Adherence and persistence associated with the pharmacologic treatment of osteoporosis in a managed care setting.

Background: The effectiveness of chronic therapies can be compromised by poor adherence and persistence.

Materials and Methods: Investigators identified a continuously benefit-eligible cohort of women from a large, geographically diverse, national managed care plan who were newly diagnosed and treated for osteoporosis with alendronate, risedronate, or raloxifene. Drug utilization parameters were evaluated over a 12-month follow-up period for the study population. Adherence was assessed using a medication possession ratio calculated as total days of therapy for medication dispensed/365 days of study follow-up. Persistence was defined as continuous therapy on the same drug for each month over the entire study period. Adherence and persistence were also evaluated for all three study agents in women [greater than or equal to]65 years of age.

Results: In the study cohort (N = 10,566), 12-month adherence/persistence rates were alendronate 61%/21%, risedronate 58%/19%, and raloxifene 54%/16%. Rates in women [greater than or equal to]65 years were similar to those in the entire study cohort. Weekly bisphosphonate users had slightly higher 12-month adherence (63% versus 54%. P < 0.05) and persistence (22% versus 19%, P = NS) rates than did daily users, independent of agent.

Conclusion: Chronic oral-dosed osteoporosis therapies are associated with poor adherence and persistence, regardless of age or dosing regimen. Drug therapies and patient management approaches associated with improved adherence and persistence could improve the likelihood of achieving the therapeutic benefits observed in rigorously controlled clinical trials.

Key Words: osteoporosis, adherence, persistence, bisphosphonates, raloxifene

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Osteoporosis is defined by the World Health Organization as "a systemic skeletal disease characterized by low bone density and microarchitectural deterioration of bone tissue with a consequent increase in bone fragility." (1) Although this disease predominantly affects females, especially postmenopausal women, it affects all races and both genders and is responsible for increased risk of bone fracture, long-term pain, deformity, and reduced quality of life. (2) It has been estimated that about 10 million Americans have osteoporosis and another 34 million experience low bone mass density (BMD). (3) Patients with osteoporosis or low BMD are at greater risk of vertebral and hip fracture and thus have increased mortality risk. Approximately 10% of those suffering osteoporotic hip fracture become functionally dependent and require assistance with activities of daily living, while another 19% require nursing home care. (4) Osteoporosis also results in substantial health care utilization and costs. The direct costs of osteoporosis were estimated to be $11.6 to $17.1 billion in 2001 (5,6) and are expected to increase as the population ages.

The oral bisphosphonates (OB) alendronate and risedronate and the selective estrogen receptor modulator (SERM) raloxifene prevent bone loss and strengthen the microarchitecture, particularly at the hip and spine. In clinical trials, these agents have been shown to increase BMD and reduce bone resorption, (7-10) thereby decreasing the incidence of hip and vertebral fractures by 40 to 50%. (8,11,12)

In osteoporosis clinical trials, adherence and persistence associated with oral therapies are generally quite high. (7,8,11,13) However, the extent to which the clinical trial drug utilization pattern carries over to real-world clinical practice is less well characterized.

Databases with medical and pharmaceutical claims information from large managed care organizations offer the opportunity to efficiently identify and evaluate patients receiving pharmacologic and medical care for osteoporosis. Refill patterns and details of individual prescription refills in concert with patient eligibility status allow evaluation of objective measures of adherence and persistence without relying on patient self-report. (6,14-16) These studies can evaluate whether the patient took the medicine consistently over an extended period of time via drug refill behavior--although they do not address whether it was taken correctly or consistently.

Previously published studies of adherence and persistence using large administrative databases in the United States have relied on data from a large plan in California, (5,6,15,17) pharmacy databases, (18) or specialty clinics and group practices. (16-19) The rates of drug adherence and persistence with osteoporosis therapies reported in these studies varied but were generally suboptimal. It is unclear, however, whether the conclusions from these studies can be extended to a larger patient population, because their patient cohorts were derived from relatively small, geographically limited populations without diversity related to prescription plan designs and because of potential biases related to both physician prescribing practices and patient drug utilization behavior associated with different areas of the country.

