Define osteoporosis & relate to fracturejsog.org/uploads/s/D1/Dr. lubna 2.pdfNormal bone Osteoporosis A disease characterized by low bone mass and microarchitectural deterioration

Define osteoporosis & relate to fracture risk

Relate ovarian physiology to skeletal health

Screening for “at risk” for fragility fractures

Review fracture risk reduction strategies and options

51 year old Caucasian female attorney, with a 6 month history of amenorrhea, bothersome VMS, and overall deteriorating QOL.

Nonsmoker, physically active History of wrist fracture

following a fall at age 45. Family history of osteoporosis –

mother & maternal aunt. Breast cancer in sister (age 58) Patient is concerned about

her risk for breast cancer. Normal BMI

Optimal fracture risk reduction strategy will include:

A. Raloxifene as her breast cancer risk is high

B. Menopausal hormone therapy

C. Bisphosphonate Rx as her lifetime fracture risk is high

D. Tamoxifen as her risk for breast cancer is high

Normal bone Osteoporosis

A disease characterized by low bone mass and microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk.

World Health Organization (WHO), 1993

Osteoporosis

J.C. Gallagher, A.J. Sai / Maturitas 65 (2010) 301–307

5 15 25 35 45 55 65 75 85

Age (Years)

Pubertal Growth Spurt Peri Menopause

BMD

Resorption

Formation

Menopause

60

70

80

90

100

30 40 50 60 70 80 90

Age

Rela

tive

BMD

(%) Forearm

SpineHip and Heel

0

1000

2000

3000

4000

30 40 50 60 70 80 90 +

Colles'VertebraeHip

Age

Ann

ual F

ract

ure

Inci

denc

e

Cooper C. Baillières Clin Rheumatol. 1993;7:459–477.

Faulkner KG. J Clin Densitom. 1998;1:279–285.

Fracture Risk

Less Bone

Lost Bone

Bad Bone

Fall Risk

GeneticsPOI

MenopauseDiseases

VisionParkinsonism

DementiaArthritisDrugs

Vitamin D DeficiencyCollagen Disease

Metastases

Advancing age Low body weight ≤ 127lbs

Race Caucasian

Reproductive profile Late menarche Early menopause

SmokingAlcohol >2 drinks/dayFracture History

Family/personal

Medical Disorders Hypogonadism Arthritis Diabetes Seizure Malabsorption Collagen disorders Chronic renal disease Chronic liver disease Hematological Fall Risk Alcoholism Impaired vision Dementia HIV

Hormones & Modulators Glucocorticoids Thyroid hormone Aromatase inhibitors Ovarian suppression

› GnRHagonist/antagonist

› High dose IM progestin

Androgen deprivation Immune modulators

› Cyclosporin

Anti-diabetic agents› Thiazolidinediones

Antidepressants› SSRI’s

Anticonvulsants Drugs used for vascular

benefit› Heparin › Oral anticoagulants

Anti-retroviral therapy Drugs used for GI

diseases› Proton pump

inhibitors

0

2

4

6

8

10

12

14

16

Age 48 Years Age 53 Years

Ost

eopo

rotic

Wom

en (%

)

Perimenopause Postmenopause

n = 5896.Modified from Smeets-Goevaers CG, et al. Osteoporos Int. 1998;8:404-9.n = 5896.Modified from Smeets-Goevaers CG, et al. Osteoporos Int. 1998;8:404-9.

At a given age osteoporosis is less prevalent in perimenopausal women compared with menopausal women.

Menopausal Pelvic Organ Prolapse … an overt marker for covert skeletal

fragility?

Pal L et al. Menopause. 2008;15(1):59-66.Pal L, et al. Menopause 2011 Sep;18(9):967-73.

POP Any Type

Rectocele

Cystocele

Risk for Incident Hip Fracture in Postmenopausal women with moderate to severe POP

Crude

Adjusted 0 0.5 1.0 1.5 2.0 2.5 3.0 3.5 4.0

Decreasing HR Increasing HR

HR 1.85 (1.22-2.80)

HR 2.12 (1.15-3.88

HR 1.81 (0.67-4.88)

HR 1.79 (1.05-3.07)

Pal L, et al. Menopause 2011 Sep;18(9):967-73.

HR 1.83 (1.16-2.89)

HR 2.18 (1.14-4.17)

5 15 25 35 45 55 65 75 85

Premenopause Peri Menopause

BMD

Resorption

Formation

Menopause

VMSDOR

DMPAOCP

POP

FRAX™. Available at: http://www.shef.ac.uk/FRAX/index.htm.

BMD Based Clinical Risk Assessment

› Normal:

T-score ≥ –1

› Low bone mass (Osteopenia):

T-score between –1 and –2.5

› Osteoporosis:

T-score at or below –2.5

WHO Study Group. WHO Technical Report Series. 1994;843:5-6.

