Osteoporosis is a metabolic bone disease characterized by reduced bone mass and deterioration of bone tissue, leading to bone fragility and increased fracture risk. Current therapies for osteoporosis include bisphosphonates, denosumab, teriparatide, and abaloparatide. Emerging therapies target various pathways like inhibiting bone resorption through RANKL inhibition, cathepsin K inhibition, or stimulating bone formation through antagonizing proteins like sclerostin, Dkk-1, or activating the Wnt signaling pathway. These emerging therapies hold promise to provide greater gains in bone mass and reconstruction of damaged bone compared to current therapies.
2. INTRODUCTION
• Osteoporosis is a metabolic bone disease characterized by reduced bone
mass and micro-architectural deterioration in bone tissue, leading to
bone fragility and an increased susceptibility to fractures.
• The World Health Organisation (WHO) defines osteoporosis as a bone
density that falls 2.5 standard deviations (SD) below the mean for young
healthy adults of the same sex —also referred to as a T-score of –2.5.
• Global health problem (WHO estimate >200 million).
3. PATHOPHYSIOLOGY
1. LOW PEAK BONE MASS
2. BONE REMODELLING
PEAK BONE MASS –
• Peak bone mass is the maximum mass of bone achieved by an individual at skeletal
maturity, typically by the age of 20 years
• After peak bone mass is attained, both men and women
start losing bone mass over the remainder of their lifetimes
• Determinants of peak bone mass
- genetic factors (50-80%) , nutrition (protein, calcium,
vit. D), gonadal function, lifestyle
4. BONE MODELING AND REMODELING
• Bone modeling : during growth and development phase in the young; it is
the increase in skeleton size by apposition of new bone tissue on outer
surface of cortex.
• Bone remodeling is the mechanism that ensures bone turnover and bone mass
maintenance in adults; it is based on the interplay between the bone resorption phase
and the bone formation phase.
Bone remodelling has two main functions-
1. to repair micro damage within skeleton to maintain skeletal strength.
2. to supply calcium to maintain serum calcium levels
OSTEOPOROSIS results from bone loss due to age related changes in bone
remodelling as well as extrinsic and intrinsic factors that exagerate this process.
5.
6.
7. Therapies for osteoporosis
• Anti-resorptive therapy
– Slow down absorption action on osteoclasts
Bisphosphonates, denozumab, cathepsin K inhibitors, Raloxifene, strontium
• Anabolic therapy
– Stimulate bone formation action on osteoblasts
Parathormone, teriparatide
Wnt inhibitors,
9. Bisphosphonates
• Synthetic analogs of naturally occuring pyrophosphates.
• MOA – impair osteoclast function and reduce osteoclast number, in
part by inducing apoptosis.
• SIDE EFFECTS- gastrointestinal toxicity (dyspepsia, abdominal pain,
gastritis, and esophagitis) , osteonecrosis of the jaw(ONJ), atypical
femur fracture, renal toxicity - contraindicated in patients with
estimated GFR below 30–35 ml/min.
• EFFICACY - reduce the incidence of vertebral fractures by 40–50% in
osteoporosis, with similar reductions in non vertebral and hip
fractures .
10.
11. RALOXIFENE
• Raloxifene (60 mg/d) is the first FDA-approved Selective Estrogen
Receptor Modulator (SERM) marketed for the prevention and
treatment of osteoporosis.
• vertebral # ↓ by about 30 % in pts with H/o vertebral# and 55 % in
patients without a prior vertebral # over three years. ↓ in risk of
nonvertebral fracture not documented. Ettinger B. et al. JAMA. 1999
• Raloxifene does not reduce the risk of coronary heart disease.
• DVT risk increased similar to estrogen.
• Newer SERMs that are in various stages of drug development include
bazedoxifene, lasofoxifene, and arzoxifene.
12. Calcitonin (Miacalcin® or Fortical®)
• Salmon calcitonin is FDA-approved for the treatment of osteoporosis in women
who are at least five years postmenopausal when alternative treatments are not
suitable.
• suppresses osteoclast activity by direct action on the osteoclast calcitonin
receptor.
