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Effect of osteoporosis medications on vascular and valvular calcification: a systematic review and meta-analysis
Open Access
07.04.2025
Review
Erschienen in:
Verfasst von
Hui Zhen Lo
Hui Zhen Lo
Peninsula Health, 3199, Frankston, Australia
Kevin Leow
Kevin Leow
Department of Cardiology, Canberra Hospital, 2605, Garran, Australia
Rachael Hii
Rachael Hii
Department of Medicine, Monash Health, 3168, Clayton, Australia
Nitesh Nerlekar
Nitesh Nerlekar
Department of Medicine, Monash Health, 3168, Clayton, Australia
Department of Medicine, School of Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, 3168, Clayton, Australia
Monash Cardiovascular Research Centre, Monash University and Monash Heart, 3168, Clayton, Australia
Peter R. Ebeling
Peter R. Ebeling
Department of Medicine, School of Clinical Sciences, Faculty of Medicine, Nursing and Health Sciences, Monash University, 3168, Clayton, Australia
Alexander J. Rodríguez
Korrespondierender Autor
Alexander J. Rodríguez
Department of Medicine, School of Clinical Sciences at Monash Health, Bone and Muscle Health Research Group, Monash University, 3168, Clayton, Australia
Vascular calcification shares many features with skeletal mineralisation and shares an inverse relationship with osteoporosis (skeletal de-mineralisation). However, medications that reduce bone loss (anti-resorptives) have had inconsistent effects on extra-skeletal mineralisation (i.e. vascular and valvular calcification). As such, this paper aims to synthesise existing literature examining the effect of anti-resorptive treatments on extra-skeletal (vascular and valvular) calcification across populations.
Methods
Medline and Embase were searched (inception to October 2024) for studies that assessed the association between anti-resorptive medication use and vascular/valvular calcification. Pooled standardised mean differences (SMDs) with 95% confidence intervals (CI) were calculated for all outcomes, using random-effects model. Leave-one-out sensitivity analyses were performed for internal validity.
Results
Of 4071 articles screened, 33 were included in the review, and 15 (2344 participants) had data available for meta-analysis. Anti-resorptive use was associated with non-significant, small magnitude improvements in abdominal aortic calcification (decreased value), coronary artery calcification (decreased value) and ejection fraction (increased value) but significant small reduction in aortic valve area (representing less calcification on the valve) with standardised mean difference of − 0.45 (95% confidence interval (CI) − 0.99; 0.08, I2 = 84%), − 1.19 (95% CI − 2.92; 0.55, I2 = 91%), − 0.67 (95% CI − 1.72; 0.38, I2 = 94%), 0.26 (95% CI − 0.14; 0.66, I2 = 62%) and 0.56 (95% CI 0.07; 1.06, I2 = 76%), respectively.
Conclusion
The significance of small positive effect of anti-resorptives on aortic stenosis is clinically uncertain. Despite strong biological links between vascular calcification and skeletal mineralisation, anti-resorptives do not appear to have a strong favourable influence on extra-skeletal mineralisation. This suggests that mechanisms that link vascular calcification with osteoporosis may be acting in pathways not influenced by anti-resorptives.
Summary
This systematic review and meta-analysis summarises the effect of anti-resorptives on vascular and valvular calcification. There is a small, positive effect of anti-resorptives on aortic stenosis, though this is of uncertain clinical importance.
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SMD
Standardised mean difference
CI
Confidence interval
CVD
Cardiovascular disease
AAC
Abdominal aorta calcification
BMD
Bone mineral density
CKD
Chronic kidney disease
PRISMA
Preferred Reporting Items for Systematic Reviews and Meta-analyses
BMI
Basal metabolic index
BP
Blood pressure
DM
Diabetes mellitus
HF
Heart failure
HTN
Hypertension
AMI
Acute myocardial infarction
TIA
Transient ischaemic attack
ACEi
Angiotensin-converting enzyme inhibitor
ARB
Angiotensin receptor blocker
CAC
Coronary artery calcification
AVA
Aortic valve area
EF
Ejection fraction
IMT
Intima-media thickness
AS
Aortic stenosis
Introduction
Cardiovascular disease (CVD) and osteoporosis share many risk factors such as ageing, smoking, unhealthy diet (high sugar, high saturated fat, low protein), low levels of exercise and increased weight leading to speculation for common causative pathways [1]. One of the most frequently described links between CVD and osteoporosis is vascular calcification. Indeed, there is a strong inverse relationship between vascular calcification and bone mineral density (BMD). For example, calcification in the abdominal aorta (AAC) is associated with reduced BMD at various clinically relevant sites, and increased fracture risk at multiple clinically relevant sites [2]. The biological mechanism that drives vascular calcification is reminiscent of mineralisation of the skeleton involving calcium deposition by vascular smooth muscle cells that have undergone cellular transdifferentiation and appear phenotypically as osteoblast-like cells [3]. Given that osteoporosis treatments target well-described key drivers of bone loss, it has thus been speculated that these same treatments could favourably influence the incidence and progression of extra-skeletal mineralisation. Specifically, osteoporosis treatment targets osteoclast action (these would include the anti-resorptive agents—bisphosphonates, which mediate osteoclasts apoptosis; denosumab which is a monoclonal antibody against RANKL that inhibits bone resorption and osteoclast activity via the RANK/RANKL pathway), and osteoblast action (teriparatide is a parathyroid hormone (PTH) analogue that upregulates osteoblastogenic growth factors; romosozumab is a monoclonal antibody sclerostin antagonist that works to promote osteoblast production) [4‐6]. To this end, several studies have explored the hypothesis that osteoporosis treatments could influence extra-skeletal mineralisation, albeit with heterogeneous responses [1, 7]. Much of the literature in this area has been directed towards understanding pathogenesis and treatment options in patient with chronic kidney disease (CKD). This is understandable given the