Expert Opinion on Drug Metabolism & Toxicology
`
`ISSN: 1742-5255 (Print) 1744-7607 (Online) Journal homepage: http://www.tandfonline.com/loi/iemt20
`
`Neridronic acid for the treatment of bone
`metabolic diseases
`
`Davide Gatti, Ombretta Viapiana, Luca Idolazzi, Elena Fracassi & Silvano
`Adami
`
`To cite this article: Davide Gatti, Ombretta Viapiana, Luca Idolazzi, Elena Fracassi & Silvano
`Adami (2009) Neridronic acid for the treatment of bone metabolic diseases, Expert Opinion on Drug
`Metabolism & Toxicology, 5:10, 1305-1311, DOI: 10.1517/17425250903029190
`To link to this article: https://doi.org/10.1517/17425250903029190
`
`Published online: 17 Sep 2009.
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`Grun. Exh. 1007
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`Downloadedby[NIHLibrary]at10:2417December2017
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`Expert
`Opinion
`
`Introduction
`
`Preclinical experiences
`2.
`3. Neridronic acid: clinical
`
`development
`
`Safety and tolerability
`4.
`5. Conclusion
`
`6.
`
`Expert opinion
`
`informa
`
`healthcare
`
`Drug Evaluation
`
`Neridronic acid for the treatment
`of bone metabolic diseases
`
`Davide Gatti, Ombretta Viapiana, Luca Idolazzi, Elena Fracassi &
`Silvano Adami’
`* University ofVerona, Rheumatology Unit, Ospedale di Valeggio, 37067 Valeggio, Verona, Italy
`
`Neridronic acid (6-amino-1-idroxyesilidene-1, 1-bisphosphonate)is a nitrogen-
`containing bisphosphonate licensedin Italy for the treatment of osteogenesis
`imperfecta and Paget's disease of bone. The pharmacodynamic profile is similar
`to that of other nitrogen-containing bisphosphonates andis characterized
`by its high affinity for bone tissue particularly at sites undergoing a process
`of remodeling.
`In growing children affected by osteogenesis imperfect,
`neridronic acid rapidly increases bone mineral density as measured by dual
`X-ray absortiometry and this is associated with a significant decrease in
`fracture cumulative number. Similar results have been obtained also in new-
`borns (< 12 month old) and in adult patients.
`In Paget's disease of bone,
`200 mg intravenous neridronic acid is associated with a 65% rate of full
`remission and a biochemical response (decrease of > 75% of bone turnover
`markers)
`in 95% of the patients. Neridronic acid treatment has been
`reported to be effective also in other skeletal diseases such as osteoporosis,
`algodystrophy, hypercalcemia of malignancy and bone metastasis. Neridronic
`acid has been developed only for parenteral use, andit is the only one used as
`intramuscular injection. This avoids all the limitations of oral bisohosphonates
`and may be offered for a home treatment with simple nursing assistance.
`
`Keywords: algodystrophy, bisphosphonates, osteogenesis imperfecta, osteoporosis,
`paget disease of bone
`
`Expert Opin. Drug Metab. Toxicol. (2009) 5(10): 1305-1311
`
`1. Introduction
`
`Neridronic acid (G-amino-1 -idroxyesilidene-1,1-bisphosphonate) is a nitrogen-containing
`bisphosphonate tested in a numberofclinical conditions and registered in Italy
`for the treatment of osteogenesis imperfecta (OI) and Paget’s disease of bone.
`The pharmacodynamic profile of neridronic acid is similar to that of other
`nitrogen-containing bisphosphonates and is characterized by its high affinity for
`bone tissue particularly at sites undergoing a process of remodeling,
`The pharmacokinetic has been investigated in young healthy subjects of both
`genders after intramuscular (i.m.) or intravenous (i.v.) administration of a single
`bolus of 25 mg andafter i.v.
`infusion of 50 and 100 mg neridronic acid. The
`results can be summarized asfollows:
`
`* Dose-dependentlinear increases in the pharmacologicaleffects.
