Inflammation of the Joint

(over 100 specific diseases)
Rheumatoid Arthritis
Gout
Degenerative Joint Diseases
Ankylosing spondylitis
JRA
Psoriatic Arthritis
Bacterial Arthritis
Systemic Lupus
Erythematosus
Scleroderma
ARTHRITIS: Inflammation of the Joint
Pain
Swelling
Redness
Warmth
IL-8
IL-6
GM-CSF
IL-1
TNF-
FGF
Fibroblast/ type
B synovial cells
Metalloproteinases
Prostaglandins
Complement
IL-6
IL-1
IL-6
IL-8
GM-CSF
M-CSF
Macrophage/ type A
synovial cells

IL-1
TNF-
Adhesion molecule
expression on
blood vessels
HLA-DR
Complement
metalloptoteinases
CYTOKINE NETWORKS IN SYNOVITIS
+ FEEDBACK
IL-8
IL-6
GM-CSF
IL-10
IL-1
TNF-
FGF
Fibroblast/ type
B synovial cells
Metalloproteinases
Prostaglandins
Complement
IL-6
TGF-
IL-4
IL-1
IL-6
IL-8
GM-CSF
M-CSF
Macrophage/ type A
synovial cells

IL-1
TNF-
Adhesion molecule
expression on
blood vessels
HLA-DR
Complement
metalloptoteinases
CYTOKINE NETWORKS IN SYNOVITIS
+ FEEDBACK
- FEEDBACK
Points to Remember
Cells involved in Inflammation:
- macrophage, fibroblast, T-cells
Pro inflammatory cytokines:
- IL-1, TNF alpha, IL-6
- IL-8, FGF, GM-CSF
Anti inflammatory cytokine:
- IL-10, TGF-B, IL-4
Degenerative Joint Disease / Osteoarthritis
• A group of disorder in which the balance between
degeneration and synthesis within the cartilage and
subchondral bone is disturbed resulting to cartilage and
subchondral bone destruction

Dippe, Paul
Osteoarthritis

• Most common form of arthritis
• 10% of the worlds population
• 50% of people over the age of 60 years
• At age 75, more than 80% of people have symptoms
of the disease
• More common in women than in men
Risk Factors for Osteoarthritis
• Age
• Female sex
• Race
• Genetic factors
• Repetitive stress
• Obesity
• Congenital / Developmental defects
• Prior inflammatory joint dse.
• Metabolic / Endocrine disorders
Clinical Features
• Deep ache, localized pain
• Aggravated by activity, relieved by rest
• Transient joint stiffness
• Bony swelling, crepitus
• Progressive cartilage loss
Biochemical markers in Osteoarthritis
Major tissue of
origin
Biochemical markers
Synovium Hyaluran, type 2 collagen
propeptide, proteases
Subchondral bone Type 1 collagen crosslinks,
osteocalcin, alk. phosphatase,
Cart. oligomeric protein (COMP)
Management of Degenerative Joint Disease
• Non-pharmacologic
• Pharmacologic
• Surgery
Changes in lifestyle for patients with Osteoarthritis
• General measures
- Maintain optimal weight
- Encourage activity and regular general exercise
- Maintain positive approach
• Specific measures
- Strengthening of local muscles
- Use of appropriate footwear and walking aids
- Pay attention to specific problems caused by disability (such as
shopping, housework, and job)
Pharmacologic Agents

1. Analgesics

 Simple Analgesics (acetaminophen)
 Other Analgesics (opioids, tramadol)
or combination


Acetaminophen is the first line agent for OA
ACR recommendation

Pharmacologic Agents

1. Analgesics

2. NSAIDs

 Anti inflammatory effects
 Safety concern
- renal, GI, platelet function
- CV risk

Phospholipids
Phospholipase A
Arachidonic Acid
( PG, thromboxanes, prostacyclins)
Lipooxygenase Cyclooxygenase
(-) NSAID’s

