In the Clinic Osteoporosis In theClinic

Inthe

ClinicIn the Clinic

Screening and Prevention page ITC1-2

Diagnosis and Evaluation page ITC1-6

Treatment page ITC1-8

Patient Education page ITC1-13

Practice Improvement page ITC1-13

Tool Kit page ITC1-14

Patient Information page ITC1-15

CME Questions page ITC1-16

Section EditorsDeborah Cotton, MD, MPHDarren Taichman, MD, PhDSankey Williams, MD

Physician WriterE. Michael Lewiecki, MD

The content of In the Clinic is drawn from the clinical information and educationresources of the American College of Physicians (ACP), including PIER (Physicians’Information and Education Resource) and MKSAP (Medical Knowledge and Self-Assessment Program). Annals of Internal Medicine editors develop In the Clinicfrom these primary sources in collaboration with the ACP’s Medical Education andPublishing divisions and with the assistance of science writers and physician writ-ers. Editorial consultants from PIER and MKSAP provide expert review of the con-tent. Readers who are interested in these primary resources for more detail canconsult http://pier.acponline.org, http://www.acponline.org/products_services/mksap/15/?pr31, and other resources referenced in each issue of In the Clinic.

CME Objective: To review current evidence for the prevention, diagnosis, andtreatment of osteoporosis.

The information contained herein should never be used as a substitute for clinicaljudgment.

© 2011 American College of Physicians

Osteoporosis

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Who should be screened forosteoporosis?All patients should be evaluated forfactors contributing to skeletalhealth. Those with clinical risk fac-tors for osteoporosis or fracture (seethe Box: Clinical Risk Factors forOsteoporosis and Low-Trauma Frac-ture) may benefit from further evalu-ation that includes BMD testing.

The National Osteoporosis Foun-dation (NOF) has developed evi-dence-based guidelines (2), whichare virtually identical to those ofthe International Society for Clini-cal Densitometry (ISCD) (3), forselecting patients to have a BMDtest (see the Box: Indications forBone Mineral Density Testing).

Other organizations have publishedvariations of these recommendations.For example, the US PreventiveServices Task Force has determinedthat all women aged 65 years andolder and women younger than 65who have a 10-year probability ofmajor osteoporotic fracture ≥ 9.3%should have a screening BMD test(4). The American College of Physi-cians (ACP) guidelines recommendthat “older men” and men “who areat increased risk for osteoporosis andare candidates for drug therapy” havea BMD test (5). As with all clinicaltests, BMD should only be measured

if the results might influence clinicaldecisions or recommendations fortreatment.

How should screening be done, andhow are the results interpreted?Bone mineral density measuredwith dual-energy x-ray absorptiom-etry (DXA) is used to screen forand diagnose osteoporosis, assessfracture risk, and monitor changesin BMD over time. The WorldHealth Organization (WHO) hasdeveloped a freely available, com-puter-based fracture risk assessmenttool, FRAX (6), that can be usedwith or without BMD, to estimatethe 10-year probability of hip frac-ture and major osteoporotic frac-ture (hip, clinical spine, proximalhumerus, forearm) in untreatedmen and women between the agesof 40 and 90. The items used forthe calculation are readily availablefrom routine clinical care and arelisted in the Box: FRAX Tool.

Expression of fracture risk as a 10-year probability provides greaterclinical utility than relative risk, be-cause relative risk is dependent onthe risk for the comparator popula-tion as well as the patient’s risk. Inaddition, the limited number of easi-ly obtainable clinical risk factors usedis more practical than the numerouspublished clinical risk factors.

© 2011 American College of Physicians ITC1-2 In the Clinic Annals of Internal Medicine 5 July 2011

Osteoporosis is a skeletal disorder characterized by compromised bonestrength that predisposes a person to an increased risk for fracture (1).Bone strength is determined by properties that include bone mineral

density (BMD), bone geometry (size and shape of bone), degree of mineraliza-tion, microarchitecture, and bone turnover. It is a common disease with seriousclinical consequences. In the United States, about 44 million people have osteo-porosis or osteopenia (low bone mass) that could lead to low-trauma fractures.About 50% of white women and 20% of men will have an osteoporosis-relatedfracture in their lifetimes. Fractures of the hip and spine may be disabling andare associated with mortality rates that are about 20% greater than that of anage-matched population. A fragility fracture (i.e., a nontraumatic fracture orone that occurs with low trauma, such as a fall from the standing position) ofany type is a sentinel event that increases the risk for future fractures. To reducethe burden of osteoporotic fractures, high-risk patients must be identified, eval-uated for factors contributing to skeletal fragility, and treated to reduce fracturerisk. Pharmacologic agents can reduce the risk for fracture in appropriately se-lected patients, with a generally favorable safety profile.

Screening andPrevention

Clinical Risk Factors forOsteoporosis and Low-TraumaFractureAdvanced ageFemale sexEstrogen deficiency (any cause after

puberty)History of fracture as an adultHistory of fragility fracture in first-

degree relativeHistory of glucocorticoid use for

more than 3 monthsCurrent cigarette smokingLow body weight (<127 lbs)Poor health/frailtyWhite raceAsian raceLow calcium intakeAlcoholismInadequate physical activityDementia; cognitive impairmentRecurrent fallsImpaired neuromuscular function

and other parameters ofimmobility

Impaired eyesight despite optimalcorrection

Residence in a nursing homeLong-term heparin therapyAnticonvulsant therapyAromatase-inhibitor therapyAndrogen-deprivation therapy


© 2011 American College of PhysiciansITC1-3In the ClinicAnnals of Internal Medicine5 July 2011

The interpretation of DXA resultsand categorization of patients ashaving osteopenia or osteoporosisare listed in the Box: Classificationof Bone Mineral Density by Dual-Energy X-Ray Absorptiometry.

What lifestyle measures arerecommended for prevention?Regular physical activity and goodnutrition, with particular regard toadequate intake of calcium and vita-min D, can help to optimize peakbone mass and reduce the subse-quent rate of bone loss. Encourageresistance exercise, recognizing theneed to adjust exercise programs ac-cording to a patient’s concurrentproblems. Avoidance of smoking andmoderate alcohol consumptionshould be recommended, and coun-seling or behavioral modificationprograms for these problems shouldbe considered when appropriate. Inaddition to the skeletal benefits, reg-ular physical activity can improvecardiovascular fitness, assist withweight control, and provide an en-hanced sense of well-being. Exces-sive exercise may be harmful toskeletal health, as seen in adolescentsand young adults with poor nutritionand hormonal abnormalities associ-ated with the female-athlete triad(eating disorder, amenorrhea, osteo-porosis). If possible, exposure tomedications known to have harmfulskeletal effects (e.g., glucocorticoids,aromatase inhibitors, androgen-dep-rivation therapy, and anticonvulsants)should be minimized or avoided. Forfrail, elderly patients, the importanceof fall prevention by means includingmodifying the home environment;leg-strengthening exercises; balancetraining; and avoiding drugs thatmay cause sedation, hypotension, ordizziness should be emphasized.

Weight-bearing exercise maintains bonestrength by stimulating bone formation (7).Observational, retrospective, and prospec-tive randomized trials have shown an asso-ciation between exercise and bone accu-mulation during growth as well as withmaintenance of bone mass in adulthood,with particular benefit from high-impact

exercise. A simple jumping exercise (10 min-utes, 3 times a week for 7 months) in a ran-domized, controlled trial (RCT) done in 121ten-year-old boys augmented total bodybone mineral content (8), which was sus-tained even after a further 7 months of “de-training.” Another RCT conducted in prepu-bescent children showed that a 7-monthexercise program that included jumpingwas better than a program that includedstretching in improving bone mass at thehip and spine (9). Weight-bearing exercisehas been associated with a small but signif-icant BMD increase in meta-analyses of 25studies in premenopausal and post-menopausal women (10) and 8 studies inmen (11).

