Biologic agents in Preventition and Treatment of Osteoporopsis

The role of Denosumab Prof. Samir Elbadawy

*Osteoporosis affect 30%-40% of women in western countries and almost 15% of men after the age of 50 years.

Life expectancy in men and women Age (in years)

Expectation of life (in years) in 1999 Male

At birth (0)

Female

75.4

80.2

5

71.0

75.7

20

56.2

60.8

30

46.7

51.0

50

27.9

32.0

60

19.4

23.0

70

12.2

15.1

80

7.0

8.7

and life expectancy is increasing Data from the UK

3250

600

400

629

378

Total number of hip fractures: 1950 = 1.66 million 2050 = 6.26 million

Projected to reach 3.250 million in Asia by 2050

668

742

Projected Number of Osteoporotic Hip Fractures Worldwide

1950 2050

100

1950 2050 195 205 0 0

1950 2050

Adapted from C. Cooper et al, Osteoporos Int. 1992; 2:285-9

Presentation Overview 1- What is Osteoporosis? 2- Osteoporotic Fractures. 3- Drug therapy in treating Osteoporosis. 4- Denosumab.

5- How long to treat?

Presentation Overview 1- What is Osteoporosis? 2- Osteoporotic Fractures. 3- Drug therapy in treating Osteoporosis. . 4- Denosumab.

5- How long to treat?

Osteoporosis Definition Normal Bone

Osteoporotic Bone

WHO Definition1 “Osteoporosis is a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility” NIH Definition2 “Osteoporosis is defined as a skeletal disorder characterized by compromised bone strength predisposing a person to an increased risk of fracture” 1. Genant HK, et al. Osteoporos Int. 1999;10:259-264. 2. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285:785-795. 8

The Osteoporosis Continuum

Kyphotic spine

Healthy spine

50 Menopausal Experiencing vasomotor symptoms

55+ Postmenopausal

75+ Kyphotic

At greater risk for vertebral fracture than any other type of fracture

At risk for hip fracture

Types of Osteoporosis

Primary Osteoporosis

Secondary

Osteoporosis 1. Postmenopausal 2. Senile

11

Risk Factors for Osteoporosis Genetic/Nonmodifiable

Potentially Modifiable

Age • Female sex • Asian or white ethnicity • Previous fragility fracture • Family history of • hip fracture or osteoporosis Small frame •

Menopause-related estrogen • deficiency Low body weight • Calcium/vitamin D deficiency • Inadequate physical activity • Excessive alcohol intake • Cigarette smoking • Long-term glucocorticoids • (secondary osteoporosis)

National Osteoporosis Foundation (NOF). Available at: http://www.nof.org/osteoporosis/diseasefacts.htm. Accessed August 31, 2007. 12

Presentation Overview 1- What is Osteoporosis? 2- Osteoporotic Fractures. 3- Drug therapy in treating Osteoporosis. 4- Denosumab.

5- How long to treat?

Common Osteoporotic Fracture Sites Include the Forearm, Hip and Spine Global Osteoporotic Fracture Sites in Men and Women Aged ≥50 Years in 2000 (n=8959) Forearm, 18.5% Other (pelvis, other femoral, tibia, fibula, ribs, clavicle, scapula, sternum),

39.6%

Hip, 18.2%

Humerus, 7.9% Johnell O, Kanis JA. Osteoporos Int 2006;17:1726–1733

Spine, 15.8%

The Classical Triad for Consideration in Osteoporosis is Morbidity, Mortality and Cost1-3

Morbidity ( ↓QOL)

Mortality

Cost

QOL: Quality of life 1. Jean-Yves Reginster. Antifracture Efficacy of Currently Available Therapies for Postmenopausal Osteoporosis. Drugs 2011; 71 (1): 65-78. 2. Papaioannou A, Kennedy CC, Ioannidis G, Sawka A, Hopman WM, Pickard L, Brown JP, Josse RG, Kaiser S, Anastassiades T, Goltzman D, Papadimitropoulos M, Tenenhouse A, Prior JC, Olszynski WP, Adachi JD (2009) The impact of incident fractures on health-related quality of life: 5 years of data from the Canadian Multicentre Osteoporosis Study. Osteoporos Int 20:703–714 3. Sawka AM, Thabane L, Papaioannou A, Gafni A, Ioannidis G, Papadimitropoulos EA, Hopman WM, Cranney A, Hanley DA, Pickard L, Adachi JD (2005) Health-related quality of life measurements in elderly Canadians with osteoporosis compared to other chronic medical conditions: a population-based study from the Canadian Multicentre Osteoporosis Study (CaMos). Osteoporos Int 16:1836–1840

