Bone 103 (2017) 144–149

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Bone

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Full Length Article

Treatment with neridronate in children and adolescents with

osteogenesis imperfecta: Data from open-label, not controlled,
three-year Italian study☆
L. Idolazzi a,⁎, A. Fassio a, O. Viapiana a, M. Rossini a, G. Adami a, F. Bertoldo b, F. Antoniazzi c, D. Gatti a
a
Rheumatology Unit, Department of Medicine, University of Verona, Italy
b
Internal Medicine Unit, Department of Medicine, University of Verona, Italy
c
Pediatric Clinic, Department of Surgical Sciences, Dentistry, Gynecology and Pediatrics, Pediatric Division, University of Verona, Verona, Italy

a r t i c l e i n f o a b s t r a c t

Article history: Introduction: The present study assessed the long-term efficacy and safety of intravenous (i.v.) neridronate in
Received 30 December 2016 children and adolescents affected by osteogenesis imperfecta (OI).
Revised 30 June 2017 Methods: 55 young patients (mean age 12.6 ± 3.9 years) affected by OI were included in the study. Neridronate
Accepted 1 July 2017 was administered by i.v. infusion at a dose of 2 mg/kg (maximum dose of 100 mg) at intervals of three-months
Available online 3 July 2017
for three years. Dual X-ray absorptiometry of the lumbar spine, hip and ultradistal and proximal radius were eval-
uated every 6 months. Blood calcium, phosphate, albumin, fasting urinary calcium/creatinine ratio were obtained
Keywords:
Neridronate
at baseline and every 3 months. Serum bone turnover markers total and bone alkaline phosphatase were per-
Osteogenesis imperfecta formed every 12 months in a proportion of patients.
Safety Results: Mean lumbar spine and total hip bone mineral density (BMD) and bone mineral content significantly in-
Tolerability creased from baseline compared to all subsequent time points (p b 0.001). Mean ultradistal radius BMD signifi-
cantly increased from month 18 (p = 0.026). Levels of bone turnover markers significantly decreased from
baseline to all post-baseline observation time points. There was no statistically significant effect on fracture
risk (p = 0.185), although a significant reduction was observed in the mean number of fractures occurring during
treatment compared to pre-treatment values. The most frequent adverse events were arthralgia, fever, joint
sprain. An acute phase reaction was reported in 26 (22.8%) patients. None of the reported serious adverse events
was considered as treatment-related.
Conclusion: Long-term i.v. neridronate treatment has positive effects on BMD, bone turnover markers and frac-
ture risk with a good safety profile.
© 2017 Elsevier Inc. All rights reserved.

1. Introduction The bone histomorphometric picture is usually characterized by the

Osteogenesis imperfecta (OI) is a fairly common heritable disorder
(one in 15–20,000 births) and represents a generalized connective tis-
sue disease. OI is mainly characterized by bone fragility and substantial
growth deficiency [1–3]. Other relevant findings are often non-skeletal
features, including blue sclerae, hearing loss, dentinogenesis imperfecta,
impaired pulmonary function and cardiac valvular regurgitation. Differ-
ent types of OI have been identified, based on clinical and hereditarily
characteristics and on biochemical defects [1–4].
☆ Summary: This study evaluated the efficacy and safety of neridronate administered
intravenously (2 mg/kg efficacy, tri-monthly) to children/adolescents with osteogenesis
imperfecta for a period of three years. Neridronate was effective and well tolerated,
resulting in a significant increase in bone mineral density, bone mineral content and
reduced number of fractures.
⁎ Corresponding author at: p.le L Scuro 2, 37100 Verona, Italy.
E-mail address: luca.idolazzi@univr.it (L. Idolazzi).
presence of an excessive number of osteoblasts with impaired activity
and consequent defective bone matrix deposition. The trabecular skele-
tal turnover is generally increased, at least up to maturity [5]. These
histomorphometric features have been confirmed by the detection of
an increase in bone turnover markers, such as serum osteocalcin, colla-
gen peptide cross-links (N-telopeptide) and calcium urinary excretion
[6–10]. Several therapies have been suggested for the treatment of OI,
including bisphosphonates [11–15], denosumab [4], growth hormone
alone or in combination with other treatments [16,17], teriparatide
(only in adults) [18,19] and bone marrow transplantation [20]. The in-
crease in bone turnover markers is a hallmark of the disease and repre-
sents the rational for therapy with anti-resorptive agents such as
bisphosphonates or denosumab [21,22]. To date, bisphosphonates
have shown to increase bone mineral density (BMD). A positive effect
on prevention of fractures both in adults and in children has been re-
ported in some studies [15,22,23], but data are generally inconsistent.

