How can we convince osteoporotic patients to take their treatment?

MBBCh (Wits), FRACP (NZ)
Johannesburg SOUTH AFRICA

How can we convince osteoporotic patients to take their treatment?

by S. Lipschitz, South Africa

Osteoporosis is a common disease with serious consequences as osteoporotic fractures are associated with increased morbidity and mortality. Although there are several treatment options available to reduce the risk of fracture, there are barriers preventing ideal patient management, which include lack of awareness of the disease and its consequences, underdiagnosis of those at risk of fracture, and lack of compliance and persistence with therapy. This paper attempts to identify these barriers to ideal patient management, in particular those causing poor compliance and persistence with therapy in those patients at increased risk of fracture. A better understanding of the reasons for poor compliance allows the development of an intervention strategy to improve compliance. Better compliance and persistence with therapy improve clinical outcomes. Various intervention strategies are discussed in this paper, including improved diagnosis of osteoporosis in at risk populations, improved patient education on the disease, the interpretation of dual-energy x-ray absorptiometry (DXA) scans, the interpretation of fracture risk, the consequences of fracture, and the benefits and risks related to specific drug treatments. Communication with patients is not ideal and many patients do not take their medication because they are not informed about osteoporosis, because they are not aware of their risk of fracture, and because they are ill-informed of the risks associated with medication. It is ultimately the responsibility of the doctor to improve compliance. Open and honest communication, sometimes assisted by specialized patient compliance programs, has proven to be the most effective tool in improving patient compliance and persistence with medication.

Medicographia. 2014;36:197-203 (see French abstract on page 203)

Osteoporosis is defined by the World Health Organization as “a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility and susceptibility to fracture.”1 It is estimated that 1 in 2 women and 1 in 5 men over the age of 50 years will sustain a fragility fracture in her/his lifetime.2 The common sites of osteoporotic fractures are the wrist, spine, and hip.

There are several treatment options available for fracture prevention, including hormone therapy, selective estrogen receptor modulators (SERMs), oral or intravenous bisphosphonates, strontium ranelate, denosumab, and human parathyroid hormone (hPTH). Despite this wealth of efficacious treatment, several problems have been identified which serve as major barriers to the goal of achieving adequate fracture prevention in at-risk patients. These include lack of awareness by doctors and patients, under-diagnosis even in patients who have had a fracture, underestimation of fracture risk, and fear by doctors and patients of the perceived risks of treatment. The outcome is nonadherence to therapy and the consequences thereof. Compliance is the extent to which a patient’s behaviour coincides with medical advice. Good compliance is assumed when the patient takes >80% of the prescribed medication. Adherence is defined as compliance plus persistence, where compliance is the percentage of pills taken over a prescribed period, and persistence is the time from initiation to discontinuation of treatment.

Lack of awareness – lack of
diagnosis – lack of adequate
assessment of fracture risk

In order to convince patients to take their treatment, it is first necessary to identify those at risk of fracture, and in this regard major problems persist, with a lack of awareness from doctors and patients alike. The importance of clinical risk factors and prevalent vertebral fractures as part of fracture risk assessment has been clearly established. Yet, in clinical practice these risks are often ignored and the focus is often only on the dual-energy x-ray absorptiometry (DXA) scan. The reason for this may relate to the fact that the DXA scan is often interpreted by nonclinicians and this interpretation is often made without knowledge of clinical risk factors.

The IMPACT study (Improving the Measurements of Persistence on ACtonel Treatment) identified newly diagnosed patients who underwent routine spinal radiography as part of their initial assessment. Images were analyzed by local radiologists and subsequently by study radiologists. False negative rates (missed fractures at local assessment) were 29.5% in Europe/South Africa/Australia, 45.2% in North America, and 46.5% in Central and South America.3 A Bone and Joint Decade/International Osteoporosis Foundation (IOF) survey of more than 3000 orthopedic surgeons in France, Germany, Italy, Spain, the UK, and New Zealand found that orthopedic surgeons often failed to recognize osteoporosis as a cause of fracture and were inconsistent in providing appropriate treatment and referral.4 A retrospective analysis of routine chest x-rays in 934 women aged 60 years and older, hospitalized for various reasons, identified 132 (14.1%) patients with moderate- to-severe vertebral fractures. Of these, 52% were mentioned in the radiology report, 23% were mentioned in the case summary, 17% were mentioned in the medical record, and only 7% received treatment for osteoporosis.5 In a study on 762 postmenopausal white women, the incidence of vertebral fracture was noted to increase with age, from 11.05% at age 55 years, 14.65% at age 65 years, 31.5% at age 75 years, 52.45% at 86 years, to 75% at age 95 years.6 Identifying vertebral fractures should, therefore, be an integral part of the initial patient assessment.

