PATHOGENESIS AND MANAGEMENT

2.  Osteo = bone
 Porosis = full of holes
 Osteoporosis = means
bones that are full of
holes

3. OsteoporosisOsteoporosis
• The most common metabolic bone disorderThe most common metabolic bone disorder
• Systemic skeletal disease characterized by:Systemic skeletal disease characterized by:
– Low bone massLow bone mass
– Microarchitectural deterioration of bone tissueMicroarchitectural deterioration of bone tissue
– Increased bone fragility and susceptibility to fractureIncreased bone fragility and susceptibility to fracture
 Not a natural part of aging
 Increased risk for women, post-menopausal, over age 65
 All races, sexes, and ages are susceptible
 Preventable and treatable!

5.  In the USA, the estimated
prevalence of osteopenia
is 15 million in women and
3 million in men.
 The estimated prevalence
of osteoporosis is 8
million in women and 2
million in men.
 Although, osteoporosis
affects >10 million
individuals in the United
States, only 10 to 20% are
diagnosed and treated
 80% are women
Osteoporosis - Prevalence

9. Osteoporosis in Perspective
Lifetime risk at age 50

10. Osteoporotic Fractures:
Comparison with Other Diseases
1996 new cases,
all ages184 300
750 000
vertebral
250 000
other sites
250 000
forearm
250 000
hip
0
500
1000
1500
2000
Osteoporotic
Fractures
Heart
Attack
Stroke Breast
Cancer
Annualincidencex1000
1 500 000
Annual incidence
all ages
513 000
annual estimate
women 29+
228 000
annual estimate
women 30+
American Heart Association,1996
American Cancer Society,1996
Riggs BL & Melton LJ 3rd, Bone, 1995;17(5 suppl):505S-511S

11. All fractures are Associated With
Morbidity
Cooper C, Am J Med, 1997;103(2A):12S-17S
40%
Unable to walk
independently
30%
Permanent
disability
20%
Death within
one year
80%
One year after an
hip fracture:
Patients(%)
Unable to carry out at
least one independent
activity of daily living

12. Osteoporosis Is a Serious Public Health
Problem
• Affects 10 million
Americans (80%
women)
• 2 million fractures yearly
• Direct cost $17 billion
Distribution of Fractures

13. Primary Care Providers Are Critical for Osteoporosis
Management, Screening, Diagnosis, and Treatment

14. Why Recognize & Treat Osteoporosis?Why Recognize & Treat Osteoporosis?
To Prevent FracturesTo Prevent Fractures
• 1.5 million fractures/yr1.5 million fractures/yr
• $17 billion direct costs$17 billion direct costs
• 300,000 hip fractures/yr300,000 hip fractures/yr
– 20% die20% die
– 25% confined to long-term care facilities25% confined to long-term care facilities
– 50% long-term loss of mobility50% long-term loss of mobility

16. launched in 2010.

17. Vision:
Towards a society free from
osteoporotic fractures.
Mission:
Promote health awareness among Saudi
society about osteoporosis and it's
relative high risk factors ,build up
screening programs and comprehensive
health care.

18. The plan contain 7 targets:
•primary prevention of Osteoporosis.
•secondary prevention of Osteoporosis.
•improve the quality of health services at
it's three levels provided to Osteoporosis
patients.
•support monitoring, follow up, evaluation
methods related to Osteoporosis control
program.
• implement and support research methods
and respective studies related to
Osteoporosis.

19. Types of osteoporosis
Primary Osteoporosis
•Postmenopausal Osteoporosis
•Senile Osteoporosis
Secondary Osteoporosis
• Diet
• Drug
• Endocrine disease
• Other Systemic Disorders.

20. Impact of OsteoporosisImpact of Osteoporosis
Signs
 Kyphosis
 Loss of height
 Abdo bulges
 Clinically
diagnosed
fracture
Symptoms
 Neck becomes
weak
 Pain in back
 Breathing
difficulties
 Indigestion & GOR
 Stress incontinence
 Difficulty with
mobility following
a fracture

23. Risk Factors
• Chronic liver disease
• Excessive secretion of cortisol (Cushing's syndrome)
• Radiographic evidence of osteopenia or vertebral
deformity
• Previous fracture not caused by a major accident
• Cancer
• Significant loss of height or an abnormal bend in the
upper spine (thoracic kyphosis)
Risk factors that have the potential to be
modified include:
• Cigarette smoking
• Excessive alcohol intake
• Inactivity
• Low body weight
• Poor general health
• Prolonged immobilization
Risk factors that cannot be
modified include:
• Caucasian race
• Advanced age
• Female sex
• Premature menopause (<45 years)
• Prolonged time (>1 year)
without a menstrual period
Conditions associated with
osteoporosis:
• Anorexia nervosa
• Malabsorption syndromes
• Excessive secretion of parathyroid
hormone
• Excessive secretion of thyroid
hormone
• Post-transplantation
• Chronic renal disease