http://dx.doi.org/10.1016/j.bone.2017.07.004
8756-3282/© 2017 Elsevier Inc. All rights reserved.
 L. Idolazzi et al. / Bone 103 (2017) 144–149
Recent systematic reviews have also summarized evidence on use of
bisphosphonates in OI [22,24,25] and they agree that the present evi-
dence is currently insufficient to conclude that bisphosphonate therapy
can improve outcomes other than BMD. It is likely that additional stud-
ies are still needed since previous trials were underpowered to assess
outcomes other than BMD and generally had short treatment periods.
Regarding bisphosphonates, large placebo-controlled long-term trials
in OI are unlikely to be conducted due to several issues such as lack of
funding or the difficulty of finding patients who are willing to risk
being randomized to placebo for a long period.
Neridronate is an amino-bisphosphonate structurally similar to
alendronate and pamidronate, differing only in the number of methyl
groups of the side chain: five for neridronate, three for alendronate,
and two for pamidronate [26]. It is available in both intramuscular and
intravenous formulations, which altogether can prevent a number of
complications caused by oral bisphosphonates. Neridronate has been
extensively investigated in patients with OI in Italy [18] where it has
been licensed for the treatment of OI (it is currently the only drug regis-
tered for this indication), Complex Regional Pain Syndrome type 1 and
Paget's disease of bone.
The aim of this study was to assess the efficacy and safety of
neridronate, when administered to children and adolescents with OI
by intravenous infusions at a dose of 2 mg/kg (up to a maximum of
100 mg) once every three months for a period of three years.
2. Methods
2.1. Study population
The study sample includes patients aged b 20 years and with a defi-
nite diagnosis of OI, enrolled by a single investigational study team. Pa-
tients were enrolled from a dedicated outpatient clinic of a National
Centre of Reference for Osteogenesis Imperfecta. All patients were pre-
viously diagnosed on the basis of a history of fragility fractures (one or
more, especially during youth), concomitant positive family history
and/or extra skeletal manifestation specific for the disease such as:
hearing loss, blue sclerae or dentinogenesis imperfecta. Exclusion
criteria were: previous treatment with bisphosphonates, serious con-
comitant diseases including cardiovascular, hematological, psychiatric
or pulmonary diseases, renal insufficiency with serum creatinine
N1.5 mg/dl, history of hypersensitivity to bisphosphonates. Prior to un-
dertaking this study, authorization of the Italian ‘Istituto Superiore di
Sanità, the Italian Ministry of Health and the reference Independent
Ethics Committee (IEC) for the participating center was obtained. All pa-
tients (or a parent) signed informed consent. All procedures performed
in the study involving human participants were in accordance with the
ethical standards of the institutional and/or national research commit-
tee and the 1964 Helsinki declaration and its later amendments or com-
parable ethical standards.
2.2. Treatment administered
Neridronate was administered by i.v. infusion at a dosage of 2 mg/kg,
up to a maximum of 100 mg in saline solution (0.9% NaCl) (approxi-
mately 10 mg/100 ml), with an infusion time of about two hours. Infu-
sions were undertaken every three months. Supplementation with
calcium (1000 mg daily) and vitamin D (800 IU daily) was also admin-
istered to the patient.
2.3. Efficacy variables
Dual X-ray absorptiometry (DXA) of the lumbar spine, hip and
ultradistal and proximal radius were evaluated every 6 months using
a full-body bone densitometer (Hologic 4500, Waltham, US). The preci-
