Medical Management of Osteoporosis

A.Arputha Selvaraj APMP-IIM Calcutta

Annual Incidence ofCommon Diseases in Women

0

500000

1000000

1500000

2000000

Case

s pe

r yea

r

OsteoporoticFractures1

HeartAttack2

Stroke2 BreastCancer3

1 1996 and 2015 Osteoporosis Prevalence Figures. State-by-state Report2 1997 Heart and Stroke Statistical Update3 Cancer Facts and Figures - 1996

Prevalence of Osteoporosis in MenNearly 1/3 of the 44 million Americans who currently have or are at risk for osteoporosis are men1

14 million men have or are at risk for osteoporosis1

This figure is expected to increase to over 17 million in 2010 and over 20 million in 20201

1 in 4 men over age 50 may have an osteoporotic fracture

Male mortality risk after a fracture may exceed that of women2

1. America’s Bone Health: The State of Osteoporosis and Low Bone Mass in Our Nation . Washington, DC: National Osteoporosis Foundation; 2002:1-2.2. Am Fam Phys. 2003;67:1521-1526.

Different Fracture Rates in Men versus Women

• Male/female differences in bone accumulation and geometric development during puberty and adolescence give a mechanical advantage to men– Formation of periosteal bone leads to bigger bones –

greater diameter and cortical thickness in long bones– Larger vertebral bodies

• Accelerated bone loss due to menopause in women

• Pattern of trabecular bone loss affects bone strength– With aging, loss of horizontal connectivity in women

versus thinning of trabeculae in men

Adv Stud Med. 2006;6:171-181.

• men are less likely to fracture than women, the lifetime risk of fracture in men is 13% to 25%.

• bone loss in men is more gradual than that observed in women until about age 65.

• after age 70-75, bone loss in men is greater than that observed in women of the same age

Bilezikian JP. J Clin Endocrinol Metab. 1999;84:3431-3434. De Laet CE, et al. J Bone Miner Res. 1998;13:1587-1593.

FracturesFractures• The main morbidity of osteoporosis

• Almost 50% of women will suffer an osteoporotic fracture in their lifetime1

• Previous fractures are strong predictors of future fractures2-4

• Overall: 46% vertebral; 16% hip; 16% wrist5

1. Seeman E. Australian Doctor 2000; 7 April: I-VIII; 2. Ross PD, et al. Ann Intern Med 1991; 114: 919-23; 3. Black DM, et al. J Bone Miner Res 1999; 14: 821-8; 4. Klotzbuecher CM, et al. J Bone Miner Res 2000; 15: 721-39; 5. Access Economics Report for Osteoporosis Australia, 2001

Projected Global Distribution of Fractures

Asia

1990

31.2

28.6

20.9

7.1

8.8

0.82.3 0.2

Asia Europe N America Latin AmericaRussia Middle East Oceania Africa

Asia

2050

51.1

13

11.9

12.5

4.45.7 0.7 0.6

Normal Bone Osteoporosis

Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture. Bone strength primarily reflects the integration of bone density and bone quality.

NIH Consensus Conference 2000

Osteoporosis Definition: 2000’s

NIH Consensus Development Panel on Osteoporosis. JAMA 285:785-95, 2001

Risk Factors for Osteoporosis and Fracture

Non-Modifiable• Age• Female Sex• Maternal family history

of hip fracture• Low birth weight• Disease predisposing to

osteoporosis

Adapted from Jordan & Cooper Best Practise & Res Clin Rheumatol 2002

Potentially Modifiable• History of falls• Body mass index• Drug therapy (e.g.

corticosteroid use,etc) • Primary or secondary

amenorrhea• Early menopause• Smoking• Alcohol• Dietary calcium and

vitamin deficiency

Pathophysiology -OsteoporosisPathophysiology -Osteoporosis

• Bone remodeling occurs throughout an individual’s lifetime

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

• With the onset of menopause (mid-forties or fifties), diminishing estrogen levels lead to excessive bone resorption that is not fully compensated by an increase in bone formation

Bone Remodeling

A continuous process of skeletal breakdown and renewal that continues throughout life.

Remodeling constitutes the fundamental means by which bone is added or subtracted from the adult skeleton.

