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Medical Therapy for Osteoporosis and Approaches to Improving Adherence
From the Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract
- Objective: To review the treatment of osteoporosis, challenges to treatment adherence, and factors associated with improved adherence.
- Methods: Review of the literature.
- Results: With the growing aging population, there is an increased number of people at risk of osteoporosis and fracture. Several medications are available that reduce the risk of fracture. However, adherence to osteoporosis medications is suboptimal. Factors related to nonadherence include dosing frequency, real side effects, and concern about potential side effects. Interventions that may improve adherence include clinician and patient education, less frequent and less complex dosing regimens, medication reminders, and adherence counseling.
- Conclusions: Improving adherence to osteoporosis medications is a complex and challenging issue. Considering and implementing strategies to improve adherence tailored to patient preferences may enhance long-term outcomes for patients with osteoporosis.
Osteoporosis is a chronic but asymptomatic disease that is characterized by an increased fragility of bones and increased risk of fractures. Hip and vertebral fractures are associated with the greatest morbidity and mortality. The prevalence of osteoporosis is estimated to be 10.3% in the US, with approximately 10.2 million adults over the age of 50 having osteoporosis based on 2010 census data and results from the National Health and Nutrition Examination Survey (NHANES) [1].
Several drugs are currently available for the treatment of osteoporosis, but adherence to treatment is low. Understanding the factors associated with low adherence and actions that can be taken to improve adherence to treatment is important given the large number of individuals with osteoporosis and the need to reduce the burden caused by fragility fracture. In this article, we review the treatment of osteoporosis, challenges to treatment adherence, and factors associated with improved adherence.
Nonprescription Medications
Calcium
There have been several published studies over the last decade evaluating calcium supplementation and its efficacy in reducing fractures. Although these studies showed that calcium reduces bone turnover by 20% and slowed postmenopausal bone loss by one third [2,3], none of these studies or a recent systematic review [4] showed any degree of fracture risk reduction with calcium supplements alone.
Although some calcium intake may be good, too much calcium has the potential to cause harm, including an increased risk of nephrolithiasis and constipation/bloating. An analysis of the Women’s Health Initiative (WHI) study reported a 17% increase in renal calculi in women who received calcium and vitamin D supplements [5]. Another recently published meta-analysis showed a 43% increase in gastrointestinal complaints in patients who were taking calcium supplements [6]. The potential for increased cardiovascular risk with calcium supplements is controversial [7]. The WHI study did not show an increased occurrence of cardiovascular events among those taking calcium supplements [8]. In a different population, men who consumed more than 1000 mg per day of supplemental calcium had higher all-cause and cardiovascular disease-specific mortality [9]. Large, well-conducted randomized controlled trials will be needed to further elucidate the question of calcium supplementation and risk of cardiovascular disease.
Vitamin D
Deficiency of vitamin D is common with one study finding more than 90% of older adults deficient in vitamin D [10]. Vitamin D is essential for proper calcium metabolism and deficiency is known to induce secondary hyperparathyroidism. Studies in mouse models have also shown that normal vitamin D receptors in enterocytes are essential for normal bone mineralization [11,12]. A systematic Cochrane database review showed that vitamin D3 supplementation decreased mortality in elderly people living independently or in institutional care [13]. Vitamin D was administered for a weighted mean of 4.4 years. Vitamin D2, alfacalcidol, and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium was associated with an increased risk of nephrolithiasis during a follow-up period of 1.25 to 7 years (relative risk [RR] 1.17, 95% confidence interval (CI) 1.02–1.34) [13]. The inconsistencies of published reports looking at benefits of vitamin D supplementation may be due in part to variability in compliance with taking the supplements and baseline vitamin D levels.
Two randomized controlled trials have shown that low vitamin D appears to be an independent predictor of fall risk, and vitamin D supplementation has been found to reduce this risk of falls, through improved musculo-skeletal function [14–16]. Thus, vitamin D may play a role in fracture risk reduction beyond direct bone effects.
Prescription Osteoporosis Treatments
Bisphosphonates
Bisphosphonates are the most commonly prescribed medication for osteoporosis. The efficacy of bisphosphonates to reduce fractures is well established. There are oral bisphosphonates, which can be dosed daily, weekly, or monthly, and intravenous bisphosphonates, which can be given every 3 months or annually. Side effects with this class of medications include gastrointestinal effects with the oral options in up to 20% to 30% of users [17]. With intravenous bisphosphonates, the greatest risk is an acute phase response, which can occur in up to 42% of patients [18]. The risk of an acute phase reaction is much lower with doses beyond the first dose and lower if patients have ever previously taken an oral bisphosphonate and/or receive acetaminophen prior to the infusion. Other potential side effects with all bisphosphonates include osteonecrosis of jaw (ONJ) and atypical subtrochanteric fractures. Post marketing studies have indicated that the incidence of ONJ is less than 2 per 100,000 patient-years among those taking bisphosphonates [19,20]. A number of database analyses have shown that ONJ-like lesions can also occur in older individuals with osteoporosis who have never been exposed to bisphosphonates [21]. A case series of an osteoporotic population showed that ONJ-like lesions are lower grade than those typically seen in cancer patients who usually are exposed to higher doses of bisphosphonates [22]. A study of Swedish older men and women reported that long-term use of bisphosphonates (4 years or more) was associated with an increased incidence of atypical fractures. The RR for women was 126.0 (95% CI, 55.1–288.1) after 4 years of bisphosphonates [23]. A U.S. health care database analysis reported that 90% of those with atypical fractures were bisphosphonate users, almost half were Asian (49%), and use beyond 6 years showed the greatest risk [24].
Non-Bisphosphonate Medications
Other osteoporosis medications include denosumab, raloxifene, estrogen, and teriparatide (calcitonin will not be discussed here). Newer options currently under study, including cathepsin K inhibitors and anti-sclerostin therapies, are not available in the United States.
Denosumab is a monoclonal antibody that interferes with the receptor activator of nuclear kappa B ligand (RANK-L), which is the principal stimulus for osteoclastogenesis. Denosumab is administered once every 6 months subcutaneously. Phase III trials of denosumab demonstrated a 68% reduction in vertebral fractures and 40% and 20% reduction in fractures at hip and non-vertebral sites, respectively [25]. Similar to bisphosphonates, other risks include atypical femoral fractures and ONJ. In addition, hypocalcemia, including severe, symptomatic hypocalcemia, has been reported at rates higher than initially reported in the original clinical trials [26]. Hypocalcemia can be severe, especially in patients who are deficient in vitamin D [10,27].
Estrogen is effective in reducing the risk of vertebral fractures. Selective estrogen receptor modulators (SERMs) have both estrogen agonist and antagonist effects. The SERM, raloxifene, has been used in osteoporosis for its antiresorptive effects through the estrogen receptor [28,29]. A newer SERM, bazedoxifene, has been studied in combination with conjugated estrogen and has been reported to improve bone mineral density and other symptoms of menopause, like vasomotor symptoms and vulvo-vaginal atrophy, but its efficacy in reducing fracture risk has not been demonstrated [30,31].
Teriparatide is an anabolic agent that works by stimulating osteoblastic bone formation which results in an increase in bone density and reduction in both vertebral and non-vertebral fracture risk. In women with postmenopausal osteoporosis, it is typically reserved for those with very low bone mineral density (BMD) or those who continue to have fractures despite a bisphosphonate [32]. Barriers to use of teriparatide include high cost, the need for daily injections, and approved use for a total of two years in a lifetime. There is also a theoretical risk of osteosarcoma shown in animal studies but human cases have not been reported when used for postmenopausal osteoporosis. Published studies have shown that combination zolendronate and teriparatide have additive benefits to spine and hip BMD [33]. Another study reported that the combination of denosumab and teriparatide resulted in additive effects, ie, an increase in lumbar, hip, and femoral neck BMD [34]. These combinations have not been studied in populations large enough or for long enough duration to evaluate fracture risk reduction.
