THINKING OUTSIDE THE BONE
Highlights from Mayo Clinic College of Medicine’s Women’s Health 2006
| LOW BONE DENSITY: ALL THAT IS THIN IS NOT NECESSARILY OSTEOPOROSIS —Michael D. Whitaker,
MD, FRCPC, Assistant Professor of Medicine, Mayo Clinic College of Medicine, Scottsdale, AZ
|
| Osteoporosis and osteomalacia: 2 distinct metabolic bone diseases; similarities—reduced bone mineral density
(BMD) on dual-energy x-ray absorptiometry (DEXA); increased fracture rate; asymptomatic more often
than not; can coexist in same patient; differences—in osteoporosis, reduced bone mass and bone microdamage;
osteomalacia is abnormal mineralization of osteoid
|
| Bone remodeling unit: bone not static organ; at stage of quiescence, osteoprogenitor cells recruited and
brought into periosteum; during sequence of activation, osteoprogenitor cells become osteoclasts and bone resorption
begins; osteoclasts dig pit into bone and apoptosis occurs; osteoblasts recruited to site and bone formation
begins; bone resorption and formation tightly linked; in any condition that increases bone turnover,
resorption generally favored slightly over formation, with net effect being bone loss; osteoid formation begins
with procollagen formation; mineralization of collagen osteoid poorly understood but involves vitamins C, D,
K, and A, calcium, and phosphorus
|
| Causes of osteomalacia: failure to mineralize newly formed bone; any condition influencing or affecting vitamin
D, calcium, or phosphorus can affect bone mineralization
|
 | Abnormal vitamin D metabolism: vitamin D absorbed from gastrointestinal (GI) tract; formed under influence
of sunlight at level of skin; factors influencing absorption or production— dietary insufficiency, intestinal
malabsorption (celiac sprue, Whipple’s disease, surgically altered gut, Crohn’s disease, hepatic
insufficiency, vitamin D-resistant rickets, and anticonvulsants); secondary hyperparathyroidism increases
bone turnover and eventually leads to profound mineralization defect; symptoms occur only in profound
cases of vitamin D deficiency; characterized by bone pain, muscle weakness (waddling gait), neuromuscular
irritability, and myopathy; pseudofracture patho-gnomonic; clinical and x-ray manifestations occur late
in disease process; laboratory diagnosis— 25-hydroxyvitamin D <20 to 25 ng/mL (if <12 ng/mL, diagnostic
of vitamin D deficiency), elevated parathyroid hormone, elevated bone alkaline phosphatase, low urine
calcium; serum calcium and phosphorous usually at lower limits of normal; once diagnosed, establish etiology
and treat; one third of women in United States have vitamin D deficiency; sunlight and vitamin D—data
show deficiency begins to be corrected with as little as 10 min of exposure to sunlight; deficiencies exist,
regardless of season; worldwide problem, not unique to northern latitudes
|
| Hypophosphatemia: normal serum phosphate 2.5 to 4 mg/dL; causes—hereditary renal tubular disorders, abnormal
binding (overuse of antacids, aluminum hydroxide, bisphosphonates [etidronate (Didronel)], renal
osteodystrophy); hypophosphatemia hallmark of oncogenic osteomalacia; bone and muscle pain clue to assess
phosphorous level; low 1,25-dihydroxyvitamin D pathognomonic for tumor-induced osteomalacia (oncogenic
osteomalacia); address phosphorous level closely in setting of bone pain and fracture
|
| Multiple myeloma: urine immunoelectrophoresis diagnostic tool; patient can look and feel well; evidence of anemia
and nonparathyroid hormone-dependent hypercalcemia valuable diagnostic tip; multifactorial etiologies tied
to fracture—lytic bone lesions, reduced bone mass, advanced age, exposure to chemotherapy; association of myeloma
with fracture so strong bone issues may bring patient to clinical attention before other issues; majority of
fractures occur around time diagnosis of myeloma made
|
| Conclusion: thin bone not always osteoporotic; vitamin D deficiency endemic in United States and can lead to
osteoporosis or osteomalacia; identify cause of hypophosphatemia; bone turnover increases with early onset
of vitamin D insufficiency, leading to osteoporosis; continued decrease in vitamin D and failure to mineralize
bone can lead to osteomalacia; consider multiple myeloma in patient with symptoms of bone and muscle
pain, weakness, and low phosphorous
|
| ANTIEPILEPTIC DRUGS: IMPACT ON BONE HEALTH— Katherine H. Noe, MD, PhD, Senior Associate
Consultant, Mayo Clinic College of Medicine, Scottsdale, AZ
|
| Epilepsy: prevalence—1% of population in United States (2.5 million people); ≈50% have partial epilepsy;
≈30% of people with epilepsy refractory to medical therapy (likely on long-term medication with multiple
drugs); incidence— highest in people <20 yr of age and >60 yr of age; incidence of seizures in United States
