Adherence to antiosteoporotic treatment: a question of tolerability, mode of administration, or merely good patient dialogue?




En C. FUNG, MB, MSc, MRCP
Department of Chemical
Pathology


Tim D. SPECTOR, MB, MSc,
MD, PhD, FRCP
Twin Research & Genetic
Epidemiology Unit
Guy’s and St Thomas’ Hospital
London, UNITED KINGDOM

Adherence to
antiosteoporotic treatment:
a question of tolerability,
mode of administration, or
merely good patient dialogue?

by E. C. Fung and T. D. Spector,UK

Osteoporotic fragility fractures are associated with increased morbidity and mortality and are increasing in prevalence. Antiosteoporotic treatments consisting of different classes of drugs and modes of delivery have broadly similar antifracture efficacy, but their benefit is hampered by nonadherence. Up to half of patients stop their treatment by the end of year one and are denied the optimal treatment benefit. The causes of nonadherence can be classified as factors relating to the medication, the patients themselves, or the doctor-patient relationship. The most common cause of nonadherence is real or perceived adverse effects caused by the medication. Although randomized trials do not show major problems, the apparent increase in adverse effects may be due to incorrect dosage administration or merely contemporaneous background incidence rates. In deciding the best treatment choice for the patient, careful consideration should be made of tolerability profiles, ease of administration, and the risk-benefit profile of the treatment. The patient’s own beliefs about osteoporosis and its treatment should be met with empathy and a frank discussion of the best clinical evidence available. Active patient involvement in their disease is to be encouraged in order to enable patient empowerment and better adherence. Finally, a good doctor-patient relationship aids all the factors discussed.

Medicographia. 2010;32:25-32 (see French abstract on page 32)

Osteoporosis affects 75 million individuals in Europe, the US, and Japan.1 Globally, the annual incidence of new osteoporotic fractures is estimated at 9 million, of which 1.6 million are hip fractures.2 The attendant morbidity and mortality pose a significant problem for any health-care economy. In Europe, osteoporosis causes more disability than rheumatoid arthritis, asthma, migraine, and all cancers, except for lung cancer.2 With a rising elderly population, osteoporosis is fast becoming a considerable public health disease with a significant personal and economic burden.

Over the last two decades, effective antiosteoporotic treatments have been shown to reduce the risk of fractures by at least 30% to 50%.3,4 Early therapeutic or lifestyle interventions can now reliably be offered to individuals early in the course of their disease, with the help of the recent FRAX® assessment tool,5 which incorporates clinical risk factors in combination with bone mineral density (BMD) to predict absolute fracture risk. However, despite these improvements, actual fracture risk reduction may fall short of expectations due to nonadherence with treatment.

Nonadherence—prevalence and impact on fracture risk

In common with other chronic diseases, osteoporosis suffers from nonadherence.6,7 The majority of patients stop taking their antiosteoporotic treatment within the first 3 months; thereafter, adherence gradually falls to a rate of 44% to 65% at 1 year (Figure 1).8-10 At 2 years, just over a quarter of patients remain highly compliant, as defined by a means possession ratio (MPR) of over 80%. Since adherence rates in trials are typically above this level, only around a quarter of patients will realistically achieve the antifracture efficacy published in these initial trials. In these randomized control trials (RCTs), high adherence was possible by selecting motivated participants, giving frequent reminders of medication instructions and use, and by frequent contacts with health providers: conditions rarely encountered in practice. Large observational studies from the US and UK have shown that no benefit is observed with poor adherence rates of 50% or less.11,12 Above this rate, benefit gradually increases with compliance, reaching statistical significance at rates above 75% (Figure 2). Nonadherence is associated with an increase in fracture risk (21%) compared with the high-adherence group. The basis of these poorer outcomes has been shown to be due to less reduction in bone resorption13 and poorer gains in BMD.14

Reasons for nonadherence of antiosteoporotic treatments

There are many reasons why patients stop their medication (Table I). Clearly, it is challenging to address them preemptively in the initial consultation, but by encouraging greater patient involvement in their treatment plan, adherence can be improved and the patient will be more inclined to openly discuss some of these issues in subsequent meetings. Qualitative observational studies have identified several factors contributing to treatment nonadherence that are categorized into medication-related factors, patient factors, and factors related to the doctor-patient relationship.3,15 The most common reason by far is, however, medication-related factors, specifically side effects.