`* When given i.m., neridronicacid is fully bioavailable with renal excretion profile
`identical to thar observedafter i.v. infusion.
`* The early half-life is ~ 7 h.
`* Approximately 50% ofthe dose given parenterally is excreted with urine in 24 h.
`* From both pharmacological and clinical studies, the antiresorptive potency of
`neridronic acid is very close to that of pamidronic acid.
`
`
`
`10.1517/17425250903029190 © 2009 Informa UK Ltd ISSN 1742-5255
`All rights reserved: reproduction in whole or in part not permitted
`
`1305
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`

`Neridronic acid
`
`2. Preclinical experiences
`
`Bisphosphonates have been extensively investigated for their
`inhibitory effects on osteoclasts with a mechanism of action
`that is largely known [1,2]. However, from a number of studies
`it seems that these compounds might have relevant extra-
`skeletal activities. Some of these studies were carried out with
`neridronic acid, namely for its action on new angiogenesis,
`on osteoblasts-osteocyte cells and IL-6 production.
`In 2005, Corrado et al. [3] investigated the effects of rising
`concentrations of neridronic acid on the activity of osteoblast
`cells derived from healthy individuals and women with
`osteoarthritis or osteoporosis. At high concentrations, the
`cellular production of osteocalcin was inhibited but at a
`lower concentration (10-6 M) the osteocalcin production
`was stimulated in cells derived from normal or osteoporotic
`subjects but not from those with osteoarthritis.
`Spreafico et al. [4] in 2006 confirmed the positive effect of
`neridronic acid on human osteoblasts cells by measuring the
`production of alkaline phosphatase and type 1 collagen. It
`should be mentioned that no in vivo studies have come out
`to corroborate these findings. A relevant inhibition of the
`synthesis of IL-6, a cytokine playing a crucial role in the
`recruitment and maturation of osteoclasts in vivo, has been
`also reported [4]. According to the authors, this last observation
`might provide the rational for using bisphosphonates, namely,
`neridronic acid in inflammatory conditions associated with
`abnormal bone resorption.
`The potential pharmacological effects of bisphosphonates
`on malignant cell lines have been extensively investigated
`over the past 2 decades [5]. Neridronic acid has been shown to
`inhibit the proliferation of umbilical stem cells and angiogenesis
`stimulated by fibroblast growth factor-2 [6].
`Muller et al. [7] evaluated the effects of three different
`nitrogen-containing bisphosphonates
`(alendronic
`acid,
`pamidronic acid and neridronic acid) on a cell line derived
`from squamocellular vulvar cancer, which is characterized
`by overproduction of EGFR, a cytokine with strong
`effects on proliferation and diffusion of tumoral cells.
`All three bisphosphonates were able to significantly suppress
`cell proliferation.
`
`3. Neridronic acid: clinical development
`
`type 1 collagen (bone, dentin, tendons, ligaments, endothelium)
`could be affected, with a variety of clinical manifestations.
`The hallmark of all OI types is the presence of severe qualitative
`and/or quantitative alterations of bone tissue.
`Skeletal growth is impaired and this, associated with
`recurrent skeletal fractures, may lead to severe deformities
`affecting life expectancy.
`Bone turnover is almost invariably abnormally high [8,9] and
`this represents the best rational for the use of bisphosphonates.
`The first experiences in the use of bisphosphonates in
`patients with OI comes from the Montreal group [10-12]
`using i.v. pamidronic acid in growing children and with
`clinical evidence of significant decrease in fracture incidence
`also in children aged < 3 years [13].
`The efficacy of bisphosphonates has been reported in a
`number of other small uncontrolled studies [14-16].
`Neridronic acid has been extensively investigated in
`patients with OI. In growing children, bone mineral density
`(BMD) as measured by dual X-ray absortiometry rapidly
`increases and this is associated with a significant 64%
`decrease in fracture numbers during the prospective study
`period (Figure 1) [17].
