Neridronate: From Experimental Data to Clinical Use

Abstract

Neridronate is an amino-bisphosphonate that has been officially approved as a treatment for osteogenesis imperfecta, Paget’s disease of bone and type I complex regional pain syndrome in Italy. Neridronate is administered either intravenously or intramuscularly; thus, it represents a valid option for both cases with contraindications to the use of oral bisphosphonates and cases with contraindications or an inability to receive an intravenous administration of these drugs. Furthermore, although the official authorized use of neridronate is limited to only 3 bone diseases, many experimental and clinical studies support the rationale for its use and provide evidence of its effectiveness in other pathologic bone conditions that are characterized by altered bone remodelling.

Introduction

Neridronate is an amino-bisphosphonate (BP) that is available in Italy as a treatment for Paget’s disease of bone, osteogenesis imperfecta (OI), and type I complex regional pain syndrome (CRPS-I). Nevertheless, many experimental and clinical studies have reported its effectiveness as a treatment for other pathologic bone conditions that are characterized by altered bone remodelling. Furthermore, neridronate represents a valid alterative for patients with contraindications to the use of oral BPs or patients who are unable to receive these drugs intravenously.

Mechanism of Action

Bisphosphonates are molecules that are structurally similar to inorganic pyrophosphate. Roles for inorganic pyrophosphate in preventing soft tissue calcification ¹ and in regulating bone mineralization processes have been reported in vivo. The substitution of an oxygen atom with a carbon atom (eg, P-O-P to P-C-P) in the basic structure of pyrophosphate molecule produces compounds that are characterized by pyrophosphate-like chemical-physical properties but are resistant to hydrolysis by pyrophosphatases, the physiological inhibitors of pyrophosphates. These molecules are called BPs because of the presence of a double bond between the phosphate group and a single carbon atom. The negative charge of the phosphate group is responsible for the high affinity of BPs for the positively charged calcium ions in the mineralized bone matrix. These compounds inhibit the formation, aggregation, and dissolution of calcium phosphate crystals, but their main biological effect is to inhibit osteoclast-mediated bone resorption. For this reason, BPs are widely used as treatments for bone diseases that are characterized by increased osteoclast activity, such as Paget’s disease of bone, malignant hypercalcaemia during myeloma, osteolytic bone metastasis, and osteoporosis. The 2 classes of BPs are characterized by 2 different mechanisms of action: the non–nitrogen-containing BPs (non-amino-BPs), such as clodronate, etidronate, and tiludronate, and nitrogen-containing BPs (amino-BPs), including pamidronate, alendronate, risedronate, zoledronate, ibandronate, and neridronate.^2–4

Most of the amino-BPs that are currently used to treat osteoporosis are available in an oral formulation, with the exception of zoledronic acid, which is administered intravenously. Nevertheless, orally administered BPs are poorly absorbed in the gastrointestinal tract and may induce possible gastrointestinal side effects and improper intake, which is potentially responsible for the lack of compliance with these treatments.

Experimental Evidence

Many in vitro studies have confirmed the inhibitory effects of neridronate on osteoclastogenesis and osteoclast activity.^5–16 The direct effects of neridronate on osteoclast recruitment, osteoclast proliferation, and activity were evaluated in an in vitro model of osteoclastogenesis obtained by co-culturing of the murine monocyte/macrophage cell line RAW 264.7 with murine osteoblasts, which simulates the bone microenvironment. In this model, the percentage of tartrate acid alkaline phosphatase (ALP)-positive cells (an early marker of osteoclastic differentiation) was significantly reduced in co-cultures treated with different concentrations of neridronate compared with that in untreated co-cultures. Furthermore, the neridronate treatment induced the degradation of the actin ring associated with the plasma membrane, along with subsequent significant morphological changes in the osteoclastic ruffled border. In contrast, in untreated cells, the actin ring was undamaged and osteoclasts showed the ruffled border. The morphological alterations in cells treated with neridronate were confirmed by electron microscopy, which showed a reduced number of vacuoles and mitochondria and a lack of ruffled borders, which is typical of functionally altered cells. Conversely, the untreated cells were characterized by the typical features of functional osteoclasts. ⁵

