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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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