Adherence to Osteoporosis Medications
Treatment of osteoporosis reduces risk of fracture, but the benefit of osteoporosis medications is dependent on adherence. Adherence is associated with improved clinical outcomes [35,36] as well as reduced costs and utilization [37,38]; however, adherence to osteoporosis medications is poor. In a meta-analysis of 24 observational studies conducted in large populations, overall adherence for all osteoporosis therapies ranged from approximately 40% to 70% [39]. A recent retrospective claims database analysis in the U.S. reported a 60% noncompliance rate among the 57,913 postmenopausal women prescribed bisphosphonates over 1 year [40]. Another administrative database analysis from a managed care population compared the 3 oral bisphosphonates (risedronate, ibandronate, and alendronate) and found a mean medication possession ratio (MPR) between 0.57–0.58 at 12 months, which dropped to 0.47–0.50 after 24 months and 0.44–0.47 after 36 months [41]. In an observational study of 3200 older women in the U.K. low adherence was self-reported in 8.5%, and 21.6% self-discontinued treatment within 2 years [42]. In a study of Medicare Advantage prescription drug plan members, a small but significant increase in adherence was seen after osteo-porosis treatment change but overall adherence remained low (51% MPR in the change cohort and vs. 44% in the no-change cohort at 24 months, P < 0.01) [43].
Some patients restart osteoporosis therapy after a prolonged lapse in medication use. In one study, re-initiation rates for bisphosphonate therapy among persons who discontinued were as high as 30% within 6 months and 50% within 2 years [44]. Predictors of treatment re-initiation included younger age, female sex, history of fracture, recent hip fracture, nursing home discharge, and BMD testing [44].
Factors that Impact Adherence
Understanding which patients are most likely to be compliant with medications can aid physicians when monitoring osteoporosis treatment responses. In a retro-spective claims analysis, older age was found to be a predictor of compliance: women 65 years and older were more likely to be compliant than younger patients (P = 0.012) [45]. Among women receiving denosumab, improved adherence was found among women with a family history of a parent with a hip fracture, and lower adherence was seen in those with higher age, decreased mobility, and further distance from the clinic where the medication was provided [46].
Major reasons for nonadherence include a fear of potential side effects, occurrence of real side effects, the complicated dosing regimens, and perceived lack of benefit from the medications due to the asymptomatic nature of osteoporosis. In the above noted observational study from the U.K., more than half of the nonadherent patients attributed their nonadherence to side effects (53.9%), with a smaller proportion reporting fear of potential side effects (20.5%) or trouble with the dosing regimen (8.0%)[42].
Patients may also be unwilling to continue to take an osteoporosis medication if a fracture develops while on it and if they are not otherwise provided evidence that the medication is working. In a study by Costa Paiva et al, an understanding and knowledge to osteoporosis was a prerequisite to adherence and the strongest predictor of knowledge was higher education level [47]. Factors that impaired adherence were lower socioeconomic status and presence of comorbidities [47]. In a phenomenological qualitative study, trust in a health care provider was the most common reason for patients’ decision to accept an osteoporosis medication, emphasizing the importance of physician-patient communication [48].
Interventions to Enhance Adherence
Current methods of improving adherence for chronic health problems are mostly complex and not very effective [49]. In a systematic review of interventions to improve medication adherence, only 37 out of 81 studies reported improved adherence in the treatment of chronic diseases, and multifaceted treatments were more likely to succeed [49]. Improving adherence to osteoporosis medications is a complex issue, and a number of interventions evaluated in systematic reviews have shown limited efficacy [50,51]. Simplification of dosing regimens have been found to have a significant impact in chronic disease management [52,53] as well as in some studies of osteoporosis medications.
Simplification of Dosing
Among women prescribed daily vs. weekly bisphosphonates, those on the weekly regimen had significantly higher compliance [54]. However, rates were suboptimal in both groups and more than 50% of women discontinued at 1 year [54]. In addition, in a meta-analysis of osteoporosis medication adherence, a nearly two-fold higher odds of discontinuation with daily vs. weekly bisphosphonates was seen (odds ratio 1.90, 95% CI 1.81–2.00) [55]. Likewise, in a retrospective study in Spain, nearly 85% of those started on a daily bisphosphonate stopped within a year [56], while discontinuation was significantly lower in those prescribed a weekly or monthly bisphosphonate or daily teriparatide; however, discontinuation was still nearly 50% in these groups [56].
Once monthly dosing may be preferred by some patients as there is less time involved in thinking about the disease being treated and a perception of lower likelihood of side effects. In one study, postmenopausal women who had previously stopped oral bisphosphonates due to GI side effects had high adherence rates after self-selecting either monthly oral or quarterly intravenous ibandronate therapy [57]. However, not all studies show significant differences in adherence between weekly and monthly preparations [58–60].
The newer parenteral treatment options that can be given every 6 months or once yearly have the potential to significantly improve adherence. Once a year parenteral administration of a bisphosphonate was preferred over once-weekly oral administration, according to a 1-year study in patients with low bone density previously treated with alendronate [61]. A recent study that looked at persistence with an infusion of zolendronic acid in Taiwanese patients for 48 months found that 85% of patients received at least 2 infusions [62]. In patients treated with denosumab in 4 European countries, adherence and persistence at 12 months were consistently > 80% [46]. Persistence in this study was defined as receiving the subsequent injection within 6 months ± 8 weeks of the previous injection; adherence was defined as receiving 2 consecutive injections within 6 months ± 4 weeks of each other [46].
In a study by Cramer et al, increased adherence and persistence was seen with weekly alendronate compared daily alendronate at the end of 12 months [54]. Similar results were seen in a large longitudinal cohort study of weekly vs. daily bisphosphonates but less than 50% of patients were adherent with the weekly regimen [63]. When once monthly preparations of bisphosphonates became available, studies continued to support a patient preference for less frequently dosed bisphosphonates, with the majority of patients preferring monthly over weekly dosed medications [64–66].
The availability of quarterly ibandronate and yearly zoledronic acid infusions have further simplified dosing. In large, randomized, multicenter studies, patients consistently expressed a preference for yearly infusions over a weekly oral medication [61,67]. Adherence and persistence to osteoporosis medications was also greater in women receiving intravenous ibandronate compared to those receiving oral alendronate [68,69]. However, a study by Curtis et al showed low persistence with intravenous bisphosphonates in a Medicare population [70]. A possible reason for the lower adherence in this population was postulated to include the provision of the infusions at an outpatient center rather than a physician office. Automated nursing reminders with either phone calls or emails have the potential to mitigate the problem of persistence with this less frequent regimen [71,72]. In a review of patient preferences, less frequent dosing of medications was a common desire, but further generalizability were limited, emphasizing the need to individualize treatment [73].
Patient-Provider Communication
Individualizing treatment with better patient-provider communication and identification of potential barriers may increase compliance [74]. In one study, increasing patient participation in determining the treatment option was associated with improved patient adherence [57]. A systematic review of literature on interventions to improve adherence found that periodic follow-up interaction between patients and their health professionals also improved adherence [50]. Positive reinforcement via physician-patient discussion of either bone turnover markers or bone mineral density test results has also been found to improve long-term adherence with osteoporosis medications [71,75].
Better perceived physician knowledge may help with patient adherence. A study by Pickney et al reported that the patient confidence in their health care providers has influence on improved adherence, and patients were more likely to comply when the medications were prescribed by a specialist rather than a general practitioner [76].
Education, Reminders, Phone-Based
Improving patient knowledge of osteoporosis, especially with education using visual aids, may help with improving adherence [47]. In a randomized controlled trial at a single health management organization, an interactive voice response phone call plus a letter 1 week later increased the rate of obtaining a prescribed oral bisphosphonate in the intervention group (48.8% vs. 30.5% control; OR 2.3, 95% CI 1.34–3.94) when adjusted for age, sex, prior BMD, and fracture [77]. Use of an encounter decision aid also improved knowledge of osteoporosis medication options and led to a doubling of medication prescription attainment. However, adherence at 6 months was not improved [78].
