BONING UP ON OSTEOPOROSIS
Educational Objectives
| The goal of this program is to improve the management of women with osteoporosis, including the management
of vitamin D deficiency. After hearing and assimilating this program, the clinician will be better able to:
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 | 1. Differentiate women with osteopenia from those with osteoporosis, and identify primary risk factors for
osteoporosis.
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| 2. Discuss modalities for screening bone mineral density, and review guidelines about candidates for and
frequency of screening.
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| 3. Prescribe the appropriate therapy for women with osteoporosis.
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| 4. Identify patients at risk for vitamin D deficiency.
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| 5. Prescribe vitamin D for appropriate patients.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and members of the planning
committee to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a
proprietary business or commercial interest. For this program, the following has been disclosed: Dr. Ko has received grant
funding from Procter & Gamble. Dr. Walsh and the planning committee reported nothing to disclose.
Acknowledgments
Dr. Walsh was recorded at Controversies in Women’s Health, sponsored by the University of California, San Francisco,
School of Medicine, and held December 6-7, 2007, in San Francisco, CA. Dr. Ko was recorded at Women’s
Health Update 2008, sponsored by Mayo Clinic Scottsdale, and held April 17-19, 2008, in Scottsdale, AZ. The Audio-Digest
Foundation thanks the speakers and the sponsors for their cooperation in the production of this program.
| Osteoporosis: Prevention and Management
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| Judith Walsh, MD, MPH, Associate Professor, Department of Medicine, University of California, San Francisco, School of
Medicine
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| Definitions: osteopenia—low bone mass; bone mineral density (BMD) -1.0 to -2.5 standard deviations (SD) below
mean for young adults; osteoporosis—T score >2.5 SD below mean for young adults; T score—compares patient
with young adult woman at peak bone mass; used for treatment decisions; Z score—compares patient with age-
matched woman; useful for ruling out other causes of bone loss
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| Major risk factors: age, sex, and ethnicity; women in their 70s and 80s at greatest risk; older women have higher
fracture rates than younger women with same BMD; previous fracture; family history; low body weight; smoking;
BMD additive risk factor; vertebral fracture—symptomatic or asymptomatic; indicates very high risk for new fracture
in year following vertebral fracture
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| Screening modalities: BMD best predictor of future fracture; hip BMD best predictor of hip fracture; vertebral
fracture may or may not be clinically significant; central dual x-ray absorptiometry (DXA) most commonly used
for screening; other modalities—peripheral DXA and single x-ray absorptiometry (SXA); quantitative ultrasonography
(US); quantitative computed tomography (CT); biochemical markers of bone turnover (not recommended for
screening); population-based screening controversial—treating women with known osteoporosis can reduce risk for
hip fractures, but no evidence that screening reduces risk for hip fracture
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| Screening guidelines: National Osteoporosis Foundation (NOF)—all postmenopausal women should take calcium
daily, engage in regular weight-bearing exercise, and avoid smoking and excessive alcohol intake; women at risk
for vitamin D deficiency should receive vitamin D; preventing falls important; hip protectors for women at high
risk; whom to screen—all women >65 yr of age; younger postmenopausal women with 1 risk factor (other than being
white, postmenopausal, and woman); confirm diagnosis and assess disease severity in postmenopausal women
presenting with fracture (rationale not entirely clear, since postmenopausal women with fracture believed to have
osteoporosis and treatment recommendations not based on disease severity); United States Preventive Services Task
Force (USPSTF)—screen all women >65 yr of age; indirect evidence for screening; screen women 60 to 64 yr of
