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Journal of Orthopaedic Surgery and Research logoLink to Journal of Orthopaedic Surgery and Research
. 2021 Aug 27;16:533. doi: 10.1186/s13018-021-02678-x

Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis

Filippo Migliorini 1,✉, Nicola Maffulli 2,3,4, Giorgia Colarossi 1, Jörg Eschweiler 1, Markus Tingart 1, Marcel Betsch 5
PMCID: PMC8393477  PMID: 34452621

Abstract

Background

Osteoporosis affects mostly postmenopausal women, leading to deterioration of the microarchitectural bone structure and low bone mass, with an increased fracture risk with associated disability, morbidity and mortality. This Bayesian network meta-analysis compared the effects of current anti-osteoporosis drugs on bone mineral density.

Methods

The present systematic review and network meta-analysis follows the PRISMA extension statement to report systematic reviews incorporating network meta-analyses of health care interventions. The literature search was performed in June 2021. All randomised clinical trials that have investigated the effects of two or more drug treatments on BMD for postmenopausal osteoporosis were accessed. The network comparisons were performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. The inverse variance method with standardised mean difference (SMD) was used for analysis.

Results

Data from 64 RCTs involving 82,732 patients were retrieved. The mean follow-up was 29.7 ± 19.6 months. Denosumab resulted in a higher spine BMD (SMD −0.220; SE 3.379), followed by pamidronate (SMD −5.662; SE 2.635) and zoledronate (SMD −10.701; SE 2.871). Denosumab resulted in a higher hip BMD (SMD −0.256; SE 3.184), followed by alendronate (SMD −17.032; SE 3.191) and ibandronate (SMD −17.250; SE 2.264). Denosumab resulted in a higher femur BMD (SMD 0.097; SE 2.091), followed by alendronate (SMD −16.030; SE 1.702) and ibandronate (SMD −17.000; SE 1.679).

Conclusion

Denosumab results in higher spine BMD in selected women with postmenopausal osteoporosis. Denosumab had the highest influence on hip and femur BMD.

Level of evidence

Level I, Bayesian network meta-analysis of RCTs

Keywords: Osteoporosis, Bone mineral density, Drugs, Denosumab

Introduction

Osteoporosis is common in postmenopausal women, with microarchitectural deterioration and low bone mass. Approximately, 19% of men and 30% of women in Europe and in the USA are at risk for osteoporosis, and annually around 9 million osteoporosis associated fractures occur [1]. Osteoporosis-associated fractures result in increased disability, mortality and health-care costs, and therefore the treatment and prevention of osteoporotic fractures carries significant clinical and public health importance [2].

Current approved pharmacological treatments for postmenopausal osteoporosis can be divided into anti-resorptive and anabolic medications [3]. Briefly, anti-resorptive drugs reduce bone resorption, whilst anabolic drugs increase bone formation. The most commonly prescribed agents are anti-resorptive drugs, which include bisphosphonates (BP) (e.g. alendronate, risedronate, zoledronic acid, ibandronate, etidronate), selective oestrogen receptor modulators (SERM) (e.g. raloxifene) and the RANK-ligand inhibitor (e.g. denosumab).

BP were discovered during the search for pyrophosphonate analogues, attempting to benefit from the inhibitory effects of pyrophosphates on calcification [4]. BP work by inhibiting the enzyme farnesyl pyrophosphonate synthase in osteoclasts, influencing their affinity for bone mineral uptake [5, 6]. During early treatment, SERMs decrease bone remodelling by about 20-30%, and thereby result in a modest transitory increase in bone mineral density (BMD) [7]. However, during prolonged therapy, SERMs lead to a decline in BMD, which may account for the only modest reduction in vertebral fracture risk [7].

Denosumab is a monoclonal antibody against the receptor activator of nuclear factor-kappa B ligand (RANK-ligand), a regulator of osteoclast development. By blocking the RANK-ligand with denosumab the activity, survival and recruitment of osteoblast are inhibited.

