OSTEOPOROSIS:OSTEOPOROSIS:A HOT TOPIC!A HOT TOPIC!

Dr Felicity Kaplan

Osteoporosis is a skeletal disorder characterised by compromised bone strength predisposing a person to

an increased risk of fracture

Osteoporosis is present when the bone mineral density or bone mineral content is over 2.5 standard deviations

below the young adult mean (–2.5 T-score)

OsteoporosisOsteoporosis

Bo

ne

Mas

s

Age (years)

Attainment of Peak Bone Mass

Consolidation Age-related Bone Loss

Men

Women

Menopause

0 10 20 30 40 50 60

FractureThreshold

Compston JE. Clin Endocrinol 1990; 33:653–682.

Age Related Changes in Age Related Changes in Bone MassBone Mass

Clinical Impact of Clinical Impact of Osteoporosis Over TimeOsteoporosis Over Time

Signs Kyphosis Loss of height Abdo bulges Clinically

diagnosed fracture

Symptoms Neck becomes

weak Pain in back Breathing

difficulties Indigestion &

GOR Stress

incontinence Difficulty with

mobility following a fracture

National Osteoporosis Society http://www.nos.org.uk/PDF/AreYouAtRisk.pdf

Risk Factors For OsteoporosisRisk Factors For OsteoporosisFor women – a lack of oestrogen caused by: Early menopause (before the age of 45 years)

Early surgical menopause (before the age of 45 years), especially if both ovaries are removed (oophorectomy)

Missing periods for 6/12 or more (excluding pregnancy) as a result of over-exercising or over-dieting

For men Low levels of testosterone (hypogonadism)

For men and women

• Low body weight

• Maternal history of a hip fracture

• Malabsorption, inflammatory bowel disease and gastric surgery

• Use of oral glucocorticoids and other Rx’s…

• Long-term immobility

• Heavy drinking

• Smoking

National Osteoporosis Society http://www.nos.org.uk/PDF/AreYouAtRisk.pdf

Risk Factors For OsteoporosisRisk Factors For Osteoporosis

Bone-unfriendly drugsBone-unfriendly drugs

TZDs PPIs (studies suggest increased fracture risk) Aromatase inhibitors eg anastrozole Ovarian suppressing agents (depot-

medroxyprogesterone acetate)– Risk assess after 2 years

Androgen deprivation therapy (PCa) Anticonvulsants esp Phenytoin/CMZ Heparin

Current treatments in OPCurrent treatments in OP

Antiresorptive– Estrogens and SERMs– Bisphosphonates– Calcitonin– Denosumab

– Anabolic (stimulate bone formation)– Parathyroid hormone

Dual action agents– Strontium ranelate

Vitamin D levelsVitamin D levels 25-OHD Vit D status Manifestation Management

<25 nmol/l Deficient Rickets/ Osteomalacia High-dose calciferol

25-50 nmol/l Disease risk Vit D supps 50-75 nmol/l Adequate Healthy Lifestyle advice >75 nmol/l Optimal Healthy None

– Divide by 2.5 for ug/L

Treatment of vitamin D deficiency Treatment of vitamin D deficiency

Deficiency (25-OHD <25 nmol/l)

10 000 IU calciferol daily or 60 000 IU calciferol weekly for 8-12 weeks*

orCalciferol 300 000 or 600 000 IU orally or

by intramuscular injection once or twice

Treatment of vitamin D insufficiencyTreatment of vitamin D insufficiency

Insufficiency (25-OHD 25-50 nmol/l) or maintenance therapy following deficiency

1000-2000 IU calciferol daily or10 000 IU calciferol weekly

*To convert IU to μg of calciferol, divide by 40.†One off high dose treatments are effective, but should be followed by a maintenance

therapy dose of calciferol.–

Hormone replacement Hormone replacement therapytherapy

HRT: A CONSENSUS HRT: A CONSENSUS

Prime role of HRT is relief of menopausal Sx

Risks/benefits need to be explained to each woman (breast Ca extra 2-6 cases per 1000 women treated with HRT for 5 years)

Use lowest effective estrogen dose, assess CV risk

Review need annually (esp aged>60)

