Musculoskeletal System

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Chapter 19 Musculoskeletal System

Bisphosphonates (BPs)

Description

Bisphosphonates are agents that prevent the breakdown of bone.

prototypes and common drugs

Aminobisphosphonates

image Prototype: alendronate
image Others: risedronate, pamidronate

Non-Aminobisphosphonates

image Prototype: etidronate
image Others: clodronate, tiludronate, zoledronate

MOA (Mechanism of Action)

image The structural integrity of bone is determined to a large extent by the balance between the activity of osteoclasts, which break down bone (resorptive), and the activity of osteoblasts, which build bone.
image Bisphosphonates (BPs) inhibit osteoclast activity through a variety of mechanisms, some better understood than others (Figure 19-1).
image Inside the osteoclast the aminobisphosphonates disrupt the mevalonate pathway, a pathway involved in the posttranslational modification of proteins that are involved in cellular signaling. Disruption of the mevalonate pathway interrupts osteoclast function and leads to apoptosis of the osteoclast.
image The non-aminobisphosphonates work by increasing the accumulation of cytotoxic metabolites within osteoclasts, interfering with their function and possibly leading to osteoclast cell death.
image The clawlike chemical structure of BPs facilitates their attachment to bone. The multiple oxygen atoms around the perimeter of the BP molecule bind to divalent cations such as Ca2+ within bone matrix. The BPs remain within the matrix until the acids released by the osteoclasts break down the matrix and liberate the BPs. Ironically, the activity of the osteoclasts seals their own fate!
image Osteoclasts contribute further to their demise by devouring the BP molecules after liberating them.
image BPs have a variety of other cellular effects, inhibiting vitamin D production, intestinal Ca2+ transport, cell growth, metabolic changes in bone cells, and changes in acid and alkaline phosphatases.
image

Figure 19-1

Pharmacokinetics

image BPs have very low oral bioavailability (<10%), and their absorption is further reduced by food and by divalent cations such as calcium. It is therefore recommended that BPs be taken on an empty stomach, with plain water.
image The BPs that are absorbed are highly bound to bone, and are not metabolized, nor do they inhibit or induce metabolizing enzymes. They are eliminated by the kidney.
image The oral BPs are typically administered once daily. A higher dose of alendronate is also available as a once weekly formulation.

Indications

image Osteoporosis
image Paget’s disease of the bone (results in enlarged, deformed bones)
image Hypercalcemia:

image Malignancy
image Primary hyperparathyroidism (continuous parathyroid hormone [PTH] release causes bone demineralization)

image Bone metastasis causing osteolysis:

image Multiple myeloma
image Bone metastases of malignant tumors

Contraindications

image Hypocalcemia: BPs have exhibited decreases in serum calcium, so it is recommended that any deficiencies in calcium be addressed before initiation of therapy.
image Poor renal function: BPs are eliminated renally, so patients with creatinine clearance <30 mL/min may experience accumulation of these agents. Patients with poor renal function who begin to take BPs should be monitored closely.

Side Effects

All

image Gastrointestinal: nausea, dyspepsia

Serious

image Esophagitis or esophageal erosion is more commonly seen with the aminobisphosphonates. It may result from a direct irritant effect from tablets lodged in the esophagus or from reflux of gastric acid including the acidic form of the BP. Patients are advised to avoid reclining for at least 30 minutes after taking a BP, reducing the chance of tablet staying in the esophagus or reflux.
image Osteonecrosis of the jaw is typically only seen at higher doses. The mechanism has not been established; however, the fact that BPs alter bone turnover is thought to play a role. Jaw bone may have a higher rate of turnover than other areas of the body, perhaps explaining why this side effect is localized to this area.

Aminobisphosphonates

image Fever, flulike symptoms are a transient, typically first-dose phenomenon seen with intravenous administration. They are believed to be caused by release of proinflammatory cytokines.

Important Notes

image The non-aminobisphosphonates were the original members of this drug class, whereas the aminobisphosphonates are newer, more potent agents.
image BPs have an established history as adjuncts in cancer therapy. They have demonstrated ability to reduce bone pain secondary to metastases and prevent treatment-induced bone loss.
image Etidronate can cause bone demineralization; therefore unlike the other BPs, which are typically taken once daily, etidronate is typically administered in 90-day cycles, with 14 days on treatment and 76 days off treatment. During the off-treatment period, calcium tablets are typically administered, and this 90-day treatment cycle (etidronate followed by calcium) is marketed in one kit.
image Estrogens appear to have a role in decreasing bone resorption; therefore one of the benefits of hormone replacement therapy in postmenopausal women is to maintain integrity of bone, hopefully leading to fewer fractures.
image Nonpharmacologic strategies for preventing osteoporosis include smoking cessation and weight-bearing exercise. Smoking is known to reduce bone mineral density (BMD), and weight-bearing exercise has been shown to substantially reduce fracture risk.

