Treatment of established
osteoporosis: a systematic
review and cost–utility analysis
M Lloyd Jones
WHO Collaborating Centre for Metabolic Bone Diseases,
University of Sheffield Medical School, Sheffield, UK
Sheffield Centre for Health and Related Research,
University of Sheffield, Sheffield, UK
Health Technology Assessment
NHS R&D HTA Programme
Health Technology Assessment 2002; Vol. 6: No. 29
Treatment of established osteoporosis
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Background and aims
Osteoporosis is a systemic skeletal disease,
characterised by low bone mass and micro-
architectural deterioration of bone tissue
with a subsequent increase in bone fragility
and susceptibility to fracture.
The most serious clinical consequence of
osteoporosis is hip fracture, which increases in
incidence exponentially with age and incurs high
morbidity, mortality and healthcare expenditure.
Other common fractures occur at the spine,
forearm and shoulder.
Osteoporosis is operationally defined by the
measurement of bone mineral density (BMD)
at the hip, and is diagnosed in women when
BMD is 2.5 standard deviations (SDs) or more
below the average for young healthy women.
Established osteoporosis denotes the disease in
the presence of one or more fragility fractures.
A variety of agents are available for the treatment
of osteoporosis. The evidence for their efficacy is
examined and their cost-effectiveness is modelled
in established osteoporosis.
A systematic review was undertaken of all random-
ised controlled trials (RCTs) in which fracture
was measured as an outcome. RCTs that studied
fracture benefits in patients in whom osteoporosis
or osteopaenia was not identified were excluded,
as were epidemiological studies, although account
was taken of these lower levels of evidence in the
interpretation and subsequent analysis of infor-
mation. The interventions reviewed were: bisphos-
phonates, vitamin D, 1-alpha hydroxylated deriv-
atives of vitamin D, calcitonin, calcium, oestrogens,
oestrogen-like agents, anabolic steroids, fluoride
salts, thiazide diuretics, raloxifene, vitamin K
protein supplements and exercise.
Epidemiology, costs and utilities
The annual risk of osteoporotic fracture was
characterised for women from the UK. Fractures
of the hip, spine, distal forearm and humerus were
designated as being osteoporotic. Collectively, they
account for approximately 70% of osteoporotic
fractures in postmenopausal women and more
than 70% of the morbidity.
The risk of osteoporotic fractures in women
at the threshold for osteoporosis was determined
from a published meta-analysis of the relationship
between BMD and fracture risk. The risk of such
a fracture in the presence of a prior osteoporotic
fracture was computed from a published meta-
analysis of the relationship between the prior
occurrence of fracture of each type and the
risk of a future fracture of each type.
The consequences of fracture on mortality were
assessed for each fracture type. The annual risk
of breast cancer, coronary heart disease (CHD)
and mortality were reviewed so that extraskeletal
risks and benefits of hormone replacement therapy
(HRT) and raloxifene could be modelled.
Costs and utilities were determined for osteo-
porosis in the UK by systematic review of
Health economics model
A model was developed comprising an individual
patient-based approach that simulated whether
or not events occurred in each subsequent year
for each patient.
Transition states included fracture states (hip,
wrist, vertebral and proximal humerus), death
from hip fracture, nursing home admission
owing to the hip fracture, fatal and non-fatal
CHD, fatal and non-fatal breast cancer, and
death from other causes.
The model simulated cohorts at fixed ages (50,
60, 70 and 80 years) with established osteoporosis.
The proportions of the population with different
fracture types were simulated from the known
distribution of these fractures at different ages.
Effectiveness was populated from the systematic
review of interventions in osteoporosis. Treatments
were given for 5 years using a 5-year offset time,
except for calcium and calcitonin for which a
Health Technology Assessment 2002; Vol. 6: No. 29 (Executive summary)
3-year offset time was used (in this context, offset
time is the duration for which an effect persists
after the treatment stops). The analytic framework
was set at 10 years. Because of the many uncertain-
ties, particularly for hip fracture and extra-skeletal
risks and benefits, extensive sensitivity analyses
were undertaken for each agent.
The results of the systematic review of RCTs indi-
cated that bisphosphonates, calcitonin, calcium,
fluoride salts and raloxifene reduced the incidence
of vertebral fracture. The bisphosphonate,
alendronate, also decreased non-vertebral
fracture, including hip fracture.
For several agents, failure to demonstrate efficacy,
particularly for hip fracture, was largely due to the
lack of appropriate RCTs. Epidemiological evidence
suggested that treatment with calcium, calcitonin,
HRT, thiazide diuretics, etidronate and anabolic
steroids decreased hip fracture risk. There was
also RCT evidence that calcium plus vitamin D
decreased fracture risk in patients for whom
BMD was not known.
The results for each agent at each age are presented
as a central estimate of cost per quality-adjusted life-
year (QALY) gained compared with no treatment.
