Added effect of 1% topical alendronate in intra-bony and inter-radicular defects as part of step II periodontal therapy: a systematic review with meta-analysis and trial sequential analysis

Abstract

Background

Periodontitis is an inflammatory disease affecting tissues surrounding teeth, characterized by destruction of connective tissue attachment and alveolar bone [1]. It is mainly caused by the bacterial biofilm which is responsible for the inflammatory and immunologic reaction that leads to the loss of connective tissue attachment and alveolar bone [2]. Therefore, second step of periodontal therapy is considered crucial to remove the bacterial biofilm both in its soft and calculus form in order to reestablish periodontal health in all patients with loss of periodontal support and/or periodontal pocket formation [3]. This is usually followed by home care measures and in the end by surgery. But while the complete disintegration of the bacterial biofilm can lead to the removal of the cause of the inflammation, several studies demonstrated the role of host inflammatory response in the breakdown of connective tissue and bone and therefore for disease progression [4]. Recent studies explored the use of host-modulators to reduce periodontal disease by altering the inflammatory response [5]. Bisphosphonates (BPs) are carbon-substituted pyrophosphate analogs that bind the mineral component of the bone interfering with the action of osteoclasts [6]. They find application in post-menopausal women for prevention and treatment of osteoporosis [7], in bone related diseases like Paget’s disease and hypercalcemia of malignancy [8]. Some studies showed that BPs induced osteoclasts to secrete inhibitors of osteoclast mediated resorption and stimulated the formation of osteoblast precursors and mineralized nodules, thus promoting bone formation [8, 9]. The role of BPs in treatment of periodontitis has been analyzed in an animal study in order to detect its potential role in retarding bone loss around teeth affected by periodontitis [10]. BPs showed a potential role against bone loss when systemically administered; moreover local adjunct to scaling and root-planning (SRP) caused a decreasing in bone loss and improving mineral density [11]. However, among different BPs, local administration of high doses of alendronate in periodontal pockets, could stimulate the release of IL-1 and IL-6 thus increasing host inflammatory response [12, 13]. Alendronate is an amino bisphosphonate commonly used as a potent inhibitor of bone resorption. However, to be effective, it needs to be administered in high dosage to maintain the necessary concentration of the drug at the osseous defect and systemic administration of BPs can cause several side effects to the gastro-intestinal tract, renal failure and severe hypocalcemia [14]. For these reasons local application might be more successful in controlling local concentration and reducing toxicities. Previous studies demonstrated its role in decreasing bone loss and increasing the bone density of alveolar bone [6]. The aim of this study was to systematically review the role of local 1% alendronate gel in non-surgical therapy of intra-bony and inter-radicular defects.

Methods

Results

Studies selection and studies features

A total of 1242 records were screened by title and abstract from electronic databases. After the first round, 12 out of these papers were considered eligible for full-text examination. At the end of full text examination, seven papers met the inclusion criteria and were included in this systematic review [19–25]. The flow chart of the selection process is reported on Fig. 1. All the included studies were RCTs comparing the combination therapy of second step of periodontal therapy + Alendronate gel 1% (test group) with second step of periodontal therapy + placebo (control group). Reasons for exclusion of the remaining paper are reported on Additional file 1. The articles publication years ranged between 2012 and 2018. Two studies reported data about furcation defects [19, 20] while 5 reported data about intra-bony defects [21–25]. All the studies reported a 6-month follow-up [22–25], while only two studies reported a 12-months follow-up [19, 20]. One study had a split mouth design [21], while six had a parallel design [19, 20, 22–25]. Five studies had 2 arms of comparison [20–24], while two had three arms [19, 25]. Six out of seven of the included studies were funded by pharmaceutical companies [19, 20, 22–25]. In all the included studies, alendronate was injected into the periodontal pockets using a syringe with a blunt cannula during step II of periodontal therapy (Table ​(Table11).