age at increased risk (eg, age, low body weight, nonusers of hormone replacement therapy [HRT]); National Institutes
of Health (NIH)—evidence insufficient to recommend screening; when should BMD be repeated?—previous result
near treatment threshold? should treatment response be monitored? study results—showed initial BMD
predictive of fracture; change in BMD over time predictive of fracture; for fracture prediction, repeat BMD added
little to original BMD 8 yr earlier; no additional benefits, even in groups with high rates of bone loss; study concluded
repeat BMD testing 8 yr later adds little to fracture prediction for patients with normal or mildly reduced
BMD; rate of bone loss 0.5% per year (ie, 0.1 on T score); repeating BMD routinely may not be necessary (suitable
frequency likely less than what patients expect); monitoring treatment—continue treatment in patients who lose
BMD initially; patients who lose BMD in first year likely to gain BMD in subsequent years; if BMD monitored,
decreases should trigger questions about adherence; monitoring of BMD probably not necessary, since most
women gain BMD with treatment, and resistance to treatment not documented (if BMD decreases, it would have
gone down without treatment; treatment continued if BMD increases); monitoring unlikely to have impact on adherence,
since most adherence problems occur early in treatment; conclusion—ordering diagnostic tests not beneficial
if management unaffected by results; BMD precise measurement, but random errors can occur
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| Whom to treat: NOF recommendations—consider treatment in women whose BMD falls below specified thresholds;
women without risk factors, but whose T scores -2.5; consider initiating treatment when T score -2.0 and risk
factors present (eg, history of fracture, family history); previous vertebral or hip fracture; fracture rates highest in
women with T scores <-2.5, but fractures can occur in women with T scores of -1.0 to -2.5; risk factor assessment
useful in guiding treatment of women in range of osteopenia; predictors of fracture risk—previous fracture; T score
≤-1.8; poor mobility; poor health status (self-rated)
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| Nonpharmacologic interventions: smoking cessation; avoidance of alcohol abuse; exercise (transient effect);
avoidance of thyroid overreplacement; hip protectors (problem with compliance, and prevention of fractures unclear)
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| Calcium with vitamin D: substudy of Women’s Health Initiative (WHI) concluded calcium and vitamin D resulted
in small increase in BMD among healthy postmenopausal women; no overall effect on fractures; increased
risk for kidney stones; women should continue to get calcium from diet, supplements, or both; calcium and vitamin
D necessary, but not sufficient
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| Estrogen: associated with significant reduction in osteoporotic fractures; WHI showed hip fracture risk reduced by
≈34%; USPSTF does not recommend use of estrogen for treatment of any long-term disease; women on estrogen
for menopausal symptoms receive added benefit of bone protection
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| Bisphosphonates: first line and mainstay of treatment; bind to bone and inhibit osteoclastic resorption; increase
BMD by ≈3%/yr; reduce risk for fracture; Fracture Intervention Trial (FIT)—results differed in women with and
without vertebral fractures; concluded that women with T scores <-2.5 or with preexisting vertebral fractures benefit
from treatment with alendronate, but women with higher BMD receive little or no benefit; risedronate—
weekly dosing; data show significant reductions in new vertebral fractures; significant reduction in hip fractures in
women with T scores <-3.0; gastrointestinal (GI) safety similar to that with placebo; data showed reduced hip fractures
in women 70 to 79 yr of age in treatment group; most beneficial in women who already had vertebral fracture;
no effect in older women (study confounder, only 300 women >80 yr of age); bisphosphonates poorly absorbed;
fewer GI effects and similar effects with weekly alendronate; continued therapeutic effects seen with alendronate
used for 10 yr; well tolerated; gradual loss of effect with discontinuation of medication; improved compliance with
weekly dosing; zoledronic acid—highly potent; taken yearly; data show major reduction in vertebral fractures; 40%
