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Selected

Instructional

Course Lectures

The American Academy of Orthopaedic Surgeons

FREDERICK M. AZAREDITOR, VOL. 58

COMMITTEE

FREDERICK M. AZARCHAIRMAN

PAUL J. DUWELIUSKENNETH A. EGOLMARY I. O’CONNORPAUL TORNETTA III

EX-OFFICIO

DEMPSEY S. SPRINGFIELDDEPUTY EDITOR OF THE JOURNAL OF BONE AND JOINT SURGERY

FOR INSTRUCTIONAL COURSE LECTURES

JAMES D. HECKMANEDITOR-IN-CHIEF,

THE JOURNAL OF BONE AND JOINT SURGERY

Printed with permission of the American Academy ofOrthopaedic Surgeons. This article, as well as other lecturespresented at the Academy’s Annual Meeting, will be availablein February 2009 in Instructional Course Lectures, Volume 58.The complete volume can be ordered online at www.aaos.org,or by calling 800-626-6726 (8 A.M.-5 P.M., Central time).

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Osteoporosis: Management and TreatmentStrategies for Orthopaedic Surgeons

By Laura Gehrig, MD, Joseph Lane, MD, and Mary I. O’Connor, MD

An Instructional Course Lecture, American Academy of Orthopaedic Surgeons

The purpose of this lecture is toprovide orthopaedic surgeons with aguide for osteoporosis managementand treatment that may be used inthe practice setting. Fracture preven-tion is the key efficacy end point inthe medical management of osteopo-rosis for any patient. Enhancementof bone mass and improvement ofbone quality are achieved by acombination of lifestyle modification,dietary supplementation withcalcium and vitamin D, and pharma-cologic treatment. This strategyhas proved effective for theprevention and treatment ofosteoporosis.

The orthopaedic surgeon is ina unique position to identify patientswith osteoporosis. As the orthopaedicsurgeon is often the only physician tosee a patient who has sustained afracture, he or she must make everyeffort to determine if the injury is afragility fracture so that the patientcan be treated to prevent futurefractures.

TreatmentNonpharmacologic TreatmentA multidisciplinary approach is essen-tial in the treatment of osteoporosis.Nonpharmacologic treatments are usedto complement pharmacologic therapyand thus optimize fracture risk reduc-tion. Commonly used nonpharmaco-logic interventions include calcium andvitamin-D supplementation, fall pre-vention, hip protectors, and balance andexercise programs.

Calcium SupplementationOptimal bone health depends on ade-quate calcium. A normal calcium statusis defined as a corrected serum calciumlevel of 9.5 to 10.5 mg/dL (2.4 to 2.6mmol/L). The National OsteoporosisFoundation recommends a daily cal-cium intake of 1000 mg/day for menand women under the age of fifty yearsand 1200 mg/day for men and womenover the age of fifty years1. Since atypical American woman consumesapproximately 600 mg of calciumthrough diet alone, supplementation is

indicated for the majority of patients.Supplementary calcium is available intwo forms, calcium carbonate andcalcium citrate. Calcium citrate is thepreferred form. The use of calciumcarbonate by individuals with a physi-ologic or pharmacologically inducedreduction in acid production results insuboptimal calcium absorption, as cal-cium carbonate requires a low pH forsalt dissociation2. The incidence of kid-ney stones is decreased in patientstaking supplemental calcium citrate in-stead of calcium carbonate as citratebinds to oxalate, reducing its intestinalabsorption. In an effort to optimizeabsorption, total daily calcium supple-mentation should be divided through-out the day with individual doseslimited to £500 mg3.

Vitamin DOrthopaedic surgeons know that vitaminD plays a critical role in promotingabsorption of calcium from the gut andthat insufficient absorption results inlower serum calcium levels. These lower

Disclosure: The authors did not receive any outside funding or grants in support of their research for or preparation of this work. One or more of theauthors, or a member of his or her immediate family, received, in any one year, payments or other benefits of less than $10,000 or a commitment oragreement to provide such benefits from commercial entities (Glaxo, Roche, P&G, Lilly, Aventis, and Novartis). Also, commercial entities (Glaxo, Roche,P&G, Lilly, Aventis, and Novartis) paid or directed in any one year, or agreed to pay or direct, benefits of less than $10,000 to a research fund, foundation,division, center, clinical practice, or other charitable or nonprofit organization with which the authors, or a member of their immediate families, areaffiliated or associated.

J Bone Joint Surg Am. 2008;90:1362-74

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TH E J O U R N A L O F B O N E & JO I N T SU R G E RY d J B J S . O R G

VO LU M E 90-A d NU M B E R 6 d J U N E 2008OS T E O P O R O S I S : MA N AG E M E N T A N D TR E AT M E N T

ST R AT E G I E S F O R OR T H O PA E D I C SU R G E O N S

levels trigger the release of parathyroidhormone, which mobilizes calcium frombone (secondary hyperparathyroidism),ultimately resulting in osteopenia andeventually osteoporosis. Recent studieshave also indicated that patients withosteoarthritis can have osteoporosis aswell as vitamin-D deficiency4.

Vitamin-D deficiency has beenshown to increase the risk of falls by theelderly5-7. In a recent randomized con-trolled trial, the impact of a high dose ofvitamin D on nursing home residents’risk of falling was compared with that ofa placebo over a five-month period6.The researchers found a 72% reductionin the risk of falls for individuals given800 IU of vitamin D2 plus calciumcompared with those who received aplacebo. Moreover, severe vitamin-Ddeficiency is associated with persistent,nonspecific musculoskeletal pain8.

