Drug Therapy for Osteoporosis - · PDF fileDrug Therapy for Osteoporosis ... written consent...

1

Drug Therapy for Drug Therapy for OsteoporosisOsteoporosis

Question 1Question 1

Which of the following medications is considered Which of the following medications is considered firstfirst--line therapy for osteoporosis?line therapy for osteoporosis?

A.A. Bisphosphonates Bisphosphonates B.B. RaloxifeneRaloxifeneC.C. CalcitoninCalcitoninD.D. Hormone replacement therapyHormone replacement therapy


Which of the following natural products Which of the following natural products has been shown to prevent osteoporosis? has been shown to prevent osteoporosis?

A.A. IsoflavonesIsoflavonesB.B. Black Black cohoshcohoshC.C. Soy milkSoy milkD.D. None of the above None of the above

This education program is a product/publication of the National Community Pharmacists Association (NCPA).Copyright © 2006. All rights reserved.

Any reproduction, photocopying, storage or transmission by magnetic or electronic means without the expressed written consent of NIPCO/NCPA and the payment of appropriate fees is strictly prohibited by law.

2


Which of the following medications is Which of the following medications is limited for use in highlimited for use in high--risk patients?risk patients?

A.A. RaloxifeneRaloxifeneB.B. CalcitoninCalcitoninC.C. Teriparatide Teriparatide D.D. IbandronateIbandronate


Which of the following does NOT have FDA Which of the following does NOT have FDA indication for the prevention of osteoporosis?indication for the prevention of osteoporosis?

A.A. EstrogenEstrogenB.B. AlendronateAlendronateC.C. Calcitonin Calcitonin D.D. RaloxifeneRaloxifene


What is the key end point of any clinical What is the key end point of any clinical trial involving therapy for osteoporosis?trial involving therapy for osteoporosis?

A.A. Patient drop out ratePatient drop out rateB.B. Effect on bone densityEffect on bone densityC.C. Effect of fracture incidence Effect of fracture incidence D.D. Incidence of adverse eventsIncidence of adverse events



3

InstructionsInstructions

While viewing this multiWhile viewing this multi--media program, you can control the slides and media program, you can control the slides and audio by using the audio by using the ““playplay””, , ““pausepause””, , ““nextnext””, and , and ““previousprevious”” controls.controls.

You can also jump to a specific slide using the thumbnail imagesYou can also jump to a specific slide using the thumbnail images at theat thebottom of the screen.bottom of the screen.

Scroll throughthumbnail images

Previous Play/Pause Next

Learning ObjectivesLearning Objectives

Describe the appropriate use of the various Describe the appropriate use of the various pharmacotherapeuticpharmacotherapeutic choices to treat osteoporosis, choices to treat osteoporosis, including indication, mechanism of action, dosing, including indication, mechanism of action, dosing, administration, adverse effects and precautionsadministration, adverse effects and precautionsExplain the role of the drugs approved for Explain the role of the drugs approved for osteoporosis in the management of this diseaseosteoporosis in the management of this diseaseEducate patients about the various Educate patients about the various pharmacotherapeuticpharmacotherapeutic choices to treat osteoporosis choices to treat osteoporosis and monitor their response to therapy and monitor their response to therapy

At the conclusion of this program participants should conclusion of this program participants should be able to:be able to:

Laura Hansen, Laura Hansen, PharmDPharmD

BS in Pharmacy from the University of Iowa BS in Pharmacy from the University of Iowa and Doctor of Pharmacy from the University and Doctor of Pharmacy from the University of Coloradoof ColoradoBoard Certified Pharmacotherapy Specialist Board Certified Pharmacotherapy Specialist and Fellow of the American College of and Fellow of the American College of Clinical PharmacyClinical PharmacyCurrently an Assistant Professor of Clinical Currently an Assistant Professor of Clinical Pharmacy and Family Medicine with the Pharmacy and Family Medicine with the University of Colorado University of Colorado



4

Overview of Drug Overview of Drug TherapyTherapy

The Osteoporosis PyramidThe Osteoporosis Pyramid

Pharmacotherapy

Identify and Address Secondary Causes

Lifestyle Changes

Role of Drug TherapyRole of Drug Therapy

Osteoporosis is preventable & Osteoporosis is preventable & treatable though not currently treatable though not currently curablecurableAvailable therapies can effectively Available therapies can effectively prevent further disease progression prevent further disease progression and reduce disability associated and reduce disability associated with fractureswith fractures



5

Categories of DrugsCategories of Drugs

Antiresporptive

agents

Formation-stimulating drugs

Drugs for Osteoporosis

AntiresorptiveAntiresorptive AgentsAgentsMajor Action: suppress bone Major Action: suppress bone resorptionresorptionpreventing further bone losspreventing further bone loss–– Decrease in number or depth of Decrease in number or depth of resorptiveresorptive sitessites–– Stops further architectural lossStops further architectural loss–– Slower turnover allows better mineralizationSlower turnover allows better mineralization

Resulting increase in BMD due to more complete Resulting increase in BMD due to more complete mineralization, not increased synthesis of bone mineralization, not increased synthesis of bone –– May increase BMD by 2May increase BMD by 2--8% 8%

AntiresorptiveAntiresorptive AgentsAgents

ERT/HRTERT/HRTAlendronate (FosamaxAlendronate (Fosamax®®))SalmonSalmon--calcitonincalcitonin ((ForticalFortical®®, MiacalcinMiacalcin®®))RaloxifeneRaloxifene ((EvistaEvista®®))RisedronateRisedronate ((ActonelActonel®®))IbandronateIbandronate ((BonivaBoniva®®))



6

FormationFormation--Stimulating DrugsStimulating DrugsMajor Action: stimulate formation of Major Action: stimulate formation of bone massbone mass

»» May increase BMD by 10May increase BMD by 10--20%20%»» May increase cortical thickness & enhance May increase cortical thickness & enhance

trabeculartrabecular microarchitecturemicroarchitecture

FormationFormation--Stimulating DrugsStimulating Drugs

Teriparatide (Teriparatide (ForteoForteo®®))

Drug Development for Drug Development for OsteoporosisOsteoporosisDiscovery of OsteoporosisDiscovery of Osteoporosis

1800s1800s------------------------

Connection between Menopause and Osteoporosis Connection between Menopause and Osteoporosis 19401940

--------------------------Postmenopausal & Senile Osteoporosis Clearly DistinguishedPostmenopausal & Senile Osteoporosis Clearly Distinguished

1980s1980s--------------------------------------

InjectableInjectable calcitonincalcitonin approved for treatment approved for treatment 19841984



7

CEE (Premarin®) Labeling revised to indicate for treatment (early 1990s)

--------------------Miacalcin Nasal Spray® (calcitonin) Approved for treatment

1995--------------------

Alendronate (Fosamax®) Approved for prevention and treatment 1995

---------------------Raloxifene (Evista®) Approved for prevention and treatment

1997----------------------

Risedronate (Actonel®) Approved for prevention and treatment 1998

Drug Development (cont.)

CEE (Premarin®) Package labeling revised to indicate for prevention

2000------------------

The first once weekly bisphosphonate approved2000

------------------Teriparatide (Forteo®) Approved for the prevention and

treatment of fracture in patients at high risk 2002

-------------------FDA approves new labeling for estrogens due to WHI

2003---------------------

Ibandronate (Boniva®) Approved for prevention and treatment 2003 marketed 2005

Drug Development (cont.)

Evaluation of DrugEvaluation of DrugTherapy EffectivenessTherapy Effectiveness

Effect on bone densityEffect on bone densityEffect on fracture incidenceEffect on fracture incidence



8

Fractures are the key endpoint of any clinical trial of therapy for osteoporosis.

KEYPOINT

Estrogen ReplacementEstrogen ReplacementTherapy (ERT)Therapy (ERT)

andandHormone ReplacementHormone Replacement

Therapy (HRT)Therapy (HRT)

ERT/HRTERT/HRT

Indication (relative to osteoporosis):Indication (relative to osteoporosis):Prevention of osteoporosisPrevention of osteoporosis



9

ERT/HRTERT/HRTMechanism of Action in Osteoporosis Mechanism of Action in Osteoporosis –– Inhibits bone Inhibits bone resorptionresorption–– Estrogen receptors are located in Estrogen receptors are located in osteoclastsosteoclasts & &

osteoblastsosteoblasts–– Estrogen accelerates the death of Estrogen accelerates the death of osteoclastsosteoclasts

while prolonging life of while prolonging life of osteoblastsosteoblasts–– Increases intestinal calcium absorption and Increases intestinal calcium absorption and

renal calcium conservationrenal calcium conservation

ERT/HRTERT/HRT

EfficacyEfficacy–– Increases cortical BMD 1Increases cortical BMD 1--3% & 3% &

trabeculartrabecular 22--5% 5% –– Decreases vertebral fractures Decreases vertebral fractures

34% and hip fractures 25%34% and hip fractures 25%

Risks & Benefits of HRT in Healthy Risks & Benefits of HRT in Healthy Postmenopausal Women (Women’s Health Postmenopausal Women (Women’s Health

Initiative)Initiative)JAMA 2002;288:329JAMA 2002;288:329--333333

Patient Population: Patient Population: 16,608 postmenopausal women aged 50-79 y with intact uterus– 7.7% had prior cardiovascular disease

Therapy: Therapy: CEE 0.625mg + medroxyprogesteroneacetate 2.5mg/d (PremPro®) or placeboResults: Results: On May 31, 2002 after a mean of 5.2 y of F/U, data & safety monitoring board recommended stopping the trial because statistic for breast cancer exceeded stopping boundary & global index statistic supported risks exceeding benefits



10

WHI ResultsWHI ResultsAmong 10,000 users of HRT there were:Among 10,000 users of HRT there were:

+ 7 heart attacks+ 7 heart attacks+ 8 strokes+ 8 strokes+ 8 breast cancers+ 8 breast cancers+ 8 blood clots+ 8 blood clots

-- 6 colon cancers6 colon cancers-- 5 hip fractures5 hip fractures

20 extra adverse outcomes/yr for every 20 extra adverse outcomes/yr for every 10,000 users10,000 users




20 extra adverse outcomes/yr for every 10,000 20 extra adverse outcomes/yr for every 10,000 usersusers


+ 7 heart attacks+ 7 heart attacks

+ 8 strokes+ 8 strokes+ 8 breast cancers+ 8 breast cancers+ 8 blood clots+ 8 blood clots





11


+ 7 heart attacks+ 7 heart attacks+ 8 strokes+ 8 strokes

+ 8 breast cancers+ 8 breast cancers+ 8 blood clots+ 8 blood clots




+ 7 heart attacks+ 7 heart attacks+ 8 strokes+ 8 strokes+ 8 breast cancers+ 8 breast cancers

+ 8 blood clots+ 8 blood clots









12



-- 6 colon cancers6 colon cancers

-- 5 hip fractures5 hip fractures





20 extra adverse outcomes/yr 20 extra adverse outcomes/yr for every 10,000 usersfor every 10,000 users

WHI: Study LimitationsWHI: Study Limitations

The trial tested only one drug regimenThe trial tested only one drug regimen–– Lower doses?Lower doses?–– Other formulations?Other formulations?

The trial does not distinguish the effects of The trial does not distinguish the effects of estrogen from progestinestrogen from progestinOnly studied a small group of women in their Only studied a small group of women in their early 50s who were recently menopausal early 50s who were recently menopausal



13

WHI: RecommendationsWHI: RecommendationsEstrogen & progestin therapy should not be Estrogen & progestin therapy should not be continued or started to prevent heart diseasecontinued or started to prevent heart diseaseShort term use for managing menopausal Short term use for managing menopausal symptoms?symptoms?–– This use was not specifically addressedThis use was not specifically addressed–– Results suggest that use Results suggest that use << 1 yr has risks for coronary 1 yr has risks for coronary

heart disease & thromboembolic diseaseheart disease & thromboembolic disease–– Must balance severity of symptoms with small absolute Must balance severity of symptoms with small absolute

risksrisksOsteoporosis prevention?Osteoporosis prevention?–– Must balance benefits with small absolute risksMust balance benefits with small absolute risks–– Alternate treatments are availableAlternate treatments are available

Menopausal Hormone Menopausal Hormone Replacement Therapy & Risk of Replacement Therapy & Risk of

Ovarian CancerOvarian CancerJAMA2002;288:334JAMA2002;288:334--341341

Patient Population: Patient Population: 44,241 postmenopausal women followed about 20 yearsTherapy: Therapy: ERT or HRTResults: Results: – Women on ERT for 10-19 yr were twice as

likely to develop ovarian cancer compared to women not using hormones

– Women in ERT for > 20 yr were three times as likely to develop ovarian cancer

ERT / HRTERT / HRT

What to doWhat to do??



