Denosumab: A novel antiresorptive drug for osteoporosis
ABSTRACTDenosumab is a novel antiresorptive drug that has been approved for use as a first-line drug for primary and secondary prevention of osteoporotic fractures. The authors discuss the mechanism of action of denosumab, review the evidence for its efficacy and safety in patients with osteoporosis, and offer recommendations for its use in clinical practice.
KEY POINTS
- Denosumab is a fully human monoclonal antibody that targets the receptor activator of nuclear factor kappa b ligand, a key mediator of osteoclastic bone resorption.
- Commpared with placebo, denosumab has been shown to significantly reduce the risk of vertebral, nonvertebral, and hip fractures in postmenopausal women with osteoporosis.
- Patients taking denosumab are more adherent, compliant, and persistent with therapy than those taking alendronate. Denosumab is also superior to alendronate in improving bone mineral density at all skeletal sites.
- Denosumab is safe, with safety data now available for up to 8 years of exposure.
HOW WELL DOES DENOSUMAB WORK FOR OSTEOPOROSIS?
Several phase 2 and phase 3 randomized controlled trials have evaluated the efficacy of denosumab, but only one, the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial, included fracture reduction as the primary outcome measure. The rest evaluated changes in bone mineral density or in markers of bone turnover, or both.
FREEDOM was a double-blind, randomized controlled trial in 7,808 postmenopausal women with T scores between –2.5 and –4.0 at the lumbar spine or hip.24 Twenty-four percent of the patients had vertebral fractures at baseline. Patients were randomized to receive either denosumab 60 mg (n = 3,902) or placebo (n = 3,906) every 6 months for up to 36 months. All patients also received adequate calcium and vitamin D supplementation.
At 36 months, compared with those who were randomized to receive placebo, those who were randomized to denosumab had lower incidence rates of:
- New vertebral fracture
(2.3% vs 7.2%, risk ratio 0.32,
95% CI 0.26–0.41, P < .001) - Nonvertebral fracture
(6.5% vs 8.0%, risk ratio 0.80,
95% CI 0.67–0.95, P = .01) - Hip fracture
(0.7% vs 1.2%, risk ratio 0.60,
95% CI 0.37–0.97, P = .04).
Increases in bone mineral density at the lumbar spine and hip, and decreases in bone turnover markers were also significantly greater in the denosumab group. The number needed to treat to prevent one new fracture over 3 years was 21 for vertebral fracture, 67 for nonvertebral fracture, and 200 for hip fracture, reflecting the relatively low event rate in the study.
In an open-label extension of the FREEDOM trial, the fracture incidence rates among participants who continued to receive denosumab for an additional 5 years remained low, and still below those projected for a “virtual placebo cohort” (total duration of exposure of 8 years). The rates among participants who switched from placebo to denosumab were similar to those of the denosumab group from the parent trial.25,26
A subgroup analysis of the FREEDOM trial suggested that denosumab reduced the risk of new vertebral fractures irrespective of age, body mass index, femoral neck bone mineral density, prevalent vertebral fractures, or prior nonvertebral fractures (risk ratio 0.32; 95% CI 0.26–0.41, P < .001), whereas the risk of nonvertebral fractures was only reduced in those women with body mass indices less than 25 kg/m2, femoral neck bone mineral density T scores less than –2.5, and in those without a prevalent vertebral fracture.27
A post hoc analysis revealed that denosumab significantly reduced the risk of new vertebral and hip fractures even in subgroups of women at higher risk of fracture.28 At 10% fracture probability (as estimated by the FRAX risk calculator), denosumab reduced the fracture risk by 11% (P = .629), whereas at 30% probability (moderate to high risk), the reduction was 50% (P = .001).29
Other phase 2 and phase 3 trials, in postmenopausal women with low bone mineral density, demonstrated that compared with placebo, denosumab significantly increased bone mineral density at all skeletal sites, increased volumetric bone mineral density at the distal radius, improved hip structural analysis parameters, and reduced bone turnover markers.30–33 Increases in bone mineral density and reductions in bone turnover markers with denosumab have been shown in men as well.34
In a randomized controlled trial,35 improvement in bone mineral density was better in those who received the combination of denosumab and teriparatide than in those who received either drug on its own.
Denosumab has also been shown to reduce the incidence of new vertebral fractures and improve bone mineral density in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer,36 and to improve bone mineral density in women with metastatic breast cancer and low bone mass who were receiving adjuvant aromatase inhibitor therapy.37
HOW DOES DENOSUMAB COMPARE WITH OTHER OSTEOPOROSIS DRUGS?
A double-blind randomized controlled trial in postmenopausal women with low bone mass demonstrated that denosumab was superior to alendronate in improving bone mineral density at all skeletal sites (3.5% vs 2.6% for total hip bone mineral density, P < .0001).38
Another double-blind trial demonstrated that in patients previously treated with alendronate, switching to denosumab resulted in significantly greater increases in bone mineral density at all skeletal sites compared with continuing with alendronate (P < .0001).39
Denosumab has also been shown to be superior to alendronate in improving cortical bone mineral density, as measured by quantitative computed tomography.40
No trial has directly compared the efficacy of denosumab with other osteoporosis drugs in reducing fracture risk, but a systematic literature review of multiple databases,41 comparing the antifracture efficacy of nine osteoporosis drugs, concluded that teriparatide, zoledronic acid, and denosumab had the highest probabilities of being most efficacious for nonvertebral and vertebral fractures, with the greatest effect sizes. Indirect comparisons of the relative risk of fracture with denosumab (based on the results of FREEDOM), alendronate, risedronate, raloxifene, and strontium (based on a meta-analysis of randomized controlled trials) are presented in Table 1.42
A 2-year randomized, open-label, crossover study43 randomized patients to receive either denosumab followed by alendronate or alendronate followed by denosumab over successive 12-month periods. The results suggested that postmenopausal women with osteoporosis were more adherent, compliant, and persistent with denosumab therapy (a subcutaneous injection every 6 months) than with alendronate therapy in the form of oral tablets, self-administered weekly (7.5% nonadherence vs 36.5% at the end of 2 years). After receiving both treatments, women reported greater satisfaction with denosumab, with 92.4% preferring it over oral alendronate. Bone mineral density remained stable when patients were switched from denosumab to alendronate, but improved further when they were switched from alendronate to denosumab.