(leukotrienes, bradykinin)

Mechanism of Action of NSAIDs – New hypothesis
Arachidonic Acid
Prostaglandins
Prostaglandins

Protection of
gastric mucosa
Homeostasis
Mediates pain
Inflammation and fever
Conventional
NSAIDs
COX-1 COX-2
Coxibs
COX-1 COX-2
- produces PG from AA - produces PG from AA
- constitutively expressed - inducible

- governs PG production - governs PG production
that mediate hemostatic that mediate
inflammation
function

- essentially important in:
gastric, bowel mucosa
kidney, platelets
Risks factors for UGI adverse events
• Age >65 y.o.
• Co-morbid clinical conditions
• Oral glucocorticoids
• History of PUD; UGIB
• Anticoagulants
Pharmacologic Agents

 Few joint involvement
 NSAIDs, capsaicin


1. Analgesics
2. NSAIDs

3.Topical Agents
Pharmacologic Agents

 (+) effusion
 Relief lasts for a few weeks



1. Analgesics
2. NSAIDs
3.Topical Agents

4. Intraarticular
Steroid Injection
Pharmacologic Agents





1. Analgesics
2. NSAIDs
3.Topical Agents
4. Intraarticular Steroid
Injection

5. DMOAD’s

 Modify morphologic changes in
the joints
- glucosamine / chondroitin
- viscosupplementation
- doxycycline


Pharmacologic Agents





1. Analgesics
2. NSAIDs
3.Topical Agents
4. Intraarticular Steroid
Injection
5. DMOAD’s

6. Other Agents

 Antidepressants
 Mild tranquilizers


Surgical Treatment for Osteoarthritis
• History of joint locking
- arthroscopy for removal of loose body
• Persistent synovitis
- arthroscopic washout or radioisotope
synovectomy
• Joint replacement is highly effective for hip & knee
- consider early referral for opinion
Points to Remember - Osteoarthritis
• Most common form of arthritis
• Identify risk factors
- age is the most powerful risk factor
• Deep ache localized pain related to activity
• Hand lesions
- heberdens, bouchards nodes
• Progressive cartilage loss
• Paracetamol – 1
st
line agent
Rheumatoid Arthritis
• Chronic, inflammatory
• Articular, extra-articular
• Oligo, polyarticular
• Young, female/male ratio (4:1)
• Remission and relapse
• Unknown etiology
- genetic predisposition (HLA-DR4)
Rheumatoid Arthritis
• Etiology is unknown
- Genetics
- HLA DR4
- Infection
- mycoplasma, EBV, CMG, parvo,
rubella virus
- “Superantigens”
- staph, strep, M. arthritidis
- Environmental
- cigarette smoking
Extra-articular manifestation of RA
• rheumatoid nodules
• vasculitis
• pulmonary
- pleural effusion, fibrosing alveolitis, nodules
• cardiac
- pericarditis, mitral valve disease, conduction defects
• skin
- palmar erythema, cutaneous vasculitis
• Feltys syndrome
- sero (+) RA, splenomegaly, neutropenia


Extraarticular Manifestations of RA
Immune Abnormalities
• Rheumatoid Factor
- anti - immunoglobulins
- anti IgG/IgM - immunologic hallmark
- Rose-Waaler assay
- (+) 80% of RA pts.
- high titer associated
- extra-articular sx
- progressive disease
- poor prognosis
• ANA




Other causes of (+) RF test:
- other CTD - leishmaniasis
- viral infections - TB
- leprosy - liver diseases
- SBE - sarcoidosis


Revised criteria for RA diagnosis
- symmetrical joint involvement*
- joint stiffness of at least1 hour duration*
- Involvement of at least 3/14 joints of the body*
- Hand joint involvement*
- (+) subcutaneous nodules
- (+) RA test
- radiographic findings
- Juxtaarticular osteoporosis, cystic lesions, evosions