What is the role of calcium andvitamin D in the prevention ofosteoporosis?Calcium and vitamin D are essen-tial nutrients for the accrual ofbone during childhood and adoles-cence and the maintenance of bonemass in adulthood. Inadequacy canresult in rickets in children and osteomalacia or osteoporosis inadults. The NOF recommends adaily calcium intake of at least 1200mg with diet plus supplements, ifneeded, for postmenopausal womenand men age 50 years and older,with a tolerable upper limit for dai-ly calcium intake set at 2500 mg(2). Excessive calcium intake maybe associated with increased risk forhypercalciuria and nephrolithiasis.In patients with malabsorption dueto intestinal disease, bariatric sur-gery, or achlorhydria (which affectsabsorption of calcium carbonate,predominantly in the fasting state),consider increasing the oral dose ofcalcium to 2000 mg/d. Because ofthe high prevalence of reduced gas-tric acidity that is either endoge-nous or due to medications (e.g.,proton-pump inhibitors), calciumcarbonate is best taken with mealsto optimize absorption. Calciumcitrate, which is well-absorbed regardless of gastric acidity, may betaken with or without food. Meas-urement of the 24-hour urinarycalcium may be helpful in monitor-ing therapy, noting that <50 to

Indications for Bone Mineral DensityTestingWomen aged 65 years and older and

men aged 70 and older, regardless ofclinical risk factors

Younger postmenopausal women andmen aged 50 to 69 about whom youhave concern based on the clinical riskprofile

Women in the menopausal transition ifthere is a specific risk factorassociated with increased fracture risk,such as low body weight, prior low-trauma fracture, or high-riskmedication*

Adults who have a fracture after age 50Adults with a condition (e.g., rheumatoid

arthritis) or taking a medication (e.g.,glucocorticoids in a daily dose ≥ 5 mgprednisone or equivalent for ≥ 3months) associated with low bonemass or bone loss

Anyone being considered for pharmaco-logic therapy for osteoporosis

Anyone being treated for osteoporosis,to monitor treatment effect

Anyone not receiving therapy in whomevidence of bone loss would lead totreatment

Postmenopausal women discontinuingestrogen should be considered forbone density testing

*High-risk medications include long-termglucocorticoids, anticonvulsants,aromatase inhibitors, and androgen-deprivation therapy.

FRAX ToolClinical items used by the FRAX tool

to estimate 10-year risk for majorosteoporotic fracture (hip, clinicalspine, proximal humerus, distalforearm) and hip fracture:• Age• Sex• Height• Weight• Ethnicity (for US calculator only:

caucasian, black, Hispanic, or Asian)• Optional item: femoral neck bone

mineral density (g/cm2)Yes/no responses to each of the

following:• Previous fracture• Parent with hip fracture• Current smoking• Glucocorticoid use• Rheumatoid arthritis• Secondary osteoporosis• Three or more units of alcohol

per dayCalculator freely available at

www.shef.ac.uk/FRAX.


1. Klibanski A, Adams-Campbell L, BassfordT, et al. Osteoporosisprevention, diagnosis,and therapy. JAMA.2001;285:785-95.

2. National OsteoporosisFoundation. Clini-cian’s Guide to Pre-vention and Treat-ment ofOsteoporosis. Ac-cessed atwww.nof.org/sites/default/files/pdfs/NOF_ClinicianGuide2009_v7.pdf on 7 March2011.

3. Baim S, Binkley N,Bilezikian JP, et al. Of-ficial Positions of theInternational Societyfor Clinical Densitom-etry and executivesummary of the 2007ISCD Position Devel-opment Conference.J Clin Densitom.2008;11:75-91.

4. U.S. Preventive Servic-es Task Force. Screen-ing for Osteoporosis:U.S. Preventive Serv-ices Task Force rec-ommendation state-ment. Ann InternMed. 2011;154:356-64.


100 mg/24 h suggests calcium mal-absorption, assuming adequate in-take and normal renal function.

The blood level of serum 25-hydrox-yvitamin D necessary for optimumskeletal health, and the dose of vita-min D required to achieve it, is notknown. Many experts believe that theminimum desirable serum level of25-hydroxyvitamin D is about 75nmol/L (30 ng/mL), requiring an av-erage daily intake of at least 800 to1000 IU in older men and women(12). The NOF recommends an in-take of vitamin D3 800 to 1000 IU/dfor all adults age 50 years and older;doses over 2000 IU/d may be neces-sary and safe for some patients. Vita-min D toxicity with hypercalcemia israre and probably requires a dailydose in excess of 40,000 IU (13).Food products fortified with vitaminD, together with modest exposure tosunlight, can be suggested. Chroni-cally ill, elderly persons who cannotget out during the day are particular-ly susceptible to vitamin D deficien-cy; therefore, oral supplementation isan acceptable alternative.

Although it is often difficult to distinguish theeffects of calcium and vitamin D in clinicaltrials, many studies suggest that the typicalintake of both is suboptimum. A meta-analysis of 15 randomized clinical trials inpostmenopausal women, representing 1806participants, showed that calcium was moreeffective than placebo at reducing rates ofbone loss after 2 or more years of treatmentwith a pooled difference in percentagechange from baseline of 2.05% (95% CI, 0.24to 3.86) for total body BMD, 1.66% (CI, 0.92 to2.39) for the lumbar spine at 2 years, 1.60%(CI, 0.78 to 2.41) for the hip, and 1.91% (CI,0.33 to 3.50) for the distal radius (14).

An 18-month prospective randomized trialin 3270 healthy ambulatory elderly women(mean age, 84 years), not selected accordingto baseline fracture risk, showed that supple-mentation with vitamin D3 (cholecalciferol)and calcium improved BMD at the proximalfemur by 7.3% compared with placebo(P<0.001), reducing the risk for hip fractureby 43% (P<0.043) and nonvertebral frac-tures by 32% (P<0.015) (15). A similar effectwas observed in a 3-year trial of 176 menand 213 women aged 65 or older who were

randomly assigned to vitamin D3 supple-mentation on BMD in men and womenaged 65 years and older (16).

When should pharmacologictreatment be considered forprevention?In the early postmenopausal years,bone remodeling accelerates inwomen due to estrogen deficiency,sometimes resulting in rapid boneloss. This is particularly troublesomewhen baseline BMD is low, which isoften due to low peak bone mass.Under these circumstances, early in-tervention with pharmacologicagents may prevent or reverse boneloss, maintain trabecular microarchi-tecture, and ultimately reduce frac-ture risk. The ACP recommendsconsideration of pharmacologictreatment “for men and women whoare at risk for developing osteoporo-sis” (17). Drugs that are approvedfor the prevention of post-menopausal osteoporosis (Table 1)have been shown in RCTs to stabi-lize or increase BMD in early post-menopausal women who do nothave osteoporosis. This has beendemonstrated with alendronate (18),risedronate (19), ibandronate (20),raloxifene (21), and estrogen (22). InRCTs for osteoporosis prevention,fracture reduction benefit has notbeen shown with risedronate, iban-dronate, or raloxifene; however, apost hoc subgroup analysis of theFracture Intervention Trial showedthat alendronate was effective in re-ducing the risk for vertebral frac-tures in women with a femoral neck T-score between −1.6 and −2.5 (23).The Women’s Health Initiative trialshowed that estrogen alone (24) orcombined with progesterone (22)reduced fractures in women notspecifically selected to be at in-creased risk for osteoporosis. Thedecision to begin pharmacologictherapy for prevention of osteoporo-sis should be based on considerationof the balance between the expectedbenefit and potential risks of eachpharmacologic agent (Table 1) foreach patient.

Classification of Bone MineralDensity by Dual-Energy X-RayAbsorptiometryIn postmenopausal women and men

aged 50 and older—apply the WHOdiagnostic criteria• Normal: T-score –0.1 or above• Low bone mass (osteopenia): T-

score below –1.0 and above –2.5• Osteoporosis: T-score –2.5 or below• Severe osteoporosis: T-score –2.5 or

below and personal history offragility fracture

In premenopausal women and menunder age 50—do not apply the WHOdiagnostic criteria• Z-scores, not T-scores, are preferred• Z-score of –2.0 or lower is defined

as “below the expected range forage”

• Z-score above –2.0 is “within theexpected range for age”

In children (males and females less thanage 20)—do not apply the WHOdiagnostic criteria• Use Z-scores, not T-scores• If the Z-score is below –2.0, use

such terminology as “low bone den-sity for chronological age” or “belowthe expected range for age”

• There are no densitometric criteriafor diagnosing osteoporosis in chil-dren

WHO = World Health Organization.



