OSTEOPOROSIS AND OTHER BONE PROBLEMS
| CURRENT ISSUES IN OSTEOPOROSIS —Douglas C. Bauer, MD, Professor of Medicine, Epidemiology and Biostatistics,
Division of General Internal Medicine, University of California, San Francisco, School of Medicine
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| Risk factors: advanced age; female sex (men develop osteoporosis 10 yr later than women); white women at highest
risk, followed by black women (Asians and Hispanics at intermediate risk); in patients with history of vertebral fracture,
likelihood of subsequent vertebral fracture 5-fold higher (likelihood of hip fracture 2-fold higher); nonspinal
fracture increases risk for subsequent osteoporotic fracture; low body weight; tobacco smoking
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| Bone mineral density (BMD): 1994 World Health Organization (WHO) classification intended for epidemiologic
studies rather than clinical practice; osteoporosis—T score (number of standard deviations below normal young population)
at or below -2.5; osteopenia—T score -1.0 to -2.5; complexities—measuring BMD at multiple sites (eg, hip
or wrist) results in different T scores; T scores may not be relevant to practitioners and patients; test results must be
converted to determine absolute risk; WHO algorithms for 10-yr fracture risk to be used in 1 to 2 yr
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| Treatment and screening: white women >65 yr of age and postmenopausal women >50 yr of age with ≥1 risk factor
should undergo dual-energy x-ray absorptiometry (DEXA) of hip; patients with T score at or below -2.0 and no
risk factors candidates for pharmacologic therapy; in patients with ≥1 risk factor and T score -1.5, begin pharmacologic
therapy; start treatment in patients with previous vertebral or hip fracture (BMD not required)
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| Vitamin D deficiency: high rates in patients >65 yr of age and patients not living independently; measure 25-hydroxyvitamin
D level rather than 1,25-dihydroxyvitamin D level; obtain serum calcium level to rule out occult hyperparathyroidism;
checking creatinine level and thyroid-stimulating hormone (TSH) reasonable; if laboratory tests normal
and patient appears to have secondary cause of osteoporosis, consider celiac sprue serology and rule out multiple myeloma;
no evidence parathyroid hormone (PTH) testing should be performed on all patients with osteoporosis; high
variability with urine calcium level (not useful)
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| Nonpharmacologic therapy: tobacco smoking cessation; excessive alcohol intake increases risk for fracture (especially
in men); no increased risk in individuals who drink socially; physical activity—rigorous exercise can increase
bone mass by 1% to 2%, but BMD drops within 1 yr of stopping exercise; people who exercise have fewer fractures;
hip protector pads—few studies show no reduction in risk for fractures; problems include compliance and bulkiness
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| Calcium and vitamin D: no evidence that increasing calcium and vitamin D consumption above basal amounts prevents
fractures in perimenopausal women; elderly women (institutionalized or in non-independent living situation)
randomized to calcium and vitamin D had fewer hip fractures than those who received placebo; follow-up studies contradictory
(large UK study randomized older independent-living individuals with ≥1 risk factor to calcium and vitamin
D or placebo and saw no benefit on hip fracture or nonspinal fracture over 3 yr); general consensus that calcium and
vitamin D important; avoid deficiency; certain populations (eg, adolescents, individuals with lactose intolerance)
likely to be calcium deficient; speaker prescribes calcium and vitamin D to all patients >65 yr of age; perform dietary
assessment in perimenopausal women and younger individuals
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| Bisphosphonates: alendronate, risedronate, and ibandronate approved by Food and Drug Administration (FDA); result
in 30% to 50% reduction in risk for nonspinal, vertebral, and hip fractures in individuals with existing vertebral
fracture or low BMD (T score <-2.5); larger body of evidence for alendronate and risedronate, than for ibandronate;
Fracture Intervention Trial (FIT)—arm looking at alendronate vs placebo in women in United States with no history
of vertebral fracture and T score ≤-1.6 saw 14% reduction in nonspinal fracture rate (not statistically significant)
at 4-yr follow-up; saw no benefit of taking alendronate for 4 yr in women with BMD -1.5 to -2.0 or -2.0 to -2.5; saw
41% reduction in risk for nonspinal fracture in women with low BMD (<-2.5); suggests bisphosphonates may not be
equally effective in all individuals, and some risk factors (eg, BMD) count more than others; Risedronate Hip Study
suggests drugs most effective in patients with low BMD; low (50%) compliance with bisphosphonates because of
