Patient treatment preferences for osteoporosis

Authors

  • Liana Fraenkel,

    Corresponding author
    1. VA Connecticut Healthcare System, West Haven, and Yale University School of Medicine, New Haven, Connecticut
    • Yale University School of Medicine, Section of Rheumatology, 300 Cedar Street, TAC#525, PO Box 208031, New Haven, CT 06520-8031
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  • Barbara Gulanski,

    1. VA Connecticut Healthcare System, West Haven, and Yale University School of Medicine, New Haven, Connecticut
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  • Dick Wittink

    1. VA Connecticut Healthcare System, West Haven, and Yale University School of Medicine, New Haven, Connecticut
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    • Dr. Wittink is deceased.


Abstract

Objective

To examine patient preferences for currently available and promising osteoporosis treatment options.

Methods

We recruited patients who had recently (within 2 weeks) undergone bone densitometry and were found to have osteoporosis. Consenting participants completed an Adaptive Conjoint Analysis questionnaire to determine their treatment preferences for oral bisphosphonates taken once per week, intravenous bisphosphonates administered every 3 months, intravenous bisphosphonates administered once per year, and subcutaneous recombinant human parathyroid hormone (rhPTH). We performed simulations based on respondents' values for route of administration, absolute reduction in risk of vertebral and hip fractures over 5 years, and risk of adverse effects to predict each respondent's treatment choice.

Results

The study sample included 201 women and 11 men (median age 73). Patients' treatment preferences were strongly influenced by route of administration. Patients' preferred treatment option, across all simulations, was bisphosphonates. Among 80 treatment-naive participants, 52 (65%) preferred an annual infusion over oral weekly bisphosphonates. Participants with poorer perceived health status, those with a high perceived risk of future fracture, and participants preferring to treat health problems without doctors or prescription drugs were more likely to prefer an annual infusion over weekly pills.

Conclusion

Patient preferences for osteoporosis treatment options are strongly influenced by route of administration. Therefore, despite the added benefits of rhPTH, patients' preferred treatment option for osteoporosis is bisphosphonates. Among those preferring bisphosphonates, many preferred annual infusions over weekly oral medications, emphasizing the need to incorporate individual patient preferences into treatment decisions for osteoporosis. The latter is especially important given the poor rates of long-term adherence to osteoporosis medications.

INTRODUCTION

In the US today, 10 million Americans have osteoporosis, and 50% of women and 25% of men will have an osteoporotic fracture their lifetime (1). The estimated national direct expenditure for osteoporotic fractures is more than 47 million dollars per day. More importantly, osteoporotic fractures result in significant functional impairment, decreased quality of life, and increased mortality (2). The impact of this major public health problem is expected to increase exponentially as the population ages.

Measures used to reduce bone loss, including calcium and vitamin D supplementation, regular weight-bearing exercise, and avoidance of tobacco and excessive alcohol, have essentially no risk and are generally recommended for all patients. Currently available prescription medications to treat osteoporosis include bisphosphonates, calcitonin, hormonal replacement therapy, raloxifene, and teriparatide (recombinant human parathyroid hormone [rhPTH]). Results from the Women's Health Initiative, however, raise concerns regarding the long-term use of hormonal replacement therapy as a first-line agent for treatment of osteoporosis (2). Similarly, the role of raloxifene will be better elucidated when results from the Study of Tamoxifen and Raloxifene and the Raloxifene Use for the Heart trials are available.

Alendronate and risedronate are 2 oral bisphosphonates approved by the Food and Drug Administration for the treatment of osteoporosis that are now available as a single tablet taken once weekly. Both have been shown to decrease the risk of vertebral and hip fractures in large randomized controlled trials (3–5). Ibandronate, a monthly oral bisphosphonate, has also recently been approved for the treatment of osteoporosis. Intravenous bisphosphonates administered every 3 months decrease bone loss, but data demonstrating their ability to decrease fracture rates are lacking (6, 7). Zoledronic acid, a more potent intravenous bisphosphonate approved for the treatment of malignant hypercalcemia, was recently shown to have the same effect on bone turnover and bone density as oral bisphosphonates when administered once yearly (8).

Unlike the antiresorptive agents, rhPTH exerts its protective effect in part by stimulating bone growth. Despite producing increased bone turnover rates, rhPTH increases bone mineral density and decreases the risk of osteoporotic fractures by ∼60% (9). Potential drawbacks associated with rhPTH include its route of administration (daily subcutaneous injections), high cost, and unknown long-term safety profile.

