Denosumab (Prolia) Injection: A New Approach to the Treatment of Women With Postmenopausal Osteoporosis (2010)

A healthy skeleton is essential for providing structural support, protection of vital organs and the hematopoietic system, and maintenance of homeostasis of calcium and other ions. Skeletal bone (composed of trabecular and cortical bone) is a dynamic tissue that constantly undergoes remodeling in response to mechanical stresses and hormonal changes.1–3 This constant remodeling is a dichotomous process, essential in repairing microdamage and renewing skeletal integrity and strength.4 Osteoblasts, osteocytes, and osteoclasts serve as key components in this parallel physiological pathway to support remodeling. Osteoblasts (which form bone lining) and osteocytes (osteoblasts that form bone matrix and transmit signals) have functions dissimilar those of osteoclasts, which break down bone. Osteoblasts and osteocytes are analogous to “building blocks” of the skeletal system because they are involved in bone formation, contrary to osteoclast-inhibiting activity, which leads to bone resorption.

Systemic and local regulators of bone-cell activity control resorption and formation; hence, these two processes are intimately intertwined. Bone resorption and bone formation are continual, and this method of remodeling replaces the entire human skeleton every decade.4 In bone metabolism, a cascade of biochemical reactions facilitates bone remodeling, including the human receptor activator of nuclear factor-κB (RANK) and RANK ligand (RANKL) succession, of which osteoblasts and osteoclasts are essential local regulators. Osteoblasts regulate osteoclastic formation and activity by secreting RANK or osteoprotegerin (OPG). RANK provides the osteoblast a pathway to stimulate formation of mature osteoclasts (increased bone resorption) whereas OPG secretion promotes inhibition of mature osteoclasts (decreased bone resorption).

Under normal circumstances, bone resorption in adults is equivalent to bone formation and represents no net loss or gain in bone mass.5 When the process of remodeling favors resorption over formation, an imbalance in activity is created and osteoporosis may occur. Osteoporosis is characterized by low bone mass and microstructural deterioration of bone tissue, leading to increased fragility and fractures. Many modifiable and nonmodifiable factors are associated with an increased risk of osteoporosis and related bone fractures; however, the key risk factors most often associated with clinical fractures are low bone mass and falls (Table 1).5–7 Although bone resorption and formation are the focal points of this discussion, other steps involved in bone remodeling include reversal and quiescence as well as an array of cytokine and hormonal activities.5,8



Table 1

Risk Factors Affecting Bone Health



The Office of the Surgeon General and the Third National Health and Nutritional Examination Survey (NHANES III, 1988–1994) have provided important data on osteoporosis.9,10 Complementary epidemiologic studies suggest that 10 million Americans have osteoporosis and another 34 million Americans 50 years of age and older are at risk.9 The Office of the Surgeon General’s report on bone health and osteoporosis in 2004 stated that 50% of women 50 years of age and older would have an osteoporotic-related fracture in their lifetime, with the risk of fracture increasing with age.9 The Surgeon General also estimated that the aging of the population in the U.S., coupled with the previous lack of focus on bone health, could result in doubling or tripling the number of hip fractures by 2020.9

NHANES III retrospective data also indicate that osteoporosis is the most common and preventable bone disease, with non-Hispanic Caucasian women having the highest prevalence of osteopenia and osteoporosis, among Americans; the prevalence of osteoporosis is even higher among nursing-home residents.10 To bolster support for and promote the importance of bone health and preventing fractures, former President George W. Bush declared the years 2002 to 2011 as the “Bone and Joint Decade,”9 part of the objectives for the Healthy People 201011 and the proposed objectives for Healthy People 202012 initiatives.

Several organizations have developed guidelines for the diagnosis and management of osteoporosis, such as the World Health Organization (WHO), the European Foundation for Osteoporosis, and the National Osteoporosis Foundation. WHO uses the T-score—the number of standard deviations (SDs) from the mean, compared with average bone mass of healthy young women—as a measurement to classify bone mass or bone mineral density (BMD). T-scores assist health care professionals in establishing the degree of bone health, assessing fracture risk, and steering prevention and treatment decisions. Diagnostic testing, however, has been reserved for use in postmenopausal women and men 50 years of age or older.6 Normal BMD is a T-score greater than −1.0 SD; osteoporosis is defined as a T-score of less than −2.5 SD.6

The armamentarium of pharmacological agents used in the effort to prevent and treat osteoporosis is expanding in terms of mechanisms of action as well as in the frequency and routes of administration. To this end, the FDA has granted approval to Amgen for its first RANK ligand inhibitor, denosumab (Prolia). Inhibition of turnover at this level of bone metabolism is a novel approach in preventing and managing osteoporosis, with many implications.