Neridronate has been shown to directly exert anticancer effects. A significant reduction in the viability and growth of various cancer cell lines in vitro is correlated with the dose of a liposomal neridronate treatment. ⁶ Moreover, liposomal neridronate has been shown to reduce the expression of matrix metalloproteinase, which correlates with a poor prognosis in patients with various types of cancer. ⁶ Neridronate has been correlated with an irreversible reduction in the viability in human squamous cell carcinoma-like cells and the inhibition of cell proliferation in a time-dependent and dose-dependent manner. ⁷ Peripheral blood mononuclear cells derived from post-menopausal women who were treated with neridronate or derived from healthy donors treated with neridronate showed increased differentiation and activation of Vγ9Vδ2 T lymphocytes in vitro, which are characterized by cytotoxic activity against neoplastic cells.^8–10 Moreover, in vitro studies have confirmed the antiproliferative and antiangiogenic effects of neridronate. ¹¹

Even if the main mechanism of action of BPs is to inhibit the recruitment, differentiation, and activity of osteoclasts, these drugs have been reported to modify bone metabolism through effects on other bone cells, such osteoblasts, in many studies, even if the results have varied.^12–14 In osteoblast cultures derived from healthy subjects undergoing total hip replacement for degenerative joint disease, treatment with various concentrations of neridronate significantly increases cell proliferation and the synthesis of type I collagen and ALP. Nevertheless, the highest concentrations induced a cytotoxic effect and inhibited proliferation and the synthesis of type I collagen and ALP. ¹⁵ A potential anabolic effect of neridronate has been confirmed using human osteoblasts obtained from healthy and osteoporotic subjects. In these cells, neridronate induced a dose-dependent increase in osteocalcin synthesis and exerted a toxic effect at higher doses. ¹⁶

Clinical Evidence

Neridronate is officially approved in Italy as a treatment for OI,^17–28 Paget’s disease of bone,^29–33 and CRPS-I,^34–38 but various evidence suggests its potential effectiveness as a treatment for other bone diseases as well.

Osteogenesis imperfecta

Osteogenesis imperfecta is a genetic disease of the bone caused by heterologous mutations in the genes encoding type I collagen and is associated with increased bone fragility. The clinical presentation of OI is highly variable, ranging from a mild disease characterized by only an increased fracture risk occurring before puberty to a more severe disease characterized by a short stature and deformity or a disease that leads to perinatal death. Bisphosphonates are the most frequently reported therapeutic treatments for OI,^17–21 and these compounds represent the most common treatment for children with OI. Bisphosphonate treatments significantly increase the bone mineral density (BMD) and decrease the fracture incidence.^17,22

In a randomized controlled trial, 23 men and 26 pre-menopausal women with OI were randomized to receive either 100 mg of intravenous neridronate every 3 months or the placebo. The placebo group received the same treatment as the treatment group 1 year after the trial began. At 6 and 12 months of follow-up, significant increases in spine and hip BMDs were observed in patients who were treated with neridronate (3.0% ± 4.6% and 4.3% ± 3.9%, respectively), whereas no significant changes were observed in the untreated patients. Markers of bone remodelling decreased significantly during the neridronate treatment period, with mean decreases of 20% in bone ALP levels, 25% in serum C-telopeptide (CTX) levels and 20% in urinary deoxypyridinoline (DPD) cross-links. The incidence of new fractures during the neridronate treatment period was significantly lower than the incidence before therapy and in the placebo group. ²³

