Zoledronate Therapy in Osteogenesis Imperfecta: Perspectives in Indonesia Tertiary Hospital

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J Bone Metab. 2024;31(4):290-295

Publication date (electronic) : 2024 November 4

doi : https://doi.org/10.11005/jbm.24.767

Tri Wahyu Martanto^,1,2, Aliefio Japamadisaw^1,2, Dian Nurhayati^3,4, Rob G. H. H. Nelissen⁵

¹Department of Orthopaedics and Traumatology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia

²Department of Orthopaedics and Traumatology, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

³Department of Radiology, Faculty of Medicine, Universitas Airlangga, Surabaya, Indonesia

⁴Department of Radiology, Dr. Soetomo General Academic Hospital, Surabaya, Indonesia

⁵Department of Orthopaedics, Leiden University Medical Center, Leiden, Netherlands

Corresponding author Tri Wahyu Martanto Department of Orthopaedics and Traumatology, Dr. Soetomo General Academic Hospital, Jl. Mayjend. Prof. Dr. Moestopo No. 6-8, Surabaya 60286, Indonesia Tel: +62-31-5501481 Fax: +62-31-5020406 E-mail: tri-wahyu-m@fk.unair.ac.id

Received 2024 June 11; Revised 2024 August 13; Accepted 2024 August 13.

Abstract

GRAPHICAL ABSTRACT

INTRODUCTION

Osteogenesis imperfecta (OI) is a rare clinical disease. The incidence is estimated to be between 1/25,000 and 1/10,000 worldwide.[1] Studies in Europe and the United States have found that the prevalence of OI at birth ranges from 0.3 to 0.7 for every 10,000 live births. While in Danish national data from 1977 to 2013, 1.5 per 10,000 live births were diagnosed with OI and Finnish national data showed a prevalence of OI of 0.5 per 10,000 individuals.[2,3] No national prevalence data on OI patients are present in Indonesia.

A multitude on different treatment strategies exist for managing patients with OI. The goal of these strategies is to minimize the incidence of fractures, pain, bone deformities and recurrence of fractures.[4] According to Folkestad,[3] the focus in OI therapy management is based on 3 main elements, namely fracture prevention, correction of bone deformities, and treatment of other (non-bone related) complications such as hearing loss, dental problems, and pain management. The main focus of pharmacotherapy in these OI patients is the treatment with bisphosphonate drugs. The latter can significantly increase bone density, decrease bone turnover rate, reshape the compressed vertebral body, decrease fracture incidence, and improve the patient quality of life (QOL).[5,6]

One of these bisphosphonate drugs, zoledronate, is 3 to 300 times more potent than risedronic acid, alendronic acid and pamidronic acid in inhibiting bone resorption.[7] Health technology assessment requests to evaluate the cost-benefit of a treatment for society. In Indonesia, zoledronate is provided free of charge through the national health insurance programme to patients with OI. Our goal was to evaluate the impact of zoledronate treatment on bone fractures and deformities (radiographs), metabolism (biochemical serum levels), QOL, and complications.

METHODS

RESULTS

From 2021 to 2023 we obtained 24 patients, however four patients were excluded, consisting of one patient with a fracture and three patients lost to follow-up. Total 20 patients which comprised of 11 boys (55%) and 9 girls (45%) and the average age of the patients was 6.9 years (4-17 years). The mean baseline body mass index (BMI) was 19.1, meanwhile the mean BMI after two years zoledronate was 19.8 (Table 1). The mean PedsQL total score of patients before and two years of zoledronate administration was respectively 66.7 and 76.9 (P=0.0001). In the examination of physical function, emotional function, social function, and school function, patients had significant differences between pre and post administration of zoledronate (Table 2).

Table 1.

Clinical characteristics of the participants

Table 2.

PedsQL score before and 2 years after zoledronate administration

Lumbar BMD and total body BMD was significantly increase before and after zoledronate. The mean lumbar BMD before zoledronate was 0.467 g/cm² and two years after zoledronate mean was 0.599 g/cm² (P=0.001) (Fig. 1A). The mean total body BMD was 0.501 g/cm² before zoledronate administration and at 2 years after zoledronate was 0.626 g/cm² (P=0.0001) (Fig. 1B).

Fig. 1.

Distribution of bone mineral density (BMD) values before zoledronate administration and 2 years after zoledronate administration. (A) Lumbar BMD value. (B) Total body BMD value.

The mean calcium values of patients before, one year and two years of zoledronate administration were respectively 9.4, 9.2, and 9.3 mg/dL (P=0.53) (Table 3). Serum creatinine values before, at 1 and 2 years after zoledronate were mean 0.36, 0.39, and 0.38 mg/dL (Table 3). In Table 3, the mean ALP values before, at 1 and 2 years after zoledronate were respectively 310.6, 233.2, and 186.4 mg/mL (P=0.0001).

Table 3.

