The American Journal of Medicine
Volume 118, Issue 12 , Pages 1414.e7-1414.e12, December 2005

Bone mineral density in subjects using central nervous system-active medications

  • Mitsuyo Kinjo, MD, MPH

      Affiliations

    • Department of Internal Medicine, Teine Keijinkai Hospital, Sapporo, Japan
    • Corresponding Author InformationRequests for reprints should be addressed to Mitsuyo Kinjo, MD, MPH, Department of Internal Medicine, Teine Keijinkai Hospital, 1-40 Maeda 1 jou 12 chou-me, Teine-ku, Sapporo, Hokkaido, 006-8555 Japan
    • ,
  • Soko Setoguchi, MD, MPH, MS

      Affiliations

    • Division of Pharmacoepidemiology, Brigham and Women’s Hospital, Harvard Medical School, Mass
    • ,
  • Sebastian Schneeweiss, MD, ScD

      Affiliations

    • Division of Pharmacoepidemiology, Brigham and Women’s Hospital, Harvard Medical School, Mass
    • ,
  • Daniel H. Solomon, MD, MPH

      Affiliations

    • Division of Pharmacoepidemiology, Brigham and Women’s Hospital, Harvard Medical School, Mass

Article Outline

Abstract 

Purpose

Decreased bone mineral density defines osteoporosis according to the World Health Organization and is an important predictor of future fractures. The use of several types of central nervous system-active drugs, including benzodiazepines, anticonvulsants, antidepressants, and opioids, have all been associated with increased risk of fracture. However, it is unclear whether such an increase in risk is related to an effect of bone mineral density or to other factors, such as increased risk of falls. We sought to examine the relationship between bone mineral density and the use of benzodiazepines, anticonvulsants, antidepressants, and opioids in a representative US population-based sample.

Subjects and methods

We analyzed data on adults aged 17 years and older from the Third National Health and Nutrition Examination Survey (NHANES III, 1988-1994). Total femoral bone mineral density of 7114 male and 7532 female participants was measured by dual-energy x-ray absorptiometry. Multivariable linear regression models were used to quantify the relation between central nervous system medication exposure and total femoral bone mineral density. Models controlled for relevant covariates, including age, sex, and body mass index.

Results

In linear regression models, significantly reduced bone mineral density was found in subjects taking anticonvulsants (0.92 g/cm2; 95% confidence interval [CI]: 0.89 to 0.94) and opioids (0.92 g/cm2; 95% CI: 0.88 to 0.95) compared with nonusers (0.95 g/cm2; 95% CI: 0.95 to 0.95) after adjusting for several potential confounders. The other central nervous system-active drugs—benzodiazepines or antidepressants—were not associated with significantly reduced bone mineral density.

Conclusion

In cross-sectional analysis of NHANES III, anticonvulsants and opioids (but not benzodiazepines or antidepressants) were associated with significantly reduced bone mineral density. These findings have implications for fracture-prevention strategies.

Keywords:  Bone mineral density , Anticonvulsants , Opioids , Benzodiazepines , Antidepressants

 

Osteoporosis is an important risk factor for many types of fractures1 and the World Health Organization defines osteoporosis according to bone mineral density criteria.2 Risk factors for low bone mineral density have been identified and include a number of medications.3 Several categories of drugs that act on the central nervous system, such as benzodiazepines, anticonvulsants, antidepressants, and opioids, have been shown to increase the risk of hip fracture.4, 5, 6, 7, 8, 9 However, it is unclear whether these medications are associated with fracture through elevating the risk of falls or through reducing bone mineral density.10, 11, 12

Reports on the association between these medications and low bone mineral density are rather limited. Although anticonvulsants appear to be associated with low bone mineral density, most reports are from small samples of patients in epilepsy clinics and may not be generalizable.13, 14, 15, 16, 17, 18, 19 No prior studies have directly assessed the relationship between bone mineral density and exposure to benzodiazepines, antidepressants, or opioids. Opioids may lead to low bone mineral density via impaired production of endogenous sex steroid.20 However, available evidence has not been clear as to whether exposure to any of these medications leads to osteoporosis.

