Sage Journals: Discover world-class research

Abstract

Background:

Subjects with a fragility fracture have an increased risk of a new fracture and should receive effective strategies to prevent new events. The medium-term to long-term strategy should be scheduled by considering the mechanisms of action in therapy and the estimated fracture risk.

Objective:

A systematic review was conducted to evaluate the sequential strategy in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines.

Design:

Systematic review and meta-analysis.

Data sources and methods:

PubMed, Embase, and the Cochrane Library were investigated up to February 2021 to update the search of a recent systematic review. Randomized clinical trials (RCTs) that analyzed the sequential therapy of antiresorptive, anabolic treatment, or placebo in patients with or at risk of a fragility fracture were eligible. Three authors independently extracted data and appraised the risk of bias in the included studies. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation methodology. Effect sizes were pooled in a meta-analysis using fixed-effects models. The primary outcome was the risk of refracture, while the secondary outcome was the bone mineral density (BMD) change.

Results:

In all, 17 RCTs, ranging from low to high quality, met our inclusion criteria. A significantly reduced risk of fracture was detected at (i) 12 or 24 months after the switch from romosozumab to denosumab versus placebo to denosumab; (ii) 30 months from teriparatide to bisphosphonates versus placebo to bisphosphonates; and (iii) 12 months from romosozumab to alendronate versus the only alendronate therapy (specifically for vertebral fractures). In general, at 2 years after the switch from anabolic to antiresorptive drugs, a weighted BMD was increased at the lumbar spine, total hip, and femoral neck site.

Conclusion:

The Task Force formulated recommendations on sequential therapy, which is the first treatment with anabolic drugs or ‘bone builders’ in patients with very high or imminent risk of fracture.

Plain language summary

A systematic review to evaluate the sequential therapy of antiresorptive (denosumab and bisphosphonate, such as alendronate, minodronate, risedronate, and etidronate), anabolic treatment (such as romosozumab, teriparatide), or placebo in patients with or at risk of a fragility fracture in the context of the development of the Italian Guidelines

Subjects with previous fragility fractures should promptly receive effective strategies to prevent the risk of subsequent events. Indeed, patients with a fragility fracture have a doubled risk of a new fracture. For this reason, it is essential to provide adequate sequential therapy based on the mechanisms and the rapidity of action. A systematic review was performed to identify the sequential strategy in patients at high- or imminent-risk of (re)fracture and to support the Panel of the Italian Fragility Fracture Guideline in formulating recommendations. Our systematic review included seventeen studies mostly focused on women and enabled us to strongly recommend the anabolic drugs as first-line treatment. Specifically, for the sequential therapy from anabolic to antiresorptive treatment, there was a significant reduction in the risk of different types of fractures after the switch from romosozumab to denosumab versus placebo to denosumab. These findings were confirmed at 24 months after the switch. Considering the sequential treatment from antiresorptive to anabolic medications, there was a decreased risk of fracture 12 months after the switch from placebo to teriparatide versus bisphosphonate or antiresorptive to teriparatide. Moreover, a greater bone mineral density increase after the switch from anabolic to antiresorptive medications was shown in the lumbar spine, total hip, and femoral neck. The results of this systematic review and meta-analysis confirm that initial treatment with anabolic drugs produces substantial bone mineral density improvements, and the transition to antiresorptive drugs can preserve or even amplify the acquired benefit. These findings support the choice to treat very high-risk individuals with anabolic drugs first, followed by antiresorptive drugs.

Keywords

anabolic antiresorptive fragility fracture sequential therapy systematic review

Introduction

In subjects with a history of fragility fracture(s), effective prevention strategies are warranted to prevent subsequent events.^1,2 Indeed, patients with a fragility fracture have a doubled risk of a new fracture.³ In particular, subjects who have recently had a fracture represent a concerning subset, defined by the term ‘imminent risk’, and are estimated to have a fivefold increased risk for a second fracture within 12–24 months.^4,5 In addition, the risk of recurrence dramatically increases with the number of previous fractures, regardless of their location.⁶

The resulting burden is significant, including limited walking, chronic pain, loss of independence, and reduced quality of life.⁷ Therefore, patients should promptly receive an effective strategy to reduce the risk of new fractures.⁸ Unfortunately, data show that many high-risk patients still do not receive any treatment.^1,2 It is crucial to enact strategies aimed at both identifying individuals at significant fracture risk and granting them an effective pharmacological treatment.⁹

Pharmacological therapies for the prevention and treatment of bone loss and mitigation of fracture risk have developed considerably in the last decades, with a significant increase in treatment options with different and innovative mechanisms of action available to the clinician. Among the antiresorptive drugs, denosumab represents the most recently developed compound, besides bisphosphonates, which are usually the first-line treatment. Denosumab is a monoclonal antibody directed against the receptor activator of NFkB ligand (RANKl) and acts by inhibiting the differentiation, activity, and survival of osteoclasts.¹⁰ Meanwhile, classified as anabolics, teriparatide and abaloparatide are parathyroid hormone (PTH) analogs that act by stimulating osteoclast activity, favoring new bone formation.¹¹ Finally, romosozumab represents the last developed drug, recently licensed and introduced in clinical practice. Romosozumab is a novel agent that differs from prior anabolic drugs by blocking the action of sclerostin, an inhibitor of the Wnt pathway.¹² Romosozumab has been defined as a ‘bone builder’ as it assures a concurrent stimulation of neoformation and inhibition of bone resorption, leading to an accelerated and amplified anabolic therapeutic window.¹³ The choice of therapy should be based on the estimated fracture risk, the mechanisms of action, and its rapidity of action as well as the medium-term to long-term strategy by scheduling combined or sequential approaches.^12,14 For this reason, it is essential to provide adequate sequential therapy after suspending these treatments.

A comparative analysis of different treatments and therapeutic strategies, both in terms of fracture protection and the onset of the protective effect, is still an unmet need. This systematic review aims to identify the sequential strategy in patients at high risk or imminent risk of (re)fracture.

