diagnosis, screening, prevention, and treatment of osteoporosis.pdf

CONCISE REVIEW FOR CLINICIANS

Diagnosis, Screening, Prevention, and Treatment of Osteoporosis

KAREN F . MAUCK, MD, MSc, AND BART L . CLARKE, MD

Osteoporosis Is the most common bone disease In humans andaffects both men and women. The clinical and public heaith impiica-tlons of the disease are substantial because of the mortailty,morbidity, and cost of medical care associated with osteoporoticfractures. Osteoporosis is diagnosed on the basis of a low-impact orfragility fracture or low bone mineral density, which was bestassessed by centrai duai-energy x-ray absorptlometry. Both non-pharmacological therapy (calcium and vitamin D supplementation,weight-bearing exercise, and fail prevention) and pharmacologicaltreatments (antlresorptive and anabolic agents) may be helpful Inthe prevention and treatment of osteoporosis. Therefore, cliniciansneed to be vigilant in instituting primary prevention measures forthose at high risk for osteoporosis and in Instituting treatment forpatients diagnosed as having the disease either by screening or ahistory of fracture. This articie provides an overview of the diagno-sis, screening, prevention, and treatment of osteoporosis.

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BMD = bone mineral density; DXA = dual-energy x-ray absorptlometry;FDA = Food and Drug Administration; ICSI = Institute for ClinicalSystems Improvement; NOF = National Osteoporosis Foundation

O steoporosis is the most common bone disease in hu-mans and affects both men and women, usually dur-

ing or beyond the seventh decade of life. Among USwomen older than 50 years, 13% tol8% meet current diag-nostic criteria for osteoporosis, and an additional 37% to50% meet criteria for osteopenia. For men of the same age,3% to 6% meet criteria for osteoporosis, and 28% to 47%meet criteria for osteopenia.' Osteoporosis has clinical andpublic health implications because of the mortality, mor-bidity, and cost of medical care associated with os-teoporotic fractures. Elderly persons constitute the fastest-growing age group in the world, and the annual number ofosteoporotic fractures is predicted to increase considerablywith the continued aging of this population in future de-cades. In the United States, about 1.5 million fractures areattributed to osteoporosis each year. Of this total, approxi-mately half are vertebral fractures and one fifth each arehip, wrist, and other fractures,^ Although therapy that canreduce the risk of osteoporotic fractures is available, os-teoporosis often remains undiagnosed until a fracture occurs.

From the Division of Generai internai Medicine (K.F.M.) and Division ofEndocrinoiogy, Diabetes, iVIetaboiism, and Nutrition (B.L.C.), Mayo CiinicCoiiege of Medicine, Rochester, Minn.

A question-and-answer section appears at the end of this articie.

individuai reprints of this articie are not avaiiabie. Address correspondence toKaren F. Mauck, MD, MSc, Division of Generai internai Medicine, Mayo CiinicCoiiege of Medicine, 200 Rrst St SW, Rochester, MN 55905 (e-maii: [email protected]).

© 2006 Mayo Foundation for Medical Education and Research

In addition, patients with osteoporosis-related fractures oftenare not evaluated or treated for osteoporosis and sustainadditional fractures. Therefore, clinicians need to be vigilantin instituting primary prevention measures for those at highrisk for osteoporosis and in instituting treatment for patientsdiagnosed with the disease either by screening or a history offracture. This article provides an overview of the diagnosis,screening, prevention, and treatment of osteoporosis.

DEFINITION

Osteoporosis is a chronic, progressive disease character-ized by low bone mass, microarchitectural bone deteriora-tion, and decreased bone strength that lead to increasedbone fragility and a consequent increase in fracture risk.'Osteoporosis may be classified as either primary or second-ary. Primary osteoporosis is bone loss associated with theaging process in both women and men and with the loss ofgonadal function in men. In priinary osteoporosis, the rate ofactivation of skeletal bone remodeling units is normal, butthe filling of bone resorption pits is incomplete. Secondaryosteoporosis is bone loss caused by a variety of chronicmedical conditions, medications, and nutritional deficien-cies. In most types of secondary osteoporosis, the rate ofactivation of skeletal bone remodeling units is increased atleast initially, such that an increased proportion of the skel-eton is undergoing remodeling at any one time. Some com-mon secondary causes of osteoporosis and disease processesassociated with the disorder are outlined in Table 1.

DIAGNOSIS

Before 1994, the diagnosis of osteoporosis required evi-dence of a fragility fracture. In 1994, the World HealthOrganization established operational definitions of os-teoporosis and osteopenia in postmenopausal white womenbased on bone mineral density (BMD) (Table 2) to helpresearchers and clinicians classify degrees of bone loss.Expert opinion, based on literature review, suggests that thecurrent World Health Organization definition of osteoporo-sis in postmenopausal white women can be applied to men aswell.̂ In current clinical practice, osteoporosis is diagnosedon the basis of either a health outcome (low-impact or fragil-ity fracture) or an intermediate outcome (low BMD). A low-impact fracture is one that occurs after a fall from standingheight or less; a fragility fracture occurs spontaneously orwith no trauma (cough, sneeze, sudden movement).

