TAKE-HOME POINTS
■ Patient-oriented outcomes should take precedence over disease-oriented outcomes.
■ Denosumab has a mechanism of action different from that of current osteoporosis medications but does not appear to improve patient–oriented outcomes such as fracture rates.
The lower cost of some oral bisphosphonate formulations, such as alendronate, is a consideration for many patients.
■ Denosumab is a twice a year injection that may improve patient adherence, but the bisphosphonate zoledronic acid (Reclast, Zometa), a once-a-year injection, is also available.
■ Patients with osteoporosis who cannot tolerate bisphosphonates should be considered for denosumab treatment.
Denosumab (Prolia), the latest drug approved to treat osteoporosis, is one type that can be prescribed safely by specialists and primary care clinicians alike.An injectable, fully human monoclonal antibody (IgG), denosumab is FDA-approved for the treatment of osteoporosis in postmenopausal women at high risk for fracture. Denosumab inhibits the receptor activator of nuclear factor ligand (RANKL), a cytokine that is essential for the formation, function, and survival of osteoclasts. This inhibition stops the maturation of osteoclasts and reduces bone resorption. Since osteoclasts tear down bone and osteoblasts build bone, a reduction in osteoclast activity increases new bone production and, eventually, bone density.
IMPROVED DOSING
The Sixth International Symposium on Osteoporosis highlighted that less frequent dosing can improve patient adherence to treatment.1 Less than 25% of patients are adherent to any osteoporosis medication after 1 year.2 Unlike other osteoporosis treatments, denosumab is an injection given twice a year.
PAs should carefully assess the efficacy, safety, and cost of the drug for patients, and priority should be given to patient-oriented outcomes over disease-oriented outcomes.
EFFICACY
Disease-oriented evidence (DOE) The primary disease-
oriented outcome of denosumab therapy is to improve bone mineral density (BMD). Studies have shown that BMD increases with denosumab therapy in patients with either osteopenia or osteoporosis.2,3 BMD increases of 3% to 7% were seen at the lumbar spine (P < .001), and the effect on total hip BMD was about one-half the results seen at the lumbar spine. Markers of bone turnover improved compared with placebo, similar to results achieved with alendronate (Fosamax).2
Consequent to improvement in BMD and reduction in bone turnover, studies in patients with multiple myeloma and rheumatoid arthritis (RA) have shown changes in baseline MRI erosion scores and a reduction in markers of bone turnover, but no change in joint narrowing scores.4 RA disease activity did not improve, nor did denosumab spare the addition of other RA medications.
Patient-oriented evidence In osteoporosis, vertebral and hip fracture rates are the most apparent patient-oriented outcomes. The FREEDOM trial is the primary patient-
oriented outcome trial with denosumab to date.5 Researchers assigned 7,868 postmenopausal women to either denosumab 60 mg SC or a placebo injection every 6 months for 36 months. All patients received calcium and vitamin D supplements. Patients were osteoporotic by bone scan with 24% having a baseline vertebral fracture. The primary outcome was new vertebral fracture. Secondary outcomes were hip fracture and nonvertebral fracture.
New vertebral fractures occurred in 2.3% of patients treated with denosumab versus 7.2% of patients treated with placebo. This equates to a 4.9% absolute risk reduction (ARR) with denosumab or a 68% relative risk reduction (RRR). New hip fractures occurred in 0.7% of patients treated with denosumab versus 1.2% of patients treated with placebo (ARR 0.5%, RRR 40%, number needed to treat [NNT] 200). For every 200 patients treated with denosumab for 36 months, 1 patient would not have a new hip fracture. The NNT is a better measure of realistic benefit than the RRR.
Table 1 summarizes key fracture reduction data for denosumab and bisphosphonates. Bisphosphonates are a mainstay in the prevention and treatment of osteoporosis-related fractures, and they continue to be described as first-line drugs for treating postmenopausal osteoporosis.6
Research has demonstrated that androgen deprivation therapy, which is commonly used in the treatment of prostate cancer, can cause increases in bone turnover markers, decreases in bone mineral density, and increases in fracture risk.7 Results from the Hormone Ablation Therapy (HALT) trial revealed that denosumab was associated with an increase in BMD at the lumbar spine and total hip BMD.8 The incidence of new vertebral fractures was reduced from 3.9% with placebo to 1.5% with denosumab.