Anabolic osteoporosis drugs, such as teriparatide, are usually reserved for patients with severe and established osteoporosis. Both medications lead to an increase in trabecular thickness and improved trabecular microstructure via the teriparatide (PTHR1) receptor [8, 9]. Finally, romosozunab is a novel sclerostin antibody recently approved for the treatment of osteoporosis. Romosozunab has antifracture and anabolic efficacy, increasing bone formation and decreasing bone resorption [10, 11].

Network analysis may provide clinically relevant evidence in the absence of randomised controlled trials (RCTs) comparing relevant pharmaceutical treatments for osteoporosis. Therefore, we conducted this network meta-analysis comparing the effects of nine osteoporosis drugs and their effects on BMD in patients with postmenopausal osteoporosis.

Methods

Search strategy

The present systematic review and network meta-analysis follows the PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of health care interventions [12]. The follow algorithm guided the preliminary search:

  • P (population): postmenopausal osteoporosis

  • I (intervention): medical treatments

  • C (comparison): denosumab, raloxifene, teriparatide, alendronate, risedronate, zoledronate, ibandronate, etidronate, strontiumranelate

  • O (outcomes): BMD

Data source and extraction

The literature search was performed by two independent authors (FM; GC). In June 2021, the databases search started. The search on PubMed was performed with the following string: osteoporosis [All Fields] AND (bone [All Fields] OR endocrinology [All Fields]) AND (postmenopausal [All Fields] OR treatment [All Fields] OR management [All Fields] OR spine [All Fields] OR femur [All Fields] AND hip [All Fields] OR BMD [All Fields]) AND (mineral density [All Fields] OR Bisphosphonates [All Fields] OR Denosumab [All Fields] OR Raloxifene [All Fields] OR Teriparatide [All Fields] OR Alendronate [All Fields] OR Risedronate [All Fields] OR Zoledronate [All Fields] OR Ibandronate [All Fields] OR Etidronate [All Fields] OR Calcium [All Fields] OR Vitamin D [All Fields] OR PTH [All Fields] OR osteoblast [All Fields] OR osteoclast [All Fields]) AND management [All Fields] OR therapy [All Fields]. The same search strings were used to search Google Scholar, Embase and Scopus. The resulting titles and subsequent abstracts were screened by the same two authors. If they matched the topic, the article full-text was accessed. A cross reference of the bibliographies was also performed. Disagreement was debated and solved by a third senior author (NM).

Eligibility criteria

All the randomised clinical trials (RCTs) investigating the effects of two or more drug treatments on BMD for postmenopausal osteoporosis were accessed. Given the authors language capabilities, articles in English, German, Italian, French and Spanish were eligible. Only levels I and II RCTs according to the Oxford Centre of Evidence-Based Medicine [13] were considered. Only articles reporting quantitative data under the outcomes of interest and articles with a minimum 12 months follow-up were considered. Studies treating patients with calcium and vitamin D without any other drugs were not included. Studies reporting data on patients with iatrogenic-induced menopause were not included, as well as those treating paediatric and/or adolescent patients. Studies on patients undergoing immunosuppressive therapies or organ transplantation were also not considered. Studies reporting data on patients with malignancies or pathological bone diseases other than osteoporosis were not included. Studies reporting data on mixed treatments or taking advantage from adjuvants were excluded. Editorials, registries, comments, expert opinions and reviews were not eligible. Animals or in vitro studies were also not eligible. Missing data under the outcomes of interest warranted the exclusion from this study.

Outcomes of interest

Two authors (FM; GC) performed data extraction. Study generalities (author, year, journal, duration of the follow-up) and patient baseline demographic information were collected: number of samples and related mean age, percentage of female, mean bone mass index (BMI) and mean BMD (overall, spine, hip, femur neck). The following drugs were considered in the analyses: denosumab, raloxifene, teriparatide, alendronate, risedronate, zoledronate, ibandronate and etidronate. The outcome of interest was BMD at last follow-up.

Methodology quality assessment

The methodological quality assessment was performed by two authors (FM; GC). The risk of bias summary tool of the Review Manager Software (The Nordic Cochrane Collaboration, Copenhagen) was used for evaluation. The following risk of bias was assessed: selection, detection, attrition and other source of bias.

