Transcript on Post-ASBMR 2012 Update - Sigma Canadian Menopause Society

November 2012
American Society for Bone and
Mineral Research (ASBMR)
2012 Update (+ videos)
D Kendler, Vancouver
J D Adachi, Hamilton
J Brown, Quebec
A Cheung, Toronto
K. S. Davison, Victoria
L Dian, Vancouver
A Khan, Oakville
D Hanley, Calgary
A Hodsman, London
R Josse, Toronto
A Jovaisis, Ottawa
S Kaiser, Halifax
L-G Ste. Marie, Montreal
C Yuen, Vancouver
Credits and Disclosures
• Sigma, Canadian Menopause Society
• Scientific Committee (reviewers)
– From across Canada, osteoporosis leaders and
community practitioners
• Unrestricted educational grant support:
– Amgen, Eli Lilly, Merck, Novartis, [Warner Chilcott]
• Speaker disclosures
ASBMR Update: Objectives
• To discuss the latest research in the area
of metabolic bone disease.
• To better understand the management of
osteoporosis patients, incorporating the
most up-to-date information.
Navigation
• Presenter will facilitate presentation with
navigation in any order to the abstracts (click on
topic: menu and submenu)
• The respective slides will detail the findings and
importance of the chosen investigation
• Click on “return” slide to return to topic menu.
• Original abstract is in the “notes” section of the
first slide.
Topics
• Fracture Risk
Assessment
• Atypical
fractures/ONJ
• Teriparatide
• Sclerostin Ab and
other Anabolics
• Denosumab
• SERM, Estrogen,
Testosterone
• Other and Upcoming
therapies
• Bisphosphonates
• Vitamin D / Calcium
Fracture Risk Assessment
•
•
•
•
TBS and fracture risk in DM
Cortical porosity in DM
Post-fracture care gap
OP treatment based on FRAX without BMD
(VIDEO)
• Fall and fracture risk assessment
• Fracture Liaison Services Models
TBS (Trabecular Bone Score) is More
Sensitive Than BMD to Diabetes-Related
Fracture Risk
• William Leslie, University of Manitoba, Canada
TBS More Sensitive Than BMD to
Diabetes Fracture Risk
• Type 2 DM (T2D) associated with increased
fracture risk but paradoxically greater BMD.
• TBS (trabecular bone score), a novel grey-level
texture measurement from DXA images.
• 29,407 women over 50 years from Manitoba
database
• 2,356 had DM (90% assumed T2D)
• Incidence of major osteoporotic fracture with
follow-up 4.7 yr
• T2D associated with higher BMD LS, femoral
neck and total hip, but lower LS TBS (all
p<0.001).
TBS More Sensitive Than BMD to
Diabetes Fracture Risk
• Osteoporotic fractures in 175 (7.4%) with and
1,493 (5.5%) without T2D (p < 0.001).
• LS TBS predicted fractures in those with T2D
(HR 1.27, 95%CI 1.10-1.46) and without T2D
(HR 1.31, 95%CI 1.24-1.38).
• LS TBS was an independent predictor of fracture
(p<0.05) when further adjusted for BMD (LS, FN,
or total hip).
• LS TBS predicts osteoporotic fractures in T2D,
and captures a large portion of the diabetesassociated fracture risk.
• Combining LS TBS with BMD incrementally
improves fracture prediction.
TBS More Sensitive Than BMD to
Diabetes Fracture Risk
Potential Importance
• TBS quantitates an aspect of bone
architecture
• TBS is a “Bone Quality” measurement
available by re-analysis of existing DXA
capture
• Particular importance in conditions such
as diabetes where DXA BMD does not
fully reflect fracture risk
return
Cortical Porosity as a Distinct
Pathomorphology in Postmenopausal,
Diabetic Women with Fragility Fractures
• Janina Patsch, University of California, San
Francisco, USA
Cortical Porosity in PMP,
Diabetic Women with Fractures
• DM2 with paradoxically increased fracture
rates in spite of high BMD
• Assess if Ct.Po in PMP DM2 with fractures
compared with non-fractured diabetics,
non-diabetic controls with prevalent
fragility fracture
• Controls [Co] n=20; controls with fractures
[Fx] n=20; diabetics without fracture [DM]
n=20; diabetics with fracture [DMFx] n=15)
Cortical Porosity in PMP,
Diabetic Women with Fractures
• Ct.Po was significantly associated with
fracture in patients with DM2 at the
ultradistal tibia (p for interaction=0.038),
but not at the radius. No significant
association with controls
• DMFx displayed the highest cortical
porosity of all groups (age-, race & BMIadjusted means +52.2% vs DM; + 36.0%
vs Fx; +34.2% vs Co)
Cortical Porosity in PMP,
Diabetic Women with Fractures
• No correlations between Ct.Po and fasting
glucose, HbA1c or c-peptide
• Patients with prevalent fractures had
significantly reduced aBMD measured with
DXA, but mean aBMD values remained
normal to osteopenic in all
• Tibial Ct.Po measured by HR-pQCT
identifies DM2 patients with prevalent
fragility fractures.
Cortical Porosity in PMP,
Diabetic Women with Fractures
Representative HR-pQCT scans of diabetic women with and without
fragilityfractures (DMFx vs. DM)
Potential Importance
• HR-pQCT may provide additional
diagnostic utility when compared to that of
DXA alone
• Differences in cortical porosity may
partially explain the increase in
appendicular fractures in DM2 as
compared to individuals without DM2
return
Osteoporosis Treatment Following
Fragility Fracture Remains Unaddressed
Despite Available Therapies and
Established Recommendations
• Cynthia O'Malley, Amgen Inc, USA
Treatment Following Fracture
Unaddressed Despite Recommendations
• Retrospective analysis 2000-2010 US data
from community-dwelling individuals aged
≥50 years with a newly diagnosed fragility
fracture and no OP treatment
• Initiated OP treatment in the year postfracture
• 88,571 women and 41,984 men mean
ages of 72.3 and 70.5 yrs.
• A minority of patients, 18.6% of women
and 9.6% of men, initiated OP treatment
post-fracture.
Treatment Following Fracture
Unaddressed Despite Recommendations
• Over age 85, only 23% women and 13%
men treated.
• Women ≥85yr accounted for 34% of hip
fractures in females
• For both genders, OP treatment initiation
was highest following vertebral fracture,
intermediate following hip and lowest
following wrist and humerus fractures
(p<0.0001).
• Treatment rates declined over the last
decade, despite recommendations for OP
treatment following fragility fracture
Treatment Following Fracture
Unaddressed Despite Recommendations
Potential Importance
• Secondary prevention of fragility fractures
is high priority with osteoporosis experts
due to the high risk of future fracture
• Large care gap indicates the need for
innovative programs to identify these high
risk patients and target them to evaluation
and therapy
return
Treatment (Rx) of Post-Menopausal
Women with High FRAX Scores may
be Cost-Effective without First
Performing Bone Densitometry
• John Schousboe, Park Nicollet Clinic University
of Minnesota, USA
Treatment of PMP Women with
High FRAX Scores prior to BMD
• In women over 65 yrs, 30% meeting FRAX
treatment threshold for major osteoporotic
fracture and 60% meeting FRAX treatment
threshold for hip fracture have FN T-scores
greater than -2.5.
• Markov model with high fracture risk by FRAX
without BMD compared to first obtaining a BMD
test plus VFA and Rx of only the subset with
either FN T-score ≤-2.5 or a prevalent vertebral
fracture.
• Prevalence of FN T-score >-2.5 in those with
FRAX w/o BMD 10-year hip and major
osteoporotic fractures risks ≥ 3% and ≥20% from
Manitoba database.
Treatment of PMP Women with
High FRAX Scores prior to BMD
• Age-specific prevalence of vertebral fracture
from Rochester Epidemiology Project.
• Costs per QALY gained for Rx of women with
high FRAX without BMD score vs. Rx of only
those with prevalent vertebral fracture or FN Tscore<-2.5;
• Treatment initiation on the basis of high fracture
risk estimated by FRAX w/o BMD may be costeffective, but this is highly sensitive to vertebral
fracture disutility and to assumed vertebral
fracture reduction on Rx for those with T-score
>-2.0 and no prevalent vertebral fracture.
• A randomized controlled trial of medication in
this population is needed.
