Content Osteoporosis Concepts, Diagnosis, Tt tTreatments · 2010-05-07 · Pathogenesis of Osteoporotic Fractures AGING MENOPAUSE OTHER RISK FACTORS INCREASED BONE LOSS LOW PEAK BONE

Osteoporosis Osteoporosis ––

Concepts, Diagnosis, Concepts, Diagnosis, T t tT t tTreatmentsTreatments

Johann Herberth, MD PhD MPH CCD FACP FASN

Division of Nephrology, Bone and Division of Nephrology, Bone and Mineral MetabolismMineral Metabolism

University of KentuckyUniversity of Kentucky

ContentContent Definition and epidemiologyDefinition and epidemiology

Primary and secondary risk factorsPrimary and secondary risk factors

Bone pathophysiologyBone pathophysiology

Division of Nephrology, Bone and Mineral MetabolismDivision of Nephrology, Bone and Mineral Metabolism

Diagnostic approachDiagnostic approach

Universal prevention Universal prevention

Pharmacologic treatment optionsPharmacologic treatment options

“Bones of glass and a heart of stone”“Bones of glass and a heart of stone”

Definition; NIH Consensus Definition; NIH Consensus ConferenceConference

“A skeletal disorder characterized by compromised “A skeletal disorder characterized by compromised bone strength…bone strength…


…predisposing to an increased risk of fracture.”…predisposing to an increased risk of fracture.”

Strength = Density + QualityStrength = Density + Quality

Dempster et al J Bone Miner Res 1986

Epidemiology of OsteoporosisEpidemiology of Osteoporosis

8 mio. Women, 2 mio. Men have osteoporosis8 mio. Women, 2 mio. Men have osteoporosis 34 mio. have low bone mass34 mio. have low bone mass In the US, 50% of women and 25% of men In the US, 50% of women and 25% of men

>50 yo. will suffer an osteoporosis related >50 yo. will suffer an osteoporosis related


50 yo su e a osteopo os s e ated50 yo su e a osteopo os s e atedfracturefracture 300.000 hip300.000 hip 400.000 wrist / forearm400.000 wrist / forearm 550.000 vertebrae550.000 vertebrae 810.000 other810.000 other

NOF 2002Chrischilles et al, Arch Intern Med 1991Burge et al, J Bone Miner Res 2007

Economic Burden (per year)Economic Burden (per year)

$25.3 billion by 2025$25.3 billion by 2025

$50 billion by 2050$50 billion by 2050

$17 billion direct medical costs$17 billion direct medical costs


>400.000 hospital admission>400.000 hospital admission

~2.5 mio. physician visits~2.5 mio. physician visits

>180.000 nursing home admissions>180.000 nursing home admissions

Burge et al, J Bone Miner Res 2007Ray et al, J Bone Miner Res 1997NOF, Osteoporosis Int 1998

Risk FactorsRisk Factors

Primary Risk FactorsPrimary Risk Factors

Caucasian / Asian backgroundCaucasian / Asian background

WomenWomen

Age / Postmenopausal statusAge / Postmenopausal status


Menopause < age 45Menopause < age 45

Small body habitusSmall body habitus

Hx. low trauma fracture in 1Hx. low trauma fracture in 1stst degree relativedegree relative

Primary Risk FactorsPrimary Risk Factors

Dementia / impaired visionDementia / impaired vision

FallsFalls

Low physical activityLow physical activity


Alcohol intakeAlcohol intake

SmokingSmoking

Low lifelong calcium intakeLow lifelong calcium intake

Secondary Risk FactorsSecondary Risk Factors

GI disorders leading to malabsorption (bariatric GI disorders leading to malabsorption (bariatric surgery, inflammatory dz., celiac dz. etc.)surgery, inflammatory dz., celiac dz. etc.)

EndocrineEndocrine Hyperparathyroidism (primary or secondary)Hyperparathyroidism (primary or secondary)


Hyperparathyroidism (primary or secondary)Hyperparathyroidism (primary or secondary) Hyper/hypothyroidismHyper/hypothyroidism HypercortisolismHypercortisolism HyperprolactinemiaHyperprolactinemia AcromegalyAcromegaly HypogonadismHypogonadism

Secondary Risk FactorsSecondary Risk Factors

Liver disease (biliary sclerosis, autoimmune and Liver disease (biliary sclerosis, autoimmune and alcoholic hepatitis, sclerosing cholangitis)alcoholic hepatitis, sclerosing cholangitis)

Rheumatoid arthritis and other autoimmune Rheumatoid arthritis and other autoimmune diseasesdiseases


Renal diseaseRenal disease TransplantationTransplantation IDDMIDDM Dietary disorders (anorexia etc.)Dietary disorders (anorexia etc.)

