Overview of OP Final Presentation

1. Overview of Osteoporosis

2. Definitions of
Osteoporosis
Albright F.Ann Intern Med.1947;27:861.
*Images used with permission of David Dempster, PhD. Copyright 2001
Normal Bone* Osteoporotic Bone*
 Old definition:
Todistinguish osteoporosis from osteomalacia
 A reduced amount of bone that is qualitatively normal
 Osteomalacia = normal amount of bone that is inadequately
mineralized

3. Definitions of
Osteoporosis
Normal Bone* Osteoporotic Bone*
• Modern definition (circa 1991):
Introduces the concept of bone quality
 A systemic skeletal disease characterized by low bone mass and
micro-architectural deterioration of bone tissue with a
consequent increase in bone fragility and susceptibility to
fracture.*
*Consensus Development Conference: Diagnosis, Prophylaxis, and Treatment of
Osteoporosis. Am J Med. 1991;90:107. *Images used with permission of David
Dempster, PhD. Copyright 2001

4. Newest Definition of Osteoporosis
NIH Consensus Conference
 Osteoporosis is a skeletal disorder characterized by
compromised bone strength predisposing to an
increased risk of fracture
 Bone strength reflects the integration of two main
features:
 Bone density
 Bone quality
NIH Consensus Development Panel. JAMA. 2001;285:785.
There are no symptoms from low bone mass unless fracture occurs

5. Osteoporosis Can be Defined by the
Presence or History of a Fragility
Fracture

6. Functions of the Skeleton
 Supports the body
 Protects internal organs
 Muscles attached for movement
 Cavities for blood formation
 Reservoir for minerals
Pathophysiology of Osteoporosis

7. DXA Terminology:
The Skeleton Has Different Regions
• Central skeleton (axial skeleton plus
hips and shoulders):
 Spine, ribs, pelvis, hips, shoulders
• Peripheral skeleton (appendicular
skeleton minus hips and shoulders):
 Extremities (arms and legs)

8. Different Skeletal Regions Have
Different Type of Bone
 Cortical or compact bone
makes up the outer envelope
of all bones and the shafts of
the long bones (appendicular
skeleton)
 Cancellous or trabecular
bone makes up the inner
parts of the bones,
particularly bones of the axial
skeleton
Cortical Bone
Trabecular Bone
Periosteum
Haversian canal
Canaliculus
Nerve
Artery
Venous sinus
Endosteum

9. Cancellous and Cortical Bone Differences
in
Mass, Surface Area and Turnover
*Up to 10% of the adult skeleton is being remodeled at
any one time (remodeling rates can be affected by age
and diseases)
Mass
Surface
area
Turnover
each year*
Cancellous 20% 80% 25%
Cortical 80% 20% 3%
Parfitt M, Osteoporosis 2nd ed; 2001, 433-447

10. Bone Modeling and Remodeling
• Modeling: Change in size and shape of
bone during growth
• Remodeling: Mature bone is renewed
through a process called remodeling
 Involves replacement of old bone with new
bone
 Occurs in response to fatigue damage,
micro-fractures, and other factors

11. Bone Remodeling
Cycle
Adapted from Watts NB. Clin Chem.
1999;45:1359.
Resting / quiscent
7
Resorption:
Osteoclasts
7-10 days
Formation:
Osteoblasts
10-12 weeks
Mineralization
Activation

12. Peak Bone Mass
 Peak bone mass is the maximum bone mass or
density achieved during a lifetime
 It is reached when the growth in the size of
bones and accumulation of bone mineral has
stabilized (consolidation)
 Different skeletal sites peak at different times
 Trochanter BMD: Mid-teens (14.2  2.0)
 Femoral neck BMD: Late teens (18.5  1.6)
 Spine BMD: Early 20s (23.0  1.4)
Lin Y-C et al, Bone. 2003;32:546.

