Denosumab: A novel antiresorptive drug for osteoporosis

A 68-year-old white woman presents with mid-  thoracic back pain. Plain radiographs reveal a compression fracture of the 10th thoracic vertebra. She is diagnosed with osteoporosis on the basis of dual energy x-ray absorptiometry (DXA) scans that show T scores of –2.9 in her lumbar spine and –2.6 in her left femoral neck. Her 10-year probability of fracture is estimated as 23% for major osteoporotic fracture and 5.9% for hip fracture (based on the World Health Organization’s absolute fracture risk assessment tool, adapted for the United States, and available at www.shef.ac.uk/FRAX).

After excluding common secondary causes of osteoporosis, her physician recommends a bisphosphonate to reduce her risk of fracture, but she develops upper-gastrointestinal adverse effects with both alendronate and risedronate despite correctly following the instructions for oral administration.

What should her physician consider next?

OSTEOPOROSIS IS A MAJOR PROBLEM

Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, predisposing to an increased risk of fragility fractures, particularly of the spine, hip, and wrist.

It is a major public health problem, affecting 200 million people throughout the world, with 9 million osteoporotic fractures reported in the year 2000.¹ The incidence of hip fracture alone is predicted to rise to 2.6 million by the year 2025, and to 4.5 million by the year 2050.² In the United States, the total burden was estimated to be about 2 million incident fractures in the year 2005, projected to rise by another 50% by the year 2025,³ primarily because of the aging of the population. Population studies have indeed suggested that about 40% of white women and 13% of white men over the age of 50 are at risk of sustaining an osteoporotic fracture during the remainder of their lifetime.⁴

The consequences of osteoporotic fractures can be devastating. Hip fractures are associated with a risk of death ranging from 8.4% to 36% during the first year after fracture.⁵ One-fifth of patients who sustain a hip fracture require long-term nursing home care, and more than half of the survivors do not regain their previous level of independence.

Patients with vertebral fractures are also at increased risk of death, although the results of some studies suggest that this could be the result of comorbid factors.^6–9 Vertebral fractures can result in chronic back pain, loss of height from spinal deformity, reduced mobility, loss of self-esteem, and in severe cases, respiratory and digestive problems because of contact between the lower ribs and pelvis.

A person with one vertebral compression fracture is five times more likely to have another vertebral fracture,¹⁰ and a person with two or more compression fractures is 12 times more likely.¹¹

The costs of treating osteoporotic fractures are greater than those of treating myocardial infarction or stroke^12,13; they include not only direct costs incurred in treating the fracture, but also indirect societal costs owing to the long-term morbidity associated with the fracture. In the United States, the total cost of treating osteoporotic fractures was estimated at $19 billion in the year 2005.³ By 2025, the annual costs are projected to rise by almost 50%.³

A NEED FOR MORE OPTIONS

Until fairly recently, bisphosphonates were the only drugs of first choice, but adherence to oral bisphosphonate therapy is generally poor (< 50% at 1 year),¹⁴ most commonly because of dyspepsia,¹⁵ and poor adherence has been shown to be associated with increased fracture risk.^16,17 Hence the need for additional therapeutic options.

In this review, we discuss denosumab, an antiresorptive drug approved by the US Food and Drug Administration (FDA) in 2010. First, we discuss its mechanism of action, efficacy, and safety, and then we offer recommendations for its use in clinical practice.

WHAT IS DENOSUMAB AND HOW DOES IT WORK?

Bone remodeling is a dynamic process involving a balance between bone resorption by osteoclasts on the one hand and new bone formation by osteoblasts on the other. A net gain in bone occurs when the activity of osteoblasts exceeds that of osteoclasts, and bone loss occurs when there is increased osteoclast activity or reduced osteoblast activity, or both. The activities of osteoblasts and osteoclasts are tightly coupled because of the opposing effects of two sets of proteins, namely, receptor activator of nuclear factor kappa b ligand (RANKL) and osteoprotegerin.

Both RANKL and osteoprotegerin are produced by osteoblasts. RANKL binds to its receptor (RANK) on preosteoclasts and osteoclasts and induces their differentiation and activation, respectively. Osteoprotegerin is the decoy receptor and natural antagonist for RANKL. By binding with RANKL, it blocks its interaction with RANK.¹⁸ In healthy individuals, a fine balance between RANKL and osteoprotegerin ensures that bone remodeling is regulated.

In postmenopausal women, estrogen deficiency leads to an imbalance between RANKL and osteoprotegerin (increased RANKL and reduced osteoprotegerin), resulting in net bone loss. This imbalance is also a feature of rheumatoid arthritis, myeloma bone disease, and osteolytic metastatic bone disease; it also occurs in those receiving androgen deprivation therapy for prostate cancer or aromatase inhibitors for breast cancer.

Denosumab is a fully human monoclonal antibody that targets RANKL.¹⁹ By binding to RANKL, this drug prevents the maturation and differentiation of preosteoclasts and promotes apoptosis of osteoclasts. Bone resorption is therefore slowed. It was parenteral osteoprotegerin that was initially developed by denosumab’s manufacturer,²⁰ but this approach failed because neutralizing antibodies developed to osteoprotegerin, rendering it ineffective. Development of neutralizing antibodies has thus far not been a problem with denosumab.

Denosumab, with its property of RANKL inhibition, has also been used to prevent skeletal events in patients with bone metastases from solid tumors and to treat unresectable giant cell tumors of the bone (both FDA-approved indications) and hypercalcemia of malignancy. There is limited clinical experience in Paget disease of the bone as well.^21–23 These other potential uses of denosumab are beyond the scope of this review.