Denosumab: Antiresorptive agent reduces fracture risk
The monoclonal antibody denosumab demonstrates potent antiresorptive effect in the treatment of osteoporosis, conferring benefit for fracture risk and averting bone loss in select oncological situations. The drug must be used without interruption to prevent a rebound effect, according to Dr Tai-Pang Ip, a consultant endocrinologist from Hong Kong who spoke at AFOS 2017 held in Kuala Lumpur, Malaysia.
Findings from multiple trials in postmenopausal women with low bone mineral density (BMD) or osteoporosis showed potent suppression of bone turnover by denosumab, with 2‒3 years of treatment yielding sustained increases in BMD, decreases in bone resorption markers, and reductions in the risk of vertebral, nonvertebral, and hip fractures. [J Bone Miner Res 2007;22:1832-1841; N Engl J Med 2009; 361:756-765]
Significant reductions in wrist fracture risk were also noted, with denosumab increasing areal and volumetric BMD, bone mineral content, and polar moment of inertia in radius cortical and trabecular bone in a subgroup of patients with femoral neck BMD T-score ≤–2.5. [Menopause 2013;20:130-137]
In a head-to-head trial vs alendronate, switching to denosumab resulted in superior increases in BMD at the total hip, lumbar spine, trochanter, femoral neck, and distal one-third radius — independent of the duration of prior alendronate use compared with continued alendronate use. [J Bone Miner Res 2009;24:153–161, 2010;25:72-81]
Furthermore, significantly more patients were more adherent, compliant, and persistent with subcutaneous injections of denosumab 60 mg every 6 months, reporting increased treatment preference and satisfaction, than with once-weekly oral alendronate tablets. [Osteoporos Int 2010;21;837-846]
FDA-approved antiresorptive drug
In 2010, the US Food and Drug Administration approved denosumab for the treatment of postmenopausal osteoporosis based on 3-year data from the landmark phase III trial FREEDOM. Additionally, the drug is approved for use in cancer patients at high risk of fracture, particularly men receiving androgen deprivation therapy (ADT) for nonmetastatic prostate cancer and women receiving adjuvant aromatase inhibitor therapy for breast cancer. [N Engl J Med 2009; 361:756–765]
The Osteoporosis Society of Hong Kong recommends the use of denosumab as a first-line treatment for postmenopausal osteoporosis, osteoporotic males on ADT, and high-risk females on aromatase inhibitor.
Ip noted that the drug is specifically indicated in patients who have contraindications to oral bisphosphonate therapy, cannot tolerate oral or intravenous bisphosphonate, have renal impairment (up to stage IV chronic kidney disease), those with poor adherence to oral drugs, on polypharmacy, and have suboptimal BMD response to other antiresorptive agents.
“Osteoporosis, being a chronic disease, logically requires long-term medical treatment,” he said, adding that 10-year data from the open-label extension study of the FREEDOM trial support the use of denosumab in the long-term management of postmenopausal osteoporosis.
In the extension study, treatment for up to 10 years yielded continual increase in BMD at both the lumbar spine and total hip—notably without a plateauing effect. The yearly incidence of new vertebral and nonvertebral fractures remained low, with rates similar to those observed in the denosumab group during the first 3 years of the FREEDOM study and lower than those projected for a virtual long-term placebo cohort. [Lancet Diabetes Endocrinol 2017;5:513-523]
Rebound bone loss upon discontinuation
As a soluble RANK ligand inhibitor, denosumab inhibits the differentiation, function, and survival of osteoclasts, Ip said, emphasizing that the drug does not incorporate into the bone matrix. As such, the effects of the drug are fully reversible once it has been eliminated and osteoclast regeneration has occurred. [Expert Opin Biol Ther 2006;6:1041–1050]
Ip noted that the notion of a drug holiday with denosumab is considered inappropriate, unlike bisphosphonates, which can be stopped after 5 years of treatment.
A previous study has reported that the effects of 24-month denosumab treatment on BMD and bone turnover markers are reversible upon discontinuation. Treatment cessation appeared to cause a rapid rebound in bone turnover markers to values above baseline within 3–6 months, with values approaching baseline by 2 years. [J Clin Endocrinol Metab 2011;96:972–980]
“The effect on bone protection will be lost rapidly once denosumab is discontinued,” Ip explained. However, it is unclear whether the rebound in bone turnover would result in an excessive increase in fracture risk.
While a recent study reported nine cases of severe rebound-associated vertebral fractures, occurring 9‒16 months following the last denosumab dose, none of the studies in the clinical trial programme was designed to appropriately examine differences in fracture rates after treatment discontinuation, Ip pointed out.
Given that the implications for fracture risk are not well characterized, Ip called for additional research to clarify whether there is a real excess fracture risk, to establish the clinical profile of patients at risk for rebound vertebral fractures, and to determine the appropriate treatment regimens after denosumab discontinuation.