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Department of Trauma and Orthopaedic Surgery, South Tyneside District Hospital, Harton Lane, South Shields, NE34 0PL, United KingdomTranslational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University, Framlington Place, Newcastle-upon-Tyne, NE2 4HH, United Kingdom
Bisphosphonates and monoclonal antibodies are drugs primarily developed to inhibit osteoclast-mediated bone resorption and are used to treat an array of skeletal pathologies. Their use is aimed at increasing bone health and therefore reducing fracture risks. The aim of this study was to evaluate the effectiveness of bone protection therapy on improving bone mineral density (BMD) in patients following a fracture.
Methods
Inclusion criteria consisted of patients who sustained a skeletal fracture and were subsequently commenced on bone protection therapy. Dual-energy X-ray Absorptiometry (DEXA) scans were performed at baseline and following a consented period of drug therapy. Bone health data included T-Scores, Z-Scores, FRAX Major, FRAX Hip and BMD. The clinical effectiveness of four bisphosphonates (alendronate, risedronate, pamidronate and zoledronate) and one monoclonal antibody (denosumab) were evaluated.
Results
A total of 100 patients were included in the study. Overall, bone protection therapy significantly improved Z-score Hip, Z-score Spine, T-score Spine and BMD Spine (p < 0.05). There was a marked difference between drug therapies. Denosumab and zoledronate were associated with the greatest treatment effect size. Alendronate only improved Z-score Spine and Z-score Hip (p < 0.05). Pamidronate and risedronate did not demonstrate any statistically significant improvement across any DEXA parameter.
Conclusion
Overall, bisphosphonates/monoclonal antibodies confer beneficial effects on bone health as measured by DEXA scans in patients following skeletal fractures. However, the magnitude of improvement varies among the commonly used drugs. Alendronate, zoledronate and denosumab were associated with greatest therapeutic benefit. Bone protection therapy did not improve fracture risk of patients (FRAX scores).
Osteoporosis is a disease characterised by loss of bone mineral density (BMD) and structural integrity of bone tissue leading to increased susceptibility to fractures.
Commonly, it is referred to as a ‘silent epidemic’ as it is often neglected and under prioritised by healthcare systems the world over. The economic burden within the UK in 2017 associated to fragility fractures (a fracture resultant from low-level trauma) was estimated at £4.5 billion and globally, the annual cost of treating osteoporosis is believed to be in the region of over 5000 billion US dollars.
Ensuring early evidenced-based intervention and subsequent prevention of worsening bone health for those with pre-existing fractures and thus increased susceptibility may therefore alleviate the growing public health concerns we now see today.
Bisphosphonates are chemical derivatives of inorganic pyrophosphate, an endogenous inhibitor of calcification, which work by preferentially binding to hydroxyapatite crystals in the bone which induces osteoclast apoptosis and thus supressing bone turnover.
Denosumab has a high affinity for receptor activator of nuclear factor kappa-Β ligand (RANKL), the principal mediator of osteoclastic bone resorption, therefore by inhibiting its action, this preserves bone mineral density.
Both classes of drugs are therefore endorsed globally for their theoretical anti-fracture properties and as such are used in an array of skeletal pathology including metastatic bone disease, Paget's disease of bone, osteogenesis imperfecta and most commonly osteoporosis.
Bisphosphonates are first line options, as per the National Institute for Health and Care Excellence (NICE) guidance, for the treatment of osteoporosis in women over 65 years and men over 75 years, as well as adults who identify as high risk of developing fragility fractures, determined by various clinical factors affecting their BMD.
They can be administered both orally and intravenously at varying doses and dosing intervals; a decision made on an individual basis with the patient and their clinician.
Within this study, the efficacy of four bisphosphonate drugs were evaluated including alendronate, risedronate, pamindronate and zolendronate as well as one monoclonal antibody, denosumab. The bisphosphonate drugs differ in their binding affinity to hydroxyapatite and this may correlate with their relative uptake and diffusion within the bone and hence the suppressive affects in bone resorption seen.
