2. Introduction
• More than 10 million people in the US
have osteoporosis
• An additional 18 million have “low bone
mass”
• 1:2 white women and 1:8 white men will
experience at least 1 clinically significant
fracture in their lifetime
3. Introduction
• 1.5 million osteoporosis-related
fractures occur annually in US
– 300,000 hip fractures
– 700,000 vertebral fractures
– 250,000 wrist fractures
• Estimated total health care costs for hip
fractures alone
– >40 billion dollars annually
– predicted costs of 82 billion by 2025
4. DEFINITION
• Osteoporosis
– “porous bone”
– disease characterized by:
• low bone mass
• microarchitectural deterioration of bone tissue
resulting in fragility
• increased susceptibility to fracture
5. Signs and Symptoms
• “Silent disease”
– bone loss occurs without
symptoms
• Osteoporosis goes undetected
until a fracture occurs
• Vertebral collapse leads to back
pain and/or spinal deformities
such as kyphosis
6. Cortical vs. Trabecular Bone
Function Mechanical
Protective
Mechanical
Metabolic
Distribution Mainly appendicular Mainly axial
Location Outer walls Inner structure
% of adult
skeleton
80% 20%
Cortical Bone Trabecular Bone
7. Bone Remodeling
• Serves two major purposes:
– renew bone continuously
– maintain mineral homeostasis
8. Bone Remodeling
• Two sequential stages
– resorption
– formation
• Bone cells involved
– Osteoclasts-bone resorptive cells
– Osteoblasts-bone forming cells
9. Impacting Factors
• Net Bone
Resorption
– inactivity
– serum calcium
– thyroid hormone
– corticosteroids
• Net Bone Formation
– weight-bearing
exercise
– estrogen
– androgen
– growth hormone
– thyroid hormone
10. Development of Osteoporosis
• Result of 2 factors:
– peak bone mass at maturity
– rate of age-related bone loss during later life
• Balance between bone formation and
bone resorption is tipped in favor of
resorption
11. Factors Affecting Peak Bone Mass
• Nutritional factors
– calcium
– Vitamin D
– anorexia
• Environmental factors
– smoking
– excessive alcohol use
– caffeine
– medications
• Physical activity
• Hormonal factors
– amenorrhea
• Genetic factors
– gender
– race
– body structure
• Medical conditions
12. Factors Affecting Age-Related Bone
Loss
• Nutritional factors
– calcium
– Vitamin D
• Environmental factors
– smoking
– excessive alcohol use
– caffeine
– medications
• Physical activity
• Hormonal factors
– menopause
• Genetic factors
– gender
– race
– body structure
• Medical conditions
13. Bone Mass in Women
• Active growth during teens and early
twenties
• Peaks around thirty
• Slow loss observed in early forties
• Rapid loss observed following
menopause
• Continuing loss throughout seventies
and eighties
14. Major Risk Factors
• Race
– Caucasian and Asian highest
• Personal history of fracture as an adult
• History of fragility fracture in a first-degree
relative
• Low body weight (< about 127 lbs)
• Current smoking
• Use of oral corticosteroid therapy for more than
3 months
15. Additional Risk Factors
• Impaired vision
• Estrogen deficiency at an early age (<45 yrs)
• Dementia
• Poor health/frailty
• Recent falls
• Low calcium intake (lifelong)
• Low physical activity
• Alcohol in amounts >2 drinks per day
16. Examples of Disease States
Associated with Increased Risk of
Osteoporosis
• Eating disorders
• Gastrectomy
• Inflammatory bowel
disease
• Type 1 diabetes
• Rhuematoid Arthritis
• Stoke
• Thyrotoxicosis
• Hyperparathyroidism
• Multiple Sclerosis
• Cushing’s syndrome
17. Drugs Associated with Reduced
Bone Mass in Adults
• Aluminum
• Anticonvulsants
• Cyctotoxic drugs
• Glucocorticosteroids
• Immunosuppressants
• Lithium
• Long term heparin
use
• Long-term
progesterone
• Supraphysiologic
doses of
levothyroxine
• Total Parentral
Nutrition
19. Primary Osteoporosis
• Type I
– postmenopausal
– age 55-70
– fracture sites:
• spine
• distal forearm
• Type II
– senile
– age 75-90
– F:M ratio 2:1
– fracture sites:
• hip
• spine
• pelvis
20. Pathophysiology of
Osteoporosis
• Type I
– estrogen deficiency leads to increased bone
resorption without increased bone formation
– “tips the balance” in favor of bone resorption,
leading to loss of bone mass
21. Pathophysiology of
Osteoporosis
• Type II
– decreased osteoblast function
– decreased calcium/Vitamin D absorption
– biochemical imbalances
– sex hormone deficiencies
After age 40 less bone is formed
than is resorbed in any given bone
mineralizing unit, thus the “balance” is
always in favor of bone loss
23. Pathophysiology of
Osteoporosis
• Type III
– drug-induced
• corticosteroids (5mg for >2 months; recent
data indicates persons on long-term inhaled
corticosteroids are also at risk
• anticonvulsants
– phenytoin
– phenobarbital
• some antineoplastics
• excessive thyroid hormone
24. Clinical Evaluation
• WHO Report of 1994
– defines osteoporosis as present if a patients bone
mineral density (BMD) is more than 2.5 standard
deviations (S.D.) below the mean BMD of young,
normal controls
– uses T-Score as the value to report the S.D. away
from this norm
– prior to WHO report, Z-score was the value used to
report the S.D. away from age-matched controls
25.