WHO BMD diagnostic classification must NOT be applied to premenopausal

women, men <50 & in children

Age BMI Prior history of fracture Parental history of fracture Current smoking Current Alcohol >3 units/day Rheumatoid Arthritis Glucocorticoid use

http://www.shef.ac.uk/FRAX/index.htm

Secondary Osteoporosis Hypogonadism IBD Prolonged Immobility Organ Transplant Type I Diabetes Thyroid Disorders

History Medical/FamilyEnvironment Nutrition

Physical ExamExisting fractureFall RiskVision

BMDSpineHipsForearmHeelLVA

FRAXLab Tests

Chemistry CBC TSH PTH (Intact) 25OHD /1,25(OH)D Bone turnover

markers› NTX/BSAP

Assess Hypogonadism› FSH/E2/AMH

24 hour urine › Ca/Cr› Na› UFC – if suspecting

Cushing Syndrome Serum protein- if

suspecting multiple myeloma

Hemoglobin electrophoresis (if indicated)

Lateral spine imaging

Formation Markers Serum Alkaline

phosphatase Serum bone–specific

alkaline phosphatase Serum Osteocalcin Serum Type 1 procollagen

(C-terminal/N-terminal): C1NP or P1NP

Resorption Markers Urinary

› Hydroxyproline › Total pyridinoline (PYD) › Free deoxypyridinoline

(DPD) › N-telopeptide (NTX) › C-telopeptide (CTX)

Serum › CTX› Bone sialoprotein (BSP) › TRAP

0

1

2

3

4

5

6

Low BMD High Bone Turnover Low BMD + High BoneTurnover

Women ≥75 Years of Age (n = 7598)

Risk

of H

ip F

ract

ure

Garnero P, et al. J Bone Miner Res. 1996;11:1531-8.

2.72.2

4.8

2.7 fold 2.2

4.8

Who to treat?›Prevention versus Treatment

When to treat? ›BMD threshold›Fracture Risk Assessment

What to treat with??

Treat all patients with existing fracture

High Risk- Treat

Moderate Risk –Treat if other risks

Low Risk-Reassess 1-2 years

T-Score *

< - 2.0

< -1.5 + ≥ 1 Risk Factor

> -1.5 - Monitor

*Based on axial skeletal DXA- NOF guidelines

Low BMD (T-score between -1.0 & -2.5 at femoral neck or spine)

AND

A 10-year fracture probability › ≥ 3% for hip fracture › ≥ 20% for a major osteoporosis-

related fracture

Drug Vertebral # Nonvertebral #Bisphosphonates + +/-Raloxifene + -Calcitonin + -Parathyroid hormone

+ +

Denosumab + +Strontium + +Estrogen/EP + +TSEC + +

Osteoporosis Falls

McClung MR, et al. Bone. 2006;38(2 suppl 2):S13–17.

•Pharmacotherapy •Vision•Cognition•Balance•Injury prevention

- Hip guards

Calcium Vitamin D

Is Treatment Working? Repeat BMD

›Timing ›Device›Data Compare absolute bone mass and not T-scores! Know LSD

Bone Markers Which? When?

› Baseline & 3-6 months after Rx initiated

How Long to Treat?› 2-5 years

Drug Holiday? Sequential therapy?

› Anabolic followed by anti resorptive

Rare Events› ONJ› Atypical fractures › Arrhythmias

Pros Established efficacy

against fracture risk reduction -vertebral and non-vertebral #

Provides symptom control in addition to bone protection

Improved QOL Cost effective given

existing generic options

Cons Risks

› Thrombo-embolism› Stroke› Breast Cancer

Rapid loss of benefit following discontinuation

Less efficacious compared to other bone sparing agents

Not approved for treatment of established osteoporosis

Consideration-Early menopausal -Symptomatic-Low risk for CVD- Uterus present?

Pros Established anti fracture

efficacy against vertebral & non-vertebral #

Prevention & Treatment Routes of administration

› Oral (tablet, liquid)› IV

Infrequent dosing option Residual effect after

discontinuation Cost effective option

with use of generic drugs

Cons Side effects

› Upper GI› Osteonecrosis of Jaw› Atrial Fibrillation› Atypical femoral # › Renal failure

Long term effects? Cost

Considerations-GI/Dentation/Arrythmias/Renal-Menopausal status?-Drug holiday -Dual therapy?

Pros Anti-fracture efficacy

› Site specific Breast cancer

chemoprophylaxis Cost effectiveness in

fracture prevention in relatively young postmenopausal women

Cons Efficacy against non-

vertebral # not established for Raloxifene

Risks:› Thromboembolism› Endometrial

hyperplasia Side effects

› Bothersome vasomotor symptoms

› Undesired urogenital effects

Considerations:-Menopausal status?-Menopausal Symptoms?-BREAST CA RISK?-Site specific #risk?