Because of the number of persons affected, the public health impact of treating osteoporosis is enormous. However, at the individual patient level, many patients will not derive any benefit from treatment. For example, if 100 women age 75 years with osteoporosis all took alendronate, assuming their 10-year probability of sustaining a hip fracture is 22% (10), 11 fractures would be prevented and 11 fractures would occur despite treatment. Thus, of 100 women receiving treatment, 89 derive no benefit (11).

Each patient's preference for treatment will therefore depend on how he or she weighs the risk of future morbidity and possible mortality over the uncertain risk of long-term toxicity, bothersome adverse effects, and costs related to treatment. Consequently, treatment decisions should be based on physician expertise and explicitly derived patient preferences. This process of decision making not only adheres to the principles of informed consent and patient autonomy, but has also been shown to increase patient satisfaction and improve compliance (12–14), both of which are essential to ensure successful long-term treatment of osteoporosis and ultimately prevent fractures.

To our knowledge, studies have not quantified patient preferences for prevention of osteoporotic fractures. Understanding these preferences is especially important given that adherence to these medications is poor (15). The objective of this study was to examine patient treatment preferences for available and promising osteoporosis treatment options using an interactive computerized questionnaire that elicits preferences based on how patients make trade-offs between the risks and benefits of the treatment options under consideration.

PATIENTS AND METHODS

Participants.

We recruited men and postmenopausal women (age >65 years) who had recently (within 2 weeks) undergone bone densitometry. Participants were drawn from 6 centers performing bone densitometry in the greater New Haven, Connecticut area.

All patients undergoing bone densitometry, who were able to understand English, were asked whether they agreed to be contacted by a research assistant to learn more about and potentially participate in a study examining patients' opinions concerning osteoporosis medications. Patients were asked to fill out a form indicating whether or not they wished to be contacted.

Persons with osteoporosis (T score [at total hip or lumbar spine] equal to or less than −2.5) and/or a Fracture Index Score ≥6 (the cutoff at which evaluation for treatment is recommended [16]) were eligible to participate. These criteria were chosen to ensure that all study participants would be considered eligible for pharmacologic treatment of osteoporosis. Only patients with known secondary causes of osteoporosis, esophagitis, severe heartburn, the inability to sit upright for at least 30 minutes, or previous allergic reactions to bisphosphonates or calcitonin (ascertained by self-report) were excluded. These criteria were meant to exclude patients for whom one or more of the treatment options might not be medically reasonable choices. The research protocol was approved by the human investigations committee at our institution.

Preference measurement.

Participants first underwent a standardized educational session with the research assistant who briefly explained the pathophysiology of osteoporosis and its complications. The information presented to participants was based on patient information materials published by the National Osteoporosis Foundation (17). The educational session was conducted to ensure that all participants had the same information available to them before performing the preference task.

Consenting participants completed an Adaptive Conjoint Analysis (ACA) questionnaire to determine their treatment preferences. This approach has been previously described in detail (18–23). Briefly, ACA collects and analyzes preference data using an interactive computer program. Preferences are derived by asking respondents to make trade-offs between the characteristics of competing treatment options under consideration rather than explicitly naming these options. ACA assumes that each treatment option is a composite of different characteristics. The characteristics included in this study were route of administration (pill taken once a week, intravenous infusion administered over 2 hours every 3 months, intravenous infusion administered over 15 minutes once a year, daily subcutaneous injection), absolute risk reduction of vertebral fractures over 5 years, absolute risk reduction of hip fractures over 5 years, and risk of adverse effects (gastrointestinal adverse effects and infusion reactions). Risk of sarcoma was not included in the questionnaire.

Medication characteristics were first explained in detail to participants using lay terminology and then, because of space constraints, presented in abbreviated format in the computerized questionnaire. In this study, the ACA survey contained 2 sets of questions. First, respondents were asked to rate the importance of the difference between the highest and lowest estimate of each characteristic on a 4-point scale, thereby allowing ACA to learn enough about each respondent's values to construct initial utility estimates. In this context, utility is a number that represents the value a respondent associates with a particular characteristic, with higher utilities indicating increased value. In the second set of questions, respondents evaluated a series of paired concepts. Each question involved choosing one option from a pair in which one option is superior in one characteristic and the opposing option is superior in the other. ACA constructs pairs by examining all the possible ways in which the characteristics can be combined and then chooses pairs of options with similar utilities for which it expects respondents to be indifferent (based on previous responses). The program uses the information obtained from each paired comparison to update the estimates of each respondent's utilities and to select the next pair of options. Final utilities are generated using regression analysis (22).