Treatment of PMP Women with
High FRAX Scores prior to BMD
Potential Importance
• Introduces debate as to whether clinical
risk factors are sufficient, without a BMD,
to identify a patient population at risk of
fracture (and likely to benefit from therapy)
• Counter to this is
– Clinical trials rely on BMD to identify treatment
candidates
– FRAX without BMD correlates imprecisely to
FRAX with BMD
– BMD may be desirable for follow-up
FRAX alone may be cost-effective in identifying
patients for pharmacotherapy: but specific
intervention trials in this population are not available
return
System-Level Approaches to the
Secondary Prevention of
Osteoporotic Fractures: A
Systematic Review and Metaanalysis
• Andrea Kirtan Ganda, Markus Seibel, Michele
Puech, Jian Sheng Chen, University of Sydney,
NSW
Systems-Level Secondary
Fracture Prevention
• Identified 43 studies of fracture prevention
programs and grouped them in four general
models of care:
•
•
•
•
Type A: patients identified, assessed & treated - a fully
integrated service
Type B, as in A, but the service only makes treatment
recommendations
Type C, provides patient education & alerts PCP re.
need for assessment and treatment
Type D,provides patient education only.
Systems-Level Secondary
Fracture Prevention
Summary Of Meta-analyses: Treatment Initiation Rates by Treatment Type
Intervention Type
Risk Difference
95% Confidence
Interval
Model of Care ‘A’ (n=8)
0.29
0.19-0.40
Model of Care ‘B’ (n=5)
0.21
0.05-0.37
Model of Care ‘C’ (n=7)
0.16
0.07-0.25
Model of Care ‘D’ (n=81)
0.03
0.00-0.07
Systems-Level Secondary
Fracture Prevention
• Better rates of BMD testing and treatment initiation
with increasing intensity of intervention.
• Only five studies examined re-fracture rates but
only one Type A had a control group and enough
power to show a significant decrease in refractures at 4 years follow-up.
• Type A & B services have been shown to be cost
effective
Potential Importance
• Fracture Liaison Service (FLS) with initiation of
assessment and therapy = most effective
approach.
• Role for the Primary Care Physician?
•
•
Simple education programs are not effective.
Perhaps the FLS could turn over the work to primary
care practitioners after long experience with success
is appreciated by the medical community.
return
Effect of a Multifactorial Fall-andFracture Risk Assessment and
Management Program on Gait and
Balance and Disability in
Hospitalized Older Adults: a
Controlled Study
• Andrea Trombetti, Division of Bone Diseases,
University Hospitals and Faculty of Medicine of
Geneva, Switzerland
Fall-and-Fracture Risk
Assessment and Management
• Effects on physical performance and ADL of falland-fracture risk assessment and management
program
• 122 in-patients (mean age, 84±7 years) with fall
• 92 multidisciplinary program re: fall and fracture
• 30 age-matched controls.
• Intervention group improved Timed Up & Go
(P=0.017), Tinetti (P<0.001), and Functional
Independence Measure (P=0.027) tests
• Decreased hospital readmission (HR, 0.30; 95%,
P=0.02).
• More beneficial than usual care in improving
physical parameters related to the risk of fall
Potential Importance
• Integrated fall and fracture risk
assessment and intervention may reduce
future hospitalization
return
Atypical Femoral
Fractures/ONJ
• TPTD and healing of AFF (VIDEO)
• Subtroch fractures and AFF criteria
• AFF histomorphometry before and after
TPTD
• BP delivery to mandible
Effect of Teriparatide on Fracture
Healing in Patients with NonDisplaced Incomplete Atypical
Femur Fractures
• Angela Cheung, University Health Network,
Canada
TPTD and Fracture Healing in
Patients with AFF
• 13 patients with incomplete AFF treated with
TPTD.
• All were PMP women (69.2% Caucasians,
15.4% Southeast Asians, 15.4% South Asians)
mean age 68.6 (range 57.5- 81.0) years
• 8/13 had previous complete AFF.
• Average duration of BP was 12.6 years (range
3.0-28.0).
• Mean BMD T-scores at diagnosis of AFF were
LS -1.87, TH -1.14 and FN -1.85.
TPTD and Fracture Healing in
Patients with AFF
• TPTD therapy mean 13.4 months (range: 1.4 to
20.2 months).
• 3 pts prophylactic surgical repair (2 for
progression of fracture and 1 for preference).
• Other 10 patients: 5 had radiographic
improvement, 4 had no change and 1
progressed despite TPTD.
• Unclear whether TPTD improves fracture
healing in patients with incomplete nondisplaced AFFs.
Potential Importance
• ASBMR Task Force on AFF indeterminate
on role of TPTD in incomplete AFF
• Potential role in fracture healing, reversal
of bone turnover suppression after BP
therapy
• Indeterminate response due to low
numbers, short duration of TPTD in some
patients, heterogeneity of patients studied
Incomplete Atypical Femoral Fractures may
respond to teriparatide therapy but a
definitive clinical trial needs to be performed
return
Evaluation of 42 Cases of
Subtrochanteric Fractures using the
ASBMR Taskforce Criteria for
Atypical Femoral Fractures
• Angela Juby, University of Alberta, Canada
42 Cases of Subtrochanteric
Fractures for AFF
• Evaluate subtrochanteric fracture for ASBMR
taskforce criteria for AFF.
• Chart review all cases coded for subtrochanteric
fracture or unspecified hip or femur fracture,
referred to two tertiary care Edmonton hospitals
over 7 years (2002-2009)
• 50 isolated subtrochanteric fracture or femoral
shaft fracture identified out of 232 probable
cases suggested by coding
• Radiologist review all 50 cases using ASBMR
Taskforce criteria to assess for AFF
42 Cases of Subtrochanteric
Fractures for AFF
• Films reviewed in 42 cases; 19 had five major
features: location; appropriate history;
transverse or short oblique; non-comminuted;
medial spike.
• 7 of these cases also had radiological minor
features (cortical thickening, delayed healing or
bilaterality).
• Clinical data review identified a further 11 cases
with positive minor features, bringing 18/19
cases having all five major and some minor
features.
42 Cases of Subtrochanteric
Fractures for AFF
• Clinical minor features included prodromal
symptoms (5 cases), comorbidities (4),
bisphosphonate use (13), glucocorticoid use (4),
anticonvulsant use(1). AFF rare fractures.
• Only 19/42 (45%) of these were true atypical
femoral fractures based on the ASBMR criteria.
• During the study period, approximately 21 000
typical osteoporotic hip fractures would have
occurred
• Much greater risk of typical v. AFF
Potential Importance
• Diagnostic coding may identify many
subtrochanteric fractures, but few meet
criteria for AFF
• Overwhelmingly greater incidence of
typical hip fractures
• Importance of evaluating thoroughly for
AFF using all criteria
return
Quantitative Bone Histomorphometry in
Patients with BisphosphonateAssociated Atypical Subtrochanteric
Femur Fractures Before and After 12
Months of Teriparatide
• Paul Miller, Colorado Center for Bone Research,
USA
Bone Histomorphometry with BPAFF after 12 months of TPTD
• 15 AFF patients had intramedullary rods inserted,
then treated with TPTD 20ug/day for 12 mo
• Baseline and 12 mo iliac crest biopsy
• Baseline mineral apposition rate (MAR) in the
group averaged 0.278 um/day (normal: 0.66-0.83
um/day) and was zero in 7 patients.
• After TPTD administration the average MAR
increased to 0.647 um/day.
• All 7 patients who had immeasurable MAR at
baseline increased their MAR following TPTD
(average: 0.673 um/day).
Bone Histomorphometry with BPAFF after 12 months of TPTD
• Following TPTD, BFR increased in all patients,
including the 7 with immeasurable MAR to an
average of 4.03 %/yr.
• Along with BP discontinuation, TPTD may
increase MAR and BFR in patients with AFF.
• Unknown if TPTD would prevent early fractures
from progressing.
Potential Importance
• TPTD (and stopping BP) can increase
bone turnover evidenced by bone biopsy
in most patients with AFF post BP
• Uncertain whether TPTD should be used
after AFF
return
Fluorescence Imaging Reveals High
Bisphosphonate Delivery to the
Mandible Regardless of Bone
Turnover Status
• Joseph E. Perosky, University of Michigan
Department of Orthopaedic Surgery, USA
Fluorescence Imaging Bisphosphonate
Delivery to the Mandible
• Role of bone turnover in the local accumulation
of BPs at mandible, femur, and tibia in mice.
• High and low bone turnover induced by PTH and
BP treatment
– fluorescent-labeled BPs to assess local drug
concentration.
• TPTD (80µg/kg daily), pamidronate (PAM, 1.07
mg/kg daily), or PBS for 1 week (n=1416/group), after which injected with single dose
far-red fluorescent pamidronate (FRFP, 100
nmol/kg).
Fluorescence Imaging Bisphosphonate
Delivery to the Mandible
• For all treatment groups, FRFP/BS in the
mandible was higher than both femur
(PTH=26%, PBS=69%, PAM=39%) and tibia
(PTH=99%, PBS=187%, PAM=120%).
• Mandibles less sensitive to treatment effects, as
FRFP/BS was equivalent across treatment
groups.
• At femur and tibia, local bone turnover regulates
local BP delivery, however the mandible may be
particularly susceptible to high levels of BP
delivery regardless of bone turnover condition.