Table I
Table I. Adverse reactions associated with antiosteoporotic medication.

After reference 10: Reginster et al. Expert Opin Drug Saf. 2013;12:507-522. © 2013, Informa UK

An incident fracture is clearly a major and independent risk factor for future fracture. The presence of a vertebral fracture is shown to increase the odds ratio of a future wrist fracture by 1.4, vertebral fracture by 4.4, and hip fracture by 2.3.7 The greater the number of incident fractures, the greater the risk, as was shown in the Study of Osteoporotic Fractures, where the odds ratio of a new fracture rose from 3 for those with one incident fracture to 5.2 and 10.5 for those with two and three or more fractures, respectively.8 Incident vertebral fractures predict the risk of future fractures, independent of bone mineral density (BMD), and without a routine “vertebral fracture assessment” this risk factor is missed. Wainwright et al examined 8065 women and identified 243 fractures, 54% of whom did not satisfy BMD criteria for the diagnosis of osteoporosis.9

Table II
Table II. Risks associated with antiosteoporotic medication.

Abbreviations: DRESS, drug rash with eosinophilia and systemic symptoms; FREEDOM, Fracture REduction Evaluation of Denosumb in Osteoporosis every 6 Months; GORD, gastroesophageal reflux disease; HR, hazard ratio; MI, myocardial infarction; ONJ, osteonecrosis of the jaw; OR, odds ratio; SERM, selective estrogen receptor modulator; RR, relative risk; VTE, venous thromboembolism.
After reference 10: Reginster et al. Expert Opin Drug Saf. 2013;12:507-522. © 2013, Informa UK Limited.

Fear by patients and doctors of perceived risks of medication

The risks relating to treatment are often misunderstood and overemphasized partly due to misinformation perpetrated by the popular press and/or the internet. It is essential that these risks be properly quantified and interpreted in relation to the risk of not taking appropriate medication. A detailed overview of the risks relating to the most common registered drugs used in osteoporosis is beyond the scope of this paper but has been extensively reviewed (Tables I and II).10

The antifracture efficacy of a variety of treatments has been studied in multiple randomized placebo-controlled clinical studies. All of them have been shown to reduce the risk of vertebral fracture (bisphosphonates, hormone therapy, teriparatide, SERMs, strontium ranelate, and denosumab), and some of them have been shown to reduce the risk of nonvertebral fracture (bisphosphonates, hormone therapy, teriparatide, strontium ranelate, and denosumab) and the risk of hip fracture (bisphosphonates, strontium ranelate, and denosumab).11 In patients at risk of fracture, the risk of the disease is far greater than any risk associated with medication.

The consequences of the failure of doctors to treat high-risk patients and/or the failure of high-risk patients to adhere to medication for whatever reason are clear. From the patients’ perspective there are many possible causes of nonadherence, including side effects (real or perceived), complicated dosing regimens, and a lack of knowledge and insight of the disease and its complications.12

Consequences of nonadherence – benefits of

Whatever the cause, nonadherence is common and the consequences of nonadherence cannot be underestimated. Complicated dosing regimens have been implicated as a cause of nonadherence and some studies do show that patients find weekly alendronate dosing preferable to daily dosing, with a resulting concomitant improvement in adherence.13,14 However, even with weekly dosing, adherence remains poor.15 Data from a large geographically diverse managed care plan shows persistence curves for daily and weekly alendronate rapidly declining over the first 3 months, followed by a slower, but consistent, decline over the rest of the 12-month period. The mean time to discontinuation was 2.44 months and 2.55 months for daily and weekly dosing, respectively.16 Weycker et al studied 18 822 women, 48% of whom initiated bisphosphonate therapy.17 The risk of adherence failure was 47% at 3 months, 70% at 1 year, and 84% at 3 years, and the risk of persistence failure was 47% and 77% at 1 and 3 years, respectively.