• * At least 6 weeks duration
• 4/7 criteria


Treatment of RA
Experimental
agents
Cyclophosphamide,
MTX, Azathioprine
Gold salts, antimalarials,
Penicillamine
Salicylates, NSAIDS, analgesics
Education, rest, exercise, social service
Intraarticular
Steroid injection
Mechanical
devices
DMARDs
• Non-analgesic
• Slow onset of action – 10-20 weeks
• More toxic than NSAIDs
• Mechanism of action:
– Decrease leukotriene B4 synthesis in
neutrophils
– Decreases IL-1 concentration in SF
Disease Modifying Drugs (DMARD’s)

• Gold salts
• Antimalarials
• Sulfasalazine
• D- Penicillamine
• Methotrexate
• Cyclosporin-A
Biologic Agents
• Anti TNF
- Etanercept
- Infliximab
- Adalimumab
• T cell inhibitor
- Abatacept
• B cell inhibitor
- Rituximab
• Interleukin 1 receptor antagonist
- Anakinra
Adverse effects of Biologic Agents

• Opportunistic infection
• CHF
• Demyelinating disease
• Systemic lupus erythematosus
• Injection site reaction
• Neutropenia

Factors Associated with Poorer Prognosis
• Insidious polyarticular onset
• Male patients
• Extraarticular manifestations
• Functional disability at one year after start of disease
• Substantially raised concentration of RF
• Presence of HLA-DR4
• X-ray evidence of erosion within three years of start of
disease
Points to Remember
• Polyarticular, symmetrical
• Joints stiffness more than 1 hour
• Cartilage destruction, bone erosions
• Asso. with deformities, extra articular features
• ACR revised criteria for diagnosis
• Disease modifying, biologic agents
Gouty Arthritis
• King of diseases; disease of Kings
• inflammatory arthritis due to urates
• acute, episodic
• monoarthritis  polyarticular
• Hyperuricemia
- biochemical hallmark

Classification of Hyperuricemia and Gout
• Primary
- Enzymatic Defect
• HGPRT deficiency
• PRPP overactivity
• Secondary
- Endogenous
• Family history
• Body build
• Kidney function, HPN
• Inc. cell breakdown
- Exogenous
• diet, drugs
• alcohol, stress
• starvation
Renal
Handling
of Urates
Gouty Arthritis
• Statements
- Hyperuricemia is not gout
- Gout is a result from hyperuricemia
- Extremely painful episodes of arthritis
- Tendency to abuse NSAIDS, steroids
- Treatable / Preventable




The most important differential diagnosis for
acute gouty attack is
infection


“ The most feared complication of Gouty
Arthritis is kidney involvement “
Risk Factors for the Development of Gout Alcohol
• Association of alcohol consumption and the risk of incident gout
- 12 year cohort study
- Biennial questionnaires
- 47,150 male health professionals with no gout at baseline
• Alcohol intake strongly associated with an increased risk of gout
- Highest risk with beer consumption
- Moderate risk with liquor consumption
- Lower risk with wine consumption

Choi et al. Lancet, 2004;363:1277-1281
Risk Factors for the Development of Gout
Diet
High meat consumption

High seafood consumption

High dairy consumption

High consumption of
purine-rich vegetable


risk gout

risk gout

risk of gout

no association


Choi et al. NEJM, 2004;350(11):1093-1103



Risk Factors for the Development of Gout
Drugs
- low dose steroids
- aspirin
- anti TB drugs - pyrazinamide
- diuretics


Treatment
• Acute Attack
- NSAIDS, Colchicine
- Analgesics
- IV/IM corticosteroids
- Non pharmacologic measures

• Hyperuricemia
- Allopurinol
- Uricosuric drugs
PROPHYLACTIC COLCHICINE DOSES
CClr > 60
CClr 40-60
CClr 30-40
CClr < 30