The primary objectives of the current study were to evaluate adherence and persistence associated with oral bisphosphonate medications and raloxifene in a geographically diverse, real-world setting of patients with osteoporosis, as well as to evaluate the impact of different oral bisphosphonate dosing regimens (daily versus weekly) on adherence and persistence. A secondary objective was to compare the rates of adherence and persistence among the agents of interest and between dosing regimens in older women ([greater than or equal to]65 years of age).

Methods

The data utilized in this study were drawn from a large national managed care administrative claims database containing 4 years of current and historical longitudinal member-level claims data from patients located in four different census regions (Northeast, South, Midwest, and West) and all marketed insurance products. The administrative claims data used in this study included outpatient, inpatient, and emergency room encounter data and diagnostic testing information as well as information related to member demographics, provider specialty and location, and insurance product information (health maintenance organizations, preferred provider organizations, Medicare).

The study cohort consisted of women over the age of 45 with a new osteoporosis diagnostic medical claim (ICD-9: 733.xx) any time between July 1, 2001, and December 31, 2002, with no such claim in the previous 6 months. Patients were also required to have a pharmacy claim for risedronate, alendronate, or raloxifene within the same 18-month identification window, with no such claim during the previous 6 months. All new therapy patients were required to be continuously eligible for benefits over the study period (from 6 mo before diagnosis to 12 mo after the index prescription). Adherence and persistence were assessed in the 12-month period following the index prescription. Comparisons between dosing regimens were conducted only for patients who did not change drug regimens. The study design is outlined in Figure 1.

Adherence was assessed using a medication possession ratio (MPR) for each patient, calculated as total days of therapy dispensed over 365 days of study follow-up. Patients with an MPR greater than 100% were capped at 100%. Persistence was defined as continuous therapy on the same drug for each month over the entire study period.

Descriptive statistics were used to compare the drug cohorts. Comparisons between cohorts were made using t tests for continuous variables and [chi square] tests for categorical variables. Monthly persistence curves were used to compare rates across the cohort. Statistical testing between the groups was performed only at the end of study follow-up (month 12). An a priori significance level of [alpha] = 0.05 was chosen for all comparisons.

[FIGURE 1 OMITTED]

Results

Patient Characteristics

A total of 10,566 women met the diagnostic and treatment requirements for study inclusion (Table). The average age of all patients was 64.4 [+ or -] 10.4 years, and approximately 40% were 65 years of age or older. Alendronate was the most common index agent (n = 6,881; 65%), followed by risedronate (n = 2,224; 21%) and raloxifene (n = 1,461; 14%). A total of 8,365 alendronate and risedronate users (91.9% of all bisphosphonate users) did not change between daily and weekly therapy regimens during the course of follow-up. Of these, 7,092 (84.8%) patients received a weekly dosing regimen. The most prevalent comorbidity in the overall sample was gynecologic disorders (49.8%). Over 40% of patients in each treatment cohort had one or more major system comorbidities of interest (eg, cardiac, endocrine or metabolic, skin, eye, or other nonspecific disorder), but there were no apparent differences among the treatment groups. The distribution of patients across census regions reflected the distribution of covered lives and differed slightly between index medication groups. Although minor differences were observed in some of the clinical and demographic characteristics of women among the three drug groups, the differences did not appear clinically meaningful (Table).

Adherence and Persistence in the Entire Study Sample

Comparison among agents. The average adherence rates for all dosage forms and ages combined (Fig. 2) were greatest for alendronate (60.7%; P < 0.001), compared with risedronate (58.4%) and raloxifene (53.9%). Twelve-month follow-up persistence curves for all three products are almost superimposable (Fig. 3). The curves show a rapid decline over the first 3 months, followed by a slower but steady decline over the remaining months. The mean times to discontinuation were not significantly different among agents, with alendronate and risedronate at 2.53 months and raloxifene at 2.45 months. Persistence rates at 12 months were 21.3% for alendronate, 19.4% for risedronate, and 16.2% for raloxifene (P < 0.001).