24. BMI less than or equal to 20

25. BMI less than or equal to 20

28. Vertebrae
Hip
Wrist
50 60 70 80
40
30
20
10
Age (Years)
Annualincidence
per1000women
Incidence of
Osteoporotic Fractures in Women
Wasnich RD, Osteoporos Int 1997;7 Suppl 3:68-72

29. Hipfracturerisk(%per10Years)
-3
60
70
80
AGE
0
5
10
15
20
50
BMD T-score
-2.5 -2 -1.5 -1 -0.5 0 0.5 1
10-Year Fracture Risk: Age
and BMD
For a given
BMD
,
risk increases with
age
Kanis JA et al, Osteoporos Int,
2001;12:989-995

30. 10-YearProbabilityof
SymptomaticFracture(%)
Age Is a Major Risk Factor
for Fracture
With kind permission from Springer Science+Business Media: Kanis JA ,et al. Ten year probabilities of osteoporotic
fractures according to BMD and diagnostic thresholds. Osteoporos Int.2001;12:989-995. Adapted from Fig. 3. ©
2001 International Osteoporosis Foundation and National Osteoporosis Foundation.
80
70
60
50
AGE
Age 70
T-score -2.5
24% Fx Risk
-3 -2 -1

31. Combined Effect of Bone DensityCombined Effect of Bone Density
and Risk Factorsand Risk Factors
Rate of
Hip Fracture/
1000
Woman-Years
Bone Density
Cummings SR et al. N Engl J Med. 1995;332:767-773.
Number of
Risk Factors
27.3
14.7
9.4
0
5
10
15
20
25
30
Lowest Third Middle Third Highest Third
≥5
3-4
0-2

35. Web Version 3.4
http://www.shef.ac.uk/FRAX/. Accessed August 2014.

37. Example of Applying the FRAX Tool
Which Woman is at Higher Fracture Risk?
54 year old smoker with a T-score of -2.0
or
81 year old with no prior fracture with a T-score of
-1.4
10 year risk of hip fracture = 2.5%; major osteoporotic fracture = 10%
10 year risk of hip fracture = 3.2%; major osteoporotic fracture = 26%

38. a 10 year probability of fracture in women
with relation to age and T-score

40. Composition of bone…

41. Determinants Of Peak Bone Mass
Peak Bone Mass
Physical activity Gonadal status
Nutritional statusGenetic factors

43. BoneMass
Age (years(
Attainment of Peak
Bone Mass
Consolidation Age-related Bone Loss
Men
Women
Menopause
0102030405060
Fracture
Threshold
Compston JE. Clin Endocrinol 1990; 33:653–682.
Age Related Changes in BoneAge Related Changes in Bone
MassMass

47. Pathogenesis
• Diminished bone mass can result from:
– failure to reach an optimal peak bone mass in early adulthood
– increased bone resorption
– decreased bone formation after peak bone mass has been
achieved
• All three of these factors probably play a role in most
elderly persons. Low bone mass, rapid bone loss, and
increased fracture risk correlate with high rates of bone
turnover (ie, resorption and formation).
• In osteoporosis, the rate of formation is inadequate to
offset the rate of resorption and maintain the structural
integrity of the skeleton

51. Osteoporosis – Screening
X-ray findings are generally insufficient for the screening of
primary osteoporosis:
• A normal x-ray of bone cannot reliably
measure bone density but is useful to
identify spinal factures, explains back
pain, height loss or kyphosis.
• X-rays may detect osteopenia only when bone
loss is > 30%.
• X-ray findings can also suggest other causes
of metabolic bone disease, such as the lytic
lesions in multiple myeloma and the pseudofractures characteristic of
osteomalacia.
Bone densitometry is the only method for diagnosing
or confirming osteoporosis in the absence of a fracture

52. Screening- Ultrasound Densitometry
Ultrasound densitometry can assess the density and
structure of the skeleton and appears to predict fracture
risk in the elderly. The apparatus is relatively inexpensive,
portable, and uses no radiation but can be used only in
peripheral sites (eg, the heel), where bone is relatively
superficial. Ultrasound devices do not expose the patient
to ionizing radiation.

