Update in Update in OsteoporosisOsteoporosis

Teresa Bryan, M.D.Teresa Bryan, M.D.

General Medicine Noon General Medicine Noon ConferenceConference

February 24, 2009February 24, 2009

ObjectivesObjectives WHO Task Force Fracture Risk Assessment Tool WHO Task Force Fracture Risk Assessment Tool

(FRAX)(FRAX) NOF Guidelines for pharmacologic intervention NOF Guidelines for pharmacologic intervention

in postmenopausal women and men ≥ age 50in postmenopausal women and men ≥ age 50 ACP Practice Guidelines for Screening in MenACP Practice Guidelines for Screening in Men ACP Practice Guidelines for Pharmacologic ACP Practice Guidelines for Pharmacologic

TherapyTherapy Association of Atrial fibrillation with Association of Atrial fibrillation with

bisphosphonatesbisphosphonates Bisphosphonate associated osteonecrosis of the Bisphosphonate associated osteonecrosis of the

jawjaw

BackgroundBackground

Estimated 44 million AmericansEstimated 44 million Americans 55% people 50 years of age or older55% people 50 years of age or older 1 out of every 2 Caucasian women 1 out of every 2 Caucasian women

will experience osteoporotic fracture will experience osteoporotic fracture and 1 out of every 5 men. and 1 out of every 5 men.

Hip fractures result in 10-20% Hip fractures result in 10-20% excess mortality in 1 year. excess mortality in 1 year.

20% hip fracture patients require 20% hip fracture patients require long-term nursing home care.long-term nursing home care.

US Preventive Services Task US Preventive Services Task Force RecommendationsForce Recommendations

Ann Int Med. 2002;137:526-528Ann Int Med. 2002;137:526-528

Routinely screen women 65 Routinely screen women 65 years of age and older.years of age and older.

Screen women at increased risk Screen women at increased risk beginning at 60 years of age.beginning at 60 years of age.

No recommendation for or No recommendation for or against routine screening in against routine screening in women younger than 60 years women younger than 60 years of age.of age.

DefinitionsDefinitions

OsteoporosisOsteoporosis: a skeletal disorder : a skeletal disorder characterized by compromised bone characterized by compromised bone strength predisposing to an increased risk strength predisposing to an increased risk for fracture. Diagnosed by:for fracture. Diagnosed by: Occurrence of fragility fractureOccurrence of fragility fracture Osteoporosis by DXA criteriaOsteoporosis by DXA criteria

Osteoporotic fractureOsteoporotic fracture: (fragility : (fragility fracture) those occurring from a fall from fracture) those occurring from a fall from a standing height or less without major a standing height or less without major trauma such as a MVA. trauma such as a MVA.

Dexa InterpretationDexa Interpretation

T scoreT score: Difference in SDs compared to : Difference in SDs compared to value of young adults same sex.value of young adults same sex.

Z scoreZ score: Difference in SDs compared to : Difference in SDs compared to value of individuals same age and sex. value of individuals same age and sex.

OsteoporosisOsteoporosis: T score ≤-2.5 : T score ≤-2.5 OsteopeniaOsteopenia: T score between -1 and -: T score between -1 and -

2.52.5

SD=Standard DeviationSD=Standard Deviation

Osteoporotic Risk Osteoporotic Risk Assessment Assessment

Majority of fracture occur in those Majority of fracture occur in those with low bone mass rather than with low bone mass rather than osteoporosis osteoporosis

WHO Fracture Risk Assessment Tool WHO Fracture Risk Assessment Tool (FRAX)(FRAX)

Considers 9 clinical risk factors for Considers 9 clinical risk factors for osteoporosisosteoporosis

FRAX Risk FactorsFRAX Risk Factors AgeAge Previous FracturePrevious Fracture Parent with h/o hip fractureParent with h/o hip fracture Current smokingCurrent smoking Glucocorticoids > 3 monthsGlucocorticoids > 3 months Rheumatoid arthritisRheumatoid arthritis Secondary osteoporosisSecondary osteoporosis Alcohol 3 or more units dailyAlcohol 3 or more units daily Bone Mineral DensityBone Mineral Density

WHO Fracture Risk WHO Fracture Risk Assessment Tool (FRAX)Assessment Tool (FRAX)

http://www.shef.ac.uk/FRAX/

WHO Fracture WHO Fracture Assessment ToolAssessment Tool

http://www.shef.ac.uk/FRAX/

Applications of FRAX in USApplications of FRAX in US

Not intended for young adults or Not intended for young adults or childrenchildren