Table 1. Pharmacologic Agents for Management of OsteoporosisAgent Mechanism of Action Dosage Benefits Side Effects Notes

Raloxifene Selective estrogen- 60 mg/d Increases bone mass; Increased Does not need to be given with proges-receptor modulator; decreases vertebral thromboembolic terone. Not recommended for premeno-suppressive effects on fractures; reduces risk risk; increased pausal women or women concurrently osteoclast and bone for invasive breast vasomotor using estrogen replacement. FDA-approved resorption; estrogen cancer symptoms; indications: prevention and treatment of antagonist in uterine increased risk for osteoporosis in postmenopausal women. and breast tissues fatal stroke No evidence for reduction of hip or non-

vertebral fracture risk.Oral ↓ bone resorption by 10 mg/d or Increases bone mass; May cause Should not be taken with food. Instruct

bisphosphonates attenuating osteoclast 70 mg/wk for decreases vertebral esophageal patient to take first thing in the morning (alendronate, activity treatment or fractures; decreases irritation with 6-8 oz water and not to recline or risedronate, 5 mg/d for in hip and nonvert- ingest anything else for at least 30 min ibandronate). prevention ebral fractures with (alendronate, risedronate) or 60 min Note that a recently (alendronate); alendronate and (ibandronate). Do not use in patients with approved novel 150 mg/mo risedronate chronic kidney disease (creatinine formulation of (ibandronate); clearance <35 mL/min [alendronate] or risedronate 5 mg/d, 35 mg/ < 30 mL/min [risedronate, ibandronate]).35 mg/wk, with wk, or 150 mg/ FDA-approved indications: prevention an enteric coating mo (risedronate) and treatment of osteoporosis in post-and a chelating menopausal women (alendronate, agent, is approved risedronate, ibandronate), treatment for treatment of of osteoporosis in men (alendronate, postmenopausal risedronate), prevention (risedronate) osteoporosis only; and treatment (alendronate, risedronate) must be taken of glucocorticoid-induced osteoporosis in immediately after women or men. No evidence for reduction breakfast. of hip or nonvertebral fracture risk for

ibandronate.Denosumab ↓ bone resorption by 60 mg/d SQ Increases bone mass; Increased risk for No restrictions in dosing according to

attenuating osteoclast every 6 mo decreases vertebral, cellulitis, eczema, renal function. FDA-approved indication: formation, activity, and hip, and nonvertebral and flatulence in treatment of osteoporosis in postmeno-survival fracture rates the phase 3 pivot- menopausal women at high fracture risk.

al fracture trialIV bisphosphonates ↓ bone resorption by 5 mg IV over no Increases bone mass; Flu-like symptoms FDA-approved for prevention (zoledronate)

(zoledronate, attenuating osteoclast less than 15 decreases vertebral after first dose and treatment (zoledronate, ibandronate) ibandronate) activity min once fracture, hip fracture, of postmenopausal osteoporosis, to

every 12 mo and other nonverte- increase bone mass in men with for treatment bral fracture rates osteoporosis (zoledronate), and treatment or once every of osteoporosis in men (zoledronate), and 24 mo for pre- prevention (zoledronate) and treatment vention (zolen- (zoledronate) of glucocorticoid-induced dronate); 3 mg osteoporosis in women and men.IV over 15-30sec every 3 mo

Calcitonin ↓ bone resorption by Nasal spray: Slight increases in Rhinitis, irritation May be beneficial in decreasing pain attenuating osteoclast 200 IU/d bone mass; decreases of nasal mucosa associated with acute or subacute activity vertebral fracture vertebral fracture. Because of availability

rates of medications with better efficacy in fracture reduction, calcitonin is not considered not considered first-line treatment for osteoporosis. FDA-approvedindications: treatment of osteoporosis inwomen who are at least 5-years post-menopausal. No evidence for reduction ofhip or nonvertebral fracture risk.

Teriparatide Stimulates bone 20 µg/d SQ Increases bone mass; Dizziness, nausea Maximum lifetime duration 2 years. formation decreases vertebral Contraindicated in patients with base-

and nonvertebral line risk for osteosarcoma, including fracture rates those with Paget disease of bone, unex-

plained elevation of AKP, open epiphyses,or history of skeletal radiation. FDA-approved indications: high risk for fracturewith postmenopausal osteoporosis, menwith primary or hypogonadal osteoporosis, and men and women with sus-tained systemic glucocorticoid therapy.

AKP = alkaline phosphatase; FDA = U.S. Food and Drug Administration; IU = international units; IV = intravenous; SQ = subcutaneous.



5. Qaseem A, Snow V,Shekelle P, Hopkins R,Jr., Forciea MA,Owens DK. Screeningfor osteoporosis inmen: a clinical prac-tice guideline fromthe American Collegeof Physicians. Ann In-tern Med.2008;148:680-684.

6. World Health Organi-zation. FRAX WHOFracture Risk Assessment Tool. Accessed atwww.shef.ac.uk/FRAX/ on 1 October 2010.

7. Recker RR, Davies M,Hinders SM, et al.Bone gain in youngadult women. JAMA.1992;268:2403-8.

8. MacKelvie KJ, McKayHA, Petit MA, et al.Bone mineral re-sponse to a 7-monthrandomized con-trolled, school-basedjumping interventionin 121 prepubertalboys: associationswith ethnicity andbody mass index. JBone Miner Res.2002;17:834-44.

9. Fuchs RK, Bauer JJ,Snow CM. Jumpingimproves hip andlumbar spine bonemass in prepubes-cent children: A ran-domized controlledtrial. J Bone MinerRes. 2001;16:148-56.

10. Wolff I, van Croo-nenborg JJ, KemperHC, et al. The effectof exercise trainingprograms on bonemass: a meta-analy-sis of published con-trolled trials in pre-and post-menopausalwomen. OsteoporosInt. 1999;9:1-12.

11. Kelley GA, Kelley KS,Tran ZV. Exercise andbone mineral densi-ty in men: a meta-analysis. J Appl Phys-iol.2000;88:1730-1736.

12. Dawson-Hughes B,Heaney RP, HolickMF, et al. Estimatesof optimal vitamin Dstatus. OsteoporosInt. 2005;16:713-16.

13. Vieth R. Vitamin Dsupplementation,25-hydroxyvitamin Dconcentrations, andsafety. Am J ClinNutr. 1999;69:842-56.

14. Shea B, Wells G,Cranney A, et al. Cal-cium supplementa-tion on bone loss inpostmenopausalwomen. CochraneDatabase Syst Rev.2004;CD004526.

Diagnosis andEvaluation reported that universal bone densitometry

testing combined with alendronate therapyfor patients found to have osteoporosis ishighly cost-effective for women aged 65years and older and may be cost-saving forambulatory women aged 85 years and old-er (whether living independently or residingin nursing homes) (26).

What should the initial evaluationof a patient newly diagnosed withosteoporosis include?The evaluation of a patient withosteoporosis begins with a focusedmedical history and physical exam-ination (see the Box: PotentiallyHelpful Findings on Physical Ex-amination for Osteoporosis).

The medical history should includeinformation about diet, lifestyle,medications, family history, falls,fractures, and a focused review ofsystems. Height should be meas-ured with a wall-mounted sta-diometer. Particular attention isgiven to signs that may indicate acause of osteoporosis (e.g., signs ofhyperthyroidism), complications(e.g., kyphosis), or the risk for falls(e.g., evaluation of gait and bal-ance). Appropriate laboratory stud-ies (Table 2) should be done to de-termine whether clinically relevantcontributing factors are present(e.g., malabsorption) and to identi-fy potential safety concerns thatcould influence the treatment deci-sions (e.g., hypocalcemia). Imagingstudies may be helpful in carefullyselected patients. For example,spine imaging may diagnose previ-ously unrecognized vertebral frac-tures in patients with height loss orkyphosis; a nuclear bone scan or an

How should osteoporosis bediagnosed?Osteoporosis may be diagnosed inpostmenopausal women and men50 years and older when the lowestT-score of the lumbar spine,femoral neck, total hip, or 33%(one third) radius (a region of in-terest in the distal radius that is de-fined by each DXA manufacturer)is −2.5 or less according to WHOcriteria. This cut-off was selectedbecause it identifies approximately30% of postmenopausal women ashaving osteoporosis by measure-ment of BMD at the lumbar spine,hip, and forearm, which approxi-mates the lifetime risk for fractureat these skeletal sites. The T-scoreis the standard deviation (SD) dif-ference between the BMD of thepatient and a sex-matched, young-adult, white reference population.A presumptive diagnosis of osteo-porosis may also be made in thepresence of a fragility (low-trauma)fracture, regardless of BMD. Inpremenopausal women and menyounger than 50 years, Z-scores(the SD difference between the pa-tient’s BMD and an age-, sex- andethnicity-matched reference popu-lation)—not T-scores—should beused, and the WHO diagnostic criteria should not be applied.

Based on a meta-analysis of 229 studies thatcompared osteoporosis screening with 2widely accepted screening methods, the pre-dictive value of a 1-SD decrease in BMD forfracture is similar to that of a 1-SD increasein blood pressure for predicting risk for strokeor a 1-SD increase in serum cholesterol con-centration for predicting coronary artery dis-ease (25). A cost-effectiveness analysis has

Screening and Prevention... A healthy lifestyle, good nutrition, and avoidance ofmedications known to be harmful to bone are fundamental components of pre-vention of osteoporosis. Pharmacologic therapy to reduce fracture risk is indicatedin patients with osteopenia who are at high fracture risk and should be consid-ered in patients without osteopenia who are anticipated to have rapid bone lossthat could soon result in osteoporosis and high fracture risk.