13. Factors Influencing Peak Bone Mass
 Heredity/Genetics (~60-80%)
 Gender
 Nutrition
 Energy intake
 Protein intake
 Calcium intake
 Vitamin D
 Endocrine factors
 Sex steroids
 Calcitriol
 GH─IGF-1 axis
 Mechanical factors
 Physical activity
 Body weight
 Smoking
 Alcohol
 Other factors
Rizzoli R. et al, J Molec Endocrinol. 2001; 26:79
Eisman J, Endocrine Rev, 1999; 20:788-804

14. 10 20 30 40 50 60 70 80 90
1.2
1.0
0.8
0.6
Changes in Bone Density with Age
Spine BMD
by DXA
(g/cm2)
White Women
Increase with adolescence
Peak bone mass
Plateau maintained
Age-related bone loss (~0.5%-1.0% per year)
Bone loss accelerates with
menopause (~1%-2% per year)
Age-related bone loss
resumes
Eventually back to
pre-adolescent levels
Age (years)
7

15. Influence of Gender on BMD
Adapted from A. Looker et al. Osteoporos Int 1998;8:468–489
White Men
White Women
Age (years)
1.5
1.0
0.5
Spine BMD
by DXA
(g/cm2)
On average, men have higher BMD as
measured by DXA than women
10 20 30 40 50 60 70 80 90

16. Cancellous and Cortical Bone Loss Occurs
at Different Times and Different Rates
Adapted from Watts NB. Am Fam Physician. 1988;38:193
Wrist
Fractures
Spine
Fractures
Hip
Fractures
Age
Percent
of peak
bone
mass

17. Trabecular Bone – Age Related Loss
Differs Between Men and Women
Adapted from Seeman E., J Appl Physiol 2003; 95:2142
Women
Resorption >> Formation
Men
Resorption > Formation
Perforation Thinning

18. Summary: Bone Mass and Bone
Loss
 Women have lower peak bone mass than men
 Whites have lower peak bone mass than
blacks
 Bone loss occurs
 With advancing age
 Because resorption is greater than formation
 As bone loss occurs, there is loss of quality as
well as quantity

19. Osteoporosis Prevalence and
Incidence Worldwide
 Prevalence: Over 200 million people
worldwide have osteoporosis
 Incidence: Hip fractures projected to increase
substantially by 2050:
 240% in women
 320% in men
 Even if no increase in the age-adjusted hip
fracture rate, the number of hip fractures will
increase from 1.7 million in 1990 to 6.3 million
in 2050
www.iofbonehealth.org/health-professionals/about-
osteoporosis/epidemiology.html

20. Projected Worldwide Increase in Hip
Fracture Number
Adapted from C. Cooper et al, Osteoporos Int. 1992;
2:285-9
1990
400
668
2050
1990
378
742
2050
1990
100
629
2050
600
3250
1990 2050
Projected to reach
3.25 million in Asia by
2050
Estimated number of hip fractures: (1000s)
Total number of
hip fractures:
1950 = 1.66 million
2050 = 6.26 million

21. Types of Fracture
 Traumatic fracture
 Pathological fracture
 Stress fracture
 Osteoporotic fracture* (sometimes called
fragility fracture or low-trauma fracture)
*Fracture occurring with minimal trauma, such as force equal to or
less than falling from standing height

22. Bimodal Distribution Of Fractures
Garraway WN et al. Mayo Clin Proc 1979; 54:701-707
© Mayo Clinic Foundation, used with permission
Annual
Incidence
of limb
fractures
per 100,000
population
Age (years)
Females
Males
0
800
1600
2400
3200
4000
0-4 5-14 15-24 25-34 35-44 45-54 55-64 65-74 75-84 >85
Second peak in older age
Females >> males
Mostly low trauma
Peak in adolescence
Males >> females
Mostly long bones, trauma

23. Pathogenesis of Osteoporotic Fracture
Adapted from Melton LJ & Riggs BL. Osteoporosis: Etiology, Diagnosis and Management
Raven Press, 1988, pp155-179
Age related
bone loss
Low peak
bone mass (PBM)
Poor bone
quality
(architecture)
Non skeletal
factors
(propensity to fall)
Postmenopausal
bone loss
FRACTURE =
Fall + Low BMD
LOW BONE MASS
Other risk
factors
LOW BMD = PBM or Loss

24. Type of Fall Affects Fracture Site
Images are courtesy of Eis, IFR, 2011
O’Neill, Ann Rheum Dis, 53;773-775, 1994
• Younger
• Intact protective
mechanisms
• Fall on hand
• Forearm fracture
• Older
• Compromised protective
mechanisms
• Fall on side
• Hip fracture

25. Vertebral Fractures
 Most common osteoporotic fracture (~550,000
per year)
 Vertebral fracture is a marker for future
fracture risk*
 Many occur with every-day activities (lifting,
pushing, pulling, etc)
 Only 25% to 30% of vertebral fractures seen on
x-ray are diagnosed clinically
 Patients with clinical vertebral fractures may
have severe pain and are confirmed with x-ray
*Klotzbuecher CM, et al. J Bone Miner Res.
2000;15:721.

