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Managing to Prevent Fracture:
Guideline-based therapy
Presented by:
John A. Goldman, MD
Chief of Rheumatology, Saint Joseph’s
Hospital, Atlanta, GA
1
Content Provided By:
Michael Maricic, MD, Catalina Pointe
Rheumatology; Clinical Associate Professor of
Medicine, University of Arizona
&
Robin K. Dore, MD, Clinical Professor of
Medicine and Rheumatology, UCLA, Los
Angeles, CA; Private Practice, Tustin, CA
2
Objectives
Apply the National Osteoporosis
Foundation’s guidelines for screening
patients for osteoporosis
Formulate evidence-based treatment plans
for patients with osteoporosis or fracture
according to WHO/NOF recommendations.
3
4
Annual incidence of common diseases
Significance of Osteoporosis
in Women
2,051,0001
2,000,000
297,000 hip
1,500,000
397,000 wrist
675,000
other sites
1,000,000
135,000 pelvic
500,000
370,0002
547,000
vertebral
0
Osteoporotic
Fractures
Heart Attack
425,0002
182,4603
Stroke
Breast Cancer
1Annual
fracture incidence in women all ages
estimate new & recurrent MI ages 35+
2Annual estimate new & recurrent stroke in women all ages
32008 new cases in situ & invasive breast cancer all ages
2Annual
© 2008. National Osteoporosis Foundation. All rights reserved.
www.nof.org
1 Burge, et al. JBMR. 2007. 465-75.
American Heart Association. Heart Disease and Stroke
Statistics – 2009 Update. 2009.
3 American Cancer Society. Surveillance Research. 2008.
Use of WHO Fracture Risk Algorithm
The WHO Fracture Risk Assessment Tool (FRAX®)
was developed to calculate the absolute 10-yr
probability of a Hip fracture and any Major
Osteoporotic Fracture
• Hip
• Vertebra
• Forearm
• Humerus
The algorithm takes into account femoral neck BMD
and clinical risk factors for fracture
Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.
6
FRAX Absolute Fracture Risk
T-score alone does not provide a
complete assessment of fracture risk
Combination of clinical risk factors with
BMD provides a better way of identifying
patients for treatment
7
Risk Factor Data Sources
12 large prospective population-based cohorts:
• CaMos, DOES, EPIDOS, EVOS/EPOS, Gothenburg I & II,
Rochester, Hiroshima, Kuopio, OLEFY, Rotterdam,
Sheffield
59,644 subjects with 252,000 person-years
5,321 fractures, including 1141 hip fractures
Validated in 11 additional study cohorts not used
in developing the original algorithm
Kanis JA et al. WHO Technical Report. 2007.
8
Non-density Related Risk Factors
Age
Previous low trauma fracture
Parental history of hip fracture
Current cigarette smoking
High alcohol intake (> 3 units/day)
Rheumatoid arthritis
Current or prior glucocorticoid use
Adapted from Kanis JA et al. Osteoporos Int. 2005;16:581-589.
9
10
FRAX Calculation Tool
http://www.shef.ac.uk/FRAX
11
WHO
Absolute Risk Prediction Model
10-Year probability of experiencing an
osteoporosis-related fracture
Treatment intervention thresholds will vary by
country
Recommendations for treatment based on
absolute fracture risk—not simply on Tscores
14
Case 1
The patient is a 65-year-old white female who
presents for her first DXA scan
She had her menopause at age 50 and never
took hormone therapy
She weighs 132 pounds and is 5’4”
She currently smokes and her father broke his
hip
Her spine and femoral neck T-score today are
both -1.8
15
Audience Response
Question
16
When to Use FRAX™ for Making
Treatment Decisions
Postmenopausal women and men age 50
and older with osteopenia- who do not
qualify for treatment based on other
treatment indications
• Have a fragility fracture or
• T-score > -2.5 at the hip or spine
19
When Not to Use FRAX for Making
Treatment Decisions
Patients who already meet treatment
indications (they have a fragility fracture or
T-score ≤ -2.5 at the hip or spine)
Patients with a normal T-score
Patients already on treatment
Premenopausal women and men under
age 50
20
Limitations of FRAX
BMD for femoral neck input only
• Spine BMD is not taken into account
“Dose effect” not taken into account
(glucocorticoids, RA, smoking, alcohol)
Many risk factors not considered
• Fall risk
• Rate of bone loss or turnover
21
NOF Guidelines for Pharmacologic Therapy in
Postmenopausal Women and in Men >50
Initiation of pharmacologic therapy recommended in presence of any one of:
Fracture
A vertebral or hip fracture
T-Score
T-score ≤ –2.5 at femoral neck, total hip
or spine
FRAX®
Assessment
if T-score between
-1.0 and -2.5
• 10-year probability of a major fracture ≥
20%
• 10-year probability of a hip fracture ≥ 3%
National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis.