Figure 1
Figure 1. Cumulative compliance rate over a 5-year follow-up.

Compliance is measured by means possession ratio, which is defined as the duration of prescription refills that covers up to the period of follow-up of interest. Red line = mean compliance level; gray lines = first and third quartiles.
Modified from reference 10: Huybrechts KF, Ishak KJ, Caro JJ. Bone. 2006;38:922-928. Copyright © 2006, Elsevier Inc.

Figure 2
Figure 2. Relative risk of osteoporotic fractures as a function of compliance rate.

The solid line represents the linear regression relationship across different levels
of compliance from about 30% to 100%.
Modified from reference 12: Gallagher AM, Rietbrock S, Olson M, van Staa TP. J Bone Miner Res. 2008;23:1569-1575. Copyright © 2008, American Society for Bone and Mineral Research.

Table I
Table I. Factors affecting oral antiosteoporotic treatment adherence.

Based on references 3 and 15.

1) Medication-related factors: adverse effects (Table II)
_Bisphosphonates
Experience with alendronate over the last decade has shown this commonly prescribed bisphosphonate to be well tolerated. In all the bisphosphonate trials, the overall tolerability of this class of treatment is similar when compared with placebo.16-21 Upper gastrointestinal symptoms, in particular, occur at similar rates in both treatment and placebo groups, provided strict administration instructions are followed: taking the tablet on an empty stomach in the morning with at least 8 fl oz of water and remaining upright for the next 30 minutes.

Nevertheless, postmarketing surveillance reveals the most common reason for nonadherence is upper gastrointestinal symptoms.22 Often, this has been shown to be due to a failure to adhere to the strict administration instructions. The most common mistakes are an inadequate duration of fasting leading to poor gastric absorption, an inadequate correct upright posture duration, and an inadequate ingestion of water with the tablet. These strict instructions pose significant adherence challenges, but these remain necessary to minimize the local irritant effect of the tablet on the mucosa and for optimal gastric absorption.

Despite taking the medication appropriately, up to 46% of patients on oral bisphosphonates still complain of gastrointestinal symptoms.16 This rate is observed in the large Fracture Intervention Trial (FIT), where patients with preexisting upper gastrointestinal symptoms were included for the study. An almost identical rate is also observed in the placebo group suggesting that this merely reflects the background prevalence of upper gastrointestinal symptoms in the elderly, where nonsteroidal antiinflammatory drug use is common and contributory. Smaller studies with different inclusion criteria reported lesser rates of upper gastrointestinal symptoms, but all show rates that are statistically no different to those in the placebo group. Gastrointestinal symptoms, such as heartburn and dyspepsia, are generally mild, with only 2% of cases severe enough to lead to treatment withdrawal.16 Nonetheless, heightened awareness and vigilance may result in early withdrawal of the bisphosphonate in some cases. Interestingly, a multicenter, double-blind clinical trial that rechallenged these patients at a later date showed a recurrence in the rate of gastrointestinal symptoms no different to that of a placebo.23 It is not clear if the lack of difference versus placebo is a real effect or due to a highly motivated, selected healthy population. In a systematic review of RCTs, other common side effects of alendronate include back pain and headache,21 with the former occurring in 10% of the treatment group versus 3%in the placebo group in one study.2425 Very rare side effects occurring in less than 1 in 10 000 people include Stevens-Johnson syndrome and osteonecrosis of the jaw. The latter has attracted considerable public attention.

Table II
Table II. List of common oral antiosteoporotic treatments and their adverse effects.

Abbreviations: DRESS, Drug Reaction with Eosinophilia and Systemic Symptoms; GI, gastrointestinal.

