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Anticonvulsant drug use and low bone mass in adults with neurodevelopmental disorders

J.G. Ray, A. Papaioannou, G. Ioannidis, J.D. Adachi
DOI: http://dx.doi.org/10.1093/qjmed/95.4.219 219-223 First published online: 1 April 2002

Abstract

Background: Use of anticonvulsant drugs among adults with neurodevelopmental disorders may be an important risk factor for both osteoporosis and skeletal fractures.

Aim: To determine the relationship between anticonvulsant drug use and both low bone mass and bone fractures in such adults.

Design: Cross‐sectional study of 273 adults with neurodevelopmental disorders, 40% of whom were receiving one or more anticonvulsant drugs.

Setting: Single Canadian long‐term care facility.

Methods: Demographic data were abstracted from each resident's chart in a standardized manner, including body mass, degree of mobility, major falls within the previous 12 months, and all medications. Quantitative calcaneal ultrasonography was performed on each resident without knowledge of their current drug use. The Quantitative Ultrasound Index was employed to express ‘bone stiffness’. Low bone mass was defined as a T‐score 2.5 SDs below the norm for young healthy adults.

Results: Compared to non‐users (15.5%), low bone mass was more prevalent among those taking either one (20.3%; OR 1.7, 95%CI 0.6–4.4) or two or more anticonvulsant agents (42.2%, OR 5.9, 95%CI 2.2–16.2). The risk of recent skeletal fractures was not significantly greater in those taking a single anticonvulsant than in non‐users (28.6% vs. 21.6%; OR 1.0, 95%CI 0.4–2.8), but tended to be higher in those taking two or more (48.7%; OR 2.2, 95%CI 0.8–5.9).

Conclusions: Adults with neurodevelopmental disorders residing in a long‐term care facility have a high rate of both low bone mass and skeletal fractures, especially with concomitant use of anticonvulsant drugs. These individuals should be assessed for the presence of low bone mass, and may warrant prophylactic treatment against bone loss, including calcium and vitamin D supplementation.

Introduction

The use of anticonvulsant medications has been implicated in the development of osteomalacia, osteoporosis, and secondary hyperparathyroidism.1 Through several postulated mechanisms, these agents alter the level and effectiveness of vitamin D and parathyroid hormone, thereby lowering the availability of calcium for bone mineralization.2,,3 In a systematic overview, we observed a consistent association between anticonvulsant use and osteoporosis,4 while in another large cohort study, the adjusted relative risk for hip fracture was 2.8 (95%CI 1.2–6.3) among women aged 65 years and older who were taking anticonvulsants.5 Thus the use of antiseizure medications may be an important risk factor for both osteoporosis and major skeletal fractures, the implications of which are a considerable increase in morbidity and mortality.6,,7

Young and middle‐aged adults with severe neurodevelopmental disabilities also appear to be at increased risk for both osteoporosis8 and skeletal fractures.9 A substantial proportion of these individuals receive high‐dose anticonvulsant drugs for prolonged periods of time, often failing attempts at drug cessation.10 Further, their risk for fractures is heightened by their limited mobility and unsteady gait, as well as a lack of exposure to adequate sunlight. Despite the available evidence, there remains much uncertainty about the degree to which anticonvulsant drug use contributes to bone fragility among adults with special needs. Specifically, previous studies have failed to control for other osteoporosis risk factors, such as mobility, age and sex.11 To better define the degree to which anticonvulsant drug use is a risk factor for low bone mass and bone fractures, we conducted a study of adults with special needs living in a long‐term care facility.

Methods

Study setting and participants

This cross‐sectional study was performed at the Huronia Regional Centre, in Orillia, Ontario, Canada. The Huronia Centre is home to a large number of adults who require special assistance with activities of daily living. All residents are assigned a case worker and a family physician, and each has their own chart that lists all previous and current medications. Most residents have received special care since childhood, typically for a major functional limitation acquired antenatally or at birth.