CLINICAL BOTTOM LINE


15. Chapuy MC, AroltME, Duboeuf F, et al.Vitamin D3 and cal-cium to prevent hipfractures in elderlywomen. N Engl JMed. 1992;327:1637-42.

16. Dawson-Hughes B,Harris SS, Krall EA, etal. Effects of calciumand vitamin D sup-plementation onbone density in menand women 65 yearsof age and older. NEngl J Med.1997;337:670-76.

17. Qaseem A, Snow V,Shekelle P, HopkinsR, Jr., Forciea MA,Owens DK. Pharma-cologic treatment oflow BMD or osteo-porosis to preventfractures: a clinicalpractice guidelinefrom the AmericanCollege of Physi-cians. Ann InternMed. 2008;149:404-15.]

18. Cranney A, Wells G,Willan A, et al. Meta-analysis of alen-dronate for thetreatment of post-menopausalwomen. Endocr Rev.2002;23:508-16.


x-ray may detect Paget disease ofbone in a patient with unexplainedelevation of serum alkaline phos-phatase levels; and a barium swallow may detect an esophageal stricture in a patient with swallow-ing difficulties and may influencechoices for treatment.

Although there is no established consensuson the optimum laboratory testing for pa-tients with low BMD, panels of expertshave recommended various combinationsof tests. In a cross-sectional study of 664women seen at an osteoporosis and meta-bolic bone disease specialty clinical, thosewithout known secondary causes werescreened with extensive laboratory testing.It was found that 32% had previously un-known contributing factors, and a strategyof measuring 24-hour urinary calcium,serum calcium, serum parathyroid hor-mone, and serum thyroid-stimulating hor-mone in women receiving thyroid replace-ment identified 85% at an estimated costof $75 per patient (27).

When should consultation beconsidered in evaluation?Consider referral to a physicianwith expertise in osteoporosis andmetabolic bone disease when sec-ondary causes of osteoporosis aresuspected or when clinical andlaboratory data are discordant.Consider referral to a gastroen-terologist for small bowel biopsywhen celiac disease is suspected.Consider referral to an oncologistwhen laboratory findings suggestmultiple myeloma or other formsof cancer. Referral to an appropriateosteoporosis specialist should be

considered when a patient withnormal BMD sustains a nontrau-matic fracture; when recurrentfractures or continued bone lossoccurs in a patient receiving ther-apy without obvious treatablecauses of bone loss; when osteo-porosis is unexpectedly severe orhas unusual features; or when apatient has a condition that com-plicates management (e.g., renalfailure, hyperparathyroidism, ormalabsorption) (28).

Potentially Helpful Findings on Physical Examination for OsteoporosisLoss of height may be associated with vertebral fractureLow body weight is an independent risk factor for fractureWeight loss may be due to hyperthyroidism or malnutritionFast heart rate may be due to hyperthyroidism or anemiaFast respiratory rate may be due to asthmaKyphosis may be the result of vertebral fractures or upper back muscle weaknessPoor gait, muscle strength, balance may increase the risk for falls and fracturesParalysis or immobility may result in bone loss, increased risk for falls, or bothJoint laxity could be due to the Marfan syndrome, osteogenesis imperfecta, or the

Ehlers-Danlos syndromeInflammatory arthritis is associated with osteoporosis and the use of glucocorticoidsOsteoarthritis or lower limb injury may result in decreased load-bearing and bone

lossBlue sclera, poor tooth development, hearing loss, and fracture deformities are

associated with osteogenesis imperfectaPoor dental hygiene is a risk factor for osteonecrosis of the jaw with bisphosphonate

therapyThyromegaly, thyroid nodules, and proptosis suggest hyperthyroidismUrticaria pigmentosa suggests systemic mastocytosisKyphosis or shortened distance between lowest ribs and iliac crest suggests vertebral

fracturesAbdominal tenderness may be due to inflammatory bowel diseaseStretch marks, buffalo hump, and bruising suggest glucocorticoid excessSigns of venous thrombosis suggest that treatment with estrogen or raloxifene may

be contraindicatedSmall testicles in men suggest hypogonadism

Diagnosis... Most patients with osteoporosis and low BMD can be evaluatedand treated by a primary care physician. Essential laboratory tests for the ini-tial evaluation of all patients with osteoporosis include a complete bloodcount; measurement of serum calcium, phosphorus, creatinine, aspartate andalanine transaminase, alkaline phosphatase, and thyroid-stimulating hormoneand 24-hour urinary calcium levels; and testosterone in men with osteoporosis.Additional tests may be appropriate depending on clinical circumstances. Thedecision to refer to an osteoporosis specialist is determined by the level of ex-pertise and comfort of the referring physician in evaluating complex or unusualdiagnostic issues.



19. Cranney A, TugwellP, Adachi J, et al.Meta-analysis of rise-dronate for thetreatment of post-menopausal osteo-porosis. Endocr Rev.2002;23:517-23.

20. McClung MR, Was-nich RD, Recker R, etal. Oral daily iban-dronate preventsbone loss in earlypostmenopausalwomen without os-teoporosis. J BoneMiner Res.2004;19:11-18.

21. Cranney A, TugwellP, Zytaruk N, et al.Meta-analysis ofraloxifene for theprevention andtreatment of post-menopausal osteo-porosis. Endocr Rev.2002;23:524-28.

22. Cauley JA, Robbins J,Chen Z, et al. Effectsof estrogen plusprogestin on risk offracture and bonemineral density: theWomen’s Health Ini-tiative randomizedtrial. JAMA.2003;290:1729-38.


Table 2. Laboratory Evaluation for Secondary Causes of Osteoporosis*Essential tests Comments/Disorder Detected

Complete blood count CancerSerum calcium High in hyperparathyroidismSerum phosphorus Low with osteomalaciaSerum creatinine High with chronic kidney diseaseSerum thyroid-stimulating hormone Low in hyperthyroidismSerum liver enzymes High with chronic liver diseaseSerum alkaline phosphatase High with chronic liver disease and Paget disease of bone, low with hypophosphatasiaSerum total/free testosterone in men Hypogonadism24-hour urinary calcium Low (< 50-100 mg/24 h) with calcium malabsorption, high (> 250 mg/24 h in women

or >300 mg/24 h in men) with excessive calcium absorption or renal calcium leakOptional tests according to clinical circumstance

Serum 25-hydroxyvitamin D Vitamin D deficiency/insufficiencySerum parathyroid hormone in patients Hyperparathyroidism

with high serum calciumSerum/urine protein electrophoresis, kappa/lambda Multiple myeloma n elderly patients

light chains Serum celiac antibodies (antigliadin, endomysial, tissue Celiac disease (small bowel biopsy needed to confirm diagnosis)

transglutaminase) when malabsorption is suspected24-hour urinary free cortisol or overnight dexamethasone The Cushing syndrome

suppression test if hypercortisolism is suspected Serum tryptase Systemic mastocytosis

*Tests not listed may be indicated according to clinical circumstances.

risk may increase with advancingage. Reduction in fall risk with suchmeasures as quadriceps strengthen-ing and balance training is importantin osteoporosis treatment, especiallyin frail, elderly patients.

What lifestyle measures arerecommended?Encourage smoking cessation and re-duced alcohol use, which may requirecounseling or behavioral modificationprograms. Encourage regular weight-bearing and muscle-strengtheningexercise, recognizing the need to ad-just exercise programs in patientswith concurrent disease. For frail,elderly patients, emphasize the im-portance of prevention of falls, bestaccomplished by evaluating homesafety, minimizing use of mind-altering medications (e.g., sedatives,hypnotics, and narcotic analgesics),and leg-strengthening exercises.

How much calcium and vitamin Dare recommended?The NOF treatment recommenda-tions include a recommendation foradequate calcium and vitamin D

What are the goals of treatment?The goal of treatment is to reducethe risk for fractures. Fractures occurwhen a force applied to a bone ex-ceeds its strength; fracture risk is re-duced by improving bone strengthand preventing falls. Bone strengthcannot be directly measured in vivo;therefore, surrogate markers of bonestrength, such as BMD and markersof bone turnover, are used to assessskeletal health at baseline and tomonitor for effectiveness of treat-ment (discussed below). BMD istypically measured about 1 to 2 yearsafter starting therapy, with the goalof maintaining or increasing BMD.Essential care for skeletal health in-cludes regular physical activity andadequate intake of calcium and vita-min D. Pharmacologic agents havebeen proven to reduce fracture risk.Fall risk can be accessed throughsimple office tests, such as observinghow easily the patient rises from achair and moves to the examinationtable, and whether he or she is ableto walk a straight line or balance on1 foot. Periodic reevaluation of therisk for falls is appropriate because

Treatment


23. Quandt SA, Thomp-son DE, SchneiderDL, et al. Effect of al-endronate on verte-bral fracture risk inwomen with bonemineral density Tscores of -1.6 to -2.5at the femoral neck:the Fracture Inter-vention Trial. MayoClin Proc.2005;80:343-49.