• 200 IU delivered as a single daily intranasal spray.
• Calcitonin reduces vertebral fracture occurrence by about 30 % in those with
prior vertebral fractures but has not been shown to reduce the risk of
nonvertebral fracture Chesnut CH, PROOF Study Group. Am J Med. 2000
• SIDE EFFECTS : rhinitis, epistaxis, allergic reactions.
• A meta-analysis of 21 RCTs suggests an increased risk of malignancies in
calcitonin-salmon-treated patients compared to placebo-treated patients.
13. Teriperatide
• given 20μg daily as subcutaneous injection
• recommended to be given for 12-18 months.
• Teriparatide reduces the risk of vertebral fractures by about 65 % and
nonvertebral fragility fractures by about 53 % in patients with
osteoporosis, after an average of 18 months of therapy .
Neer RM,N Engl J Med 344(19):1434–1441
14. Abaloparatide
• Abaloparatide (Tymlos) is a PTH-related peptide (PTHrP) analogue.
• received FDA approval in April 2017, for the treatment of PMO in
women at high risk for fracture, and in patients who have failed or are
intolerant to other available osteoporosis therapy.
• In a phase 3 clinical trial, abaloparatide reduced the incidence of new
vertebral fracture by 86% over an 18-month period and nonvertebral
fracture by 43%.
• The recommended dose is 80 mcg SC once daily
• The duration of therapy is limited to two years due to the development
of osteosarcoma in rats.
15. LIMITATIONS OF CURRENT THERAPY
1. These therapies provide substantial (but not complete) fracture risk
reduction .
Best fracture risk reduction in RCTs
- Vertebral Fx RRR= 70% (ZOLEDRONATE)
- Non-vertebral Fx RRR=53% (TERIPARATIDE)
- Hip Fx RRR =51% (ALENDRONATE)
2. Adverse events -> suboptimal patient compliance
3. Cost considerations
4. To attempt to translate new insights from
- Bone biology
- Skeletal dynamics
- Anabolic and catabolic pathways
into new therapies for osteoporosis.
18. Denozumab
• It is a human monoclonal antibody that binds receptor-activator of nuclear
factor kappa B ligand (RANKL) and inhibits its action, thus inhibiting the
activation of osteoclasts.
• recently approved by the FDA in June 2010 for the treatment of
osteoporosis in postmenopausal women at high risk of fracture
• 60 mg- Subcutaneous injection every 6 months.
• Denosumab reduces the incidence of vertebral fractures by about 68 %, hip
fractures by about 40%, and nonvertebral fractures by about 20% over 3
years. Cummings SR, N Engl J Med 2009;361(19):1914
• Some rare reported side effects include
– osteonecrosis of jaw, atypical fracture of femur, hypersensitivity reactions,
hypocalcemia
19. Cathepsin K inhibitor
• Odanacatib is a selective inhibitor of CatK, a protease that is released
by osteoclasts to promote the degradation of collagen in bones.
• Currently in phase 2 clinical trial given at a dosage of 50 mg/wk
• Side effects like adverse skin reactions and sclerosis have been
reported with its use
• In 2016, Merck discontinued development of odanacatib due to an
increased risk of stroke
20. Osteoprotegerin
• Osteoprotegerin (OPG) is a decoy receptor for RANKL. It binds to
RANKL and prevents its binding to RANK and hence the activation of
osteoclasts, thus acting as a natural antibody to the RANKL.
• In preclinical studies , low bone turnover induced by OPG
overexpression leads to increased bone mass.
21. C-src kinase inhibitors - SARACATINIB
• C-src is non-receptor tyrosine kinase, required for the development of
the osteoclast ruffled border, in final stages in the maturation of
osteoclasts.
• Saracatinib is a novel orally available competitive inhibitor of Src
kinase shown to inhibit bone resorption in vitro.
• The phase I trial of saracatinib showed that it inhibited osteoclast
mediated bone resorption in healthy men without any significant
adverse effects.
22. Chloride channel inhibitors
• An acidic environment within the sealing zone of osteoclasts facilitates
optimal activity of bone-resorbing proteases and is hence required for
process of osteoclastic bone resorption.
