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Treatment of established osteoporosis: A systematic review and cost-utility analysis

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Abstract

Background and aims Osteoporosis is a systemic skeletal disease, characterised by low bone mass and microarchitectural 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. Methods Therapeutic intervention A systematic review was undertaken of all randomised 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 information. The interventions reviewed were: bisphosphonates, vitamin D, 1-alpha hydroxylated derivatives of vitamin D, calcitonin, calcium, oestrogens, oestrogen-like agents, anabolic steroids, fluoride salts, thiazide diuretics, raloxifene, vitamin K2, 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 metaanalysis 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 osteoporosis in the UK by systematic review of the literature. 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 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 uncertainties, particularly for hip fracture and extra-skeletal risks and benefits, extensive sensitivity analyses were undertaken for each agent. Results The results of the systematic review of RCTs indicated 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 lifeyear (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 cost-effectiveness. 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 and alfacalcidol. 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 costeffective from the age of 50 years if the effects on appendicular fractures reported in epidemiological 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 cost-effectiveness. 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’ treatment was cost-effective from age 60 years solely because its therapeutic cost was lower than that for alendronate. 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 costeffective 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 determinants 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 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-effectiveness. Conclusions 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 cost-effective. 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 costeffective 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 further research. 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) on cost-effectiveness.
Treatment of established
osteoporosis: a systematic
review and cost–utility analysis
JA Kanis
1 *
JE Brazier
2
M Stevenson
2
NW Calvert
2
M Lloyd Jones
2
1
WHO Collaborating Centre for Metabolic Bone Diseases,
University of Sheffield Medical School, Sheffield, UK
2
Sheffield Centre for Health and Related Research,
University of Sheffield, Sheffield, UK
*
Corresponding author
HTA
Health Technology Assessment
NHS R&D HTA Programme
Health Technology Assessment 2002; Vol. 6: No. 29
Executive summary
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.
Methods
Therapeutic intervention
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
2
,
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
the literature.
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)
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.
Results
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
cost-effectiveness.
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
and alfacalcidol.
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
cost-effectiveness.
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
for alendronate.
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-effectiveness.
Conclusions
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
cost-effective.
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
further research.
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)
on cost-effectiveness.
Publication
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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Background: Real-world cost and effectiveness analyses of the anti-osteoporosis medications (AOM) using a nationwide database in Asia were limited. The aim of this study was to evaluate the cost and effectiveness of AOMs therapy under the reimbursement of National Health Insurance in Taiwan. Methods: Using Taiwan's National Health Insurance Research Database, patients who had hospitalization due to incident hip fractures with related operation between 2008 and 2017 were identified as our study population. Patients who initiated AOMs within 1 year post incident hip fracture were matched with those did not according to the propensity score. The direct medical cost and subsequent fracture within three years were estimated. Statistically significant differences of risk for subsequent fracture between the AOM and non-AOM groups were estimated using the COX proportional hazards model. All costs were presented as New Taiwan Dollars (NTD). Results: There were 27,357 new hip fracture patients who initiated AOMs, and 76% of them were women with a mean age of 77.7 years. Among patients ages ≥70 who encountered hip fractures, those who initiated AOMs experienced fewer non-vertebral fractures (HR = 1.07 (1.02-1.13), p = 0.0114 for those ages 70-79 years old; HR = 1.11 (1.06-1.17), p < 0.0001 for those ages ≥80 years) and mortality (HR = 1.18 (1.14-1.22), p < 0.0001 for those ages 70-79; HR = 1.20 (1.16-1.23), p < 0.0001) within 3 years post incident fracture; meanwhile, consuming fewer medical resources in the national insurance healthcare system. (Increment cost = -16011.2 NTD, p = 0.0248 for those ages 70-79; Increment cost = -17257.9 NTD, p = 0.0032 for those ages ≥80 years) CONCLUSION: Overall, under Taiwan's national health insurance, the use of AOMs is cost-saving, especially in the population aged ≥70 years. The finding of this research was valuable for policymakers in considering healthcare policy promotion and resource allocation in the future.