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DIAGNOSIS, SCREENING, PREVENTION, AND TREATMENT OF OSTEOPOROSIS

TABLE 1 . Common Secondary Causes of Disease ProcessesAssociated With Osteoporosis*

Endocrine disordersCushing syndromeHypogonadismHyperthyroidismPrimary hyperparathyroidism

Rheumatologic disordersRheumatoid arthritisSystemic lupus erythematosusAnkylosing spondylitisJuvenile polyarticular arthritis

MalignancyMultiple myeloma

PharmacotherapyGlucocorticoid excessL-thyroxine overreplacementAnticonvulsants (phenytoin or phenobarbital)Lithium, aluminumCytotoxic drugs, immunosuppressants (cyclosporine A, tacrolimus)Heparin (long-term)Drugs causing hypogonadism (aromatase inhibitors, methotrexate,

antimetabolite chemotherapy, depo-medroxyprogesterone acetate,and gonadotropin-releasing hormone agonists such as buserelin,leuprolide, and nafarelin)

Gastrointestinal diseaseChronic liver disease (especially primary biliary cirrhosis and primary

sclerosing cholangitis)Inflammatory bowel disease (particularly Crohn disease)Celiac diseaseGastric bypass or gastrectomy

Renal insufficiency or failureMiscellaneous causes

Vitamin D deficiency of any causeAlcohol abuseAnorexia nervosa, malnutritionMovement disorders (Parkinson disease)AmyloidosisAcquired immunodeficiency syndrome, human immunodeficiency virusChronic obstructive pulmonary diseaseCerebrovascular accidentMultiple sclerosisProlonged bed rest or wheelchair bound from any cause

*For a more extensive list of causes, see Annotation Appendix A of theInstitute for Clinical Systems Improvement guidelines.''

Although multiple technologies are available for mea-surement of BMD, central dual-energy x-ray absorpti-ometry (DXA) of the hip (femoral neck or total hip) is thegold standard for diagnosing osteopenia or osteoporosis.'*However, many experts, including the International Soci-ety for Clinical Densitometry, recommend using the lowestcentral DXA T score of posteroanterior lumbar spine,femoral neck, or total hip (or the 33% distal radius of thenondominant forearm, if measured) to make the diagnosis.'Dual-energy x-ray absorptiometric measurements of BMDat other sites (including the trochanter. Ward triangle, lat-eral lumbar spine, other forearm regions, heel, or totalbody) or with other technologies (calcaneal ultrasonogra-phy, peripheral DXA, quantitative computed tomography,single- or dual-photon radionuclide absorptiometry, ormagnetic resonance imaging) may be useful for assessing

TABLE 2. World Health Organization Definitions of Osteopeniaand Osteoporosis In White Women^*

Normal Hip BMD >1.0 SD below the young adultfemale reference meant (T score above -1.0)

Osteopenia Hip BMD between 1.0 and 2.5 SDs below theyoung adult female reference meant(T score between -1.0 and -2.5)

Osteoporosis Hip BMD 22.5 SDs below the young adult femalereference meant (T score at or below -2.5)

Severe osteoporosis Hip BMD a2.5 SDs below the young adult femaleor established reference meant in the presence of 1 or moreosteoporosis fragility fractures

*Based on hip bone mineral density (BMD) measurements assessed withdual-energy x-ray absorptiometry.

fThe young adult female reference mean is determined with use of themean hip BMD from the National Health and Nutrition ExaminationSurvey reference database of women aged 20-29 years.

risk of fracture, but they are not recommended for use indiagnosing osteoporosis.*•' If DXA measurements at dif-ferent sites are considerably disparate, most clinicianswould use the lowest BMD measurement.

Dual-energy x-ray absorptiometric measurement ofbone density is noninvasive, accurate, reproducible, andpredictive of short- and long-term fracture risk. The resultsare reported as a density measurement in gm/cm^, in addi-tion to T and Z scores. T scores represent the number ofSDs from the mean bone density values in normal sex-matched young adults. The T score is used to make adiagnosis of normal bone density, osteoporosis, or osteo-penia in postmenopausal women and in men age 50 yearsand older. Z scores represent the number of SDs from thenormal mean value for age- and sex-matched control sub-jects. A Z score of -1.0 or lower (many experts suggestusing a Z score of-2.0 or lower) may suggest the presenceof a secondary cause of osteoporosis, although no defini-tive data support this hypothesis. Z scores are used prefer-entially to assess bone loss in premenopausal females andin men younger than age 50 years. A Z score of -2.0 orlower is defined as "below the expected range for age"; a Zscore above -2.0 is "within the expected range for age."'

ROLE OF SCREENING

Osteoporosis is a disease in which screening of asymptom-atic individuals may be beneficial because it has a longpreclinical course before the onset of fracture and becauseof the availability of both a reliable test to establish thediagnosis and treatments that have been shown to reducethe risk of fractures. General consensus exists regardingthe recommendation that osteoporosis screening withBMD measurements should be individuahzed, but howthis individualized approach to screening should beachieved remains controversial.

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TABLE 3. National Osteoporosis Foundation Recommendationsfor Bone Mineral Density Measurements

In Postmenopausal White Women"*

All women a65 y, regardless of additional risk factors

All postmenopausal women s65 y who have 1 or more additional riskfactors (see below) for osteoporosis (other than being white,postmenopausal, and female)

Postmenopausal women of any age who present with fractures (to confirmdiagnosis and determine disease severity)

Major risk factorsPersonal history of fracture as an adultHistory of fragility fracture in a first-degree relativeLow body weight(<1271b)Current smokingCurrent or previous use of oral corticosteroid therapy for >3 mo

Additional risk factorsImpaired visionEstrogen deficiency at an early age (<45 y)DementiaPoor health, frailtyRecent fallsLow calcium intake (lifelong)Low physical activityAlcohol in amounts of >2 drinks per day

*Criteda recommended for white postmenopausal women do not necessar-ily apply to women of other races, to premenopausal women, or to men.

Many national and organizational guidelines and sys-tematic reviews have attempted to outline clinical criteriafor screening individuals for osteoporosis. Disagreementamong the published guidelines reflects, at least in part,variances in expert opinion and gaps in the available evi-dence to support these recommendations. Most guidelinesrecommend using risk factor assessment to help selectpatients for bone density testing, but because of inadequatedata, no consensus exists about which risk factors are mostimportant to consider. Several groups have suggestedguidelines for BMD testing in postmenopausal women, thepopulation group for which the most evidence is available.