14

Current RecommendationsCurrent RecommendationsUS Preventive Services Task Force US Preventive Services Task Force (Ann Intern Med 2005;142:855(Ann Intern Med 2005;142:855--860)860)–– Recommends against the routine use of combined Recommends against the routine use of combined

estrogen & progestin for the prevention of chronic estrogen & progestin for the prevention of chronic conditions conditions

Am College of Ob Am College of Ob GynsGyns & N Am Menopause & N Am Menopause SocietySociety–– Recommend caution in using HRT solely to prevent Recommend caution in using HRT solely to prevent

osteoporosis & suggest alternative therapies should be osteoporosis & suggest alternative therapies should be consideredconsidered

Labeling update for estrogen products (Wyeth):Labeling update for estrogen products (Wyeth):–– Women taking estrogen only for osteoporosis Women taking estrogen only for osteoporosis

prevention should consider alternative therapiesprevention should consider alternative therapies–– Take HRT for shortest time possible at lowest doseTake HRT for shortest time possible at lowest dose

The argument against using The argument against using postmenopausal hormone postmenopausal hormone therapy for the prevention of therapy for the prevention of chronic diseases is not that the chronic diseases is not that the likelihood of harm is high, but likelihood of harm is high, but that the potential harm that the potential harm outweighs the potential benefit.outweighs the potential benefit.

Effect of Discontinuation of Estrogen, Effect of Discontinuation of Estrogen, CalcitriolCalcitriol& the Combo on BMD & Bone Markers& the Combo on BMD & Bone Markers

J J ClinClin EndocrinolEndocrinol MetabMetab 2002;87:49142002;87:4914--2323

Patient Population: Patient Population: 489 women (mean age 72) 489 women (mean age 72) randomized to receive 3 yr course of HRT, randomized to receive 3 yr course of HRT, calcitriolcalcitriolor combo. Subset ofor combo. Subset of 178178 observed forobserved for 2yr following 2yr following D/C of D/C of txtxResults:Results:–– Spine BMD increased 6% on HRT; 2/3 of gain was lost Spine BMD increased 6% on HRT; 2/3 of gain was lost

during 2 yr off HRTduring 2 yr off HRT–– Femoral neck BMD increased 4% on HRT, 2/3 lost Femoral neck BMD increased 4% on HRT, 2/3 lost

during 2 yr off HRTduring 2 yr off HRT–– At each site, greatest decrease in BMD occurred during At each site, greatest decrease in BMD occurred during

11stst yr off HRT yr off HRT



15

Natural ProductsNatural Products

Compounded dosage formsCompounded dosage formsFood sourcesFood sources

BioidenticalBioidentical Hormone Hormone Replacement TherapyReplacement Therapy

Contain hormones identical to endogenous Contain hormones identical to endogenous hormones (hormones (estradiolestradiol, , estriolestriol, , estroneestrone, , progesterone & testosterone)progesterone & testosterone)Usually plantUsually plant--based based –– extracted & derived extracted & derived from soy or yamsfrom soy or yamsCommonly used form is Commonly used form is micronizedmicronized triple triple estrogen (Triestrogen (Tri--EstEst®) with ) with micronizedmicronizedprogesteroneprogesterone

LimitationsLimitations

Lack of well designed studies to evaluate Lack of well designed studies to evaluate these products. Risks & benefits, especially these products. Risks & benefits, especially with longwith long--term use, remain uncertainterm use, remain uncertainSpecifically, ability to prevent osteoporosis Specifically, ability to prevent osteoporosis not sufficiently studiednot sufficiently studied



16

Common MisconceptionsCommon Misconceptions

Natural hormones have no Natural hormones have no potential for risks or adverse potential for risks or adverse effectseffectsNatural hormones are obtained Natural hormones are obtained directly from plants with little or directly from plants with little or no processingno processing

TransdermalTransdermal Progesterone Cream for Progesterone Cream for Vasomotor Symptoms & Postmenopausal Vasomotor Symptoms & Postmenopausal

Bone LossBone LossObstet Gynecol 1999;94:225-8

Patient Population: Patient Population: 102 women within 5 102 women within 5 years of menopauseyears of menopauseTherapy: Therapy: Placebo OR progesterone cream Placebo OR progesterone cream (Pro(Pro--GestGest®®) 20mg once daily (1/4 tsp) ) 20mg once daily (1/4 tsp) AllAllpatients receive multivitamin + calcium 1200 patients receive multivitamin + calcium 1200 mg/dmg/dResults: Results: At one year, effects on BMD were At one year, effects on BMD were not significantly different from placebo not significantly different from placebo

DioscoreaDioscorea VillosaVillosa (Wild Yam) (Wild Yam) CreamsCreams

Widely advertised as a source of natural Widely advertised as a source of natural progesteroneprogesteroneCONCERN:CONCERN:–– Wild yam is not converted to progesterone in the body Wild yam is not converted to progesterone in the body

as often as claimed as often as claimed –– These creams do not contain progesterone unless a These creams do not contain progesterone unless a

small variable amount of pharmaceuticalsmall variable amount of pharmaceutical--grade grade progesterone has been added progesterone has been added

–– Lack of information about the effectiveness or longLack of information about the effectiveness or long--term safety of natural progesterone productsterm safety of natural progesterone products



17

PhytoestrogensPhytoestrogens(Plant Estrogens)(Plant Estrogens)

Weak estrogenic effect in the bodyWeak estrogenic effect in the bodySeem to mimic the action of estrogen Seem to mimic the action of estrogen and in other tissues they seem to block and in other tissues they seem to block the action of estrogenthe action of estrogen

Classification of Classification of PhytoestrogensPhytoestrogensIsoflavonoidsIsoflavonoids–– IsoflavonesIsoflavones

»» Over 1,000 typesOver 1,000 types»» GenisteinGenistein & & daidzeindaidzein have highest have highest

estrogenic propertiesestrogenic properties–– CoumestansCoumestansLignansLignansOthers Others –– Black Black cohoshcohosh–– Red cloverRed clover

IsoflavonesIsoflavonesAntioxidant activity Antioxidant activity Weak plant versions of estrogenWeak plant versions of estrogenMajor source = soy beans & red Major source = soy beans & red clovercloverBind to estrogen receptors 100 to Bind to estrogen receptors 100 to 1,000 times weaker than 1,000 times weaker than estradiolestradiol



18

IsoflavonesIsoflavonesDosageDosage: : Not well defined. Most studies used soy Not well defined. Most studies used soy isoflavonesisoflavones 80 mg/day80 mg/dayFood Sources:Food Sources:–– Soy flour ¼ cup = 44 mgSoy flour ¼ cup = 44 mg–– Soy milk 1 cup = 20 mgSoy milk 1 cup = 20 mg–– Uncooked tofu 4oz = 38 mgUncooked tofu 4oz = 38 mg

Commercial Products:Commercial Products:–– OneOne--AA--Day Bone Strength = Day Bone Strength = isoflavonesisoflavones 10 mg, calcium 500 10 mg, calcium 500

mg & vitamin D 100 IUmg & vitamin D 100 IU–– CaltrateCaltrate 600 + Soy = 600 + Soy = isoflavonesisoflavones 25 mg, calcium 600 mg & 25 mg, calcium 600 mg &

vitamin D 200 IUvitamin D 200 IU

IpriflavoneIpriflavone in the Treatment of in the Treatment of Postmenopausal OsteoporosisPostmenopausal Osteoporosis

JAMA 2001;285:1482JAMA 2001;285:1482--14881488

Design: Prospective, randomized, double-blind, placebo-controlled 4 yr studyPatient Population: 474 postmenopausal Caucasian women, 45 – 75yo, with BMD < 0.86 g/cm2

Therapy: Randomly assigned to ipriflavone 200 mg tid or placebo; all received calcium 500 mgResults: – No change in annual % change from baseline in BMD at any

site measured– No difference in biochemical markers– No difference in number of new vertebral fractures

Effect of Soy Protein Containing Effect of Soy Protein Containing IsoflavonesIsoflavoneson Cognitive Function, BMD, and Plasma on Cognitive Function, BMD, and Plasma

Lipids in Postmenopausal Women Lipids in Postmenopausal Women JAMA 2004;292:65JAMA 2004;292:65--7474

Patient Population:Patient Population: 175 late menopausal women, 175 late menopausal women, mean of 18 years after onset of menopause mean of 18 years after onset of menopause Therapy: Therapy: soy protein supplements (25.6 gm/day) soy protein supplements (25.6 gm/day) containing 99 mg of containing 99 mg of isoflavonesisoflavones vsvs milk proteinmilk proteinResults: Results: 1 yr comparison with baseline values, no 1 yr comparison with baseline values, no significant differences were found in either group significant differences were found in either group in cognition, lipid levels or BMDin cognition, lipid levels or BMD



19

Soy Soy IsoflavonesIsoflavones and Bone Lossand Bone LossNot wellNot well--studied in Caucasian womenstudied in Caucasian women–– No large scale, wellNo large scale, well--controlled controlled

studiesstudiesToo early to make specific health Too early to make specific health claims for soyclaims for soyIn theory, could competitively inhibit In theory, could competitively inhibit effects of ERTeffects of ERTQuestion: should these women be Question: should these women be given progesterone?given progesterone?

BisphosphonatesBisphosphonates


–– AlendronateAlendronate ((FosamaxFosamax®®))–– RisedronateRisedronate ((ActonelActonel®®))–– IbandronateIbandronate ((BonivaBoniva®®))



20


Mechanism of ActionMechanism of ActionInterferes with activity of Interferes with activity of osteoclastsosteoclasts–– Reduces amount of bone Reduces amount of bone resorbedresorbed–– Results in fewer & shallower Results in fewer & shallower resorptionresorption sitessites–– Increases bone mineralizationIncreases bone mineralization

Resulting increases in BMD due to more Resulting increases in BMD due to more complete mineralization, not increased complete mineralization, not increased synthesis of bonesynthesis of bone

BisphosphonatesBisphosphonatesPharmacokineticsPharmacokinetics

Once absorbed, about 50% is rapidly bound to active Once absorbed, about 50% is rapidly bound to active bone remodeling sitesbone remodeling sites–– Most retained in Most retained in trabeculartrabecular bonebone

Estimated halfEstimated half--life is similar to bone turnover (1life is similar to bone turnover (1--10 yr)10 yr)Amount in skeleton gradually increases over timeAmount in skeleton gradually increases over time–– Predicted max amt in bone after 10 y of 70 mg/wk would be Predicted max amt in bone after 10 y of 70 mg/wk would be

75 mg alendronate75 mg alendronate

About ½ the alendronate in bone is removed within 3 y About ½ the alendronate in bone is removed within 3 y of discontinuationof discontinuation


Dosing IntervalsDosing IntervalsLong halfLong half--life of residence on bone life of residence on bone surfacesurfaceIncreased dosing convenienceIncreased dosing convenienceIncreased patient Increased patient acceptance/complianceacceptance/complianceReduced potential for upper GI Reduced potential for upper GI ADRsADRs



21

BisphosphonatesBisphosphonatesAdministration IssuesAdministration Issues

Poor oral absorptionPoor oral absorption–– Only 1Only 1--5% is absorbed5% is absorbed–– Reduced further with the presence of food Reduced further with the presence of food

or calciumor calcium»» Less than 90% with foodLess than 90% with food»» Less than 60% with coffee or orange juiceLess than 60% with coffee or orange juice

GI irritationGI irritation–– May cause local irritation of the upper GI May cause local irritation of the upper GI

mucosa if not taken precisely as directedmucosa if not taken precisely as directed


Administration RequirementsAdministration RequirementsTake with a full glass of water in morningTake with a full glass of water in morningDo NOT eat or drink anything for at least 30 Do NOT eat or drink anything for at least 30 minutes after taking (minutes after taking (IbandronateIbandronate: 60 minutes): 60 minutes)Do NOT lie down for at least 30 minutes after Do NOT lie down for at least 30 minutes after taking and until after eating (taking and until after eating (IbandronateIbandronate: : 60 minutes)60 minutes)

Same for all dosage formsSame for all dosage forms


Adverse EffectsAdverse EffectsGI upsetGI upset–– NauseaNausea–– DyspepsiaDyspepsia–– Abdominal pain Abdominal pain



22

Upper Gastrointestinal Tract Safety Profile Upper Gastrointestinal Tract Safety Profile of Alendronateof Alendronate

Arch Intern Med. 2000;160:517Arch Intern Med. 2000;160:517--2525

Patient Population: Patient Population: FIT trial (3.8 years)FIT trial (3.8 years)Measurements: Measurements: –– Patient interview every 3 monthsPatient interview every 3 months–– Review of hospital records & Review of hospital records & endoscopyendoscopy reportsreports

Results:Results:–– Overall incidence of upper GI tract events: 47.5% Overall incidence of upper GI tract events: 47.5%

with alendronate & 46.2% with placebowith alendronate & 46.2% with placebo–– Dyspepsia was most common event: 18.2% with Dyspepsia was most common event: 18.2% with

alendronate & 19.1% with placeboalendronate & 19.1% with placebo–– No significant difference in incidence of serious No significant difference in incidence of serious

eventsevents–– Alendronate not associated with significant increase Alendronate not associated with significant increase

in events among women at increased risk (age >75; in events among women at increased risk (age >75; previous upper GI tract diseases; NSAIDs)previous upper GI tract diseases; NSAIDs)

Oral Oral BisphosphonatesBisphosphonates & Upper GI Tract & Upper GI Tract Problems: What is the Evidence?Problems: What is the Evidence?