Washington, DC: National Osteoporosis Foundation; 2008.
22
2008 NOF Guide: Treatment Initiation
Postmenopausal Women and Men ≥ 50 years
Basic Care (suitable for all)
Assess Risk Factors and BMD (if risk factors)
T-score between -1.0 and -2.5
Hip or vertebral
fractures
or
T-score ≤ -2.5 (spine,
FN, or total hip)
Other fractures
> age 50
(excluding
fingers, toes
and face)
10-year probability of
hip fractures > 3% or
probability of all major
fractures > 20% (FN or
total T-score only)
Secondary causes
with high fracture
risk*
*Such as glucocorticoid use
www.NOF.org
23
Old NOF Guidelines vs.
New NOF Guidelines
Case
55 year-old
Caucasian woman
(120 lbs, 5’-2”)
with
T-score = -2.1
80 year-old
Caucasian woman
(120 lbs, 5’-2”)
with
T-score = -1.1
Old Guide
Treat
(T-score < 2.0)
New Guide
Don’t Treat
(10 year risk of major
fracture 10%, hip
1.5%)
Don’t Treat
(T-score ≥ 1.5)
Treat
(10-year risk of major
fracture 24%, hip
2.4%)
24
25
Therapy of Patients with Osteoporosis
and at High Risk of Fracture
Lifestyle modification
Drug treatment
26
27
27
National Osteoporosis Foundation:
March 2007 Recommendations
Recommended Intake for Adults 50 Years and Older
Calcium Vitamin D3
Previous
(2003)1
March
2007
revision2
(mg/day)
(IU/day)
1200
400–800
1200
800–1000
1. National Osteoporosis Foundation. Physician’s Guide to Prevention and Treatment of Osteoporosis.
Available at: http://www.nof.org/physguide/index.asp. Accessed April 26, 2007. 2. National Osteoporosis Foundation. National
Osteoporosis Foundation’s Updated Recommendations for Calcium and Vitamin D3 Intake. Available at:
http://www.nof.org/prevention/calcium_and_VitaminD.htm. Accessed April 26, 2007.
28
What type of Calcium should we use?
Long-term Proton Pump Inhibitor Therapy and
Risk of Hip Fracture
Case-control study conducted using the GPRD in the UK
Users of PPI therapy, H2 receptor antagonists and controls
older than 50 years
13,556 hip fracture cases and 135,386 controls
The adjusted odds ratio (AOR) for hip fracture associated
with more than 1 year of PPI therapy was 1.44 (95%
CI1.30-1.59)
The strength of the association increased with increasing
dose and duration of PPI therapy
Yang Y, Lewis J, Epstein S. JAMA. 2006;296:2947-2953
29
Vitamin D Insufficiency (<30
ng/mL): Prevalence by Latitude
n=259/532
(48.7%)
42 N
n=342/642
(53.3%)
35 N
n=198/362
(54.7%)
P = NS for Test of Trend.
Holick MF et al. JCEM 2005
30
Vitamin D
25-OH D levels should be measured in patients
• At risk for osteoporosis
• Being treated for osteoporosis
• Those at risk for falls, especially the elderly
25-OH D level attained should be at least 30
ng/ml
Many patients need more than 1000 units/day
and higher intakes are safe
It is the serum level of 25-OH D attained
that is important, not the dose!
