1. OSTEOPOROSIS Topic Suggestions for Lecturer -1-hour lecture
-Use GRS slides alone or to supplement your own teaching materials.
-Refer to GRS for further content.
-Supplement lecture with handouts.
-See GRS7 questions 7, 12, 39, 72, 148, and 175 for case vignettes on osteoporosis.
-Refer to Geriatrics At Your Fingertips for updated information on patient evaluation and management.
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2. OBJECTIVES Know and understand:
How to diagnose osteopenia and osteoporosis
The pathogenesis of osteoporosis
Common secondary causes of bone loss
Prevention and treatment strategies for osteoporosis
How to diagnose and treat osteomalacia
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3. TOPICS COVERED Bone Remodeling and Changes in Bone Mass
Epidemiology of Osteoporotic Fractures
Pathogenesis of Osteoporosis
Evaluation for Osteoporosis
Prevention and Treatment of Osteoporosis
Management of Vertebral Fractures
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4. BONE REMODELING Bone repairs itself by actively remodeling
Bone resorption (osteoclasts)
Bone formation (osteoblasts)
The remodeling cycle may become unbalanced
After menopause; with aging in men & women
Bone resorption increases more than bone formation, resulting in net bone loss
Bone loss  osteopenia, osteoporosis, fractures
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5. LIFETIME CHANGES IN BONE MASS
Age
Women
Men
Puberty to mid-20s and 30s
Bone mass increases rapidly,
reaching peak bone mass
Mid-30s to 40s
A few years of stability, then slow bone loss
No risk factors:
bone loss 1%/year
With risk factors:
bone loss  6%/year
Mid-40s to 50s
Menopause, then rapid bone loss  7%/year for
 7 years
Mid-50s to late life
Continuing bone loss of 1%–2%/year
Risk factors: low calcium intake, smoking, alcoholism, certain drugs.
Both men and women lose predominantly cancellous (vertebral) bone.
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6. EPIDEMIOLOGY OF OSTEOPOROTIC FRACTURES
High prevalence
1.5 million osteoporotic fractures in US annually
250,000 hip & 500,000 vertebral fractures in US annually
Serious consequences
 quality of life, function, independence
 morbidity & mortality (50% of women do not recover prior function after hip fracture; 20% excess mortality in year after hip fracture)
Cost
In 2005, estimated to be responsible for $19 billion in costs
Experts predict that by 2025, costs will rise to $25.3 billion
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7. DEFINITIONS OF BONE LOSS DISORDERS
Osteopenia
Low bone mass
T-score < –1 but  –2.5
Osteoporosis
BMD measurement at any site >2.5 standard deviations below the young-adult standard, with or without previous fracture
T-score < –2.5
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8. PATHOGENESIS OF OSTEOPOROSIS
Estrogen deficiency
Calcium deficiency & secondary hyperparathyroidism
Androgen deficiency
Changes in bone formation
Secondary causes and medications
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9. ESTROGEN DEFICIENCY
Factors that play a role in bone loss related to estrogen deficiency:
Increased resorption
Osteoclast activity
Fracture risk is inversely related to estrogen levels in post-menopausal women
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10. CALCIUM DEFICIENCY AND SECONDARY HYPERPARATHYROIDISM
Aging skin &  sunlight exposure  conversion of 7-dehydrocholesterol to cholecalciferol (vitamin D3) by ultraviolet light  vitamin D deficiency
Vitamin D insufficiency   absorption of calcium
Older adults tend to ingest inadequate amounts of calcium and vitamin D
PTH  in order to maintain serum levels of calcium
When chronically elevated, PTH is a potent stimulator of bone resorption
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11. ANDROGEN DEFICIENCY
Men with estrogen deficiency or resistance have  bone mass and failure of epiphyseal closure
Severe male hypogonadism can cause osteoporosis
The effect of moderate decreases in testosterone levels in aging men on rate of bone loss is uncertain
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12. CHANGES IN BONE FORMATION
With aging and menopause:
Osteoblast activity decreases
Bone resorption increases
Growth factors (eg, transforming growth factor B and insulin-like growth factor 1) may be impaired, resulting in decreased osteoblast function
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13. RISK FACTORS FOR OSTEOPOROSIS
Glucocorticoids
Previous fragility fracture as adult
Androgen-deprivation therapy
Current smoking
Low dietary calcium
Spinal cord injury
Alcoholism
Age (postmenopausal in women, >70 yr in men)
Female sex
Low body weight (BMI <20)
10% decline in weight (from usual adult body weight)
Physical inactivity

