Proceedings of the First Annual Meeting of the Lebanese Society for Osteoporosis and Metabolic Bone Disorders • OSTEOS

BONE PHYSIOLOGY: CURRENT AND FUTURE THERAPYhttp://www.lebanesemedicaljournal.org/articles/58-Suppl1/doc1.pdf

Michael McCLUNG, MD, FACE, FACP

The objective of treatment of patients with or at risk of osteoporosis is to reduce the riskof subsequent fracture and, in special clinical circumstances, the prevention of rapid boneloss. In the past 15 years, several classes of drugs have become available, based on theresults of well-designed clinical trials documented therapeutic benefit. These drugs arequite effective, preventing bone loss, reducing the risk of spine fracture by 60-70%, of hipfracture by 40-50% and of other fractures. However, each of these agents is limited byinconvenient or awkward dosing regimens, real or perceived intolerance and concernsabout long-term safety. Additionally, poor acceptance and persistence with therapy sub-stantially limit the effectiveness of these treatments in daily clinical practice, providing theimpetus for the development of new treatment approaches. New dosing options for currentclasses of drugs including bisphosphonates, calcitonin and parathyroid hormone analogueshave or may improve acceptance of treatment. The use of parathyroid hormone in the man-agement of patients with glucocorticoid-induced osteoporosis provides a therapy suited tothe unique pathophysiology of this important disorder.

Additionally, the explosion of new knowledge about the molecular and metabolic reg-ulation of bone metabolism has provided intriguing new targets for therapeutic interven-tion. The discovery of the RANK/RANK ligand pathway and its pivotal role in the regu-lation of osteoclastogenesis and bone resorption has led to the development of specificinhibitors of this pathway that have completed clinical trials. Treatment with an anti-RANKL antibody, given subcutaneously every 6 months, inhibits osteoclast activity andbone resorption, prevents bone loss and reduces fracture risk in several clinical situations.Inhibitors of cathepsin K are in development. These agents have the potential, based ontheir mechanism of action, of specifically inhibiting bone resorption without significantlyreducing bone formation. By “uncoupling” bone metabolism, these agents might be shownto be more effective than current treatments.

The appreciation of the central role of osteocytes in the modulation of bone turnoverand the targeted repair of skeletal damage provides the opportunity to exploit new targetsfor treatment. Osteocyte-derived sclerostin is an inhibitor of the LRP5/Wnt signaling path-way that modulates osteoblast function and bone formation. Inhibition of sclerostinrestores bone mass, reconstitutes bone structure and architecture and normalizes bonestrength in animal models of osteoporosis by activating bone formation without inducingosteoclastic bone resorption. This treatment approach has the potential to be the “cure” forsevere osteoporosis.

We are moving away from the era of “serendipitous pharmacology” toward a time whenelegant, targeted treatments of diseases are available. The development of new drugs forosteoporosis will provide more sophisticated mechanisms of treatment, different safetyand tolerability profiles and possibly more effective strategies to reduce fracture risk.These new agents may also allow the opportunity to combine drugs with different mech-anisms of action to achieve even better fracture protection. As these new drugs becomeavailable, the clinical challenge will be to understand how the new agents fit most effi-ciently and most appropriately into our daily clinical practice to enhance the lives of ourpatients.Oregon Osteoporosis Center

Portland, Oregon USA

S4 Lebanese Medical Journal 2010 • Volume 58 (Suppl 1)

OOC

Bone Physiology:Current and Future Therapies

Osteoblasts

Bone formation

Bone resorption

Bone

Osteoclast

RANK/RANKL Eph2/Ephrin2

Michael R. McClung, MD, FACPDirector, Oregon Osteoporosis Center

Portland, Oregon, USA OOC

• Many of these agents are very effective for treatingpostmenopausal osteoporosis• Vertebral fracture by 60-70%

• Multiple vertebral fractures by 75-96%

• Hip fracture by 40-59%• Non-vertebral fracture by 20-35%

• Vertebral fracture risk reduced by 70% in GIO

• In general are well tolerated

• In clinical trials, have been very safe

Osteoporosis Treatment 2009: Benefits

Greenspan SG et al. Ann Intern Med. 2007;146:326.Black DM, et al. N Engl J Med. 2007;356:1809.Wallach S et al. Calcif Tissue Int. 2000;67:277.

