Download Metabolic Bone Dis. Consultants Mtg.

Long-term Management of Osteoporosis
March 25, 2013
Ronald C. Hamdy, MD, FRCP, FACP
Professor of Medicine
Cecile Cox Quillen Chair of Geriatric Medicine
Director, Osteoporosis Center
East Tennessee State University
R. C. Hamdy - Disclosures
Speakers’ bureau
Advisory Board
Speakers’ bureau
Speakers’ bureau
Speakers’ bureau
Long-term Management of Osteoporosis
March 25, 2013
OBJECTIVES
 Evaluate the risk/benefit of long-term therapy for
osteoporosis
 Develop a long-term management strategy tailored to
the individual circumstances of the patient.
 Recognize the possible long-term complications of
medications commonly used for osteoporosis
Mrs. DA, 68 years old WW - Osteoporosis
On alendronate for about 12 years
 Taking the medication as directed
 Pain in left thigh, 6 weeks: 6/10
not constant, gradually worse
precipitated by exertion, especially jogging
partly relieved by rest & local heat
now, often wakes her at night.
Starting to interfere with daily activities
Mrs. DA, 68 years old WW - Osteoporosis
On alendronate for about 12 years





12 years ago: T-score -2.9 lumbar vertebrae
Surgical menopause at age 32, no HRT
Family history: positive, mother fragility hip fracture
Good dietary calcium and vitamin D intake
Physically active lifestyle, exercises regularly:
daily jogging,
twice weekly: aerobic/resistive exercises
 Medication: alendronate
calcium/vitamin D supplements
Mrs. DA, 68 years old WW - Osteoporosis
On alendronate for about 12 years









Weight 152 pounds, steady; height 64”
No kyphosis
Tenderness to deep palpation upper 1/3 left femur
Pain worse when she stands on left leg
Good range of movement both hips
No pain on passively moving both hips
Leg raising test negative, both sides
No evidence of arthritis
No evidence of neurologic deficits
Mrs. DA, 68 years old WW - Osteoporosis
On alendronate for about 12 years









Weight 152 pounds, steady; height 64”
No kyphosis
Tenderness to deep palpation upper 1/3 left femur
Pain worse when she stands on left leg
Good range of movement both hips
No pain on passively moving both hips
Leg raising test negative, both sides
No evidence of arthritis
No evidence of neurologic deficits
Hamdy, RC, Lewiecki, EM.
Osteoporosis:
Oxford University Press, 2013
Warning sign:
Impending fracture
Hamdy, RC, Lewiecki, EM.
Osteoporosis:
Oxford University Press, 2013
Prevention is
better than cure
Hamdy, RC, Lewiecki, EM.
Osteoporosis:
Oxford University Press, 2013
Rod inserted prophylactically
Hamdy, RC, Lewiecki, EM.
Osteoporosis:
Oxford University Press, 2013
Reports of
femoral shaft fractures
occurring
in patients on
bisphosphonate therapy.
Atypical femoral shaft fractures
Reports of
femoral shaft fractures
occurring
in patients on
bisphosphonate therapy.
Femoral Shaft Fractures
Fractures occurring anywhere
between the
lesser trochanter
and
the supracondylar flare.
