1Dr' Thomas Tse

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TREATMENT OF OSTEOPOROSIS Current Thinking Dr.
Thomas Tse, M.D. Clinical Assistant Professor St.
Louis University School of Medicine Endocrinologis
t Belleville, Illinois
2
Topics

• Bone Quality
• Post Menopausal Osteoporosis (PMO)
• Bisphosphonates
• Raloxifene
• Glucocorticoid Induced Osteoporosis
• Male Osteoporosis
• Parathyroid Hormone (PTH)

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AGING OF THE U.S. POPULATION
Percent over age 65
Paiment GD and Perrier L in Lorrain J et al,
in Comprehensive Management of Menopause,
Springer-Verlag 1994
4
Incidence of Osteoporotic Fractures in Women
After Age 50
Annual incidence per 1000 women
Age (Years)
Wasnich RD. Primer on the Metabolic Bone Diseases
and Disorders of Mineral Metabolism. 4th ed,
Philadelphia, PA Lippincott Williams
Wilkins1999257-259
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Age and Bone Mass as Predictorsof Osteoporotic
Fracture
Age (Years)
160
?80
140
120
100
Fracture Risk per 1000 PersonYears
80
70-74
60
60-64
40
50-54
20
0
gt1.0
0.90-0.99
0.80-0.89
0.70-0.79
0.60-0.69
lt0.60
Bone Mass (g/cm)
Hui SL, et al. J Clin Invest. 1988811804-1809.
6
7.4
8
7
5.4
6
4.5
3.7
5
4
Relative risk
3
2
1
0
Black '99
McClung '99
Ross '93
Risedronate
placebo patients
Black DM, et al. J Bone Miner Res.
199914(5)821-828. McClung M, et al. JAMA.
1999282(7)687-689. Ross PD, et al. Osteoporos
Int. 19933120-126. Data on file, Procter
Gamble.
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Prevalent Vertebral Fracture PredictsRisk of
Future Hip Fracture
Adapted with permission from Melton LJ III, et
al. Osteoporos Int. 199910214-221.
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Outcomes of Hip Fractures in the U.S.

• 300,000 hip fractures annually1
• 24 excess mortality in 12 months2
• 50 do not recover baseline function3
• 25 require long-term nursing home care4

1 U.S. Congress, OTA,. Hip Fracture Outcomes.
OTA-BP-H-120, 1994. 2 Ray, N.F. et al. J. Bone
Mineral Res. 19971224-35 3 Consensus Develop.
Conf., Am. J. Med. 199394646-650 4 Riggs, B.J.
and Melton, L.J. Bone 199517505S-511S
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Vertebral Fractures Fractures Begets Fracture
in a Cascade
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Bone Remodeling Process
Osteoclasts
Lining Cells
Bone
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NEW Definition of Osteoporosis

• Skeletal disorder
• Compromised bone strength
• Bone Strengthintegration of bone density bone
  quality
• Bone qualityarchitecture, turnover, damage
  accumulation and mineralization
• Low bone mass
• Increased risk of Fracture

NIH Concensus Conference Osteoporosis
Prevention, Diagnosis and Therapy JAMA 2001
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Why the Need to Change the Definition

• With Anti-resorptive agents
• The maximum degree of fracture protection was
  seen as early as 6-12 months when Bone Mineral
  density (BMD) gains were not at their maximum.
• Degree of vertebral fracture protection was not
  proportional to the gain in BMD.

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Shifting the Osteoporosis Paradigm
Bone Strength NIH Consensus Statement 2000
Bone Quality
Bone Density
and

• Architecture
• Turnover
• Mineralization
• Damage accumulation

NIH Consensus Development Panel on Osteoporosis.
JAMA. 2001285785-795.
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Contributors to Bone Strength
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Bone Mineral Density
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Location of Cortical and Trabecular Bone
Thoracic and 75 trabecular Lumbar Spine 25
cortical
Distal Radius 25 trabecular 75 cortical
Femoral Neck 25 trabecular 75 cortical
Hip Intertrochanteric Region 50
trabecular 50 cortical
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Technical Limitations of Measuring Change in BMD

• DXA measures total bone
• - Anti-resorptives act predominately on
• trabecular bone
• - 50 75 of BMD signal comes from
• cortical bone
• - 3 BMD increase by DXA corresponds
• to a 6-12 increase in trabecular bone.