Advanced

Pregnancy

image The use of BPs in pregnancy has not been well studied, but they are believed to cross the placenta, based on animal studies. Given their effects on bone, a very careful assessment of risk versus benefit should be performed before these agents are used.

Evidence

Risedronate versus Placebo or Calcium and Vitamin D or Both in Postmenopausal Osteoporosis

image A 2008 Cochrane review (7 trials, N = 14,049 females) found no statistically significant effects for risedronate with respect to primary prevention of vertebral and nonvertebral fractures. For secondary prevention, risedronate demonstrated statistically significant relative risk reductions (RRRs) of vertebral fractures (39%), nonvertebral fractures (20%), and hip fractures (26%). The corresponding absolute risk reductions were small: 5%, 2%, and 1%, respectively. No statistically significant differences were found for adverse events.

Etidronate versus Placebo and/or Calcium and Vitamin D in Postmenopausal Osteoporosis

image A 2008 Cochrane review (11 trials, N = 1248 females) found no statistically significant effects of etidronate with respect to primary prevention of any fractures. A statistically significant RRR of 47% was found for secondary prevention of vertebral fractures but not for nonvertebral, hip, or wrist fractures. No statistically significant differences were found for adverse events.

BPs versus Placebo or No Treatment in Myeloma

image A 2002 Cochrane review (11 trials, N = 2183 patients) found that BPs prevented pathologic vertebral fractures (number needed to treat [NNT] = 10) and relieved pain (NNT = 11). BPs did not affect mortality, nonvertebral fractures, or hypercalcemia. No significant adverse events were associated with the BPs.

FYI

image One of the earliest indications that the BPs had potential in the treatment of bone diseases was the observation that they inhibit the dissolution of hydroxyapatite crystals.
image Because of their ability to localize in bone, one of the early uses for BPs was as bone scanning agents, used in the detection of malignancies and other skeletal lesions.
image The bisphosphonates are so named because of the two phosphate (P) groups that form the backbone of these molecules.
image The BPs have a clawlike chemical structure. This is a good way to remember that they attach themselves to bone matrix for long periods of time.
image The aminobisphosphonates such as alendronate have an amino (NH2-) group.

Vitamin D Replacement

Description

Vitamin D replacement consists of vitamin D and its derivatives.

Prototype and Common Drugs

image Prototype: calcitriol
image Others: ergocalciferol (vitamin D2), calcipotriene, doxercalciferol, paricalcitol

MOA (Mechanism of Action)

image The two major forms of vitamin D replacements are vitamin D2 and vitamin D3.
image Vitamin D is an important regulator of calcium and phosphate homeostasis and bone metabolism. It works in conjunction with PTH. The overall effect of vitamin D is to increase serum calcium concentrations. These effects are mediated via the following:

image Increased calcium absorption from the intestine
image Regulation of bone resorption and formation

• This occurs via stimulation of both osteoblastic and osteoclastic processes. Osteoblasts form bone, and osteoclasts dissolve bone.

image Increased calcium reabsorption in the distal renal tubules (Figure 19-2)

image Vitamin D results in a negative feedback loop and decreases transcription and secretion of PTH.

image The overall effect of PTH is to increase serum calcium levels, so increased vitamin D inhibits the actions of PTH so that both mechanisms do not drive up calcium levels too high.

image Vitamin D is lipophilic (it is one of the fat-soluble vitamins—A, D, E, and K) and thus freely crosses the cytoplasmic membrane.
image Intracellularly, it binds vitamin D receptors (VDRs) and binds DNA, where it regulates transcription of genes in the intestine, bone, kidney, and parathyroid gland.
image Vitamin D also has actions in macrophages and T cells and in proliferation and differentiation of a large number of cells, including cancer cells. Through these actions, it has immunomodulating and potentially, anticancer actions. Also, these actions are the basis of the mechanism whereby it is effective in psoriasis.
image

Figure 19-2

Pharmacokinetics

image Calcitriol is available in oral and intravenous formulations. It is a lipid-soluble vitamin and therefore can accumulate and cause toxicity (see later).

Indications

image Osteoporosis
image Hyperparathyroidism
image Osteomalacia
image Rickets

Contraindications

image None

Side Effects

image Side effects are related to long-term overadministration of vitamin D supplementation. Symptoms are primarily induced by hypercalcemia, which include gastrointestinal pain, renal stones, and psychiatric disturbances.