Pill reminders in the form of text messages, paging systems on medication devices, and alarm beeps have been studied in patients with chronic diseases, and these technologies could be utilized for osteoporosis treatment [79–81]. A study of smart phone applications showed that many apps help with adherence, especially in noncompliant patients [82]. The researchers reported that of apps studied, MyMedSchedule, MyMeds, and RxmindMe were among the most highly rated due to their ease of use and enhanced functions. Solomon et all studied the effectiveness of a telephone-based counseling program using motivational interviewing in a large randomized study. They found no significant improvement in adherence to an osteoporosis regimen with the telephonic motivational interview compared to mailed educational materials (control group) (P = 0.07) [83]. In a 12-month multicenter, prospective randomized study, Bianchi et al examined the effectiveness of an intervention of reminders or reminders plus phone calls and meetings at the referral center in postmenopausal women initiating an oral osteoporosis prescription. No significant difference was seen in adherence at 12 months compared to standard care [84]. Adherence among the entire cohort, however, was very high [84]
Pharmacist-Based
The role of pharmacists in the treatment of chronic diseases, including osteoporosis, has been studied and shown to be cost-effective. In a study by van Boven et al, an algorithm was designed to detect patients with nonadherence and then tailor an intervention that consisted of structured counseling and active monitoring by pharmacists in initial and continuous phases [85]. This effort-intensive intervention resulted in reduced discontinuation of bisphosphonates after 12 months (reduction from 31.7% to 16.2% at 12 months) [85]. Despite the effort required, findings from the study support overall cost-effectiveness of this intervention [85]. A randomized controlled study by Lai et al showed that pharmacists can play a role in improving medication adherence through counseling patients on the importance of adherence, side effects, and goals of therapy [86]. The same authors also showed that involvement of a clinical pharmacist in the care of patients helped to further improve patient knowledge of medications and osteoporosis treatments, resolve medication-related concerns, and improve overall quality of life [87]. Such pharmacist-led interventions would require pharmacists to understand their role and the potential for drug holidays in the course of osteoporosis treatments and not mislabel patients as nonadherent when in fact purposefully holding osteoporosis medications [88].
Conclusion
Osteoporosis is a growing problem with increasing numbers of patients at risk for osteoporosis and related fractures. Currently available osteoporosis medications have shown clear benefit in reducing fracture risk; however, adherence to these therapies is required to obtain benefit. Unfortunately, osteoporosis medications have several limitations to full compliance, particularly the oral treatment options, including known possible side effects acutely and chronically, potential/feared side effects, irregular dosing intervals, complicated dosing instructions, and absence of an immediate recognizable benefit/effect. Improving adherence is complex [89] and tailoring to individual patients is of importance. Successful techniques for improving adherence may include a focus on physician-patient communication, use of the less frequently dosed medications, various medication reminders, use of available technology, and use of pharmacists for patient counseling and monitoring. Recognition of this common problem by clinicians is of utmost importance.
Corresponding author: Amy H. Warriner, MD, The University of Alabama at Birmingham, Division of Endocrinology, Diabetes and Metabolism, 702 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35294, [email protected].
Financial disclosures: None.
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62. Hsieh PC. Effectiveness and safety of zoledronic acid in the treatment of osteoporosis. Orthopedics. 2016:1–8.
63. 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(7):856–61.
64. Emkey R, Koltun W, Beusterien K, et al. Patient preference for once-monthly ibandronate versus once-weekly alendronate in a randomized, open-label, cross-over trial: the Boniva Alendronate Trial in Osteoporosis (BALTO). Curr Med Res Opin. 2005;21(12):1895–903.
65. Hadji P, Minne H, Pfeifer M, et al. Treatment preference for monthly oral ibandronate and weekly oral alendronate in women with postmenopausal osteoporosis: A randomized, crossover study (BALTO II). Joint Bone Spine. 2008;75(3):303–10.
66. Ryzner KL, Burkiewicz JS, Griffin BL, Komperda KE. Survey of bisphosphonate regimen preferences in an urban community health center. Consult Pharm. 2010;25(10):671–5.
67. Saag K, Lindsay R, Kriegman A, et al. A single zoledronic acid infusion reduces bone resorption markers more rapidly than weekly oral alendronate in postmenopausal women with low bone mineral density. Bone. 2007;40(5):1238–43.
68. Hadji P, Felsenberg D, Amling M, et al. The non-interventional BonViva Intravenous Versus Alendronate (VIVA) study: real-world adherence and persistence to medication, efficacy, and safety, in patients with postmenopausal osteoporosis. Osteoporos Int. 2014;25(1):339–47.
69. Ziller V, Kostev K, Kyvernitakis I, et al. Persistence and compliance of medications used in the treatment of osteoporosis--analysis using a large scale, representative, longitudinal German database. Int J Clin Pharmacol Ther. 2012;50(5):315–22.
70. Curtis JR, Yun H, Matthews R, et al. Adherence with intravenous zoledronate and intravenous ibandronate in the United States Medicare population. Arthritis Care Res (Hoboken). 2012;64(7):1054–60.
71. 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(3):1117–23.
72. Cooper A, Drake J, Brankin E; PERSIST Investigators. Treatment persistence with once-monthly ibandronate and patient support vs. once-weekly alendronate: results from the PERSIST study. Int J Clin Pract. 2006;60(8):896–905.
73. Hiligsmann M, Bours SP, Boonen A. A review of patient preferences for osteoporosis drug treatment. Curr Rheumatol Rep. 2015;17(9):61.
74. Bond WS, Hussar DA. Detection methods and strategies for improving medication compliance. Am J Hosp Pharm. 1991;48(9):1978–88.
75. Delmas PD, Vrijens B, Eastell R, et al. Effect of monitoring bone turnover markers on persistence with risedronate treatment of postmenopausal osteoporosis. J Clin Endocrinol Metab. 2007;92(4):1296–304.
76. Pickney CS, Arnason JA. Correlation between patient recall of bone densitometry results and subsequent treatment adherence. Osteoporos Int. 2005;16(9):1156–60.
77. Cizmic AD, Heilmann RM, Milchak JL, et al. Impact of interactive voice response technology on primary adherence to bisphosphonate therapy: a randomized controlled trial. Osteoporos Int. 2015;26(8):2131–6.
78. LeBlanc A, Wang AT, Wyatt K, et al. Encounter Decision Aid vs. Clinical Decision Support or Usual Care to Support Patient-Centered Treatment Decisions in Osteoporosis: The Osteoporosis Choice Randomized Trial II. PLoS One. 2015;10(5):e0128063.
79. Tao D, Xie L, Wang T, Wang T. A meta-analysis of the use of electronic reminders for patient adherence to medication in chronic disease care. J Telemed Telecare. 2015;21(1):3–13.
80. Vervloet M, van Dijk L, Santen-Reestman J, et al. SMS reminders improve adherence to oral medication in type 2 diabetes patients who are real time electronically monitored. Int J Med Inform. 2012;81(9):594–604.
81. Vervloet M, Linn AJ, van Weert JC, et al. The effectiveness of interventions using electronic reminders to improve adherence to chronic medication: a systematic review of the literature. J Am Med Inform Assoc. 2012;19(5):696–704.
82. Dayer L, Heldenbrand S, Anderson P, et al. Smartphone medication adherence apps: potential benefits to patients and providers. J Am Pharm Assoc (2003). 2013;53(2):172–81.
83. Solomon DH, Iversen MD, Avorn J, et al. Osteoporosis telephonic intervention to improve medication regimen adherence: a large, pragmatic, randomized controlled trial. Arch Intern Med. 2012;172(6):477–83.
84. Bianchi ML, Duca P, Vai S, et al. Improving adherence to and persistence with oral therapy of osteoporosis. Osteoporos Int. 2015;26(5):1629–38.
85. van Boven JF, Stuurman-Bieze AG, Hiddink EG, et al. Medication monitoring and optimization: a targeted pharmacist program for effective and cost-effective improvement of chronic therapy adherence. J Manag Care Spec Pharm. 2014;20(8):786–92.
