Neridronate

The effectiveness of neridronate in the treatment of bone diseases

Neridronate is an amino-bisphosphonate (BP) that is available in Italy as a treatment for Paget’s disease, osteogenesis, imperfecta osteogenesis (OI) and complex regional pain syndrome type I. However, many experimental and clinical studies have reported its efficacy as a treatment for other pathological bone conditions characterized by bone remodeling alterations. In addition, neridronate represents a viable alternative for patients with contraindications to the use of oral BP or patients who are unable to receive these medications intravenously.

Bone diseases

Neridronate is used to treat bone diseases such as osteoporosis, Paget’s disease, OI and CRPS.

In some cases, these diseases affect the performance of orthopaedic implants and compromise bone regeneration. For this reason, the development of an effective surface (also thanks to the administration of neridronate) of cells and their regeneration may depend on the functionality of the cells. To verify the effectiveness of treatments, it is necessary to monitor cell physiology, the length of the number of actin filaments in order to evaluate the treatments followed. In bone, the balance between bone matrix synthesizing osteoblast and bone resorption can be influenced by local and systemic factors, as well as by physiological factors in pathological conditions, which result in unbalanced bone renewal and directed towards greater bone resorption.

Mode of action

The bisphosphonates, molecules structurally similar to inorganic pyrophosphate, act. Commonly the role of inorganic pyrophosphate is to prevent calcification of soft tissues and act in the bone regulation of mineralization processes.

The action of these molecules is to create a double bond between the phosphate group and a single carbon atom. They are compounds that inhibit the formation, aggregation and dissolution of calcium phosphate crystals, and their main biological effect is to inhibit mediated osteoblastic bone resorption.

For this reason, BP is widely used as a treatment for bone diseases characterized by increased osteoclast activity, such as Paget’s disease, malignant hypercalcemia in myeloma, osteolytic bone metastases and osteoporosis.

The 2 classes of BPs are characterized by 2 different mechanisms of action: there is BP that does not contain nitrogen (non amino-BPs), such as clodronate, ethyl dronate, ethyl dronate and tiludronate, and those that contain nitrogen or BP (amino-BPs), which includes pamidronate, alendronate, risedronate, zoledronate, ibandronate and neridronate.

Most amino-BPs are available in an oral solution, with the exception of zoledronic acid, which is administered intravenously.

However, orally administered biphosphonates are poorly absorbed in the gastrointestinal tract and may induce possible gastrointestinal side effects and improper intake, potentially responsible for non-compliance with these treatments.

Experimental trials

Many in vitro studies have confirmed the inhibitory effects of neridronate on osteoclastogenesis and osteoclastic activity. The direct effects of neridronate on the recruitment of osteoclasts, their proliferation and their activity were evaluated in an in vitro model of osteoclastogenesis, obtained by co-cultivation of monolithic/ macrophage cell lines that simulates the bone macroenvironment.

In this model, the percentage of alkaline acid tartrate was reduced in co-cultures treated with different concentrations of neridronate compared with this in untreated cultures.

In addition, neridronate treatment induced degradation of the actin ring connected to the plasma membrane, resulting in significant morphological change in the osteoclastic boundary.

Differently in untreated cells the actin ring was not damaged and the osteoclasts showed a ruffled edge. Therefore, it was thought that morphological alterations in neridronate treated cells were less likely to have vacuoles and mitochondria and were characterized by the lack of ruffled edges typical of functionally altered cells. Several studies have shown that neridronate exerts an antitumor action, an outcome that has been achieved through a significant reduction in the profitability and growth of various cancer cell lines in vitro.

Moreover, neridronate has been linked to an irreversible reduction in the profitability of human squamous cell carcinoma and has an inhibitory function on cell proliferation, which is in line with the main mechanism of action of bisphosphonate, which is to inhibit the recruitment, differentiation and activity of osteoclasts.

Neridronate as well as bisphosphonates in general, is therefore characterized by the action exerted on bone metabolism implemented through effects on other bone cells, such as osteoblasts, in many cases.

Neridronate also has a potential anabolic effect, confirmed by the use of human osteoblasts obtained from healthy and osteoporotic subjects.

In these cells, neridronate induced a dose-dependent increase in osteocalcin synthesis, exerting a toxic effect at higher doses.

Clinical trials

Neridronate is officially approved in Italy as a treatment for Paget’s disease of the bone, and various tests prove its effectiveness as a treatment for other bone diseases. Actually is used for the treatment of CRPS as well.

CPRS -I is a major complication after trauma, surgery, and/or immobilization of an extremity. The disease often starts with clinical signs of local inflammation and develops into a prolonged phase that is characterized by trophic changes and local osteoporosis and sometimes results in functional impairment of the affected limb. While the pathophysiology of CRPS remains poorly understood, increased local bone resorption plays an undisputed pivotal role. The aim of this retrospective clinical study was to assess the bone microstructure in patients with CRPS.

In fact, biphosphonates are increasingly becoming a widespread strategy for the treatment of CRPS, which is confirmed by a recently published systematic meta analysis, which has shown that drugs that act on bone metabolism are a valid choice for the treatment of CRPS. In this context, neridronate plays a major role when considering the central role of bones in CRPS.