Only applies to previously untreated Only applies to previously untreated patientspatients

Total hip density may be substituted Total hip density may be substituted for femoral neck BMDfor femoral neck BMD

Convert T score based on reference Convert T score based on reference standard used in FRAXstandard used in FRAX

Cost-effectivenessCost-effectiveness

Intervention threshold: 10 year Intervention threshold: 10 year fracture probability 2.5 to 4.9% fracture probability 2.5 to 4.9%

Assumes annual treatment cost of Assumes annual treatment cost of $600$600

““Willingness to pay” threshold of Willingness to pay” threshold of $60,000 per QALY gained$60,000 per QALY gained

Osteoporosis International Dec 2007http://www.nof.org/professionals/Cost-effective_osteoporosis_%20treatment_US.pdf

http://www.nof.org/professionals/NOF_Clinicians_Guide.pdf

National Osteoporosis National Osteoporosis FoundationFoundationScreening Screening

RecommendationsRecommendations Women 65 and olderWomen 65 and older Men 70 and olderMen 70 and older Postmenopausal and perimenopausal Postmenopausal and perimenopausal

women with increased risk factor women with increased risk factor profile (low body wt, prior fx, meds)profile (low body wt, prior fx, meds)

Men 50-70 with increased risk factor Men 50-70 with increased risk factor profileprofile

Fracture after age 50Fracture after age 50 Consider in postmenopausal women Consider in postmenopausal women

discontinuing estrogen.discontinuing estrogen.

Risk FactorsRisk Factors

NEJM 2008;358:1474-82.

Secondary OsteoporosisSecondary Osteoporosis Type 1 DMType 1 DM Osteogenesis imperfectaOsteogenesis imperfecta Untreated, longstanding hyperthyroidismUntreated, longstanding hyperthyroidism HypogonadismHypogonadism Premature menopause <45 year.Premature menopause <45 year. Chronic malnutritionChronic malnutrition MalabsorptionMalabsorption Chronic liver diseaseChronic liver disease Meds: anticonvulsants, heparin, Meds: anticonvulsants, heparin,

glucocorticoidsglucocorticoids

Clinical Assessment of Clinical Assessment of Osteoporosis in Osteoporosis in

Postmenopausal Women and Postmenopausal Women and Men >50Men >50 History and physical examHistory and physical exam

Consider laboratory tests: (esp if Consider laboratory tests: (esp if Z<2.0)Z<2.0) Ca, phos, Cr, LFTs, TSH, CBC, VIt D levelCa, phos, Cr, LFTs, TSH, CBC, VIt D level Testosterone level in men Testosterone level in men

If clinically indicated:If clinically indicated: SPEP, Urine cortisol, Urine calcium, anti-SPEP, Urine cortisol, Urine calcium, anti-

tissue transglutaminase antibodies tissue transglutaminase antibodies (Celiac sprue) (Celiac sprue)

Pharmacologic TherapyPharmacologic Therapy(NOF Recommendations for (NOF Recommendations for

Postmenopausal Women and Men >50)Postmenopausal Women and Men >50)

Hip or vertebral fractureHip or vertebral fracture T score ≤ -2.5 femoral neck, total T score ≤ -2.5 femoral neck, total

hip or spinehip or spine T score -1 to -2.5 hip or spine:T score -1 to -2.5 hip or spine:

10 year hip fx probability ≥ 3%*10 year hip fx probability ≥ 3%* 10 year all major osteoporosis related fx 10 year all major osteoporosis related fx

probability ≥ 20% *probability ≥ 20% *

*WHO absolute fracture risk model

CaseCase

57 year old woman. Healthy.57 year old woman. Healthy. FH: 80 year old mother with mult FH: 80 year old mother with mult

vertebral fx and “hump” in her backvertebral fx and “hump” in her back Prior fx: cervical spine when fell off Prior fx: cervical spine when fell off

bed playing with grandsonbed playing with grandson No smoking, no ETOH, no prior No smoking, no ETOH, no prior

prednisone, no RA or secondary prednisone, no RA or secondary causescauses

Weight: 155 lb Height 5ft 6 inWeight: 155 lb Height 5ft 6 in

Case (cont)Case (cont)