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Post-Treatment Increases in BMD Over3 to 5 Years
with Osteoporosis Therapies
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Post-Treatment Increases in BMD Over 3 to 5 Years
and Relative Risk For Vertebral Fracture
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Limitations of Areal DXA

• Though for each standard deviation (SD) reduction
  in BMD, fracture risk doubles with treatment, a
  1 SD increase in BMD does not translate into a
  proportional reduction in fracture risk because
  BMD underestimates actual amount of Bone Mineral.
• Part of this limitation is technical, and part is
  due to the fact that areal BMD does not measure
  Bone Size and Microarchitecture.

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Medical Conditions Leading to Reduced BMD

• Hyperparathyroidism
• Vitamin D insufficiency/ deficiency
• Hypogonadism (primary and secondary)
• Multiple myeloma, lymphoma
• Hyperthyroidism
• Malabsorption syndromes (sprue)
• Chronic inflammatory disorders (rheumatoid
  arthritis) inflammatory bowel desease, genetic
  disorders (osteogenesis imperfecta)
• Osteomalacia

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LABORATORY TESTING

• Complet blood count, urinalysis
• Serum chemistry
• Calcium
• Phosporus
• Alkaline phosphatase
• Albumin
• Creatinine
• Thyroid-stimulating hormone
• Serum protein electrophoresis (SPEP)
• Urine immunoelectrophoresis (UPEP)
• Serum 25-OH vitamin D
• Serum intact - parathyroid hormone
• 24-hour urine calcium

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Medications Associated With Reduced BMD

• Anticonvulsants (phenobarbital, phenytoin)
• Cytotoxic drugs
• Glucocorticoids and adrenocorticotropin
• Gonadotropin-releasing hormone agonists
• Immunosuppressants
• Long-term heparin use
• Progesterone (long-acting)

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Roles of DXA

• DXA was used to establish WHO (T-score) criteria
  for osteoporosis and Osteopenia.
• Abundant prospective epidemiological and clinical
  trial fracture prediction data with DXA.
• Best technique for monitoring.

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CADfx Computer-aided fracture assessment tool
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Bone Turnover
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Turnover in Cortical and Trabecular Bone
Cortical Bone

• 80 of all the bone in the body
• 20 of bone turnover

Trabecular Bone

• 20 of all bone in the body
• 80 of bone turnover

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High Bone Turnover Leads to Development of Stress
Risers and Perforations
Stress Risers
Perforations
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Trabecular Perforations
Reprinted with Permission from Mosekilde L. Bone
Miner. 19901013-35. Seeman Lancet.
20023591841-1850.
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Bone turnover occurs within anormal
physiological window
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What happens if bone turnover isoutside the
normal physiological range?
Physiological
Bone Quality
Bone Turnover
Too Little Turnover- Aging bone, un-repaired
micro-damage, over-mineralized bone?
Too Much Turnover- Loss of bone mass and
structure, stress risers, under-mineralized bone?
38
Biochemical Markers of Bone Turnover Released
During Remodeling Process

• Bone Resorption
• N-telopeptides
• C-telopeptides
• Deoxypyridinoline
• Pyridinium crosslinks

• Bone Formation
• Bone-specific alkaline phosphatase
• Osteocalcin
• C- and N- type I collagen propeptides

39
Relationship between Early Change in Resorption
(NTX 3-6 mo)and Reduction in Vertebral Fracture
Risk with Risedronate
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Threshold for Decrease in Bone Resorption
(NTX)Below Which There is No Added Fracture
Benefit
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Bone Half-life of Bisphosphonates