Osteonecrosis of the jaw is defined as the presence of exposed bone in the mouth which fails to heal despite appropriate treatment within 8 weeks.26,27 First described in 2003, bisphosphonate-related osteonecrosis of the jaw is largely confined to oncology patients who have received large cumulative doses of intravenous bisphosphonates. In these patients, an overall prevalence of 5% is observed in those treated for breast cancer, myeloma, or prostate cancer.26 It is believed that underlying malignancy predisposes patients to the condition, which is made even more likely by risk factors such as tooth extraction, periodontal disease, and infection.28 When intravenous zoledronate was used to treat osteoporosis in the Health Outcomes and Reduced Incidence with Zoledronic Acid ONce yearly (HORIZON) trial, only 2 out of 7736 women developed osteonecrosis of the jaw; one in the treatment group and one in the placebo arm, both of whom responded with standard therapy for the condition.29

In sharp contrast, oral bisphosphonates at the doses used in osteoporosis are associated with a far lower prevalence rate. A large German registry study has estimated a prevalence rate of 0.00038%, or less than 1 in 100 000 patientyears; a figure supported by postmarketing surveys.27,30 There is no evidence that this rate is any higher than the background population rate of spontaneous osteonecrosis of the jaw. A postal survey in Australia has recently shown a rate of 0.01% to 0.04%, but lack of adjudication of the diagnosis suggests these data need to be treated with caution.31 No specific preventative measures have been advocated by consensus, but it is reasonable to suggest the maintenance of good dental hygiene in all patients. It is clear that the benefit, in terms of fracture prevention, of oral bisphosphonates far outweighs the risk of this much overrated complication. However, it can be hard to change patients’ perceptions of risk with statistics.

_ Strontium ranelate
Strontium ranelate, which was licensed and marketed in 2004, has been shown to have significant vertebral and nonvertebral fracture protection in two large trials (SOTI32 and TROPOS33), by virtue of its anabolic and antiresorptive properties. The overall incidence of side effects did not differ significantly from placebo, although diarrhea statistically increased in the treatment group in pooled data (6.5% versus 4.6% in placebo; relative risk [RR], 1.41; 95% confidence interval [CI], 1.15-1.72; P=0.0008).34,35 These symptoms are mild and transient—occurring for up to 3 months—and did not subsequently lead to significant treatment withdrawal in the trials. Other reported side effects from pool analyses include venous thromboembolism and a transient elevation in creatinine kinase (RR, 1.42; 95% CI, 1.02-1.98; P=0.036; and RR, 1.68; 95% CI, 1.52-1.85; P<0.00001, respectively). The pathophysiology of these effects are uncertain. Common reasons for stopping strontium ranelate include nausea, diarrhea, headaches, and skin reactions, which are sufficiently troublesome in 2.4%, 1.8%, 0.5%, and 0.1% of patients, respectively, although these rates are statistically no different to those of the placebo group.34 Hypersensitivity reactions that have been reported range from mild rash and pruritus to urticaria and angioedema, and, very rarely, the full Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) syndrome.25,36 DRESS syndrome is a triad of rash, systemic symptoms, and significant eosinophilia occurring within 3 to 6 weeks of initiating treatment.36 In a European Medicine Agency (EMEA) report in 2007,37 only 16 strontium ranelate–related cases had been identified following a total of 570 000 patient-years of exposure worldwide. However, the mortality associated with this syndrome has led the EMEA to advise stopping strontium ranelate if a rash develops and to seek medical attention. Mild, isolated rashes without systemic symptoms are nevertheless common in the community, with a prevalence rate of 4.2% in a recent retrospective chart review of patients on strontium ranelate for up to 2 years’ duration.36 In the very rare instances of DRESS syndrome occurring whilst on strontium ranelate, it is safest to withdraw this treatment for that patient indefinitely.

_ Raloxifene
This selective estrogen receptor modulator (SERM) was the first of its kind for the prevention of fractures in osteoporosis. It is known to exert an estrogenic effect on bone and lipid metabolism, whilst acting as an estrogen antagonist on the breast and uterus. Increases in BMD were demonstrated at vertebral and nonvertebral sites, but antifracture efficacy is only evident in the vertebrae (RR, 0.64; 95% CI, 0.54-0.78).4

As such, its role is adjunctive in osteoporosis treatment. The Multiple Outcomes of Raloxifene Evaluation (MORE) study38 revealed that venous thromboembolism (VTE) is the only serious adverse effect, occurring up to 3 times more often when compared to placebo (RR, 1.78; 95% CI, 0.99-3.19) at a median of 40 months’ follow-up, similar in frequency to the rate observed in hormone replacement therapy (HRT). Hot flushes and leg cramps occur significantly more frequently with raloxifene than placebo (24.6% versus 18.3%; and 5.5% versus 1.9%, respectively). Nevertheless, these side effects were mild and did not lead to treatment withdrawal. On the other hand, the risk of developing all types of breast cancer is significantly reduced compared with placebo (RR, 0.38; 95% CI, 0.24-0.58), with no risk of endometrial pathology demonstrated. The role of raloxifene in cardiovascular protection is as yet unproven.