`Similar results have been obtained also in newborns
`(< 12 month old) with some evidence of improvement in
`the rate of skeletal growth [18].
`Neridronic acid has also been tested in adults with OI
`with evidence of efficacy in lowering fracture rate [19]. This
`decrease in the fracture rate seems to be greater than that
`expected from the changes in BMD. Thus, non-vertebral
`peripheral fracture decreased by 84% while spine BMD rose
`by 4%, which is the increase expected in premenopausal
`women [19]. This observation gave rise to the hypothesis that
`neridronic acid treatment is associated in these patients with
`structural bone changes not detected by dual X-ray absorti-
`ometry. For example, in a study using peripheral quantitative
`tomography, neridronic acid treatment in patients with OI
`was associated with the expected large increases in volumentric
`trabecular density but also with 7.2% increase in the cross-
`sectional area of the proximal radius with a mean expansion
`of the bone diameter of 0.56 mm [20]. This effect was
`explained by an increase in the level of mineralization of the
`periosteum rather than an anabolic effect on the bone laid
`down on the periosteal surface.
`
`Bisphosphonates developed for human use have been typically
`tested in metabolic bone disease characterized by focal and/or
`generalized excess bone reabsorption. A number of studies
`have been published on the use of neridronic acid in
`metabolic bone diseases both focal and systemic. However,
`neridronic acid has been licensed so far in Italy only for the
`treatment of OI and Paget’s disease of bone.
`
`3.1 Osteogenesis imperfecta
`OI is an inherited group of conditions of altered production
`or abnormal structure of type 1 collagen. All tissues containing
`
`3.2 Paget’s disease of bone
`Paget’s disease is characterized by focal increase in bone
`remodeling with consequent disruption of the normal
`lammelar structure of the bone tissue. The initial event
`seems to be an alteration of osteoclast size, number and
`activity, and these osteoclasts seem to be adequately responding
`to bisphosphonate therapy. Thus, bisphosphonates still
`represent the first-line treatment of Paget’s disease. The
`response to treatment has been based on the changes in
`bone alkaline phosphatase (bAP) and variably defined by the
`full normalization of bAP or a decrease by > 75 or > 50%.
`
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`Gatti, Viapiana, Idolazzi, Fracassi & Adami
`
`basis of large studies designed to demonstrate a decrease
`in fracture rate. With this evidence, bisphosphonates are
`the treatment of choice for postmenopausal, male and
`glucocorticoid osteoporosis.
`Most bisphosphonates have to be taken orally under fasting
`conditions and the patient has to stand for at least half an
`hour after dosing. These administration rules make the use
`of bisphosphonates rather cumbersome for many patients
`and inaccessible to patients compelled to bed. The registration
`of i.v. formulations for zoledronic acid and ibandronic acid
`has partially circumvented these problems although their
`administration requires medical or hospital assistance.
`Neridronic acid has been developed only for parenteral
`use, both i.v. and i.m. which avoids all the limitations of the
`oral bisphosphonates and may be offered for a home treatment
`with simple nursing assistance. However, it should be
`pointed out that antifracture efficacy has been documented
`only in patients with OI and that no clinical trials are available
`for male osteoporosis and glucocorticoid osteoporosis. Thus,
`neridronate treatment is justified in patients with postmeno-
`pausal osteoporosis only when all other treatments are either
`controindicated or are not available.
`In an early pilot randomized-controlled study in 78 women
`with postmenopausal osteoporosis [25], 50 mg neridronic
`acid was given i.v. once every 2 months over 2 years. The
`changes in BMD were 7.4 and 5.8% at the lumbar spine
`and femoral neck, respectively. During the third year of
`observation without
`treatment, spine BMD remained
`unchanged while hip BMD slightly decreased, maintaining
`highly significant the differences versus baseline.
`Similar results have been obtained in another pilot study
`in 40 postmenopausal women [26] by using 25 mg neridronic
`acid monthly i.m. The densitomentric changes were 6.6 and
`4.2% at the spine and hip, respectively.