We created 2 versions of the ACA questionnaire (high fracture risk: Fracture Index Score >7, lower fracture risk: Fracture Index Score = 6 or 7 [16]) so that each participant was presented with individualized probability estimates. Estimates of risk were obtained using the Fracture Index scoring system developed by Black et al (16).

Covariates.

All covariates were collected by self-report. Overall health status was measured using a global health status question: “In general would you say your health is: ‘Excellent,’ ‘Very good,’ ‘Good,’ ‘Fair,’ or ‘Poor’?” (24). Attitudes toward utilization of medical services were ascertained using relevant questions from the Medical Care Preference Scale (25): “I prefer to treat most health problems without help from doctors or prescription drugs” and “For most health problems I would rather take a prescription drug than a nonprescription drug,” coded on a 5-item response scale ranging from “strongly disagree” to “strongly agree.” Participants stating that they agreed or strongly agreed were classified as preferring to treat health problems without doctors or prescription drugs and preferring prescription over nonprescription drugs for the first and second statements, respectively. Perceived risk of future fracture over 5 years was coded on a 5-item response scale: “1 in 100 people like me,” “5 in 100 people like me,” “10 in 100 people like me,” “20 in 100 people like me,” and “30 in 100 people like me will have an osteoporotic fracture in the next 5 years.” Responses of “10 in 100 people like me” or higher were coded as having a high perceived risk of fracture. Concern about developing a stooped posture and hip fracture were each evaluated using a 7-item response scale ranging from “None of the time” to “All of the time.” Respondents stating that they were worried about either developing a stooped posture or experiencing a hip fracture “A good bit of the time” or more were classified as being worried about future fractures.

Statistical analyses.

Preference data derived from ACA (version 3.0; Sawtooth Software, Sequim, WA) were imported into SAS software (SAS Institute, Cary, NC) and merged with the patient characteristics data set. We calculated the relative importance of the characteristics studied by dividing the range of each characteristic (utility of highest estimate to utility of lowest estimate) by the sum of ranges of all characteristics, and multiplying by 100. The relative importance reflects how much influence each treatment characteristic has on respondents' choices.

We performed simulations to predict each respondent's treatment choice. For each simulation, ACA predicts preferences based on the utilities derived from the conjoint questionnaire using least squares regression analysis. Note that the participant does not evaluate treatment alternatives directly. Rather, the participant considers the trade-offs between conflicting characteristics. Answers to carefully selected patient-specific questions allow the investigator to infer values for specific treatment characteristics. These values are then used to predict which option most closely suits each patient's priorities. Preferences were predicted for oral bisphosphonates taken once per week, intravenous bisphosphonates administered every 3 months, intravenous bisphosphonates administered once per year, and subcutaneous rhPTH. Although not approved for the treatment of osteoporosis, bisphosphonate infusions are available and were included in this study to determine their impact on patient preferences. Once monthly oral bisphosphonates were not included because this option was not available at the time of this study. Calcitonin was not included because this choice is dominated by the other options included in the model (i.e., studies suggest that calcitonin is not as effective as bisphosphonates and similar to the latter may be associated with side effects).

In the base-case scenario, we described all bisphosphonates (regardless of route of administration) as being associated with a 50% reduction in risk of future vertebral and hip fractures; rhPTH was described as conferring a 65% decreased risk of future vertebral fractures and a 50% decreased risk of future hip fractures. Although the Neer et al trial (9) did not have the power to examine hip fractures, we chose 50% risk reduction for this outcome based on the assumption that rhPTH would be at least as effective as bisphosphonates in reducing hip fractures. We then performed sensitivity analyses to examine how increasing efficacy or risk of adverse effects altered participants' preferences.

Associations between respondent characteristics and treatment preferences were examined using t-test and chi-square or Fisher's exact tests for continuous and categorical covariates, respectively. Multivariate analyses were subsequently performed using multiple logistic regression.

RESULTS

Participant characteristics.

The study sample included 201 women and 11 men (median age 73 years, range 46–90 years). Of the 233 patients who agreed to be contacted, 217 were eligible, and 212 agreed to participate. The majority (87%) of the sample was white, 50% were married, and 68% had at least some college education. A total of 173 (82%) patients knew of bisphosphonates as a possible treatment option for osteoporosis; 1 patient was familiar with rhPTH, and other than this 1 participant, none had talked about receiving an injectable medication with their physician prior to the study. Participant characteristics are further described in Table 1.