In a cross-sectional analysis, we examined the relationship between bone mineral density and the use of benzodiazepines, anticonvulsants, antidepressants, and opioids among a representative US population participating in the Third National Health and Nutrition Examination Survey (NHANES III).

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Subjects and method 

Data source and study participants 

The NHANES III is a cross-sectional survey conducted between 1988 and 1994 by the National Center for Health Statistics of the Centers for Disease Control and Prevention. Participants were selected using a multistage, stratified probability design. The samples represent the civilian, noninstitutionalized population, aged 2 months and older, residing in the 50 states of the United States.21 Eighty-six percent of designated participants completed a household interview and were asked to undergo comprehensive physical examination within a month of completing the survey. A total of 20050 participants aged 17 years or older were available for the interview. Our requirement that participants must have undergone bone mineral density examination excluded 5404 participants.22, 23

Central nervous system-active medication use 

The product name of each prescription medication used within the past month was recorded and its container was examined by the interviewer. The participants were also asked how long they were on the medications. Each drug was assigned a standard generic name24 and was classified according to the American Hospital Formulary Service Pharmacologic Therapeutic drug categories.25 We examined the following categories: benzodiazpines, anticonvulsants, antidepressants, and opioids. Benzodiazepines included alprazolam, chlordiazepoxide, clorazepate, diazepam, estazolam, flurazepam, lorazepam, oxazepam, prazepam, quazepam, temazepam, and triazolam. The anticonvulsants consisted of carbamazepine, clonazepam, divalproex, ethosuximide, mephobarbital, methsuximide, phenobarbital, phenytoin, primidone, and valproic acid. Antidepressants were either tricyclic (TCAs, including amitriptyline, amoxapine, clomipramine, desipramine, doxepin, imipramine, nortriptyline, protriptyline, trazodone), nontricyclic (bupropion, phenelzine, tranylcypromine), or selective serotonin-reuptake inhibitors (SSRIs, including fluoxetine, paroxetine, sertraline). Opioids included were opioid agonist (codeine, fentanyl, hydrocodone, hydromorphone, levomethadyl, levorphanol, meperidine, methadone, morphine, oxycodone, oxymorphone, propoxyphene) or partial agonist (pentazocine). Antitussive medications that contained opioids, antidiarrheal drugs or cold syrups were not included in the opioids. Individuals who were exposed to more than one category of these medications were excluded. A nonuser was defined as an individual who reported use of none of these drugs.

Other measurements 

Sex and age were recorded by the interviewer. Race and ethnicity were self-reported as non-Hispanic white, non-Hispanic black, Mexican-American, and other. Other covariates included the number of chronic medical conditions,26 smoking (current vs former or never), alcohol intake (number of drinks in the prior month), self-reported health (poor vs 4 other categories), history of hip or wrist fracture, history of fall (in the past 12 months and landing on the floor or hit an object), and early menopause (before age 40). Cognitive impairment was judged to be present based on either physician’s evaluation or short-term memory loss (inability to answer at least 2 of 6 questions). Leisure-time activity level was calculated as the number of metabolic equivalents per month. The patient’s self-reported activity level in the preceding month of interview was used for this calculation.27, 28 Body mass index (kg/m2) and serum 25(OH) vitamin D level were also considered. Total calcium intake was calculated by combining supplemental and dietary calcium intake. Data on exposure to other drugs including thiazides, oral glucocorticoids, and hormone replacement therapy were also considered.29

Bone mineral density measurement 

The hip bone mineral density was estimated from the total proximal femoral region using dual-energy x-ray absorptiometry. The hologic QDR 1000 densitometer was used for the measurements, and details of bone mineral density measurements have been described elsewhere.30

Statistical analysis 

In the first exploratory analysis, the differences between users of each central nervous system medication and nonusers on categorical variables were examined by chi-squared test. Student’s t test was used to assess differences in means of continuous variables with normal distribution, and a Wilcoxon test otherwise. P values and 95% confidence intervals (CI) are reported. We then assessed the adjusted relationship between each drug exposure as an independent variable and bone mineral density as an end point. We modeled total femoral bone mineral density in a linear regression as a function of central nervous system-active medication, adjusted for sex and age. A fully adjusted model was then fit that included all additional clinical measures listed above.