_ Hormone replacement therapy
In addition to relieving postmenopausal vasomotor symptoms such as hot flushes, hormone replacement therapy in the form of estrogen and combined estrogen and progestin has been shown to reduce the risk of developing vertebral and nonvertebral fragility fractures by approximately 25% to 40% in observational and randomized studies, such as the Women’s Health Initiative (WHI) trial.39-41 These positive effects are, however, offset by an increased overall mortality rate due to an increase in the rate of coronary heart disease, stroke, pulmonary embolism, and breast cancer, particularly in women taking the drug well after the menopause. These risks outweigh any benefits gained from fracture reduction, regardless of the severity of the osteoporosis. With the availability of other antiosteoporotic treatments conferring similar antifracture efficacy, hormone replacement therapy should perhaps only be considered in postmenopausal women with osteoporosis and vasomotor symptoms, who benefit symptomatically.

Tibolone, a selective tissue estrogen activity regulator (STEAR), has been known to have beneficial estrogenic effects on bone and menopausal symptoms. Recently, the Long-term Intervention on Fractures with Tibolone (LIFT) trial, a large RCT of 4538 postmenopausal women aged 60- 85, reaffirmed this, showing antifracture efficacy similar to other established antiosteoporosis treatments at both vertebral and nonvertebral sites.42 However, this study did not show any significant protection against hip fractures (relative hazard, 0.72; 95% CI, 0.32-1.63). Furthermore, although tibolone is not associated with cardiovascular or thromboembolic risks, the risk of developing stroke doubled at a median of 34 months’ follow-up, which would restrict its use to ideally postmenopausal women with no risk factors for stroke. There is a possible protective effect against colon cancer and breast cancer, although later studies have shown conflicting results and the mechanisms involved remain unclear.

2) Medication-related factors: dose frequency and administration preferences
There is ample evidence to suggest that patients find it a challenge to adhere to the strict administration instructions of bisphosphonates and, given a choice, most would prefer a weekly to a daily dosing regime in order to minimize disruptions to their daily routines.43,44 It follows that less frequently taken oral formulations of bisphosphonates, such as ibandronate, might be expected to improve overall compliance. This notion that patients always prefer less frequent dosing has been refuted in a recent questionnaire-based population study that showed that patients value simplicity and ease of administration above dosing frequency.45 Just under half (45%) of the respondents would opt for a daily regime, such as that based on strontium ranelate, provided they could forego the strict instructions required of them by weekly and monthly bisphosphonates (opted for by 20% and 30%, respectively). The highest preference for daily dosing is found among those already on daily medication for other unrelated conditions. This is in keeping with the findings of a focus group study that showed that once a patient is able to adapt the dosing into their daily routine in a systematic fashion, it becomes easier to take the medication every day rather than once weekly.15 Furthermore, in a survey assessing patient preference for ibandronate or alendronate, most patients would prefer the latter, citing effectiveness as the most important factor above dosing procedure and dosage frequency.46

In a small study of treatment-naïve osteoporotic patients, 65% prefer an annual infusion over oral weekly bisphosphonates.47 These patients tend to have a poor health status with a perceived high risk of fracture and the desire to avoid prescription drugs altogether. As suggested by the authors, this might be due to the view that an infusion theoretically offers superior efficacy compared with the oral formulation. This finding emphasizes the importance of involving patients in treatment decision-making and of discussing the risks and benefits of their chosen treatment. Further studies are required to see if patients on IV bisphosphonates continue to adhere to their annual infusion regimes beyond 2 to 3 years.

The adherence rates for antiosteoporotic treatment gradually decline after the first few months, regardless of daily or weekly administration or the tolerability of the medication.8,48 Pharmacokinetics only partially explain this trend. This has led to a growing body of evidence that consistently shows that patients themselves and their interaction with their doctors play an integral, if not an equally important, role in adherence.

