Conclusions The proof indicated a good thing about a variety of therapies for osteoporosis in postmenopausal ladies for medical and vertebral fractures. Bone anabolic therapies have been simpler than bisphosphonates within the prevention of medical and vertebral fractures, regardless of baseline danger indicators. Therefore this evaluation offered no medical proof for limiting the usage of anabolic remedy to sufferers with a really excessive danger of fractures.
Outcomes The outcomes have been based mostly on 69 trials (>80 000 sufferers). For medical fractures, synthesis of the outcomes confirmed a protecting impact of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab in contrast with placebo. In contrast with parathyroid hormone receptor agonists, bisphosphonates have been much less efficient in decreasing medical fractures (odds ratio 1.49, 95% confidence interval 1.12 to 2.00). In contrast with parathyroid hormone receptor agonists and romosozumab, denosumab was much less efficient in decreasing medical fractures (odds ratio 1.85, 1.18 to 2.92 for denosumab v parathyroid hormone receptor agonists and 1.56, 1.02 to 2.39 for denosumab v romosozumab). An impact of all therapies on vertebral fractures in contrast with placebo was discovered. Within the energetic remedy comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab have been simpler than oral bisphosphonates in stopping vertebral fractures. The impact of all therapies was unaffected by baseline danger indicators, aside from antiresorptive therapies that confirmed a larger discount of medical fractures in contrast with placebo with rising imply age (variety of research=17; β=0.98, 95% confidence interval 0.96 to 0.99). No hurt outcomes have been seen. The understanding within the impact estimates was average to low for all particular person outcomes, primarily due to limitations in reporting, nominally indicating a severe danger of bias and imprecision.
Eligibility standards for choosing research Randomised managed trials that included non-Asian postmenopausal ladies with no restriction on age, when interventions checked out bone high quality in a broad perspective. The first end result was medical fractures. Secondary outcomes have been vertebral, non-vertebral, hip, and main osteoporotic fractures, all trigger mortality, opposed occasions, and severe cardiovascular opposed occasions.
Goal To evaluate the comparative effectiveness of osteoporosis therapies, together with the bone anabolic brokers, abaloparatide and romosozumab, on decreasing the chance of fractures in postmenopausal ladies, and to characterise the impact of antiosteoporosis drug therapies on the chance of fractures in accordance with baseline danger elements.
On this evaluation, we checked out a number of baseline danger indicators related to the efficacy of drug therapies to evaluate the proof of the impact and harms of obtainable osteoporosis therapies on main and secondary discount of the chance of fractures amongst postmenopausal ladies. We additionally critically appraised the inner validity of the randomised managed trials. 11 We used meta-regression analyses to discover the proof of the impact of antiosteoporosis drug therapies on the chance of fracture in accordance with recognised baseline danger elements.
Furthermore, most randomised managed trials included sufferers with an estimated excessive baseline danger of fractures, however this assorted between therapies and over time. Present publish hoc analyses point out that the antifracture efficacy of some therapies for osteoporosis differ in accordance with estimates of the baseline danger of fractures of people within the research, usually, however not solely, calculated with the fracture danger evaluation device (FRAX). 5 6 7 8 9 10 Subsequently, elements resembling historical past of fractures, age, bone mineral density, and physique mass index, amongst others, is likely to be potential impact modifiers.
Advances in analysis have led to a extra correct evaluation of the chance of fractures, and the vary of remedy choices out there to stop fractures has expanded. Algorithms on the chance of fractures that mix medical danger elements and bone mineral density are actually extensively utilized in medical apply to focus on remedy to people at excessive danger of fractures. 1 Though drug therapies focused at osteoporosis persistently enhance bone mineral density, stopping fractures is probably the most related affected person end result. 2 Heterogeneity has been famous for the magnitude of the discount within the danger of vertebral, non-vertebral, hip, and medical fractures between therapies. Few energetic comparator trials have immediately in contrast the results on fracture endpoints. 3 4 Larger understanding of the variations within the results of therapies throughout medical trials would affect estimates of the advantages of remedy and will due to this fact be thought-about among the many proof base that drives guideline suggestions.