Mayo Mayo ClinClin Proc 2002;77:1031Proc 2002;77:1031--10431043

Methods: Methods: Reviewed, rated & summarized Reviewed, rated & summarized published info on upper GI tract safety of published info on upper GI tract safety of bisphosphonatesbisphosphonates using principles of evidenceusing principles of evidence--based medicine based medicine Results:Results:–– Randomized controlled trials suggest little or no Randomized controlled trials suggest little or no

increase in risk of upper GI tract problems if increase in risk of upper GI tract problems if administered properlyadministered properly

–– Many Many ADRsADRs reported may reflect high background reported may reflect high background incidence of upper GI complaints and increased incidence of upper GI complaints and increased sensitivity to detection rather than causal effect to sensitivity to detection rather than causal effect to therapytherapy

BisphosphonatesBisphosphonatesAdverse EffectsAdverse Effects

GI upsetGI upset–– All oral All oral bisphosphonatesbisphosphonates can produce GI adverse effectcan produce GI adverse effect–– The background incidence of GI symptoms in older women The background incidence of GI symptoms in older women

is high, even in the absence of medicationsis high, even in the absence of medications–– In clinical trials, patients treated with either alendronate or In clinical trials, patients treated with either alendronate or

risedronaterisedronate had no greater incidence of GI had no greater incidence of GI AEsAEs than did the than did the controls controls

–– In clinical practice, it is not obvious that there is a In clinical practice, it is not obvious that there is a meaningful difference between alendronate & meaningful difference between alendronate & risedronaterisedronate



23


Severe bone, joint and muscle painSevere bone, joint and muscle pain–– Described as severe, extreme, disabling Described as severe, extreme, disabling

painpain–– Bones, joints and muscles throughout were Bones, joints and muscles throughout were

affectedaffected–– Many unable to perform usual activities, Many unable to perform usual activities,

some required bed rest, walkers or crutchessome required bed rest, walkers or crutches


Severe bone, joint and muscle painSevere bone, joint and muscle pain–– Onset ranged from same day to 52 months. Onset ranged from same day to 52 months.

Average was 14 days from therapy startAverage was 14 days from therapy start–– Most experienced relief after D/C Most experienced relief after D/C –– some had some had

immediate improvements, others more immediate improvements, others more gradual gradual

Bisphosphonate Associated Severe Bisphosphonate Associated Severe Bone, Joint and Muscle PainBone, Joint and Muscle Pain

AlendronateAlendronate–– From Sept 95 to Nov 02, 118 reportsFrom Sept 95 to Nov 02, 118 reports–– 74% at 10 mg daily, 18% at 70 mg weekly74% at 10 mg daily, 18% at 70 mg weekly

RisedronateRisedronate–– From Sept 98 to June 03, 6 reportsFrom Sept 98 to June 03, 6 reports–– Details not published Details not published

Serious bone, joint and/or muscle pain that Serious bone, joint and/or muscle pain that begins shortly after bisphosphonate initiation begins shortly after bisphosphonate initiation should be reportedshould be reported



24


Adverse EffectsAdverse EffectsOsteonecrosis of the jaw (ONJ)Osteonecrosis of the jaw (ONJ)–– Reports of ONJ primarily in cancer patients receiving Reports of ONJ primarily in cancer patients receiving

chronic IV bisphosphonates chronic IV bisphosphonates »» These IV agents are indicated for Paget’s disease, These IV agents are indicated for Paget’s disease,

hypercalcemia associated with malignancy, metastatic bone hypercalcemia associated with malignancy, metastatic bone lesions and multiple myeloma:lesions and multiple myeloma:

Pamidronate (ArediaPamidronate (Aredia®®))Zoledronic acid (ZometaZoledronic acid (Zometa®®))

–– Labeling for oral & IV agents now includes this class Labeling for oral & IV agents now includes this class osteonecrosis riskosteonecrosis risk

OsteonecrosisOsteonecrosis of the Jawof the JawJaw bone is particularly vulnerable because of Jaw bone is particularly vulnerable because of tooth and gum susceptibility to infectiontooth and gum susceptibility to infectionThe death of bone resulting in collapse of The death of bone resulting in collapse of structural architecture structural architecture Leads to bone pain, loss of function and Leads to bone pain, loss of function and destructiondestructionS/S: gum pain, swelling, poor healing, loosening S/S: gum pain, swelling, poor healing, loosening of teeth, drainage and exposed boneof teeth, drainage and exposed boneRange of severity from asymptomatic to need for Range of severity from asymptomatic to need for partial jaw removal partial jaw removal

Bisphosphonate Associated ONJBisphosphonate Associated ONJFDA Adverse Event ReportsFDA Adverse Event Reports–– 139 cases of ONJ from marketing approval 139 cases of ONJ from marketing approval

dates until May 2004dates until May 2004»» 34% 34% pamidronatepamidronate ((ArediaAredia®®))»» 24% 24% zoledroniczoledronic acid (acid (ZometaZometa®®))»» 42% receiving both agents42% receiving both agents»» 8.6% alendronate (8.6% alendronate (FosamaxFosamax®®))»» 1 case 1 case risedronaterisedronate ((ActonelActonel®®))

–– Majority occurred after a dental extraction; Majority occurred after a dental extraction; some occurred spontaneously some occurred spontaneously



25

Bisphosphonate Associated ONJBisphosphonate Associated ONJRecommendationsRecommendations–– Maintain excellent oral hygiene and have Maintain excellent oral hygiene and have

routine dental examsroutine dental exams–– Dental professionals need to give careful Dental professionals need to give careful

attention to avoid soft tissue injury during attention to avoid soft tissue injury during routine dental cleaningsroutine dental cleanings

–– Delay bisphosphonate therapy, if possible, Delay bisphosphonate therapy, if possible, to complete dental procedures with poor to complete dental procedures with poor prognosisprognosis

–– Avoid elective jaw procedures Avoid elective jaw procedures


Ocular side effectsOcular side effects–– Incidence is rare Incidence is rare –– First reported with IV First reported with IV pamidronatepamidronate ((ArediaAredia®®))–– Other agents implicated include alendronate Other agents implicated include alendronate

& & risedronaterisedronate–– Ocular problems include nonspecific Ocular problems include nonspecific

conjunctivitis, conjunctivitis, scleritisscleritis & & uveitisuveitis–– Onset within 6 to 48 hours after Onset within 6 to 48 hours after

administrationadministration

BisphosphonatesBisphosphonates and and Ocular Side EffectsOcular Side Effects

Nonspecific conjunctivitisNonspecific conjunctivitis–– Most common ocular effect reportedMost common ocular effect reported–– S/S: blurred vision, mucus dischargeS/S: blurred vision, mucus discharge–– Typically no treatment was needed & Typically no treatment was needed &

symptoms diminished over time with symptoms diminished over time with continued bisphosphonate treatment continued bisphosphonate treatment



26


ScleritisScleritis–– Required D/C of Required D/C of pamidronatepamidronate for resolutionfor resolution

UveitisUveitis–– The most serious conditionThe most serious condition–– If left untreated can seriously compromise If left untreated can seriously compromise

visionvision–– Some cases required hospitalization Some cases required hospitalization


Advise patients to report any symptoms of Advise patients to report any symptoms of possible ocular problems such as ocular possible ocular problems such as ocular pain, blurred or diminished vision or pain, blurred or diminished vision or photophobia photophobia Should be referred to ophthalmologist Should be referred to ophthalmologist


CNS toxicityCNS toxicity–– Auditory hallucinations, visual disturbances, Auditory hallucinations, visual disturbances,

amnesia, confusion, depression amnesia, confusion, depression –– Very rare; case reports with Very rare; case reports with pamidronatepamidronate, ,

etidronateetidronate & alendronate& alendronate–– Mechanism unknownMechanism unknown

»» Does not appear to be secondary to Does not appear to be secondary to hypocalcemiahypocalcemia



27

BisphosphonatesBisphosphonatesConsiderationsConsiderations

Use with caution in patients with active GI Use with caution in patients with active GI problems including problems including dysphagiadysphagia, symptomatic , symptomatic esophageal disease, gastritis, ulcersesophageal disease, gastritis, ulcersRisedronateRisedronate does not have contraindications does not have contraindications related to upperrelated to upper--GI disorders. Has general GI disorders. Has general precaution that precaution that bisphosphonatesbisphosphonates may cause uppermay cause upper--GI complicationsGI complicationsConcurrent therapy with ASA or any NSAID Concurrent therapy with ASA or any NSAID compounds increase the likelihood of esophageal compounds increase the likelihood of esophageal ulceration and will require close monitoringulceration and will require close monitoring


ConsiderationsConsiderationsSafety and efficacy have not been Safety and efficacy have not been established in pediatrics or pregnant established in pediatrics or pregnant womenwomenCategory C Category C


ConsiderationsConsiderationsEnsure patients maintain dietary and Ensure patients maintain dietary and supplemental calcium intakesupplemental calcium intake



28

BisphosphonatesBisphosphonatesPatient Monitoring/EducationPatient Monitoring/Education

Review medication administration Review medication administration procedureprocedureReview signs and symptoms suggestive Review signs and symptoms suggestive of esophageal irritationof esophageal irritation–– Difficulty swallowingDifficulty swallowing–– New or worsening heartburnNew or worsening heartburn–– RetrosternalRetrosternal painpain

Discontinue Discontinue alendronatealendronate and seek medical and seek medical attention if these symptoms occurattention if these symptoms occur

AlendronateAlendronateIndicationIndication

For the prevention and treatment of For the prevention and treatment of osteoporosis in postmenopausal osteoporosis in postmenopausal womenwomenFor treating For treating glucocorticoidglucocorticoid--induced induced osteoporosis in men and womenosteoporosis in men and womenFor treatment to increase bone For treatment to increase bone mass in men with osteoporosismass in men with osteoporosis

AlendronateAlendronate

EfficacyEfficacyIncreased BMD at lumbar spine Increased BMD at lumbar spine 55--10%, femoral neck 2.310%, femoral neck 2.3--4.8% 4.8% Reduced fracture rate at spine & wrist Reduced fracture rate at spine & wrist by 47% and hip by 51% in patients by 47% and hip by 51% in patients with osteoporosiswith osteoporosis



29

Randomized Trial of Effect of Alendronate on Randomized Trial of Effect of Alendronate on Risk of Fracture in Women with Risk of Fracture in Women with

Existing Vertebral FracturesExisting Vertebral FracturesLancet 1996;348:1535Lancet 1996;348:1535--41.41.