The same results observed in adults were confirmed in children with OI. In a randomized controlled 3-year study, 64 children with OI who had never previously been treated with BPs were randomized to receive 2 mg/kg/d intravenous neridronate every 3 months or the placebo. Patients assigned to the placebo group received the neridronate treatment after 12 months of follow-up. During the first year of treatment, the BMD values increased significantly in patients who were treated with neridronate (+30% in the spine and 25% in the hip) compared with those in patients who received the placebo. During the next 2 years, neridronate induced an annual 10% to 25% increase in the BMD values of all treated children. In addition, the mean individual height values of the treated patients improved significantly compared with those of the untreated patients, and the rate of the height increase was maintained during the second and third years of follow-up. Alkaline phosphatase levels progressively and persistently declined throughout the treatment period. The rate of fractures was significantly higher in the placebo-treated patients during the first year (45% in the placebo group vs 27% in the neridronate group), and the overall number of fractures was significantly lower for the treated patients. ²⁴ Recently, the long-term efficacy and tolerability of neridronate as a treatment for OI have been evaluated in an observational study that represented an extension of the previous 2-year randomized trial. ²³ A total of 164 patients with OI were recruited and treated with intravenous neridronate at doses ranging from 2 mg/kg to a maximum of 100 mg every 3 months for 36 months. Bone mineral density values for the lumbar spine, hip, and ultra-distal radius, and the total ALP levels were evaluated at baseline and every 6 months during the follow-up period. The mean lumbar spine BMD increased significantly from baseline to values observed at all time points and the percent variations from baseline progressively increased from month 6 to month 36. Moreover, the mean total hip BMD increased significantly from baseline to the values observed at all time points, whereas the mean BMD of the ultra-distal radius increased significantly from baseline to months 18 and 36. However, the mean BMD of the proximal radius did not change. Serum ALP levels decreased markedly throughout the observation period. The number of patients with fractures remained unchanged during the 3 years of treatment compared with that during the 3 years prior to treatment, whereas the mean number of fractures per patient decreased during the treatment period. The most frequently occurring adverse event was an acute phase reaction, which was observed in 22.8% of patients. In addition, serious adverse events were reported in 22.8% of patients, but none of them were related to the neridronate treatment. No cases of osteonecrosis of the jaw or atypical femur fracture were reported, confirming that neridronate is a safe, well tolerated, and effective treatment for adults with OI. ²⁵

A more marked reduction in the fracture risk than in BMD was observed in patients with OI who were treated with neridronate, suggesting a possible additional effect of neridronate on the bone microarchitecture. According to the results of a peripheral quantitative computed tomography evaluation of the non-dominant radius in patients with OI who were treated with neridronate, the mean changes in total volumetric BMDs of the ultra-distal radius were significantly increased in the neridronate-treated patients compared with those in the placebo-treated patients after 1 year, with a significant increase in the trabecular BMD (+2.7% ± 5.3%). A significant 7.2% increase in the cross-sectional area of the cortical bone in the proximal radius was observed only in the neridronate-treated group, which was associated with an estimated 20% increase in the bending breaking resistance. ²⁶ Neridronate is also an effective treatment for neonates with more severe forms of OI. In an open-label study, children with OI started treatment with 2 mg/kg intravenous neridronate for 2 consecutive days and every 3 months, either immediately after the diagnosis at birth or after 6 months of life. In the first 6 months, the children who started treatment immediately after birth showed better growth and a lower incidence of fractures than both the children who started treatment after 6 months of life and the untreated children, who were matched for sex, age, and clinical severity of OI and comprised a historical control group. However, in the second 6 months, all children treated with neridronate showed lower fracture rates than those in untreated historical controls and an improvement in the vertebral body area and structure of the vertebral body. ²⁷ The positive effects of neridronate on children and adolescents with OI appear to be further improved by its combination with recombinant GH (rGH), as shown in a randomized clinical trial evaluating the effects of a combined neridronate and rGH treatment in children with mild-moderate OI. In this study, patients who were previously treated with neridronate were randomly assigned to receive the combination neridronate and rGH therapy or continue receiving neridronate alone for 12 months. Significant increases in the BMD of the lumbar spine, and the distal and ultra-distal radii were observed in the combined treatment. Furthermore, the rate of linear growth velocity increased significantly in the combined treatment group compared with that in the group treated with neridronate alone. ²⁸

Paget’s disease of bone

Neridronate was officially approved in Italy as a treatment for Paget’s disease after a multicentre clinical trial was conducted in which different doses of this drug (25, 50, 100, or 200 mg intravenously for 2 consecutive days) significantly reduced the serum ALP and N-terminal telopeptide (NTX) levels and urinary collagen excretion, with a dose-response relationship and persistent response observed at the 6 month follow-up visit. ²⁹

