1. Osteoporosis Management:
the Science and the Art
Robert Lindsay, MD, PhD
Chief of Medicine
Helen Hayes Hospital
Professor of Clinical Medicine
Columbia University
New York

2. Competing Interests
• Consultant – Amgen, Eli Lilly, Azelon
• Speaker – Amgen, Eli Lilly

3. Learning Objectives
Upon completion of this educational activity, the
participant should be able to:
• Outline the signs and symptoms of osteoporosis that
warrant further evaluation.
• Delineate the risk of osteoporosis among patients of
different races.
• Describe how to utilize guideline-recommended
strategies for the prevention and treatment of
osteoporosis.
• Describe methods for improving patient adherence to
pharmacotherapies and other strategies designed to
prevent or slow the progression of osteoporosis.

4. Osteoporosis
• A serious and common disease that
causes (through fractures) significant
mortality and high morbidity
• Despite that, only about 21% of Medicare
hip fracture patients get assessed,
diagnosed, or treated!
NCQA 2011 benchmarks and thresholds

5. “If you can get people to ask
the wrong questions, you don’t
have to worry about what the
answers are.”
Pynchon T. Proverbs for paranoids. In: Gravity’s Rainbow. New York:
Penguin; 1995.

6. Question 1
• For persons with osteoporosis, should
only fractures that occur on modest
trauma be considered “osteoporotic”?

7. Answer
• Fractures are never osteoporotic, only
bones can be osteoporotic
• A person with osteoporosis is at higher
risk of fracture – any fracture (exceptions
finger toes skull and facial bones)
• The level of trauma needed to fracture is
lower, thus at higher levels of trauma
fracture is more likely

8. Fractures in patient with
osteoporosis
Trauma required to
break a normal
bone
Trauma level
Trauma required to
break a bone that
is osteoporotic

9. Question 2
• You can only have osteoporosis when
BMD falls below the normal range?

10. • Osteoporosis is diagnosed by fracture
and/or BMD testing
• BMD osteoporosis is determined when
BMD falls below the normal range (a T-
score of =/< -2.5)
• The lower BMD is the greater the fracture
risk

11. • Osteoporosis is diagnosed by fracture
and/or BMD testing
• BMD osteoporosis is determined when
BMD falls below the normal range (a T-
score of =/< -2.5)
• But is risk much different at a T score of
-2.4?

12. BMD and Fracture Risk
Osteoporotic Fracture Risk
40 Age
(% per 10 Years)
30 80
70
20 60
50
10
0
_3 _2.5 _2 _1.5 _1 _0.5 0 0.5 1
BM D T-S core
Kanis JA, et al. Osteoporos Int. 2001;12:989–995.

13. Speculation?
• The increased fragility in the skeleton
occurs mostly because of loss of tissue
and thus deteriorating architecture
• Coupled to that is the increase in risk of
injury that occurs with aging

14. MICROARCHITECTURAL CHANGES
IN OSTEOPOROSIS
Normal Osteoporosis
© 2000, David W. Dempster, PhD.

15. Thank you for referring Ms Smith (at age 65
yrs) for bone density evaluation. Her T-
score is -2.0 which increases her risk of
fracture by 4 times.

16. Thank you for referring Ms Smith (at age 65
yrs) for bone density evaluation. Her T-
score is -2.0 which increases her risk of
fracture by 4 times.
A convenient retrospectoscope tells us her
BMD T-score at age 40 was +1.0

17. Thank you for referring Ms Jones (at age 65
yrs) for bone density evaluation. Her T-
score is -2.0 which increases her risk of
fracture by 4 times.
But what if her BMD T-score at BMD T-score
at age 40 was -2.0

18. Risk Assessment
• For the first Ms Smith, risk is increased
because of loss of mass and, concurrently,
architecture
• For the second, risk may be elevated
because she is likely to be slim! (bones
are thus small)

19. • This is not an advertisement for obesity!
• Overweight folks are not immune from
fracture risk, but small slim bones like
pencils break more easily
• There is nothing we can do about small
slim bones

20. Thank you for referring Ms Jones (at age 85
yrs) for bone density evaluation. Her T-
score is -2.0 which increases her risk of
fracture by 4 times.