Statistical analysis

The statistical analyses were performed by the main author (FM). Baseline comparability was assessed through the IBM SPSS software. The analysis of variance (ANOVA) was used for analysis, with P values > 0.1 was considered satisfactory. The STATA Software/MP, Version 14.1 (StataCorporation, College Station, Texas, USA) was used for the statistical analyses. The NMA was performed through the STATA routine for Bayesian hierarchical random-effects model analysis. The placebo treatment was used as reference group. The inverse variance method was used for analysis, with standardised mean difference (STD) and standard error (SE) effect measures. The overall inconsistency was evaluated through the equation for global linearity via the Wald test, with P values< 0.05 indicating statistically significant inconsistency. Otherwise, if P > 0.05 the null hypothesis cannot be rejected, and the consistency assumption could be accepted at the overall level of each treatment. Both confidence (CI) and percentile (PrI) intervals were set at 95%. Edge plot, interval plots and funnel plots were obtained and evaluated.

Results

Search result

The primary literature search resulted in 1354 articles. Of them, 477 were RCTs. A further 101 were removed because duplicated. Additional 270 articles were excluded because of the study design (N = 26), non-clinical studies (N = 34), glucocorticoid-induced osteoporosis (N = 51), treatment of bone malignancies (N = 56), language limitations (N = 12) and others (N = 91). A further 42 articles were excluded because it did not report quantitative data under the outcomes of interests. Finally, 64 RCTs were included for analysis. The literature search results are shown in Fig. 1.

Fig. 1.

Fig. 1

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Flow chart of the literature search

Methodological quality assessment

The risk of bias summary evidenced some point of strength of the present study. First, the randomised design of all the included studies leads to low risk of selection bias. Moreover, most studies performed assessors, patients and personnel blinding, thus leading to a low risk of performance and detection bias. The risk of attrition and reporting bias were both low. The risk to incur in unknown/other bias was low to moderate. Concluding, the risk of bias was low, attesting to the methodological assessment of the present study is a very good quality. The score of each risk of bias item for each included study is shown in Fig. 2.

Fig. 2.

Fig. 2

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Methodological quality assessment

Patient demographics

Data from 82,732 patients were retrieved. The mean follow-up was 29.7 ± 19.6 months. The mean age of the patients was 67.3 ± 6.1 years. The mean BMI was 25.0 ±1.7 kg/m2. The mean BMD at baseline of the spine was 0.83 ± 0.11, of the hip was 0.74 ± 0.07 and of the femoral neck was 0.63 ± 0.07 g/cm2. The ANOVA test found baseline comparability (P > 0.1) with regards to age, BMI and BMD. Studies’ generalities and patients’ demographics are shown in Table 1.

Table 1.