26. Vertebral Fractures
Images adapted from Watts NB. Am Fam Phys. 1988;38:193.
© American Family Physician, used with permission
Graph modified from Cooper C et al. Trends Endocrinol Metab. 1992;3:224.
Wedge
Endplate
Crush
Normal
Incidence/1,000,000
person-years 0
1000
2000
3000
40 60 80
4000
Women
Men

27. Consequences of
Vertebral Fractures
 Back pain
 Loss of height
 Deformity (kyphosis, protuberant abdomen)
 Reduced pulmonary function1
 Diminished quality of life (loss of self-esteem,
distorted body image, dependence on narcotic
analgesics, sleep disorder, depression, loss of
independence)2
 Increased mortality
1Harrison, et al. J Bone Miner Res. 2007;22:447-457.
2Gold, et al. Rheum Dis Clin North Am. 2001;27:255-262

28. Hip Fractures
 2nd most common osteoporotic fracture
 Approximately 1.6 million per year worldwide (2000)
 Estimated to increase to 6.3 million annually by 2050
 Hip fracture is a marker for future fracture risk*
 Most are caused by fall from standing height
 Only about 5% are “spontaneous”
 Only 1% of falls lead to hip fracture
 Diagnosis
 Most are diagnosed clinically
 Often confirmed with radiography
 Most are hospitalized and require surgery
*Klotzbuecher CM, et al. J Bone Miner Res. 2000;15:721
Cooper C, et. al, Osteoporos Int, 22; 2011:1277-88

29. Hip Fractures
Graph modified from Cooper C et al.
Trends Endocrinol Metab. 1992;3:224.
Femoral Neck
~40%
Intertrochanteric Region
~40%
Incidence/1,000,000
person-years
0
2000
1000
3000
40 60 80
4000
Women
Men

30. Complications of Hip
Fracture
 Up to 24-30% excess mortality within 1
year1,2
 Nearly 65,000 American women die from
complications of hip fracture each year3
 ~50% of hip fracture survivors are
permanently incapacitated4
 ~20% of hip fracture survivors require long-
term nursing home care5
1 Ray NF et al. J Bone Miner Res. 1997;12:24.
2 Kiebzak GM et al Arch Intern Med. 2002; 162:2217.
3 Col NF et al. JAMA. 1997; 227:1140.
4 Consensus Development Conference. Am J Med. 1993;94:646.
5 Chrischilles EA et al. Arch Intern Med. 1991;151:2026.

31. Distal Forearm Fractures
 Third most common osteoporotic fracture (~250,000/year)
 Prior forearm fracture is a marker for future fracture1
 Most are caused by fall on outstretched hand
 Most are diagnosed clinically and usually confirmed with
radiography
 Complications
 Pain
 Temporary disability; difficulty dressing, toileting, meal preparation
 Degenerativearthritis
 Complex regional pain syndrome (reflex sympathetic dystrophy syndrome)
 Six months after fracture, 23% report fair to poor recovery in functional
outcome2
1Klotzbuecher CM, et al. J Bone Miner Res.
2000;15:721.
2Kaukonen JP et al, Ann Chir Gynaecol. 1988;77:27.

