O Diseases Of Bone Tissue Utilizing Approved Drug Therapies

Paget Disease of Bone (Osteo Deformans)

Paget disease can be thought of as improper resorption of bone. Essentially, bones grow larger leading to deformation of the affected bones and become weaker than normal with increasing risk of fracture. It can occur on several bones or be isolated to one bone. It most likely occurs in the pelvis, skull, spine, or leg bones. The bones may become misshapen and break more easily. There may or may not be pain. Manifestations of Paget disease tend to appear in the patient's late 40s. Although there is some evidence of hereditary factors, slow viruses also have been considered a cause. Diagnosis begins with a determination of the patient's alkaline phosphatase levels followed by bone scans and x-rays. Drug therapy includes bisphosphonates and calcitonin.1

Heterotopic Ossification

This diagnosis consists of various diseases resulting in abnormal formation of true bone within extraskeletal soft tissues. The latter include fascia, tendons, and other mes-enchymal soft tissues. Many times the cause is related to traumatic injury. Treatment includes surgery, radiation, nonsteroidal anti-inflammatory drugs (NSAIDS, Chapter 24) and bisphosphonates.

Hypercalcemia of Malignancy

A malignancy is the most common cause of hypercalcemia and can be an indication of a malignancy, the most common being multiple myeloma, breast, or lung cancer. It is caused by increased osteoclastic activity within the bone. Primary hyperparathyroidism is the second most common cause of hypercalcemia. In addition to treating the cause, approved drug treatments for hypercalcemia of malignancy include bisphosphonates, calcitonin, gallium nitrate, and cinacalcet.

Osteoporosis

Osteoporosis is the most common of the bone diseases. It is a pathological condition characterized by decreased bone mass and structural deterioration of bone tissue.2 The result is bone fragility leading to increased risk of fractures of the hip, spine, and wrist. Many times the broken hip is considered the result of the patient falling when, in actuality, the broken hip was the initial event causing the fall. The economic impact of this disease is tremendous. Osteoporosis is responsible for more than 1.5 million fractures annually distributed among 300,000 hips, 700,000 vertebrae, 250,000 wrists, and 300,000 other sites. It is more common in women than men because women, on average, have a smaller bone mass than men. Diagnosis, prior to an actual fracture, is done by bone density measurements.

Osteoporosis has been considered a disease of aging, but inflammation may be an important variable. Calcium flux favors bone mineralization through adolescence. Bone resorption and deposition are in balance in adults and become negative beginning in the late 50s. Loss of calcium from bone increases relative to calcium deposition onto bone increases with menopause. The importance of estrogen is shown by it acting directly on osteoblasts and possibly inhibiting osteo-clasts. The loss of estrogen production results in a significant alteration of the osteoblast-osteoclast ratio because of increased osteoclastogenesis and decreased osteoclast apopto-sis. The role of estrogen on osteoblast function has led to the development of selective estrogen receptor modifiers (SERM)

for the prevention and treatment of osteoporosis. These are discussed in more detail in Chapter 25.

Associated with menopause and the loss of estrogen is an increase in the production of proinflammatory cytokines including interleukin-1 (IL-1), tumor necrosis factor-a (TNF-a), and interleukin-6 (IL-6). Paralleling this increased production of proinflammatory cytokines is increased osteoclastic bone resorption. Of particular importance for osteoclast differentiation and activation and, therefore, progression of osteoporosis, is the receptor activator of nuclear factor-KB (RANK), a membrane-bound receptor on osteoblast precursor cells and the receptor's functional ligand, RANK ligand (RANKL), also a cytokine. When RANKL binds to RANK, there is increased osteoclastic activity and increased osteoclast numbers because of decreased osteoclast apoptosis. Opposing RANKL is osteoprotegerin, an endogenous inhibitor of RANKL, specifically binding it and blocking its interaction with RANK. Osteoprotegerin, by inhibiting RANKL, normalizes the osteoblast-osteoclast ratio decreasing bone resorption and loss of calcium from bone.3

There are medical conditions that can increase the risk of osteoporosis (secondary osteoporosis) or exacerbate an existing osteoporotic condition. Chronic use of glucocorti-coids can accelerate calcium loss. In addition, some anticon-vulsants (i.e., phenobarbital and phenytoin) can negatively affect calcium flux involving bone. Medical conditions that immobilize individuals for extensive time periods can also lead to calcium loss.

