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Bisphosphonates have a long history in the treatment of osteoporosis and bone-related disease. This review focuses on the use of a specific nonaminobisphosphonate, clodronate, which appears to be much better tolerated than other bisphosphonates and free of high-risk contraindications. Specifically, this paper reviews its use in the prevention of osteoporosis in postmenopausal women, taking into account its tolerability profile and recent safety issues arising regarding the use of bisphosphonates.
Osteoporosis is the most common bone disease in humans, characterized by low bone mass, deterioration of bone tissue, disruption of bone architecture, compromised bone strength, and increased bone fracture risk over time. Indeed, in recent years, osteoporosis has become one of the major concerns for health care policies in industrialized countries, where improved life expectancy has greatly increased the average age of the population.
Given the relevance of the obvious societal and economical burden of the disease, the European Union has set prevention of osteoporosis among its main health care objectives and prevention policies since the late s. Alongside prevention campaigns, international scientific societies have developed a number of guidelines on prevention, treatment, and bone threshold values to address the problem.
Bisphosphonates are characterized by a high affinity for bone but not for other tissues, their main cellular targets being mesenchymal cells, osteocytes, osteoblasts, and osteoclast precursors. Bisphosphonates are synthetic analogs of pyrophosphate, an endogenous regulator of bone mineralization, which contains a nonhydrolyzable P-C-P backbone with two side chains R1 and R2.
The two phosphonate groups are required for binding to bone mineral and for antiresorptive potency. Modification of one or both phosphonate groups significantly reduces the binding affinity as well as antiresorptive potency of the bisphosphonates. The R1 and R2 side chains have a wide range of activities. Acting together with the two phosphonate groups, the presence of a hydroxyl group —OH or an amino group —NH 2 , rather than an H group in the R1 chain, enhances binding to calcium minerals.
The presence of a nitrogen or amino group in the R2 side chain significantly increases the antiresorptive potency of bisphosphonates and also affects binding to hydroxyapatite. Figure 1 shows the bisphosphonate pathway, and the genes involved in the effects of bisphosphonates on osteoclasts. Bisphosphonate pathway, and the genes involved in the effects of bisphosphonates on osteoclasts. Pharmacogenetics and genomics On this basis, bisphosphonates can be broadly classified into two major classes with distinct mechanisms of action, ie, the non-nitrogen-containing class and the nitrogen-containing class.
The earlier non-nitrogen-containing bisphosphonates eg, clodronate, tiludronate, and etidronate act by incorporation into adenosine triphosphate, whereas the newer, more potent nitrogen-containing bisphosphonates eg, pamidronate, alendronate, ibandronate, risedronate, and zoledronate act by inhibiting farnesyl pyrophosphate synthase in the mevalonate pathway.
In the clinical setting, the most commonly used bisphosphonates are zoledronate, alendronate, pamidronate, risedronate, and clodronate. These agents are available for intravenous, intramuscular only in Italy , and oral administration. For this reason, oral administration is used only for treatment that requires minimal amounts to control bone turnover, such as in postmenopausal women. Bisphosphonates are generally well tolerated, with few side effects, which include gastrointestinal symptoms nausea, vomiting, diarrhea and occur more frequently among patients prescribed oral bisphosphonates.
However, recent findings that bisphosphonates induce osteonecrosis of the jaw, atrial fibrillation, acute phase response, and renal insufficiency have raised safety and ethical concerns around the use of bisphosphonates.
In reality, several clinical investigations addressing the topic have ascribed these effects to aminobisphosphonates, thus excluding the nonaminobisphosphonates.
Specifically, we will approach the tolerability and safety issues mentioned earlier, compare clodronate with other bisphosphonates, and discuss some of the literature regarding indications for its use in the prevention of osteoporosis, particularly in postmenopausal women.
Clodronate is a well established medication in the treatment of patients with breast cancer to prevent bone metastases and improve survival rates. Although mainly used against cancer-induced bone disease, the undoubted efficacy and relatively low toxicity of clodronate also makes it an attractive candidate for the management of osteoporosis.
In addition, while bisphosphonates are usually administered according to a continuous oral schedule for osteoporosis, clodronate is available in several formulations and can be used in a number of different schedules for prevention and treatment of the condition. IV, intravenous; IM, intramuscular. Oral formulations consist of mg and mg tablets and mg capsules. The intravenous formulation may be used on a short-term basis at a dosage of mg every 3—4 weeks.
The remainder has a very high affinity for bone tissue, and is rapidly absorbed onto the bone surface. Indeed, its efficacy in the prevention of osteoporosis in postmenopausal women has been documented in several studies that have shown the efficacy of the drug, not only in increasing bone mineral density, but also in reducing fragility-related fractures.
