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Treatment

Treatment. Bisphosphonates Promotes bone formation and decreases bone resorption Mechanism of Action First line treatment for osteoporosis in both men

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Treatment

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

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

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

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

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.

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

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

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

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

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.

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

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

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

Calcium & Vitamin D

NOF Recommended Daily Intake:

Calcium

Men: 1000 mg Women: 1200 mg

Vitamin D

Men & Women: 800 –

1000 units

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

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

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

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

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.

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

Denosumab

Increased vertebral, hip and non-vertebral BMD1.

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

Efficacy in Females

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,