Recent Advances in Osteoporosis

DR ADRIJA HAJRA 1ST YEAR PGT

GENERAL MEDICINE,IPGME&R

Osteoporosis, a condition characterized by decreased bone strength, is prevalent among postmenopausal women but also occurs inmen and women with underlying conditions or major risk factors associated with bone demineralization. Its chief clinical manifestationsare vertebral and hip fractures, although fractures can occur at any skeletal site.

• Affects 50% of women over 50 years of age and 20% of all men

• People with vertebral fracture have close to 20% risk of a second fracture within the first year.

• For women, risk of suffering a hip fracture in her lifetime is about 17%

• 50 million people in India are osteoporotic or have low bone mass,

according to 2013 Asia-Pacific Regional Audit of International

Osteoporosis foundation reports..

• In 2012, European Medicines Agency and later in 2013 US FDA

advisory panel, recommended against the use of calcitonin salmon

for treatment of osteoporosis in women greater than 5 years after

menopause.

• In early 2014, European Medicines Agency’s Pharmacovigilance Risk

Assessment Committee recommended that strontium ranelate no

longer be used to treat osteoporosis.

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RISK FACTORS FOR OSTEOPOROSIS

Bone remodeling

• coordinated resorption and formation of bone in basic multicellular units.– Bone is renewed in small units

• Temporally regulated.• Process similar in both cortical and trabecular

bone.

• More active in trabecular bone.• Occurs throught out life

Coupling and balanced

• Process of osteoblasts appearing at sites vacated by osteoclasts.

• In young adults, remodeling cycles tightly coupled.

• Thereby new bone formation almost equals bone resorption.

Bone resorption greater than new bone formation in menopausal women.

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,

Currently FDA approved medications for treatment of osteoporosis

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Bisphosphonates

• Synthetic analogs of naturally occuring pyrophosphates.

• Nitrogen containing groups • Oral absorption very low 0.6% to 1.5%• 40 – 60 % of dose binds to bone, no

substantial affinity to other organs. • Remaining dose excreted unchanged in urine.

• reduce the incidence of vertebral fractures by 40–50% in women known to have osteoporosis ,

• with similar reductions in nonvertebral fractures .

• to reduce the risk of hip fractures by 40–60% in women with severe osteoporosis

• men and patients with glucocorticoid-induced osteoporosis (GIOP), have shown that bisphosphonates confer similar benefits in and reduced vertebral fracture risk

Mode of action

• Uptake by osteoclasts• inhibit a key enzyme in the mevalonic acid pathway,

farnesyl pyrophosphate synthase.• blocks prenylation (posttranslational modification) of small GTPases, such as Ras, Rho, and Rac.• signaling molecules in key osteoclastic functions

--maintenance of the cytoskeleton and --ruffled border formation

Leads to osteoclast apoptosis

Monitering response to bisphosphonates

• Bone mineral Density– No change in BMD is also considered an

acceptable outcome • fracture risk not completely eliminated

Anabolic agents

• Enhance bone formation– Increase in osteoblast number

• BMP and WNT– Enhance the function of mature osteoblasts

• IGF 1

• Parathormone does both

Parathormone

• Trabecular bone volume, connectivity, bone microarchitecture were increased after treatment as well as biomechanical properties of bone.

• PTH appears to increase bone volume by increasing the number of bone trabeculae,.

• In humans, the anabolic effects of PTH on cortical bone are lower than in cancellous bone.

• induces IGF-I synthesis, inhibits sclerostin expression, and activates Wnt signaling

Reconstructed micro-QCT images of transiliac crest bone biopsies, taken before and after 21 months of teriparatide therapy, 20 μg/d.

Hodsman A B et al. Endocrine Reviews 2005;26:688-703

©2005 by Endocrine Society

Reasons for strontium ranelate withdrawal

• Increased incidence of cardiac events and thromboembolism

• Serious skin reactions

• Liver inflammation

• Reduction in RBCs

• These risk did not justify the benefits that may accrue with strontium use.

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Reasons for calcitonin salmon withdrawal

• Risk of developing cancer was 2.4% higher in patients using calcitonin nasal spray compared with in those who took placebo.

