Newer and future therapies for osteoporosis

Current FDA-approved pharmacologic options

• Bisphosphonates (alendronate, ibandronate, risedronate and zoledronic acid)

• Estrogens (estrogen and/or hormone therapy) • Estrogen agonist/antagonist (raloxifene)(December 9, 1997)• Calcitonin (August 12, 2005)• Parathyroid hormone (teriparatide) (November 26, 2002)• RANKL inhibitor denosumab (June 1, 2010)• Tissue-selective estrogen complex (conjugated

estrogens/bazedoxifene) (October 3, 2013)

Efficacy of current treatment regimens ( Bisphosphonates)

• Alendronate ↓ vertebral # and hip # by about 50 percent over three years in patients with a prior vertebral fracture or in patients who have osteoporosis at the hip site.

• It reduces the incidence of vertebral fractures by 48 percent over three years in patients without a prior vertebral fracture.

• Ibandronate ↓ vertebral # by about 50 % over 3 years.• Reduction in risk of nonvertebral fracture not documented.

Black DM et al. Lancet. 1996;348

Cummings et al, JAMA.1998

• Risedronate ↓ vertebral # by 41 to 49 %and non-vertebral # by 36 % over three years, with significant risk reduction occurring within one year of treatment in patients with a prior vertebral fracture.

• Zoledronic acid ↓ vertebral # 70 percent (with significant reduction at one year), hip # by 41 % and non-vertebral # by 25 percent.

Eastell R, Osteoporos Int. 2000

Efficacy of current treatment regimens ( Bisphosphonates)

Black et al, HORIZON PFT, NEJM May, 2007

Teriparatide• Data from 8 randomised controlled trials – (n= 2388) to

evaluate the efficacy of daily subcutaneous teriparatide injection in postmenopausal osteoporosis.

• Increase of bone mass of 8.14% (n = 2206) in spine and 2.48% (n = 1303) at the hip.

• 70% risk reduction in vertebral fractures (three trials, n= 1452) and 38% risk reduction in non- vertebral fractures (risk ratio 0.62)

• Caused an increase in the incidence of osteosarcoma in rats- caution in conditions where osteosarcoma risk+.

Review by SL Han, IJCP, Jan 2012

Calcitonin• 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.

• Calcitonin ↓ vertebral # about 30 percent in those with prior vertebral fractures but has not been shown to reduce the risk of non-vertebral fractures.

Chesnut CH, PROOF Study Group. Am J Med. 2000

Raloxifene• vertebral # ↓ by about 30 % in pts with H/o vertebral#. • 55 % in patients without a prior vertebral # over three years. • Reduction in risk of nonvertebral not documented.

• Raloxifene is also indicated for the reduction in risk of invasive breast cancer in postmenopausal women with osteoporosis.

• Raloxifene does not reduce the risk of coronary heart disease.• DVT risk increased similar to estrogen.

Ettinger B. et al. JAMA. 1999

Summary of current treatment regimens

Dose Interval Route BMD H % BMD S% #H % # S% A/E

Alendronate 70 mg Weekly Oral - - 50 48 ONJ,STF Femur

Risedronate 35 mg Weekly Oral - 9.3 36 49 Esophgitis

Ibandronate 150 mg Monthly Oral - 6.6 - 50 A/C Phase rn

Zoledronate 5mg Yearly IV 6.02 6.71 41 70 ↓Ca, Renal Dysfn

Raloxifene 60 mg Daily Oral 2.8 2.1 30,55 Thromboemboism

Teriparatide 20 mcg Daily SC 8.14 2.14 70 38 ↑ Ca, Diarea,Vom

Strontium 2g Daily Oral 9.8 - 36 39 TE,Skin rash,AbdD

Need for newer agents• All bisphosphonates can affect renal function and are

contraindicated in patients with estimated GFR below30-35 ml/min.

