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OSTEOPOROSIS

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“There is no conflict of interests to disclose.”

Management and Prevention of Osteoporosis Learning Objectives: 

The participant will be able to identify four major risks factors for osteoporosis.

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The participant will be able to identify the two elements that determine bone strength.

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The participant will be able to understand the pathogenesis of osteoporosis and the basis for treatment with the current medications.

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Clinical problem of Osteoporosis Every 20 seconds a new osteoporosis fracture occurs.

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30 million women and 14 million men over age 50 are at risk for fracture due to low bone mass or osteoporosis.

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By 2020 this will increase with an estimated cost of 17 billion dollars annually to health care.

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Osteoporosis is the most common bone disease in humans.

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The Challenge 

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The challenge and impact of osteoporosis is that is remains largely under-diagnosed and undertreated. Less than 20% of eligible patients have had a BMD test.

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50% hospitalized for hip fractures never recover their pre-fracture activities.

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20% incidence of mortality in the first year after a hip fracture.

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One third enter a nursing facility within 1 year of fracture.

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Definition 

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Osteoporosis is now defined as a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture. Bone strength is determined by BMD and bone quality. Risk of fracture is determined both by BMD and age. BMD and age are each independent risk factors.

Image provided by: Osteoporosis - Mayo Clinic . 2015. Osteoporosis - Mayo Clinic . [ONLINE]

Age and risk of fracture 

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Fracture risk increases with age and specific fracture status. Age is associated with microdamage to the bone and indicates change in bone quality.

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Spinal fracture status is an independent risk facture. One vertebral fracture increases risk 4 fold and two fractures increase risk by 12 fold. Hip fracture increase risk by 2.5 fold.

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Men have higher mortality with hip fracture than women.

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Common sites of fracture

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The most common fracture sites are the forearm and hip. A history of a vertebral fracture is the most important risk factor and one of the strongest indications that a patient may have more fragility fractures. Only 1/3 of fragility fractures are clinically recognized. A fragility fracture is a fracture resulting from a fall from standing height or less that normally would not cause a fracture. Vertebral fracture in ages between 60-69 is 15%; in ages 70-79 is 32%. This fragility fracture increases with age.

Pathogenesis 

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Pathogenesis of osteoporosis is an imbalance between bone absorption and bone formation. 10% of bone matrix is remodeling at any one time. 3 mechanisms are involved in leading to an inadequate peak bone mass. 1. Insufficient bone mass and strength during growth. 2. Excessive bone being reabsorbed. 3. Inadequate formation of new bone during remodeling. Bone health is maintained by remodeling. Coordinated sequence of activation, resorption, and formation.

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The Lifecycle of Bone Activation

Resorption

Osteoclasts

Resting

Reversal Apoptotic Osteoclasts

Osteoblasts

Bone lining cells

Formation Osteoblasts

Mineralization

Osteoid

Illustration Copyright © 2009 Nucleus Medical Art, All rights reserved. www.nucleusinc.com. Adapted from: Baron R. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. 2003:1‐8; Bringhurst FR, et al. Harrison’s Principles  of Internal Medicine. 16th ed. 2005:2238‐2249; Lindsay R, et al. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2nd ed. 1999:305‐314.

Formation of the Bone

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Bone architecture

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Architecture of the bone is divided into cancellous (trabecular)bone and cortical bone.

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Cortical bone forms the hard shell around the more delicate trabecular bone. 80% of bone is cortical bone. Peripheral skeleton is primarily cortical bone.

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Trabecular bone is found in the distal ends of the long bone and the axial skeleton. It is more metabolically active and more affected by osteoporosis. 20% of bone.

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Menopause: trabecular bone loss is 3 times that of cortical bone in the first 3 years of menopause. The vertebrae and the radius are primarily trabecular bone. Understandable why the vertebrae is the most frequent site of fracture.

Major risk factors for OP 

Age and gender

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Previous osteoporotic fracture

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Low body weight ( under 127#)

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Current smoking

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Rheumatoid arthritis

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Oral steroids-5mg for 3 months or long term steroids.

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Alcohol of 3 or more drinks a day

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Femoral neck BMD

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Family history of hip fracture.

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Mechanisms of Bone Loss Postmenopausal bone loss is due to increase in the number of osteoclasts in the trabecular bone (vertebrae, wrists, and forearm ) results is resorption being increased and bone loss.

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Senile osteoporosis ( 60+ years old) is due to a negative calcium balance, increased resorption and reduced number of osteoblasts so formation is slowed.

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Both cortical and trabecular bones are affected.

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Effect of Increased Bone Resorption on Bone Loss Over Time

Osteoporosis Normal

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Increased osteoclast activity leads to bone loss with: Impaired bone architecture Compromised bone strength  Increased risk of fracture  

Images courtesy of David W. Dempster, PhD 2000.  Reproduced with permission. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. NIH Consensus Statement. JAMA. 2001;285:785‐795.