Comparison between dosing regimens. The evaluation of 12-month adherence for daily and weekly users of oral bisphosphonate agents (n = 8,365) demonstrated that weekly users were more adherent (62.5%) than daily users (53.8%; P < 0.05) (Fig. 4). Persistence, however, was comparable between the two administration regimens (Figs. 4 and 5). Both weekly and daily users exhibited the same pattern of early drop-off within the first 3 months, followed by a steady decline through month 12. There were no significant differences in the mean times to discontinuation (2.44 mo and 2.55 mo) or rates of 12-month persistence (18.5% and 22.1%) for daily and weekly users, respectively.

Adherence and Persistence in Women 65 Years of Age or Older

Comparison among agents and dosing regimens. Twelve-month adherence rates were similar for all three agents in a subgroup analysis of older women ([greater than or equal to]65 yr of age): 59.6% for alendronate, 57.5% for risedronate, and 56.3% for raloxifene (Fig. 2). Compared with the overall study population, 12-month persistence rates in older women were similar, with a slightly lower rate for alendronate (20.1%) and risedronate (17.7%) and a slightly higher rate for raloxifene (17.0%). In older patients, adherence to the weekly dosing regimen was slightly higher (62.2%) than adherence to the daily regimen (58.8%; P < 0.05). Twelve-month persistence rates were not statistically different (21.6% for weekly users, compared with 18.7% for daily users).

[FIGURE 3 OMITTED]

Discussion

This study of more than 10,000 women with newly diagnosed osteoporosis evaluated real-world utilization patterns for three commonly prescribed oral antibone resorption therapies across a geographically diverse, commercially insured population. In this population, it was observed that patient adherence and persistence associated with oral osteoporosis medications were suboptimal and did not appear to vary appreciably by drug, dosing regimen, or age category. In general, these results are consistent with previous studies in smaller, more homogeneous populations that have reported suboptimal adherence and persistence associated with osteoporosis therapies, (5,17,20-22) including a recent large study in which adherence to weekly oral bisphosphonate regimens was found to be higher than adherence to daily regimens (65% versus 54%; P < 0.001). (23)

[FIGURE 5 OMITTED]

A recent study by Cramer et al (24) used nationwide administrative claims data to follow the adherence and persistence of 2,741 women with osteoporosis who had been newly prescribed once-weekly alendronate or once-daily alendronate or risedronate. The adherence rates reported in this study were 57.6% for once-daily oral bisphosphonates and 69.2% for once-weekly alendronate--similar to the rates observed in our study. Although persistence was defined somewhat differently in the two studies, both support the conclusion that a majority of female patients do not persist with oral bisphos-phonate therapies. In this study, these results have been further corroborated and extended by including raloxifene among the oral therapies studied, with a similar low level of adherence and persistence.

In the real-world setting, patients can have difficulty adhering to and persisting with chronic therapy for a variety of reasons--including the tolerability of the agent, the convenience of dosing regimens, the number of other medications taken, patients' financial contributions to drug costs, and the relationship of their health-belief model to their perception of requiring the medication.

Antibone resorptive therapy with oral bisphosphonate agents can pose a particular challenge, since these medications require more effort than simply swallowing a pill. Treatment instructions generally mandate that the medication be taken on an empty stomach, often in the early morning hours, with sufficient water, and with an upright postural position maintained for at least half an hour after ingestion of the medication. (12,15) This regimen can contribute to poor adherence and persistence. Studies of self-reported drug-taking behavior have shown that even when complete instructions are given, between 25% and 50% of patients disregard at least one requirement. (16,25) Such disregard can potentially lead to upper gastrointestinal adverse events--which, in turn, may result in discontinuation or reduced adherence.

The often asymptomatic nature of osteoporosis may also affect adherence to and persistence with a medication regimen. Since the condition manifests itself episodically through traumatic events such as fall-related fractures or stress-related fragility fractures, patients may not perceive the daily risk of these events that is related to bone loss. Thus, as with other asymptomatic chronic conditions, patients may require more targeted patient education and message reinforcement on the need to continue taking their osteoporosis medications.