HRT: A CONSENSUSHRT: A CONSENSUS

Can give up to age 50 if prem menopause

Do not use as primary or secondary prev. of CAD/CVA, or Alzheimers

Transdermal estrogen has lower DVT risk

RALOXIFENERALOXIFENE

SERM licensed for OP Reduces vertebral (not non-vertebral) fracture risk

Reduces development of new breast Ca. No increased risk of CVD (reduces CV events!) Increased risk of thromboembolism May worsen flushes Well tolerated, easy dosing

NICE TA 2005: SERMs NICE TA 2005: SERMs (secondary prevention)(secondary prevention)

Raloxifene - alternative in women for whom bisphosphonates are contraindicated or not tolerated

Patients not responding to bisphosphonatesPatients physically unable to comply with

the recommendations for use of bisphosphonates

National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005

BISPHOSPHONATESBISPHOSPHONATES

Etidronate, risedronate, alendronate, ibandronate, zoledronate

Interfere with action of osteoclastsAlendronate and risedronate firstline option

in postmenopausal osteoporosis Strict dosing instructionsConsider renal function!

PARATHYROID HORMONE PARATHYROID HORMONE PEPTIDE (Teriparatide / PEPTIDE (Teriparatide /

Forsteo)Forsteo)

NICE 2005: NICE 2005: (secondary prevention)(secondary prevention)

Teriparatide – use in women >65 years unresponsive to / intolerance of bisphosphonates, and:– with extremely low BMD (<-4)– with very low BMD (<-3), multiple

fractures PLUS an additional risk factor

National Institute for Clinical Excellence, Technology Appraisal 87, Jan 2005

Strontium ranelateStrontium ranelateProtelosProtelos

Clinical use of strontium Clinical use of strontium ranelateranelate

In women with postmenopausal osteoporosis:

– alternative to bisphosphonates, particularly in the elderly

– if potential for upper gastrointestinal complications

– failed (intolerance or inadequate response) to treatment with other osteoporosis therapies

– Beware rash (DRESS) and VTE (RR 1.4)

DENOSUMAB:DENOSUMAB:A NEW TREATMENTA NEW TREATMENT

Emerging Rx’s in osteoporosisEmerging Rx’s in osteoporosisProf CompstonProf Compston

20102010 Denosumab

– Monoclonal Ab to RANKL which drives osteoclasts

– Subcut every 6/12! 60mg– Dramatic and quick effect– Fracture reduction similar to Zoledronate– Cost similar to risedronate (in 2010)!– NICE appraised

Denosumab Binds RANK Ligand and Inhibits Denosumab Binds RANK Ligand and Inhibits Osteoclast Formation, Function, and SurvivalOsteoclast Formation, Function, and Survival

RANKL

RANK

OPG

Denosumab

Bone Formation Bone Resorption Inhibited

Osteoclast Formation, Function, and Survival Inhibited

CFU-GM PrefusionOsteoclast

Osteoblasts

HormonesGrowth Factors

Cytokines

Adapted from: Boyle WJ, et al. Nature. 2003;423:337-342.

The Effect of Denosumab on Fracture Risks at The Effect of Denosumab on Fracture Risks at 36 Months36 Months

Phase 3: The FREEDOM TrialPhase 3: The FREEDOM Trial

ARR = absolute risk reduction; RRR = relative risk reductionCummings SR, et al. N Engl J Med. 2009;361:756-765.

7.2%

8.0%

1.2%

6.5%

0.7%

2.3%

0%

1%

2%

3%

4%

5%

6%

7%

8%

9%

New Vertebral Nonvertebral Hip

Inc

ide

nc

e a

t M

on

th 3

6 (

%)

PlaceboDenosumab

ARR = 0.5%RRR = 40%

P = 0.04

ARR = 1.5%RRR = 20%

P = 0.01ARR = 4.8%

RRR = 68%P < 0.001

Primary Endpoint

Proven osteoporotic fracture reductionProven osteoporotic fracture reductionthroughout the skeleton throughout the skeleton

In the pivotal FREEDOM study (published in the New England Journal of Medicine), Denosumab reduced the risk of fracture at key osteoporotic fracture sites versus placebo

PROLIA®: PROTECTION AGAINST FRACTURE

The absolute risk reductions demonstrated for Prolia® versus placebo were 4.8%, 1.5% and 0.5% for vertebral, non-vertebral and hip fractures respectively. 1