Compliance with weekly bisphosphonate treatment was no better that with daily dosing. Compliance and persistence with medication are associated with fracture prevention. Siris et al18 collected data on 35 537 women aged 45 years and older who received a bisphospho- nate prescription. Of these patients, 43% were refill compliant and 20% persisted with bisphosphonates throughout the 24-month study period. Total vertebral, nonvertebral, and hip fractures were significantly lower in the refill-compliant and persistent patients, with relative risks of 20% and 45%, respectively. A progressive relation was seen between refill compliance and risk reduction, commencing at a compliance of about 50% and becoming more significant at compliance rates of 75% and over.

A study reviewing health data from the files of 11 249 women with osteoporosis (mean age 68.4 years) from Saskatchewan in Canada, with an average follow-up of 2 years between 1996 and 2001, showed an overall fracture rate of 4.5% per year. At compliance rates of 80% or more, the fracture rate was 16% lower.19

A large study from 1999-2004 identified 14 760 new female bisphosphonate users. A total of 387 fractures were recorded. Increased duration of compliant bisphosphonate use was associated with a reduction in fracture risk. When compared with less than 1 year of compliance, 1 to 2 years of compliance was associated with a 12% reduction in fracture risk, and 3 to 4 years with a 46% reduction in risk. Paradoxically, 5 to 6 years of compliant bisphosphonate use was no longer associated with a reduction in fracture risk.20 This may strengthen the case for discontinuing bisphosphonates after 4 or 5 years of continued use.

Huybrechts et al studied more than 35 000 women with postmenopausal osteoporosis who received a prescription for a bisphosphonate, and found that low compliance was associated with a 31% increase in fracture risk and 47% higher hospitalization rates.21

Penning-van Beest et al showed, in 8822 female bisphosphonate users, that compliance of <20% was associated with an 80% increase in the risk of fracture when compared with subjects with >90% compliance.22

Practical approach to convince patients to adhere
to osteoporotic treatments

The problem of nonadherence is particularly evident in chronic and asymptomatic diseases—including osteoporosis—and this poses a major problem to the treating practitioner. For the asymptomatic patient the perceived threat (without full education) will not motivate adherence. Furthermore, the risk of nonadherence increases with duration of therapy, a particular problem in diseases such as osteoporosis, where the actual threat to the patient may be several years down the line.23 In addition, for whatever reason, patients are often more fearful of the threat of the medication than the threat of the disease. When attempting to define a strategy to reduce nonadherence, it is useful to try to understand the factors that are associated with nonadherence. In a large osteoporosis registry review study, the factors likely to improve adherence were increased age and the presence of an incidental nonvertebral fracture, whereas the factors associated with reduced adherence were related to the use of alendronate as opposed to etidronate.24 In a telesurvey of >950 women,25 the factors associated with reduced adherence included having experienced an adverse event to a medication and perceptions regarding the bone densitometry result. Women who believed that bone density did not show osteoporosis and women who were unsure of the result were 1.6 times more likely to be nonadherent. Women who were “somewhat bothered” by adverse events were 4 times more likely to be nonadherent, and women who were “very or extremely bothered” by adverse events were 25 times more likely to be nonadherent. Other studies have identified predictors of poor adherence to be benzodiazepine use, use of gastroprotective medication, and unavailability of bone densitometry.26 Predictors of improved adherence were found to include early menopause, osteoporosis on bone densitometry, family history of osteoporosis, presence of a vertebral fracture, use of glucocorticoid medication, and use of nonsteroidal anti-inflammatory medication,26 as well as younger age, previous fracture, fracture after initiating treatment, fewer comorbidities, using fewer osteoporosis medication combinations, and nursing home residence.27 Applying this information to the clinical setting, several strategies may improve compliance and adherence:

Improving the diagnosis of osteoporosis at population level has been addressed with varying success by such bodies as IOF, NOF (National Osteoporosis Foundation [USA]), NOFSA (National Osteoporosis Foundation of South Africa), and various other national bodies. At the individual doctor/practitioner level, diagnosis can be improved using appropriate DXA screening (European guidelines,11 South African guidelines35). Assessment of fracture risk should be performed for each patient. The NOFSA fracture risk algorithm,25 and the FRAX® fracture risk assessment tool can easily and rapidly be applied in day-to-day practice. FRAX® was developed by the World Health Organization, who recognized that clinical risk factors increase the risk of fractures independently of BMD and that the risk of fracture increased with the number of risk factors.36 This tool integrates the risk associated with clinical risk factors (identified from meta-analyses of large epidemiological studies) as well as BMD at the femoral neck, to calculate the 10-year probability of fractures for men and women. The FRAX® score improves the prediction of future fractures; however, the intervention thresholds derived are dependent on epidemiological and health economic data and are, therefore, country specific. FRAX® does, however, have a number of limitations, which should be taken into account when assessing individual risk. These include: no assessment of dose-response (number of incident fractures, severity of incident fractures, dose and duration of glucocorticoid exposure, smoking, alcohol),11 as well as no assessment of falls risk, vitamin D status, and bone turnover markers.

A patient who is aware of the potential complications of osteoporosis is more likely to be compliant. In practice, visual aids such as macroscopic and microscopic pictures/photographs of normal and osteoporotic bone, x-rays of wrist, hip, vertebral, and other osteoporotic fractures, and photographs of severe kyphosis can be used to enhance full understanding. Microscopic pictures of bone assist with the understanding of the importance of bone mass and bone quality. The patient should be made aware that bone loss, as seen in osteoporosis, is associated with qualitative and quantitative impairment of bone, and that the consequences of this are fractures. The effects of fractures on morbidity37,38,39 and mortality40,41 can be highlighted.

Specifically designed patient support programs may also be of assistance in this regard. An unpublished analysis (done in South Africa) of patient compliance with osteoporotic treatment, compared patients enrolled on a patient support program with patients not on any support program(control group). The aim of the support program was to improve compliance in patients taking osteoporotic treatment. The patient support program included education regarding the disease and the treatment, with the aim of improving compliance and persistence. A total of 2791 patients completed the program over a period of 13 months. In the control group, 40% of patients failed to fill their repeat prescription after month 1. This noncompliance was reduced by 20% in the intervention group. Patients enrolled on the patient support program achieved compliance rates (measured from the day of enrolment on the program until completion of the program) of >90% on a month-to-month basis, compared with patients who were not on a patient support program, where compliance rates averaged 55%. In this study, patient education and support was shown to significantly improve compliance and persistence to treatment.


Patient-doctor communication clearly affects patients’ acceptance of their disease and compliance and persistence with their medication. Up to 51% of women do not recall anything being said to them about osteoporosis at the time of diagnosis, and 20% to 30% of patients cannot recall receiving proper instructions on taking their osteoporosis medication. So, what is communicated and how it is communicated will clearly have a major effect on whether patients take their medication and whether they benefit from the process. There are numerous challenges facing doctors attempting to educate patients. These include not frightening them excessively, while at the same time frightening them sufficiently to be appropriately concerned, empowering the patients to take control of, and accept responsibility for, their illness, and coping with multiple sources of misinformation (magazines, internet, and women’s groups).

At the time of diagnosis a considerable effort should be put into educating patients as described above. Patients should be encouraged to ask questions about the disease and the treatment of the disease. They should be offered treatment based on their specific profile. Where possible, more than one option should be offered and the patients should be involved in selecting the best option for themselves. Possible adverse events should be explained in detail and put into context (risk of disease versus risk of drug). A first follow-up visit should take place after 3 months to discuss whether the patients are taking the drug, whether they are taking it correctly, whether they are happy to continue, and whether they have experienced any side effects. At this visit the patients should be reeducated as necessary, and the importance of compliance and persistence should be reemphasized. In patients deemed “high risk” bone markers may be of assistance.

At year 1, a repeat bone densitometry is useful, as an increase such as that seen in patients using strontium ranelate, denosumab, and teriparatide is an extremely strong motivator for continued compliance. Patients taking bisphosphonates, hormone therapy, and SERMs should be informed that maintenance of bone density is the aim of treatment in order to avoid disappointment and inappropriate discontinuation of medication when they fail to see “improvement.” In problem patients, bone markers may once again be of assistance. Most importantly, time should be spent with the patients, explaining and reexplaining—as necessary—about the disease, the complications, and the drug therapy. Adherence is an issue and it is the responsibility of the treating clinician to improve it. ■

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Keywords: compliance; fracture; medication; non-adherence; non-compliance; osteoporosis; persistence