Generalities and patients baseline of the included studies

Author, year Journal Follow-up (months) Calcium daily supplement (mg) Vit D daily supplement (UI) Treatment Administration Samples (n) Mean age Mean BMI (kg/m2) BMD
Spine (g/cm2)		 BMD
Hip
(g/cm2)		 BMD
Femur neck (g/cm2)
Anastasilakis et al. 2015 [29] Osteoporos Int 12 1000 800 Denosumab IM 32 63 28.80 0.97
Zoledronate IV 26 63 28.70 0.94
Placebo IV 241 57 23.73 0.92 0.65 0.63
Black et al. 2007 [30] New England J Med 36 1000-1500 400-1200 Zoledronate IV 3875 73 25.10 0.79 0.65 0.53
Placebo IV 3861 73 25.40 0.79 0.65 0.53
Body et al. 2002 [31] J Clin Endocrinol Metab 14 1000 400-1200 Alendronate OS 73 65 24.40 0.80
Teriparatide SC 73 66 23.90 0.80
Black et al. 1996 [32] The Lancet 36 652 Alendronate OS 1022 71 25.50 0.79 0.57
619 Placebo OS 1005 71 25.60 0.79 0.56
Black et al. 2006 [33] JAMA 60 655 Alendronate OS 329 73 25.70 0.90 0.73 0.62
667 Alendronate OS 333 73 25.90 0.89 0.73 0.61
635 Placebo OS 437 74 25.80 0.90 0.72 0.61
Black et al. 2012 [34] J Bone Min Res 36 1000-1500 400-1200 Zoledronate IV 616 76 25.30 0.81 0.69 0.56
Placebo IV 617 76 25.60 0.82 0.69 0.57
Black et al. 2015 [35] J Bone Min Res 36 1000-1500 400-1200 Zoledronate IV 95 78 24.60 0.69 0.58
Placebo IV 95 78 25.00 0.71 0.58
Bone et al. 1997 [36] J Clin Endocrinol Metab 24 813 Alendronate OS 86 71
880 Alendronate OS 89 70
831 Alendronate OS 93 71
900 Placebo OS 91 71
Brown et al. 2014 [37] Osteoporos Int 12 Denosumab SC 852 68
Ibandronate OS 851 67
Risedronate OS
Brumsen et al. 2002 [38] J Bone Min Res 60 500 400 Pamidronate OS 26 66 0.76 0.64
Placebo OS 27 64 0.74 0.64
Chesnut et al. 2004 [39] J Bone Min Res 36 500 400 Ibandronate OS 977 69 26.20
Ibandronate OS 977 69 26.20
Placebo OS 975 69 26.20
Clemmesen et al. 1997 [40] Osteoporos Int 36 1000 Risedronate OS 44 67 25.50 0.80 0.61
Risedronate/placebo OS 44 68 24.40 0.79 0.61
Placebo OS 44 70 25.10 0.75 0.61
Cosman et al. 2016 [10] New England J Med 12 500-1000 600-800 Romosozumab SC 3589 71
Placebo SC 3591 71
24 500-1000 600-800 Denosumab SC 3589 71
Denosumab SC 3591 71
Cummings et al. 1998 [41] JAMA 48 634 Alendronate OS 2214 68 24.90 0.84 0.59
638 Placebo OS 2218 68 25.00 0.84 0.59
Cummings et al. 2009 [42] New England J Med 36 1000 400-800 Denosumab SC 3902 72 26.00
Placebo SC 3906 72 26.00
Delmas et al. 2002 [43] J Clin Endocrinol Metab 48 500 400-600 Raloxifene OS 2259 66 25.30 0.82 0.62
Raloxifene OS 2277 66 25.20 0.81 0.62
Placebo OS 2292 67 25.30 0.81 0.62
Ettinger et al. 1999 [7] JAMA 36 500 400-600 Raloxifene OS 2259 67
Raloxifene OS 2277
Placebo OS 2292
Fogelman et al. 2000 [44] J Clin Endocrinol Metab 24 1000 Risedronate OS 184 65 24.80 0.73 0.63
Risedronate OS 177 65 24.80 0.75 0.64
Placebo OS 180 64 25.50 0.74 0.64
Frediani et al. 1998 [45] Clin Drug Invest 24 Alendronate OS 30 63 20.90 0.81
Calcitriol OS 30 63 21.80 0.81
Alendronate/calcitriol OS 30 63 21.00 0.80
Calcium OS 30 63 21.20 0.80
Garg et al. 2015 [46]

