Effect Of Bisphosphonate Use On Fracture Incidence In Older Persons With Osteoporosis: A Systematic Review

Osteoporosis is a type of skeletal disease that is associated reduction in bone mass and decline in bone tissue that increases the risk of fracture. The risk of the condition is common in elderly people and the prevalence is found to be 30% in people above 50 years and 15% in men (Kemmak et al., 2020). According to Salari et al. (2021), osteoporosis has been defined based on bone mineral density (BMD) assessment. The World Health Organization (WHO) defined osteoprosis as a BMD that lies 2.5 standard deviations or more below the average value. It is classified into two types such as primary and secondary osteoporosis. The incidence of primary osteoporosis is mostly seen in post-menopausal men and women above 70 years of age. Secondary osteoporosis is mostly caused by conditions such as systemic diseases and endocrine diseases. The growing incidence of osteoporosis in elderly is a concern as it increases the risk of bone fractures related complications. In addition, the chances of increased medical cost, disability and mortality also increased to the burden of the disease (Mohd-Tahir & Li, 2017). 

Apart from global estimates, research been done to investigate the burden of osteoporosis in Australia. The study by Tatangelo et al. (2019) estimated about the cost of osteoporosis and associated fractures in Australia in 2017. The main rationale for the investigation was the lack of appropriate data on current incidence and prevalence of health care costs. The investigation revealed that the total direct cost of osteoporosis in Australia was around AUD $3.4 billion dollar.  The total direct cost linked to fracture was found to be around 68% and hip fracture accounted for the highest proportion of fracture. The non-fracture management of osteoporosis was also found to be around 32%. The majority of cost was attributed to fracture treatment. A systematic review by Kemmak et al. (2020) revealed about the cost of osteoporosis in different parts of the world. The direct annual cost of treating osteoporosis was found to be around 5000 and 6500 billion USD in Canada, Europe and USA. The cost component analysis revealed that hospitalization and surgery was one of the main causes behind the total cost. The length of hospital stays varied from 8 to 29 days. In addition to economic consequences, the incidence of osteoporosis can contribute to adverse physical health consequences too. One of the serious consequences of osteoporosis is fractures and the primary cause behind fracture risk is the increase in bone fragility. The risk of fracture is high in older individuals because with increase in age, the rate of BMD decreases. In addition, osteoporotic fracture is the cause behind increased hospitalization, poor quality of life, disability and death (Li et al., 2017). A study done in Thailand revealed that osteoporotic hip fractures resulted in increased Health related quality of life (HRQoL) and the impairment was worst in the first 3 months (Amphansap & Sujarekul, 2018). Hence, from the above discussion, it is clear that osteoporosis is a significant public health concern for elderly.

Prevalence of Osteoporosis and Associated Fracture Risk

The research studies on evaluation of bisphosphonates have given controversial results. Zullo et al. (2015) gave the evidence that BPs are seldom used in frail and older adults. However, the study on the estimates of BPs effectiveness in frail older patients revealed a meaningful reduction in frailty. A systematic review reported about the real-world persistence and adherence with oral BPs for osteoporosis. Based on the use of data from prospective and retrospective observational studies, the persistence of BPs for six months, 1 year and 2 months varied from 34.8% to 71.73% respectively. The potential determinants of adherence included hospitalization, medication type and frequency, history of fractures, effect of co-medications, tobacco use, rheumatoid arthritis and diabetes (Fatoye et al., 2019). Hence, these areas need to be targeted for preventing BPs.

To effectively manage osteoporosis and minimize adverse effects due to the condition, there is a need to have understanding about the risk factors and cause. Knowledge in this area would help to identify appropriate public health initiatives for the condition. The common issue is that the incidence has been found to be higher in women group compared to males. The participants with low level of education were found to have high risk than individuals with low education (Tian et al., 2017). The study by Cheraghi, Cheraghi & Bozorgmehr (2018) also gave the insight that ageing, low level of education, smoking and living in urban areas and family history of osteoporosis. It is a multifactorial disease and it can be caused due to history of other conditions such as Cushing’s syndrome, gonadal dysfunction and being underweight. In case of youths, low BMI, being underweight and physical activity contributed to risk.    