0.6 mg BID
0.6 mg QD
0.6 mg Q2 Days
0.6 mg Q3 Days



- COLCHICINE NOT EXTRACTED BY DIALYSIS
- DO NOT USE IN DIALYSIS PATIENTS

- REDUCE COLCHICINE BY 50% FOR AGE >= 70
- CAUTION WITH DRUG INTERACTIONS:
e.g., CSA, Statins, Macrolides, Gemfibrozil
Points to Remember
• Acute, episodic; mono/oligoArthritis
• Hyperuricemia – biochemical hallmark
• (+) uric acid crystal on SF, tophi – definitive Dx
• Young male, post menopausal women
• Provocative factors:
- inc. purine foods
- trauma, surgery
- alcohol ingestion
- ACTH, glucocorticoid withdrawal
- hypouricemic therapy
- medical illness – stroke, MI
- drugs – diuretics, PZA, low dose aspirin
Spondyloarthropathies
• Ankylosing spondylitis
• Psoriatic arthritis
• Reiters disease / Reactive arthritis
• Enteropathic arthritis (IBD)
General Features
• Familial aggregation – HLA-B27
• ( - ) rheumatoid factor test
• Asymmetric peripheral oligoarthritis
• Axial skeleton involvement
• Sacroiliitis – low back pain
• Enthesopathic

Ankylosing Spondylitis
• Marie Strumpell disease, Bechterews disease
• 2
nd
– 3
rd
decade of life
• Male preponderance – 3:1 ratio
• Syndesmophyte formation ( bamboo spine )
• Enthesitis, sacroiliitis
Clinical Features
• Dull pain, insidious onset
• Low back morning stiffness
- relieved by activity, aggravated by rest
• Peripheral asymmetric oligoarthritis
• Acute anterior uveitis
- most common extra articular Mx
• Aortic insufficiency
• ( + ) Schobers test
Radiographic Findings
• Syndesmophyte formation
- ossification of annulus fibrosus
• Vertebral body disk margin erosion
• “Squaring” of vertebral bodies
• Sclerosis of SI joint, sacroiliitis
Diagnosis
• Modified NY criteria (1984)
- Hx of inflammatory back pain
- LOM sagittal, frontal planes of LS
- limited chest expansion
- definite radiographic sacroiliitis

Definite AS:
- evidence of sacroiliitis + any of the other 3
criteria

AS vs other causes of LBP
• Age of onset before 40
• Insidious onset
• Duration of sx > than 3 months before medical attention is sought
• Prolonged morning stiffness
• Improvement with exercise
Treatment
• No definitive treatment
- appropriate exercise program
- NSAID’s
- sulfasalazine
- methotrexate
- intralesional cortisone injection
- biologic agents
Reactive Arthritis / Reiters Disease
• Asymmetric oligoarthritis
• Urethritis
• Conjunctivitis
• Mucocutaneous lesion
- balanitis
- keratoderma blenorrhagica
Clinical Forms
• Post enteric infection
- shigella (flexneri), salmonella,
yersinia, campylobacter

• Post genital infection
- chlamydia trachomatis
Psoriatic Arthritis
• 5 - 42 % of patients with psoriasis
• Unknown cause
• Indirect evidence:
- infection
- trauma
- inc. humoral / cellular immunity
- cytokine driven
- abn. fibroblast, dendritic cell, PMN function
Major Types of Psoriatic Arthritis
• Asmmetric oligoA
- most common
• Symmetric polyA
- RA like features
• DIP involvement
- nail lesion
• Arthritis mutilans
- deformities, young patients
• Psoriatic spondylitis
Treatment
• Patient education
• Physical / occupational therapy
• NSAID’s
• Methotrexate + folic acid
• Sulfasalazine
• Gold salts
• Antimalarials

