36
CHAPTER
Bone Health
Christa B. Swisher and Aatif M. Husain
It was first reported about 40 years ago that antiepileptic drugs (AEDs) were associated with poor bone health, such as osteoporosis and pathologic fractures. Previously, osteoporosis was thought to be primarily a disease of older women; however, studies have found that men with epilepsy treated with AEDs are also susceptible to the development of bone disorders (1). In addition, it has been shown that children with epilepsy taking AEDs can also develop bone disease (2). As the population ages, bone health will become an increasingly important issue for patients with epilepsy.
The issues pertaining to bone health in epilepsy patients are unfortunately still underrecognized. Despite the growing body of literature linking chronic AED therapy and poor bone health, a survey showed that only 28% of adult and 41% of pediatric neurologists perform screening for bone disease in their epilepsy patients (3). Further research must be performed to determine the optimal method and timing of screening and to identify the most effective treatment. This chapter will discuss the pathophysiology of bone metabolism, an overview of osteoporosis, the relationship between epilepsy and bone loss, the effect of various AEDs on bone health, and the current methods for screening and treatment of bone health in patients with epilepsy.
PATHOPHYSIOLOGY
Bone Structure and Metabolism
Bone is a dense connective tissue and has three main categories of function: mechanical, synthetic, and metabolic. Although the mechanical and synthetic properties are important to providing structural support and the production of blood components, this chapter will primarily focus on the metabolic properties of bone. The metabolic function of bone primarily includes the storage of minerals (most notably calcium and phosphorous), fat, and growth factors. In addition, bones function as an endocrine organ involved in the control of phosphate metabolism.
The formation and breakdown of bones is a constant, dynamic process referred to as bone turnover or remodeling. Interestingly, approximately 10% of the skeletal mass of an adult is remodeled each year (4). Osteoblasts and osteoclasts are the cell types that function to remodel bone with the goal of maintaining calcium homeostasis and repair of micro-damages in bone. Osteoblast activity results in bone formation and osteoclast activity results in resorption of the bone matrix. These two processes occur simultaneously and are closely linked. Osteoclasts remove bone by acidification and proteolytic digestion. After this occurs, osteoblasts then initiate bone formation by secreting osteoid, which eventually becomes mineralized into new bone. Growth factors, cytokines, systemic hormones, and mechanical signals determine the development and differentiation of osteoblasts and osteoclasts (4). The balance of osteoblast and osteoclast activity determines bone mineral density and how well bone homeostasis is maintained.
Calcium Metabolism
There is normally 1 to 2 kg of calcium present in the adult body and over 99% of this resides in the skeleton. Skeletal calcium provides stability to bones and also functions as a reservoir of calcium needed elsewhere in the body. Skeletal calcium reaches its peak values in early adulthood and then gradually declines by 1% to 2% per year (5).
About 0.5% to 1% of total body calcium is readily available in the extracellular fluid as ionized calcium. The calcium concentration in blood is normally 2.2 to 2.6 mM (8.5–10.5 mg/dL) and about 50% of this is in the form of ionized calcium. In the extracellular fluid, the concentration of ionized calcium must be kept within a narrow range (1.1–1.3 mmol/L). The rest of calcium is bound to negatively charged proteins (primarily albumin and immunoglobulins) or complexed with phosphate, citrate, sulfate, or other anions (5). Since calcium is heavily protein bound, blood calcium concentration can be affected by changes in protein level and acidosis.
The level of ionized calcium concentration is affected by parathyroid hormone (PTH) and vitamin D in the form of 1,25-hydroxyvitamin D (1,25(OH)2D) by modifying the rate of calcium movement across intestinal and renal epithelia (5). In turn, ionized calcium in the blood also affects levels of PTH and 1,25(OH)2D.
Phosphorous Metabolism
The average amount of total body phosphorous is 600 g and the majority of this is contained in bone mineral. The rest is contained in the intracellular compartment as free anions and as a component of organophosphate compounds, which include proteins, nucleic acids, adenosine triphosphate (ATP), and carbohydrates. In serum, approximately 12% of phosphate is bound to protein. The normal blood concentration of phosphate is 0.75 to 1.45 mmol/L (2.5–4.5 mg/dL).
