< alendronate < pamidronate < zoledronate (highest). As noted in later discussion, this order does not completely parallel antiresorptive potency. A key difference between the non-N-containing and N-containing bisphosphonates is the ability of the latter to form positive charges on their nitrogens at physiological pH. In general, the more positively charged bisphosphonates (zoledronate, ibandronate, and alendronate) produce a positive surface on the bone, attracting additional bisphosphonates to bone.
The non-N-containing and N-containing bisphospho-nates differ in their mechanism of action. The former's (etidronate, tiludronate) site of action is the osteoclast's aminoacyl-transverse ribonucleic acid (tRNA) synthetase reversing the reactions normally involved in activating amino acids during protein synthesis. These two bisphos-phonates replace the terminal pyrophosphate moiety of adenosine triphosphate (ATP). This initiates apoptosis in the osteoclast leading to a decrease in bone resorption. There is some evidence that the bisphosphonate-modified ATP may affect mitochondrial function that also would lead to apop-tosis. The two non-N-containing bisphosphonates are indicated for Paget disease and, in the case of etidronate disodium, also heterotopic ossification and hypercalcemia of malignancy.
The N-containing bisphosphonates have a different site of action. They interfere with the mevalonate pathway required for biosynthesis of cholesterol and subsequent sterols. The specific sites appear to be that portion of the pathway utilizing isoprenoid diphosphates as substrates for farnesyl diphosphate synthase (FPPS) as the primary target. The bisphosphonates may be false substrates for the iso-prenoid diphosphates. The impact of FPPS inhibition may be more than inhibiting sterol synthesis. FPPS is required for the synthesis of farnesyl pyrophosphate, which is the precursor for geranylgeranyl diphosphate. Both farnesyl pyrophosphate and geranylgeranyl pyrophosphate are required for lipid modification (prenylation) of subcellular membranes where signaling proteins are located. This causes loss of osteoclast function and may be more important than apoptosis of the cells necessary for bone resorption to occur.
X-ray crystallography indicates the bisphosphonate nitrogen binds to the FPPS threonine (T201) or the backbone car-bonyl of lysine (K200). The optimal distance between the drug's nitrogen and the amino acid oxygen is approximately 3 A. From lowest to highest, binding to FPPS is pamidronate
< alendronate < ibandronate < risedronate < zoledronate, which closely matches antiresorptive potency. The latter two with their heterocyclic nitrogens are significantly better inhibitors of FPPS than the other three.8
No drug is without adverse reactions, and this is true of bisphosphonates. They can be very irritating to the gastrointestinal mucous linings. The recommended procedure for oral administration directs the patient to sit upright, consume a full glass of water with the tablet, and remain in the upright position for at least 30 minutes. Oral bisphospho-nates should be taken an hour before food. They are poorly absorbed.
A rare but serious adverse reaction is osteonecrosis of jaws. A suggested mechanism is oversuppression of bone turnover.9 In the majority of reported cases, there had been a previous dental surgical procedure. In this model, bis-phosphonates, by disrupting the osteoblast-osteoclast balance, impair proper healing of the jaw following surgery. Unfortunately, there are no definitive guidelines that help the clinician decide if the patient has medical condition that increase his or her risk of osteonecrosis when using bisphosphonates.10
The bisphosphonates also may cause severe and sometimes incapacitating pain in bone, joint, and/or muscle (musculoskeletal). This adverse reaction is difficult to define because it can appear within days, months, or years after starting treatment. Some patients report that the pain disappears after discontinuing the bisphosphonate, whereas others have reported slow or incomplete resolution after stopping the drug.11
It is difficult to describe any type of rank ordering of efficacy for bisphosphonates. There have been no head-to-head comparisons of several of the drugs in a single trial using the same diagnostic criteria. Measurements of efficacy include incidence of vertebral fracture, nonvertebral fracture, and bone mineral density. Comparisons are more likely focusing on convenience of dosing. Because bisphos-phonates adhere strongly to the bone surface, dosing has moved from daily to weekly or monthly for oral administration. Depot injections permit annual administration.
o HORMONE THERAPY
It is important to keep in mind that calcium's biochemical functions include much more than being the main mineral component of bones and teeth. All cells have calcium channels that strictly control calcium flux into and out of cells. Therefore, it is important that blood calcium levels be tightly regulated. This is done with three hormones: parathyroid, calcitonin, and 1,25-dihydroxycholecalciferol (1,25-diOH-D3). Parathyroid hormone (PTH) is produced by the parathyroid gland located behind the thyroid gland. The parathyroid gland has calcium receptors that sense blood calcium levels. If there is hypocalcemia, PTH is released increasing osteoclastic activity on bone, resulting in increased bone resorption.12 PTH also acts on the kidney, maximizing tubular reabsorption of calcium and activating the cytochrome P450 mixed function oxidase hydroxyla-tion of 25-hydroxycholecalciferol to 1,25-diOH-D3. The latter travels to the intestinal mucosa where it is a ligand for the vitamin D receptor (VDR). The result is active transport of dietary calcium into systemic circulation. 1,25-diOH-D3 can be thought of as a kidney hormone. A patient with kidney failure is prescribed 1,25-diOH-D3 because of the inability to carry out the final hydroxylation. In addition to regulating the uptake of dietary calcium from the intestinal tract, 1,25-diOH-D3, along with PTH, enhances calcium flux from bone.