The Classical Triad for Consideration in Osteoporosis is Morbidity, Mortality and Cost1-3

Morbidity ( ↓QOL)

QOL: Quality of life 1. Drugs 2011; 71 (1): 65-78. 2. Osteoporos 2005; Int 16:1836–1840 3. Osteoporos Int 2009; 20:703–714 4. Ann Intern Med 1998 May; 128 (10): 793-800 5. JAMA 2001 Jan; 285 (3): 320-3 6. JAMA 2007 Jan; 297 (4): 387-94 7. Bone 2004 Aug; 35 (2): 375-82

 Vertebral fractures (the common Fractures):

Mortality

Cost

 Not always symptomatic .  Result in acute or chronic pain & spinal deformity.4  Associated with a significantly increased risk for subsequent fracture.5-7

The Classical Triad for Consideration in Osteoporosis is Morbidity, Mortality and Cost1-3

 Hip fractures (The fatal fractures):  Widely regarded as a lifethreatening event in the elderly.1  Associated with many 2ry complications: − Rapid loss of physical and mental health and functional capacity,4,5 − Increased risk of mortality.

Morbidity ( ↓QOL)

QOL: Quality of life 1. Drugs 2011; 71 (1): 65-78. 2. Osteoporos 2005; Int 16:1836–1840 3. Osteoporos Int 2009; 20:703–714 4. Curr Med Res Opin 2008 Jun; 24 (6): 1781-8 5. CMAJ 2009 Sep; 181 (5): 265-71 6. Cooper C, et al. Amj Epidemiol. 1993;13]:1001-1005. 7. Leibson CL, et ai.J Am Geriatr Soc. 2002;50:1644-1650. 8. Magaziner J, et al. Am J Public Health. 1997;87:1630-1636

Mortality

Mortality rates can be up to 20%-24% Cost in the first year after a hip fracture.78

Clinical syndrome of established senile osteoporosis, H.M. 85 y.

The Classical Triad for Consideration in Osteoporosis is Morbidity, Mortality and Cost1-3

 Osteoporosis is a costly disease in terms of public health.  The bulk of the cost is attributable to hip fracture.1  Health care costs include:4

Morbidity

( ↓QOL)    

Mortality

Acute hospital care, Loss of working days for family carers, Long term care, and Medication.

QOL: Quality of life 1. Drugs 2011; 71 (1): 65-78. 2. Osteoporos 2005; Int 16:1836–1840 3. Osteoporos Int 2009; 20:703–714 4. Ann Intern Med 1998 May; 128 (10): 793-800

Cost

Presentation Overview 1- What is Osteoporosis? 2- Osteoporotic Fractures. 3- Drug therapy in treating Osteoporosis. 4- Denosumab.

5- How long to treat?

Real-World Obstacles in the Management of Osteoporosis  Silent disease; some fractures may initially go

unnoticed

 Insufficient rates of diagnosis and treatment  Global challenge of persistence to therapy in

chronic diseases, compromising effectiveness

 Poor adherence to prescribed doses  Low persistence over time  Lack of compliance with dosing instructions Southern Medical Journal • Volume 99, Number 6, June 2006 The Journal of Family Practice, Vol 59, No 6 | JUNE 2010

Treatment of osteoporosis: Challenges of a chronic treatment

• Efficacy on fractures • Long term safety

• Long term compliance

GOALS 1-TO PREVENT FRACTURES. 2-TO ALLEVIATE PAIN.

3-TO IMPROVE QUALITY OF LIFE.

= We have very effective treatments to reduce fracture risk in patients with or at risk of osteoporosis. = The clinical challenges are: * To IDENTIFY the appropriate patients to treat

* To SELECT among the treatment options * To USE drugs in the most effective way

1- Whom to Treat ? 2- How to Treat ?

3- How long to treat ?