In the United States, a commonly accepted guidehne isthat of the National Osteoporosis Foundation (NOF)*

TABLE 4. Summary of US Preventive Services Task ForceRecommendations for Osteoporosis Screening

in Postmenopausal Women'

All women a65 yWomen a60 y who are at increased risk for osteoporotic fractures. Exact

risk factors are difficult to specify on the basis of available evidence.Body weight <70 kg is the single best predictor. Current nonuse ofestrogen therapy is also predictive. Some evidence supports the use ofindividual risk factors (smoking, family history, alcohol or caffeine use,sedentary lifestyle, and low calcium and vitamin D intake) as a basis foridentifying high risk in women <65 y

No studies have evaluated the optimal intervals for repeated screening.Because of limitations in the precision of testing, a minimum of 2 y isgenerally needed to reliably detect a major change in bone density.However, longer intervals may be adequate for repeated screening. Theyield of screening is higher in older women. No data are available thatindicate the appropriate age at which to stop screening

(Table 3). However, use of this guideline may result inmore frequent testing because the risk factors listed are socommon in this population. The US Preventive ServicesTask Force has also made recommendations regarding os-teoporosis screening in postmenopausal women' (Table 4).These guidelines are conservative and formulated fromevidence-based literature review. Unfortunately, they maynot be useful clinically because they do not clearly addresswhich postmenopausal women who are younger than 65years should be tested and do not recommend screeningany postmenopausal women younger than age 60 for anyreason, even though women between menopause and age60 experience rapid early postmenopausal bone loss.

Although the NOF and US Preventive Services TaskForce guidelines provide recommendations for postmeno-pausal women, they offer no recommendations for pre-menopausal women or for men. The Institute for ClinicalSystems Improvement (ICSI) guidelines provide a reason-able (evidence- and expert opinion-based) summary ofwho should be screened according to pretest probability offracture based on risk factors.'' These guidelines may helpclinicians determine which patients should undergo BMDtesting. The ICSI guidelines incorporate the NOF recom-mendations in addition to recommendations for men andboth premenopausal and postmenopausal women. Mea-surement of BMD is recommended for patients at high riskfor future fractures, as outlined in Table 5.

TABLE 5. ICSI Guidelines for BMD Testingin High-Rlsk Indlviduais*

1. Men or women with previous fragility fracture (spontaneousfracture or fracture after a fall from standing height or less)

2. Men or women currently or previously treated with >3 mo ofglucocorticoid therapy at a dosage of a5 mg/d of prednisone

3. Men or women with radiographic osteopenia or vertebral fracturedocumented radiographically

4. All women >65 y5. Postmenopausal women <65 y with at least 1 of the following

additional risk factorsLow body weight (<127 Ib or BMI s20)Family history of fracture (any fracture in a first-degree relative

that occurred after age 45 y)Current smoker (>1 pack/d)Not using HRTMenopause before age 40 (surgical or natural)Taking HRT for >10-15 y

6. Men or women with a chronic disease known to be associated withbone loss*

1. Premenopausal women with amenorrhea for >1 y8. Men with hypogonadism for >5 y9. Men or women with prolonged immobilization (bed rest or wheel

chair bound for >1 year)10. Men or women who have received solid organ or allogenic bone

marrow transplants

*The most common causes are outlined in Table 1; for a more extensivelist, see Annotation Appendix A of the ICSI guidelines.'' BMD = bonemineral density; BMI = body mass index; HRT = hormone replacementtherapy; ICSI = Institute for Clinical Systems Improvement.

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How often should screening BMD testing be repeated?The US Preventive Services Task Force addressed this issueand reported no evidence for or against repeated screening.'"However, estimations can be made based on the age-specificprevalence of osteoporosis and the precision of the bonedensity test used. In clinical practice, BMD is often mea-sured at 2- to 3-year intervals for recently postmenopausalwomen because this age group has a higher rate of bone loss,at 5-year intervals for younger postmenopausal women afterthe immediate postmenopausal bone loss has stabilized, andat 2- to 5-year intervals for older women. No data support anappropriate age at which to stop screening.

Clinical guidelines help guide practice but should notreplace clinical judgment and patient preferences. The finaldecision about when and how often to perform BMD testingis ultimately at the discretion of the physician and the patient.

LABORATORY TESTING FOR SECONDARY CAUSES

Among men, 30% to 60% of osteoporosis cases are associ-ated with secondary causes (most commonly hypogo-

nadism, glucocorticoid use, and alcoholism); amongperimenopausal women, more than 50% of cases are asso-ciated with secondary causes (most commonly hypoestro-genemia, glucocorticoid use, thyroid hormone excess, andanticonvulsant therapy). The prevalence of secondary con-ditions is thought to be lower in postmenopausal women,but the actual proportion is unknown.'"

General consensus exists among osteoporosis special-ists that a minimum screening laboratory profile should beconsidered for all patients who are diagnosed as havingosteoporosis. However, no consensus exists regarding whichtests should be done. Many experts have also suggested thatpatients who have osteoporosis and a Z score of less than-1.0 (some suggest using a Z score of less than -2.0) shouldhave more extensive laboratory screening for secondarycauses of osteoporosis. A diagnosis of osteoporosis in menshould also prompt a thorough work-up for secondary causesregardless of their Z score because about half will have anidentifiable cause for the bone loss. The ICSI guidelinesprovide recommendations regarding laboratory testing inpatients with newly diagnosed osteoporosis" (Table 6).

TABLE 6. ICSI Guidelines for Laboratory Testing In Patients With Newly Diagnosed Osteoporosis"*

Laboratory test Rationale

Z score above -1.0 (patients less likely to have secondary causes of osteoporosis)Serum creatinineLiver function tests

Serum calcium

Alkaline phosphatase

Serum phosphorusThyroid studies (thyrotropin and thyroxine)