24. Anderson GL, Li-macher M, Assaf AR,et al. Effects of con-jugated equine es-trogen in post-menopausal womenwith hysterectomy:the Women’s HealthInitiative random-ized controlled trial.JAMA.2004;291:1701-12.

25. Marshall D, JohnellO, Wedel H. Meta-analysis of how wellmeasures of bonemineral density pre-dict occurrence ofosteoporotic frac-tures. BMJ.1996;312:1254-59.

26. Schousboe JT, En-srud KE, Nyman JA,et al. Universal bonedensitometryscreening combinedwith alendronatetherapy for those di-agnosed with osteo-porosis is highlycost-effective forelderly women. JAm Geriatr Soc.2005;53:1697-704.

27. Tannenbaum C,Clark J, Schwartz-man K, et al. Yield oflaboratory testing toidentify secondarycontributors to os-teoporosis in other-wise healthywomen. J Clin En-docrinol Metab.2003;87:4431-37.

28. Watts NB, BilezikianJP, Camacho PM, etal. American Associ-ation of Clinical En-docrinologists Med-ical Guidelines forClinical Practice forthe diagnosis andtreatment of post-menopausal osteo-porosis: executivesummary of recom-mendations. EndocrPract. 2010;16:1016-19.

29. Jackson RD, LaCroixAZ, Gass M, et al.Calcium plus vitaminD supplementationand the risk of frac-tures. N Engl J Med.2006;354:669-83.


intake in postmenopausal womenand men age 50 and older, regardlessof whether osteoporosis is present.Suggest oral calcium supplements(e.g., calcium carbonate or calciumcitrate) to patients whose daily di-etary calcium intake is less than1200 mg. Advise the patient thatcalcium carbonate supplementsshould be taken with meals to ensurethe presence of stomach acid, whichenhances absorption. Calcium citratemay be taken with or without meals.Since a reduction in stomach acidwill also decrease absorption of calci-um carbonate formulations; consideradvising all elderly patients andthose receiving acid-suppressiontherapy to take calcium citrate ratherthan other calcium formulations.Recommend an intake of vitaminD3, 800 to 1000 IU/d, for all adultsage 50 and older; doses over 2000IU/d may be necessary and safe forsome patients. The effectiveness ofvitamin D intake is assessed bymeasurement of the serum 25-hy-droxyvitamin level, not by the dosethat is taken. Since it requires at least3 months to achieve a new steadystate after changing the vitamin Ddose, it is prudent to wait at leastthat amount of time before measur-ing the serum 25-hydroxyvitamin Dlevel. Suggest using fortified foodproducts and moderate exposure tosunlight, keeping in mind that sun-block that prevents tanning andburning also reduces vitamin D pro-duction in the skin.

A large RCT of more than 36 000 healthypostmenopausal women reported that cal-cium and vitamin D supplementation in-creased BMD at the hip but did not signifi-cantly reduce the risk for hip fracture (29);however, the dose of vitamin D (400 IU) wassuboptimum and adherence to therapy waspoor (59% at the end of the study). The studyfound that among women who were ad-herent to therapy (i.e., took at least 80% ofstudy medication), even with the subopti-mum dose of vitamin D, there was a signifi-cant 29% reduction in hip fracture risk. Mostmajor modern trials of antiresorptive thera-pies (such as bisphosphonates, discussedbelow) have provided basal calcium intake

for all participants; thus, the efficacy of allcurrently available antiresorptive agents hasbeen shown only in women who maintainadequate calcium intake. Histamine-2 re-ceptor antagonists and proton-pump in-hibitors may decrease calcium bioavail-ability (30).

What pharmacologic interventionsare effective for treatment, andhow should they be chosen?The NOF has established indica-tions for initiation of pharmacologictherapy to reduce the risk for frac-ture as assessed by BMD testing,history of spine or hip fracture, anduse of FRAX in patients with os-teopenia. The ACP recommends of-fering pharmacologic treatment to“men and women who have knownosteoporosis and to those who haveexperienced fragility fractures” (17).Pharmacologic agents proven to re-duce fracture risk in patients withosteoporosis are listed in Table 1; inaddition, estrogen with or withoutmedroxyprogesterone also improvesBMD and reduces the risk for frac-ture in postmenopausal women (24,31); however, estrogen is not ap-proved for treatment of osteoporosisdue to evidence that the risks out-weigh the benefits, even in womenat high risk for fracture (22) Drugselection should be based on allavailable clinical information, including estimation of fracture risk,comorbid conditions, patient prefer-ences, efficacy, safety, expectations ofadherence to therapy, and affordabil-ity (32–44). Effective communica-tion of risk and shared decisionmaking allow the patient to fullyparticipate in treatment decisions(45). In addition to pharmacologictherapy, measures should be taken toensure adequate intake of calciumand vitamin D; limit exposure tomedications known to have harmfulskeletal effects; and reduce the riskfor falls, especially in frail elderly patients (see section on falls).

The oral bisphosphonates alen-dronate, risedronate, and ibandronateare each first-line therapy for thetreatment of osteoporosis for many


30. Graziani G, Como G,Badalamenti S, et al.Effect of gastric acidsecretion on intes-tinal phosphate andcalcium absorptionin normal subjects.Nephrol Dial Trans-plant. 1995;10:1376-80.

31. Writing Group forthe Women’s HealthInitiative Investiga-tors. Risks and bene-fits of estrogen plusprogestin in healthypostmenopausalwomen. JAMA.2002;288:321-33.

32. Liberman UA, WeissSR, Broll J, et al. Ef-fect of oral alen-dronate on bonemineral density andthe incidence offractures in post-menopausal osteo-porosis. N Engl JMed. 1995;333:1437-43.

33. Black DM, Cum-mings SR, Karpf DB,et al. Randomisedtrial of effect of alen-dronate on risk offracture in womenwith existing verte-bral fractures.Lancet.1996;348:1535-41.

34. Cummings SR, BlackDM, Thompson DE,et al. Effect of alen-dronate on risk offracture in womenwith low bone den-sity but without ver-tebral fractures - Re-sults from thefracture interventiontrial. JAMA.1998;280:2077-82.

35. McClung MR,Geusens P, Miller PD,et al. Effect of rise-dronate on the riskof hip fracture inelderly women. NEngl J Med.2001;344:333-40.

36. Reginster J-Y, MinneHW, Sorensen OH, etal. Randomized trialof the effects of rise-dronate on vertebralfractures in womenwith establishedpostmenopausal os-teoporosis. Osteo-poros Int.2000;11:83-91.


patients due to proven efficacy, gener-ally favorable safety profiles, and lowcost (particularly with generic alen-dronate). Instruct patients to take oralbisphosphonates on an empty stom-ach with 8 oz of water, without anyfood or other medications to maxi-mize absorption and to remain up-right for at least 30 minutes (60 min-utes with ibandronate) to reduce riskfor esophageal injury. A newly approved formulation of weekly rise-dronate is taken immediately afterbreakfast, thereby avoiding the incon-venience of the pre- and postdosefasting required with other oral bis-phosphonates. Do not use theseagents in patients with hypocalcemia,renal insufficiency (creatinine clear-ance <30 to 35 mL/min), oresophageal stricture, and use cautious-ly in those with difficulty swallowing,severe gastroesophageal reflux, gastricbypass, or disorders treated with long-term anticoagulation. Patients with aremote history of peptic ulcer diseaseor gastroesophageal reflux that is wellcontrolled with medications are oftenable to take oral bisphosphonateswithout difficulty. Discontinue ifsymptoms of esophageal irritation(retrosternal pain, significantly wors-ened reflux symptoms) or severe mus-culoskeletal pain develops. Considerreferral to an appropriate specialist ifsymptoms persist despite discontinua-tion. An association of bisphospho-nates with osteonecrosis of the jaw(46) and atypical femur fractures (47)has been reported, without clear evi-dence of a causal relationship. In partbecause of these safety concerns, theconcept of a “drug holiday” after long-term bisphosphonate therapy has beenraised. A drug holiday can be consid-ered in patients treated with bisphos-phonates, but not other osteoporosismedications, because of their longskeletal half-life and evidence of per-sistence of effect in some patients for aperiod after discontinuation (48).There are no clinical practice guide-lines for starting or ending a drug hol-iday. Potential candidates are patientswho should not have been treated inthe first place and those who have

been treated for at least 5 years andare no longer at sufficiently high fracture risk to justify continuingtreatment.

