Physiology of Bone Remodeling and Bone Turnover

Bone is a dynamic, living tissue that continuously remodels itself throughout the lifetime of the patient. Bone homeostasis consists of three phases. The initial resorption phase is mediated primarily by osteoclasts, which are activated through the interaction of an osteoclast surface protein, receptor activator of nuclear factor-κB (RANK), with its ligand (RANKL). RANKL is primarily expressed by the osteoblast lineage and by stromal cells. During the reversal phase, osteoclasts become less numerous on the bony surfaces and are increasingly replaced by mononuclear cells. These mononuclear cells prepare the bony surface for the introduction of bone-forming osteoblasts and provide cytokine signaling, which stimulates the differentiation of osteoblasts and their subsequent migration to the surface of the bone. During the final formation phase, osteoblasts lay down newly formed woven bone to replace bone that had been previously resorbed.

Bone remodeling is a complex process that is regulated both locally and systemically. As previously mentioned, RANKL/RANK interactions at the local level promote induction of osteoclast activity and subsequent remodeling. Conversely, osteoprotegerin (OPG) is a soluble receptor for RANKL that acts as an antagonist to decrease osteoclastic activation and thereby reduce the rate of bone resorption. Interestingly, there are a number of systemic signaling mechanisms that act through the RANKL/RANK/OPG pathway to regulate bone homeostasis.⁴ For example, parathyroid hormone (PTH) and the glucocorticoids both act to increase local expression of RANKL but decrease concomitant expression of OPG, resulting in a net increase in osteoclast activation and bone resorption. Alternatively, estrogens act to increase the local expression of OPG and decrease RANKL, which results in a net decrease in osteoclast activity and bone resorption (Figure 12-1). Derangement of these pathways can alter the delicate balance between bone resorption and bone formation, and may result in a net decrease of bone formation that contributes to the development of osteoporosis.

FIGURE 12-1 Receptor activator of nuclear factor-kB (RANK) on the osteoclast precursor’s surface interacts with its ligand (RANKL), expressed by the osteoblasts and stromal cells, thereby activating the differentiation of the osteoclast precursor to activated osteoclast and subsequent bone resorption. Osteoprotegerin (OPG) is a soluble receptor for RANKL that competitively inhibits the RANKL-RANK interaction. Various systemic modulators (estrogen, parathyroid hormone [PTH], or glucocorticoids) influence the activation of the osteoclasts via their effects on the RANK/RANKL/OPG pathway. (+), Activation; (−), Inhibition.

Based upon the varying influences of bone resorption and formation, osteoporosis is subdivided into two categories: low-turnover and high-turnover osteoporosis. The low-turnover state describes a situation in which normal bone homeostasis is altered by decreased osteoblast activity; however, the osteoclast activity remains normal. Low bone mineral density (BMD) in this setting, therefore, is a result of reduced bone formation. Conversely, the high-turnover state is characterized by increased activity of both osteoblasts and osteoclasts. However, osteoclasts are activated to a greater extent. The bone remodeling process is shifted toward bone resorption, resulting in an imbalance of bone turnover that causes osteoporosis. High turnover osteoporosis is the most common form and appears at menopause, while low turnover osteoporosis occurs following drug interventions including chemotherapy, steroids, and prolonged bisphosphonate use.

Diagnosis of Osteoporosis

Although a good clinical understanding of osteoporosis takes into account the pathophysiology of bone remodeling, mineralization changes, and variable bone quality of the patient, the diagnosis of osteoporosis until recently has relied upon a single criterion: the bone mineral density. The current gold standard of measuring BMD is dual-energy x-ray absorptiometry (DXA), which uses an x-ray beam to calculate the patient’s BMD. The most preferred skeletal sites for evaluation of BMD are the spine and hip, because these two locations provide the best data for correlating low BMD with the risk of future fracture BMD is reported as the T-score, which is a measurement of how many standard deviations the patient’s bone density is below the mean of young, healthy individuals at their peak bone mass. Based on this T-score, the World Health Organization (WHO) developed a classification system to define osteoporosis (Table 12-1).

TABLE 12-1 WHO-Based Criteria for Diagnosis of Osteoporosis

Generally, osteoporosis is classified as either primary or secondary. Primary osteoporosis is further subdivided, based on its pathogenesis. Type I, or postmenopausal osteoporosis, is related to the abrupt decline of estrogen levels that occurs in menopausal women. Type II osteoporosis, known as senile or age-related osteoporosis, is due to the progressive decrease of BMD in both men and women that occurs with aging. Patients may suffer from both subtypes of primary osteoporosis.

Secondary osteoporosis is defined by the presence of some preexisting disease process or other causative factor, which causes a secondary decline in BMD (Table 12-2). Forty-five percent of osteoporotic women and 66% of osteoporotic men have their osteoporosis secondary to some underlying condition. Therefore patients with secondary osteoporosis must be identified because definitive treatment of the underlying cause is necessary to prevent further bone loss, and thus lower the risk of fracture. In this regard, it is important to consider the patient’s BMD using the Z-score. The Z-score indicates how many standard deviations the patient’s BMD is below the expected value for his or her own age. The Z-score cannot be used to diagnose osteoporosis, but it is useful for screening the patient for secondary causes. A Z-score of −2.0 or lower should increase the index of suspicion that underlying medical problems, medications, or other factors may be responsible for the patient’s low BMD.⁶

TABLE 12-2 Causes of Secondary Osteoporosis5

Evaluation for Osteoporosis

Once diagnosed with osteoporosis, a complete medical history should be obtained with particular attention to the risk factors for osteoporosis. These include age of 65 years or older, a history of vertebral fracture or any fracture during childhood, a family history of hip fracture, low body weight (BMI < 21 or weight < 127 lb), cigarette smoking, and use of corticosteroids for more than 3 months.⁶ The physical examination should be performed particularly at the spine region. Height should be measured and compared with the greatest known height to determine height loss, which is an indicator of the presence of vertebral compression fractures. Balance and walking gait should be observed in each individual. The assessment of functional balance is performed by using the single limb stance test and the 6-minute walking test.