The literature supports treatment related changes in BMD as a surrogate for fracture risk reduction, drawing on the strong correlation between BMD and whole bone strength as seen in cadaveric specimens.
Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials.
Thus, utilising data from dual-energy X-ray Absorptiometry (DEXA) scans may play a valuable role in estimating their relative bone health and subsequent response to anti-osteoporotic drugs. This in turn will draw light onto the efficacy of the commonly used drugs and the potential changes in management required to optimise bone health. The aim of this study was to evaluate the effectiveness of bone protection therapy on improving BMD in patients following a skeletal fracture.
2. Methods
This study followed a retrospective observational cohort study design. This study was exempt from Institutional Review Board (IRB)/Ethics Committee approval as it was a pragmatic study evaluating the existing clinical practice within the institution. A database of patients who had undergone a DEXA scan conducted between December 2012 to July 2020 was obtained from the medical physics department. The inclusion criteria was defined as patients who had sustained a skeletal fracture, had a baseline DEXA scan, were subsequently commenced on bone protection therapy followed by a repeat DEXA scan to assess treatment response. Patients who were receiving bisphosphonates for secondary osteoporosis prevention such as breast cancer patients following the introduction of an aromatase inhibitor or those commenced on long-term steroids for chronic conditions in the absence of a documented fracture were excluded. Furthermore, those patients who had both a baseline and follow-up DEXA scan following the introduction of a bone protective agent in the absence of a fracture were excluded. Prior to commencing one of the five drug therapies included in the study, serum bone profile including vitamin D and calcium studies were evaluated as a matter of routine by the Orthogeriatric doctors and corrected if there were any deficiencies identified. Calcium and vitamin D were not included as treatment options within this study, and it was not known whether a patient had been taking either of these concurrently with their bone protection therapy.
Data from both the baseline DEXA scan and the repeat DEXA scan following a consented period of drug therapy was collected. Standard patient demographics and details of the skeletal fracture were collated. A total of five bone protection therapy drugs were evaluated. This included four bisphosphonates (alendronate, risedronate, pamidronate and zoledronate) and one monoclonal antibody (denosumab) and the choice of drug was noted for each patient.
Alendronate was delivered orally once weekly, a single zolendronate IV infusion was delivered annually, denosumab was administered via 6-monthly subcutaneous injections, pamidromate was delivered via 6-monthly IV infusions and risedronate was given orally as a daily tablet. Patients were treated in an out-patient setting via clinics for zolendronate and pamidronate infusions or facilitated by the General Practitioner/community services for alendronate, risendronate and denosumab. NICE guidance was consulted and applied when deciding an appropriate treatment option by the Orthogeriatricians and General Practitioners. Where patients were unable to tolerate oral bisphosphonates, had adverse effects of a particular bone protective agent or had a particular preference, they were offered an alternative option, at the discretion of the physicians responsible for their care. Hence, off-licence prescribing was seen within this study (pamidronate).
Bone health data was obtained from both the initial and post-intervention DEXA scans to enable direct longitudinal comparison. The same scanner was used for all subjects (Hologic Discovery C S/N 49771). T-Scores (hip/spine), Z-Scores (hip/spine), FRAX Major and FRAX Hip (fragility fracture prediction scores), BMD (hip/spine) and the World Health Organisation (WHO) classification (hip/spine) were obtained from the DEXA scanner. The population-based reference ranges for BMD T-Scores was calculated from the National Health and Nutrition Examination Survey (NHANES) III database.
Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.
The time interval between both DEXA scans was calculated in months. As changes in BMD were reported, the Least Significant Change (LSC) for our centre was 0.027 g/cm2.