Beyond the musculoskeletal sys-tem, vitamin D influences many otherorgan systems (the brain, heart, gut,skin, pancreas, and immune system).These organs have cells with vitamin-Dreceptors and may even express theenzyme to convert vitamin D to itsactive form9. Furthermore, insufficientvitamin D has been associated withtype-1 diabetes, multiple sclerosis,Crohn disease, hypertension, cardio-vascular disease, schizophrenia, depres-sion, rheumatoid arthritis, andosteoarthritis10. With insufficient vita-min D, the serum level of calcium is alsoat risk of being insufficient. This couplesthe physiologic state of low calcium andvitamin D to these diseases and to theskeleton of those who have these dis-eases. The skeletons of those with thesediseases are at risk for low bone density,osteoporosis, and fracture.

Sources of Vitamin DVitamin D can be obtained from threesources: exposure of skin to sunlightof adequate ultraviolet strength, diet(such as salmon, tuna, sardines, and codliver oil) including fortified foods(breakfast cereals, milk, some orangejuices, and yogurts), and dietary sup-plements. Synthesis of vitamin D fromthe skin occurs with exposure of7-dehydrocholesterol, a lipid in the

dermis, to pre-vitamin D3. Approxi-mately one to fifteen minutes of sunexposure to the hands and arms two orthree days per week is thought to beadequate. However, the intensity of thesunlight is critical. In northern latitudessuch as Boston and Seattle, there is novitamin production from Novemberthrough February regardless of thelength of sun exposure11. In Los Angelesand Atlanta, vitamin-D3 synthesis isadequate throughout the year. Use ofsunscreen dramatically reduces vita-min-D3 synthesis, with 99% eliminatedwith the use of a sunscreen with a sunprotection factor (SPF) of 15 and 92.5%eliminated with use of a SPF-8 sun-screen9,12. Synthesis is decreased, po-tentially by as much as 99%12, inindividuals with dark skin pigmenta-tion. Furthermore, the epidermis thinswith aging. Lipid content is lost with aresultant estimated 75% reduction invitamin-D synthesis in a person who isseventy years old9.

Dietary supplements, therefore,are a very important source of vitaminD. Both vitamin D2 (usually labeled ascalciferol or ergocalciferol) and vitaminD3 (usually labeled as cholecalciferol)are used in over-the-counter supple-ments, but the form available by pre-scription in the United States is vitaminD210. Vitamin D3 is the preferredform, as vitamin D2 is only approxi-mately 30% as effective in maintainingserum 25-hydroxyvitamin-D levels13,14.If vitamin D2 is used, up to three timesas much of the vitamin may berequired10.

Vitamin-D Supplements and Risk of FractureIt is well established that many patientswith osteoporosis or a history of afragility fracture have suboptimal levelsof vitamin D. Furthermore, the preva-lence of low vitamin-D levels is greater inindividuals in nursing homes than inthose living in the community. A meta-analysis of studies in which individualswere given 400 IU of vitamin D3 per dayshowed little benefit in terms of reduc-tion of hip or vertebral fractures. How-ever, higher doses of vitamin D havebeen found to have benefits. In individ-uals with inadequate vitamin-D levels of

17 ng/mL (42.4 nmol/L), 700 to 800 IUof vitamin D per day resulted in a meanincrease in vitamin-D levels of approxi-mately 40 ng/mL (99.8 nmol/L) and areduction in the prevalence of bothnonvertebral and vertebral fractures5.

Ethnic differences have also beenobserved relative to vitamin D andfragility fractures. In a series of eighty-five patients with acute fragility frac-tures, black and Hispanic patients weresignificantly younger than whites (p <0.001) and more likely to have seriouscomorbidities such as diabetes or hy-pertension. Perhaps of even greaterinterest is the fact that, despite signifi-cantly higher bone mineral densityvalues (p < 0.01), blacks had the highestrate of vitamin-D deficiency and sec-ondary hyperparathyroidism15.

Recommendations for Vitamin-DSupplementationThe current recommendations from theInstitute of Medicine are 200 IU dailyfrom birth to the age of fifty years, 400IU daily for adults fifty-one to seventyyears of age, and 600 IU daily for thoseseventy-one years of age and older16.Many experts in the field consider theserecommendations to be too low andbelieve that the minimum adult intakeshould be 800 to 1000 IU daily.

Higher doses of vitamin D arerequired to replenish depleted totalbody stores. Fifty thousand interna-tional units of ergocalciferol (vitaminD2) can be taken orally twice a week forsix to eight weeks, followed by a main-tenance dose of 1000 IU per day.Toxicity, even with these higher doses,is very rare. Doses of up to 10,000 IUper day for up to five months have notcaused toxicity17.

Evaluation of the vitamin-D levelfollowed by treatment if a deficiency isfound is now part of the managementof osteoporosis. This is essential asvitamin-D deficiency is completelypreventable and reversible.

LifestyleLifestyle evaluation is an importantcomponent of the comprehensivetreatment for osteoporosis. In additionto encouraging smoking cessation and

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moderation of alcohol consumption,physicians should also counsel patientsabout fall prevention and appropriateexercise training to further reduce therisk of fracture.

Fall Prevention and Hip ProtectorsThe evaluation of osteoporotic patients’risk of falling and the initiation ofappropriate intervention are importantfor fracture prevention. Fracture pre-vention is most effective when bothintrinsic and environmental risk factorsfor a fall are taken into consideration.Physicians should limit sedative medi-cations when possible, recommendregular weight-bearing exercise, con-sider physical and occupational therapyfor fall prevention, and facilitate envi-ronment modification such as the in-stallation of assistive devices in thehome. In addition, clinicians may en-courage their patients to wear hipprotectors, which effectively attenuateforce from a fall and are associated with>50% reductions in the risk of hipfracture as well as improvement in thepatient’s self-confidence that they canavoid a fracture if they fall2,18. However,compliance is low as many patients findhip protectors difficult to manipulatewhen they dress and undress2.