The main complication for elderly patients with risk of osteoporosis is the risk of bone fractures. According to the recent guidelines for osteoporosis, oral bisphosphonates (BPs) are the mainstay of treatment. The efficacy of BPs is debatable as adherence has been found to be low. A systematic review evaluating the effects of oral treatment with BPs revealed that bisphosphonates do not increase the risk of severe gastrointestinale (GI) adverse events (Dömötör et al., 2020).

Evidence suggests the role of much therapeutic advancement in the diagnosis and management of osteoporosis. Many research scholars advocate for screening to detect osteoporosis at an early stage. A randomized controlled trial revealed about the benefit of screening by randomizing women to screened or not screened groups. After nine years of follow-up, it was found that screening method increased the initiation of early treatment such as hormone replacement therapy and other treatment. In addition, there was decrease in fracture risk by 25.9% compared to the control group. Based on this method, use of BMD measurements particularly in the hip and lumbar spine area is considered best for occurrence of hip or vertebral fracture (Tu et al., 2018). In addition to screening method, pharmacological intervention is the mainstay of treatment. Bisphosphonate is most recommended for pharmacological treatment of osteoporosis. However, more insight is needed to explore its clinical effectiveness (Byun et al., 2017).

Cost of Osteoporosis and Associated Fractures

From the evaluation of past studies, it has been identified that there is bisphospohonates is a mainstay of treatment of osteoporosis in elderly. However, despite positive results, the adherence to the therapy has been found to be low. Nayak and Greenspan (2019) gave the insight that poor adherence to bisphosphonate (BPs) increase the risk of fracture. Hence, there is a need for increased understanding about the benefits of BP in preventing fracture. To address gap in previous research and facilitate understanding about the beneficial impact of BPs in preventing fracture, it is planned to conduct a systematic review to further explore the research topic.

The aim of the systematic review is to explore the effect of bisphosphonate use on fracture incidence on older persons with osteoporosis. The objectives of the research are as follows:

• To explore the clinical effectiveness of BPs in preventing fractures in elderly people with osteoporosis
• To evaluate the long-term efficacy of BPs in preventing osteoporotic fractures in elderly
• To recommend health promotion measures to increase adherence to BPs among elderly

Developing a clear and good research question is also paramount for appropriate research. If the research question is developed in a clear way, it can help to determine appropriate research methodology too. PICOT is a common framework for developing research questions and it helps in categorizing research questions into population, intervention, outcome and comparison. The PICO question for the research process was as follows:

What is the effect of bisphosphonates on the incidence of fracture among older persons with osteoporosis?

Primary and secondary outcomes

The primary outcome of interest for the studies was osteoporotic fractures evidenced by incidence of fractures in elderly people with osteoporosis. All types of fractures such as vertebral and non-vertebral fractures were considered

The secondary outcome of interest included the following:

• Percentage change of BMD using dual X-ray absorptiometry at lumbar spine and femoral neck
• Presence of other complications such as risk of side-effects and other complications

Search strategy:

The search for journal articles linked to the research was done using databases such as CINAHL and PubMed. All these databases were selected for the quality of publications and availability of full-text articles peer-reviewed articles in English language. In each database, basic and advanced search option was used to proceed with literature searching. The keywords used for the search process included ‘bisphosphonates’, ‘osteoporosis’, ‘fractures’ and ‘elderly’. In addition to this, synonyms were used to widen the search process. The common synonyms used were as follows:

• Osteoporosis or bone density or bone loss
• Elderly people or Older adults or geriatric population or older
• Bisphosphonates or alendronic acid or zolendronic acid

Furthermore, the search process was widened or narrowed using the Boolean operators. The Boolean operator ‘OR’ was used to select articles that had either of the two terms; whereas the Boolean operator ‘AND’ was used to retrieved articles that had both the key terms (Grewal, Kataria & Dhawan, 2016). The keywords were arranged using Boolean operators in the following ways:

• Bisphoshonates AND fracture risk in elderly people with osteoporosis
• Bisphosphonates OR Alendronic acid AND fracture incidence in older adults with osteoporosis
• Efficacy of bisphosphonates AND osteoporotic fracture risk in older adults 