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Results 

Population characteristics 

A total of 20050 adults were interviewed and 14646 underwent bone mineral density measurement as part of NHANES III. There was no important difference in any of the patient characteristics between participants with and without bone mineral density examination. The mean age was 48 years for those with bone mineral density data and 46 years for those without. Women comprised 51% of the sample with bone mineral density data and 58% without. The percent that was white was nearly identical in the two groups. Body mass index was 27.1 kg/m2 among those included and 26.2 kg/m2in the others. Of the persons who underwent bone mineral density examination, 114 (0.8%) used at least one benzodiazepine, 154 (1.1%) used an antidepressant, 78 (0.5%) used an anticonvulsant, and 55 (0.4%) used an opioid.

The characteristics of participants reporting the medication exposures of interest were compared with those of nonusers (Table 1). Participants using benzodiazepines, anticonvulsants, or antidepressants but not opioids tended to be older and more likely to be white. The distribution of sex, smoking, hip or wrist fracture, and total calcium intake was not significantly different between central nervous system-active medication users and nonusers, except that 71% of antidepressant users were female, and opioid users were more likely to be current smokers. Higher rates of falls, comorbidity, and self-assessed poor health were reported by users of benzodiazepines, anticonvulsants, and antidepressants compared with nonusers. Early menopause and decreased activity level were more frequently reported by benzodiazepine and antidepressant users compared with nonusers. Opioid users had similar characteristics except less cognitive impairment and fewer falls than nonusers.

Table 1. Characteristics of participants
VariableNonuser (n=14360)Benzodiazepine (n=114)Anticonvulsant (n=78)Antidepressant (n=154)Opioid (n=55)
Mean (± SD) or n (%)
Age, years48.1±19.061.3±15.4†54.7±19.4‡54.3±15.2†44.7±17.4
Female7377(51)67(59)40(51)110(71)‡25(45)
White6023(42)82(72)†41(53)91(59)†20(36)
Current smoker3773(26)30(26)16(21)35(23)20(40)§
Poor health610(4)21(18)†8(10)§19(12)†8(15)†
History of
Hip fracture180(1)2(2)2(3)1(1)0(0)
Wrist fracture1012(7)14(12)7(9)15(10)2(4)
≥1 fall1026(7)19(17)§15(19)†17(11)3(5)
≥1 comorbidity⁎3064(21)58(41)†36(46)†72(47)†19(34)§
Menopause before age 40 years1186(8)23(20)†7(9)36(23)†7(13)
Cognitive impairment866(6)15(13)‡11(14)‡12(8)2(4)
Body mass index, kg/m227.1±5.627.7±5.626.9±6.428.3±5.9§27.7±7.5
Exercise, METs/month84.1±114.869.8±94.1‖90.3±147.545.3±74.5†83.2±130.4
Serum vitamin D, ng/mL25.8±11.129.9±11.0†25.1±11.727.5±12.8‡27.2±12.4
Total Ca intake, mg/day768±547749±595§781±535766±574750±477
Current use of
HRT305(2)12(11)†0(0)17(11)†2(4)
Steroid135(1)2(2)0(0)4(3)‖2(4)‖
Thiazide diuretic48(0.3)1(0.9)0(0)1(0.7)0(0)

MET = metabolic equivalents; SD = standard deviation; Ca = calcium; HRT = hormone-replacement therapy.

⁎ History of one or more selected comorbidities including myocardial infarction, congestive heart failure, peripheral vascular disease, stroke, rheumatoid arthritis or lupus, diabetes, hemiparesis, and nonskin cancer.

† P ≤.001 compared with nonusers.

‡ P ≤.01 compared with nonusers.

§ P ≤.05 compared with nonusers.

‖ P ≤.10 compared with nonusers.

Intensity rating of each activity is multiplied by the frequency in the past month.