Balance, Posture, and Exercise TrainingOsteoporotic patients are likely to ben-efit from programs that target balance,posture, and strength. Balance trainingprograms are ass-ociated with an ap-proximate 50% reduction in the inci-dence of falls. Postural exerciseprograms have been shown to increaseback extensor strength. Activities suchas tai chi may be particularly helpful,with intense training programs reduc-ing the risk of falls in elderly popula-tions by as much as 47%19. Carefulattention must be paid to identifyingappropriate weight-bearing activities, asfragile patients with severe osteoporosisare known to sustain new fracturesduring routine activities such as bend-ing over and turning in bed18.

Pharmacologic TreatmentThe pharmacologic agents currentlyavailable are commonly divided into

two classes, antiresorptive and anabolic.Antiresorptive agents such as the bis-phosphonates limit bone resorptionthrough inhibition of osteoclast activity.The anabolic agent parathyroid hor-mone promotes active building of bonemass. Both antiresorptive and anabolicagents have demonstrated antifractureefficacy in randomized clinical trials18.

Antiresorptive AgentsThe antiresorptive agents currentlyapproved for use in patients withosteoporosis include calcitonin, hor-mone replacement therapy, selectiveestrogen receptor modulators, andbisphosphonates.

CalcitoninCalcitonin effectively inhibits bone re-sorption by decreasing osteoclast for-mation and activity20,21. Calcitonin actsquickly. Its effects are reversible andtransient. This is likely due to its rapidclearance from the body and desensi-tization and internalization of thecalcitonin receptor with prolongedexposure21,22. Calcitonin has beenapproved by the U.S. Food and DrugAdministration for treatment of estab-lished osteoporosis but not for preven-tion of postmenopausal osteoporosis. Itis available as both a parenteral injectionand nasal spray. The intranasal formu-lation of calcitonin is the most widelyprescribed because of its ease of use andsuperior tolerability21.

Nasal calcitonin has proven todecrease bone turnover and modestlyincrease bone mineral density over oneto five years20,21. Despite this increase,gains in bone mineral density are notmaintained after discontinuation oftreatment21. The efficacy of calcitonin inreducing the risk of vertebral fractureswas best examined in the PROOF(Prevent Recurrence of OsteoporoticFractures) study20. This five-year,double-blind, randomized, placebo-controlled study of 1255 postmeno-pausal osteoporotic women showedthat treatment with 200 IU of nasalcalcitonin daily reduced the risk of newvertebral fractures by 33% as comparedwith the risk in individuals taking aplacebo. The effects of calcitonin treat-

ment on the risks of hip and othernonvertebral fractures remain uncer-tain20,21. The fact that calcitonin sub-stantially reduces the risk of vertebralfracture with only modest increases inbone mineral density suggests that yet tobe elucidated calcitonin-mediated en-hancement of bone quality may con-tribute to fracture risk reduction22. Inaddition to its antiresorptive action,patients with painful new vertebralcompression fractures who were treatedwith calcitonin had, by two weeks,reduced pain, consumed fewer tradi-tional analgesic medications, and re-gained mobility sooner, which mayreduce bone loss secondary to pro-longed bed rest21,23. Calcitonin-inducedanalgesia may be mediated by increasesin plasma b-endorphins. This impli-cates involvement of the endogenousopiate system, while animal studiesdemonstrating calcitonin-binding sitesin brain areas involved in pain percep-tion suggest that calcitonin may directlymodulate nociception in the centralnervous system23.

Hormone Replacement TherapyEstrogen formulations were approvedby the U.S. Food and Drug Adminis-tration for use in prevention of osteo-porosis, but not for treatment ofosteoporosis. Estrogen, both with andwithout progestin, has consistently beenshown to not only maintain, but alsoincrease, bone mineral density24,25. TheWomen’s Health Initiative (WHI) clin-ical trials of hormone replacementtherapy showed that long-term therapywith estrogen alone reduced the rate ofhip, clinical vertebral, and total osteo-porotic fractures by 30% to 39% ascompared with the rates in patientstaking a placebo26. Fracture reductionrates of a similar magnitude were foundamong participants randomized to re-ceive long-term treatment with estrogenplus progestin. Hip and clinical verte-bral fracture rates were reduced by 34%.Total osteoporotic fracture rates werereduced by 24% when compared withthe rates in patients taking a placebo25-27.While the majority of studies and meta-analyses support the bone health bene-fits of hormone replacement therapy,

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some studies, most notably the Heartand Estrogen/Progestin ReplacementStudy (HERS), have not demonstratedevidence of fracture risk reduction inwomen similarly treated with hormonereplacement therapy25,28,29. However,HERS had limited power to detectfracture risk reduction; it was able todetect only large reductions of at least80%25.

While improvements in bonemineral density and reductions in therate of fracture occur, the associatedrisks of treatment preclude the use ofestrogen formulations as primary agentsin the treatment of osteoporosis.Women treated with estrogen alonehave no change in the incidence ofcoronary heart disease; however, theyhave been found to have increased ratesof stroke and deep vein thrombosis27,29,30.In addition, estrogen plus progestinincreases the risk of breast cancer,dementia, and gallbladder disease27,29,31.The risks for cardiovascular disease,breast cancer, and dementia far exceedthe benefits of estrogen and estrogenplus progestin therapy with respect toosteoporosis. This is true even forwomen at greatest risk for osteoporoticfracture26. This unfavorable safety pro-file restricts use of hormone replace-ment therapy for osteoporotic patients.However, women receiving short-termhormone replacement therapy formenopausal symptoms are likely to reapadditional benefits with regard to bonehealth. Referral to a primary care phy-sician or a gynecologist is the safestapproach if hormone replacementtherapy is planned.