T score -2.4T score -2.4 Frax assessment toolFrax assessment tool: 10 year : 10 year

probability of fxprobability of fx Major osteoporoticMajor osteoporotic: 21%: 21% HipHip: 4.9: 4.9

Universal Universal RecommendationsRecommendations

Adequate intake of calcium and vitamin D:Adequate intake of calcium and vitamin D: Adults > 50: 1200 mg elemental calcium /day Adults > 50: 1200 mg elemental calcium /day All adults > 50: 800-1000 IU/dayAll adults > 50: 800-1000 IU/day

Regular Weight Bearing Exercise: Regular Weight Bearing Exercise: At least 30 min 3x weekly At least 30 min 3x weekly

Fall prevention strategies: Fall prevention strategies: Correct vision and hearing problemsCorrect vision and hearing problems Evaluate neuro problemsEvaluate neuro problems Review meds for Side effects Review meds for Side effects

Avoid tobacco and alcoholAvoid tobacco and alcohol

Treatment OptionsTreatment OptionsFDA ApprovedFDA Approved

BisphosphonatesBisphosphonates EstrogenEstrogen SERMS (Selective Estrogen SERMS (Selective Estrogen

Receptor Modulators)Receptor Modulators) CalcitoninCalcitonin Forteo (parathyroid hormone)Forteo (parathyroid hormone)

BisphosphonatesBisphosphonates Alendronate (fosamax): 10 mg qd or 70 q Alendronate (fosamax): 10 mg qd or 70 q

weekweek Risedronate (actonel): 5 mg qd or 35mg q Risedronate (actonel): 5 mg qd or 35mg q

weekweek Ibandronate (Boniva): 2.5mg qd, 150 mg q Ibandronate (Boniva): 2.5mg qd, 150 mg q

month, 3mg IV q3 monthsmonth, 3mg IV q3 months Zolendronic acid (Reclast): 5mg IV yearlyZolendronic acid (Reclast): 5mg IV yearly Treatment efficacy: Treatment efficacy:

Bisphosphonates decrease risk vertebral Bisphosphonates decrease risk vertebral fracture by approx 50%fracture by approx 50%

Risk of hip fracture decreased by 37%Risk of hip fracture decreased by 37%

Estrogen Agonists/AntagonistsEstrogen Agonists/Antagonists(Formerly SERMS)(Formerly SERMS)

Raloxifene (Evista) Raloxifene (Evista) Decreased vertebral fx 30%-55%Decreased vertebral fx 30%-55% 60 mg qd 60 mg qd Increase risk DVT Increase risk DVT No effect on endometriumNo effect on endometrium Decreases risk of breast cancerDecreases risk of breast cancer Causes hot flashes (6%)Causes hot flashes (6%)

CalcitoninCalcitonin

Miacalcin: nasal, SQ or IMMiacalcin: nasal, SQ or IM 200 IU intranasally qd200 IU intranasally qd 25-39% reduction vertebral25-39% reduction vertebral Possible analgesic action for acute Possible analgesic action for acute

osteoporotic fractureosteoporotic fracture

PTH (Teriparatide)PTH (Teriparatide)

Forteo 20 ug SQ daily Forteo 20 ug SQ daily Previous failed therapyPrevious failed therapy Decrease vertebral fx 65%Decrease vertebral fx 65% Osteosarcoma in ratsOsteosarcoma in rats Expensive Expensive

EstrogenEstrogen

FDA approvedFDA approved Osteoporosis preventionOsteoporosis prevention Vasomotor symptomsVasomotor symptoms Vulvovaginal atrophyVulvovaginal atrophy

Progesterone combination if no Progesterone combination if no hysterectomyhysterectomy

Risk MI/Stroke/Breast CARisk MI/Stroke/Breast CA Consider non-estrogen treatment firstConsider non-estrogen treatment first

Monitoring EffectivenessMonitoring Effectiveness

Monitor and encourage complianceMonitor and encourage compliance Review risk factor modificationReview risk factor modification Calcium and vitamin D intakeCalcium and vitamin D intake Repeat BMD q 2 years (medicare Repeat BMD q 2 years (medicare

guidelines)guidelines)

Osteoporosis in MenOsteoporosis in Men

1.5 million men over age 65 in US have 1.5 million men over age 65 in US have osteoporosisosteoporosis

Mortality with hip fractures higher in men Mortality with hip fractures higher in men up to 37.5%up to 37.5%

Absolute BMD in men who fracture hip is Absolute BMD in men who fracture hip is higher than in women. higher than in women.

