Treatment duration, adherence,

compliance and concordance and

management of osteoporosis in other

groups

SIGN guideline 142Glasgow meetingDr Jamie FraserGP

“NON-ADHERENCE TO TREATMENT ACROSS CHRONIC DISEASES IS A WORLD WIDE PROBLEM OF STRIKING MAGNITUDE” Adherence to long-term therapy for chronic illnesses in developed countries averages 50%1.

1. Sabate E.WHO Adherence Meeting Report. Geneva,World HealthOrganization, 2001.

"We find that compliance improves when you only have to take one pill a day."

ADHERENCE-the extent to which a person’s

behaviour – taking medication,

following a diet, and/or

executing lifestyle changes,

corresponds with agreed

recommendations from a

health care provider.2

2. Adherence to long-term therapies: evidence for action WHO 2001

Spheres affecting adherence

REINFORCEMENT AND BIOMARKER FEEDBACK

Biomarker feedback behaviour varied by resultOne RCT study included 2382 post-menopausal women (Delmas 2007)With positive reinforcement there was a significant improvement in persistence (OR 0.71, 95%CI 0.53 to 0.95) versus standard careAlso associated with reduction in vertebral fracture (OR 0.4, 95% CI 0.2 to 1.0)No effect in another study by Silvermann 2012

GENERAL AND MIXED INTERVENTIONSHeterogeneous populations and interventions 3 systematic reviewsCombined data from 4 RCTs indicated that biomarker feedback and motivational interventions led to a relative reduction in non-persistence of 22% (pooled rr: 0.78, 95% ci 0.65–0.95, p-value = 0.01) Smith 2010 Intervention

Effect of exercise

BMD/ BTM feedback

Effect of education

Home assessment falls and fracture risk

RECOMMENDATIONInterventions by healthcare professionals, with or without feedback of biomarker results, aimed at improving adherence are recommended in patients who are being given drug treatment for osteoporosis

Duration of therapy

What is the optimal duration of therapy?• Do treatments remain effective and what are the

longterm risks especially considering drugs with long bone retention?

• No evidence identified regarding drug holidays• No evidence regarding restarting treatments

following drug holidays

Effects of stopping Alendronate on BMD and vertebral fracture

Black et al JAMA 2006

Vertebral Fractures

0

2

4

6

8

10

0 1 2 3 4 5 6 7 8 10

FIT Study FLEX Study

ALN

Placebo

p<0.001

Femoral Neck BMD

9

15

10

5

00 12 24 36 48 60 72

OR = 0.45 [0.25-0.88]

Placebo

ALN

Verte

bral

Fra

ctur

e (%

)

Fracture reduction with three years Zoledronic acid is equal to six years

0

1

2

3

4

5

6

0 2 3 6Time (Years)

Cha

nge

in F

N B

MD

(%)

VariableZ3P3 Z6

Any fracture 8.2% 7.6%

Hip fracture 1.3% 1.4%

TIA/Stroke 2.6% 5.1%

Black et al. JBMR 2012

1

ZOL x 3

ZOL (Z6)

Placebo (Z3P3)

RECOMMENDATIONS

• Alendronic acid may be continued for up to 10 years in postmenopausal women with osteoporosis, especially those that are at high risk of vertebral fracture

• Risedronate may be continued for up to seven years in postmenopausal women with osteoporosis

• Zoledronic acid may be continued for three years in postmenopausal women with osteoporosis. After an interval of at least three years without treatment, fracture risk may be reassessed to determine the need for further therapy

Potential longterm harms of anti-resorptive therapies

• Subtrochanteric atypical fractures (rare)

• Osteonecrosis of the jaw (very rare)

• Baseline dental check suggested

• Re-evaluation of the risk and benefit of bisphosphonate treatment every 5yr is considered a good practice point

Exposed bone of ONJ

Subtrochanteric atypical femoral fracture

Risks and Benefits of Bisphosphonates

Management of osteoporosis in other groupsMen• Lack of significant fracture

outcome evidence • Men suffer fragility fractures

and there is an unmet need with no agent being SMC approved

• Bioequivalence data shows comparable BMD responses in men versus women

• Zoledronic acid has been shown to reduce the risk of morphometric vertebral fractures versus placebo in an RCT involving 1199 men (RR 0.33, 95% CI 0.16 to 0.70).