Materials and methods

We performed a systematic review to support the Panel of the Italian Fragility Fracture Guideline (published on the platform of the Italian National Institute of Health)¹⁵ in formulating recommendations. In accordance with the GRADE-ADOLOPMENT methodology¹⁶ and the standards elaborated by the Sistema Nazionale Linee Guida,^17,18 the clinical question defined by the multidisciplinary panel was as follows: ‘Which therapeutic strategy should be recommended in the short- and long-term treatment of patients at high- or imminent-risk of (re) fracture?’ Specifically, we have updated a recent systematic review,¹⁹ which assessed the sequential treatment in women with postmenopausal osteoporosis.

Inclusion and exclusion criteria

Randomized clinical trial (RCT) studies were detected if they met the following criteria: (1) population: patients who experienced a fragility fracture or were affected by osteoporosis; (2) intervention: antiresorptive (denosumab and bisphosphonate, such as alendronate, minodronate, risedronate, and etidronate), anabolic therapies (romosozumab, teriparatide, and PTH), or placebo; (3) comparison: sequential therapy of drugs abovementioned; (4) outcome: the primary outcome was a risk of the fracture using the dichotomized measure of risk ratio (RR), while the secondary outcome was mean change in bone mineral density (BMD) (at the lumbar spine, total hip, and femoral neck) considering the sequential treatment.

Studies were excluded if they (i) were not published in English; (ii) did not report original findings (i.e. letters, case report); (iii) did not identify patients affected by a fragility fracture or osteoporosis; or (iv) did not consider a sequential drug treatment.

Data source and search strategy

We performed a PubMed, Embase, and Cochrane Library search from 2019 to February 2021 and identified publications on sequential therapy among patients with fragility fracture or osteoporosis. The systematic review was conducted according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses,^20,21 as reported in Supplemental Table S1. The search strategy (Supplemental Table S2) specified keywords and corresponding Medical Subject Headings (MeSH) terms related to fragility fracture/osteoporosis AND sequential therapy AND anabolic/antiresorptive drugs. We checked the reference lists of the studies and the systematic reviews identified during the search process.

Study selection and data extraction

Three independent authors (AB, GP, and RR) screened titles and abstracts according to the search strategy and then assessed the full text of the potentially relevant studies. Discrepancies between readers were discussed and resolved at the conference.

For each included RCT, the following information was extracted the name of the first author, year and country of publication, study setting, type of population, intervention and comparator, and follow-up period (Supplemental Table S3).

Studies quality

The updated systematic review was evaluated using the AMSTAR-2 checklist,²² while the quality of each included publication was assessed using the Cochrane risk of bias (RoB) tool for RCTs.²³ The following domains of the Cochrane RoB tool were appraised: selection bias (random sequence generation and allocation concealment), performance bias (blinding of participants and personnel), detection bias (blinding of outcome assessment), attrition bias (incomplete outcome data), reporting bias (selective reporting), and other bias (such as funding bias). Each domain was classified as ‘high’, ‘low’, or ‘unclear’ RoB if the publication did not provide sufficient information to be classified (Supplemental Figure S1).

Quality of evidence

The quality of evidence of the primary outcome was judged through five dimensions (RoB, consistency of effect, imprecision, indirectness, and publication bias) by the GRADE approach.²⁴ The evidence was downgraded from ‘high quality’ by one level if serious or by two levels if very serious limitations were found for each of the five dimensions (Supplemental Table S4).

Statistical analysis

The measure of interest was the summary RR that evaluated the effect of sequential therapy (anabolic to antiresorptive, or vice versa) on the risk of fragility fracture. Estimates were summarized if at least three studies reported the association of interest. Heterogeneity between study-specific estimates was tested using χ² statistics²⁵ and measured with the I² index (a measure of the percentage variation across the studies).²⁶

Moreover, a pooled estimate of BMD (mean change, %) was obtained for each site (lumbar spine, total hip, and femoral neck). A weighted average of the BMD was obtained by considering the sample size of the ith study and summing them across all studies.²⁷ p Values less than 0.05 for all tests were considered statistically significant.

Results

Study selection

A total of 283 studies were detected, as shown in Figure 1. After screening the title and abstract, eight papers were eligible for inclusion. Subsequently, six studies were discarded reading the full texts because they were duplicates (1) or because the intervention (1), outcome (1), population (1), or study design (2) were incorrect. In all, 14 studies were also included after the review of the references^28–41 and 3 by hand-searching.^13,42,43 The main characteristics of the included studies are reported in Supplemental Material (Table S3).

Figure 1.

Flow chart of study selection.

Study characteristics

The included papers were conducted in the United States,^29,33,43 Italy,³¹ UK,³⁵ Japan,³⁷ Austria, and Czech Republic,⁴² in addition to multicenter studies carried out in various countries.^{13,28,30,32,34,36,38–41} Nine studies considered the sequential therapy from anabolic to antiresorptive treatment,^{13,28,29,34,37,39–41,43} specifically (a) romosozumab to denosumab versus placebo to denosumab^13,34,40; (b) teriparatide to denosumab or alendronate or minodronate³⁷; (c) romosozumab to alendronate versus only alendronate^28,41; (d) teriparatide to bisphosphonate versus placebo to bisphosphonate³⁹; (e) PTH to bisphosphonate versus PTH to placebo²⁹; and (f) romosozumab to denosumab versus romosozumab to placebo.⁴³ Seven papers evaluated the sequential treatment from antiresorptive to anabolic medications,^{30–32,35,36,38,42} specifically (g) alendronate to teriparatide versus placebo to teriparatide⁴²; (h) antiresorptive to teriparatide versus no treatment to teriparatide^35,38; (i) antiresorptive to teriparatide versus only antiresorptive³¹; (j) alendronate to romosozumab or teriparatide³²; and (k) risedronate or alendronate^30,36 or etidronate or non-bisphosphonate³⁰ to teriparatide.^30,36 Finally, one study reported the sequential treatment from anabolic to antiresorptive medications and vice versa.³³

All studies, except one,³⁷ were focused on women. The proportion of patients with previous fragility fractures was reported by nine studies,^{28–30,32,33,36,37,41,42} whereas the nature and severity of prior fractures were documented in eight^{13,28,34–37,40,41} and five^{13,28,34,40,41} studies, respectively. Moreover, secondary osteoporosis was indicated as an exclusion criterion in eight studies^{30,31,33,35–38,42} (Supplemental Table S5).