1- Whom to Treat ? 2- How to Treat ? 3- How long to treat ?

Whom to treat ? = Patients with vertebral or hip fracture • = Patients with a T score ≤ -2.5 • = Patients with Osteopenia & Risk factors •

Who Should Be Treated?

Individual clinician judgment on patient risk factors is most important*

Journal of the American Academy of Orthopaedic Surgeons 2010;18: 278-285 *Adapted from WHO Technical Report Series 921. Geneva: World Health Organization; 2003.

32

1- Whom to Treat ? 2- How to Treat ? 3- How long to treat ?

Which Drugs do we have? (1) = Hormone Replacement Therapy (HRT). = Calcitonin ( Withdrawn). = Bisphosphonates ( Oral & IV).

= Selective Estrogen Receptor Modulators (SERM’s). = Dual acting drugs ( Strontium Ranelate).

Which drugs do we have? (2) = Intermittent PTH ( Teriparatide). = RANK- RANK Ligand inhibition (Denosumab). = Drugs we don’t have.

= Drugs we don’t know about. = Calcium & Vitamin “D” for everyone.

DRUGS WE DO NOT HAVE YET: = Anti-cathpsin K ( Odanacatib). = Anti-sclerostin antibodies.

DRUGS WE DO NOT KNOW YET.

Presentation Overview 1- What is Osteoporosis? 2- Osteoporotic Fractures. 3- Drug therapy in treating Osteoporosis. 4- Denosumab.

5- How long to treat?

RANKL and RANK RANKL & RANK are members of the tumor necrosis factor superfamily that are expressed by a variety of lymphoid cells. It has been theorized that the inhibition of RANKL might increase the risk of cancer or infection.

Denosumab It is a monoclonal antibody which has been approved for: = Treatment of PMO. = Prevention of PMO. = Treatment & prevention of bone loss in patients undergoing hormone ablation therapy for breast and prostate cancer.

Denosumab is a fully human IgG2 monoclonal antibody that neutralizes RANKL . It acts in a similar manner to osteoprotegrin, a cytokine of the tumor necrosis family, that inhibits binding of RANKL to RANK. Denosumab competes with RANKL for RANK binding sites and prevents the maturation of osteoclasts suppressing osteoclast-mediated bone resorption.

Menopause Initiates Changes Adversely Affecting Bone Structure and Function Molecular and Cellular Changes Estrogen

RANK Ligand

OPG

Osteoclast

or

Osteoblast or

Changes to Microstructure Bone mass

Trabecular architecture

Cortical thickness

Cortical porosity

Mineral content or

Chavassieux P, et al. Endrocrine Rev. 2007;28:151-164. Eghbali-Fatourechi G, et al. J Clin Invest. 2003;111:1221-1230. Hofbauer LC, et al. Endocrinology. 1999;140:4367-4370. Riggs BL, et al. J Bone Miner Res. 1998;13:763-773. Shevde NK, et al. Proc Nat Acad Sci U S A. 2000;97:7829-7834. © 2008 Amgen. All rights reserved.

Provided as an educational resource. Do not copy or distribute.

The Effect of Denosumab on Trabecular and Cortical Bone Table of Contents Distribution and Remodelling of Trabecular and Cortical Bone FREEDOM Study & FREEDOM Extension Treatment Effects on Trabecular and Cortical Bone Distal Radius QCT & HRpQCT Analysis MOA Vs Bisphosphonates

CMCE/DNB/0126/12 Sep 2012

The Effect of Denosumab on Trabecular and Cortical Bone Table of Contents Distribution and Remodelling of Trabecular and Cortical Bone FREEDOM Study & FREEDOM Extension Treatment Effects on Trabecular and Cortical Bone Distal Radius QCT & HRpQCT Analysis MOA Vs Bisphosphonates

CMCE/DNB/0126/12 Sep 2012

Distribution and Remodelling of Trabecular and Cortical Bone

CMCE/DNB/0126/12 Sep 2012

The Distribution of Trabecular and Cortical Bone Varies Throughout the Skeleton 80% of bone mass is cortical bone and accounts for 20% of bone turnover Spine ≥75% trabecular

Vertebrae

Long bones >75% cortical

Femur Adapted from: Dempster DW. Primer on the metabolic bone diseases and disorders of bone metabolism. 6th ed. 2006; Chapter 2; p. 7–11.