0

1

2

3

4

5

6

7

0 12 24

Time (months)

Cha

nge

in S

pine

BM

D (%

) Women

Men

Zoledronic acid in men and women

Boonen et al JAGS 2011

GLUCOCORTICOID-INDUCED OSTEOPOROSIS• Around 1% of the UK adult population are taking oral

glucocorticoids at any given time (2.5% aged 70-79yr)1

• Associated with rapid loss of bone mineral and increased risk of fractures

• RCT 48wk study alendronate (2.5mg, 5mg, 10mg) versus placebo among men and women aged 17-83yr on doses of prednisolone >7.5mg daily (Saag 1998)

• Rate of morphometric fractures 2.3 versus 3.7% (CI 0.1 to 4.4)

• Extension study to 2yr (poorly representative of original study cohort) did demonstrate significant morphometric fracture reduction (Adachi 2001)

1. Van TP, Cooper C, Abenhaim L, Begaud B, Zhang B, Leufkens HGM. Utilisation of oral corticosteroids in the United Kingdom. Q J Med 2000;93:105–1

GLUCOCORTICOID-INDUCED OSTEOPOROSIS• Risedronate (2.5 and 5mg daily doses) versus placebo

studied in 2 trials which included 518 men and women taking prednisolone >7.5mg daily (NICE 2008)

• Vertebral fracture risk reduction was significant RR 0.33 95%CI 0.13 to 0.81

• Zoledronic acid was compared to risedronate in an RCT trial over 12months in a population of men and women taking daily glucocorticoids 7.5mg or greater (Reid 2009)

• New vertebral fractures occurred in 5% of the Zol group and 3% Ris group a difference that was not significant

• Greater number of patients had adverse reactions of myalgia and pyrexia in zoledronic acid group

GLUCOCORTICOID-INDUCED OSTEOPOROSIS• RCT teriparatide 20mcg daily versus alendronate 10mg daily

in 428 men and women aged 22-89 taking at least 5mg daily prednisolone (Saag 2009)

• Double blind double dummy design with an extension to 3yr• 3yr vertebral fractures occurred in 1.7% v 7.7%, p=0.007• Greater number of discontinuations in TPD group and cases

of nausea adverse events• Teriparatide is not SMC approved for this indication

PATIENTS WITH GLUCOCORTICOID INDUCED OSTEOPOROSIS

• Alendronic acid may be considered to prevent vertebral fractures in men and women on prednisolone doses of 7.5mg or greater (or an equivalent dose of glucocorticoids) for three months or more.

• Risedronate should be considered to prevent vertebral fracture in men and women on prednisolone doses of 7.5mg daily or greater (or an equivalent dose of glucocorticoids) for three months or more.

• Zoledronic acid should be considered to prevent vertebral fracture in men and women on prednisolone doses of 7.5mg daily or greater for three months or more. The treatment should be considered in patients who are intolerant of oral bisphosphonates and in those whom adherence to oral therapy may be difficult.

Management of painful vertebral fracturesThe guideline considers the evidence for physiotherapy, electrical field therapy, surgical interventions and pharmacological agents in management of painful vertebral fracturePhysiotherapy• 2 small RCTs including

postmenopausal women compared exercise/ information physiotherapy interventions versus control measuring QOL end points

ELECTRIC FIELD THERAPY

• RCT compared 2 types of transcutaneous electrical stimulation versus sham -same pads applied but no current used(Zambito 2006)

• Participants had low back pain due to OA or stable vertebral fracture

• Regimen was treatment 5 days per week for 2 weeks• All patients provided with exercise program• Greater functional scores in the intervention groups v control

• RCT investigated coupled electric field therapy in patients with back pain due to vertebral fractures (Rossini 2010)

• Devices worn 10hr per day for 8weeks and low intensity pulse control

• QUALEFFO scores improved in both groups

RECOMMENDATIONS

• Electric field therapy, with or without an exercise programme, may be considered to reduce pain and improve function in patients with painful vertebral fractures

• Physiotherapist-supervised exercise programmes, with or without an information package, are recommended to reduce pain and improve quality of life in patients with painful vertebral fracture

Interferential treatment

VERTEBROPLASTY

• Early RCTs set the scene for better designed trials

• Placebo response controlled for with sham

• Natural history of vertebral fracture associated pain

• 2 vertebroplasty versus sham procedures systematically reviewed

• Attention to detail e.g. cement opened so the odour permeates the room in sham

• No significant difference in pain or QOL outcomes after 6 months

• Risk of harms greater in intervention vs control

End of presentation

Not recommended in the interests of osteoporosis/ fracture prevention and lack of approved treatments in men!