RoB assessment and certainty of the evidence

According to the RoB assessment (Supplemental Figure S1), eight studies had an unclear risk for random sequence generation,^{29–31,38–40,42,43} nine for allocation concealment,^{29–31,35,38–40,42,43} one for blinding of participants and personnel,³⁵ four for incomplete outcome data,^29,35,39,42 and other biases, such as funding bias.^31,35,37,40 A high RoB was found for random sequence generation in one study³⁵ and other biases in seven papers.^{28,30,32,36,38,39,41}

The certainty of evidence ranged from moderate to high RoB for the sequential therapy from anabolic to antiresorptive treatment, while a low RoB was attributed to the sequential treatment from antiresorptive to anabolic medications (Supplemental Figure S1).

Primary outcome

The risk of refracture was measured after the switch from anabolic to antiresorptive or vice versa (Table 1). Regarding the sequential therapy from anabolic to antiresorptive treatment, there was a significant reduction in the risk of different types of fractures (vertebral, nonvertebral, major nonvertebral, and major osteoporotic fracture) after the switch from romosozumab to denosumab versus placebo to denosumab (RR from 0.25 to 0.75; 95% CI, 0.16–0.99), while a nonsignificant risk reduction was only detected for hip fracture (RR, 0.50; 95% CI, 0.24–1.04).¹³ These findings were confirmed at 24 months after the switch.^34,40 Moreover, a reduced risk of nonvertebral fracture was reported 30 months after the switch from teriparatide to bisphosphonates versus placebo to bisphosphonates (RR, 0.54; 95% CI, 0.32–0.91).³⁹ Finally, there was a significant decrease in risk of vertebral and hip fractures (RR 0.52 and 0.60, respectively; 95% CI, 0.40–0.97)^28,41 12 months after the switch from romosozumab to alendronate versus the only alendronate therapy, while a nonsignificant risk reduction in nonvertebral fracture was detected (RR, 0.81; 95% CI, 0.63–1.04).⁴¹

Table 1.

Risk of refracture: switching from anabolic to antiresorptive, or vice versa.

First author, year	Months from baseline	Months from switch	Site of fracture	Incidence of fracture
First author, year	Months from baseline	Months from switch	Site of fracture	Group 1	Group 2		RR (95% CI)
Group 1: Romo to Dmab; Group 2: placebo to Dmab
Cosman 2016 FRAME Study	24	12	Vertebral fracture	21/3325 (0.6%)	84/3327 (2.5%)		0.25 (0.16–0.40)
			Nonvertebral fracture	96/3589 (2.7%)	129/3591 (3.6%)		0.75 (0.57–0.97)
			Major nonvertebral fracture	67/3589 (1.9%)	101/3591 (2.8%)		0.67 (0.49–0.91)
			Hip fracture	11/3589 (0.3%)	22/3591 (0.6%)		0.50 (0.24–1.04)
			Major osteoporotic fracture	68/3589 (1.9%)	110/3591 (3.1%)		0.62 (0.46–0.84)
Lewiecki 2019Extension of FRAME study	36	24	Vertebral fracture	32/3325 (1.0%)	94/3327 (2.8%)		0.34 (0.23–0.51)
			Nonvertebral fracture	139/3589 (3.9%)	176/3591 (4.9%)		0.79 (0.64–0.98)
			Major nonvertebral fracture	100/3589 (2.8%)	138/3591 (3.8%)		0.73 (0.56–0.93)
			Hip fracture	18/3589 (0.5%)	31/3591 (0.9%)		0.58 (0.33–1.04)
			Major osteoporotic fracture	103/3589 (2.9%)	147/3591 (4.1%)		0.70 (0.55–0.90)
Miyuachi 2019Subgroup analysis of FRAME Study	36	24	Vertebral fracture	4/237 (1.7%)	11/243 (4.5%)		0.37 (0.12–1.15)
			Nonvertebral fracture	7/247 (2.8%)	15/245 (6.1%)		0.46 (0.19–1.12)
			Major nonvertebral fracture	4/247 (1.6%)	7/245 (2.9%)		0.57 (0.17–1.91)
			Hip fracture	0/247 (0.0%)	2/245 (0.8%)		0.20 (0.01–4.11)
			Major osteoporotic fracture	5/247 (2.0%)	8/245 (3.3%)		0.62 (0.21–1.87)
Group 1: Romosozumab to ALN; Group 2: only ALN
Cosman 2020 Post hoc analysis of ARCH Study	24	12	Nonvertebral fracture	105/1739 (6.0%)	127/1726 (7.4%)		0.81 (0.63–1.05)^a
			Hip fracture	25/1739 (1.4%)	42/1726 (2.4%)		0.60 (0.37–0.99)^a
Saag 2017ARCH Study	24	12	Vertebral fracture	127/2046 (6.2%)	243/2047 (11.9%)		0.52 (0.40–0.66)^b
Group 1: Teriparatide 20 µg to BPs; Group 2: teriparatide 40 µg to BPs; Group 3: placebo to BPs
Prince 2005		30	Nonvertebral fracture	Group 1 30/436 (6.9%)	Group 2 22/412 (5.3%)	Group 3 38/414 (9.2%)	20 µg: 0.70 (0.43–1.13)^c 40 µg: 0.54 (0.32–0.91)^c
Group 1: BPs or AR to teriparatide; Group 2: placebo to teriparatide
Obermayer-Pietsch 2008EUROFORS Study		24	Any fracture	3/134 (2.2%)	5/84 (5.9%)		0.38 (0.09–1.53)

Adjusted for baseline BMD, age strata, and the presence of severe vertebral fracture at baseline.

