Medical Therapy for Osteoporosis and Approaches to Improving Adherence

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].