14. MODIFICATIONS TO REDUCE THE RISK OF OSTEOPOROSIS (1 of 2)
Exercise: Encourage regular, weightbearing exercise at least 5 times per week for 30 minutes
Nutrition: Encourage adequate intake of calcium (1,200–1,500 mg/d in divided doses) and vitamin D3 (800–1000 IU/d)
Smoking cessation

15. MODIFICATIONS TO REDUCE THE RISK OF OSTEOPOROSIS (2 of 2)
Medications that can increase risk of osteoporosis—use with caution:
Glucocorticoids
Anticonvulsants
Cyclosporine
Long-term heparin
Excess thyroid hormone replacement
Methotrexate
GnRH agonists used for prostate cancer
Aromatase inhibitors (eg, anastrozole, letrozole, exemestane) used for breast cancer
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16. SECONDARY CAUSES OF BONE LOSS
Women
Primary hyperparathyroidism
Glucocorticoid use
Men
Hypogonadism
Malabsorption syndrome including gastrectomy
Glucocorticoids result in bone loss primarily through direct suppression of bone formation, although they further reduce levels of sex hormone and cause secondary hyperparathyroidism by decreasing intestinal calcium absorption. The prevalence of vertebral fractures in individuals taking glucocorticoids for 1 year is estimated to be 11%. The rate of trabecular bone loss is dose-dependent and generally occurs in the first 6 months of therapy.
Although inhaled corticosteroids have not been as well studied, high doses of high-potency inhaled steroids can also result in bone loss.
The best strategy for older adults who require long-term glucocorticoid therapy is to maximize bone health by a variety of interventions, including using the lowest possible dosage of glucocorticoids and ensuring adequate intake of calcium and vitamin D. In addition, alendronate and risedronate have successfully prevented bone loss that is caused by glucocorticoid therapy when begun at the same time as the steroids.
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17. Measure Vitamin D level Measure bone density
EVALUATION
Measure Vitamin D level
Measure bone density
Assess for secondary causes of bone loss
Use of biochemical markers in clinical practice is controversial
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18. BMD MEASUREMENT Best predictor of fracture
Relative risk of fracture is 10 greater in women in the lowest quartile than in those in highest quartile
Dual-energy x-ray absorptiometry (DEXA)
Preferred method of measurement
Can measure hip, anterior-posterior spine, lateral spine, and wrist
Cost = $200 to $300; covered by Medicare and Medicaid if indications for use are met
Lateral vertebral assessment
Technology available for diagnosis of vertebral fractures as part of DEXA
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19. INDICATIONS FOR BMD TESTING (1 of 2)
Disease
Recommended Laboratory Tests
Hyperparathyroidism
Calcium, PTH level
Hyperthyroidism
TSH, thyroxine levels
Hypogonadism (men only)
Bioavailable testosterone or total testosterone, free testosterone with sex hormone-binding globulin
Multiple myeloma
CBC, serum protein electrophoresis, urine electrophoresis
Gold font = recommended routinely
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20. INDICATIONS FOR BMD TESTING (2 of 2)
Disease
Recommended Laboratory Tests
Osteomalacia
Bone-specific alkaline phosphatase, 25(OH)D level
Paget’s disease
Bone-specific alkaline phosphatase, urine NTx
Cushing’s disease
Electrolytes, 24-h urinary free cortisol
NTx = type I collagen N-telopeptide
Slide 20
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21. LATERAL VERTEBRAL ASSESSMENT
Vertebral fractures are highly associated with future fracture risk and morbidity
Can be present in patients with T-scores > ‒2.5
Used as an adjunct to BMD testing
Suggested indications for vertebral fracture assessment:
Results will influence clinical decision making (eg, regarding beginning medical therapy for bone loss)
Documented height loss >2 cm or historical height loss >4 cm (1.5 in)
History of fracture after age 50
Long-term glucocorticoid use
History or findings suggestive of vertebral fracture not previously documented
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22. BIOCHEMICAL MARKERS OF BONE TURNOVER
May be early indicator of treatment efficacy
Bone resorption markers
Cross-linked C-telopeptides of type I collagen (serum CTX)
Cross-linked N-telopeptides of type I collagen (NTx – urine or serum)
Bone formation marker
Bone alkaline phosphatase
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23. LIMITATIONS ON THE USE OF BIOCHEMICAL MARKERS
Clinical use is controversial because of substantial overlap of values in women with high and low bone density or rate of bone loss
Few studies have compared the response of a particular marker and bone density with goals of therapy
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24. WHOM TO TREAT