Adjusted for age (<75 versus ⩾75 years), the presence or absence of severe vertebral fracture at baseline, and baseline bone mineral density T score at the total hip.

Adjusted for the duration of osteoporosis drug treatment.

ALN, alendronate; AR, antiresorptive; BPs, bisphosphonates; BMD, bone mineral density; CI, confidence interval; RR, risk ratio.

Considering the sequential treatment from antiresorptive to anabolic medications, there was a decreased risk of fracture 12 months after the switch from placebo to teriparatide versus bisphosphonate or antiresorptive to teriparatide (RR, 0.38; 95% CI, 0.09–1.53).³⁸

Secondary outcome

Table 2 reports the change in BMD 2 years after the sequential therapy from anabolic to antiresorptive medications or vice versa. A greater BMD increase after the switch from anabolic to antiresorptive medications was shown in the lumbar spine (16.84%), total hip (8.47%), and femoral neck (7.31%).^28,34 Conversely, a lower BMD increase occurred in the (i) lumbar spine (7.50%) after the switch from placebo to antiresorptive drugs³⁴; (ii) total hip (2.42%) after switching from antiresorptive to anabolic treatment³⁰; and (iii) femoral neck (2.70%) for the only antiresorptive therapy²⁸ (Figure 2).

Table 2.

Bone mineral density changes from the switching: anabolic to antiresorptive, or vice versa.

First author, year	Months from baseline	Months from switch	Comparative LS BMD change from baseline (mean%)					Comparative TH BMD change from baseline (mean%)					Comparative FN BMD change from baseline (mean%)
First author, year	Months from baseline	Months from switch	Group 1		Group 2		p Value	Group 1		Group 2		p Value	Group 1		Group 2		p Value
Group 1: Romo to Dmab; Group 2: placebo to Dmab
Cosman 2016FRAME Study	18	6	N = 6515.1		N = 613.3		p < 0.001	N = 668.4		N = 621.6		p < 0.001	N = 666.7		N = 62−0.2		p < 0.001
	24	12	17.6		5.0		p < 0.001	8.8		2.9		p < 0.001	6.6		0.6		p < 0.001
Lewiecki 2019Extension of FRAME study	24	12	N = 316916.6		N = 31765.5		p < 0.001	N = 32378.5		N = 32563.2		p < 0.001	N = 32377.3		N = 32562.3		p < 0.001
	36	24	18.1		7.5		p < 0.001	9.4		4.2		p < 0.001	8.2		3.4		p < 0.001
Miyauchi 2019Subgroup analysis of FRAME Study	24	12	N = 20520.2		N = 1907.3		p < 0.001	N = 2057.9		N = 2002.9		p < 0.001	N = 2057.8		N = 2003.6		p < 0.001
	36	24	N = 20722.1		N = 1959.5		p < 0.001	N = 2188.7		N = 2104.5		p < 0.001	N = 2188.6		N =2 104.4		p < 0.001
Group 1: Teriparatide to Dmab; Group 2: TPTD to ALN; Group 3: TPTD to minodronate
Niimi 2018		12	Group 1N = 1004.3 ± 3.5		Group 2N = 1001.3 ± 5.1	Group 3N = 1000.5 ± 4.6	p < 0.01Dmab versus Mino or ALN						Group 1N = 1001.4 ± 3.4		Group 2N = 1000.7 ± 4.6	Group 3N = 1000.2 ± 4.6	p = 0.16
Group 1: Romosozumab to ALN; Group 2: only ALN
Saag 2017Extension of ARCH study	36	24	N = 204614.9		N = 20478.5		p < 0.001	N = 20467.0		N = 20473.6		p < 0.001	N = 20465.9		N = 20472.7		p < 0.001
Cosman 2020ARCH Study	24	12	N = 173915.5 ± 0.4		N = 17267.3 ± 0.3		p < 0.001	N = 17397.3 ± 0.2		N = 17263.5 ± 0.2		p < 0.001	N = 17396.1 ± 0.4		N = 17262.3 ± 0.3		p < 0.001
Group 1: PTH to BPs; Group 2: PTH to placebo
Black 2005PATH study	24	12	N = 1212.1		N = 74.0		p < 0.05	N = 124.0		N = 70.0		p < 0.05	N = 124.0		N = 71.0		p < 0.05
Group 1: Romosozumab to Dmab; Group 2: Romosozumab to placebo
Kendler 2019	24–36	0–12	N = 162.5 ± 1.5		N = 19−9.1 ± 1.6			N = 162.0 ± 1.3		N = 19−5.3 ± 2.0			N = 161.3 ± 1.3		N = 19−4.3 ± 2.3
Group 1: ALN to Teriparatide; Group 2: treatment naïve to TPTD
Fahrleitner-Pammer 2016		12	N = 291.1		N = 166.2		p = 0.004
		24	5.3		10.2		p = 0.077
Group 1: BisP or AR to TPTD; Group 2: no treatment to TPTD
Middleton 2007		12	N = 389.0		N = 147.8		p = 0.54	N = 381.0		N = 14−0.3		p = 0.36
		18	9.8		6.1		p = 0.30	2.8		1.3		p = 0.44
Obermayer-Pietsch 2008EUROFORS Study		6	N = 1343.5		N = 845.8		p < 0.001	N = 134−0.3		N = 840.5			N = 134−0.3		N = 841.2		p < 0.05
		12	6.6		9.3		p < 0.001	0.6		1.8		p < 0.05	1.1		2.2
		18	8.6		11.1		p < 0.01	0.6		2.7		p < 0.05	2.1		3.1
		24	10.2		13.1		p < 0.01	2.3		3.8		p < 0.01	3.4		4.8
Group 1: AR to Teriparatide; Group 2: no change AR
Gonnelli 2006		6	N = 275.6 ± 6.7		N = 281.2 ± 3.4		p < 0.05	N = 27−2.1 ± 3.5		N = 280.20 ± 2.9		NS	N = 27−1.8 ± 8.7		N = 281.6 ± 3.1		NS
		12	7.1 ± 5.9		1.5 ± 4.3		p < 0.05	−0.8 ± 2.7		1.2 ± 4.2		NS	2.6 ± 5.1		1.1 ± 3.8		NS
Group 1: ALN to Romosozumab; Group 2: ALN to TPTD
Langdhal 2017STRUCTURE study		6	N = 2067.2 (6.6–7.8)		N = 2093.5 (2.9–4.0)		p < 0.0001	N = 2062.3 (1.9–2.7)		N = 209−0.8 (−1.2 to −0.4)		p = 0.0001	N = 2062.1 (1.6–2.7)		N = 209−1.1 (−1.6 to −0.5)		p = 0.0003
		12	9.8 (9.0–10.5)		5.4 (4.7–6.1)		p < 0.0001	2.9 (2.5–3.4)		−0.5 (−0.9 to −0.0)		p = 0.0357	3.2 (2.6–3.8)		−0.2 (−0.8 to 0.4)		p = 0.4566
Group 1: RIS to Teriparatide; Group 2: ALN to TPTD
Miller 2008		6	N = 1583.0		N = 1662.0			N = 158−1.2		N = 166−1.9		p = 0.07
		12	5.1		3.6		p < 0.05	−0.3		−1.7		p = 0.07
Group 1: RIS to Teriparatide; Group 2: ALN to TPTD; Group 3: ETN to TPTD; Group 4: Non-BPs to TPTD
Boonen 2008EUROFORS study		6	Group 1N = 592.3	Group 2N = 1073.0	Group 3N = 305.8	Group 4N = 494.0	p < 0.05ETN versus RIS, ALN	Group 1N = 59−1.6	Group 2N = 107−1.2	Group 3N = 30−0.7	Group 4N = 49−0.3	NS	Group 1N = 59−1.1	Group 2N = 107−1.8	Group 3N = 30−0.9	Group 4N = 49−1.4	NS
		12	5.6	5.4	8.8	5.3	p < 0.05ETN versus RIS, ALN	−0.4	−0.6	1.1	−0.4	NS	0.2	−0.5	1.5	−0.3	NS
		18	7.7	7.8	11.6	8.2	p < 0.05ETN versus NON-BPs	0.9	0.6	2.4	1.4	NS	1.6	1.3	3.8	2.3	p < 0.005ALN versus ETI
		24	9.4	9.2	13.5	9.3	p < 0.05ETN versus NON-BPs	2.9	2.1	3.7	1.8	NS	4.1	3.4	3.7	2.7	NS