Black DM, et al. Lancet. 1996;348:1535Reginster J, et al. Osteoporos Int. 2000;11:83Neer RM, et al. N Engl J Med. 2001;344:1434

OOC

• Real or perceived intolerance

• Concerns about safety, especially the long-termsafety of bisphosphonates

• Inconvenient or awkward dosing regimens

• Poor adherence to therapy

• No agent restores skeletal structure or strengthto normal levels

• i.e., no “cure” for osteoporosis

• Expense

Osteoporosis Treatment 2009: Limitations

M McClung. Personal opinionOOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6

OOC

Bone Physiology:Current and Future Therapies

Osteoblasts

Bone formation

Bone resorption

Bone

Osteoclast

RANK/RANKL Eph2/Ephrin2

Michael R. McClung, MD, FACPDirector, Oregon Osteoporosis Center

Portland, Oregon, USA OOC

• Many of these agents are very effective for treatingpostmenopausal osteoporosis• Vertebral fracture by 60-70%

• Multiple vertebral fractures by 75-96%

• Hip fracture by 40-59%• Non-vertebral fracture by 20-35%

• Vertebral fracture risk reduced by 70% in GIO

• In general are well tolerated

• In clinical trials, have been very safe

Osteoporosis Treatment 2009: Benefits

Greenspan SG et al. Ann Intern Med. 2007;146:326.Black DM, et al. N Engl J Med. 2007;356:1809.Wallach S et al. Calcif Tissue Int. 2000;67:277.

Black DM, et al. Lancet. 1996;348:1535Reginster J, et al. Osteoporos Int. 2000;11:83Neer RM, et al. N Engl J Med. 2001;344:1434

OOC

• Real or perceived intolerance

• Concerns about safety, especially the long-termsafety of bisphosphonates

• Inconvenient or awkward dosing regimens

• Poor adherence to therapy

• No agent restores skeletal structure or strengthto normal levels

• i.e., no “cure” for osteoporosis

• Expense

Osteoporosis Treatment 2009: Limitations

M McClung. Personal opinionOOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

• Longer duration of “anabolic window”

• Possibility of “cure” with short-term treatment

• Caveat: Tissue specificity is required

(stimulation of only bone formation)

M McClung. Personal opinion

What Might New Anabolic Agents Offer?

OOC

Bone Physiology:Current and Future Therapies

Osteoblasts

Bone formation

Bone resorption

Bone

Osteoclast

RANK/RANKL Eph2/Ephrin2

Michael R. McClung, MD, FACPDirector, Oregon Osteoporosis Center

Portland, Oregon, USA OOC

• Many of these agents are very effective for treatingpostmenopausal osteoporosis• Vertebral fracture by 60-70%

• Multiple vertebral fractures by 75-96%

• Hip fracture by 40-59%• Non-vertebral fracture by 20-35%

• Vertebral fracture risk reduced by 70% in GIO

• In general are well tolerated

• In clinical trials, have been very safe

Osteoporosis Treatment 2009: Benefits

Greenspan SG et al. Ann Intern Med. 2007;146:326.Black DM, et al. N Engl J Med. 2007;356:1809.Wallach S et al. Calcif Tissue Int. 2000;67:277.

Black DM, et al. Lancet. 1996;348:1535Reginster J, et al. Osteoporos Int. 2000;11:83Neer RM, et al. N Engl J Med. 2001;344:1434

OOC

• Real or perceived intolerance

• Concerns about safety, especially the long-termsafety of bisphosphonates

• Inconvenient or awkward dosing regimens

• Poor adherence to therapy

• No agent restores skeletal structure or strengthto normal levels

• i.e., no “cure” for osteoporosis

• Expense

Osteoporosis Treatment 2009: Limitations

M McClung. Personal opinionOOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

• Longer duration of “anabolic window”

• Possibility of “cure” with short-term treatment

• Caveat: Tissue specificity is required

(stimulation of only bone formation)

M McClung. Personal opinion

What Might New Anabolic Agents Offer?