32. Distal Forearm Fractures
Graph adapted from Cooper C, et al.
Trends Endocrinol Metab. 1992;3:224.
Incidence/1,000,000
person-years
2000
1000
0
40 60 80
4000
Women
Men
3000

33. Patients With Prior Fracture
Are at High Risk for Future
Fragility Fractures
Klotzbuecher CM et al. J Bone Miner Res. 2000;15:721.
Relative Risk of Future Fractures
Prior Fracture Wrist Vertebra Hip
Wrist 3.3 1.7 1.9
Vertebra 1.4 4.4 2.5
Hip NA 2.5 2.3

34. www.share.iofbonehealth.org/WOD/2012
Fractures Reduce Not Only Quantity
But Also Quality of Life

35. In Summary: Hip Fractures Have a
Devastating Toll
 Mortality rate same as breast
cancer
 ~20% excess mortality in the
first year (higher for men)
 ~50%incapacitation
 ~20% of women need assisted
living or nursing home
 ~80% of older adults preferred
death to living in a nursing
home
Cooper C, et. al., Am J Epidemiol 1993;137:1001

36. Cost of Osteoporosis in
USA
(US Dollars)
Adapted from Burge, et. al., J Bone Min
Res 2007; 3:465-475.
$16.9 Billion
Long-term
care
Total Annual Cost
In-patient
$5.1 billion
(30%)
$9.6 billion
(57%)
$2.2 b
(13%)
Outpatient

37. Clinical Utility of Bone
Densitometry (DXA)*
 Diagnosis
 WHO T-scoreclassification
 Prognosis
 Facilitates fracture riskassessment
 Monitoring
 Requires knowledge of precision and least
significant change (LSC)

38. WHO Classification for
Postmenopausal Osteoporosis
World Health Organization. Technical Report Series 843; WHO, Geneva.1994.
Kanis JA et al. J Bone Miner Res. 1994;9:1137.
The T-score compares an individual’s BMD with the mean value for young
normals and expresses the difference as a standard deviation score
T-score (SD)
Normal Equal to -1.0 or higher
Low Bone Mass (Osteopenia) Between -1.0 and -2.5
Osteoporosis Equal to -2.5 or lower
Severe Osteoporosis Equal to -2.5 or lower with fracture

39. Limitations of 1994 WHO
Classification
• Not intended as treatment guidlines
• Definitions do not necessarily apply to other populations
(e.g., men, non-caucasians, premenopausal women)
• Does not recognize that a presumptive diagnosis of osteoporosis can be
made by a low trauma (Fragility) fracture regardless of the patient’s
BMD
• Does not differentiate between osteoporosis and other causes of low
BMD

40. T-score Equal to or Lower than -2.5 is
Not Always Due to Osteoporosis

41. Examples of Non-Osteoporotic
causes of Low BMD
• Osteomalacia
• Genetic disorders, e.g. osteogenesis imperfecta
• Renal bone disease
• Multiple myeloma/other malignancies
• Marrow infiltrative diseases, e.g., mastocytosis

42. Why the WHO choose a T-Score of
-2.5
Kanis JA, et al. J Bone Miner Res. 1994; 9:1137
“Such a cutoff value identifies approximately 30% of postmenopausal
women as having osteoporosis using measurement made at the spine,
hip or forearm. This is approximately equivalent to the lifetime risk of
fracture at these sites.”

43. Advantage of T Score instead of
BMD
• If there were only one type of densitometer and one skeletal site to
measure bone density, absolute BMD criteria would be preferable
• Multiple devices exist that use different approaches to BMD
measurement
• Theoretically, T-score provides a way of using the same diagnostic
criteria for all devices and skeletal sites

44. Caveats of Diagnosis Based
on BMD
 Diagnosis of osteoporosis by DXA is based on the
WHO classification as a T-score of -2.5 or below
 Some patients with T-score –2.5 or below do not
have osteoporosis
 Some patients with T-score above –2.5 may be
diagnosed with osteoporosis
 T-scores may differ at different skeletal sites
 Patients with a diagnosis of osteoporosis may have
substantially different fracture risk
 Diagnosis of osteoporosis does not explain etiology

45. Clinical Management: Non-
Pharmacologic, Estrogen & SERM
Treatment

46. Evolution in osteoporosis
Assessment
 Prior to 1987; x-ray, SPA and DPA
 1987: DXA – current diagnostic
standard
 1990s – to present:
Vertebral fracture assessment
Body composition
Strength/structure analysis
- HAS (Hip Structural analysis)
- FEA (Finite element analysis)
- TBS (Trabecular bone score)
- HRpQCT (High resolution peripheral quantitative
CT)