Article
Age-specific intervention and assessment thresholds based on FRAX® were developed for eight Eurasian countries participating in the EVA study (Armenia, Belarus, Georgia, Moldova, Kazakhstan, the Kyrgyz Republic, the Russian Federation, and Uzbekistan). The intervention thresholds (major osteoporotic fracture) ranged from 3.6 (Armenia and Georgia) to 12.3% (Uzbekistan) for people at age 50 years, and from 16 (Armenia) to 27% (Belarus) at the age of 90 years. These thresholds enable a substantial advance in the ease of detection of individuals at high fracture risk.IntroductionThe purpose of this study was to derive and compare FRAX-based intervention and BMD assessment thresholds for 8 Eurasian countries in the EVA study.Methods The intervention threshold (IT) was set at a 10-year probability of a major osteoporotic fracture (MOF), calculated without BMD, equivalent to a woman with a prior fragility fracture but no other clinical risk factors, and a body mass index (BMI) of 25.0 kg/m2. The lower assessment threshold was set at a 10-year probability of a MOF in women with BMI of 25.0 kg/m2, without previous fracture or other clinical risk factors. The upper assessment threshold was set at 1.2 times the IT.ResultsThe age-specific intervention thresholds ranged from 3.6 (Armenia and Georgia) to 12.3% (Uzbekistan) for men and women at the age of 50 years and from 16 (Armenia) to 27% (Belarus) at the age of 90 years. The difference between countries was most evident at younger ages and become progressively less with advancing age.Conclusions For the 8 Eurasian countries, the newly established FRAX-based intervention thresholds provide an opportunity to improve the clinical detection of both men and women with a high risk of fracture and improve treatment rates.
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Background Fragility fractures are fractures that result from mechanical forces that would not ordinarily result in fracture. Objectives The objectives were to evaluate the clinical effectiveness, safety and cost-effectiveness of non-bisphosphonates {denosumab [Prolia ® ; Amgen Inc., Thousand Oaks, CA, USA], raloxifene [Evista ® ; Daiichi Sankyo Company, Ltd, Tokyo, Japan], romosozumab [Evenity ® ; Union Chimique Belge (UCB) S.A. (Brussels, Belgium) and Amgen Inc.] and teriparatide [Forsteo ® ; Eli Lilly and Company, Indianapolis, IN, USA]}, compared with each other, bisphosphonates or no treatment, for the prevention of fragility fracture. Data sources For the clinical effectiveness review, nine electronic databases (including MEDLINE, EMBASE and the World Health Organization International Clinical Trials Registry Platform) were searched up to July 2018. Review methods A systematic review and network meta-analysis of fracture and femoral neck bone mineral density were conducted. A review of published economic analyses was undertaken and a model previously used to evaluate bisphosphonates was adapted. Discrete event simulation was used to estimate lifetime costs and quality-adjusted life-years for a simulated cohort of patients with heterogeneous characteristics. This was done for each non-bisphosphonate treatment, a strategy of no treatment, and the five bisphosphonate treatments previously evaluated. The model was populated with effectiveness evidence from the systematic review and network meta-analysis. All other parameters were estimated from published sources. An NHS and Personal Social Services perspective was taken, and costs and benefits were discounted at 3.5% per annum. Fracture risk was estimated from patient characteristics using the QFracture ® (QFracture-2012 open source revision 38, Clinrisk Ltd, Leeds, UK) and FRAX ® (web version 3.9, University of Sheffield, Sheffield, UK) tools. The relationship between fracture risk and incremental net monetary benefit was estimated using non-parametric regression. A probabilistic sensitivity analysis and scenario analyses were used to assess uncertainty. Results Fifty-two randomised controlled trials of non-bisphosphonates were included in the clinical effectiveness systematic review and an additional 51 randomised controlled trials of bisphosphonates were included in the network meta-analysis. All treatments had beneficial effects compared with placebo for vertebral, non-vertebral and hip fractures, with hazard ratios varying from 0.23 to 0.94, depending on treatment and fracture type. The effects on vertebral fractures and the percentage change in bone mineral density were statistically significant for all treatments. The rate of serious adverse events varied across trials (0–33%), with most between-group differences not being statistically significant for comparisons with placebo/no active treatment, non-bisphosphonates or bisphosphonates. The incremental cost-effectiveness ratios were > £20,000 per quality-adjusted life-year for all non-bisphosphonate interventions compared with no treatment across the range of QFracture and FRAX scores expected in the population eligible for fracture risk assessment. The incremental cost-effectiveness ratio for denosumab may fall below £30,000 per quality-adjusted life-year at very high levels of risk or for high-risk patients with specific characteristics. Raloxifene was dominated by no treatment (resulted in fewer quality-adjusted life-years) in most risk categories. Limitations The incremental cost-effectiveness ratios are uncertain for very high-risk patients. Conclusions Non-bisphosphonates are effective in preventing fragility fractures, but the incremental cost-effectiveness ratios are generally greater than the commonly applied threshold of £20,000–30,000 per quality-adjusted life-year. Study registration This study is registered as PROSPERO CRD42018107651. Funding This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment ; Vol. 24, No. 29. See the NIHR Journals Library website for further project information.