• Zoledronic acid CI for Cr Cl< 35 mL/min• ONJ• Atypical femur fractures of bisphosphonates ( >5 years of

use).• Cost of Teriparatide.

Bone Remodelling

Molecular mediators of remodelling

Points where intervention can be made- Antiresorptive

The Lancet 2011

Points where intervention can be made- Anabolic

The Lancet 2011

Newer agentsAntiresorptive agents:•Denozumab•Cathepsin k inhibitors•Osteoprotegerin •C-src kinase inhibitors•Αvβ3 integrin antagonists•Chloride channel inhibitors•Nitrates.

Anabolic agents:•Calcilytics•Antibodies against sclerostin and Dickkopf-1 (PC)•Statins (Ob)•Matrix extracellular phosphoglycoprotein fragments activin inhibitiors•Endo-cannabinoid agonists •Misc agents- Phytoestrogens, Once a week PTH

Denozumab

• Denosumab, a human monoclonal antibody that specifically binds RANKL blocks the binding of RANKL to RANK thereby reducing bone resorption and increasing bone density.

• Subcutaneous injection every 6 months.• Denosumab 60 mg- FDA approved for osteoporosis. • Also approved in Europe for treatment of bone loss

associated with hormone ablation in men.

Comparison with alendronate-DECIDE study

• 1,189 postmenopausal women with low bone mineral density (T score ≤−2.0 at the lumbar spine or total hip)

• Randomly assigned to denosumab 60 mg S/c for 6 months or to oral alendronate 70 mg once weekly.

• At the end of 1 year, there was a significant increase in BMD at the – total hip (3.5 versus 2.6%),– femoral neck (2.4 versus 1.8 %), – lumbar spine (5.3 versus 4.2 %) in denosumab group when compared to that of alendronate

(p<0.0001 at all sites).

Brown JP et al. J B M R 2009

STAND trial • In 504 postmenopausal women (aged >55 years) with low

BMD (T score between −2.0 and −4.0) who were on alendronate were randomly assigned to switch to denosumab 60 mg subcutaneously once every 6 months or to continue alendronate 70 mg once weekly.

• At the end of 1 year, there was a small but significant increase in BMD in denosumab cohort when compared to that of alendronate group (1.9 % increase in total hip versus 1.0 %, lumbar spine 3.0 versus 1.8 % increase) (p<0.0001).

Kendler DL, J B M R 2010

Denozumab-Comparison with placebo- FREEDOM

• 7,868 PM osteoporosis women (60 to 90 years of age).• Randomly assigned to subcutaneous denosumab (60 mg every

6 months) or placebo for 3 years. • Denosumab increased lumbar spine BMD and total hip BMD

compared to that of placebo (9.2 versus 0 % and 4.0 versus −2.0 %, respectively)

• Significantly ↓ the risk of new vertebral # by 68 % (P<0.001), hip # by 40 % (P=0.04), and non-vertebral # by 20 %.

• Denosumab group had a lower rate of new vertebral fractures (cumulative incidence 2.3 versus 7.2 %, relative risk 0.32 (95 % CI 0.26–0.41)), a lower rate of hip (0.7 versus 1.2 %) and non-vertebral (6.5 versus 8.5 %) fractures.

Cummings SR et al Denosumab for preventionof fractures in postmenopausal women with osteoporosis. N E J M 361

FREEDOM extension trial • FREEDOM denosumab group was continued on three more

years of denosumab for a total of 6 years and women from the FREEDOM placebo group were given 3 years of denosumab.

• Lumbar spine and hip BMD increased significantly at the end of 6 years (15.2 and 7.2 %, respectively).

• In the crossover group, lumbar spine and total hip BMD increased by 9.4 and 4.8 %, respectively.

HG Bone et al J. Clin. Endocrinol. Metab. (2013

Denosumab-Effects on bone histology, microarchitecture and mineralization

• Qualitative evaluation of iliac crest bone biopsies collected after 2 and/or 3 years in the FREEDOM trial showed normal trabecular and cortical microarchitecture and normal mineralization.