Phosphate is present in many foods and absorbed easily from the GI tract, even in the absence of vitamin D. However, the absorption of phosphate is increased by 1,25(OH)2D. Low levels of circulating phosphate stimulates the renal production of 1,25(OH)2D. Phosphate levels are primarily regulated by the renal resorption or excretion of filtered phosphate.
Hormones: Vitamin D and Parathyroid Hormone
The two main hormones that control calcium homeostasis are vitamin D and PTH. Vitamin D and its metabolites are actually hormones since they can be synthesized endogenously. Vitamin D is metabolized in the liver to 25-hydroxyvitamin D (25OHD), which is then metabolized in the kidney to 1,25(OH)2D, the biologically active form. Vitamin D increases dietary calcium absorption and bone mineralization.
PTH has actions on bone, kidney, and intestinal mucosa. PTH increases bone remodeling by stimulating osteoclast activity and thus resulting in loss of calcium from bone. PTH increases calcium resorption in the kidneys and also increases GI absorption of calcium.
Calcitonin is another hormone involved in calcium homeostasis. Numerous other hormones are involved in calcium homeostasis, such as estrogen, androgen, glucocorticoids, and thyroid hormone (4).
OSTEOPOROSIS
Osteoporosis is characterized by low bone mass and an increased risk for fractures. The World Health Organization (WHO) defines osteoporosis as a bone mineral density (BMD) of 2.5 standard deviations or more below the mean peak bone mass of young, healthy adults as measured by dual-energy X-ray absortiometry (DEXA). This reduction in BMD may or may not be associated with the presence of fragility fractures. Osteoporosis is classified as primary (type 1 or type 2) or secondary. Primary type 1 is postmenopausal osteoporosis. Primary type 2 is also known as senile osteoporosis and occurs in both males and females after the age of 75. This type is more common in females than in males (2:1).
Secondary osteoporosis can occur at any age and affects women and men at similar rates. There are numerous causes of secondary osteoporosis. Some common causes include renal insufficiency, immobilization, various endocrine disorders, malnutrition, and the use of certain medications such as glucocorticoids, antidepressants, and AEDs. A list of common secondary causes of osteoporosis is shown in Table 36.1.
TABLE 36.1 Secondary Causes of Osteoporosis
– Hypogonadism – Hypercortisolism – Diabetes mellitus – Growth hormone deficiency – Estrogen deficiency – Hyperthyroidism – Hyperparathyroidism – Hyperprolactinemia – Low testoserone – Calcium deficiency – Adrenal insufficiency
– Chronic renal insufficiency
– Inflammatory bowel disease – Celiac disease – Cirrhosis – Chronic liver disease
– Multiple myeloma – Lymphoma – Leukemia
– Vitamin D deficiency – Alcohol – Malabsorption syndrome – Anorexia nervosa
– Glucocorticoids – Antidepressants – Heparin – Anticonvulsant drugs – Cyclosporine – Chemotherapy – Diuretics – Lithium
– Osteogenesis imperfecta – Marfan syndrome – Ehlers-Danlos syndrome – Homocystinuria – Glycogen storage diseases
– Cigarette smoking – Cystic fibrosis – Physical inactivity – Pregnancy |
EPILEPSY AND OSTEOPOROSIS
Overview
There have been several retrospective, case–control, and cross-sectional studies that have shown higher rates of osteoporosis and low BMD in adult and pediatric patients with epilepsy when compared to age-matched nonepileptic controls (6). The approximate rate of low BMD or osteoporosis in patients with epilepsy treated with AEDs is 38% to 60% (7–9). In a 2005 meta-analysis, there was a significantly lower BMD in both the spine and hip in patients with epilepsy taking AEDs when compared with age-matched controls (10).