86. Lai PS, Chua SS, Chan SP. Pharmaceutical care issues encountered by post-menopausal osteoporotic women prescribed bisphosphonates. J Clin Pharm Ther. 2012;37(5):536–43.
87. Lai PS, Chua SS, Chan SP. Impact of pharmaceutical care on knowledge, quality of life and satisfaction of postmenopausal women with osteoporosis. Int J Clin Pharm. 2013;35(4):629–37.
88. Murphy-Menezes M. Role of the pharmacist in medication therapy management services in patients with osteoporosis. Clin Ther. 2015;37(7):1573–86.
89. Salter C, McDaid L, Bhattacharya D, et al. Abandoned acid? Understanding adherence to bisphosphonate medications for the prevention of osteoporosis among older women: a qualitative longitudinal study. PLoS One. 2014;9(1):e83552.
From the Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract
- Objective: To review the treatment of osteoporosis, challenges to treatment adherence, and factors associated with improved adherence.
- Methods: Review of the literature.
- Results: With the growing aging population, there is an increased number of people at risk of osteoporosis and fracture. Several medications are available that reduce the risk of fracture. However, adherence to osteoporosis medications is suboptimal. Factors related to nonadherence include dosing frequency, real side effects, and concern about potential side effects. Interventions that may improve adherence include clinician and patient education, less frequent and less complex dosing regimens, medication reminders, and adherence counseling.
- Conclusions: Improving adherence to osteoporosis medications is a complex and challenging issue. Considering and implementing strategies to improve adherence tailored to patient preferences may enhance long-term outcomes for patients with osteoporosis.
Osteoporosis is a chronic but asymptomatic disease that is characterized by an increased fragility of bones and increased risk of fractures. Hip and vertebral fractures are associated with the greatest morbidity and mortality. The prevalence of osteoporosis is estimated to be 10.3% in the US, with approximately 10.2 million adults over the age of 50 having osteoporosis based on 2010 census data and results from the National Health and Nutrition Examination Survey (NHANES) [1].
Several drugs are currently available for the treatment of osteoporosis, but adherence to treatment is low. Understanding the factors associated with low adherence and actions that can be taken to improve adherence to treatment is important given the large number of individuals with osteoporosis and the need to reduce the burden caused by fragility fracture. In this article, we review the treatment of osteoporosis, challenges to treatment adherence, and factors associated with improved adherence.
Nonprescription Medications
Calcium
There have been several published studies over the last decade evaluating calcium supplementation and its efficacy in reducing fractures. Although these studies showed that calcium reduces bone turnover by 20% and slowed postmenopausal bone loss by one third [2,3], none of these studies or a recent systematic review [4] showed any degree of fracture risk reduction with calcium supplements alone.
Although some calcium intake may be good, too much calcium has the potential to cause harm, including an increased risk of nephrolithiasis and constipation/bloating. An analysis of the Women’s Health Initiative (WHI) study reported a 17% increase in renal calculi in women who received calcium and vitamin D supplements [5]. Another recently published meta-analysis showed a 43% increase in gastrointestinal complaints in patients who were taking calcium supplements [6]. The potential for increased cardiovascular risk with calcium supplements is controversial [7]. The WHI study did not show an increased occurrence of cardiovascular events among those taking calcium supplements [8]. In a different population, men who consumed more than 1000 mg per day of supplemental calcium had higher all-cause and cardiovascular disease-specific mortality [9]. Large, well-conducted randomized controlled trials will be needed to further elucidate the question of calcium supplementation and risk of cardiovascular disease.
Vitamin D
Deficiency of vitamin D is common with one study finding more than 90% of older adults deficient in vitamin D [10]. Vitamin D is essential for proper calcium metabolism and deficiency is known to induce secondary hyperparathyroidism. Studies in mouse models have also shown that normal vitamin D receptors in enterocytes are essential for normal bone mineralization [11,12]. A systematic Cochrane database review showed that vitamin D3 supplementation decreased mortality in elderly people living independently or in institutional care [13]. Vitamin D was administered for a weighted mean of 4.4 years. Vitamin D2, alfacalcidol, and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium was associated with an increased risk of nephrolithiasis during a follow-up period of 1.25 to 7 years (relative risk [RR] 1.17, 95% confidence interval (CI) 1.02–1.34) [13]. The inconsistencies of published reports looking at benefits of vitamin D supplementation may be due in part to variability in compliance with taking the supplements and baseline vitamin D levels.
Two randomized controlled trials have shown that low vitamin D appears to be an independent predictor of fall risk, and vitamin D supplementation has been found to reduce this risk of falls, through improved musculo-skeletal function [14–16]. Thus, vitamin D may play a role in fracture risk reduction beyond direct bone effects.
Prescription Osteoporosis Treatments
Bisphosphonates
Bisphosphonates are the most commonly prescribed medication for osteoporosis. The efficacy of bisphosphonates to reduce fractures is well established. There are oral bisphosphonates, which can be dosed daily, weekly, or monthly, and intravenous bisphosphonates, which can be given every 3 months or annually. Side effects with this class of medications include gastrointestinal effects with the oral options in up to 20% to 30% of users [17]. With intravenous bisphosphonates, the greatest risk is an acute phase response, which can occur in up to 42% of patients [18]. The risk of an acute phase reaction is much lower with doses beyond the first dose and lower if patients have ever previously taken an oral bisphosphonate and/or receive acetaminophen prior to the infusion. Other potential side effects with all bisphosphonates include osteonecrosis of jaw (ONJ) and atypical subtrochanteric fractures. Post marketing studies have indicated that the incidence of ONJ is less than 2 per 100,000 patient-years among those taking bisphosphonates [19,20]. A number of database analyses have shown that ONJ-like lesions can also occur in older individuals with osteoporosis who have never been exposed to bisphosphonates [21]. A case series of an osteoporotic population showed that ONJ-like lesions are lower grade than those typically seen in cancer patients who usually are exposed to higher doses of bisphosphonates [22]. A study of Swedish older men and women reported that long-term use of bisphosphonates (4 years or more) was associated with an increased incidence of atypical fractures. The RR for women was 126.0 (95% CI, 55.1–288.1) after 4 years of bisphosphonates [23]. A U.S. health care database analysis reported that 90% of those with atypical fractures were bisphosphonate users, almost half were Asian (49%), and use beyond 6 years showed the greatest risk [24].
Non-Bisphosphonate Medications
Other osteoporosis medications include denosumab, raloxifene, estrogen, and teriparatide (calcitonin will not be discussed here). Newer options currently under study, including cathepsin K inhibitors and anti-sclerostin therapies, are not available in the United States.
Denosumab is a monoclonal antibody that interferes with the receptor activator of nuclear kappa B ligand (RANK-L), which is the principal stimulus for osteoclastogenesis. Denosumab is administered once every 6 months subcutaneously. Phase III trials of denosumab demonstrated a 68% reduction in vertebral fractures and 40% and 20% reduction in fractures at hip and non-vertebral sites, respectively [25]. Similar to bisphosphonates, other risks include atypical femoral fractures and ONJ. In addition, hypocalcemia, including severe, symptomatic hypocalcemia, has been reported at rates higher than initially reported in the original clinical trials [26]. Hypocalcemia can be severe, especially in patients who are deficient in vitamin D [10,27].
Estrogen is effective in reducing the risk of vertebral fractures. Selective estrogen receptor modulators (SERMs) have both estrogen agonist and antagonist effects. The SERM, raloxifene, has been used in osteoporosis for its antiresorptive effects through the estrogen receptor [28,29]. A newer SERM, bazedoxifene, has been studied in combination with conjugated estrogen and has been reported to improve bone mineral density and other symptoms of menopause, like vasomotor symptoms and vulvo-vaginal atrophy, but its efficacy in reducing fracture risk has not been demonstrated [30,31].