A number of findings are consistent with the central role of bone in triggering and maintaining the early stages of the disease. Events triggering the disease, such as a fracture or trauma that could cause micro-fractures and surgery involving the bone, which are often recognised as an inciting event in most CRPS patients, should be considered. Secondly, CRPS, which occurs most frequently in postmenopausal women, is significantly associated with osteoporosis, particularly in patients who suffer most often from fractures due to frailty. Consistently, CRPS is reported in patients with clinical disorders characterized by skeletal fragility, with a high propensity to fracture. Bone scintigraphy and sometimes magnetic resonance imaging always show a specific pattern in the early stages of the disease, consistent with manifest bone involvement. Planimetric radiography detects skeletal changes during CRPS, in varying percentages, but with specific characteristics that do not simply evoke disused osteoporosis. In addition, the animal model that most closely resembles human CRPS is induced by the fracture of the tibia.

The bones diseases include imperfecta osteogenesis, a genetic disease of the bone caused by heterologous mutations in collagen type I coding. Biphosphonates are reported therapeutically for OI, as they significantly increase bone density and decrease the incidence of fracture.

Proof of this is a study conducted on a sample of 23 men and 26 women in premenopause with randomized OI to receive 100 mg of intravenous neridronate or placebo on a quarterly basis.

The placebo group received the same treatment as the treatment group 1 year after the start of the study. After 6 and 12 months of follow-up, significant improvements in the spine and hip were observed in patients receiving neridronate treatment, while no improvement was observed in untreated patients. The results observed in adults were confirmed in children with OI.

Also in a randomised trial of 64 3-year-old children with OI who had never been treated with BPs, 2mg of neridronate was administered intravenously again at 3 months intervals. During the first year of treatment, BMD values increased significantly in patients treated with neridronate, unlike patients treated with placebo. Over the next two years, the percentage of fractures decreased and a more marked reduction in fracture risk was observed in patients with OI treated with neridronate, suggesting a possible additional effect of neridronate on bone microarchitecture. Neridronate is therefore very effective in the treatment of bone diseases, including complex regional pain syndrome type I, a disabling syndrome that develops after trauma or surgery and is characterized by allodynia, hyperalgesia, edema, instability, movement disorders, joint stiffness. Currently, this disease is not accurately diagnosed and lacks specific treatment, but studies conducted on several samples of patients have demonstrated the effectiveness of neridronate in in the control of pain, functional symptoms and in the reduction and prevention of focal bone loss. Neridronate was therefore also an effective treatment for CRPS-I in a recent study involving a sample of 82 patients.

The results obtained by patients who had received placebo treatment at an early stage were subsequently treated with neridronate during the open extension phase. Following neridronate treatment, pain was reduced and allodynia and hyperalgesia gradually disappeared.

Effectiveness and results

Neridronate, as well as the other elements belonging to the family of bisphosphonates, are the most frequently used treatment for bone diseases, including osteoporosis in menopause and induced in clinical practice.

Although neridronate is not an official treatment for those, numerous studies have recognized its effectiveness in treating these disorders. The effects of neridronate on bones, the variation in bone density and bone turnover have been tested on numerous occasions and particularly in a clinical study conducted on a sample of 188 postmenopausal women with a densitometric diagnosis of osteoporosis who had been assigned to receive 4 different treatment regimens for 12 months. In particular, patients were assigned 25 mg of intramuscular neridronate every 2 weeks (50mg of monthly dose), 25 mg of monthly intramuscular neridronate, 12.5 mg of monthly neridronate, or placebo.

At the end of the follow-up period, a significant increase in the vertebral column and BMD values of bone density was detected in the group to which neridronate was administered.

In patients treated with neridronate, serum ALP levels were decreased, without any clarification.

 dose-response relationship, as well as serum levels of CTX. After treatment was discontinued, the values remained significantly above the reference values. Glucocorticoid-induced osteoporosis is another form of osteoporosis typical of patients with chronic inflammatory diseases, who often require the long-term use of systemic GC. In these cases, bisphosphonates or neridronate are administered intramuscularly. Patients receiving this treatment have experienced a significant reduction in lumbar and femoral BMD values.

BMD values have improved significantly in patients given neridronate, where there has also been a reduction in bone resorption.

Other studies have shown that in some patients treated with neridronate there was a significant increase in trabecular BMD, even in the transverse section of the cortical bone in the proximal area, which was associated with an estimated 20% increase in flexural and rupture resistance.  Neridronate is also an effective treatment for newborns with more severe forms of OI. In a study conducted on a sample of children, the effectiveness of neridronate was tested on children who were given neridronate for two consecutive days in the first 3 months and 6 months of life. In the first 6 months of life, children who started treatment immediately after birth showed better growth and lower incidence of fractures than children who started treatment after 6 months of life and children who received no treatment at all.

All children who received treatment showed a lower percentage of fracture rates than children who received no treatment, and an improvement in the area of the vertebral body and structure of the vertebral body.

Therefore, the positive effects of neridronate on children and adolescents with OI, who seem to be further improved by its combination with recombinant GH, cannot be denied.

Conclusions

On the basis of these studies, confidence in the beneficial effects of neridronate on the treatment of bone diseases can be affirmed. In particular, long-term treatments provide significant and definitive results.