Trabecular bone

Cortical bone

Bone Mass Rapidly Decreases With the Onset of Menopause Attainment of peak bone mass

Peak bone mass

Onset of Menopause*

Bone loss

Formation >

Bone mass

Resorption

Resorption > Formation

0

10

20

30

40

50

60

70

80

Age (years) *Menopause occurs for approximately 1 year during this time frame Lanham-New SA. Proc Nutr Soc 2008;67:163176; Burger H et al. Am J Epidemiol 1998;147:871879; Recker R et al. J Bone Miner Res 2000;15:19651973; Sambrook P. Bone structure and function in normal and disease states. Chapter 5; p.67–84; Weaver CM et al. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 7th ed. 2008:206208.

Bone Remodeling: Key Features

Life-long, continuous process • Old bone removed by osteoclastic resorption – Replacement bone created through osteoblastic formation – Repairs microdamage in bone • Contributes to calcium homeostasis • Contributes to adaptation to mechanical stress • Assessed in bone biopsies after tetracycline double labeling •

Bone remodeling cycle Pre-osteoblasts

Monocytes Osteoclasts

Osteoblasts Osteocytes

Bone Resorption by Osteoclasts Requires ‘Working’ Surfaces Trabecular compartment More surface per volume

Osteoclasts erode accessible surfaces, removing trabecular structures

Cortical compartment Less surface per volume

Sambrook P. Bone structure and function in normal and disease states. Chapter 5; p. 67–84; Clarke B. Clin J Am Soc 2008;3:S131–S139; Dempster DW. Primer on the metabolic bone diseases and disorders of bone metabolism. 6th ed. 2006; Chapter 2; p. 7–11; Chavassieux P et al. Endocr Rev 2007;28:151–164.

Osteoclasts tunnel through the cortex, increasing cortical porosity

Mean bone loss (mg hydroxyapatite)

Early After Menopause Women Lose Primarily Trabecular Bone Whereas Cortical Bone is Lost Later in Life

90

*

80

Distal radius:

70

Cortical loss

60 50

22%

40 30

Trabecular loss *

4%

20 10 0

50−64 years

Zebaze RM et al. Lancet 2010:9727:17291736.

64−79 years

≥80 years

*p < 0.0001

Remodelling is Increasingly Important in Cortical Bone Over Time

Surface remodelling Anterior sub-trochanteric cross-sectional images Zebaze RM et al. Lancet 2010:9727:17291736.

Intracortical remodelling

Cortical Porosity Increases With Age After Menopause

29-year-old woman

Cross-sectional images of distal radius Zebaze RM et al. Lancet 2010:9727:17291736.

90-year-old woman

Cortical Bone Loss Has More Impact on Bone Strength Than Trabecular Bone Loss Principal strain distribution in the distal radius* Simulated bone atrophy at the distal radius Change in bone volume

Mechanism of bone loss

Decrease in strength

20%

 Trabecular number

11%

20%

20%

Yellow–red: compressive strain, blue–green: tensile strain

 Trabecular thickness

 Cortical thickness

9%

39%

 Bone strength was affected most in the reduced cortical thickness model1

*Contour plot of the microfinite element calculated principal strain distribution in the distal radius for a distributed load of 1000 Newtons acting normal to the articular surface

1. Pistoia W et al. Bone 2003;33:937945.

Incidence per 10,000 women per year

As Trabecular and Cortical Bone Loss Progresses, Vertebral and Hip Fracture Rates Increase Exponentially

Vertebral fractures Hip fractures 400

300

Early increased incidence of vertebral fracture correlating with early trabecular bone loss

Later increased incidence of hip fracture correlating with accumulation of trabecular and cortical bone loss

200

100

0

50−54

55−59

60−64

65−69

70−74

Age (years) Adapted from: Sambrook P & Cooper C. Lancet 2006;367:2010–2018.