need for fasting before and after taking medication; less frequent administration improves compliance; can be given
intermittently; daily alendronate results in same increase in BMD as weekly alendronate
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 | Zoledronate (Zometa): potent bisphosphonate; given intravenously (IV) once yearly; >7000 postmenopausal women
randomized to once-yearly IV placebo or once-yearly IV zoledronate; after 3 yr, women who received zoledronate
had increased BMD at hip (6% difference between zoledronate group and placebo group), 70% reduction in risk for
new vertebral fractures, 25% reduction in risk for nonspinal fracture, and 40% reduction in risk for hip fracture,
compared to placebo; statistically significant; to be approved by FDA during 2007; currently available for hypercalcemia
of malignancy and for Paget’s disease; osteonecrosis of jaw (ONJ)—side effect of IV bisphosphonates; exposed
bone that does not heal with conservative measures for ≥6 wk; 94% associated with IV zoledronate or IV
ibandronate; 4% of cases found in patients treated for osteoporosis; most cases in patients with metastatic bone disease
treated for hypercalcemia of malignancy with doses 5 to 8 times osteoporosis dose; 60% of cases identified after
tooth extraction; suggested risk factors include poor dental hygiene and exposure to extremely high doses of IV
bisphosphonates; worsens with debridement; patients with oral complaints taking high doses of IV bisphosphonates
should be evaluated by oral surgeon; performing oral examinations before initiating bisphosphonates or stopping
bisphosphonates before tooth extractions unreasonable due to long (10 yr) half-life of bisphosphonates
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| Duration of treatment: bisphosphonates often lifelong treatment; prolonged treatment can result in excessive suppression
of bone turnover; FIT Long-Term Extension (FLEX) Study—>1000 women treated with alendronate for 5 yr
randomized to 5 more years of alendronate or placebo; BMD of femoral neck remained “more or less the same”
with continued alendronate and declined by ≈2% in placebo group; rate of new vertebral fractures ≈10% in both
groups and no trend toward benefit of continuing alendronate on nonvertebral and hip fracture rates; 50% reduction
in subset of women with morphometric painful fractures who continued alendronate; after 4 to 5 yr of treatment,
bisphosphonates may be discontinued in some patients (eg, patients who have done well on bisphosphonates with
no subsequent fractures, modest BMD at beginning of treatment, and no prevalent vertebral fractures); no clear consensus
or data about follow-up
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| Treatment guidelines: begin treatment in patients with T score -2.0 (speaker recommends -2.5); patients with T
score of -1.5 with risk factors may not need treatment; consider therapy in patients with many risk factors and T score
-2.0 to -2.2; current data suggest BMD dictates efficacy; treat patients with hip or vertebral fracture, regardless of
BMD; patients >70 yr of age with many risk factors require BMD testing and risk stratification
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| Anabolic agents: prevent bone resorption; promote bone formation; randomized trial demonstrated increase in BMD
and dramatic effects on fracture (effects on hip fracture unknown) with parathyroid hormone (PTH; Teriparatide); balancing
antiresorptive therapy and PTH—start with bisphosphonate; after 2 yr of PTH therapy, benefits quickly lost
in patients not followed with bisphosphonate; when using PTH, stop bisphosphonate and resume after PTH therapy
complete; safety concerns include effects on cortical bone (particularly in hyperparathyroidism), reduction of BMD in
wrist (no increased risk for wrist fracture seen in clinical trials), carcinogenesis (high doses cause osteosarcoma in rats
[no evidence in humans]); expensive ($10,000-$12,000/yr); speaker limits use to patients with severe disease who can
tolerate daily injections and costs; new therapies, eg, strontium, in development
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| Questions and answers: woman 70 yr of age with osteoporosis recently treated for high-grade ductal carcinoma
in situ (DCIS) and placed on selective estrogen receptor modulator (SERM)—study showed raloxifene prevented
vertebral fractures, but no effect on nonspinal or hip fractures; consider woman’s risk; if T score less than -2.5 or
woman has existing vertebral fracture, consider treatment with SERM and bisphosphonate; calcium and vitamin D
supplementation for patients on bisphosphonates—clinical trials performed on patients replete with calcium and vitamin
D, except FIT study; premature menopause—risk factor; shift screening guidelines (eg, in women with menopause
at age 40 yr, begin routine screening at age 55 yr); no good evidence-based guidelines; tetracycline—
bisphosphonates not contraindicated in patients taking tetracycline; adverse effects of long-acting
bisphosphonates—serum concentrations of IV bisphosphonates no longer than 1 to 2 wk; bone complications may