Numerous studies have been conducted in recent years in order to assess the precise mechanisms by which each bisphosphonate inhibits bone resorption, 4 , 13 , 14 and it seems that the specific action of each bisphosphonate depends on its ability to bind rapidly and with high affinity to the bone surface.
As for clodronate, in vitro studies have demonstrated its ability to inhibit reversibly the growth and glycolysis of fibroblasts and osteoclasts. Inhibition of osteoclastic activity reduces the firing rate of new bone remodeling units, with an altered balance between bone formation and resorption in favor of the latter, accounting for why use of clodronate is encouraged in the prevention and treatment of postmenopausal osteoporosis.
Clodronate had a positive effect on bone mineral density that persisted for eight months after stopping administration of the drug. The positive action of oral clodronate was confirmed by another study 15 , 17 in which postmenopausal women with osteoporosis were treated every two months with mg of clodronate, taken for a total of 12 months. In , a randomized trial by Filipponi et al 15 , 18 involving postmenopausal women with osteoporosis showed that six months of cyclical treatment with clodronate for up to four years, intravenously administered at a dose of mg per month, resulted in a significant reduction in markers of bone remodeling, indicating a protective action against loss of bone mass, and these results were significant after 12 months and maintained even at 24 months.
Another study conducted in the same year 15 , 19 seemed to confirm the effectiveness of intramuscular administration of the drug in preventing bone loss in postmenopausal women with osteoporosis.
In particular, Rossini et al showed that after two years of treatment with clodronate, administered at a dose of mg intramuscularly every two weeks with oral calcium supplementation , the treated group showed significant differences in lumbar and femoral bone mineral density compared with the control group treated only with calcium supplementation and a significant reduction in circulating levels of alkaline phosphatase. In , Filipponi et al published an open-label study 18 that evaluated changes in bone mineral density in postmenopausal women with osteoporosis treated every three weeks with mg of clodronate intravenously and followed annually for six years, compared with a control group of women observed retrospectively.
The results showed a significant increase in bone mineral density in the first year of treatment, an effect maintained over six years and showed the positive effect of the drug in preventing lumbar fractures, particularly in patients with a history of fracture at the beginning of treatment. However, studies show that the two formulations of clodronate now used in osteoporosis intramuscular and oral show similar increases in bone mineral density, with slightly higher values for the intramuscular formulation.
This reduction reached statistical significance after one year of therapy. These studies also assessed the effectiveness of intramuscular clodronate at a dose of mg every week or every two weeks. Nevertheless, it seemed that the largest increases in bone mineral density at the lumbar spine and femoral neck was recorded in the patient group treated with clodronate mg per week. In addition to preventing and reducing bone loss, clodronate has extraskeletal biological effects, ie, anti-inflammatory and antiarthritic activity in both animal and human models.
In particular, clodronate has demonstrated the anti-inflammatory in vitro effect of nonaminobisphosphonates and the proinflammatory effect of aminobisphosphonates.
Beneficial effects have also been observed in rats. The efficacy of oral clodronate in reducing the risk of skeletal fractures was demonstrated in a study by McCloskey et al 12 in patients with postmenopausal or secondary osteoporosis and then in a larger sample of approximately older women with osteoporosis. Twenty percent of the product remains in the body and most likely where the bone is removed over the years, depending on bone turnover. The rate of deposition on the bone surface is rather fast, similar to calcium and phosphate.
However, patient adherence with osteoporosis therapy, and thus improvement of therapeutic results, can be achieved by reducing the frequency of drug administration or increasing the interval between doses. The results suggest similar effects on bone mineral density with the two administration schedules, but with important implications in clinical practice.
In fact, reducing the frequency of administration appeared to improve patient adherence to therapy with a good tolerability profile. Moreover, the inconvenience of pain at the injection site has been overcome through the development of a new formulation of clodronate higher pH and addition of lidocaine 41 although the intensity of pain symptoms in situ is certainly related to the amount of drug administered mg of clodronate equal to a 6.
Hence, everything considered, formulation and dosing interval can create the conditions for better patient adherence with treatment protocols and better long-term therapeutic results. As mentioned, clodronate is generally well tolerated. However, unlike other bisphosphonates, it does not appear to be contraindicated in patients with renal failure, although its dose should be modified according to renal function. In , Ruggiero et al performed a retrospective chart review of patients with a diagnosis of refractory osteomyelitis and a history of chronic bisphosphonate therapy.