Poor adherence and persistence associated with osteoporosis therapies can also have an untoward impact on patient outcomes, including suboptimal reduction of fracture risk. In one study, the BMD increases observed in women with poor adherence (<66%) to osteoporosis therapy were significantly reduced, compared with those observed in patients showing higher levels of adherence. (19) Similarly, inconsistent oral bisphosphonate users recorded significantly lower improvements in lumbar spine BMD than did consistent users during a 3-year follow-up of women treated for osteoporosis. (26) Furthermore, these changes in BMD were accompanied by a 27% greater 10-year fracture risk in the inconsistent bisphosphonate users. (26) Other studies have also found a link between poor compliance with osteoporosis therapies and increased fracture risk--including a study of 11,249 women with osteoporosis that reported a 16% lower fracture rate in patients who adhered to therapy compared with those who did not (27) and another study of medical and pharmaceutical claims data showing a 26% lower risk of bone fracture in adherent patients and a 21% lower risk in persistent patients. (28)

This study has some notable strengths--including its larger sample size, compared with most previous studies, and its broad geographic representation of women. The study also has some potential limitations, mainly related to the retrospective use of pharmacy and medical claims data. For example, a lack of corroboration of a new diagnosis and treatment for osteoporosis through chart review or patient self-report leaves open the possibility that some prevalent patients may also have been included. Similarly, the potential for coding errors in the database may have led to misclassification of clinical and/or demographic characteristics. Specific reasons for discontinuation could also not be determined, and these could have included physician recommendation to stop therapy. Finally, the study's use of a refill proxy to approximate actual drug-taking behavior may have led to an over-estimation of adherence and persistence.

Conclusion

The results of this study suggest that in a real-world setting, adherence and persistence associated with currently available pharmacologic therapy for osteoporosis are suboptimal--independently of agent type, dosing regimen, or age.

Acknowledgment 

The authors wish to thank Fred Myers of BioScience Communications for his editorial assistance in the preparation of this manuscript.

References

1. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA 2001;285:785-795.

2. Iqbal MM. Osteoporosis: epidemiology, diagnosis, and treatment. South Med J 2000;93:2-18.

3. National Osteoporosis Foundation Fast Facts. Available at: http://www.nof.org/osteoporosis/diseasefacts.htm. Accessed October 16, 2005.

4. Bone Health and Osteoporosis: A Report of the Surgeon General. Rockville, MD: US Dept of Health and Human Services, Public Health Service, Office of the Surgeon General; 2004.

5. McCombs JS, Thiebaud P, McLaughlin-Miley C, Shi J. Compliance with drug therapies for the treatment and prevention of osteoporosis. Maturitas 2004;48:271-287.

6. Tosteson AN, Grove MR, Hammond CS, et al. Early discontinuation of treatment for osteoporosis. Am J Med 2003;115:209-216.

7. Lufkin EG, Whitaker MD, Nickelsen T, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res 1998;13:1747-1754.

8. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial: Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA 1999;282:637-645.

9. Eastell R, Barton I, Hannon RA, et al. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 2003;18:1051-1056.

10. Bauer DC, Black DM, Garnero P. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res 2004;19:1250-1258.

11. Black DM, Cummings SR, Karpf DB, et al. Randomised trial of effect of alendronate on risk of fracture in women with existing vertebral fractures: Fracture Intervention Trial Research Group. Lancet 1996;348:1535-1541.

12. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlled clinical experience. Bone 2003;32:120-126.

13. Greenspan S, Field-Munves E, Tonino R, et al. Tolerability of once-weekly alendronate in patients with osteoporosis: a randomized, double-blind, placebo-controlled study. Mayo Clin Proc 2002;77:1044-1052.

14. Clowes JA, Peel NF, Eastell R. The impact of monitoring on adherence and persistence with antiresorptive treatment for postmenopausal osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab 2004;89:1117-1123.

15. Ettinger B, Schein J, Pressman A, et al. Alendronate use among 812 women: prevalence of gastrointestinal complaints, noncompliance with patient instructions, and discontinuation. J Manag Care Pharm 1998;4:488-492.

