Review of osteoporotic fracture research in Endocrinology and Metabolism Research Institute; where we started and where to go

Abstract

Purpose

Osteoporotic fractures impose a vast burden on the health system, especially in countries with an old population or an ageing trend such as Iran. This study reviews the articles published by the Endocrinology and Metabolism Research Institute (EMRI) to map and summarize the evidence, identify key themes and highlight research gaps to plan future research.

Method

We searched for studies affiliated with EMRI on osteoporotic fracture. Scopus, PubMed, Google Scholar, Scientific Information Database (SID) and Persian databases were used, without restricting time and language. All papers published up to December 2019 were retrieved and merged using Endnote software. Two independent researchers reviewed documents, and non-related papers were removed from the collection. The reference lists of the relevant articles were reviewed to avoid missing any publication. All papers addressing any aspects of fragility fractures were included. Meeting abstracts and letters to the editor were excluded. The visualization of the co-authorship network was illustrated with VOSveiwer program software.

Results

The total number of 20 papers, published between 2004 and 2019 were included in our study. “Larijani, B” with 12, “Keshtkar, A”, “Abolhassani, F”, and “Soltani, A” with five papers were the most prolific authors. Six out of 20 (30 %) of the papers were published in the last three years. Among different perspectives of osteoporotic fractures, addressed by EMRI, four main categories of articles were defined including incidence (n = 7), related factors (n = 9), fracture risk assessment (n = 2), and the burden of osteoporotic fractures in Iran (n = 4). There was no updated information about the incidence of osteoporotic fracture and its burden in recent years.

Conclusions

Considering the importance of osteoporotic fractures in Iran with an ageing trend, Osteoporosis Research Centers can play an essential role in providing evidence for policymakers. Worldwide, there is a large care gap to assess bone health and start treatments after fragility fractures. Accordingly, following international recommendations, practical interventions are required to fill this gap. EMRI began developing the “Registry of osteoporosis” and also pilot the “Fracture Liaison Services”, as an operative model to address the existing care gap and implement applied research in this science area.

Supplementary Information

The online version contains supplementary material available at 10.1007/s40200-021-00733-2.

Introduction

Osteoporosis is a common disease resulting in nearly 9 million bone fractures globally per year [1]. Fragility fractures happen spontaneously or as a result of minor trauma. Incidence of hip fractures differed across the Eastern Mediterranean Region (EMR) between 71 and 200 per 100,000 person-years in men and 100 and 295 per 100,000 person-years in women. Mortality rates after hip fracture in the Middle East and North Africa region overdone 25 % and 60 % in 2nd and 3rd year, respectively, with more emphasis on the lower mean age of hip fracture in the region than the values in more developed countries [2].

In Iran, a significant demographic change in the elderly population was detected as rising from 7.27–8.20 % from 2006 to 2011, and to 8.65 % in 2016 [3]; so, osteoporosis and osteoporotic fractures are among important health problem which can impose a significant burden on the health system. To deal with these changes, appropriate and comprehensive interventions are required. Accordingly, coherent and purposeful studies can provide systematic information to show the gaps and help policymakers for evidence-based planning. During the last decades, in line with the goals and prospects of Endocrinology and Metabolism Research Institute (EMRI), several important areas have been addressed by research centres in this institute, including Osteoporosis Research Center (ORC) [4]. Considering the importance of fragility fractures, this article aimed to overview the available research evidence on fragility fractures, provided by EMRI, as a pioneer institute of research in Iran. We wanted to find general themes emerging from the review, summarize and classify the results and highlight the information gaps and the needs for further studies.

Materials and methods

To find a list of published papers addressing osteoporotic fractures directly, a systematic search was conducted in the online databases of PubMed, Scopus, Scientific Information Database (SID), and Google Scholar and also Persian databases for relevant publications up to December 2019. Fracture, broke‎, fragility, osteoporosis, were used as the search keywords. The search strategy is provided in the supplementary file 1. Additionally, an expletive search was conducted by searching through all the references of related articles. No restriction was made as to the time of publication and language. Bibliographic data from all sources were imported to the Endnote software, and after merging duplicate items, the papers were reviewed by two independent researchers to exclude the non-related articles. Moreover, the reference lists of the relevant articles were reviewed to avoid missing any publication. All papers that addressed any aspects of fragility fractures were included and methodologically assessed. Meeting abstracts and letters to the editor were excluded.

Finally, 20 documents were included in this study. We applied VOSviewer software (version 1.1.16) to visualize the network analysis of the co-authorships.

