osteoporosis 2016 | what are the properties of the perfect therapy? prof. jon tobias #osteo2016
TRANSCRIPT
What are the properties of the perfect therapy for
osteoporosis?Professor Jon Tobias
Musculoskeletal Research Unit Southmead Hospital
Disclosure statementSpeaker fees from Amgen, Lilly and UCB
Summary• Bone quality changes in osteoporosis• Effects of drug treatment on bone quality• Clinical implications of therapeutic effects on bone
quality
The Perfect Therapy for Osteoporosis• Easy to administer
• Oral as opposed to parenteral• Extended interval dosing
• Low cost• Safe and well tolerated• Persistent benefit on stopping
The Perfect Therapy for Osteoporosis• Easy to administer
• Oral as opposed to parenteral• Extended interval dosing
• Low cost• Safe and well tolerated• Persistent benefit on stopping• OPTIMAL EFFICACY
Assessing efficacy of anti-osteoporotic therapy• Clinical end-points
• Vertebral and non vertebral fracture risk• Intermediate end-points
• Bone mineral density• Bone turnover markers
• Evaluating bone strength• Measurement of individual determinants of ‘bone quality’
e.g histomorphometry on iliac crest bone biopsies, high resolution imaging (HR-pQCT)
Use of HR-pQCT to examine structural changes of cortical and trabecular bone with osteoporosis therapy
Summary• Bone quality changes in osteoporosis• Effects of drug treatment on bone quality• Clinical implications of therapeutic effects on bone
quality
Determinants of Bone QualityMacroarchitecture/Geometry Microarchitecture
Material properties
Periosteal circumference Hip axis length Trabecular bone structure Cortical bone structure
Skeletal mineralisation
Determinants of Bone QualityMacroarchitecture/Geometry Microarchitecture
Material properties
Periosteal circumference Hip axis length Trabecular bone structure Cortical bone structure
Skeletal mineralisation
Osteoporosis and Trabecular Bone
Increased activation frequency Increased erosion depth. Reduced trabecular thickness. Trabecular perforation and removal
Normal Osteoporosis
Structural changes in trabecular bone associated with osteoporosis
Normal Osteoporotic
Images courtesy of Alan Boyde
Osteoporosis and Cortical Bone Increase in size and number of Haversian canals
leading to greater cortical porosity Endosteal expansion leading to cortical thinning
OsteoporosisNormal
Haversian canalPeriosteum
Endosteum
Increased age-related intra-cortical remodelling and porosity of the inner cortex(female post-mortem samples)
(A) Micrograph of a specimen from a 29-year-old woman. Pores are regular in shape and evenly distributed in the cortex. (B) Micrograph of a specimen from a 67-year-old woman. Pores are large, irregularly shaped, and have coalesced in cortex adjacent to the marrow producing cortical remnants.
(C) Micrograph of a specimen from a 90-year-old woman. Most of the cortex is trabecularised by large and coalesced pores. R Zebaze et al, Lancet 2010 375: 1672-3
Summary• Bone quality changes in osteoporosis• Effects of drug treatment on bone quality• Clinical implications of therapeutic effects on bone
quality
Treating Osteoporosis
Overactive bone resorption Underactive bone formation
Treating Osteoporosis
Overactive bone resorption Underactive bone formation
Anti-resorptive agenteg zoledronate
Anabolic agenteg teriparatide
Summary• Bone quality changes in osteoporosis• Effects of anti-resorptives on bone quality
• Bisphosphonates• Oral eg Alendronic acid• IV eg Zoledronate
• Denosumab
Preservation of trabecular architecture after 3 years treatment with annual IV Zoledronate as assessed on iliac crest bone biopsies
R Recker et al Journal of Bone and Mineral Research Volume 23, Issue 1 pages 6-16, 10 SEP 2007
Whole Biopsy Thick Section Thin Section
Differing effects of PTH 1–34, PTH 1–84, and zoledronate on cortical microarchitecture using HR‐pQCT
S Hansen et al JBMR Volume 28, Issue 4, pages 736-745, 18 MAR 2013
Increased cortical thickness with anti-resorptive agents due reversal of endosteal resorption?