OOC

Bone Physiology:Current and Future Therapies

Osteoblasts

Bone formation

Bone resorption

Bone

Osteoclast

RANK/RANKL Eph2/Ephrin2

Michael R. McClung, MD, FACPDirector, Oregon Osteoporosis Center

Portland, Oregon, USA OOC

• Many of these agents are very effective for treatingpostmenopausal osteoporosis• Vertebral fracture by 60-70%

• Multiple vertebral fractures by 75-96%

• Hip fracture by 40-59%• Non-vertebral fracture by 20-35%

• Vertebral fracture risk reduced by 70% in GIO

• In general are well tolerated

• In clinical trials, have been very safe

Osteoporosis Treatment 2009: Benefits

Greenspan SG et al. Ann Intern Med. 2007;146:326.Black DM, et al. N Engl J Med. 2007;356:1809.Wallach S et al. Calcif Tissue Int. 2000;67:277.

Black DM, et al. Lancet. 1996;348:1535Reginster J, et al. Osteoporos Int. 2000;11:83Neer RM, et al. N Engl J Med. 2001;344:1434

OOC

• Real or perceived intolerance

• Concerns about safety, especially the long-termsafety of bisphosphonates

• Inconvenient or awkward dosing regimens

• Poor adherence to therapy

• No agent restores skeletal structure or strengthto normal levels

• i.e., no “cure” for osteoporosis

• Expense

Osteoporosis Treatment 2009: Limitations

M McClung. Personal opinionOOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

• Longer duration of “anabolic window”

• Possibility of “cure” with short-term treatment

• Caveat: Tissue specificity is required

(stimulation of only bone formation)

M McClung. Personal opinion

What Might New Anabolic Agents Offer?

OOC

Bone Physiology:Current and Future Therapies

Osteoblasts

Bone formation

Bone resorption

Bone

Osteoclast

RANK/RANKL Eph2/Ephrin2

Michael R. McClung, MD, FACPDirector, Oregon Osteoporosis Center

Portland, Oregon, USA OOC

• Many of these agents are very effective for treatingpostmenopausal osteoporosis• Vertebral fracture by 60-70%

• Multiple vertebral fractures by 75-96%

• Hip fracture by 40-59%• Non-vertebral fracture by 20-35%

• Vertebral fracture risk reduced by 70% in GIO

• In general are well tolerated

• In clinical trials, have been very safe

Osteoporosis Treatment 2009: Benefits

Greenspan SG et al. Ann Intern Med. 2007;146:326.Black DM, et al. N Engl J Med. 2007;356:1809.Wallach S et al. Calcif Tissue Int. 2000;67:277.

Black DM, et al. Lancet. 1996;348:1535Reginster J, et al. Osteoporos Int. 2000;11:83Neer RM, et al. N Engl J Med. 2001;344:1434

OOC

• Real or perceived intolerance

• Concerns about safety, especially the long-termsafety of bisphosphonates

• Inconvenient or awkward dosing regimens

• Poor adherence to therapy

• No agent restores skeletal structure or strengthto normal levels

• i.e., no “cure” for osteoporosis

• Expense

Osteoporosis Treatment 2009: Limitations

M McClung. Personal opinionOOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

New estrogen agonists/antagonists (EAAs) 1

Oral calcitoninRANKL inhibitors 2

Cathepsin K inhibitors 3

New analogs of PTH 4

CalcilyticsBiological activators of bone formation

Anti-sclerostin antibody 5

DKK inhibitors 6

Emerging Treatments

4 Greenspan S et al. Osteoporos Int. 2005;16(suppl 3):S11.5 Warmington K, et al. J Bone Miner Res. 2005;20(Suppl 1):S22.

6 Grisanti M et al. J Bone Miner Res. 2006;21(Suppl 1):S25.

1 McClung M, et al. Osteoporos Int. 2005;16(Supp 3):S57-S58.2 McClung MR, et al. New Engl J Med. 2006;354:821-831.3 Roy SK et al. J Bone Miner Res. 2005;20(Suppl 1):S293.

Anti-resorptive agents

Anabolic agents

OOC

• Longer duration of “anabolic window”

• Possibility of “cure” with short-term treatment

• Caveat: Tissue specificity is required

(stimulation of only bone formation)

M McClung. Personal opinion

What Might New Anabolic Agents Offer?

Lebanese Medical Journal 2010 • Volume 58 (Suppl 1) S5