Results

We found a total of 20 papers in our search ranging from 2004 to 2019, with six articles (30 %) in the last three years. Eighteen papers were in English, and two of them were written in Persian. These papers were written by 66 independent authors with an average contribution of 3.33 authors per paper. “Larijani, B” with 12, “Keshtkar, A”, “Abolhassani, F”, and “Soltani, A” with 5, and “Hossein-Nezhad, A”, “Moayyeri, A”, “Khashayar, P” and “Esmalzadeh, A” with four papers were the most prolific authors. Figure 1 shows the co-authorship network for authors contributing to this collection. As shown in the figure, Larijani with the most documents had the greatest total link strength.

Fig. 1.

Co-authorship network of researchers in the field of osteoporotic fracture at EMRI. (The size of the nodes is based on the number of papers by the author)

The included articles were reviewed and categorized into four main subjects: (1) incidence of osteoporotic fractures; (2) fracture risk assessment; (3) factors related to osteoporotic fractures; and (4) the burden of osteoporotic fractures in Iran. Some articles were summarized in more than one category. As shown in Table 1, there were 7, 2, 9, and 4 articles in the following categories, respectively, (Some articles had addressed more than one subject):

Table 1.

Papers published on osteoporotic fractures, affiliated by Endocrinology and Metabolism Research Institute

Authors	Title	Journal	Citation*	Category
Abolhassani et al. [5]	Burden of osteoporosis in Iran	Iran J Public Health	NI	Burden
Moayyeri et al. [6]	Incidence of Hip Fractures among Iranian Elderly Population	Iran J Public Health	NI	Incidence
Zolfaghari et al. [7]	The incidence of osteoporotic hip fracture in 3-years fallow up of Iranian Multicenters Osteoporosis Study (IMOS) (Persian).	J Reprod Infertil	NI	Incidence
Abolhassani et al. [8]	Incidence and characteristics of falls leading to hip fracture in Iranian population	Bone	36	Incidence
Moayyeri et al. [9]	Epidemiology of hip fracture in Iran: results from the Iranian Multicenter Study on Accidental Injuries	Osteoporos Int	38	Incidence
Ahmadi-Abhari et al. [10]	Burden of hip fracture in Iran	Calcif Tissue Int	17	Burden
Saghafi et al. [11]	Osteoimmunological Insight in to Vertebral Fractures in Osteoporosis	Iran J Public Health	3	Related Factors
Aliasgarzadeh et al. [12]	Incidence of osteoporotic hip fracture in above 50 year old peoples of Tabriz in years 2004–2006 (Persian)	Iranian Journal of Endocrinology and Metabolism	NI	Incidence
Rahnavard et al. [13]	The incidence of osteoporotic Hip fracture: Iranian Multicenter osteoporosis study (IMOS)	Res j Biol sci	NI	Incidence
Hossein-Nezhad et al. [14]	Variation in the COX-2 gene may modify the effect of Alendronate on vertebral fracture prevention	European Journal of Inflammation	7	Related Factors
Salari and Abdollahi [15]	Long term bisphosphonate use in osteoporotic patients; a step forward, two steps back	J Pharm Pharm Sci	16	Related Factors
Shahnazari et al. [16]	Estimating the avoidable burden of certain modifiable risk factors in osteoporotic hip fracture using Generalized Impact Fraction (GIF) model in Iran	J Diabetes Metab Disord	NI	Burden- Related Factors
Ghafoori et al. [17]	The risk of osteoporotic fractures and its associating risk factors according to the FRAX model in the Iranian patients: a follow-up cohort	J Diabetes Metab Disord	NI	Incidence- Related Factors
Amininezhad et al. [18]	Evaluation of the validity of the FRAX® algorithm for predicting risk of osteoporotic fracture in Iran	Osteologie	1	Fracture risk assessment
Maghbooli et al. [19]	Direct costs of osteoporosis-related hip fractures: protocol for a cross-sectional analysis of a national database	BMJ open	2	Burden
Sadeghi et al. [20]	Abdominal obesity and risk of hip fracture: a systematic review and meta-analysis of prospective studies	Adv Nutr	20	Related Factors
Malmir et al. [21]	Adherence to Mediterranean diet in relation to bone mineral density and risk of fracture: A systematic review and meta-analysis of observational studies	Eur J Nutr	18	Related Factors
Malmir et al. [22]	Consumption of milk and dairy products and risk of osteoporosis and hip fracture: a systematic review and Meta-analysis	Crit Rev Food Sci Nutr	5	Related Factors
Salari-Moghaddam et al. [23]	Metformin use and risk of fracture: a systematic review and meta-analysis of observational studies	Osteoporos Int	5	Related Factors
Khashayar et al. [24]	FRAX-based intervention and assessment thresholds for osteoporosis in Iran	Osteoporos Int	0	Fracture risk assessment