Patient Population:Patient Population: 2,027 postmenopausal 2,027 postmenopausal women with prewomen with pre--existing vertebral fractureexisting vertebral fractureTherapy: Therapy: Placebo OR alendronate 5 mg/d for 2 Placebo OR alendronate 5 mg/d for 2 years followed by 10 mg/d for 1 yearyears followed by 10 mg/d for 1 yearAll patients with dietary calcium < 1,000 mg/d All patients with dietary calcium < 1,000 mg/d received 500 mg/d and vitamin D 250 IU/dreceived 500 mg/d and vitamin D 250 IU/dResults:Results: Reduced risk of new vertebral fractures Reduced risk of new vertebral fractures by 47%, hip fracture by 51% and wrist fracture by 47%, hip fracture by 51% and wrist fracture by 47%by 47%

Alendronate Reduces Risk of Multiple Alendronate Reduces Risk of Multiple Symptomatic Fractures: Results from FITSymptomatic Fractures: Results from FIT

J Am J Am GeriatrGeriatr Soc 2002;50:409Soc 2002;50:409--415415

Patient Population: Patient Population: Subset of women from FIT Subset of women from FIT Therapy: Therapy: Placebo or alendronate (5 mg/d x 2 yr; Placebo or alendronate (5 mg/d x 2 yr; 10 mg/d x 1year) 10 mg/d x 1year) AvgAvg f/u = 4.3 yrf/u = 4.3 yrResults: Results: –– Over 3Over 3--4 years alendronate reduced occurrence rate 4 years alendronate reduced occurrence rate

of all symptomatic fractures by 33% and vertebral of all symptomatic fractures by 33% and vertebral fractures by 67%fractures by 67%

–– Benefit was seen within a few months of starting Benefit was seen within a few months of starting treatmenttreatment

AlendronateAlendronateHow Supplied

– Daily dosing» 5 mg tablet» 10 mg tablet

– Weekly dosing» 35 mg tablet» 70 mg tablet» 70 mg oral solution» 70 mg alendronate / 2,800 IU vitamin D

Fosamax Plus D®



30

AlendronateAlendronateRecommended DoseRecommended Dose

–– For the treatment of osteoporosis in For the treatment of osteoporosis in postmenopausal women and men = 10 mg once postmenopausal women and men = 10 mg once daily or 70 mg weeklydaily or 70 mg weekly

–– For the prevention of osteoporosis in For the prevention of osteoporosis in postmenopausal women = 5 mg once daily or postmenopausal women = 5 mg once daily or 35 mg weekly35 mg weekly

–– For the treatment of For the treatment of glucocorticoidglucocorticoid--induced induced osteoporosis = 5 mg once daily or 35 mg osteoporosis = 5 mg once daily or 35 mg weeklyweekly

AlendronateAlendronateContraindicationsContraindications

Severe renal insufficiency Severe renal insufficiency ((creatininecreatinine clearance clearance <35 ml/min) <35 ml/min) Abnormalities of the esophagus that delay Abnormalities of the esophagus that delay esophageal emptyingesophageal emptyingHypocalcemiaHypocalcemiaInability to stand or sit upright for at least 30 Inability to stand or sit upright for at least 30 minutesminutesHypersensitivityHypersensitivity

AlendronateAlendronate

Drug/Drug InteractionsDrug/Drug InteractionsDrug Description

Ranitidine IV ranitidine doubled alendronate bioavailability. Unknown clinical significance.

Calcium supplements and antacids

Products containing calcium and other multivalent compounds interfere with alendronate absorption.

All medications Wait at least 30 minutes after taking alendronate before taking any other drug due to absorption interference.



31

Fosamax Plus DFosamax Plus D®®

Alendronate 70 mg / vitamin D 2,800 IUAlendronate 70 mg / vitamin D 2,800 IU–– 10 mg/day + 400 IU/day = once10 mg/day + 400 IU/day = once--weekly doseweekly dose

IndicationsIndications–– Treatment in postmenopausal womenTreatment in postmenopausal women–– Treatment in menTreatment in men

Dosage & AdministrationDosage & Administration–– 1 tablet once weekly1 tablet once weekly–– Same administration procedureSame administration procedure

Adverse EffectsAdverse Effects–– Safety profile similar to Safety profile similar to FosamaxFosamax®® 70 mg 70 mg

RisedronateRisedronate

IndicationIndicationFor the prevention and treatment of For the prevention and treatment of osteoporosis in postmenopausal womenosteoporosis in postmenopausal womenFor the prevention and treatment of For the prevention and treatment of glucocorticoidglucocorticoid--induced osteoporosisinduced osteoporosis


EfficacyEfficacyIncreased BMD at lumbar spine 5.4%; Increased BMD at lumbar spine 5.4%; femoral neck 1.6% & femoral neck 1.6% & trochantertrochanter 3.3%3.3%Reduced fracture rate at spine by 41% Reduced fracture rate at spine by 41% and non vertebral fractures by 39% in and non vertebral fractures by 39% in patients with osteoporosispatients with osteoporosis



32

Effects of Effects of RisedronateRisedronate Treatment on Treatment on Vertebral and Vertebral and NonvertebralNonvertebral Fractures in Fractures in

Women with Postmenopausal OsteoporosisWomen with Postmenopausal OsteoporosisJAMA 1999;282:1344JAMA 1999;282:1344--5252

Patient Population: Patient Population: 2,458 postmenopausal women 2,458 postmenopausal women with radiographic evidence of at least 2 vertebral with radiographic evidence of at least 2 vertebral fractures OR 1 vertebral fracture + low lumbar fractures OR 1 vertebral fracture + low lumbar BMDBMDTherapy: Therapy: Placebo OR Placebo OR risedronaterisedronate 2.5 or 5 mg/d. 2.5 or 5 mg/d. All patients received calcium 1,000 mg/d + All patients received calcium 1,000 mg/d + vitamin D if level < 40 vitamin D if level < 40 nmolnmol/L/LResults:Results: BMD changes: lumbar spine increased BMD changes: lumbar spine increased 5.4% and 5.4% and trochantertrochanter 3.3%3.3%–– Decreased vertebral fractures by 41% and Decreased vertebral fractures by 41% and nonvertebralnonvertebral

fracture by 39%fracture by 39%


Recommended DoseRecommended Dose5 mg once daily or 35 mg weekly 5 mg once daily or 35 mg weekly for all osteoporosis related for all osteoporosis related indicationsindications

ActonelActonel®® with Calciumwith CalciumCoCo--packaged product containing packaged product containing risedronaterisedronate35 mg and calcium carbonate 1,250 mg (500 mg 35 mg and calcium carbonate 1,250 mg (500 mg elemental calcium)elemental calcium)IndicationsIndications–– Treatment and prevention of osteoporosis in Treatment and prevention of osteoporosis in

postmenopausal women postmenopausal women

Dosage and Administration Dosage and Administration –– RisedronateRisedronate 35 mg on day 135 mg on day 1–– Calcium carbonate 1,250 mg on days 2 through 7Calcium carbonate 1,250 mg on days 2 through 7

Adverse EffectsAdverse Effects–– Safety profile similar to individual agents Safety profile similar to individual agents



33

IbandronateIbandronate

IndicationIndicationFor the prevention and treatment of For the prevention and treatment of osteoporosis in postmenopausal osteoporosis in postmenopausal womenwomen


EfficacyEfficacyIncreased BMD at lumbar spine 6.5% Increased BMD at lumbar spine 6.5% & at the hip by 3.4% after 3 yr& at the hip by 3.4% after 3 yrReduced fracture rate at spine by 52% Reduced fracture rate at spine by 52% after 3 yr. No statistically significant after 3 yr. No statistically significant reduction in reduction in nonvertebralnonvertebral fracturesfractures

Effects of Oral Effects of Oral IbandronateIbandronate Administered Administered Daily or Intermittently on Fracture Risk Daily or Intermittently on Fracture Risk

in Postmenopausal Osteoporosis in Postmenopausal Osteoporosis J Bone Miner Res 2004:19;1241J Bone Miner Res 2004:19;1241--12491249

Patient Population: Patient Population: 2,946 postmenopausal women 2,946 postmenopausal women with osteoporosiswith osteoporosisTherapy: Therapy: placebo or oral placebo or oral ibandronateibandronate either either 2.5 mg daily or 20 mg 2.5 mg daily or 20 mg qodqod for 12 doses every 3 for 12 doses every 3 months months Results:Results:–– After 3 years, rate of new vertebral fractures was After 3 years, rate of new vertebral fractures was

significantly reduced with daily (4.7%) and intermittent significantly reduced with daily (4.7%) and intermittent ibandronateibandronate (4.9%) relative to placebo (9.6%)(4.9%) relative to placebo (9.6%)

–– No statistically significant reduction in No statistically significant reduction in nonvertebralnonvertebralfractures fractures



34


Recommended DoseRecommended Dose––150 mg once monthly150 mg once monthly––2.5 mg once daily2.5 mg once daily

The compelling hip fracture The compelling hip fracture data with the data with the

bisphosphnatesbisphosphnates is often is often justification for selecting justification for selecting

these agents.these agents.

Alendronate Use Alendronate Use J Managed Care Pharm. 1998; 4:488J Managed Care Pharm. 1998; 4:488--492492

Patient Population: Patient Population: 812 women, mean age 69812 women, mean age 69Study Design: Study Design: Women were interviewed an average of 8 months Women were interviewed an average of 8 months after starting alendronate.after starting alendronate.Results:Results: During the course of treatmentDuring the course of treatment——–– 56% did not comply with at least 1 instruction for taking the 56% did not comply with at least 1 instruction for taking the

drugdrug–– 52% disregarded rules on consumption of food, liquids & 52% disregarded rules on consumption of food, liquids &

other medsother meds–– 33% reported it caused upper GI problems33% reported it caused upper GI problems–– 30% reported discontinuing the drug within the 1st 30% reported discontinuing the drug within the 1st

6 months6 monthsBased on refill recordsBased on refill records——−− 35% discontinued the drug35% discontinued the drug



35

AlendronateAlendronate Use Use J Managed Care Pharm. 1998; 4:488J Managed Care Pharm. 1998; 4:488--492492

Interesting pointInteresting point::

–– In clinical trials In clinical trials alendronatealendronate is well tolerated with few is well tolerated with few ADRsADRs significantly different from placebo. But outside significantly different from placebo. But outside the clinical trial settingthe clinical trial setting-- as reported here as reported here -- there are there are increased reports of increased reports of ADRsADRs

–– As part of routine health care, women do not receive As part of routine health care, women do not receive the education, encouragement and support given to the education, encouragement and support given to research subjects and may not be as highly motivated. research subjects and may not be as highly motivated. As a result, improper use and adverse gastrointestinal As a result, improper use and adverse gastrointestinal effects are common.effects are common.

ZoledronicZoledronic Acid (Acid (ZometaZometa®®))Most potent bisphosphonate to be used in Most potent bisphosphonate to be used in clinical trialsclinical trialsCurrent indications:Current indications:–– HypercalcemiaHypercalcemia of malignancyof malignancy–– Multiple Multiple myelomamyeloma & bone metastases of solid & bone metastases of solid

tumors (in addition to standard tumors (in addition to standard antineoplasticantineoplastictherapy)therapy)

Dosing for current indicationsDosing for current indications–– Max of 4 mg infused over no less than 15 minMax of 4 mg infused over no less than 15 min–– May repeat after 7 daysMay repeat after 7 days

A deterioration in renal function requires A deterioration in renal function requires careful monitoringcareful monitoring

Intravenous Intravenous ZoledronicZoledronic Acid in Acid in Postmenopausal Women with Low BMDPostmenopausal Women with Low BMD

N N EnglEngl J Med 2002;346:653J Med 2002;346:653--6161

Patient Population: Patient Population: 351 postmenopausal women with 351 postmenopausal women with low BMDlow BMDTherapy: Therapy: Placebo or IV Placebo or IV zoledroniczoledronic acid 0.25 mg, acid 0.25 mg, 0.5 mg or 1 mg @ 3 mo intervals. One group received 0.5 mg or 1 mg @ 3 mo intervals. One group received 4 mg once & another 2 mg q6 mo. All received 4 mg once & another 2 mg q6 mo. All received calcium (1 gm/day)calcium (1 gm/day)Results:Results:–– Similar increases in BMD in all study groupsSimilar increases in BMD in all study groups–– Results comparable to those with oral daily dosing with Results comparable to those with oral daily dosing with

bisphosphonatesbisphosphonates–– ADRsADRs: most common were musculoskeletal pain, nausea : most common were musculoskeletal pain, nausea

and fever and fever –– generally rated mildgenerally rated mild–– Suggest that an annual infusion of Suggest that an annual infusion of zoledroniczoledronic acid might be acid might be

an effective therapyan effective therapy



36

SalmonSalmon--CalcitoninCalcitonin

SalmonSalmon--CalcitoninCalcitoninNasal: Nasal: MiacalcinMiacalcin®®

ForticalFortical®®

Injection: (various)Injection: (various)

CalcitoninCalcitonin

IndicationIndicationFor the treatment of postmenopausal For the treatment of postmenopausal osteoporosis in females greater than 5 osteoporosis in females greater than 5 years post menopauseyears post menopause



37


Mechanism of ActionMechanism of ActionAntiresorptive agentAntiresorptive agentNaturally occurring hormoneNaturally occurring hormoneProduced by the thyroidProduced by the thyroidInhibits production & activity of Inhibits production & activity of osteoclastsosteoclasts

CalcitoninCalcitonin ((MiacalcinMiacalcin®®))Increased BMD at the spine 3%Increased BMD at the spine 3%Reduced vertebral fractures 36%Reduced vertebral fractures 36%Has not been studied in Has not been studied in nonvertebralnonvertebralfracturesfractures

A Randomized Trial of Nasal Spray Salmon A Randomized Trial of Nasal Spray Salmon CalcitoninCalcitonin in Postmenopausal Women with in Postmenopausal Women with

Established Osteoporosis: the Prevent Established Osteoporosis: the Prevent Recurrence of Osteoporotic Fracture Study Recurrence of Osteoporotic Fracture Study

(PROOF) (PROOF) Am J Med 2000;1099:267Am J Med 2000;1099:267--276.276.

