Atypical Femoral Fractures and Bisphosphonates Treatment ...
Treatment. Bisphosphonates Promotes bone formation and decreases bone resorption Mechanism of Action...
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Transcript of Treatment. Bisphosphonates Promotes bone formation and decreases bone resorption Mechanism of Action...
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
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
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
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
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,