burden of extra-skeletal calcification in this patient group, owing to the underlying bone and mineral disturbance from their CKD. Given that renal bone disease has its own distinct pathophysiology, there is a need to understand the overall effect of anti-osteoporosis medications in all patient groups, whose underlying bone and mineral pathophysiology could be reversed by available anti-osteoporosis treatments. A recent meta-analysis attempted to address this topic but was limited in its scope of included trials. This meta-analysis only included two trials with anti-resorptive agents which showed mixed results [8]. Another systematic review focused solely on the effect of anti-osteoporotic medications on coronary artery calcification (CAC) only and did not investigate other forms of vascular calcification and as such this study is limited by assessing only one calcification outcome [9]. Their review which included four observational studies and one randomised controlled trial (RCT) with a total of 377 patients also showed mixed results. Furthermore, very little attention is given to valvular calcification with respect to understanding extra-skeletal mineralisation in osteoporosis, despite several observational studies demonstrating potential for slower progression of valvular calcification in patients receiving anti-resorptive medications [10, 11]. It has been hypothesised that the pathophysiology behind valvular and vascular calcification belong to the same causal pathway, and for this reason, there is a need to systematically and comprehensively examine the evidence for anti-resorptive medications on extra-skeletal (valvular and vascular) calcification across indications. Therefore, we aimed to synthesise existing literature examining the effect of anti-resorptive medications on the calcification process on valves and arteries, at clinically actionable sites, in any population.
Materials and methods
Data sources and searches
We searched two databases (Medline and Embase) from inception to 15 October 2024 for relevant papers. There were no language restrictions. Studies were identified using the search strategy detailed in Supplementary Table 1. Records were then stored using a citation manager and duplicates were removed. All titles and abstracts were screened before evaluating the eligibility of the full texts. Manual screening of cited references of eligible texts and online related article lists were also done to identify publications that were potentially relevant.
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Study selection
This systematic review and meta-analysis was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement, and it is registered with PROSPERO (CRD42024518650) [12]. We included studies that specifically reported any of the following outcomes: incidence and/or progression of vascular calcification (at any site) or incidence and/or progression of (any) valvular calcification (including any echocardiographic measure of such) or progression of ejection fraction. Studies were included if the trial was randomised or a controlled prospective cohort study and provided any of the above outcomes. Specific exclusion criteria included non-controlled studies, systematic reviews, reviews, conference abstracts, letters, case reports and animal or cell-based studies.
Data extraction and quality assessment
Data was extracted by a single reviewer (HZL) using a data extraction form and was checked for accuracy by another reviewer (AJR). We obtained data on the total number of enrolled patients, treatment used; comparator used; patient demographics (age, sex, basal metabolic index (BMI), blood pressure (BP), alcoholic, smoking status); medical conditions (diabetes mellitus (DM), hypertension (HTN), hyperlipidaemia, coronary artery disease, peripheral artery disease, heart failure (HF), CKD, osteoporosis, chronic liver disease, previous aortic stenosis, previous acute myocardial infarction (AMI), previous percutaneous coronary intervention, previous coronary artery bypass graft, previous stroke/transient ischaemic attack (TIA) and malignancy); medications (statins, angiotensin-converting enzyme inhibitor (ACEi)/angiotensin receptor blocker (ARB), steroids, vitamin D, calcium, phosphate binder) and osteoporotic features (baseline vertebral BMD, baseline lumbar spine BMD, baseline femoral neck BMD, previous vertebral fracture); and outcomes of interest with units of measurable change (AAC volume, CAC volume and Hu, aortic valve area and ejection fraction). Potentially relevant but missing data was sought directly from study authors via email.
Two independent reviewers (HZL and AJR) used the Cochrane Collaboration risk-of-bias tool for randomised trials to assess risk of bias [13]. This tool evaluates bias across seven domains: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective reporting and other bias (e.g. representativeness). A judgement of low, unclear or high risk of bias was made for each domain. An overall risk of bias per study was evaluated based on the following criteria: low—all domains low; low/unclear—all domains low except for one that was unclear; unclear—greater or equal to two unclear domains; high—any domain was high. The Newcastle–Ottawa Scale was used to assess risk of bias in cohort studies [14]. This scale evaluates bias across three broad domains: selection of cohorts, comparability of cohorts and the assessment of outcome of the studies. A judgement of overall good, fair or poor quality was determined for each study according to the ‘star system’. Good-quality studies were evaluated as having three or four stars in the selection domain and one or two stars in the comparability domain and two or three stars in the outcome domain. Fair quality studies were evaluated as having two stars in the selection domain and one or two stars in the comparability domain and two or three stars in the outcome domain. Poor-quality studies were evaluated as having zero or one star in the selection domain or zero stars in the comparability domain or zero or one stars in the outcome domain. For studies where there were inconsistencies between the reviewers regarding the overall risk of bias, a consensus meeting was held to resolve disagreements.