Teriparatide is an anabolic agent that works by stimulating osteoblastic bone formation which results in an increase in bone density and reduction in both vertebral and non-vertebral fracture risk. In women with postmenopausal osteoporosis, it is typically reserved for those with very low bone mineral density (BMD) or those who continue to have fractures despite a bisphosphonate [32]. Barriers to use of teriparatide include high cost, the need for daily injections, and approved use for a total of two years in a lifetime. There is also a theoretical risk of osteosarcoma shown in animal studies but human cases have not been reported when used for postmenopausal osteoporosis. Published studies have shown that combination zolendronate and teriparatide have additive benefits to spine and hip BMD [33]. Another study reported that the combination of denosumab and teriparatide resulted in additive effects, ie, an increase in lumbar, hip, and femoral neck BMD [34]. These combinations have not been studied in populations large enough or for long enough duration to evaluate fracture risk reduction.
Adherence to Osteoporosis Medications
Treatment of osteoporosis reduces risk of fracture, but the benefit of osteoporosis medications is dependent on adherence. Adherence is associated with improved clinical outcomes [35,36] as well as reduced costs and utilization [37,38]; however, adherence to osteoporosis medications is poor. In a meta-analysis of 24 observational studies conducted in large populations, overall adherence for all osteoporosis therapies ranged from approximately 40% to 70% [39]. A recent retrospective claims database analysis in the U.S. reported a 60% noncompliance rate among the 57,913 postmenopausal women prescribed bisphosphonates over 1 year [40]. Another administrative database analysis from a managed care population compared the 3 oral bisphosphonates (risedronate, ibandronate, and alendronate) and found a mean medication possession ratio (MPR) between 0.57–0.58 at 12 months, which dropped to 0.47–0.50 after 24 months and 0.44–0.47 after 36 months [41]. In an observational study of 3200 older women in the U.K. low adherence was self-reported in 8.5%, and 21.6% self-discontinued treatment within 2 years [42]. In a study of Medicare Advantage prescription drug plan members, a small but significant increase in adherence was seen after osteo-porosis treatment change but overall adherence remained low (51% MPR in the change cohort and vs. 44% in the no-change cohort at 24 months, P < 0.01) [43].
Some patients restart osteoporosis therapy after a prolonged lapse in medication use. In one study, re-initiation rates for bisphosphonate therapy among persons who discontinued were as high as 30% within 6 months and 50% within 2 years [44]. Predictors of treatment re-initiation included younger age, female sex, history of fracture, recent hip fracture, nursing home discharge, and BMD testing [44].
Factors that Impact Adherence
Understanding which patients are most likely to be compliant with medications can aid physicians when monitoring osteoporosis treatment responses. In a retro-spective claims analysis, older age was found to be a predictor of compliance: women 65 years and older were more likely to be compliant than younger patients (P = 0.012) [45]. Among women receiving denosumab, improved adherence was found among women with a family history of a parent with a hip fracture, and lower adherence was seen in those with higher age, decreased mobility, and further distance from the clinic where the medication was provided [46].
Major reasons for nonadherence include a fear of potential side effects, occurrence of real side effects, the complicated dosing regimens, and perceived lack of benefit from the medications due to the asymptomatic nature of osteoporosis. In the above noted observational study from the U.K., more than half of the nonadherent patients attributed their nonadherence to side effects (53.9%), with a smaller proportion reporting fear of potential side effects (20.5%) or trouble with the dosing regimen (8.0%)[42].
Patients may also be unwilling to continue to take an osteoporosis medication if a fracture develops while on it and if they are not otherwise provided evidence that the medication is working. In a study by Costa Paiva et al, an understanding and knowledge to osteoporosis was a prerequisite to adherence and the strongest predictor of knowledge was higher education level [47]. Factors that impaired adherence were lower socioeconomic status and presence of comorbidities [47]. In a phenomenological qualitative study, trust in a health care provider was the most common reason for patients’ decision to accept an osteoporosis medication, emphasizing the importance of physician-patient communication [48].
Interventions to Enhance Adherence
Current methods of improving adherence for chronic health problems are mostly complex and not very effective [49]. In a systematic review of interventions to improve medication adherence, only 37 out of 81 studies reported improved adherence in the treatment of chronic diseases, and multifaceted treatments were more likely to succeed [49]. Improving adherence to osteoporosis medications is a complex issue, and a number of interventions evaluated in systematic reviews have shown limited efficacy [50,51]. Simplification of dosing regimens have been found to have a significant impact in chronic disease management [52,53] as well as in some studies of osteoporosis medications.
Simplification of Dosing
Among women prescribed daily vs. weekly bisphosphonates, those on the weekly regimen had significantly higher compliance [54]. However, rates were suboptimal in both groups and more than 50% of women discontinued at 1 year [54]. In addition, in a meta-analysis of osteoporosis medication adherence, a nearly two-fold higher odds of discontinuation with daily vs. weekly bisphosphonates was seen (odds ratio 1.90, 95% CI 1.81–2.00) [55]. Likewise, in a retrospective study in Spain, nearly 85% of those started on a daily bisphosphonate stopped within a year [56], while discontinuation was significantly lower in those prescribed a weekly or monthly bisphosphonate or daily teriparatide; however, discontinuation was still nearly 50% in these groups [56].
Once monthly dosing may be preferred by some patients as there is less time involved in thinking about the disease being treated and a perception of lower likelihood of side effects. In one study, postmenopausal women who had previously stopped oral bisphosphonates due to GI side effects had high adherence rates after self-selecting either monthly oral or quarterly intravenous ibandronate therapy [57]. However, not all studies show significant differences in adherence between weekly and monthly preparations [58–60].
The newer parenteral treatment options that can be given every 6 months or once yearly have the potential to significantly improve adherence. Once a year parenteral administration of a bisphosphonate was preferred over once-weekly oral administration, according to a 1-year study in patients with low bone density previously treated with alendronate [61]. A recent study that looked at persistence with an infusion of zolendronic acid in Taiwanese patients for 48 months found that 85% of patients received at least 2 infusions [62]. In patients treated with denosumab in 4 European countries, adherence and persistence at 12 months were consistently > 80% [46]. Persistence in this study was defined as receiving the subsequent injection within 6 months ± 8 weeks of the previous injection; adherence was defined as receiving 2 consecutive injections within 6 months ± 4 weeks of each other [46].
In a study by Cramer et al, increased adherence and persistence was seen with weekly alendronate compared daily alendronate at the end of 12 months [54]. Similar results were seen in a large longitudinal cohort study of weekly vs. daily bisphosphonates but less than 50% of patients were adherent with the weekly regimen [63]. When once monthly preparations of bisphosphonates became available, studies continued to support a patient preference for less frequently dosed bisphosphonates, with the majority of patients preferring monthly over weekly dosed medications [64–66].
The availability of quarterly ibandronate and yearly zoledronic acid infusions have further simplified dosing. In large, randomized, multicenter studies, patients consistently expressed a preference for yearly infusions over a weekly oral medication [61,67]. Adherence and persistence to osteoporosis medications was also greater in women receiving intravenous ibandronate compared to those receiving oral alendronate [68,69]. However, a study by Curtis et al showed low persistence with intravenous bisphosphonates in a Medicare population [70]. A possible reason for the lower adherence in this population was postulated to include the provision of the infusions at an outpatient center rather than a physician office. Automated nursing reminders with either phone calls or emails have the potential to mitigate the problem of persistence with this less frequent regimen [71,72]. In a review of patient preferences, less frequent dosing of medications was a common desire, but further generalizability were limited, emphasizing the need to individualize treatment [73].
Patient-Provider Communication
Individualizing treatment with better patient-provider communication and identification of potential barriers may increase compliance [74]. In one study, increasing patient participation in determining the treatment option was associated with improved patient adherence [57]. A systematic review of literature on interventions to improve adherence found that periodic follow-up interaction between patients and their health professionals also improved adherence [50]. Positive reinforcement via physician-patient discussion of either bone turnover markers or bone mineral density test results has also been found to improve long-term adherence with osteoporosis medications [71,75].