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Fig. 1

PRISMA flow chart showing different phases of the selection process

Table 1

Characteristics of the included studies

Authors		Year	Follow-up	Design of the study	Type of defect	Type of intervention		Number of defects		Funding
						Test	Control	Test	Control
Ipshita et al. [19]	India	2018	6–12 months	Parallel	Inter-radicular	SRP + ALN 1%	SRP + Placebo	30	30	Yes
Dutra et al. [21]	Brasil	2017	6 months	Split-mouth	Intra-bony	ALN 1%	Placebo	20	20	No
Sharma et al. [22]	India	2017	6 months	Parallel	Intra-bony	ALN 1%	Placebo	39	42	Yes
Pradeep et al. [25]	India	2017	6–9 months	Parallel	Intra-bony	ALN 1%	Placebo	30	30	Yes
Sharma and Pradeep [23]	India	2012	6 months	Parallel	Intra-bony	ALN 1%	Placebo	33	33	Yes
Sharma and Pradeep [24]	India	2012	6 months	Parallel	Intra-bony	ALN 1%	Placebo	26	26	Yes
Pradeep et al. [20]	India	2013	6–12 months	Parallel	Inter-radicular	ALN 1%	Placebo	29	28	Yes

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Outcomes, for which meta-analysis of the included studies was not performed due to lack of data, are resumed in Table ​Table2.2. Results of the risk of bias assessment are summarized in Fig. 2. One study showed unclear risk of bias for randomization [21] while two studies showed unclear risk of bias for allocation concealment [19, 22] and one study had high risk of bias for allocation concealment [21]. Six studies had low risk of bias [19, 20, 22–25] while one reported high risk of bias [21] (Fig. ​(Fig.22).

Table 2

Quantitative synthesis of the included studies

	Parameter	Time interval		Placebo	Alendronate		AV		p value
Ipshita et al. [19]	mSBIa	Baseline		2.03 ± 0.61	2.10 ± 0.66		2.06 ± 0.73		0.92
		6 months		1.23 ± 0.62	0.70 ± 0.65		0.66 ± 0.60		0.001
		12 months		0.90 ± 0.71	0.50 ± 0.50		0.40 ± 0.49		0.003
	PI	Baseline		2.03 ± 0.40	1.99 ± 0.37		2.01 ± 0.30		0.89
		6 months		0.78 ± 0.10	0.76 ± 0.10		0.77 ± 0.09		0.60
		12 months		0.57 ± 0.09	0.54 ± 0.11		0.55 ± 0.13		0.71
	PD	Baseline		7.06 ± 1.04	7.03 ± 1.12		7.06 ± 1.32		0.99
		6 months		5.53 ± 0.81	4.03 ± 0.55		5.00 ± 0.83		< 0.001
		12 months		5.20 ± 0.66	2.93 ± 0.78		4.63 ± 0.71		< 0.001
	RVCAL (mm)a	Baseline		6.23 ± 1.13	6.13 ± 1.00		6.30 ± 0.79		0.80
		6 months		5.06 ± 0.78	3.63 ± 1.10		4.26 ± 0.82		< 0.001
		12 months		4.76 ± 0.72	2.36 ± 0.71		3.76 ± 1.35		< 0.001
	RHCAL (mm)a	Baseline		6.06 ± 1.08	5.91 ± 0.92		6.16 ± 0.92		0.56
		6 months		5.03 ± 0.71	3.56 ± 1.07		4.20 ± 1.20		< 0.001
		12 months		4.60 ± 0.62	2.20 ± 0.61		3.93 ± 1.48		< 0.001
	Bone defect depth (mm)a	Baseline		5.21 ± 0.33	5.22 ± 0.63		5.49 ± 0.78		0.14
		6 months		5.09 ± 0.37	3.21 ± 0.46		4.73 ± 0.42		< 0.001
		12 months		5.02 ± 0.36	2.86 ± 0.32		4.53 ± 0.90		< 0.001

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	Parameters			Baseline		3 months		6 months
Dutra et al. [21]	PPD (mm)
	ALN			6.4 ± 1.4		4.3 ± 1.6		4.3 ± 1.6
	Placebo			6.2 ± 1.6		4.4 ± 1.8		4.4 ± 1.7
	P value			0.468		0.239		0.127
	CAL (mm)
	ALN			6.9 ± 1.2		4.3 ± 1.1		3.6 ± 0.7
	Placebo			6.7 ± 1.1		5.1 ± 0.9		4.3 ± 0.7
	p value			0.356		0.010		0.021