* Citations in Web of Science; NI: Not indexed in Web of Science

Incidence of osteoporotic fractures

Our review found seven papers addressing the incidence of osteoporotic fracture [6–9, 12, 13, 17]. In 2004, Moayyeri et al. used the data of the Iranian Multicenter Study on Accidental Injuries (IMSAI) that was designed to report any incident injury resulted from unintentional accidents. They reported the hip fracture incidence rates as 191.6 and 227.2 in 100,000 person-years, in men and women aged 70–79 years, respectively [6]. In 2006, another study in this context showed the hip fracture incidence rate of 115.2 and 115.6 per 100,000 person-years in men and women aged ≥ 50, respectively; of these,73.2 and 89.2 % were fall-related fractures [9]. Hip fractures are the most severe outcomes of falls in the elderly population. Abolhassani et al. presented data from the IMSAI. Including 2186 patients admitted because of any injurious fall events, 572 individuals suffered from a hip fracture. The incidence rate of fall-related hip fractures in people over 50 years was 93.6 per 100,000 person-years. They showed that 76 % of hip fractures happened indoors [8].

In 2009, Rahnavard et al. estimated the cumulative incidence of osteoporotic hip fracture based on findings available of the Iranian Multi-Centre Osteoporosis Study (IMOS). After three years, a phone survey was conducted on men and women aged 50 and over to ask about the occurrence of fractures (n = 389). Finally, 286 participants with a mean age of 65 ± 7 years were included; of them, 11 (3.8 % over three years) hip fractures were reported. They showed that the fracture was increased by age as it was 8.2 % over three years among participants ≥ 70 years old [7, 13].

The incidence of osteoporotic hip fracture in Iran was also estimated in a retrospective study on the population aged over 50 years. Aliasgarzadeh et al. in 2009 examined the medical records of all patients who were admitted with hip fracture in the city hospitals of Tabriz; they found 779 patients (398 males) with non-traumatic hip fractures with a mean age of 75 years. The rate of non-traumatic hip fracture in Tabriz was estimated as 175 per 100,000 population annually, with a female to male ratio of 0.96. Concluding the high frequency of non-traumatic osteoporotic hip fracture, the results showed that the surge of osteoporotic hip fracture occurs ten years earlier in our country. The female to male ratio is lower than those of other countries [12].

Ghafoori et al. in 2014 conducted a phone survey on the population aged 40 to 90 years who referred to the BMD clinic of Shariati Hospital for central bone densitometry by Dual-energy X-ray absorptiometry. This retrospective cohort study based on the follow-up data estimated the incidence rate of osteoporotic fractures through survival analysis and Kaplan-Meier product-limit method. In all, 1233 participants were included; the incidence rate was estimated at 35.9 in 1000 person-years. They acknowledged that due to Shariati hospital’s referral nature, the results might be higher than the other BMD clinics.[17].

Fracture risk assessment

We found two papers published directly on fracture risk assessment [18, 24]. Aminizade et al. (2015) conducted a cross-sectional study to determine the most applicable FRAX® model for the Iranian population. Fracture probabilities were calculated using FRAX® models from Jordan, Lebanon, and the US among 236 Iranian men and women ( 74 individuals with a positive history of fragility fracture and mean age of 70 years, along with 162 participants without fragility fracture and mean age of 66 years) [18]. All three country-specific versions showed good discrimination values in women. The authors found a significant difference between the rates in the cases and the controls; while considering the resulted rates, lower than the recommended threshold for intervention, the Lebanese and the Jordanian models should be adopted in the Iranian population.

In men, the Jordanian model showed low discrimination. For the Lebanese model, despite acceptable discrimination, a revision was also recommended regarding its threshold. The most compatible model was the US one [18].

The FRAX® algorithm has been recently calibrated for Iran. Using the Iranian FRAX tool, a recent study examined two scenarios for assessing women at high risk of fracture. The first one concerned the current Iranian guidelines that considered BMD T-score ≤ − 2.5 SD for the intervention. As the approach worked without BMD, the second one used fracture probabilities that were equivalent to a woman with a history of fragility fracture [24]. The authors showed that the 10-year probability of a major osteoporotic fracture increased with age from 4.9 % in the population aged 50 years to 17 % in the population aged 80 years. Using BMD alone, the intervention thresholds may not effectively identify high-risk women, especially in the elderly.

Factors related to osteoporotic fractures

In all, nine papers discussed the risk or protective factors related to osteoporotic fractures [11, 14, 15, 17, 20–23, 25]; of them six papars were systematic review and meta-analysis.