Femoral Shaft Fractures
 7 to 10% of all femoral shaft fractures
 Bimodal age distribution
Femoral Shaft Fractures
 7 to 10% of all femoral shaft fractures
 Bimodal age distribution
 75% due to severe trauma
• Usually good prognosis
Femoral Shaft Fractures
 7 to 10% of all femoral shaft fractures
 Bimodal age distribution
 75% due to severe trauma
• Usually good prognosis
 25% due to low trauma or no trauma
Femoral Shaft Fractures
 7 to 10% of all femoral shaft fractures
 Bimodal age distribution
 75% due to severe trauma
• Usually good prognosis
 25% due to low trauma or no trauma
• Osteoporosis
• More frequent in women than men
• Poor prognosis
• Mortality: 14% first year, 25% second year
• 50% do not achieve pre-fracture level
• 71% need alternative accommodation
Femoral Shaft Fractures
 7 to 10% of all femoral shaft fractures
 Bimodal age distribution
 75% due to severe trauma
• Usually good prognosis
 25% due to low trauma or no trauma
• Osteoporosis
• More frequent in women than men
• Poor prognosis
• Mortality: 14% first year, 25% second year
• 50% do not achieve pre-fracture level
• 71% need alternative accommodation
Femoral Shaft Fractures
Typical: underlying osteoporosis
v/s
Atypical: osteoporosis treatment
Atypical Femoral Shaft Fractures
ASBMR Task Force - Major Features
Between lesser
trochanter &
supracondylar
flare
• No/minimal trauma
• Unilateral or bilateral
• Complete or incomplete
Non-comminuted
Medial
spike
Short
transverse or
oblique
configuration
Shane E, et al. JBMR
2010;25:2267-2294
Atypical Femoral Shaft Fractures
ASBMR Task Force - Minor Features
• Prodromal symptoms
• Localized pain
• Localized bone tenderness
• Imaging studies
• Insufficiency/stress fractures
• Localized periosteal reaction
• Localized increased
Technetium uptake
• Other morbidities
Shane E, et al. JBMR 2010;25:2267-2294
Hamdy, RC, Lewiecki, EM. Osteoporosis:
Oxford University Press, 2013
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced
Fracture Risk
Reduced Bone Resorption
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced Bone Resorption
Increased Mature
Cross-Links
Micro-damage
AGE Products
Reduced
Fracture Risk
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced Bone Resorption
Increased Mature
Cross-Links
Micro-damage
AGE Products
Reduced
Fracture Risk
Micro-architectural
Deterioration
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced Bone Resorption
Increased Mature
Cross-Links
Micro-damage
AGE Products
Micro-architectural
Deterioration
Increased Bone
Brittleness
Reduced
Fracture Risk
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced Bone Resorption
Increased Mature
Cross-Links
Micro-damage
AGE Products
Micro-architectural
Deterioration
Increased Bone
Brittleness
Reduced
Fracture Risk
Stress Fractures
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced Bone Resorption
Increased Mature
Cross-Links
Micro-damage
AGE Products
Micro-architectural
Deterioration
Increased Bone
Brittleness
Reduced
Fracture Risk
Stress Fractures
Atypical Femoral
Shaft Fractures
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced Bone Resorption
Increased Mature
Cross-Links
Micro-damage
AGE Products
Micro-architectural
Deterioration
Increased Bone
Brittleness
Reduced
Fracture Risk
Impaired Healing
Process
Stress Fractures
Atypical Femoral
Shaft Fractures
Basic Science Considerations
Bisphosphonates
Prevent Bone Loss
Increase Bone Mass
Reduced Bone Resorption
Increased Mature
Cross-Links
Micro-damage
AGE Products
Micro-architectural
Deterioration
Increased Bone
Brittleness
Reduced
Fracture Risk
Reduced Bone
Angiogenesis
Impaired Healing
Process
Stress Fractures
Atypical Femoral
Shaft Fractures
Atypical Femoral Shaft Fractures
Bisphosphonate Therapy

Bisphosphonates:
 2004: 57 million prescriptions in USA
 2007: 225 million prescriptions worldwide

Largest case series of Atypical Femoral Shaft Fractures:
 320: Shane et al, 2010
 141: Giusti et al, 2010
Placebo-controlled Studies
 Double-blind, randomized, prospective studies
Alendronate
Risedronate
Ibandronate
Zoledronic acid
Denosumab
2,027
5,445 + 2,458 + 1,116
2,946
7,736
7,736
 Extension studies
No increased risk
 Re-analysis of data including extension studies
No increased risk*
*Black DM et al. NEJM 2010;362(19):1761-71
Retrospective Population Studies
Danish registry-based cohort study:
11,944 subjects > 60 years
2-matched cohorts:
• 5,187
• 10,374
Patients with FSF were not more likely than patients
with hip fractures to be on alendronate, but more
patients were on corticosteroids.
Abrahamsen B, et al. JBMR 2009;24:1095-1102
Retrospective Population Studies
Positive effect of bisphosphonates on FSF
Higher reduction of FSF in patients highly compliant with
bisphosphonate therapy.
• Abrahamsen B, et al. Subtrochanteric and diaphyseal femur fractures in
patients treated with alendronate: a register-based national cohort study.
JBMR 2009; 24(6):1095-102.
• Hsiao FY, et al. Hip and subtrochanteric or diaphyseal femoral fractures
in alendronate users: a 10-year, nationwide retrospective cohort study in
Taiwanese women. Clin Ther. 2011;33(11):1659-67.
ASBMR Task Force
Atypical Femoral Shaft Fractures
&
Anti-resorptive Therapy
A causal relationship between bisphosphonates
and femoral shaft fractures could not be
established.
