Clodronate: new directions of use

Abstract

Clodronate is the father of bisphosphonates. For over three decades it has been subject of study in biological and clinical areas, proving to be an extremely interesting molecule from different points of view. It has been the first drug for osteoporosis that can be administered pulsatorily (once every 15 days or once a week). This, along with good tolerability, has been the first cause of its success, when there were no solid data in literature about its antifracture efficacy. There are three published studies that prove its antifracture effect: two by McCloskey published in 2004 and 2007 on BMR, and our study about fracture prevention in corticosteroids OP. In these studies a dose of 800 mg/day orally administered or 100 mg/week I.M. was used, and they are basically the same if you consider that clodronate absorption, orally administered, is on average 1.9%. However, a series of works where higher doses were used (1600 mg orally administered) with greater effectiveness on bone mass, especially in higher risk populations, lead us to consider the use of 200 mg i.m. formulation. First of all, we proved densitometric equivalence of 200 mg i.m./14 days and 100 mg i.m./week in a first study; then, in a second study, we proved a greater densitometric efficacy of 200 mg/week compared to 100 mg/week, clearer at femoral level, where the drug had not proven to prevent femoral fracture because of inadequate bone mass increase at that level. Moreover, as for ibandronate case, monthly dose was doubled compared to pivotal trial, in order to maximize the effects on femoral bone mass and therefore prevent femoral fractures. Consequently, on the basis of the risk envelope, whether it is identified according to BMD and the presence of one risk factor at least or more correctly identified through risk chart (FRAX or DeFRA), you can put forward a differential use of 100 mg i.m. and 200 mg i.m., weekly, "off-label" or every 14 days, adjusting doses in relation to fracture risk and painful symptoms gravity, as well as improving its ease of use and therefore assist compliance. Common experience and clinical and biological works have proved that clodronate has an analgesic effect that can be increased by doubling the doses. The analgesic effect is present not only with patients with fractures, but also with patients suffering from osteoarthritis or arthritis. Therefore, the drug would fit well in the therapeutic program of rheumatic patient, also because of its symptomatic effects. Clodronate at small doses (2 mg) could also have protective effects on cartilage (introduction of intra-articular formulation is expected) and at 10-100 fold higher doses it has certainly anti-inflammatory effects and more specifically antimacrophage and anticytokine effects (IL-1, IL-6, TNFalpha, PGE). These effects are amplified by putting clodronate in monolayer liposomes. This drug, therefore, has to be considered as adjuvant in arthritis therapy, whose origin can be linked to a strong osteoclastic activation caused by an increase of cytokines and the RANKL/OPG relationship. It is clear that clodronate can work on cytokine at first and on osteoclastic effector in the end. The drug has been used "off-label" for decades intravenously in complex regional pain syndrome (CRPS type 1) in relation to schemes that change according to different Authors and according to cumulative doses ranging from 3 to 5 g. The introduction on the market of the 200 mg i.m. formulation could allow to get more practical but equally effective schemes. For example, we used this scheme: 200 mg/day for 10 days and then 200 mg every other day for 20 days (cumulative dose of 4 g in a month). Said scheme can be repeated in the following months in particular cases. Results, as for efficacy and lack of relapses, show that clodronate is the leader drug for this syndrome. In recent years, relationship between costs and benefits has started to matter, especially after the creation of some algorithms, such as FRAX, that let us choose patients with a higher fracture risk in 10 years, and after pharmaceutic-economic models that let us calculate FRAX intervention threshold, on the basis of drug price and monitoring, antifracture efficacy, quality of life and how much a community can or wants to spend. In this respect, a sub-analysis of McCloskey's study on people over the age of 75, conducted on 3974 subjects, shows that clodronate is more efficient with patients with a higher fracture risk, calculated according to FRAX. Furthermore, another study by McCloskey revealed that, for a 100-pound/year drug (very similar to clodronate), 'cost effective' intervention threshold is about 7-10%. In conclusion, clodronate prevents fractures, decrease osteo-articular pain, is easy to handle, tolerable and had a great cost/benefit relationship.

Keywords: algodistrophy; analgesic; anti-inflammatory; bisphosphonates; bone edema; fractures; osteoporosis; periprosthetic loosening.

Figure 1

Chemical structure of bisphosphonates.

Figure 2

a, b, c - Variations of lumbar, total femur and femoral neck BMD after 1 and 2 years of treatment with clodronate 100 mg/week vs 200 mg/week. Data of statistical significance. *vs basal p<0,05 **vs basal p<0,01 $ 200mg/week vs 100mg/week p<0,05 ° t24 vs t12 p<0,05

Figure 3

Lumbar and femoral BMD variations after 1 and 2 years of treatment with Clodronate 100 mg/week and 200 mg every 2 weeks.

Figure 4

Mechanism of action of nitrogen-containing BPs.

Figure 5

Mechanism of action of nitrogen-free bisphosphonates.

Figure 6

Anti-inflammatory effect of clodronate on various pro-phlogogenic mediators.

Figure 7. Vertebral fractures and pain

Study in 30 patients with fragility vertebral fracture and with acute vertebral pain, diagnosed 1–5 days earlier than usual. They were treated with clodronate 300 mg i.v. according to the following regimen: 5 slow infusions/week for 4 weeks (total: 6 g) or paracetamol 3 g/day. Using clodronate 200 mg i.m., you could get in 1–2 months the same result keeping the same cumulative dose (6 gr) (81).

Figure 8. Algodistrophic syndrome

Variations of visual analogic scale (VAS 0–100) and of clinical global evaluation (CGA 0–3) at basal level and after Clodronate therapy for 10 consecutive days (Varenna et al, 17).

Figure 9. Periprosthetic loosening

Interaction between wear particles and macrophages leads to the activation of bone resorption mechanisms (adapted by Denis Nam et al. Clin Orthop Relat Res. 2013) (98).

Figura 10. Periprosthetic Loosening

Randomized double-blind study with radiostereometric evaluation in 50 patients with gonarthrosis subjected to total limb prostheses surgery (NexGen) and treated with: clodronate 1,6 g/day per os or placebo with the following dosing schedule: 3 weeks before surgery and up to 6 months in post-operative [using 200 mg i.m this is the dosing schedule: 200 mg/week for 3 weeks before surgery and up 200 mg/week for to 6 months in post-operative]. (Hilding M, Aspenberg P. Postoperative Clodronate decreases prosthetic migration: 4-years follow-up of a randomized radiostereometric study of 50 total knee patients. Acta Orthop. 2006 Dec; 77(6):912–6).