Enteropathic Arthritis ( IBD )
• Ulcerative colitis / Crohn’s disease
• Intestinal bypass surgery
• Whipples disease (intestinal lipodystrophy)
Features
• oligoA, asymmetric
• Spondylitis, sacroiliitis
• Clubbing of fingers
• Development of amyloid – crohn’s
• Osteoporosis – inactivity malabsorption, steroids
Points to Remember
• HLA - B27 association
• (-) RA factor exam
• Clinical features
- Musculoskeletal
- peripheral oligoA
- enthesitis
- sacroiliitis, spondylitis
- Systemic
- psoriasis
- IBD
- conjunctivitis, iritis
- genito urinary inflammation
- carditis
Systemic Lupus Erythematosus
• chronic, inflammatory
• multiorgan, multisystemic
• unknown etiology
– autoantibodies
– immune complexes

Theories
• Immunologic
– autoantibodies, immune complexes
–  activity of polyclonal T;B cells
• Genetics
– concordance in monozygotic than dizygotic twins (24 – 58%: 0 – 6%)
– complement deficiencies – C1q, C2, C3, C4
• Genetics
– HLA-DR2 – DR3 tissue types
– Defective C4AQO allele
• marker for ethnic groups
• Environment
– UV-B, UV-A rays
– alfalfa, chemicals (hydrazine)
– virus, type-C oncorna
• Hormonal
– woman, reproductive life
– NZ mice
• estrogen  activates disease
• androgens  protective



Clinical Manifestations
• Musculoskeletal
- arthritis
• polyarticular, rheumatoid like
• joint deformities
• non-erosive
- myopathy
• active disease
• drug-induced (hypoK, steroids, antimalarials)
Clinical Manifestations
• Malar rash
– photosensitive, flat
or raised
– non-scarring
Cutaneous
Clinical Manifestations
• Discoid rash
– 20 %
– circular, raised borders
– central, atrophic,
hypopigmented area
– scarring
– photosensitive
Cutaneous
Clinical Manifestations
• Oral ulcers
– painless, shallow
– buccal mucosa
– disease activity
• Lupus band test
- deposition of IgG at dermal-
epidermal junction
• Renal
- pyuria, hematuria, proteinuria, casts (UA)
- subendothelial, subepithelial mesangial deposits (E/M)
- renal biopsy  best guide to nephritis severity
- focal, mesangial, membranous, diffuse proliferative
Clinical Manifestations
• Nervous system
- overdiagnosed
- CNS, PNS
- cognitive dysfunction  most frequent
- seizures, psychosis
- neuropathy, autonomic dysfunction
- MRI (contrast)  acute, chronic
- lumbar tap  active disease, infection
Clinical Manifestations
• Hematologic
- anemia  NN, hemolytic
- leukopenia, lymphopenia
- thrombocytopenia
- arterial, venous thrombosis
- lupus anticoagulant, anticardiolipin
• prolong PTT (APS)
Clinical Manifestations
• Cardiopulmonary
– carditis
• pericarditis  most common
• myocarditis  arrhythmias
• endocarditis  valvular insufficiency 
transesophageal echocardiogram
– Libmann-Sacks
Laboratories
• ANA
- best screening test (WIL-2 or Hep-2 cells)
- (+) test nonspecific; supports diagnosis
- other conditions:
• Elderly
• chronic inflammatory conditions
• other CTDs
• viral infections
Laboratories
• Autoantibodies in SLE
- anti-dsDNA
• nephritis, activity
• relatively disease specific
- anti-Sm
• cutaneous, musculoskeletal
- anti-Ro (SS-A)
• neonatal, elderly lupus
• ANA negative lupus
• may cause nephritis


- anti-La (SS-B)
• always associated with Ro
• Sjogrens syndrome, low risk for nephritis
- anti-histones
 drug-induced
- anti-phospholipids
 3 types – LA, aCL, false VDRL test
  LA, aCL  clotting abnormalities, fetal loss,  platelet
antibodies for B
2
glycoprotein