Ghafoori et al. showed a significant effect of diabetes, history of fracture, and having immobility for > 90 days on the 10-year risk of major osteoporotic fractures. In a retrospective study, they included 1233 men and women from individuals who were referred for bone densitometry to the Shariati Teaching Hospital [17].

To show the effect of abdominal obesity on the risk of hip fracture, a meta-analysis of prospective studies was undertaken, including 12 cohort and two nested case-control studies. The result showed that abdominal obesity (based on WHR) was significantly associated with a higher risk of hip fracture. In contrast, abdominal obesity (based on WC) had a marginally significant positive association with hip fracture [20].

The relation between adherence to the Mediterranean diet (MD) and fracture risk was evaluated in a systematic review and meta-analysis [21]. Malmir et al. showed that adherence to the Mediterranean diet might reduce the risk of hip fracture by 34 %; Adherence to MD was positively associated with bone densitometry measures in the lumbar spine, femoral neck, and total hip.

Another systematic review was undertaken to summarize the association between milk and dairy products and the risk of osteoporosis and hip fracture [22]. In summary, milk consumption was negatively associated with the risk of hip fracture, although in cohort studies, linear meta-regression showed a 9 % higher risk of hip fracture for every additional 200-gram milk consumption per day [22].

Salari-moghadam et al. evaluated the association between taking metformin and fracture risk in a systematic review and meta-analysis, including six observational studies [23]. A significant inverse association was detected between taking metformin and the risk of fracture.

A systematic review was conducted in 2010 to review the relationship between β-blockers and bone health. Although the study showed controversial documents on the association between β-blockers and BMD, several papers were found to indicate the negative association of β-blockers usage with the risk of fracture, proposing the preventive effects of β-blockers on fracture [25].

A review was done to summarize the risk-benefit of bisphosphonates. The results showed that in terms of fracture, short term use of bisphosphonate could reduce the rate of vertebral fractures; however, increased risk of atypical fractures and dynamic bone disease may be caused in long-term consumption [15].

The burden of osteoporotic fractures in Iran

We found four papers published on the burden of osteoporosis and osteoporotic fractures [5, 10, 16, 19]. In 2001, a study was conducted to estimate the burden of osteoporosis in Iran, considering the fractures of the hip, spine, and forearm as the most common sites of fractures in older ages. The main sources of information included the risk of post-osteoporotic-fractures mortality (international literature), the results of the study on unintentional injuries (MOH), and the study on bone density (EMRI). The authors calculated the DALYs indicators for the hip, spine, and forearm fractures using the information on mortality and incidence rates, disability weights, and mean duration of the disability. In all, these fractures were responsible for 18,757 and 17,270 mortality- and morbidity-related lost years of life in men and women, respectively, which were predominantly contributed by hip fracture. They proposed that the higher burden in men, mainly attributed to the higher risk of post-fracture mortality in men. [5].

Another study in 2005 estimated the burden of hip fractures in Iran, applying the Global Burden of Disease (GBD) method and compared the results with the global burden of hip fractures. Hip fracture imposed 16,708 DALYs (8,812 YLL and 7,896 YLD). This figure comprised 12.4 % of the burden of hip fractures in the Middle East. The female to male ratio was lower in Iran (1.1 in Iran compared to 1.4 and 2.2 in the world and the Middle East, respectively). They suggested that the burden of hip fracture in Iran is not as high as in the developed world [10]; however, there was incomplete evidence. It assumed that a dramatic rise in hip fracture will be expected due to the country’s population aging [19].

Considering the burden of hip fracture, Shahnazari et al. estimated the preventable burden of the known modifiable risk factor of osteoporotic hip fractures in Iran, using the Generalized Impact Fraction model [16]. They considered different scenarios showed that the highest impact in reducing the prevalence of osteoporotic hip fractures could be achieved by reducing the prevalence of low vitamin D, low physical activity, and low vitamin D and calcium intake, respectively. Since low serum vitamin D, low intake of calcium, and low intake of vitamin D can be considered simultaneously, the authors assessed the interventions in three scenarios and showed a 5 %, 11 %, and 17 % reduction in the burden of osteoporotic hip fractures in the easy, moderate and difficult scenarios, respectively. Adding the interventions focusing on insufficient physical activity resulted in an 8 %, 21 %, and 35 % decrease in the burden of osteoporotic hip fractures in the easy, moderate, and challenging scenarios, respectively. They concluded that calcium and vitamin D supplementations and improving physical activity could be the most effective interventions to reduce the burden of osteoporotic hip fractures in Iran [16].

