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Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Dec 24, 2015

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Page 1: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Osteoporosis

Page 2: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Introduction

Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.”

- National Osteoporosis Foundation

Currently, there are 6 million people diagnosed with osteoporosis in the United States

Most of them are FEMALE

But MEN have worse outcomes

Page 3: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Anatomy

Compared to men, women have:

Weaker bones:

• Smaller bone cross-sectional area1,4

• Less cortical bone thickness4

• Lower peak bone mass1,2

Higher risk for osteoporosis:

• Less bone mineral density2,4

• Bone density that decreases more with age1

Normal Bone Osteoporosis

Corticalthickness

Page 4: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Physiology

Osteoclast

RANK LigandRANK ReceptorOsteoprotegerinCells of bone remodeling:

• Osteoblasts build bone

• Osteoclasts resorb bone

Proteins that regulate bone remodeling:

• RANK Ligand stimulates osteoclasts1

• Osteoprotegerin inhibits RANK Ligand2

OsteoblastsOsteoclasts

Page 5: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Pathology

Higher Peak Bone Mass3,4

0 20 40 60 80 100

MenWomen

Age (in years)

Bone Mass Menopause

(rapid bone loss) 2

Page 6: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Estrogen

Estrogen promotes bone formation1

RANK LigandOsteoprotegerin

• After menopause, estrogen levels drop

• Women experience rapid bone loss after menopause due to estrogen deficiency2

Page 7: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Testosterone

Testosterone:• Stimulates osteoblasts3

• Inhibits osteoclasts3

• Increases bone size and BMD3

• Mediated by an androgen receptor3

Men with low testosterone are susceptible to osteoporosis3

Page 8: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Epidemiology

80%20%

Will suffer an osteoporosis related fracture within their lifetimes2

Reported Cases of Osteoporosis1

- Total: about 6 million people

20% of Men

50% of Women

Page 9: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Fracture Incidence

Estimated annual incidence2

• Total fractures: 9 million

• Hip fractures: 1.6 million

• Forearm fractures: 1.7 million

• Vertebral fractures: 1.4 million

Hip

Forearm

Spine

Humerus

Other Sites

Page 10: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Fracture Comparison

Page 11: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Treatment

Page 12: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Bisphosphonates

• Promotes bone formation and decreases bone resorption

Mechanism of Action

• First line treatment for osteoporosis in both men and post-menopausal women1

Application• Approved in both

sexes for the prevention and treatment of osteoporosis

Aledronate2, Risedronate3 and Zoledronic Acid4

Page 13: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Bisphosphonates

Ibandronate (Boniva)

Only FDA approved for treatment (not prevention) of osteoporosis in post-menopausal women

Not FDA approved for males

• Paucity of studies1 • Similar

pharmocokinetics in men and women2

• Similar efficacy in men and women probable3

Page 14: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Bisphosphonates

Drug Vertebral Fracture RR

Hip Fracture RR

Non-vertebral RR

Route/ Frequency

Indicated for which gender

Alendronate PO/QDay, QWeek

WomenMen

Risedronate PO/QDay, QWeek, QMonth

WomenMen

Ibandronate NE NE PO/QMonthIV/Q3Month

Women

Zoledronic Acid

IV/QYear WomenMen

RR = Risk Reduction NE = No effect demonstrated

Page 15: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Other Agents

Drug Vertebral Fracture RR

Hip Fracture RR

Non-vertebral RR

Route/ Frequency

Indicated for which gender

Raloxifene NE NE PO QDay Women

Calcitonin NE NE Nasal QDaySQ QDay

Women

Teriparatide SQ QDay WomenMen

Denosumab SQ Q6Months

WomenMen

RR = Risk Reduction NE = No effect demonstrated

Page 16: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Estrogen & Bone Metabolism

Sati Patel
Figure Source, Khosla et al. Estrogen and the skeleton. Trends Endocrinol Metab., 2012; 23 (11): 576-581Online Link: http://dx.doi.org.ezproxy.ttuhsc.edu/10.1016%2Fj.tem.2012.03.008Journal: http://www.cell.com/trends/endocrinology-metabolism/homeFigure 2, page 12.
Page 17: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Estrogen in Females

Estrogen’s protective role in bone metabolism has long been appreciated1

Decline of estrogen in postmenopausal females provides a ready example of estrogen’s protective role in bone metabolism2

Estrogen HRT in postmenopausal women has been shown to: • prevent bone loss (Maintain BMD) • decrease bone remodeling and incidence of vertebral fracture3

HRT- Hormone Replacement Therapy

Page 18: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Estrogen in Males

Testosterone & estrogen decline

with aging1

Estrogen has a greater role in

preventing bone resorption in both males & females2

Testosterone’s influence on bone

metabolsm is minimal in both

sexes2

Page 19: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Raloxifene

• Mechanism of Action: selective estrogen-receptor modulator

– Benefits• Increases BMD of hip and spine in women1

• Females: approved for treatment and prevention of osteoporosis in women.