Data synthesis and analysis
Studies were suitable for meta-analysis if they initially satisfied the inclusion–exclusion criteria and reported at least one outcome of interest. Analyses were performed separately by outcome of interest. We meta-analysed data for outcomes that were reported in at least three studies. Data was pooled together in an inverse-variance model assuming random-effects (and fixed/common effects reported for completeness) where a standardised mean difference (SMD) for the overall effect estimate was obtained together with the 95% confidence interval (95% CI). For studies which examined at different anti-resorptive treatments (for example using a bisphosphonate and using denosumab), where pooled results were not provided, we reported our analysis using both treatments in separate analyses. This was done for Geers et al. (2024) where the authors looked at treatment with denosumab or alendronate and so we reported our analysis first using the denosumab data and then again using the alendronate data [15]. Heterogeneity was evaluated by calculating the tau2 statistic (an estimate of the between-study variance) and the proportion of total variability due to between-study heterogeneity was evaluated by the I2 statistic. All data were computed using the meta package in R (version 4.1.3). For assessment of internal validity, a leave-one-out sensitivity analysis was performed for each analysis. Finally, assessment of publication bias was done by visual inspection of a funnel plot. In certain instances, key data such as a standard deviation or error was not reported in published papers. An example of this is Hill et al. (2002) where change in coronary artery calcification (CAC) volume was recorded but the variation for the mean effect was not [16]. In such instances, these data were sought directly from authors, where no timely response was forthcoming (2-week response deadline given); the missing data was imputed from the linear prediction of a model including study mean and populations, in an effort to include as much known literature as possible to minimise publication bias (i.e. avoid exclusion of a known publication).
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Results
Literature search
The literature search yielded 6373 results, and 2302 duplicates were removed, leaving 4071 records for title and abstract screening. Reports were excluded due to being irrelevant (n = 3914), no full text (n = 35), non-human studies (n = 42), ineligible study design (n = 47) and case reports (n = 6). Additional hand searching found another six eligible articles. Overall, 33 studies [11, 15‐46] were included in the qualitative analysis (Fig. 1).
There were no restrictions to the population and we collected data on studies that included any patients (general population/community dwelling older adults) (n = 29), patients with osteoporosis (n = 6), patients on haemodialysis (n = 8), patients on post-menopausal (n = 8), patients with aortic stenosis (n = 4), patients with type 2 DM (n = 2), patients with CKD (n = 2), patients at high risk for atherosclerotic aortic plaques (n = 1), patients on bisphosphonate therapy (n = 1), patients with pseudoxanthoma elasticum (n = 2), patients with secondary hyperparathyroidism (n = 2) and patients with AMI (n = 1). Twelve studies used alendronate, eight studies used etidronate, eight studies used denosumab, three studies used ibandronate, three studies used zoledronate, two studies used risedronate, one study used calcitonin and one study used teriparatide (Table 1).
Table 1
Literature summary
Characteristics
All studies, n
Studies included in meta-analysis, n
Year of publication
Pre-2010
12
5
2010–2016
8
3
2017–2024
13
7
Setting
Any
1
0
Osteoporosis
6
4
Haemodialysis
8
5
Post-menopausal
7
2
Aortic stenosis
4
4
T2DM
2
1
CKD
1
0
Bisphosphonate therapy
1
0
Hypercholesterolaemia
1
0
Kidney transplant recipients
2
1
Pseudoxanthoma elasticum
2
1
Secondary hyperparathyroidism
2
2
Incident AMI
1
0
Region
North America
6
4
Europe
11
3
Asia
14
8
Oceania
2
0
Number of patients
< 100
22
11
> 100
11
4
Study design
Cohort
19
10
Case control
1
0
RCT
13
5
AMI acute myocardial infarction, CKD chronic kidney disease, RCT randomised controlled trial, T2DM type 2 diabetes mellitus
Ten studies were conducted in the United States of America (USA), seven in Japan, two in Australia, two in Netherlands, two in Spain, one in Denmark, one in Italy, two in Taiwan, one in Iran, two in the UK and one in Turkey. The smallest study included 12 patients [19] and the largest study included 141,202 patients [35]. Follow-up time varied between a minimum of 1 month and a maximum of 3.9 years (Table 2).
Table 2
Study demographics
Authors, country, year
Study type
Mean time period of study
Treatment group (size/age/female %/smoker %)
Comparator group (size/age/female %/smoker %)
Population
Treatment
Comparison
Outcomes
Major finding
Hill et. al, USA, 2002
Observational study
24.1 months
56/62.0/NR/NR
56/60.0/NR/NR
Osteoporotic
Alendronate
No treatment
CAC progression—volume (change in score per month), Hu (change in score per month)
No difference in CAC progression with alendronate or control group
Denosumab or alendronate are not associated with CAC or aortic calcification progression
Chen et. al, Taiwan, 2024
Observational study
6 months
24/59.4/83/NR
21/54.8/57/NR
Haemodialysis and secondary hyperparathyroidism
Denosumab
No treatment
CAC progression—volume (mm3), Hu
Less progression in CAC with denosumab
AAC abdominal aortic calcification, AMI acute myocardial infarction, AVA aortic valve area, AVC aortic valve calcification, AVRC aortic valve ring calcification, CAC coronary artery calcification, IMT intima-media thickness, MAC mitral annulus calcification, NR not reported, RCT randomised controlled trial, TAC thoracic aorta calcification
Literature quality
Cohort studies were rated as good/good (n = 9), good/fair (n = 3), fair/fair (n = 5) or fair/poor (n = 1) quality by both reviewers (Supplementary Table 2). A case control study included was rated as good by both reviewers (n = 1) (Supplementary Table 3). RCTs were rated as low/low (n = 2), low/low-unclear (n = 5), low-unclear/low-unclear (n = 2) and low/high (n = 4) risk of bias by both reviewers (Supplementary Table 4). There was some publication bias as visualised in the funnel plots (Supplementary Figs. 1–6).