53. Dual-Energy X-Ray
Absorptiometry
• “Gold Standard” test to determine a
diagnosis
• Measures hip & spine
• Painless, safe and requires no
injections
• Takes 5-10 minutes
• Determines risk for fracture

55. Screening - DEXA
Dual energy x-ray absorptiometry (DEXA)
• DEXA measures areal density (ie, g/cm2) rather than
true volumetric density.
• The test is non-invasive and involves no special
preparation.
• Radiation exposure is minimal, and the procedure is
rapid. This is the most popular and accurate test to
date and the test only takes about 20 to 40 minutes,
with a 5 mrem dose of radiation (a full dental x-ray is
300 mrem).

58. #1:Questions about
Osteoporosis
When should Bone Density
Measurement be performed?

59. USPSTF 2010 Recommendations :
Screening for Osteoporosis
 BMD testing for women 65 & older
 BMD in 60-64 yo if ↑ fx risk
- Use WHO FRAX® risk tool
 If clinical based fracture risk of 9.3%
then order bone density
measurement
Nelson et al Ann Int Med July 2010

60. Who Should Have a Bone Density Test?
AAFP and NOF
AAFP: Sweet MG, et al. Am Fam Physician. 2009;79(3):193-200.
NOF: National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis.
www.nof.org. Accessed August 2014.
Women age 65 and older Men age 70 and older
Postmenopausal women and men ages 50–69
with clinical risk factors
Adults who have a fracture after age 50
Adults with a condition (e.g., rheumatoid arthritis) or
taking a medication (e.g., glucocorticoids(
associated with low bone mass or bone loss

61. T-score
Normal ≥ -1
Osteopenia < -1 and > -2.5
Osteoporosis ≤ -2.5
Severe
Osteoporosis
≤ -2.5 with Fracture
Osteoporosis
World Health Organization Criteria
Postmenopausal Caucasian with DXA measure
WHO Study Group JBMR 1994

62. Screening - DEXA
DEXA of the proximal femur in a young
woman, age 37, with unsuspected
femoral-neck osteopenia (T score, -1.6).
DEXA of the lumbar spine in a young
woman, age 37, with unsuspected lumbar
spine osteopenia (T = -1.8)

63. Screening - DEXA

65. T scores vs. Z scores
T score – number of SDs a patient’s BMD
deviates from a reference population of
normal young adults
Z score – number of SDs a patient’s BMD
deviates from a reference population of
subjects of the same age and sex
Z scores indicate whether the BMD result is
expected for the patient’s age. If it is
much less than expected, suspect a
secondary cause of osteoporosis (use –2
as a cutoff(

72. 2014Universal Recommendations
http://www.nof.org/hcp/practice/tools. Accessed August 2014.
Counsel on the risk of fractures
Eat a diet rich in fruits and vegetables (supplemented
if necessary) to a total calcium intake of
•1000 mg per day for men 50-70
•1200 mg per day for women ≥ 51
•1200 mg per day for men ≥ 71
Vitamin D intake should be 800-1000 IU per day (age
≥50), supplemented if necessary
Regular weight-bearing and muscle-strengthening
exercise
Fall prevention evaluation and training
Cessation of tobacco use and avoidance of excessive
alcohol intake

73. The good news: Osteoporosis is
preventable for most people!

75. 75
Calcium requirements vary by age
Source: The 2004 Surgeon General’s Report on Bone Health and Osteoporosis:
What It Means to You at http://www.surgeongeneral.gov/library/bonehealth
If this is your age
Then you need
this much calcium
each day (mg)
0 to 6 months 210
7 to 12 months 270
1 to 3 years 500
4 to 8 years 800
9 to 18 years 1,300
19 to 50 years 1,000
Over 50 years 1,200
Growth
spurt

76. FOOD SERVING SIZE CALCIUM(mg)
MILK - WHOLE 1 GLASS (190ML) 225
MILK - SEMI-SKIMMED 1 GLASS (190ML) 231
MILK - SKIMMED 1 GLASS (190ML) 236
YOGHURT 1 POT (150g) 225
CHEDDAR CHEESE S MALL PIECE (30g) 216
COTTEGE CHEESE 2 TABLESPOONS 58
ICE-CREAM 2 SCOOPS 156
SARD DIINES (with bones) 2 CAN NED 230
ORANGE 1 MEDIUM 75
WHITE BREAD 2 SLICES 72
BAKED BEANS 3 TABLESPOONS 64

77. 77
Calcium
An easy way to meet calcium needs
is consuming 3 cups
(8 oz.) each day of fat-free or low-
fat* milk or equivalent milk products
in combination with
a healthy diet. Children ages
2–8 years need 2 cups.
MyPyramid equivalents:
• 8 oz. milk
• 1 cup yogurt
• 1-1/2 oz. natural
..or 2 oz.
processed ..cheese
* Fat-free and low-fat are for
health but not for calcium
differences