Prevalence: Prevalence: 7% white men7% white men 5% black men5% black men 3% Hispanic men3% Hispanic men

CaseCase

68 year old WM68 year old WM COPDCOPD Stopped smoking 9 years agoStopped smoking 9 years ago 2 prior pred tapers x 2 weeks2 prior pred tapers x 2 weeks Wt 180 lb, Ht 5 ft 8inWt 180 lb, Ht 5 ft 8in No alcohol, RANo alcohol, RA FH negativeFH negative Frequent yard workFrequent yard work

ACP Guidelines for Screening ACP Guidelines for Screening in Men Risk Factorsin Men Risk Factors

Age >70 yearsAge >70 years Low body weight (BMI<20-25 kg/mLow body weight (BMI<20-25 kg/m2)2)

Weight loss > 10%Weight loss > 10% Physical inactivityPhysical inactivity Use of oral corticosteroidsUse of oral corticosteroids Previous fragility fracturePrevious fragility fracture

Ann Intern Med 2008;148:680-684.

Common Secondary Causes Common Secondary Causes in Menin Men

Cushing’s or steroid therapyCushing’s or steroid therapy Excessive alcohol useExcessive alcohol use HypogonadismHypogonadism Low calcium intake of Vit D Low calcium intake of Vit D

insufficiencyinsufficiency SmokingSmoking Family history of minimal trauma Family history of minimal trauma

fracturefracture Ann Intern Med 2008;148:680-684

ACP Guidelines in MenACP Guidelines in MenRecommendationsRecommendations

1- Perform individualized assessment of 1- Perform individualized assessment of risk factors for osteoporosis in older risk factors for osteoporosis in older men (Strong recommendation; high-men (Strong recommendation; high-quality evidence)quality evidence)

2- Obtain DXA for men who are at 2- Obtain DXA for men who are at increased risk for osteoporosis and are increased risk for osteoporosis and are candidates for drug therapy (Strong candidates for drug therapy (Strong recommendation; moderate-quality recommendation; moderate-quality evidence)evidence)

3- Further research to evaluate 3- Further research to evaluate osteoporosis screening tests in menosteoporosis screening tests in men

Ann Intern Med 2008;148:680-684

Treatment in MenTreatment in Men

Treat secondary causesTreat secondary causes Bisphosphonates reasonable first Bisphosphonates reasonable first

lineline Teriparatide Teriparatide CalcitoninCalcitonin Raloxifene not well studied in menRaloxifene not well studied in men

Pharmacologic Treatment of Low Bone Pharmacologic Treatment of Low Bone Density or Osteoporosis to Prevent Fractures: Density or Osteoporosis to Prevent Fractures:

A Clinical Practice Guideline from the ACP A Clinical Practice Guideline from the ACP (Ann Intern Med 2008;149:404-415.)(Ann Intern Med 2008;149:404-415.)

What are the comparative benefits in What are the comparative benefits in fracture reduction among treatments for fracture reduction among treatments for low bone density?low bone density?

How does fracture reduction resulting How does fracture reduction resulting from treatments vary among individuals from treatments vary among individuals with different fracture risks? with different fracture risks?

What are the short and long-term What are the short and long-term adverse effects and do these vary by adverse effects and do these vary by specific subpopulations? specific subpopulations?

Effect of Bisphosphonates on Effect of Bisphosphonates on Fracture Risk ReductionFracture Risk Reduction

VertebrVertebralal

NonvertebrNonvertebralal HipHip

AlendronatAlendronatee

↓ ↓ ↓ ↓ ↓ ↓

IbandronateIbandronate ↓ ↓ ↔ ↔ Not Not studiedstudied

RisedronateRisedronate ↓ ↓ ↓ ↓ ↓ ↓ Zoledronic Zoledronic acidacid ↓ ↓ ↓ ↓ ↓ ↓

Annals 2008;149:404-415Annals 2008;149:404-415

Copyright restrictions may apply.

Black, D. M. et al. JAMA 2006;296:2927-2938.

BMD Change in FLEX Participants

Copyright restrictions may apply.

Black, D. M. et al. JAMA 2006;296:2927-2938.