47. Advances in Osteoporosis -
Medications
1984: Estrogen
1986: sc calcitonin
1990: etidronate
1995: alendronate, nasal calcitonin
1999: raloxifen
2000: risedronate
2002: teriparatide
2003: strontium ranelate
2005: ibandronate
2007: zoledronic acid IV
2010: denosumab
2011: bazedoxifene
Approval for osteoporosis
treatment varies by country

48. Despite Major Advances in Diagnosis and Therapy, Most Patients
with Osteoporosis Receive No Evaluation or Treatment: Even
Patients Who Have Had a Fragility Fracture

49. Literature Review: Treatment of
Osteoporosis After Fragility fracture
• 37 articles 1/94-1/03
• Treatment
Calcium 8-62% (median 18%)
HT 0.5-55% (median 10%)
SERM <4%
Bisphosphonate 0.5-38% (6 studies>10%)
Elliot-Gibson Osteoporos Int 2004;15:767-778

50. Prevention and Treatment Goals
• Decrease fracture risk
- Stabilize or increase bone mass
- Maintain or improve bone quality
- Prevent falls
• Fracture management
- Relieve pain
- Stabilize fracture and restore anatomy
- Manage co-morbidities
- Restore level of function
- Psychosocial support

51. Non-Pharmacological Therapy
NOF Recommendations
• Adequate intake of dietary calcium and vitamin D
Calcium: 1200mg/day for women age 51+ and men age 71+
- No evidence that taking more than 1200-1500mg/day is beneficial
- Increasing dietary calcium is the first line approach
Vitamin D: 800-1000 IU/day f or adults 50+
- many patients will need more
• Regular weight-bearing and muscle strengthening
exercises
• Avoidance of smoking and excess alcohol
• Fall prevention
NOF Guide 2013 www.NOF.org

52. Prevention of Falls
• Correct visual and hearing
impairment
• Optimize medications
• Bathroom grab-bars and nonskid
mats
• Avoid throw-rugs and slippery
mats
• Keep electic and telephone cords
away
Michael, YL, et., AHRQ Publication # 11-05150-EF-1, Dec 2010
• Reduce clutter from walking
areas
• Nightlight in bedroom and
bathroom
• Handrails on steps and stairs
• Walking aids, if needed
• Exercise for strength and balance
(Tai Chi)

53. Recommended Calcium Intake per
2010 IOM Report
RDA (mg) Upper limit (mg)
9-18 (boys/girls) 1300 3000
Women 19-50 1000 2500
Pregnancy No adjustments
Women over 50 1200 2000
Men 19-50 1000 2500
Men 50-70 1000 2000
Men over 70 1200 2000
Institute of Medicine 2011 Dietary reference intakes for calcium and
vitamin D. Washington, DC: The national Academies Press

54. Recommended Vitamin D Intake per
2010 IOM Report
• Practically all persons are sufficient at 25-OH vitamin D levels of
20ng/ml(50nmol/L) or above
• No consistent evidence for extra skeletal benefit above a level of
20ng/ml
• Levels between 20-50 ng/ml appear to be safe
• RDA to cover 97.5% of the population
0-12 months 400 IU daily
1-70 years old 600 IU daily
Over 70 years old 800 IU daily
Institute of Medicine 2011 Dietary reference intakes for calcium and
vitamin D. Washington, DC: The national Academies Press

55. AACE Response to IOM Report
• “ …it would be appropriate to use a range from 30-50 ng/ml (75-100
nmol/L) for most patients as an optimal and safe range.”
• “For many patients, 1000-2000 IU of vitamin D daily is required to
maintain a 25(OH)D level at 30 ng/ml (75 nmol/L) or above.”
• “For now, it is important to use the recommendations in conjunction
with clinical judgement to determine the proper vitamin D requirement
for any given patient.”
www.aace.com/alert/alert11302010.php

56. Summary: Calcium and Vitamin D
• Low calcium intake and vitamin D deficiency should be corrected in all
patients
• Hip fractures occur often in patients aged > 75-80 years and this
population is particularly prone to calcium and vitamin D deficiency
• In patients with low calcium intake, calcium alone induces small increase
in bone mineral density and possibly reduces fracture incidence
• Low dose vitamin D (400 IU/d) alone did not reduce fracture incidence in
a free living population

57. FDA-Approved Medications
Drug PMO
Prevention Treatment
GIO
Prevention Treatment
Men
Estrogen +
Calcitonin +
Alendronate + + + +
Risedronate + + + + +
Ibandronate + +
Zoledronic acid + + + +
Raloxifene + +
Denosumab + +
Teriparatide + + +

58. Raloxifene
• Class: antiresorptive, selective estrogen receptor modulator
• BMD: increases at spine and hip
• Bone turnover markers: decreased
• Fractures: reduces risk of vertebral fractures, no proven benefit for hip
or non vertebral fractures
• Extraskeletal: reduces risk of breast cancer, does not reduce hot flashes,
VTE risk, leg cramps, does not stimulate endometrium.