• Boniva 2 years
• Actonel 4.5 years
• Fosamax 10 years

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Bone Mineralization
Factors of Bone Quality
BoneDensity
BoneTurnover
BoneMineralization
BoneArchitecture
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Visualization of Trabecular Remodeling
AreasRisedronate 5mg
Baseline
3 Year
White high mineralized bone Green low
mineralized bone
Low mineralized (Green) fraction decreased with
risedronate(p lt 0.05), as expected with a
reduction in bone turnover.
Ritman Borah et. al., European Connective
Tissue Society, May 8-12, 2003, (CTI 72(4),
Poster P-202.
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Visualization of Trabecular Remodeling
AreasRisedronate 5mg
Baseline
3 Year
Ritman Borah et. al., European Connective
Tissue Society, May 8-12, 2003, (CTI 72(4),
Poster P-202.
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Mineralization Affects Brittleness
Hypermineralized (osteopetrosis)
X
Optimum
X
Force
Hypomineralized (osteomalacia)
X
Displacement
Adapted from Turner CH, et al. Osteoporos Int.
20021397-104.
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Bone Architecture
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Changes in Trabecular Architecture
20 years

• Decrease in trabecular thickness, more pronounced
  for non load-bearing horizontal trabeculae.
• Decrease in connections between horizontal
  trabeculae.
• Decrease in trabecular strength and increased
  susceptibility to fracture.

50 years
80 years
Mosekilde L. Calcified Tissue Inter. 53(Suppl
1) S121-S126. 1993
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Importance of Horizontal Trabeculae

• Structure 1
  Structure 2

• Assume Volume 1 Volume 2
• Identical material and dimensions for both
• Structure 1 is 16 x stronger than Structure 2

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Trabecular Architecture and Bone Strength

• A column will buckle at critical load as a
  function of
• Column material
• Cross-sectional geometry
• The length of the column

Adding horizontal struts to a structure
exponentially increases strength by decreasing
the effective length of a column
16 lb
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Cross-Bracing Improves Strength
Courtesy Dr. David Dempster
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Antiresorptive Agents Help to Preserve
Supporting Ties
Reprinted with Permission from Mosekilde L. Bone.
19889247-250.
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3-D Micro CTHealthy vs Osteoporotic Bone
52 year old Female
84 year old Female (w/ vertebral fracture)
Borah et al Anat. Rec.(2001)
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Placebo-Treated Postmenopausal Women Rapidly Lose
Microarchitectural Elements
1 Year
Baseline
Dufresne, et al, Calcified Tissue International,
in press 2003.
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Risedronate-Treated Postmenopausal WomenMaintain
Microarchitectural Integrity
1 Year
Baseline
Dufresne, et al, Calcified Tissue International,
in press 2003.
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Structure of Bisphosphonates
Structure of Bisphosphonates
Structure of Bisphosphonates
When R
1
is an OH
group binding to
R
1
OH
OH
hydroxyapatite,
is
enhanced
O
O
P
P
C
P
-
C
-
P is essential for
OH
OH
binding to
The R
2
side chain
hydroxyapatite
determines potency
R
2
R
2

-
CH
-
3
-
pyridine risedronate
2
R
2

-
CH
CH
CH
NH
alendronate
2
2
2
2
2
R

-
CH
CH
NH

pamidronate
2
2
2
2
R

-
CH
etidronate
3
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Bisphosphonates Pharmacokinetics
Bisphosphonates Pharmacokinetics
Food (eg, Ca) interferes with absorption
Fast and complete uptake into bone 20-80
Slow release from bone
Intestinal absorption is low 0.5-10.0
No biliary secretion
Urine is main route of elimination no metabolites
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Antiresorptive Agents Increase Bone Mass by
Filling in Remodeling Space and/or Prolonging
Mineralization Phase
High Turnover
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Pathophysiology of GIO
Glucocorticoids
GI Ca absorption Urinary Ca excretion

Osteoblast bone formation
estrogen testosterone adrenal androgens
apoptosis function
serum Ca

Osteoclast bone resorption
PTH
Osteoporosis
Lukert BP et al. Ann Intern Med. 1990 112
352-364
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Glucocorticoid-Induced Osteoporosis