*, P < .05 vs baseline; **, P < .05 vs 12-months for 12- to 24-month change; a, P < .05 vs TPTD alone; b, P < .05 vs DMAB alone.
J. N. Tsai et al The Journal of Clinical Endocrinology & Metabolism 2016, 101, 2023-2030.
Effects of Two Years of Teriparatide, Denosumab, or Both on Bone Microarchitecture (DATA-HRpQCT study)
Denosumab Reduces Cortical Porosity of the Proximal Femoral Shaft in Postmenopausal Women With Osteoporosis
R Zebaze JBMR 19 MAY 2016 DOI: 10.1002/jbmr.2855
Cortical porosity from low resolution hip CT scans using Straxcorp software
BMD gains are more sustained with denosumab versus zoledronate: role of cortical bone changes?
Horizon Extension (zoledronate)
1 2 3 4 50 6
†
18.4%†
†
**
*
*
*
*
†
†
† 13.7%
7 8–2
02468
10121416
2018
Lumbar Spine
–2
0
2
4
6
8
10
Total Hip
Perc
enta
ge C
hang
e Fr
om B
asel
ine
Study Year Study Year
FREEDOM EXTENSION FREEDOM EXTENSION
1962 14572086 1567
118‡
139‡
120‡
140‡
20222149
19972124
20062132
18952017
20052111
14881589
119‡
139‡
122‡
140‡
120‡
140‡
122‡
141‡
20292148
19242041
* **
1 2 3 4 50 6
**
**
*
8.3%†
††
†
†
† 4.9%
7 8
†
†
†
†
14631551
14231518
Long-term Denosumab Cross-over DenosumabPlacebo
FREEDOM extension (denosumab)
DM Black et al 2012 JBMR 27:243 Papapoulos S, et al. 2015 OI 26:2773
Effects of osteoporotic treatments on bone quality
Effect on bone quality
Anti-resorptive
Trabecular architecture
Preserved
Cortical thickness Increased +
Cortical porosity Reduced
Summary• Bone quality changes in osteoporosis• Effects of anti-resorptives on bone quality• Effects of anabolic agents on bone quality
• Teriparatide (PTH1-34)/PTH 1-84• Second generation anabolic agents
• Abaloparatide• Romosozumab
3-D µCT images of iliac crest biopsies before and after 1-84 PTH treatment for 18 months
RR Recker et al 2009 Bone 44:113
Before After
Differing effects of PTH 1–34, PTH 1–84, and zoledronate on cortical microarchitecture using HR‐pQCT
S Hansen et al JBMR Volume 28, Issue 4, pages 736-745
Effect of teriparatide on cortical bone of the radius
JR Zanchetta et al 2003 JBMR 18:539
Does periosteal apposition contribute to the increased cortical thickness after treatment with anabolic agents?
Cross sectional moment of inertia (CSMI) is strongly dependent on overall bone size
Anti-resorptive agent Anabolic agent
Bone accumulation
Effects of osteoporotic treatments on bone quality
Effect on bone quality
Anti-resorptive Anabolic(Teriparatide)
Trabecular architecture
Preserved Improved
Cortical thickness Increased + Increased ++
Cortical porosity Reduced Increased
*, P < .05 vs baseline; **, P < .05 vs 12-months for 12- to 24-month change; a, P < .05 vs TPTD alone; b, P < .05 vs DMAB alone.