Injectable denosumab, ibandronate, orzoledronate are useful for treatment ofosteoporosis when oral bisphospho-nates are ineffective (e.g., significantdecrease in BMD, failure to suppressbone turnover markers), contraindi-cated (e.g., esophageal stricture, acha-lasia), associated with gastrointestinalintolerance (e.g., heartburn, abdomi-nal pain), likely to be poorly absorbed(e.g., uncontrolled celiac disease, in-flammatory bowel disease), or if thepatient is unable to remain upright for30 to 60 minutes after dosing (Table1). The most common adverse reac-tion with intravenous bisphospho-nates is an acute-phase reaction, usu-ally consisting of mild, transient,flu-like symptoms, particularly afterthe first injection. Denosumab hasbeen associated with a small but sig-nificant increased risk for adverse der-matologic events, such as eczema andserious cellulitis. Intravenous bisphos-phonates should not be given to pa-tients with severely impaired renalfunction, although there are no suchrestrictions with denosumab.

Consider raloxifene therapy for treat-ment of postmenopausal osteoporosis,particularly in early postmenopausalwomen at high risk for breast cancer(raloxifene reduces the risk for invasivebreast cancer), no history of throm-boembolic disease, low risk for stroke,low risk for hip fracture, and few orno problems with hot flashes. Do notuse raloxifene in patients who are athigh risk for stroke or have a historyof thromboembolic events, pre-menopausal women, or women re-ceiving concurrent estrogen therapy.

Nasal salmon calcitonin is approvedfor the treatment of osteoporosis inwomen who are at least 5 years post-menopausal and are not able to takeother U.S. Food and Drug Adminis-tration (FDA)–approved agents. It isadministered as a nasal spray at a


37. Harris ST, Watts NB,Genant HK, et al. Ef-fects of risedronatetreatment on verte-bral and nonverte-bral fractures inwomen with post-menopausal osteo-porosis: a random-ized controlled trial.Vertebral EfficacyWith RisedronateTherapy VERT. StudyGroup. JAMA.1999;282:1344-52.

38. Chesnut III CH, SkagA, Christiansen C, etal. Effects of oralibandronate admin-istered daily or inter-mittently on fracturerisk in post-menopausal osteo-porosis. J Bone Min-er Res.2004;19:1241-49.

39. Black DM, DelmasPD, Eastell R, et al.Once-yearly zole-dronic acid for treat-ment of post-menopausalosteoporosis. N EnglJ Med.2007;356:1809-22.

40. Lyles KW, Colon-Emeric CS, Magazin-er JS, et al. Zoledron-ic acid and clinicalfractures and mor-tality after hip frac-ture. N Engl J Med.2007;357:1799-809.

41. Cummings SR, SanMartin J, McClungMR, et al. Denosum-ab for prevention offractures in post-menopausal womenwith osteoporosis. NEngl J Med.2009;361:756-65.

42. Ettinger B, Black DM,Mitlak BH, et al. Re-duction of vertebralfracture risk in post-menopausal womenwith osteoporosistreated with ralox-ifene - Results from a3-year randomizedclinical trial. JAMA.1999;282:637-45.


dose of 200 IU daily, using alternat-ing nostrils. The only contraindica-tion to calcitonin is hypersensitivityto the drug. Do not use as a first-linetreatment for osteoporosis becauseother available medications have bet-ter efficacy in fracture reduction.

Consider prescribing teriparatide(synthetic recombinant parathyroid[PTH] 1-34) for treatment of patients at high risk for fracture, defined by the FDA as having a his-tory of osteoporotic fracture, multiplerisk factors for fracture, or failure ofor intolerance to other available os-teoporosis therapy. It is used at a doseof 20 µg, injected subcutaneously,once daily for 18 to 24 months forpatients at high risk for fracture. In-termittent PTH injections directlystimulate bone formation. Teri-paratide is the only osteoanabolicagent approved for the treatment ofosteoporosis. It has been associatedwith an increased risk for osteosarco-ma in rats given very large doses, butno such increased risk has been re-ported in humans treated accordingFDA recommendations.

How should patients bemonitored?Serial BMD measurements byDXA can be used to monitor forresponse to therapy. It is appropri-ate to measure BMD 12 to 24months after initiating or changingtherapy and periodically thereafter.Consider testing more frequently(e.g., every 6 months until stable)in conditions associated with rapidbone loss, such as glucocorticoidtherapy. In untreated patients, sig-nificant bone loss may influence adecision to initiate treatment (e.g.,treatment is indicated if a recalcula-tion of fracture risk with FRAXshows values that exceed the inter-vention thresholds or if the T-scoregoes to –2.5 or below). In treatedpatients, an increase or stability inBMD is considered an acceptableresponse to therapy that is associat-ed with a reduction in fracture risk.A significant loss of BMD usually

represents nonresponse or a subop-timum response to therapy, sug-gesting the need for reevaluation oftreatment and evaluation for sec-ondary causes of osteoporosis. Al-ways compare BMD (g/cm2), notT-score or Z-score when assessingchanges in BMD. In order to de-termine whether an apparentchange in BMD is statistically sig-nificant, the DXA facility must cal-culate the precision error and leastsignificant change according to es-tablished guidelines (3).

Consider serial measurement of abone turnover marker to evaluate ef-ficacy of drug therapy. Bone resorp-tion markers include urine andserum N-telopeptide, serum C-telopeptide, urine pyridinoline, andurine deoxypyridinoline, urine hy-droxyproline; bone formation mark-ers include serum osteocalcin, serumbone-specific alkaline phosphatase,and serum procollagen type 1 N-terminal propeptide. Bone turnovermarkers are biochemical byproductsof bone remodeling that providesome insight into the dynamicprocess of bone resorption and for-mation. In clinical trials, antiresorp-tive therapy is associated with a reduction in bone turnover markersand anabolic therapy is associatedwith an increase in bone turnovermarkers. However, due to “coupling”of resorption and formation due to“crosstalk” between osteoclasts andosteoblasts, markers of bone resorp-tion and formation usually change inthe same direction. Expert consensussuggests that markers of boneturnover provide potentially usefulinformation to supplement follow-up BMD measurement, and theNOF suggests measurement of abone turnover marker as a methodfor monitoring the effects of therapy(2). One way to use a bone markerto monitor therapy is to measure itat baseline before therapy and repeatabout 3 months later, obtaining thespecimen under identical circum-stances each time. A significant decrease in a bone turnover marker


43. Chesnut CH, III, Sil-verman S, AndrianoK, et al. A random-ized trial of nasalspray salmon calci-tonin in post-menopausal womenwith established os-teoporosis: the pre-vent recurrence ofosteoporotic frac-tures study. PROOFStudy Group. Am JMed. 2000;109:267-76.

44. Neer RM, ArnaudCD, Zanchetta JR, etal. Effect of parathy-roid hormone (1-34)on fractures andbone mineral densi-ty in post-menopausal womenwith osteoporosis. NEngl J Med.2001;344:1434-41.

45. Lewiecki EM. Riskcommunication andshared decisionmaking in the careof patients with os-teoporosis. J ClinDensitom.2010;13:335-45.

46. Khosla S, Burr D,Cauley J, et al. Bis-phosphonate-associ-ated osteonecrosisof the jaw: report ofa task force of theAmerican Society forBone and MineralResearch. J BoneMiner Res.2007;22:1479-89.

47. Shane E, Burr D,Ebeling PR, et al.Atypical sub-trochanteric and dia-physeal femoral frac-tures: report of atask force of theAmerican Society forBone and MineralResearch. J BoneMiner Res.2010;25:2267-94.


with antiresorptive therapy or a sig-nificant increase in a bone turnovermarker with anabolic therapy is sug-gestive of a beneficial effect of thera-py and predictive of a subsequentBMD response. There is high prean-alytic and analytic variability withbone markers, so that the changemust often be large to be consideredsignificant (e.g., the least significantchange for urinary N-telopeptide isabout 40%).

If measurement of BMD or a boneturnover marker does not show theexpected response, then evaluationfor contributing factors should beconsidered and corrected if possible(49). It should be determinedwhether the patient is taking med-ication regularly and correctly(which is particularly importantwith the oral bisphosphonates) andwhether calcium and vitamin D in-take is sufficient. Examples of dis-eases, conditions, and medicationsthat may result in a suboptimum re-sponse to therapy include malab-sorption, immobilization, and glu-cocorticoid therapy. When thefactors responsible for poor re-sponse cannot be corrected, achange may be necessary (e.g.,changing an oral bisphosphonate toan injectable antiresorptive agent, orswitching from an antiresorptiveagent to teriparatide).