There are controllable risk factors that reduce the risk and severity of the disease. These include anorexia in the age span when humans are accumulating dietary calcium, a diet low in calcium and vitamin D (cholecalciferol), inactive lifestyle, cigarette smoking, and excessive use of alcohol. Staying as physically active as possible throughout one's life span is important, particularly focusing on activities that include working against gravity (walking, hiking, jogging, stair climbing, and dancing). It is important for all age groups to consume calcium, but because calcium deposition onto bone is at its greatest through adolescence, it is important to consume quantities of calcium equal to the daily adequate intake (AI) of, depending on age, 500 to 1,300 mg/day. Younger people can obtain their calcium from diet, primarily dairy. Older individuals may need to take calcium supplements. Paralleling adequate calcium intake is vitamin D consumption. The current adult AI is 5 to 10 ^g (200-400 IU). This has been considered too conservative with recommendations that it be increased to 20 to 25 ^g (800-1,000 IU). A person's vitamin D status can be checked by measuring 25-hydroxycholecalciferol blood levels.

Osteoporosis is a greater problem in women mainly because women live longer and have less bone mass than men. Nevertheless, osteoporosis is a disease of older men. A 60-year-old white man has a 25% lifetime risk for an osteoporotic fracture, with consequences more severe than in women.4 The 1-year mortality rate in men after hip fracture is twice than in women.5 The factors that increase the risk of osteoporotic facture in men are the same as those found in women.6

Osteomalacia

Osteomalacia is caused by a vitamin deficiency and can be thought of as the adult version of rickets. Whereas osteo porosis is caused by loss of both calcium and cartilage from bone, the cartilage matrix of bone remains with osteomalacia. Because of the vitamin D deficiency, dietary calcium is not transported across the intestinal mucosa to be deposited onto adult bone. The latter process is referred to as mineralization of the bone. The result is "soft" bone that becomes misshapen, because the bones cannot support the body. Inward curvature of the vertebral column and collapsed pelvis are two common results from osteomalacia. Treatment is increased vitamin D intake, but it may not be possible to correct the misshapen bone.

o drugs used to treat diseases

OF THE BONE Bisphosphonates

The general bisphosphonate structure is illustrated in Figure 21.1. Bisphosphonates should not be confused with bisphosphates. Bisphosphonates have covalent carbon-phosphorous bonds, and bisphosphates carbon-oxygen-phosphorous bonds. In other words, the latter are phosphate esters very similar in chemistry to biochemical phosphate esters. Most in vivo bisphosphates are substrates for phosphatase enzymes, whereas bisphosphonates are stable in the presence of hy-drolytic phosphatases. The phosphonate groups are required both for binding to bone hydroxyapatite and cell-mediated antiresorptive activity.

Bisphosphonates were first reported in 1897. The discovery for treating and preventing osteoporosis began in the early 1960s with Procter & Gamble's detergent division searching for better additives for use in hard water areas. Bisphosphonates have excellent affinity for Ca2+ and Mg2+. The research moved to the company's dental division where it was discovered that bisphosphonates prevent tartar buildup by forming a thin film on the surface of teeth because it is strongly chemisorbed onto hydroxyapetite.7

Bisphosphonates approved for treating bone diseases can be divided into two groups: non-N-containing and ^-containing (Table 21.1). The rank order of bisphosphonates binding to hydroxyapatite, from weaker to stronger binding is clo-dronate (lowest) < etidronate < risedronate < ibandronate

Bisphosphonate Binding
Figure 21.1 • Bisphosphonate and bisphosphate chemistry. Bisphosphonates have carbon-phosphorous bonds, whereas bisphosphates are phosphate esters with carbon-oxygen-phosphorous bonds. The therapeutic bisphosphonates (Table 21.1) differ by the substituents at positions R1 and R2.

TABLE 21.1 Bisphosphonates

Generic Name

Brand Name R2

Approved Indications

Nonapproved Indications Contraindications

Dosing

Non-/V-containing Bisphosphonates

Etidronate disodium

Tiludronate disodium

Didronel —OH —CH3 Skelid —OH

Heterotopic ossification; Hypercalcemia of malignancy; Paget disease Paget disease

Clinically overt osteomalacia

Daily Daily

/V-Containing Bisphosphonates

Alendronate sodium

Fosamax

Pamidronate disodium

Risedronate sodium

Aredia

Actonel

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