Article
Vitamin D and calcium are considered crucial for the treatment of bone diseases. Both vitamin D and calcium contribute to bone homeostasis but also preserve muscle health by reducing the risk of falls and fractures. Low vitamin D concentrations result in secondary hyperparathyroidism and contribute to bone loss, although the development of secondary hyperparathyroidism varies, even in patients with severe vitamin D deficiency. Findings from observational studies have shown controversial results regarding the association between bone mineral density and vitamin D/calcium status, thus sparking a debate regarding optimum concentrations of 25-hydroxyvitamin D and calcium for the best possible skeletal health. Although most of the intervention studies reported a positive effect of supplementation with calcium and vitamin D on bone in patients with osteoporosis, this therapeutic approach has been a matter of debate regarding potential side effects on the cardiovascular (CV) system. Thus, the aim of this review is to consider the current evidence on the physiological role of vitamin D and calcium on bone and muscle health. Moreover, we provide an overview on observational and interventional studies that investigate the effect of vitamin D and calcium supplementation on bone health, also taking into account the possible CV side-effects. We also provide molecular insights on the effect of calcium plus vitamin D on the CV system.
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Objective to investigate differences in length of hospital stay after hip fracture. Design prospective survey of a consecutive series of patients admitted with an acute hip fracture and followed-up for 90 days after admission. Setting eight hospitals in the East Anglian region. Subjects 580 patients admitted with a hip fracture. Main outcome measures mortality, length of hospital stay, place of discharge and transfer of patients between hospitals. Results there was a significant difference in the median lengths of hospital stay between centres (range 13–28 days). A prolonged hospital stay was associated with increased age, decreased activities of daily living score and delay from surgery to mobilization. Hospitals which had a policy of transferring patients to other wards prior to discharge tended to have a longer length of hospital stay. Conclusions large differences in the duration of inpatient stay exist between hospitals. Centres which transferred a high proportion of patients before discharge had a longer length of stay.
Article
There is now substantial evidence for the efficacy of cyclical etidronate therapy (ICT-etidronate) in the prevention of bone loss and, in some circumstances, reduction of fracture rates. Ultimately, however, the challenge is to determine how best to use the drug in clinical practice. Some guidance can be gained on this matter by considering the economics of ICT-etidronate in differing clinical circumstances. Unfortunately, the economic data available on the use of ICT-etidronate are relatively limited and there are none derived from randomized controlled trials. The cost-effectiveness of ICT-etidronate, and of other treatments for osteoporosis, will be based not only on their antifracture efficacy and costs of prescription, but also on any negative effects on quality of life induced by adverse effects. It is concluded that ICT-etidronate may be used in the most cost-effective way in older women with established fractures but may be economically acceptable in the immediately postmenopausal years if HRT use is not an option and there are major risks of future osteoporotic fractures.
Article
Background. Alendronate is a potent aminobisphosphonate which specifically inhibits osteoclastic bone resorption and has been found to reserve bone loss. The aim of this study is to determine if daily oral alendronate treatment could prevent or reserve bone loss in osteoporotic postmenopausal women. Methods. Between December 1993 and May 1996 we have studied, at the Obstetric and Gynaecologic Clinic of II University of Naples, 136 women, 44-73 aged, in postmenopause from 5 years, with osteoporosis (defined as a bone mineral density of the lumbar spine that was at least 2.5 SD below the mean value in premenopausal women). Bone mineral density was measured by dual-energy X-ray absorptiometry. During this period of two and half years of observation, the effects of alendronate were monitored on the biochemical indicators of bone remodelment and on the metabolism of the calcium; the degree of certainty and tolerability of this drug has also been assessed. Results. The women receiving alendronate had significant, progressive increases in bone mineral density in the spine, whereas those receiving placebo has decreases in bone mineral density. The relative risk of a new fracture among the women treated with alendronate, as compared with those receiving placebo, was 0.55. Conclusions. The therapy with alendronate has, on the basis of data proposed from this study, a good tolerability and is very effective in the treatment of postmenopausal osteoporosis.