ALN, alendronate; AN, anabolic; AR, antiresorptive; BMD, bone mineral density; ETN, etidronate; FN, femoral neck; LS, lumbar spine; PTH, parathyroid hormone; RIS, risedronate; TH, total hip; TPTD, teriparatide.

Figure 2.

BMD change (mean % change) 24 months after the switch from anabolic, antiresorptive, or placebo.

Discussion

This systematic review evaluated a clinical question for the Italian Guidelines,¹⁵ and a panel of experts formulated recommendations through a structured and transparent process. Specifically, we conducted a systematic review and meta-analysis on sequential therapy in patients at very high risk of or with a fragility fracture that enabled us to strongly recommend the anabolic drugs as first-line treatment (moderate quality of evidence) as confirmed by the European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases.⁴⁴

We found a relevant reduction in fracture risk at almost every skeletal site, especially when we considered the effects of the sequence: (i) romosozumab to denosumab versus placebo to denosumab; (ii) romosozumab to alendronate versus alendronate by alone; and (iii) teriparatide to bisphosphonates versus placebo to bisphosphonates. On the contrary, the sequence from bisphosphonate or antiresorptive to teriparatide versus no treatment to teriparatide³⁸ did not find a significant reduction of fracture risk 12 months after the switch (RR, 0.38; 95% CI, 0.09–1.53). Furthermore, the percent BMD changes were calculated by merging studies that evaluated the different therapeutic strategies. Greater improvement in BMD has been obtained using an anabolic by alone, such as romosozumab, or (a better choice) an anabolic followed by an antiresorptive drug, such as denosumab. We confirmed a significantly greater BMD benefit for the sequence: (i) romosozumab to denosumab versus placebo to denosumab; (ii) teriparatide to denosumab versus teriparatide to oral bisphosphonates; (iii) romosozumab to alendronate versus alendronate by alone; (iv) PTH to bisphosphonates versus PTH to placebo; and (v) romosozumab to denosumab versus romosozumab to placebo. In a representative open study, the DATA study,³³ postmenopausal women starting with teriparatide for 24 months and subsequently switching to denosumab for 24 months showed greater spine and hip BMD gains compared to the opposite treatment sequence. Notably, the results seen in the combination group (teriparatide plus denosumab followed by denosumab alone) showed an early BMD gain at the spine and hip sites.⁴⁵ This negative influence of antiresorptive pretreatment seems to be related to the antiresorptive potency of the used drug; the higher the antiresorptive potency (alendronate > risedronate > risedronate > etidronate > non-bisphosphonates), the lower the BMD gains induced by teriparatide.^30,36 Moreover, the study of Gonnelli et al.³¹ showed an increase in spine BMD after switching from antiresorptive to teriparatide compared to only antiresorptive therapy, despite the limited sample size. Thus, the impact of post-anabolic treatment on the retention of densitometric gains is substantial, as evidenced by studies on both teriparatide³⁷ and romosozumab.⁴¹ We believe the analysis by Cosman provides a valuable perspective. For patients at low risk, antiresorptive therapy on its own suffices, whereas the subsequent strategy for high-risk patients post-anabolic therapy should be contingent upon the densitometric outcome attained. Should the densitometric increase be deemed satisfactory, maintenance with bisphosphonates is appropriate; however, if the desired endpoint is not achieved, continuation with denosumab may be advisable until the target T-score (possibly −2.5) is reached. At that juncture, transitioning to bisphosphonates may be considered.