Marcus R. 1987

Microarchitectural Changes in Osteoporosis

Bone Mass

Trab Thickness

Trabecular Number

Horizontal Struts

Connectivity

Anisotropy

Osteoporosis is a disease not a number !

Several factors assist in identifying those at risk

age

prior fracture

BMD

falls

Bone Turnover Markers• Bone turnover markers are components of bone matrix or

enzymes that are released from cells or matrix during the process of bone remodeling (resorption and formation).

• Bone turnover markers reflect but do not regulate bone remodeling dynamics.

Diagnosis of Osteoporosis

• Physical Examination• Measurement of Bone Mineral Content Dual X-ray absorptiometry(DXA) Ultrasonic measurement of bone CT Scan Radiography

Diagnostic criteria* Classification

T is above or equal to -1 Normal

T is between -1 and -2.5 Osteopenia (low bone mass)

T is -2.5 or lower Osteoporosis

T is -2.5 or lower + fragility fracture(s) Severe or established osteoporosis

*Measured in "T scores." T score indicates the number of standard deviations below or above the average peak bone mass in young adults.

WHO Criteria for Diagnosis of Bone Status

Therapeutic options for osteoporosis

Stimulators of bone formation• (Fluoride)• Parathyroid hormone

Mixed mechanism of action• Vitamin D and metabolites• Strontium ranelate

Recommended for all women at risk for osteoporosis• Calcium and vitamin D

Inhibitors of bone resorption (in alphabetical order)• Bisphosphonates

– Alendronate– Etidronate– Risedronate

• Calcitonin – Nasal

• Estrogen ± progestin

• Selective estrogen receptor modulators (SERMs)

– Raloxifene

Antiresorptive Agents Increase BMD by Decreasing Remodeling Space and Prolonging Mineral

Acquisition

Remodeling space

Antiresorptive Agent

High Turnover

Low Turnover

New relatively under-mineralized bone

Adapted from David Dempster, Ph.D.

Older, relatively highlyMineralized bone

Hypothetical Effects of Increasing Bone Hypothetical Effects of Increasing Bone MineralizationMineralization

Percentage MineralizationPercentage Mineralization

ResistanceResistance to fracture to fracture forcesforces

Improved resistance to bending Improved resistance to bending = stiffness= stiffness

Increasing brittlenessIncreasing brittleness

Normal =65%

The Mechanical Consequences of Mineralization

Turner C et al., Osteopor. Int 2002; 13:97.

x

x

x

Displacement

Forc

e

Hyper-mineralized (Ostepetrosis)

Optimal

Hypo-mineralized (Osteomalacia)

Tough but not Stiff

Stiff but not Tough

Clinical Need for New Osteoporosis Treatment

Seeman Osteoporos Int. 2003;14 Suppl 3:S2-8Jiang et al. J Bone Min Res 2003;18(11):1932-1941

• Current antiresorptive treatments reduce bone loss and decrease fracture risk

• Antiresorptive agents are unable to form new bone or restore microarchitecture

• Some patients remain at high risk for fracture after antiresorptive treatment

• Teriparatide forms new bone and restores microarchitecture, thus reversing osteoporosis

2004

Goal of osteoporosis management:prevention of the first fracture

• Women who have 1 vertebral fracture have an 11-fold increased risk of ever having another vertebral fracture1

• Women with 1or more pre-existing vertebral fractures have an 5.1-fold increased risk of another vertebral fracture within the next year2

1. Melton et al. Osteoporos Int 1999: 10; 214-212. Lindsay et al. JAMA 2001: 285; 320-3

Management of Osteoporosis Management of Osteoporosis Goals of TherapyGoals of Therapy

• Prevent first fragility fracture or future fractures if one has already occurred

• Stabilize/increase bone mass

• Relieve symptoms of fractures and/or skeletal deformities

• Improve mobility and functional status

Role of Exercise in Management of Role of Exercise in Management of OsteoporosisOsteoporosis

• Exercise can maintain or increase BMD and improve muscle mass, strength, and balance, decreasing risk of hip fracture

• Studies have demonstrated a protective effect of previous physical activity on the risk of hip fracture

• Caution when prescribing specific exercises for osteoporotic patients to avoid injury

• Exercise programs should be tailored to the individual

Clinical Need for New Osteoporosis Treatment

While current treatments reduce fracture risk and allay bone loss, they are unable to restore bone matrix or architecture and many patients remain at high risk for fracture.