Fluorescence Imaging Bisphosphonate
Delivery to the Mandible
Potential Importance
• ONJ of uncertain pathogenesis
• Selective concentration of BP in mandible
may contribute to pathology
• Blood supply to mandible may contribute
to BP accumulation at sites of bone
trauma
return
SERM/Estrogen/Testosterone
• Sex steroid and Fx in WHI
• Sex steroid and Fx in MrOs
• HRpQCT in early menopause:
KEEPS
Sex Steroid Hormones and Fracture
in a Multi-ethnic Cohort of Women:
The Women’s Health Initiative (WHI)
• Jane Cauley, University of Pittsburgh Graduate
School of Public Health, USA
Sex Steroid Hormones and
Fracture in WHI
• Nested case-control study within WHI
• Incident fractures in 381 Black, 192 Hispanic,
112 Asian, and 46 Native American women over
8.6 years.
• Mean age 63-66 yrs.
• BioE2 (pg/ml) lowest in Asian (5.3) and highest
in Black and Native American (8.1).
• BioT (ng/dL) lowest in Asian women (9.5) and
highest in Black (12.1).
• SHBG (nmol/L) lowest in Black (37.9) and
highest in White (48.1).
Sex Steroid Hormones and
Fracture in WHI
• Serum E2 important biomarker for fracture
risk in both White and Black women.
• Testosterone has greater influence on
fracture risk in Black and Native American
women.
Sex Steroid Hormones and
Fracture in WHI
Potential Importance
• Sex steroids in postmenopausal women
may be dependent on ethnicity (reference
ranges not ethnicity dependent)
• Different fracture risk prediction may be
seen in different ethnic groups with various
sex steroid assays.
return
Lack of Value of Serum Sex Steroid
Measures in the Prediction of
Osteoporosis and Fracture Risk in
Community-Dwelling, Ambulatory
Older Men
• Eric Orwoll, Oregon Health and Science
University, USA
Sex steroid measures in
osteoporosis in men
• Estradiol (E), SHBG and testosterone (T)
associated with BMD and fracture risk in
older men.
• MrOS: 1563 men > 65 yrs, baseline
assays of E, T and SHBG.
• Ability of T, E and SHBG to predict BMD
status (T score<-2.5 vs >-2.5) and fracture
risk was assessed.
Sex steroid measures in
osteoporosis in men
• T, E and SHBG provided virtually no benefit for
the prediction of BMD status, BMD loss or
fracture risk.
• Results were unchanged when bioavailable T
and E were examined.
• In older men there is low predictive value for sex
steroid and SHBG measurements in assessing
BMD status, rate of BMD change or fracture risk.
Potential Importance
• Male sex steroid determinations may not
be predictive of bone density, bone loss or
fracture risk
• OP therapies (ALN, RIS, ZOL, TPTD,
DMAB) generally work well in either the
presence or absence of sex steroid
• Non-sex steroid therapies should be the
standard of care for men with idiopathic
male osteoporosis
return
HRpQCT Reveals That Four Years of
Estrogen Therapy in Early
Postmenopausal Women Prevents
Cortical, but Not Trabecular, Bone Loss
• Joshua Farr, Mayo Clinic, USA
HRpQCT in KEEPS Trial: Estrogen in
Early Postmenopause Prevents Cortical,
But Not Trabecular, Bone Loss
• HRpQCT cortical and trabecular bone at radius
in early PMP women (mean age, 53 yrs) in
Kronos Early Estrogen Prevention Study
(KEEPS)
• Randomized to 4yr PBO, oral (0.45 mg/d CEE)
or transdermal (50 µg/d 17β-estradiol) E (with
progesterone, 200 mg/d for 12 d each month).
• 31 PBO and 45 ET
• ET prevented decreases in cortical vBMD and
increases in cortical porosity observed in PBO
group.
• ET unable to prevent decreases in trabecular
bone volume fraction or trabecular thickness
HRpQCT in KEEPS Trial: Estrogen in
Early Postmenopause Prevents Cortical,
but Not Trabecular, Bone Loss
• ET prevented decreases in hip, spine, and
distal radius areal BMD, suggesting that
changes in cortical bone at these sites
may have masked ongoing trabecular
bone loss.
• Different regulation of cortical versus
trabecular bone by E.
• Further studies needed to define
mechanisms for the differential responses
of trabecular and cortical bone to E
HRpQCT in KEEPS Trial: Estrogen in
Early Postmenopause Prevents Cortical,
but Not Trabecular, Bone Loss
Potential Importance
• Different cortical and trabecular bone
effects of estrogen therapy
– Preservation of cortical envelope with
decreases in trabecular bone
– Possibly related to lower than usual dose of
estrogen
return
Bisphosphonate
• BMD changes and fracture risk: ZOL extn
• Drug access to bone compartments
(VIDEO)
Relationship Between Change in Total Hip
BMD in Response to Zoledronic Acid 5 mg and
Post-treatment Change in Total Hip BMD: the
HORIZON-PFT Extension Study
• Richard Eastell, University of Sheffield, UNITED
KINGDOM
Change TH BMD and Post-ZOL
Change in TH BMD
• Bone loss after stopping ZOL associated with
greater BMD gain in response to initiation of
ZOL or to baseline bone turnover and change in
bone turnover.
• HORIZON-PFT Extension, Z3P3 group, n=617
• Change in TH BMD in years 0-3 related to
change in TH BMD on PBO in years 3-6 (r= 0.15, P=0.0015).
• Those with greater gains during years 0-3 had
greater loss during years 3-6.
Change TH BMD and Post-ZOL
Change in TH BMD
• Baseline P1NP correlated with change in
THBMD in years 0-3 on ZOL (r= 0.32, P=0.0002)
and to change in TH BMD in years 3-6 after
stopping (r= -0.26, P=0.007).
• Change in P1NP (years 0-3) correlated with
change in THBMD in years 0-3 on ZOL (r= 0.35, P=0.0003) and the change in PINP (years
3-6) was correlated with change in THBMD in
years 3-6 on zoledronic acid 5 mg annually (r=0.18, P=0.0005).
• BMD loss after stopping ZOL greater in those
with greater gains in BMD on ZOL
Potential Importance
• Bone turnover markers corresponded to
changes in BMD, especially P1NP
– Potential utility of BTM as an early predictor of
BMD response
• Possible “regression to the mean” with
greatest gainers in first 3 years the
greatest losers in next 3 years
return
Antiresorptive Action is Dependent on
Access to Remodeling Upon Cortical
and Trabecular Surfaces: Comparison
of Denosumab and Alendronate
• Roger Zebaze, Austin Health, University of
Melbourne, Australia
ALN v. Dmab Porosity
• The degree to which antiresorptives suppress
remodeling could be due, in part, to differences
in their access to bone compartments.
• Cortical bone access may be more difficult than
trabecular bone
• PMP women randomized to Dmab (N=83) or
ALN (N=82), or PBO (N=82) for 12 months.
• HRpQCT distal radius at 0, 6, and 12 months
• Both Dmab and ALN improved trabecular BV/TV
v. PBO.
ALN v. Dmab Porosity
• ALN reduced porosity at month 6 in the cortex;
at month 12 no difference ALN v. PBO.
• Dmab reduced porosity in all cortical
compartments with reductions larger than ALN
• Access to cortical bone by therapeutic agents
may be a challenge
• Broader distribution of Dmab v. ALN associated
with greater and more uniform reductions in
porosity throughout the cortex, effects likely to
increase bone strength.
Porosity effects of ALN v. Dmab
Access of medications to the cortical compartment
of bone may be crucial to their efficacy.
Bisphosphonates (v. Dmab) may be limited in their
ability to access cortical bone.
return
Denosumab
•
•
•
•
•
BMD changes and Fx risk: FREEDOM ext
BTM profile: FREEDOM extn
Dmab v. RIS in ALN non-adherent pts
Dmab in men: Baseline BTM effects
Histomorphometry after 5 yr Dmab
(VIDEO)
• Dmab and TBS (Trabecular Bone Score)
• Dmab in men v. Women v. men with
prostate ca
Relationship Between Changes in
Bone Mineral Density and Incidence
of Fracture With 6 Years of
Denosumab Treatment
• Paul D. Miller, University of Colorado Health
Sciences Center and Colorado Center for Bone
Research, USA
BMD and Fracture With 6 Years
of Denosumab Treatment
• BMD gains with 6 yrs (3 yr core 3 yr extension)
DMAb and fracture
• 3 additional years of DMAb treatment (N=2343
enrolled), further increases BMD for 6-year
gains of 15.2% (LS), 7.5% (TH), and 6.7% (FN)
• At year 6, responders (gains in BMD) with DMAb
were 98% at LS BMD, 96% at TH, and 91% at
FN
BMD and Fracture With 6 Years
of Denosumab Treatment
• 99% of women had gains in BMD at any of these
sites
– >3% in 98% of women
– >6% in 95% of women
• Gains in BMD LS TH or FN >6% in 95%
• On denosumab, the risk of new or worsening
vertebral fracture and nonvertebral fracture
decreased with increasing percentage change in
total hip BMD over 6 years.