We carried out separate analyses by sort of remedy and comparator group within the following teams to extend statistical energy: antiresorptive medicine (selective oestrogen receptor modulators, bisphosphonates, and denosumab) versus placebo; bisphosphonates versus placebo; anabolic therapies (romosozumab and parathyroid hormone receptor agonists) versus placebo; and anabolic therapies (romosozumab and parathyroid hormone receptor agonists) versus bisphosphonates. We quantified inconsistency throughout trials with the usual I 2 statistic, describing the share of whole variation brought on by heterogeneity relatively than likelihood. 31 We estimated the variation defined by every baseline danger indicator by %τ 2 defined =(τ 2 0 −τ 2 )/τ 2 0 ×100%, the place τ 2 0 is the variation between trials for the meta-regression with out the baseline danger indicator within the mannequin. Statistical analyses have been carried out in R (model 3.6.1) 32 33 and SAS (model 9.4). Grading of suggestions, evaluation, growth, and evaluations (GRADE) fitted to the community meta-analysis was used to charge the general certainty of proof for every end result. 34
Within the meta-regression evaluation, for every mixture of end result and baseline danger indicator, we carried out a meta-regression with restricted most chance estimation as a part of combined linear fashions. The ensuing slope β signifies the rise (or lower) in remedy impact when it comes to log danger ratio. For ease of interpretation, we used again transformation, so the slope is interpreted because the proportional improve (or lower) within the remedy impact (ie, danger ratio) per unit improve within the baseline danger indicator. A slope of exp(β)=1 signifies no affiliation with the remedy impact. For brevity, exp(β) is β.
We ranked medical efficacy with rankograms, floor below the cumulative rating, and common ranks. The transitivity assumption was evaluated by evaluating the distribution of medical and methodological variables that might act as impact modifiers, whereas statistical consistency (ie, settlement between direct and oblique proof) was evaluated with node splitting.
In a community meta-analysis, when two or extra medicine are in contrast with a typical normal, the distinction in impact between these medicine with respect to the widespread normal kinds the premise of oblique comparisons (ie, formation of a star community). In our evaluation, most drug therapies have been in contrast with placebo and the identical baseline remedy. We used the star design 26 for oblique remedy comparisons and included one energetic and one placebo group from every out there trial, impartial of concomitant drug remedy use. 27 To analyse fracture outcomes, we calculated odds ratios by default after use of a random results community meta-analysis mannequin with binomial chance and logit hyperlink. For the first (arm based mostly) community meta-analyses, we used generalised linear combined fashions combining a collection of two×2 tables, with the percentages ratio modelled as a linear mixture of research degree covariates and random results, representing variation between research. 28 Though the prior selection for heterogeneity between research is important in bayesian community meta-analysis with empirical Bayes strategies, 29 the prior chance distribution for heterogeneity between research is estimated from the information. 30 Becoming the community meta-analysis mannequin estimates the abstract remedy results for every drug relative to others, permitting for clustering of sufferers and medicines inside trials, and for heterogeneity between trials in remedy results (as measured by τ 2 , assuming the identical for each remedy impact). Moreover, to evaluate the robustness of those outcomes, we carried out sensitivity analyses adjusting every group for the size of the research multiplied by the precise variety of individuals randomly allotted (ie, a proxy for affected person years).