59. The Heart (RUTH) Trial (10,000+ patients with 5+ year follow up): RLX had no
significant effect on the risk of coronary events(HR 0.95). There were no
differences in overall stroke risk, but raloxifene was associated with an increased
risk of fatal stroke (HR 1.49; absolute risk increase 0.7 per 1000), and venous
thromboembolism (HR 1.44; absolute risk increase 1.3 per 1000

60. Clinical Management Part:
Pharmacologic Treatment

61. Osteoporosis - Treatment
 Ideal treatment:
 Increase bone mass
 Improve bone architecture and strength
 Reduce the risk of fracture

62. How Do Osteoporosis Medications
Work?
Anti-resorptive
Alter quality
Anabolic
Extra-skeletal
e.g. reduce falls
The Result of
These Changes is
That Fracture Risk
is Reduced

63. Aging and Bone Loss
 Negative balance at remodeling site =
structural basis of bone loss and
progressive erosion of skeletal architecture
characterized by:
 Cortical thinning
 Intracortical porosity
 Trabecular thinning
 Loss of connectivity

64. Bisphosphonates: Alendronate, Risedronate,
Ibandronate, Zoledronic Acid
 Class: antiresorptive
 BMD: increases BMD at various skeletal sites
 Bone turnover markers: decreased
 Fractures: reduces risk of fractures
 Extra-skeletal considerations
 Specific dosing requirements
 Interval and IV/oral dosing available
 Occasional GI irritation
 Infrequent – musculoskeletal pain
 Very rare - hypocalcemia, osteonecrosis of jaw, atypical femoral fracture
 Effect on bone resorption persists after discontinuation
 Unique to bisphosphonates
Russell RG. Bone 2011; 49, 2-19

65. Bisphosphonates Structure and
Function OH enhances binding to OH-Apatite
O = P - C - P = O
HO OH
OH
OH
HO
R2
P-C-P essential for action
R2 side chain determines potency
P-C-P = bone hook
R2 = -CH3 : Etidronate
R2 = -CH2CH2CH2NH2 : Alendronate
R2 = -CH2CH2NH2 : Pamidronate
……
……

66. Bisphosphonates
Mechanism of Antifracture Efficacy
B.L.Riggs and M.Parfitt J Bone Miner Res.
2005;20:177
Refilling
Remodeling space
Mineralization 
Remodeling
balance positive
Prevents microstructural damage
• trabecular plate perforation
• loss of trabeculae
• resorption “stress risers“
Increase BMD
• trabecular + to ++
• cortical 0 to +
Preservation of
architecture
Fracture risk 
Bone
remodeling


67. Bisphosphonate are Antiresorbers,
Increase
BMD and Reduce Fracture Risk
Spine
Bone
Turnover
Bone
Mineral
Density
Time Time
Femur
BR
BF
Fracture
Rate
PreMP Range
Rapid decrease in bone
resorption (BR), followed by a
decrease in bone formation (BF)
Refill remodeling space +
secondary mineralisation 
 Increase in BMD spine > hip
Reduction in
fracture risk
HOWEVER: trabecular thickness does not increase

68. Reduction of Vertebral Fracture
Risk
1Black DM, et al. N Engl J Med. 2007;356:1809-1822.
2Harris ST, et al. JAMA. 1999;282:1344.
3Actonel Prescribing Information.
4Black D, et al. J Clin Endocrinol Metab. 2000;85:4118-4124.
5Chesnut CH, et al. J Bone Miner Res. 2004;19:1241.
ZOL 5 mg1
Alendronate
(FIT)4
Risedronate
(VERT-NA)2,3
Ibandronate5
Years
0-1 0-3
0-2
Years
0-1 0-3
0-2
Years
0-1 0-3
0-2
Years
0-1 0-3
0-2
Relative
Risk
Reduction
(%)
71%
0
10
20
30
40
50
60
70
60%
70%
65%
55%
41%
62%
48%
58%
61%
52%
65%
Data not from comparative trials – no head to head comparison