In general, antiresorptive agents, such as bisphosphonates, were the first developed drugs, and only later did an anabolic agent, such as teriparatide, become available.⁴⁶ Some pharmacological therapies can be used only for a limited timeframe, such as romosozumab and PTH analogs, which require a treatment cycle of 12 and 24 months, respectively. Furthermore, the discontinuation of certain treatments is followed by an undesired rebound effect, characterized by rapid bone loss that can undermine most of the densitometric benefits obtained over time and, consequently, loss of the clinical benefit in terms of fracture prevention. This can occur with anabolic, but it is especially alarming for denosumab.⁴⁷ Drugs currently available for the treatment of osteoporosis are classified by their mechanism of action. Antiresorptive drugs reduce osteoclastic bone resorption, and they include estrogens and selective estrogen receptor modulators, bisphosphonates, and denosumab. In addition, anabolic drugs increase osteoblastic bone formation activity, including teriparatide and abaloparatide. Finally, dual-action drugs, such as romosozumab, increase osteoblastic bone formation activity and reduce osteoclastic bone resorption.

Anabolic drugs, such as teriparatide, abaloparatide, and romosozumab, reduce the risk of fracture more rapidly and to a greater extent than antiresorptive medications.⁴¹ Several head-to-head studies^28,48–50 showed that anabolic agents are more effective in reducing fracture incidence than oral bisphosphonates in the next 1 or 2 years, which have a higher refracture risk.^6,51–53 Anabolic medications not only provide bone mass accrual but are also associated with microstructural improvement, resulting in greater skeletal strength and resistance to fracture. Then, the sequential antiresorptive agents could sustain the BMD and strength gains, extending the protection against fractures over time.⁵⁴ With the newer drugs (denosumab and romosozumab), only head-to-head comparisons on densitometric effects are available.⁵⁵ However, there is increasing consensus on the appropriateness of estimating fracture risk reduction obtained with the densitometric gain associated with the therapy.⁵⁵ Unfortunately, anabolic drugs are widely underutilized in clinical practice, mostly due to their higher costs. For this reason, they are often used in high-risk patients, especially after the failure of a previous antiresorptive treatment for a new fracture or refracture.⁴⁵

Sequential therapy in osteoporosis offers a pivotal means to augment the efficacy of individual treatments, provided the proper sequence (from anabolic to antiresorptive) is employed. Yet, it is regrettable that the reverse order is still prevalent in clinical settings, which is counterproductive and is thus inadvisable. It is now acknowledged that the increase in bone density achieved through therapy can be translated into a reduced risk of subsequent fractures. Consequently, the study’s conclusions are pertinent to both high-risk and low-risk populations. Of course, in absolute numbers, the prevention of fractures will be considerably greater in the higher-risk cohort. This assertion is further corroborated by studies on romosozumab, where the romosozumab–alendronate sequence has demonstrated superiority over the alendronate–alendronate sequence in fracture outcomes, even though the study participants were of medium–low risk.

Limitations and strengths

Some limitations must be acknowledged. First, most studies were conducted in Europe, which may limit the generalizability of the results. Second, we have some concerns regarding the characteristics of patients and fracture sites at baseline. Moreover, few RCTs were included in each sequential therapeutic strategy, which might affect the interpretability of our findings. Third, the certainty of the evidence ranged from moderate to high RoB when considering anabolic as a first-line treatment. Conversely, a low RoB was attributed to sequential treatment from antiresorptive to anabolic medications.

Despite the above limitations, this study presents some strengths. The exhaustive search strategy identified an overview of RCTs focused on the sequential therapy from anabolic to antiresorptive and vice versa. In addition, the internal validity of the included studies was assessed using the RoB tool for RCTs.

Conclusion

The results of this systematic review and meta-analysis confirm that initial treatment with anabolic drugs produces substantial BMD improvements, both at the spine and at the hip sites, and the transition to antiresorptive drugs can preserve or even amplify the acquired benefit. These findings support the choice to treat very high-risk individuals with anabolic drugs first, followed by antiresorptive drugs, rather than using a reverse sequence.

Since osteoporosis is a chronic disease often requiring long-term treatments, clinicians are now asked not only to start a single drug but also to schedule long-term strategies based on the current and future fracture risk.

Supplemental Material

sj-docx-1-tab-10.1177_1759720X241234584 – Supplemental material for The sequential antifracturative treatment: a meta-analysis of randomized clinical trials

Supplemental material, sj-docx-1-tab-10.1177_1759720X241234584 for The sequential antifracturative treatment: a meta-analysis of randomized clinical trials by Angelo Fassio, Davide Gatti, Annalisa Biffi, Raffaella Ronco, Gloria Porcu, Giovanni Adami, Rosaria Alvaro, Riccardo Bogini, Achille P. Caputi, Luisella Cianferotti, Bruno Frediani, Stefano Gonnelli, Giovanni Iolascon, Andrea Lenzi, Salvatore Leone, Raffaella Michieli, Silvia Migliaccio, Tiziana Nicoletti, Marco Paoletta, Annalisa Pennini, Eleonora Piccirilli, Maurizio Rossini, Maria Luisa Brandi, Giovanni Corrao and Umberto Tarantino in Therapeutic Advances in Musculoskeletal Disease

Supplemental Material

sj-docx-2-tab-10.1177_1759720X241234584 – Supplemental material for The sequential antifracturative treatment: a meta-analysis of randomized clinical trials

Supplemental material, sj-docx-2-tab-10.1177_1759720X241234584 for The sequential antifracturative treatment: a meta-analysis of randomized clinical trials by Angelo Fassio, Davide Gatti, Annalisa Biffi, Raffaella Ronco, Gloria Porcu, Giovanni Adami, Rosaria Alvaro, Riccardo Bogini, Achille P. Caputi, Luisella Cianferotti, Bruno Frediani, Stefano Gonnelli, Giovanni Iolascon, Andrea Lenzi, Salvatore Leone, Raffaella Michieli, Silvia Migliaccio, Tiziana Nicoletti, Marco Paoletta, Annalisa Pennini, Eleonora Piccirilli, Maurizio Rossini, Maria Luisa Brandi, Giovanni Corrao and Umberto Tarantino in Therapeutic Advances in Musculoskeletal Disease

Footnotes

Acknowledgements

We thank Charlesworth Author Services for the English Academic Editing.