Aside from a direct effect of AEDs on bone health, patients with epilepsy may have additional risk factors for the development of osteoporosis. Immobility and inactivity are strong risk factors for osteoporosis. Participation in weight-bearing exercise has been shown to improve BMD. Many patients with epilepsy are immobile or inactive and not able to participate in weight-bearing exercise, placing them at an increased risk for osteoporosis. The lack of weight-bearing exercise may be due to various physical and cognitive deficits. In addition, patients with epilepsy and physical restrictions may have limited exposure to sunlight, which is the primary source for vitamin D. Furthermore, patients taking carbamazepine may develop a sunlight-induced rash and limit their sunlight exposure to prevent such a rash.
Fractures
Patients with epilepsy often experience bone fractures in the setting of seizures, either from seizure-related falls or trauma due to altered mental status (ie, motor vehicle collision). Studies have shown that patients with epilepsy are 2 to 6 times more likely to experience a fracture than the general population in the United States (11). This fracture risk is similar to the fracture risk seen in patients taking chronic steroids. In a meta-analysis, there was a higher fracture risk in patients with epilepsy compared to the general population (relative risk of any fracture 2.2, 95% CI 1.9–2.5) (10). There was an increased relative risk for all fractures studied: hip, forearm, and spine. However, the overall increase in fracture risk was higher than expected from the BMD values. The authors postulated that seizures might account for the higher than expected fracture risk since one-third of all fractures were associated directly with seizures. However, about two-thirds of falls in patients with epilepsy are not related directly to seizures. Why patients with epilepsy have a higher rate of falls when compared to age-matched controls is unknown. It has been postulated that epilepsy may be associated with other neurologic deficits such as weakness, impaired sensation, poor balance, and impaired cognition, leading to an increased susceptibility to falls. AEDs often have side effects such as ataxia and drowsiness, which may contribute to epilepsy patients having an increased risk of falls and fractures.
There is a higher rate of fractures in patients with epilepsy who receive prescriptions for rectal benzodiazepines, have AED polypharmacy, and have more medical visits (1). These factors are all associated with a greater severity of epilepsy. In addition, there is a higher fracture risk in older patients with epilepsy. Among epilepsy patients, it is not clear if there is a higher risk of fractures in men or women since the data are variable (1).
Antiepileptic Drugs
The use of antiepileptic drugs has been shown to be an independent risk factor for the development of low BMD (6,10). Although there is a consensus that patients with epilepsy taking AEDs have higher rates of bone loss and pathologic fractures, the exact mechanism has not been identified. The data on calcium concentrations has been inconsistent, with some studies reporting reduced calcium concentrations and other studies showing no significant effect on calcium levels. Overall, most studies have shown normal calcium concentrations in this patient population (12). Although studies have not been able to show a consistent effect on vitamin D concentration, the majority of studies shown that vitamin D levels are reduced in patients taking AEDs, particularly in patients taking enzyme-inducing AEDs (12). PTH elevation may cause low BMD in patients taking AEDs by increasing bone resorption, but, again, studies have had inconsistent results regarding the levels of PTH in a patient taking AEDs (6). It has been theorized that AED-treated patients are resistant to PTH action on bone, due to several observations that PTH levels are increased in the presence of decreased or normal serum calcium concentration (12).
Table 36.2 lists the potential mechanisms for AED-induced bone loss. Despite the inconsistent results regarding the mechanism of bone loss in patients with epilepsy, there have been consistent results showing elevations in bone resorption markers associated with the use of AEDs. This suggests that there is long-term increased bone turnover that eventually leads to loss of BMD. In addition to increased bone turnover, studies have shown that phenytoin and carbamazepine inhibit cell growth in bone cell cultures taken from surgical patients (13). Studies in children with epilepsy taking AEDs have demonstrated poor bone formation (2). These data suggest that both increased turnover and impaired synthesis are mechanisms by which AED use leads to decreased BMD.
There does appear to be a sex difference regarding the effect of AEDs on BMD with women showing a more marked decline in BMD when compared with men (3). In addition to the type of AED a patient is taking, AED polypharmacy appears to be an independent risk factor for the development of fractures (2). In a meta-analysis, the duration of AED use was also shown to be associated with an increased risk of fractures, particularly in women (10).