• All ages and genders are at risk
• Long-term use of oral glucocorticoids in chronic
  diseases
• Asthma
• COPD
• Rheumatoid arthritis
• Inflammatory bowel disease
• Lupus
• Significant bone loss can occur in as little as 3
  months
• 50 chance of developing osteoporosis if on
  steroid for
• 6 months
• Up to 50 of patients taking gt7.5 mg/day will
  fracture

Lukert BP et al. Ann Intern Med. 1990 112
352-364
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Oral Glucocorticosteroid Dose StronglyCorrelates
to Fracture Risk
6 4 2 0
Relative risk
gt 7.5 mg/day
lt2.5 mg/day
2.57.5 mg/day
Daily Oral Glucocorticosteroid Dose
van Staa et al, J. Bone and Mineral Res.
200015(6)993-1000
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Vertebral Fracture Incidence 1 Year
Fracture Risk Reductions Prevention Study
71 Treatment Study 70 Combined
Analysis 70



5mg vs. control p 0.072 5mg vs.
control p 0.125 5mg vs. control p 0.01
Cohen, et. al. Arthritis Rheum.
199942(11)2309-18. Reid, et. al., JBMR
200015(6)1006-1013. Reid, et. al. Arthritis
Rheum. 199841(Suppl) S136 abstract.
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Incidence of Fracture in Men and Women
Cooper et al. Trends Endocrinol Metab 1992.
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Mortality Associated with Fracture
Mortality (deaths/1,000 person-years)
Center et al. Lancet 1999.
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Recommendations for Prevention and Treatment of
Osteoporosis in Men

• General recommendations for all
• Exercise to improve strength and balance
• Calcium 12001500 mg/day
• Vitamin D 6001000 IU/day
• Biphosphonates

Rubenstein et al. Causes and prevention of falls
in elderly people. 1992. Orwoll ES. Academic
Press, 1999.
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Potential complications of Vertebroplasty

• Infection and bleeding (rare)
• Pulmonary embolism (usually occur but do not
  result in respiratory compromise
• Localized trauma to the cord
• Localized trauma to the lung or adjacent soft
  tissues
• Leakage of cement materials
• Paraplegia
• Exacerbation of pain (seen in 1-2 of cases)
• Death

Blake Johnson, M.D., 26th Annual Scientific
Meeting of the Society of Cardiovascular and
Interventional Radiology
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Approved Therapies in the United States for
Osteoporosis
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Approved Therapies in the United States for
Osteoporosis
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Human Parathyroid Hormone 1-34 and 1-84
1
10
H2N-
20
30
40
50
60
70
80
COOH
-
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FORTEO teriparatide (rDNA origin) injection
Stimulates New Bone Formation
After 21 months
Baseline
These microCT images of iliac crest bone biopsies
were obtained from a 65 year-old women who had a
BMD response that is representative of the
treatment group.
Jiang et al, J Bone Miner Res. 200217(Suppl
1)S135
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Positive Effective on All 4 Essential Bone
Qualities Contributing to Bone Strength Are
Important for the Optimal Therapeutic Effect
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Osteoporosis Treatment Objective

• OLD THINKING 1990s
• Osteoporosis Fracture
• Treat those with fractures to improve quality of
  
• life and prevent future fractures
• NEW THINKING 2006
• Osteoporosis RISK for fracture
• Identify those at risk and prevent first fracture

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Thank you !!!
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Bone Health and Osteoporosis A Report of the
Surgeon General

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• BMD testing remains the gold standard test for
  those at risk of osteoporosis.
• Bone strength is strongly related to BMD. More
  importantly, BMD remains a strong independent
  predictor of fracture risk. In fact, there is a
  clear relationship between BMD and fracture risk
  in older women.
• The relationship between BMD and fracture is as
  strong as the relationship between blood pressure
  and stroke.
• Although the most important study outcome is
  fracture risk reduction, changes in BMD or
  markers of bone turnover can be used (in the
  conduct of clinical studies) as supportive
  evidence of the effectiveness of treatment.