointed out that the sample size was inadequate to study some of the newer anti-seizure drugs individually (e.g., lamotrigine, pregabalin, and topiramate).
In addition, anticonvulsants and antidepressants are often used together, and selective serotonin reuptake inhibitors can accelerate bone loss.
Multiple mechanisms have been proposed for the association between anticonvulsants and nontraumatic fractures, including impairments in absorption of calcium and increases in homocysteine.
Two of the investigators received unrestricted research grants from Amgen Pharmaceuticals Canada, and a third received research grants from several companies, including Merck Frosst, sanofi-aventis, Novartis, and Amgen, is on a speakers' bureau for Merck Frosst, and is on advisory boards for Genzyme, Novartis, and Amgen.
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Association of Antiepileptic Drugs With Nontraumatic Fractures
A Population-Based Analysis
Nathalie Jettˇ, MD, MSc; Lisa M. Lix, PhD; Colleen J. Metge, PhD; Heather J. Prior, MSc; Jane McChesney, BN; William D. Leslie, MD
Arch Neurol. Jan 1 2011
ABSTRACT
Objective - To explore the relationship between antiepileptic drug (AED) use and nontraumatic fractures in those aged 50 years and older.
Design - Retrospective matched cohort study.
Participants - A total of 15 792 persons, identified through the Population Health Research Data Repository from Manitoba, Canada, with nontraumatic fractures of the wrist, hip, and vertebra occurring between 1996 and 2004. Each patient was matched for age, sex, ethnicity, and comorbidity with up to 3 controls (n = 47 289).
Interventions - Prior AED use (carbamazepine, clonazepam, ethosuximide, felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, phenobarbital, phenytoin, pregabalin, primidone, topiramate, valproic acid, and vigabatrin) was determined from pharmacy data in the repository. Odds ratios (OR) for fracture from AED exposure were adjusted for sociodemographic and comorbidity factors known to affect fracture risk.
Results - A significant increase in fracture risk was found for most of the AEDs being investigated (carbamazepine, clonazepam, gabapentin, phenobarbital, and phenytoin). The adjusted ORs ranged from 1.24 (95% confidence interval [CI], 1.05-1.47) for clonazepam to 1.91 (95% CI, 1.58-2.30) for phenytoin. The only AED not associated with increased fracture risk was valproic acid (adjusted OR, 1.10; 95% CI, 0.70-1.72).
Conclusions - Most AEDs were associated with an increased risk of nontraumatic fractures in individuals aged 50 years or older. Further studies are warranted to assess the risk of nontraumatic fractures with the newer AEDs and to determine the efficacy of osteoprotective medications in this population.
INTRODUCTION
Osteoporosis affects more than 50 million people worldwide, with 9 million osteoporosis-related fractures reported annually.1-2 More than 80% of fractures in those aged 60 years and older are osteoporosis related.3 In the United States alone, costs of treatment of incident osteoporotic fractures exceeded $30 billion in 2004.4
There are many secondary risk factors for osteoporosis.5 Antiepileptic drugs (AEDs) are of particular concern, considering that epilepsy is highly prevalent in elderly persons, a population already at risk for osteoporosis.6
Antiepileptic drugs are associated with greater bone density reduction in postmenopausal women with epilepsy compared with controls.7 Two population-based studies also confirmed that AED use increases the rate of bone loss in adults older than 65 years but, aside from phenytoin and gabapentin, these studies were unable to examine the association of individual AEDs with bone loss.8-9
A meta-analysis and 2 population-based studies described an association between AEDs and fractures, but most studies focused on patients with epilepsy.10-12 The use of AEDs extends beyond seizure management (eg, pain and psychiatric disorders). One large population-based study that included persons using an AED for any indication found that carbamazepine, oxcarbamazepine, clonazepam, phenobarbital, and valproate were associated with fractures.13
Population-based studies assessing the association between AEDs and fractures are scarce, and none have focused solely on older individuals. With expected increases in the incidence of osteoporosis owing to the aging population, we embarked on a population-based, pharmaco-epidemiological, matched cohort study to explore the relationship between AED use and nontraumatic fractures in those older than 50 years.