21. Fracture Risk Treatment
Threshold
Age Recommendations for
treatment are based on
Osteoporotic Fracture
40 absolute risk of an
(% per 10 Years)
80 individual patient, based
on BMD and other
30 70 important risk factors 1
Risk
20
60
50
10
0
0 1
-0.5 0.5
BMD T-Score
Core data from Kanis JA, et al. Osteoporos Int. 2001;12:989–995.
1
Kanis JA, et al. Bone. 2002;31:26–31.
Bone.

22. Thank you for referring Ms Smith for bone
density evaluation. Her T-score is -2
which increases her risk of fracture by 4
times.
4 times what and over what time?

23. • One in a million?
• One in ten?
• One year?
• Lifetime?

24. “Absolute” Risk Assessment
• Defines the likelihood that an event will occur
specifically for an individual over a reasonable
horizon (e.g. a 20% risk in next 10 years)
• Model built from epidemiologic data bases
• Includes common risk factors + BMD to calculate
risk
• Intervention depends on absolute risk and threshold
depends on cost effectiveness

25. • Thank you for referring Ms Smith for BMD
evaluation. Given her age, fracture history,
weight, cigarette use, family history, and BMD,
her estimated risk of fracture in the next five
years is 25% with a variance of +/- 5% (range
20-30%)

26. Fracture Risk Treatment
Threshold
Age Recommendations for
treatment are based on
Osteoporotic Fracture
40
absolute risk of an
(% per 10 Years)
80 individual patient, based
30 High Fracture Risk on BMD and other
70 important risk factors 1
Risk
20 60
50
10
0
0 1
-0.5 0.5
BMD T-Score
Core data from Kanis JA, et al. Osteoporos Int. 2001;12:989–995.
1
Kanis JA, et al. Bone. 2002;31:26–31.
Bone.

27. The Problems:
The clinical community is still not equating
most fractures with osteoporosis – nor is the
public
Defining osteoporosis as a T-score below –2.5 does
not effectively capture many patients at risk for
fracture
It has been difficult for clinicians to identify persons
with elevated fracture risk but with T-score above -2.5

28. Fracture Rates, Population BMD
Distribution and Number of Fractures
Primary Care Arm
Fracture rate per 1000 person-years
60 450
 BMD distribution
400
50
350
40 300
# Fractures
250
30
200
20 150
100
10
50
0 0
0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0
>1.0 1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5 < –3.5
BMD T-scores
Adapted from Siris ES, et al.JAMA. 2001;286:2815-22.
al.JAMA.

29. Fracture Rates, Population BMD
Distribution and Number of Fractures
Primary Care Arm
Fracture rate per 1000 person-years
60 450
 BMD distribution
Fracture Rate 400
50
350
40 300
# Fractures
250
30
200
20 150
100
10
50
0 0
0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0 –3.5
>1.0 1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5 <-3.5
BMD T-scores
Adapted from Siris ES, et al.JAMA. 2001;286:2815-22.
al.JAMA.

30. Fracture Rates, Population BMD
Distribution and Number of Fractures
Primary Care Arm
Fracture rate per 1000 person-years
60 450
 BMD distribution
Fracture Rate 400
50 # Fractures
350
40 300
# Fractures
250
30
200
20 150
100
10
50
0 0
0.5 to 0.0 –0.5 to –1.0 –1.5 to –2.0 –2.5 to –3.0
>1.0 1.0 to 0.5 0.0 to –0.5 –1.0 to –1.5 –2.0 to –2.5 –3.0 to –3.5 < –3.5
BMD T-scores
Adapted from Siris ES, et al. JAMA. 2001;286:2815-22.

31. Hip Fractures in Women without
Osteoporosis
160
Total n = 8065
140 Hip Fractures = 243
120 (54%) above -2.5
No of subjects (*10)
100
80 Hip Fractures
60 Subjects
40
20
0
-4 -3 -2 -1 0
Total hip BMD T-Score
Modified from Wainwright et al JCEM 90 2787 2005

33. Let’s shift gears
• What about the persons who present with
fracture over age 50 yrs?
• These are our patients at the highest risk
of future fractures!