31
Higher 25(OH)D Levels Are Associated With Better
Lower Extremity Function in Ambulatory Women
Timed Sit-to-Stand Test
 4,100 ambulatory adults
— 8-ft walking speed test
— Timed sit-to-stand test
LOWESS = locally weighted regression plot.
Reference range of 22.5–94.0 nmol/L (9.0–37.7 ng/mL).
N = 4,100; P<0.001.
32
Sit-to-stand time, s
included in NHANES III
 60 to 90 years
 Functional measurements
used to assess lower
extremity function:
LOWESS regression plot of
lower extremity
function vs vitamin D levels
Reference
range
15
14
0
8
16
24
32
40
48
Serum 25(OH)D, ng/mL
Adapted with permission by the American Journal of Clinical Nutrition. © Am J Clin Nutr. American Society for Clinical Nutrition.
56
64
Agents for
Postmenopausal Osteoporosis
Documented Fracture Reduction
Spine
Nonvertebral
Hip
Antiresorptive Agents (Bisphosphonates)
Alendronate
X
X
X
Ibandronate
X
-
-
Risedronate
X
X
X
Zoledronic acid
X
X
X
Calcitonin
X
-
-
Estrogen+progesterone
X
X (all fractures)
X
Raloxifene
X
-
-
X
X
-
Antiresorptive Agents (Other)
Anabolic Agent
Teriparatide
No head-to-head trials compare fracture outcomes
33
Reduction in Fracture Risk
With Calcitonin
The primary efficacy end
point was the risk of new
vertebral fractures in the
salmon calcitonin nasal
spray 200 IU group
compared with placebo
Placebo
Calcitonin 100 IU
Calcitonin 200 IU
Calcitonin 400 IU
30
Percent with New Fractures (%)
1,255 postmenopausal
women with established
osteoporosis were randomly
assigned to salmon
calcitonin nasal spray (100,
200, or 400 IU) or placebo
daily
26.0%
25
22.0%
20
22.0%
*
18.0%
15
10
5
0
* P<0.05 versus placebo
Chesnut CH III, et al. Am J Med. 2000;109:267-276.
Vertebral Fractures
34
Reduction in Risk for Fractures With Estrogen
Therapy and Estrogen-Progestogen Therapy
Postmenopausal women aged 50-79 years
Prior hysterectomy
Percent with Any Osteoporotic
Fractures (%)
0.17%
Placebo)
0.17%
0.15%
*
*
0.11%
0.11%
Vertebral
* P<0.05 vs placebo
ET
Percent with Any Osteoporotic
Fractures (%)
Placebo
No prior hysterectomy at baseline
Hip
EPT
0.15%
*
*
0.10%
0.09%
Vertebral
Hip
ET, estrogen therapy; EPT, estrogen-progestogen therapy
Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.
Women’s Health Initiative Investigators. JAMA. 2004;291:1701.
35
Risks and Benefits of
Estrogen + Progestin
*
*
*
*
*
*
*
CHD = coronary heart disease
VTE = venous thromboembolism
Women’s Health Initiative Investigators. JAMA. 2002;288:321-333.
* P<0.05 versus no treatment
36
Risks and Benefits of Estrogen
*
*
*
*
* P<0.05 versus no treatment
Women’s Health Initiative Investigators. JAMA. 2004;291:1701-1712.
37
Effect of HT on CHD: Timing of Initiation
Years Since
Menopause
WHI-E+P
Absolute Risk per
10,000 Women per
Year of HT Use
0.88
P for trend=0.05
<10
-4
1.23
10-19
7
1.66
>20
30
WHI-E
0.48
-14
P for trend=0.15
<10
0.96
-1
10-19
1.12
7
>20
WHI-Combined
0.76
-6
P for trend=0.02
<10
1.10
4
10-19
1.28
16
>20
0
0.5
1.0
Rossouw JE, JAMA 2007;297:1465-1477.