Less Common Secondary Risk Less Common Secondary Risk FactorsFactors

Ankylosing spondylitisAnkylosing spondylitis

COPDCOPD

EndometriosisEndometriosis

Lymphoma/LeukemiaLymphoma/Leukemia

Multiple MyelomaMultiple Myeloma

AmyloidosisAmyloidosis


HemophiliaHemophilia

HemochromatosisHemochromatosis

HypophosphatasiaHypophosphatasia

Osteogenesis imperfectaOsteogenesis imperfecta

SarcoidosisSarcoidosis

MedicationsMedications Glucocorticoids (PO and Glucocorticoids (PO and

inhaled)inhaled)

GrH AgonistsGrH Agonists

DepoDepo--ProveraProvera

LongLong--term heparin / term heparin / coumadincoumadin

PPIPPI

SSRISSRI


ImmunosuppressantsImmunosuppressants

AnticonvulsantsAnticonvulsants

Cytotoxic drugsCytotoxic drugs

LithiumLithium

Mas

s Peak Bone Mass


20 50 60 80

Age in Years

Bo

ne

M

10 40 70 9030

Active Growth

Type II Loss

Rapid Type I Loss

Continuing Loss

Type II Loss

Vertebral vs. HipVertebral vs. Hip Clinically evident: 25Clinically evident: 25--30%30% Future risk vertebral Future risk vertebral

fracture: 5fracture: 5--foldfold Future risk hip fracture: Future risk hip fracture:

22 foldfold

Excess mortality: 31% Excess mortality: 31% men, 17% womenmen, 17% women

Able to walk without Able to walk without assistance 6 months assistance 6 months later: 15%later: 15%


22--foldfold Patients with additional Patients with additional

fracture in 3 years: 50%fracture in 3 years: 50% Excess mortality: 30%Excess mortality: 30%

Recovers prefracture Recovers prefracture status: 20%status: 20%

Nursing home care: 30%Nursing home care: 30%

Lindsay et al JAMA 2001Black et al J Bone Miner Res 1999Hasserius et al Calcif Tissue Int 2005

Forsen et al Osteoporosis Int 1999Van Balen et al Disabil Rehabil 2003

Glucocorticoids and FractureGlucocorticoids and Fracture

2 59

5.18

3

4

5

6

actu

re


Van Staa et al Rheumatology 2000

1.17 1.1 0.99

1.551.36

1.04

1.77

2.59

1.64

1.19

2.27

0

1

2

all

fore

arm hip vert

all

fore

arm hip vert all

fore

arm hip vert

RR

fra

Orcel Joint Bone Spine 2005

<2.5mg 2.5 – 7.5mg >7.5mg

Bone PathophysiologyBone Pathophysiology

Division of Nephrology, Bone and Mineral MetabolismDivision of Nephrology, Bone and Mineral Metabolism Division of Nephrology, Bone and Mineral MetabolismDivision of Nephrology, Bone and Mineral Metabolism


ABD HPT


f r

f r

f r

f r

f r

f r

f rf r

f r

f rf r

f r

f r

f r

f rf r


f r

f r

f rf rf r

f r Remodeling sites in negative balance

Low Turnover State

Slow bone lossRapid bone loss

High Turnover State

Bone remodeling abnormalities Bone remodeling abnormalities resulting in bone lossresulting in bone loss

Bone BalanceNeutral

Bone


Bone Balance

ffff rrrr ffff rrrr ffff rrrr ffff ffff rrrr ffff rrrr

f = bone formation

r = bone resorption

rr rr

Pathogenesis of Osteoporotic Pathogenesis of Osteoporotic FracturesFractures

AGING MENOPAUSE OTHER RISK FACTORS

INCREASEDBONE LOSS

LOW PEAK BONE MASS


Modified from Riggs BL, Melton LJ. Osteoporosis: Etiology, Diagnosis, and Management, New York: Raven Press: 1998