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			Baseline (mm)			6 months (mm)		p value
	CBCT based measurements of bone fill according to the treatment groups over time
	ALN		4.5 ± 1.8			3.8 ± 2.0		0.003
	Placebo		5.1 ± 2.2			4.9 ± 2.0		0.099

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	Parameters	Visits		ALN		Placebo		p value
Sharma et al. [22]	Probing depth	Baseline		7.84 ± 2.04		7.62 ± 1.97		0.645
		2 month		5.05 ± 1.78		6.38 ± 1.84		< 0.002
		6 month		3.68 ± 1.93		5.57 ± 1.88		< 0.001*
	Periodontal attachment level	Baseline		6.43 ± 1.77		6.19 ± 1.54		0.531
		2 month		4.05 ± 1.94		5.22 ± 1.73		< 0.008*
		6 month		2.49 ± 1.53		4.41 ± 1.83		< 0.001*
	Intrabony defect depth	Baseline		5.18 ± 1.00		5.10 ± 0.95		0.727
		6 month		3.07 ± 0.94		4.97 ± 0.95		< 0.001*

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		Baseline		3 months		6 months		12 months
		ALN	Placebo	ALN	Placebo	ALN	Placebo	ALN	Placebo
Pradeep et al. [20]	Full mouth PI	1.73 ± 0.31	1.80 ± 0.46	0.91 ± 0.27	1.00 ± 0.28	0.20 ± 0.40	0.52 ± 0.24	0.45 ± 0.19	0.55 ± 0.25
	p value	0.217		0.251		0.369		0.047*
	GI (mSBI)	2.54 ± 0.17	2.53 ± 0.16	1.01 ± 0.41	1.15 ± 0.44	0.79 ± 0.12	0.88 ± 0.29	0.85 ± 0.17	0.90 ± 0.21
	p value	0.751		0.165		0.059		0.132

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	Parameters	Visit		ALN group		Placebo group		p value
	Clinical and radiographical parameters
	PD (mm)	Baseline		6.93 ± 0.69		6.77 ± 0.82		0.407
		3 months		4.43 ± 0.73		5.53 ± 0.73		< 0.001†
		6 months		3.10 ± 0.71		5.17 ± 0.79		< 0.001
		12 months		3.14 ± 0.71		5.39 ± 0.74		< 0.001
	RVCAL	Baseline		7.30 ± 0.79		7.27 ± 0.78		0.846
		3 months		5.07 ± 0.64		6.33 ± 0.66		< 0.001
		6 months		4.07 ± 0.64		6.03 ± 0.76		< 0.001
		12 months		4.07 ± 0.66		6.14 ± 0.89		< 0.001
	RHCAL	Baseline		8.07 ± 0.64		8.03 ± 0.81		0.994
		3 months		6.10 ± 0.66		7.17 ± 0.79		< 0.001
		6 months		5.03 ± 0.56		6.97 ± 0.76		< 0.001
		12 months		5.00 ± 0.54		7.03 ± 0.79		< 0.001
	BD depth	Baseline		3.94 ± 0.24		3.94 ± 0.25		0.828
		6 months		2.67 ± 0.26		3.83 ± 0.25		< 0.001
		12 months		2.64 ± 0.23		3.84 ± 0.24		< 0.001