- antierythrocyte
• hemolysis
- antineuronal
• diffuse CNS lupus
- antiribosomal
• CNS lupus –
• Psychosis
- antiRNP
• MCTD
Revised Criteria for SLE
• Malar rash
• Discoid rash
• Photosensitivity
• Oral ulcers
• Arthritis, non-erosive, polyarticular
• Serositis  carditis, pleuritis, effusion
Revised Criteria for SLE
• Renal
– +++ protein (U/A), >500mg/24hrs
• Hematologic
– blood “-penias”
• Neurologic
– seizures, psychosis
• Immunologic
– dsDNA, Sm, antiphospholipid
• (+) ANA
Revised Criteria for SLE
• 4/11 criteria
• 97 % sensitivity; 98 % specificity
• SOAP, BRAIN, MD
Treatment
• no cure, rare complete sustained remission
• non-pharmacologic
- doctor-patient relationship
- education
- support group
Pharmacologic Therapy
• NSAIDs, analgesics
– MS Sx
• antimalarials
– cutaneous vasculitis
– opthalmologic consult
• Steroids
– major organ
– monitor side effects
– oral / pulse therapy
• Immunosuppressives
– azathioprine, cyclophosphamide, chlorambucil, MTX
– oral / pulse therapy

• Others
– plasmapheresis
– cyclosporins
– immunoablation
• high dose CYP
– antibodies to CD
4

• suppress T/B cell
– IVIG
– stem cell transplant
Prognosis
• Factors assoc’d w/ poor prognosis
-  creatinine levels
- hypertension
- nephrotic syndrome
- anemia, albumin, low C
3
/C
4
at diagnosis
- low socioeconomic status
Cause of Death
• 1
st
decade
- infection, active disease
• 2
nd
decade
- thromboembolic events
Osteoporosis
• Silent disease
• Systemic skeletal disease
1
– Low bone mineral density (BMD)
• BMD 2.5 standard deviations below the mean
BMD of young adults
– Microarchitectural deterioration of bone
tissue
– Bone fragility
– Increased risk for fracture


1
Consensus Development Conference. Am J Med. 1991.
Wasnich RD: Primer on the Metabolic Bone Diseases
and Disorders of Mineral Metabolism. 4th edition,
1999, p 257
Incidence Rates for Vertebral, Wrist and Hip
Fractures in Women After Age 50
40
30
20
10
50 60 70 80
Vertebrae
Hip
Wrist
Age (Years)
A
n
n
u
a
l

i
n
c
i
d
e
n
c
e

p
e
r

1
0
0
0

w
o
m
e
n

Non-Modifiable
• Age
• Female sex
• Maternal family history of
hip fracture
• Low birth weight
• Disease predisposing to
osteoporosis
Risk factors taken from Jordan & Cooper Best Practice and Res Clin Rheumatol, 2002
Categorized by Eli Lilly & Co.
Potentially Modifiable
• History of falls
• Body mass index
• Drug therapy (e.g. corticosteroid
use, use of anti-convulsants)
• Primary or secondary
amenorrhea
• Early menopause
• Smoking
• Excessive alcohol consumption
• Dietary calcium and vitamin D
deficiency

Risk Factors for Osteoporosis and Fracture
Indirect
effects
Unitary model for postmenopausal
bone loss: role of oestrogen deficiency
Directly increases
osteoclast number
and longevity
Dietary
calcium
(decreased
absorption)
Secondary
hyperparathyroidism
Increased bone
resorption
Bone
loss
Decreased
bone
formation
Remodelling
imbalance
?
Adapted from: Riggs BL, et al. J Bone Miner Res 1998;13:763–73
Oestrogen
deficiency
Glucocorticoid dose Dependent Effect on Fracture Risk
0.99
1.77
5.18
1.55
2.59
2.27
0
1
2
3
4
5
6
Hip Vertebral
Type of Fracture
Relative Risk
of Fracture
<2.5 mg
2.5 mg-7.5 mg
>7.5 mg
Dose*
Van Staa TP, et al. J Bone Miner Res. 2000.
*Prednisolone equivalent
N = 488 470
Most rapid bone loss occurs in the first 6-12 months of
Steroid therapy
WHO definition of osteoporosis
• The T-score
– the number of SDs from the mean (average) value of BMD at peak bone
mass
Patient category T-score
Normal Above –1
Osteopenia Between –1 and –2.5
Osteoporosis <–2.5
Established osteoporosis <–2.5 with non-traumatic fracture