Table 1. Participant characteristics (n = 212)*
CharacteristicValue
  • *

    Values are the number (percentage) unless otherwise indicated. rhPTH = recombinant human parathyroid hormone.

Age, median (range) years73 (46–90)
Women201 (95)
White race185 (87)
Married106 (50)
At least some college education143 (68)
High Fracture Index81 (38)
High perceived risk of fracture55 (26)
Currently taking bisphosphonates120 (57)
Currently taking rhPTH1 (0.5)
Health status very good or excellent102 (48)
Previous vertebral fracture20 (9)
Previous hip fracture5 (2)
Preferring to treat health problems without doctors or prescription drugs37 (18)

Relative importance of treatment characteristics.

The relative importance of each medication characteristic on participants' treatment choices is displayed in Figure 1. Patients' treatment preferences were strongly influenced by route of administration. Study participants believed that prevention of vertebral fractures was as important as prevention of hip fractures.

Figure 1.

Relative importance of specific medication characteristics. Values sum to 100. Yellow = route of administration; green = vertebral fractures; blue = hip fractures; red = adverse effects.

Participants' treatment preferences.

Participants' treatment preferences are described in Table 2. For the base-case scenario, preferences were strongest for and equally distributed between oral and intravenous bisphosphonates. Three percent of respondents were willing to take rhPTH over bisphosphonates in this scenario, and preferences changed little when the benefits of rhPTH were broadened to include increased effectiveness over bisphosphonates in preventing both vertebral and hip fractures. The distribution of treatment preferences did not differ by history of fracture or level of concern regarding future fracture (Table 3).

Table 2. Participants' treatment preferences*
ScenarioTreatment preferences
Oral bisphosphonatesBisphosphonate infusions every 3 monthsBisphosphonate infusions every 12 monthsrhPTHUndecided
  • *

    Values are the number (percentage). rhPTH = recombinant human parathyroid hormone.

Base-case85 (40)6 (3)94 (44)6 (3)21 (10)
rhPTH is more effective at preventing both hip and vertebral fractures82 (38)6 (3)91 (43)14 (7)19 (9)
rhPTH is more effective at preventing hip and vertebral fractures and rhPTH and oral bisphosphonates have no added risk of gastrointestinal adverse effects106 (50)4 (2)65 (31)18 (8)19 (9)
Table 3. Treatment preferences with regards to history of previous fracture and concern about fractures*
PreferencePrevious hip or spine fractureWorried about future fracture
Yes (n = 24)No (n = 188)Yes (n = 66)No (n = 146)
  • *

    Values are the number (percentage). rhPTH = recombinant human parathyroid hormone.

Oral bisphosphonates11 (46)74 (39)26 (39)59 (40)
Bisphosphonate infusions every 3 months1 (4)5 (3)0 (0)6 (4)
Bisphosphonate infusions every 12 months9 (38)85 (45)29 (44)65 (45)
rhPTH1 (4)5 (3)1 (2)5 (3)
Undecided2 (8)19 (10)10 (15)11 (8)

When oral bisphosphonates and rhPTH were described as not being associated with an increased risk of dyspepsia or nausea (to reflect equivalent rates of these adverse effects in both experimental and control groups in randomized controlled trials), the former became the preferred choice among all options studied.

Preference for annual infusions versus oral medications.

Among treatment-naive participants (n = 80), 52 (65%) preferred an annual infusion over oral weekly bisphosphonates. Treatment preferences for annual infusions versus weekly oral medication were not associated with age, education, or prescription drug coverage (Table 4). We did not evaluate the association of sex or race with treatment preferences because of inadequate numbers of men and minority participants. In bivariate analyses, participants with poorer perceived health status, those with a high perceived risk of future fracture, and participants preferring to treat health problems without doctors or prescription drugs were more likely to prefer an annual infusion over weekly pills (Table 4). Health status and attitude towards doctors and prescription medicines remained positively associated with preference for annual infusions in a multivariate model (Table 4).

Table 4. Associations between participants' characteristics and treatment preference among treatment-naive participants*
CharacteristicTreatment preferencePAdjusted OR (95% CI)
Oral bisphosphonates (n = 28)IV bisphosphonates (n = 52)
  • *

    Values are the percentage unless otherwise indicated. IV = intravenous; OR = odds ratio; 95% CI = 95% confidence interval.