Background of skeletal risk
Table 3 provides a summary of patient characteristics in terms of their background skeletal risk (baseline vertebral BMD (n = 6), lumbar spine BMD (n = 9), femoral neck BMD (n = 9), previous vertebral fracture (n = 2), vitamin D intake (n = 8), calcium intake (n = 11) and phosphate binder intake (n = 5)).
BMD bone mineral density, IV intravenous, NR not reported
Background of cardiovascular risk
Table 4 provides a summary of patient characteristics in terms of their cardiovascular risk (DM (n = 19), HTN (n = 12), hyperlipidaemia (n = 5), HF (n = 2), CKD (n = 10), osteoporosis (n = 9), previous MI (n = 2), previous stroke or TIA (n = 3)).
Table 4
Background of cardiovascular risk
Authors, country, year
DM (treatment/control)
HTN (treatment/control)
HLD (treatment/control)
HF (treatment/control)
CKD (treatment/control)
Osteoporosis (treatment/control)
Previous MI (treatment/control)
Previous stroke or TIA (treatment/control)
Hill et. al, USA, 2002
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
56/56
NR/NR
NR/NR
Nitta et. al, Japan, 2004
8/NR
NR/NR
NR/NR
NR/NR
NR/NR
35/NR
NR/NR
NR/NR
Tanko et. al, Denmark, 2005
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
263/NR
NR/NR
NR/NR
Ariyoshi et. al, Japan 2006
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
6/NR
NR/NR
NR/NR
Skolnick et. al, USA, 2009
5/8
18/33
NR/NR
NR/NR
NR/NR
18/6
NR/NR
NR/NR
Innasimuthu et. al, USA, 2009
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
8/NR
NR/NR
NR/NR
Elmariah et. al, USA, 2009
20(9)/461(13)
80(37)/1449(41)
100(47)/1432(41)
NR/NR
NR/NR
214/NR
NR/NR
NR/NR
Kanazawa et. al, Japan, 2010
13/13
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Toussaint et. al, Australia, 2010
14/15
23/25
NR/NR
NR/NR
25/25
NR/NR
NR/NR
NR/NR
Aksoy et. al, USA, 2012
34(16)/30(14)
98(45)/97(44)
74(34)/7(32)
NR/NR
5(2.3)/5(2.3)
NR/NR
NR/NR
NR/NR
Kawahara et. al, Japan, 2013
26/atorvastatin: 26
Combination: 26
10/atorvastatin: 11
Combination: 9
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Samelson et. al, USA, 2014
217(25.7)/203 (26.0)
692(82.1)/652 (83.4)
542(64.3)/525 (67.1)
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Okamoto et. al, Japan, 2014
2/3
4/5
NR/NR
NR/NR
5/7
NR/NR
NR/NR
NR/NR
Kranenburg et. al, Netherlands, 2018
NR/NR
NR/NR
NR/NR
NR/NR
0/0
NR/NR
Treatment: 113 (13.4)
Control: 94 (12.0)/
Treatment: 113 (13.4)
Control: 94 (12.0)
NR/NR
Iseri et. al, Japan, 2019
Denosumab: 20
Alendronate: 9/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Passeri et. al, Italy, 2019
NR/NR
Zoledronate: 5
Teriparatide: 6/5
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Chen et. al, Taiwan, 2020
3/2
19/20
NR/NR
NR/NR
21/21
NR/NR
NR/NR
NR/NR
Alishiri et. al, Iran, 2020
10/10
NR/NR
NR/NR
0/0
NR/NR
37/33
NR/NR
NR/NR
Cai et. al, Australia, 2020
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Bartstra et. al, Netherlands, 2020
NR/NR
NR/NR
NR/NR
NR/NR
0/0
NR/NR
NR/NR
NR/NR
Mazzucchelli et. al, Spain, 2020
6398/19,460
12,157/50,503
11,045/41,217
876/2967
900/2817
NR/NR
NR/NR
1574/6171
Suzuki et. al, Japan, 2021
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Pawade et. al, United Kingdom, 2021
Denosumab: 12
Alendronate: 11/12
Denosumab: 35
Alendronate: 38/41
Denosumab: 34
Alendronate: 22/35
NR/NR
Denosumab: 6
Alendronate: 4/2
0/0
NR/NR
Denosumab: 9
Alendronate: 5/6
Saito et. al, Japan, 2022
6/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Koshiyama et. al, Japan, 2000
57/57
28/25
NR/NR
NR/NR
NR/NR
NR/NR
Denosumab: 8
Alendronate: 5/4
3/5
Delibasi et. al, Turkey, 2007
0/NR
NR/NR
NR/NR
NR/NR
0/NR
NR/NR
NR/NR
NR/NR
Hashiba et. al, Japan, 2006
3/2
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Torregrosa et. al, Spain, 2010
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Hashiba et. al, Japan, 2004
3/4
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Celiloglu et. al, Turkey, 2008
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Gonnelli et. al, Italy, 2013
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
NR/NR
Geers et. al, United Kingdom, 2024
Denosumab: 12
Alendronate: 11/12
Denosumab: 35
Alendronate: 38/41
Denosumab: 34
Alendronate: 22/35
NR/NR
Denosumab: 6
Alendronate: 4/2
0/0
NR/NR
Denosumab: 9
Alendronate: 5/6
Chen et. al, Taiwan, 2024
NR/NR
NR/NR
NR/NR
NR/NR
24/21
NR/NR
NR/NR
NR/NR
CKD chronic kidney disease, DM diabetes mellitus, HF heart failure, HLD hyperlipidaemia, HTN hypertension, MI myocardial infarction, NR not reported, TIA transient ischaemic attack
Outcomes of interest
Data were collected from 33 studies. Seven studies reported CAC; eight studies reported AAC; one study reported common carotid artery calcification; two studies reported mitral annulus calcification; one study reported iliac arteries calcification; one study reported lower limb arterial calcification; one study reported femoral artery calcification; one study reported total arterial calcification; nineteen reported aortic calcification (any site); five studies reported aortic valve area (AVA) (Table 2). Three studies reported ejection fraction (EF). EF is not strictly a marker of vascular/valvular calcification; we reasoned that EF would be influenced by valvular and vascular calcification and is included as an exploratory, hypothesis generating endpoint. Of interest, six studies reported on carotid intima-media thickness (IMT), but, as this represents atherosclerotic plaque not necessarily calcified, we chose to not analyse these data. Furthermore, as there was not a specific search term for IMT, we also cannot be certain that we have captured all literature reporting on osteoporosis medications and IMT.
