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 COST-EFFECTIVE IS DENOSUMAB?
The wholesale acquisition cost is $825 per 60-mg prefilled syringe of denosumab, although this may vary depending on where the drug is obtained. This does not include physician-related service costs associated with administration of denosumab.
Cost-effectiveness analyses conducted in the United States, the United Kingdom, and Sweden have all concluded that denosumab would offer a cost-effective alternative to other osteoporosis medications for primary prevention and secondary prevention of fractures.59–61
The Swedish study also incorporated adherence in the cost-effectiveness model and showed that denosumab was a cost-effective alternative to oral bisphosphonates, particularly for patients who were not expected to adhere well to oral treatments.61
WHICH OSTEOPOROSIS PATIENTS ARE CANDIDATES FOR DENOSUMAB?
The FDA has approved denosumab for the treatment of postmenopausal women and men at high risk of fracture (defined as having a history of osteoporotic fracture or multiple risk factors for fracture), or in those who cannot tolerate other osteoporosis medications or for whom other medications have failed.
Denosumab is also approved for men at high risk of fracture receiving androgen deprivation therapy for nonmetastatic prostate cancer, and for women at high risk of fracture receiving adjuvant aromatase inhibitor therapy for breast cancer.
WHAT DO THE GUIDELINES RECOMMEND?
The National Osteoporosis Foundation guidelines recommend pharmacologic treatment for patients with hip or vertebral fractures (clinical or asymptomatic); T scores lower than –2.5 at the femoral neck, total hip, or lumbar spine; and those with a 10-year probability of hip fracture of more than 3% or of a major osteoporotic fracture more than 20% based on the US-adapted FRAX calculator.62 The American College of Endocrinology guidelines have proposed similar thresholds for pharmacologic treatment, and they recommend alendronate, risedronate, zoledronate, and denosumab as first-line agents.63
The 2010 Osteoporosis Canada guidelines recommend denosumab, alendronate, risedronate, and zoledronate as first-line therapies for preventing hip, nonvertebral, and vertebral fractures in postmenopausal women (grade A recommendation).64 The National Institute of Health and Clinical Excellence in England and Wales, on the other hand, recommends denosumab only for patients who are unable to take a bisphosphonate.65
PRACTICAL PRESCRIBING TIPS
The patient described at the beginning of this article has already sustained a vertebral compression fracture, and her DXA scan shows T scores in the osteoporotic range. She is therefore at increased risk of another fragility fracture (with a fivefold higher risk of another vertebral fracture). Pharmacologic therapy should be considered. In addition, she should be encouraged to adhere to lifestyle measures such as a healthy diet and regular weight-bearing exercise, her risk of falling should be assessed, and adequate calcium and vitamin D supplementation should be given.
Secondary causes of osteoporosis are present in about 30% of women and 55% of men who have vertebral fractures.66 A complete blood count, erythrocyte sedimentation rate, bone biochemistry, 25-hydroxyvitamin D, thyroid-stimulating hormone, and renal and liver function tests should be requested in all patients. Further tests should be considered depending on the clinical evaluation and results of initial investigations.
Because this patient cannot tolerate oral bisphosphonates, she could be offered the option of annual intravenous zoledronic acid infusions or 6-monthly subcutaneous denosumab injections. In clinical trials, gastrointestinal adverse effects were noted with intravenous bisphosphonates as well, but the adverse effects reported were no different than those with placebo. The potential advantages with denosumab include better bone mineral density gains, adherence and patient satisfaction compared with oral bisphosphonates, convenient twice-yearly administration, safety in patients with renal impairment, and absence of gastrointestinal effects.
Raloxifene, a selective estrogen receptor modulator, has estrogen-like action on the bone and antiestrogen actions on the breast and uterus. Unlike standard hormone replacement therapy, raloxifene can therefore increase bone mineral density without increasing the risk of breast and endometrial cancers. However, it has only been shown to reduce the risk of vertebral fracture, not hip fracture. Hence, it would be a more appropriate choice for younger postmenopausal women. Moreover, it may cause troublesome menopausal symptoms.
