What is Osteoporosis?

Systemic skeletal diseasecharacterized by:

low bone mass (T-score < -2.5)

biochemically normal bone

microarchitectural deterioration of bonetissue

Hallmark-

Increased bone fragility andsusceptibility to fracture

Riggs B. N Engl J Med 1986;314:1676

Age (years)

An

nu

alF

ract

ure

Inci

den

ce,

per

100,

000

0

1000

2000

3000

4000

35 45 55 65 75 85+

Vertebrae

Hip

Wrist

Effect of Age on FractureIncidence in Women

70

75

80

Healthy Trabecular Bone vsOsteoporotic Bone: 3-D Micro CT

52 year old Female 84 year old Female(w/ vertebral fracture)

Borah et al Anat. Rec.(2001)

Prevalence of Low Femoral NeckBMD in U.S. Adults Ages 50+

0

10

20

30

40

50

60

<- 2.5 SD - 1 to - 2.5SD

Men

Women

Looker, J Bone Miner Res 1997; 12:1761-8.

Prevalence and Epidemiology ofPostmenopausal Osteoporosis (PMO)

Primarily affects Caucasians andAsians

40-50% of Caucasian women over age 50are expected to fracture in their remaininglifetime

Lower risk exists for Latina and African-American women

Lower risk for men (20-30% will fracture)

Factors Leading to IncreasedFracture Risk

US Economic Burden of PMO

Fractures associated with osteoporosisaccount for:

~ $14 -17 billion direct medical costs($140-170 million KPNC)

> 400,000 hospital admissions

~ 2.5 million physician visits

> 180,000 nursing home admissions

Costs of osteoporosis associated fractures by2040:

~ $50 billion

Burden of disease – hip fracture

4-6 million women in US fracture

13-17 million in US with low bone densityare at risk for hip fracture

Men have about 1/3 - 1/2 this risk

Hip Fractures - Associated Morbidity and Mortality

Death within oneyear

Permanentdisability

Unable to walkindependently

Unable to carry out at leastone independent activity of

daily living

20%

30%

40%

80%

Pa

tie

nts

(%)

Prevention of Osteoporosis(Improving Bone Mineral Density)

Heredity predicts about 20%

Attainment of peak bone density and avoiding

bone loss thereafter = skeletal hygiene

– Calcium intake: 1000 -1200mg in children and adults,

1500mg after menopause

– Weight-bearing exercise

– Adequate gonadal steroids

– Avoid smoking and excess EtOH

– Adequate vitamin D –

400 IU in youth, then 800-1200 IU

Management of Osteoporosis:Prevent first fragility fracture

Primary prevention– Skeletal hygiene– Look for secondary causes of bone loss– Fall prevention– Medication

Secondary preventionPrimary prevention +

– stabilize/increase bone mass– medications– This is the HEDIS goal – to treat with effective meds

to prevent further fracturing.

Risk Factors for Hip Fracture in White Womenfrom the Study of Osteoporotic Fractures

Factor

Calcaneal BMD (per 1 SD)

Age (per 5 yrs)

Hx maternal hip Fracture

Any Fracture since age 50

Increase in Risk (%)

60

40

80

50

Cummings et al. NEJM 1995

On feet < 4 hr/day

Inability to rise from chair

Reduced depth perception

Current benzodiazepine use

Walk for exercise

70

70

40

60

- 30

Pathophysiology of PMO:Overview

Bone remodeling occurs throughout life torepair microfractures and supply Ca++

In normal adults, the activity of osteoclasts(bone resorption) is balanced by that ofosteoblasts (bone formation)

With diminishing estrogen levels (mid-forties orfifties) excessive bone resorption is not fullycompensated by an increase in boneformation

Bone RemodelingStable bone maintainedby health osteocytes.

Activation of resorption• Repair microfractures• Supply calcium• Remodel bone• Inflammation

Multinucleated giant cellsIn acidic environment digpits and recruit osteoblasticformation of osteoid.

This is passivelymineralized into new bone- hydroxyapatite matrix.

Osteocytes maintain bonemetabolism.Normal skeletal turnovertakes about 2-4 years.