Major findings from the included studies are described in Table 2. Etidronate resulted in less progression in coronary artery, femoral artery, thoracic and abdominal aortic calcification in seven studies [17, 19, 26, 29, 34, 41, 43]. Alendronate resulted in less progression in AAC and aortic stenosis in two studies [11, 28], and no difference in progression of CAC, aortic calcification and aortic stenosis in five studies [15, 16, 24, 30, 37]. Ibandronate resulted in no difference in AAC progression in one study [18]. Risedronate resulted in less progression in AAC and vascular calcification in two studies [23, 42]. Denosumab resulted in less progression in CAC and AAC in three studies [32, 35, 46], and no difference in AAC, aortic stenosis and CAC progression in three studies [15, 27, 37]. Zoledronate resulted in no difference in AAC progression in one study [33].
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Meta-analysis
Fifteen studies, including a total of 2344 patients, had data available for meta-analysis (Fig. 2A–E). Specifically, studies that reported aortic calcification (any site) were not able to be analysed as varying units of measurements were used, for example, reporting on a percentage of the cohort that experience regression/progression of calcification as opposed to some measure of change in calcification. Therefore, we focused our analysis on outcomes for which units of measurable change were reported for a more targeted and clinically relevant analysis. Other studies not included were due to a lack of control group or specific results that were required for analysis. Parameters like mitral annular calcification and pulse wave velocity were unable to be analysed due to a lack of sufficient data.
Fig. 2
A Forest plot of standardised mean difference for change in abdominal aortic calcification (AAC) and coronary artery calcification (volume) (CAC-volume). B Forest plot of standardised mean difference for change in abdominal aortic calcification (AAC) and coronary artery calcification (volume) (CAC-volume) in patients on etidronate. C Forest plot of standardised mean difference for change in abdominal aortic calcification (AAC) and coronary artery calcification (volume) (CAC-volume) in patients on haemodialysis. D Forest plot of standardised mean difference for change in coronary artery calcification (Hu) (Geers et al. (denosumab users)) and coronary artery calcification (Hu) (Geers et al. (alendronate users)). E Forest plot of standardised mean difference for change in aortic valve area/aortic stenosis (AVA-AS) and change in ejection fraction (EF)
Six studies, including 1815 patients, reported on change in AAC as an outcome of anti-resorptive therapy [23, 27, 28, 34, 36, 41]. Suzuki included patients on haemodialysis and treated them with denosumab; Hashiba included patients on haemodialysis and treated them with etidronate; Bartstra included patients with pseudoxanthoma elasticum and treated them with etidronate; Okamoto included patients with kidney transplant and treated them with denosumab; Samelson included post-menopausal and osteoporotic patients and treated them with denosumab as a secondary analysis of a larger fracture reduction trial; Kanazawa included patients who were post-menopausal, were osteoporotic and had type 2 diabetes mellitus. When pooled together, the rates of AAC progression were similar (SMD = − 0.45 [95% confidence interval − 0.99 to 0.08, tau2 = 0.33; n = 935; I2 = 84%; Fig. 2A]), where SMD represents the difference in the change in vascular outcome (AAC) between treatment and control groups. Focusing specifically on patients on etidronate, four studies with a total of 1721 patients studied the effects of etidronate on change in AAC [23, 27, 28, 36]. When pooled together, the rates of AAC progression were similar (SMD = − 0.41 [95% confidence interval − 1.24 to 0.41, tau2 = 0.58, n = 889; I2 = 89%; Fig. 2B]). Focusing specifically on haemodialysis patients, four studies with a total of 1736 patients, studied the effects of haemodialysis on change in AAC [23, 27, 28, 34]. When pooled together, the rates of AAC progression were similar (SMD = − 0.08 [95% confidence interval 0.31 to 0.16, tau2 = 0.019, n = 898; I2 = 2%; Fig. 2C]).