1.5
2.0
2.5
Estrogen/Hormone Therapy
Side Effects
Hormone Therapy
Estrogen Therapy
Venous thrombosis
Not Significant
Heart Disease
Not Significant
Stroke
Gallbladder Disease
Breast Cancer
Not Significant
Dementia
2009. National Osteoporosis Foundation.
www.nof.org
39
FDA Recommendations
about ET/HT
The FDA recommends the following:
When prescribing medication to prevent
osteoporosis, consider all nonestrogen preparations
first
When prescribing ET/HT, prescribe smallest dose for
shortest time to achieve treatment goals
Prescribe ET/HT products only when benefits are
believed to outweigh risks for a specific patient
US Food and Drug Administration. FDA News. January 8, 2003.
2009. National Osteoporosis Foundation. www.nof.org
40
Hormone/Estrogen Therapy
It is important to consider all of the risks and
benefits of HT/ET when prescribing to individual
patients
HT/ET are very effective agents for prevention of
bone loss and fractures
Risks differ according whether using HT versus ET,
and the age of the patient
No need to combine full dose HT with a
bisphosphonate
41
Reduction in Risk for Vertebral
Fractures With Raloxifene
* Results for patients with no fractures at baseline
Ettinger B, et al. JAMA. 1999;282:637-645.
5
4.5%
Percent with New Vertebral
Fractures (%)*
The Multiple Outcomes of
Raloxifene Evaluation
(MORE) study enrolled 7,705
women aged 31-80 years
who had been
postmenopausal for ≥2
years and who met World
Health Organization criteria
for osteoporosis
Participants were
randomized to 60 or 120
mg/day raloxifene or placebo
Primary end point: incident
vertebral fracture
Placebo
Raloxifene (60 mg/day)
Raloxifene (120 mg/day)
4
**
3
**
2.8%
2.3%
2
1
0
** P<0.05 versus placebo
42
Risk-Benefit Considerations
with Raloxifene
The risks for both hip
and vertebral fractures
also increase with age4
The clinician may want
to consider removing a
patient from raloxifene
therapy at about age 65
Increase in Fractures
with Age in Women4
160,000
140,000
Number of Fractures
Raloxifene is associated
with both VTE and stroke
and the risk for both
events increases with
age1-3
Hip
Vertebral
120,000
100,000
80,000
60,000
40,000
20,000
0
50-64
65-74
75-84
≥85
Age (years)
Evista (raloxifene) [package insert]. Indianapolis, IN: Eli Lilly and Company; 2007. Silverstein MD, et al. Arch Intern Med.
1998;158:585-593. American Heart Association. 2008. Available at:
http://www.americanheart.org/presenter.jhtml?identifier=9217. Burge R, et al. J Bone Min Res. 2007;22:465-475.
43
Oral Bisphosphonates
Alendronate- Weekly
Risedronate- Weekly, monthly
Ibandronate- Monthly
44
Reduction in Risk for Vertebral
Fractures with Alendronate
Black DM, et al. Lancet. 1996;348:1535-1541.
16
15.0%
Placebo
Alendronate
14
Percent with New
Vertebral Fractures (%)
2,027 women aged 55-81 years
with low femoral-neck BMD and
at least one vertebral fracture at
baseline were randomly assigned
placebo (1,005) or alendronate
(1,022) and followed up for 36
months
The dose of alendronate (initially
5 mg/day) was increased to 10
mg /day at 24 months
Lateral spine radiography was
done at baseline and at 24 and 36
months
Primary end point: new
morphometric or clinical vertebral
fractures
12
10
*
8.0%
8
6
5.0%
*
4
2.3%
2
0
Morphometric
Fractures
Clinical
Fractures
* P<0.05 versus placebo
45
Reduction in Risk for Vertebral and
Nonvertebral Fractures With Risedronate
Randomly assigned to
3 years of risedronate (2.5
or 5 mg/day) or placebo
18
Percent with New Fractures (%)
Randomized, double-blind
placebo-controlled trial of
2,458 postmenopausal
women <85 years old with
≥1 vertebral fracture at
baseline
16.3%
Placebo
Risedronate
16
14
12
**
11.3%
10
8
6
8.4%
*
5.2%
4
2
Primary end point:
incidence of new vertebral
0
fractures as detected by
Vertebral Fractures
radiography
* P=0.02 versus placebo
Nonvertebral
Fractures
** P=0.003 versus placebo
46
Harris ST, et al. JAMA. 1999;282:1344-1352.