When should consultation beconsidered for management?After the diagnosis of osteoporosis ismade, consider consultation if specialexpertise is needed for managementof associated disorders. These mayinclude hyperparathyroidism, hyper-thyroidism, vitamin D deficiency orosteomalacia, hypocalciuria unre-sponsive to oral calcium supplemen-tation, hypercalciuria, Cushing syn-drome, glucocorticoid-inducedosteoporosis, hypopituitarism, or hy-pogonadism in males. Elevated alka-line phosphatase levels or markedlyelevated bone turnover markers sug-gest an underlying metabolic bonedisease, such as Paget disease ofbone, metastatic disease, or recentfracture, that would benefit from ex-pert consultation.

Consider consultation with an os-teoporosis specialist when routinetherapy is not possible or effective,including significant bone loss after1 to 2 years of drug therapy, whencombination therapy for osteoporo-sis is being considered, or when thestandard therapies have not beentolerated. Consultation is also re-quired to manage patients withfractures, including vertebroplastyor kyphoplasty for painful acutespinal fractures resistant to medicaltherapy, or an orthopedist whensurgery may be required.

Treatment... Patients at high risk for fracture, identified by BMD testing and clini-cal risk factors, are most likely to benefit from medication to reduce fracture risk.The NOF suggests treating postmenopausal women and men 50 years and olderwho have a T-score of −2.5 or less at the lumbar spine or femoral neck, thosewho have had a hip or vertebral fracture, and those with a T-score between −1.0and −2.5 who have a 10-year FRAX probability of major osteoporotic fracture ≥20% or a 10-year probability of hip fracture ≥ 3%. The selection of the best drugfor the patient should be individualized according to clinical circumstances andconsidering factors that include the magnitude of fracture risk, comorbid condi-tions, and patient preference. All patients should be counseled on the importanceof a healthy lifestyle and adequate intake of calcium and vitamin D. Monitoringfor treatment effect with BMD testing and/or bone turnover markers assures thatthe patient is responding to therapy. Patients with suboptimum response shouldbe evaluated for factors contributing to poor skeletal health and considered for achange in therapy.



48. Black DM, SchwartzAV, Ensrud KE, et al.Effects of continuingor stopping alen-dronate after 5 yearsof treatment: theFracture Interven-tion Trial Long-termExtension (FLEX): arandomized trial.JAMA.2006;296:2927-38.

49. Lewiecki EM. Nonre-sponders to osteo-porosis therapy. JClin Densitom.2003;6:307-14.

50. Gillespie LD, Robert-son MC, Gillespie WJ,et al. Interventionsfor preventing fallsin older people liv-ing in the communi-ty. Cochrane Data-base Syst Rev.2009;CD007146.

51. Clowes JA, Peel NF,Eastell R. The impactof monitoring onadherence and per-sistence with antire-sorptive treatmentfor postmenopausalosteoporosis: a ran-domized controlledtrial. J Clin En-docrinol Metab.2004;89:1117-23.]

52. National Committeefor Quality Assur-ance. The state ofhealth care quality.Accessed atwww.ncqa.org/por-tals/0/state%20of%20health%20care/2010/SOHC%202010%20-%20Full2.pdf on 7March 2011.


of patients with osteoporosis.Home safety evaluations, whichcan be done by occupationaltherapists or home health careservices, may be helpful to assessfor potential physical or structur-al problems that might causefalls. Concerns, such as slipperyfloors and and impeded path-ways, should also be identifiedand corrected.

Falls in the elderly can be reduced with acomprehensive fall-reduction program,including home safety evaluations, exer-cises that improve strength and balance,and reduction in the use of drugs that im-pair cognitive abilities (50). Sources of pa-tient education may include one-on-oneinstruction; community resources; con-sultation with nutritionists, physical ther-apists, and exercise physiologists; hand-outs; and the Internet. After startingtherapy, patient education through regu-lar contact with a health care profession-al has been shown to improve adherenceto therapy and be associated with agreater increase in BMD compared withno monitoring (51).

What should patients be taught?Patients should be informed aboutthe association between low BMDand fracture risk. They should un-derstand the importance of adequatecalcium and vitamin D intake, asthe maximum beneficial effects ofall drugs for osteoporosis are seen incalcium- and vitamin D–repletepersons. The role of weight-bearingexercise in maintaining bone massshould be explained. Patients shouldbe told of the importance of avoid-ing or changing certain habits thatmay detrimentally affect bone mass,such as smoking and excess alcoholconsumption. The benefit and po-tential risks of pharmacologic agentsfor the prevention and treatment ofosteoporosis should be discussed. Inpatients treated with oral bisphos-phonates, precise dosing instructionsneed to be followed.

How can falls and bone fracturesbe prevented?Risk factor modification is a keyelement in successful management

Patient Education... A well-informed patient is best equipped to make appropriatedecisions on lifestyle and nutrition to optimize skeletal health. Understanding theconsequences of osteoporosis and the balance of benefits and risks of pharmaco-logic therapy may lead to improved clinical outcomes.


PracticeImprovementare the number of Medicare

women aged 65 years and olderwho report ever having a BMD test for osteoporosis (“testing rate”)and the percentage of women aged67 years and older who had aBMD test or prescription for adrug to treat or prevent osteoporo-sis within 6 months of a fracture.(“treatment rate”). The NCQA re-ported an osteoporosis testing rateof 68.0% and a treatment rate of20.7% for 2009 (52), suggestingthat there is much room for im-provement in reducing the burdenof osteoporotic fractures.

What measures do U.S.stakeholders use to evaluate thequality of osteoporosis care?The Healthcare Effectiveness Dataand Information Set (HEDIS) is aset of performance measures developed and maintained by theNational Committee for QualityAssurance (NCQA), an independ-ent 501(c)(3) nonprofit organiza-tion. HEDIS measures are widelyused in managed care and by theCenters for Medicare & MedicaidServices to improve health carequality in the United States. TheHEDIS measures for osteoporosis

PatientEducation


53. Assessment of frac-ture risk and its ap-plication to screen-ing for postmeno-pausal osteoporosis.Report of a WHOStudy Group. WorldHealth Organ TechRep Ser. 1994;843:1-129.

54. National Osteoporo-sis Foundation. Clini-cian’s Guide to Pre-vention andTreatment of Osteo-porosis. Washington,DC: National Osteo-porosis Foundation;2008.

Inthe

C linicTool Kit

In the Clinic

Osteoporosis

PIER Modulehttp://pier.acponline.org/physicians/diseases/d297/d297.htmlPIER module on osteoporosis. PIER modules provide evidence-based,

updated information on current diagnosis and treatment in an electronicformat designed for rapid access at the point of care.

Patient Informationhttp://pier.acponline.org/physicians/diseases/d297/d297-pi.htmlPatient information that appears on the following page for duplication and

distribution to patients.www.effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-and

-reports/?pageaction=displayproduct&productID=92A consumer guide for postmenopausal women from the Agency for

Healthcare Research and Quality, released in 2008.

Clinical Guidelineswww.annals.org/content/149/6/404.fullClinical practice guideline for the pharmacologic treatment of low BMD or

osteoporosis to prevent fractures from the ACP.www.aace.com/sites/default/files/OsteoGuidelines2010.pdfClinical practice guideline for the diagnosis and treatment of postmenopausal

osteoporosis from the American Association of Clinical Endocrinologists.

Diagnostic Tests and Criteria/Quality-of-Care Guidelineswww.uspreventiveservicestaskforce.org/uspstf10/osteoporosis/osteors.htmRecommendations for screening for osteoporosis in postmenopausal women,

from the US Preventive Services Task Force.www.qualitymeasures.ahrq.gov/search/search.aspx?term=osteoporosisGuidelines available from the National Quality Measures Clearinghouse.

5 July 2011Annals of Internal MedicineIn the ClinicITC1-14© 2011 American College of Physicians

femoral neck BMD, if available.Evidence-based treatment recom-mendations have been developedfor the United States by the NOF(54). Treatment with pharmacolog-ic agents should be considered in apostmenopausal woman or managed 50 years and older with a T-score of −2.5 or less at the femoralneck or lumbar spine, a history offracture of the hip or spine, or a T-score between −1.0 and −2.5 with aFRAX 10-year probability of hipfracture that is 3% or greater or a10-year probability of major osteo-porotic fracture that is 20% orgreater. Treatment decisions for in-dividual patients should be basedon all available clinical informationin addition to clinical practiceguidelines.