78. % DV calcium: Milk group
• Yogurt
1 cup (8 oz.) = 30% DV
• Milk
1 cup = 30% DV
• Cheese
1 ½ oz. natural/2 oz. processed = 30% DV
• Milk pudding
1/2 cup = 15% DV
• Frozen yogurt, vanilla, soft serve
½ cup = 10% DV
• Ice cream, vanilla
½ cup = 8% DV
• Soy or rice milk, calcium-fortified
1 cup = varies—check label
Choose fat-free
or low fat
most often

79. % DV calcium: Grain products
group
• Cereal,
calcium-
fortified
Serving size
and amount of
calcium varies
—check label

80. % DV calcium: Vegetable
group
• Broccoli, raw
1 cup = 9% DV
• Collards ‫كرنب‬
1/2 cup = 20% DV
• Turnip greens, ‫لفت‬
1/2 cup = 10% DV

81. % DV calcium: Fruit group
• Orange juice and
other calcium-fortified
beverages
6 oz. = 20 to 30% DV,
varies—check label
Look for 100% juice

82. % DV calcium:
Meat & Beans Group
• Baked beans
1 cup = 14% DV
• Salmon, canned, with edible
bones
3 oz. = 18% DV
• Sardines, canned, in oil, with
edible bones
3 oz. = 32% DV
• Soybeans, cooked
1 cup = 26%
• Tofu, firm, with calcium
½ cup = 20% DV; check label

83. Calcium supplementCalcium supplement
considerationsconsiderations

84. Calcium carbonate vs. citrate
Calcium carbonate
• Needs acid to
dissolve and for
absorption
• Less stomach acid
as we age
• Often taken at
meals when more
stomach acid
Calcium citrate
• Doesn’t require
stomach acid for
absorption
• May be taken
anytime—check with
your healthcare
provider
• May cost more

85. Limit calcium to 500 mg at
a time
Our bodies can best
handle about 500
mg calcium at one
time from food
and/or supplements.
Spread your calcium
sources throughout
the day.

86. Increase amount slowly
• Start supplements with 500 mg
calcium daily for about a week,
gradually adding more.
• Gas and constipation can be
side effects:
– Increase fluids and high fiber
foods if diet is low in whole grains
and fruits and vegetables.
– Try a different type of supplement
if side effects continue.

87. 87
Vitamin D from sunlight exposure
• Vitamin D is manufactured in your skin
following direct exposure to sun.
• Amount varies with time of day, season,
latitude and skin pigmentation.
• 10–15 minutes exposure of hands, arms
and face 2–3 times/week may be
sufficient (depending on skin sensitivity).
• Clothing, sunscreen, window glass and
pollution reduce amount produced.
Source: National Osteoporosis Foundation Web site; retrieved July 2005 at http://www.nof.org

88. You need more vitamin D as
you age
Age
Daily
vitamin D needs
in International
Units (IU)

89. Food Sources of Vitamin DFood Sources of Vitamin D
 Cod liver oil – 1 TBS
 Salmon 3.5 oz.
 Mackerel 3.5 oz.
 Tuna, canned, in oil, 3 oz.
 Sardines 3.5 oz.
 Milk (fortified) 8 oz.
 Ready to eat cereal (fortified) ¾ -
1 cup
 Egg 1 whole
 Liver, 3.5 oz.
 Cheese, swiss 1 oz.
 1,360 IU
 360
 345
 200
 250
 98
 40
 20
 15
 12

90. 90
Sources of Vitamin D?
Main dietary sources of vitamin D are:
• Fortified milk
(400 IU per quart)
• Some fortified cereals
• Cold saltwater fish
(Example: salmon, halibut, herring,
tuna, oysters and shrimp)
• Some calcium and vitamin/mineral
supplements

91. Vitamin D PreparationsVitamin D Preparations

94. FALL PREVENTION

95. Osteoporosis
Falls Break Bones
• You can prevent most falls
– Improve your balance, coordination, and strength
through weight-bearing physical activity such as
dancing or Tai Chi
– Review medicines with a health care professional
(some medicines may cause drowsiness or
dizziness)
– Have your vision checked
– Make your home safer

96. Protect Your Bones
Ways to Make Your Home Safer
1
2
3
4
5
6
7
8
9
10
11
Have handrails and plenty of light in all stairways.
Wear shoes that give good support and have non-slip soles.
Don’t use stepstools. Keep items you need within easy
reach.
Maintain a clear path to the bathroom.
Make sure your walkways are wide enough.
Remove all small rugs. They can make you trip.
Move phone and electrical cords away from walkways and
open areas.
Make sure that all areas are well lit. Use bright light bulbs.
Be aware that some medications, including over-the-counter
medicines, can make you dizzy or sleepy.
Get your vision checked.
Remove things that you may trip over from stairs and places
where you walk.

