American Society for Bone and Mineral Research (ASBMR) 2012 Update (+ videos) D Kendler, Vancouver J D Adachi, Hamilton J Brown, Quebec A Cheung, Toronto

American Society for Bone and Mineral Research (ASBMR)

2012 Update (+ videos)D Kendler, VancouverJ D Adachi, HamiltonJ Brown, QuebecA Cheung, TorontoK. S. Davison, VictoriaL Dian, VancouverA Khan, OakvilleD Hanley, CalgaryA Hodsman, LondonR Josse, TorontoA Jovaisis, OttawaS Kaiser, HalifaxL-G Ste. Marie, MontrealC Yuen, Vancouver

November 2012

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

• SERM, Estrogen, Testosterone

• Bisphosphonates

• Teriparatide

• Sclerostin Ab and other Anabolics

• Denosumab

• Other and Upcoming therapies

• 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).


• 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 diabetes-associated fracture risk.

• Combining LS TBS with BMD incrementally improves fracture prediction.


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

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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)


• 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 & BMI-adjusted means +52.2% vs DM; + 36.0% vs Fx; +34.2% vs Co)


• 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.


Representative HR-pQCT scans of diabetic women with and without fragilityfractures (DMFx vs. DM)


• 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

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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 post-fracture

• 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.


• 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



• 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

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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 T-score<-2.5;

• Treatment initiation on the basis of high fracture risk estimated by FRAX w/o BMD may be cost-effective, 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


• 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

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System-Level Approaches to the Secondary Prevention of

Osteoporotic Fractures: A Systematic Review and Meta-

analysis

• 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.


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


• 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 re-fractures at 4 years follow-up.

• Type A & B services have been shown to be cost effective


• 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.

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Effect of a Multifactorial Fall-and-Fracture 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 fall-and-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


• Integrated fall and fracture risk assessment and intervention may reduce future hospitalization

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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 Non-

Displaced 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 non-displaced AFFs.


• 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

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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


• 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.


• 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


• 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

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Quantitative Bone Histomorphometry in Patients with Bisphosphonate-

Associated Atypical Subtrochanteric Femur Fractures Before and After 12

Months of Teriparatide

• Paul Miller, Colorado Center for Bone Research, USA

Bone Histomorphometry with BP-AFF 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 BP-AFF 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.


• 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

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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=14-16/group), after which injected with single dose far-red fluorescent pamidronate (FRFP, 100 nmol/kg).


• 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.



• 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

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• Sex steroid and Fx in WHI• Sex steroid and Fx in MrOs• HRpQCT in early menopause:

KEEPS

SERM/Estrogen/Testosterone

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).


• 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 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.

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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.


• 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

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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


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


but Not Trabecular, Bone Loss


• 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

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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


• 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

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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.

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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




• 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

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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.


• 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

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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 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.



• BMD and BTM benefits in ALN-nonadherent 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

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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 –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 efficacy not dependent on baseline bone turnover

• BTM not necessary to determine treatment choice in men with osteoporosis

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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 cross-over and long-term groups.

5 Yr Dmab on Bone Histomorphometry: FREEDOM• Resorption decreased in both cross-over and

long-term subjects compared with placebo-treated subjects

• 10/13 (77%) cross-over subjects and 14/28 (50%) long-term subjects had double-tetracycline 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


• 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

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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 T-score –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


• 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

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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


• 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

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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.




• 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

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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


• 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

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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.


• 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

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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)


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


Osteoporosis unresponsive to TPTD


• 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

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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).


• 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.




• 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

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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 (C-D3, 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.


• 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 daily-monthly intervals

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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).


• 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 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

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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


• 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.


• 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.


• 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

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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


• 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

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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 (1984-2006) 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.


• Nurse’s health study observational, but over long timeframe

• Confirms no CV risk of calcium supplements in this non-randomized population

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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. non-

users. • No association between calcium

supplementation and coronary artery disease and survival

Ca Supplements and CVD

Ca Supplements and CVD


• 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

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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


• 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.


• 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.



• 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

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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


• 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.


• 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

• 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 dose-dependently 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 (+33-92%) 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




• Apparent long-term safety in cynos

• Long-term improvements in bone strength despite return to baseline BTMs

• Self-regulation of anabolic effect with long-term 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.


• 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

• 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


• 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.



• 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 T-score

-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


• 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


• 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)


• 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



• 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


• 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


• 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)


• 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 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



• 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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Documents

American Society for Bone and Mineral Research (ASBMR) 2012 Update (+ videos) D Kendler, Vancouver J D Adachi, Hamilton J Brown, Quebec A Cheung, Toronto