sion error for BMD, BMC (bone mineral content) and area at different
145
skeletal sites ranged from 1% to 2.5% in subjects, with a wide range in
bone mass values.
All fractures that occurred over the three years prior to treatment
and during the study were validated by X-ray film or radiology reports
and regularly collected during the study.
Serum calcium, phosphate, albumin and fasting urinary calcium/cre-
atinine ratio were obtained at baseline and every three months. Total al-
kaline phosphatase (ALP: Roche Diagnostics) was measured by an
immunoassay analyzer and serum bone alkaline phosphatase (BAP,
Alkphase–B; Metra Biosystems) by an enzyme-linked
immunoabsorbent assay. All biochemical measurements were per-
formed every 12 months only in a small proportion of patients. Inter-
and intra-assay variations ranged from 7% to 12%.
Unfortunately, the frequent collection of urine samples in the major-
ity of patients was not possible and therefore urinary free-deoxy
pyridinoline analysis was not undertaken.
2.4. Safety
Adverse events (AEs) were categorized by System Organ Class (SOC)
and Preferred Term (PT) by using the MedDRA dictionary (version
11.0). The occurrence of clinical AEs and biochemical alterations (hema-
tology, blood chemistry, and urinalysis) were recorded at every visit.
2.5. Statistical analysis
Statistical analysis was performed on data obtained from the safety
population, defined as all patients who received at least one dose of
study medication, and the intention-to-treat population (ITT), defined
as all patients who received at least one dose of study medication and
with post-baseline data. These two populations were considered in
the present study.
Demographic and baseline characteristics were summarized by
means of descriptive statistics, and expressed as the number of observa-
tions, mean, standard deviation, minimum and maximum for continu-
ous variables, and frequency distributions (number and percentages)
for categorical variables. Medical history, concomitant diseases (coded
using the MedDRA dictionary version 11.0), and previous and concom-
itant medication (coded with WHO Drug Dictionary) were collected.
The percent change from baseline of DXA parameters evaluated at
the different body sites were analyzed by means of descriptive statistics
and the mean values of the percent changes from baseline were com-
pared with 0 by means of a one-sample Student t-test. In order to take
account of multiple tests, Bonferroni's correction was applied to the
probability associated with each test.
The percent change from baseline of bone markers parameters was
also analyzed for the densitometric efficacy parameters.
The frequency of fractures was recorded and the definition of fre-
quency of fracture was considered as the number of patients with
new fractures per year observed during the treatment period or record-
ed in the three years prior to commencement of the trial. The number of
fractures per year before and during the study was also considered
(Table 5). The distribution of rates of patients with fractures observed
before and during the treatment period was analyzed by the McNemar
test. Furthermore, the distribution in the number of patients' fractures
in the two periods were compared using the Wilcoxon signed-rank
test. All statistical analysis was performed using SPSS version 11 (SPSS
Inc., Chicago, IL, USA) and a p-value of b0.05 was considered statistically
significant.
3. Results
The study population comprised 55 patients (mean age 12.6 ±
3.9 years), mainly affected by type 1 OI (type 1 OI; 65.4%, type 3 OI;
18.2%, or type 4 OI; 16.4%). Demographic characteristics are reported
in Table 1. The population included a similar proportion of female and
146 L. Idolazzi et al. / Bone 103 (2017) 144–149