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NEW MOLECULAR TARGET FOR OSTEOPOROSIS MANAGEMENT

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EMERGING THERAPIES

Anti body therapy:• Sclerostin Inhibitor – Romosozumab• RANKL inhibitor – Denosumab• DKK-1 inhibitor

Anti-seretonin therapyStem cells therapy:

• Mesenchymal Stem Cells• Hematopoietic Stem Cells

Cathepsin K inhibitors: Odanocatib

Biomaterials: • Chitosan biopolymers• Strontium – modified calcium phosphate cement (SrCPC)• Titanium

• Coated with Calcium phosphate• Coated with collagen type 1 • Polycaprolactone – magnesium composite• calcium phosphate/ silk scaffold

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Denosumab• Only anti-osteoporotic therapy approved in the past decade

which is still in use• Fully human monoclonal antibody that inhibits RANKL

(receptor activator of nuclear factor κβ ligand)• RANKL is a member of tumor necrosis factor family and is

expressed on surface of osteoblasts.• RANKL, by binding to RANK, which is present on surface of

osteoclast precursors, promotes the proliferation and differentiation of osteoclasts.

• Denosumab inhibits the interaction of RANKL and RANK, and acts to inhibit bone resorption.

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Denosumab

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Denosumab

• Dosage: 60 mg dose by subcutaneous injection, every 6 months.

• Some rare reported side effects include – osteonecrosis of jaw– atypical fracture of femur

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Romosozumab• Humanized monoclonal antibody that inhibits sclerostin• Sclerostin is an osteocyte-derived inhibitor of osteoblastic activity• Sclerostin inhibition with romosozumab leads to immediate,

transient increases in bone formation markers and moderate sustained reduction in bone resorption markers

• Sclerostin gene is expressed only in skeletal tissue and the potential for systemic side effects is minimal

• Currently there are no data on anti-fracture efficacy and long term safety

• Romosozumab is presently in phase 3 trials administered by subcutaneous injection at monthly or 3 monthly intervals

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Romosozumab

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Odanatib

• Orally administered inhibitor of Cathepsin K• Cathepsin K is a major collagenase secreted by

osteoclasts to degrade organic bone matrix during bone remodeling process

• 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

• Drug is not approved as of date

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Stem Cell Therapy

• Mesenchymal Stem cells, sourced from bone marrow, adipose tissue and cord blood have been studied.

• Easily available, devoid of ethical issues, possess immunosuppressant properties, are multipotent and are safe.

• MSCs differentiate into osteoblasts upon systemic administration

• Hematopoietic Stem Cells have also been found to produce osteoblasts.

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Gut seretonin inhibition

• Seretonin has catabolic action on bone• Most of body’s seretonin is derived from

enterochromaffin cells of gut• Inhibition of gut derived seretonin represents

a novel approach• Still in preclinical trials

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Dkk 1

• Gain of function mutation of Lrp5 increases bone mass.

• Glucocorticoids increase Dkk 1 levels

• Dkk 1 neutralisation causes increase in BMD in rodent models

• Human studies awaited.

Bone Morphogenetic Protein

• TGF β superfamily• Broad family with actions on

chondrocytes,osteoblasts,osteoclasts.

• On osteoblasts lineage, leads to maturation of osteoblasts.( except BMP 3)

– Also have ability to induce osteoclastogenesis and have a potential for bone loss.

Activin receptor

• BMP related protein• Mitogenic properties for cells of the osteoblastic

lineage, favors osteoblastogenesis, and enhances osteoclastogenesis

• BMP 3 acts through activin receptor• BMP 3 inhibits bone formation.• Soluble activin receptor fused to IgG-Fc can

decrease bone resorption and enhance bone formation

IGF 1 and bone

• Mediates effect of GH on longitudinal bone growth.• In bone IGF 1 is PTH dependent.• Necessary to obtain anabolic response to PTH.• Enhances function of differentiated osteoblast Circulating IGF-I contributes to cortical bone integrity,• Skeletal IGF-I plays a more significant role in the

maintenance of trabecular bone integrity• Anorexia nervosa pts have low IGF 1 and low BMD

Conclusion

Among the drugs discussed only denosumab is approved for use in US and Europe

India still awaits the availability of these molecules

Optimal use of available anti-resorptive therapies to manage osteoporosis and prevent its complications is hence required

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Thank You