last ≥1 yr; ≤20% of individuals have acute-phase reaction (pretreat with antipyretic); DEXA of hip—treatment guidelines
based on BMD of hip and site of lowest BMD; BMD of spine useful in patients <65 yr of age; clinical trials
based on BMD of femoral neck
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| ALL THAT IS THIN IS NOT OSTEOPOROSIS —Michael D. Whitaker, MD, Consultant in Endocrinology, Mayo
Clinic, Scottsdale, AZ
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| Osteoporosis and osteomalacia: reduced BMD on DEXA; increased fracture rate; can be asymptomatic; may coexist
in same patient; osteoporosis—reduced bone mass results in microdamage; osteomalacia—abnormal mineralization
of osteoid; clinical and biochemical presentation different
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| Bone mineralization: not well understood; primary mineralization occurs under influence of vitamin D, calcium, and
phosphorus
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| Causes of vitamin D abnormalities: insufficient intake; malabsorption; sprue; liver or kidney problems; vitamin
D–resistant rickets due to 1-á-hydroxylase deficiency rare; drugs (eg, phenytoin [Dilantin] and phenobarbital)
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| Vitamin D insufficiency and deficiency: vitamin D insufficiency (25-hydroxyvitamin D level ≤20 ng/mL); vitamin
D deficiency (25-hydroxyvitamin D level ≤15 ng/mL); 18% of postmenopausal women in United States have vitamin
D insufficiency; worldwide problem; biochemical consequences—1,25-dihydroxyvitamin D required to
absorb calcium through gut; PTH production results in secondary hyperparathyroidism; patients with high PTH levels
have normal calcium levels; results in decreased phosphorus and increased bone turnover (elevated bone alkaline
phosphatase); osteoporosis can occur; osteomalacia can result over many months to years
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| Diagnosis of vitamin D deficiency: patients present with thin bones and complaints of bone pain; muscle weakness
consequence of hypophosphatemia; waddling gait; neuromuscular irritability; myopathy; pseudofractures on pelvic x-
ray pathognomonic; obtain 25-hydroxyvitamin D level (20-25 ng/mL red flag); if 25-hydroxyvitamin D level 20 ng/
mL and patient has elevated PTH, diagnose secondary hyperparathyroidism; elevated bone alkaline phosphatase due
to increased bone turnover; urine calcium level low; serum calcium and phosphorus at lower limits of normal; establish
etiology—osteoporosis or bone disease occurs in 2% to 3% of patients with sprue, 30% of patients with sprue
have bone disease; failure of vitamin D intake or poor sun exposure
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| Treatment: current recommended daily allowance (RDA) for vitamin D (400 U) insufficient for preventing fractures
(should be 800-1000 U/day); in moderate to severe deficiency, 50,000-U capsule once or twice weekly or once
monthly (monitor serum calcium and 25-hydroxyvitamin D levels); calcitriol (Rocaltrol) for renal patients; all patients
require calcium supplementation (1500 mg daily); conclusions of Women’s Health Initiative about inefficacy of calcium
supplementation for bone improvement and creation of kidney stones invalid (other studies show reduced incidence
of fractures in patients taking calcium and vitamin D)
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| Hypophosphatemia: man 61 yr of age with 7-yr history of weakness, fractures, and severe bone pain; wheelchair
bound; no medication history; small nodule in scrotal area previously thought to be lipoma; laboratory test results normal,
except serum phosphorus and 1,25-dihydroxyvitamin D levels extremely low; T score poor; on magnetic resonance
imaging (MRI), soft tissue mass not consistent with lipoma; man underwent surgery; man had tumor-induced
osteomalacia (rare condition); phosphatonin causes loss of phosphorus through urine and prevents formation of 1,25-dihydroxyvitamin
D; postoperative phosphorus and 1,25-dihydroxyvitamin D levels returned to normal; after 4 mo, bone
density doubled; after 1 yr, bone density normal; use of phosphate-binders (eg, antacids, particularly in kidney patients)
and etidronate can result in overbinding; renal osteodystrophy rare; be aware of hereditary disorders (eg, vitamin D–resistant
rickets) and renal tubular disorders (oncogenic osteomalacia)
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| Case presentation: woman 60 to 64 yr of age with severe osteoporosis; history of several fractures; menopause at age
52 yr; history of estrogen replacement therapy; healthy active woman; no gastrointestinal (GI) symptoms; failing alendronate
(Fosamax) therapy; laboratory findings included low hemoglobin, slightly elevated calcium, and extremely
low PTH; serum protein electrophoresis (SPEP) normal; liver, kidney, and thyroid tests unremarkable; widespread osteopenia
on x-ray, with fractures and lytic lesions “everywhere”; urine immunoelectrophoresis positive; monoclonal