• Not approved in males2

– Narrow study contexts3,5

– Was not shown to significantly impact BMD in males4

Page 20: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Tissue Selective Estrogen Complex

• Bazedoxifine/Conjugated Estrogen (Duavee)– Mechanism of Action: SERM that selectively stimulates

lipid metabolism and bone, however, has no effect on the uterus and breast.

– Benefits• FDA approved for – postmenopausal moderate/severe vasomotor

symptoms – prevention of postmenopausal osteoporosis.

• Increased hip and lumbar BMD

Page 21: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Tissue Selective Estrogen Complex

• Bazedoxifene/Conjugated Estrogen (Cont’d)– Approved in Women for2 • prevention of osteoporosis• osteopenia • post menopausal vasomotor and sleep disturbances

– Men: None of the three major clinical trials included men, despite that estrogen has been demonstrated to play a significant role in bone formation3,4,5.

Page 22: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Calcitonin-Salmon

• Mechanism of Action– Analogous to endogenous calcitonin

• Indications– Approved for the treatment (not prevention)

of osteoporosis in women who are ≥5 years post-menopausal

– Not utilized in men

Page 23: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Teriparatide (Forteo)

• Mechanism of Action: recombinant parathyroid hormone (PTH); stimulates bone formation.

• Approved for

– Treatment & prevention of osteoporosis in men and postmenopausal women1

– Especially those at high risk for vertebral fracture2

Page 24: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Teriparatide Efficacy

Extent of lumbar BMD increase similar in both males1 and postmenopausal females2

Significantly increased lumbar BMD from baseline levels3

Sati Patel
Both figures are from shutterstock.com, 1. http://www.shutterstock.com/pic-93236422/stock-photo-symbolic-image-of-red-pain-in-intervertebral-discs-of-spine.html?src=Z9lt3nDweg6IH3TpO-CK1w-2-142. http://www.shutterstock.com/pic-163344545/stock-vector-illustration-of-thinking-concept-male-face-with-like-symbol.html?src=fpZXuMOLKHKeYI1HDibiww-1-36
Page 25: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Calcium & Vitamin D

NOF Recommended Daily Intake:

Calcium

Men: 1000 mg Women: 1200 mg

Vitamin D

Men & Women: 800 –

1000 units

Page 26: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Calcium and Vitamin D

Total Fracture Incidence

• DIPART Group analysis of 7 major Vitamin D and Calcium trials in the US and Europe.

• Analysis included 68,500+ patients• Only 14% of subjects

were males

Page 27: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Calcium and Vitamin D

Hip Fracture Incidence

Sati Patel
Graphic Source, - article: The DIPART Group. Patient level pooled analysis of 68,500 patients from seven major Vitamin D fracture trials in US and Europe. BMJ 2010; 340:b5463 (Level 1)Article weblink: 10.1136/bmj.b5463Figure 4, page 4. - Journal Website: http://www.bmj.com
Page 28: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Calcium & Vitamin D

• Efficacy: combination Calcium (1200 mg) and Vitamin D (800 mg) reduces the risk of hip, vertebral and total fractures in both men and women1

• Study Demographics• Men were understudied• 2010 DIPART Group Meta-Analysis: only14% of

68,500 subjects studied were men1 • 2007 Tang et al2. Meta-Analysis included only 8% men3

Page 29: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

RANK-L Inhibitor (Denosumab)

• Mechanism of Action: monoclonal antibody; prevents osteoclast maturation.

“RANK-L”, RANK-Ligand

Sati Patel
Graphic Source- Article: Sidlauskas et al. Osteoprososis in men: epidemiology and treatment with denosumab. Clinical Interventions in Aging, 2014; 9: 593-601.Article Link: 10.2147/CIA.S51940Figure 1, page 596Journal website: https://www.dovepress.com/clinical-interventions-in-aging-journal
Page 30: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Denosumab (Prolia)

• Approved to increase BMD in1,2

–Women: • With non-metastatic breast cancer • post-menopausal women with osteoporosis at high

risk for fracture.