2.1 Statistical methods
All continuous data distributions were evaluated by plotted histograms with fitted curve lines, boxplots, normal Q-Q plots and the Shapiro-Wilks test. All the T-scores and Z-scores displayed a normal distribution and were analysed using the appropriate parametric statistical tests. All the FRAX scores and BMD scores displayed a skewed distribution and the appropriate non-parametric statistical test was used in their analyses. The effect size was classified using Cohen
criteria: 0.1 = small effect; 0.3 = medium effect; 0.5 = large effect. The Chi-squared test for independence was used for the categorical data analysis of the WHO classification. The level of statistical significance was set at p < 0.05. Statistical analysis was performed using SPSS for Windows version 26.0 (IBM Corp., Armonk, New York).
3. Results
A total of 100 patients were included in the study. Table 1 presents the patient demographics. Fig. 1 illustrates the fracture site anatomical locations and shows the most common fracture was of the distal radius (27 patients), the second most common was the thoracic spine (15 patients) and the joint third most common was the neck of femur (hip) and the ankle (distal tibia/fibula) with 10 patients each.
Table 2 through to 7 show the longitudinal analysis of bone health data from the DEXA scans across all bone protection therapy drugs. Table 2 showed significantly improved scores for the overall therapeutic effect of bone protection therapy. However, there was a marked difference between individual drug therapies. Denosumab and zoledronate were associated with the greatest treatment effect size (Table 4, Table 7 respectively). Alendronate only improved Z-score hip (p = 0.006) and Z-score spine (p < 0.001) (Table 3). Risedronate and pamidronate did not demonstrate any statistically significant improvement across any DEXA parameter (Table 5, Table 6 respectively). Overall, FRAX scores did not improve following any of the bone protection therapies. WHO Osteoporosis Classification
Kanis JA on behalf of the World Health Organization Scientific Group. Technical Report World Health Organization Collaborating Centre for Metabolic Bone Diseases.
This study shows that overall, the use of bone protection therapy beneficially increases bone health parameters in patients who have sustained a skeletal fracture.
Following the introduction of bone protection therapy, the WHO classification for osteoporosis, as defined by T-Scores, showed marked improvement for both the hip and spine, clinically correlating to enhanced bone health. More noticeable changes were seen at the spine, with a greater proportion of patients moving from the ‘severe osteoporosis’ category to either the ‘osteopenia’ or ‘normal’ categories. This is reflected in the overall analysis for all bone protective agents as there was marked improvement in the T-score spine when compared to the T-score hip. Moreover, the Z-score spine and the BMD spine also showed greater improvement across overall analysis, suggesting a discrepancy in the efficacy on bone protective therapy at specific fracture sites. Various literature has been published to support this, including a large meta-analysis evaluating data on the incidence of hip, vertebral and non-vertebral fractures following bisphosphonate use.
It concluded that zolendronate was most effective at preventing vertebral fractures, and alendronate was most effective at preventing hip fractures, closely followed by zolendronate. The results of the current study are partially consistent with this as we saw a greater improvement in T-score and Z-score for the spine following the introduction of zolendronate when compared to the hip as well as a greater improvement in the BMD spine. However, significant changes were seen for alendronate both within the Z-score hip and the Z-score spine suggesting a comparable level of efficacy. It has been theorised that serial zolendronate infusions over a 3-year period significantly reduces bone turnover, decreasing the surface area of active remodelling and thus preserving bone architecture, enhancing overall bone strength.
This leads to greater reductions in fracture incidence supporting the notion that zolendronate is the most effective bisphosphate across multiple fracture sites.
There were discrepancies among the drug therapies used in their bone health data as a measure of efficacy, with denosumab, zoledronate and alendronate showing the greatest treatment effect. These differences can be attributed to multiple factors. When assessing the comparative effectiveness of bisphosphonates, a significant determinant to consider is the relative affinity for hydroxyapatite, an essential mineral supressing bone turnover, as well as the anti-resorptive potency and duration of action.
It is well documented that zolendronate has the highest affinity for hydroxyapatite, followed by alendronate, and as such the highest relative potency of adsorption to bone mineral.