• On histomorphometric analysis, the significant reduction in bone formation and bone resorption and osteoclast number were noted in denosumab cohort.

• No significant difference between the denosumab and placebo groups was noted in terms of trabecular volume and cortical width.

• In FREEDOM trial, at the end of 2 years.– Denosumab cohort had lower cortical porosity (3.64

versus 4.58 %; p=0.011) – higher cortical volumetric BMD (866 versus 851 mg/cm3;

p=0.018) compared to placebo.• In the biopsies that were obtained from STAND trial

participants, – 82% less bone resorption in denosumab cohort when

compared to alendronate group.

Denosumab-bone histology, microarchitecture and mineralization

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.

• The binding of Wnt proteins to the LRP5/6-Frizzled co-receptor on the cell membrane of osteoblasts

• Regulate gene transcription that promotes osteoblastic bone formation

Animal Studies on sclerostin inhibitors

• Animal models showed a significant improvement in BMD in mice.

• In estrogen-deficient ovariectomized rats, antisclerostin antibodies increased the osteoblasts and decreased osteoclast surfaces thereby reversing the bone loss that is caused by estrogen deficiency.

Sclerostin Ab preclinical• Monkeys administered with antisclerostin antibodies for two

consecutive months had significant improvement of bone formation markers (osteocalcin).

• No change in the bone resorption markers (CTX). • Increase in bone mineral content (BMC) and BMD at the

femoral neck, radius, and tibia, with dose-dependent increases in bone formation were noted.

• Beneficial effects on fracture healing were also noted.

Phase 1• Compared with placebo, significant improvements in lumbar

spine BMD was noted (p<0.01).

• Injection site erythema, back pain, headache, arthralgia, and dizziness -considered mild.

• Non-specific hepatitis one patient- recovered in a week.

Single-dose, placebo-controlled, randomized study of AMG 785, a sclerostin monoclonal antibody. J Bone Miner Res

Phase 2 • Efficacy and tolerability of romosozumab was evaluated in a

phase 2 randomized, placebo-controlled study in 419 postmenopausal women aged 55–85 years (mean age 67 years) with lumbar spine, total hip, or femoral neck T score up to −2.0 and at least −3.5.

• The study subjects were randomized to one of nine groups, receiving once monthly romosozumab subcutaneously (70 mg, 140 mg, 210 mg) or once monthly subcutaneous placebo, thrice monthly romosozumab (140 mg, 210 mg) or thrice monthly subcutaneous placebo, or an open-label active comparator of either subcutaneous teriparatide 20 μg daily or oral alendronate 70 mg once weekly.McClung M (2012) Inhibition of sclerostin with AMG 785 in postmenopausal women with low bone mineral density: phase 2 trial results. J Bone Miner Res

Phase 2..• There was a significant increase in lumbar spine, total hip, and

femoral neck BMD at end of 12 months with all doses of romosozumab when compared to that of placebo (p<0.005) and teriparatide and alendronate (p<0.0001), and all doses significantly increased serum P1NP and reduced serum CTX from baseline as early as week 1.

• The greatest BMD increase was seen with once monthly subcutaneous romosozumab 210 mg, with a reported increase of 11.3 % at the lumbar spine and 4.1 % at the total hip.

• Romosozumab was generally well tolerated except Mild Inj. site reactions (12% vs 4%)

Phase 3 • Romosozumab was evaluated in a randomized placebo-

controlled trial over a period of 1 year in 419 postmenopausal women aged 55–85 years with low BMD (T score in range −2.0 to −3.5).

• Subjects were randomized to receive monthly romosozumab at doses 70 mg, 140 mg, and 210 mg or every three monthly doses of 140 mg and 210 mg or placebo or alendronate 70 mg weekly or 20 μg teriparatide daily.

