Overcoming Problems with Adherence to Osteoporosis Medication

Véronique Rabenda; Jean-Yves Reginster

Disclosures

Expert Rev Pharmacoeconomics Outcomes Res. 2010;10(6):677-689. 

In This Article

Poor Adherence to Osteoporosis Medications & its Impact on Clinical & Economic Outcomes

Adherence to Bisphosphonates

Multiple large observational studies from countries with different health systems have reported low rates of long-term adherence with oral bisphosphonates (daily or weekly). A meta-analysis of observational studies reported that only 53% of the study population achieved a MPR of 80% or higher 6 months after initiating therapy, and only 43% achieved a MPR of 80% or higher 7–12 months after initiating treatment.[9] It has been estimated that only 46% of new users of osteoporosis medications persist with therapy for a treatment period of 7–12 months. This pattern of early discontinuation has been supported by numerous other studies. In an analysis of peer-reviewed literature including more-recent studies, it was found that more than half of the patients failed to comply or persist (or both) with the prescribed regimen during the first year of treatment of osteoporosis.[10,11] However, it has been demonstrated that many patients restart osteoporosis therapy after a prolonged lapse in medication use.[12–14] Approximately a third of women who discontinued weekly alendronate (gap in refill: ≥60 days) restarted treatment within 6 months.[12] Brookhart et al. examined the rate of restarting osteoporosis treatment after prolonged discontinuation.[13] Out of 40,002 Medicare beneficiaries enrolled in Pharmaceutical Assistance Contract for the Elderly (PACE), 67% had lapses in osteoporosis drug use that were longer than 60 days. In this cohort, 30% restarted treatment within 6 months after discontinuation and 50% within 2 years. Factors associated with restarting osteoporosis treatment were younger age, female sex, history of previous fracture, recent hip fracture, discharge from nursing home and bone mineral density testing.[13] Although it is encouraging that patients have been reinitiating use of their medications, the effect of these long breaks on clinical outcomes is unknown. The protective therapeutic time window following a stop or interruption in treatment needs to be further investigated.

Patient preference studies comparing daily and weekly medications for osteoporosis have consistently shown a trend towards preferences for the less-frequent regimens. Across these studies, most patients considered the weekly regimens as their drug regimens of choice, citing convenience and greater likelihood of achieving long-term compliance.[15–19] However, although the introduction of weekly formulations improved adherence compared with daily regimens, levels still remain suboptimal.[20–23]

Results from preference surveys and observational studies comparing monthly and weekly bisphosphonates are conflicting and were influenced by the information provided to patients relating to medication profiles. Gold et al. reported that adherence with weekly risedronate versus monthly ibandronate measured by MPR was significantly higher (72.7 vs 52.8%).[24] In addition, persistence with weekly risedronate was significantly longer (144 vs 100 days). The authors attributed the better rates to patient knowledge of each medication's proven fracture efficacy. This was also demonstrated in both the Preference for Effective Regimes (PREFER)-US and PREFER-International studies, where a significant majority of patients with osteoporosis stated preference for the weekly regimen (96% in PREFER-US, 78% in PREFER-International) after being offered two medication profiles: monthly ibandronate or weekly alendronate.[25–27] The main difference between the drug profiles presented was that weekly medication was stated to be superior to the monthly medication in nonvertebral-fracture prevention. A similar result was demonstrated in a survey by Richards et al..[28] In this study, patients were asked for their preference of three scenarios (daily dosing to be taken 2 h after eating before bed time, no fasting or upright position required; weekly dosing requiring fasting for 30 min in upright position post-medication; and monthly dosing requiring fasting for 30 min in upright position post-medication). Nearly half (45%) of the surveyed patients preferred daily dosing with minimal administration inconvenience, 20% preferred weekly therapy with moderate administration inconvenience and 30% preferred monthly therapy. When informed about the differences in fracture efficacy with weekly and monthly bisphosphonates, a significantly greater proportion (82%) of women preferred a weekly bisphosphonate with proven fracture efficacy at the spine and hip over a monthly bisphosphonate with proven fracture efficacy only at the spine.[29]

In the absence of differences in medication efficacy, there is an apparent trend for patient preferences towards the monthly regimens. Two clinical studies (Boniva Alendronate Trial in Osteoporosis [BALTO] I and II) of patient preference demonstrated that more than 70% of patients preferred treatment with the monthly regimen of ibandronate versus the weekly regimen of alendronate.[30,31] More recently, a retrospective study using a large primary-care database showed that adherence to a monthly bisphosphonate treatment regimen was higher than that to weekly regimens in postmenopausal women. The authors observed that patients treated with a monthly regimen were 37% less likely to be nonpersistent and were more compliant, with a 5% higher absolute MPR compared with women treated with weekly regimens.[32] Moreover, it was shown that women who discontinued daily or weekly oral bisphosphonates because of gastrointestinal intolerance reported decreased gastrointestinal symptoms and improved adherence on quarterly intravenous or monthly oral ibandronate.[33] A total of 83% of quaterly intravenous ibandronate recipients and 70% of monthly oral ibandronate recipients remained adherent at 12 months.

