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Cost of non-persistence with oral bisphosphonates in post-menopausal osteoporosis treatment in France
© Cotté and De Pouvourville; licensee BioMed Central Ltd. 2011
Received: 6 December 2010
Accepted: 25 June 2011
Published: 25 June 2011
During the last decade, oral bisphosphonates (BP) became the most widely prescribed pharmacologic class for post-menopausal osteoporosis. However, many surveys revealed the important issue of poor persistence with those drugs resulting in a failure of treatment to reduce fracture risk sufficiently. Using a published Markov model, this study analyses the economic impact of non-persistence with bisphosphonates in the context of the introduction of generics in France.
Direct costs of vertebral, hip and wrist fracture were assessed and included in an existing 10-year Markov model developed to analyse consequences of non-persistence. Three alternatives of comparison were set: no treatment, real-world persistence, and ideal persistence. Simulated patients' characteristics matched those from a French observational study and the real-world adherence alternative employed persistence data from published database analysis. The risk of fracture of menopausal women and the risk reduction associated with the drugs were based on results reported in clinical trials. Incremental cost-effectiveness ratios (ICERs) were calculated first between real-world adherence and no treatment alternatives, and second between ideal and real-world persistence alternatives. The cost of non-persistence was defined as the difference between total cost of ideal and real-world persistence alternatives.
Within fractured women population, mean costs of 10-year management of fracture were significantly different between the three alternatives with €7,239 (± €4,783), €6,711 (± €4,410) and €6,134 (± €3,945) in the no-treatment, the real-world and ideal persistence alternatives, respectively (p < 0.0001). Cost-effectiveness ratio for real-world treatment persistence compared with no-treatment alternative was found dominant and as well, alternative of ideal persistence dominated the former. Each ten percentage point of persistence gain amounted to €58 per patient, and extrapolation resulted in a global annual cost of non-persistence of over €30 million to the French health care system, with a substantial transfer from hospital to pharmacy budgets.
Within term, improving persistence with oral bisphosphonates should be economically dominant on levels currently known in real-world. Given this potential savings, ambitious adherence-enhancing interventions should be considered in osteoporotic patients.
Keywordsosteoporosis bisphosphonate adherence persistence cost modelling study
Osteoporosis is characterised by low bone mass and microarchitectural deterioration of bone responsible for 8.9 million fractures each year worldwide . With at least 150,000 clinical fractures every year, preventing osteoporosis within elderly represents an important issue for public health stakeholders in France . This was brought to light in 2007 by reimbursement decisions for osteoporosis screening (i.e. bone mineral densitometry examination) and for primary prevention (i.e. osteoporotic patient without fracture history).
Randomized clinical trials providing evidence for clinical relevant fracture protection by the bisphosphonates [3, 4], international guidelines recommended bisphosphonates for the treatment of postmenopausal osteoporosis in the late 1990s . During the following decade, bisphosphonates became the most widely prescribed pharmacologic class for this pathology , with nearly 80% of specific drug prescriptions  and also corresponding to over €300 million reimbursement by French health system (called Assurance Maladie) for 2008 . Recently, authorities stress the pressure on oral bisphosphonates prices strengthened by near future genericisation of the whole class, as it already occurred in 2008 to the first historical molecule (i.e. alendronate).
Post-menopausal osteoporosis prevalence was estimated at around 30% in women fifty years of age and over . In 2006, a study in French general population showed that this diagnosis was already done to almost 10% of those women highlighting an underdiagnosis issue . At the time of this survey, only 61% claimed receiving an osteoporosis treatment also revealing a significant health management issue with those drugs, in accordance to many other findings . A report of data pooled from the US, UK and France also revealed a one-year discontinuation rate of approximately 50% in women treated with bisphosphonates . Alarmed by low rates of treatment adherence in developed countries for many chronic diseases such as osteoporosis, the World Health Organisation has emphasised the growing body of evidence that supports the notion that increasing the effectiveness of adherence interventions may have a far greater impact on the health of the population than any improvement in the efficacy of specific medical treatments . An expert consensus in osteoporosis defined adherence as a general term encompassing both compliance and persistence . The International Society for Pharmacoeconomic and Outcomes Research (ISPOR) tended to consider terms "adherence" and "compliance" as synonym  representing "the extent to which a patient acts in accordance with the prescribed interval and dose of a dosing regimen". Persistence was defined as "the duration of time from initiation to discontinuation of therapy" which corresponds to a continuous variable (i.e. number of days with drug availability) or a dichotomous variable (i.e. being "persistent" or "nonpersistent" at the end of a predefined time period). Graphical illustration of persistence is generally performed according survival analysis following the Kaplan-Meier method so called persistence curve .