26. T-score
• Normal: BMD is within 1 SD of a “young normal”
adult (T-score at -1.0 and above)
• Low bone mass (osteopenia): BMD is between
1 and 2.5 SD below that of a “young normal”
adult (T-score between -1 and -2.5)
• Osteoporosis: BMD is 2.5 SD or more below
that of a “young normal” adult (T-score at or
below -2.5). Women in this group who have
already experienced one or more fractures are
deemed to have severe or “established”
osteoporosis.
27. Clinical Evaluation
• 1994 WHO report
– emphasized that fractures are NOT diagnostic
and are a consequence of the disease
– emphasized that determination of a patient’s
BMD is the only way to diagnose and monitor
osteoporosis
28. Bone Mineral Density
• BMD is the single most accurate predictor
of fracture risk
– fracture risk increases 50-100% for each S.D.
decrease in BMD
– in the elderly, the risk for falls is also
important to consider
29. Bone Mineral Density
• Currently no national recommendations
exist that specify the technique or the site
by which bone mineral density should be
measured.
• Peripheral vs. Central
– peripheral for screening?
– central for diagnosis and monitoring?
30. When is Bone Densitometry
Warranted?
• all women age 65 or older
• Younger postmenopausal women with 1 or more
additional risk factors for osteoporosis
• Premenopausal women with known risk factors
for osteoporosis
32. BMD Testing
• Clinical Bone Sonometry
– quantitative ultrasound
– heel
– doesn’t actually measure BMD
– estimates BMD via the Quantitative
Ultrasound Index
– highly correlated with X-ray BMD
measurements
33. BMD Testing
• Clinical Bone Sonometry
– heel bone different from Hip/Spine
– WHO classification based on Hip/Spine DEXA
– WHO classification doesn’t apply to heel
testing
– 3 categories of risk defined by heel
measurements
34. BMD Testing
Clinical Bone Sonometry:
T-score >0 = low risk
T-score 0 to -1 = moderate risk
T-score <-1 = high risk
35. Follow-up for Peripheral Scan
• Follow-up scanning should be every 1 to 2
years depending on age and T-score
• Heel testing not approved currently for
diagnosis of low BMD or monitoring of
treatment regimen.
36. Follow-up for Central Screening
• AACE Guidelines for follow-up testing based
on WHO Criteria
• Time until follow-up BMD test dependent
upon:
– Patient’s T-score
– Is patient receiving preventive therapy?
– Is patient receiving treatment therapy?
37. Follow-up for Central Screening
• T-score >-1.5 follow-up every 2-3 years
• Receiving preventative therapy follow-up
every 1-2 years until bone mass stabilizes, then
every 2-3 years
• Receiving treatment therapy follow-up
yearly for 3 years, then every 2 years after bone
mass stabilized
38. Prevention of Osteoporosis
• Two primary goals
• maximize peak bone mass in
men/women under the age of 35
• decrease bone loss in
peri/postmenopausal women
–HOW is this achieved?