Miller et al. ASBMR; Minneapolis, MN; October 14, 2012
Miller et al. ASBMR; Minneapolis, MN; October 14, 2012
Miller et al. ASBMR; Minneapolis, MN; October 14, 2012
Potential Importance
• The percent of fracture risk reduction
accounted for by increases in BMD has
led to confusion as to the role of BMD
follow-up testing
• Significant and progressive increases in
BMD on DMAB
– BMD improvement with Dmab may provide
assurance of fracture risk reduction
return
The Dynamic Profile of CTX Observed
With Denosumab Is Maintained Over 6
Years of Treatment: Results From the
First 3 Years of the Pivotal Phase 3
Fracture Trial (FREEDOM) Extension
• Christian Roux, Paris Descartes University,
France
CTX with Dmab Over 6 Years:
FREEDOM Extension
• FREEDOM extension, CTX in 50 subjects every 6
months for 6 years on DMAb
• 79 subjects who received 6 years of DMAb had CTX at
FREEDOM extension baseline and year 6.
• 10 days after 1st DMAb dose in extension, CTX
decreased 91%, and 6 mo after DMAb, CTX reduced
77% (n=50).
• At year 6, pre-dose CTX was decreased 57% (n=79).
• CTX at year 6 correlated with CTX at FREEDOM
baseline (p<0.01) and time since the last DMAb dose at
year 5.5 (p<0.0001)
CTX with Dmab Over 6 Years:
FREEDOM Extension
• CTX at year 6 correlated with CTX at the
extension study baseline (after 3 years of DMAb
in FREEDOM, p<0.0001).
• Long-term DMAb treatment is associated with a
dynamic profile of CTX reduction.
• Pre-treatment CTX values and time since the
last DMAb injection continue to be significant
predictors of CTX at year 6.
Potential Importance
• No tachyphylaxis seen with DMAB to 6
years
• Dynamic BMT changes persist with
recovery prior to next dose
– Reversibility of Dmab effect does not diminish
over time
return
Denosumab Compared With Risedronate
in Postmenopausal Women Suboptimally
Adherent With Alendronate Therapy:
Efficacy and Safety Results From a
Randomized Open-label Study
• JP Brown, CHUQ-CHUL Research Centre,
Canada
Dmab v. RIS In PMO pts not
adherent to ALN
• Compare efficacy and safety of DMAb with RIS
over 12 months in PMO transitioned from ALN
and were non-adherent
• Randomized to DMAb or mthly RIS for 12 mo.
• 870 randomized (435, DMAb; 435, RIS), age 68
years, BMD T-score –1.6, –1.9, and –2.2 at the
total hip, FN, and LS, respectively
Dmab v. RIS In PMO pts not
adherent to ALN
• DMAb increased BMD total hip v. RIS (2.0% v.
0.5%; p < 0.0001)
• Overall adverse events similar between groups.
• In postmenopausal women who were
suboptimally adherent with ALN, switching to
DMAb is more effective than RIS
– Greater increases in BMD
– Greater reductions in CTX with DMAb.
Dmab v. RIS In PMO pts not
adherent to ALN
Potential Importance
• BMD and BTM benefits in ALNnonadherent patients switched to DMAB v.
RIS monthly
• Fracture endpoints not available in this
small group
• May reinforce data suggesting improved
adherence to DMAB over oral BP
return
The Effect of Denosumab on Bone
Mineral Density (BMD) Assessed by
Baseline Bone Turnover in Men With Low
BMD
• Paul Miller, Colorado Center for Bone Research,
USA
Dmab Effect on BMD by
Baseline Bone Turnover in Men
• Efficacy of DMAb in men across a range of
baseline bone turnover in ADAMO.
• Men randomized to DMAb or placebo for 1 year
• 30 to 85yrs; BMD T-score -2.0 to -3.5 LS or FN,
or prior osteoporotic fracture and a T-score -1.0
to -3.5 at the LS or FN.
• 242 subjects (121, placebo; 121, DMAb)
• With DMAb, BMD increased 5.7%, 2.4%, 2.1%,
3.1%, and 0.6% at the LS, TH, FN, TR, and
1/3R, respectively (all p<0.02 v. placebo).
• sCTX reduced by 81% (DMAb) vs 7% (placebo)
from baseline at day 15.
Dmab Effect on BMD by
Baseline Bone Turnover in Men
• DMAb –associated greater gains in LS and TH
BMD at month 12 at each tertile of baseline
sCTX
• Highest tertile of baseline resorption had
numerically greatest gains in BMD when
compared with the lowest tertile (p=NS)
• Men with low BMD treated 1 year with DMAb, v.
PBO, demonstrated greater gains in BMD
independent of baseline sCTX
• Men at all levels of bone turnover may benefit
from DMAb therapy.
Dmab Effect on BMD by
Baseline Bone Turnover in Men
Potential Importance
• DMAB efficacy not dependent on baseline
bone turnover
• BTM not necessary to determine treatment
choice in men with osteoporosis
return
Effects of 5 Years of Denosumab on
Bone Histology and Histomorphometry:
the FREEDOM Study Extension
• Jacques Brown, CHUQ Research Centre Laval
University, CANADA
5 Yr Dmab on Bone
Histomorphometry: FREEDOM
• 41 subjects at month 24, (year 5 of study
13 cross-over and 28 long-term subjects)
• Normally-mineralized lamellar bone.
• 5 pts in long-term group had no
observable osteoid
• Structural indices, including cancellous
bone volume, trabecular number and
surface were similar between the crossover and long-term groups.
5 Yr Dmab on Bone
Histomorphometry: FREEDOM
• Resorption decreased in both cross-over and
long-term subjects compared with placebotreated subjects
• 10/13 (77%) cross-over subjects and 14/28
(50%) long-term subjects had doubletetracycline label in trabecular and/or cortical
compartments
• DMAb treatment through 5 years results in
normal bone quality with reduced bone turnover,
consistent with its mechanism of action.
5 Yr Dmab on Bone
Histomorphometry: FREEDOM
Potential Importance
• Histomorphometry essential for
demonstration of long-term safety of OP
medications
• At 5 years, no safety issues identified with
DMAB.
• Suppression of bone turnover is marker of
DMAB efficacy
Histomorphometry evidence of bone turnover
suppression in patients five years on Denosumab
is expected given the mechanism of action
return
Denosumab Significantly Improved
Trabecular Bone Score (TBS), an Index of
Trabecular Microarchitecture, in
Postmenopausal Women With
Osteoporosis
• Michael R. McClung, Oregon Osteoporosis
Center, USA
Dmab and TBS in PMO
• Trabecular bone score (TBS), a novel gray-level
texture index from lumbar spine DXA images,
correlates with 3D parameters of trabecular
bone microarchitecture known to predict
fracture.
• TBS may improve risk stratification for vertebral
fracture independently of BMD
• Effect of DMAb on TBS over 36 mo and
association between TBS and LS BMD
• FREEDOM, TBS iNsight® v1.9, Med-Imaps, to
LS DXA
• TBS >1.35 normal microarchitecture, between
1.35 and >1.20 partially deteriorated, and ≤1.20
degraded microarchitecture.
Dmab and TBS in PMO
• 285 women age 73, mean LS BMD Tscore
–2.79, and mean LS TBS 1.20.
• DXA LS BMD with DMAb increased 9.8%
at 36 mo, also increases in TBS compared
with PBO
• Variance in the TBS change was largely
unrelated to BMD change, indicating that
TBS provides distinct information,
independent of BMD.
• In PMO, DMAb significantly improved
TBS, independent of BMD.
Dmab and TBS in PMO
Potential Importance
• TBS may be a marker of bone quality
(bone architecture) independent of BMD in
prediction of fracture risk
• Most important, TBS may be a parameter
which could be determined from existing
DXA data
• Indication of independent fracture
prediction from DXA and TBS with DMAB
TBS analyzes the DXA image of the spine
potentially giving information regarding bone
architecture and quality beyond what would be
obtained from BMD alone
return
Effects of Denosumab on Bone Mineral Density
(BMD) and Bone Resorption Marker in Men
With Low BMD Compared With Men With
Prostate Cancer Receiving Androgen
Deprivation Therapy and Women with
Postmenopausal Osteoporosis (PMO)
• Michael McClung, Oregon Osteoporosis Center,
USA
Dmab in Men With Low BMD,
Prostate Ca and PMO Women
• Analysis to evaluate consistency of DMAb
across these 3 populations in first 12 months
• Men on DMAb in ADAMO showed gains in LS
BMD of 5.7% compared to 4.3% and 5.5% in
HALT and FREEDOM, respectively
• DMAb reduced sCTX by 81% at day 15 in
ADAMO compared to 90% at month 1 in both
HALT and FREEDOM.