Although non-persistence was found to systematically reduce treatment effectiveness, this issue was not often taken into account in pharmacoeconomic models . On behalf of the Economics of Medication Compliance Working Group of ISPOR, Hughes et al.  have formulated methods that may be appropriate for integrating these aspects in economic evaluations. Especially, Markov models were identified to allow direct inclusion of persistence variable in the analysis, as patients transit during each cycle. In 2009, such model was designed to simulate the impact of improving persistence rates on osteoporosis treatment effectiveness . Compared to a non-treatment hypothesis, the relative risk of fracture over ten years was 0.83 for weekly bisphosphonate treatment and decreased to 0.73 if hypothetical full-treatment persistence was achieved. Moreover, improving persistence by 20% was found to have the same clinical impact as a 20% increase in clinical efficacy. In observational studies, women considered as persistent appeared to benefit from a significant decrease of fracture risk ranging from 26% to 32% when compared to nonpersistent ones [19–21]. Nonpersistent patients (i.e. under one-year compliance) were shown to be associated with higher hospitalization rates and higher charges for in-and outpatient health care resources . However, drug expenditures related to non-persistence rates appeared lower  and impact of overall incremental direct costs and savings on healthcare budget remains unclear. To our knowledge, no previous study proposed a global approach to estimate cost of non-persistence in the field of osteoporosis.
The modelling study described here proposes an estimation of the budget impact of non-persistence with bisphosphonates, by assessing cost-effectiveness of "ideal persistence" compared to current persistence in real-world and estimating the annual total cost of non-persistence for France.
This modelling study used a validated Markov model that has been developed (TreeAge Software, Williamstown, MA, USA) to predict the incidence of osteoporotic fractures in women with post-menopausal osteoporosis (PMO) in relation with persistence rates with bisphosphonates . The main adaptation is that cost information was linked to the model by assigning each Markov state rewards for costs. These rewards contributed to the total accumulated sum of costs depending on the patient's path through the health states.
Costs and events were firstly estimated for three alternatives: no-treatment, real-world persistence, and ideal persistence. No-treatment alternative modelized the natural history of PMO without assistance of any pharmacologic therapy. The ideal persistence alternative considered bisphosphonates benefits from clinical trials. The real-world persistence alternative assumed all patients were treated by weekly or monthly bisphosphonates and was based on current persistence rates from observational studies. Costs of fractures management and rehabilitation were also added as well as costs of bisphosphonates as per the persistence rate.
The fracture events evaluated were restricted to the hip, the vertebrae and the wrist, since these are the specific sites where the most frequent osteoporotic fractures occur  and were particularly well documented compared to less common sites. Morphometric (ie identified by radiography) and symptomatic (ie clinically diagnosed) vertebral fractures were differentiated. Input variables for the model included the prevalence of diagnosed PMO, fracture rates at the sites of interest, efficacy and residual beneficial effect of bisphosphonate treatment, and treatment persistence rates. Fracture events were modelled over a ten-year period.
Transition probabilities between the different health states were defined in the model by features of the French patients diagnosed with PMO in terms of age distribution and proportion of patients with a prior fracture . Annual absolute fracture risks in women with post-menopausal osteoporosis were from estimations based on general population data  and relative risk ratios for the association between subsequent and prior fractures from a meta-analysis . Pooled bisphosphonates efficacies for each fracture sites were given by the Health Technology Assessment guidance for health economic models in osteoporosis . Residual effect data from a follow-up of postmenopausal Danish women during 7 years after treatment withdrawal  were modelized to determine the relation of treatment duration and treatment global protection i.e. 10-year protection achieved with around 4 years of continued treatment .
Insertion of persistence with bisphosphonates treatments occurred in this model only for real-world alternatives. Data were from the Longitudinal Patient Database (LPD) which is constituted by a French representative network of over 1,200 computerized general practitioners (Thales network). Analyses of treatment discontinuation within women newly treated with weekly bisphosphonates showed that 49% of them were nonpersistent after 1-year of follow-up  and this rate increased to 59% after 2 years . Persistence curves were extrapolated using the best-fit logarithmic derivations from which functions were combined with those of residual protection following interruption of treatment. Proportion of women with effective protection at each cycle of simulation was then calculated to allow the path of patients from the initial model (Figure 1 - Part A) where they benefit from treatment protection to a twin model (Figure 1 - Part B) where it is not the case anymore. Alternatives as ideal persistence and no-treatment have been individually run in one of the two parts giving extreme values this proportion, respectively one and null.