6

P

Effects of Treatment on Femoral Neck BMD Over 12 Effects of Treatment on Femoral Neck BMD Over 12 MonthsMonths

Phase 3: The STAND TrialPhase 3: The STAND Trial

n = number of patients who have a baseline and ≥ 1 postbaseline evaluation.*P < 0.01.Adapted from: Kendler DL, et al. J Bone Miner Res. 2010;25:72-81

Per

cen

t C

han

ge

Fro

m B

asel

ine

(Lea

st S

qu

ares

Mea

n ±

95%

CI)

Alendronate 70 mg QW (n = 241)

Denosumab 60 mg Q6M (n = 246)

Study Month

0 6 12

0.0

0.4

0.8

1.2

1.6

2.0

*

*

Adverse Events Over 36/12Adverse Events Over 36/12

Adverse events, n (%)

Placebo

(n = 3,876)

Denosumab 60 mg Q6M

(n = 3,886)P

value

Serious adverse events Malignancy 125 (3.2) 144 (3.7) 0.28 Infection 133 (3.4) 159 (4.1) 0.14 Cardiovascular events 178 (4.6) 186 (4.8) 0.74 Stroke 54 (1.4) 56 (1.4) 0.89 Coronary heart disease 39 (1.0) 47 (1.2) 0.41 Peripheral vascular disease 30 (0.8) 31 (0.8) 0.93

Atrial fibrillation 29 (0.7) 29 (0.7) 0.98

Serious adverse events occurring with 0.1% incidence and P 0.01

Cellulitis (includes erysipelas) 1 (< 0.1) 12 (0.3) 0.002 Concussion 11 (0.3) 1 (< 0.1) 0.004

Adapted from: Cummings SR, et al. N Engl J Med. 2009;361:756-765.

Factors influencing treatmentFactors influencing treatment

PROLIA®: REAL WORLD

Efficacy

Adherence Cost

Safety/tolerability

Convenience/patient choice

Approximate annual costs Approximate annual costs 2012 (£)2012 (£)

Denosumab 366Alendronate 12Risedronate 22Zoledronate IV 267Raloxifene 259Strontium 353Teriparatide sc 3308

–In a head-to-head, double-dummy study, 77%* of patients preferred a 6-monthly injection to a weekly oral tablet

* Among patients who reported a preference (n = 1322, p < 0.0001)

NICE: Denosumab recommended by NICE for the NICE: Denosumab recommended by NICE for the primary and secondary prevention of osteoporotic primary and secondary prevention of osteoporotic

fractures in postmenopausal women fractures in postmenopausal women 1818 Denosumab is a cost effective use of NHS resources in the primary and secondary prevention of

fractures in postmenopausal women for whom oral bisphosphonates* are unsuitable

There is good quality evidence to support the clinical effectiveness of denosumab compared with placebo.

Denosumab may improve adherence to therapy, particularly for women who have problems swallowing or standing to take oral bisphosphonates.

Secondary and primary care have a role to play in the delivery of denosumab.

*

NICE: Denosumab for the secondary prevention NICE: Denosumab for the secondary prevention

of fracturesof fractures

a treatment option for secondary prevention of osteoporotic fragility fractures only in postmenopausal women at increased risk of fractures: who are unable to comply with the special instructions for

administering alendronate and either risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments.

NICE: Denosumab for the primary NICE: Denosumab for the primary prevention of fractures prevention of fractures

– a treatment option for the primary prevention of osteoporotic fragility fractures only in postmenopausal women at–increased risk of fractures: who are unable to comply with the special instructions for administering alendronate and either

risedronate or etidronate, or have an intolerance of, or a contraindication to, those treatments and who also have a combination of T-score, age and number of independent clinical risk factors for

fracture as indicated in the following table:

Number of independent clinical risk factors for fracture

Age (years) 0 1 2

65–69 –a -4.5 -4.0

70–74 -4.5 -4.0 -3.5

75 or older -4.0 -4.0 -3.0

QOFQOF

Osteoporosis indicators approved for inclusion on QOF menu from 4/2012

Payment for– prospective register of patients with fragility

fractures– Treating those with fragility fracture with

appropriate Rx

40

The Domino Fracture EffectThe Domino Fracture Effect