3) Patient factors: belief in diagnosis and treatment
Denial about their illness, lack of knowledge about osteoporosis, patients’ own views on how best they ought to be treated, and their perceptions of the appropriateness and risk-benefit judgment of initiating and continuing treatment are just some of the barriers to adherence.3,15 Being asymptomatic, many osteoporotic patients consider themselves in relatively good health, and the concept of future risk of developing fractures may be hard to grasp, although visual and objective tools, such as a FRAX score and DXA scan report, can help convey this message. Patient motivation and interest usually arise from a personal or family history of fractures or the fear of developing debilitating fractures in the future.15 Age and educational levels cannot be used to predict adherence, one way or another.

The reason why the biggest drop in adherence occurs within the first month of treatment (Figure 1) is that some patients do not even start their medication. A patient may not be ready to initiate treatment unless all lifestyle changes have been exhausted, and until a sufficient ‘watch and wait’ period has elapsed to convince them of the persistence of the disease. A clear discussion on the diagnostic process and a realistic outlook on the risk of nontreatment, together with better information on treatment options, will help to address these issues.

A distrust of all “artificial” medication is a common issue in many countries—the view that it is not good if it is not natural. This may arise from previous negative personal experiences or anecdotal reports from friends or family members or, indeed, from negative publicity in the media. The long list of side effects in the product leaflets have instilled many an anxiety, particularly among the risk-averse. Again, reassuring advice and knowledge about the prevalence and severity of side effects will allay many of these unfounded fears in some, but not all. In most cases, the benefits of treatment far outweigh the risks associated with antiosteoporotic medication.

4) The doctor-patient relationship: trust, quality of care, and follow-up monitoring
The importance of the doctor-patient relationship as a framework for the treatment process discussed above cannot be overemphasized. The quality of care and trust fostered are arguably critical and key to adherence. Impartiality, the ability to listen and address the patient’s concerns, and sound practical advice are valued characteristics of a good consultation. Like all treatment in medicine, the treatment of osteoporosis involves making value judgements and elements of uncertainty, which can be shared with patients who wish to estimate the risk-benefit ratio of their treatment choices for themselves.

Polypharmacy patients with multiple comorbidities appreciate practical advice on issues concerning dosage instructions, such as timing and possible interactions of their medications. Wherever possible, dosing should be tailored to suit a patient’s lifestyle and routine to facilitate adherence. Nevertheless, at times, switching medications may become necessary.

As both the diagnosis and treatment benefit may not be apparent to the patient, regular feedback about progress is desirable to encourage continuation of treatment. BMD has been shown to positively influence adherence,49,50 but the results of feedback regarding biochemical markers of bone turnover are more complex. An improvement in levels of resorption markers (reduction) positively reinforced adherence, but a lack of improvement in these markers may worsen adherence in an already adherent patient.51

Table III
Table III. Strategies to improve adherence.

Abbreviations: DXA, dual-energy x-ray absorptiometry. After reference 52: Osterberg L, Blaschke T. N Engl J Med. 2005;353:487-497.
Copyright © 2005, Massachusetts Medical Society.

The primary care family physician offers various aspects of medical care, and it is considered good practice to involve and update them on a patient’s treatment plan. Local and regional support groups are helpful sources of peer advice, with regular informal meets and talks. For the patient, a proactive approach is always to be encouraged in these activities (Table III).52 In some centers, the specialist nurse and pharmacist offer valuable advice and support to the overall care of the patient. Since most instances of nonadherence occur within the first few months of starting treatment, nurse-led telephone monitoring at 3 months, for example, could help address any patient concerns and promote adherence in the long term.53,54 This is increasingly being done in osteoporotic clinics where patients may not normally be seen for at least a year.

Summary

Good antifracture treatment efficacy requires adherence, which is often suboptimal. The most common reason for nonadherence is real or perceived intolerance to the medication. Although dosage frequency plays a significant role, pharmacokinetics is but one of many barriers to adherence. Patient- related factors are an important consideration, but a good doctor-patient relationship with clear communication can enable patients to make more-informed choices when deciding their treatment. It is possible to improve adherence, but a multimodal approach is needed to achieve this aim. _

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