Baseline age-specific, all-cause mortality rates were derived from 2004 (French national population statistics, INSEE). Mortality following a hip fracture was estimated by adjusting baseline, age-specific, and all-cause mortality using Swedish data . Concerning vertebral fractures, relative risks of mortality in the subsequent year was taken from the European Prospective Osteoporosis Study (EPOS) . This model did not apply incremental mortality to the post-wrist fracture state as neither early nor medium term mortality has been shown .
Clinical inputs for transition probabilities
Age distribution (mean in years)
Blotman et al. 2007 
Prior fracture (%)
Absolute risk by age (% per year)
Cotté et al. 2009 
> 84 years
associated with any prior fracture at baseline
post-vertebral fracture health state
Klotzbuecher et al. 2000 
post-hip fracture health state
post-wrist fracture health state
Relative risk reduction with BP
for any women at baseline
from post-vertebral fracture health state
Kanis et al. 2002 
from post-hip fracture health state
from post-wrist fracture health state
Loss of bisphosphonate protection
Treatment duration (T; in months)
Persistence rates (P; in %)
Fardellone et al. 2005 
*Source data were fitted to an exponential function to generate persistence curve over 24 months:
P = 1 - 0.196 × ln(T)
60 to simulation ending time
Treatment duration (T; in months)
Protection duration** (y; in months)
Cotté et al. 2009 
**Residual effect of BP was modeled as follow:
y = 13.5 × e0.048 × T
All simulation period
60 to simulation ending time
All simulation period
All costs are given in Euro (€) for the year 2010. An annual discount rate of 5% was used. A sensitivity analysis was also performed without any discounting.
Cost of bisphosphonate treatments were set based on the public price in 2010 extracted from the Caisse Nationale d'Assurance Maladie database . The French authorities have approved generic forms of alendronate 70 mg in 2006 , and although risedronate is still protected by a market patent, the base case model assumed by default the generic price of alendronate for bisphosphonates corresponding to €52.23 for 12 weeks of treatment. In a sensitivity analysis, risedronate branded price of €87.46 for 12 weeks was also tested. In the ideal persistence alternative, drug costs were equal to one year of medication at each cycle, whereas in the real-world persistence alternative, those costs were multiplied by persistence rates associated for each cycle.
Direct costs of osteoporotic fractures management in France (euros 2010)
M485(0-9); S22(0-1); S2200; S2210; S320(0); S327(0); S328(0)
Cost of disease-related groups*
€1,992 - €15,720
€614 - €3,363
€640 - €15,720
Direct cost of fracture hospitalizations
Weighted average cost per unit
Direct cost of management of fracture **
A Student t-test was performed to compare mean values of cost with a significance threshold P value of 0.05.
Ten-year period was considered as an appropriate horizon in the field of osteoporosis , and the model simulations were also ran over 10 cycles. After stability of the model was checked using predictable random sequences, 30,000 Monte Carlo microsimulations were performed for each alternative, and fractures, costs, and deaths were recorded.
Cost criterion (μ C ) encompassed both management of fracture as well as drug consumption, while two effectiveness criteria (μ E ) were assessed: the proportion of fractured women and the proportion of premature deaths at the model horizon. Additional simulations assessed the influence of discounting on the ICERs results.
The cost of non-persistence was defined as the difference between costs balance sheet of ideal and real-world persistence alternatives. Global cost of non-persistence has been estimated by extrapolation of this result to the overall population of diagnosed osteoporotic women estimated at 1.13 million women in France . Cost of management of fracture, drug cost and sum of both, were also studied in function of persistence rate.
10-year Monte-Carlo simulation outcomes
Monte-Carlo simulations (N = 30,000)
Distribution of fracture costs
Cost-effectiveness of bisphosphonates for real-world and ideal persistence alternatives
Average per patients
Average per patients
Cost of non persistence
In a context of generic prices, the hypothetical alternative of ideal persistence with oral bisphosphonates was shown economically dominant on the real-world persistence. Moreover, the savings came to €58 per patient for each ten percentage points of persistence gain. The extrapolated global cost of non-persistence in France was also estimated to around €30.5 million per year.
