Osteoporosis Updated March 2019 Introduction Osteoporosis Osteoporosis is
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Osteoporosis Updated: March, 2019
Introduction Osteoporosis
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 Introduction
Anatomy Osteoporosis
Compared to men, women have: Cortical thickness Weaker bones: • Smaller bone cross-sectional area 1, 4 • Less cortical bone thickness 4 • Lower peak bone mass 1, 2 Higher risk for osteoporosis: • Less bone mineral density 2, 4 • Bone density that decreases more with age 1 Anatomy Normal Bone Osteoporosis
Physiology Osteoporosis
Cells of bone remodeling: RANK Ligand RANK Receptor Osteoprotegerin • Osteoblasts build bone • Osteoclasts resorb bone Osteobla Osteoclast sts Osteocla sts Proteins that regulate bone remodeling: • RANK Ligand stimulates osteoclasts 1 • Osteoprotegerin inhibits RANK Ligand 2 Physiology
Pathology Osteoporosis
Higher Peak Bone Mass 3, 4 Bone Mass (ra Meno pid p bo ause ne los s) 2 0 20 40 60 Age (in years) Pathology Men Women 80 100
Estrogen promotes bone formation 1 Osteoprotegerin RANK Ligand • After menopause, estrogen levels drop • Women experience rapid bone loss after menopause due to estrogen deficiency 2 Estrogen
Testosterone: • • Stimulates osteoblasts 3 Inhibits osteoclasts 3 Increases bone size and BMD 3 Mediated by an androgen receptor 3 Men with low testosterone are susceptible to osteoporosis. 3 Testosterone
Epidemiology Osteoporosis
• 200 million women worldwide suffer from osteoporosis • Approximately 30% of all postmenopausal women in the U. S. and Europe have osteoporosis. • At least 40% of these women, and 15 -30% of men, will sustain one or more fragility fractures in their remaining lifetime. Epidemiology
Estimated Annual Incidence: 2 • Total fractures: 9 million • Hip fractures: 1. 6 million • Forearm fractures: 1. 7 million • Vertebral fractures: 1. 4 million Fracture Incidence Hip Forearm Spine Humerus Other Sites
Fracture Comparison
Treatment Osteoporosis
Treatment
• Promotes bone formation and decreases bone resorption Mechanism of Action Application • First line treatment for osteoporosis in both men and postmenopausal women 1 Bisphonates • Approved in both sexes for the prevention and treatment of osteoporosis Aledronate 2, Risedronate 3 and Zoledronic Acid 4
Ibandronate (Boniva) Only FDA approved for treatment (not prevention) of osteoporosis in postmenopausal women Not FDA approved for males • Paucity of studies 1 • Similar pharmocokinetics in men and women 2 • Similar efficacy in men and women probable 3 Bisphonates
Drug Route/ Frequency Indicated for which gender Alendronate PO/QDay, QWeek Women Men Risedronate PO/QDay, QWeek, QMonth Women Men Ibandronate Vertebral Fracture RR Hip Fracture RR Nonvertebral RR NE Zoledronic Acid Bisphonates NE PO/QMonth Women IV/Q 3 Mont h IV/QYear RR = Risk Reduction Women Men NE = No effect demonstrated
Drug Vertebral Fracture RR Hip Fracture RR Nonvertebral RR Route/ Frequency Indicated for which gender Raloxifene NE NE PO QDay Women Calcitonin NE NE Nasal QDay SQ QDay Women Teriparatide SQ QDay Women Men Denosumab SQ Q 6 Months Women Men RR = Risk Reduction Other Agents NE = No effect demonstrated
Estrogen & Bone Metabolism
Estrogen’s protective role in bone metabolism has long been appreciated 1 Decline of estrogen in postmenopausal females provides a ready example of estrogen’s protective role in bone metabolism 2 Estrogen HRT in postmenopausal women has been shown to: • prevent bone loss (Maintain BMD) • decrease bone remodeling and incidence of vertebral fracture 3 HRT- Hormone Replacement Therapy Estrogen in Females
Testosterone’s influence on bone metabolism is minimal in both sexes 2 Testosteron e& estrogen decline with aging Estrogen has a greater role in preventing bone resorption in both males & females 2 1 Estrogen in Males
• Mechanism of Action: selective estrogen-receptor modulator • Benefits • Increases BMD of hip and spine in women 1 • Females: approved for treatment and prevention of osteoporosis in women. • Not approved in males 2 • Narrow study contexts 3, 5 • Was not shown to significantly impact BMD in males 4 Raloxifene