Older men and women with osteoporosis diagnosed by DEXA or with history of fragility fracture
FRAX is an algorithm that uses clinical and BMD information to model the 10-year fracture probability in men and women (

25. PREVENTING AND TREATING OSTEOPOROSIS
Exercise
Calcium and vitamin D
Bisphosphonates
Selective estrogen receptor modulators
Calcitonin
Estrogen replacement
Investigational agents
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26. EXERCISE
Marked decrease in physical activity or immobilization  decline in bone mass
Walking, a weight-bearing exercise, can be recommended for all adults
Start slowly and gradually increase the number of days and time spent walking each day
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27. CALCIUM & VITAMIN D RECOMMENDED REQUIREMENT
1200 mg/day of calcium: men 65 years and older & postmenopausal women
IU/day of vitamin D
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28. BISPHOSPHONATES
Rationale: Approved for osteoporosis prevention in post- menopausal women and treatment in men and women
 bone density of spine & hip (alendronate and risedronate)
 vertebral fracture rate (ibandronate)
Optimal duration of treatment unclear
Side effects: GI (abdominal pain, dyspepsia, esophagitis, nausea, vomiting, diarrhea); musculoskeletal pain; osteonecrosis of the jaw (rare in patients being treated for osteoporosis); atypical fractures; there have been cases of atrial fibrillation after doses of zoledronate
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29. BISPHOSPHONATES COMPARED (1 of 2)
Medication
Dosage
Special Considerations
Observed Beneficial
Treatment Outcomesa
Bisphosphonates should not be used if CrCl <30 mL/min
Alendronate
70 mg/wk; 35 mg/wk for prevention
Adherence to dosing instructions required; used in men and women to prevent glucocorticoid-induced osteoporosis
Vertebral fracture: absolute risk reduction (ARR)=7.1%, number needed to treat (NNT)=14 over 3 yr
Hip fracture: ARR=1.1%, NNT=91 over 3 yr
Risedronate
35 mg/wk or 150 mg/moh
Adherence to dosing instructions required
Vertebral fracture: ARR=5%, NNT=20 over 3 yr
Nonvertebral fracture: ARR=4%, NNT=25 over 3 yr
aPatient populations were not comparable, so direct comparisons of ARR and NNT may not be valid
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30. BISPHOSPHONATES COMPARED (2 of 2)
Medication
Dosage
Special Considerations
Observed Beneficial
Treatment Outcomesa
Bisphosphonates should not be used if CrCl <30 mL/min
Ibandronate
150 mg/mo or 3 mg IV every 3 mo
Adherence to dosing instructions required
Vertebral fracture: ARR=4.9%, NNT=20 over 3 yr
Zoledronic acid
5 mg/year IV
Morphometric vertebral fracture: ARR=7.6%, NNT=13 over 3 yr
Clinical vertebral fracture: ARR=2.1%, NNT=48 over 3 yr
All nonvertebral fractures: ARR=2.7%, NNT=37 over 3 yr
Hip fracture: ARR=1.1%, NNT=91 over 3 yr
aPatient populations were not comparable, so direct comparisons of ARR and NNT may not be valid

31. INSTRUCTIONS FOR TAKING BISPHOPHONATES
Take first thing in the morning before eating or drinking anything else
Take with at least 8 oz of plain tap water
Take while upright in a chair or standing, and remain upright for 30 minutes after ingestion
With alendronate and risedronate, do not eat or drink anything for 30 minutes after ingestion (60 minutes for ibandronate)
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32. SELECTIVE ESTROGEN RECEPTOR MODULATORS (SERMs)
Act as estrogen agonists in bone and heart
Act as estrogen antagonists in breast and uterine tissue
Potential for preventing osteoporosis or cardiovascular disease without the increased risk of breast or uterine cancer
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33. SERMs: RALOXIFENE
Approved for osteoporosis prevention & treatment in postmenopausal women
Dose: 60 mg/d
In comparison with placebo:
 vertebral fractures
 breast cancer (relative risk 0.24)
 bone turnover & maintains BMD
Side effects: Flu-like symptoms, hot flushes, leg cramps, peripheral edema
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34. CALCITONIN Rationale Dosing Hormonal inhibitor of bone resorption
In comparison with placebo:
 vertebral fractures and  spine bone density
No  in hip or nonvertebral fractures
Possible analgesic effect in women with painful vertebral compression fractures
Dosing
Subcutaneous injection (50–100 IU 3–5 times/week
Nasal spray 200 IU/day, alternate nostrils (fewer reported side effects, greater patient acceptance, may be less effective)
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35. ESTROGEN REPLACEMENT
Prevents bone loss at hip & spine when initiated within 10 years of menopause
An option for osteoporosis prevention but not recommended as first-line choice