Those results demonstrate the extent of the economic impact of non-persistence with oral bisphosphonates and as a corollary, the potential lever of improving this parameter. Although achieving an ideal persistence for the whole osteoporotic women seems illusive, few strategies have already demonstrated relevant efficacy in enhancing persistence. The first of all was the development of intermittent administrations allowed by pharmacokinetics specificity of bisphosphonates . Alendronate and risedronate have been formerly available with oral daily regimen and then both developed with oral weekly regimen. Although persistence with bisphosphonate treatments has been improved with those weekly formulations, it was still shown to be suboptimal in many western countries . The search for adherence optimization leads other bisphosphonates providers to develop further the concept of intermittent dosing regimen. In 2006, ibandronate was the first within the bisphosphonate class being proposed with a monthly regimen to post-menopausal women, recently followed by risedronate . Topical data confirmed this strategy with a proportion of persistent patients achieving 17 percentage points higher with monthly regimen compared to weekly users after 1-year . Seeing the quick and almost full switch of bisphosphonates with daily to weekly dosing regimen , it is plausible that monthly dosing regimen would become one day the standard of oral bisphosphonates dosing frequency. However, due to a lack of proven efficacy on hip site, French authorities recently decided that ibandronate would not be reimbursed anymore. Intravenous bisphosphonates are now available with yearly or quarterly dosing regimen with, in essence, a sustained persistence. Those intravenous bisphosphonates may be particularly useful to treat patients with a high risk of non-persistence who could be simply identified by validated tools, such as the recent ADEOS-12 items questionnaire . Institutionalized patients may also easily benefit from those specific administration routes. However, experience has shown higher patient's preference and acceptability for oral administration than for hospital infusion, in the case of chemotherapy notably .
In the past twenty years, the global cost of non-adherence with medications was successively estimated in US at 20 million lost work days and $1.5 billion in lost earnings annually in 1990 , at $100 billion annually in 1997  and finally more than $300 billion annually in 2004 . Outdated but frequently cited in literature introductions, those macro-economic data suffered from numbers of methodological biases and have to be used with caution according to the author of the latter. In general, when taking the drug costs into account, it is not clear whether improving adherence with chronic medications reduces or increases costs and treatment-specific or target-population-specific studies are needed. Very few surveys identified increased healthcare costs due to medication non-adherence against offsets from reduced drug intake. In Parkinson's disease and epilepsy, recent database analyses showed a large net positive effect of non-adherence on total annual health care costs remained despite savings in pharmacy costs [45, 46].
Four previous studies used mathematical simulation models to calculate the lost benefits associated with real-world non-adherence in very different populations: renal transplanted subjects , HIV , hypertensive  and schizophrenic patients . Unlike in our present results, ideal adherence with renal transplant, HIV and hypertension medications was not found as a dominant strategy, but cost-effective with €35,000 per Quality-Adjusted-Life-Year (QALY), $29,400 per QALY and $22,100 per life-year saved, respectively. In those cases, results were equivalent of an estimation of the cost-effectiveness of interventions to improve adherence to levels observed in clinical trials. The latter study predicts that increases in compliance with anti-psychotics may lead to considerable cost savings and health improvements. Hence, each percentage point of compliance gain was predicted cost saving over 5 years of around €650 and a QALY gain of 0.004. According to our study, spending up to €270 per osteoporotic patients in an effective adherence-enhancing intervention would result in economic neutrality. Over this amount a cost-effectiveness trade-off would be needed. In comparison, adherence-enhancing interventions to asthmatic and lipid patients were evaluated as $32  and $182  offsets, respectively.
Model type, structure, validation have been already fully discussed in a previous publication as well as its stability . Estimation of fracture costs were based from the analysis of an exhaustive National database and, regarding hip and wrist fractures, were consistent with previous ones . However, it was not possible to identified vertebral fractures caused by trauma or malignant tumours from those effectively due to osteoporosis and, it was assumed that management and also hospitalization costs were similar, whatever the original causes of fractures. Several factors may contribute to a probable underestimation of the actual costs in this model. The majority of the vertebral fractures do not require hospitalization and were assumed as asymptomatic with no associated cost. However, many of those fractures probably lead to other ambulatory resource utilizations (e.g. back pain treatment). As well, due to the lack of data, our estimations of fractures costs did not take into account the patient transport or indirect costs.
Our clinical assumptions and input data were also clearly stated and justified as required by guidelines for pharmacoeconomic research. Cost-effectiveness results were expressed with non conventional ICERs compared to those mostly used in the literature, especially QALYs. The latter are actually not recommended by French economic evaluation guidelines for public decision making . Furthermore, outcomes chosen in this model (i.e. proportion of fractured women and premature deaths) could be considered as more clinically meaningful than aggregate ones.
Based on the results of the model, improving persistence with oral bisphosphonates was shown economically dominant on the real-world persistence. When extrapolated to the whole of France, savings could rise to over €30 million per year, with a substantial transfer from hospital to pharmacy budgets. Pharmacoeconomic environment in the field of osteoporosis offers new opportunity to optimize patients' management on the condition that cost-effective adherence-enhancing interventions be identified and carried out.
The authors would like to thank Sebastien Branchoux (Marly le Roi, France) for his assistance with the statistical analysis of the data.
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