Reduction in Risk for Vertebral
Fractures with Ibandronate
Percent with New
Vertebral Fractures (%)
2,946 postmenopausal
12
women with
osteoporosis were
10
randomized to placebo
or oral ibandronate
8
administered daily (2.5
mg/day) or
6
intermittently (20 mg
every other day for
4
12 doses every 3
months)
2
Primary end point:
incidence of new
0
vertebral fractures after
* P<0.05 versus placebo
3 years
** P=0.0006 versus placebo
*** P=0.0001 versus placebo
Placebo
Daily Ibandronate
Intermittent Ibandronate
9.6%
***
4.7%
**
4.9%
5.3%
*
2.8%
Morphometric
Fractures
Chesnut CH III, et al. J Bone Min Res. 2004;19:1241-1249.
*
2.8%
Clinical
Fractures
47
Adherence With Oral Bisphosphonates
Is Poor, Regardless of Dosing
100
Patients on Therapy (%)
90
Percentage of Patients on Therapy
(defined as having at least 1 day of medication supply in the month)
80
70
60
54.6%
50
40
36.9%
30
Weekly Bisphosphonates (n=177,552)
20
Daily Bisphosphonates (n=33,767)
P<0.001 vs daily
therapy
10
Oct
Nov
Dec
Jan Feb
Mar
Apr May Jun
Jul
Aug
Sep Oct
2002
2003
A HIPAA-compliant, longitudinal patient database of prescriptions dispensed from ~25% of US retail pharmacies
was used to assess discontinuation of bisphosphonates over a 12-month period in women aged ≥50 years.*
* Primary usage in osteoporosis; however, data may include use in other indications.
Ettinger M, et al. Arthritis Rheum. 2004;50(suppl):S513-S514. Abstract 1325.
48
Poor Compliance and Persistence Lead to
Compromised Fracture Risk Reduction
N = 11,249
Fracture Risk Hazard Ratio
1.0
16% Risk
Reduction
P < .001
0.8
0.6
0.4
0.2
0
Low
Compliance
High
Compliance
Siris et al, 20062
N = 35,537
14
24 Month Fracture Risk (%)
Caro et al, 20041
12
12.6%
29% Risk
Reduction
P < .001
10
8
9.4%
6
4
2
0
1. Caro JJ, et al. Osteoporos Int. 2004;15:1003-1008.
2. Siris E et al. Mayo Clin Proc 2006;81:1013-1022
NonPersistent
Persistent
49
I.V. Bisphosphonates:
Potential Clinical Usage
Assure compliance where there is evidence
for non-compliance
Assure absorption when in doubt clinically
Oral bisphosphonate intolerance or
contraindications
• Dysphagia, severe GERD, Bed-ridden
patients
50
I.V. Bisphosphonates
Ibandronate- 3 mg Q 3 months
• Treatment of postmenopausal OP
Zoledronic acid- 5 mg once yearly
• Treatment of postmenopausal OP
• Treatment of men with low bone mass
• Treatment of patients on glucocorticoids
• Prevention of osteoporosis (5 mg every 2
years)
51
Reduction in Risk for Vertebral and
Hip Fractures With Zoledronic Acid
12
Percent with New Fractures (%)
3,889 patients (mean age,
73 years) were randomly
assigned to receive a single 15minute infusion of zoledronic acid
(5 mg) and 3,876 were assigned
to receive placebo at baseline,
12, and
24 months
Patients were followed for 36
months
Primary end points were:
• New vertebral fractures (in
patients not taking
concomitant osteoporosis
medications)
• Hip fractures (in all patients)
10
8
6
4
**
3.3%
2.5%
2
*
1.4%
0
* P=0.002 versus placebo
** P<0.001 versus placebo
Black DM, et al. N Engl J Med. 2007;356:1809-1822.