reduction in hip fractures; improved BMD and biomarkers of bone metabolism; increased rate of atrial fibrillation
in zoledronic acid group; reanalysis of FIT data showed nonsignificant trend toward increased rate of atrial fibrillation
with alendronate; fewer GI side effects with less frequent dosing; osteonecrosis of jaw—more common with
potent bisphosphonates; more common among patients treated with intravenous (IV) bisphosphonates for cancer;
risk factors include duration of treatment and oversuppression of bone turnover; identify condition early, stop medication,
and treat conservatively; risk in those treated for osteoporosis probably <1/100,000 patient-years; duration
of use—study looked at effects of discontinuing alendronate after 5 yr vs continuing for 10 yr; those who discontinued
had decrease in BMD at hip and spine, but levels remained above pretreatment levels from 10 yr earlier; markers
of bone turnover increased after discontinuation, but remained above pretreatment levels; no difference in
morphometric vertebral fractures; lower risk for clinically recognized vertebral fractures for those who continued;
study concluded discontinuing alendronate after 5 yr may not increase fracture risk for many women; those at high
risk for clinical vertebral fractures may benefit from continuing >5 yr; summary—bisphosphonates reduce risk for
vertebral and hip fractures in women with vertebral fracture or low BMD (<-2.5); fracture risk may not be reduced
in women who do not have osteoporosis; intermittent dosing appears effective; best evidence for efficacy of any
osteoporosis treatment; some women may discontinue after 5 yr, but question remains who, how to monitor, and
for how long they can stop
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| Other therapies: probably less effective than bisphosphonates; raloxifene—selective estrogen receptor modulator
(SERM); increases BMD; standard dose 60 mg; reduces vertebral fractures; no effect on nonvertebral fractures; not
shown to reduce risk for hip fracture; increased risk for thromboembolic events; no effect on vaginal bleeding and
endometrial cancer; increase in spine BMD ≈50% that observed with bisphosphonates; similar reduction in vertebral
fractures; calcitonin—approved for women postmenopausal ≥5 yr; intranasal spray; associated with 15% increase
in BMD and reduction in vertebral fractures; not shown to reduce risk for hip fracture; analgesic effect;
parathyroid hormone (PTH)—increased risk for bone loss with hyperparathyroidism; however, pulsatile administration
of PTH (daily injection) stimulates bone growth and reduces vertebral and nonvertebral fractures; no comparative
data with other treatments; daily subcutaneous (SC) injection; alendronate plus PTH—PTH alone shown to
have biggest effect on BMD; alendronate may reduce some anabolic effects of PTH; no fracture outcomes; study
looked at sequential PTH then alendronate; women randomized to PTH, alendronate, or both had similar increases
in BMD in year one; spinal BMD increased in alendronate group; study too small to look at fracture outcomes; estrogen
plus alendronate—no studies with fracture as end point; no clear evidence that combining agents better than
one alone; strontium ranelate—oral agent available in health food stores; data show significantly reduced risk for
vertebral fracture; not approved by Food and Drug Administration (FDA) in United States; may be in some complementary
medicine preparations (dosage and efficacy unknown); folate and vitamin B12 —elevated homocysteine
risk factor for fracture; significant reduction in hip fractures shown in women with stroke and hemiplegia; potentially
promising
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| Vitamin D: An Essential Nutrient
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| Marcia G. Ko, MD, Assistant Professor of Internal Medicine, Mayo College of Medicine, Scottsdale, AZ
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| Biochemistry: vitamin D precursor to steroid hormones; 1,25-dihydroxyvitamin D active steroid hormone; physiologic
effects—skeletal and nonskeletal; facilitates calcium absorption in GI tract; bone development and growth in
children and adults; prevention of osteoporosis and fractures (has independent effect on muscle strength); involved
in regulation of >200 genes; receptors for vitamin D on nonskeletal tissue; potential benefits in cancer and heart
disease currently under investigation; role in immunomodulation (eg, tuberculosis [TB] ); synthesis—UV light converts