kappa chains; multiple myeloma; patients who present with thin bones, mild anemia, and mild hypercalcemia (that is
not PTH-dependent) have myeloma until proven otherwise; 5% of patients with light-chain disease have normal blood
chemistry; woman’s bone health and myeloma improved after 5 yr; etiology of myeloma and fracture—reduced bone
density with older age; chemotherapy (particularly if patients on steroids); patients with myeloma may present initially
with bone problems; if patients have thin bones and do not fit usual osteoporosis criteria, consider SPEP; after diagnosis,
fracture incidence increases over time; most fractures occur at time of diagnosis
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| Questions and answers: alcohol intake—most alcoholic patients have osteoporosis; alcohol has direct toxic effect
on bone; many patients with alcohol-associated liver disease have low 25-hydroxyvitamin D levels; 25-hydroxyvitamin
D level often <10 ng/mL in patients with end-stage liver disease; check PTH and calcium (if normal, treat as osteoporosis
rather than osteomalacia); sunscreen—reduces vitamin D production; yearlong study found 10 min per
day of sun exposure improves vitamin D dynamics, reduces risk for fracture, and improves BMD; vitamin D deficiency
and PTH—25 to 30 ng/mL affects PTH; normal PTH levels do not affect bone
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Suggested Reading
Bauer DC et al: Biochemical markers of bone turnover and prediction of hip bone loss in older women: the study of osteoporotic
fractures. J Bone Miner Res 14:1404, 1999; Bauer DC et al: Change in bone turnover and hip, non-spine,
and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res 19:1250, 2004;
Black DM et al: Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial.
FIT Research Group. J Clin Endocrinol Metab 85:4118, 2000; Chapurlat RD et al: Incidence and risk factors for a
second hip fracture in elderly women. The Study of Osteoporotic Fractures. Osteoporos Int 14:130, 2003; Ensrud KE et
al: Randomized trial of effect of alendronate continuation versus discontinuation in women with low BMD: results from
the Fracture Intervention Trial long-term extension. J Bone Miner Res 19:1259, 2004; Kocjan T et al: Vitamin d status
in patients with osteopenia or osteoporosis - an audit of an endocrine clinic. Int J Vitam Nutr Res 76:307, 2006; Ladha
SS et al: Oncogenic osteomalacia: muscular weakness and multiple fractures. Neurology 67:364, 2006; Lufkin EG et
al: Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 13:1747,
1998; Nguyen DN et al: Primary aldosteronism and secondary hyperparathyroidism of the vitamin D deficiency. South
Med J 99:1403, 2006; Recker R et al: Alendronate with and without cholecalciferol for osteoporosis: results of a 15-
week randomized controlled trial. Curr Med Res Opin 22:1745, 2006; Ruggiero SL et al: Bisphosphonate-related osteonecrosis
of the jaw: background and guidelines for diagnosis, staging and management. Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 102:433, 2006; Schott AM et al: Should age influence the choice of quantitative bone assessment
technique in elderly women?. The EPIDOS study. Osteoporos Int 15:196, 2004; Wong P et al: Osteoporotic
fractures and vitamin D deficiency. Aust Fam Physician 35:519, 2006.
Educational Objectives
| The goal of this program is to improve the management of osteoporosis and other bone problems. After hearing and assimilating
this program, the participant will be better able to:
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| 1. Stratify risk for osteoporosis and fracture based on bone mineral density and risk factors.
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| 2. Choose effective therapy for osteoporosis.
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| 3. Identify risks and benefits of bisphosphonates and parathyroid hormone therapy.
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| 4. Discuss effects of vitamin D deficiency.
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| 5. Recognize bone conditions that present differently from osteoporosis, such as hypophosphatemia and myeloma.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty members 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. Bauer has received research support
from Amgen Inc., SKB, and Procter & Gamble Co. Dr. Whitaker has received research support from Eli Lilly and Co.
Acknowledgements
Dr. Bauer spoke in San Francisco, CA, at Primary Care Medicine: Principles and Practice, presented October 25-27,
2006, by the University of California, San Francisco, School of Medicine. Dr. Whitaker was recorded on September
15, 2006, in Durango, CO, at Primary Care Update 2006: A Four Corners Experience, presented by the Mayo Clinic
College of Medicine, Scottsdale, AZ, and Mercy Medical Center. The Audio-Digest Foundation thanks the speakers
and the sponsors for their cooperation in the production of this program.
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