Evaluation of Bisphosphonate Use in Frail and Older Adults

In addition to the above, search for similar terms were done from thesaurus. The search process is guided by the PRISMA guideline. The advantage of using the PRISMA framework is that it is designed to transparently report about the review process and what results were obtained. The PRISMA statement consists of 27 item checklist that defines the process for reporting in systematic reviews. The checklist suggests defining all elements in the method section such as eligibility criteria, search strategy, selection process, data collection and reporting bias assessment method (Page et al., 2021). The eligibility criteria for article selection were as follows:

• All the studies should have older persons with a diagnosis of osteoporosis as the population of interest
• All the studies should have different BPs such as alendronic acid as the main intervention of interest.   
• Both primary and secondary research design will be included as long as it addresses the research
• The included studies should be published from 2012 to 2021
• The articles should be published in English language
• All articles should be peer reviewed and full-text papers
• Participants using other therapies apart from BPs were excluded
• Participants with other comorbidities such as diabetes, rheumatoid arthritis, pregnancy and tumor organ transplantation were excluded
• Studies published before 2012 were excluded

The search engine for one database has been described in Appendix 1. 

Using the PRISMA guidelines, the articles were first screened by reviewing the title and abstract. Articles were selected based on reviewing title and abstract if it had all the PICO elements. At this stage, review of reference list and bibliography was also done to identify other relevant papers related to the research question. In addition, screening for analysis of duplicate papers was done. For instance, some studies had the same group of authors or some studies were same but published in different journals. Hence, by this process, relevant studies were filtered from redundant studies. The finding eligibility of the criteria was done by full-text review of the paper and comparing them with the inclusion and exclusion criteria. The advantage of using this approach is that all relevant papers were included and studies which did not had the desired population or intervention group were excluded. The PRISMA flow chart of the search process has been summarized below in table 1:  

Table 1: PRISMA flow chart for the search process

The extraction of data from selected studies was done by two research staffs. As the aim of the systematic review is to extract data and synthesize findings, using appropriate data collection method is essential to influence policy makers and stakeholders. For the research on the effect of bisphosphonates on fracture incidence in elderly people with osteoporosis, the data was extracted in a summary table. The main details that were recorded included author details, sample group, research setting, research design, outcome measures, findings and conclusion. To increase the validity of the results, a single reviewer engaged in the data extraction process first and this was reviewed by the second staff. The quality assessment of article was done using similar process. In case of any disagreements, discussion between staffs was done and the final data was entered after achieving consensus. Structured consensus is a good facilitation technique to avoid conflict and promote validity of the research data (Iphofen, 2017).

Risk Factors and Causes of Osteoporosis

A descriptive analysis of data was carried out and meta-analysis was avoided due to heterogeneity in the reporting process. It involves evaluating all statistical calculations in the research papers by creating a table for study of mean, variance or standard deviation. In addition to this, qualitative content analysis was conducted by reading and rereading the transcripts several times. The intention was to extract important concepts from the data and arrange them into different categories as per similarity of meanings. Group of phrases with similar meanings were given a code and these were further categorized into a theme (Terry et al., 2017). The thematic approach will help to evaluate different clinical outcomes associated with use of bisphosphonates for preventing fractures.

Quality assessment is an important element in research as it reflects rigour in the research work and ensures that the selected articles are the best quality of evidence. The quality assessment of the articles was done using the CASP tool and the scores obtained based on the checklist helped to identify the quality of evidence. The quality of papers was categorized into high, medium and low category.

Results of the search process:

Based on the review of articles from the CINAHL and PubMed databases, total 1235 articles were retrieved. The search for grey literatures and government reports were also done and 12 articles were found from these databases. Out of 1247 papers, total 10 articles were found to be duplicated. The screening of total 1237 article was done and out of these around 945 articles was excluded as the title did not matched with the research question or it had different population groups. In some cases, elderly participants were missing and studies were conducted in children. Out of the remaining 292 articles, the eligibility assessment was conducted by comparing the papers with the inclusion and exclusion criteria.  At this stage, total 284 articles were excluded at it did not met the eligibility criteria. The primary reasons for exclusion included lack of bisphosphonates as the intervention, poor sample size, publication related concerns or absence of full-text papers. Total 8 articles were finally found to be eligible for the review. The PRISMA flow chart for the search result has been described in Appendix 1.