Declarations

ORCID iDs

Angelo Fassio

Giovanni Adami

Giovanni Iolascon

Salvatore Leone

Silvia Migliaccio

Marco Paoletta

Eleonora Piccirilli

Maurizio Rossini

Supplemental material

Supplemental material for this article is available online.

References

Wang

Zhuang

, et al. Influence of bone densitometry on the anti-osteoporosis treatment after fragility hip fracture. Aging Clin Exp Res 2019; 31: 1525–1529.

Keshishian

Boytsov

Burge

, et al. Examining the treatment gap and risk of subsequent fractures among females with a fragility fracture in the US Medicare population. Osteoporos Int 2017; 28: 2485–2494.

Kanis

Johnell

De Laet

, et al. A meta-analysis of previous fracture and subsequent fracture risk. Bone 2004; 35: 375–382.

Johansson

Siggeirsdóttir

Harvey

, et al. Imminent risk of fracture after fracture. Osteoporos Int 2017; 28: 775–780.

Borgström

Karlsson

Ortsäter

, et al. Fragility fractures in Europe: burden, management and opportunities. Arch Osteoporos 2020; 15: 59.

Balasubramanian

Zhang

Chen

, et al. Risk of subsequent fracture after prior fracture among older women. Osteoporos Int 2019; 30: 79–92.

Johnell

Kanis

. An estimate of the worldwide prevalence and disability associated with osteoporotic fractures. Osteoporos Int 2006; 17: 1726–1733.

Lewiecki

. Secondary fracture prevention via a fracture liaison service. Womens Health (Lond) 2015; 11: 269–271.

Gupta

Shah

Peterson

, et al. Rush fracture liaison service for capturing ‘missed opportunities’ to treat osteoporosis in patients with fragility fractures. Osteoporos Int 2018; 29: 1861–1874.

10.

Fassio

Rossini

Viapiana

, et al. New strategies for the prevention and treatment of systemic and local bone loss; from pathophysiology to clinical application. Curr Pharm Des 2017; 23: 6241–6250.

11.

Anagnostis

Gkekas

Potoupnis

, et al. New therapeutic targets for osteoporosis. Maturitas 2019; 120: 1–6.

12.

Cheng

Wentworth

Shoback

. New frontiers in osteoporosis therapy. Annu Rev Med 2020; 71: 277–288.

13.

Cosman

Crittenden

Adachi

, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med 2016; 375: 1532–1543.

14.

Compston

Cooper

, et al. UK clinical guideline for the prevention and treatment of osteoporosis. Arch Osteoporos 2017; 12: 43.

15.

Sistema Nazionale Linee Guida (SNLG). Diagnosi, Stratificazione del rischio e continuità assistenziale delle Fratture da Fragilità, 2021 https://snlg.iss.it/.

16.

Schünemann

Wiercioch

Brozek

, et al. GRADE evidence to decision (EtD) frameworks for adoption, adaptation, and de novo development of trustworthy recommendations: GRADE-ADOLOPMENT. J Clin Epidemiol 2017; 81: 101–110.

17.

Manuale metodologico per la produzione di linee guida di pratica clinica, v. 1.3.2 April 2019. Centro Nazionale per l’Eccellenza Clinica, la Qualità e la Sicurezza delle Cure. Istituto Superiore di Sanità.

18.

SNLG ISS. Sistema nazionale per le linee guida – Istituto superiore di sanità. Come produrre, diffondere e aggiornare raccomandazioni per la pratica clinica. Manuale metodologico. Roma: PNLG, 2019.

19.

Anastasilakis

Polyzos

Yavropoulou

, et al. Combination and sequential treatment in women with postmenopausal osteoporosis. Expert Opin Pharmacother 2020; 21: 477–490.

20.

Page

Moher

. Evaluations of the uptake and impact of the preferred reporting items for systematic reviews and meta-analyses (PRISMA) statement and extensions: a scoping review. Syst Rev 2017; 6: 263.

21.

Page

McKenzie

Bossuyt

, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ 2021; 372: n71.

22.

Shea

Reeves

Wells

, et al. AMSTAR 2: a critical appraisal tool for systematic reviews that include randomised or non-randomised studies of healthcare interventions, or both. BMJ 2017; 358: j4008.

23.

Higgins

JPT

Altman

Gøtzsche

, et al. The Cochrane Collaboration’s tool for assessing risk of bias in randomised trials. BMJ 2011; 343: d5928.

24.

Balshem

Helfand

Schünemann

, et al. GRADE guidelines: 3. Rating the quality of evidence. J Clin Epidemiol 2011; 64: 401–406.

25.

Cochran

. The combination of estimates from different experiments. Biometrics 1954; 10: 101–129.

26.

Higgins

JPT

Thompson

Deeks

, et al. Measuring inconsistency in meta-analyses. BMJ 2003; 327: 557–560.

27.

Deeks

Higgins

JPT

Altman

. Chapter 10: Analysing data and undertaking meta-analyses. In: Higgins

JPT

Thomas

Chandler

, et al. (eds) Cochrane handbook for systematic reviews of interventions version 6.3 (updated February 2022). Cochrane, 2022.

28.

Saag

Petersen

Brandi

, et al. Romosozumab or alendronate for fracture prevention in women with osteoporosis. N Engl J Med 2017; 377: 1417–1427.

29.