Microarchitectural Instability

Pathophysiology of PMO:Overview

Trabecular bone accounts for most boneturnover

– Only 25% of the skeletal mass

– >> 50% bone turnover

– Vertebrae, distal radius and femoral neck

The process is not 100% efficient and there isnet loss of bone after the third decade

Anything which increases the activity ornumber of osteoclasts or decreasesosteoblasts causes increased bone loss

Cooper C et al. J Bone Miner Res. 1992; 7:221Riggs BL et al. NEJM1986;314(26):1676-86

Fractures Increase with Age

3,000

2,000

1,000

500

0-44 > 85 > 90

Age ( years)

Fra

ctu

res/

1,00

0,00

0P

erso

n-Y

ears Men Women

Hip Hip

VertebraeVertebrae

2,500

1,500

045-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84 0-44 45-49 50-54 55-59 60-64 65-69 70-74 75-79 80-84

The steep rise in fractures among men occurs about 10 years later than it does in women.

Bone Gain and Loss Over a Woman’sLifetime

Adapted from Wasnich, R.D. et al.: Osteoporosis: Critique and Practicum, Honolulu, Banyan Press, 1989, pp. 179-213.

60

70

80

90

100

30 40 50 60 70 80 90

Age

Rela

tiv

eB

MD

(%)

Forearm

Spine

Hip and Heel

0

1000

2000

3000

4000

35 85+

Colles'

Vertebrae

Hip

Age

An

nu

alF

ractu

reIn

cid

en

ce

Cooper C. Baillières Clin Rheumatol. 1993;7:459–477.Faulkner KG. J Clin Densitom. 1998;1:279–285.

BMD and Fracture Risk AreInversely Related

Indications for DXA ScanWomen 65+

Men 70+

Adults >55 with Fractures or Risk Factors

Other circumstances:– Primary hyperparathyroidism

– Chronic glucocorticoid use

– Male hypogonadism or androgen deprivation therapy

– Premature menopause, aromatase inhibitors

– Prolonged hyperthyroidism

– DM1 55+ women, 65+ men

Monitoring Treatment (Q 3-5 yrs)

Case

GR: 67 yr old post menopausal female

Off HRT for 6 years

Exercises regularly, BP okay on HCTZ

122#, 5’ 4”, quit smoking 15 yr ago, no h/o Fx

Takes calcium and a multivitamin occasionally

Mom had a “hump” but age 84 from CVA

BMD ?

YES! > 65

Bone Density Scans

Purpose:1. Screening for disease2. Fracture risk assessment3. Monitor treatment

Account for only 60-80% of bone strength.

50% of patients with osteoporotic fractureDO NOT have osteoporotic T scores.

Who Has Osteoporosis?

Patient Age Fragility fx? T score

A 84 F N -2.2

B 56 F N -2.8

C 66 F Y -2.2

Who Has Osteoporosis?

Patient Age Fragility fx? T score

A 84 F N -2.2

B 56 F N -2.8

C 66 F Y -2.2

Risk Factors For Osteoporosis

AgeHistory of FractureEthnicity

Highest risk = Caucasian women

Family HistoryGlucocorticoid use

≥7.5mg prednisone daily for > 3 mo

Low BMIHypogonadism

Low estrogen in women, low testosterone in men

Risk Factors For Osteoporosis

Inadequate calcium and vitamin D intake

Immobilization

Smoking

Heavy alcohol use

– 3 or more drinks/day

Causes of Secondary Osteoporosis

Medications– Glucocorticoids

– Antiepileptics

– Lithium

– Methotrexate

– PPI’s

– SSRI’s (?)

– Thiazolidinediones

Connective tissue dz– Rheumatoid arthritis

– Ankylosis spondylitis

– Lupus

Nutritional factors– Anorexia nervosa

Ca++ intake

Vitamin D intake

– Excess caffeine or alcohol

– Excess Sodium

Lifestyle– Smoking

– Immobilization

– Excessive exercise

– Sedentary lifestyle

Causes of Secondary Osteoporosis

Endocrine causes– Hypogonadism

– Hyperthyroidism

– Hyperparathyroidism

– Glucocorticoids

– Type 1 Diabetes

– Type 2 Diabetes

Hemochromatosis

COPD

DepressionChronic Renal Failure

Pregnancy

Malignancy– Multiple myeloma

– Systemic mastocytosis

– Leukemia

GI diseases– Liver failure

– Biliary cirrhosis

– Inflammatory bowel disease

– Post gastrectomy, Roux-en-Yor duodenal switch

– Gluten-sensitive enteropathy(sprue)

Most Important Risk Factors forOsteoporotic Fracture

1. Age

2. History of Fracture

3. Everything else….

Riggs B. N Engl J Med 1986;314:1676

Age (years)

An

nu

alF

ract

ure

Inci

den

ce,

per

100,

000

0

1000

2000

3000

4000

35 45 55 65 75 85+

Vertebrae

Hip

Wrist

Effect of Age on FractureIncidence in Women

70

75

80

Fracture History = ↑ Fracture Risk

20% of patients with vertebral fractures willhave another one in the subsequent year.