Costs were discounted at 6% and QALYs at 1.5% in
base-case scenarios. The estimate was bounded by a
90% confidence interval representing the range
of cost–utility that was incurred by 90% of the
combinations of relative risks (RRs) for efficacy.
Cost-effectiveness was graded A–D from the
range of cost-effectiveness ratios using a threshold
value of £30,000/QALY gained to denote good
Only those agents that RCT data showed to
have significant effectiveness for at least one
fracture outcome were tested – raloxifene, HRT,
calcium (with and without vitamin D), calcitonin,
alendronate, other bisphosphonates, fluoride
It was not cost-effective to treat established
osteoporosis with raloxifene in the time frame
modelled. If cardiovascular benefits were assumed,
treatment was only cost-effective compared with
no intervention at ages of at least 70 years.
HRT was not cost-effective except below the age
of 60 years. However, treatment became cost-
effective from the age of 50 years if the effects
on appendicular fractures reported in epidemi-
ological studies were included. Additional benefits
from reductions in CHD, with additional risks
from an increased incidence of breast cancer,
did not markedly change the conclusions on
Treatment with calcium alone was cost-effective
compared with no intervention from age 60 years,
assuming an effect only on vertebral fracture risk.
Treatment was cost-effective at all ages if effects on
appendicular fractures were included, as shown
by the RCT data for calcium with vitamin D.
Treatment with calcitonin was not cost-effective at
any age largely because of its high costs. Treatment
with alendronate was only cost-effective from age
70 years onwards.
Since no difference in efficacy between the
bisphosphonates could be shown, a pooled analysis
was undertaken using the cost of intervention
equivalent to etidronate. ‘Bisphosphonate’ treat-
ment was cost-effective from age 60 years solely
because its therapeutic cost was lower than that
Using the meta-analysis of RCTs, treatment with
fluoride was not cost-effective, largely because of
a high point estimate for hip fracture risk (RR =
1.78). If no adverse effect on hip fracture was
assumed, then treatment became cost-effective
from age 60 years.
Compared with no treatment, it was not cost-
effective to treat established osteoporosis with
alfacalcidol except at ages of 70 years or more.
Further sensitivity analyses were undertaken,
focussing on those agents with cost-effectiveness
grades A or B.
Age and cost of intervention were important deter-
minants of cost-effectiveness. Cost-effectiveness
ratios were sensitive to changes in discount rates
for benefits and in the assumption relating to
offset of effect (offset time). Cost-effectiveness was
markedly improved when women with T-scores
under –2.5 SD were selected.
The results were not markedly affected by
the threshold used for cost-effectiveness, poor
compliance, variations in the assumptions about
mortality after hip fracture, duration of treatment
and duration of analysis. The inclusion of costs for
added years of life had little effect in the elderly
Health Technology Assessment 2002; Vol. 6 No. 29 (Executive summary)
but improved cost-effectiveness in women aged
up to 60 years. In contrast, the inclusion of all
vertebral fractures (in addition to clinically overt
fractures) had a marked effect on improving
Cost-effective scenarios for several interventions
in the management of established osteoporosis
were identified. Cost-effectiveness ratios decrease
with age. At age 50 years, only HRT and calcium
plus vitamin D were cost-effective (assuming that
the agent would decrease the risk of appendicular
fractures at this age). At age 80 years, HRT,
calcium with or without vitamin D, alfacalcidol,
alendronate and bisphosphonate were all
The conclusions derived are conservative, mainly
because of the assumptions made in the absence
of sufficient data. The conservative assumptions
included the following:
(i) not all osteoporotic fractures are included
(ii) not all vertebral fractures are included
(iii) base-case scenarios are modelled at the
threshold for osteoporosis
(iv) risks of re-fracture in the few years after a
fracture are likely to be underestimated
(v) vertebral fracture incurs no reversible mortality
(vi) long-term effects of osteoporotic fractures
on utilities are ignored.
Thus conclusions that treatments are cost-
effective are reasonably secure. In contrast,
scenarios shown to be cost-ineffective are less
secure. As information in these areas becomes
available, the implications on cost-effectiveness
of interventions should be reappraised.
Recommendations for research
Intervention thresholds differ substantially from
diagnostic thresholds, and should be based on the
absolute fracture probability that depends not only
on the T-score but also on other independent risk
factors. Health economics assessment based on
probability of fracture is an important area for
Other areas for further research arise from gaps
in empirical knowledge on utilities and side-effects
that are amenable to primary research. Further
secondary research should be undertaken to more
closely evaluate the impact of vertebral deformities
(rather than clinically overt vertebral fractures)
Kanis JA, Brazier JE, Stevenson M, Calvert NW,
Lloyd Jones M. Treatment of established
osteoporosis: a systematic review and cost–utility
analysis. Health Technol Assess 2002;6(29).
Health Technology Assessment 2002; Vol. 6 No. 29 (Executive summary)
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