Patient Population: Patient Population: 1,255 women with at 1,255 women with at least 1 but not > 5 vertebral fracturesleast 1 but not > 5 vertebral fracturesTherapy: Therapy: Randomized to receive Randomized to receive MiacalcinMiacalcin®®100, 200, 400 IU or placebo daily. All 100, 200, 400 IU or placebo daily. All received 1,000 mg calcium + 400 IU vitamin received 1,000 mg calcium + 400 IU vitamin DDResults:Results: 36% reduction in risk of new 36% reduction in risk of new vertebral fractures with 200 IU daily vertebral fractures with 200 IU daily



38

MiacalcinMiacalcin®®: Questions Remain: Questions Remain

Poor trial design & executionPoor trial design & executionWhy the lack of a dose response Why the lack of a dose response effect?effect?What is the impact on What is the impact on nonvertebralnonvertebralfractures?fractures?

CalcitoninCalcitoninAnalgesic effectAnalgesic effect––Not well supported by medical literatureNot well supported by medical literature––Mechanism of action unclearMechanism of action unclear

»»Increase in blood CSF ßIncrease in blood CSF ß--endorphinsendorphins»»Direct action on CNSDirect action on CNS

––Has been used for pain management of acute Has been used for pain management of acute vertebral compression fracturesvertebral compression fractures

––Effect may begin within few weeks of therapyEffect may begin within few weeks of therapy

CalcitoninCalcitoninAnalgesic effectAnalgesic effect––Considerations Considerations

»»May be tried if patient does not respond to May be tried if patient does not respond to traditional pain managementtraditional pain management

»»Should be continued only if patient has Should be continued only if patient has documented responsedocumented response

»»Should not preclude starting firstShould not preclude starting first--line line osteoporosis therapy in these high risk osteoporosis therapy in these high risk patientspatients



39

How SuppliedHow SuppliedMiacalcinMiacalcin®®

––2 ml bottles containing 14 doses2 ml bottles containing 14 doses––Each activation releases Each activation releases calcitonincalcitonin 200 IU in 0.09 200 IU in 0.09

ml of solutionml of solutionForticalFortical®®

––3.7 ml bottles containing 30 doses3.7 ml bottles containing 30 doses––Each activation releases Each activation releases calcitonincalcitonin 200 IU in 0.09 200 IU in 0.09

ml of solutionml of solution


ContraindicationsContraindicationsAllergy to Allergy to calcitonincalcitonin

CalcitoninCalcitoninDrug/Drug InteractionsDrug/Drug Interactions

None known to dateNone known to date



40

CalcitoninCalcitoninDosage and AdministrationDosage and Administration

200 IU spray to one nostril daily200 IU spray to one nostril daily––Before first dose, necessary to activate Before first dose, necessary to activate the pumpthe pump

––Place nozzle into nostril with head in upright Place nozzle into nostril with head in upright position and depress the pumpposition and depress the pump

––Alternate nostrils dailyAlternate nostrils daily––May be administered at any time during May be administered at any time during the daythe day


Adverse EffectsAdverse EffectsRhinitisRhinitisNasal symptoms = nasal crusts, irritation, Nasal symptoms = nasal crusts, irritation, redness, sores, nose bleedredness, sores, nose bleedBack painBack painArthralgiaArthralgiaHeadacheHeadache


ConsiderationsConsiderationsProvision of adequate calcium and Provision of adequate calcium and vitamin D in the diet or as supplements is vitamin D in the diet or as supplements is recommended in conjunction with recommended in conjunction with calcitonincalcitonin



41

CalcitoninCalcitoninPatient Monitoring/EducationPatient Monitoring/Education

Patient should receive a nasal examination Patient should receive a nasal examination prior to the start of therapy and at any time prior to the start of therapy and at any time nasal complaints occurnasal complaints occur


Review medication administration Review medication administration procedureprocedureIt is unnecessary to inhale the spray as the It is unnecessary to inhale the spray as the medication is absorbed through the nasal medication is absorbed through the nasal mucosamucosa


Store unopened bottles of the nasal Store unopened bottles of the nasal product in the refrigerator. Once the product in the refrigerator. Once the pump has been activated, store at room pump has been activated, store at room temperaturetemperatureUnopened or opened bottles of spray left Unopened or opened bottles of spray left at room temperature for more than 4 at room temperature for more than 4 weeks should be discardedweeks should be discarded



42

RaloxifeneRaloxifeneEvistaEvista®®

RaloxifeneRaloxifene

IndicationIndicationIndicated for the treatment and Indicated for the treatment and prevention of osteoporosis in prevention of osteoporosis in postmenopausal womenpostmenopausal women

RaloxifeneRaloxifeneMechanism of ActionMechanism of Action

Selective estrogen receptor modulator Selective estrogen receptor modulator (SERM)(SERM)ActionsActions–– Prevents bone lossPrevents bone loss–– Lowers serum cholesterol levelsLowers serum cholesterol levels–– Inhibits growth of breast cancerInhibits growth of breast cancer–– Does not stimulate the Does not stimulate the endometriumendometrium



43

RaloxifeneRaloxifeneEfficacyEfficacy

Increases BMD in femoral neck by Increases BMD in femoral neck by 2.1% and in spine by 2.6%2.1% and in spine by 2.6%Reduces rate of vertebral fractures about Reduces rate of vertebral fractures about 40%40%No apparent effect on No apparent effect on nonvertebralnonvertebralfracturesfractures

Reduction of Vertebral Fracture Reduction of Vertebral Fracture Risk in Postmenopausal Women with Risk in Postmenopausal Women with

Osteoporosis Treated with Osteoporosis Treated with RaloxifeneRaloxifene

JAMA 1999;282:637JAMA 1999;282:637--645.645.Patient Population: Patient Population: 7,705 postmenopausal women 7,705 postmenopausal women 31 31 –– 80 years old with osteoporosis80 years old with osteoporosisTherapy: Therapy: Randomized to 60 or 120 mg/d Randomized to 60 or 120 mg/d raloxifeneraloxifeneOR placebo. All received supplemental calcium + OR placebo. All received supplemental calcium + cholecalciferolcholecalciferolResults: Results: 2 2 –– 3% increase in spine & hip BMD 3% increase in spine & hip BMD

30% reduction in risk for vertebral fracture 30% reduction in risk for vertebral fracture with 60 mg; 50% reduction with 120 mgwith 60 mg; 50% reduction with 120 mg

–– No change in risk of No change in risk of nonvertebralnonvertebral fracturefracture

Effects on Lipid Metabolism & Effects on Lipid Metabolism & Clotting FactorsClotting Factors

+NeutralFibrinogen

Neutral-Triglycerides

Neutral+HDL

++LDL

++Total Cholesterol

RaloxifeneHRT



44

RaloxifeneRaloxifene & Cardiovascular Events in & Cardiovascular Events in Osteoporotic Postmenopausal WomenOsteoporotic Postmenopausal Women

JAMA 2002;287:847JAMA 2002;287:847--857857

Patient Population: Patient Population: Secondary analysis of MORE trialSecondary analysis of MORE trial

Outcome Measures: Outcome Measures: –– Cardiovascular events (MI, unstable angina, coronary Cardiovascular events (MI, unstable angina, coronary

ischemia)ischemia)–– CerebrovascularCerebrovascular events (stroke or TIA)events (stroke or TIA)

Results: Results: –– RaloxifeneRaloxifene therapy for 4 yr did not significantly affect risk therapy for 4 yr did not significantly affect risk

of CV events in overall cohort but did significantly reduce of CV events in overall cohort but did significantly reduce risk of CV events in subset of women with increased CV risk of CV events in subset of women with increased CV riskrisk

–– No evidence that No evidence that raloxifeneraloxifene caused an early increase in caused an early increase in risk of CV events risk of CV events


ContraindicationsContraindicationsPregnancyPregnancyHistory of or active History of or active thromboembolicthromboembolicevents including deep vein thrombosis, events including deep vein thrombosis, pulmonary embolism, retinal vein pulmonary embolism, retinal vein thrombosisthrombosis

RaloxifeneRaloxifeneDrug/Drug InteractionsDrug/Drug Interactions

CholestyramineCholestyramine –– coadministrationcoadministration will will significantly reduce absorption of significantly reduce absorption of raloxifeneraloxifeneWarfarinWarfarin –– closely monitor closely monitor PTsPTs and and INRsINRs; ; PT decreased 10% in singlePT decreased 10% in single--dose studiesdose studiesProtein bound drugs (Protein bound drugs (clofibrateclofibrate, diazepam, , diazepam, ibuprofen, ibuprofen, indomethacinindomethacin, naproxen) , naproxen) –– use with use with caution. caution. RaloxifeneRaloxifene is more than 95% bound to is more than 95% bound to plasma proteinsplasma proteins



45


Dosage and AdministrationDosage and AdministrationUsual dose is 60 mg once daily Usual dose is 60 mg once daily without regard to mealswithout regard to meals

RaloxifeneRaloxifeneAdverse EffectsAdverse Effects

Hot flashesHot flashes–– Most common in first 6 monthsMost common in first 6 months–– 7% incidence7% incidence

Leg crampsLeg cramps–– Generally mildGenerally mild–– 4% incidence4% incidence

Venous Venous thromboembolicthromboembolic eventsevents–– Greatest risk in first 4 monthsGreatest risk in first 4 months–– 3 fold increase incidence3 fold increase incidence

RaloxifeneRaloxifeneUterine cancerUterine cancer–– Preliminary evidence suggests Preliminary evidence suggests nono

increased riskincreased riskBreast cancerBreast cancer–– MORE results: among women taking MORE results: among women taking

raloxifeneraloxifene, incidence of all types of breast , incidence of all types of breast cancer decreases by 62% & incidence of cancer decreases by 62% & incidence of invasive breast cancer decreases by 72%invasive breast cancer decreases by 72%



46

Continuing Outcomes Relevant to Continuing Outcomes Relevant to EvistaEvista: : Breast Cancer Incidence in Breast Cancer Incidence in

Postmenopausal Osteoporotic Women in a Postmenopausal Osteoporotic Women in a Randomized Randomized

Trial of Trial of RaloxifeneRaloxifeneJ J NatlNatl Cancer Inst 2004; 96:1751Cancer Inst 2004; 96:1751--6161

Patient Population: Patient Population: 5,000 participants from 5,000 participants from the MORE trial received an additional 4 yr of the MORE trial received an additional 4 yr of raloxifeneraloxifene or placeboor placeboResults:Results:–– 59% reduction in risk of invasive breast cancer 59% reduction in risk of invasive breast cancer

& 66% reduction in risk of invasive estrogen& 66% reduction in risk of invasive estrogen--positive breast cancer positive breast cancer

RaloxifeneRaloxifeneConsiderationsConsiderations

RaloxifeneRaloxifene is of no benefit for hot is of no benefit for hot flashes. Studies show it may actually flashes. Studies show it may actually increase the incidence of hot flashesincrease the incidence of hot flashesSafety and efficacy have not been Safety and efficacy have not been evaluated in menevaluated in men

RaloxifeneRaloxifeneConsiderationsConsiderations

Supplemental calcium should be added Supplemental calcium should be added to the diet if daily intake is inadequateto the diet if daily intake is inadequate



47

RaloxifeneRaloxifenePatient Monitoring/EducationPatient Monitoring/Education

Review possible side effects and what to do if they occur.Review possible side effects and what to do if they occur.–– Unexplained uterine bleeding should be reported to Unexplained uterine bleeding should be reported to

physicianphysicianReview signs and symptoms of possible venous thrombosis:Review signs and symptoms of possible venous thrombosis:–– Pain in the calves or leg swellingPain in the calves or leg swelling–– Sudden chest pain, shortness of breath or coughing bloodSudden chest pain, shortness of breath or coughing blood–– Changes in visionChanges in vision

The occurrence of any of these should be reported to physician The occurrence of any of these should be reported to physician immediately and patients should stop therapy immediately.immediately and patients should stop therapy immediately.