In theory, these molecular changes support the notion that zolendronate is the most effective bisphosphonate, which was consistent with the present study as well as current literature.
There have been various comprehensive meta-analyses published suggesting greater net improvement in skeletal BMD when directly compared to bisphosphonates, however this did not translate to improved fracture risk reduction.
Whilst this may seem contradictory, possible explanations include (a) the time interval over which the BMD increased was not long enough to see any significant changes in fracture risk, and (b) the multifactorial nature of fractures (geometry, microarchitecture, material properties, frequency of falls).
Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD.
J Bone Miner Res Off J Am Soc Bone Miner Res.2005 Dec; 20: 2097-2104
Overall, however, there is a plethora of high-level evidence to support the use of bisphosphonates and denosumab in enhancing bone health when compared with placebo/no-treatment.
Whilst there is well established data to support the efficacy of bisphosphonates/monoclonal antibodies for the prevention of vertebral and non-vertebral fractures, there is limited published data evaluating the efficacy of anti-osteoporotic medication in preventing subsequent fractures after an initial skeletal fracture. A large retrospective study conducted in 2015 encompassing over 31000 subjects showed a significant decrease, estimated at 40%, in the 3-year risk of developing a subsequent fracture after a consented period of anti-osteoporotic therapy in patients with index fragility fractures, compared to those who were not treated.
This was adjusted for both age and sex. This is promising evidence to support the hypothesis that bone protection drugs are effective agents in enhancing bone health and the subsequent prevention of further fragility fractures. Additionally, a smaller retrospective study evaluating the incidence of a second hip fracture in those compliant with bisphosphonate therapy compared to non-users showed a significant fracture reduction.
This result, although of limited sample size and accounting for only one specified fracture type (neck of femur) confers beneficial effects of bisphosphonates on bone health in the subset of patients with pre-existing fractures, as demonstrated within the present study.
The current study utilised quantitative data generated from DEXA scans to guide our conclusions and ultimately act as a surrogate marker for clinical efficacy of the bone protection therapy drugs being evaluated. DEXA scans are widely used for the assessment, diagnosis and subsequent monitoring of osteoporosis related changes and as such are integral to treatment recommendations.
As the primary outcome of the study was evaluating treatment related changes in BMD following bone protection, only changes that met or exceeded the LSC individually calculated for the scanner were considered true changes. This is in contrast to measurement variability that may mask true biological changes falsely attributed to the medications being used.
Within the present study, true changes in BMD were observed for both denosumab and zolendronate, enhancing the premise that bone protection therapy improves bone health and thus subsequent fracture risk. This in agreement with a comprehensive meta-regression analyses involving over 91,000 participants from 23 placebo-controlled trials whereby BMD was measured as a surrogate marker for fracture risk reduction.
Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials.
They found strong evidence to suggest a correlation between reduced risk of hip, vertebral and non-vertebral fractures and treatment-induced changes in BMD, concluding that greater changes in BMD following a consented period of drug therapy were associated with reduced fracture risk.
There was no significant improvement in the 10-year probability (FRAX) of having a fracture in either the hip or elsewhere in the body following the introduction of a bisphosphonate/monoclonal antibody. FRAX is a multifactorial algorithm used to identify those at risk of fractures and screening out those that are not, prior to offering treatment options.
It uses femoral neck BMD within the calculation and so for the cohort of patients within the present study, femoral neck BMD did not show any statistically significant improvement. As such, the FRAX score was adversely affected. FRAX also does not take into consideration patient compliance, which was not a factor evaluated here, as this was a retrospective study, as well as monitoring modifiable risk factors such as smoking status, weight and alcohol consumption. One cannot therefore draw any reliable conclusions in the follow-up assessment as there is no definitive way to ensure improved fracture risk is attributed to treatment related changes in BMD. Moreover, there is data to suggest that the use of the FRAX calculation is invalidated for patients currently receiving osteoporosis therapy, as this factor (treatment effects) was not considered in the model when initially designed.