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Bone Mass in Women Over the Lifecycle Attainment of  peak bone mass

Peak bone mass

Bone loss

Menopause

100

80

60

40

20 Formation > Resorption

0

10

20

Resorption > Formation

30

40

Age (years)

50

60

70

80

Adapted from: Lanham‐New SA. Proc Nutr Soc. 2008;67:163‐176. Burger H, et al. Am J Epidemiol. 1998;147: 871‐879. Recker R, et al. J Bone Miner Res. 2000;15:1965‐1973. Sambrook P, et al. Baillieres Clin Rheumatol. 1993;7:445‐457. Weaver CM, et al. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 7th ed. 2008:206‐208.

Menopause 

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Lack of estrogen increases the bone resorption as well as decreasing the deposition of new bone. Deficiency of calcium and Vit D lead to decreased bone deposition. Low calcium stimulates PTH secretion which increases bone resorption. This ensures sufficient calcium in the blood.

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Guidelines for BMD testing-NOF 

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April, 2014: Women age 65 + and men 70 + years Postmenopausal women/men 50-69 years of age with risk factors. Endocrine disorders, mal-absorption, and FRAX model. Post menopausal women or men age 50 or older who have had any adult fracture.

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Frax as a tool in detecting those at absolute risk of fracture. 

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Developed by WHO to detect intended for postmenopausal women and men age 50 and older and applies only to untreated patients. Calculates the 10 year probability of a hip fracture or major osteoporotic fracture. Calculates the 10 year probability of fracture in those with low bone mass. If hip Frax is greater than 3 or major osteoporotic fracture is greater than 20 then they should be treated. Treatment decisions based on T-score alone will miss over half of those who will fracture.

Frax

Vertebral Imaging 

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All women age 70 or men age 80 of BMD score is -1.0 or lower at the spine, total hip, or femoral neck. Women age 65-69 or men age 7070 if BMD less than -1.5 or lower. Postmenopausal women/men age 50+ with risk factors such as low trauma fracture, loss of height 1.5 inches, or long term steroid use. Fragility fracture is a fracture resulting from a fall from standing height or less that normally would not cause a fracture.

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Benefits of BMD screening/testing Multiple, randomized trials and meta-analyses have shown treatment of OP reduces fracture rates. This reduces the cost and the morbidity of osteoporosis. Reduction of fracture rates reduces human cost. Harm of screening tests-none.

Treatment and Intervention 

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Knowledge and Education. Patients have to understand the need, the rational of treatment, and be given specific plan of care. Basics need to be emphasized. Calcium, Vitamin D, Exercise, avoiding falls, decreasing risks factors. Medicine cannot do it all.

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Calcium and Vitamin D

VITAMIN D

CALCIUM

 Postmenopausal:

1500 mg elemental calcium per day.

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is a hormone produced by the kidneys, 1,25 dihydroxyvitamin D is active hormone. 

 Premenopausal:

1200 mg calcium per day.

 90%

of women and 75% of men do not get adequate calcium.

Promotes GI absorption of calcium and phosphorus. 

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Is necessary for bone mineralization.

Stimulates bone reabsorption when given in high doses. Vitamin D insufficiency –> elevated PTH –> reabsorption of bone = elevated bone turnover.

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 Bariatric surgery – need increased amounts of vitamin D – fat soluble.

Medications for Osteoporosis/ Mechanisms of action 

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Bisphosphonates bind to hydroxyapatite and inhibit osteoclast activity leading to reduced bone resorption and turnover. Bisphosphonates are effective agents for reducing bone turnover, improving bone mineral clarity and reducing fracture risk. Significant fracture risk reduction observed at vertebral sites for all agents. Evidence support for risk reduction

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Medications 

First Line Drugs: All anti-resorptive (except Denosumab) and decrease risk of fracture in the spine, hip, and non-vertebral fractures. Alendronate Risedronate Zolendronic Acid Denosumab and Estrogen

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Mechanism of action: fully human monoclonal antibody binds and inhibits RANKL. Acts as anti‐resorptive agent.

Second Line Drugs for PMO: Fracture risk reduction in spine and non-vertebral fractures. Data on the hip insufficient.  

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Ibandronate: Anti-resorptive Raloxiphene: selective estrogen receptor modulator. Oral, daily. Teriparatide: Biologic agent. For women at high risk of fracture and men is hypogonadal OP at high risk of fracture.

Medications Medication

How it’s taken

Frequency

Ibandronate

Oral/ IV

Every 3  months

Raloxiphone

Oral

Daily

Sub‐Q Teriparatide Romosozumab: in trial. Sclerostin is an osteocyte derived inhibitor of osteoblast activity. Monoclonal antibody binds to sclerostin and N/A increases bone formation. Has Romosozumab shown increased BMD and bone formation and decreased bone resorption.