Selective Estrogen Receptor ModulatorsSelective estrogen receptor modulatorsare a class of compounds that bindestrogen receptors. They act as estrogenreceptor agonists in some tissues and asestrogen receptor antagonists in others.Of the selective estrogen receptor mod-ulators currently approved for clinicaluse, only raloxifene has been approvedfor the prevention and treatment ofosteoporosis32. The effects of raloxifeneon bone are known. Raloxifene hasconsistently proven to increase bonemineral density in the lumbar spine and

femoral neck by 2% to 3% and tomoderately decrease levels of bone-turnover markers by 30% to 40% (levelscomparable with mean levels found inpremenopausal women), suggesting anantiresorptive effect on bone tissue33-35.More importantly, raloxifene has alsobeen shown to reduce the risk ofvertebral fracture34,35. However, reduc-tions in the overall risk of nonvertebralfractures did not reach significance34-36.The effect of raloxifene on fracturereduction is greater than what would beexpected in light of the modest increasesin bone mineral density. This suggeststhat raloxifene may also contribute toimprovements in other components ofbone quality34.

As a result of raloxifene’s selectiveestrogen receptor antagonist propertiesin breast tissue, women treated withraloxifene also benefit from a 62%reduction in the incidence of all types ofbreast cancer, with a 72% reduction inthe risk of invasive breast cancer and an84% reduction in the risk of invasiveestrogen receptor-positive breast can-cer28. Additionally, raloxifene is notassociated with an increased risk ofendometrial cancer28. The risk of venousthromboembolic events is increasedthreefold, which is comparable with theelevated risk seen with hormone re-placement therapy. Use of raloxifene alsoincreases the incidence of vasomotorsymptoms and may increase the risk offatal stroke34,37. Clinicians must weigh thebenefits of the reduced risks of vertebralfracture and invasive breast canceragainst the increased risks of venousthromboembolism and fatal stroke whenconsidering osteoporosis management.

Tamoxifen, a selective estrogenreceptor modulator approved for use forthe prevention and treatment of breastcancer, has been associated with reduc-tions in the risk of vertebral fracture of amagnitude similar to those seen withraloxifene38-40. However, the greater riskof venous thromboembolism impartedby tamoxifen, as compared with thatassociated with raloxifene, and its asso-ciation with an increased risk of en-dometrial cancer preclude its use inthe treatment of postmenopausalosteoporosis32,38-40.

BisphosphonatesThe bisphosphonates, a class of anti-resorptive agents, are the current cor-nerstone of osteoporosis treatment andprevention. These nitrogen-containingcompounds bind to the bone surface.There they exert their effect on the bonereabsorbing osteoclasts, decreasing os-teoclastic activity and reducing cellularlife span. Treatment with bisphospho-nates reduces the rate of bone resorp-tion, increases bone mineral density,and improves trabecular connectivity.These resultant effects serve to improvebone strength and reduce fracture risk.Both oral and intravenous forms of thetreatment exist.

Currently, four bisphosphonateshave been approved by the U.S. Foodand Drug Administration for the treat-ment of postmenopausal osteoporosis:alendronate (Fosamax), risedronate(Actonel), ibandronate (Boniva), andzoledronic acid (Reclast). These drugsdiffer in their potency, dosing schedules,and mode of administration. All havebeen shown to possess antifractureefficacy. Placebo-controlled trials in-volving postmenopausal women treatedwith one of these agents have demon-strated reductions in the risk of verte-bral fractures, ranging from 45% to70%, relative to the risks for patientstaking a placebo.

Alendronate, an oral bisphospho-nate currently given in doses of 70 mg/wk for the treatment of osteoporosis,has been shown to increase bone min-eral density in the spine, hip, and femuras well as to reduce the risk of fractureby an average of 50%41. Women withlow bone mineral density and a historyof vertebral fracture treated with dailyalendronate for three years had a 47%reduction in the risk of vertebral frac-ture compared with the risk for thosetreated with a placebo41. Participantswithout a prior vertebral fracture had areduction in the risk of a future verte-bral fracture of 44%42. A meta-analysisof studies involving the effect ofalendronate on the risk of hip fracturedemonstrated an overall risk reductionof 45%43. Alendronate therapy hasproven efficacious in the treatment ofosteoporosis in men. Bone mineral

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density in the hip, spine, and total bodyis increased. The risk of vertebral frac-ture is decreased44. These antifractureeffects of alendronate have been ob-served as early as one year after theinitiation of therapy and have persistedten years into the treatment period.Concerns regarding prolonged treat-ment are beginning to arise, as de-scribed below45. In a twelve-monthhead-to-head trial comparing two bis-phosphonates, alendronate and rise-dronate (discussed below), patients inthe alendronate group were found tohave greater gains in bone mineral den-sity and reductions in bone-turnovermarkers46. However, another studycomparing the two agents failed toshow any significant difference47,48.

Risedronate, an oral bisphospho-nate given in doses of 35 mg/wk, hasalso been shown to increase bone min-eral density and reduce the risk ofvertebral, nonvertebral, and hip frac-tures in osteoporotic women. In theplacebo-controlled Vertebral Efficacywith Risedronate Therapy (VERT)study, daily treatment of postmeno-pausal women with osteoporosis (asdefined by the previous occurrence of avertebral insufficiency fracture) with 5mg of risedronate decreased the cumu-lative incidence of new vertebral frac-tures by 41% and reduced the incidenceof nonvertebral fractures by 39%49. Areduction of vertebral fracture risk of upto 61% has been found after only oneyear of treatment50. In another study,specifically assessing the effect ofrisedronate on the risk of hip fracture,that risk was found to be reduced by30% compared with that associatedwith a placebo51.