75−79

80−84

85+

Summary (1) • Bone mass rapidly decreases with the onset of menopause1 • Initial bone loss is mainly trabecular • Later after menopause, bone loss is mainly cortical with increased cortical porosity

• Fracture incidence progression over time seems to correlate with trabecular and cortical bone loss1,2 • Vertebral fracture incidence is high immediately after menopause and increases continuously over time2 • Hip fracture incidence remains very low until the age of about 70, when it increases dramatically2 • Loss of cortical bone has more impact on bone strength than trabecular bone loss3 1. Zebaze RM et al. Lancet 2010:9727:17291736. 2. Sambrook P & Cooper C. Lancet 2006;367:2010–2018. 3. Pistoia W et al. Bone 2003;33:937945.

The Effect of Denosumab on Trabecular and Cortical Bone Table of Contents Distribution and Remodelling of Trabecular and Cortical Bone FREEDOM Study & FREEDOM Extension Treatment Effects on Trabecular and Cortical Bone Distal Radius QCT & HRpQCT Analysis MOA Vs Bisphosphonates

CMCE/DNB/0126/12 Sep 2012

FREEDOM Study and

FREEDOM Extension

CMCE/DNB/0126/12 Sep 2012

FREEDOM Study ‒ Study Design Study Month Day 1 Visit

S C R E E N I N G

R A N D O M I Z A T I O N

1

6

12

24

Study population 36

• 7808 postmenopausal women • T-score –2.5 ≤–2.5 Baseline femoral neck T-score

Relative risk reduction (95% CI) n = number of patients with ≥1 wrist fracture; N = number of randomized patients; CI = confidence interval Simon J et al. J Bone Miner Res 2011;26;S20:A1062.

Summary (4) Denosumab treatment increases BMD at the 1/3 distal radius; a site that represent a pure cortical region1,2

•

Denosumab unique mode of action is associated with • improvements in radius trabecular and cortical vBMD and cortical porosity, which are relevant to improve bone strength1,2 In the sub-analysis of the FREEDOM trial, the positive • effects of denosumab on the radius trabecular and cortical compartment is associated with significant wrist fracture reductions in osteoporotic postmenopausal women at higher risk of fracture3 1. Seeman E et al. J Bone Miner Res 2010;25:1886‒1894. 2. Boyd SK et al. ECTS Congress 2011; Abstract and poster PP264. 3. Simon J et al. J Bone Miner Res 2011;26;S20:A1062.

The Effect of Denosumab on Trabecular and Cortical Bone Table of Contents Distribution and Remodelling of Trabecular and Cortical Bone FREEDOM Study & FREEDOM Extension Treatment Effects on Trabecular and Cortical Bone Distal Radius QCT & HRpQCT Analysis MOA Vs Bisphosphonates

CMCE/DNB/0126/12 Sep 2012

MOA Vs

Bisphosphonates

Denosumab (Dmab), a RANKL Inhibitor, Inhibits Osteoclast Formation, Function and Survival Osteoclast precursor

2

Dmab prevents RANKL from binding to RANK

RANK Ligand RANK

3

Dmab inhibits osteoclast formation

OPG Denosumab

4 1

Differentiated osteoclast

Dmab binds to and inhibits RANKL

Osteoblasts Kostenuik PJ et al. Curr Pharm Des 2001;7:613‒635. Denosumab (Prolia® ) Summary of Product Characteristics, Amgen 2012. ©2011 Amgen Inc. All rights reserved.

Dmab inhibits osteoclast function and survival

Activated osteoclast Mechanism of action representations are for illustrative purposes only and are not meant to imply any clinical efficacy. Do not copy or distribute.

Bisphosphonates Bind to Bone and Inhibit Osteoclasts at the Bone Surface Osteoclast precursor

RANK Ligand RANK OPG Differentiated osteoclast

1

Osteoblasts

Owens G et al. Am J Manag Care 2007;13:S290‒S308. Jung A et al. Calcif Tissue Res 1973;11:269‒280. Russell RG et al. Ann NY Acad Sci 2007;1117:209‒257. ©2011 Amgen Inc. All rights reserved.

2

Bisphosphonate

Bisphosphonates bind to bone and are taken up by mature osteoclasts

Activated osteoclast

Bisphosphonates inhibit osteoclastmediated resorption Mechanism of action representations are for illustrative purposes only and are not meant to imply any clinical Do not copyefficacy. or distribute.