Ultimately, FRAX scores act as guidance for clinicians to support tailor made treatment options based on the patients BMD status, fracture risk as well as predisposing risk factors. Their use in monitoring treatment response therefore adds no clinical significance and hence should not be taken into consideration when assessing the efficacy of bone protection agents.
There was no response seen in any DEXA parameter for pamidronate or risedronate. Whilst the latter drug can be explained by the small sample size and thus excluded from our conclusions, the available literature on pamidronate contradicts with the present findings. Various studies, with low participant representation, concluded pamidronate showed a significant reduction in fracture risk and thus provided an effective intravenous option for bone protection.
Due to the small sample sizes of the available data and lack of studies specifically evaluating fracture risk reduction in the treatment of osteoporosis, one can therefore question the strength of these conclusions and subsequent therapeutic recommendations. Pamidronate is currently not licenced within the United Kingdom as a treatment option for established osteoporosis, as there is more compelling data for other intravenous bisphosphonates, such as zolendronate.
The main limitation of this study was the small sample size and therefore power of the data obtained for risedronate as it was a relatively infrequently used drug in this study's institution. Consequently, minimal conclusions can be drawn regarding the relative efficacy of risedronate. Suggestions for future studies includes having a larger sample size across all bone protection therapy agents to ensure high powered data is obtained. Furthermore, the lack of data available for the use of vitamin D and/or calcium supplements during the consented period of drug therapy was not considered as a factor within the present study. As they directly affect bone metabolism, their role within the context of osteoporosis treatment in patients sustaining a skeletal fracture should be studied further. Thirdly, men were under-represented within our study and so the conclusions made from a predominantly female population have been extrapolated, which may not be entirely accurate. Moreover, a further limitation to our study was the lack of data available for the time of the post-intervention DEXA scan after the commencement of treatment, attributed to the retrospective study design, as all information was collected from a database which excluded these values. Finally, the side-effects of drugs and the compliance with medication was not assessed due to the nature of the study design. Future qualitative studies could examine these areas so as to gain evidence of patient compliance and side-effect profiles they may have experienced.
5. Conclusion
This study has shown that overall, the use of bone protection therapy for patients sustaining a skeletal fracture offers beneficial therapeutic outcomes, as assessed by changes in BMD and other DEXA parameters. Whilst the magnitude of improvement may differ between the commonly used drugs, with the greatest treatment effects seen in denosumab, zolendronate and alendronate, these findings highlight the potential benefits anti-osteoporotic medications can offer to those at risk of subsequent fragility fractures. The FRAX score did not show any significant improvement however its use may be questionable in patients already receiving osteoporosis treatment. Moreover, given the limited literature available for investigating the effectiveness of anti-osteoporotic therapy use after an initial skeletal fracture, further multi-centre studies with larger sample sizes are needed to comprehensively evaluate this.
Ethical approval
This was a retrospective observational cohort study which did not require IRB/Ethics Committee approval.
Credit author statement
Author I (Priya Sharma): Formal analysis, Methodology, Investigation, Data Curation, Writing - Original Draft. Author II (Oday Al-Dadah): Conceptualization, Data Curation, Writing - Review & Editing.
Funding
This study did not receive any funding from any source.
Declaration of competing interest
No potential conflict of interest relevant to this article was reported.
Acknowledgements
The authors wish to thank David Donohue (clinical technologist) from the Medical Physics Department at South Tyneside District Hospital for his technical assistance and insights.
References
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A systematic review and economic evaluation of bisphosphonates for the prevention of fragility fractures.
Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials.
Centers for Disease Control and Prevention (CDC). National Center for Health Statistics (NCHS). National Health and Nutrition Examination Survey Data. Hyattsville, MD: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention.
Relationship between changes in BMD and nonvertebral fracture incidence associated with risedronate: reduction in risk of nonvertebral fracture is not related to change in BMD.
J Bone Miner Res Off J Am Soc Bone Miner Res.2005 Dec; 20: 2097-2104
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