In patients with Paget’s disease who did not respond to pamidronate, treatment with a single 100 mg infusion of neridronate for 2 consecutive days was effective at achieving biochemical remission in 93% of patients, in terms of normalizing the serum ALP levels; thus, neridronate shows a similar efficacy to pamidronate. ³⁰ No significant differences have been observed in the long-term effects of the same doses of neridronate administered via different routes as a treatment for Paget’s disease given. About 200 mg of intravenous neridronate (a 100 mg infusion for 2 consecutive days) or a 25 mg weekly intramuscular injection for 2 months exhibited similar effects on reducing the ALP and CTX levels, and these reductions persisted at 6, 25, and 27 months of follow-up. Both regimens were well tolerated. The adverse events were mainly influenza-like symptoms, which resolved within a few days and occurred both with the intravenous and intramuscular neridronate injections in a few patients (14%). ³¹

Similarly, 200 mg of intravenous neridronate is a safe and effective treatment for Paget’s disease in patients who were previously treated with a 300 mg intravenous clodronate infusion for 5 consecutive days and patients with a recent diagnosis of Paget’s disease who had never been treated with any anti-resorptive agent. In both groups of patients, neridronate reduced bone pain and the levels of bone turnover markers (serum ALP, urinary DPD, and urinary type 1 collagen NTX, CTX levels) within the first month, showing a good safety profile, with 18.7% of patients experiencing an acute phase reaction lasting for no more than 24 to 48 hours. ³² The usefulness of neridronate as a treatment for Paget’s disease of the mandible has also been described in one case report. ³³

Type I complex regional pain syndrome

Type I complex regional pain syndrome is a disabling pain syndrome that develops after trauma or surgery and is characterized by allodynia, hyperalgesia, oedema, signs of vasomotor instability, movement disorders, joint stiffness, and typical bone alterations that occur beginning in the first stages of disease, which are represented by areas of patchy osteopenia on X-rays, followed by diffuse severe bone loss and cortical erosions in the latest stages of disease and a focal over-uptake on bone scintigraphy and bone marrow oedema on magnetic resonance imaging (MRI), suggesting a condition of increased bone turnover in the area of interest. Currently, this disease lacks a definitive treatment, although various pharmacologic and non-pharmacologic therapies have been proposed with contrasting results. Nevertheless, various BPs have shown evidence of effectiveness in controlling pain and functional symptoms and in reducing and preventing focal bone loss in randomized controlled trials with limited sample sizes.^34–37 Neridronate has also been evaluated as a treatment for CRPS-I in a recent large multicentre, randomized, double-blind, placebo-controlled trial. About 82 patients with CRPS-I in either their hand or foot were randomly assigned to receive either an intravenous infusion of 100 mg of neridronate every 3 days for a total of 4 times or the placebo. After 50 days of the last infusion, the placebo group was treated with the same regimen of neridronate. In the double-blind phase, the visual analog scale (VAS) for pain was significantly lower in the neridronate-treated group after 20 days of treatment than in the placebo group and only continued to decrease for the next 20 days in the neridronate group. Oedema, pain induced by passive motion, allodynia, and hyperalgesia were significantly reduced in patients who were treated with neridronate compared with those in patients in the placebo group, and various functional indexes were increased. All neridronate-treated patients and only 45% of the patients who were treated with the placebo discontinued the symptomatic drugs within 2 weeks. The results obtained from patients had previously received the placebo, were subsequently treated with neridronate during the open-extension phase, and were similar to obtained from the neridronate-treated group during the blind phase, as represented by significant reductions in the VAS, oedema, and pain on passive motion; the disappearance of allodynia and hyperalgesia; and an improvement in functional scores after 40 days of follow-up. A complete normalization of the abnormal uptake was reported in patients undergoing bone scintigraphy, and a disappearance of localized bone oedema was observed on MRIs from 12 treated patients. ³⁸