`Neridronic acid was more recently tested in a dose-finding
`clinical, multicenter trial in 188 postmenopausal osteoporotic
`women randomized to i.m. treatment with 25 mg neridronic
`acid every 2 weeks, neridronic acid 12.5 or 25 mg every 4 weeks,
`or placebo [27]. The patients were treated over 12 months
`with a 2-year posttreatment follow-up. After 12-months of
`treatment, all three doses were associated with significant
`BMD increases at both the total hip and spine. A significant
`dose–response relationship over the three doses was observed
`for the BMD changes at the total hip but not at the spine
`(Figure 2). bAP decreased significantly by 40 – 55% in
`neridronic acid-treated patients, with an insignificant dose–
`response relationship. Serum type I collagen C-telopeptide
`decreased by 58 – 79%, with a significant dose–response
`relationship (p < 0.05) (Figure 2). Two years after treatment
`discontinuation, BMD declined by 1 – 2% in each dose
`group, with values still significantly higher than baseline at
`both the spine and the total hip. Bone turnover markers
`progressively increased after treatment discontinuation, and
`on the second year of follow-up, the values were significantly
`higher than pretreatment baseline. These results indicate
`
`RR = 0.36 (0.15 – 0.87)
`
`25
`
`20
`
`15
`
`10
`
`5
`
`0
`
`prospective study period
`
`Number of fractures occurred during
`
`Placebo group
`(22 patients)
`
`Active group
`(42 patients)
`
`Figure 1. Reduction of fractures occurred in active and placebo
`groups during the prospective study period in growing
`patients with OI [17].
`OI: Osteogenesis imperfecta.
`
`Although almost all bisphosphonates developed for human
`use have been tested in Pagetic patients, at the moment only
`three have been licensed for this indication (zoledronic acid,
`risedronic acid and neridronic acid). Zoledronic acid is given
`as a 1 day 5 mg i.v. infusion and is widely available
`in Europe, and was found to be superior to risedronic
`acid 30 mg daily over 2 months in terms of proportion of
`full remission [21].
`Neridronic acid is licensed in Italy for the treatment of
`Paget’s disease at the dose of 100 mg dissolved in 250 ml of
`saline solution given i.v. for 2 consecutive days.
`The registration was achieved after a Phase II-III multi-
`center clinical trial testing four different doses: 25, 50, 100 and
`200 mg [22]. The highest dose was the most effective and was
`associated with a 65% rate of full remission and a biochemical
`response (decrease of > 75%) in 95% of the patients.
`Neridronic acid therapy (100 mg i.v. over 2 days) was
`found to be effective in decreasing bAP by > 50% also in
`patients who had an inadequate response (bAP falling by < 50%)
`to i.v. clodronate [23].
`Pagetic patients with an inadequate response to one or
`two treatment courses with pamidronic acid (30 mg i.v. for
`2 consecutive days) were randomized to treatment with
`either neridronic acid (100 + 100 mg i.v.) or zoledronic acid
`5 mg i.v. The rate of adequate response and of full remission
`was comparable with the two treatments, 93 and 80%, respec-
`tively, for neridronic acid and 83 and 94%, respectively, for
`zoledronic acid [24].