• 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 for: 2 • 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 formation. 3, 4, 5 Tissue Selective Estrogen Complex
• Mechanism of Action • Analogous to endogenous calcitonin • Indications • Approved for the treatment (not prevention) of osteoporosis in women who are ≥ 5 years postmenopausal • Not utilized in men Calcitonin-Salmon
• Mechanism of Action: • Recombinant parathyroid hormone (PTH) • Stimulates bone formation. • Approved for: • Treatment & prevention of osteoporosis in men and postmenopausal women 1 • Especially those at high risk for vertebral fracture 2 Teriparatide (Forteo)
Significantly increased lumbar BMD from baseline levels 3 Extent of lumbar BMD increase similar in both males 1 and postmenopausal females 2 Teriparatide Efficacy
NOF Recommended Daily Intake: Calcium Men: 1000 mg Women: 1200 mg Vitamin D Men & Women: 800 – 1000 units Calcium & 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 and 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 women. 1 • Study Demographics • Men were understudied • 2010 DIPART Group Meta-Analysis: only 14% of 68, 500 subjects studied were men 1 • 2007 Tang et al. 2 Meta-Analysis included only 8% men 3 Calcium & Vitamin D
Mechanism of Action: monoclonal antibody; prevents osteoclast maturation. “RANK-L”, RANK-Ligand RANK-L Inhibitor (Denosumab)
• Approved to increase BMD in 1, 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 (Prolia)
Efficacy in Males 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 Denosumab
Efficacy in Females Increased vertebral, hip and non-vertebral BMD 1. Decreased incidence of vertebral, hip and nonvertebral fractures 1, 3 Denosumab
In Males, • No data for fracture incidence in males without nonmetastatic prostate cancer 1. • 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 Females, • Major phase III clinical trials studied Denosumab efficacy in >2000 postmenopausal females 2– no equivalent in males. • Examples: FREEDOM, DEFEND, DECIDE & STAND studies 3 Denosumab Research Disparities
Prognosis Osteoporosis
90% 80% 70% 60% 50% 40% Men Women 30% 20% 10% 0% Return to Independent Living Independent Mobility Mortality within 1 Yr. Fracture Prognosis
Compared to men, Women: - Are almost twice as WOMEN 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 postoperative mortality -Are less likely to return to independent living or mobility. Fracture Morbidity
The Dubbo Osteoporosis Epidemiology Study 1 Men 197 out of 343 died Women 461 out of 952 died 60% 58% 56% 54% 52% 50% 48% 46% 44% 42% Men Fracture Mortality Women
80% 70% 60% 50% 40% Men Women 30% 20% 10% 0% Receive Treatment after Fracture 1 Receive Treatment within 1 Yr. 2 Osteoporosis Treatment after Hip Fracture
Risk Factors Osteoporosis
Cannot Change 1 Potential for Change 1 Menopause Smoking History of fracture in first-degree relative Low body weight (<127 lbs) Caucasian race Estrogen deficiency, including menopause onset <age 45 Excessive Alcohol Advanced age Low calcium intake (lifelong) Female Vitamin D Insufficiency Specific Diseases Specific Medications Sedentary – lack of weigh-bearing exercise Female Athlete Triad Risk Factors Eating disorders
Screening Osteoporosis
Criterion 1 Age-Based on Risk Factors Women • • Regardless of Gender • • • 65 years and older Men 70 years and older Postmenopausal, < 65 with 1+ risk 50 -70 years with factor(s) 1+ risk factor(s) Perimenopausal with specific high-risk factor associated with increased fracture risk Postmenopausal, discontinuing estrogen 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 Screening
• The gold standard test for diagnosis 1 • Measures 1 • Spine • Hip • Forearm • Less radiation than in the environment 1 • Provides the T Score 1 DXA Scan
Diagnosis 1 T-Score 1 Normal 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 that of 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 T-Score Definitions
Screening is Cost-Effective in Women >651 Screening is NOT Cost-Effective in Men >701 Cost-Effectiveness
Gender Awareness Osteoporosis
• Osteoporosis considered a “Woman’s Disease” 1 • 20% of men will suffer from osteoporosis 1 • Research is biased towards women 2 • Men have worse outcomes 3 Gender Awareness
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