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)

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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