Of a total of 63 patients, 56 had received intravenous bisphosphonates for at least one year, and seven patients were on chronic oral bisphosphonate therapy. The authors concluded that the risk of osteonecrosis of the jaw should alert practitioners to monitor for this previously unrecognized potential complication.
An early diagnosis might prevent or reduce the morbidity resulting from advanced destructive lesions of the jaw bone. The task force defined osteonecrosis of the jaw as the presence of exposed bone in the maxillofacial region that did not heal within eight weeks of identification by a health care provider.
Based on review of both published and unpublished data, the risk of osteonecrosis of the jaw associated with oral bisphosphonate therapy for osteoporosis seems to be low, and estimated to be between one in 10, and less than one in , patient-treatment years. However, the task force recognized that information on the incidence of osteonecrosis of the jaw is rapidly evolving and that the true incidence may be higher.
The risk of osteonecrosis of the jaw in patients with cancer treated with high doses of intravenous bisphosphonates is clearly higher, in the range of 1—10 per patients depending on duration of therapy. Complete prevention of this complication is not currently possible. However, dental care before embarking on bisphosphonate therapy reduces this incidence, and non-surgical dental procedures can prevent new cases.
For those who present with painful exposed bone, effective control in a pain-free state without resolution of the exposed bone is Bisphosphonates, as well as preventing and reducing bone loss, have extraskeletal biological effects, ie, anti-inflammatory and antiarthritic activity, in both animal and human models. In particular, it has demonstrated the in vitro anti-inflammatory effects of the nonaminobisphosphonates and the proinflammatory effects of the aminobisphosphonates.
Several clinical studies have recently shown a potential risk of atrial fibrillation in women with postmenopausal osteoporosis treated with aminobisphosphonates and it seems that this is attributable to a proinflammatory action.
Following this study, several meta-analyses of clinical trials have been published, but they covered only a small number of the hundreds of comparative trials evaluating bisphosphonates, few of which mentioned atrial fibrillation. In , a meta-analysis of placebo-controlled trials of bisphosphonates in a total of 26, patients with osteoporosis showed an increased risk of atrial fibrillation. Pending publication of more data, the potential risk of atrial fibrillation in some patients treated with bisphosphonates should be taken into account.
There is no evidence of an increased risk with a specific bisphosphonate, route of administration, patient subpopulation, or treatment duration. Some experts have even proposed a combination therapy with clodronic acid and alendronic acid to counteract the proinflammatory effects of the latter.
In murine pain models, clodronate showed central and peripheral antinociceptive effects. The main objective today in the treatment of osteoporosis is not only treating osteoporosis and osteoporotic fractures, but also reducing the risk of fractures 59 with a cost-effective therapy.
Numerous studies have demonstrated the efficacy of bisphosphonates in lowering the risk of fracture significantly by reducing bone turnover and maintaining or increasing bone mineral density.
However, an epidemiological study, known as NORA, conducted in , postmenopausal women aged 50— years average age approximately Other important factors appear to be relevant in determining the risk of fracture including clinical risk factors independent of bone mineral density 66 ie, a history of a previous fracture, family history of hip fracture, glucocorticoid therapy, osteoporosis, and secondary underlying conditions such as rheumatoid arthritis, smoking, and alcohol.
Using algorithms to estimate the absolute year risk, clinicians can define a threshold pharmacological intervention that should be calculated more accurately based on a careful evaluation of the drug economy, ie, the cost-effectiveness of drugs for osteoporosis. In particular, an analysis conducted by McCloskey et al 12 found that subjects identified as at high risk of fracture with the FRAX algorithm respond to treatment with clodronate taken orally.
Among the drugs available to date, as stated previously, clodronate seems to have good tolerability and safety. It appears that, unlike other bisphosphonate, this drug reduces the risk of developing osteonecrosis of the jaw. Nevertheless, specialists should fully understand the mechanisms of action of different classes of bisphosphonates, including minimizing unwanted side effects.
In addition, the minor gastrointestinal complications and easy mode of administration, and not least its anti-inflammatory and analgesic effects, would seem to improve compliance and patient adherence to treatment with clodronate. National Center for Biotechnology Information , U. Drug Des Devel Ther. Published online Oct Received Oct This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. This article has been cited by other articles in PMC.
Abstract Bisphosphonates have a long history in the treatment of osteoporosis and bone-related disease. Epidemiology and societal cost of osteoporosis Osteoporosis is the most common bone disease in humans, characterized by low bone mass, deterioration of bone tissue, disruption of bone architecture, compromised bone strength, and increased bone fracture risk over time.