• Education and awareness
• behavioral and lifestyle modification
39. Prevention of Osteoporosis
• Adequate Calcium + Vitamin D
• Weight-bearing Exercise
• Lifestyle Modification
• Fall Prevention
• Drug Therapy
40. Optimal Daily Calcium Intake
Children 4-8 800mg
9-17 1300mg
Women 19-49 1000mg
>50 1200mg
Pregnant/nursing 1000-1300mg
41. Calcium
• May be especially valuable in older
women
• Deficiency contributes to fracture risk
• Important at all ages
• Always use as adjunct to other
pharmacotherapy for osteoporosis
• Contraindications
– hypercalciuria
– kidney stones
42. Calcium
• Estimate actual daily intake
– dairy vs non-dairy food sources
– current multivitamin or supplement
• Determine recommended intake based
on patient age
• Calculate additional calcium required to
meet recommended intake
• Select appropriate calcium
supplement
43. Calcium: Important Facts
• Average absorption = 30%
• Best absorbed in acidic environment
(take with food)
• Chewable products increase
absorption
• Lactate or citrate salt may be preferred
in elderly
44. Calcium: Important Facts
• Avoid supplements derived from bonemeal,
dolomite or unrefined oyster shell (LEAD)
• Take with 8 oz liquid
• Maximum absorption 500mg/dose (take
BID/TID)
• May cause constipation, gas, or bloating
• Hypercalcemia unlikely at doses less than
1.5g/day
46. Vitamin D
• Necessary to maintain normal serum
calcium levels
– increases intestinal calcium absorption
– increases bone resorption
• Adults under age of 50
– 400-800IU
• 50 and older
– 800-1000 IU
47. Vitamin D
• Elderly at increased risk for mild deficiency
– reduces exposure to sunlight
– decreased intake of fortified dairy products
– decreased intestinal absorption of Vitamin D
from other dietary sources
• fish, liver, eggs
• fortified cereals
48. Vitamin D
• Assess Vitamin D intake:
– dietary sources
– sun exposure
• Adequate sun exposure is 5-15 minutes of sun on
lower arms, face and neck approximately 2-3 times
a week
49. Isoflavones
Found in soybeans
Include lignans and coumestans
May increase BMD and also have estrogenic
properties
Ipriflavone (e.g. Bone Strength Formula
from GNC), a synthetic isoflavone, has been
shown to have beneficial properties of
increasing BMD without the estrogenic
effects.
50. Weight-bearing Exercise
• Prevention of bone loss
• Improves muscle tone & decreases falls
• Resistance training:
2 x per week for 40 minutes
3 x per week for 35 minutes
4 x per week for 30 minutes
51. Weight-bearing Exercise
• Best bets include jogging, jumping rope,
hiking, and aerobics
• Walking, dancing, and cross country skiing
are less effective but still beneficial
• Swimming and biking not very effective
53. Fall Prevention
• Risk factors for falls
– certain neurological conditions
– certain cardiovascular conditions
– impaired cognition and balance
– poor vision
– foot-associated problems
– medications that slow reflexes and decrease
coordination
– environmental hazards
54. Fall Prevention
• Fall Prevention checklist
– common sense
– check vision
– check for postural hypotension and arrhythmia
– review drug therapy
– check for appropriate footwear
– check environment for hazards
55. Medications to Prevent Bone Loss
• Estrogen Replacement Therapy
• Raloxifene (Evista)
• Bisphosphonates:
Alendronate (Fosamax)
Risedronate (Actonel)
• Calcitonin (Miacalcin)
57. When to Treat?
• Patients with hip or vertebral fractures.
• Patients with BMD T-scores ≤ -2.5 at the
femoral neck or spine
• Postmenopausal women and men age 50
and older with osteopenia at the femoral
neck or spine and a 10-year hip fracture
probability ≥ 3% or a 10-year major
osteoporosis-related fracture probability ≥
20% based on FRAX® score
58. When to Treat?
• Frax Score
– 10-year hip fracture probability and 10-year major
osteoporosis-related fracture probability
– http://www.shef.ac.uk/FRAX/
59. Estrogen Replacement Therapy
• Historically has been the mainstay of therapy
for postmenopausal women without
contraindications
– Up to 20% of bone mass can be lost in first 5-7
years following menopause
• Data from WHI has brought ERT under
scrutiny
• SEE WHI ARTICLE ON BLACKBOARD
60. ERT
• Effects of ERT
– decreased bone loss
– increased bone density of spine/hip
– decreased risk of hip/spine fractures
61. ERT
Mechanism of Action
– specific estrogen receptors identified on osteoblasts,
osteoclasts and macrophages; stimulation of estrogen
receptors leads to:
• decreased bone resorption
• increased calcitriol concentrations
• increased intestinal calcium absorption and
calcium retention
62. Additional Benefits of ERT
• Decreased signs and symptoms of menopause
– decreased hot flashes
– improved memory
– improved mood and energy level
– maintenance of genitourinary structure and function
• decreased vaginal atrophy
• decreased UTIs
66. Contraindications to ERT
• Estrogen-dependent breast cancer
• Active liver disease
• Abnormal genital bleeding
• Current thromboembolic disease
• History of thromboembolic disease
– during pregnancy
– during COC therapy
• Hx of cardiovascular disease
68. Risks of ERT
• Endometrial Cancer
– unopposed ERT for >6 months increase risk
for endometrial cancer by 10X
– addition of progestin to therapy for 10-14 days
a month returns risk to baseline
69. Risk of ERT
• Patients s/p hysterectomy will not require
combination therapy with progestin
• All others on ERT should receive therapy
with both estrogen and progestin to
minimize risk of endometrial cancer
70. Risks of ERT
• Breast Cancer
– controversial
– short-term users appear to NOT be at
increased risk
– long-term users (15-20 years therapy) may
have increased risk; more data needed to
determine relative risk
71. Risks of ERT
• Breast Cancer
– New data suggests that persons taking a
combination of ERT and Progestin are at
much higher risk for breast cancer than
those taking ERT alone
– ??? Is synthetic progestin the culprit ???