The chart of each resident was reviewed by a research assistant. Using a standardized data collection form, the following information was abstracted from each chart: age, sex, weight, degree of mobility, use of calcium or vitamin D containing supplements, as well as a complete list of all current and recently discontinued medications. Since major falls were typically documented in each resident's chart, we abstracted that number for the previous 12 months. By consulting his or her caregivers, the degree of mobility for each individual was categorized as ‘walking with or without an assistive device’, or ‘crawling or confined to a bed or chair’. The number of skeletal fractures within the past 12 months was based on chart documentation and plain X‐ray reports.

Each resident underwent quantitative calcaneal ultrasonography, performed by a second research assistant who was unaware of the participant's list of medications or past medical history. A routinely calibrated portable Sahara Clinical Bone Sonometer (Hologic) was used to measure both Speed of Sound (SOS) and Broadband Ultrasound Attenuation (BUA) at the calcaneus. The bone sonometer automatically calculates the Quantitative Ultrasound Index (QUI), a linear derivation of the SOS and BUA, and a measure of ‘bone stiffness’.12 The sonometer also estimates the femoral neck bone mineral density (BMD).13 and its respective T‐score for young healthy adults.14 On a practical level, we chose to use quantitative ultrasonography because many residents could not undergo dual‐photon absorptiometry (DXA) testing in the presence of joint contractures or behavioural problems. Further, quantitative ultrasonography is a valid and reliable estimator15 of both bone density16 and fracture risk.17,,18 Participants were respectively categorized as either having or not having low bone mass, based on a sonographic BMD‐equivalent T‐score equal to or less than 2.5 SDs of young healthy adults.14 Permission to conduct this study was obtained from the Huronia Centre's advisory board.

Statistical analysis

For the primary analysis, the association between anticonvulsant drug use and the presence of low bone mass, we performed multiple logistic regression analysis. This method was also applied for the analysis of anticonvulsant use and the rate of bone fractures within the past 12 months. We studied the relationship between the number of anticonvulsants used (i.e. one vs. none, and two or more vs. none) and the risk of both low bone mass and skeletal fractures. All odds ratio (OR) estimates were adjusted for specific covariates, defined a priori. These covariates included age (5‐year increments), sex, weight (5‐kg increments), mobility (walks with or without an assistive device vs. crawls or needs wheelchair), number of falls in the past 12 months (none vs. one or more), and current use of calcium or vitamin D supplements. Baseline characteristics of those with and without low bone mass were compared using an unpaired t‐test for continuous variables, or a χ2 test for categorical data. All analyses were performed using SAS Version 6.12 (SAS Institute), with statistical significance set at a two‐sided p‐value <0.05.

Results

General characteristics

Table 1 presents the characteristics of all 273 adult residents, of whom 62 (22.7%) had low bone mass. Those with low bone mass were more likely to be women (56.4%), and were a mean of 6.8 years older and 6.0 kg lighter than unaffected residents. Those with low bone mass were also more likely to be non‐ambulatory (11.3% vs. 4.3%), and to be taking anticonvulsants (51.6% vs. 36.5%). Fifty‐eight individuals (21.0%) were diagnosed with at least one skeletal fracture during the previous 12 months.

View this table:
Table 1 

Characteristics of 273 adults with special needs residing in a long‐term care facility, according to the presence or absence of low bone mass