Sedimentation rate or C-reactive protein

Complete blood cell count

Urinary calcium excretion

Serum 25-hydroxyvitamin DSerum intact (whole-molecule) PTH

Renal failure is associated with secondary hyperparathyroidismIntrinsic liver diseases and cholestatic disorders are associated with multifactorial

causes of increased risk of osteoporosisIncreased in patients with hyperparathyroidism and decreased in those with

malabsorption or vitamin D deficiencyIncreased in patients with Paget disease of bone, prolonged immobilization, acute

fractures, and other bone diseasesDecreased in patients with osteomalaciaHyperthyroidism-associated bone lossMay indicate an inflammatory process or monoclonal gammopathy associated with

bone loss)To evaluate for bone marrow malignancy, infiltrative processes (anemia, low WBC,

or low platelets), or malabsorption (anemia, microcytosis, or macrocytosis)24-hour urinary calcium excretion on a high calcium intake diet screens for

malabsorption and hypercalciuria—a correctable cause of bone loss; low 24-hoururinary calcium excretion suggests vitamin D deficiency, osteomalacia, ormalabsorption due to small bowel disease such as celiac sprue

To identify vitamin D deficiencyScreening for hyperparathyroidism

Z score below -1.0 or premature osteoporotic fracture (patients at higher risk of having secondary causes of osteoporosis)All the above tests plus the following

additional testsSerum testosterone (total and free)

Serum estradiol

Tissue transglutaminase antibodies24-hour urinary free cortisol and overnight

dexamethasone suppression testSerum and urine protein electrophoresis

with immunoelectrophoresis as indicated

Screening for hypogonadism in men; if abnormal, LH, FSH, and prolactinmeasurements may be indicated to determine the cause of the hypogonadism

Screening for hypogonadism in premenopausal or perimenopausal women; ifabnormal, LH, FSH, and prolactin measurements may be indicated to determinethe cause of the hypogonadism

If gluten enteropathy is suspected clinicallyIf hypercortisolemia is suspected

If monoclonal gammopathy is suspected

*FSH = follicle-stimulating hormone; ICSI = Institute for Clinical Systems Improvement; LH = luteinizing hormone; PTH = parathyroidhormone; WBC = white blood cell count.

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The cost-effectiveness of testing for secondeuy causes ofosteoporosis is unknown because cost-effectiveness analy-ses have yet to be performed. In a chart review study,Tannenbaum et al" examined this issue in perimenopausaland postmenopausal women and found that a testing strat-egy consisting of 24-hour urinary calcium, serum calcium,and serum parathyroid hormone determinations in allwomen and serum thyrotropin measurements in womenreceiving thyroid replacement therapy would be sufficientto diagnose secondary causes of osteoporosis in 86% ofwomen; adding 25-hydroxyvitamin D would diagnose sec-ondary causes in up to 98%. However, this study wasobservational and small. More recently, in a secondaryanalysis of data collected as part of the Fracture Interven-tion Trial that included 15,316 postmenopausal women,Jamal et al'^ reported that the prevalence of abnormal testresults in postmenopausal women with and without os-teoporosis was similar, with the exception of low thyrotro-pin. These authors concluded that routine laboratory testing(other than thyrotropin measurements) in otherwise healthywomen with osteoporosis was not useful.

Clearly, more research is needed in this area, especiallyin premenopausal and perimenopausal women and in menbecause the prevalence of secondary causes of osteoporosisin these groups is high. Until more cost-effectiveness dataare available, it is reasonable to follow the strategy outlinedin the ICSI guidelines (Table 6) for premenopausal orperimenopausal women, for postmenopausal women withcomorbidities, and for men. For otherwise healthy post-menopausal women who have no clinical history or physi-cal examination finding suggestive of a secondary cause ofosteoporosis, it may be reasonable to only obtain a serumthyrotropin level.

Importantly, the aforementioned recommendationsshould be used only to direct testing for individuals who areasymptomatic or do not have clinical evidence of second-ary osteoporosis on history and physical examination. If aspecific secondary cause of osteoporosis is suspected onthe basis of the history and physical examination findings,further directed testing is indicated.

NONPHARMACOLOGICAL THERAPY FORPREVENTION AND TREATMENT OF BONE LOSS

CALCIUM AND VITAMIN D

Calcium absorption normally decreases with advancingage. In addition, aging is associated with decreasing serum1,25-dihydroxyvitamin D levels, less sun exposure, andreduced skin capacity for vitamin D production. Supple-mentation of calcium and vitamin D should be consideredin all elderly patients if dietary intake and sun exposure areinadequate to meet recommended targets.

Calcium supplementation may prevent bone loss oreven mildly increase BMD,'^'" and some data suggest that itmay minimally reduce fracture risk.'^ However, for patientswith osteoporosis, calcium supplementation should be usedas an adjunct to other pharmacological interventions ratherthan as monotherapy. The National Institutes of Health con-sensus conference guidelines" suggest that women shouldoptimize their elemental calcium intake to 1000 mg/d untilmenopause and increase it to 1500 mg/d thereafter. Menshould optimize their elemental calcium intake to 1000 mg/duntil age 65, then increase it to 1500 mg/d.

The preferred source of calcium is foods such as dairyproducts. Some dietary sources of calcium include yogurt(400 mg per cup), milk (300 mg per cup), calcium-enrichedorange juice (300 mg per cup), cheese (150-180 mg/oz),and canned salmon with bones (180 mg per 3 oz). Calciumsupplements are an alternative means by which optimalcalcium intake can be reached in those who cannot meetthis need by diet alone. Numerous calcium supplements areavailable in a variety of salts that can be used to supplementdiet£iry calcium intake. The most commonly used calciumsupplements are calcium carbonate or calcium citrate. Fac-tors to consider in selecting an agent include absorption,convenience, and cost. Calcium absorption is generallymaximal at individual doses of 500 mg of elemental cal-cium. Calcium carbonate contains 40% elemental calcium,requires stomach acid for digestion and absorption, and isthe least expensive option. It should be taken with meals indoses of no more than 500 mg of elemental calcium at atime. Calcium citrate contains 21% elemental calcium,does not require stomach acid for digestion, and is morebioavailable but is more expensive than calcium carbonate.Calcium citrate can be taken with or without food in dosesof no more than 500 mg of elemental calcium at a time.Calcium citrate is the preferred calcium supplement forpatients who are hypochlorhydric or achlorhydhc (includ-ing those taking gastric acid-inhibiting drugs) and for pa-tients with a history of kidney stones. The most commonadverse effects of all calcium supplements are constipation,bloating, and gas; however, these adverse effects may beless frequent with calcium citrate. Patients taking medica-tions whose absorption may be impaired by calcium (ie,levothyroxine, fluoroquinolones, angiotensin-convertingenzyme inhibitors) should also be advised to avoid takingcalcium supplements within several hours of taking thesemedications.