Osteoporosis

Bisphosphonates are the most frequently used treatment for post-menopausal osteoporosis and male glucocorticoid (GC)-induced osteoporosis (GIO) in clinical practice. Although neridronate is not an officially approved treatment for these conditions, some studies have reported its potential beneficial effects on these forms of osteoporosis. In a pilot randomized controlled trial, 78 women with post-menopausal osteoporosis were randomized to receive either 50 mg of intravenous neridronate every 2 months for 2 years or a placebo. The BMD values for the spine and femoral neck increased progressively in neridronate-treated patients (+7.4% ± 6.1% and 5.8% ± 8.2%, respectively) after 24 months, whereas significant increases in the BMD values or changes in bone remodelling markers were not observed in the control. The increase in the BMD values was maintained in the successive follow-up period. The bone ALP level significantly decreased within 4 months compared with the baseline value and the control group and was persistently suppressed throughout the entire treatment course. A significant reduction in the serum CTX levels was observed 2 months after the first neridronate infusion. ³⁹ These results were confirmed in another pilot randomized study evaluating the effects of 25 mg of neridronate administered monthly for 12 months on 20 women with post-menopausal osteoporosis compared with 20 control subjects who were treated with the placebo. The spine and hip BMDs were significantly increased in the treated patients compared with those in the placebo patients (+6.6% ± 3% and 4.2% ± 2.3%, respectively), and markers of bone turnover were significantly decreased after 3 months of neridronate treatment and progressively decreased during the observation period. ⁴⁰ The effects of neridronate on bone density and bone turnover were further tested in a phase 2 clinical trial in which 188 post-menopausal women with a densitometric diagnosis of osteoporosis were randomly assigned in a double-blind manner to receive 4 different treatment regimens for 12 months. In particular, patients were assigned to receive 25 mg of intramuscular neridronate every 2 weeks (50 mg monthly dose), 25 mg of intramuscular neridronate monthly, 12.5 mg of neridronate monthly, or the placebo. At the end of the follow-up period, all 3 of the neridronate dosage regimens induced a significant increase in the spine and hip BMD values compared with both the baseline values and the placebo group, with a significant dose-dependent effect on the hip BMD values. However, the 25 mg/mo and 50 mg/mo doses were characterized by superimposable BMD changes in the lumbar spine, which were significantly higher than the BMD changes induced by the 12.5 mg/mo neridronate dose. Serum ALP levels were significantly decreased in all neridronate-treated subjects, without a clear dose-response relationship, whereas the serum CTX levels were significantly decreased in a dose-dependent manner. After treatment discontinuation, the spine BMD slightly decreased in each group, but the values remained significantly higher than the baseline values. Similarly, a rapid and progressive increase in ALP and type I collagen CTX levels was observed within the first year of follow-up after treatment. The changes in BMD and bone turnover markers induced by the intermittent administration of intramuscular neridronate were similar to the changes observed after treatment with other BPs that have officially been approved as treatments for post-menopausal osteoporosis. ⁴¹

Glucocorticoid-induced osteoporosis is another form of osteoporosis that is typically observed in patients with chronic inflammatory rheumatic diseases, who often require long-term use of GCs. A substantial proportion of rheumatic patients who have received long-term treatment with systemic GCs develop GIO and osteoporosis-related fractures. Orally and intravenously administered BPs are usually used to prevent and treat GIO. Nevertheless, the use of intramuscular neridronate has been evaluated in 69 rheumatic patients with osteopenia and osteoporosis who received chronic treatment with low-dose GCs; oral BPs were contraindicated in these patients because of their gastric or oesophageal diseases. Patients were randomly assigned to either treatment with 25 mg of intramuscular neridronate monthly or a placebo for 12 months. At the end of the study, patients who received the placebo showed a significant reduction in the lumbar and femoral BMD values, whereas the BMD values were significantly improved in the neridronate-treated patients (+6.3% and +4.2% at the lumbar and femoral neck, respectively, compared with the placebo-treated patients); a reduction in the levels of bone resorption markers was already observed in the neridronate group at 6 months. These results were similar to the results observed in rheumatic patients undergoing GC treatment following the administration of oral risedronate and alendronate. ⁴² In one case report, a child with Crohn disease who developed severe and symptomatic bone loss due to GC treatment was successfully treated with 3 infusions of neridronate, confirming that parenteral neridronate represents a valid alternative treatment for young patients requiring an anti-resorptive treatment who have contraindications for the use of oral formulations. ⁴³