Ibandronate, one of the newerbisphosphonates made popular byits monthly (150-mg) oral dosing sched-ule and monthly intravenous (3-mg)formulation option, confers similarantiosteoporotic effects. As withalendronate and risedronate, patientstreated with ibandronate have substan-tial increases in bone mineral density atall sites. In addition, they have decreasesin vertebral fracture risk. However,ibandronate’s anti-hip-fracture efficacyis still to be shown52,53. If compliance is

an issue, ibandronate may be a usefuloption in certain patient groups. Patientcompliance with weekly dosing regi-mens remains suboptimal, with ratesranging from 58% to 76% at one year54.If patient compliance is increased,treatment with ibandronate may im-prove therapeutic outcome.

The side effects of the oral bis-phosphonates are similar and are due totheir inherent toxicity to epithelial cellslining the gastrointestinal tract. Theresult may be gastrointestinal irritationand ulceration. Therefore, it is recom-mended that patients take the medica-tion first thing in the morning on anempty stomach along with 8 oz (0.2 L)of water and then remain upright forthirty minutes. Osteonecrosis of the jaw,defined as exposed bone in the maxil-lofacial region that fails to heal withineight weeks after identification by ahealth-care provider, is a troubling po-tential complication of bisphosphonateuse55. It has been reported that thepatients who are at greatest risk arethose with multiple myeloma or meta-static carcinoma of the skeleton who arebeing treated with relatively high dosesof the intravenous bisphosphonateszoledronic acid and pamidronate. Thispatient population has included 94% ofthe reported cases56. In a recent report,the American Society for Bone andMineral Research estimated the risk ofosteonecrosis of the jaw in patientstaking oral bisphosphonates for thetreatment of osteoporosis to be betweenone in 10,000 and less than one in100,000 patient-treatment years55. Thisis lower than the estimated incidence ofone to ten cases per 100 patients withcancer receiving intravenous treat-ment55. Sixty percent of the cases ofosteonecrosis that do occur are precededby a surgical dental procedure. Theoriesregarding potential mechanisms for thedevelopment of osteonecrosis of the jawinclude oversuppression of bone turno-ver and bisphosphonate toxicity of thesoft tissues overlying the jaw56-58. Limiteddata exist regarding prevention andmanagement of the condition. It isrecommended that patients in need ofa dental procedure establish meticulousoral hygiene and consider completing

dental work prior to starting bi-sphosphonate treatment58,59. No evidencesupports the discontinuation of estab-lished bisphosphonate therapy prior toa dental procedure60.

Zoledronic acid is available in anintravenous formulation given onceyearly as an infusion. It has demon-strated efficacy in increasing bonemineral density and reducing fracturerisk61,62. In the multinational, multicen-ter, placebo-controlled HORIZON(Health Outcomes and Reduced Inci-dence with Zoledronic Acid OnceYearly) Pivotal Fracture Trial, womenwho received an infusion of 5 mg ofzoledronic acid once yearly had a 70%reduction in the risk of new spinefractures (p < 0.0001) and a 41%reduction in the risk of hip fractures(p = 0.0032) over three years comparedwith the risks for women taking aplacebo62. In a group of osteoporoticpatients who had received an infusion ofzoledronic acid within ninety days aftera hip fracture repair, the risk of anyfracture decreased by 35% and mortal-ity from any cause decreased by 28%compared with the rates for patientsgiven a placebo63. Patients being treatedwith weekly oral alendronate can switchto zoledronic acid and maintain thebeneficial bone effects for twelvemonths after a single infusion. The mostcommon side effects associated with useof zoledronic acid include influenza-likepost-infusion symptoms of fever, mus-cle pain, headache, and bone pain. Themajority of symptoms resolve withinthree days. Osteonecrosis of the jaw wasnot seen in any of the trials investigatingthe use of zoledronic acid in postmen-opausal women with osteoporosis61-63.Atrial fibrillation has also been seen.This association is yet to be defined62,63.Given the convenience of a yearly dosingschedule, zoledronic acid may be asuitable option for osteoporotic patientsin need of bisphosphonate treatment forwhom gastrointestinal toxicity is aproblem.

Once a decision has been made tobegin treatment with bisphosphonates,optimization of the mineral environ-ment and monitoring of the boneturnover state ensure that the best

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possible result is achieved. The impor-tance of adequate vitamin-D and cal-cium status is highlighted by casereports of bisphosphonate-induced hy-pocalcemia in patients with unrecog-nized vitamin-D deficiency. Animalstudies have also demonstrated ablunting of the bisphosphonate re-sponse in the setting of vitamin-Ddeficiency64,65. All patients should re-ceive 1500 mg of calcium citrate and 800IU of vitamin D3. Those found to havedeficiencies (a serum calcium level of<9.5 mg/dL [<2.4 mmol/L] and/or aserum 25-hydroxyvitamin-D level of<32 ng/mL [<79.9 nmol/L]) may re-quire greater doses for a short time untilthey are considered calcium and/orvitamin-D-replete.