Important Notes

image Vitamin D is synthesized in the skin, liver, and kidney. Vitamin D supplementation is therefore frequently required in patients with renal failure.
image Rickets is a childhood disease characterized by impeded growth and deformity (curvature) of the long bones caused by vitamin D deficiency. The fortification of milk with vitamin D has dramatically reduced the incidence of rickets in developed countries.
image Osteomalacia is a condition of bone softening resulting from abnormality in the mineralization of the organic portion of the bone matrix called osteoid. It can be caused by vitamin D deficiency and is like an adult form of rickets. It is characterized by proximal muscle weakness, pain, and bone fragility.
image Osteoporosis is characterized by reduced bone mineral density (BMD) and increased bone fragility. It is caused by abnormal osteoblastic and osteoclastic activity. The bone is porous, hence the name of the disease.

Advanced

image Vitamin D supplements are sometimes used in the treatment of psoriasis, a common skin condition involving rapid turnover and inflammation of the skin. The evidence for this use, however, is not strongly conclusive.
image The various forms of vitamin D are referred to by several different names, summarized in Table 19-1.

TABLE 19-1 Various Forms of Vitamin D

Common Name Drug Name Abbreviation
Vitamin D2 Ergocalciferol D2
1-Hydroxyvitamin D2 Doxercalciferol 1(OH)D2
Vitamin D3 Cholecalciferol D3
25-Hydroxyvitamin D3 Calcifediol 25(OH)D3
1,25-Dihydroxyvitamin D3 Calcitriol 1,25(OH)2D3
24,25-Dihydroxyvitamin D3 Secalcifediol 24,25(OH)2D3

Evidence

Vitamin D Alone and Bone Fractures in the Elderly

image A meta-analysis in 2008 showed that vitamin D alone in the elderly was unlikely to be effective in preventing hip fractures (9 trials, N = 24,749 participants), vertebral fractures (5 trials, N = 9138 participants), or any new fracture (10 trials, N = 25,016 participants).

Vitamin D Plus Calcium and Bone Fractures in the Elderly

image The same meta-analysis in 2008 showed that vitamin D plus calcium supplements do reduce hip fractures in the elderly (8 trials, N = 46,658 participants, relative risk [RR] 0.84). Hypercalcemia is significantly more common in people receiving vitamin D or an analogue, with or without calcium (18 trials, N = 11,346 participants, RR 2.35). There is a significant but modest increase in gastrointestinal symptoms (RR 1.04) and a small but significant increase in renal disease (RR 1.16).

FYI

image The concept that vitamin D comes from the sun is inaccurate; the inert precursor (7-dehydrocholesterol) is present in the skin, and exposure to ultraviolet light converts it to cholecalciferol, which is then isomerized to vitamin D3. Reduced exposure to sunlight is one cause of vitamin D deficiency.
image Calcitonin is another hormone secreted by the thyroid gland. It has the opposing action of PTH: it “tones down” (lowers) the serum calcium levels.
image Vitamin D is a secosteroid: this is a steroid with one of the rings (the B ring) broken. Vitamin D2 is from ergosterol, whereas vitamin D3 is from cholesterol. Ergosterol is not produced in vertebrates, and therefore vitamin D2 is not produced in humans.

Parathyroid Hormone

Description

This agent (teriparatide) is a recombinant form of naturally occurring PTH.

Prototype

image Prototype: teriparatide

MOA (Mechanism of Action)

image PTH is released from the parathyroid gland. It regulates calcium and phosphate flux across cell membranes in bone and kidney. The key effects of PTH are as follows:

image Increased serum calcium
image Decreased serum phosphate
image Increased osteoclast activity in bone

image The effects on osteoclasts are indirect. PTH increases activity of the RANK (receptor activator of nuclear factor κ) ligand (RANKL). RANKL regulates osteoclast activity (see the discussion of RANKL inhibitors in this chapter). Increasing the activity of RANKL in turn stimulates an increase in the activity and number of osteoclasts.
image The stimulation of osteoclasts increases bone remodeling. PTH increases both bone resorption and formation; however, the net effect of excess PTH is to increase bone resorption (Figure 19-3).
image Low levels of intermittent PTH, however, can enhance bone formation. The actions of PTH are largely mediated through the PTH-1 receptor. The anabolic effects are mediated by direct effects of PTH on osteoblasts, increasing their number and inhibiting their apoptosis. PTH also stimulates insulin-like growth factor (IGF-1) in osteoblasts, and IGF-1 also has anabolic effects on bone.
image It is still not clear why high, sustained PTH has a catabolic effect, whereas low, intermittent administration has an anabolic effect on bone.
image In addition to these factors, PTH has several effects on the kidney:

image Increased reabsorption of Ca2+ and Mg2+
image Decreased reabsorption of phosphate, amino acids, bicarbonate, Na+, Cl−, and sulfate
image Stimulation of production of 1,25 dihydroxyvitamin D

image

Figure 19-3

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