Lindsay R, et al., JAMA 2001;285(3):320-3.

Case

GR: 67 yr old post menopausal female

Off HRT for 6 years

Exercises regularly, BP okay on HCTZ

122#, 5’ 4”, quit smoking 15 yr ago, no h/o Fx

Takes calcium and a multivitamin occasionally

Mom had a “hump” but age 84 from CVA

BMD ?

YES! > 65

Using FRAX

What if she had a fracture?

FRAX 10 year fracture risk:

Treatment advised

With major fracture risk over 20-30%

or

hip fracture risk over 3-4%

Previous Vertebral Fx PredictsRisk of Future Hip Fx

Adapted with permission from Melton LJ III, et al. Osteoporosis Int. 1999;10:214-221.

25

20

15

10

5

0

%S

usta

inin

ga

hip

Fx

Who Has The GreatestFracture Risk?

Patient Age Fragility fx? T score

A 84 F N -2.2

B 56 F N -2.8

C 66 F Y -2.2

84 y/o with Osteopenia

56 y/o with Osteoporosis 65 y/o with T score -2.2 and Fx

Who Has The GreatestFracture Risk?

Patient Age Fragility Fx? T score

A 84 F N -2.2

B 56 F N -2.8

C 65 F Y -2.2

10 yrFracture

Risk

Any 17%

Hip 5.6%

Any 11%

Hip 2.7%

Any 19%

Hip 3.4%

Treatment of Osteoporosis =Prevention of Fracture

Calcium and Vitamin D

Exercise

– Osteoblast Stimulation

– Fall Prevention

Fall Risk Reduction

Minimize Other RiskFactors

– Tobacco and alcohol

– Glucocorticoids

– Hypogonadism

Pharmacologic– Bisphosphonates

PO or IV

– Estrogen

– SERM’s (Evista)

– Teriparatide (Forteo)

– Denosumab (Prolia)

Other Factors

Calcium

Vitamin D

Ethnic factors

Exercise – just do it!

Daily Calcium Intake

NHANES III

All calcium salts are not created equal

Elemental Calcium in common products

40 percent of calcium carbonate

– take after meals: need low pH to dissociate

21 percent of calcium citrate

– take any time

13 percent of calcium lactate

9 percent of calcium gluconate

Aim for 1200-1500 mg TOTAL DAILYELEMENTAL CALCIUM intake

Is calcium either necessary orsufficient?

Many studies suggest benefit of adequate calcium intakein post-menopausal women

Many studies show improved BP and CV outcomes incalcium sufficient populations

The safety of calcium supplements (without vitamin Dsupplements) has been questioned

All medication studied include calcium and vitamin D inboth placebo and intervention groups

Current knowledge:

Dietary calcium may be better

Supplement deficient patients

Supplement patient you are treating for osteoporosis

Vitamin D Levels –Lower in Higher Latitudes

↑ Ca ++

absorption ingut

↑ Osteoclastic

resorption of bone

↓ Serum Ca ++

PTH ↑

1,25 diOH vitamin D25 OH vitamin D

↑ Renal calcium reabsorption

7-deoxycholesterol

Vitamin Dfor Muscle and Bone Health

Metabolism and signaling decrease with age.

Prevents fall and fractures

– Multiple studies show fracture preventionwith calcium and vitamin D.

– Negative studies had poor compliance(<60%), inadequate doses (< 800 IU)

or 25OH D levels < 30 ng/ml

Vitamin D and PTH

290 consecutive pts. ona general medical ward

– MGH

Thomas 1998. NEJM

Measuring Vitamin D

1 ng/mL = 2.5 nmol/L

40ng/mL = 100 nmol/l

One caveat:

Most clinical assays are inaccurate

CV up to 20%

e.g. 24 ng/mL could be <20 or over 30

Vitamin D and Ca absorption

32 ng/mL

Optimal Vitamin D

Desirable level begins at 30 -32ng/mL

(75-80 nmol/L)

Do my patients need vitamin D?

Evidence on fractures tells the story

Calcium and vitamin D supplementation inambulatory elder population - hip fracture

0

1

2

3

4

5

6

7

8

9

3 6 9 12 15 18

Hip

Fra

ctu

res,

%

Time, months

Placebo

Ca/D

Chapuy MC et al NEJM 327:637, 1992

How much Vitamin D?