16. Hamilton B, McCoy K, Taggart H. Tolerability and compliance with risedronate in clinical practice. Osteoporos Int 2003;14:259-262.

17. Kayser J, Ettinger B, Pressman A. Postmenopausal hormonal support: discontinuation of raloxifene versus estrogen. Menopause 2001;8:328-332.

18. Faulkner DL, Young C, Hutchins D, et al. Patient noncompliance with hormone replacement therapy: a nationwide estimate using a large prescription claims database. Menopause 1998;5:226-229.

19. Yood RA, Emani S, Reed JI, et al. Compliance with pharmacologic therapy for osteoporosis. Osteoporos Int 2003;14:965-968.

20. Papaioannou A, Ioannidis G, Adachi JD, et al. Adherence to bisphosphonates and hormone replacement therapy in a tertiary care setting of patients in the CANDOO database. Osteoporos Int 2003;14:808-813.

21. Watts NB, Worley K, Solis A, et al. Comparison of risedronate to alendronate and calcitonin for early reduction of nonvertebral fracture risk: results from a managed care administrative claims database. J Manag Care Pharm 2004;10:142-151.

22. Turbi C, Herrero-Beaumont G, Acebes JC, et al. Compliance and satisfaction with raloxifene versus alendronate for the treatment of postmenopausal osteoporosis in clinical practice: an open-label, prospective, nonrandomized, observational study. Clin Ther 2004;26:245-256.

23. Recker RR, Gallagher R, MacCosbe PE. Effect of dosing frequency on bisphosphonate medication adherence in a large longitudinal cohort of women. Mayo Clin Proc 2005;80:856-861.

24. Cramer JA, Amonnkar MM, Hebborn A, et al. Compliance and persistence with bisphosphonate dosing regimens among women with postmenopausal osteoporosis. Curr Med Res Opin 2005;21:1453-1460.

25. Ettinger MP. Aging bone and osteoporosis, strategies for preventing fractures in the elderly. Arch Intern Med 2003;163:2237-2246.

26. Sebaldt RJ, Shane LG, Pham B, et al. Longer term effectiveness outcomes of noncompliance and nonpersistence with daily regimen bisphosphonate therapy in patients with osteoporosis treated in tertiary specialist care. Osteoporos Int 2004;15 (Suppl 1):S107. Abstract P391SA.

27. Caro JJ, Ishak KJ, Huybrechts KF, et al. The impact of compliance with osteoporosis therapy on fracture rates in actual practice. Osteoporos Int 2004;15:1003-1008.

28. Siris ES, Rosen CJ, Bangor ME, et al. Adherence to bisphosphonate therapy: relationship to bone fractures at 24 months in women with postmenopausal osteoporosis. Presented at the Sixth International Symposium on Osteoporosis; April 6-10, 2005; Washington, DC.

Read not to contradict nor to believe, but to weigh and consider.
--Francis Bacon

Timothy W. Downey, MS, Susan H. Foltz, MS, Stephen J. Boccuzzi, PHD, MBA, Mohamed A. Omar, PHD, RPH, and Kristijan H. Kahler, SM, RPH

From Aetna Health Information Solutions, Blue Bell, PA, and Novartis Pharmaceuticals Corporation, East Hanover, NJ.

Reprint requests to Mohamed A. Omar, PhD, RPh, Novarlis Pharmaceuticals Corporation, US CD & MA/Health Economics & Outcomes Research, One Health Plaza, East Hanover, NJ 07936.

This study was funded by Novartis Pharmaceuticals Corporation of East Hanover, NJ. Dr. Omar and Mr. Kahler are employees of Novartis.

Accepted March 6, 2006.

RELATED ARTICLE: Key Points

* In a large, geographically diverse managed care cohort, women with newly diagnosed osteoporosis showed low rates of adherence to and persistence with three oral antibone resorptive therapies (alendronate, risedronate, and raloxifene).

* Weekly oral bisphosphonate regimens were associated with higher rates of adherence and persistence compared with daily dosed agents, but these rates were still suboptimal (adherence <65%, persistence <25%).

