rheumatology

ARTHRITIS 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

PhospholipidsPhospholipase A

Arachidonic Acid

( PG, thromboxanes, prostacyclins)

LipooxygenaseCyclooxygenase

(-) NSAID’s

(leukotrienes, bradykinin)

Mechanism of Action of NSAIDs – New hypothesisArachidonic Acid

Prostaglandins Prostaglandins

Protection of gastric mucosa

Homeostasis

Mediates painInflammation 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 Agents1. 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 – 1st 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

IntraarticularSteroid 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 Handlingof 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 GoutDrugs

- 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 2nd – 3rd 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

- arthritispolyarticular, rheumatoid likejoint deformitiesnon-erosive

- myopathyactive diseasedrug-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 conditionsother CTDs viral infections

Laboratories Autoantibodies in SLE

- anti-dsDNAnephritis, activityrelatively disease specific

- anti-Smcutaneous, musculoskeletal

- anti-Ro (SS-A)neonatal, elderly lupusANA negative lupusmay 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 B2 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 CD4

suppress T/B cell– IVIG– stem cell transplant

Prognosis

Factors assoc’d w/ poor prognosis

- creatinine levels

- hypertension

- nephrotic syndrome

- anemia, albumin, low C3/C4 at diagnosis

- low socioeconomic status

Cause of Death

1st decade

- infection, active disease 2nd decade

- thromboembolic events

Osteoporosis

Silent disease Systemic skeletal disease1

– 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

1Consensus 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 7080

Vertebrae

Hip

Wrist

Age (Years)

Ann

ual i

ncid

ence

pe

r 10

00 w

omen

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, 2002Categorized 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

IndirectIndirecteffectseffects

Unitary model for postmenopausal bone loss: role of oestrogen deficiency

Directly increases Directly increases osteoclast number osteoclast number

and longevityand longevity

DietaryDietarycalciumcalcium

(decreased (decreased absorption)absorption)

SecondarySecondaryhyperparathyroidismhyperparathyroidism

Increased boneIncreased boneresorptionresorption

BoneBonelossloss

Decreased Decreased bonebone

formationformation

RemodellingRemodellingimbalanceimbalance

??

Adapted from: Riggs BL, et al. J Bone Miner Res 1998;13:763–73Adapted from: Riggs BL, et al. J Bone Miner Res 1998;13:763–73

OestrogenOestrogendeficiencydeficiency

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 Most rapid bone loss occurs in the first 6-12 months of Steroid therapymonths of Steroid therapy

WHO definition of osteoporosis

The T-score– the number of SDs from the mean (average) value of BMD at

peak bone massPatient category T-score

Normal Above –1

Osteopenia Between –1 and –2.5

Osteoporosis <–2.5

Established osteoporosis <–2.5 with non-traumatic fracture

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 WHO Study Group. WHO Technical Report Series 843, Geneva Switzerland: WHO;1994:1–129Switzerland: 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 AACE Osteoporosis Task Force. Endocr Pract 2003;9:545–64 http://www.nof.org/professionals/clinical.htmhttp://www.nof.org/professionals/clinical.htm

Diagnosis and assessment

X-rays

BMD

Ultrasound

Bone markers

Bone biopsy and histomorphometry

Indications for Bone Density MeasurementsIndications for Bone Density Measurements

• estrogen deficient women estrogen deficient women

-- perimenopauseperimenopause

-- early menopause early menopause

-- premenopausepremenopause• radiologic osteoporosisradiologic osteoporosis• previous low-trauma fractureprevious low-trauma fracture• corticosteroid therapycorticosteroid therapy

>7.5mg/day x 3 months>7.5mg/day x 3 months• diseases causing secondary osteoporosisdiseases causing secondary osteoporosis• monitor treatment responsemonitor treatment response

Biochemical markersof 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)*

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*CrossLapsTMTM

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;9:545–64AACE Osteoporosis Task Force. Endocr Pract 2003;9:545–64

Therapeutic options for osteoporosisStimulators 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 preventionT-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 CalciumIntake (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 EuropeanCommunities 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 Daccording 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 clinicalstudy 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.

Pre

vale

nce

(%

)

0

10

30

40

60

80

90

LatinAmerica

51%

63%

AsiaAll

59%

Australia

59%

Europe

52%

Regions

N=1285 81%

MiddleEast

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.

Appropriateneuromuscular

function

Appropriateneuromuscular

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 mineraldensity

Bone mineraldensity

Parathyroidhormone

Parathyroidhormone

Calcium absorptionCalcium

absorption

Risk of fractureRisk of fracture

Artistic rendition

Bisphosphonate mechanismof action

Adapted from: Bone H, et al. Clin Ther 2000;22:15–25 Adapted from: Bone H, et al. Clin Ther 2000;22:15–25

RESTINGRESTING

RESORPTIONRESORPTION

OsteoclastOsteoclast

FORMATIONFORMATION

OsteoblastsOsteoblasts

BISPHOSPHONATES BISPHOSPHONATES INHIBIT OSTEOCLAST INHIBIT OSTEOCLAST

-MEDIATED BONE-MEDIATED BONERESORPTIONRESORPTION

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 silentOsteoporosis has been thought of as a silent

epidemic….this is not true anymore. At present,epidemic….this is not true anymore. At present,

there is much noise in the field of research for there is much noise in the field of research for

its prevention, diagnosis and treatment.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