Pros Symptom control Anti-fracture

efficacy No effect on

endometrium- no need for progesterone

No effect on breast tissue› Potential

chemoprophylaxis?

Cons Risks:

› Thromboembolism New Kid…

› Real use data awaited

Considerations:-Menopausal status?-Menopausal Symptoms?-BREAST CA RISK?

Pros Most efficacious of

available agents against fracture risk.

Only anabolic available

Efficacy against vertebral and non-vertebral fracture prevention

Cons Expensive

› Cost effective only if fracture risk is markedly elevated

Daily subcutaneous injection

Risks/side effects› Concerns for

osteosarcoma› Bone pain› Injection site reaction

Rapid loss of benefit following discontinuation

Considerations: -HIGH FRACTURE RISK-Existing vertebral fractures?-Sequential therapy?

Pros Established efficacy against

fracture risk reduction in:› patients with severe

osteoporosis › When other therapies are

inefficacious or not tolerated.

Vertebral and non-vertebral # risk reduction

Targeted skeletal therapy with minimal systemic concerns

Infrequent subcutaneous dosing (q6mth)

Approved for prevention of skeletal related events in patients with bony metastases

Cons Long term data are lacking Rapid loss of benefit following

discontinuation Expensive Risks/side effects:

› Infections/cellulitis› ONJ

Consideration :- Not tolerating other agents-High fracture risk-Renal failure

Pros Efficacy against

vertebral fracture risk reduction

Nasal and subcutaneous or IM dosing option

Analgesic effect –benefit when existing vertebral #

Cons Less efficacious than

other options Not effective against

non-vertebral # prevention

Risks/side effects:› Nasal bleeding› Runny nose› Headache› Back pain› Flushing, nausea, skin

rashes› Allergic reactions

Consideration-Back pain & existing vertebral # -Pain secondary metastases-Poor tolerance to other agents

Pros Efficacy against

fracture risk reduction for vertebral and non-vertebral sites.

Estrogen Agonist effects on:› Skeleton› Vagina› Symptoms

Estrogen Antagonist effects on:› Breast› Uterus

Cons Long term data are

lacking

Consideration:Future of HT? FDA ApprovedAccess/availability

Osteoporotic Patient Profile Suggested 1st Line RxCompliant older patient without GI concerns Bisphosphonates (PO)

Older patient with GERD Bisphosphonates (IV) or Denosumab

48 yo symptomatic early menopausal woman MHT

48 yo asymptomatic with family h/o breast cancer

SERM

Older patient, poor dentation Calcitonin, PTH

Older patient with compliance issues Bisphosphonate (IV) or Denosumab

Renal insufficiency Denosumab

Nursing Home Patient Bisphosphonate (IV) or Denosumab

High Risk for Fracture PTH, Denosumab

Back Pain Secondary to Metastases Calcitonin

51 year old Caucasian female attorney, with a 6 month history of amenorrhea, bothersome VMS, and overall deteriorating QOL.

Nonsmoker, physically active History of wrist fracture

following a fall at age 45. Family history of osteoporosis –

mother & maternal aunt. Breast cancer in sister (age 58) Patient is concerned about

her risk for breast cancer. Normal BMI

Optimal fracture risk reduction strategy will include:

A. Raloxifene as her breast cancer risk is high

B. Menopausal hormone therapy

C. Bisphosphonate Rx as her lifetime fracture risk is high

D. Tamoxifen as her risk for breast cancer is high

1. Fracture risk is determined by bone quantity & quality

2. Advancing age & loss of estrogen result in decline in bone

quantity & quality

3. Fracture risk assessment must be individualized

› Age/Fall risk / Comorbidities/Bone mass /Bone turnover

4. Choice of anti-fracture Rx should be tailored to unique

patient profile & magnitude of fracture risk

5. MHT is an effective strategy for the relatively young early

menopausal women deemed at an enhanced fracture risk

Define osteoporosis & relate to fracture risk

Relate ovarian physiology to skeletal health

Screening for “at risk” for fragility fractures

Review fracture risk reduction strategies & options

Cooper C , et al. Long-term treatment of osteoporosis in postmenopausal women: a review from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO) and the International Osteoporosis Foundation (IOF). Curr Med Res Opin. 2012; 28 (3): 475-91.

Ebeling PR. Role of biochemical markers in the management of osteoporosis. Best Pract Res Clin Rheumatol. 2001;15(3):385-400.

Reginster JY. Antifracture efficacy of currently available therapies for postmenopausal osteoporosis. Drugs. 2011;71(1):65-78.

Laster AJ. Duration of treatment in postmenopausal osteoporosis: how long to treat and what are the consequences of cessation of treatment? Rheum Dis Clin North Am. 2011 Aug;37(3):323-36, v.