• LS BMD increase demonstrated consistency of
effects of DMAb across these 3 populations.
Dmab in Men With Low BMD,
Prostate Ca and PMO Women
Potential Importance
• RANK-RANKL-OPG pathway is the
seminal pathway for bone resorption
• Demonstration of similar BMD and BTM
effects between trials of PMO, men, and
men with prostate cancer are reassuring
that clinical trial data are in keeping with
preclinical data and mechanism of action
return
Teriparatide
•
•
•
•
TPTD v. ZOL histomorphometry:SHOTZ
TPTD add or switch after ALN or RLX
TPTD in OI: RCT
PreMP OP and TPTD: Predicting
response
• Dmab and TPTD combo in PMP OP:DATA
Differential Effects of Teriparatide and
Zoledronic Acid on the Outer and Inner
Surfaces of Cortical Bone in Postmenopausal
Women with Osteoporosis: Results from the
SHOTZ Trial
• David Dempster, Columbia University, USA
TPTD and ZOL Effects on Outer
and Inner Cortical Bone: SHOTZ
• Cortical bone important for fracture resistance:
endocortical and periosteal envelopes.
• Transiliac bone biopsies from 58 PMO F on
TPTD or ZOL after 6 mo.
• Tetracycline labels higher in all 3 envelopes in
TPTD compared to ZOL (p<0.001)
• Endocortical, 100% TPTD displayed double
labels; 21% ZOL group had double labels.
• Periosteal, 70% TPTD displayed labels; 17%
ZOL
• Possibility of periosteal expansion and,
therefore, an increase in bone size with TPTD.
TPTD and ZOL Effects on Outer
and Inner Cortical Bone: SHOTZ
TPTD and ZOL Effects on Outer
and Inner Cortical Bone: SHOTZ
Potential Importance
• Confirmation of differences between
anabolic and antiresorption medications
• Modelling effects of TPTD (35%) v.
remodelling effects (65%) indicated by
histomorphometry data
• Periosteal effects of TPTD may account
for increases in bone size over time
return
Hip and Spine Strength Effects of
Adding Versus Switching to
Teriparatide in Postmenopausal
Women with Osteoporosis Treated
with Prior Alendronate or Raloxifene
• Felicia Cosman, Helen Hayes Hospital, USA
Add v. Switch to TPTD in PMO
with Prior ALN or RLX
• PMO treated 18mo with ALN or RLX, Adding versus
Switching to TPTD on bone strength
• QCT baseline, 6,18 mo FEA
• Spine strength and vBMD increased in all groups,
no differences between Adding and Switching
• ALN stratum, at the hip, Adding TPTD increased
volumetric BMD relative to Switching at mo 6 (0.9%
vs -0.5%, P=0.004) and mo 18 (2.2% vs 0.0%,
P=0.002).
• At 18 mo in hip, increases in strength only observed
in Add group (2.7%, P<0.001 vs baseline; P=0.076).
Add V. Switch to TPTD in PMO
with Prior ALN or RLX
• RLX stratum, at hip, both volumetric BMD and
strength increased at 6 and 18 mo in Add group,
but only at 18 mo in Switch group.
• With prior ALN or RLX, Adding and Switching to
TPTD conferred similar effects on the spine.
• In ALN stratum at 18 months, hip strength
increased in the Add but not the Switch group.
• At 18 months, hip strength increased similarly in
both RLX groups.
Add V. Switch to TPTD in PMO
with Prior ALN or RLX
Potential Importance
• In patients after ALN therapy, hip strength
may benefit more from adding TPTD to
ALN rather than switching to TPTD by
FEA analysis
• Spine strength not different with Add v.
Switch
return
Teriparatide Improves BMD and Bone
Strength in Adults with Osteogenesis
Imperfecta: A Randomized, Blinded,
Placebo Controlled Trial
• Eric Orwoll, Oregon Health and Science
University, USA
TPTD Improves BMD and
Strength in Adults with OI
• 77 adults with OI (33 men, 44 women), mean
age 41 years (18-75)
– 51 OI type I, 14 type III and 12 type IV.
• No recent therapy
• RDBPCT 18 months TPTD or PBO.
• BMD increased more in the TPTD group than in
PBO group at total hip (2.7% vs -0.6%; p=
0.007) but not LS (5.3% vs 3.1%; p= 0.18) or
total body (-0.1% vs 1.0%; p= 0.32).
TPTD Improves BMD and
Strength in Adults with OI
• vBMD by QCT increased 13% with TPTD
and decreased 6% with PBO (p= 0.03).
• Vertebral strength FEA increased 13% in
TPTD and decreased 2.4% in PBO (p=
0.003).
• Fractures and AEs not different
• TPTD in adults with OI well tolerated
– Increased areal hip, volumetric spine BMD, as
well as estimated vertebral strength.
Potential Importance
• OI is a rare disease with the only
demonstrated effective therapy being
bisphosphonate
• First controlled trial demonstrating
effectiveness of TPTD bone anabolic
therapy in this disease
return
Absence of the Anabolic Window
Characterizes Premenopausal
Women with Idiopathic
Osteoporosis Who Do Not Respond
to Teriparatide
• Adi Cohen, Columbia University Medical Center,
USA
•
•
•
•
•
Absence of Anabolic Window in
Premenopausal Women with Idiopathic
Osteoporosis unresponsive to TPTD
Idiopathic osteoporosis (IOP) in premenopausal
women characterized by cortical and trabecular
microarchitectural deterioration
21 premenopausal women with IOP (17 with
fractures, age 39±6 yrs) treated with TPTD
24mo increases in BMD LS (12.2±8.3%), total
hip (6.4±5.6%) and FN (7.8±3.4%).
4 women unresponsive (nonRES) to TPTD
Bone remodeling activity lower in NonRES than
RES, as evidenced by lower CTX; 201 vs 431
pg/mL;p=0.001), OC; 12.0 vs 19.5
ng/mL;p=0.003), PINP; 32 vs 46; p=0.1)
•
•
•
•
•
•
Absence of Anabolic Window in
Premenopausal Women with Idiopathic
Osteoporosis unresponsive to TPTD
After TPTD, PINP increased in RES by 1mo,
peaked at 180% above baseline by 6mo and
returned to baseline by 24mo
In NonRES, the PINP peak was blunted (108%
above baseline) and delayed (12mo).
CTX rose comparably in RES and NonRES
1mo change in BTMs significantly predicted
percent change in LS BMD at 12mo
Most premenopausal women with IOP
responded to TPTD
Those with attenuated responses to TPTD had
low bone turnover at baseline and no evidence
of an anabolic window
Absence of Anabolic Window in
Premenopausal Women with Idiopathic
Osteoporosis unresponsive to TPTD
Potential Importance
• Premenopausal OP difficult to manage
and more difficult to understand.
• Often with fracture, bone anabolic therapy
is considered
• Predictors of efficacy of TPTD in these
patients previously unreported
– Low baseline bone turnover predicts poorer
TPTD response
return
The Effects of Combined Denosumab
and Teriparatide Administration on Bone
Mineral Density in Postmenopausal
Women: The DATA (Denosumab And
Teriparatide Administration) Study
• Benjamin Leder, Massachusetts General
Hospital Harvard Medical School, USA
Combined Dmab and TPTD in
PMO: The DATA Study
• 92 PMO women (age 51-91), 12-mo RCT comparing
TPTD (n=31), DMAB (n=33), or both (combo) (n=30)
• 12-mo, total hip BMD increased more in combo (4.9% ±
2.9%) than in either the TPTD (0.7% ± 2.7%), P<0.0001)
or DMAB (2.5% ± 2.6%, P=0.0001).
• FN BMD increased more in combo (4.7% ± 4.3%) than
TPTD (0.8% ± 4.1%, P<0.001) and DMAB (2.1% ± 3.8%,
P=0.013).
• Spine BMD increased more in combo (9.1% ± 3.9%)
than in either TPTD (6.2% ± 4.6%, P=0.0005) or DMAB
(5.5% ± 3.3%, P<0.0001)
• DMAB alone increased BMD more than TPTD alone at
the total hip (p=0.003) but TPTD and DMAB produced
similar gains at LS (P=0.7) and FN (p=0.09).
Combined Dmab and TPTD in
PMO: The DATA Study
• Unlike the combination of TPTD and BPs,
the combination of TPTD and DMAB
increased BMD at the hip and spine more
than either drug alone.
• DMAB-TPTD co-administration may prove
to be an important treatment option in
patients at high risk of fracture.