Subgroup evaluation by danger of bias was deliberate however was not thought-about possible as a result of many of the included research have been rated as having some considerations or had a excessive danger of bias. The meta-analyses, funnel plots, and forest plots have been produced in Assessment Supervisor Software program (model 5.2, Nordic Cochrane Centre, Cochrane Collaboration, Copenhagen, Denmark). Statistical energy is normally too low to differentiate likelihood from actual asymmetry, so we didn’t carry out any checks for funnel plot asymmetry as a result of many of the meta-analysis subgroups have been based mostly on <10 trials (information factors). For the meta-analysis, dichotomous outcomes have been analysed by calculating the relative danger for the direct comparisons (with 95% confidence intervals). Relative danger was additionally transformed into the corresponding anticipated absolute danger within the research inhabitants, for every 1000 people, 24 calculated because the distinction between the baseline danger of the result (median within the management group) and the chance of end result after the intervention was utilized. The I 2 statistic was used to measure the proportion of whole variability brought on by heterogeneity between the trials. 25 Heterogeneity between research was quantified by the estimate τ 2 . An inverse variance random results mannequin was utilized because the default to permit for heterogeneity in remedy results throughout trials. The Cochrane danger of bias device 2 23 (parallel trials) was used for important appraisal of the reporting of the included research. Two reviewers independently carried out a danger of bias appraisal. Discrepancies have been resolved by dialogue. Research information have been extracted with a predefined extraction template in Covidence. Extraction of background information was carried out by one reviewer and extraction of quantitative information was independently carried out by two reviewers. Disagreements have been resolved by dialogue. Data from journal article(s), convention summary(s), trial protocol, or trial registry report was used as sources within the information extraction and the chance of bias evaluation. Authors have been contacted by e mail to supply extra info to resolve uncertainties or receive lacking information (desk S2). No deadlines got. One creator offered information on hip fractures amongst postmenopausal ladies. 17 When a number of studies of 1 research have been recognized, the publication with the longest follow-up and probably the most full information was included, and if all research had full info, these research have been handled as one research with reference made to all the publications. Intention-to-treat analyses have been prioritised within the information extraction. In multi-arm trials, outcomes from therapies that have been the identical however at numerous doses have been mixed into one group. In 4 research, 18 19 20 21 lacking information on lumbar backbone bone mineral density T rating have been changed with estimates calculated by Bouxsein et al. 22 Duplicates have been recognized and excluded in EndNote. The remaining references have been imported to Covidence ( www.covidence.org/residence ); two reviewers independently screened titles and abstracts, adopted by screening of the complete textual content. Disagreements have been resolved by dialogue. Convention abstracts have been thought-about if information weren't printed elsewhere. One of many authors (MNH) carried out the literature search on 24 November 2021. Databases searched have been Medline and Embase through Ovid, and the Cochrane Central Register of Managed Trials (CENTRAL) 15 (acceptable protection for musculoskeletal problems has been proven 16 ). The search technique (desk S1) included medical topic headings and textual content phrases associated to the inhabitants, intervention, comparability, and end result framework, and was restricted to human and printed research written in English from 1 January 1996 onwards. Reference lists of earlier printed systematic evaluations and meta-analysis, and of the included research have been screened. Content material consultants ensured that any related research weren't missed by the search. The first end result was all medical fractures (excluding fingers and toes), and secondary outcomes have been vertebral fractures (medical, morphometric, or each), non-vertebral fractures, hip fractures, and main osteoporotic fractures, as outlined within the randomised managed trials. Hurt outcomes have been all trigger mortality, variety of sufferers with any opposed occasions, and variety of sufferers with severe cardiovascular opposed occasions. The time-frame was the longest follow-up after the beginning of the preplanned intervention. Interventions thought-about for inclusion have been bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate), denosumab, selective oestrogen receptor modulators (raloxifene hydrochloride, bazedoxifene, and