CharacteristicWith low bone massWithout low bone massp*
Men:women (% male)27:35 (43.6%)157:54 (74.4%)<0.0001
Mean age (SD), years55.0 (16.1)48.2 (12.2)   0.005
Mean (SD) body weight, kg58.5 (13.1)64.5 (13.0)   0.002
No. (%) non‐ambulatory** 7 (11.3) 9 (4.3)   0.06
No. (%) with ⩾1 fall during past 12 months22 (35.5)41 (19.4)   0.006
No. (%) taking ⩾1 anticonvulsants32 (51.6)77 (36.5)   0.006
No. (%) currently taking corticosteroids 4 (6.4) 1 (0.5)   0.01
No. (%) currently taking calcium supplements11 (17.7)11 (5.2)   0.002
No. (%) currently taking vitamin D supplements12 (19.4)14 (6.6)   0.003
No. (%) with ⩾1 fracture during the past 12 months20 (32.2)38 (18.0)   0.02
Mean (SD) QUI52.1 (8.6)85.0 (19.1)<0.0001
Mean (SD) BMD (g/cm2) 0.306 (0.302) 0.464 (0.129)   0.0002
  • *With vs. without low bone mass. **Resident either crawls or requires a wheelchair for mobility. QUI, quantitative ultrasound index; BMD, bone mineral density, estimated at the calcaneus.

Low bone mass and fracture risk

Figure 1 represents a breakdown of the types of anticonvulsant agents used by the 108 residents (39.1%) who required therapy. Carbamazepine and valproic acid each accounted for almost one third of these drugs, phenytoin for 26%, and phenobarbital and primidone for another 10%. Thirty‐eight anticonvulsant users (35.2%) were taking two or more agents.

Compared to non‐users (15.5%), low bone mass was more prevalent among those taking either one (20.3%; OR 1.7, 95%CI 0.6–4.4) or two or more anticonvulsant agents (42.2%, OR 5.9, 95%CI 2.2–16.2) (Table 2). The risk of recent skeletal fractures was not significantly greater among single‐agent anticonvulsant users than non‐users (28.6% vs. 21.6%; OR 1.0, 95%CI 0.4–2.8), but there was a trend for it to be higher among those taking two or more agents (48.7%; OR 2.2, 95%CI 0.8–5.9) (Table 2).

Women were significantly more likely than men to have both low bone mass (OR 3.2, 95%CI 1.4–7.0) and a recent history of bone fractures (OR 3.0, 95%CI 1.3–7.0) (Table 2). Each 5‐year age increment was significantly associated with low bone mass (1.2, 95%CI 1.0–1.3), but not fractures (OR 1.0, 95%CI 0.9–1.2). Each 5‐kg weight increment attenuated the risk for low bone mass, but at a borderline level of statistical significance (OR 0.9, 95%CI 0.7–1.0). Degree of mobility was not a significant risk factor for either low bone mass or recent fractures, but one or more recent falls was associated with bone fractures (OR 5.9, 95%CI 2.5–13.9) (Table 2).

Figure 1. 

Types of anticonvulsants used by 108 adults with special needs.

View this table:
Table 2 

Adjusted odds ratios (OR) for low bone mass and recent fractures among 273 adults with special needs residing in a long‐term care facility

CharacteristicLow bone mass⩾1 fracture at any site during the past 12 months
Rate (%)*OR (95%CI)**Rate (%)OR (95%CI)
Anticonvulsant use
Non‐user15.51.021.61.0
1 agent20.31.7 (0.6–4.4)28.61.0 (0.4–2.8)
2 or more agents42.25.9 (2.2–16.2)48.72.2 (0.8–5.9)
Sex
Men14.71.023.61.0
Women39.33.2 (1.4–7.0)42.43.0 (1.3–7.4)
Age
5‐year increments1.2 (1.0–1.3)1.0 (0.9–1.2)
Weight
5‐kg increments0.9 (0.7–1.0)1.0 (0.9–1.2)
Mobility
Walks20.81.026.81.0
Non‐ambulatory***43.81.6 (0.5–5.8)46.72.8 (0.7–10.5)
No. falls in past 12 months
018.31.018.41.0
⩾134.91.2 (0.5–2.8)62.05.9 (2.5–13.9)
  • *Rate indicates the percentage of residents with the specific characteristic who also had either low bone mass or a recent fracture. **Adjusted odds ratios were determined by logistic regression analysis, using all characteristics listed in column 1 of the current table, as well as calcium and vitamin D supplement use. ***Crawls or needs wheelchair. –, Not applicable.