Patient preference studies comparing weekly medications and annual infusions have consistently demonstrated a trend towards preferences for the less-frequent regimens. In two separate trials, yearly intravenous zoledronate was preferred to weekly oral alendronate by 79%[34] and 66%[35] of patients, respectively. Reasons cited included greater convenience, more satisfaction and the patients were more willing to take the annual therapy for a longer time.[35]

However, it is important to note that results from studies comparing different dosing regimens should be interpreted with caution because the source of study funding may not be unbiased. In fact, some studies are industry supported and, consequently, the reported results are largely expected. In addition, adherence is likely to be better in a clinical trial setting than in normal clinical practice.

Moreover, recent surveys suggest that even after a diagnosis of osteoporosis, which is usually precipitated by a fragility-related fracture, patients often do not receive the recommended or adequate treatment, and that among patients who do receive treatment, many have difficulty continuing with treatment on a long-term basis. Carnevale and colleagues investigated the patterns of treatment and persistence with prescribed therapies in 2191 ambulatory patients with previous hip fractures.[36] Results showed a low rate of primary prevention: 53% of patients had never received any kind of treatment and less than 20% had taken an antiresorptive drug. A total of 21% of those treated with a fracture-prevention medication at the time of or immediately after the fracture had stopped their treatment after the occurrence of a fracture. Moreover, among patients who were untreated before fracture, 61% continued not to take any drugs after fracture. In a prospective study among 174 patients admitted for hip-fracture rehabilitation, less than half of the patients (81 out of 174) were taking risedronate, 31 patients remained on vitamin D and only five patients were taking calcium 12 months after discharge from the rehabilitation program.[37] In another recent study, it was demonstrated that among the very small proportion of patients treated following a hip fracture (6%), only 41% of women continued to take their treatment at the end of the first year of therapy and less than half were found to be compliant with bisphosphonates therapy (MPR ≥80%).[38]

Adherence to other Osteoporosis Treatments

More than a quarter of women receiving hormone-replacement therapy and one in five among those receiving a selective estrogen receptor modulator stop their treatment within 6–7 months.[39] Moreover, even if calcium and vitamin D are well-tolerated drugs, adherence is also poor. For instance, a study conducted in Italy showed that among treatments prescribed for osteoporosis, calcium plus vitamin D was the treatment with the lowest adherence rate.[40] In that study, 23% of patients discontinued calcium plus vitamin D therapy 1 year after initiation of treatment. In another study, compliance (MPR <80%) with calcium and vitamin D supplementation was poor in 60% of cases.[41] Even among well-motivated patients taking part in randomized clinical trials, compliance rates ranged from 50 to 60%.[42,43] It should be kept in mind that the efficacies of currently used fracture-preventive treatments were only demonstrated in the presence of calcium and vitamin D supplementation; therefore, adherence to these supplements is required. However, it was recently demonstrated that the presence of vitamin D insufficiency did not appear to inhibit the bone density response to alendronate therapy.[44]

Very few studies have chosen to evaluate the adherence to teriparatide as a primary outcome in real-world practice. While few data have been published on compliance, one study did demonstrate a very high persistence rate in a UK population.[45] Arden et al. reported that of 1104 patients, 87% were continuing treatment with teriparatide at 1 year.[45] These data are significant in light of other osteoporosis therapies, which are associated with less-appealing adherence rates. In another recent study conducted by Ziller and colleagues, it was reported that 79% of patients still taking teriparatide at 12 months and 80% of the patients treated with teriparatide were compliant.[46] However, the authors stated that teriparatide was prescribed in only severe cases of osteoporosis and that this high degree of severity of the disease stage may have influenced adherence.

Recently approved denosumab, a RANKL-specific recombinant humanized monoclonal antibody, is another therapeutic agent for the management of postmenopausal osteoporosis.[47] A study of preference demonstrated that denosumab, given as a 60-mg subcutaneous injection every 6 months, was preferred to weekly oral bisphosphonates.[48]

Strontium ranelate constitutes another therapeutic option, given its long-term safety and its user-friendly profile.[49–52] In a post hoc analysis of data from the Spinal Osteoporosis Therapeutic Intervention (SOTI) and Treatment Of Peripheral Osteoporosis (TROPOS) studies, it was shown that 75% of patients were compliant with strontium ranelate therapy over a 3-year follow-up.[53] Women who achieved compliance with therapy had a 38% reduction in nonvertebral fractures overall compared with those who were not compliant. A prospective observational study showed that 12 months after their inclusion, 80% of patients were continuing therapy with strontium ranelate.[54] Compliance measured on a five level scale was 'very good' or 'good' in 85.8% of patients at 12 months.