`
`3.3 Postmenopausal osteoporosis
`A number of bisphosphonates have been thoroughly
`investigated for osteoporosis treatment (alendronic acid,
`risedronic acid, ibandronic acid, zoledronic acid) and they
`have been registered worldwide for this indication on the
`
`
`
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`

`12.5 mg
`
`25 mg
`50 mg
`
`25 mg
`
`12.5 mg
`50 mg
`
`Bone alkaline phosphatase
`
`Placebo
`
`Serum CTX
`
`Placebo
`
`40
`30
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`
`40
`30
`20
`10
`0
`-10
`-20
`-30
`-40
`-50
`-60
`-70
`-80
`-90
`
`Changes (%)
`
`50 mg
`25 mg
`12.5 mg
`
`50 mg
`
`25 mg
`12.5 mg
`
`24
`
`30
`
`36
`
`0
`
`6
`
`12
`
`18
`Months
`
`24
`
`30
`
`36
`
`Neridronic acid
`
`Spine BMD
`
`Placebo
`
`Total hip BMD
`
`0
`
`6
`
`12
`
`Placebo
`
`18
`Months
`
`7.0
`
`6.0
`
`5.0
`
`4.0
`
`3.0
`
`2.0
`
`1.0
`
`0.0
`
`-1.0
`
`5.0
`
`4.0
`
`3.0
`
`2.0
`
`1.0
`
`0.0
`
`-1.0
`
`Changes (%)
`
`Figure 2. Sequential changes in BMD and in bone turnover markers in patients with postmenopausal osteoporosis. The
`different monthly doses of neridronate or placebo are shown in the figure. Blind treatment was given over 12 months with a posttreatment
`follow-up of 24 more months. The changes of BMD and bone turnover markers observed during the treatment are all significant versus
`placebo and baseline [27].
`BMD: Bone mineral density.
`
`that the 25 mg i.m. neridronic acid monthly administration
`is the dose providing the maximum effects. At this dose,
`neridronic acid treatment seems to be somewhat the most
`effective among registered bisphosphonates in lowering bone
`turnover markers and in terms of BMD changes.
`Neridronic acid has also been tested in two studies in
`patients with glucocorticoid-induced osteoporosis. The
`adopted dose was 25 mg once a month. The first study by
`Benucci et al. [28] in 62 patients with a variety of rheumatic
`disease was mostly devoted to urinary bone marker changes:
`after 6 months, hydroxyproline fell by 42%, urinary deoxy-
`pyridinoline by 35% and cross-linked N-telopeptide of type
`I collagen by 51%. In the second study [29] in 46 patients,
`neridronic acid treatment for 1 year was associated with
`significant increases in both spine and femoral BMD.
`Neridronic acid 25 mg i.m. monthly is also effective in
`fully preventing the changes in bone turnover markers
`and BMD associated with androgen deprivation therapy for
`prostatic cancer [30,31].
`Neridronic acid is under investigation in patients with
`osteoporosis associated with thalasemia, mastocytosis and
`cystic fibrosis.
`None of the above mentioned trials were designed to test
`the efficacy of neridronic acid in decreasing fracture risk.
`
`3.4 Reflex sympathetic syndrome or algodystrophy
`Intravenous high doses of bisphosphonates are increasingly
`used for the treatment of reflex sympathetic dystrophy
`syndrome or algodystrophy [32,33]. In a Phase II trial, we
`have shown (unpublished results) that the most effective
`dose is 100 mg diluted in 250 ml of saline solution given
`intravenously over 4 days. With this treatment regimen, the
`proportion of patients experiencing rapid (in 7 – 12 days)
`> 70% symptomatic improvements is close to 80%.
`The efficacy was assessed by visual analogue scale for
`spontaneous pain and tenderness and by an arbitrary score
`(from 0 = normal to 4 = worst finding) of motion as
`assessed by physicians as we used in a previous study [32].
`On the basis of these preliminary observations, the first formal
`registrative randomized double-blind clinical trial comparing
`400 mg neridronic acid to placebo in patients with foot
`or forearm algodystrophy syndrome has been designed and
`is underway.
`
`3.5 Other conditions
`Neridronic acid treatment has been reported to be effective also
`in other focal conditions, such as the transient osteoporosis
`of proximal hip, avascular bone necrosis [34,35] and tuberculous
`spondylodiscitis [36].
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`Gatti, Viapiana, Idolazzi, Fracassi & Adami
`
`In 45 patients with rheumatoid arthritis, a single i.v.
`infusion of 25 mg neridronic acid was associated with a
`significant decrease for both erythrocyte sedimentation
`rate (21%) and C-reactive protein (35%) in 3 weeks. Inter-
`estingly, this effect could not be seen by doubling the dose
`to 50 mg [37].