• Passive movement of chloride through chloride channel (ClCN7) located in
the cell membrane of the osteoclast is required for secretion of acid from
osteoclasts. Type 7 transmembrane ClCN7 is specifically found in the
osteoclasts.
• In vitro studies have also shown that ClCN7 inhibitors decrease osteoclast
acidification and inhibit the formation of resorption pits and inhibit bone
resorption in ovariectomized rats without inducing obvious toxicity.
23. αVβ3 integrin antagonists
• αVβ3 integrin receptor or vitronectin receptor is present on the
surface of osteoclasts and is required for the attachment of
osteoclasts with bone matrix proteins.
• L-000845704 is an orally acting non-peptide antagonist of αVβ3
integrin receptor on osteoclasts which decreases osteoclast
attachment and causes inhibition of bone resorption.
24. Nitrates
• The role of nitric oxide (NO) in skeletal homeostasis has been realized
lately.
• Augmentation of osteoblast function and inhibition ofosteoclast
development and function by NO has been depicted by in vitro studies.
• Low-dose isosorbide mononitrate acts as a NO donor and has shown
to decrease markers of bone resorption while increasing the markers of
bone formation in post-menopausal women. Jamal SA, JBMR, 2004
• Another pharmaco-epidemiological case-control study also indicates
less incidence of fractures in persons receiving nitrates.
Rejnmark L, JBMR,2006
25. Anti-sclerostin antibodies
• Sclerostin -a protein produced by osteocytes in bone - acts by antagonizing
the anabolic Wnt signaling system on osteoblasts, thus leading to anti-anabolic
effect on bone.
• In animal models, administration of sclerostin antibodies has shown to
increase bone mass. Grey A, Expert Opin Emerg Drugs. 2007
26. • Romosozumab (Evenity, Amgen/UCB) is a humanized monoclonal antibody
that inhibits sclerostin, is presently in phase 3 trials administered by
subcutaneous injection at monthly or 3 monthly intervals.
• At the end of 12 months of phase 3, there were 11.3% increase in BMD at
lumbar spine with 210 mg dose of romosozumab compared to 4.1 and 7.1
% alendronate, and teriparatide, respectively
• As of July 2017, the FDA had rejected approval of romosozumab for
osteoporosis treatment due to a higher rate of serious adverse
cardiovascular events compared with alendronate.
• Other antisclerostin monoclonal antibodies being developed and tested
include blosozumab and BPS804
27. Dickkopf-1 (Dkk-1) inhibiton
• Dkk-1 is another negative regulator of WNT signaling pathway that
acts by directly binding to LRP5 and LRP6.
• Blocking these receptors lead to inhibition of osteoblastogenesis in
various osteogenic cell lines.
• A human monoclonal antibody to Dkk-1 has been tested in
ovariectomised monkeys and found to stimulate bone formation,
suggesting promise as a skeletal anabolic agent. Li X, JBMR 2011
28. Calcium-sensing receptor antagonism (calcilytics)
• Calcium-sensing receptor antagonists (calcilytics) are a new drug class
of orally administered agents that stimulate endogenous PTH release
and have bone forming action.
• Calcilytics have shown to increase bone formation and prevent bone
loss in ovariectomised rats
• ATF 936 and ronacaleret are still under clinical trials for the
establishment of their role in the treatment of osteoporosis.
Wilder L, JBMR 2008
29. Statins
• Statins are drugs that were developed and are widely used to lower
serum cholesterol by inhibiting HMG CoA reductase, the rate-limiting
Enzyme for cholesterol synthesis.
• lovastatin, Simvastatin, mevastatin and fluvastatin were shown
to markedly increase bone formation in rodents, both intact
and ovariectomized.
• Thus, statins, particularly newer ones, are of potential value
for treatment of osteoporosis
30. Conclusion
• New forms of treatment, based on new or refined knowledge about
the molecular mechanisms regulating bone metabolism, hold the
promise of providing large gains in bone mass and reconstructing
damaged skeletal architecture.
• The clinical challenge will be to most appropriately use these new
medications to treat our patients most effectively.