– Increased risk may not be observed in
patients using natural progesterone in
combination with ERT
72. Risks of ERT
• Increased mortality from cardiovascular
disease
73. Considerations with ERT
• Stress compliance
– most common reasons for D/C are breast tenderness
and vaginal bleeding
• Stress benefits over adverse effects
• Stress importance of adequate
calcium/Vitamin D intake
• Stress importance of other lifestyle changes
74. Raloxifene (Evista)
• A Selective Estrogen Receptor Modulator
or “SERM”
• Works by binding to and activating specific
estrogen receptors on bone and other
tissues
• Has antagonist effects at select estrogen
receptors
75. Effects of Raloxifene
• Increases in bone mass
• Decreases in spine fractures recently
reported
• Decreases in risk of breast cancer
• Decreases in serum lipids
76. Raloxifene
• Recommended Dose
– 60 mg QD for prevention & treatment of
osteoporosis
– 60 - 120 mg QD for prevention of breast
cancer
77. Adverse Effects of Raloxifene
• Common
– hot flashes
– leg cramps
• Rare
– thromboembolism
79. Considerations with Raloxifene
• Stress compliance
• Stress benefits over adverse effects
• Stress importance of adequate
calcium/Vitamin D intake
• Stress importance of other lifestyle changes
80. Alendronate
• Classified as a bisphosphonate
• Mechanism of action:
– decreased activity of osteoclasts leads to a
decrease in bone resorption
– decreased bone resorption in face of
unchanged rate of bone formation “tips the
balance” in favor of bone formation
81. Effects of Alendronate
• Decreased bone loss
• Increased bone density of spine and hip
• Decreased risk of both spine and hip
fractures
82. Alendronate (Fosamax)
• Used for both prevention and treatment of
osteoporosis
– 5 mg daily or 35 mg weekly for prevention
– 10 mg daily or 70 mg for treatment
• 70mg Alendronate plus 2800 IU of vitamin D3 also
available
83. Alendronate (Fosamax)
• Used for the treatment of glucocorticoid
induced osteoporosis
– 5 mg daily for men and woman
– 10 mg daily for postmenopausal women not
receiving estrogen
• Renally eliminated
• Use caution if patient has renal impairment
84. Dosing Instructions
• Take dose first thing in the AM, at least 30 minutes
before eating
• Take dose with a full glass of water (8 oz)
• Remain upright for at least 30 minutes to avoid reflux
and esophageal irritation
• Do not take any other medications for at least 30
minutes
• If miss AM dose, skip daily dose and resume next AM
85. Adverse Effects of Alendronate
• Common
– dyspepsia
– heartburn
• Uncommon
– abdominal pain
– nausea
– flatulence
– esophageal irritation
• Rare
– esophageal ulceration
– esophageal stricture
– Osteonecrosis of the
jaw
86. Considerations with Alendronate
• Stress compliance, especially with dosing
instructions
• Stress benefits over adverse effects
• Stress importance of adequate
calcium/Vitamin D intake
• Stress importance of other lifestyle changes
• detrimental long-term effects on bone
structure??
87. Risedronate (Actonel)
• Classified as a bisphophonate
• Used for prevention & treatment of
postmenopausal osteoporosis/
glucocorticoid-induced osteoporosis
– 5mg daily or 35mg weekly or one 75 mg
tablet taken on 2 consecutive days once a
month (total of 2 tablets/month) or 150 mg
once a month .