Table 1 Analysis of the distribution of the number of patients with or with-

Demographic features and type of OI in the study population. out fractures and their rate during the three years of treatment or in
Characteristic (N = 55) the three years prior to treatment showed that a significant proportion
Gender, N (%)
of patients (38.2%) had at least one fracture before the study and did not
Males, N (%) 30 (54.5) have fractures during the treatment period (p b 0.001 in the distribution
Females, N (%) 25 (45.5) of patients with or without fractures) (Table 5). When the number of
Age, years (mean ± SD) 12.6 ± 3.92 (range 5–19) fractures was taken in account, the mean number of fractures observed
Height, cm (mean ± SD) 131.2 ± 22.85 (range 90–176)
in the three years of treatment was also found to be significantly lower
Weight, kg (mean ± SD) 34.7 ± 14.78 (range 11–70)
Type of OI, N (%) than that observed in the three years before treatment (Wilcoxon
1 36 (65.4%) signed-rank test; p b 0.001) (Table 5).
3 10 (18.2%) The most frequent AEs observed were pyrexia (23.6%), back pain
4 9 (16.4%) (12.7%) and arthralgia (10.9%). An acute phase reaction with flu-like ill-
N = number of patients. ness was reported in 26 (47.3%) patients and was the most frequent AE,
OI = osteogenesis imperfecta. mainly related to the drug. No fatal events occurred. Serious adverse
events (SAEs) were reported in 19 (34.5%) patients. None of the report-
ed SAEs were considered treatment-related. No cases of osteonecrosis of
the jaw (ONJ) or atypical femur fracture were reported.
male patients (45.5% vs. 55.5%) and pathological fractures were report- Laboratory tests (blood count, general blood chemistry and urinaly-
ed in all (N = 55) patients. sis) did not show substantial changes in the results from baseline up to
A total of 51 (92.7%) patients completed the scheduled 36-month 36 months. Clinically significant and non-treatment-related abnormali-
treatment period, while 4 (7.3%) of them discontinued the study early. ties in laboratory parameters were reported in a very small number of
The patients received 11.1 ± 2.49 infusions (minimum 3, maximum patients (N = 3): one with thrombocytopenia, one with AST elevation,
13). A summary of patients who completed or discontinued the study and one with ALT elevation.
and the different reasons for their withdrawal is presented in Table 2.
Spine DXA was only performed in 43 of the 55 (78.2%) patients for 4. Discussion
the presence of dimorphism or more of 2 vertebral fractures involving
the lumbar spine. DXA at the hip was performed in 30 of 55 (54.5%) pa- The present study showed that i.v. neridronate treatment was asso-
tients for the presence of fractures of both femurs. ciated with a marked and statistically significant increase in both BMD
The mean lumbar spine BMD significantly increased from baseline to and BMC at the lumbar spine and total hip from baseline up to
all follow-up time points with percentage changes that progressively in- 36 months of the study (Table 3). Hip DXA is not currently considered
creased from month 6 (+15%) to month 36 (+51%) (Table 3). The in- a diagnostic tool in the pediatric age, but the significant and relevant
crease in BMD was also associated with a concomitant increase in changes documented (also in this skeletal site) are, in our opinion,
BMC and in Area (Table 3). None of the patients with repeated measure- one important effect of neridronate treatment in this severe form of os-
ments of lumbar spine BMD had any lumbar vertebral fractures for the teoporosis. The increase in BMD (about 40–50% after 36 months of ther-
duration of the study. apy) is likely caused by suppression of bone resorption and reduction of
Mean total hip BMD significantly increased from baseline at all sub- bone remodeling as direct consequence [27].
sequent time points, with percentage changes that progressively in- The concomitant increase in bone Area has also important conse-
creased from month 6 (+ 11%) to month 36 (+ 41%) (Table 3). The quences. DXA measures areal BMD and this increase in projected Area
increase in BMD was also associated with a concomitant increase in produces an underestimation of the gain in BMD. On the other hand,
BMC and in Area (Table 3). the increase in bone Area confirms that this anti-reabsorptive drug
The mean lumbar spine and total hip area increased from baseline to would not appear to exert negative effects on skeletal growth [28].
all further time points, except for month 6 for the total hip (Table 3). Neridronate is an amino-bisphosphonate with proven efficacy since
As expected, mean ALP and BAP levels significantly decreased from 2003, when the positive results of a randomized trial involving 46 adults
baseline to all post-baseline time points by about 50% (Table 4). with OI treated for 24 months were published [23]. Two years later data
In the three years before treatment was undertaken, 43 of the 55 pa- from a RCT with similar design on pediatric patients was published [15]
tients (78.2%) incurred at least one fracture. Over the three year study demonstrating that neridronate significantly increases BMD and lowers
period the rate of patients with new fractures decreased to 24/55 the risk of clinical fracture in prepubescent children with OI. These two
(43.6%). positive experiences led to the registration of neridronate for osteogen-
All the fractures taken into account were fragility fractures (sponta- esis imperfecta in Italy for both children and adults [15,23]. Actually,
neous or due to minimal trauma) and the most relevant involved: hip (7 neridronate is also licensed in Italy for the treatment of Paget's disease
patients), shinbone (5 patients), thoracic vertebrae (1 patients), radius of bone and for CRSP1 [18,29]. Bisphosphonate therapy has been used
(1 patient), humerus (1 patient) and pelvis (1 patent). to treat patients with OI for the past three decades [30] and is currently
the most widely available medical treatment for OI, even though many
different compounds, dosage, and protocols have been proposed. The
positive effects of bisphosphonates on areal BMD (by DXA) at the
Table 2
Reasons for study withdrawal.
spine and other skeletal sites are widely recognised [4]. More controver-
sial is the question of what clinically relevant benefit children with OI
Number (%) may have from higher areal BMD due to the fact that some clinically rel-
Patients who completed the study 51 (92.7) evant outcomes such as fracture rate, mobility, and quality of life are dif-
Patients who discontinued the study 4 (7.3) ficult to assess in OI [22,24,25,31].
Reasons for discontinuation
The reported densitometric results appear to be in line with ones fol-
Adverse event 0 (0.0)
Serious adverse events 1 (1.8) lowing other i.v. bisphosphonate therapies such as pamidronate and
Exclusion criteria 0 (0.0) zoledronate [22,24,25]. However, to the best of our knowledge, most
Patient compliance 1 (1.8) of these studies currently available concerning bisphosphonates in OI
Consent withdrawal 2 (3.6) were of shorter duration (12–24 months) than ours (36 months). In-
Economic issues 0 (0.0)
deed, this is one of the strengths of our study, showing that the positive
 L. Idolazzi et al. / Bone 103 (2017) 144–149 147

