¿De que forma actuan los bifosfonatos?farma.

¿De que forma actuan los bifosfonatos?farma.

Revision del clinic.
http://www.sefh.es/revistas/vol24/n2/240203.pdf castellano
Y la Revision de la clinica mayo
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2667901/. English

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— This topic review provides an overview of the pharmacology of the bisphosphonates and of the differences between the preparations that are either currently available or undergoing clinical testing. Because bisphosphonates inhibit bone resorption, they are used in the treatment of hypercalcemia, osteoporosis, metastatic bone disease, and Paget disease. These uses are discussed separately.

PHARMACOLOGY — Bisphosphonates all have in common the P–C–P structure, which is similar to the P–O–P structure of native pyrophosphate (figure 1) [1]. Bisphosphonates differ from each other only at the two "R" groups in the accompanying figures (figure 1 and figure 2). Alendronate, neridronate, ibandronate, pamidronate, risedronate, and zoledronic acid have a nitrogen group and are called nitrogen-containing bisphosphonates in contrast to etidronate and tiludronate, which do not (figure 2).

Mechanism of action — The bisphosphonates inhibit osteoclastic bone resorption via a mechanism that differs from that of other antiresorptive agents [2-4]. Bisphosphonates attach to hydroxyapatite binding sites on bony surfaces, especially surfaces undergoing active resorption. When osteoclasts begin to resorb bone that is impregnated with bisphosphonate, the bisphosphonate released during resorption impairs the ability of the osteoclasts to form the ruffled border, to adhere to the bony surface, and to produce the protons necessary for continued bone resorption [2,3,5]. Bisphosphonates also reduce osteoclast activity by decreasing osteoclast progenitor development and recruitment and by promoting osteoclast apoptosis [6].

In addition to their inhibitory effect on osteoclasts, bisphosphonates appear to have a beneficial effect on osteoblasts. In a murine model of glucocorticoid-induced osteoporosis, bisphosphonates prevented osteocyte and osteoblast apoptosis [7]. The mechanism of this effect involves connexin 43, a gap junction protein that facilitates activation of protein kinases. This anti-apoptotic effect, however, probably does not contribute significantly to the anti-osteoporotic efficacy of bisphosphonates, above their potent antiresorptive actions.

Bone formation is often reduced by bisphosphonates, which is probably an indirect effect of inhibition of bone resorption. In normal bone remodeling, bone resorption and formation are coupled. Changes in resorption drive formation, so, when bone resorption decreases, bone formation also decreases. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Remodeling'.)

Despite their structural similarities, there are important differences among the bisphosphonates in potency and toxicity. The nitrogen-containing bisphosphonates (zoledronic acid, risedronate, ibandronate, alendronate, neridronate, and pamidronate) are more potent inhibitors of bone resorption than the simple bisphosphonates (etidronate, clodronate, tiludronate) (table 1).

Nitrogen-containing bisphosphonates — The nitrogen-containing bisphosphonates act primarily by inhibiting the enzyme farnesyl pyrophosphate (FPP) synthase in the mevalonate pathway (cholesterol biosynthetic pathway). Inhibition of FPP synthase disrupts protein prenylation, which creates cytoskeletal abnormalities in the osteoclast, promotes detachment of the osteoclast from the bone perimeter, and leads to reduced bone resorption [8-11]. The relative antiresorptive potency of the individual nitrogen-containing bisphosphonates is related to the potency within which they inhibit FPP synthase [12].

In a histomorphometric study of bone biopsy specimens from postmenopausal women treated with alendronate for two to three years, a dose-dependent increase in the number of normal-appearing and abnormal osteoclasts was reported [13]. Approximately one-third of the osteoclasts were giant, multinucleated, and detached, a finding that theoretically could be attributed to a nitrogen-containing bisphosphonate-induced prolongation of apoptosis, secondary to decreased osteoclast exposure to the high calcium concentration (an important signal for osteoclast death) that would normally be released during active bone resorption. Similar multinucleated giant cells are present in bone biopsy specimens from patients with Paget disease of bone or hyperparathyroidism, which could lead to an incorrect diagnosis. However, in the latter two conditions, there is evidence of active bone formation (abundant osteoblasts and osteoid), whereas long-term nitrogen-containing bisphosphonate therapy is associated with a reduction in bone formation (decreased osteoblasts, osteoid). (See "Clinical manifestations and diagnosis of Paget disease of bone".)

When FPP synthase is disrupted, there is an accumulation of a precursor, isopentenyl pyrophosphate (IPP), which can bind to a receptor and cause the release of tumor necrosis factor (TNF) alpha. This pathway, leading to the production of TNF alpha, is hypothesized to cause the acute-phase reaction, a well-recognized side effect of intravenous bisphosphonates [14]. (See "Bisphosphonates in the management of osteoporosis in postmenopausal women", section on 'Flu-like symptoms'.)

Simple bisphosphonates — Bisphosphonates that do not contain nitrogen have a different mode of action. They are metabolized by osteoclasts to metabolites that exchange with the terminal pyrophosphate moiety of ATP, resulting in an ATP that cannot be used as a source of energy. The osteoclasts then undergo apoptosis [9].

Mineralization — Pyrophosphate is an important inhibitor of mineralization, and it is prevented from entering the bone by alkaline phosphate in the bone lining cells. The bisphosphonates, which have a structure similar to native pyrophosphate, have a strong affinity to mineral and they are not cleaved by the alkaline phosphatase. Thus, they can inhibit mineralization.

However, there are differences among the bisphosphonates in their potential to inhibit mineralization and cause osteomalacia. Etidronate, as an example, inhibits bone resorption and mineralization at the same concentration. This unfavorable therapeutic index (1:1) is the reason why etidronate is used infrequently for the treatment of osteoporosis. In comparison, the dose of nitrogen-containing bisphosphonates that inhibits bone mineralization is 1000 times the dose that inhibits bone resorption. One study of transiliac bone biopsies 24 or 36 months after the start of alendronate treatment confirmed that bone mineralization was normal and trabecular bone resorption was markedly decreased [15]. Thus, the circulating concentrations of the nitrogen-containing bisphosphonates currently in use inhibit skeletal resorption but do not cause osteomalacia [1].


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