Re-fracture risk in older
patients prescribed
bisphosphonates
Chiara Sorge
Rome, 15th October 2012
BACKGROUND
• Osteoporosis and associated fractures:
a public health issue of growing importance
• Almost 9 million osteoporotic fractures every
year worldwide
• Italy has one of highest life expectancies in the
world: 79.4 years for males and 84.5 for females
• In 2010 Italy had the second higher expenditure
attributable to fractures in Europe
BACKGROUND
PREVENTION & TREATMENT
Primary prevention:
• Diet, exercise, reduced alcohol consumption,
smoking
• Vitamin D and calcium intake
• Hormone related therapy
Secondary prevention:
• Pharmacological treatments
–
–
–
–
Bisphosphonates
SERM (e.g. raloxifene)
Strontium ranelate
Teraparatide hormone
NICE guidelines (2011 update)
Aifa nota 79 (2011 update)
METHODS
OBJECTIVE:
To estimate the association between adherence to
anti-osteoporotic drug therapy and risk of
subsequent fractures
METHODS
Study design: nested case-control study
Study period: enrolment 2006-2009, 1 year follow-up
Study population: patients aged 50 years or more
discharged from hospital/ER of Lazio region with a
diagnosis of a fracture of any bone and prescribed any
drugs registered for osteoporosis treatment
Exclusion criteria:
–
–
–
–
Not residents/not in charge of Regional Health System
Previous fractures
Multiple trauma
History of malignancies, Paget’s disease
METHODS
Data sources:Lazio Health Information Systems
–
–
–
–
Hospital Information System (HIS) + ER visits
Drug dispensing registry (PHARM)
Health-tax exemption registry
Mortality Information System (MIS)
METHODS
Cases: patients with a second fracture within 1 year
after discharge (excluding the first month)
Controls: patients without a second fracture whithin
the case follow up time
Ratio: 4 controls for each case
Matching variables: age, gender and case follow-up time
METHODS
Exposure: adherence to anti-osteoporotic therapy
Measure: proportion of days covered by drug (PDC)
PDC=days of treatment/days of follow-up
Adherent: PDC≥80%
Partially adherent: 20%≤PDC<80%
Not adherent: PDC<20%
METHODS
Assumptions:
- prescriptions equals to consumption
- patients take drugs at the defined daily dose
- patients finish the current fill before starting a new one
- subtraction of the total number of days spent in
inpatient regimen
- for patients already on treatment at enrolment,
remaining days from the last prescription were added
- truncation of days of utilization that falls after the end
of follow-up time
METHODS
Potential confounders:
- chronic medical conditions (rheumatoid arthritis,
epilepsy, malabsorption sindromes, diabetes,
cardiovascular diseases….)
- use of certain drugs (corticosteroids, antidepressants,
opioid analgesics….)
RESULTS
191638 patients admitted to hospital/ER
for fracture
Exclusion criteria
10722 patients (re-fracture rate: 7.1 per 100pys)
835
cases
3337
controls
RESULTS: CHARACTERISTICS OF THE STUDY
POPULATION (1)
Baseline characteristics
Age (mean, sd)
Gender (females)
Place of residence
Lazio region
Rome
Fracture site
Vertebra
Rib
Pelvis
Upper limbs
Hip
Lower limbs
Other/unspecified
Admission type
E.R. only
Hospital admission only
E.R + hospital admission
Controls
Cases
N
74.6
3120
%
9.4
93.5
N
74.7
780
%
9.4
93.4
1601
1736
48.0
52.0
376
459
45.0
55.0
473
291
104
1280
642
493
54
14.2
8.7
3.1
38.4
19.2
14.8
1.6
132
78
34
349
141
91
10
15.8
9.3
4.1
41.8
16.9
10.9
1.2
1758
572
52.7
17.1
372
213
44.6
25.5
1007
30.2
250
29.9
988
1230
29.6
36.9
267
313
32.0
37.5
1119
33.5
255
30.5
Exposure
PDC
<20%
20-80%
>80%
Median follow up time
151 days
RESULTS: CHARACTERISTICS OF THE STUDY
POPULATION (2)
Co-morbidities*
Dementia and Alzheimer's
Parkinson's disease
Hemiplegia and other paralytic syndromes
Epilepsy
Depression/psycosis/anxiety/sleep disorders
Thyroid disorders
Diabetes
Obesity
Anaemia
Upper gastrointestinal tract disorders
Chronic conditions (liver, pancreas, intestine)
Kidney disease
Cardiovascular disease
Cerebrovascular disease
COPD (including respiratory failure)
Rheumatoid arthritis
Controls
N
77
43
39
31
144
72
327
67
272
209
126
94
1532
450
361
82
Cases
%
2.3
1.3
1.2
0.9
4.3
2.2
9.8
2.0
8.2
6.3
3.8
2.8
46.1
10.9
10.9
2.5
N
21
20
14
8
47
16
101
23
112
63
46
35
428
107
122
39
* Previous hospitalizations + health tax exemptions
%
2.5
2.4
1.7
1.0
5.6
1.9
12.1
2.8
13.4
7.5
5.5
4.2
51.3
12.8
14.6
4.7
RESULTS: CHARACTERISTICS OF THE STUDY
POPULATION (3)
Drugs use*
Anticonvulsants
Opioid analgesics
Antipsychotics
Antidepressants
Thyroid hormones
Oral glucose lowering agents
Insulin
Cardiovascular system agents
Proton pump inhibitors
Corticosteroids
Oestrogens
Controls
N
250
198
54
568
378
287
72
2258
1366
574
69
Cases
%
7.5
5.9
1.6
17.0
11.3
8.6
2.2
67.9
40.9
17.2
2.1
N
82
89
16
166
90
75
25
591
427
212
13
%
9.8
10.7
1.9
19.9
10.8
9.0
3.0
68.5
51.1
25.4
1.6
* at least 2 prescriptions in the year before enrolment
RESULTS OF CONDITIONAL LOGISTIC
REGRESSION
PDC
<20% (ref.)
20-80%
>80%
OR crude 95% CI OR adj 95% CI
1.0
1.0 0.94 0.78-1.13
0.95 0.79-1.16
0.84 0.70-1.01
0.84 0.69-1.02
Adherence to anti-osteoporotic therapy seems to
decrease re-fracture risk
CRITICAL ASPECTS
Observational study/Use of administrative database/
Assumptions/
• Exposure misclassification: assumptions in PDC
calculation, switching to non-oral medications
• Outcome misclassifcation: fractures not receiving
medical attention, recurrences of same fracture
• Misclassification of covariates: undereporting of chronic
conditions in administrative databases, misspecification
following combination of different diseases/drugs
• Residual confounding (BMI, smoking, alcohol
consumptions, vitamin D intake, ….)
CONCLUSIONS
• Sub-optimal compliance to osteoporosis treatment
• Adherence to anti-osteoporotic treatment seems to decrease
re-fracture risk
• Claims data can be used to assess co-morbidities, to evaluate
prescribing appropriateness according to international
guidelines, treatment effectiveness
Future projects
Collaboration with orthopaedists and geriatricians of Campus
biomedico (Rome): effect of long-term therapy on atypical hip
fractures.