* Older women ([greater than or equal to]65 years of age) did not demonstrate improved rates of adherence and persistence compared with the cohort as a whole.

* Low rates of adherence and persistence may be associated with poor clinical and economic outcomes.

Table. Select demographic characteristics of patients taking
alendronate, risedronate, or raloxifene

                                      Alendronate   Risedronate
                                      (n = 6,881)   (n = 2,224)

Age, n (%)
  <65 years                           4,101 (59.6)  1,377 (61.9)
  [greater than or equal to]65 years  2,780 (40.4)    847 (38.1)
Single dosing regimen, n (%) (a)      6,382 (92.7)  1,983 (89.2)
  Weekly dose                         5,552 (80.7)  1,540 (69.2)
Comorbid disorders, n (%)
  Gynecologic                         3,352 (48.7)  1,127 (50.7)
  Nonspecific                         3,335 (48.5)  1,151 (51.8)

  Cardiac                             3,313 (48.1)  1,082 (48.7)
  Endocrine/metabolic                 3,289 (47.8)  1,076 (48.4)
  Skin                                2,935 (42.7)  1,001 (45.0)
  Eye                                 2,878 (41.8)    908 (40.8)
  Digestive                           2,492 (36.2)    858 (38.6)
  Rheumatologic                       1,784 (25.9)    621 (27.9)
  Ear/nose/throat                     2,193 (31.9)    764 (34.4)
  Respiratory                         1,927 (28.0)    629 (28.3)
Census region, n (%)
  Northeast                           2,401 (34.9)    698 (31.4)
  South                               2,560 (37.2)    910 (40.9)
  Midwest                               721 (10.5)    252 (11.3)
  West                                1,170 (17.0)    351 (15.8)

                                      Raloxifene
                                      (n = 1,461)   Total (N = 10,566)

Age, n (%)
  <65 years                           4,101 (59.6)  4,101 (59.6)
  [greater than or equal to]65 years  2,780 (40.4)  2,780 (40.4)
Single dosing regimen, n (%) (a)                    8,365 (91.9) (b)
  Weekly dose                                       7,092 (77.9) (b)
Comorbid disorders, n (%)
  Gynecologic                           781 (53.5)  5,260 (49.8)
  Nonspecific                           703 (48.1)  5,189 (49.1)
  Cardiac                               764 (52.3)  5,159 (48.8)
  Endocrine/metabolic                   733 (50.2)  5,098 (48.2)
  Skin                                  635 (43.5)  4,569 (43.2)
  Eye                                   615 (42.1)  4,401 (41.7)
  Digestive                             573 (39.2)  3,923 (37.1)
  Rheumatologic                         361 (24.7)  2,766 (26.2)
  Ear/nose/throat                       489 (33.5)  3,446 (32.6)
  Respiratory                           391 (26.8)  2,947 (27.9)
Census region, n (%)
  Northeast                             498 (34.1)  3,597 (34.0)
  South                                 573 (39.2)  4,043 (38.3)
  Midwest                               180 (12.3)  1,153 (10.9)
  West                                  205 (14.0)  1,726 (16.3)

(a) Patients who did not change therapy regimens during follow-up;
alendronate and risedronate users only.
(b) Percent of all alendronate and risedronate users.

Days on Drug (%)

             12-Month Adherence  12-Month Adherence Rates
             Rates (All)         (Age [greater than or equal to] 65)

Risedronate  58.4%*              57.5% ([dagger])
Alendronate  60.7%*              59.6% ([dagger])
Raloxifene   53.9%*              56.3% ([dagger])

*P < 0.05, ([dagger]) P = NS

Fig. 2 Twelve-month adherence rates by index agent and age group.

Note: Table made from bar graph.

Patients (%)

             Daily  Weekly

Adherence    53.8   62.5
Persistence  18.5   22.1

P < 0.05 P = NS

Fig. 4 Twelve-month adherence and persistence among daily and weekly
users of oral bisphosphonates (limited to patients treated with
alendronate or risedronate who did not change medication or dosing
regimen during study follow up).

Note: Table made from bar graph.