34. Osteoporosis, Fracture Risk Vary
by Ethnicity
• Ethnic differences in BMD are strongly
influenced by body weight
• Fracture risk is strongly influenced by
BMD in each group
• Ethnic differences in absolute fracture risk
remain, which may warrant ethnic-specific
clinical recommendations
Barrett-Connor E, et al. J Bone Miner Res. 2005; 20:185-194.

35. Odds of Osteoporosis
(T score −2.5 and 95% CI) by Ethnicity
Barrett-Connor E, et al. J Bone Miner Res. 2005; 20:185-194.

36. Confirmed: Prevalent Vertebral
Fractures Predict Future Fracture
RR = Fractures in Patients With Prevalent Fractures vs Those Without
8 7.4
7
6 5.0
4.5
Relative 5 4.0
Risk 4
(RR) 3
2
1
0
Black '99 McClung '99 Ross '93 Risedronate vs
Placebo Patients
3.7 years 3 years 3 years 3 years
Black DM, et al. J Bone Min Res. 1999;14:821-828.
McClung M, et al. Abstract.
Ross PD, et al. Osteoporos Int. 1993;3:120-126.
Data on File. Procter & Gamble Pharmaceuticals Inc.

37. Fracture Risk is Higher Immediately
Following an Incident Fracture
20% Will Fracture Again Within 1
Year of Incident Fracture
24
20%
20
16
Patients
(%) 12
8 7%
4
0
Incidence of Vertebral Incidence Within 1 Year
Fracture in Year 0-1 Following First Fracture
Lindsay R, et al. JAMA. 2001;285:320-323.

38. • Bones break when load exceeds strength
• Low BMD and architecture contribute to
strength
• Loads are dependent on other things
(Falls, frailty, height, weight, nutrition, co-
morbidities, medicines etc)

39. Risk Factors for Fracture
Falls
Osteoporosis and
Trauma
Therapy:
Bisphosphonates Calcium and Vitamin Injury prevention
D

40. Reducing Fall Risk
• Eliminate sedatives
• Monitor antihypertensives
• Ensure adequate vitamin D intake
• Modify environment (i.e., lighting, floor
coverings, pets, grab-bars, etc.)
• Gait and transfer training
• Exercises (i.e., Tai Chi)
• Correct vision and hearing problems
• Use proper footwear

41. FATIGUE CRACKS :
MECHANICAL STRESS RISERS
www.tam.uiuc.edu

42. What about treatment?
• Background therapy refers to calcium and
vitamin D
• What do we know about these as nutrients
and for D a hormone?

43. The calcium controversy
• Having too little calcium in the diet
increases bone remodeling which when
imbalanced leads to bone loss
• Diets with averages of less than
800-1000mg/day cited as too low.
• Calcium intakes above this do not produce
further skeletal effects
• Higher intakes, especially with
supplements may be harmful

44. The calcium controversy
• An adequate diet with average intakes
between 1000 and 1500mg/day is
sufficient
• Supplements should only be used when
these averages cannot be met from diet,
and only enough to bring total intake to
that level
• For calcium calculator go to nof.org

45. The vitamin D story
• Vitamin D has become the vitamin of the
decade
• There is a lot of basic science evidence
supporting the effects of 1,25(OH)2D on
multiple tissues
• Most human studies are observational
• IOM recommendations may be set too low
for many older individuals

46. Vitamin D
• A large study is now underway to evaluate
non-skeletal outcomes of vitamin D intake

47. Pharmacology
• How well do we understand available
treatments?

48. Pharmacology
• All treatments reduce bone remodeling,
except teriparatide which stimulates
formation and remodeling in bone
• Teriparatide is used only for a maximum of
2 yrs in any lifespan
• Most patients will require long-term
treatment
• How do you choose the treatment for any
particular patient?

49. Drug Therapy Classes 1
Antiresorptive Agents
Reduce the risk of all fractures:
• Calcium +/- vitamin D
• Hormone therapy (ET/HT)
• Bisphosphonates – Alendronate Risedronate Zoledronate
• RANK-L Inhibitor - Denosumab
Reduce vertebral fracture risk:
• Selective Estrogen Receptor Modulators (SERMs)
• Ibandronate
• Calcitonin
All drug therapies are usually given in conjunction with lifestyle
modification, calcium and vitamin D.