HOW SAFE IS DENOSUMAB?
The most frequent adverse events with denosumab reported in the long-term extension of one phase 2 study were upper respiratory tract infections (13.5%), arthralgia (11.5%), and back pain (9.0%).30
Increased risk of infection, cancer, and dermatologic reactions has been a concern, as RANKL and RANK are expressed by a wide variety of cells, including T lymphocytes, B cells, and dendritic cells.44 However, there were no significant differences in the overall incidences of adverse events between patients who received denosumab and those who received placebo or alendronate in any of the phase 2, phase 3, or extension studies.
In the FREEDOM trial,24 there was no significant difference between the two groups in the overall incidence of infection (52.9% with denosumab vs 54.4% with placebo, P = .17), or serious infection (4.1% with denosumab vs 3.4% with placebo, P = .14), although the incidence of “serious” cellulitis requiring hospitalization was higher in the denosumab group (0.3% vs < 0.1%, P = .002). There were more serious infections involving the gastrointestinal system, urinary tract, and ear and cases of endocarditis in the denosumab group, but the number of events was small, and there was no relationship with the timing of administration or duration of exposure to denosumab.45 Eczema was more common in the denosumab than in the placebo group (3.0% vs 1.7%, P < .001), but the extension data from the first 3 years did not provide any evidence for an increased risk of cellulitis or eczema with denosumab.26
Although randomized controlled trials reported more cases of neoplasms in the denosumab than in the placebo groups, meta-analyses have failed to detect a statistically significant difference (risk ratio 1.11, 95% CI 0.91–1.36).46 The overall incidence of adverse and serious adverse events reported in the 8-year extension of FREEDOM were consistent with data reported in the previous extension studies.25
In the FREEDOM extension trial, four events in the long-term group (n = 2,343), and two in the crossover group (n = 2,207) were adjudicated as being consistent with osteonecrosis of the jaw.26 One mid-shaft fracture in the crossover group was adjudicated as an atypical femoral fracture. There were, however, no reports of osteonecrosis of the jaw or atypical femoral fracture in the long-term phase 2 trial after 8 years of follow-up.30 By September 2013, postmarketing safety surveillance data for denosumab (estimated exposure of 1.2 million patient-years) had recorded four cases of atypical femoral fracture. All four patients had previously been on bisphosphonates. There were also 32 reports of osteonecrosis of the jaw.47
Denosumab’s manufacturer aims to communicate the risks of treatment to health care professionals and patients. Information is available online at www.proliahcp.com/risk-evaluation-mitigation-strategy/.
WHAT ARE THE PRECAUTIONS?
Several precautions need to be taken when considering treatment with denosumab.
Antiresorptives can aggravate hypocalcemia by inhibiting bone turnover. Serum calcium should therefore be checked and preexisting hypocalcemia should be corrected before starting denosumab.48
Denosumab is contraindicated in women who are pregnant or are planning to become pregnant, as fetal loss and teratogenicity have been reported in animal experiments. (Denosumab is unlikely to be used in premenopausal women, as it is not approved for use in this group.)
There are no data on excretion of denosumab in human milk, so it should not be given to nursing mothers.
Renal impairment is not a contraindication, and no dose adjustment is necessary (even for patients on renal replacement therapy), as denosumab, being an antibody, is eliminated through the reticuloendothelial system.49,50 However, in practice, any antiresorptive agent should be used with caution in patients with severe renal impairment because of the possible presence of adynamic bone disease. Further reduction of bone turnover would be detrimental in such patients. Also, severe hypocalcemia has been reported in patients with a creatinine clearance rate less than 30 mL/min and in those receiving dialysis.51,52 Postmarketing surveillance data have reported eight cases of severe symptomatic hypocalcemia, of which seven were in patients with chronic kidney disease.47
The manufacturer suggests that patients receive a dental examination with appropriate preventive dentistry before starting denosumab to reduce the incidence of osteonecrosis of the jaw, despite the lack of evidence in support of this strategy. The American Dental Association recommends regular dental visits and maintenance of good oral hygiene for patients already established on antiresorptive therapy.53,54
SHOULD PATIENTS ON DENOSUMAB BE OFFERED A DRUG HOLIDAY?
A drug holiday (temporary discontinuation of the drug after a certain duration of treatment) has been proposed for patients receiving bisphosphonates because of the risk of atypical femoral fracture and osteonecrosis of the jaw (although small) consequent to long-term continuous suppression of bone turnover.55 The antifracture efficacy of bisphosphonates is likely to persist for an unknown length of time after discontinuation because of their long skeletal half-life, while the risks gradually diminish.
By contrast, denosumab targets RANKL in the extracellular fluid and does not become embedded within the bone tissue.56 Pharmacokinetic studies have shown that denosumab has a rapid offset of action, with a half-life of only 26 days and biological activity lasting only 6 months.57 The results of a phase 2 extension study suggest that bone mineral density starts to decline and bone turnover markers start to rise within 12 months of discontinuing denosumab.58
Although fracture risk did not increase in those who were randomized to stopping the treatment and bone mineral density increased further when treatment was restarted, a drug holiday cannot presently be recommended for patients receiving denosumab because of the lack of supportive data.