LOW BONEDENSITY

POOR BONEQUALITY

FRACTURES

PROPENSITYTO FALL

DiagnosisDiagnosis

WHO DefinitionWHO Definition

Distribution of BONE Distribution of BONE MINERAL DENSITY in MINERAL DENSITY in young, healthy adultsyoung, healthy adults

TT--score = standard score = standard deviation (SD) below ordeviation (SD) below or


deviation (SD) below or deviation (SD) below or above mean of young above mean of young healthy adultshealthy adults

Specific to vertebrae, Specific to vertebrae, hip, wristhip, wrist

BMD measurementBMD measurement

Goal: to diagnose low bone mineral density Goal: to diagnose low bone mineral density AND estimate fracture riskAND estimate fracture risk

Population (NOF guidelines):Population (NOF guidelines):


Women >65 yo regardless of risk factorsWomen >65 yo regardless of risk factors

Postmenopausal women with risk factors (except Postmenopausal women with risk factors (except race)race)

Postmenopausal women with fracturesPostmenopausal women with fractures

Serial BMD measurementsSerial BMD measurements

Monitor therapy: recommended every 1Monitor therapy: recommended every 1--2 years2 years Change must exceed least significant differenceChange must exceed least significant difference Medicare coverage every 2 years:Medicare coverage every 2 years:

Postmenopausal womenPostmenopausal women


Postmenopausal womenPostmenopausal women LongLong--term steroid therapyterm steroid therapy Vertebral abnormalitiesVertebral abnormalities Primary hyperparathyroidismPrimary hyperparathyroidism Monitor response to therapyMonitor response to therapy

Combined Effect of Bone Combined Effect of Bone Density and Prevalent FracturesDensity and Prevalent Fractures

25

30

Relative Ri k f

Prevalent V t b l


25.1

14.910.2

7.4 4.4 10

5

10

15

20

Lowest Third Middle Third Highest Third

None

One

Risk for New

Vertebral Fractures

Vertebral Fractures

Bone DensityRoss et al Ann Intern Med 1991

Laboratory tests for OsteoporosisLaboratory tests for OsteoporosisMt. Sinai StudyMt. Sinai Study

CrossCross--sectional chart review sectional chart review

664 peri664 peri-- or postmenopausal women (or postmenopausal women (≥≥ 45 yrs) 45 yrs)


pp p p (p p ( y )y )with BMD Twith BMD T--score < score < --2.52.5

309 without known osteoporosis risk factors309 without known osteoporosis risk factors

173 had complete set of laboratory tests173 had complete set of laboratory tests

Tannenbaum et al J Clin Endocrinol Metab 2002

Mt. Sinai Study: FindingsMt. Sinai Study: Findings

0.60.6

8.1

9.82.3

4.1

6.9

55 / 173 patients with ≥ 1 new diagnosis

32.4% of 173 patients =


8.1

Hypercalciuria MalabsorptionHyperparathyroidism Vitamin D deficiencyExogenous hyperthyroidism Hypocaciuric hypercalcemiaCushing's disease

Tannenbaum et al J Clin Endocrinol Metab 2002

Suggested Screening Tests for Suggested Screening Tests for Contributory Causes of OsteoporosisContributory Causes of Osteoporosis 2424--hour urine:hour urine:

Ca, creatinine and NaCa, creatinine and Na

Serum:Serum:


Ca, P, creatinine, alkaline phosphatase, albumin, Ca, P, creatinine, alkaline phosphatase, albumin, PTH and 25PTH and 25--OH vitamin D, TSH, SPEPOH vitamin D, TSH, SPEP

Moderate cost, misses only rare causes of secondary Moderate cost, misses only rare causes of secondary osteoporosisosteoporosis

Turnover marker???Turnover marker???

Universal Preventive MeasuresUniversal Preventive Measures

Fracture PreventionFracture Prevention

Risk prevention (falls, balance etc.)Risk prevention (falls, balance etc.)