Better perceived physician knowledge may help with patient adherence. A study by Pickney et al reported that the patient confidence in their health care providers has influence on improved adherence, and patients were more likely to comply when the medications were prescribed by a specialist rather than a general practitioner [76].
Education, Reminders, Phone-Based
Improving patient knowledge of osteoporosis, especially with education using visual aids, may help with improving adherence [47]. In a randomized controlled trial at a single health management organization, an interactive voice response phone call plus a letter 1 week later increased the rate of obtaining a prescribed oral bisphosphonate in the intervention group (48.8% vs. 30.5% control; OR 2.3, 95% CI 1.34–3.94) when adjusted for age, sex, prior BMD, and fracture [77]. Use of an encounter decision aid also improved knowledge of osteoporosis medication options and led to a doubling of medication prescription attainment. However, adherence at 6 months was not improved [78].
Pill reminders in the form of text messages, paging systems on medication devices, and alarm beeps have been studied in patients with chronic diseases, and these technologies could be utilized for osteoporosis treatment [79–81]. A study of smart phone applications showed that many apps help with adherence, especially in noncompliant patients [82]. The researchers reported that of apps studied, MyMedSchedule, MyMeds, and RxmindMe were among the most highly rated due to their ease of use and enhanced functions. Solomon et all studied the effectiveness of a telephone-based counseling program using motivational interviewing in a large randomized study. They found no significant improvement in adherence to an osteoporosis regimen with the telephonic motivational interview compared to mailed educational materials (control group) (P = 0.07) [83]. In a 12-month multicenter, prospective randomized study, Bianchi et al examined the effectiveness of an intervention of reminders or reminders plus phone calls and meetings at the referral center in postmenopausal women initiating an oral osteoporosis prescription. No significant difference was seen in adherence at 12 months compared to standard care [84]. Adherence among the entire cohort, however, was very high [84]
Pharmacist-Based
The role of pharmacists in the treatment of chronic diseases, including osteoporosis, has been studied and shown to be cost-effective. In a study by van Boven et al, an algorithm was designed to detect patients with nonadherence and then tailor an intervention that consisted of structured counseling and active monitoring by pharmacists in initial and continuous phases [85]. This effort-intensive intervention resulted in reduced discontinuation of bisphosphonates after 12 months (reduction from 31.7% to 16.2% at 12 months) [85]. Despite the effort required, findings from the study support overall cost-effectiveness of this intervention [85]. A randomized controlled study by Lai et al showed that pharmacists can play a role in improving medication adherence through counseling patients on the importance of adherence, side effects, and goals of therapy [86]. The same authors also showed that involvement of a clinical pharmacist in the care of patients helped to further improve patient knowledge of medications and osteoporosis treatments, resolve medication-related concerns, and improve overall quality of life [87]. Such pharmacist-led interventions would require pharmacists to understand their role and the potential for drug holidays in the course of osteoporosis treatments and not mislabel patients as nonadherent when in fact purposefully holding osteoporosis medications [88].
Conclusion
Osteoporosis is a growing problem with increasing numbers of patients at risk for osteoporosis and related fractures. Currently available osteoporosis medications have shown clear benefit in reducing fracture risk; however, adherence to these therapies is required to obtain benefit. Unfortunately, osteoporosis medications have several limitations to full compliance, particularly the oral treatment options, including known possible side effects acutely and chronically, potential/feared side effects, irregular dosing intervals, complicated dosing instructions, and absence of an immediate recognizable benefit/effect. Improving adherence is complex [89] and tailoring to individual patients is of importance. Successful techniques for improving adherence may include a focus on physician-patient communication, use of the less frequently dosed medications, various medication reminders, use of available technology, and use of pharmacists for patient counseling and monitoring. Recognition of this common problem by clinicians is of utmost importance.
Corresponding author: Amy H. Warriner, MD, The University of Alabama at Birmingham, Division of Endocrinology, Diabetes and Metabolism, 702 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35294, [email protected].
Financial disclosures: None.
From the Division of Endocrinology, Diabetes, and Metabolism, University of Alabama at Birmingham, Birmingham, Alabama.
Abstract
- Objective: To review the treatment of osteoporosis, challenges to treatment adherence, and factors associated with improved adherence.
- Methods: Review of the literature.
- Results: With the growing aging population, there is an increased number of people at risk of osteoporosis and fracture. Several medications are available that reduce the risk of fracture. However, adherence to osteoporosis medications is suboptimal. Factors related to nonadherence include dosing frequency, real side effects, and concern about potential side effects. Interventions that may improve adherence include clinician and patient education, less frequent and less complex dosing regimens, medication reminders, and adherence counseling.
- Conclusions: Improving adherence to osteoporosis medications is a complex and challenging issue. Considering and implementing strategies to improve adherence tailored to patient preferences may enhance long-term outcomes for patients with osteoporosis.
Osteoporosis is a chronic but asymptomatic disease that is characterized by an increased fragility of bones and increased risk of fractures. Hip and vertebral fractures are associated with the greatest morbidity and mortality. The prevalence of osteoporosis is estimated to be 10.3% in the US, with approximately 10.2 million adults over the age of 50 having osteoporosis based on 2010 census data and results from the National Health and Nutrition Examination Survey (NHANES) [1].
Several drugs are currently available for the treatment of osteoporosis, but adherence to treatment is low. Understanding the factors associated with low adherence and actions that can be taken to improve adherence to treatment is important given the large number of individuals with osteoporosis and the need to reduce the burden caused by fragility fracture. In this article, we review the treatment of osteoporosis, challenges to treatment adherence, and factors associated with improved adherence.
Nonprescription Medications
Calcium
There have been several published studies over the last decade evaluating calcium supplementation and its efficacy in reducing fractures. Although these studies showed that calcium reduces bone turnover by 20% and slowed postmenopausal bone loss by one third [2,3], none of these studies or a recent systematic review [4] showed any degree of fracture risk reduction with calcium supplements alone.
Although some calcium intake may be good, too much calcium has the potential to cause harm, including an increased risk of nephrolithiasis and constipation/bloating. An analysis of the Women’s Health Initiative (WHI) study reported a 17% increase in renal calculi in women who received calcium and vitamin D supplements [5]. Another recently published meta-analysis showed a 43% increase in gastrointestinal complaints in patients who were taking calcium supplements [6]. The potential for increased cardiovascular risk with calcium supplements is controversial [7]. The WHI study did not show an increased occurrence of cardiovascular events among those taking calcium supplements [8]. In a different population, men who consumed more than 1000 mg per day of supplemental calcium had higher all-cause and cardiovascular disease-specific mortality [9]. Large, well-conducted randomized controlled trials will be needed to further elucidate the question of calcium supplementation and risk of cardiovascular disease.
Vitamin D
Deficiency of vitamin D is common with one study finding more than 90% of older adults deficient in vitamin D [10]. Vitamin D is essential for proper calcium metabolism and deficiency is known to induce secondary hyperparathyroidism. Studies in mouse models have also shown that normal vitamin D receptors in enterocytes are essential for normal bone mineralization [11,12]. A systematic Cochrane database review showed that vitamin D3 supplementation decreased mortality in elderly people living independently or in institutional care [13]. Vitamin D was administered for a weighted mean of 4.4 years. Vitamin D2, alfacalcidol, and calcitriol had no statistically significant beneficial effects on mortality. Vitamin D3 combined with calcium was associated with an increased risk of nephrolithiasis during a follow-up period of 1.25 to 7 years (relative risk [RR] 1.17, 95% confidence interval (CI) 1.02–1.34) [13]. The inconsistencies of published reports looking at benefits of vitamin D supplementation may be due in part to variability in compliance with taking the supplements and baseline vitamin D levels.
Two randomized controlled trials have shown that low vitamin D appears to be an independent predictor of fall risk, and vitamin D supplementation has been found to reduce this risk of falls, through improved musculo-skeletal function [14–16]. Thus, vitamin D may play a role in fracture risk reduction beyond direct bone effects.