WHO Study Group. WHO Technical Report Series 843, Geneva Switzerland:
WHO;1994:1–129
How should patients be evaluated to determine if they have
osteoporosis?
• AACE recommend that evaluation include
– a comprehensive medical examination
– X-rays in patients with suspected vertebral fractures
– BMD measurements
– assessment of risk factors for fractures
• NOF guidelines are generally similar, but with greater emphasis on BMD
testing
• Neither guidelines take into account bone markers for diagnosing
osteoporosis
AACE Osteoporosis Task Force. Endocr Pract 2003;9:545–64
http://www.nof.org/professionals/clinical.htm
Diagnosis and assessment
• X-rays
• BMD
• Ultrasound
• Bone markers
• Bone biopsy and histomorphometry
Indications for Bone Density Measurements

• estrogen deficient women
- perimenopause
- early menopause
- premenopause
• radiologic osteoporosis
• previous low-trauma fracture
• corticosteroid therapy
>7.5mg/day x 3 months
• diseases causing secondary osteoporosis
• monitor treatment response
Biochemical markers
of bone turnover in osteoporosis
Formation
(reflect osteoblast activity)
Resorption
(reflect osteoclast activity)
 Serum osteocalcin
 Serum total and bone
alkaline phosphatase
 Serum type I collagen
propeptide
 Urinary pyridinolines and deoxypyridinoline
 Urinary and serum CTX*
 Urinary and serum N-telopeptide of the
alpha chain of type I collagen (NTX)*

*CrossLaps
TM
Candidates for therapy: the AACE guidelines
• The AACE guidelines indicate that the following women may benefit from
pharmacologic therapy
– women with a prior vertebral or hip fracture
– women with BMD T-score –2.5 without risk factors
– women with borderline-low BMD if risk factors are present
– women in whom nonpharmacologic preventive measures are
ineffective
AACE Osteoporosis Task Force. Endocr Pract 2003;9:545–64
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

Bisphosphonates
- Alendronate
- Etidronate
- Risedronate

Calcitonin

Estrogen ± progestin

Selective estrogen receptor
modulators (SERMs)
- Raloxifene
Osteoporosis prevention
T-score >–2.5
Osteopenia
treatment with or without
previous fracture
Osteoporosis treatment
with multiple fractures and at
risk for hip fracture
50 55 60 65 70 75 80 85
Raloxifine
Age (years)
HRT
Therapeutic Management of Postmenopausal Osteoporosis
Teriparatide
Bisphosphonates
Adapted from Seeman & Eisman, MJA Vol 180 15 March 2004, p298-303

Optimal Daily Calcium Requirements
1300 mg
1000 mg
1200 mg
Recommended Calcium
Intake (Daily)
Age
1997 Recommended Dietary Intakes
9-18 years
19-50 years
51 years or older
National Academy Press. Available at: http://books.nap.edu/catalog/5776.html. 1999.