Total six articles were included for the review process. Out of these studies, two were RCT papers, two were cohort study and the remaining towas systematic review papers. The selection of RCT papers and systematic review papers can enhance the validity of the results as they come under top level in evidence hierarchy. In the evidence pyramid, systematic review comes at the top level due to rigorous analysis process and systematic presentation of findings. In addition, RCT is the method for the evaluation of interventions and it uses measures such as randomization, blinding and allocation concealment to ensure that true effect of the intervention can be established (Katz et al., 2019). A narrative overview of the included studies has been given in the summary table in appendix 2.

Role of Screening and Pharmacological Intervention in Osteoporosis

Primary outcome:

The main purpose of the study was to evaluate the clinical benefit of bisphosphonate in preventing fractures in elderly patients. The primary outcome of interest was to evaluate the reduction in the incidence of osteoporotic fractures in elderly. Based on the analysis of six papers, it was found that BPs reduced the rate of fractures for all treatment conditions. Zullo et al. (2019) revealed that the rate of hip fracture was found to be 0.83 times lower in residents receiving BPs with a hazard ratio of 0.83 and CI value of 0.71-0.98. Users of BPs were less likely to have a non-vertebral fracture (HR = 0.91; 95% CI = 0.80-1.03). Zhou et al. also had new vertebral fracture as one of the primary outcome. Based on the meta-analysis of research papers, it was reported that compared with placebo, all types of BPs such as alendronate, zolendronic acid and ibandronate increased the risk of fractures. The confidence interval and odds ratio (OR) for each of the drug was recorded.  Similar to the above, the systematic review by Byun et al. (2017) indicated that use of BPs decreased the overall fracture risk (OR 0.62, P<0.001), vertebral fracture (Or 0.55, P<0.001) and non-vertebral fracture risk (0.73, P,0.001).

A cohort study by Izano et al. (2020) investigated about the efficacy of BP therapy beyond five years in older women. The outcome measure for the study was proximal femur (hip) fracture risk and the findings revealed that out of 666 participants, 2% experienced hip fracture, 11% experienced humerus or wrist fracture and 28% experienced clinical fracture. The risk of fracture was found to be similar after five years of treatment. The results are found to be consistent with results from RCT paper too. Both Reid et al. (2018) and Greenspa et al. (2015) revealed about the positive effect of BP drugs on the risk of fracture rates. Reid et al. (2018) investigated about the effect of non-vertebral fragility and vertebral fractures and the risk decreased for participants after the therapy. The significance of the above outcome is that each one of them has been supported with statistical analysis tool and use of odds ratio or hazards ratio for each outcomes. Hazards ratio gives an insight about relative risk or risk of an event due to relative exposures.

In majority of studies, secondary outcome has been less explored. In three studies (Zullo et al., 2018; Izano et al. (2020); Byun et al., 2017), no secondary outcome was measured. Zhou et al. (2016) used vertebral fracture as the primary outcome and other types of fracture such as hip, wrist and non-vertebral fracture as the primary outcome. BP therapy such as the use of etidronate, clodronate and zoledronic acid was associated with a reduction in non-vertebral fracture risk. In contrast, secondary end points taken by the RCT study by Reid et al. (2018) were the occurrence of a symptomatic fracture, vertebral fracture, change in height and mortality. In case of symptomatic fracture, the hazard ratio using zoledronate was 0.73 and the risk of zoledronate fracture and height loss was lower in the intervention group. The study recorded adverse events following Zoledronate therapy too. Serious adverse events were found in 400 participants with an odds ratio of 0.84. The odds ratio of death or mortality was found to be 0.65. The above studies provide positive implication regarding the use of BP in frail elderly client with osteoporosis. However, the finding is inconsistent with the study by Greenspan et al. (2015) as it reported increase in the risk of multiple falls in the treatment group. These differences in outcome for adverse events suggest the need for further evaluation.

Low Adherence to Bisphosphonate Use and Fracture Risk

Thus, from the evaluation of primary and secondary outcomes, it can be said that the included studies addressed the PICO element and the prevention of fractures following the initiation of BPs.