ASBMR Task Force. JBMR 2010;25:2267-2294
Atypical Femoral Shaft Fractures
&
Anti-resorptive Therapy
Over-use, or over-dose
not adverse effect
Atypical Femoral Shaft Fractures
&
Anti-resorptive Therapy
Over-use, or over-dose
not adverse effect
Often can be anticipated
Femoral Fractures per 100,000
National Hospital Discharge Survey &
MarketScan® 1996-2006
Nieves JW, et al Osteoporos Int 2010;21(3):399-408
Femoral Fractures per 100,000
National Hospital Discharge Survey &
MarketScan® 1996-2006
Let’s be vigilant,
but not stop positive
effects of therapy
Nieves JW, et al Osteoporos Int 2010;21(3):399-408
Mrs. BD, 68 years old WW - Osteoporosis
 T-score -2.7, left femoral neck
 Post surgical menopause at age 34 years, no HRT
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
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

Positive family history: mother fragility hip fracture
Good daily calcium and vitamin D intake
No excessive sodium/caffeine intake
Exercies regularly: aerobic/resistive exercises
No medications
No secondary causes
Mrs. BD, 68 years old WW - Osteoporosis
 Refuses bisphosphonates
Concerned about Atypical femoral shaft fractures
Mrs. BD, 68 years old WW - Osteoporosis
 Refuses bisphosphonates
Concerned about Atypical femoral shaft fractures
 Probability of sustaining:
Atypical femoral shaft fracture
1:10,000
to
1:20,000
Mrs. BD, 68 years old WW - Osteoporosis
 Refuses bisphosphonates
Concerned about Atypical femoral shaft fractures
 Probability of sustaining:
Atypical femoral shaft fracture
1:10,000
to
1:20,000
Osteoporotic fracture
Hip #
33% 1:3
Other #
50% 1:2
Mrs. OJ, 68 years old WW - Osteoporosis
 Has been on oral bisphosphonates for about 12 years
 Taking them as directed, no adverse effects
 Dentist concerned about impending tooth extraction
Mrs. OJ, 68 years old WW - Osteoporosis
 Natural menopause at age 47 years, no HRT
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

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Positive family history: mother fragility hip fracture
Daily dietary calcium intake about 1,200 mg
No excessive sodium/caffeine intake
Exercies regularly: aerobic/resistive exercises
No medications, except alendronate
Mrs. OJ, 68 years old WW - Osteoporosis
 Should bisphosphonates be discontinued?
 What else can be done
to prevent
Osteonecrosis of the jaw?
Tooth to be
extracted
Cavity left
after tooth
extraction
Necrotic tissue removed,
Larger cavity left, lined by
injured bone
Some of injured
bone: recovers
Undergoes
necrosis
Osteonecrosis of
the jaw
Tooth to be
extracted
Cavity lined by
injured bone
Cavity left
after tooth
extraction
Some of injured
bone: recovers
Undergoes
necrosis
Osteonecrosis of
the jaw
Tooth to be
extracted
Cavity lined by
injured bone
Osteoclasts remove
injured bone
Cavity left
after tooth
extraction
Some of injured
bone: recovers
Undergoes
necrosis
Osteonecrosis of
the jaw
Tooth to be
extracted
Cavity lined by
injured bone
Osteoclasts remove
injured bone
Access denied
Cavity left
after tooth
extraction
Some of injured
bone: recovers
Undergoes
necrosis
Osteonecrosis of
the jaw
Tooth to be
extracted
Cavity lined by
injured bone
Osteoclasts remove
injured bone
Cavity left
after tooth
extraction
Some of injured
bone recovers
Some undergoes
necrosis
Tooth to be
extracted
Cavity lined by
injured bone
Cavity left
after tooth
extraction
Necrotic tissue removed,
Larger cavity left, lined by
injured bone
Some of injured
bone: recovers
Undergoes
necrosis
Tooth to be
extracted
Cavity lined by
injured bone
Cavity left
after tooth
extraction
Necrotic tissue removed,
Larger cavity left, lined by
injured bone
Some of injured
bone: recovers
Undergoes
necrosis
Osteonecrosis of
the jaw
Mrs. OJ, 68 years old WW - Osteoporosis
 Stop bisphosphonates/anti-resorptives
?? Effect ??
 Ensure no vitamin D deficiency
 ? Discuss case with dentist
If invasive procedure required:
experienced oral surgeon/dentist
 ? Assay bone markers ??