Black

Bilezikian

Ensrud

, et al. One year of alendronate after one year of parathyroid hormone (1–84) for osteoporosis. N Engl J Med 2005; 353: 555–565.

30.

Boonen

Marin

Obermayer-Pietsch

, et al. Effects of previous antiresorptive therapy on the bone mineral density response to two years of teriparatide treatment in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2008; 93: 852–860.

31.

Gonnelli

Martini

Caffarelli

, et al. Teriparatide’s effects on quantitative ultrasound parameters and bone density in women with established osteoporosis. Osteoporos Int 2006; 17: 1524–1531.

32.

Langdahl

Libanati

Crittenden

, et al. Romosozumab (sclerostin monoclonal antibody) versus teriparatide in postmenopausal women with osteoporosis transitioning from oral bisphosphonate therapy: a randomised, open-label, phase 3 trial. Lancet 2017; 390: 1585–1594.

33.

Leder

Tsai

Uihlein

, et al. Denosumab and teriparatide transitions in postmenopausal osteoporosis (the DATA-Switch study): extension of a randomised controlled trial. Lancet 2015; 386: 1147–1155.

34.

Lewiecki

Dinavahi

Lazaretti-Castro

, et al. One year of romosozumab followed by two years of denosumab maintains fracture risk reductions: results of the FRAME extension study. J Bone Miner Res 2019; 34: 419–428.

35.

Middleton

Steel

Doherty

. The effect of prior bisphosphonate exposure on the treatment response to teriparatide in clinical practice. Calcif Tissue Int 2007; 81: 335–340.

36.

Miller

Delmas

Lindsay

, et al. Early responsiveness of women with osteoporosis to teriparatide after therapy with alendronate or risedronate. J Clin Endocrinol Metab 2008; 93: 3785–3793.

37.

Niimi

Kono

Nishihara

, et al. Efficacy of switching from teriparatide to bisphosphonate or denosumab: a prospective, randomized, open-label trial. JBMR Plus 2018; 2: 289–294.

38.

Obermayer-Pietsch

Marin

McCloskey

, et al. Effects of two years of daily teriparatide treatment on BMD in postmenopausal women with severe osteoporosis with and without prior antiresorptive treatment. J Bone Miner Res 2008; 23: 1591–1600.

39.

Prince

Sipos

Hossain

, et al. Sustained nonvertebral fragility fracture risk reduction after discontinuation of teriparatide treatment. J Bone Miner Res 2005; 20: 1507–1513.

40.

Miyauchi

Dinavahi

Crittenden

, et al. Increased bone mineral density for 1 year of romosozumab, vs placebo, followed by 2 years of denosumab in the Japanese subgroup of the pivotal FRAME trial and extension. Arch Osteoporos 2019; 14: 59.

41.

Cosman

Lewiecki

Ebeling

, et al. T-score as an indicator of fracture risk during treatment with romosozumab or alendronate in the ARCH trial. J Bone Miner Res 2020; 35: 1333–1342.

42.

Fahrleitner-Pammer

Burr

Dobnig

, et al. Improvement of cancellous bone microstructure in patients on teriparatide following alendronate pretreatment. Bone 2016; 89: 16–24.

43.

Kendler

Bone

Massari

, et al. Bone mineral density gains with a second 12-month course of romosozumab therapy following placebo or denosumab. Osteoporos Int 2019; 30: 2437–2448.

44.

Curtis

Reginster

Al-Daghri

, et al. Management of patients at very high risk of osteoporotic fractures through sequential treatments. Aging Clin Exp Res 2022; 34: 695–714.

45.

Cosman

Nieves

Dempster

. Treatment sequence matters: anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res 2017; 32: 198–202.

46.

Gatti

Fassio

. Pharmacological management of osteoporosis in postmenopausal women: The current state of the art. J Popul Ther Clin Pharmacol 2019; 26: e1–e17.

47.

Elbers

LPB

Raterman

Lems

. Bone mineral density loss and fracture risk after discontinuation of anti-osteoporotic drug treatment: a narrative review. Drugs 2021; 81: 1645–1655.

48.

Saag

Emkey

Schnitzer

, et al. Alendronate for the prevention and treatment of glucocorticoid-induced osteoporosis. Glucocorticoid-induced osteoporosis intervention study group. N Engl J Med 1998; 339: 292–299.

49.

Hadji

Zanchetta

Russo

, et al. The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures. Osteoporos Int 2012; 23: 2141–2150.

50.

Leder

Mitlak

, et al. Effect of abaloparatide vs alendronate on fracture risk reduction in postmenopausal women with osteoporosis. J Clin Endocrinol Metab 2020; 105: 938–943.

51.

Roux

Briot

. Imminent fracture risk. Osteoporos Int 2017; 28: 1765–1769.

52.

van Geel

TACM

Huntjens

KMB

van den Bergh

JPW

, et al. Timing of subsequent fractures after an initial fracture. Curr Osteoporos Rep 2010; 8: 118–122.

53.

Center

Bliuc

Nguyen

, et al. Risk of subsequent fracture after low-trauma fracture in men and women. JAMA 2007; 297: 387–394.

54.

Kanis

Cooper

Rizzoli

, et al.; Scientific Advisory Board of the European Society for Clinical and Economic Aspects of Osteoporosis (ESCEO) and the Committees of Scientific Advisors and National Societies of the International Osteoporosis Foundation (IOF). European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int 2019; 30: 3–44.

55.

Bouxsein

Eastell

Lui

, et al. Change in bone density and reduction in fracture risk: a meta-regression of published trials. J Bone Miner Res 2019; 34: 632–642.

Supplementary Material

Please find the following supplemental material available below.

For Open Access articles published under a Creative Commons License, all supplemental material carries the same license as the article it is associated with.

For non-Open Access articles published, all supplemental material carries a non-exclusive license, and permission requests for re-use of supplemental material or any part of supplemental material shall be sent directly to the copyright owner as specified in the copyright notice associated with the article.

0.00 MB

0.13 MB

0.03 MB