Pharmacology of bisphosphonates

INTRODUCTION — 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 with 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 with which they inhibit FPP synthase [12].

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 [13]. (See "Risks of bisphosphonate therapy in patients with osteoporosis", 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 adenosine triphosphate (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 phosphatase 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 [14]. Thus, the circulating concentrations of the nitrogen-containing bisphosphonates currently in use inhibit skeletal resorption but do not cause osteomalacia [1].

Pharmacokinetics — Bisphosphonates are poorly absorbed orally (1 to 5 percent of an oral dose), and absorption is best when they are given on an empty stomach [15]. We recommend that oral bisphosphonates be taken only with water and that the patient then wait at least 30 minutes before ingesting food or other medications. More convenient oral dosing regimens, eg, once weekly or monthly, are available and are preferred by most patients. Intravenous preparations, which require even less frequent dosing, are also available for those unable to tolerate oral regimens.

Approximately 70 percent of the absorbed bisphosphonate is cleared by the kidney, and the remaining 30 percent is taken up by bone. Relative bone uptake is increased in conditions of high bone turnover, with less of the drug being excreted by the kidneys. Conversely, uptake in bone is reduced and kidney excretion is increased when turnover is low [16]. Bisphosphonates are cleared rapidly from the plasma (half-life is approximately one hour) but may persist in bone for the patient's lifetime [15].

CLINICAL USE AND ADVERSE EFFECTS — Bisphosphonates can be given to patients with any condition characterized by excessive bone resorption, such as osteoporosis, hypercalcemia of any cause, metastatic bone disease, and Paget disease. They are also used to treat heritable skeletal disorders in children, such as osteogenesis imperfecta. The clinical efficacy and adverse effects of bisphosphonates are discussed in greater detail separately.

●(See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Practical management issues'.)

●(See "Risks of bisphosphonate therapy in patients with osteoporosis".)

●(See "Treatment of hypercalcemia", section on 'Choice of antiresorptive agent: Bisphosphonates'.)

●(See "Osteoclast inhibitors for patients with bone metastases from breast, prostate, and other solid tumors".)

●(See "Use of osteoclast inhibitors in early breast cancer".)

●(See "Multiple myeloma: The use of osteoclast inhibitors".)

●(See "Treatment of Paget disease of bone".)

●(See "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)

SUMMARY

●Mechanism of action – Bisphosphonates potently inhibit bone resorption by reducing osteoclast number and function. The nitrogen-containing bisphosphonates are more potent than the simple bisphosphonates. (See 'Pharmacology' above and 'Mechanism of action' above.)

•Nitrogen-containing bisphosphonates – The nitrogen-containing bisphosphonates work primarily by inhibiting the enzyme farnesyl pyrophosphate (FPP) synthase in the mevalonate pathway (cholesterol biosynthetic pathway), thereby disrupting protein prenylation, which creates cytoskeletal abnormalities in the osteoclast, promotes detachment of the osteoclast from the bone perimeter, and leads to reduced bone resorption. Antiresorptive potency is directly related to potency for inhibition of FFP synthase. (See 'Nitrogen-containing bisphosphonates' above.)

•Simple bisphosphonates – Simple bisphosphonates have a different mechanism of action. They are metabolized by osteoclasts to metabolites that exchange with the terminal pyrophosphate moiety of adenosine triphosphate (ATP), resulting in an ATP that cannot be used as a source of energy. The osteoclasts then undergo apoptosis. (See 'Simple bisphosphonates' above.)

●Pharmacokinetics – Bisphosphonates are poorly absorbed orally (1 to 5 percent of an oral dose), but absorption is best when they are given on an empty stomach. (See 'Pharmacokinetics' above.)

●Clinical use – Bisphosphonates may be clinically useful in any condition characterized by excessive bone resorption. (See 'Clinical use and adverse effects' above.)