bazedoxifene with conjugated oestrogen), parathyroid hormone receptor agonists (teriparatide and abaloparatide), and sclerostin inhibitor (romosozumab). Research have been included in the event that they examined the results in contrast with placebo or with an energetic comparator. Calcium and vitamin D supplementation have been allowed as co-interventions. Research analyzing sequential remedy or mixture remedy have been additionally thought-about for inclusion. No restrictions have been set on dose or size of remedy. The baseline danger indicators thought-about have been earlier historical past of fractures, imply age, imply backbone T rating, imply physique mass index, and imply FRAX rating for main osteoporotic fractures. We thought-about randomised managed trials that included postmenopausal ladies (with no restriction on the definition of intercourse or gender), with no restriction on age, and the place interventions thought-about bone mineral density or fractures. As a result of the doses utilized in randomised managed trials in Asian settings are totally different from doses utilized in the remainder of the world, we excluded research carried out solely in Asian settings. Trials in combined populations have been included if the information have been reported for the populations of curiosity individually. Our outcomes are reported, and our analyses carried out, in accordance with the rules of the Cochrane Collaboration and the Most popular Reporting Objects for Systematic evaluate and Meta-analysis (PRISMA) for Community Meta-Evaluation, 12 13 and structured in accordance with the inhabitants, intervention, comparability, and end result framework. 14 The protocol was registered and accepted in March 2019. Minor protocol changeswere made: hurt outcomes have been evaluated publish hoc and antiresorptive or bone anabolic medicine have been grouped within the meta-regression analyses to extend statistical energy. Meta-regression on danger of medical fractures with baseline imply age as danger indicator, for antiresorptive brokers (selective oestrogen receptor modulators, bisphosphonates, and denosumab) versus placebo. Primarily based on restricted most chance based mostly meta-regression for affiliation between (log danger ratio) medical fractures and imply age. Bisphosphonates versus placebo are indicated by purple dots and selective oestrogen receptor modulators versus placebo by yellow dot; colors don't mirror the utilized mannequin and are just for illustrative functions. Meta-regression was performed on log danger ratio scale, however for ease of interpretation, the again reworked danger ratio is proven. Identification quantity in determine, trial title, and reference: 3=FIT1 (Fracture Intervention Trial 1) 18 ; 4=HORIZON-PFT (Well being Outcomes and Lowered Incidence with Zoledronic Acid As soon as Yearly Pivotal Fracture Trial) 19 ; 7=FIT2 (Fracture Intervention Trial 2) 20 ; 11=ZEST (Zoledronic acid in frail Elders to STrengthen bone) 85 ; 12=ACTRN12607000576426 87 ; 15=Hosking 1998 21 ; 18=IBAN IV 183 ; 20=ACTRN1260900593235 139 ; 50=ACTRN12605000278639 88 ; 51=Hosking 2003 93 ; 52=Greenspan 2003 86 ; 53=Downs 2000 73 ; 55=Miller 2008 121 ; 78=Bell 2002 44 ; 79=Bone 2000 49 ; 82=McClung 2009 182 ; 93=NCT00271713 165 The impact of all therapies was unaffected by the baseline danger indicators (desk S11), aside from antiresorptive therapies that confirmed a larger discount of medical fractures in contrast with placebo with rising imply age (β=0.98, 95% confidence interval 0.96 to 0.99, τ 2 defined =97%, P=0.031, based mostly on 17 research) ( fig 6 and desk S11). In contrast with placebo or different comparators, the energetic therapies didn't improve the chance of all trigger mortality, variety of sufferers with any opposed occasions, or variety of sufferers with severe cardiovascular opposed occasions ( fig 4 and desk S8). This end result was reported in solely a small variety of trials, which restricted the ability of the evaluation. For main osteoporotic fractures, the community meta-analysis confirmed a protecting impact of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab in contrast with placebo, however not of denosumab or selective oestrogen receptor modulators ( fig 3 ). We discovered no variations within the energetic remedy comparisons. The community meta-analysis confirmed a protecting impact of bisphosphonates, denosumab, parathyroid hormone receptor agonists, and romosozumab for hip fractures in contrast with placebo, however not of selective oestrogen receptor modulators ( fig 3 ). Within the energetic remedy comparisons, romosozumab was simpler in stopping hip fractures than oral bisphosphonates or selective oestrogen receptor modulators ( fig 3 ). The outcomes have been strong to adjustment for affected person years (desk S8). We discovered an impact of all therapies on vertebral fractures in contrast with placebo. Within the energetic remedy comparisons, denosumab, parathyroid hormone receptor agonists, and