B3D-MC-GHACUCSF Jiang et al

Patient 1124

Baseline Follow-up

Female, age 65Teriparatide 20 g/day: 637 days (approx 21 mos)

BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%)

Teriparatide improves bone architectureTeriparatide improves bone architecture

Structural IndicesStructural Indices

Quantitative analysis - Significant changesQuantitative analysis - Significant changes

Trabecular bone volumeTrabecular bone volume

Structure model indexStructure model index

Connectivity densityConnectivity density

Cortical thicknessCortical thickness

P <0.05P <0.05

P <0.05P <0.05

P <0.001P <0.001

P <0.05P <0.05

Jiang et al. JBMR 2003, Vol 18.Jiang et al. JBMR 2003, Vol 18.Eriksen ACR 2002Eriksen ACR 2002

Age and Bone Mass as Predictors of FractureAge and Bone Mass as Predictors of Fracture

Hui SL, et al. J Clin Invest. 1988;81:1804-1809.

Bone Mass (g/cm2)

Frac

ture

Ris

k Pe

r 100

0 Pe

rson

–Yea

rsAge (Years)

0

20

40

60

80

100

120

140

160

>1.0 0.90-0.99 0.80-0.89 0.70-0.79 0.60-0.69 <0.60

<45

50-5445-49

55-5960-6465-69

70-74

75-79

80+

Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999

Incidence Rates for Vertebral, Wrist and Hip Fractures in Women After Age 50

50 60 70 80

Vertebrae

Hip

Wrist

40

30

20

10

Age (Years)

Annu

al in

cide

nce

per 1

000

wom

en

1 10

20

30

Ser Val Ser Glu Ile Gln Leu Met His AsnLeu

GlyLysHisLeuAsnSerMetGluArgValGlu

Trp

LeuArg Lys Lys Leu Gln Asp Val His Asn Phe

50

40

6070

80

- COOH

H2 N -

hPTH 1-34(crystal structure)Adapted from Proc Natl Acad Sci USA (1974);71:384

Adapted from Jin et al. J Biol Chem (2000);35:27238

Human Parathyroid Hormone1-34 and 1-84

2004

hPTH/PTHrPReceptor

hPTH (1-34)

PTH Paradox

Mode and Dose Effect

Continuous Infusion CatabolicHigh Dose

Once-daily Administration AnabolicLow Dose (duration less than 2 h)

Intermittent PTHMechanism of Action

PTH binds to cell surface G protein-coupled receptor

Stimulates differentiation of osteoblasts followed

by osteoclasts

Activates lining cells.Inhibits apoptosis

of osteoblasts

Net increase in number and activity of osteoblasts,

which outpace osteoclast activity

2004Eli Lilly and Company

VehicleSC1 h/day2 h/dayContinuous

Effects of Continuous vs. Intermittent hPTH(1-34) on Osteoblasts and Osteoclasts in Male Rats

T ra b

ecu l

a r B

one

P eri m

ete r

%

Sourced from Dobnig and Turner, Endocrinology 1997;138:4607-4612

*P<0.05, †P<0.01, ‡P<0.001 vs Vehicle

*

†

‡

Osteoblast Osteoclast

2004

once-daily continuous

RANKL OPG

osteoclast

bone resorption

serum Ca++

osteoblast apoptosis

boneliningcells

cbfa1 BMPPPARWntIGF 1,2amphiregulin

osteoblast number/function

bone formation

bone mass/strength

RANKL OPG

PTH

2004Eli Lilly and Company

Bone

Str

engt

h(M

ass

+ Q

ualit

y)

Time

Theoretical Action of Anabolic vsAntiresorptives on Bone Strength

anabolic

antiresorptive

Bone Strength and QualityDXA is not the Whole Story

•Reflected in dual-energy x-ray absorptiometry (DXA) measurements::

– bone size

– bone mineral content per unit area

– amount of mineralization in bone and surrounding tissues

•NOT reflected in DXA measurements:– trabecular connectivity and number

– collagen quality

– repair of microscopic damage (e.g. microcracks)

– bone shape2004

• After 6 and 18 months, patients treated with teriparatide show significantly higher bone formation activity in cancellous and endocortical bone than patients treated with alendronate.