Incidence of Fracture by Treatment Group

Effect on Fracture Risk Effect on Fracture Risk ReductionReduction

VertebralVertebral NonvertebrNonvertebralal HipHip

CalcitoninCalcitonin ↓ ↔ ↔ Not Not studied studied

EstrogenEstrogen ↓ ↓ ↓↓ ↓↓

TeriparatideTeriparatide ↓ ↓ ↓↓Not Not studiedstudied

RaloxifeneRaloxifene ↓↓ ↔↔ ↔↔

TamoxifeneTamoxifene ↔↔ Not studiedNot studied ↔ ↔ Calcium +Vit Calcium +Vit DD modest ↓modest ↓ modest ↓ modest ↓ modest ↓ modest ↓ Annals 2008;149:404-415Annals 2008;149:404-415

MacLean, C. et. al. Ann Intern Med 2008;148:197-213

Risk for hip fractures relative to placebo for participants who are at high risk for fracture, by agent

MacLean, C. et. al. Ann Intern Med 2008;148:197-213

Risk for hip fracture relative to placebo for participants who are not at high risk for fracture, by agent

ACP RecommendationsACP Recommendations

1- Offer pharmacologic treatment to men and 1- Offer pharmacologic treatment to men and women who have known osteoporosis and to women who have known osteoporosis and to those with h/o fragility fractures. (Strong those with h/o fragility fractures. (Strong recommendation; high-quality evidence)recommendation; high-quality evidence)

2- Consider treatment for men and women at 2- Consider treatment for men and women at risk for developing osteoporosis. (weak risk for developing osteoporosis. (weak recommendation; moderate-quality evidence)recommendation; moderate-quality evidence)

3- Choose treatment options based on 3- Choose treatment options based on assessment of risk and benefit to individual assessment of risk and benefit to individual patients. (Strong recommendation; moderate-patients. (Strong recommendation; moderate-quality evidence)quality evidence)

4- ACP recommends further research to evaluate 4- ACP recommends further research to evaluate treatment of osteoporosis in men and women. treatment of osteoporosis in men and women.

Ann Intern Med 2008;149:404-415Ann Intern Med 2008;149:404-415

Risk of Afib with Risk of Afib with BisphosphonatesBisphosphonates

Health Outcomes and Reduced Incidence with Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly -Pivotal Fracture Zoledronic Acid Once Yearly -Pivotal Fracture TrialTrial (HORIZON)* (HORIZON)*

RCCT: 7765 postmenopausal women with RCCT: 7765 postmenopausal women with osteoporosis yearly zoledronic acid vs placebo x 3 osteoporosis yearly zoledronic acid vs placebo x 3 yrs.yrs.

Significant reduction in hip and vertebral fractures Significant reduction in hip and vertebral fractures Increased incidence of Afib classified as serious Increased incidence of Afib classified as serious

adverse event adverse event ((1.3% vs 0.4%)1.3% vs 0.4%) P<0.001 P<0.001 Overall freq of AF no different in 2 groups Overall freq of AF no different in 2 groups (2.4 vs (2.4 vs

1.9%)1.9%) Subsequent Subsequent HORIZON-Recurrent Fracture TrialHORIZON-Recurrent Fracture Trial

failed to find increased AF in treatment group. failed to find increased AF in treatment group.

Rate of AF serious adverse Rate of AF serious adverse eventsevents

Horizon-Pivotal Fracture TrialHorizon-Pivotal Fracture TrialZoledronic Zoledronic AcidAcid PlaceboPlacebo

Year 1Year 1 0.47%0.47% .29%.29%

Year 2Year 2 0.53% 0.53% .17%.17%

Year 3Year 3 0.51%0.51% .09%.09%

Association of other Association of other Bisphosphonates with AF Bisphosphonates with AF

RiskRisk Fracture Intervention Trial (FIT):Fracture Intervention Trial (FIT): RCCT RCCT

of alendronate in 6459 postmenopausal of alendronate in 6459 postmenopausal women. Serious adverse AF events women. Serious adverse AF events alendronate alendronate (1.5%) vs placebo (1.0%) P=.07(1.5%) vs placebo (1.0%) P=.07 NEJM 2007;356:1895-1896.

Case control studyCase control study:: More AF patients (719) More AF patients (719) than controls(966) had ever used than controls(966) had ever used alendronate alendronate (6.5% vs 4.2%, P=.03)(6.5% vs 4.2%, P=.03) Arch Int Med. Arch Int Med. 2008;168(8):826-31.2008;168(8):826-31.

