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].