β-thalassaemia major

Reduced bone mass represents an important cause of morbidity in patients with β-thalassaemia major, due to the increased bone turnover observed in patients with this disease, which justifies the use of anti-resorptive drugs such as BPs. Neridronate treatments were evaluated in a phase 2, randomized, parallel-arm, open-label study that included 118 patients having β-thalassaemia–induced osteoporosis. The recruited patients were randomly assigned to receive 100 mg of intravenous neridronate every 3 months plus calcium and vitamin D daily or only calcium with vitamin D daily. An increase in the mean BMD of the lumbar spine was observed in both study groups, and this increase was statistically significant in the neridronate-treated group at both 6 and 12 months compared with the baseline value, whereas an increase in the hip BMD was observed only in the neridronate-treated patients. The mean percent increases in the lumbar and femoral BMDs were significantly higher in patients treated with neridronate than in patients treated with placebo at both 6 and 12 months. Neridronate also induced a significant reduction in the serum ALP and CTX levels, even 3 months after the first administration. An improvement in the quality of life due to a reduction in back pain and a reduced need for analgesic drugs became evident after 3 months of neridronate therapy. ⁴⁴

Malignant hypercalcaemia

The efficacy of neridronate in treating malignant hypercalcaemia has been reported and is similar to the results observed for pamidronate. In 20 patients with cancer-induced hypercalcaemia that persisted following rehydration, a single intravenous infusion of 125 mg of neridronate induced a rapid and significant decrease in adjusted serum calcium levels, and only 2 patients experienced mild hyperpyrexia after the neridronate infusion. ⁴⁵

Primary hyperparathyroidism

In patients with primary hyperparathyroidism (PHPT) who have contraindications for surgical correction, BPs represent a rational pharmacologic treatment to prevent and retard bone resorption. Nevertheless, the long-term effects of the discontinuation of BP treatments are not well known. In an observational study, 54 post-menopausal women with PHPT were treated with an intravenous administration of 100 mg of neridronate every 2 months for 2 years. During the follow-up period, the BMDs of the lumbar spine, femoral neck, and total hip progressively increased to +6.6% ± 7.6%, +2.9% ± 4.5%, and +5.0% ± 3.9%, respectively. Nevertheless, during the post-treatment follow-up period (2 years), the mean spine BMD progressively decreased but was still 3.9% ± 5.5% higher than the baseline values at month 48, whereas the femoral BMDs returned to the baseline values 2 years after treatment discontinuation. The bone ALP and serum CTX levels decreased significantly within 6 months, with a nadir value observed after 18 to 24 months. ⁴⁶

Androgen deprivation therapy

Osteoporosis is a well-known complication of androgen deprivation therapy (ADT), which is the usual treatment for locally advanced or metastatic prostate cancer. In 2 different clinical trials, patients with osteoporosis complicated with locally advanced prostate cancer who were treated with ADT were randomly assigned to receive monthly intramuscular 25 mg neridronate infusions plus daily calcium and vitamin D supplementation or daily calcium and vitamin D supplementation alone for 1 year. According to the results from both studies, the neridronate treatment increased the BMD or prevented the reduction in the BMD observed in patients treated with calcium and vitamin D supplementation alone. Levels of bone remodelling markers (ALP and DPD) were significantly decreased in neridronate-treated patients at 6 and 12 months.^47,48

Osteoarthritis

Neridronate exerts an analgesic effect on degenerative joint diseases, such as osteoarthritis (OA). According to the results of a randomized, double-blind, placebo-controlled study, daily 100 mg intravenous neridronate injections for 10 days significantly reduced pain and improved the quality of life of patients with acute pain caused by knee OA compared with the placebo. Furthermore, the neridronate group exhibited a significant decrease in bone marrow lesions evaluated by MRI, ⁴⁹ suggesting a possible structural effect based on the hypothesis that altered bone metabolism plays a role in the pathogenesis of OA.^50–53

Other conditions

The possible positive effects of neridronate on various pathologic conditions involving the bone tissue have been shown in different case reports and in some clinical studies with limited sample sizes.