Central nervous system medication use and bone mineral density 

Unadjusted total hip bone mineral density was lower among participants using benzodiazepines, anticonvulsants, and antidepressants, but not opioids, compared with nonusers (P <.02) (Table 2). After adjustment for age and sex, the bone mineral density of anticonvulsant users was significantly lower than nonusers (P=.024), which persisted after adjusting for all other potential confounders. Opioid users showed reduced bone mineral density compared with nonusers after adjusting for all covariates (P=.043). Participants using benzodiazepines and antidepressants did not have reduced total hip bone mineral density compared with nonusers. In assessing the mean total hip bone mineral density associated with specific anticonvulsants (Table 3), we found some small potential differences between users of phenobarbital and other anticonvulsants. Participants using anticonvulsants other than phenobarbital still had significantly lower total hip bone mineral density compared with nonusers (P=.045). The median durations of use of these medications were all over 2 years. Although the bone mineral density in the quartile with the longest use of anticonvulsants did not follow a smooth trend, the overall trend toward a reduced bone mineral density with longer duration of anticonvulsant use was significant (P=.028) (Table 4). There was a trend toward longer-term opioid users (>243 days, equivalent to the 4th quartile) having lower bone mineral density (0.90 g/cm2) than shorter-term users (0.95 g/cm2) (P=.3).

Table 2. Total hip bone mineral density (g/cm2) with and without central nervous system-active medication
MedicationUnadjustedAge and sex adjustedFully adjusted⁎
Mean (95% CI)
Nonuser0.95(0.95,0.96)0.95(0.95,0.95)0.95(0.95,0.95)
Benzodiazepines0.91(0.88,0.94)0.97(0.96,1.00)0.98(0.95,1.21)
Anticonvulsants0.88(0.84,0.92)0.91(0.88,0.95)0.92(0.89,0.94)
Antidepressants0.90(0.88,0.93)0.95(0.93,0.98)0.95(0.93,0.97)
Opioids0.94(0.90,0.99)0.92(0.88,0.96)0.92(0.88,0.95)

CI = confidence interval.

⁎ Adjusted for age, sex, race, number of comorbidities, smoking, use of alcohol, self-reported health, hip and wrist fracture, fall, early menopause, cognitive impairment, body mass index, exercise, serum vitamin D level, total calcium intake, use of steroids, hormone-replacement therapy and thiazide diuretics.

Table 3. Mean total hip bone mineral density (g/cm2) by specific anticonvulsant
AnticonvulsantnTotal hip bone mineral density⁎ mean (95% CI)Duration, days median (IQR)
Carbamazepine250.90(0.84,0.96)730(152,4015)
Phenytoin240.90(0.83,0.98)2008(274,3650)
Phenobarbital⁎110.75(0.64,0.85)5475(1460,9125)
Phenytoin and phenobarbital120.83(0.72,0.94)4015(365,6570)

BMD = bone mineral density; IQR = interquartile range.

⁎ Age- and sex-adjusted.

Table 4. Mean total hip bone mineral density (g/cm2) by duration of anticonvulsant use
Quartile of duration (days)
1st (1-365)2nd (365-1825)3rd (1825-5475)4th (5475-18250)
n14151514
Hip BMD⁎0.930.890.820.86

BMD = bone mineral density.

⁎ Age- and sex-adjusted.

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Discussion 

In this cross-sectional study among a large representative US adult sample, we observed significantly lower bone mineral density among participants exposed to anticonvulsants or opioids, but not benzodiazepines or antidepressants, when adjusting for all covariates. These results suggest that the increased risk of hip fracture observed among users of benzodiazepines and antidepressants is likely due to non-bone mineral density factors, such as falls and frailty, whereas anticonvulsants and opioids may directly affect the bone.