romosozumab have been simpler in stopping vertebral fractures than bisphosphonates ( fig 3 ). The outcomes have been strong to adjustment for affected person years (desk S8). For medical fractures, the community meta-analysis confirmed a protecting impact of bisphosphonates, parathyroid hormone receptor agonists, and romosozumab in contrast with placebo, however not of denosumab and selective oestrogen receptor modulators ( fig 3 ). Evaluation of the information for denosumab didn't embody the FREEDOM (Fracture Discount Analysis of Denosumab in Osteoporosis Each 6 Months) pivotal trial, nevertheless, due to lack of aggregated information for medical fractures within the publication. In contrast with parathyroid hormone receptor agonists, bisphosphonates have been much less efficient in decreasing medical fractures (odds ratio for bisphosphonates v parathyroid hormone receptor agonist 1.49, 95% confidence interval 1.12 to 2.00). In contrast with parathyroid hormone receptor agonists and romosozumab, denosumab was much less efficient in decreasing medical fractures (odds ratios for denosumab v parathyroid hormone receptor agonist 1.85, 95% confidence interval 1.18 to 2.92 and v romosozumab 1.56, 1.02 to 2.39). The outcomes have been strong after adjustment for affected person years (desk S8). Determine 5 is a forest plot illustrating the outcomes of node splitting, evaluating the direct, oblique, and community estimates. For our community meta-analysis, we discovered no indication of inconsistency between direct and oblique proof ( fig 5 ), and we thought-about that the related impact modifiers have been balanced throughout the totally different comparisons. Determine S3 studies the potential baseline danger indicators facilitating the judgments concerning the assumption of transitivity. Community plot of research included in community meta-analysis on medical fractures. Every circle represents an intervention and is known as a node. Nodes are sized proportionally to the variety of trials that included every intervention. Traces between nodes characterize direct comparisons, and their thickness is proportional to the variety of trials contributing to every comparability. Variety of trials for every direct comparability is proven. No connecting line between two therapies signifies no direct comparability All osteoporosis therapies had not less than one placebo managed trial, and all therapies have been immediately in contrast with not less than one energetic drug in any of the networks ( fig 2 ), besides within the analyses of main osteoporotic fractures. Determine 3 and determine 4 present the outcomes from the community meta-analysis for all outcomes. Desk S8 exhibits the sensitivity analyses. Determine S4, desk S9, and desk S10 current the rankogram, imply ranks, and floor below the cumulative rating values that summarise the proof and comparisons. Parathyroid hormone receptor agonists had the best rankogram and floor below the cumulative rating worth, and the bottom imply rank, indicating higher rating of the remedy (fig S4). The intense danger of bias was primarily due to unclear reporting of how random sequence and allocation concealment have been carried out (desk S7). Some research additionally had incomplete end result information 74 83 105 129 145 151 and selective end result reporting 74 83 105 129 145 151 (desk S7). Potential involvement of the funding events was judged to extend the chance of bias associated to battle of curiosity. A severe danger of imprecision was assigned for outcomes the place information have been out there from one research solely. From visible inspection of the funnel plots, we didn't detect proof of small research results (fig S1). The general GRADE analysis of the understanding within the impact estimates was average to low for all particular person outcomes due to the intense danger of bias and imprecision ( desk 1 and secondary outcomes in desk S6). Thirty 4 research reported on medical fractures, 40 reported on vertebral fractures, 52 on non-vertebral fractures, 30 on hip fractures, and 9 research reported on main osteoporotic fractures. For information completeness for the baseline danger indicators, 52 research reported on a historical past of fractures (75%), all research reported imply age (100%), 49 research reported backbone T scores (71%), 51 research reported physique mass index (74%), and 6 research reported FRAX scores (9%). The prevalence of a historical past of fractures ranged from 0 to 100% within the research populations, imply age from 51.5 to 85.5 years, imply backbone T rating from −0.4 to −3.9, imply physique mass index from 23.7 to 29.1, and imply FRAX rating for the chance of a significant osteoporotic fracture inside the subsequent 10 years from 13.2% to 30%. Dialogue Remedy choices for postmenopausal osteoporosis have elevated significantly prior to now 20 years. No Cochrane-type evaluations or meta-analyses on this subject, nevertheless, have been performed not too long ago.184185 