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		Visits		ALN	Placebo	T value		p value
Sharma and Pradeep [23]	PD	Baseline		7.85 ± 2.20	7.69 ± 2.22	0.06		0.008
		2 months		6.04 ± 1.99	6.96 ± 2.10	2.63		0.111
		6 months		3.96 ± 1.28	6.04 ± 1.68	25.05		< 0.001
	CAL	Baseline		6.12 ± 1.77	5.96 ± 1.88	0.09		0.763
		2 months		4.46 ± 2.43	5.19 ± 2.29	1.23		0.271
		6 months		2.85 ± 1.82	4.54 ± 2.12	9.50		0.003
	IBD Depth	Baseline		5.45 ± 1.18	5.48 ± 0.92	0.006		0.937
		6 months		2.95 ± 0.86	5.37 ± 0.90	97.08		< 0.001
	Mean PD (mm)	2 months		1.81 ± 1.20	0.73 ± 1.58	7.60		0.008
		6 months		3.88 ± 1.39	1.65 ± 1.35	34.21		< 0.001
	Mean CAL (mm)	2 months		1.65 ± 1.09	0.77 ± 1.68	5.06		0.029
		6 months		3.27 ± 1.11	1.42 ± 1.70	21.41		< 0.001
	Mean IBD depth (mm)	6 months		2.50 ± 0.73	0.10 ± 0.06	273.12		< 0.001
	Percentage of bone defect fill (%)	6 months		46.1 ± 9.48	2.0 ± 1.20	555.41		< 0.001

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			Alendronate group	Placebo group		t*		p
Sharma and Pradeep [24]	PD	Baseline	7.58 ± 2.13	7.24 ± 2.18		0.39		0.533
		2 months	4.39 ± 1.45	5.88 ± 1.78		13.74		< 0.014
		6 months	3.09 ± 1.82	5.09 ± 1.54		23.02		< 0.001
	CAL	Baseline	6.06 ± 1.82	5.64 ± 1.72		0.95		0.333
		2 months	3.61 ± 1.99	4.82 ± 1.91		6.33		< 0.001
		6 months	2.03 ± 1.48	4.03 ± 2.02		20.91		< 0.001
	IBD depth	Baseline	4.70 ± 1.00	4.71 ± 1.04		0.01		0.971
		6 months	2.82 ± 0.87	4.60 ± 1.06		5.43		< 0.001

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			Alendronate group	Placebo group		t*		p
	Change in PD, CAL, IBD, and Bone Fill in ALN and Placebo Groups from baseline to 2 and 6 months
	PD (mm; mean—SD)	2 months	3.18 ± 1.28	1.36 ± 0.85		45.60		< 0.001
		6 months	4.48 ± 1.27	2.15 ± 1.12		62.16		< 0.001
	CAL (mm; mean–SD)	2 months	2.45 ± 0.75	0.82 ± 0.58		97.20		< 0.001
		6 months	4.03 ± 0.84	1.61 ± 0.86		132.47		< 0.001
	IBD depth (mm; mean–SD)	6 months	1.88 ± 0.58	0.10 ± 0.03		304.86		< 0.001
	Bone-defect fill (%; mean–SD)	6 months	40.4 ± 11.71	2.5 ± 1.02		344.45		< 0.001

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		Placebo		ATV		ALN		p value
Pradeep et al. [25]	Probing depth, clinical attachment level, and intrabony defect depth in placebo, ATV, and ALN at different time intervals
	PD	Baseline	6.76 ± 1.22	6.56 ± 1.38		6.96 ± 1.12		0–466
		3 months	6.43 ± 1.22	5.50 ± 1.07		5.43 ± 0.89		< 0.0001*
		6 months	5.70 ± 0.87	4.10 ± 0.84		3.40 ± 0.49		< 0.0001*
		9 months	5.26 ± 0.63	3.03 ± 0.71		2.66 ± 054		< 0.0001*
	CAL	Baseline	6.13 ± 1.13	6.13 ± 0.89		5.93 ± 0.94		0.671
		3 months	5.96 ± 1.18	4.46 ± 0.73		4.86 ± 0.81		< 0.0001
		6 months	4.96 ± 0.71	2.43 ± 0.50		3.6 ± 1.10		< 0.0001
		9 months	4.63 ± 0.61	1.86 ± 0.43		2.43 ± 0.77		< 0.0001
	IBD depth	Baseline	5.17 ± 0.35	5.46 ± 0.81		5.18 ± 0.65		0.145
		6 months	5.07 ± 0.38	3.56 ± 0.54		3.05 ± 0.36		< 0.0001
		9 months	5.04 ± 0.38	3.47 ± 0.70		2.79 ± 0.30		< 0.0001