Teriparatide, the recombinant parathyroid hormone, is an anabolic agent. It is very expensive, and because of this, guidelines in several countries restrict its use to women with severe osteoporosis and multiple fractures who fail to respond to standard treatments. It cannot be used for longer than 2 years because of its association with osteosarcoma in rats.
If our patient prefers denosumab, therapy should be initiated after appropriate counseling (see precautions above). The dose is 60 mg, given subcutaneously, once every 6 months.
Monitoring
There is no consensus regarding the optimal frequency for monitoring patients on treatment, owing to the lack of prospective trial data. The National Osteoporosis Foundation recommends repeating the bone mineral density measurements about 2 years after starting therapy, and about every 2 years thereafter.62 Some studies suggest that changes in bone mineral density correlate with reduction in fracture risk.67,68 A change in bone mineral density is considered significant when it is greater than the range of error of the densitometer (also known as the least significant change).69 If the bone mineral density is stable or improving, therapy could be continued, but if it is declining and the decline is greater than the least significant change, a change in therapy should be considered if no secondary causes for bone loss are evident (but see What are the areas of uncertainty? below).
The National Osteoporosis Foundation also recommends measuring a bone turnover marker at baseline and then 3 to 6 months later, as its suppression predicts greater bone mineral density responses and fracture risk reduction.70 If there is a decrease of more than 30% in serum carboxy-terminal collagen crosslinks (CTX) or more than 50% in urinary N-telopeptide (NTX),71 the patient can be reassured that the next bone mineral density measurement will be stable or improved. In patients on oral bisphosphonates, measurement of bone turnover markers also provides evidence of compliance.
Clinical trials suggest that a numerical increase in bone mineral density can be expected in most patients on treatment, though this depends on the measurement site and the length of time between examinations. In one phase 3 trial of denosumab in postmenopausal women, only 5% of the participants had unchanged or diminished bone mineral density at the lumbar spine, and 8% at the hip, after 36 months of treatment.72 However, the CTX levels fell to below the lower limit of the reference interval as early as 1 month after commencing treatment in all denosumab-treated patients.68
Hence, bone turnover markers may be a more sensitive indicator of treatment effect than bone mineral density, but this would ultimately need to be evaluated against fracture rates in a real-world setting.
WHAT ARE THE AREAS OF UNCERTAINTY?
There are currently no guidelines for long-term management of patients on denosumab, and also no data to suggest whether patients should be switched to a weaker antiresorptive drug after a certain number of years in order to reduce the possible risk of atypical femoral fracture or osteonecrosis of the jaw.
No head-to-head trials have directly compared the antifracture efficacy of denosumab with that of other standard osteoporosis therapies. The antifracture efficacy and safety of combination therapies involving denosumab are also uncertain. For adherent patients who have a suboptimal response, there is no evidence to guide the further course of action. The International Osteoporosis Foundation guidelines suggest replacing a stronger antiresorptive with an anabolic agent, but acknowledge that this is only based on expert opinion.71
The very-long-term effects (beyond 8 years) of continuous denosumab administration on increasing the risk of atypical femoral fracture, osteonecrosis of the jaw, malignancy, or infection or the duration after which risks would start to outweigh benefits is not known. However, postmarketing safety data continue to be collected through the voluntary Post-marketing Active Safety Surveillance Program (for prespecified adverse events) in addition to the FDA’s MedWatch program.
CASE PROGRESSION
The patient described in the vignette is presented with two options—zoledronate and denosumab. She chooses denosumab. Her renal function and serum calcium are checked and are found to be satisfactory. She undergoes a dental examination, which is also satisfactory. She is counseled about the possible increased risk of infection, and then she is started on 60 mg of denosumab subcutaneously, once every 6 months.
When reviewed after 2 years, she reports no further fractures. Her bone mineral density remains stable compared with the values obtained before starting treatment. She reports no adverse effects and is happy to continue with denosumab.