Prescription Osteoporosis Treatments
Bisphosphonates
Bisphosphonates are the most commonly prescribed medication for osteoporosis. The efficacy of bisphosphonates to reduce fractures is well established. There are oral bisphosphonates, which can be dosed daily, weekly, or monthly, and intravenous bisphosphonates, which can be given every 3 months or annually. Side effects with this class of medications include gastrointestinal effects with the oral options in up to 20% to 30% of users [17]. With intravenous bisphosphonates, the greatest risk is an acute phase response, which can occur in up to 42% of patients [18]. The risk of an acute phase reaction is much lower with doses beyond the first dose and lower if patients have ever previously taken an oral bisphosphonate and/or receive acetaminophen prior to the infusion. Other potential side effects with all bisphosphonates include osteonecrosis of jaw (ONJ) and atypical subtrochanteric fractures. Post marketing studies have indicated that the incidence of ONJ is less than 2 per 100,000 patient-years among those taking bisphosphonates [19,20]. A number of database analyses have shown that ONJ-like lesions can also occur in older individuals with osteoporosis who have never been exposed to bisphosphonates [21]. A case series of an osteoporotic population showed that ONJ-like lesions are lower grade than those typically seen in cancer patients who usually are exposed to higher doses of bisphosphonates [22]. A study of Swedish older men and women reported that long-term use of bisphosphonates (4 years or more) was associated with an increased incidence of atypical fractures. The RR for women was 126.0 (95% CI, 55.1–288.1) after 4 years of bisphosphonates [23]. A U.S. health care database analysis reported that 90% of those with atypical fractures were bisphosphonate users, almost half were Asian (49%), and use beyond 6 years showed the greatest risk [24].
Non-Bisphosphonate Medications
Other osteoporosis medications include denosumab, raloxifene, estrogen, and teriparatide (calcitonin will not be discussed here). Newer options currently under study, including cathepsin K inhibitors and anti-sclerostin therapies, are not available in the United States.
Denosumab is a monoclonal antibody that interferes with the receptor activator of nuclear kappa B ligand (RANK-L), which is the principal stimulus for osteoclastogenesis. Denosumab is administered once every 6 months subcutaneously. Phase III trials of denosumab demonstrated a 68% reduction in vertebral fractures and 40% and 20% reduction in fractures at hip and non-vertebral sites, respectively [25]. Similar to bisphosphonates, other risks include atypical femoral fractures and ONJ. In addition, hypocalcemia, including severe, symptomatic hypocalcemia, has been reported at rates higher than initially reported in the original clinical trials [26]. Hypocalcemia can be severe, especially in patients who are deficient in vitamin D [10,27].
Estrogen is effective in reducing the risk of vertebral fractures. Selective estrogen receptor modulators (SERMs) have both estrogen agonist and antagonist effects. The SERM, raloxifene, has been used in osteoporosis for its antiresorptive effects through the estrogen receptor [28,29]. A newer SERM, bazedoxifene, has been studied in combination with conjugated estrogen and has been reported to improve bone mineral density and other symptoms of menopause, like vasomotor symptoms and vulvo-vaginal atrophy, but its efficacy in reducing fracture risk has not been demonstrated [30,31].
Teriparatide is an anabolic agent that works by stimulating osteoblastic bone formation which results in an increase in bone density and reduction in both vertebral and non-vertebral fracture risk. In women with postmenopausal osteoporosis, it is typically reserved for those with very low bone mineral density (BMD) or those who continue to have fractures despite a bisphosphonate [32]. Barriers to use of teriparatide include high cost, the need for daily injections, and approved use for a total of two years in a lifetime. There is also a theoretical risk of osteosarcoma shown in animal studies but human cases have not been reported when used for postmenopausal osteoporosis. Published studies have shown that combination zolendronate and teriparatide have additive benefits to spine and hip BMD [33]. Another study reported that the combination of denosumab and teriparatide resulted in additive effects, ie, an increase in lumbar, hip, and femoral neck BMD [34]. These combinations have not been studied in populations large enough or for long enough duration to evaluate fracture risk reduction.
Adherence to Osteoporosis Medications
Treatment of osteoporosis reduces risk of fracture, but the benefit of osteoporosis medications is dependent on adherence. Adherence is associated with improved clinical outcomes [35,36] as well as reduced costs and utilization [37,38]; however, adherence to osteoporosis medications is poor. In a meta-analysis of 24 observational studies conducted in large populations, overall adherence for all osteoporosis therapies ranged from approximately 40% to 70% [39]. A recent retrospective claims database analysis in the U.S. reported a 60% noncompliance rate among the 57,913 postmenopausal women prescribed bisphosphonates over 1 year [40]. Another administrative database analysis from a managed care population compared the 3 oral bisphosphonates (risedronate, ibandronate, and alendronate) and found a mean medication possession ratio (MPR) between 0.57–0.58 at 12 months, which dropped to 0.47–0.50 after 24 months and 0.44–0.47 after 36 months [41]. In an observational study of 3200 older women in the U.K. low adherence was self-reported in 8.5%, and 21.6% self-discontinued treatment within 2 years [42]. In a study of Medicare Advantage prescription drug plan members, a small but significant increase in adherence was seen after osteo-porosis treatment change but overall adherence remained low (51% MPR in the change cohort and vs. 44% in the no-change cohort at 24 months, P < 0.01) [43].
Some patients restart osteoporosis therapy after a prolonged lapse in medication use. In one study, re-initiation rates for bisphosphonate therapy among persons who discontinued were as high as 30% within 6 months and 50% within 2 years [44]. Predictors of treatment re-initiation included younger age, female sex, history of fracture, recent hip fracture, nursing home discharge, and BMD testing [44].
Factors that Impact Adherence
Understanding which patients are most likely to be compliant with medications can aid physicians when monitoring osteoporosis treatment responses. In a retro-spective claims analysis, older age was found to be a predictor of compliance: women 65 years and older were more likely to be compliant than younger patients (P = 0.012) [45]. Among women receiving denosumab, improved adherence was found among women with a family history of a parent with a hip fracture, and lower adherence was seen in those with higher age, decreased mobility, and further distance from the clinic where the medication was provided [46].
Major reasons for nonadherence include a fear of potential side effects, occurrence of real side effects, the complicated dosing regimens, and perceived lack of benefit from the medications due to the asymptomatic nature of osteoporosis. In the above noted observational study from the U.K., more than half of the nonadherent patients attributed their nonadherence to side effects (53.9%), with a smaller proportion reporting fear of potential side effects (20.5%) or trouble with the dosing regimen (8.0%)[42].
Patients may also be unwilling to continue to take an osteoporosis medication if a fracture develops while on it and if they are not otherwise provided evidence that the medication is working. In a study by Costa Paiva et al, an understanding and knowledge to osteoporosis was a prerequisite to adherence and the strongest predictor of knowledge was higher education level [47]. Factors that impaired adherence were lower socioeconomic status and presence of comorbidities [47]. In a phenomenological qualitative study, trust in a health care provider was the most common reason for patients’ decision to accept an osteoporosis medication, emphasizing the importance of physician-patient communication [48].
Interventions to Enhance Adherence
Current methods of improving adherence for chronic health problems are mostly complex and not very effective [49]. In a systematic review of interventions to improve medication adherence, only 37 out of 81 studies reported improved adherence in the treatment of chronic diseases, and multifaceted treatments were more likely to succeed [49]. Improving adherence to osteoporosis medications is a complex issue, and a number of interventions evaluated in systematic reviews have shown limited efficacy [50,51]. Simplification of dosing regimens have been found to have a significant impact in chronic disease management [52,53] as well as in some studies of osteoporosis medications.