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			Placebo	ATV		ALN		p value
	PD	Baseline-3 months	0.33 ± 0.47	1.06 ± 0.63		1.53 ± 0.50		< 0.001
		Baseline-6 months	1.06 ± 0.90	2.46 ± 0.97		3.56 ± 1.13		< 0.001
		Baseline-9 months	1.50 ± 1.07	3.53 ± 1.27		4.30 ± 1.39		< 0.001
	CAL	Baseline-3 months	0.16 ± 0.37	1.66 ± 0.60		1.06 ± 0.52		< 0.001
		Baseline-6 months	1.16 ± 0.94	3.7 ± 0.91		2.33 ± 1.34		< 0.001
		Baseline-9 months	1.50 ± 1.07	4.26 ± 1.08		3.50 ± 1.16		< 0.001
	IBD depth	Baseline-6 months	0.09 ± 0.17	1.90 ± 0.44		2.12 ± 0.34		< 0.001
		Baseline-9 months	0.12 ± 0.17	1.98 ± 0.72		2.38 ± 0.45		< 0.001
	Radiographic DDR	Baseline-6 months	1.86 ± 3.56	34.61 ± 5.11		40.87 ± 2.73		< 0.001
		Baseline-9 months	2.44 ± 3.48	35.92 ± 10.04		45.82 ± 3.83		< 0.001

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Fig. 2

Risk of bias assessment according to the Cochrane Collaboration tool

Meta-analysis and trial sequential analysis

A total number of 408 patients were treated in the included studies in both test and control groups. A total of 207 sites were treated in the test group while 209 sites were treated in the control group.

PD reduction

Meta-analysis of PD reduction showed a significant difference (p < 0.00001) when alendronate was topically applied during step II periodontal therapy compared to placebo; MD = 2.01 (95% CI [1.60, 2.43]). Such results were characterized by a high rate of heterogeneity (I² = 82%), for such reason a random effects model was used for data interpolation. A subgroup analysis was performed based on study design (parallel-groups vs split-mouth) to test for a possible influence of study design on the analyzed outcome. The effect estimate for parallel group studies was 2.11 (95% CI [1.69, 2.51]) and for split-mouth 0.30 (95% CI [− 1.23, 1.83]) and although both groups showed a benefit for alendronate compared to placebo an important difference was detected. Results of the TSA confirmed the previously performed meta-analysis with the z-curve crossing the lower alpha spending boundary, in addition the meta-analysis was characterized by a good power of evidence since the RIS (74 patients) was crossed (Fig. ​(Fig.33).

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Fig. 3

Meta-analysis (A) and Trial sequential analysis (B) for the effects of Alendronate therapy on PD reduction

CAL gain

Meta-analysis of CAL gain revealed a significant improvement (p < 0.00001) when alendronate was topically applied, MD = 1.72 (95% CI [1.30, 2.15]). Such results were characterized by a high rate of heterogeneity among studies (I² = 88%) and for this reason a random effect model was used for data interpolation. A sub-group analysis was performed based on study design (parallel groups vs split-mouth); the effect estimate for parallel group studies was 1.82 (95% CI [1.37, 2.28]) and for split-mouth 0.90 (95% CI [0.08, 1.72]), also in this case study design influenced the effect size of results. The TSA confirmed the previously performed meta-analysis with the z-curve crossing the lower alpha spending boundary, in addition the meta-analysis was characterized by a good power of evidence since the RIS (74 patients) was also crossed (Fig. ​(Fig.44).

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Fig. 4

Meta-analysis (A) and Trial sequential analysis (B) for the effects of Alendronate therapy on CAL gain

Bone defect depth reduction

The analysis of bone defect depth reduction shows a significant difference between the therapy with alendronate compared to control: MD = 1.86 (95% CI [1.53, 2.19]), with results characterized by a high rate of heterogeneity (I² = 97%). TSA confirmed such findings with the z-curve crossing the lower alpha spending boundary and RIS threshold (99 patients). No differences were detected between intra-bony and inter-radicular defects (p = 0.18) (Fig. ​(Fig.55).