In a 38-year-old pregnant woman with pregnancy-associated osteoporosis and vertebral fractures, 2 monthly intravenous administrations of 50 mg of neridronate followed by 25 mg/mo intramuscular neridronate injections for 6 months reduced pain after 1 month and induced a marked recovery of the BMD values for both the spine (+9.4%) and hip (+5%) and a reduction in the excretion of the bone resorption marker DPD. ⁵⁴ Similarly, in a 36-year-old woman having transient osteoporosis of the hip, a rare clinical syndrome characterized by transient osteopenia, increasing pain and disability without deformity that occurs in middle-aged men or in women in the third trimester of pregnancy, monthly treatments with 25 mg of neridronate for 6 months induced a progressive improvement in pain 3 weeks after the first administration and a complete remission of symptoms after 2 months, which was associated with the disappearance of bone marrow oedema on a follow-up MRI 4 months after treatment. ⁵⁵

After 4 months, monthly intramuscular treatments with 25 mg of neridronate clearly improved the symptoms of a 59-year-old woman with osteonecrosis of the knee diagnosed by MRI; the improvements were visualized as signal alterations on the MRI. ⁵⁶ In a 1-year-old girl with polyostotic fibrous dysplasia, the administration of neridronate at the same dosage used for OI (2 mg/kg every 3 months) promoted the disappearance of bone pain and the normalization of the ALP and DPD levels after the third month of follow-up. ⁵⁷

Significant improvements in pain, functional status, and activity were observed after 1 year of treatment with an intramuscular neridronate injection (25 mg every 2 weeks for 3 months, followed by a monthly injection) in 4 post-menopausal women affected by periprosthetic osteolysis after total hip replacement, whereas an increase in periprosthetic BMDs was observed after an average follow-up period of 21 months. ⁵⁸

Treatment with 2 mg/kg/d neridronate every 3 months induced a reduction in bone lesions in a 16-year-old patient with chronic recurrent mutifocal osteomyelitis. ⁵⁹

In a 64-year-old woman affected by tuberculous spondylodiscitis, treatment with neridronate in combination with the standard antibiotic treatment for bone tuberculosis was associated with a rapid improvement in clinical symptoms, a disappearance of the MRI contrast enhancement, fatty reconstitution of bone marrow, and a decrease in the size of the osteolytic vertebral lesions. ⁶⁰

Neridronate reduces the clinical symptoms and improves the functional status of patients with ankylosing spondylitis (AS). In a 6-month open-label, 4-week study of patients with active AS, 60 patients were consecutively assigned to receive either monthly 100 mg intravenous neridronate or infliximab injections for 6 months. Both treatments reduced the disease activity index, functional index and pain (VAS) at 3 and 6 months compared with those at the baseline, without significant differences between the 2 treatment groups. Nevertheless, a significant increase in the lumbar spine BMD was observed in neridronate-treated patients compared with that in patients treated with infliximab. ⁶¹ Conversely, neridronate seems to be ineffective at treating multiple diaphyseal sclerosis (Ribbing disease). ⁶²

Safety

The main side effects observed in patients treated with neridronate include mild to moderate arthralgias and myalgias. Fever, which never exceeded 38°C and disappeared 3 days after the first infusion, has been reported, as have flu-like symptoms, similar to an acute phase reaction. These reactions occur in response to both intravenous and intramuscular administrations of the drug. The symptoms usually appear 24 to 36 hours after the first administration, mainly in previously untreated patients, and persist for less than 36 hours.^{24,27,29,31,43} Other reported adverse events include headache, diarrhoea, and dermatitis. ³⁰ No cases of jaw osteonecrosis have been reported in patients treated with neridronate, even after longer periods of treatment. ⁶³ Some patients develop hypocalcaemia, but symptomatic hypocalcaemia has not been reported. In one case report, an 84-year-old woman developed acute pseudogout after a single intravenous injection of neridronate. ⁶⁴ Overall, neridronate was well tolerated and showed a good safety profile in both adults and children.

Conclusions

Neridronate is officially approved in Italy as a treatment for OI, Paget’s disease of bone, and CRPS-I. Nevertheless, based on evidence from many clinical and experimental studies, this drug is potentially useful as a treatment for other pathologic bone conditions, although studies with larger patient populations are needed to extend its use. Furthermore, neridronate represents a valid alternative for patients with contraindications or who are intolerant to oral BPs. In particular, neridronate is the ideal medication for patients with difficulties associated with intravenous infusions because of its possible intramuscular administration. In conclusion, based on this clinical and experimental evidence, neridronate represents a new treatment for patients with various bone diseases.