Phase 3..• At the end of 12 months, there were 11.3, 4.1, and 7.1 % increase

in bone mineral density at lumbar spine with 210 mg dose of romosozumab, alendronate, and teriparatide, respectively (p<0.001%),while placebo arm experienced decrease of BMD by 0.1 % (p<0.006).

• Similar positive results were noticed in total hip and femoral neck BMDs (p<0.02).

• No significant difference in adverse events was noticed between the study cohorts except for increased injection site reactions in romosozumab arm.

Blosozumab• Two randomized placebo-controlled phase 1 trials involving

healthy postmenopausal women. • It was noted that there was a significant increase in the levels of

bone formation markers, and there was 3.41 and 7.71 % increase in lumbar spine BMD with single dose and multiple doses of blosozumab, respectively .

• Phase 2 study that involved 154 postmenopausal women with baseline age of 65 years and baseline T score of −2.76.

• Subjects were randomized to receive blosozumab 180 mg or 270 mg or placebo every 2 weeks subcutaneously (SC), blosozumab 180 mg every 4 weeks SC.

McColm et al Blosozumab, a humanized monoclonal antibody against sclerostin, demonstrated anabolic effects on bone in postmenopausal women. JBMR 2012

• At the end of 52 weeks, there was 6.7, 8.4, 13.9, and 17.8 % increase in lumbar spine BMD with doses of blosozumab 270 mg every 12 weeks, 180 mg every 4 weeks, 180 mg every 2 weeks, and 270 mg every 2 weeks, respectively.

• No difference in adverse events was noted among the groups except increased injection site reactions in blosozumab group.

Blosozumab

Cathepsin K inhibitors

• Cathepsin K is a protease expressed in osteoclasts.• Cathepsin K degrades type 1 collagen in organic bone. • Cathepsin K inhibitors (e.g., odanicatib) inhibit matrix

dissolution, decrease bone resorption, and thus improve BMD in postmenopausal women.

• Several cathepsin K inhibitors have been developed, while the development was blocked in one of them because of serious side effects (scleroderma-like changes in the skin).

Odanicatib• In phase 1 studies, it was determined that once-daily regimen is

almost equal in efficacy to once-weekly dosage regimen.

• Promising results were seen in phase 2 studies of odanicatib that showed significant linear increase in BMD at the lumbar spine (11.9 %), femoral neck (9.8 %), and total hip (8.5 %) in 5 years.

• During this time frame, bone resorption markers were well maintained while bone formation markers showed a slight reduction.

• No fracture data of odanicatib is published yet.

Stoch et. al. Pharmacol Ther 2009

Brixen K et al JCEM 2013

Odanacatib..• Phase 3 randomized placebo-controlled trial with 214 postmenopausal

women with osteoporosis, and subjects were randomized to receive either odanicatib 50 mg or placebo.

• At 1 year, lumbar spine BMD was increased by 3.5 % and bone resorption marker CTX decreased (p<0.001).

• 24 months, femoral neck BMD and BMC significantlyincreased in odanicatib group (p<0.001).

• Currently, the drug is being evaluated in phase 3 trial involving more than 16,000 postmenopausal women in which subjects were randomized to odanicatib 50 mg tablet once weekly.

Eisman et al JBMR 2011

Tissue specific estrogen analogues• Newer SERMs that are in various stages of drug development

include bazedoxifene, lasofoxifene, and arzoxifene.

• Effective in preventing bone loss, preserving bone strength, and reducing total cholesterol levels without evidence of endometrial stimulation and fewer incidences of hot flushes.

Bazedoxifine• At 1 year, no cases of endometrial hyperplasia were identifi

ed in the BZA 20-mg/CE 0.45-mg group, while three cases (1.1%) were confi rmed for the BZA 20-mg/CE 0.625-mg group (95% one-sided confidence interval upper limit 4%).

• Both BZA/CE doses signifi cantly increased lumbar spine and total hip BMD versus placebo ( p 0.001) and showed low incidences of bleeding and breast tenderness, similar to placebo and signifi cantly lower than for CE 0.45 mg/MPA 1.5 mg.