Vitamin D supplementation may prevent bone loss ormildly increase BMD''' and modestly reduces vertebral andnonvertebral fracture risk in vitamin D-deficient individu-als."'* A recent meta-analysis concluded that oral vitaminD supplementation of 700 to 800 IU/d appears to reduce therisk of hip and nonvertebral fractures in ambulatory or

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institutionalized elderly persons, whereas a dose of 400IU/d was insufficient for fracture prevention." Sufficientvitamin D intake is necessary to maintain circulating se-rum levels of 1,25-dihydroxyvitamin D adequate tostimulate calcium absorption; therefore, a combinationsupplement containing both calcium and vitamin D ispreferred if dietary intake is inadequate. Dietary sourcesof vitamin D include vitamin D-fortified milk or orangejuice (400 IU per quart) and cereals (40-50 IU per serv-ing), egg yolks, saltwater fish, and liver. Some calciumsupplements and most multivitamin tablets also containvitamin D. An intake of 400 to 600 IU of vitamin D perday is recommended by the National Academy of Sci-ences for all adults older than age 50. The NOF recom-mends 800 IU/d for those at risk of deficiency, such aselderly, chronically ill, housebound, or institutionalizedindividuals.

WEIGHT-BEARING EXERCISE

Weight-bearing exercise appears to be effective in main-taining or increasing bone density at the lumbar spine andhip in postmenopausai women, but currently, no evidencesuggests that it decreases fractures.^" Recommendationsinclude weight-bearing exercise in the form of walking,mild- to moderate-impact aerobics, and resistance exer-cises as tolerated. Regular exercise also increases musclemass and strength, improves balance and coordination, andhas been shown to reduce the risk of falls by about 25% infrail elderly persons.^'

FALL PREVENTION

Randomized clinical trials have supported the value ofassessing risk factors for falls in elderly patients and mak-ing appropriate interventions for those at high risk.̂ ^ Riskfactors include visual impairment, cognitive impairment,poor balance or gait, neuromuscular and musculoskeletaldisabilities, muscle weakness, postural hypotension, mul-tiple medications, and environmental hazards. Interven-tions for modifiable risk factors should include physicaltherapy to improve strength and balance, gait aids ifneeded, prevention or treatment of hypotension, and avoid-ance of medications that may potentially alter mental statusor gait stability. Elimination of environmental hazards inthe home is also helpful in preventing falls. This includesrecommending shoes with nonskid soles, placing nonslipmats under area rugs, removing any nonessential throwrugs in the home or clutter on the floors, and installing grabbars in the tub, shower, and toilet areas, sturdy stairwayrailings, and night-lights. In a recent meta-analysis, vitaminD supplementation was reported to reduce the risk of fallsamong ambulatory or institutionalized older individualswith stable health by more than 20%."

PHARMACOLOGICAL INTERVENTIONS FORPREVENTION AND TREATMENT OF BONE LOSS

Treatment thresholds for osteoporosis are not the same asdiagnostic thresholds, although some experts have recom-mended that they should be. In the United States, mostexperts agree on the treatment thresholds outlined by theNOF,^'' which recommends that the following individualsbe considered for pharmacological intervention: (1) pa-tients with a BMD T score below -2.0, (2) patients with aBMD T score below -1.5 if additional risk factors arepresent (previous fracture as an adult, history of fragilityfracture in a first-degree relative, body weight <57 kg,current smoking, use of oral corticosteroid therapy for >3months), and (3) any patient with a previous vertebral orhip fracture.

Pharmacological interventions with Food and Drug Ad-ministration (FDA) approval for treatment of osteoporosisshould be recommended first. These include the oralbisphosphonates (alendronate, risedronate, and ibandro-nate), raloxifene, nasal calcitonin, and teriparatide. TheFDA has withdrawn approval of estrogen or hormonetherapy for treatment of osteoporosis but has continuedapproval of their use for osteoporosis prevention in se-lected postmenopausai women.

The primary goal of pharmacological therapy in patientswith osteoporosis is to reduce the risk of future fracture, notjust increase bone density. Currently, the pharmacologicalagents available for treatment of osteoporosis fall into 1 of2 categories: antiresorptive agents or anabolic agents. Allthe currently available drugs except teriparatide are anti-resorptive agents. These agents reduce bone resorptionmore than promote bone formation and thereby suppressbone turnover and loss, whereas anabolic agents stimulatebone formation more than reduce bone resorption. Table 7summarizes the currently available FDA-approved medi-cations for the prevention and/or treatment of osteoporosis.

No head-to-head clinical trials have compared the frac-ture efficacy of the antiresorptive agents, and only a fewhead-to-head clinical trials have compared the bone densityeffects of these agents. Most studies with fracture endpoints have involved postmenopausai women. In short-term clinical trials, alendronate increased BMD more thandid raloxifene or calcitonin and produced a slightly greaterincrease than risedronate. Evidence from the current litera-ture suggests that the antiresorptive therapies (includingbisphosphonates, raloxifene, calcitonin, and estrogen) re-duce vertebral fracture risk by 30% to 50%. Hip fracturereduction has been shown consistently with only some ofthe oral bisphosphonates (alendronate and risedronate) andwith hormone therapy.^' However, because the efficacy ofthe oral bisphosphonates in reducing hip fracture risk has

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TABLE 7. Agents Currently Approved by the Food and Drug Administration for Prevention andTreatment of Osteoporosis