RaloxifeneRaloxifenePatient Monitoring/EducationPatient Monitoring/Education

Assess adherence with calcium intake planAssess adherence with calcium intake planReview what to do in the event of prolonged Review what to do in the event of prolonged immobilization.immobilization.–– Discontinue drug at least 72 hours prior to and Discontinue drug at least 72 hours prior to and

during prolonged immobilization (postduring prolonged immobilization (post--surgical surgical recovery, prolonged bed rest)recovery, prolonged bed rest)

–– Avoid prolonged restrictions of movement such Avoid prolonged restrictions of movement such as during travelas during travel

FormationFormation--Stimulating DrugsStimulating Drugs



48

Drug Therapy for Drug Therapy for OsteoporosisOsteoporosis

AntiresorptiveAntiresorptive AgentsAgentsFormationFormation--Stimulating DrugsStimulating Drugs

TeriparatideTeriparatideForteoForteo®®

TeriparatideTeriparatide

IndicationIndicationFor the treatment of postmenopausal women For the treatment of postmenopausal women with osteoporosis who are at high risk for with osteoporosis who are at high risk for fracturefractureTo increase bone mass in men with primary To increase bone mass in men with primary or or hypogonadalhypogonadal osteoporosis who are at high osteoporosis who are at high risk for fracturerisk for fracture



49

TeriparatideTeriparatideMechanism of ActionMechanism of Action

Recombinant human parathyroid hormone Recombinant human parathyroid hormone (PTH)(PTH)–– Identical sequence to 34 NIdentical sequence to 34 N--terminal amino terminal amino

acids of 84acids of 84--amino acid PTHamino acid PTHActions of PTH:Actions of PTH:–– Regulation of bone metabolismRegulation of bone metabolism–– Regulation of renal tubular Regulation of renal tubular resorptionresorption of of

calcium & phosphatecalcium & phosphate–– Regulation of intestinal calcium absorptionRegulation of intestinal calcium absorption

Calcium HomeostasisCalcium HomeostasisSERUM CALCIUM STIMULATES PARATHYROID GLANDS

PARATHYROID HORMONE

PROMOTES ACTIVATION OF VITAMIN D

INCREASES CALCIUM REABSORPTION IN

RENAL TUBULE

BONE RESORPTION

CALCIUM ABSORPTIONIN GI TRACT

CALCIUM RELEASE

CALCIUM RELEASE


Mechanism of ActionMechanism of ActionSkeletal effects depend upon pattern of Skeletal effects depend upon pattern of systemic exposuresystemic exposureIntermittent lowIntermittent low--dosedose–– Increases Increases osteoblasticosteoblastic activityactivity–– Increases BMD and reestablishes connectivityIncreases BMD and reestablishes connectivity



50


EfficacyEfficacyIncreased BMD at lumbar spine 9% and Increased BMD at lumbar spine 9% and femoral neck 3%femoral neck 3%Reduced fracture rate at the spine by Reduced fracture rate at the spine by 65% and 65% and nonvertebralnonvertebral fractures by 53%fractures by 53%

Effect of Parathyroid Hormone on Fractures & Effect of Parathyroid Hormone on Fractures & BMD in Postmenopausal Women with BMD in Postmenopausal Women with

OsteoporosisOsteoporosisN N EnglEngl J Med 2001;344:1434J Med 2001;344:1434--4141

Patient Population: Patient Population: 1,637 postmenopausal women with prior vertebral 1,637 postmenopausal women with prior vertebral fracturesfracturesTherapy: Therapy: Randomly received parathyroid hormone (1Randomly received parathyroid hormone (1--34) 20 mcg or 34) 20 mcg or 40 mcg OR placebo administered subcutaneously daily by the women40 mcg OR placebo administered subcutaneously daily by the womenfor about 18 months All received calcium & for about 18 months All received calcium & vitvit DDResults:Results:–– Occurrence of new vertebral fractures: 14% on placebo, 5% on 20 Occurrence of new vertebral fractures: 14% on placebo, 5% on 20 mcg & mcg &

4% on 40 mcg4% on 40 mcg–– Occurrence of new Occurrence of new nonvertebralnonvertebral fractures: 6% on placebo, 3% on 20 & 40 fractures: 6% on placebo, 3% on 20 & 40

mcgmcg–– Compared to placebo, 20 & 40 mcg increased BMD by 9% & 13% in Compared to placebo, 20 & 40 mcg increased BMD by 9% & 13% in

lumbar spine and 3% & 6% in femoral necklumbar spine and 3% & 6% in femoral neck


Drug InteractionsDrug InteractionsNone knownNone knownNone anticipatedNone anticipated



51

TeriparatideTeriparatideDosage and AdministrationDosage and Administration

20 mcg once daily administered as 20 mcg once daily administered as subcutaneous injection into thigh or subcutaneous injection into thigh or abdominal wallabdominal wallTake at any time of the dayTake at any time of the daySupplied as a preSupplied as a pre--assembled disposable pen assembled disposable pen device with 28 dosesdevice with 28 dosesAfter 28 days discard the pen even if it still After 28 days discard the pen even if it still contains unused solutioncontains unused solutionUse for longer than 2 yrs not recommended Use for longer than 2 yrs not recommended due to lack of safety & efficacy datadue to lack of safety & efficacy data


Store under refrigeration at all times. Time Store under refrigeration at all times. Time out of refrigerator should be minimizedout of refrigerator should be minimizedDose may be delivered immediately Dose may be delivered immediately following removal from refrigeratorfollowing removal from refrigeratorAfter the 2 year point, patient should be After the 2 year point, patient should be started on started on antiresorptiveantiresorptive treatment to treatment to maintain gains in BMDmaintain gains in BMD

TeriparatideTeriparatideAdverse EffectsAdverse Effects

DizzinessDizzinessLeg crampsLeg crampsTransient orthostatic hypotensionTransient orthostatic hypotension–– Infrequent event seen within first several Infrequent event seen within first several

dosesdoses–– Begins within 4 hr of dosing and then Begins within 4 hr of dosing and then

resolvesresolvesTransient increases serum calciumTransient increases serum calcium



52

TeriparatideTeriparatideAdverse EffectsAdverse Effects

Increased incidence of Increased incidence of osteosarcomaosteosarcoma in ratsin rats–– Black Box WarningBlack Box Warning

»» Do not use in patients with:Do not use in patients with:Paget’s diseasePaget’s diseaseUnexplained elevation of alkaline Unexplained elevation of alkaline phosphatasephosphataseOpen epiphysesOpen epiphysesPrior skeletal radiationPrior skeletal radiation

TeriparatideTeriparatideFDA RequirementsFDA Requirements–– RPh must give patients FDARPh must give patients FDA--approved approved

information sheet each time drug is information sheet each time drug is dispenseddispensed

–– Eli Lilly must fund 10Eli Lilly must fund 10--year studyyear study–– Can not advertise directly to consumers Can not advertise directly to consumers

& must restrict free samples& must restrict free samples–– Eli Lilly must do physician education Eli Lilly must do physician education

programprogram

TeriparatideTeriparatidePatient Monitoring/EducationPatient Monitoring/Education–– Review possible side effects & what to Review possible side effects & what to

do if they occurdo if they occur»» Orthostatic hypotensionOrthostatic hypotension

Initial admin should occur where patient can sit or lie Initial admin should occur where patient can sit or lie downdown

»» HypercalcemiaHypercalcemiaNotify health care provider if persistent Notify health care provider if persistent s/ss/s–– N&VN&V–– ConstipationConstipation–– LethargyLethargy



53

TeriparatideTeriparatidePatient Monitoring/EducationPatient Monitoring/Education–– Review drug administrationReview drug administration

»» Use new needle for each injectionUse new needle for each injection»» Prime pen prior to each dosePrime pen prior to each dose»» Store under refrigerationStore under refrigeration»» Discard pen after 28 daysDiscard pen after 28 days»» Administer at same time each dayAdminister at same time each day

–– Ensure adequate calcium & vitamin D intakeEnsure adequate calcium & vitamin D intake–– Do NOT store with needle attachedDo NOT store with needle attached

»» Solution may leak from cartridge and permit air Solution may leak from cartridge and permit air bubbles to form in cartridgebubbles to form in cartridge

Sodium FluorideSodium Fluoride

Major ActionMajor Action = increases number of = increases number of osteoblastsosteoblasts

Sodium FluorideSodium FluorideConcernsConcerns

The bone formed is poor quality and more fragile The bone formed is poor quality and more fragile than normal bone.than normal bone.Primarily affects Primarily affects trabeculartrabecular bone increasing BMD bone increasing BMD and appears to have the opposite effect on cortical and appears to have the opposite effect on cortical bone mass.bone mass.Adverse experiences with sodium fluoride are Adverse experiences with sodium fluoride are numerous.numerous.–– Gastrointestinal side effects (Gastrointestinal side effects (epigasticepigastic pain, nausea and pain, nausea and

vomiting)vomiting)–– Lower extremity pain syndromeLower extremity pain syndrome



54


Possible strategies for improvement Possible strategies for improvement ——Lower the doseLower the doseUse a slowUse a slow--release preparationrelease preparationAddition of calcium supplementsAddition of calcium supplementsCyclic/intermittent dosing regimenCyclic/intermittent dosing regimenAddition of estrogenAddition of estrogen

The Effect of Sodium The Effect of Sodium MonofluorophosphateMonofluorophosphatePlus Calcium on Vertebral Fracture Rate in Plus Calcium on Vertebral Fracture Rate in

Postmenopausal Women with Postmenopausal Women with ModerateModerateOsteoporosisOsteoporosis

Ann Intern Med.1998;129:1Ann Intern Med.1998;129:1--8.8.

Patient Population:Patient Population: 200 postmenopausal 200 postmenopausal women with osteoporosis women with osteoporosis

Therapy:Therapy: • Sodium fluoride 20 mg/d + 1,000 mg Sodium fluoride 20 mg/d + 1,000 mg calcium ORcalcium OR

• 1,000 mg calcium1,000 mg calciumResults:Results: • 10% increase in BMD of spine was 10% increase in BMD of spine was

found for fluoride and calciumfound for fluoride and calcium• 7.6% decrease in vertebral fractures7.6% decrease in vertebral fractures


The use of sodium fluoride is The use of sodium fluoride is considered experimental because of considered experimental because of insufficient data on longinsufficient data on long--term use, term use, effective dosage, and duration of effective dosage, and duration of therapytherapy



55

Other Therapy ConsiderationsOther Therapy Considerations

ThiazideThiazide diureticsdiureticsHMGHMG--CoACoA reductasereductase inhibitors inhibitors

ThiazideThiazide DiureticsDiuretics

ThiazideThiazide diuretics promote a decrease diuretics promote a decrease in renal calcium excretion and thus in renal calcium excretion and thus reduce bone reduce bone resorptionresorptionRecent populationRecent population--based case based case controlled studies have shown a controlled studies have shown a reduction in risk of hip fracture when reduction in risk of hip fracture when thiazidethiazide was used for more than 6 was used for more than 6 yearsyears

LowLow--Dose HCTZ & Preservation Dose HCTZ & Preservation of BMD in Older Adultsof BMD in Older Adults

Ann Intern Med 2000;133:516Ann Intern Med 2000;133:516--526.526.

Patient Population: Patient Population: 320 320 normotensivenormotensiveadults ages 60 adults ages 60 –– 79 with normal BMD79 with normal BMDTherapy: Therapy: HCTZ 12.5 mg/d; 25 mg/d OR HCTZ 12.5 mg/d; 25 mg/d OR placeboplaceboResults: Results: After 3 years, BMD at hipAfter 3 years, BMD at hip–– Placebo Placebo -- 0.3%0.3%–– HCTZ 12.5 mg + 0.5%HCTZ 12.5 mg + 0.5%–– HCTZ 25 mg + 0.6%HCTZ 25 mg + 0.6%–– No significant difference in BMD at spine orNo significant difference in BMD at spine or

total body BMDtotal body BMD



56

HMGHMG--CoACoA ReductaseReductase InhibitorsInhibitorsSeveral observational and animal studies Several observational and animal studies suggest they may increase BMDsuggest they may increase BMDProposed MOA:Proposed MOA:–– BisphosphonatesBisphosphonates & statins inhibit synthesis of & statins inhibit synthesis of

mevalonatemevalonate–– MevalonateMevalonate is a precursor in synthesis of is a precursor in synthesis of

cholesterol & certain compounds in regulation cholesterol & certain compounds in regulation of of osteoclastosteoclast activityactivity

–– Statins may increase bone formationStatins may increase bone formation

An Overview of the Pathway An Overview of the Pathway of Cholesterol Biosynthesisof Cholesterol Biosynthesis

Acetyl CoA

HMG-CoAHMG-CoA reductase (inhibited by HMG-CoA

reductase inhibitors)

MevalonateFarnesyl pyrophosphate synthase (inhibited by bisphosphonates)

Squalene

Cholesterol(CoA = coenzyme A, HMG = hydroxymethylglutaryl)