Mirkin S. CLIMACTERIC 2013

Effi cacy of tissue-selective estrogen complex of bazedoxifene/conjugated estrogens for osteoporosis prevention in at-risk

postmenopausal women .

Lindsay R Fertil Steril 2009

Phytoestrogens

• Genistein- An isoflavone phytoestrogen which is the main ingredient in the prescription “medical food” product Fosteum® and generally regarded as safe by the FDA.

• Genistein may benefit bone health in postmenopausal women but more data are needed to fully understand its effects on bone health and fracture risk.

Statins• Enhance bone morphogenetic protein-2 gene expression and

bone formation in vivo. • Increase of osteoblast number and promotion of osteoblastic

differentiation, leading onto increased bone formation by simvastatin has been seen in animal models.

• The beneficial effect of statins on bone formation has also been depicted in clinical studies

• However, the dose required for enhancing bone formation is much higher than that of hypolipidemic action.

• Thus, there is a need to develop potent and preferably bone-specific statin-related molecules.

Echistatin, a potential new drug for osteoporosis.." Endocrinology

Osteoprotegerin• Decoy receptor for RANKL. • Preclinical studies that low bone turnover induced by OPG

overexpression leads to increased bone mass with no evidence for deleterious effects on bone material properties.

• In a phase 1 clinical trial, OPG markedly decreased the resorption marker urinary N-terminal telopeptide NTx by 80% by day 4 after a single dose.

• Antibodies to OPG after its use that may hinder its future use as a treatment for osteoporosis.

Bekker PJ, JBMR 2001

C-src kinase inhibitors• The non-receptor tyrosine kinase c-src is required for the

development of the osteoclast ruffled border, one of the final stages in the maturation of osteoclasts.

• Functional sealing zone and resorptive surface.• Preliminary studies with c-src kinase inhibitors show inhibition of

bone resorption in vitro.• Saracatinib is a novel orally available competitive inhibitor of Src

kinase shown to inhibit bone resorption in vitro. • A randomized, double-blind, placebo-controlled, multiple-

ascending-dose phase I trial of saracatinib showed that it inhibited osteoclast mediated bone resorption in healthy men without any significant adverse effects.

Hannon RA, JBMR 2010

αv β3 integrin antagonists• αv β3 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 αv β3 integrin receptor on osteoclasts and causes inhibition of bone resorption.

• In a phase 2 trial involving 227 women with post-menopausal osteoporosis, L-000845704 significantly decreased bone resorption markers by 40% and increased spine BMD by 3.5% at a dose of 200 mg bid.

• Preliminary data from in vitro studies suggested that a neutralizing antibody α β decreases osteoclast attachment and therefore, bone resorption.

Murphy MJ JCEM 2005

Chloride channel inhibitors• Passive movement of chloride through chloride channel

(ClCN7) located in the cell membrane of the osteoclast is required for secretion of acid from osteoclasts.

• In vitro studies have 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.

• In vitro studies of osteoclasts from human patients with inactivating ClCN7 mutations depict normal osteoclastogenesis, but a 80-90% reduction in the bone-resorbing activity of the cells.

Henrikson et al. Am J Pathol. 2004

Sorenson, American Society for Bone and Mineral Research 2006

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.

• Another pharmaco-epidemiological case-control study also indicates less incidence of fractures in persons receiving nitrates.

Jamal SA, JBMR, 2004

Rejnmark L, JBMR,2006

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.

• JTT-305/MK-5442 and SB-423557 are two calcilytics that were 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

Fitzpatrick LA, JBMR 2008

Dickkopf-1 (Dkk-1) inhibiton• Negative regulator of the 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.

• However, the performance of these antibodies in humans is awaited.

Li X, JBMR 2011

Cannabinoid agonists• Endocannabinoids and their receptors have been seen to be

involved in the regulation of osteoblast differentiation and bone formation.