Drug/dose Cost* Indications

AlendronateP: 5 mg/d; 35 mg/wk $72T: 10 mg/d; 70 mg/wk

RisedronateP.T: 5 mg/d; 35 mg/wk $71

IbandronateP, T: 2.5 mg/d; 150 mg/mo $76

RaloxifeneP,T:60mg/d $85

Calcitonin nasal sprayT: 200 IU/d $93

EstrogenP: Multiple formulations

TeriparatideT: 20 ng/d injection $590

P, T: Postmenopausal women with osteoporosisT; Men with osteoporosis

Glucocorticoid-induced osteoporosis (women of men)

P, T: Postmenopausal women with osteoporosisGlucocorticoid-induced osteoporosis (women or men)

P, T: Postmenopausal women with osteoporosis

P, T: Postmenopausal women with osteoporosis

T; Postmenopausal women with osteoporosis

$32-$41 P: Postmenopausal women with osteoporosis

T: Postmenopausal women with osteoporosisMen with primary or hypogonadal osteoporosis

*Approximate monthly cost fromtreatment.

www.dnigstore.com (accessed August 1, 2005). P = prevention; T =

been shown in osteoporotic patients or subgroups of os-teoporotic patients in these trials, many experts suggest thatoral bisphosphonates be considered as first-line therapy forpatients with established osteoporosis (those with T scoreslower than -2.5 and prevalent vertebral fractures).

BISPHOSPHONATES

Bisphosphonates block bone resorption by inhibiting os-teoclast activity and are currently the most potent oralantiresorptive agents available for prevention or treatmentof osteoporosis. Only 3 bisphosphonates are currentlyFDA-approved for osteoporosis treatment and prevention:alendronate, risedronate, and ibandronate. The recom-mended doses and FDA indications for use are summarizedin Table 7. Intravenous bisphosphonates, including pam-idronate and zoledronic acid, are not FDA-approved forprevention or treatment of osteoporosis but are occasion-ally used off-label for patients who cannot tolerate oralbisphosphonates. Strong clinical trial evidence supports theuse of alendronate, risedronate, and ibandronate for pre-venting fractures in women with postmenopausal os-teoporosis or osteopenia.^'•^'' These agents have beenshown to reduce vertebral and hip fractures by 50% to 60%in postmenopausal women .̂ *'"' Clinical trial evidence alsosupports the use of alendronate for preventing fractures inmen with osteoporosis."

For all oral bisphosphonates, patients should be in-structed to take each tablet with 6 to 8 ounces of plain waterfirst thing in the morning and at least 30 minutes beforeingesting the first meal, beverage, or medication of the day.Patients should not recline for at least 30 minutes (60

minutes with ibandronate) to reduce the potential foresophageal injury. If symptoms of esophageal disease (dif-ficult or painful swallowing, retrostemal pain, new orworsening heartburn) or severe musculoskeletal pain de-velops, discontinuation may be appropriate. Rarely, pa-tients may develop jaw osteonecrosis or eye inflammationwith oral or intravenous bisphosphonates. However, if oneoral bisphosphonate is not tolerated, occasionally an alter-native oral bisphosphonate is. Oral bisphosphonates arecontraindicated in patients with hypocalcemia, hypersensi-tivity to bisphosphonates, renal insufficiency (creatinineclearance <30-35 mL/min), or esophageal irritation orstricture. Oral bisphosphonates should be used cautiouslyin patients who have difficulty swallowing or severe gas-troesophageal reflux and those who have undergone gastricbypass or are receiving long-term anticoagulant therapy.

RALOXIFENE

Raloxifene is a selective estrogen receptor modulator thatis approved for both the prevention and the treatment ofpostmenopausal osteoporosis at a dose of 60 mg/d. It hasbeen shown to decrease vertebral fractures by about 50%,but because of inadequately powered trials, no evidence iscurrently available on hip fracture reduction .̂ '•'̂

Raloxifene selectively interacts with estrogen receptors,exerting an estrogen agonist effect in some areas (bone andlipid metabolism) while acting as an estrogen antagonist inothers (breast and uterus). Because of this selective effecton estrogen receptors, raloxifene potentially has the addedbenefits of breast cancer risk reduction and cardiovasculardisease prevention, although this has not yet been shown

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definitively in clinical trials. Raloxifene decreases total andlow-density lipoprotein cholesterol but has no effect onhigh-density lipoprotein cholesterol. Common adverse ef-fects include increased risk of venous thromboembolismand increased vasomotor symptoms. Raloxifene is con-traindicated in patients with a history of venous throm-boembolic events and should not be recommended forpremenopausal women or women concurrently using estro-gen replacement therapy. Although clinical trial evidencesuggests that raloxifene may reduce breast cancer risk, itsuse in breast cancer patients is not recommended at thistime.

CALCITONIN

Salmon calcitonin nasal spray is FDA-approved for thetreatment of osteoporosis at a dose of 200 IU in alternatingnostrils each day. It inhibits bone resorption by osteoclasts,thereby preventing bone loss and vertebral fractures, but ithas not been shown to reduce nonvertebral or hip frac-tures .''• '̂' This drug may also decrease the pain associatedwith acute or subacute vertebral fractures. There are nocontraindications to calcitonin use other than hypersensi-tivity to the drug; common adverse effects include nasalsymptoms and rhinitis in about 12% of patients. Because ofthe availability of other medications that have better effi-cacy in fracture reduction, calcitonin is not consideredfirst-line treatment for osteoporosis.

ESTROGEN/HORMONE THERAPY

The role of hormone therapy in the prevention and treat-ment of osteoporosis remains controversial. The US Na-tional Institutes of Health-funded Women's Health Initia-tive trial showed that estrogen alone," or in combinationwith progesterone,'* decreased bone turnover, bone loss,and fractures. Combination hormone therapy is associatedwith a mildly increased absolute risk of serious adverseevents, including coronary heart disease, stroke, venousthromboembolism, and breast cancer^*; estrogen therapyalone also has been shown to be associated with an in-creased risk of stroke and venous thromboembolism butdoes not appear to be associated with an increase in coro-nary heart disease or invasive breast cancer.̂ ^ In the UnitedStates, hormone therapy is approved only for the preven-tion, not treatment, of osteoporosis. The revised FDAguidelines recommend that approved nonestrogen productsbe considered for prevention of osteoporosis; however, ifhormone therapy is used, it is recommended in doses as lowas possible for as short a time as possible. Nevertheless,some experts believe that estrogen therapy is still the first-line therapy for osteoporosis prevention in younger womenwith surgical menopause who have no contraindications toits use. In addition, some experts advocate the short-term

use (5-7 years) of combination hormone therapy in theimmediate postmenopausal years for the prevention of os-teoporosis (and often for the treatment of hot flashes) inwomen who have no contraindications to its use.