–Men:2 • With non-metastatic prostate cancer who are

receiving Androgen Deprivation Therapy. • With osteoporosis who are at high risk for fracture.

Page 31: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Denosumab

Increased: BMD at all skeletal sites (lumbar spine, femoral neck, trochanter, radius & total hip)

Decreased: serum bone turnover markers, incidence of vertebral fracture in those with non-metastatic prostate cancer.

Efficacy in Males

Page 32: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Denosumab

Increased vertebral, hip and non-vertebral BMD1.

Decreased incidence of vertebral, hip and non-vertebral fractures1,3

Efficacy in Females

Page 33: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Denosumab Research Disparities

• No data for fracture incidence in males without non-metastatic prostate cancer1.

• Few phase III clinical trials have thoroughly investigated the efficacy of Denosumab in males, though it has been shown to be a beneficial treatment option.

In Males,

• Major phase III clinical trials studied Denosumab efficacy in >2000 postmenopausal females2– no equivalent in males.

• Examples: FREEDOM, DEFEND, DECIDE & STAND studies3

In Females,

Page 34: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Fracture Prognosis

Return

to In

depe

nden

t Liv

ing

Inde

pend

ent M

obili

ty

Mor

tality

with

in 1

Yr.

0%

20%

40%

60%

80%

MenWomen

Page 35: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Fracture Morbidity

Compared to men, Women:

- Are almost twice as likely to survive

- Are more likely to return to home

- Are more likely to return to walking independently

Compared to women, Men:

- Have higher early post-operative mortality

-Are less likely to return to independent living or mobility.

WO

ME

NM

EN

Page 36: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Fracture MortalityMen Women

42%

44%

46%

48%

50%

52%

54%

56%

58%

60%

Men197 out of 343 died

Women461 out of 952 died

The Dubbo Osteoporosis Epidemiology Study1

Page 37: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Osteoporosis Treatment after Hip Fracture

0%

20%

40%

60%

80%

MenWomen

1 2

Page 38: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Risk Factors

Cannot Change1 Potential for Change1

Menopause

History of fracture infirst-degree relative

Caucasian race

Advanced age

Female

Smoking

Estrogen deficiency, including menopause onset <age 45

Low calcium intake (lifelong)

Excessive Alcohol

Vitamin D Insufficiency

Specific MedicationsSpecific Diseases

Sedentary

Female Athlete Triad

Malnutrition

Page 39: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Screening

Criterion1 Women MenAge-Based • 65 years and older 70 years and older

Based on Risk Factors

• Postmenopausal, < 65 with 1+ risk factor(s)

• Perimenopausal with specific high-risk factor associated with increased fracture risk

• Postmenopausal, discontinuing estrogen

50-70 years with 1+ risk factor(s)

Regardless of Gender

• Fragility fracture (after age 50)

• High-risk condition or exposure to high-risk medication associated with low bone mass or bone loss

• Anyone being considered for pharmacologic therapy

Page 40: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

DXA Scan

• The gold standard test for diagnosis1

• Measures1

– Spine– Hip– Forearm

• Less radiation than in the

environment1

• Provides the T Score1

Page 41: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

T-Score Definitions

Diagnosis1 T-Score1

Normal BMD BMD is within 1 SD of a healthy young adult: T-score > -1.0

Osteopenia BMD is between 1.0 and 2.5 SD below thatof a healthy young adult:T-score between -1.0 and -2.5

Osteoporosis BMD is 2.5 SD or more below that of a healthy young adult:T-score < -2.5

Established Osteoporosis BMD representing a T-score ≤ –2.5 and the presence of one or more fragility fractures

Page 42: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Cost-Effectiveness

Screening is Cost-Effective in

Women >651

Screening is NOT Cost-Effective in

Men >701

Page 43: Osteoporosis. Introduction Osteoporosis is “a disease of the bones that happens when you lose too much bone, make too little bone, or both.” - National.

Gender Awareness

• Osteoporosis considered a “Woman’s Disease”1

• 20% of men will suffer from osteoporosis1

• Research is biased towards women2

• Men have worse outcomes3


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