Table 3
Percentage variation in DXA parameters from baseline values.

Month BMD (g/cm2) mean ± SD (95% CI) BMC (g) mean ± SD (95% CI) Area (cm2) mean ± SD (95% CI)

Lumbar spine
6 14.8 ± 11.1 (11.4–18.2)⁎⁎ 31.3 ± 26.4 (23.2–39.5)⁎⁎ 14.7 ± 24.2 (7.2–22.1)⁎
12 26.1 ± 20.3 (19.7–32.4)⁎⁎ 41.1 ± 42.3 (27.9–54.3)⁎⁎ 13.5 ± 35.5 (2.4–24.5)
18 32.8 ± 24.3 (24.7–40.9)⁎⁎ 58.7 ± 46.9 (43.1–74.4)⁎⁎ 19.4 ± 29.7 (9.5–29.3)⁎
24 40.3 ± 28.2 (31.4–49.2)⁎⁎ 69.6 ± 53.7 (52.6–86.5)⁎⁎ 19.9 ± 26.9 (11.5–28.4)⁎⁎
30 43.3 ± 30.7 (33.7–52.9)⁎⁎ 75.3 ± 58.0 (57.2–93.4)⁎⁎ 20.8 ± 25.5 (12.9–28.8)⁎⁎
36 50.7 ± 33.1 (40.0–61.4)⁎⁎ 90.8 ± 68.7 (68.5–113.1)⁎⁎ 24.9 ± 30.1 (15.2–34.7)⁎⁎