69. Alendronate Also Increases BMD and
Reduces Vertebral Fracture Risk in
Males
E.Orwoll et al. NEJM 2000;343:604
0
1
2
3
4
5
6
7
8
0
1
2
3
4
5
6
7
8
ALN
Placebo
12
6 24
18
P = 0.02
Mean
BMD
Percent
Change
Lumbar Spine BMD Fracture Risk at 2 yrs
Months

70. Risedronate Efficacy in Patients with
Prevalent Vertebral Fractures
Harris ST et al, JAMA,1999;282:1344-1352
Reginster JY et al, Osteoporos Int, 2000;11:83-91
MN=Multinational;
NA=North American
Year 0-1 Years 0-3
0
5
10
15
20
25
30
%
of
patients
with
fractures
PBO
660
n =
RIS
669
PBO
334
RIS
333
PBO
678
RIS
696
PBO
346
RIS
344
-65%
p < 0.001
-61%
p < 0.001
-41%
p < 0.003
-49%
p < 0.001
NA MN NA MN
Radiological vertebral fractures

71. Risedronate Treatment Reduces Hip
Fracture Risk with in those with Osteoporosis…
McClung M et al. NEJM 2001;344:333
..but not in patients selected on the basis of clinical risk factors in this study
Incidence (%) RR p
Risedronate Placebo
Overall 2.8 3.9 0.7 (0.6-0.9) 0.02
Age 70-79 yrs
with OP 1.9 3.2 0.6 (0.4-0.9) 0.009
with vert. Fx 2.3 5.7 0.4 (0.2-0.8) 0.003
no vert. Fx 1.0 1.6 0.6 (0.3-1.2) ns
Age > 80 yrs
with > 1 clinical risk factor 4.2 5.1 0.8 (0.6-1.2) ns

72. Overall, a 35%
fracture reduction
28% reduction
in relative risk of death
Zoledronic Acid After Hip Fracture:
Reduces Clinical Fractures and Mortality
Adapted from Lyles, et. al., NEJM, 357, 1799-1809, 2007
ZA
PBO
10
5
0
Clinical Non-vertebral Hip
Mortality
(%)
Fracture
rate
(%)
10
5
0
15

73. Alendronate Increases Bone Strength by
Increasing Bone Tissue Mineralization
Completed and adapted from G.Boivin et al. Bone 2000;27:687
0.00
2.00
4.00
6.00
8.00
10.00
12.00
14.00
16.00
18.00
0.5 0.7 0.9 1.1 1.3 1.5
%
of
the
total
measurments Degree of Bone Mineralization
(g mineral/cm3 bone)
PLA
ALN
Photos used with permission of G.Boivin
Placebo ALN 3 yrs ALN 6 yrs

74. Bisphosphonates – Possible Side
Effects
 GI-Intolerance (oral)
 Hypocalcemia
 Renal dysfunction
 Segmental glomerulosclerosis (PAM)
 Tubular dysfunction – interstitial nephritis (ZOL)
 Flu-like symptoms (myalgia, arthralgia, fever)
 Common In 12-48 hours after IV dosing
 Lasts usually for 1-2 days, sometimes 1 week
 Ocular effects
 Osteonecrosis of the jaw
 Atypical fractures
Check calcium and creatinine prior to treating

75. Calcitonin Nasal Spray
 Class: antiresorptive, biologic agent
 BMD: slight increase
 Bone turnover markers: decreased
 Fractures: reduces risk of vertebral fractures,
no proven benefit for hip or nonvertebral
fractures
 Extra-skeletal considerations
 Possible analgesic effect
 Occasional nasal irritation, rarely epistaxis
 No known drug interactions

76. Nasal Calcitonin Produces Minimal BMD
Change
Adapted from Chesnut CH III, et al. Am J Med. 2000;109:267.
5-year study of 1255 women, average age 68,
with 1-5 prevalent vertebral fractures
No significant change in spine BMD in
treatment groups compared to placebo
PROOF Trial: Prevent Recurrence of Osteoporotic Fractures