J South Asian Feder Menopause

Soc

 12 Zoledronate IV 50
Teriparatide SC 50
Gonnelli et al. 2014 [47] Bone 12 841 400 Zoledronate IV 30 66 26.10 0.82 0.79
870 Ibandronate IV 30 67 25.70 0.82 0.79
Greenspan et al. 2015 [48] JAMA 24 807 163 Zoledronate IV 89 85 28.20 0.93 0.68 0.61
763 168 Placebo IV 92 86 26.90 0.97 0.70 0.62
Grey et al. 2009 [49] J Clin Endocrinol Metab 24 935 Zoledronate IV 25 62 1.06 0.85
916 Placebo IV 25 65 1.03 0.86
Grey et al. 2012 [50] J Clin Endocrinol Metab 12 960 Zoledronate IV 43 64 1.01 0.85
880 Zoledronate IV 43 66 1.03 0.84
850 Zoledronate IV 43 66 1.05 0.84
950 Placebo IV 43 65 1.03 0.87
Guanabens et al. 2013 [51] Hepatology 24 1000 Ibandronate OS 14 65 26.60 0.90 0.84 0.79
Alendronate OS 19 63 26.60 0.88 0.81 0.77
Harris et al. 1993 [52] Am J Med 48 500 Phosphate-etidronate OS 63 0.89 0.67
Placebo-etidronate OS 65 0.87 0.69
Phosphate-placebo OS 62 0.87 0.67
Placebo OS 63 0.86 0.68
Harris et al. 1999 [53] JAMA 36 1000 500 Risedronate OS 817 69 26.60 0.84 0.60
Risedronate OS 821 69 26.60 0.83 0.59
Placebo OS 820 68 26.50 0.83 0.60
Hooper et al. 2005 [54] Climacteric 24 Risedronate 1OS 128 53 1.08
Risedronate OS 129 53 1.08
Placebo OD 126 53 1.08
Iwamoto et al. 2008 [55] Yonsei Med J 12 800 Alendronate OS 61 70 21.90 0.62
Raloxifene OS 61 69 21.70 0.65
Kendler et al. 2019 [56] Osteoporosis Int 12 > 1000 > 800 Romosozumab SC 16 69
Romosozumab SC 19 68
Romosozumab SC 14
Romosozumab SC 12
Langdahl et al. 2017 [57] The Lancet 12 500-1000 600-800 Romosozumab SC 198 72
Teriparatide SC 200 71
Leder et al. 2015 [58] The Lancet 48 Teriparatide-denosumab SC 27 66 25.50 0.82 0.64
Denosumab-teriparatide SC 27 65 23.80 0.86 0.64
Combined-denosumab SC 23 65 25.90 0.85 0.64
Leder et al. 2014 [59] J Clin Endocrinol Metab 24 Teriparatide SC 31 66 25.50 0.82 0.64
Denosumab SC 33 66 24.10 0.87 0.64
Combined SC 30 66 25.40 0.86 0.64
Lewiecki et al. 2018 [60] J Clin Endocrinol Metab 12 Denosumab SC 3003 71 24.70
Denosumab SC 3042 71 24.70
Liang et al. 2017 [61] Orthop Surg 24 Zoledronate IV 155 57 21.80 0.63 0.75
Placebo IV 95 57 21.60 0.63 0.75
Placebo OS 355 64 24.10
Lufkin et al. 1998 [62] J Bone Min Res 12 Raloxifene OS 48 67 24.80 0.75 0.64
Raloxifene OS 47 67 26.20 0.81 0.69
750 400 Calcium/vit D OS 48 68 25.30 0.77 0.67
Lyritis et al. 1997 [63] Clin Rheumatol 48 500 Etidronate OS 39 72 27.60 0.57 0.42
Calcium/vit D OS 35 72 26.80 0.57 0.43
McClung et al. 2014 [64] New England J Med 12 1000 800 Romosozumab SC 44 67
Romosozumab SC 46 67
Romosozumab SC 49 67
Romosozumab SC 52 67
Romosozumab SC 53 67
Alendronate OS 47 67
Teriparatide SC 46 67
Placebo SC 47 67
McClung et al. 2009 [65] ObstetGynecol 24 500-1200 400-800 Zoledronate IV 181 60 26.50 0.86 0.69
Zoledronate-placebo IV 154 60 27.30 0.86 0.69
Placebo IV 188 61 27.20 0.86 0.69
McClung et al. 2018 [66] J Bone Min Res 12 1000 800 Denosumab SC 127 67
Placebo SC 131 67