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Fig. 5

Meta-analysis (A) and Trial sequential analysis (B) for the effects of Alendronate therapy on bone defect depth reduction

Discussion

This systematic review aimed to provide a clear focus on the role of alendronate 1% as an adjunct to second step of periodontal therapy in treatment of intra-bony and inter-radicular defects. Since the introduction of host-modulators in the treatment of periodontal disease [26], several studies have been performed to analyze the role of different substances in combination with second step of periodontal therapy [27–31].

Results of the present study showed that the topical application of Alendronate gel 1% can provide a significant benefit in PD reduction, CAL gain and bone defect depth reduction when applied after non-surgical periodontal treatment. A significant difference between parallel groups and split-mouth design was detected when subgroup analysis was performed for PD reduction and CAL gain. No significant differences were detected between intra-bony and inter-radicular defects when subgroup analysis was performed for bone defect depth reduction. BPs are often administered orally for the treatment of post-menopausal osteoporosis showing a wide range of adverse events including gastro-intestinal side effects, acute phase syndrome, secondary hyperparathyroidism, hypocalcemia, musculoskeletal pain and osteonecrosis of the jaw; therefore local application of alendronate might appear to be safer and devoid of side effects since none of the studies had drop-out patients that seemed to be related to local treatment; furthermore local administration offers the advantage of reaching a higher concentration of drug at the osseous defect with a reduced dosage [32]. However, even if these results might seem promising in providing a beneficial effect as an adjunct to subgingival instrumentation of intra-bony and inter-radicular defects, there are several concerns that must be taken into account when interpreting these results.

First of all, only two of the included studies [19, 20] reported data about inter-radicular defects, hence further studies are needed to confirm the results obtained of a potential beneficial effect of alendronate in this subtype of defects.

Of the seven included studies, only one provided more detailed information about the subgingival instrumentations performed [21]; in the remaining six it was not considered the number of sessions performed, the kind of instruments that were used or the experience of the operators who had performed the treatment. Moreover, the adjunct of alendronate during subgingival instrumentation is an adjunctive cost to conventional step II of periodontitis treatment.

We did not set the smoking status as an exclusion criterion, so this factor should be considered in the outcome of treatment, even if the use of alendronate as a host modulator in intraosseous defects could be particularly important for smokers whose healing capacity is impaired [33, 34]. Since only two studies [19, 20] had a 12-months follow-up, studies with a longer follow-up are necessary to confirm such results. An important point that should be considered when interpreting these results is that six studies [19, 20, 22–25] out of seven were conducted in the same country (India). Therefore, it must be considered the risk of a geographical bias, data from a more heterogeneous population would play an important role in confirming these findings. In addition, six [19, 20, 22–25] out of seven studies were funded by external pharmaceutical companies providing a potential confounding effect in the interpretation of results. An important issue is that one of the included studies [21] had a split-mouth design. Since its introduction by Ramfjord et al. in 1968 [35], split-mouth design has been widely used in oral health related studies. It generally requires less patients since the same individual serves as both test and control. However this kind of design presents some critical aspects as carry-across effect and needs a more complicated analysis in comparison with whole mouth studies [17, 36]. These results are consistent with the findings of Donos et al. [37] and the EFP Stage I-III periodontitis guideline [3] which affirm that only the adjunct of antiseptics and antibiotics may provide a beneficial effects to step II of periodontal therapy.

Conclusion

Based on the results available from these RCTs, this review shows that local delivery of alendronate seems to be effective in improving PD, CAL and bone defect depth. However, studies conducted by different research groups and on a geographically more heterogeneous population with a more standardized protocol are necessary to confirm these findings. Therefore, even if topical administration of Alendronate could have a potential beneficial effect on periodontitis clinical parameters, multicentric studies with a longer follow-up are needed to clarify this point.

Supplementary Information

Abbreviations

Authors' contributions

All authors have read and approved the final manuscript.

Funding

The work has no funding.

Availability of data and materials

Not applicable.

Declarations

Footnotes

References