Article
The effectiveness and safety of a long-term treatment with ipriflavone were investigated in 49 elderly osteoporotic women (age 65-79) with at least one vertebral fracture and forearm bone mineral density (BMD) below 2 SD of age-matched average. Women were randomly allocated to treatment with either oral ipriflavone (200 mg x 3/day) or placebo plus 1 g oral calcium supplementation per day for 2 years. Forty subjects completed one year, and 27 two years of treatment. Women treated with ipriflavone (n= 14) experienced a 4.1±1.9% increase in the distal radius BMD at year 1 (p<0.05 vs placebo), and a 7.1±3.0% increase (p<0.05 vs placebo) at year 2. No changes occurred in the control group (n=13): 0.6±1.4% at year 1, and 0.4±1.5% at year 2. BMD of the proximal femur, measured in a subgroup of patients, showed no changes in the ipriflavone-treated patients, and a not significant tendency to decrease in the placebo group. The fracture rates for new vertebral fractures were significantly different for the study period between the ipriflavone and placebo groups (11 vs 22 per 100 patient-years; p<0.05). A significant (p<0.05) decrease of urinary hydroxyproline excretion in the ipriflavone group, and an increase in serum calcium (p<0.01) and phosphate (p<0.01) in the placebo group were observed. Adverse reactions (ARs), primarily gastrointestinal symptoms, occurred in 14 ipriflavone-treated women and in 12 control subjects: 3 patients treated with ipriflavone and 2 receiving the placebo were withdrawn for ARs. Modest abnormalities of liver function test were detected, with no differences between the groups. In conclusion, long-term treatment with ipriflavone may represent a safe and useful modality to improve bone density and perhaps prevent vertebral fractures in elderly women with osteoporosis.
Article
Eighty-two osteoporotic women with radiological evidence of two or more vertebral atraumatic compressions were randomly allocated to treatment with oral calcium (1 g/day) alone or oral calcium (1 g/day) plus salmon calcitonin (sCT), 100 MRC.U. every day or 100 MRC.U. every second day. The data for 45 women (15 for each group) who completed one year of treatment have been analyzed. The Bone Mineral Contents (BMC) of the lumbar spine and of the femoral diaphysis of the calcium-control group both showed significant decreases from basal values after 9 and 12 months. The BMC significantly increased in the group given sCT 100 MRC.U. every second day (about 4% after one year) and the group given sCT 100 MRC.U every day (up to 8.5% after one year). The study, in addition to confirming the positive effects of salmon calcitonin on bone mass recovery in post-menopausal osteoporotic patients, suggests that its effect on bone is dose dependent.
Article
Sullivan (1971) first suggested weighting life expectancy (LE) to account for the health of a population using a single indicator. Known as disability free life expectancy (DFLEs), this measure was somewhat limited due to a overly simplistic weighting scheme. Its introduction, however, spurred the development of a whole new class of measures known as health expectancy indicators. One of the first, disability-adjusted life expectancy (DALEs) (Wilkins and Adams, 1983), identified the period of time in a particular level of disability and weighted each level accordingly. While the weighting allowed for a health related quality-of-life distinction to be introduced into the DALE measure, the weights, by level of disability, were arbitrarily chosen and fixed for all ages and gender. To overcome this limitation, a health-adjusted life expectancy (HALE) was developed based in large part on the DALE methodology but utilizes more refined weights. The McMaster Health Utility Index Mark III (HUI3)) scores health on a continuum from 0 to 1 and when included on a national health survey, provides estimates that reflect important age, gender, and socio-economic factors. All three measures were calculated for the years 1986, 1991, and 1994 (household and institutional populations). Analysis revealed that HALEs were more appropriate for policy purposes due to their ability to account for indirect morbidity in both a disabled and non-disabled population.