Recommendations for Vitamin D Intake
Europe
The Scientific Committee for Food of the Commission of the European
Communities recommends
 400 IU of vitamin D daily for the elderly (age 65)
United States
The Institute of Medicine has defined adequate daily intake of vitamin D
according to age
 Adults up to age 50 200 IU
 Adults 51–70 400 IU
 Adults >70 600 IU
No toxic effects reported in 61 healthy adults given 4000 IU/day in a clinical
study to assess the efficacy and tolerability profile of high vitamin D intake
Adapted from European Commission. Report on osteoporosis in the European community: Action on prevention. Luxembourg: Office for Official
Publications of the European Communities, 1998; Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D,
and Fluoride. Washington, DC: Institute of Medicine, National Academy Press, 1997; Vieth R et al Am J Clin Nutr 2001;73:288–294.
Widespread Prevalence of Vitamin D Inadequacy* Regardless of Geographic
Location
*Vitamin D inadequacy was defined as serum 25(OH)D <30 ng/ml; **Interim results of ongoing study
Study Design: Observational, cross-sectional study of 1285 community-dwelling women with osteoporosis from 18 countries to evaluate serum 25(OH)D distribution.
Adapted from Lim S-K et al. Poster presented at ISCD, February 16–19, 2005, New Orleans, Louisiana,USA; Heaney RP Osteoporos Int 2000;11:553–555.
P
r
e
v
a
l
e
n
c
e

(
%
)

0
10
30
40
60
80
90
Latin
America
51%
63%
Asia All
59%
Australia
59%
Europe
52%
Regions
N=1285
81%
Middle
East
50
70
20
In a cross-sectional observational international study in 1285 postmenopausal
women with osteoporosis**
Probable Reasons for High Prevalence of Vitamin D Inadequacy in Postmenopausal
Women
• Lack of sunlight exposure
• Vitamin D is not common in the diet
• The ability to synthesize vitamin D in the skin
decreases with age
• Lack of compliance taking daily supplements
Adapted from Marcus R Goodman & Gilman’s The Pharmacological Basis of Therapeutics. 10th ed. New York: McGraw-Hill Medical Publishing
Division, 2001:1715–1743; Bringhurst FR Harrison’s Principles of Internal Medicine. 16th ed. New York: McGraw-Hill Medical Publishing, 2005:2238–
2249; Matsuoka LY J Clin Endocrinol Metab 1987;64:1165–1168; Parfitt AM Am J Clin Nutr 1982;36:1014–1031; Lawson RM Clin Nutr 2000;19:171–
175.
Appropriate
neuromuscular
function
Vitamin D Inadequacy* Has Important Consequences
*Vitamin D inadequacy is defined as serum 25(OH)D <30 ng/ml.
Adapted from Parfitt AM et al Am J Clin Nutr 1982;36:1014–1031; Allain TJ, Dhesi J Gerontology 2003;49:273–278; Holick MF Osteoporos Int
1998;8(suppl 2):S24–S29; DeLuca HF Metabolism 1990;39(suppl 1):3–9; Pfeifer M et al Trends Endocrinol Metab 1999;10:417–420;
Lips P. In: Draper HH, ed. Advances in Nutritional Research. New York, Plenum Press, 1994:151–165.
Bone mineral
density
Parathyroid
hormone
Calcium
absorption
Risk of
fracture
Artistic rendition
Bisphosphonate mechanism
of action
Adapted from: Bone H, et al. Clin Ther 2000;22:15–25
RESTING
RESORPTION
Osteoclast
FORMATION
Osteoblasts
BISPHOSPHONATES
INHIBIT OSTEOCLAST
-MEDIATED BONE
RESORPTION
PTH - Mechanism of Action
PTH binds to cell surface
G protein-coupled receptor
Stimulates differentiation
of bone lining cells and
preosteoblasts to osteoblasts
Decreases apoptosis
of osteoblasts
Net increase in number and
action of bone forming
osteoblasts
Osteoporosis has been thought of as a silent
epidemic….this is not true anymore. At present,
there is much noise in the field of research for
its prevention, diagnosis and treatment.

Ego Seeman
ARCOS meeting, Feb 2002
One of the Many Faces of Osteoporosis

“You could have floored me when they told me. It’s very frightening, very
frightening…
I don’t want to end up in a nursing home incapacitated.”
Thank You !
Please visit:
http://crisbertcualteros.page.tl