 Meticulous oral hygiene
Osteonecrosis of the jaw
Exposed bone for at least 8 weeks
 Stage I:
 Stage II:
 Stage III:
Exposed bone, asymptomatic
Infected exposed bone
Fistulae, purulent discharge
 ? Stage 0:
Pain in gums in patient on antiresorptive
therapy
Radiological features
Osteonecrosis of the jaw
Relatively few cases
Mostly in patients:
with neoplasia
on high doses bisphosphonates
on glucocorticoids
Other predisposing factors:
underlying dental problems
cigarette smoking
poor dental hygiene
Mrs. PRP, WW, 82 years
 Diagnosed with osteoporosis about 9 years ago
Fragility fracture T10: moderate wedge
 Secondary causes excluded.
 Started risedronate (Actonel) 35 mg weekly, then
converted to 150 mg once a month
 No adverse effects, taking it as directed, own routine
 Good compliance
 Good daily calcium/vitamin D intake
Mrs. PRP, WW, 82 years
Right Total Hip
Scan
Date
Age
BMD
T-scores
% BMD Change
Baseline Previous
2004
2006
73
75
0.633
0.649
- 3.0
- 2.9
2007
2009
76
78
0.682
0.691
-2.8
- 2.7
2011
79
0.704
-2.6
2013
82
0.710
- 2.5
+ 2.3
+ 7.7
+ 9.2
+ 11.2
+ 12.2
+ 2.3
+ 5.1
+ 1.3
+ 1.8
+ 0.8
Continue Bisphosphonate ?
Mrs. PRP, WW, 82 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
Baseline Previous
2003
2005
73
75
0.633
0.649
- 3.0
- 2.9
2006
2008
76
78
0.682
0.691
-2.8
- 2.7
2010
79
0.704
-2.6
2012
82
0.710
- 2.5
+ 2.3
+ 7.7
+ 9.2
+ 11.2
+ 12.2
+ 2.3
+ 5.1
+ 1.3
+ 1.8
+ 0.8
Continue Bisphosphonate ?
Mrs. PRP, WW, 82 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
Baseline Previous
2003
2005
73
75
0.633
0.649
- 3.0
- 2.9
2006
2008
76
78
0.682
0.691
-2.8
- 2.7
2010
79
0.704
-2.6
2012
82
0.710
- 2.5
+ 2.3
+ 7.7
+ 9.2
+ 11.2
+ 12.2
+ 2.3
+ 5.1
+ 1.3
+ 1.8
+ 0.8
Continue Bisphosphonate ?
Mrs. PRP, WW, 82 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
Baseline Previous
2003
2005
73
75
0.633
0.649
- 3.0
- 2.9
2006
2008
76
78
0.682
0.691
-2.8
- 2.7
2010
79
0.704
-2.6
2012
82
0.710
- 2.5
C-TX 320 pg/mL
+ 2.3
+ 7.7
+ 9.2
+ 11.2
+ 12.2
+ 2.3
+ 5.1
+ 1.3
+ 1.8
+ 0.8
Continue Bisphosphonate ?
Mrs. PRP, WW, 82 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
Baseline Previous
2003
2005
2006
2008
2010
73
75
76
78
79
0.633
0.649
0.682
0.691
0.704
- 3.0
- 2.9
-2.8
- 2.7
-2.6
+ 2.3
+ 7.7
+ 9.2
+ 11.2
+ 2.3
+ 5.1
+ 1.3
+ 1.8
2012
82
0.710
- 2.5
+ 12.2
+ 0.8
C-Tx 320 pg/mL
Continue Bisphosphonate
Mrs. XEV, WW, 78 years
 Diagnosed with osteoporosis about 8 years ago
 Secondary causes excluded.