Larger case control study in DenmarkLarger case control study in Denmark: : No assn of bisphosphonate use with AF in No assn of bisphosphonate use with AF in 13,586 patients w/AF and 68,054 controls. 13,586 patients w/AF and 68,054 controls. (3.2% vs 2.9%)(3.2% vs 2.9%) BMJ 2008;336:813-16.BMJ 2008;336:813-16.

SummarySummary

Some suggestion of increased AF Some suggestion of increased AF serious adverse events with serious adverse events with bisphosphonate therapybisphosphonate therapy

Not a consistent findingNot a consistent finding Prior RCCT were not designed to Prior RCCT were not designed to

examine the occurrence of Afib. examine the occurrence of Afib. Unlikely that there is causal relation Unlikely that there is causal relation

between AF and bisphosphonates. between AF and bisphosphonates.

CaseCase

68 year old WF calls you saying that her 68 year old WF calls you saying that her dentist wants to extract a tooth, but he is dentist wants to extract a tooth, but he is very concerned because she is on very concerned because she is on alendronate 70mg weekly. She wants to alendronate 70mg weekly. She wants to know your opinion regarding her risk for know your opinion regarding her risk for ONJ. ONJ.

PMH: 2 prior fragility fractures, T score PMH: 2 prior fragility fractures, T score <2.5<2.5

MEDS: alendronate 70 mg x 8 years MEDS: alendronate 70 mg x 8 years

ONJONJ

Bisphosphonate Associated Bisphosphonate Associated ONJ:ONJ: DefinitionDefinition

Current or previous treatment with a Current or previous treatment with a bisphosphonatebisphosphonate

Exposed, necrotic bone in the Exposed, necrotic bone in the maxillofacial region > 8 weeksmaxillofacial region > 8 weeks

No history of radiation therapy to No history of radiation therapy to the jawsthe jaws

American Academy of Oral and Maxillofacial Surgeons

Case Series 119 patientsCase Series 119 patients

. J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75

Case Series 119 patientsCase Series 119 patients

J Oral Maxillofac Surg. 2005 Nov;63(11):1567-75

EpidemiologyEpidemiology

Annals systematic review: 368 ONJ Annals systematic review: 368 ONJ patientspatients 84% with multiple myeloma or breast cancer84% with multiple myeloma or breast cancer 4% with osteoporosis4% with osteoporosis 60% after dentoalveolar surgery60% after dentoalveolar surgery Remaining 40% probably related to infection, Remaining 40% probably related to infection,

denture trauma or other traumadenture trauma or other trauma Prevalence of ONJ in cancer patients 6-10%Prevalence of ONJ in cancer patients 6-10% Prevalence in osteoporosis patients unknownPrevalence in osteoporosis patients unknown

Ann Intern Med 2006;144:753-761.

EpidemiologyEpidemiology

ASBMR task force review of case reportsASBMR task force review of case reports estimated risk as 1 in 10,000 to 1 in 100,000 patient estimated risk as 1 in 10,000 to 1 in 100,000 patient years of treatment. years of treatment.

Post-marketing surveillancePost-marketing surveillance Merk: 170 cases/20 million patient years (0.7/100,000patient Merk: 170 cases/20 million patient years (0.7/100,000patient

years)years) Proctor and Gamble: 1/10,000 patient yearsProctor and Gamble: 1/10,000 patient years

RCCTsRCCTs: : No cases of ONJ reported alendronate, risedronate, No cases of ONJ reported alendronate, risedronate,

ibandronateibandronate HORIZON: 2 cases (control, and placebo equal) HORIZON: 2 cases (control, and placebo equal)

Population based prevalence studies Population based prevalence studies :: 3 cases in 780,000 patients receiving bisphosphonates for 3 cases in 780,000 patients receiving bisphosphonates for

osteoporosis.osteoporosis. <1 in 100,000 patient-years<1 in 100,000 patient-years

CaseCase

Patient later informed you that she Patient later informed you that she underwent procedure without underwent procedure without incident. The dentist had drawn incident. The dentist had drawn “blood-work” which indicated that “blood-work” which indicated that her risk for ONJ was very low. her risk for ONJ was very low.