Meunier et al. 2004 [67] New England J Med 36 1000 400-800 Strontium ranelate OS 719 69 26.20 0.73 0.69 0.59
Placebo OS 723 69 26.20 0.72 0.68 0.59
Meunier et al. 2009 [68] Osteoporos Int 12 1000 400-800 Strontium ranelate OS 221 72 0.85 0.66
Strontium ranelate OS 434 72 0.72 0.58
Placebo OS 225 72 0.86 0.64
Miller et al. 2016 [69] J Clin Endocrinol Metab 12 1000 800 Denosumab SC 321 69 24.30
Zoledronate IV 322 70 24.30
Miyauchi et al. 2019 [68] Arch Osteoporos 36 500-1000 600-800 Denosumab SC 247 71 21.10
Denosumab SC 245 70 21.40
Montessori et al. 1997 [70] Osteoporos Int 36 Etidronate OS 40 62 0.68 0.67 0.60
Calcium OS 40 63 0.67 0.69 0.61
Morii et al. 2003 [71] Osteoporos Int 13 Raloxifene OS 90 65 21.50 0.66
Raloxifene OS 93 65 21.90 0.67
Placebo OS 97 64 22.00 0.64
Mortensen et al. 1998 [72] J Clin Endocrinol Metab 36 937 Risedronate OS 37 52 0.93 0.74
1057 Risedronate OS 38 51 0.93 0.71
936 Placebo OS 36 51 0.96 0.74
Neer et al. 2001 [73] New England J Med 24 1000 400-1200 Teriparatide SC 444 69 0.82 0.70 0.64
Teriparatide SC 434 70 0.82 0.70 0.64
Placebo SC 448 69 0.82 0.71 0.64
Paggiosi et al. 2014 [74] Osteoporos Int 24 1200 800 Alendronate OS 57 68 25.90 0.79 0.75 0.64
Ibandronate OS 58 67 26.40 0.80 0.78 0.64
Risedronate OS 57 67 26.80 0.81 0.80 0.67
Control 226 38 25.10 1.,07 0.97 0.86
Papapoulos et al. 2012 [75] J Bone Min Res 24 Denosumab SC 2343 75
Denosumab SC 2207 75
Papapoulos et al. 2015 [76] Osteoporos Int 60 > 1000 > 400 Denosumab SC 2343 79
Denosumab SC 2207 79
Popp e t al. 2013 [77] Maturitas 36 1000-1500 400-1200 Zoledronate IV 55 77 24.60 0.77 0.67 0.56
Placebo IV 55 77 24.40 0.77 0.67 0.55
Recknor et al. 2013 [26] ObstetGynecol 12 500 800 Denosumab SC 417 67 25.50
Ibandronate OS 416 66 25.10
Reginster et al. 2009 [78] Osteoporos Int 36 500-1000 400-800 Strontium ranelate OS 879 79 25.90 0.93 0.73 0.61
Control OS 892 74 25.90 0.77 0.67 0.57
Reginster et al. 2011 [79] Osteoporos Int 60 500-1000 400-800 Strontium ranelate OS 233 77 25.80 0.76 0.69 0.58
Placebo OS 458 76 25.20
Roux et al. 2014 [80] Bone 12 ≥ 1000 ≥ 800 Denosumab SC 435 68
Risedronate OS 435 68
Saag et al. 2017 [11] New England J Med 24 Alendronate OS 2047 74 25.40
Romosozumab-alendronate SC-OS 2046 74 25.50
Tsai et al. 2013 [81] The Lancet 12 Teriparatide SC 31 66 25.50 0.82 0.76 0.64
Denosumab SC 33 66 24.10 0.87 0.77 0.64
Teriparatide/denosumab SC 30 66 25.40 0.86 0.76 0.64
Tsai et al. 2019 [82] The Lancet 15 Teriparatide-denosumab SC 35 66 23.00 0.83 0.74 0.65
Teriparatide-denosumab SC 34 67 22.80 0.79 0.74 0.62
Tucci et al. 1996 [83] Am J Med 36 500 Alendronate OS 98 67 23.90
Alendronate OS 94 64 23.30
Alendronate OS 94 64 23.70
Placebo OS 192 64 23.80
Jiang et al. 2003 [84] J Bone Min Res 19 1000 400-1200 Teriparatide SC 18 68 0.77 0.61
Teriparatide SC 14 68 0.84 0.62
Placebo SC 19 68 0.86 0.65
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Outcomes of interest