Though efficient, comparatively protected, and reasonably priced therapies can be found,186187188189190191192193194195196197198199 the remedy of sufferers at excessive danger of fractures must be checked out and the very best interventions recognized. Our community meta-analyses help a helpful impact of most, however not all, therapies on all fracture outcomes in contrast with placebo. These therapies have already been authorised by the suitable authorities in Europe, the US, and elsewhere for the remedy of postmenopausal osteoporosis. Though most randomised managed trials have preferentially included sufferers with a excessive baseline danger of fractures, the prevalence of those sufferers has assorted between totally different therapies and research. Increased baseline danger is a significant factor for absolutely the danger of fractures, however in most research the relative discount within the danger of fractures was discovered to be largely impartial of baseline danger elements. Affirmation that the authorised therapies cut back the chance of fractures in contrast with placebo isn't a surprise, however whether or not all therapies are equally efficient is an attention-grabbing query. The community meta-analyses confirmed that bone anabolic therapies (teriparatide62638389129200 and romosozumab4113) diminished the chance of medical and vertebral fractures in contrast with bisphosphonates. The understanding of the pooled outcomes on bone anabolic therapies, particularly romosozumab, nevertheless, was discovered to be low due to the small variety of research recognized. Head-to-head randomised managed trials are tougher than research evaluating energetic remedy with placebo. In head-to-head trials, the variety of people with fractures is far decrease, and due to this fact these research might need low statistical energy and are additionally unlikely to be replicated due to the monetary and operational challenges. Therefore most head-to-head randomised managed trials have been performed evaluating anabolic and antiresorptive therapies, the place a clinically related distinction in antifracture efficacy was anticipated. Due to the shortage of constant reporting on non-vertebral fractures, hip fractures, and main osteoporotic fractures throughout research, we couldn't draw extra particular conclusions. The VERO (VERtebral fracture remedy comparisons in Osteoporotic ladies) trial is an illustrative instance of the impact of various definitions of teams of fractures. When non-vertebral main osteoporotic fractures have been outlined in accordance with the European Drugs Company (hip, radius, humerus, ribs, pelvis, femur, and tibia), the discount seen with teriparatide in contrast with risedronate was not important, however when main osteoporotic fractures have been outlined in accordance with FRAX (medical, vertebral, hip, humerus, and forearm fractures), the discount was important (hazard ratio 0.40, P<0.001).168 Estimates for non-vertebral, hip, and main osteoporotic fractures have been considerably unsure due to low statistical energy and ranging definitions, however the outcomes have been largely in settlement with estimates for medical and vertebral fractures. Meta-regression evaluation The advantages of antiresorptive brokers normally, and bisphosphonates particularly, in addition to bone anabolic therapies, gave the impression to be impartial of baseline danger indicators on the research degree. However, the meta-regression analyses confirmed that antiresorptive therapies (bisphosphonates, selective oestrogen receptor modulators, and denosumab) appeared simpler in decreasing the chance of medical fractures with rising imply age (imply age reported in research ranged from 50 to 85 years), indicated by the estimated slope <1 and that together with imply age within the mannequin diminished the variance between research. This statement is vital as a result of a typical perception is that the oldest sufferers may not profit from osteoporosis remedy, whereas the proof offered right here means that antiresorptive therapies is likely to be much more efficient in decreasing medical fractures on this excessive danger inhabitants. The outcomes of the meta-regression are susceptible to aggregation bias and research degree confounding, nevertheless, and have to be confirmed in research of particular person affected person information. Bone anabolic therapies diminished the chance of fractures greater than antiresorptive brokers in postmenopausal ladies, and their comparative efficacy was largely impartial of baseline danger indicators. The outcomes for bone anabolic therapies have been based mostly on seven included research, nevertheless, and solely a modest unfold of danger elements between research was discovered, making it tougher to detect these associations. Particular person comparability trials have proven the larger advantages of teriparatide or romosozumab in contrast with oral bisphosphonates alone in excessive danger teams, characterised