StatinStatin Use, BMD and Fracture Use, BMD and Fracture RiskRisk

Arch Intern Med 2002;162:537Arch Intern Med 2002;162:537--540540

Patient Population: Patient Population: CaseCase--control evaluation control evaluation of 1,375 women from Australia; 573 with of 1,375 women from Australia; 573 with fractures & 802 withoutfractures & 802 withoutResults: Results: –– StatinStatin use associated with 3% greater adjusted use associated with 3% greater adjusted

BMD at femoral neck. BMD at spine & whole BMD at femoral neck. BMD at spine & whole body greater but not statistically significantbody greater but not statistically significant

–– 60% reduction in fracture risk associated with 60% reduction in fracture risk associated with statinstatin useuse



57

More Research NeededMore Research Needed

All the studies to date are observationalAll the studies to date are observationalUnknowns:Unknowns:–– Any differences between specific agents Any differences between specific agents

in the classin the class–– Optimal dose & durationOptimal dose & duration

Need randomized controlled clinical trialsNeed randomized controlled clinical trials

SummarySummaryERT/HRTERT/HRT–– Prevention indicationPrevention indication–– Guidelines suggest it should not be used to Guidelines suggest it should not be used to

prevent chronic disease prevent chronic disease Alendronate, Alendronate, RisedronateRisedronate, , IbandronateIbandronate–– Prevention & treatment indicationPrevention & treatment indication–– Decreases fracturesDecreases fractures

»» Vertebral Vertebral –– AlendronateAlendronate, , RisedronateRisedronate, , IbandronateIbandronate»» NonvertebralNonvertebral –– AlendronateAlendronate, , RisedronateRisedronate

–– Generally considered first line therapyGenerally considered first line therapy

SummarySummaryCalcitoninCalcitonin–– Treatment indicationTreatment indication–– Vertebral fracture data only Vertebral fracture data only –– Safe but somewhat less effectiveSafe but somewhat less effective

RaloxifeneRaloxifene–– Prevention & treatment indicationPrevention & treatment indication–– Decreases vertebral fractures; no effect on Decreases vertebral fractures; no effect on nonvertebralnonvertebral

fractures fractures –– Role in therapy unclearRole in therapy unclear

TeriparatideTeriparatide–– Treatment indication Treatment indication –– Decreases vertebral & Decreases vertebral & nonvertebralnonvertebral fracturesfractures–– Use limited to high risk patients Use limited to high risk patients



58

BisphosphonatesBisphosphonatesProduce the greatest increases in BMD Produce the greatest increases in BMD of all available of all available antiresorptiveantiresorptive therapiestherapiesRapidly decreases risk of vertebral Rapidly decreases risk of vertebral fracturesfracturesThe only approved The only approved antiresorptiveantiresorptive agents agents that have demonstrated that have demonstrated antifractureantifractureefficacy at the hip are efficacy at the hip are AlendronateAlendronate and and RisedronateRisedronate

Case: Postmenopausal WomanCase: Postmenopausal WomanTR, a 67TR, a 67--year old female in generally good health, year old female in generally good health, is concerned about osteoporosis due to a family is concerned about osteoporosis due to a family history of hip fracture in her grandmother and history of hip fracture in her grandmother and kyphosiskyphosis in her motherin her motherShe has not suffered any fractures and has no She has not suffered any fractures and has no history of secondary causes of bone losshistory of secondary causes of bone lossTR’sTR’s TT--scoresscores–– Spine: Spine: --2.92.9–– Hip: Hip: --2.72.7

TR was started on calcium, vitamin D and TR was started on calcium, vitamin D and risedronaterisedronate 35 mg weekly35 mg weekly

Questions for CaseQuestions for Case

How do you interpret the bone density How do you interpret the bone density findings in this case?findings in this case?What are your treatment What are your treatment recommendations?recommendations?



59

Approach to TreatmentApproach to TreatmentAACE Guidelines: Women who may benefit from AACE Guidelines: Women who may benefit from pharmacologic treatmentpharmacologic treatment

–– Women with BMD TWomen with BMD T--scores scores -- 2.5 & below2.5 & below–– Women with BMD TWomen with BMD T--scores scores --1.5 & below with risk 1.5 & below with risk

factorsfactors–– NonpharmacologicNonpharmacologic preventive measure were preventive measure were

ineffectiveineffectiveNOF Guidelines: Initiate therapy to reduce fracture risk in NOF Guidelines: Initiate therapy to reduce fracture risk in women withwomen with

–– Prior vertebral or hip fracturePrior vertebral or hip fracture–– BMD TBMD T--scores < scores < --2 in the absence of risk factors2 in the absence of risk factors–– BMD TBMD T--scores < scores < --1.5 if other risk factors are present1.5 if other risk factors are present

Therapeutic OptionsTherapeutic OptionsCalcium, vitamin D and exercise are Calcium, vitamin D and exercise are minimums, but not sufficientminimums, but not sufficientPatient has no known Patient has no known contraindications to therapies for contraindications to therapies for osteoporosisosteoporosis

Case VariationCase VariationQ: How would your treatment approach change Q: How would your treatment approach change

if TR had a BMD Tif TR had a BMD T--score of score of ––1.5 and a 1.5 and a history of compression or fragility fractures?history of compression or fragility fractures?

A: Treatment should be offered, despite BMD, A: Treatment should be offered, despite BMD, as previous fractures are the strongest as previous fractures are the strongest predictor of future fracturespredictor of future fractures



60

Application Exercise #3Application Exercise #3Therapy AssessmentTherapy Assessment

Case PresentationCase PresentationToni Baloney is a 76Toni Baloney is a 76--year old Caucasian year old Caucasian female who was started on female who was started on AlendronateAlendronateabout 2 years agoabout 2 years agoShe wants to know if this is working for She wants to know if this is working for herherMrs. Baloney is in good health and enjoys Mrs. Baloney is in good health and enjoys playing with her grandchildrenplaying with her grandchildren

Medical HistoryMedical HistoryCurrent medical problemsCurrent medical problems–– Hypertension: well controlled on HCTZ 25 mg Hypertension: well controlled on HCTZ 25 mg –– Arthritis: occasional knee pain Arthritis: occasional knee pain –– Osteoporosis: diagnosed 2 years ago; Osteoporosis: diagnosed 2 years ago;

TT--score = score = --2.52.5Current medicationsCurrent medications–– HCTZ 25 mg once dailyHCTZ 25 mg once daily–– OTC ibuprofen 200 mg, 2 tabs OTC ibuprofen 200 mg, 2 tabs prnprn joint painjoint pain–– Alendronate 70 mg once weeklyAlendronate 70 mg once weekly–– ViactivViactiv®® 1 twice daily 1 twice daily



61

Risk Factor AssessmentRisk Factor AssessmentNonNon--smokersmokerNonNon--drinkerdrinkerUnknown family history of osteoporosis Unknown family history of osteoporosis Drinks about 2 cups of coffee every Drinks about 2 cups of coffee every morning and occasionally drinks sweet teamorning and occasionally drinks sweet teaCurrent weight: 135 lbCurrent weight: 135 lbNo history of fracture No history of fracture

BMD ResultsBMD Results

Mrs. Baloney had central Mrs. Baloney had central DEXA test about 2 years agoDEXA test about 2 years agoTT--score = score = --2.5 2.5

According to WHO diagnostic According to WHO diagnostic categories, where does Mrs. Baloney’s categories, where does Mrs. Baloney’s

TT--score fall?score fall?A.A. Normal Normal B.B. OsteopeniaOsteopeniaC.C. Osteoporosis Osteoporosis



62

WHO Diagnostic CategoriesWHO Diagnostic CategoriesNormal = BMD > Normal = BMD > --1.0 SD of young adult 1.0 SD of young adult meanmeanOsteopeniaOsteopenia = BMD > = BMD > --1 SD but < 1 SD but < --2.5 SD 2.5 SD below young adult meanbelow young adult mean

Osteoporosis = BMD Osteoporosis = BMD --2.5 SD or more 2.5 SD or more below young adult meanbelow young adult mean

Is alendronate 70 mg weekly an Is alendronate 70 mg weekly an appropriate drug choice for this appropriate drug choice for this

patient?patient?A.A. Patient does not appear to have any Patient does not appear to have any

contraindications however she should be on contraindications however she should be on 35 mg weekly35 mg weekly

B.B. This is a good choice for this patient This is a good choice for this patient C.C. CalcitoninCalcitonin would be a better choice in view would be a better choice in view

of patient's age of patient's age D.D. Teriparatide would be a better choice in Teriparatide would be a better choice in

view of patent's Tview of patent's T--score score

Best AnswerBest AnswerB.B. This is a good choice for this patient This is a good choice for this patient

–– Indication: treatment of osteoporosis in Indication: treatment of osteoporosis in postmenopausal womanpostmenopausal woman

–– 70 mg weekly is the dose for this indication70 mg weekly is the dose for this indication–– No known contraindicationsNo known contraindications–– CalcitoninCalcitonin = age really has nothing to do with = age really has nothing to do with

selecting this drug. Considered less effective selecting this drug. Considered less effective than than bisphosphonatesbisphosphonates

–– TereparatideTereparatide = NOT appropriate since this is not = NOT appropriate since this is not a high risk patienta high risk patient



63

Drug Therapy AssessmentDrug Therapy Assessment

Administration procedureAdministration procedureTolerability (adverse effects)Tolerability (adverse effects)AdherenceAdherence

What key points should you assess What key points should you assess regarding the patient’s regarding the patient’s

administration procedure?administration procedure?A.A. Wait 60 minutes before eating or lying Wait 60 minutes before eating or lying

downdownB.B. Wait 30 minutes before eating or lying Wait 30 minutes before eating or lying

downdownC.C. Take with a full glass of water in the Take with a full glass of water in the

morningmorningD.D. Do not take with coffee or orange juice Do not take with coffee or orange juice

Best AnswerBest Answer

B.B. Wait 30 minutes before eating or lying Wait 30 minutes before eating or lying downdown

IbandronateIbandronate = wait 60 minutes= wait 60 minutesAlendronateAlendronate and and risedronaterisedronate = wait 30 minutes= wait 30 minutes

C.C. Take with a full glass of water in the Take with a full glass of water in the morningmorning

D.D. Do not take with coffee or orange juiceDo not take with coffee or orange juice



64

If patient complains of GI upset while If patient complains of GI upset while on bisphosphonate, what additional on bisphosphonate, what additional

information do you need?information do you need?Did you have these complaints before Did you have these complaints before starting the drug?starting the drug?What do you do when this happens?What do you do when this happens?Is it mild, moderate or severe?Is it mild, moderate or severe?What administration procedure do you What administration procedure do you follow when taking this drug?follow when taking this drug?

““ What do you do during What do you do during the 30 (or 60) minutes the 30 (or 60) minutes after you take your after you take your dose and before you dose and before you eat?”eat?”

Assessing Patient AdherenceAssessing Patient Adherence

““How many times a month do you think you How many times a month do you think you miss a dose?”miss a dose?”“What do you do to help you remember your “What do you do to help you remember your dose?”dose?”Is anything possibly interfering with drug Is anything possibly interfering with drug absorption? absorption?



65

What should the patient do if What should the patient do if she missed a dose of her she missed a dose of her

alendronate?alendronate?A.A. No action necessary. Just be sure to take No action necessary. Just be sure to take

your dose the next weekyour dose the next weekB.B. Take 2 tablets the following weekTake 2 tablets the following weekC.C. Take the dose on the morning after you Take the dose on the morning after you

remember & then return taking 1 tablet remember & then return taking 1 tablet once weekly on your original chosen dayonce weekly on your original chosen day

Best AnswerBest AnswerC.C. Take the dose on the morning after Take the dose on the morning after

you remember & then return taking you remember & then return taking 1 tablet once weekly on your 1 tablet once weekly on your original chosen dayoriginal chosen day

–– Do not take 2 doses the same dayDo not take 2 doses the same day

Summary of Mrs. Baloney’s Summary of Mrs. Baloney’s Experience with Experience with AlendronateAlendronateReports excellent adherenceReports excellent adherence–– Takes dose on Mondays; written on calendar as Takes dose on Mondays; written on calendar as

reminderreminderConsistently follows correct administrative Consistently follows correct administrative procedure procedure –– Spends the 30 minutes doing the crossword Spends the 30 minutes doing the crossword

puzzle in the paper puzzle in the paper Tolerating well; denies GI complaints Tolerating well; denies GI complaints



66

General Preventive StrategiesGeneral Preventive Strategies

Physical activityPhysical activityCalciumCalciumVitamin DVitamin D

Physical Activity HistoryPhysical Activity History

Mrs. Baloney’s physical activity Mrs. Baloney’s physical activity consists of doing routine housework consists of doing routine housework and working her gardenand working her garden

What is your assessment of What is your assessment of Mrs. Baloney’s physical activity Mrs. Baloney’s physical activity

in terms of bone health?in terms of bone health?A.A. Meets recommendations for her ageMeets recommendations for her ageB.B. Needs to start resistance exercise 2Needs to start resistance exercise 2--3 times 3 times

weekly for 30 weekly for 30 –– 60 minutes60 minutesC.C. Should consult with a professional to Should consult with a professional to

design an appropriate physical activity design an appropriate physical activity regimen regimen



67

Best AnswerBest AnswerC.C. Should consult with a professional to Should consult with a professional to

design an appropriate physical design an appropriate physical activity regimen activity regimen

–– In view of osteoporosis diagnosis, age In view of osteoporosis diagnosis, age and current lack of activity and current lack of activity

Calcium Intake Assessment Calcium Intake Assessment for Mrs. Baloneyfor Mrs. Baloney

Takes Takes ViactivViactiv®® 1 twice daily1 twice dailyGenerally does not eat calcium Generally does not eat calcium rich foods rich foods

What is Mrs. Baloney’s What is Mrs. Baloney’s current daily calcium intake?current daily calcium intake?