Weight bearing + muscle strength exercisesWeight bearing + muscle strength exercises


Weight bearing + muscle strength exercisesWeight bearing + muscle strength exercises

Smoking cessation, EtOH avoidanceSmoking cessation, EtOH avoidance

Exercise guidelinesExercise guidelines

AvoidAvoid

Forward flexion of spineForward flexion of spine

Bending forward from the waistBending forward from the waist


Twisting / jerking of spineTwisting / jerking of spine

One foot to remain on the groundOne foot to remain on the ground

Balance trainingBalance training

Face countertop and hold on with both handsFace countertop and hold on with both hands

Bend one leg and bring foot behind bodyBend one leg and bring foot behind body

Count to 5Count to 5


Then repeat withThen repeat with

One hand holding onOne hand holding on

FingertipFingertip

Without holding onWithout holding on

Closed eyesClosed eyes

General fall preventionGeneral fall prevention

HandrailsHandrails

Wear shoes with low heelsWear shoes with low heels

Sufficient lighting, use flash lightSufficient lighting, use flash light


Rubber mat in showerRubber mat in shower

SkidSkid--proof carpets / rugsproof carpets / rugs

Cordless phoneCordless phone

Emergency service / neighborsEmergency service / neighbors

Calcium Calcium –– daily intakedaily intake 1 1 –– 3 years3 years 500 mg500 mg

4 4 –– 8 years8 years 800 mg800 mg

9 9 –– 18 years18 years 1300 mg1300 mg

1919 4949 10001000


19 19 –– 49 years49 years 1000 mg1000 mg

> 50 years> 50 years 1200 mg1200 mg

Pregnancy:Pregnancy:

< 18 years< 18 years 1300 mg1300 mg

> 19 years> 19 years 1000 mg1000 mgNational Academy of Sciences 1997

Food SourcesFood Sources Yoghurt, low fat, 8 oz.Yoghurt, low fat, 8 oz. 250250--380 380 mgmg

Shredded cheddar, 1.5 oz.Shredded cheddar, 1.5 oz. 306 306 mgmg

Milk 2%, 8 oz.Milk 2%, 8 oz. 297 297 mgmg

Soy beverage, 8 oz.Soy beverage, 8 oz. 8080--500 500 mgmg


Tofu, processed with CaTofu, processed with Ca 204 204 mgmg

Instant breakfast, 8 oz.Instant breakfast, 8 oz. 100100--500 500 mgmg

Orange juice with Ca, 8 oz.Orange juice with Ca, 8 oz. 260260--325 325 mgmg

Cereal, 1 cupCereal, 1 cup 100100--1000 1000 mgmg

Ice cream, 1 cupIce cream, 1 cup 85 85 mgmg

Vitamin DVitamin D

Active vit. D essential for Ca absorptionActive vit. D essential for Ca absorption

Calcitriol (1,25 (OH) Calcitriol (1,25 (OH) –– vit. D)vit. D)

Target serum 25Target serum 25--(OH) vit. D > 30 ng/ml(OH) vit. D > 30 ng/ml


gg ( ) g/( ) g/

Daily need:Daily need:

< 50 years: 400< 50 years: 400--800 IU/d800 IU/d

> 50 years: 800> 50 years: 800--1000 IU/d1000 IU/d

Holick et al Am J Nutr 2004Dawson-Hughes et al Osteoporosis Int 2005

Pharmacologic TreatmentPharmacologic Treatment

Alendronate / RisedronateAlendronate / Risedronate Alendronate / RisedronateAlendronate / Risedronate

CalcitoninCalcitonin

RaloxifeneRaloxifene

ET/HTET/HT

TeriparatideTeriparatide

Therapy IndicationsTherapy Indications

Central T score < Central T score < --2, no risk factors2, no risk factors

Central T score < Central T score < --1.5, with risk factors1.5, with risk factors


History of lowHistory of low--trauma vertebral or hip fracturetrauma vertebral or hip fracture

Therapeutic ClassesTherapeutic Classes

Bone retaining (antiBone retaining (anti--resorptive):resorptive):

BisphosphonatesBisphosphonates



Estrogen / Hormone therapyEstrogen / Hormone therapy


Bone forming (anabolic):Bone forming (anabolic):

TeriparatideTeriparatide

BisphosphonatesBisphosphonates

FDA approved:FDA approved: AlendronateAlendronate

RisedronateRisedronate

IbandronateIbandronate

Early in the morningEarly in the morning

8 oz. tap water8 oz. tap water

NPO for 30 min (Alendronate, NPO for 30 min (Alendronate, Risedronate) or 60 min Risedronate) or 60 min