stable, but prescriptions for antiepileptic drugs (AEDs) increasing; prescriptions for AEDs written primarily
for nonepilepsy indications, eg, neuropathic pain, headache, psychiatric disorders; bone disease not believed
to be result of epilepsy, but drug class effect
|
| Risk factors for fractures related to loss of bone mass: study data showed relative risk (rr) 2.8 with current
use of AEDs; only 8% of adult and pediatric neurologists surveyed in 2001 prescribed prophylactic calcium
and vitamin D when prescribing seizure medication; women on long-term AEDs have abnormal hormone levels
throughout treatment and at significant risk for early menopause; patients using AEDs from childhood or
adolescence likely never achieve normal peak bone mass, increasing risk for osteoporosis or other bone disease
|
| Mechanisms of AED-related bone loss: AEDs interfere with calcium absorption; normal mineralization of
bone impaired; altered vitamin D metabolism with enzyme-inducing AEDs—carbamazepine (Tegretol), phenobarbital,
phenytoin (Dilantin); increased inactivation of cytochrome P450; increased activation of 1,25-dihydroxyitamin
D (active form of vitamin D); decreased vitamin D leads to decreased absorption of calcium
and lowered serum calcium, resulting in poor bone mineralization and osteomalacia; several AEDs have potential
to alter kidney function, causing abnormal resorption of calcium at kidney level; in vitro studies show
several older medications directly impair activity of osteoclast, creating imbalance between osteoclast and osteoblast
activity; medications can affect estrogen, insulin-like growth factor, calcitonin, and vitamin K
|
| Long-term effects on bone: laboratory evidence of metabolic bone disease in epilepsy patients on AEDs—
decreased serum calcium and vitamin D, abnormalities of urine calcium, increased levels of parathyroid hormone
and other markers of bone turnover; BMD in patients on enzyme-inducing AEDs—data show osteopenia
in one third of patients <50 yr of age or >50 yr of age; ≈25% of patients >50 yr of age met criteria for osteoporosis;
data showed longer patient on medication, lower BMD at hip; BMD in ambulatory epilepsy
patients—60% of patients screened met criteria for osteopenia; 50% of patients had abnormally low 25-hydroxyvitamin
D levels; risk factors identified include enzyme-inducing AEDs, long duration of AED use,
polypharmacy, and generalized epilepsy; frequency of fractures in AED users—40,000 persons on active treatment
with AED for epilepsy compared to 80,000 aged-matched controls; risk for fracture in men and women
increased significantly across all age groups; risk for hip fracture significantly increases after 50 yr of age (rr
2.79)
|
| Enzyme-inducing AEDs: phenytoin, phenobarbital, primidone, carbamazepine, ethosuximide; activate cytochrome
P450 pathway; lead to increased inactivation of 1,25-dihydroxyvitamin D, poor calcium absorption,
lower calcium levels, decreased levels of bioactive estrogen (causing pseudomenopause and risk for early
menopause), and altered vitamin D metabolism; data show only patients taking ≈4,000 IU of vitamin D
weekly had normal serum calcium; valproic acid (Depakote)—inhibitor of cytochrome P450 system; frequency
of osteopenia and osteoporosis in long-term users of depakote by DEXA comparable to that seen with
users of enzyme–inducing AEDs; serum calcium and vitamin D levels normal; degree of bone loss correlates
with duration of drug usage; mechanism unknown (some evidence that insulin-like growth factor may play
role); newer medications— potential risk with several new drugs, including topiramate (Topamax) and
zonisamide (carbonic anhydrase inhibitors; known to cause renal tubular acidosis); show decreased serum bicarbonate;
laboratory evidence of renal tubular acidosis seen in ≈30% of adults on topiramate; limited data on
other new drugs
|
| Additional epilepsy-specific risk factors for bone fracture: significant muscle contraction occurring during
generalized tonic-clonic seizure can cause fracture; drugs can contribute to instability and falls; survey of 8,000
community-dwelling women >65 yr of age showed risk of falling increased 75%
|
| Prevention of AED-related bone disease: indications for discontinuing medication—patient seizure-free for 2
yr; history suggests benign epilepsy syndrome with remission; no known symptomatic cause and normal electroencephalogram
(EEG); consider use of different medication; calcium and vitamin D supplementation—
dosage for patients on AEDs unknown; consider checking laboratory values for calcium and vitamin D; discuss
other modifiable risk factors, ie, smoking cessation, alcohol avoidance, limiting caffeine intake, and importance
of weight-bearing exercise
|