Coronary artery calcification (volume)
Four studies, including 239 patients, reported on change in volume of CAC (CAC-volume) as an outcome of anti-resorptive therapy [16, 19, 32, 34]. Chen included patients who were on haemodialysis and had secondary hyperparathyroidism and treated them with denosumab; Hill included osteoporotic patients and treated them with alendronate; Ariyoshi included patients on haemodialysis and treated them with etidronate; Bartstra included patients with pseudoxanthoma elasticum and treated them with etidronate. When pooled together, the rates of CAC-volume progression were similar (SMD = − 1.19 [95% confidence interval − 2.92 to 0.55, tau2 = 2.96; n = 120; I2 = 91%; Fig. 2A]), where SMD represents the difference in the change in vascular outcome (CAC-volume) between treatment and control groups. Focusing specifically on patients on etidronate, two studies with a total of 154 patients studied the effects of etidronate on change in CAC (CAC-volume) [16, 32]. When pooled together, the rates of CAC-volume progression were similar (SMD = − 2.34 [95% confidence interval − 5.26 to 0.58, tau2 = 4.27, n = 77; I2 = 96%; Fig. 2B]). Focusing specifically on haemodialysis patients, four studies with a total of 185 patients studied the effects of haemodialysis on change in CAC (CAC-volume) [16, 34]. When pooled together, the rates of CAC-volume progression were similar (SMD = − 0.46 [95% confidence interval − 1.33 to 0.42, tau2 = 0.0.35, n = 93; I2 = 88%; Fig. 2C]).
Coronary artery calcification (Hu)
Three studies, including 218 patients, reported on change in volume of CAC (CAC-Hu) as an outcome of anti-resorptive therapy [15, 16, 46]. Chen included patients who were on haemodialysis and had secondary hyperparathyroidism and treated them with denosumab; Hill included osteoporotic patients and treated them with alendronate; Geers included patients with aortic stenosis and treated them with either denosumab or alendronate. When pooled together, the rates of CAC-Hu progression were similar (when including those treated with denosumab in Geers et al.) (SMD = − 0.28 [95% confidence interval − 2.09 to 1.53, tau2 = 2.48; n = 112; I2 = 97%; Fig. 2D]) and CAC-Hu (when including those treated with alendronate in Geers et al.) (SMD = − 0.67 [95% confidence interval − 1.72 to 0.38, tau2 = 0.784; n = 104; I2 = 94%; Fig. 2D]), where SMD represents the difference in the change in vascular outcome (CAC-Hu) between treatment and control groups.
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Aortic valve area (aortic stenosis)
Four studies, including 353 patients, reported on change in aortic valve area or aortic stenosis (AVA-AS) as an outcome of anti-resorptive therapy [11, 20, 21, 37]. Skolnick had no specific exclusion criteria for the population and treated the patients with bisphosphonates, calcitonin or selective oestrogen receptor modulators; Pawade included patients with aortic stenosis and treated them with denosumab or alendronate, but helpfully provided data for ‘any antiresorptive use’; Alishiri included patients with aortic stenosis and osteoporosis and treated them with alendronate; Innasimuthu included patients with aortic stenosis and treated them with alendronate or risedronate. When pooled together, there was a significant small increase in AVA-AS (SMD = 0.56 [95% confidence interval 0.07 to 1.06, tau2 = 0.18; n = 165; I2 = 76%; Fig. 2E]), where SMD represents the difference in the change in vascular outcome (AVA-AS) between treatment and control groups. This means that the rate of progression in stenosis was marginally slower in those on anti-resorptives.
Ejection fraction
Three studies, including 201 patients, reported on percentage change in EF as an outcome of anti-resorptive therapy [11, 20, 21]. Skolnick had no specific exclusion criteria for the population and treated the patients with bisphosphonates, calcitonin or selective oestrogen receptor modulators; Innasimuthu included patients with aortic stenosis and treated them with alendronate or risedronate; Alishiri included patients with aortic stenosis and osteoporosis and treated them with alendronate. When pooled together, there was no increase in EF (SMD = 0.26 [95% confidence interval − 0.14 to 0.66, tau2 = 0.038; n = 63; I2 = 62%; Fig. 2E]).
Sensitivity analysis
To account for clinical heterogeneity (e.g. study populations and interventions trialled), a leave-one-out sensitivity analysis was conducted for the above outcomes (Supplementary Table 5). Exclusion of Samelson only resulted in an overall significant reduction in AAC. Exclusion of any study except Hill resulted in an overall significant reduction in CAC-volume. Exclusion of any study except Hill resulted in an overall significant reduction in CAC-Hu (Geers et al. (denosumab users) and Geers et al. (alendronate users)) and overall significant increase in AVA-AS. Exclusion of Skolnick only resulted in an overall significant increase in EF.
Discussion
In this systematic review and meta-analysis, we attempted to evaluate whether anti-resorptive medications could influence the incidence or progression of various measures of vascular and valvular calcification. We demonstrated that there was significant, small favourable effect on AVA and non-significant, small favourable effects on AAC, CAC (volume), CAC (Hu) and EF associated with anti-resorptive use. A recent review also concluded that there is currently insufficient evidence to support the correlation between anti-resorptive use and CAC which we have again demonstrated but have extended on these previous findings by quantifying the putative association and inclusion of a broader range of indications to explore whether specific indications influence the overall outcome [9]. Taken together, these results indicate that the putative mechanisms that have been hypothesised to link vascular calcification with osteoporosis may be acting in pathways not influenced by anti-resorptives. Therefore, it could be speculated that interventions that target the shared causative pathways of both osteoporosis and vascular calcification (such as smoking, inflammation) may be more likely to yield favourable effects on both outcomes. While there is a small magnitude positive effect of anti-resorptive use on aortic stenosis, the clinical significance is still uncertain.