Total hip
6 11.3 ± 11.0 (7.3–15.5) 13.1 ± 16.2 (6.8–19.4)⁎ 2.1 ± 8.6 (−1.3–5.4)
12 22.4 ± 20.7 (14.5–30.3)⁎⁎ 33.8 ± 31.6 (21.8–45.8)⁎⁎ 8.7 ± 13.7 (3.5–13.9)⁎
18 33.6 ± 26.7 (22.6–44.6)⁎⁎ 56.0 ± 39.5 (39.7–72.3)⁎⁎ 16.2 ± 16.2 (9.5–22.9)⁎
24 34.1 ± 27.8 (23.7–44.5)⁎⁎ 54.1 ± 44.0 (37.7–70.6)⁎⁎ 13.8 ± 17.3 (7.4–20.3)⁎
30 37.0 ± 29.6 (26.1–47.9)⁎⁎ 60.9 ± 51.3 (41.7–80.1)⁎⁎ 16.5 ± 19.4 (9.3–23.7)⁎⁎
36 41.4 ± 31.4 (29.4–53.4)⁎⁎ 66.1 ± 53.9 (45.2–87.0)⁎⁎ 16.5 ± 22.9 (7.6–25.3)⁎

BMD = bone mineral density. BMC = bone mineral content.

⁎ p b 0.05 vs. baseline.
⁎⁎ p b 0.001 vs. baseline.

densitometric gain of bisphophonates also increases in the third year of
treatment, with a protective effect on fracture risk. A recent study has
now analyzed data from children with OI treated with pamidronate
up to 4 years [32]. This study showed an increase in LS BMD for all OI
types and also confirmed a reduction in the incidence of fractures.
Placebo-controlled studies should provide high quality data but
there are issues related to the lack of funding and also to the likely reluc-
tance of patients to risk to being treated with placebo while a licensed
pharmacological treatment is already available. For these reasons it
may be necessary, meanwhile, to obtain clinical data from observational
studies. Ideally, these studies should aim to have a long treatment peri-
od and should provide a comparison between the rate of fractures ob-
served before and during treatment.
The main strength of the present study is the finding of a statistically
significant effect on fracture risk. The hallmark of OI are the fragility
fractures and these patients have an increased fracture rate throughout
their life. In this study, the percentage of patients with fractures was al-
most halved during treatment compared to the three years prior to
treatment (43/55 vs. 24/55 respectively) and a significant rate of pa-
tients (37%) who experienced at least one fracture in the three years be-
fore the study, had no fracture during the treatment period (p b 0.001 in
the distribution of patients with or without fractures). This protective
effect was also confirmed when the number of fracture was taken in
account.
Besides efficacy, what is considered essential for a treatment is safety
and tolerability.
Bisphosphonates have a good safety profile with a low incidence of
serious adverse events such as atypical femur fracture or ONJ. In OI,
the risk of ONJ induced by bisphosphonates seems to be very low [33,
34]. Furthermore, the pattern of femoral fracture in OI should be
considered different from other bone diseases such as osteoporosis: in
fact in OI the fractures mostly involve the femoral diaphysis and this
pattern seems to be changed by bisphosphonate treatment [35].
Regardless, during the three years of the study, we did not observe
any drug-related SAE. Furthermore, no cases of atypical fracture or
ONJ were observed, though we should keep in mind that these two
events are extremely rare and hard to be seen in a study with this sam-
ple size.
The most common side effects were related to the acute phase re-
sponse, that sometimes follows aminobisphosphonate administration,
especially if given intravenously and in young patients [36]. These
symptoms are not serious, transient and usually appear only after the
very first infusion. They never led to treatment discontinuation during
this study for any patient. Patients that exited the study did it mainly be-
cause of practical reasons which prevented them from being able to at-
tend regular visits. This trial was monocentric and as a consequence of
this design many patients had to traveled from distant regions, often
with difficulties in attending visits.
The results of laboratory tests (hematology, blood chemistry and uri-
nalysis) did not show substantial changes from baseline up to 36 months
of any parameters. In particular, there were no alterations in hepatic or
renal function.
The i.v. route for administering bisphosphonates guarantees a com-
plete adherence and probably the best bioavailability and it prevents
Table 5
Number of patients with fractures in the 3 years prior to treatment compared with 3 years
of treatment.
Number of patients with fractures