What do professionalorganizations recommendregarding care?Osteoporosis is diagnosed accord-ing to WHO criteria (53) based onBMD measurement by DXA usingquality standards established by theISCD (3). A T-score of –2.5 or lessat the lumbar spine, femoral neck,total hip, or 33% radius (if meas-ured) in a postmenopausal womanor man aged 50 years or older isconsistent with a diagnosis of os-teoporosis. The 10-year probabilityof hip fracture and major osteo-porotic fracture can be estimatedusing the WHO fracture risk algo-rithm, FRAX (6), with input thatincludes the patient’s age, sex,height, weight, information on 7clinical risk factors for fracture, and

Practice Improvement... Despite the availability of excellent clinical tools to as-sess fracture risk and widely available drugs to reduce fracture risk, osteoporosisremains underdiagnosed and undertreated. Familiarity with clinical practiceguidelines for the evaluation and treatment of osteoporosis can lead to improvedclinical outcomes with reduced burden of osteoporotic fractures.



In the ClinicAnnals of Internal Medicine

Pati

ent

Info

rmat

ion

THINGS YOU SHOULDKNOW ABOUTOSTEOPOROSIS

What is osteoporosis?• Osteoporosis is a disease that makes bones weak

and susceptible to fractures (broken), even whenthere has been no trauma or only a low level oftrauma that would not cause a normal bone tobreak.

• Osteoporosis can be diagnosed before a fractureoccurs with a bone mineral density (BMD) test usingdual-energy x-ray absorptiometry (DXA).

• If a low-trauma fracture occurs in a postmenopausalwoman or a man aged 50 or older, a presumptivediagnosis of osteoporosis may be made regardless ofBMD.

Why is it important?• About 44 million Americans have osteoporosis or

low bone mass (osteopenia) that could lead to low-trauma fractures.

• A 50-year-old white woman has a 50% chance ofhaving an osteoporotic fracture in her remaininglifetime, and a man the same age has about a 20%chance.

• The risk for osteoporotic fractures is high in whites,low in blacks, and intermediate in Hispanics andAsians, although individuals of any ethnicity candevelop osteoporosis and have fractures.

• Osteoporotic fractures can result in chronic pain,disability, loss of independence, and increased riskfor death.

How is it treated?• All adults should take care to be physically active

and maintain an adequate amount of calcium andvitamin D.

• A daily intake of about 1200 mg calcium in the dietplus supplements, if needed, and vitamin D 800 to1000 IU is recommended.

• In the frail elderly, fall prevention measures includean evaluation of the home to look for ways toreduce the risk for falls, leg-strengthening exercises,and balance training.

• Medications are helpful to reduce fracture risk whenit is high.

For More Information

www.nof.orgNational Osteoporosis Foundation: information, education, and

support for people with osteoporosis in the United States.

www.iof.orgInternational Osteoporosis Foundation: information and

education on osteoporosis from a worldwide perspective.

www.iscd.orgInternational Society for Clinical Densitometry: information on

the role of high quality BMD testing in the care of people withosteoporosis.


CME Questions

5 July 2011Annals of Internal MedicineIn the ClinicITC1-16© 2011 American College of Physicians

Questions are largely from the ACP’s Medical Knowledge Self-Assessment Program (MKSAP, accessed at http://www.acponline.org/products_services/mksap/15/?pr31). Go to www.annals.org/intheclinic/

to complete the quiz and earn up to 1.5 CME credits, or to purchase the complete MKSAP program.

1. A 72-year-old man is evaluated for a 2-week history of low back pain. The patienthas a history of alcoholism but stoppeddrinking alcohol 10 years ago. He also hasstage 3 chronic kidney disease and a 50-pack-year smoking history. Currentmedications are hydrochlorothiazide,ramipril, and a multivitamin.

On physical examination, vital signs arenormal. Lumbar lordosis, decreasedmobility and spasm of the paravertebralmuscles, and tenderness to palpation atL4-L5 are noted. Neurologic screeningexamination findings are normal.Laboratory studies showed the following:calcium, 9.0 mg/dL (2.25 mmol/L),creatinine, 2.1 mg/dL (185.6 µmol/L),phosphorus, 3.2 mg/dL (1.0 mmol/L),parathyroid hormone, 50 pg/mL (50 ng/L),testosterone, 400 ng/dL (13.9 nmol/L),25-hydroxy vitamin D, 34 ng/mL (85nmol/L), estimated glomerular filtrationrate, 40 mL/min/1.73 m2.

A radiograph of the lumbosacral spineshows a compression fracture of L4. Adual-energy x-ray absorptiometry scanshows a T-score of –3.0 in thelumbosacral spine and –3.2 in the lefthip.

Which of the following is the besttreatment for this patient?

A. AlendronateB. CalcitoninC. TeriparatideD. Testosterone

2. A 58-year-old man is evaluated forpossible osteoporosis. He recentlyunderwent removal of a 1.6-cmnonfunctioning pituitary adenoma andwas placed on levothyroxine therapy.

On physical examination, vital signs arenormal. Examination of the neck revealsno palpable goiter. The testes are smalland soft. Laboratory studies showed thefollowing: follicle-stimulating hormone,<1.0 mU/mL (1.0 U/L), luteinizinghormone, <1.0 mU/mL (1.0 U/L),testosterone, 50 ng/dL (1.7 nmol/L),

thyroxine (t4), free , 1.2 ng/dL (15.5

pmol/L). A dual-energy x-rayabsorptiometry scan shows T-scores of–2.5 in the left hip and –2.6 in thelumbar spine.

In addition to calcium and vitamin Dsupplementation, which of the followingis the most appropriate initial treatmentfor this patient?

A. BromocriptineB. CalcitoninC. Decreased dosage of levothyroxineD. Testosterone

3. A 62-year-old woman is evaluated duringa follow-up visit for hypertension. She hasno complaints and is monogamous withher husband of 35 years. Her only currentmedication is hydrochlorothiazide. Onphysical examination, blood pressure is136/72 mm Hg and weight is 62 kg (136lb). Physical examination is normal. Totalcholesterol is 188 mg/dL (4.87 mmol/L)and HDL cholesterol is 54 mg/dL (1.40mmol/L). She received an influenzavaccination 3 months ago and a herpeszoster vaccination 1 year ago. Her last Papsmear was 14 months ago and it wasnormal, as were the previous three annualPap smears.

Which of the following is the mostappropriate health maintenance optionfor this patient?

A. Abdominal ultrasonographyB. Dual-energy x-ray absorptiometryC. Pap smearD. Pneumococcal vaccine

4. A 70-year-old woman is evaluated forworsening gastroesophageal refluxdisease with heartburn. She first noticedthis symptom 1 month ago when shebegan taking alendronate, 70 mg orallyonce weekly, for osteoporosis. Currentmedications are alendronate, calcium,and ergocalciferol.

A dual-energy x-ray absorptiometry scanreveals a T-score of –3.0 in the lumbarspine and –2.5 in the left hip.

After the alendronate is discontinued,which of the following is now the mostappropriate treatment for this patient?

A. CalcitoninB. Intravenous ibandronateC. Intravenous zoledronateD. Raloxifene

5. A 72-year-old woman comes to theoffice for a follow-up evaluation ofosteoporosis. She has a history ofvertebral compression fractures. For thepast 5 years, the patient has been takingoral formulations of elemental calcium,1500 mg/d; ergocalciferol, 800 U/d; andalendronate, 70 mg once weekly. She isadherent to her therapy.

On physical examination, the patientappears frail. Vital signs are normal, andBMI is 19. There is obvious kyphosis. Mildtenderness in the region of the priorcompression fractures is noted.

Laboratory studies showed the following:calcium , 9.5 mg/dL (2.4 mmol/L),phosphorus, 3.8 mg/dL (1.2 mmol/L),parathyroid hormone, 33 pg/mL (33 ng/L),thyroid-stimulating hormone, 1.8 µU/mL(1.8 mU/L), 25-hydroxy vitamin d, 35ng/mL (87 nmol/L), urine calcium, 315mg/24 h (7.9 mmol/24 h).Results of abone mineral density study show T-scoresof −3.8 in the spine and −3.7 in the hip,compared with scores obtained 3 yearsago of −3.4 and −3.3, respectively.

Which of the following is the best nextstep in management?

A. Add teriparatideB. Change to high-dose ergocalciferolC. Discontinue the alendronate and

start teriparatideD. Substitute intravenous zoledronate

for the alendronate


In the Clinic Osteoporosis In theClinic

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