A.A. 400 mg400 mgB.B. 600 mg600 mgC.C. 800 mg800 mgD.D. 1,000 mg1,000 mg



68


D.D. 1,000 mg 1,000 mg –– Each Each ViactivViactiv®® contains 500 mg contains 500 mg

elemental calcium as calcium elemental calcium as calcium carbonate, 100 IU vitamin D and carbonate, 100 IU vitamin D and 40 mcg vitamin K40 mcg vitamin K

What is your recommendation What is your recommendation regarding Mrs. Baloney’s regarding Mrs. Baloney’s

calcium intake?calcium intake?

A.A. Increase Increase ViactivViactiv®® dose to 1 three times dose to 1 three times dailydaily

B.B. Add a MVI Add a MVI C.C. Change to a calcium citrate product Change to a calcium citrate product

and take a dose that provides 1,200 mg and take a dose that provides 1,200 mg of elemental calcium dailyof elemental calcium daily

Best AnswerBest AnswerC.C. Change to a calcium citrate product and Change to a calcium citrate product and

take a dose that provides 1,200 mg of take a dose that provides 1,200 mg of elemental calcium dailyelemental calcium daily

–– In view of patient’s age, calcium citrate is In view of patient’s age, calcium citrate is a better choice due to the decrease in GI a better choice due to the decrease in GI acidity that comes with ageacidity that comes with age

–– Dose needs to be increased to at least Dose needs to be increased to at least 1,200 mg elemental calcium daily 1,200 mg elemental calcium daily



69

Vitamin D Intake Assessment Vitamin D Intake Assessment for Mrs. Baloneyfor Mrs. Baloney

No longer taking No longer taking ViactivViactiv®®

May receive some sun exposure May receive some sun exposure while working in the garden but while working in the garden but unlikely to produce enough due to unlikely to produce enough due to ageage

How much vitamin D should How much vitamin D should Mrs. Baloney receive on a Mrs. Baloney receive on a

daily basis?daily basis?A.A. 200 IU200 IUB.B. 400 IU400 IUC.C. 600 IU600 IUD.D. 800 IU800 IU


D.D. 800 IU daily800 IU daily–– NOF recommends that the elderly NOF recommends that the elderly

ingest 800 IU of vitamin D dailyingest 800 IU of vitamin D daily



70

How could Mrs. Baloney meet How could Mrs. Baloney meet her her vitaminvitamin D intake D intake

requirement?requirement?

A. Drink 8 glasses of milk dailyA. Drink 8 glasses of milk dailyB. Take 2 multivitamin tablets dailyB. Take 2 multivitamin tablets dailyC. Take a calcium supplement that also C. Take a calcium supplement that also

contains vitamin D contains vitamin D D. Switch to Fosamax Plus DD. Switch to Fosamax Plus D®® and take and take

1 multivitamin tablet daily 1 multivitamin tablet daily


C.C. Take a calcium supplement that Take a calcium supplement that also contains vitamin D also contains vitamin D

oror

D.D. Switch to Fosamax Plus DSwitch to Fosamax Plus D®® and and take 1 multivitamin tablet daily take 1 multivitamin tablet daily

Fall Prevention PlanFall Prevention Plan

Essential component for Essential component for individuals with osteoporosis individuals with osteoporosis Ask patient about fall history Ask patient about fall history –– Mrs. Baloney denies fallingMrs. Baloney denies falling



71

Fall Prevention ChecklistFall Prevention ChecklistCheck environmentCheck environment–– Remove or firmly anchor rugsRemove or firmly anchor rugs–– Have good lighting throughout. Do not try to walk Have good lighting throughout. Do not try to walk

in the darkin the dark–– Keep electrical and telephone cords away from Keep electrical and telephone cords away from

walking areaswalking areas–– Equip bathroom, halls and stairways with handrailsEquip bathroom, halls and stairways with handrails–– Reduce slipperiness of tub or shower floorReduce slipperiness of tub or shower floor–– Adjust seating and bed so easy to get into and out ofAdjust seating and bed so easy to get into and out of

Address Mrs. Baloney’s Address Mrs. Baloney’s concernconcern

““Is this alendronate working Is this alendronate working for me?” for me?”

Monitoring Response to Monitoring Response to TherapyTherapy

Response to therapy can be assessed by Response to therapy can be assessed by fracture history and repeat BMD testingfracture history and repeat BMD testingAlthough repeat BMD tests are not required Although repeat BMD tests are not required in someone on therapy, it may serve as in someone on therapy, it may serve as reassurance to the clinician and patient that reassurance to the clinician and patient that the therapy has had impact the therapy has had impact



72

Monitoring Response to Monitoring Response to TherapyTherapy

Use the same machine at the same center and Use the same machine at the same center and test the same sitetest the same siteError of precisionError of precision–– Changes must exceed about 4% in the spine and Changes must exceed about 4% in the spine and

6% in the hip to be considered significant 6% in the hip to be considered significant –– May take medications several years to produce May take medications several years to produce

changes of this magnitude changes of this magnitude Do not repeat testing any more often than Do not repeat testing any more often than every 2 years every 2 years

Interpreting Monitoring Interpreting Monitoring ResultsResults

Magnitude of increase in BMD does not Magnitude of increase in BMD does not correlate directly with fracture protection correlate directly with fracture protection –– Fracture protection benefit may be realized Fracture protection benefit may be realized

before BMD gains are detectedbefore BMD gains are detected–– In clinical trials, In clinical trials, raloxifeneraloxifene & & calcitonincalcitonin

produced modest improvements in BMD yet produced modest improvements in BMD yet significant vertebral fracture reduction significant vertebral fracture reduction

Regression to the mean patternRegression to the mean pattern

Monitoring Osteoporosis Therapy Monitoring Osteoporosis Therapy With Bone DensitometryWith Bone Densitometry

JAMA. 2000;283:1318JAMA. 2000;283:1318--2121..Patient Population: Patient Population: –– FIT patients on alendronate 5 mg/d with 2 yr of BMD FIT patients on alendronate 5 mg/d with 2 yr of BMD

monitoringmonitoring–– MORE patients on MORE patients on raloxifeneraloxifene 60 or 120 mg/d with 2 yr 60 or 120 mg/d with 2 yr

of BMD monitoringof BMD monitoringMeasure: Measure: Baseline, 12 & 24 month hip & spine BMDBaseline, 12 & 24 month hip & spine BMD

Results: Results: –– Women with greatest loss of BMD during 1Women with greatest loss of BMD during 1stst yr of yr of

treatment were most likely to gain BMD during treatment were most likely to gain BMD during continued treatmentcontinued treatment

–– This phenomenon occurred with 2 drugs & This phenomenon occurred with 2 drugs & measurements at 2 sitesmeasurements at 2 sites



73

Regression to the MeanRegression to the MeanPrinciple: Principle: Individuals who have Individuals who have measurements that differ from the measurements that differ from the mean for a population tend to have mean for a population tend to have repeat measurements closer to the repeat measurements closer to the mean. This tendency is greatest for mean. This tendency is greatest for measurements farther from the measurements farther from the mean.mean.

Practice ImplicationsPractice ImplicationsTreatment should be continued in patients Treatment should be continued in patients who appear to lose BMD initially because who appear to lose BMD initially because most patients will gain it with continued most patients will gain it with continued treatmenttreatmentThe gains usually exceed losses of 1The gains usually exceed losses of 1stst yearyearWhen patients make unusually large gains the When patients make unusually large gains the 11stst year, they will likely lose or have modest year, they will likely lose or have modest gains during the 2gains during the 2ndnd yearyear

Practice ImplicationsPractice Implications

NIH Consensus Panel: Lack of NIH Consensus Panel: Lack of improvement in BMD does not justify improvement in BMD does not justify stopping treatment strategies in patients stopping treatment strategies in patients with osteoporosiswith osteoporosis



74

Possible Causes for a True Possible Causes for a True Decrease in BMDDecrease in BMD

NonadherenceNonadherencePoor drug absorptionPoor drug absorptionImproper dosingImproper dosingSecondary causes of bone lossSecondary causes of bone lossTrue True nonresponsenonresponse

Summarize Assessment of Summarize Assessment of Mrs. BaloneyMrs. Baloney

Consider consulting with a professional about safe Consider consulting with a professional about safe & effective ways to increase physical activity for & effective ways to increase physical activity for bone health bone health Consider switching to a calcium citrate supplementConsider switching to a calcium citrate supplementConsider switching to Fosamax Plus DConsider switching to Fosamax Plus D®® and adding and adding a multivitamin or selecting a calcium supplement a multivitamin or selecting a calcium supplement that also contains vitamin D that also contains vitamin D Consider talking to her physician about having her Consider talking to her physician about having her DXA scan repeated to assess response to therapy DXA scan repeated to assess response to therapy

Osteoporosis Care Certificate ProgramOsteoporosis Care Certificate ProgramDrug Therapy for OsteoporosisDrug Therapy for Osteoporosis

OverviewOverviewERT and HRTERT and HRTBisphosphonatesBisphosphonatesSalmonSalmon--CalcitoninCalcitoninRaloxifeneRaloxifeneFormation Formation -- Stimulating DrugsStimulating Drugs



75

Describe the appropriate use of the various Describe the appropriate use of the various pharmacotherapeuticpharmacotherapeutic choices to treat osteoporosis, choices to treat osteoporosis, including indication, mechanism of action, dosing, including indication, mechanism of action, dosing, administration, adverse effects and precautionsadministration, adverse effects and precautionsExplain the role of the drugs approved for Explain the role of the drugs approved for osteoporosis in the management of this diseaseosteoporosis in the management of this diseaseEducate patients about the various Educate patients about the various pharmacotherapeuticpharmacotherapeutic choices to treat osteoporosis and choices to treat osteoporosis and monitor their response to therapymonitor their response to therapy

√√ Check Point Check Point How Well Are You Able to:How Well Are You Able to:

Take Time to Review if Take Time to Review if NecessaryNecessary

Describe the appropriate use of the various Describe the appropriate use of the various pharmacotherapeuticpharmacotherapeuticchoices to treat osteoporosis, including indication, mechanism choices to treat osteoporosis, including indication, mechanism of action, dosing, administration, adverse effects and of action, dosing, administration, adverse effects and precautions precautions [Overview of Drug Therapy] [ERT and HRT] [Overview of Drug Therapy] [ERT and HRT] [[BisphosphonatesBisphosphonates] [Salmon] [Salmon--CalcitoninCalcitonin] [] [RaloxifeneRaloxifene] ] [Formation[Formation--Stimulating Drugs]Stimulating Drugs]Explain the role of the drugs approved for osteoporosis in the Explain the role of the drugs approved for osteoporosis in the management of this disease management of this disease [Overview of Drug Therapy][Overview of Drug Therapy]Educate patients about the various Educate patients about the various pharmacotherapeuticpharmacotherapeutic choices choices to treat osteoporosis and monitor their response to therapy to treat osteoporosis and monitor their response to therapy [Overview of Drug Therapy] [ERT and HRT] [Overview of Drug Therapy] [ERT and HRT] [[BisphosphonatesBisphosphonates] [Salmon] [Salmon--CalcitoninCalcitonin] [] [RaloxifeneRaloxifene] ] [Formation[Formation--Stimulating Drugs]Stimulating Drugs]

Thank you for your participation.Thank you for your participation.Click below to proceed to Click below to proceed to

the Postthe Post--Test.Test.

Post-Test Button



Date post:	12-Mar-2018
Category:	Documents
Upload:	nguyencong
View:	225 times
Download:	1 times

Drug Therapy for Osteoporosis - · PDF fileDrug Therapy for Osteoporosis ... written consent...

Documents