| American Epilepsy Society guidelines: BMD screening with DEXA for all patients >12 yr of age taking
AEDs for 2 yr; normal T score—calcium 1200 mg/day; vitamin D 400 IU/day; repeat scan in 2 to 4 yr, depending
on presence of additional risk factors; osteopenia—laboratory evaluation, eg, active vitamin D level,
thyroid function; higher doses of calcium and vitamin D; weight-bearing exercise; repeat scan in 18 mo;
osteoporosis—refer to rheumatologist or endocrinologist
|
| Conclusion: long-term use of many AEDs associated with increased risk for osteoporosis and osteopenia; discontinue
AEDs when no longer needed; consider changing to lower-risk medication; counsel patient about
preventive measures; institute appropriate screening measures in patients on chronic AEDs
|
| AEDs for migraine prevention: counsel patient about risk for bone disease; prescribe calcium and vitamin D
supplementation; follow guidelines in screening patient with DEXA after 2 yr on AED
|
| Risk for osteoporosis in black women using AEDs: no studies specifically looking at minority women; unknown
whether black women at increased risk or more protected; recommended treatment likely same, regardless
of race
|
| Bisphosphonate therapy used in conjunction with AEDs: currently, no good studies evaluating assorted
treatments for AED-related osteoporosis; no reason to expect bisphosphonate would be less effective; many
women with epilepsy have hormone-sensitive seizures; estrogen may cause seizures to worsen
|
| Bone turnover markers: great individual variability; markers cannot be used to diagnose osteoporosis; can be
used only to predict risk for fracture; 24-hr urinary N-telopeptide (NTx) useful in determining whether antiresorptive
therapy effective and whether patient compliant; should be in premenopausal or suppressed range
|
| Reports of “frozen” bone: associated with long-term use of alendronate therapy; drug holiday proposed for
women on bisphosphonate therapy for >4 yr; speaker concerned about long-term effects of alendronate
|
Educational Objectives
| The goal of this program is to educate the listener about conditions and diseases that can affect bone health. After
hearing and assimilating this program, the clinician will be better able to:
|
| 1. Cite the similarities and differences between osteoporosis and osteomalacia.
|
| 2. Summarize the sequence of events in bone remodeling and the vitamins and minerals necessary for optimum
bone health.
|
| 3. Identify conditions and diseases affecting bone health.
|
| 4. Recognize the impact that antiepileptic drugs (AEDs) have on bone health.
|
| 5. Identify and effectively manage patients on AEDs who are at risk for bone disease.
|
Discussed on This Program
Carbamazepine [Carbatrol, Epitol, Tegretol, Tegretol-XR]
Ethosuximide [Zarontin]
Etidronate disodium [Didronel, Didronel IV]
Phenobarbital [Bellatal, Luminal Sodium, Solfoton]
Phenytoin [Dilantin Infatab, Dilantin-125]
Primidone [Mysoline]
Topiramate [Topamax]
Valproic acid [Depacon, Depakene, Depakote, Depakote ER]
Zonisamide [Zonegran]
Suggested Reading
Favus MJ: Postmenopausal osteoporosis and the detection of so-called secondary causes of low bone density. J
Clin Endocrinol Metab 90(6):3800, 2005; Frame B et al: Osteomalacia: current concepts. Ann Intern Med
89(6):966, 1978; Gaasbeek A et al: Hypophosphatemia: an update on its etiology and treatment. Am J Med
118(10):1094, 2005; Holick MF: High prevalence of vitamin D inadequacy and implications for health. Mayo
Clin Proc 81(3):353, 2006; Sato Y et al: Amelioration of osteoporosis and hypovitaminosis D by sunlight exposure
in hospitalized, elderly women with Alzheimer’s disease: a randomized controlled trial. J Bone Miner Res
20(8):1327, 2005; Jan de Beur SM: Tumor-induced osteomalacia. JAMA 294(10):1260, 2005; Souverein PC et
al: Incidence of fractures among epilepsy patients: a population-based retrospective cohort study in the General
Practice Research Database. Epilepsia 46(2):304, 2005; Valmadrid C et al: Practice patterns of neurologists regarding
bone and mineral effects of antiepileptic drug therapy. Arch Neurol 58(9):2369, 2001; Vestergaard P et
al: Fracture risk associated with use of antiepileptic drugs. Epilepsia 45(11):1330, 2004.
Faculty Disclosure
In adherence to ACCME guidelines, the Audio-Digest Foundation requests all lecturers to disclose any significant
financial relationship with the manufacturer or provider of any commercial product or service discussed.
For this issue, the faculty reported nothing to disclose.
Drs. Whitaker and Noe were recorded at Women’s Health 2006 sponsored by Mayo Clinic College of Medicine,
Scottsdale, AZ, and held on March 9-11, 2006 in Phoenix, AZ. The Audio-Digest Foundation thanks the speakers and
the sponsor for their cooperation in the production of this program.
|