RESULTS
A total of 15 792 patients met our case definition for nontraumatic (osteoporotic) fracture between April 1996 and March 2004. These cases were successfully matched for age, sex, ethnicity, and number of ADGs to 47 289 controls. Baseline characteristics of cases and controls are shown in Table 1. Fracture cases were more likely to live in urban dwellings (OR, 1.07; 95% CI, 1.03-1.10), fall in the lowest income group (OR, 1.10; 95% CI, 1.06-1.14), and have used home care services (OR, 1.74; 95% CI, 1.66-1.82) compared with controls. The most common fracture site was the wrist (52.0%) followed by the hip (26.2%) and, lastly, the vertebra (21.7%).
The prevalence of comorbidities in fracture cases and controls is shown in Table 2. Cases were more likely to have epilepsy (OR, 2.89; 95% CI, 2.12-3.94), arthritis (OR, 1.29; 95% CI, 1.13-1.48), COPD (OR, 1.13; 95% CI, 1.08-1.19), substance abuse (OR, 2.19; 95% CI, 1.95-2.45), depression (OR, 1.47; 95% CI, 1.38-1.56), schizophrenia (OR, 2.17; 95% CI, 1.75-2.69), or dementia (OR, 1.96; 95% CI, 1.81-2.13). Those with fractures were less likely to have hypertension (OR, 0.85; 95% CI, 0.82-0.88).
The odds of fracture, based on the type of AED, are shown in Table 3 and the Figure. In both the partially (models 1 and 2) and fully adjusted (model 3) models, all AEDs except for valproic acid were associated with fractures. Odds ratios in the fully adjusted model ranged from a low of 1.24 (95% CI, 1.05-1.47) for clonazepam to 1.49 (95% CI, 1.10-2.02) for gabapentin, 1.60 (95% CI, 1.16-2.19) for phenobarbital, 1.81 (95% CI, 1.46-2.23) for carbamazepine, and a high of 1.91 (95% CI, 1.58-2.30) for phenytoin. The odds of fracture was 1.65 (95% CI, 1.07-2.56) for other AEDs group. Similar results were obtained when we tested the effect size of AEDs in monotherapy on fractures (Table 3, model 4), with the greatest risk seen for those in the polytherapy subgroup (OR, 2.97; 95% CI, 2.26-3.89). All AEDs used in monotherapy were associated with significantly increased fracture risk except for valproic acid (OR, 0.71; 95% CI, 0.36-1.37), phenobarbital (OR, 1.31; 95% CI, 0.80-2.16), and other AEDs (OR, 1.29; 95% CI, 0.69-2.43).
COMMENT
A significant increase in fracture risk was found for most individual AEDs studied (except for valproic acid) in this large population-based pharmaco-epidemiologic study of older adults. This increased risk persisted after adjusting for sociodemographic variables, comorbidities, and use of home care services.
Our study is consistent with other population-based studies, demonstrating an increased risk of fractures in individuals receiving AEDs.10-12 Most of these studies were small, poorly controlled, or focused on individuals with epilepsy. One large pharmaco-epidemiologic study by Vestergaard et al13 examined the risk of fractures in individuals on AEDs, regardless of epilepsy status. One difference compared with our study is that they included patients of all ages, unlike our study, which focused on older individuals. Although their results were similar to ours, some contradictory findings are worth noting. First, our study found an association between phenytoin and the risk of fracture, while the study by Vestergaard et al13 did not report such an association. This is surprising considering that phenytoin has been associated with bone loss.8, 22-23 For example, Pack et al23 followed up 93 premenopausal women with epilepsy who were receiving AED monotherapy (carbamazepine, lamotrigine, phenytoin, or valproate) and noted significant bone loss at the femoral neck as little as 1 year after treatment initiation in the phenytoin group but not in the other groups. These results must be interpreted cautiously, as no control groups were enrolled in the latter study.23 Second, the study by Vestergaard et al,13 contrary to our study, reported an association between valproic acid and fractures. Once again, the literature on the association between valproic acid and bone loss or fracture is inconsistent. In our study, valproic acid was significantly associated with the odds of fracture in a model only adjusted for sociodemographic variables but, after adjusting for home care use and the presence of comorbid conditions, this association was no longer statistically significant. Similar to prior studies by Vestergaard et al13, 24 and Souverein et al,12 the odds of fracture were statistically significant for carbamazepine, clonazepam, and phenobarbital, but the association between phenobarbital and fracture risk was no longer significant once examined as monotherapy, possibly owing to the smaller sample size. Our finding of an association between gabapentin and nontraumatic fracture has not, to our knowledge, been described in previous research. However, an association between gabapentin and bone loss has previously been described in men in 1 large prospective study.9 The association between gabapentin and fractures is surprising, although it is frequently used to treat chronic pain syndromes. It is plausible that many persons who are taking gabapentin are limited in their mobility (owing to pain), which can result in deconditioning, bone loss, and fractures.