• In the teriparatide group, bone formation and turnover appeared higher at 6 months than at 18 months, corroborating bone marker changes. In the alendronate group, bone formation and turnover remained constantly low.

• Bone histomorphometric indices pertaining to bone resorption remained constant throughout the study in both groups.

Summary

Meunier, et al. Calcif Tissue Int 2004;74(Suppl 1):p. S33 2004

• After 6 and 18 months, patients treated with teriparatide show significantly higher bone formation activity in cancellous and endocortical bone than patients treated with alendronate.

• In the teriparatide group, bone formation and turnover appeared higher at 6 months than at 18 months, corroborating bone marker changes. In the alendronate group, bone formation and turnover remained constantly low.

• Bone histomorphometric indices pertaining to bone resorption remained constant throughout the study in both groups.

Summary

Meunier, et al. Calcif Tissue Int 2004;74(Suppl 1):p. S33 2004

Jiang et al. J Bone Min Res 2003;18(11):1932-1941

Paired-Biopsy Study (Treatment Duration 12-24 Months)

Teriparatide has Positive Effects on Bone Histology

• No woven bone, mineralization defects, hypercellularity or abnormal architecture.

• Significantly increased trabecular bone volume and reduced marrow star volume (vs. placebo).

• No increase in cortical porosity in TPTD20 group. In the TPTD40 group, increased porosity at 12 months had resolved by 21 months.

2004

Patient treated with teriparatide 20µg

Female, age 65Duration of therapy: 637 days (approx 21 months)

BMD Change: Lumbar Spine: +7.4% (group mean = 9.7 ± 7.4%) Total Hip: +5.2% (group mean = 2.6 ± 4.9%)

Effect of Teriparatide onSkeletal Architecture

Baseline Follow-up Jiang UCSF

2004Data from Jiang, J Bone Min Res 2003;18(11):1932-1941

Jiang et al. J Bone Miner Res. 2003; 18(11):1932-1941

Teriparatide Has Positive Effects on Bone Structure

Summary

2004

Mechanism of ActionSummary

Once-daily PTH:• Increases bone remodeling • Stimulates new bone formation on quiescent surfaces• Promotes positive balance at bone remodeling sites

Improves: • Bone structure

- increases trabecular volume and connectivity- increases cortical thickness

• Bone geometry and increases cross-sectionalmoment of inertia

• Bone strength

2004

BoneDensity

BoneQuality and

1. Architecture/Dimensions2. Turnover3. Damage Acc.4. Mineralization5. Matrix quality

TERIPARATIDEEffects on Bone Quality

6. Osteocyte apt.

BoneStrength

Bone Forming and Anabolic Drug- PTH

From Riggs and Parfitt, JBMR, 2005, 20: 177-184

Fracture Prevention TrialAdverse Events

Dizziness

Nausea

Headache

Leg cramps

Withdrawn for AE

Placebo (n=544)

N (%)

33 (6)

41 (8)

45 (8)

6 (1)

32 (6)

TPTD20(n=541) N (%)

50 (9)*

51 (9)

44 (8)

17 (3) *

35 (7)

TPTD40 (n=552) N (%)

44 (8)

98 (18)‡

72 (13) *

13 (2)

59 (11) †

* P<0.05, †P<0.01 , ‡ P<0.001 vs. PlaceboNeer et al. N Engl J Med 2001; 344(19):1434-1441 2004

Fracture Prevention TrialSummary of Teriparatide Effects on Serum and Urine

Biochemical Tests

• Hypercalcemia absent or mild and transient (normal 24 hours after dose)

• Mean 24-hour urinary calcium increased 0.75 mmol/day (30 mg/day)

• Mean serum uric acid concentrations increased 13-25% (no clinical symptoms)

• Changes reversed after withdrawal of teriparatide• No increase in the incidence of nephrolithiasis

or impaired renal function

Neer et al. N Engl J Med 2001; 344(19):1434-1441 FORTEO USPI (United States Package Insert) 2004 2004

Fracture Prevention TrialTeriparatide Safety Profile

• No change in blood pressure or heart rate• No effect on incidence of cardiovascular

disease• No effect on incidence of life-threatening

illnesses • No increased cancer incidence • No effect on total mortality

2004Neer et al. N Engl J Med 2001; 344(19):1434-1441

AAA Study: HypothesisTeriparatide Treatment after Antiresorptives

• Prior exposure to alendronate would retard the skeletal response to parathyroid hormone while prior exposure to raloxifene would not.