50. Non-vertebral fracture efficacy
WHI Not head to head studies
1.4 BONE PROOF
1.3
1.2
RELATIVE RISK
1.1
1.0
---------------------------------------------------------------------------------------------
0.9
0.8
MORE
*
0.7 HIP
0.6 * Zoledronate
FIT2
FIT1
0.5 Liberman
0.4 VERT-MN
VERT-NA
0.3
2 8 9 10 11 12 13 14 15 16 17 18
PLACEBO FRACTURE INCIDENCE [%] * stat sig
TREATMENT: Aln Ris Ibn
Ral Calcitonin Adapted from Boonen S et al. OI 2005; 16: 1291

51. Bisphosphonates
• Concern about long term adverse events
Esophageal cancer
ONJ
Subtrochanteric fractures
• Led to concept of “drug holiday”
• Evidence to support this mostly lacking

52. Bisphosphonates and esophageal
cancer: what is more likely?*
• Incidence of esophageal cancer in women over 65: 111/
million/year
• Alendronate: 35 million years of experience
• If consider 20% who take Alendronate for more than 5
years
• Expected number of cases based upon epidemiology
should be around 800, not 23!
• Similar data for Risedronate (Unpublished data, Klemes
et al, 2009)
*Siris E, Oster M, Bilezikian JP, NEJM Ltr , 2009

53. Definition of ONJ
An area of exposed bone in the maxillofacial region in
which there is no healing over 8 weeks after being
recognized by a healthcare provider
 Related conditions:
• Usually a triggering event/condition:
– Recent tooth extraction or oral surgical procedure
– Abrasion in trauma-vulnerable anatomical location (eg,
mylohyoid ridge [edentulous patients], tori)
– smoldering infection (eg, chronic severe periodontitis)
 May be:
• symptomatic or asymptomatic
• infected or non-infected

55. ONJ and Comparative Risks1-4
Any Fragility Fracture (1)
2668
Hip Fracture (1)
387
Anaphylaxis from PCN Shot 32
Death by MVA 11
Death by Murder 6
ONJ- Osteoporosis Patient 0.7
Death by Lightning Strike in NM 0.6
(1) Women age 65–69 (from Swedish
National Bureau of Statistics and 0 10 20 30 40 50 60 70 80 90 100
database of Olmsted County, MN )
Risk per 100,000 People per Year
1. Kanis JA et al. Osteoporosis Int. 2001;12:417-427.
2. Kaufman DW. Pharmcoepidemiol Drug Saf. 2003;12:195-202.
3. National Center for Health Statistics. JADA. 2006;137:1144-1150.
4. NOAA Web site. www.nssl.noaa.gov/papers/techmemos/NWS-SR-193/techmemo-sr193-4.html. Accessed September 2008.

56. Subtrochanteric Fractures
• Epidemiology mostly unknown at present
• Publications mostly case series or from
data derived from claims databases
• Shorter use of BPs
• Suggest incidence about 1/20 that of hip
fracture
• No time trend toward increased incidence

58. Hip and Subtrochanteric Fractures in the United
States
’96 ’’98 ’00 ’02 ’04 ‘06 p
Women*
Hip 546 489 497 449 445 428 <.001
SubT** 56 68 63 65 65 53 NS
Men*
Hip 274 327 265 252 261 248 <.03
SubT** 36 27 27 27 28 32 NS
*per 100,000
**Includes Subtrochanteric, femoral shaft, and distal femur fractures
Nieves et al.Osteoporosis International 2010

59. Potential Mechanisms
• Prolonged residence in the skeleton
non-metabolized
• Irreversible functional osteoclast deficiency and OC
apoptosis
• Atypical non-functional large inactive osteoclast forms
• Dramatic suppression of remodeling
– increased secondary mineralization, crystal size and
tissue mineral density
– loss of heterogenity in tissue mineral density causes
increased stiffness and perhaps propagation of micro-
cracks
– Aged collagen- weakened bone
– Accumulated microdamage
• Heterozygous osteopetrosis profile with intermediate
degree of osteoclast dysfunction