97. Protect Your Bones
Ways to Make Your Home Safer
12
5 Remove all small rugs. They can make you trip.
Use non-slip mats in the bathtub or shower. Have grab bars
put in next to your toilet and in the bathtub or shower.

100. Whom to Treat: NOF Guidelines 2014Whom to Treat: NOF Guidelines 2014
Women ≥ 65 and men ≥ 70
(younger with risk factors)
T-score between -1.0 and
-2.5
T-score ≤ -2.5 in the lumbar spine,
total hip, or femoral neck
or
Hip or spine fracture (clinical or radiographic)
DXA test
≥ 3% for hip fracture
or
≥ 20% for major osteoporotic fractures
FRAX
10-y fracture risk
Candidate for
TREATMENT
YES
YES
nof.org/hcp/resources/913. Accessed August 2014.

101. Osteoporosis Therapy Algorithm
Postmenopausal Women
At Risk/Osteopenia Osteoporosis Severe OsteoporosisSTAGE
LowerHigher
-2.5BMD (T-score)
Raloxifene
PTH
CalcitoninHRTHRT
HRTHRT
During Hot
Flushes
Post Vasomotor Symptoms
Pre fracture
Post Fracture
Risk
of Fracture
AGE
Bisphosphonates Or
Strontium Ranelate
50 55 60 65 70 75 80 85 90

102. Osteoporosis Prevention and Treatment
Age
Hormonal Replacement
Bisphosphonates
Strontium
SERM
20 40 60 80
Vitamin D
PTH
Life Style
Treatment
choice

103. One-Minute Treatment DecisionOne-Minute Treatment Decision
Therapy Decision
Treat all patients with
an existing fracture
High Risk-
Treat
Moderate Risk -
Treat if other risk factors
Low Risk-
Check again in 1-2 years
T-Score *
Below -2.0
-1.5 to -2.0
Above -1.5
National Osteoporosis Foundation, Physician’s Guide to Prevention and Treatment of
Osteoporosis. Belle Mead, NJ: Excerpta Medica, Inc.; 1998.

104. Osteoclast
Inhibition of resorption
Osteoblast
Stimulation of formation
Pharmacologic Treatment
Targets

106. Prevention Treatment
FDA-Approved Therapeutic Options
Estrogen
Alendronate
Risedronate
Ibandronate
Zoledronic acid
Raloxifene
Calcitonin
PTH (teriparatide)
Denosumab

108. FDA-approved Medications
Osteoporosis
Post-
menopausal
Glucocorticoid-
induced Male
Drug Prevent Treat Prevent Treat
Estrogen 
Calcitonin* (Miacalcin®, Fortical®) 
Raloxifene (Evista®)  
Ibandronate (Boniva®)  
Alendronate (Fosamax®)    
Risedronate (Actonel®)     
Risedronate (Atelvia®) 
Zoledronate (Reclast®)     
Denosumab (Prolia™)  
Teriparatide (Forteo®)   
Diab DL, Watts NB. Endocrinol Metab Clin North Am. 2013;42(2):305-317.

109. Drug
Vertebra
l
Fracture
Nonvertebral
Fracture
Hip
Fracture
Calcitonin 
Raloxifene 
Ibandronate 
Alendronate   
Risedronate   
Zoledronic acid   
Denosumab   
Teriparatide  
Evidence for Fracture Reduction
Diab DL, Watts NB. Endocrinol Metab Clin North Am. 2013;42(2):305-317.

112. Estrogen Treatment (ET)
• Several approved oral and transdermal preparations
• Treats symptoms of estrogen deficiency
• Skeletal effects:
– Decrease in biochemical markers of 50% to 60%
– 2-year BMD increase of 4% to 6% at hip and spine
– Decreased incidence of vertebral and hip fractures (34%) after 5
years in the Women’s Health Initiative (WHI)
– Effects in women with osteoporosis have not been evaluated in
randomized controlled trials
• Concern about adverse effects
• Long-term use not recommended
Rossouw JE, et al. Writing Group for the Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.