• Dosing instructions same as
alendronate
• Renally eliminated
88. Considerations with
Risedronate
• Use caution if patient has renal
impairment
• Gastrointestinal irritation/ diarrhea most
common adverse effects
• Compliance to same dosing
instructions as alendronate can
minimize GI ADR’s
• Maximal absorption achieved if taken
on empty stomach
89. Considerations with
Risedronate
• Stress compliance, especially with dosing
instructions
• Stress benefits over adverse effects
• Stress importance of adequate calcium/
vitamin D intake
• Stress importance of other lifestyle
changes
90. Alendronate vs Risedronate
• Both bisphosphonates have poor
bioavailability, which decreases further if
taken with food, coffee, or juice
• Taking on empty stomach is essential for
both medications
91. Ibandronate (Boniva)
• Bisphosphonate
• Efficacy in clinical trials similar to other
bisphosphonates
• Oral dosage forms
– 2.5mg po daily
– 150mg po once monthly
• IV oral dosage forms
– 3mg every 3 months
– Injection given IV over 15-30 seconds
• Similar side effect profile to other
bisphosphonates
92. Calcitonin (Miacalcin)
• Salmon calcitonin nasal spray
• Approved for treatment of osteoporosis
in women who:
– are at least 5 years postmenopausal
and
– Refuse or cannot tolerate other therapies
93. Effects of Calcitonin
• Slows bone loss
• Increases spinal bone density
• Decreases risk of spine and hip fractures
(only proven with nasal route)
• Relieves pain associated with fractures
94. Calcitonin
• Mechanism of Action
– acts as an antiresorptive agent
– has direct inhibitory effect on osteoclast
activity
• decreased osteoclast attachment, mobility and
lifespan observed
95. Calcitonin (Miacalcin)
• Dosing
– 200 IU daily equivalent to 1 spray in 1 nostril
daily
– alternate nostrils to minimize irritation
• Adverse Effects
– nasal irritation
– runny nose
96. Considerations with Calcitonin
• Length of time patient has been post-
menopausal
– no significant effects observed in women less than 5
years
• Stress importance of compliance
• Stress importance of adequate calcium/Vit D
intake
• Stress importance of lifestyle changes
97. Considerations with Calcitonin
• “Escape phenomenon”
– patients become refractory to therapy after prolonged
treatment
– due to down-regulation of calcitonin receptors
– intermittent therapy (one year on/one year off) may
circumvent down regulation
99. Teriparatide (Forteo)
• Recombinant human parathyroid hormone
– primarily to produce new bone by increasing the
number and action of osteoblasts.
– It is identical in structure to amino acids 1 – 34 in the
active portion of human parathyroid hormone (PTH)
and thus induces the same effects as endogenous
PTH.
– PTH is primary regulator of calcium and phosphate
metabolism in bone and kidney, with physiologic
effects including the
• regulation of bone metabolism
• renal tubular reabsorption of calcium and phosphate
• intestinal calcium absorption.
100. Teriparatide (Forteo)
– PTH and teriparatide stimulate both
osteoblast and osteoclast function
• effects on the skeleton depend upon the pattern of
exposure.
– Once-daily or intermittent administration of teriparatide
results in new bone formation by preferentially
– continuous exposure to endogenous PTH may produce
detrimental effects on the skeleton because osteoclast
activity and bone resorption may predominate.
101. Teriparatide (Forteo)
• Indications
– postmenopausal women who are at high risk of
fracture
– increase bone mass in men with primary or
hypogonadal osteoporosis who are at high risk for a
fracture.
– high risk for fracture =
• history of osteoportoic fracture
• those with multiple risk factors for fracture
• those who have failed or are intolerant to previous
osteoporosis therapy.
102. Teriparatide (Forteo)
• Effectiveness
– Decreases vertebral fractures by 65% and
non vertebral fractures by 54%
• Dosage
– 20 mcg subcutaneous injection once daily
• Supplied in pen injectable device
103. Teriparatide (Forteo)
• Safety
– Black Box Warning
• Osteosarcoma found in rat studies
– No cases in humans
– Avoid use in patients at risk for osteosarcoma
» Paget’s disease
» Prior radiation
» Unexplained elevation in Alk Phos
» Other bone disease
» Children
– Adverse effects
• Leg Cramps
• Dizziness
• Orthostatic hypotension
• Hypercalcemia
104. Teriparatide (Forteo)
• Patient Info
– Must store pen syringe in refrigerator
– Teach patient how to give injection
• Thigh or abdomen
• Rotate injection sites
• Sit or lay down to minimize orthostatic hypotension
105. Premenopausal Osteoporosis
• Combination Oral Contraceptive indicated
for prevention of osteoporosis in women of
child-bearing potential
• Adequate Calcium/Vitamin D necessary
• Bisphosphonates teratogenic
• Raloxifene contraindicated in pregnancy