Women’s Health Initiative showed  risk of hip fracture, vertebral fracture, and colon cancer but ↑ risk of breast cancer, heart disease, stroke, and venous thromboembolism
USPSTF Guidelines advise against routine use of estrogen plus progesterone for the prevention of chronic conditions in postmenopausal women
USPSTF = US Preventive Services Task Force
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36. PARATHYROID HORMONE Increases bone formation and resorption
Reduces vertebral and nonvertebral fractures in postmenopausal women
Increases BMD at all sites
Typically reserved for those with severe osteoporosis and fracture history
Teriparatide dose 20 mcg/d SC for patients who cannot tolerate other treatment
FDA-approved for only 2 years of use
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37. DENOSUMAB
Human monoclonal antibody that inhibits RANKL (receptor activator for nuclear factor κB ligand)
↓ bone turnover and ↑ BMD
Approved in US for postmenopausal women at high risk of fractures
Slide 37
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38. STRONTIUM RANELATE
Anabolic agent that ↑ bone formation and ↓ bone resorption
Not approved in US
Many patients are taking other forms of strontium bought OTC
No data available
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39. VERTEBRAL FRACTURES Asymptomatic (the majority)
Diagnosed by spinal radiographs
 kyphosis or  height
Chronic back pain due to spinal changes that occur with vertebral compression
Symptomatic
Pain usually lasts 2 to 4 weeks
Can be debilitating
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40. MANAGING VERTEBRAL FRACTURES (1 of 2)
Medications
NSAIDs and calcitonin
Narcotics commonly required for pain control
Physical therapy
Important for both acute and chronic pain
Postural exercises
Alternative modalities for  pain
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41. MANAGING VERTEBRAL FRACTURES (2 of 2)
Education, support groups
Vertebroplasty and kyphoplasty
Surgical options for treatment of painful compression fractures
Complications can occur (eg, emboli, infection)
Limited randomized, controlled trials
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42. SUMMARY (1 of 2)
Osteoporosis is prevalent among older adults and is associated with high personal and financial costs as well as mortality
Osteopenia and osteoporosis can be diagnosed by measuring BMD using dual-energy x-ray absorptiometry
Evaluation of patients with osteoporosis should include assessment for secondary causes of bone loss
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43. SUMMARY (2 of 2)
Osteoporosis prevention and treatment combines risk reduction, exercise, calcium and vitamin D supplementation, hormones, and other pharmacotherapies
Pain of osteoporotic vertebral fractures can be treated with NSAIDs, calcitonin, and narcotics, as well as physical therapy with surgical options of vertebroplasty and kyphoplasty
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44. CASE 1 (1 of 3)
A 69-year-old man comes to the office to establish care.
His wife is being treated for osteoporosis.
She wants to know whether her husband should also undergo a screening assessment.
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45. CASE 1 (2 of 3)
Which of the following is the strongest risk factor for osteoporosis in men?
Androgen deprivation therapy
Low dietary intake of vitamin D
Respiratory disease
Thyroid replacement therapy
Type 2 diabetes mellitus
Slide 45
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46. CASE 1 (3 of 3)
Which of the following is the strongest risk factor for osteoporosis in men?
Androgen deprivation therapy
Low dietary intake of vitamin D
Respiratory disease
Thyroid replacement therapy
Type 2 diabetes mellitus
ANSWER: A
Osteoporosis is a problem in older men, but data on screening guidelines are still being accrued. Literature review indicates that the most important risk factors for osteoporotic fractures in men are age ≥70 years old and low body weight (body mass index <25 kg/m2 or weight <70 kg [154 lb]). Other risk factors include weight loss, physical inactivity, corticosteroid use, previous osteoporotic fracture, and androgen deprivation therapy. Androgen deprivation therapy (pharmacologic or by orchiectomy) is a strong predictor of both osteoporosis and fracture.
Multiple other risk factors for osteoporosis in men have been reported, but the strength of the association is inconclusive in most cases. Some of the other reported risk factors include cigarette smoking, alcohol use, vitamin D and calcium intake, respiratory disease, thyroid replacement therapy, and type 2 diabetes mellitus. These possible risk factors have plausible physiologic rationales, and some are supported by data on osteoporosis and fractures in women or inconsistent data in men.