TERIPARATIDE

Recombinant human parathyroid hormone analogues arepotent bone anabolic agents that increase bone turnover(formation more than resorption). Teriparatide is the firstanabolic drug approved for treatment of osteoporosis. It isFDA-approved for the treatment of osteoporosis in post-menopausal patients with severe bone loss who are at highrisk for fracture^' and for the treatment of hypogonadal orprimary osteoporosis in men at high risk for fracture.'^ Thisdrug increases bone density, thereby reducing vertebralfractures by 65% and nonvertebral fractures by 53%. Thereduction in vertebral fracture risk continues for at least 18months after therapy is discontinued.'' Teriparatide maypotentially be used in combination or in sequence withantiresorptive agents but is not yet approved for such use(see Combination Therapy section).

Teriparatide is given as a once-daily 20-ng subcutane-ous injection for a maximum duration of 2 years. Adverseeffects include light-headedness, dizziness, nausea, arth-ralgias, leg cramps, and occasionally a postinjection in-crease in serum calcium level. The risk of postinjectionhypercalcemia is insufficient to warrant monitoring of se-rum calcium levels during treatment. A "black box warn-ing" indicates that teriparatide produced an increased inci-dence of osteosarcoma in rats and that it should not be usedin patients with a history of bone malignancy, Paget diseaseof bone, unexplained hypercalcemia, or skeletal radiationexposure or those younger than 18 years. Its use is bestreserved for men or postmenopausal women with severebone loss and preexisting osteoporotic fractures. Teripara-tide should also be considered for individuals at high riskfor fractures (T scores less than -3.5), even in the ab-sence of preexisting fracture. In addition, teriparatide is analternative for patients who are unable to tolerate oralbisphosphonates.

COMBINATION THERAPY

To date, no studies of combination therapy have had suffi-cient power to assess its effects on fracture outcomes.However, risedronate and alendronate, as well as calcito-nin, have been shown to have an additive effect of increas-ing BMD when combined with hormone replacementtherapy ."̂ Teriparatide used in combination with alendro-nate has been reported to be less effective in increasingbone density than teriparatide alone in postmenopausalwomen"" and in men.'* Combination treatment with ralox-ifene and teriparatide may enhance the bone-forming ef-

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fects of teriparatide in postmenopausai women ,''̂ and pre-vious treatment with raloxifene does not blunt the expectedteriparatide-induced BMD increases when these agents areused in sequence."'' However, previous treatment withalendronate does prevent the expected teriparatide-inducedBMD increase, particularly in the first 6 months."' For now,combination therapy is reserved for patients who havesevere osteoporosis and should be initiated and monitoredby a bone specialist.

FOLLOW-UP TESTING AFTERPHARMACOLOGICAL INTERVENTION

The need for routine follow-up BMD testing to monitor theeffect of pharmacological intervention is still controversial.Serial measurements of BMD or markers of bone turnoverare potentially useful methods to monitor response totherapy.

Specific evidence addressing the most efficient use ofBMD measurements for monitoring treatment is lacking.Many experts have advocated a role for serial BMD mea-surements in monitoring the effects of therapy. If follow-upBMD testing is done, the results should be interpretedcautiously. Central DXA, although one of the most precisemeasurements used in medical practice, is still limited bythe calculated precision of the machine and the expertise ofthe technician performing the test (coefficient of variationis between 1% and 2%, depending on the machine). Fol-low-up BMD testing should be performed on the samemachine, preferably by the same technologist, to achievethe lowest precision error and greatest accuracy in docu-menting true change. An antiresorptive agent will gener-ally affect trabecular bone (spine) earlier and to a greaterdegree than cortical bone (hip). Therefore, considerableimprovement of BMD at the lumbar spine can be ex-pected earlier than at the hip. Lack of bone-density re-sponse at the hip should not be interpreted as treatmentfailure if the repeat testing is done within 2 years. Sta-bility or an increase in BMD indicates successful therapy.

In normal circumstances, bone is lost from the lumbarspine at a rate of approximately 1% per year during latepostmenopause. With treatment, bone loss should be nota-bly decreased. However, the DXA machine is not preciseenough to detect such small differences in BMD after ashort interval. Therefore, a period of at least 2 years isusually needed to ensure that the change in BMD seen onDXA is true change and not just due to random variationsin measurement. In general, repeated BMD testing to moni-tor treatment in a patient with normal rates of bone loss isrecommended after a period of 2 to 5 years. An exceptionto this strategy would be patients who are at high risk foraccelerated bone loss (bone lost at a higher rate than usual)

such as patients taking corticosteroids or suppressive dosesof thyroid hormone, women in early menopause who arenot taking hormone replacement therapy, and women whohave recently stopped hormone replacement therapy. Insuch patients, follow-up DXA may be indicated at an ear-lier interval (6-12 months). Medicare provides coverage forBMD evaluation with central DXA every 2 years to moni-tor osteoporosis therapy or for screening of patients withrisk factors for osteoporosis and includes a provision forBMD testing at an earlier interval when "medically neces-sary." Patients in whom bone density declines considerablyduring therapy may require further evaluation. This declinemay be due to treatment failure, but other considerationsinclude noncompliance, inadequate calcium or vitamin Dintake, or a secondary cause of osteoporosis.