PedsQL score before and 2 years after zoledronate administration

DISCUSSION

The increase of bone density in OI correlates with a lower incidence of fractures and reduced pain, both having an impact on the QOL of these patients.[8] The group of bisphosphonate drugs that is often given to OI patients is pamidronate. However, in some countries including Indonesia, pamidronate is not available. Only zoledronate is available and is also covered by national health insurance. In comparison to pamidronate, zoledronate has superior potency on bone metabolism and a longer-lasting effect.[9] Also, in comparison to monoclonal antibody class of drugs, like denosumab, zoledronate remains superior since it has less adverse events and good outcomes on fracture risk in children.[10]

In our study, the lumbar and total body BMD values were significantly increased in the pre- and post-treatment of zoledronate, which is in line with Otaify et al. [11] who used a two-year infusion protocol in 33 children with OI and five cases of Bruck syndrome. They also observed a decrease in fracture frequency and less pain during follow-up and an increase in BMD. Finally, Li et al. [12] found low lumbar BMD values increased by zoledronate, preventing spinal compression fractures in OI patients.

In our study, the efficacy of zoledronate treatment in OI patients by measuring the patients’ QOL using PedsQL score. Our study showed significant improvement in each domain of the PedsQL score including physical, social, emotional, and school functioning domains. This is similar to research conducted by Fano et al. [13], showing an association between better PedsQL scores and treatment adherence. In a study which conducted by Vanz et al. [14] showed there was a significant improvement in the QOL of patients based on PedsQL in the dominant physical and social functions and pain was the variable most related to PedsQL improvement. About 52 children and adolescents with OI (aged 5-17 years) were observed in the study. In the study of OI patients with zoledronate therapy reported a mean perceived pain intensity of 2 (0-10 scale).[15] This supports that an increase in BMD in OI can lead to an increase in QOL of these patients, probably because of the decrease in the number of fractures and the presence of the bone pain.

OI affects COLIA1 and COLIA2 production, leading to poor production of collagen type I and a considerable decrease in bone tensile strength. Diminished bone strength is influenced by various factors, including bone porosity, architecture, connectivity, the quality of collagen fibres, and the collagen-to-mineral ratio.[16] In our study, the administration of zoledronic acid aims to enhance bone strength by the augmentation of bone density.

Zoledronic acid reduces bone resorption by osteoclasts, thereby shifting the balance between bone resorption and formation towards increased bone formation in OI. While zoledronic acid treatment can decrease pore percentage and improve BMD, it cannot address all factors that contribute to the decreased bone strength in OI.[16] Zoledronic acid is a compound that specifically reduces the breakdown of bone tissue by efficiently blocking the activity of farnesyl pyrophosphate synthase in the mevalonate pathway to reduce osteoclast activity.[17,18]

In our study, ALP levels decreased 40% after zoledronate treatment. In Senthilnathan’s study [19], the average serum ALP decreased from 235 IU/L at the baseline to 170 IU/L after 12 months or approximately decreased 28% in ALP. This indicates that zoledronate effectively inhibits bone turnover through inhibitory pathways that are also responsible for the observed effects of zoledronate, such as stimulation of osteoblast growth, enhancement or initiation of osteoblast differentiation and enhancing bone marrow stromal cell proliferation.[7]

The results of calcium and serum creatinine levels in our study did not change significantly after 2 years of treatment with zoledronate. Sakai et al. [20] showed that no clinically significant changes in laboratory data, including blood biochemistry, haematology or urine examination was present, nor calcium serum levels or urinary calcium excretion. No significant differences were observed between the two groups and the incidence of adverse events respectively.[20,21] The absence of changes in serum creatinine and calcium levels suggests that the use of zoledronate is safe in OI therapy.

In developing economy countries, zoledronate also has other advantages besides its good effectiveness and safe clinical profile for patients. zoledronate can be administered less frequently than other bisphosphonates (i.e., pamidronate three times per year). This low frequency of administration reduces not only costs of treatment but also lower travel costs for patients and families to travel to hospitals. Saraff et al. [22] showed that zoledronate saved 50% less expenditure than pamidronate each year. Another advantage of zoledronate administration is that children stay less long and also reduce the frequency of drug administration.[8,23]

Our research has several limitations. The first is the limited sample size, thus extrapolating our results to a broader population of OI patients is difficult. The second limitation pertains to the relatively short follow-up period of two years, which should ideally be extended. The third limitation is that our study didn’t collect and report fracture incidents before and after the administration of zoledronate.

Zoledronate was found to be effective and safe as a medical therapy for OI patients, judging by the significant increase in bone density using BMD parameters and the improvement in PedsQL scores in OI patients. Serum creatinine and blood calcium in OI patients given zoledronate did not change significantly. This suggests zoledronate does not cause side effects of renal impairment and decreased calcium levels in paediatric patients with OI who are given zoledronate. Further research with a longer time period needs to be done to be able to get a more comprehensive picture of the outcomes of OI patients who are given zoledronate.

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