Measures of bone mineral densitymay clinically diagnose osteoporosis butare of limited value for assessing apatient’s response to bisphosphonatetreatment66. Fractures are a key efficacyend point in bisphosphonate trials.Studies have demonstrated an incon-sistent relationship between changes inbone density and fracture risk67. Datarelating changes in bone turnover tosubsequent fracture outcomes suggestthat high turnover itself may be anindependent risk factor for fracture68.Thus, markers of bone turnover may beuseful for assessing a patient’s responseto treatment. The markers most com-monly used in clinical practice includethe markers of bone formation, bone-specific alkaline phosphatase andosteocalcin; and the markers of boneresorption, urine N-telopeptide of col-lagen cross links (NTx) and serumC-telopeptide of collagen cross links.In the Fracture Intervention Trial (FIT),greater reductions in bone turnoverwith alendronate therapy were associ-ated with fewer hip, non-spine, andvertebral fractures68. Despite these re-sults, controversy remains regarding theuse of bone turnover markers in mon-itoring response to treatment. For pa-tients taking bisphosphonates, the idealtherapeutic range of urine levels of NTxis 20 to 40 nmol BCE (bone collagenequivalents)/mmol of creatinine.

Long-term use of bisphospho-nates may suppress bone turnover to

such an extent that a paradoxical de-crease in bone strength and resiliencedevelops; this is referred to as adynamicbone. In this state of oversuppression,microfractures generated through thewear and tear of normal daily life beginto accumulate and coalesce, leading tospontaneous nonspinal fractures69. Ac-cumulation of microdamage is as-sociated with a reduction in bonetoughness, defined in animal studies asthe ability of the bone to sustain defor-mation before breaking70. In anotherstudy, this decrease in toughness wasfound to be offset by an increase in bonevolume and mineralization, the combi-nation of which resulted in no signifi-cant impairment in bone mechanicalproperties71. Odvina et al. reported onnine women treated with high-dosealendronate who presented with aspontaneous fracture of a long bone72.Six of these women also displayedevidence of delayed or absent fracture-healing during alendronate therapy.Histomorphometric analysis of bonebiopsy specimens from these patientsrevealed marked suppression of boneturnover, demonstrated by a reduced orabsent osteoblastic surface, a dimin-ished osteoclastic surface, and minimalmatrix synthesis. For these patients,changes in therapy such as a rest periodfrom bisphosphonates or the use of ananabolic agent such as teriparatide (asdiscussed below) should be considered.In a study comparing women whostopped taking alendronate after anaverage of five years of use with thosewho continued to use the drug, thosewho stopped did not have acceleratedbone loss or a marked increase in boneturnover73. These results indicate a per-sistence of alendronate’s effect on boneafter therapy is stopped73. Currently, it isunknown whether long-term treatmentwith bisphosphonates beyond five yearsis indicated. More studies are needed toinvestigate the potential positive andnegative impact that prolonged bonesuppression can have on fracture risk.

Anabolic AgentsParathyroid HormoneApproved by the U.S. Food and DrugAdministration in 2002, teriparatide

(parathyroid hormone [PTH1-34]) isthe only anabolic agent available for thetreatment of postmenopausal osteopo-rosis. Self-administered subcutaneouslywith use of a pen-like device, dailyteriparatide injection is the most effec-tive therapy for restoring bone qual-ity74,75. The effects of parathyroidhormone are mediated by enhancementof bone turnover. When administeredintermittently, the anabolic effects pre-dominate, increasing bone mass up to13% over two years of therapy. Thisincrease is greater than that achievedwith bisphosphonate therapy76. Theantifracture efficacy of teriparatide issimilar to that seen with bisphospho-nates. After treatment of postmeno-pausal women with osteoporosis (asdefined by bone mineral density) withdaily 20-mg injections of parathyroidhormone, the risk of vertebral fractureand nonvertebral fracture was reducedby 65% and 53%, respectively76. Theantifracture efficacy of parathyroidhormone may be related to more thanjust increases in bone mineral density.Microcomputer tomographic analysishas demonstrated an increase in tra-becular number as well as trabecularthickness77.

Although it has been proven to beefficacious across the spectrum of oste-oporosis disease severity, the use ofparathyroid hormone has been lim-ited78, most likely as a result of thecombination of high cost, relative in-convenience, and potential adverse re-actions associated with use of the drug.Evidence of osteosarcoma in rodentsexposed to prolonged high doses ofteriparatide led the U.S. Food and DrugAdministration to prohibit its use inpatients at high risk for skeletal can-cer79,80. The use of teriparatide is con-traindicated in patients with active Pagetdisease of bone, metastatic cancer in theskeleton, or a history of skeletal irradi-ation, and in children with openepiphyses. In an estimated more than300,000 exposures to teriparatide forthe treatment of postmenopausal oste-oporosis, a single case of osteosarcomawas recently reported81, and the exis-tence of a causal relationship betweenteriparatide use and osteosarcoma in

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humans remains uncertain. Additionaladverse reactions associated with teri-paratide include nausea, swelling, pain,weakness, erythema around the injec-tion site, and elevation in plasmacalcium levels. Plasma calcium may beadjusted, and vitamin-D supplementa-tion may be needed82,83. Hypercalcemiamay be monitored by measuring serumcalcium levels at one month followingthe initiation of treatment84.

Antiresorptive therapies have longbeen, and continue to be, the mainstayof osteoporosis treatment. Patients whohave been previously treated with anti-resorptive therapy constitute a largegroup in whom parathyroid hormonetreatment may be indicated. Data sug-gest that previous treatment with potentinhibitors of bone turnover, such asalendronate, appears to diminish theinitial response to teriparatide85. It alsoappears that the degree of the initialteriparatide effect depends on the po-tency of the previously used antire-sorptive agent, and this effect has notbeen demonstrated in association withless potent agents such as raloxifene86.Many practitioners advocate a brief(six-month) rest period between thediscontinuation of the antiresorptiveagent and the start of teriparatidetreatment.

