medical management of osteoporosis
DESCRIPTION
Medical Management of OsteoporosisTRANSCRIPT
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