Placebo
Zoledronic Acid
10.9%
Vertebral
Fractures
Hip
Fractures
52
Zoledronic acid –
Adverse Reactions
Incidence rate (%)
The most common adverse events were post dose
flu-like symptoms
53
Zoledronic Acid –
Adverse Reactions
Acute Renal Failure• 24 cases of ARF and 3 deaths reported in
July FDA newsletter
• Many of these patients should not have
been candidates for ZA
• Do not give if creatinine clearance < 35
mg/ml
• Infuse over minimum of 15 minutes
54
Case 2
The patient is a 75-year-old diabetic, hypertensive
white female with osteoporosis
Her meds include glyburide, lisinopril, furosemide
and ibuprofen prn for arthritis
Her spine T-score is -2.4 and femoral neck T-score
is -3.0
She cannot tolerate oral bisphosphonates due to
GI discomfort
Her creatinine clearance is 36 ml/min
55
Audience Response
Question
56
Answer to Case 2
NO
Although her creatinine clearance is 36 ml/min (above
the FDA exclusionary limit of 35 ml/min), she has
other risk factors for chronic renal disease which
include chronic diabetes and hypertension
Also she is taking a number of other meds which can
influence renal function including ibuprofen, lisinopril,
and furosemide
She would be a significant risk of acute renal failure
from IV zoledronic acid, and this agent should be
avoided
Teriparatide would be a preferred option
58
Osteonecrosis of the Jaw
 A confirmed case of bisphosphonate-associated
ONJ
 was defined as an area of exposed bone in the
 maxillofacial region that did not heal within 8
weeks after identification by a health care
provider
 In a patient who was receiving or had been
exposed to a bisphosphonate
Osteonecrosis of the Jaw
A condition in which bone in the jaw becomes
exposed, typically after a dental extraction or some
other trauma and the wound that occurs fails to
heal in the usual time frame.
In patients receiving bisphosphonates for
appropriate indications, the benefits far outweigh
the risks.
2009. National Osteoporosis Foundation. www.nof.org
60
Osteonecrosis of the Jaw
Low incidence, most often in cancer patients
receiving high doses of IV bisphosphonates, but also
rarely diagnosed in patients on oral bisphosphonates
for nonmalignant conditions.
In 2005 FDA required addition of statement on ONJ
risk for all bisphosphonate products.
2009. National Osteoporosis Foundation. www.nof.org
61
ONJ Comparative Risks
M. Lewiecki 2007
Kanis JA et al. Osteoporos Int. 2001;12:417-427. Pharmcoepidemiol Drug Saf.
2003;12:195-202. National Center for Health Statistics. JADA. 2006;137:1144-1150.
Alendronate: Is Long Term Use Linked
to Subtrochanteric Femoral Fractures?
ABC News
Good Morning America
March 9, 2010
63
Radiograph Showing a Subtrochanteric Stress
Fracture Associated with a Typical Cortical Stress
Reaction
Kwek E et al. N Engl J Med 2008;359:316-318
64
Atypical Fractures of Femoral Shaft
Transverse fractures of the femoral shaft
Bilateral in 2/3 of patients
Delayed healing or non-healing common
Prolonged use (> 5 years) of alendronate +/other anti-resorptive medications
Severely suppressed bone turnover?
65
Atypical Fractures of Femoral Diaphysis
Visekruna, J Clin Endocrinol Metab 2008;93:2948-2952
66
Subtrochanteric and Diaphyseal Femur Fractures
in Patients Treated With Alendronate:
Note the proportional increase in the risk of both typical and atypical fractures in the alendronate cohort
Abrahamsen B., Eiken P., Eastell R. J Bone Miner Res. 2009 Jun;24(6):1095-102
69
Comparison of Number of Patients Who Would Need to Be Treated for 3
Years with Bisphosphonates to Prevent One Fracture and the
Hypothetical Number Associated with an Increase of One
Subtrochanteric or Diaphyseal Fracture
Black D et al. N Engl J Med 2010;362:1761-1771
70
FDA Drug Safety Communication:
Ongoing safety review of oral
bisphosphonates and atypical
subtrochanteric femur fractures
March 10,2010
“At this point, the data that FDA has reviewed
have not shown a clear connection between
bisphosphonate use and a risk of atypical
subtrochanteric femur fractures”.
