New Treatment Modalities for Osteoporosis

Sophie A. Jamal, M.D., PhD, FRCPC
Toronto, ON

Introduction
Over the past decade there have been numerous advances concerning the pharmacologic treatment of osteoporosis and related fractures. For example, the bisphosphonates, alendronate and risedronate can now be prescribed once weekly, and our treatment armamentarium has expanded to include the anabolic agent - parathyroid hormone.

In addition, there has been an increased understanding of the factors which regulate osteoclast and osteoblast activity. This has led to the development of targeted pharmacologic agents which influence bone remodeling. The advantage of these highly specific agents is that they may be more potent and may be associated with fewer side effects than the treatments currently available for osteoporosis. The following section will review three of these targeted treatment modalities: 1) denosumab, a monoclonal antibody to receptor activator of nuclear factor κ ligand (RANKL), 2) strontium ranelate an agent that can both stimulate bone formation and inhibit bone resorption and 3) inhibitors to cathepsin K that, in vitro, are potent antiresorptives.

Denosumab
RANKL is a protein expressed by osteoblastic stromal cells that binds to the receptor activator of nuclear factor κ (RANK) and is the primary mediator of osteoclast differentiation, activation and survival1-3. RANKL is responsible for osteoclast mediated bone resorption in a broad range of conditions. Osteoprotegerin, a soluble RANKL decoy receptor that binds RANKL, is the key endogenous regulator of the RANKL-RANK pathway. This pathway is illustrated in Figure 1.

jamal_fig1.jpg

Figure 1. The RANK, RANKL, OPG Axis

Based on our recent understanding of the role of the RANKL/RANK/OPG system in bone remodeling, Denosumab was developed. Denosumab is a fully monoclonal antibody that binds to RANKL with high affinity and specificity and blocks the interaction of RANKL with RANK, mimicking the endogenous effects of osteoprotegerin4.

A recent phase 2 study reported on the efficacy and safety of denosumab in 412 postmenopausal women with low bone mineral density (BMD) followed for 12 months. Subjects were randomly assigned to denosumab either every three months (at a dose of 6, 14, or 30 mg) or every six months (at a dose of 14, 60, 100 or 210mg), open label oral alendronate (70mg weekly) or placebo5. Percent change from baseline in spine, hip and distal radius BMD was assessed in each group. Denosumab increased spine BMD by 3.0 to 6.7%, total hip BMD by 1.9 to 3.6% and radial BMD by 0.4 to 1.3%. Increases in BMD with denosumab were superior to those with placebo and similar to or greater than those with alendronate. Compared with placebo, there was no difference in type and rates of adverse events in the denosumab group. These preliminary findings suggest that denosumab might be an effective treatment for osteoporosis. Further studies to test the effects of denosumab on fractures are needed.

Strontium Ranelate
Strontium Ranelate has been recently licensed in Europe for the treatment of osteoporosis. The mechanism of action of strontium ranelate is not yet fully understood, but at the cellular level strontium ranelate enhances osteoblast replication and inhibits osteoclast differentiation and activity6. As a result, and in contrast to other currently available treatments, strontium ranelate has the unique ability to both inhibit bone resorption and stimulate bone formation. Figure 2 illustrates the sites at which strontium ranelate is thought to act.

jamal_fig2.jpg

Figure 2. The site of action of strontium ranelate

There have been two international, doubleblind, placebo controlled studies on the effects of daily Strontium ranelate at 2g. The Spinal Osteoporosis Therapeutic Intervention (SOTI) trial enrolled 1649 postmenopausal women with low bone mineral density and at least one vertebral fracture to strontium ranelate or placebo for three years7. New vertebral fractures occurred in fewer patients in the strontium ranelate group compared with the placebo group (relative risk reduction: 0.59; 95% confidence interval: 0.48 to 0.73) and there were no significant differences between the groups in the incidence of serious adverse events. The Treatment of Peripheral Osteoporosis (TROPOS) study enrolled 5091 postmenopausal women with osteoporosis and assessed the efficacy of strontium, compared with placebo in preventing nonvertebral fractures8. Strontium ranelate decreased nonvertebral fractures, such as the hip, pelvis, sacrum, clavicle and humerus by 18% (p = 0.031) and significantly reduced the risk of hip fracture (36%; p =0.046) in a subset of women at high risk. Again, there were no differences in adverse events between the strontium and the placebo groups. Strontium ranelate is being considered for approval in Canada.