Number (%) of patients with During treatment (3 years)

fractures
Before treatment (3 years) Patients without Patients with
Table 4 fractures, N (%) fractures, N (%)
Percent changes of bone markers considering baseline values. Patients without fractures, N 10 (18.2) 2 (3.6)
= 12 (21.8)
Alkaline phosphatase Bone alkaline phosphatase Patients with fractures, N = 21 (38.2) 22 (9.4)
43 (78.2)
Baseline value 239,6 ± 108,5 (U/L) 100,4 ± 39,4 (mcg/L)
McNemar's test p-value b0.001
Mean (95% CI) N Mean (95% CI) N
Mean number of fractures
Month 12 −25.9 (−31.0 to −20.5)⁎⁎ 48 −28.0 (−36.6 to −18.3)⁎⁎ 57
Month 24 −41.9 (−47.4 to −35.9)⁎⁎ 48 −36.7 (−46.3 to −25.4)⁎⁎ 47 Number of fractures, mean ± SD (range)
Month 36 −49.1 (−56.2 to −40.8)⁎⁎ 44 −52.2 (−64.6 to −35.3)⁎ 24 Before treatment (3 years) 2.7 ± 2.37 (0–8)
During treatment (3 years) 0.9 ± 1.43 (0–7)
N = number of patients.
Wilcoxon signed-rank test p-value b0.001
⁎ p b 0.01 vs. baseline.
⁎⁎ p b 0.001 vs. baseline. N = number of patients.
148 L. Idolazzi et al. / Bone 103 (2017) 144–149
the well-known gastrointestinal side effects responsible for a significant
rate of treatment discontinuation with bisphosphonates [36].
Our study does have some limitations, such as the sample size and
lack of a control group. However, we obtained clinically important re-
sults on the anti-fracture effects of this treatment. Furthermore, in this
study, a repeated evaluation on spine plan RX was not scheduled and
thus it was not possible to look for the typical vertebral reshaping effect
following bisphosphonate therapy. Another limitation of the study is
the change of pubertal status, possibly involving some of the patients
during the three-year follow-up. This feature could be a possible con-
founding factor in our analysis, particularly with regard to densitomet-
ric change.
5. Conclusion
In conclusion, i.v. administration neridronate in OI children and ad-
olescents over a three-year period was shown to be effective, safe and
well tolerated. This study demonstrated a positive effect in terms of
fracture risk expressed as the number of fractures occurring in patients
in the three years of treatment compared to the three years prior to
treatment and confirmed the positive densitometric effects of bisphos-
phonate therapy that appears to be important for obtaining increased
peak bone mass.
Funding
This research did not receive any specific grant from funding agen-
cies in the public, commercial, or not-for-profit sectors.
Conflict of interest
Ombretta Viapiana has received speaking fees from Abiogen, Amgen,
Merck Sharp & Dohme Corp. Luca Idolazzi has received speaking fees
from Eli Lilly, UCB, Abbvie, Novartis. Angelo Fassio declares no conflict
of interest. Francesco Bertoldo reports personal fees from Abiogen, per-
sonal fees from Amgen, personal fees from Eli Lilly, personal fees from
Bayer, personal fees from Italfarmaco, outside the submitted work.
Maurizio Rossini has received speaking and consulting fees from
Abiogen, Amgen, Eli-Lilly and Merck Sharp & Dohme Corp. Franco
Antoniazzi declares no conflict of interest.
Giovanni Adami declares no conflict of interest. Davide Gatti has re-
ceived speaking fees from Abiogen, Amgen, Eli-Lilly and Neopharmed-
Gentili.
Acknowledgements
The Authors would like to kindly thank Abiogen Pharma (Pisa) for
providing neridronate (Nerixia®) for the treatment of OI patients for
the entire study duration. The Authors would also like to thank Dr.
Fraccarollo Caterina for the ELISA assays, Dr. Poli Fabio for technical as-
sistance and the LURM (Laboratorio Universitario di Ricerca Medica)
Research Center, University of Verona where the biochemical analyses
were performed.
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