Denosumab resulted in a higher spine BMD (SMD −0.22; SE 3.38; 95% CI −6.84 to 6.40), followed by pamidronate (SMD −5.66; SE 2.64; 95% CI −10.83 to −0.50) and zoledronate (SMD −10.70; SE 2.87; 95% CI −16.33 to −5.07). Denosumab resulted in a higher hip BMD (SMD −0.26; SE 3.18; 95% CI −6.50 to 5.98), followed by alendronate (SMD −17.03; SE 3.19; 95% CI −23.29 to −10.78) and ibandronate (SMD −17.25; SE 2.26; 95% CI −21.69 to −12.81). Denosumab resulted in a higher femur BMD (SMD 0.10; SE 2.09; 95% CI −4.00 to 4.20), followed by alendronate (SMD −16.03; SE 1.70; 95% CI −19.37 to −12.69) and ibandronate (SMD −17.00; SE 1.68; 95% CI −20.29 to −13.71). The equation for global linearity found no statistically significant inconsistency (P > 0.05) in all comparisons. Edge, funnel and interval plots of these comparisons are shown in Fig. 3.

Fig. 3.

Fig. 3

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Edge, funnel and interval plots of the comparisons

Discussion

Over the last decades, effective pharmaceutical treatments have been developed for the management of osteoporosis. However, most studies have not included multiple active comparators because of cost constraints, ethical problems and government regulations. This network meta-analysis is the first to include 64 RCTs with a total of 82,732 patients, including only studies with levels of evidence 1 and 2. This study compared and evaluated the influence of currently available pharmacological treatments for osteoporosis with one another in terms of BMD. The present investigation shows that denosumab was associated with the highest BMD of all evaluated osteoporosis drugs in selected women with postmenopausal osteoporosis.

Meta-analyses are considered valuable tools to analyse different studies. However, they only allow a pair-wise assessment of treatments. In contrast, network meta-analyses allow to blend together information over a network of comparisons to compare the relative effects of different treatments used for the same condition. Network meta-analysis provides vital clinical information by ranking the relative efficacy of all interventions, even those which have not been compared with one another directly.

Most previous network meta-analyses have investigated the effects of osteoporosis treatments on fracture risk, which is in contrast to our analysis which instead focused on the influence of drugs on BMD. A recent network meta-analysis of 22 RCTs studied the relative efficacy of 10 osteoporosis drugs in postmenopausal women at high risk of fragility fractures [14]. Abaloparatide had the highest probability of preventing vertebral, non-vertebral, and wrist fractures compared to placebo and all other treatment options. This was also confirmed by another network meta-analysis of 67,524 patients: both abaloparatide and teriparatide significantly reduced the fracture risk compared to placebo and other osteoporosis medications [15]. In addition, a further network meta-analysis confirmed that teriparatide seemed to be most effective in preventing new non-vertebral fractures in patients with osteoporosis [16]. A systematic review and network meta-analysis of RCTs evidenced that non-bisphosphonate interventions (including denosumab, raloxifene, teriparatide, romosozunab) are clinically effective in reducing vertebral fractures compared to placebo, and that they are beneficial for change in femoral neck BMD [17]. Romosozunab, followed by alendronate, resulted in the greatest effect on femoral BMD.

Previous studies suggest that anabolic osteoporosis treatments, such as abaloparatide and teriparatide, exert the highest influence on reducing the overall fracture risk. The present study shows that denosumab has the greatest effect on BMD, independent of the fracture risk. Denosumab demonstrates a high affinity and specificity to the RANKL, and therefore prevents it from binding to the RANKL receptors on osteoclasts and their precursors, with a direct effect on the activity and life span of existing osteoblasts [18]. Denosumab increases BMD by inhibiting bone resorption and remodelling [19]. The FREEDOM trial confirmed that denosumab, administrated every 6 months, significantly reduces the hip fracture risk by 40%, the non-vertebral fracture risk by 20% and the vertebral fracture risk by 68% [20].