Cathepsin K Inhibitors
Cathepsin K is a cysteine proteinase that is expressed by osteoclasts and degrades key bone and cartilage matrix proteins including type 1 collagen, the major type of collagen in bone. Cellular studies demonstrate inhibiting cathepsin K reduces bone resorption with minimal effects on bone formation9. Further, animal models have demonstrate that a selective inhibitor of cathepsin K (SB-462795), given orally or subcutaneously, decreases bone resorption and increases the amount of trabecular and cortical bone10

Recently, another direct inhibitor of cathepsin K, AAE581, has been developed. Results from a double-blind placebo controlled trial designed to assess the safety, tolerability and effects on markers of bone turnover in 44 subjects treated with AAE581 has been published in abstract form11. This trial enrolled 25 men and 19 women who ranged in age from 18 to 45 years and found that oral administration of AAE581 decreased markers of bone resorption by about 90% within 6-12 hours. Values returned to pre-treatment levels by 48 hours. These data suggest that, AAE581 given as a single dose to a non-osteoporotic population is well tolerated and potently decreases serum markers of bone resorption. Several cathepsin K inhibitors are currently under development.

Conclusion
Our increased understanding of the molecular mechanisms that regulate osteoclast and osteoblast activity has led to the development of highly targeted potent agents for the prevention and treatment of osteoporosis. These agents will increase our treatment options for patients with osteoporosis, ultimately decreasing the number of men and women who develop osteoporotic fractures.

References

  1. Lacey, D.L., et al., Osteoprotegerin ligand is a cytokine that regulates osteoclast differentiation and activation. Cell, 1998. 93: p. 165-76.
  2. Hofbauer, L.C., Osteoprotegerin ligand and osteoprotegerin: novel implications for osteoclast biology and bone metabolism. Eur J Endocrinol, 1999. 141(3): p. 195-210.
  3. Hofbauer, L.C., et al., The roles of osteoprotegerin and osteoprotegerin ligand in the paracrine regulation of bone resorption. J Bone Miner Res, 2000. 15: p. 2-12.
  4. Bekker, P.J., et al., A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. 2004. J Bone Miner Res, 2005. 20: p. 2275-82.
  5. McClung, M.R., et al., Denosumab in postmenopausal women with low bone mineral density. N Engl J Med, 2006. 354: p. 821-31.
  6. Marie, P.J., et al., Mechanism of action and therapeutic potential of strontium in bone. Calcif Tissue Int, 2001. 69: p. 121-9.
  7. Meunier, P.J., et al., The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med, 2004. 29: p. 459-68.
  8. Reginster, J.Y., et al., Strontium ranelate reduces the risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab, 2005. 90: p. 2816-22.
  9. Zaidi, M., et al., Cathepsin K, osteoclastic resorption and osteoporosis therapy. J Bone Miner Res, 2001. 16: p. 1747-49.
  10. Yamada, H., et al., A potent and orally active inhibitor of cathepsin K selectively suppresses bone resorption without affecting bone formation in cynomolgus monkeys. J Bone Miner Res (supp), 2005. 20; supp1: p. S253.
  11. Roy, S.K., et al., Safety, effects on markers of bone resorption and pharmacokinetics of Cathepsin K inhibitor, AAE581, in healthy subjects. J Bone Miner Res (supp), 2005. 20; supp 1: p. S293.

Submit Community Content

If you have orthopedic information that you would like to share with the Orthogate Community, please register/login and submit your news, event, job, article, case or workshop from the Submit Content menu under the My Account area. Learn more!