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It should be noted that we did demonstrate small, significant favourable effects on AVA and small, non-significant favourable effects on AAC, CAC (volume), CAC (Hu) and EF. The small number of studies and patients enrolled in the included studies possibly account for the weak findings and one may speculate that inclusion of further and larger trials may alter outcomes and thus further research is warranted to explore this possibility.
In the case of bisphosphonates (which accounts for the majority of included trials), there is plausible biological evidence for them having favourable effects on vascular calcification. Bisphosphonates inhibit the farnesyl pyrophosphate synthase enzyme which acts downstream of HMG-CoA reductase in the malonate pathway of cholesterol synthesis [47]. Statins (inhibitors of HMG-CoA reductase) have well described effects on reducing plaque burden and clinical outcomes; thus, it is assumed that bisphosphonates would deliver similar benefit. Indeed, a secondary analysis of a large fracture reduction trial demonstrated reduced myocardial infarction mortality in those treated with zoledronate [48]. However, the results of our meta-analysis and previous meta-analysis of statins on calcification outcomes do not support this as the mechanism [49‐51]. We observed a subtle difference in the effect of anti-resorptives on CAC versus AAC, where the effect was more pronounced in CAC. This could possibly reflect a small study effect (epiphenomenon). However, further analysis was done focusing on the effect of etidronate also showed a more positive effect in CAC. As etidronate is a non-nitrogen-containing-bisphosphonate, the main mode of action is slightly different—interfere with the mitochondrial adenosine diphosphate (ADP)/adenosine triphosphate (ATP) translocase [52]. However, during the process, it binds to hydroxyapatite crystals which helps in ectopic mineralisation that potentially reducing vascular and valvular calcification [34]. It has also been shown to reduce arterial calcification in patients with pseudoxanthoma elasticum [34, 53]. Furthermore, in a trial examining etidronate in thoracic and abdominal plaques, there appeared to be differential effects of the bisphosphonate on these sites [26]. Etidronate appeared to reduce abdominal plaques (distal vessel) but have little impact on thoracic plaques (proximal). We speculate that a similar phenomenon may be occurring, albeit with the associations reversed. That is to say, more proximal vessels such as the coronary vessels are being favourably altered, while the distal vessels such as the abdominal aorta are not. This could be related to the different vessel architecture/cellular constituents between the aorta and the coronaries and how bisphosphonates interact with them [54]. A separate analysis was also done to look at the effects of anti-resorptives on patients undergoing haemodialysis considering the extra-skeletal burden in CKD patients. Though insignificant, CAC was more favourable to anti-resorptives compared to AAC.
We demonstrated small, non-significant effects on EF. EF is not a direct marker of vascular/valvular calcification but was included as an exploratory, hypothesis-generating endpoint as the calcific burden on valvular or coronary structures would negatively impact EF. Analysis of effects of anti-osteoporosis medications on ejection fraction is included opportunistically in the setting of our primary aim. We hypothesise that peripheral vascular calcification (e.g. AAC) would affect total peripheral resistance, augmenting afterload which may promote ventricular remodelling, ultimately resulting in dilated cardiomyopathy. As such, EF may be preserved in this instance, but may predispose to declines in EF in untreated disease (such as advancing atherosclerotic disease). Hence, any small effect of anti-resorptives on EF may thus be reflective of an overall mixed effect of differing homeostatic forces. There might be a small reduction in total peripheral vascular resistance that would occur from a reduced peripheral vascular calcification burden together with a preserved EF due to left ventricular hypertrophy and improved myocardial perfusion from reduced coronary calcification burden. It should be noted, however, that heart failure and ejection fraction itself have multiple aetiologies and contributing factors and this may account for why no meaningful change in response to anti-resorptive treatment (assumed to the reduce calcification) was observed.
Our study also demonstrated small, significant favourable effects on change in aortic stenosis (there was a slower progression of valvular disease in patients on anti-resorptives compared with those who were not), but the clinical significance is uncertain. This reflects the possibility that anti-resorptives act on the same pathway and have the same effect on valvular and vascular calcification. Previous animal studies also showed that bisphosphonates were able to inhibit vascular and valvular calcification [55]. Interestingly, there is a recent case report of an older osteoporotic women experiencing rapid progression of previously very stable aortic stenosis after commencing an anabolic agent (a parathyroid hormone analogue), suggestive of direct mineral metabolism effect on the pathophysiology of valvular calcification [56]. PTH results in increased renin secretion, reactive-oxygen species production and endothelin levels which could all result in hypertension and induce valvular stiffening, contributing to valvular calcification [57].
Previous meta-analyses on this topic had showed differing findings. Meta-analyses in 2016 and 2017 demonstrated that bisphosphonates were able to reduce arterial wall calcification. Kranenburg further found that bisphosphonates were also able to reduce the risk of cardiovascular mortality and all-cause mortality [58, 59]. In our meta-analysis, we revealed that anti-resorptive therapy provided significant, small favourable effects on AVA and non-significant, small favourable effects on AAC, CAC (volume), CAC (Hu) and EF. This contrasts with the meta-analyses mentioned. More clinical trials with a long follow-up period need to be conducted to reasonably conclude the role of anti-resorptive therapy in vascular calcification—further understanding the relationship between anti-resorptive therapy and valvular/vascular calcification may allow clinicians to better tailor osteoporosis therapies to individual patient risk factors and comorbidities, particularly those pertaining to valvular/vascular calcification.