Ettinger et al., J Bone Miner Res. 2004;19(5):745-751

AAA Study: Conclusions - 1Teriparatide Treatment after Antiresorptives

• TPTD stimulates bone turnover and increases BMD in both alendronate and raloxifene pretreated patients

• Prior raloxifene does not alter TPTD response

• Prior alendronate exposure yields: - early delay in bone turnover response - unexpected early BMD changes - dissociated BMD-bone turnover relationships - less BMD increment after 18 months

Ettinger et al., J Bone Miner Res. 2004;19(5):745-751

Assessment of Fracture Risk

• DXA Risk of fracture=1.5-3.0 with each SD decrease

in BMD Low sensitivity Screening is not recommendedQuantitative Ultrasound Risk of fracture= 1.5-2.0 with each SD

decrease in BMD

Markers of bone turnover

Bone formation markers Alkaline Phosphatase Bone Isoenzyme AP Osteocalcin Procollagen propeptides

of type I collagen

• Bone Resorption Markers

Hydroxyproline Pyrridium crosslinked

and associated peptides.

Treatment

• Calcium and Vitamine D• Hormone replacement Therapy• Selective estrogen receptor modulators(SERM)• Bosphosphonates• Calcitonin• Parathyroid Hormone• Other Treatments• Non-pharmacological Interventions

Calcium

Benefits1.Slower rate of bone loss.2.Reduction of fracture in

some studies.3Adjunct to other

osteoporosis Treatment.

Risk1.Mild GI Upset.2.Constipation.3.?Renal Stone.

Calcium Dose

1994 consensus on optimum calcium intake.

Adolescent 1200-1500mg/dayAdult upto 65yr 1000mg/dayPostmenopausal 1500mg/day

Vitamin D

• Essential for intestinal absorption of Calcium.• Daily Recommendation:400-800IU/day• ?Decreased risk of fracture in healthy elderly

with normal intake and BMD.

HRT

• 27%Risk reduction in non-vertebral fracture.• 33%risk reduction in vertebral fracture. Drawbacks 1.Effective only in age<60yr. 2.Nonsustainable effect.

Bisphosphonates

Benefits1.Potent inhibitor of bone

resorption.2.Reduces osteoclast

recruitment.3.Safe.4.Effective

Risk1.Low oral bioavailablity.2.Food,Ca,Ir,Coffie,Tea

interferes with absorption.

3.GI Discomfort.4.Rarely oesophagitis.

Calcitonin

• Peptide from Thyroid C-cell.• Direct inhibition of osteoclast activity.• Less effective in cortical bone.• Salmon Calcitonin nasal spray• Dose 200IU/Day

Thank you all

Bone Loss Accelerates After Menopause Bone Loss Accelerates After Menopause

MenopausePeak Bone Mass

Bone

Mas

s

0 10 20 30 40 50 60 70 80

Age (years)Byyny and Speroff 1996

The Osteoporosis Continuum

75+ KyphoticAt risk for hip fracture

55+ PostmenopausalAt greater risk for vertebral fracture than any other type of fracture

Healthy spine

Kyphotic spine

50 MenopausalExperiencing vasomotor symptoms

FracturesFractures• The main morbidity of osteoporosis

• Almost 50% of women will suffer an osteoporotic fracture in their lifetime1

• Previous fractures are strong predictors of future fractures2-4

• Overall: 46% vertebral; 16% hip; 16% wrist5

1. Seeman E. Australian Doctor 2000; 7 April: I-VIII; 2. Ross PD, et al. Ann Intern Med 1991; 114: 919-23; 3. Black DM, et al. J Bone Miner Res 1999; 14: 821-8; 4. Klotzbuecher CM, et al. J Bone Miner Res 2000; 15: 721-39; 5. Access Economics Report for Osteoporosis Australia, 2001

• Low baseline bone mineral density (BMD) predicts increased risk of subsequent fractures

• However, the relationship between changesin BMD with antiresorptive therapy and the reduction in risk of new fractures is not well understood

• The magnitude of the increases in BMD with antiresorptive therapies differs greatly, yet the vertebral fracture risk reductions are similar

Relationship Between BMD and FractureRelationship Between BMD and Fracture