Combination TherapyDespite an initial attractiveness of thecombined use of anabolic and anti-catabolic therapy, a synergistic effectbetween teriparatide and the bisphos-phonates has not been seen. On thecontrary, concurrent use of a bi-sphosphonate has been shown to bluntthe bone-building potential of parathy-roid hormone87,88. However, in a recenttrial by Deal et al., concurrent admin-istration of raloxifene was found toenhance the bone-forming effects ofteriparatide89. Postmenopausal womenwho received a combination of teri-paratide and raloxifene over a period ofsix months had a greater increase inbone mineral density in the hip com-pared with groups that received ralox-ifene or teriparatide alone. A similarsynergistic effect has been seen follow-ing coadministration of teriparatide and

hormone replacement therapy90. Addi-tional studies that include the assess-ment of fracture outcome as well areneeded.

The bisphosphonates, while notrecommended during teriparatidetreatment, can play a valuable role aftercompletion of teriparatide therapy.Soon after discontinuation of teripara-tide treatment, gains in bone mineraldensity begin to regress rapidly. De-clines in bone mineral density begin asearly as eighteen months after the lastdose of teriparatide is given91. Theimmediate use of bisphosphonates orother antiresorptive therapy has beenshown to optimize valuable gains inbone mineral density. The use of bis-phosphonates not only prevents a de-cline in bone mineral density but alsoenhances additional densitometricgains92,93. Subsequent treatment withbisphosphonates facilitates the miner-alization of osteoid laid down duringthe previous period of increased meta-bolic activity. In an effort to ‘‘lock in’’and ‘‘protect’’ the valuable gains in

bone mineral density achieved duringthe two years of teriparatide treatment,many practitioners advocate startingor restarting antiresorptive therapyon completion of the anabolic therapy.

Tables I and II present the phar-macologic agents recommended totreat osteoporosis and reduce fracturerisk18.

Future DirectionsThe treatment of osteoporosis is cur-rently associated with numerous prob-lems ranging from adverse drugreactions to suboptimal patient com-pliance94-98. Better drugs with morespecific targets will reduce the adverseeffects and improve the outcome oftherapy. The understanding of cellularmechanisms regulating bone formationand remodeling has improved substan-tially in the last few years. In the arena ofantiresorptive agents, denosumab, ahuman monoclonal antibody againstreceptor activator of nuclear factor-kBligand (RANKL), has been shown inpreclinical trials to increase bone min-

TABLE I Recommended Pharmacologic Agents to Treat Osteoporosis and

Reduce Fracture Risk18

*

Antiresorptive AgentVertebralFracture†

HipFracture†

NonvertebralFracture†‡

BisphosphonatesAlendronate A§ A ARisedronate A A AEtidronate A C C

Estrogen replacementtherapy/hormonereplacement therapy

A A A

Selective estrogen receptormodulators (raloxifene)

A C C

Calcitonin, intranasal A C C

Teriparatide (parathyroidhormone [1-34])

A — A

Calcium and vitamin-D preparationsVitamin-D monotherapy andanalogs (calcitriol, alfacalcidol, etc.)

C C C

Calcium monotherapy B C CVitamin D plus calcium C A A

*From randomized, placebo-controlled clinical trials of women with prior vertebral fractures orwith osteoporosis. †A = convincing evidence of antifracture efficacy, B = inconsistent results,and C = ineffective or insufficient evidence of efficacy. ‡Osteoporosis fractures exclusive ofthose of the spine. §Also seen in men.

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eral density and decrease bone resorp-tion in postmenopausal women withosteoporosis. Used commonly in pa-tients with multiple myeloma andmetastatic disease of the skeleton,denosumab exerts its action throughinhibition of RANKL, a key mediatorin osteoclast activation99,100. Denosumabis now awaiting approval for entryinto the market. Cathepsin-K inhibitorsare another group of novel antiresorp-tive agents. It is hoped that thesedrugs, which were designed to reducethe activity of cathepsin K (a powerfulosteoclast protease), can limit the en-zymatic degradation of bone matrixproteins101. The efficacy of cathepsin-Kinhibitors in the treatment of post-menopausal osteoporosis is still underinvestigation in clinical trials.

New anabolic agents are currentlyon the treatment horizon. Strontiumranelate, used routinely in Europe butunavailable in the United States, isconsidered to be the only agent to have adual mechanism of action, acting as

both an antiresorptive and an anabolicagent. Treatment of postmenopausalosteoporotic women with strontiumranelate has been shown to decreasefracture risk and increase bone mineraldensity. While the long-term effectsremain unknown, strontium may proveto be an attractive option for patientsunwilling or unable to use parathyroidhormone102,103. The development of al-ternative forms of parathyroid hor-mone, including noninjectable forms(oral, nasal, sublingual, and transdermalmodes), is also under way. These newanalogs of parathyroid hormone appearto possess longer half-lives, allowingsustained exposure in the setting of lessfrequent dosing94,96-98,104-106.

Osteoporosis Therapy in CommonOrthopaedic SituationsCalcium and Vitamin-DSupplementation for Patientswith a FractureCalcium and vitamin-D supplementa-tion is a baseline critical component of

any fracture treatment therapy. Theincreased bone turnover stimulated byfracture repair and remodeling leads toan increased metabolism and demandfor calcium and vitamin D. The esti-mated daily intake required for fracture-healing is 1500 to 2500 mg of calciumand 1000 to 2000 IU of vitamin D.