114. The Concept of a SERM
Selective Estrogen Receptor Modulator
(EAAs: Estrogen Agonist/Antagonists(
 Binds to the estrogen receptors
 Produces an estrogen agonist effect in some
tissues
 Produces an estrogen antagonist effect in
others

115. Raloxifene
• Raloxifene (60 mg daily)
• Skeletal effects:
–Decrease in biochemical markers of 30%
–3-year BMD increases of 2% to 3% at hip and spine
–Decreased incidence of vertebral fractures (30% to 50%) in
women with pre-existing vertebral fractures or low bone density. No
effect on nonvertebral or hip fractures has been observed
• Extra-skeletal effects: reduction in invasive
breast cancer
Ettinger B, et al. JAMA. 1999;282:637-645.

116. Raloxifene
 Adverse effects
 Hot flashes
 2- to 3-fold increased risk of venous
thromboembolic events
 No increased risk of stroke, but Black Box
Warning for increased risk of death following
stroke
 Leg cramps
Sontag A, Wan X, Krege JH. Curr Med Res Opin. 2010;26:71-76.

117. Calcitonin
 Calcitonin (200 units daily by nasal spray)
 Skeletal effects:
 Decrease in biochemical markers of 20%
 Small effect (1% to 2%) on bone density in spine
 Reduced incidence of vertebral fractures (36%) in women with pre-
existing vertebral fractures
 No effect on nonvertebral or hip fractures has been observed
 Adverse effects
 Nasal stuffiness
 Possible increased cancer risk
Chesnut CH 3d, et al. Am J Med. 2000;109:267-276. http://effectivehealthcare.ahrq.gov/slides/?
pageaction=displaySlides&tk=49&dpg=9&scroll=314. Accessed: September 13, 2013. European Medicines Agency.
Press release. July 20, 2012. Available at:
http://www.ema.europa.eu/docs/en_GB/document_library/Press_release/2012/07/WC500130122.pdf. Accessed:
September 13, 2013.

118. Bisphosphonates
Alendronate, Risedronate, Ibandronate, and Zoledronic Acid
• Alendronate: 10 mg daily (tablet) or 70 mg weekly (tablet or
liquid) for treatment, 5 mg daily or 35 mg weekly for
prevention
• Risedronate: 5 mg daily or 35 mg weekly (tablet); 150 mg
monthly (tablet)
• Ibandronate: 150 mg monthly by tablet; 3 mg intravenously
over 15 to 30 seconds every 3 months
• Zoledronic acid: 5 mg by intravenous infusion over a minimum
of 15 minutes once every year for treatment—and every other
year for prevention
*
2012 Jun 25;172(12):930-6
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. Washington, DC: National
Osteoporosis Foundation; 2013. Available at: http://www.nof.org/hcp/clinicians-guide. Accessed September 13, 2013.

119. Clinical Benefit of Bisphosphonates
• Relative risk reduction for fractures
• Postmenopausal women with osteoporosis
• 3 years bisphosphonate treatment
Vertebrae Hip
Khosla S, et al. J Clin Endocrinol Metab. 2012;97(7):2272-2282.

121. Bisphosphonates: Indications
 Treatment and prevention of postmenopausal
osteoporosis
 Alendronate, risedronate, ibandronate, zoledronic acid
 Prevention and/or treatment of glucocorticoid-
induced osteoporosis
 Risedronate, zoledronic acid, alendronate
 Treatment of men with low bone density
 Alendronate, risedronate, zoledronic acid

122. Contraindications/Warnings/Precautions
– Hypocalcemia
– Creatinine clearance <30 cc/min (<35 cc/min for zoledronic acid)
– For oral dosing: Esophageal stricture or impaired esophageal motility (alendronate);
inability to stand or sit for at least 30 minutes (alendronate/risedronate) or 60
minutes (ibandronate)
Notes: UGI symptoms per se are not a contraindication to oral dosing.
Use in pregnancy: Class C
Oral dosing requirements
– Tablets (with exception of delayed release risedronate) taken on an empty stomach
after overnight fast with 6 to 8 oz of plain water while in an upright position
– Patients should not eat or lie down for at least 30 minutes (alendronate
and risedronate) or 60 minutes (ibandronate)
– Calcium and vitamin D supplements, if needed, should be taken at a different time
of day than the oral bisphosphonate
Bisphosphonates
National Osteoporosis Foundation. Med Lett. 2011;53(1360):24.