Biochemical markers of bone turnover have also beenadvocated for monitoring response to therapy. Many ex-perts believe that the markers of bone turnover may offeradditional value in assessing the effectiveness of drugtherapy because the effects of most osteoporosis therapieson bone markers are rapid (3-6 months) compared to BMD,in which 1 to 2 years may be necessary to determine theeffect of treatment. Markers of bone turnover typically areseparated into those associated with bone formation vsthose associated with bone resorption. Markers of boneformation include bone alkaline phosphatase, osteocalcin,and the type I collagen propeptides. Markers of bone re-sorption include urinary calcium, tartrate-resistant acidphosphatase, bone sialoprotein, type I collagen cross-linked telopeptides, and pyridinium derivatives. Currently,however, the daily and seasonal fluctuations in these mark-ers, in addition to intraindividual variation, have limitedtheir clinical use. Because no single marker is accurateenough to reliably identify nonresponders to treatment andfurther research is necessary to clarify which markersshould be used and when, routine measurement of markersof bone turnover is not recommended for monitoring re-sponse to osteoporosis treatment at this time.

SUMMARY

Osteoporosis is an important growing public health con-cern that is underrecognized, undertreated, and largely pre-ventable. Most patients at high risk for fractures do notreceive adequate evaluation or treatment for prevention offuture fractures. More concerning is that most patients whoare diagnosed as having fragility or low-impact fracturesare not being evaluated or treated for osteoporosis. In fact, arecent review of the literature concluded that treatment ratesfor osteoporosis were low across all populations, but menand patients treated by generalists are at an especially highrisk of not receiving treatment.'" Many factors likely contrib-

670 Mayo Clin Proc. May 2006:81(5):662-672 www.mayoclinicproceedings.com


ute to these poor statistics and have not been well defined inthe literature. Intuitively, however, generalists have a ma-jor role in educating patients about osteoporosis, assessingtheir risk for the disease, facilitating screening, and admin-istering treatment. This concise review provides a straight-forward and useful approach to these issues for practicingclinicians.

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27. Quandt SA, Thompson DE, Schneider DL, Nevitt MC, Black DM,Fracture Intervention Trial Research Group. Effect of alendronate on vertebralfracture risk in women with bone mineral density T scores of-1.6 to -2.5 at thefemoral neck: the Fracture Intervention Trial. Mayo Clin Proc. 2005;80:343-349.

28. Liberman UA, Weiss SR, Broil J, et al, Alendronate Phase III Os-teoporosis Treatment Study Group. Effect of oral alendronate on bone mineraldensity and the incidence of fractures in postmenopausal osteoporosis. N EnglJMed. 1995:333:1437-1443.

29. Bauer DC, Black DM, Gamero P, et al. Fracture Intervention Trial StudyGroup. Change in bone turnover and hip, non-spine, and vertebral fracture inalendronate-treated women: the Fracture Intervention Trial. 7 Bone Miner Res.2004;19:1250-1258.

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33. Chesnut CH III, Silverman S, Andriano K, et al, PROOF Study Group. Arandomized trial of nasal spray salmon calcitonin in postmenopausal womenwith established osteoporosis: the Prevent Recurrence Of Osteoporotic Frac-tures (PROOF) Study. Am JMed. 2000;109:267-276.

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Questions About Osteoporosis

1. Which one of the following statements regardingcalcium supplementation is false'!

a. Calcium absorption is limited to about 500 mg ofelemental calcium at a time

b. A 500-mg tablet of calcium carbonate contains500 mg of elemental calcium

c. After menopause, calcium intake should be at least1500 mg of elemental calcium daily

d. Calcium citrate is the preferred supplement forpatients who are taking acid suppression therapy

e. Adequate calcium intake is a necessary adjunct to allosteoporosis pharmacotherapy

2. In which one of the following situations would BMDtesting not be necessary?

a. All women older than 65 yearsb. A 65-year-old man taking hormone therapy for

metastatic prostate cancer for the past 5 yearsc. A 56-year-old moderately obese but otherwise

healthy recently postmenopausal (<5 years)woman who is taking honnone replacementtherapy, is a nonsmoker, and has no personal orfamily history of fracture

d. A 38-year-old woman who received a kidneytransplant 3 years ago from a living related donor

e. A 45-year-old man with severe multiple sclerosiswho has been wheelchair-bound for the past 10years

3. Which one of the following statements regarding BMDtesting is falsel

a. T scores represent the number of SDs from normalsex-matched young adult mean bone density values

b. Z scores represent the number of SDs from normalmean bone density values for age- and sex-matched control subjects

c. A Z score of-1.0 or lower may suggest the presenceof a secondary cause of osteoporosis

d. A peripheral DXA T score of-2.5 or lower isdiagnostic of osteoporosis

e. The central DXA T score at the femoral neck or hipis the gold standard for diagnosing osteopenia orosteoporosis

4. In which one of the following should pharmacologicaltreatment of osteoporosis be recommended based onthe NOF guidelines?

a. A 75-year-old woman with a femoral neck T score of-1.5 and no additional osteoporosis risk factors

b. All postmenopausal women with a T score of-1.5 orlower, regardless of risk factors

c. A 45-year-old woman with an ankle fracture after askiing accident

d. A postmenopausal woman with a recent hip fracturecaused by a fall from standing height

e. A 68-year-old woman with "osteopenia" noted on arecent x-ray of the hand

5. Which one of the following statements regarding thecurrently available FDA-approved medications forosteoporosis is true!

a. All available FDA-approved medications forosteoporosis have equal antifracture efficacy

b. Combination therapy with alendronate andteriparatide provides improvements in bonedensity above and beyond what can be achievedby teriparatide alone

c. Bisphosphonates have been shown to decrease theincidence of vertebral fractures but not hipfractures

d. Bisphosphonates are currently the most potent oralantiresorptive agents available for the preventionor treament of osteoporosis

e. Estrogen replacement therapy was recently shown tohave antifracture efficacy in the Women's HealthInitiative trial and therefore is now approved by theFDA as an effective treatment for postmenopausalosteoporosis

Correct answers:l.b, 2.C, 3.d, 4.d, 5.d

672 Mayo Clin Proc. May 2006:81(5):662-672 www.mayoclinicproceedings.com

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