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47. CASE 2 (1 of 3)
A 75-year-old woman with established osteoporosis wishes to discuss advertisements she has seen for ibandronate and risedronate.
She currently takes alendronate and wonders whether she would benefit more from a different agent.
She has not had a fracture.
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48. CASE 2 (2 of 3)
Which of the following is the best agent for preventing fracture?
Alendronate
Ibandronate
Pamidronate
Risedronate
Data are not available to answer her question
Slide 48
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49. CASE 2 (3 of 3)
Which of the following is the best agent for preventing fracture?
Alendronate
Ibandronate
Pamidronate
Risedronate
Data are not available to answer her question
ANSWER: E
Bisphosphonates are effective in reducing fracture risk among postmenopausal women with osteoporosis. When compared with placebo, these agents prevent vertebral, nonvertebral, and hip fractures. Patients are exposed to considerable advertising about the benefits of these agents, different dosing regimens, and convenience. Studies have not been identified that demonstrate the superiority of one agent over another in preventing fractures. A systematic review of studies of agents used to treat osteoporosis identified the following design issues: 1) few studies compared different agents within the same class; 2) most head-to-head comparisons of agents from different classes reported intermediate outcomes (eg, changes in bone mineral density or in markers of bone turnover) rather than differences in fracture incidence; and 3) no trial with head-to-head comparisons of ≥2 agents had a sufficient sample size to detect even large differences in fracture risk.
Only 2 head-to-head trials were designed to compare fracture outcomes. In one, no difference was found between risedronate and etidronate for the prevention of vertebral fractures. In the other, which compared raloxifene and alendronate, not enough participants were recruited to test differences in fracture outcomes. The authors of the above-mentioned systematic review concluded that “1) within the bisphosphonate class, superiority for prevention of fractures has not been shown for any agent; 2) superiority for the prevention of vertebral fractures has not been demonstrated for bisphosphonates compared with calcitonin, calcium, or raloxifene; and 3) on the basis of 6 inadequately powered randomized trials, fracture prevention did not differ between bisphosphonates and estrogen.”
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50. CASE 3 (1 of 3)
An 80-year-old woman comes to the office for follow-up because a recent evaluation identified significant osteoporosis.
She agrees to begin oral bisphosphonate therapy.
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51. CASE 3 (2 of 3)
What is the most common adverse effect of oral bisphosphonate therapy?
Atrial fibrillation
GI effects
Osteogenic sarcoma
Osteonecrosis of the jaw
Thromboembolic disease
Slide 51
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52. CASE 3 (3 of 3)
What is the most common adverse effect of oral bisphosphonate therapy?
Atrial fibrillation
GI effects
Osteogenic sarcoma
Osteonecrosis of the jaw
Thromboembolic disease
ANSWER: B
In a well-done systematic review, the most consistently noted adverse effects of bisphosphonates were GI effects. Esophageal ulcers and mild GI symptoms such as acid reflux, appear to increase very slightly, and not statistically significantly over placebo with most bisphosphonates. The excess risk is probably minimal to nonexistent if administration instructions are strictly adhered to. The risk of more serious events, such as perforations, ulcerations, and bleeding, was slightly increased with etidronate in a pooled analysis of 3 trials.
Among cardiac events, an increased risk of atrial fibrillation was found in one placebo-controlled trial of zoledronic acid. This finding was contradicted by the findings of another large trial published the same year. Another placebo-controlled trial suggested a possible increased risk of atrial fibrillation with alendronate.
There are many reported cases of osteonecrosis of the jaw in patients receiving IV bisphosphonates. The vast majority of cases are in patients who receive high doses of IV bisphosphonates for a cancer-related diagnosis; cases are much less common in patients being treated for osteoporosis. The risk posed by oral bisphosphonates is much less certain. Most patients who develop osteonecrosis of the jaw have had recent dental surgery, jaw trauma, or oral infection.
Osteosarcoma risk has been reported for teriparatide but not for bisphosphonates. Thromboembolic events are an issue for estrogens and SERMs when used in treating osteoporosis, but not for bisphosphonates.
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53. Copyright © 2010 American Geriatrics Society
ACKNOWLEDGMENTS
Editor: Annette Medina-Walpole, MD
GRS7 Chapter Author: Pamela Taxel, MD
Leen Bakkali, MD
GRS7 Question Writer: C. Bree Johnston, MD, MPH
Pharmacotherapy Editor: Judith L. Beizer, PharmD
Medical Writers: Beverly A. Caley
Faith Reidenbach
Managing Editor: Andrea N. Sherman, MS
Copyright © 2010 American Geriatrics Society
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