123. • “Class warning” regarding UGI symptoms
(no increase in UGI complaints in randomized
controlled trials)
• Influenza-like symptoms may occur after first
monthly oral dose of IV bisphosphonate
• “Class warning” regarding infrequent bone,
joint, and/or muscle pain
• “Class warning” regarding jaw osteonecrosis
• “Class warning” about atypical fractures
following long-term therapy
Bisphosphonates: Side Effects

124. “Osteonecrosis” of the Jaw (ONJ(
 An area of exposed alveolar or palatal bone that typically
shows poor healing over several months
 95% of cases have been reported with high-dose,
chronic IV bisphosphonate treatment of myeloma and
cancer metastatic to bone1
 Can occur with denosumab2
 Pain in 2/3 cases: infection may or may not be present
 Known risk factors: invasive dental procedures, oral
trauma, periodontitis, poor oral hygiene, radiotherapy to
the jaw, chemotherapy, corticosteroids, infection
 Pathogenesis is not known3
1. Woo SB, et al. Ann Intern Med. 2006;144:753-761. 2. Sutton EE, Riche DM. Ann Pharmacother. 2012;46:1000-1009.
3. Khosla S, et al. J Bone Miner Res. 2007;22:1479-1491.

125. Atypical Fractures of Femur in Patients
Taking Anti-Resorptive Agents Long Term
Park-Wyllie LY, et al. JAMA. 2011;305:783-789. Shane E, et al. J Bone Miner Res. 2013 May 28. [Epub ahead of print].
Watts NB, Diab DL. J Clin Endocrinol Metab. 2010;95:1555-1565. Meier RP. Arch Intern Med. 2012;172:930-936.
• May begin with stress reaction or stress
fracture of lateral femoral cortex (A)
• Transverse fractures of femoral diaphysis
or in subtrochanteric region (B)
• Often bilateral
• Prodromal pain in thigh or groin in 70%
• Occurs in untreated patients, but
increased incidence with long-term
antiresorptive therapy, particularly
bisphosphonates and denosumab

126. Bisphosphonate Therapy:
“Long-Term” Treatment Stopping treatment in high-risk patients
 After 5 years of alendronate-decline in BMD, rise in biochemical
markers, no increased fracture risk except clinical vertebral fractures1
 After 3 years of risedronate, spine BMD rose, vertebral facture risk
was still reduced compared with control patients2
 After 3 years of zoledronic acid, slight increase in morphometric
fractures vs clinical vertebral fractures3
 Long-term treatment has not clearly been associated with safety
issues or loss of efficacy
 Cessation of treatment after 2 to 5 years is associated with some
persisting effect on biochemical markers, as well as BMD; this has
been best characterized for alendronate and zoledronic acid
1. Black DM, et al. JAMA. 2006;296:2927-2938. 2. Watts NB, et al. Osteoporosis Int. 2008;19:365-372. 3. Black DM, et
al. J Bone Miner Res. 2012;27:243-254.

127. Recently Approved
• Boniva – 150 mg monthly
– 2.5 mg daily approved May, 2003
– Vertebral fracture efficacy shown with daily
– Based on 1 year BMD data, 150 mg monthly is
superior to the 2.5 mg daily
– 60 minute post dose fast, not 30 minute
• Fosamax PLUS D – 70 mg/2800 IU
weekly

128. How Long to Treat with bisphosphonates?
 5–10 years appears to be safe for most patients
 Assess for risk:
and Diab D. J Clin Endocrinol Metab. 2010;95(4):1555-1565.
Drug Holiday
After 3-5 years
Drug Holiday
After 3-5 years
Drug Holiday
After 10 years
Drug Holiday
After 10 years
Higher RiskLower Risk

129. Baseline 3 Years
VERT-NA: Placebo Patient
Increased perforation
Trabecular
thinning
Borah, et al, JBMR 16 (Suppl 1),

130. Similar thickness of trabeculae and number of perforations
Baseline 3
Years
Borah, et al, JBMR 16 (Suppl 1), 2001
VERT-NA: Risedronate Patient

131. Bisphosphonates for Osteoporosis
• Benefit: reduction of fracture risk (alendronate,
risedronate, ibandronate)
• Problem: poor adherence to therapy
• Cause: multifactorial, including issues of
convenience (complexity of dosing) and
tolerability (GI irritation in clinical experience)
• Possible solutions: larger doses given less
frequently, parenteral administration

132. Bisphosphonates:
Molecular Mechanisms of Action
• Interfere with the action of osteoclasts
– Recruitment, differentiation, and action
– Two mechanisms:
• Incorporated into cytotoxic ATP analogs (etidronate)
– Affect cellular activity
• Interfere with the mevalonate pathway (nitrogen-containing BPs)
– Cause apoptosis
Russell R, et al. Osteoporos Int. 1999;(suppl 2):S68-S80.

133. Bisphosphonates:
Contraindications and Warnings
• Contraindications
– Hypocalcemia
– Known hypersensitivity to any component of this product
– Inability to stand or sit upright for at least 30 minutes
• Warnings
– Bisphosphonates may cause upper gastrointestinal disorders such
as dysphagia, esophagitis, and esophageal or gastric ulcer
.

