The Pathophysiology and Treatment of Osteoporosis
Introduction
As described in the National Institutes of Health Consensus Development Conference Statement,1 osteoporosis is a skeletal disorder characterized by diminished bone strength that results in increased fracture risk, with bone strength a function of both bone mineral density (BMD) and bone quality. BMD is commonly assessed clinically by dual-energy x-ray absorptiometry (DXA), a technology that measures integrated cortical and trabecular areal (2-dimensional) BMD at several skeletal sites. Bone quality refers to the non-BMD determinants of bone strength that are less easily measured, including bone microarchitecture, degree of mineralization, remodeling activity, and microdamage accumulation.1
Epidemiologic data have convincingly indicated that bone loss, as assessed with BMD testing by DXA, occurs in both women and men as part of the natural aging process.2 Associated with this bone loss is an increased fracture risk. Current estimates are that ~40% of white women aged >50 years will experience an osteoporosis-related fracture, with this risk rising to nearly 50% if vertebral fractures identified by imaging, rather than clinical history, are included.3 Similarly, it is estimated that ~13% of men will experience an osteoporosis-related fracture.4 Accordingly, osteoporosis and osteoporosis-related fractures are a major public health concern and impose enormous health care costs. In 2005, annual costs for osteoporosis-related fractures were US$13.7 to US$20.3 billion, an amount expected to rise to US$25.3 billion annually by 2025 due to a projected 48% increase in fractures.5 Therefore, identifying and treating persons at greatest fracture risk is of critical importance. Evidence supports the cost-effectiveness of pharmacologic intervention for the treatment of patients with prior fragility fractures, low bone mass (osteopenia) and additional clinical risk factors, or osteoporosis as defined by the World Health Organization (DXA T-score ≤ –2.5).6
As our understanding of human bone biology has evolved over the past several decades, so too has our ability to provide increasingly targeted therapies for the treatment of osteoporosis. Central to this has been development of an ever-growing pharmacologic armamentarium of medications proven in clinical trials to reduce fracture risk by limiting ongoing bone loss and/or augmenting existing bone mass. The objectives of this article are to review the pathophysiology of bone loss associated with aging and to review current pharmacologic approaches for the treatment of osteoporosis.
Section snippets
Methods
A literature search through PubMed was performed with the terms osteoporosis and pathophysiology and osteoporosis and treatment and limited to studies written in English that were published within the preceding 10 years. Given the large number of studies identified, we selectively reviewed those studies that contained primary data related to osteoporosis pathophysiology or osteoporosis pharmacologic treatments and references included within selected studies identified from abstract review.
Age-Associated Changes in Bone Mass and Microarchitecture
Until recently, it was believed that from the end of the pubertal growth spurt (the time point at which peak bone mass is attained) until the onset of middle age, both men and women maintained their skeletons without substantial bone loss or changes in skeletal microarchitecture. This belief was predicated on cross-sectional and longitudinal skeletal measurements performed by DXA. Although it was well recognized that bone remodeling was active during this period of adulthood, it was generally
Hormonal Basis for Bone Loss with Aging
As noted in the section above, trabecular bone loss in both men and women, as measured by QCT, begins in the third decade, a period when sex steroid concentrations (estrogen in women and testosterone in men) are typically within the normal range and thus sufficient. Reasons for trabecular bone loss at this stage of life remain unclear, but they suggest that our current understanding of skeletal changes with aging remains incomplete.
Factors Beyond Age-Associated Bone Loss
In addition to normal age-related bone loss, numerous secondary causes of bone loss and/or increased fracture risk also exist. Such risk factors can be placed into broad categories, including medications such as glucocorticoids, antiestrogens, and antiepileptics; endocrine disorders such as hyperparathyroidism, hyperthyroidism, hypogonadism, diabetes mellitus, and vitamin D deficiency; rheumatologic conditions, including systemic lupus erythematosus and rheumatoid arthritis; neurologic
Treatment of Osteoporosis
Although treatment is most frequently associated with a pharmacologic approach, it is important to recognize that for the optimal treatment of osteoporosis, nonpharmacologic approaches are also important to limit fracture risk.52 Nonpharmacologic interventions include limiting the risk of falls; using proper techniques when lifting; maintaining adequate intake of calcium, vitamin D, and protein; performing adequate weight-bearing physical activity and exercise to maintain or improve balance and
Conclusions
Major advances have been made in understanding the pathophysiology of osteoporosis, with ongoing research devoted to more fully understanding the genetic and molecular causes of osteoporosis. It is increasingly clear that the pathophysiology is complex and that causes of bone loss depend on the complex interplay of numerous genetic, hormonal, and molecular factors. The search for new targets for therapy continues, because all currently available agents were developed on the basis of the
Conflicts of Interest
Dr Lewiecki has received institutional grant/research support from Amgen, Merck, and Eli Lilly; he has served on scientific advisory boards for Amgen, Merck, Eli Lilly, Radius Health, AgNovos Healthcare, Alexion, NPS, and AbbVie. The authors have indicated that they have no other conflicts of interest regarding the content of this article.
Acknowledgments
All authors contributed to the literature search, writing, and revision of this manuscript.
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