The extension of the FREEDOM study showed that treatment with denosumab up to 10 years results in a cumulative gain in BMD of 21.7% at the lumbar spine, and 9.2% at the total hip, compared to baseline [21]. Denosumab resulted in lower rates of new vertebral and non-vertebral fractures throughout the study period [21]. Denosumab is administrated subcutaneously every 6 months, and therefore it is likely that the adherence to the medication is better compared to BP. This was confirmed by Kendler et al., who showed greater satisfaction when patients transitioned to denosumab as compared to a monthly oral BP [22]. Palacios et al. also confirmed a higher adherence of patients to denosumab compared to BP, and that most patients do prefer denosumab over BP for the treatment of osteoporosis [23]. The advantages of denosumab over BP seem the more favourable side-effect profile (low rates of infections and malignancies), and, as shown in the present study, the more pronounced beneficial effects on BMD. This was also confirmed previously, with denosumab more effective than ibandronate and alendronate [24–28].

Limitations of this network meta-analysis include the focus on the effects of osteoporosis treatments on spinal and hip BMD without an assessment of fracture risk reduction, adverse events or costs. The investigation of adverse effects seems to be particularly important, since adverse effects can affect adherence to treatment. Also, we only included studies which evaluated the effects of anti-osteoporosis medications for postmenopausal osteoporosis, but not for age-related, senile, or secondary osteoporosis. Further studies are necessary to examine these aspects. The minimum follow-up for a study to be included in the present network meta-analysis was 1 year. However, osteoporosis requires long-term treatment to produce clinically relevant benefits. This is especially important when certain medications, such as denosumab, have to be discontinued, and thereby lead to a potential increase in fracture risk. Another potential limitation is related to the limited variety of drugs included for analysis. Given the lack of studies in the literature, some commonly used medications, such as abaloparatide and romosozumab, were not included in the analyses. In light of these limitations, data from the present Bayesian network meta-analysis must be interpreted with caution.

Strengths of our study are the comprehensive literature search of multiple databases in multiple languages, which led to the inclusion of 64 evidence levels I and II RCTs with a total of 82,732 interventions. We also performed a rigorous review process, which was performed by two independent reviewers. Finally, we summarised and analysed the latest evidence of anti-osteoporosis medications on BMD in postmenopausal women from RCTs with the highest levels of evidence, which to our knowledge has not been performed before.

Conclusion

The present network meta-analysis shows that denosumab followed by pamidronate and zoledronate is associated with higher spine BMD in selected women with postmenopausal osteoporosis. Denosumab followed by alendronate and ibandronate had the highest influence on hip and femoral BMD. Future studies should evaluate the effects of anti-osteoporosis drugs on the overall fracture risk and on other types of osteoporosis.

Acknowledgements

None

Abbreviations

BMD

Bone mineral density

RANK-ligand

Receptor activator of nuclear factor-kappa B ligand

SERM

Selective oestrogen receptor modulators

BP

Bisphosphonates

PTHR1

Teriparatide

RCTs

Randomised controlled trials

SMD

Standardised mean difference

ANOVA

Analysis of variance

STD

Standardised mean difference

SE

Standard error

CI

Confidence interval

PrI

Percentile interval

BMI

Body mass index

Authors’ contributions

FM: literature search, data extraction, methodological quality assessment, statistical analyses, writing; NM: supervision, revision, final approval; GC: literature search, data extraction, methodological quality assessment; MB: writing; JE, MOB; MT: supervision.

Funding

No external source of funding was used. Open Access funding enabled and organized by Projekt DEAL.

Availability of data and materials

This study does not contain any third material.

Declarations

Ethics approval and consent to participate

This article does not contain any studies with human participants or animals performed by any of the authors.

Consent for publication

All the authors approved the manuscript.

Competing interests

The authors declare that they have no competing interests.

Footnotes

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

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Data Availability Statement

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