New Guidelines recommend:

800 IU vitamin D and 1000mg calciumdaily for pre-menopausal women

800 IU vitamin D and 1500mg Calciumdaily for post-menopausal women and

men over 50.

Pharmacologic Treatment ofPMO: Overview

Treatment

Action

Hormone therapy (HT)* or ET

Selective estrogen receptormodulators (SERMs):raloxifene

Calcitonin

Bisphosphonates*

Inhibit bone resorptionMaintain or increase bone massReduce fracture risk

rPTH (Forteo)Increases bone formationincreases bone mass

* decrease hip fractures

Denosumab (Prolia)

AB 4/04 57

Slowing down the osteoclasts allow boneremodeling ‘space’ to be refilled.

Hundreds of bone remodelingunits effected over years

Usually entire skeletonremodels over 3 years

Bone Turnover

Month

0 3 6 9 120

5

10

15

20

Month

0 3 6 9 12

NT

XM

ea

nV

alu

e(n

mo

l/m

mo

l)

0

10

20

30

40

50

60

70

80

N-Telopeptide Bone Specific Alkaline

Phosphatase ALN 10 mg daily ALN 35 mg Twice Weekly ALN 70 mg Once Weekly

ALN 10 mg daily ALN 35 mg Twice Weekly ALN 70 mg Once Weekly

Schnitzer T, et al. Aging Clin Exp Res. 2000;12:1-12.

Effect of Unopposed Estrogen and HRT on Spine and

Hip BMD in Postmenopausal Women: The PEPI Trial

Placebo CEE (0.625 mg/d) CEE-MPA (cyc) CEE-MP (cyc)CEE-MPA (con)(n=125) (n=94) (n=139) (n=146) (n=136)

Spine* Hip*

The Writing Group for the PEPI Trial. JAMA. 1996;276:1389-1396.

Data shown are for compliant subjects.*P< vs. placebo for all comparisons.0.05

0.92

0.93

0.94

0.95

0.96

0.97

0.98

0.99

1.00

1.01

1.02

Baseline 12 36

0.84

0.85

0.86

0.87

0.88

Baseline 12 36

Unadju

sted

BM

D(g

/cm

2)

Months Months

Unadju

ste

dB

MD

(g/c

m2)

Effect of Raloxifene on BMD in PostmenopausalWomen Without Osteoporosis

Lumbar spine* Total hip*

Months

%cha

nge

fro

mba

se

line

–2

–1

0

1

2

3

0 6 12 18 24

Months

–2

–1

0

1

2

0 6 12 18 24

%cha

nge

fro

mba

se

line

*P< vs. placebo for all treatment groups at 24 months.0.03

Reprinted with permission from Delmas PD, et al. N Engl J Med. 1997;337:1641-1647.

Placebo(n=150)

30 mg raloxifene(n=152)

60 mg raloxifene(n=152)

150 mg raloxifene(n=147)

Cost Effectiveness of OsteoporoticTreatment

NOF guidelines suggest benefit at 10 yearfracture risk

20% major osteoporotic fracture

or > 3% hip fracture

Bisphosphonates:

Women over 67 with fractures

Vitamin D and calcium

Elderly patients

Alendronate 70mgweekly PO

Weekly $17

Alendronate/cholecalciferol(Fosamax Plus D)

70 mg/2,800IU PO

weekly $354

Risedronate (Actonel) 35 mg PO weekly $925

Ibandronate (Boniva) 150 mg PO monthly $70

Ibandronate (Boniva) inj 3 mg IV over15-30”

Q 3 months $1616 peryear

Zoledronic Acid (Reclast) 5 mg IV in 1h Annually $500 peryear*

Bisphosponates approved for PostmenopausalOsteoporosis

Medication Dose Interval Cost/3 Mon

When prescribingbisphosphonates…work the patient up

Ensure adequate Ca and vitamin D intake

Discuss:– cost

– projected duration of Rx

– potential side effects: mostly GI.

– use TAV to follow-up

NEVER cut pills

IV meds may cause flu-like symptoms, rarelyrenal compromise – may vary dose forpatients with CKD stage II and III

Unknown knowns

unproven side effects:

a fib and esophageal cancer

Possible issues– Osteonecrosis of the jaw (<1/1000 over 5 years)

– Possible risk of diaphyseal fractures withlong-term Rx (<<1/1000 over 5 years)

Black, DM et al N ENGL J MED 2012; 366:2051

+++-

+--

++?