Combined Dmab and TPTD in
PMO: The DATA Study
Combined Dmab and TPTD in
PMO: The DATA Study
Potential Importance
• Combination therapy increases cost, side
effects, and the potential for drug-drug
interactions
– BP-PTH therapies are not synergistic
• Dmab-TPTD therapies may be synergistic
and open the opportunity to open the
“anabolic window” further if needed
• Fracture results are not available
return
Vitamin D/Calcium
•
•
•
•
•
•
D3 v. D2 in liver disease
IOM guidelines and long-term care
3-monthly Vit D in “fallers”
D3+Ca in Caucasians and Blacks: safety
Ca Supplement and CV disease: women
Ca Supplement and CV disease: CV
database
• Ca Supplement and CV disease: 5yr after
WHI
Vitamin D2 and D3 Replacement
Effectiveness in Patients with
Chronic Liver Disease
• Julia (Julianna) Barsony, Georgetown University
Hospital, USA
Vitamin D2 and D3 Chronic
Liver Disease
• Liver disease (CLD) patients: high incidence of
vitamin D deficiency and osteoporotic fractures
• Determine D2 and D3 doses required to
normalize serum 25OHD (above 32 ng/ml) in
vitamin D deficient patients with CLD
• CLD patients responding to D2 (CLD-D2, n=53)
or D3 (CLD-D3, n=45) and controls (C) without
CLD responding to D2 (C-D2, n=53) or D3 (CD3, n=45).
• Effective D2 and D3 doses were both doubled in
CLD compared to C (p<0.001).
• Effective doses of D2 were higher than D3
doses (p<0.01) in every group.
Vitamin D2 and D3 Chronic
Liver Disease
• Obesity (BMI>35) in controls increased the
effective D3 doses by 42±15% (p<0.05) and D2
by 33±15% (NS)
• Many CLD patients (LC, n=33; PBC, n=6; FLD,
n=60) were nonresponsive to weekly 50,000 IU
D2 given for more than 3 months.
• Patients with CLD require higher vitamin D
doses, proportional to the severity of liver
disease
• CLD patients should be preferentially treated
with D3 rather than D2.
Potential Importance
• CLD is a known risk factor for OP
• Some effects on bone health may be
mediated through Vit D, which is
hydroxylated in the liver to 25OH-D
• Differential dosing and D2-D3 effects are
important in this population
• Best to use D3 preparations at dailymonthly intervals
return
Are the IOM Vitamin D Guidelines
Sufficient for Long Term Care
Residents?
• Mary Anne Ferchak, University of Pittsburgh,
USA
IOM Vitamin D Guidelines and
Long Term Care Residents
• Institute of Medicine guidelines for vitamin D suggest
25OHD above 20 ng/dL sufficient for adults.
• 25-OH D in 181 women (age 85 years) in LTC
• Women grouped as deficient (< 20 ng/dL), insufficient
(20-29.9 ng/dL), or sufficient (≥30 ng/dL).
– Deficient women received vitamin D 50,000 IU/week for 8 weeks
to achieve a level of 25-OH D≥20 ng/dL.
– All received vitamin D 800 IU/day, followed for 1 year.
• D-deficient tended to fall more (p=NS)
• Vitamin D deficiency had lower scores for IADL, PPT
and cognitive status (p<0.05), but no difference between
insufficiency vs sufficiency.
• Gait speed, IADL and cognitive status were better in
women with insufficiency than deficiency (p<0.05).
IOM Vitamin D Guidelines and
Long Term Care Residents
• Frail women in LTC with vit D deficiency are at
risk for functional and cognitive status
impairment which may not be reversed by
reaching 25OHvitD above 20 ng/dL
– May require levels or doses above recommended by
the IOM.
• 1 year on 800 IU/day, LTC residents with
insufficient to sufficient 25OHD (≥20ng/dL) have
better functional and cognitive status than those
who are initially deficient.
IOM Vitamin D Guidelines and
Long Term Care Residents
Potential Importance
• IOM Vitamin D recommendations are
population-based and not for specific risk
groups
• Elderly patients and fall-risk patients may
require higher vitamin D supplements
– Those Vit D deficient have poorer functional
parameters than sufficient or insufficient
• Results show that higher Vit D doses in
elderly and fall-risk patients are warranted
return
Effects of 3 Monthly Vitamin D
Supplementation Strategies among
Fallers age 70 Years and Older: a
Double-blind Randomized
Controlled Trial
• Heike Bischoff-Ferrari, University of Zurich,
SWITZERLAND
3 Monthly Vitamin D
Supplementation Strategies
among Fallers over age 70
• 200 seniors with fall in the year prior
– 1) Monthly vitamin D 24’000 IU D3 = control
– 2) 60’000 IU D3
– 3) 24’000 IU D3 plus 300 µg 25(OH)D
• Primary endpoint 25(OH)D > 30 ng/ml and prevention of
functional decline
• Baseline age = 78; 67% women; mean 25(OH)D = 18.5
ng/ml.
• Increment in 25(OH)D and probability of reaching 25(OH)D
threshold of 30 ng/ml in groups 1 to 3 were: (1) 9.9 ng/ml /
39%, (2) 18.3 ng/ml / 81%, (3) 25.5 ng/ml / 89% at 12
month
3 Monthly Vitamin D
Supplementation Strategies
among Fallers over age 70
• Probability of maintained or improved function at 6
and 12 months did not differ between groups: 80%.
• In the 12 month of treatment 121 participants fell
(60.5%)
• Group (2) had a 58% (95% CI: 14 to 102%), and
group (3) had a 45% increased rate of falls (95% CI:
-2 to +92%) compared to group 1.
• Higher doses of vitamin D3 or a combination with
25(OH)D supplementation are needed to shift senior
fallers to a threshold of 30 ng/ml 25(OH)D.
3 Monthly Vitamin D
Supplementation Strategies
among Fallers over age 70
• Probability of maintained or improved function
was similar for 24’000 IU vitamin D3 per month
(800 IU / day) compared to the two higher dose
groups.
• Fall risk may be increased with higher dose
vitamin D, unexplained by a toxic effect on any
muscle / function endpoints.
Potential Importance
• Strategies for Vit D supplementation need
to be evaluated
– Skeletal effects
– Fall effects
– Use of novel forms of Vit D (such as 25OHD)
• Evaluation of anti-fall effects of Vit D
requires large numbers of patients
return
The Safety of Long-Term Use
of Different Doses of Vitamin
D3 Plus Calcium in Older
Caucasian and African
American Women
• Vinod Yalamanchili, Creighton University
Medical Center, USA
Vit D and Ca Safety
• Long-term data on the incidence of
hypercalcemia and hypercalciuria with Ca
supplements
• WHI 7 year increase in renal stones with vit D3
400IU/d and Ca1000 mg/d
• 163 Caucasian and 110 African American
women, ages 57-94 yrs, (25OHD) < 20ng/ml ,
randomized to vit D3 - 400, 800, 1600, 2400,
3200, 4000, 4800 IU/day or PBO for 1 yr.
• Ca intake 1200-1400mg/d
Vit D and Ca Safety
• No relationship between hypercalcemia or
hypercalciuria and the vit D3 dose or serum
25OHD.
• High incidence of hypercalciuria especially in
Caucasian women compared to African
American women
– Both groups had some hypercalcemia events
• Measurement of serum and 24-hour urine
calcium advisable with long-term use of vitamin
D3 and calcium.
Vit D and Ca Safety
Potential Importance
• Higher Vit D doses may be required in the
elderly to achieve sufficiency
• Monthly dosing is an option
• Hypercalcemia and hypercalciuria are
potential risks
– No excess renal stone was observed
– Monitoring serum and urine calcium may be
required in some patients
return
A Prospective Study of Calcium
Supplement Intake and Risk of
Cardiovascular Disease in Women
• Julie Paik, Brigham and Women's Hospital,
Harvard Medical School, USA
Prospective Study of Calcium
Supplement and CV Risk
• 2 observational prospective studies to date of
calcium supplements and CVD risk in women
with follow-up 7 to 8 years
• 74,272 women in Nurses’ Health Study (19842006) free of CVD and cancer at baseline.
• 22 years of follow-up, 4,857 cardiovascular
events occurred (2,634 CHD and 2,223 stroke
events).
Prospective Study of Calcium
Supplement and CV Risk
• Age-adjusted RR of CVD was 0.67 (95% CI
0.62, 0.72) for women taking >500mg/day of
calcium supplements compared to no calcium
supplements.
• In Nurses Health Study, calcium supplements
not associated with increased cardiovascular
risk, including MI, in women.
Potential Importance
• Nurse’s health study observational, but
over long timeframe
• Confirms no CV risk of calcium
supplements in this non-randomized
population
return
Calcium Supplementation and
Cardiovascular Events
• Vaishali Patel, The University of Kansas
Medical Center, USA
Ca Supplements and CVD
• Retrospective study for association of calcium
supplements with CVD in a CV practice.