Simplification of Dosing
Among women prescribed daily vs. weekly bisphosphonates, those on the weekly regimen had significantly higher compliance [54]. However, rates were suboptimal in both groups and more than 50% of women discontinued at 1 year [54]. In addition, in a meta-analysis of osteoporosis medication adherence, a nearly two-fold higher odds of discontinuation with daily vs. weekly bisphosphonates was seen (odds ratio 1.90, 95% CI 1.81–2.00) [55]. Likewise, in a retrospective study in Spain, nearly 85% of those started on a daily bisphosphonate stopped within a year [56], while discontinuation was significantly lower in those prescribed a weekly or monthly bisphosphonate or daily teriparatide; however, discontinuation was still nearly 50% in these groups [56].
Once monthly dosing may be preferred by some patients as there is less time involved in thinking about the disease being treated and a perception of lower likelihood of side effects. In one study, postmenopausal women who had previously stopped oral bisphosphonates due to GI side effects had high adherence rates after self-selecting either monthly oral or quarterly intravenous ibandronate therapy [57]. However, not all studies show significant differences in adherence between weekly and monthly preparations [58–60].
The newer parenteral treatment options that can be given every 6 months or once yearly have the potential to significantly improve adherence. Once a year parenteral administration of a bisphosphonate was preferred over once-weekly oral administration, according to a 1-year study in patients with low bone density previously treated with alendronate [61]. A recent study that looked at persistence with an infusion of zolendronic acid in Taiwanese patients for 48 months found that 85% of patients received at least 2 infusions [62]. In patients treated with denosumab in 4 European countries, adherence and persistence at 12 months were consistently > 80% [46]. Persistence in this study was defined as receiving the subsequent injection within 6 months ± 8 weeks of the previous injection; adherence was defined as receiving 2 consecutive injections within 6 months ± 4 weeks of each other [46].
In a study by Cramer et al, increased adherence and persistence was seen with weekly alendronate compared daily alendronate at the end of 12 months [54]. Similar results were seen in a large longitudinal cohort study of weekly vs. daily bisphosphonates but less than 50% of patients were adherent with the weekly regimen [63]. When once monthly preparations of bisphosphonates became available, studies continued to support a patient preference for less frequently dosed bisphosphonates, with the majority of patients preferring monthly over weekly dosed medications [64–66].
The availability of quarterly ibandronate and yearly zoledronic acid infusions have further simplified dosing. In large, randomized, multicenter studies, patients consistently expressed a preference for yearly infusions over a weekly oral medication [61,67]. Adherence and persistence to osteoporosis medications was also greater in women receiving intravenous ibandronate compared to those receiving oral alendronate [68,69]. However, a study by Curtis et al showed low persistence with intravenous bisphosphonates in a Medicare population [70]. A possible reason for the lower adherence in this population was postulated to include the provision of the infusions at an outpatient center rather than a physician office. Automated nursing reminders with either phone calls or emails have the potential to mitigate the problem of persistence with this less frequent regimen [71,72]. In a review of patient preferences, less frequent dosing of medications was a common desire, but further generalizability were limited, emphasizing the need to individualize treatment [73].
Patient-Provider Communication
Individualizing treatment with better patient-provider communication and identification of potential barriers may increase compliance [74]. In one study, increasing patient participation in determining the treatment option was associated with improved patient adherence [57]. A systematic review of literature on interventions to improve adherence found that periodic follow-up interaction between patients and their health professionals also improved adherence [50]. Positive reinforcement via physician-patient discussion of either bone turnover markers or bone mineral density test results has also been found to improve long-term adherence with osteoporosis medications [71,75].
Better perceived physician knowledge may help with patient adherence. A study by Pickney et al reported that the patient confidence in their health care providers has influence on improved adherence, and patients were more likely to comply when the medications were prescribed by a specialist rather than a general practitioner [76].
Education, Reminders, Phone-Based
Improving patient knowledge of osteoporosis, especially with education using visual aids, may help with improving adherence [47]. In a randomized controlled trial at a single health management organization, an interactive voice response phone call plus a letter 1 week later increased the rate of obtaining a prescribed oral bisphosphonate in the intervention group (48.8% vs. 30.5% control; OR 2.3, 95% CI 1.34–3.94) when adjusted for age, sex, prior BMD, and fracture [77]. Use of an encounter decision aid also improved knowledge of osteoporosis medication options and led to a doubling of medication prescription attainment. However, adherence at 6 months was not improved [78].
Pill reminders in the form of text messages, paging systems on medication devices, and alarm beeps have been studied in patients with chronic diseases, and these technologies could be utilized for osteoporosis treatment [79–81]. A study of smart phone applications showed that many apps help with adherence, especially in noncompliant patients [82]. The researchers reported that of apps studied, MyMedSchedule, MyMeds, and RxmindMe were among the most highly rated due to their ease of use and enhanced functions. Solomon et all studied the effectiveness of a telephone-based counseling program using motivational interviewing in a large randomized study. They found no significant improvement in adherence to an osteoporosis regimen with the telephonic motivational interview compared to mailed educational materials (control group) (P = 0.07) [83]. In a 12-month multicenter, prospective randomized study, Bianchi et al examined the effectiveness of an intervention of reminders or reminders plus phone calls and meetings at the referral center in postmenopausal women initiating an oral osteoporosis prescription. No significant difference was seen in adherence at 12 months compared to standard care [84]. Adherence among the entire cohort, however, was very high [84]
Pharmacist-Based
The role of pharmacists in the treatment of chronic diseases, including osteoporosis, has been studied and shown to be cost-effective. In a study by van Boven et al, an algorithm was designed to detect patients with nonadherence and then tailor an intervention that consisted of structured counseling and active monitoring by pharmacists in initial and continuous phases [85]. This effort-intensive intervention resulted in reduced discontinuation of bisphosphonates after 12 months (reduction from 31.7% to 16.2% at 12 months) [85]. Despite the effort required, findings from the study support overall cost-effectiveness of this intervention [85]. A randomized controlled study by Lai et al showed that pharmacists can play a role in improving medication adherence through counseling patients on the importance of adherence, side effects, and goals of therapy [86]. The same authors also showed that involvement of a clinical pharmacist in the care of patients helped to further improve patient knowledge of medications and osteoporosis treatments, resolve medication-related concerns, and improve overall quality of life [87]. Such pharmacist-led interventions would require pharmacists to understand their role and the potential for drug holidays in the course of osteoporosis treatments and not mislabel patients as nonadherent when in fact purposefully holding osteoporosis medications [88].
Conclusion
Osteoporosis is a growing problem with increasing numbers of patients at risk for osteoporosis and related fractures. Currently available osteoporosis medications have shown clear benefit in reducing fracture risk; however, adherence to these therapies is required to obtain benefit. Unfortunately, osteoporosis medications have several limitations to full compliance, particularly the oral treatment options, including known possible side effects acutely and chronically, potential/feared side effects, irregular dosing intervals, complicated dosing instructions, and absence of an immediate recognizable benefit/effect. Improving adherence is complex [89] and tailoring to individual patients is of importance. Successful techniques for improving adherence may include a focus on physician-patient communication, use of the less frequently dosed medications, various medication reminders, use of available technology, and use of pharmacists for patient counseling and monitoring. Recognition of this common problem by clinicians is of utmost importance.
Corresponding author: Amy H. Warriner, MD, The University of Alabama at Birmingham, Division of Endocrinology, Diabetes and Metabolism, 702 Faculty Office Tower, 510 20th Street South, Birmingham, AL 35294, [email protected].
Financial disclosures: None.
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87. Lai PS, Chua SS, Chan SP. Impact of pharmaceutical care on knowledge, quality of life and satisfaction of postmenopausal women with osteoporosis. Int J Clin Pharm. 2013;35(4):629–37.
88. Murphy-Menezes M. Role of the pharmacist in medication therapy management services in patients with osteoporosis. Clin Ther. 2015;37(7):1573–86.
89. Salter C, McDaid L, Bhattacharya D, et al. Abandoned acid? Understanding adherence to bisphosphonate medications for the prevention of osteoporosis among older women: a qualitative longitudinal study. PLoS One. 2014;9(1):e83552.
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