It is interesting that those with fractures were less likely to have hypertension compared with those without fractures, suggesting a possible osteoprotective benefit from hypertension. This is consistent with prior studies suggesting higher bone mineral density in those with hypertension (possibly mediated through associations with overweight and obesity)25-27 but contrary to other studies reporting that hypertension is associated with fractures28-29 and bone density loss.30 Antihypertensives have been found to be osteoprotective by reducing blood pressure, which can lead to decreased urinary calcium loss and subsequent decreased fracture risk or increased bone mineral density.31-35
Four different logistic regression models to assess effect size were used in the current study, each of varying complexity. The OR of sustaining a fracture decreased in magnitude when we added markers of frailty (eg, home care use) and comorbidity measures, suggesting a common mechanism to promote fracture risk in this population that may not be specifically AED related. Some of these mechanisms may be related to underlying health issues such as deconditioning, lack of antigravity activity, lack of sun exposure, low calcium intake, and overall poor vitamin D intake.8 Unfortunately, we did not have the ability to specifically adjust for these in our study, although adjustment for home care use was chosen as a surrogate marker for lack of antigravity activity and deconditioning.
There are other confounding factors that could contribute to bone loss in our population besides the ones for which we were able to adjust. For example, psychotropic drugs, in particular selective serotonin reuptake inhibitors, have been associated with bone density loss and fracture risk.36-37 There is often overlap between antidepressant and antiepileptic drug use. However, to minimize confounding from psychotropic agents, we adjusted for depression as a surrogate marker for psychotropic drug use.
There are strengths and limitations to our study. One strength is the population-based nature of the data source, making it unlikely that selection bias occurred. Another is the large sample size with matching for important risk factors (age, sex, ethnicity, and number of comorbidities). We were able to adjust for many potential confounders (sociodemographic variables, multiple diagnoses, and home care use) but could not specifically adjust for vitamin D or calcium intake, physical activity level, or other lifestyle factors. We also did not have bone mineral density measurements for these individuals, and only fractures for which medical attention was sought are captured in administrative databases. Similarly, we had inadequate sample size to study some of the newer AEDs individually (eg, lamotrigine, pregabalin, topiramate).
Our study was not designed to address the possible mechanisms explaining the association between AEDs and fractures, but proposed mechanisms of AED-related bone disease include hepatic induction of cytochrome P450 enzymes leading to increased vitamin D metabolism, direct action of AEDs on osteoblasts, impaired calcium absorption, elevated homocysteine, inhibition of response to parathyroid hormone, hyperparathyroidism, reduced reproductive sex hormones, and reduced vitamin K level.38
In conclusion, our study showed that most AEDs except for valproic acid are associated with an increased likelihood of nontraumatic fracture in individuals aged 50 years or older. Future prospective studies of AEDs in newly treated drug-naive patients are needed to better examine the individual effects of AEDs on bone health. Second, the benefits of screening with bone densitometry also need to be studied before any recommendations can be made regarding the timing and frequency of bone densitometry screening in those on AEDs. Finally, randomized controlled trials assessing the effects of vitamin D and calcium prophylaxis as well as other osteoprotective medications in individuals who are receiving AEDs are also warranted.
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