60. Bisphosphonates: Key
Pharmacological Characteristics
Binding to Hydroxyapatite1
4
• Binding affinity for bone in
KL (L/mol x 106)
3
vitro
2
– Determines attachment to
bone and duration of effect 1
0
CLO ETD RIS IBA ALN ZOL
• FPP synthase inhibition in rhFPP synthase2
vitro 50
40
– Determines antiresorptive
30
IC50 (nM)
potential
20
10
0.0
ALN IBA RIS ZOL
1. Nancollas GH, et al. Bone. 2006;38: 617-627.
2. Dunford JE, et al. J Pharmacol Exp Ther. 2001;296:235-242.

61. LOC NOC
Inactive Osteoclast vs. Normal Osteoclast
50 µm
50 µm
< 22 nuclei/cell profile < 8 nuclei/cell profile
Dempster et al ASBMR Abstract 2007

62. Drug Therapy Classes 2
• “Anabolic” agents
Teriparatide (1-34rhPTH)
Parathyroid Hormone (1-84PTH)
• Unclassified
Strontium Ranelate

63. 1-34hPTH increases trabecular
connectivity and cortical width
Ct.Th: 0.32 mm Ct.Th: 0.42 mm
CD: 2.9/mm3 CD: 4.6/mm3
Dempster et al JBMR 2001

64. Who should get Teriparatide?
• Persons with high fracture risk
Patients with osteoporosis related fractures
Patients with very low BMD
Patients who fail other therapies(?)
• How long to treat?
Label – not more then 2 years in any
lifetime
Treat and review after one year

65. Tetracycline Labels After 6 Months
in Cancellous Bone
Zoledronic Acid Teriparatide
MS/BS = 0.20% MS/BS = 5.38%
These samples are representative of the median values for MS/BS
for each treatment group (0.16%, zoledronic acid vs 5.60%, teriparatide)
65

66. Patients already on treatment
• Mostly bisphosphonate treated, and
effects linger after BP discontinuation
• One study implies that patients should
stay on BP while on TPTD

67. What are the Possible Causes of
Poor Adherence?
• Cost
• Osteoporosis eclipsed by other
chronic conditions
• Concern about side effects
• Poor patient education
• Disruption to daily routine
• Complex dosing guidelines
• Lack of positive reinforcement
Sebalt, et al. J Bone Miner Res. 2004:19(Suppl 1): Abstract M423.

68. THE FUTURE BELONGS
TO THOSE WHO BELIEVE
IN THE BEAUTY
OF THEIR DREAMS
Eleanor Roosevelt

69. Pieter Brueghel

70. Oliviero Toscani

71. BODY IMAGE
IT’S A MULTIFACTORIAL
MENTAL CONSTRUCT
DYNAMICALLY SHAPED LIFELONG
ROOTED BOTH
IN THE PSYCHOLOGICAL
AND BIOLOGICAL DOMAIN
PSYCHOLOGY WITHOUT BODY
& MEDICINE WITHOUT SOUL

72. LIFE EXPECTANCY (LE)
VS HEALTH
EXPECTANCY(HE)
Country LE HE Difference
Canada 73.0 67.0 6.0
U.K. 71.8 58.7 13.1
France 70.7 61.9 8.8
United States 70.1 55.5 14.6
Poland 67.0 60.0 7.0
China 66.6 61.6 5.1
from Bruno Lunefeld, Aging for men, 2000

73. Conclusions
• Bones break when load exceeds strength
• Low BMD and architecture contribute to
skeletal strength
• Loads are dependent on other things
(Trauma, falls, frailty, height, weight,
nutrition, co-morbidities, medicines etc)
• Persons with high fracture risk encompass
either or both

74. Conclusions 2
• Any fracture in a person over 50 yrs,
should trigger an osteoporosis evaluation
• Risk assessment (e.g. FRAX) is one
method of evaluating the need for
treatment
• Treatment must include risk reduction as
well as pharmacology