 Started oral bisphosphonate weekly, then
converted to 150 mg once a month
 No adverse effects, taking it as directed, own routine
 Good compliance
 Good daily calcium/vitamin D intake
Mrs. XEV, WW, 78 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
2002
2004
2005
63
65
66
0.700
0.721
0.724
- 2.0
- 1.8
- 1.8
+ 3.0
+ 3.4
+ 3.0
+ 0.4
2007
2008
68
69
0.727
0.707
- 1.5
-1.9
+ 3.8
+ 1.0
+ 0.4
- 2.8
2010
72
0.695
- 2.1
- 0.7
- 1.7
Baseline Previous
Mrs. XEV, WW, 78 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
2002
2004
2005
63
65
66
0.700
0.721
0.724
- 2.0
- 1.8
- 1.8
+ 3.0
+ 3.4
+ 3.0
+ 0.4
2007
2008
68
69
0.727
0.707
- 1.5
-1.9
+ 3.8
+ 1.0
+ 0.4
- 2.8
2010
72
0.695
- 2.1
- 0.7
- 1.7
Baseline Previous
Mrs. XEV, WW, 78 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
2002
2004
2005
63
65
66
0.700
0.721
0.724
- 2.0
- 1.8
- 1.8
+ 3.0
+ 3.4
+ 3.0
+ 0.4
2007
2008
68
69
0.727
0.707
- 1.5
-1.9
+ 3.8
+ 1.0
+ 0.4
- 2.8
2010
72
0.695
- 2.1
- 0.7
- 1.7
Baseline Previous
Mrs. XEV, WW, 78 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
2002
2004
2005
63
65
66
0.700
0.721
0.724
- 2.0
- 1.8
- 1.8
+ 3.0
+ 3.4
+ 3.0
+ 0.4
2007
2008
68
69
0.727
0.707
- 1.5
-1.9
+ 3.8
+ 1.0
+ 0.4
- 2.8
2010
72
0.695
- 2.1
- 0.7
- 1.7
Baseline Previous
C-Tx 76 pg/mL
Mrs. XEV, WW, 78 years
Right Total Hip
Scan
Date
Age
BMD
T-scores % BMD Change
2002
2004
2005
63
65
66
0.700
0.721
0.724
- 2.0
- 1.8
- 1.8
+ 3.0
+ 3.4
+ 3.0
+ 0.4
2007
2008
68
69
0.727
0.707
- 1.5
-1.9
+ 3.8
+ 1.0
+ 0.4
- 2.8
2010
72
0.695
- 2.1
- 0.7
- 1.7
Baseline Previous
C-Tx 76 pg/mL
D/C Bisphosphonate
Mrs. WF, 68 yrs,
Wt: 140 lbs Ht: 62 in
 Known to have osteoporosis
 CBC, Blood Chem. Profile, TSH: within
normal limits.
 Prescribed an oral bisphosphonate.
Mrs. WF, 68 yrs,
Wt: 140 lbs Ht: 62 in
DXA Scan
Results
Baseline
BMD T-score
2 yrs later % Change
BMD T-score
BMD
Right Total Hip
0.721 -2.5
0.689 - 2.9
- 4.5
2.2
Left Total Hip
0.688 -2.7
0.657 - 2.9
- 5.1
2.8
Lumbar Vertebrae
Multiple vertebral compression fractures
Bisphosphonates, good compliance
Complete blood picture
Blood chemistry profile
Thyroid stimulating hormone
Normal
LSC
Mrs. WF, 68 yrs,
Wt: 140 lbs Ht: 62 in
DXA Scan
Results
Baseline
BMD T-score
2 yrs later % Change
BMD T-score
BMD
LSC
Right Total Hip
0.721 -2.5
0.689 - 2.9
- 4.5
2.2
Left Total Hip
0.688 -2.7
0.657 - 2.9
- 5.1
2.8
Lumbar Vertebrae
Multiple vertebral compression fractures
Bisphosphonates, good compliance
Complete blood picture
Blood chemistry profile
Thyroid stimulating hormone
Normal
25(OH) Vitamin D
12 ng/mL
Mrs. RV, 60 years, WW, Second visit
RIGHT HIP
Fem Neck
Total Hip
4-years ago
T oday
BMD T-score BMD T-score
0.676 - 1.6
0.655 - 1.7
0.750 - 1.6
0.688 - 2.1
% Change
BMD
- 3.3
- 8.3
LEFT HIP
Fem Neck
Total Hip
0.609
0.735
- 2.0
- 12.2
L1-L4
Cannot be interpreted: scoliosis and artifacts
- 2.2
- 1.7
0.597
0.646
- 2.3
- 2.4
Prescribed alendronate 4-years ago
Mrs. RV, 60 years, WW, Second visit
RIGHT HIP
Fem Neck
Total Hip
Baseline
BMD T-score
0.676 - 1.6
0.750 - 1.6
4 years later
BMD T-score
0.655 - 1.7
0.688 - 2.1
% Change
BMD
- 3.3
- 8.3
LEFT HIP
Fem Neck
Total Hip
0.609
0.735
0.597
0.646
- 2.0
- 12.2
L1-L4
Cannot be interpreted: scoliosis and artifacts
- 2.2
- 1.7
- 2.3
- 2.4
Did not refill her
second prescription
of Alendronate
Non-response to oral bisphosphonates
• Compliance/adherence
• Inadequate Calcium/vitamin D
• Secondary osteoporosis
Long-term Management of Osteoporosis
March 25, 2013
OBJECTIVES
 Evaluate the risk/benefit of long-term therapy for
osteoporosis
 Develop a long-term management strategy tailored to
the individual circumstances of the patient.
 Recognize the possible long-term complications of
medications commonly used for osteoporosis