While our review focused mainly on anti-resorptive medications, there has been ongoing discussions about the utility of vitamin D and its role in vascular calcification. In fact, vitamin D and CVDs have a U-shaped association between them [60, 61]. With insufficient vitamin D, it triggers a pro-inflammatory reaction which causes stress on the endothelium, leading to calcification or through inhibition of vascular smooth muscle cell (VSMC) into osteoclast-like cells [60, 61]. Excessive vitamin D instead causes calcification through differentiation of VSMC into osteoblast-like cells or with concomitant increases in calcium and phosphate [60, 61]. Hence, the biphasic actions of vitamin D make it especially vital to ensure patients have a healthy level of vitamin D to prevent vascular calcification and CVDs.
Our study has some limitations. Despite inclusion of many studies (33), only 15 of the papers had data included in the final meta-analysis totalling 2344 patients. Therefore, there is potentially a large amount of un-analysed, already published data and so overall findings are incomplete from this perspective. We urge and encourage custodians of these data to consider reporting on these outcomes. Also, the relatively small sample size of our data analysis may not be entirely reflective of the total population using anti-resorptives that may be at risk of vascular/valvular calcification. The wide confidence intervals of our results confirm this probable data limitation. In addition, as we placed no restrictions on study populations, our study extracted data from a heterogeneous cohorts (for example, pseudoxanthoma elasticum). This could potentially skew our dataset as different populations could have different risk factors that put them at increased risk of osteoporosis or valvular/vascular calcification or indeed have differing responses to anti-resorptives. However, we believe that inclusion of this diversity of cohorts only serves to increase the generalisability of our findings. Another further limitation was the heterogeneity of outcomes included. As there are few studies published that directly address the topic of anti-resorptive effects on valvular/vascular calcification in randomised settings, we collected a variety of outcomes that could be considered subclinical markers of valvular/vascular calcification in an effort to collect as much relevant data as possible. Random effects models were employed in an attempt to overcome this heterogeneity which generates conservative estimates. Some of the data collected were used for secondary analyses to affirm the primary outcomes that were statistically significant. For instance, EF was reported as an exploratory endpoint which had a non-significant small increase. This may be due to the vastly differing aetiologies of heart failure that are not directly related to extra skeletal calcification. There was also substantial heterogeneity in the outcomes for and changes in AAC, CAC (volume), CAC-Hu (Geers et al. (denosumab users) and Geers et al. (alendronate users)) and AVA (tau2 = 0.33, 2.96, 2.49, 0.784 and 0.18, respectively). We also performed leave-one-out sensitivity analyses to explore small study effects and indication specific effects. Furthermore, some of the published papers had missing data that we were unable to collect. For example, some of the standard deviations (SDs) had to be imputed based on the mean of the studies included in the analysis. Data on the background of patients with osteoporosis were also limited. Hence, future studies could aim to include relevant information such as DEXA measurements, previous fractures and use of vitamin D or calcium, so that a deeper analysis could be undertaken to look at risk factors or any potential new associations linking risk factors, anti-resorptive medications and valvular/vascular calcification. Lastly, the follow-up of patients included in the analyses was relatively short, ranging from 6 months to 2 years. As calcification is a long and slow process that takes several years, the data obtained from these studies could potentially lead to misleading results. Different studies also used differing methods of measurement for calcification which may have a big measurement error in comparison with real changes that occur in the human body.
In conclusion, this systematic review and meta-analysis identified non-significant, marginal effects of osteoporosis medications on markers of vascular calcification and significant, marginal effects of osteoporosis medications on valvular calcification; but studies were limited by small sample sizes, short follow-up durations, heterogeneous populations and outcome reported limiting interpretation about whether a true effect can be seen. Given significant biological evidence for osteoporosis mechanisms being involved in extra-skeletal calcification, our data would do well to be corroborated in future trials with larger sample size with longer follow-up times in cohorts representative of those taking osteoporosis medications and at risk of valvular/vascular calcification.
Declarations
Conflict of interest
None.
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Grundlagenwissen der Arthroskopie und Gelenkchirurgie erweitert durch Fallbeispiele, Videos und Abbildungen. Zur Fortbildung und Wissenserweiterung, verfasst und geprüft von Expertinnen und Experten der Gesellschaft für Arthroskopie und Gelenkchirurgie (AGA).
Es ist jetzt auch schon wieder rund 600 Millionen Jahre her, dass sich mit dem Erscheinen der Zweiseitentiere die Lateralität ausgebildet hat. In chirurgischen Fächern wie der Orthopädie hat das Folgen bis auf den heutigen Tag. Linkshänder wissen, wovon die Rede ist.
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Ob nun Sonogerät, Praxiscomputer oder gar TI-Konnektor: Einfach zum nächsten Wertstoffhof sollten Praxisteams ausgediente Elektrogeräte nicht bringen. Was bei der Entsorgung zu beachten ist. Und wie die Teams sicher sensible Daten auf PC-Festplatte, externem Datenspeicher und TI-Komponenten löschen.