71
FDA recommends that Patients should:
Not stop taking medication unless told to do so by
your healthcare professional.
Talk to their healthcare professional if they develop
new hip or thigh pain, or have any concerns with
their medications.
Report any side effects with bisphosphonates to
FDA's MedWatch program
FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical
subtrochanteric femur fractures March 10,2010
72
FDA recommends that Healthcare
Professionals should:
Be aware of the possible risk of atypical
subtrochanteric femur fractures in patients taking
oral bisphosphonates.
Continue to follow the recommendations on the
drug label when prescribing oral bisphosphonates.
Discuss with patients the known benefits and
potential risks with using oral bisphosphonates.
Report any adverse events with the use of oral
bisphosphonates to FDA's MedWatch program
FDA Drug Safety Communication: Ongoing safety review of oral bisphosphonates and atypical
subtrochanteric femur fractures March 10,2010
73
Subtrochanteric Fractures
Occur in patients never exposed to
bisphosphonates
Case control studies to date do not indicate an
increase with bisphosphonate use
In patients on bisphosphonates complaining
of lower extremity “loading” pain, check x-ray
and/or MRI
74
Bisphosphonate Holiday?
75
Bisphosphonate Holiday?
FLEX Trial
ALN/PLB (n = 437)
ALN/ALN (n = 662)
Fracture Incidence, %
RR = 1.0
CI (0.8, 1.3)
RR = 0.9
CI (0.6, 1.2)
RR = 0.45
CI (0.2, 0.8)
5%
2%
Clinical Vertebral
RR = 1.0
CI (0.5, 2.1)
11%
10%
Vertebral
Morphometric
1. Black DM et al. JAMA. 2006;296:2927–2938.
19%
19%
Nonvertebral
3%
3%
Hip
76
Bisphosphonate Holiday?
Warranted in those who never needed
treatment in the first place
Use FRAX if BMD before starting Rx if available
Continue treatment in those who have had
fractures and those whose T-scores are < -2.5
Not clear when to end holiday
Arbitrary restart after 1-2 years?
Follow BMD, markers?
77
Teriparatide or Parathyroid Hormone
(1-34) (PTH)
Classified as an anabolic agent that builds new bone
Administered daily by subcutaneous injection
Decreases risk of vertebral fractures and
nonvertebral fractures after an average of 18
months of therapy
Neer RM et al. N Engl J Med. 2011;344(19):1434-1441.
2009. National Osteoporosis Foundation. www.nof.org
78
Teriparatide
Teriparatide (human parathyroid hormone (1-34), is the
only currently approved anabolic agent for osteoporosis.
It is indicated for the treatment of postmenopausal women
with osteoporosis who are at high risk for fracture.
These include those who (based on physician assessment)…
• Have a history of osteoporotic fracture
• Have multiple risk factors for fracture
• Failed previous osteoporosis therapy
• Are intolerant to previous osteoporosis therapy
79
Teriparatide Indications
continued
“High-risk” includes:
Men/women with previous osteoporotic fracture(s)
Men/women with multiple risk factors for fracture
Men/women with extremely low BMD (-3.0 and
below)
Patients unresponsive or intolerant of other
osteoporosis therapies
US Food and Drug Administration. FDA Talk Paper. November 26, 2002.
2009. National Osteoporosis Foundation. www.nof.org
80
Patients (%)
Effect of Teriparatide (PTH) on New Vertebral
and Nonvertebral Fractures at 18 Months
 65%*
 53%*
*P<.05 for all values with PTH.
Neer RM et al. N Engl J Med. 2001;344:1434–1441.