by 100% presence of vertebral fractures at baseline.3483 Our information recommend that the benefit of bone anabolic remedy versus antiresorptive remedy may not be restricted to the best danger teams. The rationale for recommending bone anabolic therapies particularly in sufferers at excessive danger of fractures is due to this fact based mostly extra on price issues (ie, decrease price per fracture prevented if the fracture charge is excessive) than on strong proof favouring its use on this group over others. With the introduction of biosimilars and generics of teriparatide at a decrease price, our outcomes might immediate a evaluate of present tips for an earlier use of those brokers within the remedy of osteoporosis. Strengths and limitations of included research We used standardised strategies permitting us to guage the understanding of the outcomes. The potential dangers of bias recognized throughout a number of of the included research, predominantly within the type of selective reporting, lowered the speed of certainty within the impact estimates of the outcomes. Different reporting gadgets might need favoured newer research as a result of older research wouldn't at all times have anticipated a future normal. Reporting gadgets which may have favoured newer research have been domains associated to the outline of randomisation sequence era and allocation concealment (choice bias), however not the domains associated to incomplete end result information, selective end result reporting (publish hoc analyses), and potential energetic involvement of funding events. We adhered to greatest apply and reviewed solely the standard of printed scientific papers. The supposedly poor high quality of reporting in randomised managed trials shouldn't be distinctive to drug trials of osteoporosis and is a typical downside throughout medical disciplines.201202 Efforts in direction of extra clear and stringent reporting are urgently wanted. Strengths and limitations of systematic evaluate Together with the 2020 replace to the Endocrine Society’s tips for the remedy of postmenopausal osteoporosis,203204 our evaluation included the not too long ago launched medicine, abaloparatide and romosozumab, and offered an up-to-date and complete systematic evaluate of all out there head-to-head trials on this area. A serious energy of our systematic evaluate was that the strategies have been rigorous and clear, with a priori outlined standards in accordancewith standardised tips. Different strengths have been the big variety of randomised managed trials included and restriction of our affected person inhabitants to postmenopausal ladies, which ensured strong outcomes and diminished the heterogeneity brought on by intercourse and comorbidity. The community meta-analysis and meta-regression evaluation have been restricted by a considerable quantity of lacking information on outcomes and baseline danger indicators of curiosity, which required combining remedy teams on an advert hoc foundation to make the very best use of the variety of information factors. Additionally, we didn't differentiate between outcomes reported as opposed occasions, or main or secondary outcomes, leading to numerous and non-standardised definitions of fractures throughout research. In our community meta-analysis, denosumab didn't considerably cut back the chance of medical fractures in contrast with placebo. Critically, the FREEDOM research from 2009, which was pivotal for nearly all approvals made for denosumab, didn't present the outcomes included within the evaluation. We can't exclude the chance that information on opposed occasions might have been inadequately monitored and often reported, additional introducing bias. As a result of we relied on printed imply baseline traits, as an alternative of particular person affected person information, a danger of aggregation bias exists that might improve or lower the associations discovered. Moreover, meta-regression analyses, regardless of together with solely randomised managed trials, are observational and the outcomes is likely to be confounded by different traits.205 Interpretation may also be difficult by overlapping outcomes (eg, in some research non-vertebral fractures would additionally rely as medical fractures8087104) and overlapping remedy teams. Instructions for future analysis Future analysis might embody particular person affected person information from the trials to advance our understanding of the affect of baseline danger indicators on the efficacy of therapies. Progress has been made for antiresorptive therapies by the Basis for the Nationwide Institutes of Well being Bone High quality undertaking, the place particular person affected person information have been collected for 28 000 individuals in 11 trials of bisphosphonates and selective oestrogen receptor modulators.206 We encourage randomised managed trial information to be made out there to supply the proof wanted for a personalised method to the administration of osteoporosis.