FREEDOM: Prolia® significantly increased BMD throughout the skeleton FREEDOM: percentage increase in BMD vs placebo at 3, 6 and 8 years1-4 P < 0.0001

At 3 years At 6 years At 8 years

Percentage Change in BMD (%)

20 18

18.5%

16 14

15.2%

12 10 8

9.2% 7.5%

6 4

8.2%

6.7% 6.8% *

6.0% 4.8%

2 0

LUMBAR TOTAL SPINE HIP * Phase 2, McClung M et al. Osteoporos Int 2012 1. Prolia®, Summary of Product Characteristics, 2010. 2. Cummings SR et al. N Engl J Med 2009;361:756–765. 3. Bone HG et al. J Clin Endocrinol Metab 2013; 98: 4483-4492; doi:10.1210/jc.2013-1597. 4.Papapoulos S. Abstract LB-MO26 presented at the ASBMR 2013 meeting.

FEMORAL NECK

97

The bioavailability of one SC Denosumab injection is 61% & serum conc. are detected within one hour. Maximum serum. conc. are achieved in 5-21days and Denosumab may be detectable for nine monthsor longer. It is cleared by the reticuloendothelial system with minimal renal infiltration and excretion. The elimination half life is 32 days & the terminal half-life is 5-10 days. Denosumab does not incorporate in bone.

= Increased risk of serious infections which includes skin infections has been reported. = Patients with impaired immune systems or those on immunosuppressant agents may be at an increased risk of infections.

= Osteonecrosis of the jaw as well as atypical fractures and delayed fracture healing have been also reported.

The most common adverse effects include: = Arthralgia. = Nasopharyngitis. = Back pain. = Headache. = Extremity pain. = Respiratory infection. = Constipation. = Urinary tract infection. = Shoulder pain. = Sore throat. = Asymptomatic hypocalcemia. Denosumab is contraindicated in patients with severe hypocalcemia & caution should be taken in patients with impaired renal function.

Denosumab 60 mg every six months is administered as a SC injection in the upper arm, upper thigh or abdomen. All patients should take 1000 mg. of calcium and 800 IU of Vit. “D” daily. Prior to administration, Denosumab should be removed from the refrigrator and brought to room Temp.

Presentation Overview 1- What is Osteoporosis? 2- Osteoporotic Fractures. 3- Drug therapy in treating Osteoporosis. 4- Denosumab.

5- How long to treat?

How long to treat ? •HRT: as short as possible ( FDA, NAMS, EMEA) •Raloxifene: no limitation •Teriparatide: 18 months, in GIO 24 months.

•Strontium Ranelate: at least 5 years •Bisphosphonates: controversial at least five years & more. •Denosumab: Eight years.

Treating Osteoporosis: Ideal Scenario

Goal: fewer fractures

Improve bone quality

Ensure exposure to drug

Provide treatment to improve BMD: Bisphosphonates have proven efficacy

Treating Osteoporosis: Real-world Scenario

Goal: fewer fractures

Improve bone quality

Current unmet need

Ensure exposure to drug

Provide treatment to improve BMD: Bisphosphonates have proven efficacy

Compliance and Persistence with Oral Bisphosphonates are Poor and Suboptimal in Clinical Practice1

100 90

% of Patients

80 70

Daily Weekly

60 50 40 30 20 10 0

P = NS

1

2

3

4

5

6

7

8

9

10 11 12

Months of Continuous Persistence

2

1. Véronique Rabenda , Poor adherence to oral bisphosphonate treatment and its consequences: a review of the evidence, Expert Opin. Pharmacother. (2009) 10(14):2303-2315 2. Downey TW, et al. South Med J 2006;99:570-575.

Presentation Review 1- What is Osteoporosis? 2- Osteoporotic Fractures. 3- Drug therapy in treating Osteoporosis. 4- Denosumab.

5- How long to treat?

CONCLUSIONS 1- The incidence of Osteoporosis continues to rise with the progressive aging population. 2- Osteoporotic fractures apart from imposing a financial burden are life threatening. 3- We do have many drugs for management of PMO, PMO, GIOP which help in reducing Osteoporotic fractures as well as preventing Osteoporosis. 4- Denosumab is the first targeted biologic therapy in treatment of PMO, PMO increasing the bone mineral content in both cortical as well as trabecular bones thus reducing the risk of fractures. 5- It has a high compliance rate as it is given every 6 months .