ZolendronateZolendronate

Binds irreversibly to Binds irreversibly to hydroxyhydroxy--appatite at the appatite at the osteoclastosteoclast--bone bone interfaceinterface

))(Ibandronate)(Ibandronate)

Upright for 30 minUpright for 30 min

Alendronate IndicationsAlendronate Indications

Osteoporosis prevention (5 mg QD, 35 mg qweek)Osteoporosis prevention (5 mg QD, 35 mg qweek)


Osteoporosis treatment (10 mg QD, 70 mg qweek)Osteoporosis treatment (10 mg QD, 70 mg qweek)



MenMen

SteroidSteroid--induced in men and womeninduced in men and women

Alendronate Alendronate –– GIO 2 yearsGIO 2 years


Saag et al N Engl J Med 1998

Risedronate IndicationsRisedronate Indications

Osteoporosis prevention (5 mg QD, 35 mg qweek)Osteoporosis prevention (5 mg QD, 35 mg qweek)




Osteoporosis treatment (10 mg QD, 70 mg qweek)Osteoporosis treatment (10 mg QD, 70 mg qweek)


MenMen


Risedronate Risedronate –– 1 year1 year


Harris et al JAMA 1999


Reduces vertebral fracturesReduces vertebral fractures

Not shown to reduce nonNot shown to reduce non--vertebral fracturesvertebral fractures

Indication: postmenopausal (>5 years) womenIndication: postmenopausal (>5 years) women


Indication: postmenopausal (>5 years) women Indication: postmenopausal (>5 years) women who are unable to tolerate other treatmentswho are unable to tolerate other treatments

Nasal spray or SQ Nasal spray or SQ

Calcitonin Calcitonin –– 5 years5 years

Division of Nephrology, Bone and Mineral MetabolismDivision of Nephrology, Bone and Mineral MetabolismChesnut et al Am J Med 2000

Cumulative percentage of participants with at least one new fracture per year. Number ofparticipants with follow-up radiographs (placebo = 270, 100 IU = 273, 200 IU = 287, 400IU = 278). The asterisk indicates P <0.05 versus placebo.


Selective ESelective E22 receptor modulatorreceptor modulator

Agonist on boneAgonist on bone

Antagonist on breast + uterusAntagonist on breast + uterus


Osteoporosis preventionOsteoporosis prevention


Osteoporosis treatmentOsteoporosis treatment


Raloxifene Raloxifene –– 5 years5 years

Division of Nephrology, Bone and Mineral MetabolismDivision of Nephrology, Bone and Mineral Metabolism Ettinger et al JAMA 1999

Reduction in new vertebral fractures among women (n=6828)

Raloxifene Raloxifene –– Breast CancerBreast Cancer

MORE: 4 years Raloxifene = 72% reduction MORE: 4 years Raloxifene = 72% reduction breast cancer in incidencebreast cancer in incidence


CORE: 8 years Raloxifene = 66% reduction in CORE: 8 years Raloxifene = 66% reduction in breast cancer incidence breast cancer incidence

Cauley et al Breast Cancer Res Treatment 2001Martino et al, J Nat Cancer Inst 2004

Women’s Health InitiativeWomen’s Health Initiative

ET: Conj Estrogen (PremarinET: Conj Estrogen (Premarin®®))

HT: Conj Estrogen + Medroxyprogesterone HT: Conj Estrogen + Medroxyprogesterone acetate (Premproacetate (Prempro®®))


acetate (Premproacetate (Prempro ))

FDA believes that findings of the WHI study FDA believes that findings of the WHI study apply to all ET/HT combinationsapply to all ET/HT combinations

WHI WHI –– Fracture, CADFracture, CAD


Writing Group for the Women’s Health Initiative, JAMA 2002

WHI WHI –– Cancer DataCancer Data


Writing Group for the Women’s Health Initiative, JAMA 2002

WHI limitationsWHI limitations

Looked at 0.625 mg qd EE and 2.5 mg MPALooked at 0.625 mg qd EE and 2.5 mg MPA

Not investigated other formulationsNot investigated other formulations


No distinction between estrogen and progestinNo distinction between estrogen and progestin

Transdermal application?Transdermal application?