• Cannabinoid CB1/2 agonist CP 55,940 and cannabinoid (CB) 2 selective agonists HU 308 have shown stimulation and early differentiation of bone marrow derived osteoblast precursors and enhancement of bone nodule formation in osteoblast cultures in vitro.

• Currently, their role in the treatment of osteoporosis ?

Matrix extracellular phosphoglycoprotein (MEPE) fragments

• MEPE is highly expressed in differentiated osteoblasts and osteocytes and acts as an endogenous inhibitor of bone mineralization.

• Deletion of the MEPE gene in mice leads to an increase in the number and activity of osteoblasts leading to increased bone mass.

• But it has been seen that MEPE 242-264, a fragment of MEPE stimulate new bone formation and fracture healing in preclinical studies.

• Thus full-length MEPE and MEPE fragments derived from proteolytic cleavage may exert opposite effects.

Other bisphosphonates (etidronate, pamidronate, tiludronate)

• These medications vary chemically from alendronate, ibandronate, risedronate and zoledronic acid but are in the same drug class.

• At this time, none is approved for prevention or treatment of osteoporosis.

PTH (1-84)• This medication is approved in some countries in

Europe for treatment of osteoporosis in women. • RCT-DB with 2532 postmenopausal women with low

bone mineral density at the hip or lumbar spine.• 100 mcg of recombinant human PTH or placebo daily

by subcutaneous injection. • All received calcium, 700 mg/d, and vitamin D3, 400

U/d.• Relative risk to the # incidence observed in the

placebo group was 0.62 [CI, 0.37 to 1.04] [P = 0.07]).

Greenspan SL, Ann Intern Med. 2007

PTH 1-84..• Mean bone mineral density increased at the spine by 6.9%

and at the hip by 2.1% but decreased at the forearm in the PTH-treated group.

• Parathyroid hormone treatment increased the percentage of participants with hypercalciuria, hypercalcemia, and nausea by 24% (CI, 20% to 27%), 23% (CI, 21% to 26%), and 14% (CI, 11% to 16%), respectively, compared with placebo.

Greenspan SL, Ann Intern Med. 2007

Teriparatide Once-Weekly Efficacy Research(TOWER) Trial for Examining the Reduction in New

Vertebral Fractures in Subjects with PrimaryOsteoporosis and High Fracture Risk

• Randomized, multicenter, double-blind, placebo-controlled trial conducted in Japan.

• Subjects were 578 Japanese patients between the ages of 65 and 95 yr who had prevalent vertebral fracture.

• Subjects were randomly assigned to receive once-weekly sc injections of teriparatide (56.5 g) or placebo for 72 wk.

• The primary endpoint was the incidence of new vertebral fracture.

Nakamura et al. JCEM , September 2012

TOWER..• Once-weekly injections of teriparatide reduced the risk of

new vertebral fracture with a cumulative incidence of 3.1% in the teriparatide group, compared with 14.5%

• Relative risk of 0.20 (95% confidence interval, 0.09 to 0.45). • At 72 wk, teriparatide administration increased bone mineral

density by 6.4, 3.0, and 2.3% at the lumbar spine, the total hip, and the femoral neck, respectively, compared with the placebo (P0.01).

• Adverse events (AE) and the dropout rates by AE were more frequently experienced in the teriparatide group, but AE were generally mild and tolerable

Nakamura et al. JCEM , September 2012

Summary• Present antiresorptive treatments are effective, but some are limited

by side-effects, concurrent comorbidities, and inadequate long-term compliance.

• The number of available drugs will increase considerably in the coming years.

• Many of the new drugs combine efficacy with convenient administration.

• Odanacatib and saracatinib represent a distinct class of antiresorptives that inhibit osteoclast activity rather than impairing osteoclast viability.

• There is a great need for additional and affordable anabolic treatments in situations of severe osteoporosis, extensive bone loss, and impaired fracture healing.

Thank You..