`
`3.6 Malignant conditions
`In seven patients with over bone lesions for multiple
`myeloma, 100 mg neridronic acid i.v. monthly over a year
`was associated with significant increases in spine BMD and
`decrease in bone turnover markers [38].
`In patients with hypercalcemia owing to solid metastaic
`tumors, 125 mg neridronic acid dissolved in 500 ml of saline
`solution and infused i.v. over 4 h was able to significantly
`decrease serum calcium with a nadir after 7 days and
`normalization of serum calcium in 65% of the patients [39].
`
`4. Safety and tolerability
`
`Neridronic acid is generally well tolerated and remains the
`only bisphosphonate widely used in children even under
`3 years of age.
`Flu-like symptoms occur in a large proportion of the patients
`after the first infusion, as with other nitrogen-containing
`bisphosphonates [40], particularly at high doses (100 mg),
`but it is rather common also after the first administration
`of 25 mg.
`is
`The
`i.m. administration 25 mg neridronic acid
`associated with local pain, disappearing almost invariably in
`a few minutes. Higher i.m. doses have never been tested.
`As for all other bisphosphonates, doses higher than 25 mg
`should be infused by slow i.v. (generally not > 100 mg/h).
`No cases of osteonecrosis of the jaw [41], atypical sub-
`trochateric fractures [42] or persitent muscular pain [43] have
`ever been
`reported during clinical
`trials, but
`these
`three long-term complications should be taken into consid-
`eration for neridronic acid as with any other type of
`nitrogen-containing bisphosphonate.
`
`5. Conclusion
`
`In conclusion, neridronic acid is a nitrogen-containing
`bisphosphonate with pharmacological characteristics very
`similar to pamidronic acid or alendronic acid. It is licensed
`only in Italy for the treatment of OI and Paget’s disease of
`bone. Neridronic acid is the only available bisphosphonate
`licensed for the use in children that can be administered
`intramuscularly. This may represent a unique advantage for
`some of the patients who cannot take oral bisphosphonates.
`This is the case for patients compelled to bed, with serious
`esophageal diseases, gastrointestinal malabsorption or unable
`to fast. In these patients, the i.v. infusion is the typical alter-
`native, but i.m. neridronate might be used when the access
`to hospital services for i.v. infusions is either cumbersome or
`too expensive.
`
`6. Expert opinion
`
`The chemical structure of neridronic acid is very close to
`that of pamidronic acid and alendronic acid, sharing most
`of the pharmacological properties. Its potency is somewhat
`close to that of pamidronic acid for the biochemical response
`in Paget disease of bone. Neridronic acid has been fully
`developed and then licensed only for the treatment of OI
`and Paget’s disease. Neridronic acid has three peculiarities of
`some clinical value: i) it is the only registered treatment for
`OI; ii) it can be given intramuscularly, and this may be of
`remarkable practical value in some conditions and iii) it is
`the only bisphosphonate licensed for the treatment of bone
`diseases in growing individuals. Of some interest is also the
`continuing randomized clinical trial
`in algodystrophy,
`and this is likely to make shortly neridronic acid the only
`registered therapy for this condition.
`
`Declaration of interest
`
`S Adami has received a research grant from Eli-Lilly and is
`a speaker for Roche, Eli-Lilly and Abiogen.
`
`
`
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`Neridronic acid
`
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`Affiliation
`Davide Gatti1, Ombretta Viapiana1,
`Luca Idolazzi2, Elena Fracassi1 &
`Silvano Adami†3
`1Director assistant,
`University of Verona,
`Rheumatology Unit,
`Ospedale di Valeggio,
`37067 Valeggio, Verona, Italy
`2University of Verona,
`Rheumatology Unit,
`Ospedale di Valeggio,
`37067 Valeggio, Verona, Italy
`3Director,
`University of Verona,
`Rheumatology Unit,
`Ospedale di Valeggio,
`37067 Valeggio, Verona, Italy
`Tel: +390456338607; Fax: +390457952000;
`E-mail: silvano.adami@univr.it
`
`
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