Daily for 2  years

N/A

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Osteoclast

Bone surface resorbed by  osteoclast Adapted from: http://www.brsoc.org.uk/gallery/arnett_osteoclast.jpg. Electron micrograph photo reproduced with permission.© Tim Arnett, The Bone Research Society.

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RANKL Pathway Involvement in  Bone Remodeling RANK Ligand RANK

Osteoclast Precursors

RANK

Differentiated Bone Resorption and Osteoclast

OPG

Formation Are Balanced in  Premenopausal Women

RANK

Estrogen

RANK Ligand

OPG Binds to RANK Ligand

OPG Estrogen Limits  the Expression  of RANK Ligand

Osteoblasts

Osteoblasts Activated Osteoclast

OPG = osteoprotegerin Adapted from: Boyle WJ, et al. Nature. 2003;423:337‐342. Kostenuik PJ, et al. Curr Pharm Des. 2001;7:613‐635.

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Effect of Estrogen on RANKL  Expression and Bone Resorption Differentiated Osteoclast Osteoclasts RANK Ligand is an Essential Precursors Mediator forRANK Osteoclast Formation, FunctionRANK and Survival

Estrogen Decreased Estrogen Leads to Increased RANK Ligand

RANK Ligand RANK OPG

Increased RANK Ligand in Postmenopausal Women Leads to Resorption Pits Are Not Completely Refilled RANK Ligand Excessive Bone Resorption OPG Excess

RANKOsteoblasts Ligand Activated Osteoclasts Overwhelms OPG

Osteoblasts OPG = osteoprotegerin Adapted from: Boyle WJ, et al. Nature. 2003;423:337‐342. Eghbali‐Fatourechi G, et al. J Clin Invest. 2003;111:1221‐1230.

Forteo

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Teripeptide/Forteo 1. Biologic agent (rhPTH 1-34) 2. Mechanism of action: anabolic agent. 3. FDA approved for post-menopausal women with osteoporosis at high risk for fracture. 4. Approved for men with primary or hypogonadal osteoporosis at high risk for fracture. 5. Daily subcutaneous injection at 20 micrograms.

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Non-invasive, easily repeated. Independent predictors of risk fracture.

Bone Turnover Markers

Cannot be used to diagnose osteoporosis. May be useful in assessing bone dynamics, monitoring response to therapy, can promote adherence. Markers of bone resorption: Ntelopeptide, C-teleopeptide, Deoxypridinoline. Markers of bone formation: Bone specific alkaline phosphatase, Osteocalcin, Procollagen Type 1 N-terminal Propedtide (PINP).

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Osteonecrosis of the Jaw due to Biphosphonates:

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2003 first reports – characterized by an area of exposed bone in the mandible, maxilla, or palate that heals poorly over 6-8 weeks. 95% of cases reported were associated with zolendronic acid or Pamidronate IV given for metastatic bone disease. Predisposing factors – dental disease, dental surgery, oral trauma, periodontitis, and poor oral hygiene. 1 in 100,000 patients per year is the incidence. Steps to prevent this complication include: excellent oral hygiene, dental care, and withholding the medication temporarily during dental surgery.

Fracture associated with the biphosphonate treatment. Atypical fracture of the subtrochanteric femur has occurred. It is not clear if this is due to the biphosphonates but that possibility is there.

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Take Away Points 

Major risks factors recognition lead to care for those at greatest risk. Current smoking, previous OP fracture, BMD of femoral neck, low body weight, steroids, RA, family history.

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Bone strength is BMD and quality of bone. These two factors can be improved with treatment.

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Current basis of treatment of OP is based on improving the balance between bone absorption and bone formation. Building bone mass as a youth, health habits to protect bone, and adequate calcium, Vitamin D, exercise to maintain bone balance is the basis for bring this silent disease under control.

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Medications that decrease reasorption of bone and build new bone are the backbone of treatment.

Staying YOUNG, Staying STRONG

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Suggested Reading 

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Blume SW,Curtis JR. Medical costs of osteoporosis in the elderly Medicare population. Osteoporosis Int. 2011;22(6):1835-1844. Cosman F, deBeur SJ. LeboffMS, et.al.Clinician’s quide to prevention and treatment of osteoporosis. Osteoporosis Int. 2014;25(10):2359-2381.Leib ES,Lenchik L, Lilezikian JP, et. al. Position statements of the International Society for Clinical Densitometry: methodology. J Clin Densitom. 2002;5(suppl):S5-S10.

Suggested Reading 

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Miller PD, Bonnick SL, et. Consensus of an international panel on the clinical utility of bone mass measurements in the detection of low bone mass in the adult population. Calcif Tissue Int. 1996;58:207-214. Bischoff-Ferrari H, et. Al. Fracture prevention with vitamin D supplementation/. JAMA, 2005, 293. Fechtenbaum, J.Cropet, C., Kolta S et al.(2005) The severity of vertebral fractures and hea2170.lth-related quality of life in osteoporotic postmenopausal women. Osteoporosis Int 16:2175

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