Effects of Two Years of Teriparatide, Denosumab, or Both on Bone Microarchitecture (DATA-HRpQCT study)
J. N. Tsai et al The Journal of Clinical Endocrinology & Metabolism 2016, 101, 2023-2030.
Effects of osteoporotic treatments on bone quality
Effect on bone quality
Anti-resorptive Anabolic(Teriparatide)
Combined(Denosumab + teriparatide)
Trabecular architecture
Preserved Improved Improved
Cortical thickness Increased + Increased ++ Increased ++
Cortical porosity Reduced Increased Reduced
Summary• Bone quality changes in osteoporosis• Effects of anti-resorptives on bone quality• Effects of anabolic agents on bone quality
• Teriparatide (PTH1-34)/PTH 1-84• Second generation anabolic agents
• Abaloparatide• Romosozumab
ACTIVE: Change in bone turnover markers following treatment with Teriparatide or Abaloparatide
Miller PD et al JAMA. 2016;316(7):722-733. doi:10.1001
ACTIVE: Change in BMD following treatment with Teriparatide or Abaloparatide
Miller PD et al JAMA. 2016;316(7):722-733. doi:10.1001
Change in Bone-Turnover Markers with Alendronate, Teriparatide and Romosozumab
McClung MR et al. N Engl J Med 2014;370:412-420.
Change in BMD with Alendronate, Teriparatide and Romosozumab
McClung MR et al. N Engl J Med 2014;370:412-420.
Effects of 12 months Romosozumab and Teriparatide at the Spine and Hip by QCT
H Genant et al Journal of Bone and Mineral Research 20 SEP 2016 DOI: 10.1002
Spine
Hip
Effects of osteoporotic treatments on bone quality
Effect on bone quality
Anti-resorptive Anabolic(Teriparatide)
Combined(Denosumab + teriparatide)
Second generation anabolic
Trabecular architecture
Preserved Improved Improved Improved
Cortical thickness Increased + Increased ++ Increased ++ Increased +++
Cortical porosity Reduced Increased Reduced Unaffected or reduced ?
Summary• Bone quality changes in osteoporosis• Effects of drug treatment on bone quality• Clinical implications of therapeutic effects on bone
quality
Summary• Bone quality changes in osteoporosis• Effects of drug treatment on bone quality• Clinical implications of therapeutic effects on bone
quality• Do therapeutic agents influence bone quality at critical
sites for fracture?• Do effects of different therapeutic agents on bone quality
translate into reduced fracture risk?
Cortical thickness maps from hip CT scans before and 24 months after Teriparatide
K Poole et al PloS One 2011 6: e16190
Baseline:
Post-teriparatide:
Statistical change map:
C = subcapital superior femoral neck
Fracture risk ratio after treatment with anabolic versus anti-resorptive agentsClass Drug Trial
(duration in months)
Vertebral fractures
Anti-resorptive Alendronate FIT (36) 0.53
Zoledronate HORIZON (36) 0.30
Denosumab FREEDOM (36) 0.32
Anabolic Teriparatide ACTIVE (18) 0.20
Abaloparatide ACTIVE (18) 0.14
Romosozumab FRAME (12) 0.27*
*F Cosman et al, NEJM 2016, In Press
Fracture risk ratio after treatment with anabolic versus anti-resorptive agentsClass Drug Trial
(duration in months)
Vertebral fractures
Non-vertebral fractures
Anti-resorptive Alendronate FIT (36) 0.53 0.70
Zoledronate HORIZON (36) 0.30 0.67
Denosumab FREEDOM (36) 0.32 0.80
Anabolic Teriparatide ACTIVE (18) 0.20 0.70
Abaloparatide ACTIVE (18) 0.14 0.57
Romosozumab FRAME (12) 0.27 0.75
Conclusions• Optimal treatments for osteoporosis enhance bone
quality by improving trabecular architecture, increasing cortical thickness and overall bone size, and reducing cortical porosity
• This may require a combination of anabolic and anti-resorptive actions, which may or may not be possible using a single agent alone
• Anabolic agents may have improved skeletal safety compared to anti-resorptive drugs, given atypical femoral fractures and other complications arise from over-suppression of bone resorption
Horizontal trabeculae are important for bone strength: Eular Buckling Theory
Structure 1 is 16x stronger than Structure 2
Assume: Volume 1 = Volume 2Identical Material and dimensions for both
Structure 1 Structure 2
Osteoporosis affects both trabecular and cortical bone
Cortical bone:•85% of bone•EndoskeletonTrabecular
bone:•15% of bone•Endoskeleton•Calcium reservoir•Haematopoeisis