Bone Turnover Markers as Bone Turnover Markers as

Predictors of Risk?Predictors of Risk? Serum levels of morning fasting C terminal Serum levels of morning fasting C terminal

telopeptide (CTX)telopeptide (CTX) Based on data from 17 ONJ patients receiving Based on data from 17 ONJ patients receiving

bisphosphonates bisphosphonates <100 low risk<100 low risk 100-150 moderate risk100-150 moderate risk >150 high risk>150 high risk

Limitations: Limitations: No controlsNo controls Reduced markers of resorption expected in patients Reduced markers of resorption expected in patients

receiving bisphosphonatesreceiving bisphosphonates Low normal range in healthy women falls within range Low normal range in healthy women falls within range

proposed as high risk.proposed as high risk.J Oral Maxillofac Surgery 2007;65:2397-J Oral Maxillofac Surgery 2007;65:2397-24102410

Clinical ApplicationClinical Application

Risk of ONJ <1 in 100,00 patient years in Risk of ONJ <1 in 100,00 patient years in non-cancer patients using non-cancer patients using bisphosphonate treatment suggests a bisphosphonate treatment suggests a positive benefit-risk profile. positive benefit-risk profile.

All patients taking bisphosphonates All patients taking bisphosphonates should be informed of the benefits and should be informed of the benefits and risks of treatment.risks of treatment.

Patients taking bisphosphonates should Patients taking bisphosphonates should be encouraged to maintain good oral be encouraged to maintain good oral hygeine.hygeine.

SummarySummary

Consider screening postmenopausal women Consider screening postmenopausal women and men over 50 at increased risk for and men over 50 at increased risk for osteoporosisosteoporosis

Educate patients on universal Educate patients on universal recommendationsrecommendations

Consider treating patients with:Consider treating patients with: Prior fragility fracturePrior fragility fracture T<-2.5T<-2.5 Osteopenic patients with elevated risk profileOsteopenic patients with elevated risk profile

Review risk/benefit profile with all patientsReview risk/benefit profile with all patients

Medicare Coverage for Medicare Coverage for BMD TestingBMD Testing

Estrogen deficient women at clinical Estrogen deficient women at clinical riskrisk

Individuals with vertebral Individuals with vertebral abnormalitiesabnormalities

Individuals receiving or planning to Individuals receiving or planning to receive long term glucocorticoid receive long term glucocorticoid therapytherapy

Primary hyperparathyroidismPrimary hyperparathyroidism To assess response to therapyTo assess response to therapy

Screening: Pros and Screening: Pros and ConsCons

Pros: Pros: Common disease with significant morbidity Common disease with significant morbidity Screening methods availableScreening methods available Interventions available to reduce riskInterventions available to reduce risk Knowledge of risk could improve complianceKnowledge of risk could improve compliance

Cons:Cons: Little direct evidence that screening improves Little direct evidence that screening improves

outcome.outcome. No cutoff value for BMD that delineates fracture No cutoff value for BMD that delineates fracture

risk. risk. Other risk factors may be more important than Other risk factors may be more important than

BMD BMD Cost efficiency issuesCost efficiency issues Knowledge of normal value may hinder complianceKnowledge of normal value may hinder compliance

Non-FDA Approved Non-FDA Approved DrugsDrugs

CalcitriolCalcitriol Other bisphosphonates: (etidronate, Other bisphosphonates: (etidronate,

pamidronate, tiludronate)pamidronate, tiludronate) Parathyroid Hormone (PTH-84)Parathyroid Hormone (PTH-84) Sodium FlourideSodium Flouride Strontium renelateStrontium renelate TiboloneTibolone

Adverse Effects of DrugsAdverse Effects of Drugs

Bisphosphonates: Bisphosphonates: Gastrointestinal:Gastrointestinal:

Esophageal ulcerations Esophageal ulcerations Mild upper GI events (reflux, nausea)Mild upper GI events (reflux, nausea)

Osteonecrosis of the jaw:Osteonecrosis of the jaw: Atrial fibrillation: Atrial fibrillation:

Alendronate and zolendronic acidAlendronate and zolendronic acid

Adverse EffectsAdverse Effects EstrogenEstrogen

Thromboembolic eventsThromboembolic events Breast cancer (estrogen + progesterone)Breast cancer (estrogen + progesterone)

TeripartideTeripartide RCCTS RCCTS no evidence of serious adverse events no evidence of serious adverse events

SERMsSERMs Pulmonary embolismPulmonary embolism ThromboembolicThromboembolic

Calcium and vitamin DCalcium and vitamin D RCCTs no clinically important serious adverse RCCTs no clinically important serious adverse

events. events.