136. Denosumab
 Monoclonal antibody to RANKL
 60 mg subcutaneous injection every 6 months
 9% increase in spinal BMD after 3 years in the pivotal
FREEDOM trial; 4% to 5% increase in hip BMD
 Reduction in fracture risk after 3 years:
 68% decrease in new vertebral fractures
 40% decrease in hip fractures
 20% decrease in nonvertebral fractures
 8-year data: continued increase BMD, reduced bone
turnover, good safety
Cummings SR, et al. N Engl J Med. 2009;368:756-765
Prolia (prescribing information). Thousand Oaks, CA: Amgen; June 2012.
McClung MR, et al. Osteoporos Int. 2013;24(1):227-235.

137. Denosumab Binds RANK Ligand and Inhibits Osteoclast
Formation, Function, and Survival
RANKL
RANK
OPG
Denosumab
Bone Formation Bone Resorption
Inhibited
Osteoclast Formation, Function,
and Survival Inhibited
CFU-GM Prefusion
Osteoclast
Osteoblasts
Hormones
Growth Factors
Cytokines
Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.

138. Proven osteoporotic fracture reduction
throughout the skeleton
In the pivotal FREEDOM study (published in the New England Journal of
Medicine), Denosumab reduced the risk of fracture at key osteoporotic
fracture sites versus placebo
PROLIA®: PROTECTION AGAINST FRACTURE
The absolute risk reductions demonstrated for Prolia® versus placebo
were 4.8%, 1.5% and 0.5% for vertebral, non-vertebral and hip
fractures respectively. 1
6
P

139. Denosumab Adverse Events
Adverse events that occurred more commonly in
denosumab group (as listed in the PI):
 Serious infections leading to hospitalization
 Dermatitis, eczema, rashes
 Back pain, pain in the extremity, musculoskeletal pain,
hypercholesterolemia, cystitis
 Pancreatitis
 Osteonecrosis of the jaw
 Significant suppression of bone remodeling
Prolia (prescribing information). Thousand Oaks, CA: Amgen; June 2012.

140. Teriparatide: rhPTH [1-34[
• The only treatment agent that is anabolic—stimulates bone
formation rather than inhibiting bone resorption
• 20 μg daily (subcutaneously) for no more than 2 years
• Indication: treatment of men and postmenopausal women
with osteoporosis who are at high risk for fracture
• Effects:
– Increased bone density in spine by 9% and hip by
3% vs placebo over 18 months
– Reduced incidence of vertebral fractures (65%) and
nonvertebral fragility fractures (53%) in women with
pre-existing vertebral fractures
– Studies too small to evaluate effect on hip fractures
• Adverse reactions: arthralgia, pain, nausea; warning about
osteosarcoma risk in rats
Neer RM, et al. N Engl J Med. 2001;344:1434-1441.
Forteo (prescribing information). Indianapolis, IN: Eli Lilly and Company; March 21, 2012.

142. Latest in Osteoporosis Treatment
1.Carotenoids, Lycopene Reduce Fracture Risk
(Antioxidants)
“…reactive oxygen intermediates may be involved in the bone-
resorptive process and that fruit and vegetable-specific
antioxidants, such as carotenoids, are capable of decreasing this
oxidative stress. Therefore carotenoids may help in preventing
osteoporosis.
In particular, an inverse relation of carotenoids and lycopene
with biochemical markers of bone turnover has recently
been demonstrated.”

143. 2.Omega-3 Fatty Acids Reduce hs-CRP1
“This study provides evidence that in healthy individuals,
plasma n-3 fatty acid concentration is inversely related to
hs-CRP…”
“High sensitivity C-reactive protein (hs-CRP) is a marker of
low grade sustained inflammation.”
“Increased hs-CRP by just 1SD increases fracture risk by an
amazing 23 percent2
.”
Consider supplementing the diet with omega-3 fatty acids
(fish oil). They’re a great way to help reduce inflammation,
hs-CRP, cardiovascular disease, and fractures related to
osteoporosis.
1. Micallef M A et al., European Journal of Clinical Nutrition, 2009; April 8 [Epub ahead of print].
2. Pasco et al. JAMA. 2006;296(11):1353-1355

144. 3.Vitamin K Improves Bone Strength and Reduces
Fractures
Review of RCTs showed that vitamin K(1) and vitamin K(2)
supplementation reduced serum undercarboxylated
osteocalcin levels regardless of dose but that it had
inconsistent effects on serum total osteocalcin levels and
no effect on bone resorption.”
Iwamoto J et al., Nutrition Research, 2009; 29(4): 221-228.