77. Teriparatide: rhPTH (1-34)
 Class: anabolic, hormone
 BMD: increases at spine and hip
 Bone turnover markers: increased
 Fractures: decreases at spine and
nonvertebral, no proven benefit for hip
 Extra-skeletal considerations:
 Osteosarcoma in rats, daily subcutaneous
injection, refrigeration, hypercalcemia, leg
cramps, dizziness, high cost, limit of 2 years of
therapy

78. Intermittent PTH is Anabolic
BUT Continous PTH is Catabolic
Adapted from Dobnig et al. Endocrinology, 138: 4607-4612, 1997
0
5
10
15
20
25
30
35
Vehicle PTH (sc) PTH pump
(1h/day)
PTH pump
(2h/day)
PTH
(continuous)
Osteoblast
Perimeter
(%)
80ug/kg/day
0
5
10
15
20
25
Vehicle PTH (sc) PTH pump
(1h/day)
PTH pump
(2h/day)
PTH
(continuous)
Osteoclast
Perimeter
(%)
Programmed Infusion of PTH in Rats

79. PTH Treatment
Mechanism of Antifracture Efficacy
B.L.Riggs and M.Parfitt J Bone Miner Res. 2005;20:177
Bone
Remodleing

(formation>resorption)
Stimulated periosteal
modeling
Positive remodeling
balance
Microstructure repair
Renewed trabecular
modeling
Improved bone geometry
Increase BMD
trabecular +++
cortical ++
Improved
architecture
Fx risk 

80. Changes in Cortical Geometry and
Trabecular Architecture with PTH
Treatment
 Bone volume 
 Periosteal diameter 
 Cortical thickness 
 Porosity (near endocortical surface )
 Endocortical diameter 
 Bone volume 
 Trabecular thickness 
 Trabecular number 
 Connectivity 
M.Allen et al. Clin Rev Bone Miner Metabol. 2006;4:259

81. Teriparatide Increases BMD
Adapted from Neer RM, et al. N Engl J Med. 2001;344:1434.
RCT of 1637 women with postmenopausal osteoporosis and 1 vertebral fractures
treated an average of 18 months with placebo, 20 µg PTH (1-34)
NS
NS
P<0.001
P<0.001

82. RCT of 1637 women with postmenopausal osteoporosis and 1 vertebral fractures
treated an average of 18 months with placebo, 20 µg PTH (1-34)
Teriparatide Reduces Fracture
Risk
Adapted from Neer RM, et al. N Engl J Med. 2001;344:1434.
65%**
53%*
*P<0.02
**P<0.001

83. Effects of PTH (1-84) on
Bone Mineral Density
S.Greenspan et al. Ann Int Med. 2007;146:326
n=2532, age 64.5±7.9, T-score ≤ -3.0
-2
-1
0
1
2
3
4
5
6
7
0 6 12 18 0 6 12 18
%
Change
from
baseline
Months
Lumbar Spine Total Femur
PTH
Placebo

84. Effect of PTH (1-84) on New or
Worsened Vertebral Fractures
Adapted from S.Greenspan et al. Ann Int Med. 2007;146:326
Placebo PTH (1-84)
3.4%
1.4%
↓ RR -58%
(0.24 to 0.72)
%
of
Patients
Month 18
0
1
2
3
4
5

85. Teriparatide Treatment
Effects on Bone Microarchitecture
Y.Jiang et al. J Bone Miner Res. 2003;18:1932
Paired biopsies
BV/TV +7.2%*
Tb.Th-0.9%
Tb.N +3.3%
CD +19.1%*
Ct.Th. +22%*

86. Summary :
 The different therapeutic options include several anti-
resorptive drugs and more recently new anabolic compounds
 Bisphosphonates reduce fracture risk for vertebral and non-
vertebral fractures
 Anti-fracture efficacy is already evident after one year of
treatment
 Raloxifene (SERM) has skeletal effects similar to those of
estrogen and reduces vertebral fracture risk
 Parathyroid hormone treatment induces significant increases
in bone mass and decreases of fracture risk

87. Thank you