Is there magic in the dosinginterval?

No

Several studies show prolonged effect on Boneturnover markers and maintenance of BoneDensity for months to YEARS after stoppingbisphosphonates

Grey A. Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial. J of Bone & MineralResearch. 25(10):2251, 2010

Monitor calcium, vitamin D and consider drugholidays

New Drugs

Denosumab - humanized mouse monoclonalantibody to RANKL (a ligand that activates theosteoclasts) - blocks osteoclast differentiation,proliferation, and function.

Increased BMD (McClung MR et al 2006 NEJM 354:821)

and preliminary data suggest decreased FX -sub-cutaneous injection twice a year

Change in bone density anddecrease in bone turnover markers

Similar decrease in fracture riskover 3 years

Recombinant PTH - Forteo

Daily SQ injection 20 mcg for up to 2 years(limit due to osteosarcoma in rats)

Very expensive but unique mode ofaction – increases osteoblast function.

May cause hypercalcemia.

Contraindicated in: active malignancy

renal insufficiency

renal stone disease

B3D-MC-GHACUCSF - Jiang

Patient 1124

Baseline Follow-up

Effect of Teriparatide (20µg)on Skeletal Architecture

rPTH

Daily 20 µg SQ injection

Stimulates osteoblasts

Increases bone mass

Decreases fracture rate

Time limited

$8000-10,000 per year

Must be followed by antiresorptive or BMD islost again.

Is there magic in the dosinginterval?

No

Several studies show prolonged effect on Boneturnover markers and maintenance of BoneDensity for months to YEARS after stoppingbisphosphonates

Grey A. Prolonged antiresorptive activity of zoledronate: a randomized, controlled trial. J of Bone & MineralResearch. 25(10):2251, 2010

Monitor calcium, vitamin D and consider drugholidays

When/Why Should I Consider aDrug Holiday?

And for How Long?

Drug Holidays: FLEX Trial

Black, et al., JAMA 2006.

After 5 years of oral alendronate (FIT), 1099 postmenopausal women randomized to 5 more years of

alendronate or placebo (FLEX).

Drug Holidays and FLEX: BMD

FLEX trial Drug Holidays and FLEX: Fractures

10 yrs

5yrs +holiday

Conclusions from FLEX:5 vs. 10 yrs of alendronate

Compared to 5 years, 10 years ofalendronate offers:

– Stabilization of BMD– Reduction in the risk of vertebral fractures– No impact on the rate of non vertebral fractures

Bottom Line: consider 10 yrs instead of 5for those at highest risk of vertebralfracture:

– Prior hx of vertebral fracture– Very low T scores or highest FRAX scores

FLEX Results: Highest Risk WomenFor women at highest risk, defined as femoral neck

T score <-2.5, five additional years of bisphosphonate didresult in fewer non vertebral fractures.

HORIZON Extension Trial

HORIZON:

– Zoledronic acid 5mg IV or placebo annuallyfor 3 years

HORIZON EXTENSION:

Those who received ZOL randomized to moreZOL (Z6)

or placebo for more three years (Z3P3)

HORIZON Extension: Results

BMD: declined slightly in the Z3P3 group vs. Z6– True for all sites (spine and hip)– Z3P3 BMD still above Z0 baseline

Vertebral fractures: lower in Z6 group– 3.0% vs. 6.2%

Non vertebral fractures: no difference– 8.2 vs. 7.6%

Hip fractures: no difference– 1.3 vs. 1.4%

Discussing side effects andfollow-up

Chronic disease

– Fracture patients may require long-termtreatment (>5 years)

– Preventive (prophylactic) therapy. Consider‘drug holiday’ and reassess risk

Very high risk

– Consider combination or sequential therapy

– Consultation with osteoporosis expert

FLEX trial follow-up

Initial bone density and age predicted futurefracture

Bone turnover markers did not predictfracture at baseline or at 1 year post ALN.

This does not help us with prevention ofONJBauer et al.JAMA Internal Medicine 2014, 174(7):1126

Conclusions

Risk of fracture should be high beforeinitiating treatment with antiresorptiveagents

Reassessing risk and discontinuingmedications is an option

Communication between providers mayimprove patient outcomes

No known protection from ONJ

Prevent fractures

Screen patients at risk

Preventive measures

Treat high risk patients

A fracture in a susceptible patient requireswork-up and treatment

Have a treatment goal and re-visit the issueannually.

THANK YOU!

Comments, Questions?