Discussion

This study summarizes the articles published by the researchers affiliated with EMRI on osteoporotic fractures and related risk factors. Incidence of fragility fractures, fracture-related factors, and the burden of fragility fractures were the most frequent topics studied by the investigators in EMRI.

Based on the studies reviewed, there was a high incidence of fragility fractures in Iran that arose ten years earlier than in other countries.

According to the literature, the most burden was related to the hip fracture as it imposed more than 16,000 DALYs. That’s why, in 2006, Iran accounted for 12.4 % of the burden of hip fractures in the Middle East [10]. It was also estimated that 50,000 hip fractures occurred in 2010 in Iran and was projected to increase to 62,000 by 2020 [26]. Despite the research conducted in EMRI on the incidence of fragility fracture, there is still considerable evidence gap in this area. The EMRI, in collaboration with the ministry of health, has recently intended to establish the registry of osteoporosis. The program is in the development phase and aims to help identify gaps in patient care, and show opportunities to the policymakers to improve the clinical practice. This approach use patient information to address clinical quality gaps promptly. Moreover, the evidence provided on the incidence of osteoporotic fractures needs to be updated. A population-based fracture registry is needed to provide valid data on the incidence, and it’s time trend. There is also a need for a comprehensive and updated information regarding the direct and indirect costs of osteoporosis.

It is well recognized that osteoporosis is a multifactorial disease initiated by the interaction between predisposing factors, including lifestyle factors and genetic factors that might vary in different populations [27]; Fracture risk assessment models are widely used in the routine practice of osteoporosis management. FRAX® is among the most commonly used risk assessment models specifically adapted for many countries worldwide [28]. Researchers in EMRI has contributed to developing the model for Iran with the developers [24], and the Irans’ specific FRAX® is now available on the website [29]. However, the remaining question is if the developed model could be practically used at the primary health care as a screening tool to identify high-risk people and if the intervention in this group can reduce the burden of osteoporosis and fragility fracture. That’s why it is recommended that prediction models such as the FRAX model be validated in each community separately. As we have shown, the studies undertaken in EMRI, addressing the related factors to osteoporosis, were mainly systematic review/meta-analysis. Considering the high importance of osteoporotic fractures, providing comprehensive evidence on the related risk and preventive factors in Iranian population seems necessary. In reviewed studies, the higher burden of fragility fracture was reported in Iran among men and the lower female to male ratio compared to other countries (1.1 in Iran compared to 2.2 in the Middle East). This might be partly due to higher rates of underreporting in women. Some studies showed that the mortality risk after a hip fracture is twice in men than the women [30], although the rate of osteoporosis in men is lower. Among all fragility fractures, 30–40 % arises in men [31], and it shows that osteoporosis and fragility fractures in older men might be unrecognized and untreated.

Besides the increased rate of mortality and many problems leading to lower quality of life in survived patients, a previous osteoporotic fracture increases the risk of the subsequent fracture by nearly twofold in men and women [29]; however, there is a large care gap, worldwide and only 9–50 % of fractures have been formally assessed for bone health and take treatments [32]. Fracture liaison service (FLS) has been introduced as an operative model to address this care gap by identifying patients presenting with fragility fractures, referring them to bone mineral density testing, recommending, or initiating the appropriate treatment, and osteoporosis education for lifestyle modification [32, 33]. The effectiveness of this program has been documented by several studies [34, 35]. In line with the prospect of EMRI, Osteoporosis Research Center helped the Ministry of Health establish such service in Iran, as piloting the FLS in defined centres throughout the country. Besides, to complete the whole picture of fragility fractures in Iran and update the previous findings, several studies are being conducted in ORC such as estimating the economic burden of osteoporosis and osteoporotic fractures, estimating the incidence rate of fragility fractures, post-fracture mortality, and re-fractures, using meta-analysis and also retrospective studies. The results of the pilot phase of FLS and the mentioned studies can guide policymakers to determine the applied and beneficial approaches to provide appropriate prevention programs in Iran.

Conclusions

Several studies were undertaken in EMRI, focusing on osteoporotic fracture, related risk factors, and its burden. Considering the aging trend of the Iran population, osteoporotic fractures may impose a significant burden on the health system in the future. Following international recommendations, practical interventions such as developing a registry for osteoporosis and also establishing the “Fracture Liaison Services” are suggested to fill the gaps. EMRI, as a pioneer research center, was started to pilot these interventions, to implement applied research in this science area.

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Compliance with ethical standards

Conflicts of interest/Competing interests

The authors declare that they have no conflict of interest.

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