The quality assessment of the study was completed based on CASP checklist for systematic reviews, RCT and cohort study. Depending on the score obtained for each question, the papers were given different scores. Out of six studies, most study had a score of 6/9 and one study by Byun et al. (2017) had a score of 8/8. Overall, it can be said that best quality or moderate quality research evidence were taken and the methodology given was complete as different aspects of rigor was maintained. For instance, the main outcome of frequency of fractures or prevention of fractures was mentioned in all studies. In addition, use of rigor during sample recruitment, follow up process and completeness in result was assessed in majority of the study. The results of the quality appraisal have been described in appendix 3. Overall, it can be seen that top quality research design were included in the review and methodological rigour will increase the validity of the findings too.

The systematic review was concerned with addressing the gap found in past research related to the use of BPs for fracture prevention and identifies different clinical benefits of the therapy in reducing the rate of fractures in older adults with osteoporosis. The intention behind exploration of research in this area was to promote awareness about the therapeutic benefits of BP therapy and reduce the problem of poor adherence to BP. From the analysis of six studies, it was found that BP was effective in reducing the risk of different types of fractures such as hip fractures, vertebral and non-vertebral fractures. The six included studies captured benefits in different ways. For instance, Zullo et al. (2018) indicated that BPs may start influencing the risk of fractures as early as six months. In the study, follow-up period of 2.5 years was taken and proper benefit was obtained. Another important finding was that the effectiveness of result did not changed with age. In contrast, the significance of the study by Zhou et al. (2016) was that it explored the performance of different types of BPs such as alendronate, risedronate and zoledronate and indicated positive results in terms of preventing fractures. In addition, by the use of odds ratio and confidence interval, a more precise estimate for the efficacy of BPs was found. In this study, each types of BPs were given ranking in preventing different fractures. This outcome can have practice change implications as the rankings can be used as a reference when providing recommendations in clinical practice. The study finding is consistent with the study by Axelsson et al. (2017) which showed a reduction in hip fracture by 40% in postmenopausal women using alendronate.

Aim

The systematic review yielded a mix of systematic reviews, cohort studies and RCT papers that evaluated about the target intervention. There were some studies which considered heterogeneity analysis too. Heterogeneity analysis was missing in the study by Zhou et al. (2016). The systematic review by Zhou et al. (2016) regarded vertebral and non-vertebral fractures as some of the secondary symptoms. The outcome were compared with finding from previous studies too. It was found that many studies gave similar outcomes. The comparative evaluation of findings gave a more robust estimate of side-effects. In addition, the study by Reid et al. (2018) explored other secondary outcomes such as mortality, change in height, vertebral fracture and occurrence of clinical fractures. The risk of mortality also decreased for patients after taking bisphosphonates. A decrease in height was an indication for incident fracture and the height was measured using Harpendiometer. Thus, the main clinical implication of the systematic review is that it gives health professional the insight that health care professionals should consider BPs as the key intervention while treating older people with fracture risk. There are some frail elderly people who still experience fractures despite initiating bisphosphonates. In this condition, health care professionals should be encouraged to follow the patient and take update regarding adherence to treatment. In many case, risk of side-effects could be the reason behind leaving the therapy. The studies on secondary outcomes such as the risk of side-effects give the implication to provide training to nurses and other staffs regarding education before starting BPs. It would ensure that elderly patients or their family members are better equipped with information to handle complications and adhere with the therapy too.

Each study had its different strengths and limitation. The systematic review paper are considered good quality evidence because of the rigorous method used for data analysis. The strength of the systematic review by Zhou et al. (2018) was that it gave a precise estimate of the effect of the intervention by considering hazard ratio, confidence interval and p-valyue. In addition, a comparative efficacy of data from each study was provided. By ranking the BPs for different types of fractures, it can give practice implications to health care staffs. However, one gap identified in the paper was that heterogeneity analysis was not conducted and there were less studies done with men. Thus, it may lead to generalizability of the findings only for the women group. In contrast, the systematic review by Byun et al. (2017) was done taking twenty four RCT papers. The use of RCT paper was appropriate as it a gold standard method for evaluation of intervention. In addition, rigour in the research process was seen as pair-wise meta-analysis and subgroup analysis was conducted. However, the limitation was that the study did not considered other outcomes that would affect adherence with the therapy such as adverse effects. Hence, the limitation gives the implication to explore these areas in future research.