7-dehydrocholestrol to cholecalciferol (vitamin D3 ); cholecalciferol hydroxylated to 25-hydroxycholecalciferol
in liver; in kidneys becomes 1,25-dihydroxyvitamin D (1,25(OH)2 D)
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| Diagnosing deficiency: measure serum 1,25 (OH) vitamin D level; sufficiency—>40 ng/mL; insufficiency—<20
ng/mL; increase in PTH levels provides secondary indication of deficiency; intoxication—>150 ng/mL; effect on
calcium intestinal transport—calcium absorption increases from 45% to 65% with sufficient level of vitamin D
(only 10%-15% without sufficient vitamin D); ≈1 billion people vitamin D deficient; lifetime risk for hip fracture
50% in those ≥50 yr of age; strategies to maximize BMD from childhood into adulthood should be implemented;
bisphosphonates carry precaution that adequate calcium and vitamin D necessary with therapy
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| Calcium and vitamin D: Chapuy (1997) showed reduction in risk for hip fracture with 1200 mg calcium and 800
IU vitamin D; Dawson-Hughes (1997) showed 58% reduction in nonvertebral fractures with 500 mg calcium and
700 IU vitamin D; Bischoff-Ferrari (2006) showed reduction in hip and nonvertebral fractures with just adequate
dosing of vitamin D; WHI (2007) showed no statistically significant difference in risk for hip fracture with 1000
mg calcium and 400 IU vitamin D; estrogen had effect on hip fracture, but not calcium and vitamin D (study confounder,
400 IU of vitamin D recognized as insufficient after study designed); vitamin D and prevention of falls—
data show improved muscle strength and speed with increased vitamin D level; vitamin D reduces risk for falls by
22%; 800 IU more effective than 400 IU; data show 72% reduction in risk for falls in nursing home residents, compared
to rate with placebo
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| Causes: reduced oral intake; reduced skin synthesis (SPF 15 blocks 99% of vitamin D synthesis); synthesis of vitamin
D reduced in darker-skinned people and in people with skin grafts (lower precursor levels); season and latitude;
aging (less precursor in skin with aging); malabsorption (eg, celiac disease, bypass surgery); obesity (vitamin
D sequestered in body fat); drugs (eg, steroids, anticonvulsants, antiretrovirals; increased catabolism of vitamin D);
breast-feeding (low vitamin D content in breast milk); acquired disorders (eg, primary hyperparathyroidism, granulomatous
disease [sarcoidosis, TB]; hyperthyroidism; nonmodifiable causes—liver failure, nephrotic syndrome,
chronic kidney disease, heritable disorders (eg, rickets), and tumor-induced acquired disorders
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| Replacement strategies: literature shows clinical recommendations for dosing significantly below that necessary;
measuring and replacement recommended; sources of supplementation—daily intake of 800 to 1000 IU recommended;
sun exposure to point of turning red provides ≈10,000 IU of vitamin D; tanning beds; insufficient level—
replace with 25,000 to 50,000 IU/wk for 8 wk, then reduce to daily dose; vitamin D intoxication—results in hypercalcemia
and hyperphosphatemia; baseline level recommended for patients at risk; dietary sources—≈400 IU in
teaspoon of cod liver oil; wild salmon, sardines, mackerel, tuna, shiitake mushrooms, egg yolk, and fortified foods
(eg, milk, juice, yogurt, butter, margarine, cheese, cereal, bread, and infant formulas); over-the-counter supplements
and prescription formulations (oral, drops, capsules, and injectables); data show low vitamin D levels even
in people who believed they received abundant sun exposure
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Suggested Reading
Binkley N et al: Low vitamin D status despite abundant sun exposure. J Clin Endocrinol Metab 92:2130, 2007; Bischoff-
Ferrari HA et al: Effect of vitamin D on falls: a meta-analysis. JAMA 291:1999, 2004; Chapuy MC et al: Prevalence of
vitamin D insufficiency in an adult normal population. Osteoporos Int 7:439, 1997; Demir B et al: Identification of the risk
factors for osteoporosis among postmenopausal women. Maturitas Sept 6 [Epub ahead of print]. Hillier TA et al: Evaluating
the value of repeat bone mineral density measurement and prediction of fractures in older women: the study of osteoporotic fractures.
Arch Intern Med 22:155, 2007; Holick MF: Vitamin D deficiency. N Engl J Med 357:266, 2007.
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