Earlier studies have reported an association between anticonvulsant use and reduced bone mineral density. These analyses used relatively small populations of institutionalized persons or single-center outpatient samples.16, 18, 19, 31 Studies have identified anticonvulsant use as a risk factor for low bone mineral density in various age groups.13, 14, 17, 19, 32 However, prior studies did not control for important potential confounding factors, such as early menopause, self-reported poor health status, body mass index, physical activity level, and use of steroids or hormone replacement therapy. In our study, phenobarbital was associated with lowest bone mineral density among anticonvulsant users. After phenobarbital was excluded from the analysis, the association between anticonvulsant use and reduced bone mineral density adjusted for age and sex remained significant, indicating that other anticonvulsants are also associated with reduced bone mineral density. It has been suggested that anticonvulsants increase catabolism of vitamin D and parathyroid hormone with subsequent bone resorption.13, 17, 33, 34, 35, 36 It is controversial whether anticonvulsants lower levels of serum 125(OH) or 25(OH) vitamin D.37 We observed slightly reduced mean serum 25(OH) vitamin D levels among anticonvulsant users but adjustment did not affect the results. A direct effect of anticonvulsants on bone cells is also speculated,38 but we have no data on markers of bone mineral metabolism.

This is the one of the few studies of the effects of opioid analgesics on bone mineral density. In the Study of Osteoporotic Fractures, unadjusted bone mineral density for opioid users was lower than for nonusers.6 We observed a similar reduction in bone mineral density among opioid users, a finding supported by the duration-response effect that we also noted. These data support the association between exposure to opioids and reductions in bone mineral density, which may be mediated by suppressing endogenous sex hormone production and interfering with bone formation.39, 40 Because we have no data on testosterone or estradiol levels for our study participants, we cannot comment on the potential mechanism for this reduction.

The relationship between these central nervous system-active medications and bone mineral density is difficult to study because of the potential confounding by the indications for the medications and the concomitant frailty of many individuals taking them. For example, it is possible that antidepressant medications or depression itself might be associated with reduced bone mineral density. Depression is also thought to be an independent risk factor for hip fracture and low bone mineral density.41, 42, 43, 44, 45, 46 This may be because the altered levels of IL-6 and prolactin seen in depression may lead to osteoporosis.44 In addition, it is possible that depression leads to inactivity, lowering bone mineral density and predisposing toward fractures. The NHANES survey allowed us to simultaneously assess medication use, underlying medical conditions, and markers of frailty such as body mass index, physical activity, and history of falls. We found no association between antidepressant use and low bone mineral density. Unlike TCAs, SSRIs may act on bone metabolism.47, 48, 49 In the present study, however, reduced bone mineral density was not detected among either TCA or SSRI users (data not shown). It is interesting to note that in NHANES III, in which participants aged 20-39 years were interviewed for diagnosis of major depression, less than half of antidepressant users actually met the DSM-III criteria for major depression,50, 51 and only 2% of subjects diagnosed with depression took antidepressants.

This study has several limitations. It is cross-sectional and therefore cannot prove a causal relationship between drug exposure and reduced bone mineral density. The fact that people on more than one class of drug were eliminated might bias results. Yet this study is consistent with prior literature6, 13, 16, 19 in finding an association between exposure to anticonvulsants or opioids and reduced bone mineral density. Second, the study lacks data on daily drug dose and precise dates of drug exposure. This limits any detailed analysis of dose or duration effects on bone mineral density. However, the positive correlation between duration of anticonvulsant use and low bone mineral density is reassuring. Third, because NHANES III was conducted between 1988 and 1994, newer anticonvulsants and antidepressants were not included. This requires further study, but our data are still crucial, because older anticonvulsants are still widely used. Last, NHANES III does not include information on spinal bone mineral density. The data on hip bone mineral density among central nervous system-active medication users has greater clinical relevance on risk of hip fracture.

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Conclusion 

There is no significant association between benzodiazepines or antidepressants and bone mineral density. However, use of anticonvulsants and opioids is associated with reduced bone mineral density. Strategies to increase bone mineral density may be considered for users of anticonvulsants and opioids, whereas fall prevention or intervention may be worthwhile for persons using other central nervous system-active medications.

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PII: S0002-9343(05)00627-3

doi:10.1016/j.amjmed.2005.07.033

The American Journal of Medicine
Volume 118, Issue 12 , Pages 1414.e7-1414.e12, December 2005

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