Methods

The strength of the RCT papers taken in the review was that both had long follow-up period of more than 2 years and dose-wise effect was considered. In addition, Hip and bone mineral density at 12 and 24 months was measured. The study gave a clear idea about how one dose of zoledronic acid can improve BMD in 2 years. It also considered other secondary outcomes such as mortality rates and risk of falls. However, one limitation that affected the generalizability of the result was that it included participants with a history of falls and those taking anticonvulsant medications (Greenspan et al., 2015). Gap in this area can contribute to confounding elements and effect the local application of the findings too. In addition, cohort studies had gaps because of missing data on BMD. However, the wider details on different types of osteoporotic fractures altered the gaps in the study. The study also highlighted that the clinical benefit cannot improve after 5 years of treatment.

Conclusion

The systematic review provided a critical insight about six studies that explored the efficacy or effect of BPs in preventing fracture risk in frail older client with osteoporosis. Based on the search for literature in CINAHL and PubMed database, totl six papers were found relevant to the research topic. It included two systematic reviews, two RCTs and two cohort studies. The common findings obtained from all the study was that use of BP was successful in preventing fracture risk in elderly. The primary outcome of interest in all studies was incidence of different types of fractures such as hip fractures, vertebral and non-vertebral fractures. The participants included in the review included frail older patient, postmenopausal women or older adults above 65 year of age. The clinical benefit of BPs in preventing fracture risk was identified all the groups and there was no difference by age too. Some studies gave a comparative insight about different BPs such as alendronic acid, zoledronic acid anad ibandronate. The efficacy of each of them in controlling different types of fracture was defined. For instance, Zoledronic acid was found to control both vertebral and non-vertebral fracture. In contrast, Alendronate was successful in preventing hip fractures. Thus, in accordance with risk assessment for fractures, the study gives the guidance on types of BPs to be initiated for different patient group.

The advantage of the systematic review is that instead of focusing on the primary outcome, the review considered secondary outcome in research too such as the mortality rate, adverse events and risk of other complications. Although secondary outcomes were not considered in all the studies, two papers explored this in detail. Greenspan et al. (2015) gave insight about adverse events in institutionalized elderly people. The study gave the most contrasting result compared to all other studies. It reported that participants in the treatment group are at high risk of falls. The potential of adverse effect of BPs was not explored in other studies. As there is lack of studies showing similar results, it gives future research implication. Future clinical trials need to be conducted to identify different ways in which BP therapy have effect on adverse events. It should be done with larger population group and effect should be explored for all types of bisphosphonates.

Primary and Secondary Outcomes

The significance of the systematic review finding is that it provides positive clinical implications in the management of older people with osteoporosis. Older people are at higher risk of complications due to incidence of fractures. The evidence on positive fracture related outcomes suggest the need to implement intervention program that raise awareness about the therapeutic effects of BPs. Collaboration with health care administrative staff, health promotion staffs and multiprofessional team is needed so that the therapy is effectively integrate in routine.

The strength of the systematic review is that it is based on accumulation of evidence from high quality research designs. Studies coming under top level of the evidence hierarchy have been included in the review such as systematic reviews and RCT. In addition, quality assessment confirmed the validity and methodological rigour in each paper. Most of the papers were high quality or moderate quality of resources. In addition, good detail about the findings and outcomes in each study have been provided. However, one limitation in the review is that due to time constraints, only six studies were included in the analysis. The systematic evaluation of more number of papers could have increased the validity and reliability of the findings. The research in the area and critical evaluation helped in identifying many practice related changes too. The recommendations for practice change are as follows:

• Conduct larger trials to investigate about adverse effects of BPs and its impact on fracture outcomes
• Educate health care professionals about giving education about BPs to elderly client
• Encourage policy makers to use drugs such as alendronate and zolendronic acid as part of main treatment in hospital settings
• Increase awareness about the importance of follow-up with patients to improve clinical outcomes 

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Search Strategy

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