81
Teriparatide: Contraindications
Hypercalcemia
Paget's disease of bone
Growing children and young adults
Pregnant or nursing women
A history of bone cancer
A history of cancer that has metastasized to
the bones
Radiation to the skeleton from any condition
US food and drug administration. FDA talk papers. November 26, 2002
82
Denosumab
June 1, 2010
Denosumab (Prolia – Amgen) –
approved for treatment of
postmenopausal women with
osteoporosis at high risk for fracture
83
OPG / RANKL / RANK Receptor
RANKL and OPG are
secreted by osteoblasts
and bone marrow stromal
cells
RANKL functions to
promote osteoclast
formation and activation
and inhibit apoptosis
Hormones
Cytokines
RANK
Ligand
RANK
OPG
Osteoblasts
Osteoclast
Precursor
RANK
Osteoclast
Bone
OPG functions as a decoy
receptor to prevent RANKL signaling; ratio of RANKL to
OPG dictates bone mass and structural properties
Current extensive research is elucidating the role of OPG
and RANKL in a wide variety of bone-related diseases
84
Denosumab (OPG mimetic)
Denosumab is a fully
human monoclonal
antibody against the
receptor activator of
nuclear factor-kB ligand RANK Ligand (RANKL)
IgG2
High affinity for RANK
Ligand (Kd 3 x 10–12 M)
Does not bind to TNFα,
TNFß, TRAIL, or CD40L
Bekker PJ, et al. J Bone Miner Res. 2004;19:1059-1066.
Boyle WJ, et al. Nature. 2003;423:337-342.
Monoclonal Antibody Model
85
Mechanism of Action for Denosumab
Osteoclast Activation
Osteoclast Formation, Function and
Survival Inhibited
Denosumab
CFU-M
OPG
RANKL
Pre-Fusion
Osteoclast
RANK
Multinucleated
Osteoclast
Growth Factors
Hormones
Cytokines
Mature
Osteoclast
Bone
Adapted from Boyle WJ, et al. Nature. 2003;423:337-42.
Original Article
Denosumab for Prevention of Fractures in
Postmenopausal Women with Osteoporosis
Steven R. Cummings, M.D., Javier San Martin, M.D., Michael R. McClung, M.D., Ethel S.
Siris, M.D., Richard Eastell, M.D., Ian R. Reid, M.D., Pierre Delmas, M.D., Ph.D., Holly B.
Zoog, Ph.D., Matt Austin, M.S., Andrea Wang, M.A., Stepan Kutilek, M.D., Silvano
Adami, M.D., Ph.D., Jose Zanchetta, M.D., Cesar Libanati, M.D., Suresh Siddhanti,
Ph.D., Claus Christiansen, M.D., for the FREEDOM Trial
N Engl J Med, Volume 361(8):756-765, August 20, 2009
87
Incidence of New Vertebral, Nonvertebral, and Hip
Fractures
Cummings SR et al. N Engl J Med 2009;361:756-765
Percent Changes in Bone Mineral Density
and Biochemical Markers of Bone Turnover
Cummings SR et al. N Engl J Med 2009;361:756-765
89
Annual incidence of common diseases
Significance of Osteoporosis
in Women
2,051,0001
2,000,000
297,000 hip
1,500,000
397,000 wrist
675,000
other sites
1,000,000
135,000 pelvic
500,000
547,000
vertebral
0
Osteoporotic
Fractures
425,0002
370,0002
182,4603
Stroke
Heart Attack
fracture incidence in women all ages
estimate new & recurrent MI ages 35+
2Annual estimate new & recurrent stroke in women all ages
32008 new cases in situ & invasive breast cancer all ages
Breast Cancer
1Annual
2Annual
1 Burge, et al. JBMR. 2007. 465-75.
American Heart Association. Heart Disease and Stroke
Statistics – 2009 Update. 2009.
3 American Cancer Society. Surveillance Research. 2008.
© 2008. National Osteoporosis Foundation. All rights reserved.
www.nof.org
“We enter the world
through the brim of the
pelvis, and frequently exit
by the neck of the femur”
C.A. Newhall, MD