• 5.7 years (1/1/2004 to 10/8/2009) from Kansas
EMR
• 8060 subjects calcium supplement user vs. nonusers.
• No association between calcium
supplementation and coronary artery disease
and survival
Ca Supplements and CVD
Ca Supplements and CVD
Potential Importance
• In patients within a cardiology practice, no
indication of increased CVD risk with Ca
supplements
• If there is a CVD concern with Ca
supplements, it is likely very small
return
The Women’s Health Initiative (WHI)
Calcium plus Vitamin D Supplementation
Trial: Health Outcomes 5 years after Trial
Completion
• Jane Cauley, University of Pittsburgh Graduate
School of Public Health, USA
WHI Calcium/Vit D Supp’n: 5
yrs after Trial
• WHI 1000 mg calcium with 400 IU Vit D3 (CaD)
versus PBO in 36,282 women age 50 to 79 yrs
• After 7 yrs non-significant reductions hip, clinical
vertebral and total fracture.
• CHD and cancer similar in the 2 groups.
• Current analysis effects of CaD over 7 yrs (trial)
and 5 additional yrs of follow-up among 86% of
participants, CaD, n=15025 and PBO, n=14837.
• Fractures were self-reported
WHI Calcium/Vit D Supp’n: 5
yrs after Trial
• Risk (annualized) of hip fracture in CaD was
0.28% compared with 0.30% in PBO HR=0.95;
95% confidence interval (CI) (0.78, 1.15);
• 0.36% vs 0.43%, for clinical vertebral fractures,
HR=0.83; 95% CI (0.71, 0.98);
• 3.31% vs 3.30%, respectively, for total fractures
HR=1.00; 95% CI (0.94, 1.06).
• Total cancers did not differ between the CaD
and placebo groups.
WHI Calcium/Vit D Supp’n: 5
yrs after Trial
• No difference in CVD or disease mortality in the
post-intervention period.
• Vertebral fractures 13% lower with CaD vs PBO,
HR=0.87; 95% CI (0.76, 0.98).
• Among postmenopausal women followed for up
to 12 yrs, CaD was associated with a decreased
risk of vertebral fractures
– Little effect on other skeletal and non-skeletal
outcomes.
WHI Calcium/Vit D Supp’n: 5
yrs after Trial
Potential Importance
• In WHI long-term follow-up, no cancer or
CVD endpoints were increased 5 years
after the end of the trial
– Vertebral fractures remained lower 5 years
after stopping the Ca –VitD supplement
protocol
• There are no long term cancer or bone
adverse events associated with having
taken Ca and Vit D supplements for 5 yr
return
Sclerostin Ab and other
anabolics
• Romosozumab (AMG785) Phase 2 trial in
PMO (VIDEO)
• Blosozumab Phase 1 trial
• Romosozumab effect on vertebra in cynos
• Sclerosteosis bone material properties
Inhibition of Sclerostin With AMG
785 in Postmenopausal Women With
Low Bone Mineral Density: Phase 2
Trial Results
• Michael R. McClung, Oregon Osteoporosis
Center, USA
Sclerostin-Ab (Romosozumab)
in PMO: Phase 2 Results
• Women 55 to 85 years with LS, TH, or FN T-score
–2.0 to –3.5.
• 12 mo, randomized to AMG 785 (ROM) (70 mg
QM, 140 mg QM, 210 mg QM, 140 mg Q3M, 210
mg Q3M) or PBO, and open-label active: 70 mg/w
ALN or 20 μg/d TPTD
• Women (N=419) age 67 years
• All ROM doses increased BMD v. PBO at each site
at mo 12 (p<0.005).
• ROM 210 mg QM increased BMD LS 11.3% and
4.1% at TH
• Increases greater than with ALN and TPTD
(p<0.0001).
– ALN 3%; TPTD 7%
Sclerostin-Ab in PMO Phase 2
Results
• ROM increased PINP and reduced CTX by wk 1.
• AEs balanced with exception of mild injection
site reactions (4% placebo; 12% ROM).
• ROM led to rapid and marked increases in LS
and hip BMD superior to ALN and TPTD.
• Simultaneous stimulation of bone formation and
decrease in bone resorption.
• ROM was generally well tolerated.
– Ab in 20%, neutralizing Ab in 3%
Sclerostin-Ab (Romosozumab)
in PMO: Phase 2 Results
Potential Importance
• ROM novel anabolic with increases in
bone formation and no increases in bone
resorbtion
• BMD superiority to ALN and TPTD
• Fracture results needed
Romosozumab is a novel bone anabolic therapy
showing superior effects on bone density to
alendronate or teriparatide as well as distinctive
bone turnover marker effects
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Blosozumab, a Humanized
Monoclonal Antibody against
Sclerostin, Demonstrated Anabolic
Effects on Bone in Postmenopausal
Women
• Juliet McColm, Eli Lilly and Company, Erl Wood,
United Kingdom
Blosozumab, a MAb Sclerostin,
in Postmenopausal Women
• Blosozumab in postmenopausal women,
including prior/current alendronate users.
• 8 subjects randomized, Phase 1 trial
• Blosozumab well tolerated
• Bone biomarker responses with sclerostin,
P1NP, BSAP, OC, and CTx.
• LS BMD increased up to a 7.71% (5.74, 9.67) at
Day 85
• Prior alendronate did not have a major impact.
Potential Importance
• Dramatic and very early increases in BMD
regardless of prior ALN
• Need Phase 2 and 3 trials (fracture
endpoints) for confirmation
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Long-term Sclerostin Antibody Treatment in
Cynomolgus Monkeys: Sustained
Improvements in Vertebral Microarchitecture
and Bone Strength Following a Temporal
Increase in Cancellous Bone Formation
• Michael Ominsky, Amgen Inc., USA
Long-term Sclerostin Ab in Cyno Monkeys
• Prior studies of up to 10 weeks duration
• Cynos 6 mo on weekly vehicle (Veh), 3, 10, or 100
mg/kg Scl-Ab (n=4/group)
• Osteocalcin peaked at 3 months, returned toward
baseline levels at month 6, when L2 bone formation rate
(BFR/BS) similar across all treatment groups
• Tibia diaphysis, endocortical BFR/BS remained dosedependently elevated
• Despite the normalization of cancellous BFR/BS at
month 6, Scl-Ab dose-dependently increased DXA BMD
by 15-30% at the LS compared with Veh .
Long-term Sclerostin Ab in Cyno Monkeys
• MicroCT increases in BMD at L3 vertebrae and L6
cancellous cores, and in bone area, cortical thickness
(Ct.Th), trabecular bone volume (BV/TV), and trabecular
thickness (Tb.Th)
• The improvements in bone microarchitecture resulted in
increases in yield load for all dose levels at both L3 (+3392%) and L6 (+83-142%)
• Positive correlations between BMD and yield load
• 6 months of Scl-Ab treatment in cynos resulted in
marked improvements in vertebral BMD, cortical and
trabecular microarchitecture, and bone strength, with
maintenance of bone material properties
Long-term Sclerostin Ab in Cyno Monkeys
Potential Importance
• Apparent long-term safety in cynos
• Long-term improvements in bone strength
despite return to baseline BTMs
• Self-regulation of anabolic effect with longterm therapy
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Alterations in Intrinsic Bone Material
Properties of Sclerosteosis Patients
• Socrates Papapoulos, Leiden University Medical
Center, THE NETHERLANDS
Alterations in Bone Material
Properties in Sclerosteosis
• Sclerosteosis (SC) autosomal recessive, bone
sclerosing dysplasia, caused by loss-of-function
in the SOST gene encoding for sclerostin
• Sclerostin is a protein by osteocytes that
decreases bone formation by inhibiting the Wnt
signaling pathway with unrestrained bone
formation and protection from fracture
• Compact bone from 4 children and 2 adults with
SC, and 4 controls analyzed by quantitative
Backscattered Electron Imaging (qBEI) and
Raman spectroscopy (RS).
Alterations in Bone Material
Properties in Sclerosteosis
• qBEI information on the bone mineral density
distribution (BMDD), RS mineral/matrix ratio,
proteoglycan content, and mineral crystallinity
• Human bone formed in the absence of sclerostin
has decreased mineral crystallinity, lower
mineralization with higher heterogeneity.
• These favorable bone properties in the presence
of highly increased bone mass may be
responsible for the increased bone strength of
patients with sclerosteosis.
Potential Importance
• Corroborative data that increases in BMD
in patients with absence of sclerostin over
a long timeframe are indicative of
improved bone material properties
– Bone tissue remains heterogenous
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Other topics and upcoming
Therapies
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Odanacatib in PMO after ALN
Odanacatib in PMO: HRpQCT
Odanacatib in PMO: femur QCT
Odanacatib in PMO: femur FEA
Stressful life events and bone loss: MrOs
Prevalence of renal failure in PMO:
NHANES
• Calcitonin and malignancy metaanalysis
Effects of Odanacatib on BMD and
Overall Safety in the Treatment of
Osteoporosis in Postmenopausal
Women Previously Treated with
Alendronate
• Tobias De Villiers, Mediclinic Panorama, South
Africa
Odanacatib in PMO Previously
Treated with ALN
• ODN 50mg OW on BMD and BTM in
patients previously treated with ALN
for ≥3years
• RDBPC 24-month study.