ET/HT ET/HT –– FDA RecommendationsFDA Recommendations

ET/HT IS approved to PREVENT osteoporosisET/HT IS approved to PREVENT osteoporosis

Consider nonConsider non--estrogen preparations firstestrogen preparations first


“smallest dose for shortest time”“smallest dose for shortest time”

Weigh benefit and risks (DVT, CAD, breast Weigh benefit and risks (DVT, CAD, breast cancer)cancer)

Teriparatide = PTH (1Teriparatide = PTH (1--34)34)

First 1First 1--34 aminoacids of the PTH molecule34 aminoacids of the PTH molecule

SQ QDSQ QD


Max use for 2 yearsMax use for 2 years

Decreases vertebral AND nonDecreases vertebral AND non--vertebral vertebral fractures after mean 18 months treatmentfractures after mean 18 months treatment

Teriparatide IndicationsTeriparatide Indications

LOW TURNOVER bone disease!LOW TURNOVER bone disease! Postmenopausal women osteoporosisPostmenopausal women osteoporosis MenMen

Primary osteoporosisPrimary osteoporosis


Hypogonadal osteoporosisHypogonadal osteoporosis High riskHigh risk

Previous osteoporotic fracturePrevious osteoporotic fracture Multiple risk factorsMultiple risk factors TT--score <score <--33 Intolerant to other therapiesIntolerant to other therapies

Teriparatide WarningsTeriparatide Warnings

HypercalcemiaHypercalcemia

Paget’s diseasePaget’s disease

Children / adolescentsChildren / adolescents


PregnancyPregnancy

Bone cancer (esp. osteosarcoma)Bone cancer (esp. osteosarcoma)

Cancer history (esp. with bone metastasis Cancer history (esp. with bone metastasis potential) or radiation to bonepotential) or radiation to bone

RANKL/RANK/OPG SystemRANKL/RANK/OPG System


RealReal--World Obstacles in the World Obstacles in the Management of OsteoporosisManagement of Osteoporosis

Insufficient rates of diagnosisInsufficient rates of diagnosis

Low awareness the necessity to treatLow awareness the necessity to treat

Low persistence: patient stops taking Low persistence: patient stops taking


p p p gp p p gmedicationmedication

Poor compliance: patient does not follow Poor compliance: patient does not follow dosing instructionsdosing instructions

Siris et al Mayo Clin Proc. 2006

Probability of fracture in 24 months in bisphosphonate-treated patients


Siris et al Mayo Clin Proc. 2006

MPR = medication possession ratio

““Bones of Glass Bones of Glass and and

a Heart of Stonea Heart of Stone””

Aortic Calcifications and Bone Loss Aortic Calcifications and Bone Loss (157 women)(157 women)

Division of Nephrology, Bone and Mineral MetabolismDivision of Nephrology, Bone and Mineral Metabolism Schulz et al JCEM 2004;

Coronary Calcifications and Bone Coronary Calcifications and Bone VolumeVolume

(38 dialysis patients)(38 dialysis patients)30 yr old pt

50 yr old pt

75 yr old pt


75 yr old pt

Adragao, Herberth et al Clin J Am Soc Nephrol 2009.

ConclusionConclusion Osteoporosis pervasive health problem of major proportions Osteoporosis pervasive health problem of major proportions

incurring enormous healthcare expendituresincurring enormous healthcare expenditures

Underdiagnosed and undertreated Underdiagnosed and undertreated

Different types of bone loss requires different therapeutic Different types of bone loss requires different therapeutic


yp q pyp q papproachesapproaches

Therapies for high turnover might be harmful to patients Therapies for high turnover might be harmful to patients with low turnoverwith low turnover

Prevention and treatment of osteoporosis not only desirable Prevention and treatment of osteoporosis not only desirable for prevention of fractures but possibly also for slowing for prevention of fractures but possibly also for slowing progression of vascular calcifications progression of vascular calcifications

Thank YouThank You

Content Osteoporosis Concepts, Diagnosis, Tt tTreatments · 2010-05-07 · Pathogenesis of Osteoporotic Fractures AGING MENOPAUSE OTHER RISK FACTORS INCREASED BONE LOSS LOW PEAK BONE

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