  • Multivariate logistic regression model including health status, perceived risk of fracture, and preference to avoid doctors and prescription drugs.

Age ≥65 years86750.3
Some college education61620.9
Has prescription drug plan54690.2
Health status very good or excellent64370.023.0 (1.0–8.5)
High perceived risk of fracture7310.020.2 (0.04–1.2)
Preferring to treat health problems without doctors or prescription drugs7310.020.1 (0.03–0.7)

Among respondents currently taking bisphosphonates, only attitude towards use of prescription drugs was associated with treatment preference for oral versus intravenous medication. More respondents choosing oral bisphosphonates preferred to treat most health problems with prescription drugs compared with respondents choosing the intravenous option (51% versus 31%; P = 0.05).

DISCUSSION

In this study, despite the added benefit of rhPTH, participants preferred bisphosphonates for the treatment of osteoporosis. Although prevention of fractures was important in participants' decision making, the added benefit conferred by rhPTH was not sufficient to overcome participants' dislike of daily subcutaneous injections. In addition, although associated with less morbidity and mortality, respondents in this study believed that prevention of vertebral fractures was as important as prevention of hip fractures. This finding may be due to fear of developing a cosmetic deformity, i.e., kyphosis.

Despite an overall strong preference for bisphosphonates, we found considerable variation in individual respondent's treatment preferences for weekly oral medication versus annual infusions. Variability in preferences was not related to sociodemographic characteristics; however, participants with poorer self-reported health status as well as those with a high perceived risk of fracture were more likely to prefer an annual infusion, suggesting that patients might view infusions as being more effective than oral medications, even when oral medications are described as being associated with the same outcomes. The association between perceived fracture risk and preference for annual infusions did not reach statistical significance, which may have been due to the small number of participants in the multivariate analysis. Participants preferring to treat health problems without doctors or prescription drugs were also more likely to prefer annual infusions over weekly oral bisphosphonates. This finding suggests that an annual infusion should be discussed with patients who prefer to minimize utilization of traditional health care resources.

Strengths of this study include the methods used to elicit preferences. First, outcome data were individualized based on individual respondent's risk factors. Second, respondents' preferences were predicted based on how respondents made trade-offs between medication characteristics and therefore were not biased by recognition of specific treatment options. Careful evaluation of salient trade-offs is considered an essential component of high- quality decision making (26). Third, numerous studies have demonstrated that ACA produces internally consistent responses, and that it is a reliable and valid method of measuring preferences (20–23, 27). Moreover, use of interactive computer questionnaires minimizes interviewer bias, increases participants' interest and involvement in the task, and ensures that respondents evaluate all characteristics under consideration.

In view of the known difficulties associated with communicating probabilistic information, we facilitated understanding of risk magnitude by providing both numerical estimates (natural frequencies) as well as graphic representations of probability data (28–30). In addition, we provided outcomes for treated as well as untreated patients and we used the same denominator throughout the survey (30).

Our results must be interpreted in view of the limitations of this study. We could not include all medication characteristics or copays, because this would have overly complicated the questionnaire. For the same reason, we described bisphosphonates as being associated with the same risks and benefits, even though fracture data are not equivalent, or not available, for all types of bisphosphonates (e.g., zoledronic acid). Descriptions of route of administration and adverse effects were abbreviated to ensure readability at a fifth-grade level. Although full disclosure of all details is ideal, patients' willingness to engage in making trade-offs decreases when the task is too difficult. For this reason we chose the most salient details for each medication characteristic. Inclusion of additional adverse effects (such as the theoretical possibility of osteogenic sarcoma) and cost, however, would be expected to further widen the gap between patient preferences for bisphosphonates over rhPTH.

Many of the participants interviewed were already receiving treatment for osteoporosis, therefore we could not recruit sufficient numbers of treatment-naive persons. The results in this study may therefore have been influenced by current medication use. In addition, most participants were white, female, and well educated, thereby limiting the generalizability of the results.

In summary, we found that patient preferences for osteoporosis treatment options were strongly influenced by route of administration. Therefore, despite the added benefits of rhPTH, patients' preferred treatment option for osteoporosis is bisphosphonates. Among patients preferring bisphosphonates, many preferred annual infusions over weekly oral medications. This finding emphasizes the need to incorporate individual patient preferences into treatment decisions for osteoporosis. The latter is especially important given the poor rates of long-term adherence to osteoporosis medications.

Acknowledgements

We would like to thank all participants for their time and effort.

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