• 243 PMO women ≥60 years of age
with BMD T-score –2.5 to -3.5 at the
TH, FN or trochanter
Odanacatib in PMO Previously
Treated with ALN
• ODN, BMD increased 1.73%, 1.83%, 0.83% and
2.28%, respectively, for the FN, trochanter, total
hip and LS.
• ODN 50mg OW decreased u-NTx/Cr, and
increased bone formation, s-P1NP and s-BSAP
• AEs were comparable between 2 treatments
• ODN provided incremental BMD gains in
osteoporotic women following ALN treatment.
• ODN decreases bone resorption while preserving
bone formation.
Odanacatib in PMO Previously
Treated with ALN
Potential Importance
• Inhibition of cathepsin K would be
expected to have novel effects on bone
metabolism
• After long-term ALN therapy, increases in
BMD associated with increases in bone
formation markers may be favourable to
patients transitioning from ALN
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Effects of Odanacatib on the Distal
Radius and Tibia in Postmenopausal
Women: Improvements in Cortical
Geometry and Estimated Bone
Strength
• Angela Cheung, University Health Network,
Canada
Odanacatib: Radius and Tibia in
PMO
• In OVX primates, ODN increases cortical thickness at
femoral neck.
• RDBPC using HR-pQCT distal radius and distal tibia.
• 214 PMO women, age 64.0 ±6.8 yrs, baseline LS Tscore -1.81 ±0.83, randomized to ODN 50 mg or PBO
weekly for 2 years.
• LS BMD % at 1 year increased 3.49% more for ODN v.
PBO (p<0.001).
• After 2 years, greater improvements with ODN than PBO
in total, trabecular, and cortical volumetric BMD; cortical
thickness; and estimated strength (failure load) of the
distal radius using HR-pQCT-based finite element
analysis
• Radius had reduced cortical porosity with ODN (-7.68,
p=0.066)
Odanacatib: Radius and Tibia in
PMO
Potential Importance
• ODN improvements in cortical porosity
and bone strength may differentiate from
other osteoporosis therapies
• Identification of bone structural parameters
potentially valuable in predicting fracture
risk and response to therapy
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Femur QCT Analysis using MIAF in
Postmenopausal Women Treated
with Odanacatib - Results of a 2-year
Placebo-controlled Trial
• Klaus Engelke, University of Erlangen,
GERMANY
Femur QCT with ODN in PMO
• 2-year trial enrolled 214 PMO mean age 64 yr,
mean BMD T-scores of -1.8 at the LS and FN.
• ODN 50 mg/w or PBO
• Hip QCT scans at 2 yrs (n=158).
• Total femur BMC differential treatment effect
(ODN-PBO)
– Proportion of BMC attributed to cortical gain was
45%, 44% 52%, 40% for the total, neck, trochanter
and intertrochanter subregions, respectively.
Femur QCT with Odanacatib
in PMO
• ODN improved integral, trabecular and
cortical BMD as well as BMC at all regions
of the femur relative to PBO.
• Increase in cortical volume and BMC
paralleled the increase in cortical BMD,
demonstrating a consistent effect of ODN
on cortical bone.
• Approximately one-half of the absolute
BMC gain occurred in cortical bone.
Femur QCT with Odanacatib
in PMO
Potential Importance
• Study differentiating cortical from
trabecular bone compartments
• Dramatic improvements in cortical
compartment may differentiate from other
antiresorbtive therapies
• May predict eventual non-vertebral
fracture risk reduction
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Odanacatib Improved Estimated Femoral
Strength in Postmenopausal Women Results of a 2-year Placebo-controlled
Trial
• Tony Keaveny, University of California,
Berkeley, USA
Odanacatib Improved Estimated
Femoral Strength in PMO
• In primate model, ODN increased cortical
thickness and periosteal bone formation, and
maintained normal biomechanical properties of
the femoral neck and central femur
• RDBPC, 2-year trial of 214 PMP women mean
age 64 years and mean BMD T-scores -1.8 at
LS and FN
• Hip QCT at 2 years (n=129)
• Simulated sideways fall using finite element
analysis (FEA)
Odanacatib Improved Estimated
Femoral Strength in PMO
• ODN increased FEA femoral strength
• Femoral neck, integral (cortical and trabecular
combined) vBMD and trabecular vBMD were higher in
ODN, whereas cortical vBMD did not differ from PBO
• Femoral neck cortical thickness, cortical volume, and
cortical BMC higher in ODN
• Cortical bone mass increased due to accrual of bone
mass at endosteal envelope of the FN
• ODN improved proximal femoral strength by FEA by
increasing cortical thickness and endosteal bone
apposition along with integral and trabecular BMD at the
femoral neck
Odanacatib Improved Estimated
Femoral Strength in PMO
Potential Importance
• FEA prediction of bone strength may be a
good surrogate for fracture trials
• Improvements in femoral strength by FEA
may be attributable to cortical effects on
bone
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Association of Stressful Life Events
with Accelerated Bone Loss in Older
Men: the Osteoporotic Fractures in
Men (MrOS) Study
• Howard Fink, GRECC, Minneapolis VA Medical
Center, USA
Stressful Life Events and
Bone Loss in Men: MrOS
• Stressful life events (LE) may lead to various
adverse health outcomes.
• LE independently associated with increased risk
of falls
• MrOS, 5229 men, 76% reported >1 type of LE
• TH BMD loss was -0.36% (SD 0.88)
• 13.9% of men with accelerated TH BMD loss.
• Stressful life events associated with increase in
accelerated TH bone loss independent of other
factors.
Stressful Life Events and
Bone Loss in Men: MrOS
Potential Importance
• Stressful life events may predict bone
fragility either directly or indirectly (frailty)
– Possible stress hormone mediators of this
effect on bone
• Which comes first: stressful life event or
bone loss event?
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Prevalence of Renal Impairment among
Osteoporotic Women in the US: Analysis
of NHANES survey 2005-2008.
• Allison Nguyen, Merck & Co., Inc., USA
Renal Impairment in PMO:
NHANES 2005-2008
• Proportion of PMO over 50 yrs with renal
impairment
• 2005-2008 National Health and Nutrition
examination survey (NHANES)
• OP defined as prior hip or spine fracture, reported
OP diagnosis or a lumbar spine or femoral neck
BMD T-score <-2.5.
• Prevalence of OP among women aged 50+ (mean
age 68.7) was 27% (12.7 million).
Renal Impairment in PMO:
NHANES 2005-2008
• 23% of women with OP had moderate
renal impairment and 637,504 (5.2%) had
severe renal impairment.
• Unmet medical need in patients with both
osteoporosis and renal impairment
Potential Importance
• Renal failure contraindication to
bisphosphonate therapy
• Prevalence of CRF is high in PMP women
• In this population, non-BP treatment
options need to be studied
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Calcitonin Use and Risk of Malignancy: A
Meta-Analysis of 17 RCTs in Patients
with Osteoporosis
• Markus Heep, Novartis Pharma AG, Switzerland
Calcitonin and Malignancy:
Meta-Analysis of 17 RCTs
• Reported imbalance in prostate cancers in
trials of salmon calcitonin
• Meta-analysis of 17 RCTs in osteoporosis
treated with salmon calcitonin nasal spray
• 2258 patients treated with nSCT and 976
PBO-treated patients.
• OR of nSCT vs PBO for any malignancy
was 1.61 (95% CI: 1.11–2.34)
Calcitonin and Malignancy:
Meta-Analysis of 17 RCTs
• No correlation of malignancy risk with
dose
• Mean time of exposure before event was
21.8 months for nSCT compared with 22.4
for PBO
• Malignancy incidence similar in the 0–6
mo period (0.9% vs 0.8%)
Calcitonin and Malignancy:
Meta-Analysis of 17 RCTs
• Calcitonin had higher cancer incidence 6–
12 mos (1.2% vs 0.2%), 12–18 mos (0.7%
vs 0.2%), 18–24 mos (0.6% vs 0.3%), 24–
36 mos (3.2% vs 1.2%) and 36–48 mos
(1.4% vs 0.6%)
• Small increase in the risk of any
malignancy with nSCT with long-term
treatment (>6 months).
• No identified mechanism
Calcitonin and Malignancy:
Meta-Analysis of 17 RCTs
Potential Importance
• EMEA change to label for calcitonin
contraindicated for use in long term
(>6mo) therapy
• Small effect but significant in RCT
• No pathogenetic mechanism identified
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