Calcitonin is produced in the thyroid gland and sometimes is called thyrocalcitonin. It is released when there is hypercalcemia. This hormone reduces blood calcium levels by suppressing tubular reabsorption of calcium, thereby enhancing calcium urinary excretion and inhibiting bone resorption minimizing calcium flux from bone.
Calcitonin-Salmon (sCT; Miacalcin, Calcimar)
Human and salmon calcitonins differ from each other by 16 of the total 32 amino acids. Although each calcitonin has a
cys-S-S-cys disulfide bridge between cysteines 1 and 7 at the amino terminal end, and each ends at the carboxyl end with a prolinamide, the differences in the other amino acids between the two differ in their tertiary structures. These differences cause calcitonin-salmon to be one order of magnitude greater than human calcitonin in reducing calcium concentration in the blood stream of mammals.13,14 Nevertheless, these significant differences in amino acid sequence increase the risk of adverse reactions caused by the patient's immune system.
There are two dosage forms: intramuscular and nasal. Because of the adverse effects, there can be inflammation at the injection site plus flushing, nausea, and vomiting following an injection. Use of the nasal dosage form can cause backache and rhinitis. The approved indications for calcitonin-salmon are hypercalcemia, Paget disease, and post-menopausal osteoporosis.
Teriparatide Injection [hPTH(1-34); Forteo]
Teriparatide contains the first 34 amino acids of the 84 amino acid human parathyroid hormone and is produced by recombinant DNA technology. The N-terminal region of endogenous PTH contains most of the biological activity. Timing the administration of PTH determines the response. Teriparatide is administered once daily because once-daily administration stimulates new bone formation by stimulation of osteoblastic activity over osteoclastic activity. In contrast, continuous infusion leads to greater bone resorption than formation.
Teriparatide is indicated for primary postmenopausal osteoporosis in women who are at high risk of fracture and for increasing bone mass in men with primary or hypogo-nadal osteoporosis who are at high risk for fracture. It is not indicated for pseudohypoparathyroidism or secondary hypoparathyroidism. "True" hypoparathyroidism is caused by a PTH deficiency, and teriparatide acts as a PTH replacement. Pseudohypoparathyroidism usually is caused by a PTH receptor defect. Treatment for the latter includes calcium supplements and vitamin D with the goal to maintain blood calcium levels.
There is a boxed warning regarding a potential risk of developing osteosarcoma. It is based on studies in male and female rats. The effect was observed at systemic exposures to teriparatide ranging from 3 to 60 times the exposure in humans given a 20-^g dose. The boxed warning also warns against administering teriparatide to patients with Paget disease because of the active osteoblastic activity associated with this disease.
The focus on this chapter has been on diseases that interfere with bone remodeling. A key gland is the parathyroid, particularly when there is hypoparathyroidism. The opposite can occur with an overactive gland or hyperparathyroidism. There are two vitamin D analogs that are indicated for renal failure when patients are on dialysis. These patients cannot carry out the final cytochrome P450-catalyzed hydroxylation of 25-hydroxycholecalciferol (25-OH-D3) to 1,25-diOH-D3 (cal-citriol). It is common to prescribe calcitriol to prevent vitamin D-resistant rickets or osteomalacia. Because of the defective kidney, or lack of kidney, there is inactive feedback to the parathyroid, and the patient's parathyroid can over secrete parathyroid hormone to maintain blood calcium levels. There are two drugs (Fig. 21.2) based on the ergocalciferol structure that better regulate the parathyroid gland with less transport of dietary calcium and phosphorous. These are paricalcitol (19-nor-1,3,25-trihydroxyergocalciferol) and doxercalciferol (25-norhydroxy-1,3-dihydroxyergocalciferol). A third drug, cinacalcet (Fig. 21.3), either mimics calcium because it is a ligand for the calcium-sensing receptor on the parathyroid
gland or sensitize the receptor's sensitivity to extracellular calcium. The end result is that the parathyroid gland secretes less hormone. Cinacalcet is indicated for secondary hyperparathyroidism in patients undergoing renal dialysis and hypercalcemia caused by parathyroid carcinoma.
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