Use of Bisphosphonates forPatients with a FractureHealing of both stabilized and unstabi-lized fractures involves stages of osteo-clastic activity107. The limited datacurrently available indicate that the useof bisphosphonates does not impair, andmay actually enhance, fracture-healing108.Studies have shown that, while develop-ment and remodeling of the fracturecallus is delayed in the setting of bi-sphosphonate use, the overall mechani-cal strength of the callus is eitherunchanged or increased109,110. Concernregarding a bisphosphonate-driven in-crease in the rate of nonunion alsocontinues to be unsupported in the

TABLE II Recommended Pharmacologic Agents to Treat Osteoporosis and Reduce the Risk of Future Fracture in Patients

with a Fragility Fracture18

*

Generic Name Trade Name Approved Indication Recommended DoseDosing Instructions and

Contraindications

Alendronate Fosamax Osteoporosis inpostmenopausalwomen and in men

10 mg orally onceper day or 70 mgorally weekly

With full glass of water,>30 min before food in morning.Contraindications: severe renalinsufficiency, esophageal motilityproblem, hypocalcemia, or inabilityto stand or sit upright for 30 min

Risedronate Actonel Osteoporosis inpostmenopausalwomen and in men

5 mg orally onceper day or 35 mgorally weekly

With full glass of water, >30 minbefore food in morning.Contraindications: severe renalinsufficiency, hypocalcemia, orinability to stand or sit uprightfor 30 min

Raloxifene Evista Osteoporosis inpostmenopausalwomen

60 mg orallyonce per day

With meals at any time ofthe day. Contraindications:premenopausal women andthose with history of or activevenous thromboembolic events

Teriparatide (parathyroidhormone [PTH1-34])

Forteo Postmenopausal womenwith osteoporosis whoare at severe risk forfracture

20-mg subcutaneousinjection onceper day

Injection into thigh or abdominalwall. Contraindications: Pagetdisease, prior radiation therapy,bone metastases, history ofskeletal malignant tumors, orhypercalcemia

*See prescribing information for each drug for additional recommendations and guidelines.

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literature108-110. Timing may play a role inthe effect of bisphosphonates on fracture-healing. The administration of zole-dronic acid to rats two weeks aftercreation of a fracture resulted in agreater increase in the mechanicalstrength of callus compared with whatwas seen with administration prior tothe fracture111. Given the developmentof the primary callus during the firsttwo weeks of fracture-healing, somestudies support initiation or continua-tion of bisphosphonate treatment afterthis time108. Animal fracture data com-bined with the known efficacy of bis-phosphonates in preventing futurefractures are compelling enough tosupport initiation of treatment in a‘‘timely fashion’’ for all patients with anosteoporotic fragility fracture112.

Since bisphosphonates inhibitosteoclastic resorption and osteoclasticactivity is involved in fracture repair, apatient who is already being treated withbisphosphonates may have an initialdelay in the early stages of the fracturerepair process. Some animal studieshave shown interference with fracturerepair and the mechanical strength ofthe fracture site dependent on thechemical structure, dosage potency,and duration of the treatment withthe bisphosphonate. Additional studiesof humans are needed to determinethe ultimate effect on union and onthe restoration of mechanical strengthand anatomic architecture after frac-ture-healing. Physicians may chooseto stop the bisphosphonate treat-ment for two weeks—i.e., until theinitial fracture-repair period haspassed.

Use of Teriparatide for Patientswith a FractureRecent animal studies have suggestedthat teriparatide may also play a valuablerole in the treatment of fractures. Anacceleration of fracture-healing has beendemonstrated in animals treated withintermittent doses of parathyroid hor-mone113-116. Stimulation of proliferationand differentiation of chondrocytes andosteoprogenitor cells, leading to an in-crease in the production of bonematrix proteins, is believed to be themechanism113,117. The fracture callus inparathyroid-hormone-treated animalsforms more rapidly, remodels morequickly, and possesses superior biome-chanical properties when compared withthat of controls114,115. Parathyroid hormone(PTH1-34) may prove to be an attractiveagent to enhance healing and limit the riskof nonunion of poorly healing or high-risk fractures when human trials onfracture-healing have been performed.

Use of Bisphosphonates for PatientsWho Have Undergone ArthroplastyAseptic loosening and osteolysis are themost common causes of failure of totaljoint arthroplasty. Osteolysis is causedby wear-debris-mediated stimulation ofthe osteoclast. This leads to subsequentbone resorption. Drugs used to treatosteoporosis inhibit the osteoclast andalso increase endosteal bone forma-tion118. They have therefore been usedexperimentally119-126 as possible therapiesto improve the life of prostheses; how-ever, additional animal and humanstudies are needed.

Most studies have shown thatpatients being treated with bisphos-

phonates maintain more periprostheticbone mineral density and have lessperiprosthetic bone loss127-131. Bisphos-phonates have a larger effect on boneloss following arthroplasties with ce-ment, and especially knee arthroplastieswith cement132. With anabolic bonetherapy, uncemented prostheses mayhave the potential for better ingrowthand survival. However, future humanstudies may demonstrate better pros-thetic survival in patients using drugsfor reduced bone mass. Nevertheless,patients undergoing total joint replace-ment should be evaluated and treatedfor decreased bone mass if they have anumber of risk factors for osteoporosis.

NOTE: The authors acknowledge the contributions of the follow-ing individuals: Nakul Karkare, MD, Lisa Shindle, NP, LjiljanaBogunovic, BA, Natalie Casemyr, BA, and Ania Rodney, BA.

Laura Gehrig, MD242 Patton Avenue, Shreveport, LA 71105.E-mail address: [email protected]

Joseph Lane, MDThe Hospital for Special Surgery, 535 East 70thStreet, New York, NY 10021

Mary I. O’Connor, MDMayo Clinic, 4500 San Pablo Road,Jacksonville, FL 32224

Printed with permission of the AmericanAcademy of Orthopaedic Surgeons. This article,as well as other lectures presented at theAcademy’s Annual Meeting, will be available inFebruary 2009 in Instructional Course Lectures,Volume 58. The complete volume can beordered online at www.aaos.org, or by calling800-626-6726 (8 A.M.-5 P.M., Central time).

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