These results should be interpreted with caution because the source of study funding may not be unbiased.[48,53]

Clinical & Economic Impact of Poor Adherence

This inadequate therapeutic adherence reduces the effectiveness of treatment and, consequently, compromises therapeutic outcomes, resulting in lower bone mineral density gains,[55,56] reduced effects on bone turnover[57] and subsequently increased fracture rates.[58–63] A recent meta-analysis found that the risk of fracture was 46% higher for patients with poor compliance to bisphosphonates (MPR <80%) compared with compliant patients.[64] The effect of low compliance to bisphosphonates was lower for nonvertebral (16%) and hip (28%) than for clinical vertebral (43%) fractures. A Belgian database analysis showed that the relative reduction in the risk of hip fracture was 60% for women who were persistent with bisphosphonate treatment compared with those who were nonpersistent.[58] In addition, for each incremental decrease of 1% in compliance, as measured by the MPR, the risk of hip fracture increased by 0.4%. In another study, at a MPR from 0 to 50%, the probability of fracture during a period of 24 months remained consistent at approximately 11% and declined progressively once a threshold value of 50% was achieved.[61]

However, it was demonstrated that, in a real-word setting, compliant/persistent patients can obtain a benefit from bisphosphonates similar to that of randomized trial participants.[65] In a recent cross-design synthesis, it was reported that total fractures were similarly reduced by bisphosphonates among postmenopausal women in randomized trials (23.8%) and highly compliant/persistent patients in observational studies of large databases from routine practice (20.3%). The magnitude of reduction in all clinical fractures was remarkably similar between database studies and randomized controlled trials (pooled odds ratio: 0.797 vs 0.762, respectively).[65] The authors concluded that compliant/persistent patients can indeed realize the full treatment benefit attained by randomized trial participants.[65]

Concerning calcium and/or vitamin D therapy, the reduction of risk fractures shown in clinical trials is highly correlated to adherence. The majority of studies show a reduction in the risk of fracture when the adherence rate is approximately 75–80%. In the Women's Health Initiative (WHI) study, adherence to combined vitamin D and calcium supplementation was low, estimated at less than 60%, and a significant (29%) reduction in hip fracture risk was found only in those subjects who were adherent to therapy.[43] When Jackson et al. assessed the influence of calcium and vitamin D on the risk of fracture, they observed, in a secondary analysis of a subgroup of patients with good adherence (59% of the sample), that intake of 1 g of calcium and 400 IU of vitamin D per day reduced the risk of hip fracture by 29%. In a meta-analysis of 29 randomized trials (n = 63897) in which calcium, or calcium in combination with vitamin D, was used to prevent fracture and osteoporotic bone loss, fracture risk reduction was significantly greater (by 24%) in trials in which the adherence rate was high (>80%).[66,67]

Aside from having a detrimental effect on the patient's health, poor adherence to treatment also has a major impact on healthcare systems and resources, including increased amounts of unused prescriptions, increased visits to healthcare providers, unnecessary treatment costs (e.g., for changes in prescribed agents), and admission to care because of associated treatment failure.[68–72] Owing to the occurrence of symptoms, it is estimated that at least 10% of hospital admissions and almost a quarter of nursing home admissions are due to nonadherence to treatment. Direct hospital costs from nonadherence were estimated to be US$8 billion in the USA alone, with a further $17–$25 billion in indirect costs.[73,74] In a recent retrospective database study, it was demonstrated that persistence and compliance with bisphosphonate therapy among women were associated with lower direct costs for nonosteoporosis- and osteoporosis-related inpatient admissions and outpatient visits.[75] The likelihood of hospitalization was significantly reduced for persistent patients, which could have a major impact on reducing overall expenditures due to the large costs of inpatient stays. The mean length of hospitalizations was also significantly lower for persistent and compliant patients. Moreover, as demonstrated by a recent modeling study, nonadherence with osteoporosis medications results not only in worsening health outcomes, but also in a significant change in the cost–effectiveness of treatments.[76] In another study, the estimated number of osteoporotic fractures that could be avoided among compliant patients (MPR ≥80%) was 110 in the primary-prevention cohort and 19 in the secondary-prevention cohort.[77] The costs of these avoidable fractures per patient were US$62.9 in the primary-prevention cohort and $330.8 in the secondary-prevention cohort.

Analysis of the relationship between mortality in clinical studies and adherence to treatment regardless of indication and diagnosis has proved that good adherence is associated with lower mortality.[78]

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