Discussion

We studied a group of neurodevelopmentally challenged adults living in a long‐term care setting and found that a substantial proportion were at increased risk for both low bone mass and skeletal fractures, the latter being present among 21% of all individuals. Use of two or more anticonvulsant drugs was independently associated with an increased risk for low bone mass, and there was a non‐significant trend toward increased risk for fractures. Finally, both female sex and a recent history of falls were also independent risk factors for skeletal fractures.

One main limitation to the current study was that neither menopausal status nor dietary intake were included in the analyses. Because we could not obtain a direct history from the resident herself, we had difficulty establishing the menstrual history and post‐menopausal status of most women participants. Similarly, a dietary questionnaire could not be effectively administered, despite our attempts to do so. Another limitation of this study was our inability to systematically and objectively assess either vertebral or other‐site fractures among all participants, and our reliance on a single‐site (i.e. calcaneal), single‐time assessment of bone mass using quantitative calcaneal ultrasonography.19 Finally, our inability to demonstrate a significant association between use of two or more anticonvulsant drugs and skeletal fractures (i.e. OR 2.2, 95%CI 0.8–5.9) might be explained by inadequate statistical power, especially since the rate of fractures was more than twice as high in this group compared to non‐users.

Our study adds to a growing body of evidence that adults with neurodevelopmental disorders are at an increased risk for low bone mass and fractures, particularly those receiving anticonvulsants. For example, in a study of adults aged 50 years of age and older who were living in a long‐term care facility, the annual fracture rate was 10% among those with a seizure disorder.9 In that study, bone biopsies were consistent with osteomalacia in the majority of cases. In a second study, 56% of mentally challenged adults had BUA values at least 2 SDs below the expected values for age and sex, suggesting an increased future risk for fractures. A subset of these patients had lumbar spine BMD that confirmed osteoporosis.8 A third study, published in abstract form, found a 7.3% incidence of atraumatic fractures in a group of 391 individuals with special needs. Of those with atraumatic fractures, 84% were taking anticonvulsants, compared to 47% of controls (crude OR 6.0, 95%CI 1.4–26.2).20 In our study, skeletal fractures were quite common among those taking one (28.6%) and two or more (48.7%) anticonvulsant agents, and were more prevalent among those with (32.2%) than without (18.0%) measured low bone mass.

We have identified a group of individuals at potentially high risk for fractures. Since adults with neurodevelopmental disorders are now living longer,21 their risk of fractures will likely continue to rise, especially in the presence of anticonvulsant drug use. Since these individuals often cannot express the pain associated with skeletal fractures, nor initiate their own prophylaxis against further bone loss, they must rely on their caregivers for such recognition and action. Accordingly, among these individuals it is sensible to initiate simple prophylactic measures against bone loss, such as the use of vitamin D and calcium supplementation,3,,4 while minimizing anticonvulsant drug use or combined therapy whenever possible. Consideration of which individuals warrant periodic screening for low bone mass should be heightened by the use of long‐term anticonvulsant therapy, lack of weight‐bearing activity, and female sex. The optimal method of assessing bone density in this group must take into account not only the operating characteristics of the test, but also whether an individual will remain motionless during testing.

Future investigators should attempt to document which anticonvulsant drugs, and at what dose, affect bone mass the most. In addition, there is a need for a randomized clinical trial of calcium and vitamin D supplementation among neurodevelopmentally challenged adults, both those who are and those who are not taking anticonvulsant therapy.

Acknowledgments

Thanks to our research assistants, Mr Robert Bensen and Ms Christine Brenckmann, as well as Dr Nancy Harris and the staff of the Huronia Centre, for their patience and help in completing this study.

Footnotes

  • Address correspondence to Dr J. Ray. rayjgmcmaster.ca

References

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