Is a treat-to-target strategy in osteoporosis applicable in clinical practice? Consensus among a panel of European experts

Treat-to-target (T2T) is a proactive treatment strategy with a clear endpoint (‘the target’) and a commitment to change the therapy if the target is not achieved. In a T2T approach, the patient is reassessed periodically to see whether the target has been achieved [1‐4]. T2T encourages physicians to assess treatment outcomes more often and revise treatments accordingly [1‐3]. Additionally, T2T has potential to improve patients’ treatment adherence, as patient buy-in and shared decision-making have been identified as essential components of a T2T approach [2, 5, 6].

A T2T approach has been endorsed by professional organisations as a fundamental therapeutic strategy in type II diabetes and rheumatoid arthritis (RA) as, when applied, it yields improved outcomes to standard of care. The American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) recommend that glycated haemoglobin (HbA_1c) targets should be specified for individual patients and treatment should aim to bring HbA_1c values to those levels or lower, with treatment re-assessed and adjusted every 3–6 months [1]. In more recent applications of a T2T strategy in RA, the target has been identified as remission or low disease activity as defined by the European League Against Rheumatism (EULAR) [2]. Sustained use of a T2T strategy is associated with greater likelihood of remission in patients with RA [7]; in newly diagnosed patients, T2T may increase the odds of remission by around 50% [8].

Based on its success in other chronic diseases, T2T is now being considered as a strategy for the management of osteoporosis, which remains underdiagnosed and undertreated despite enormous public health implications [9, 10]. Notably, almost half of patients with a hip fracture have a history of a previous fragility fracture [11]. Approximately 2.7 million fragility fractures occurred across six European countries (France, Germany, Italy, Spain, Sweden and the UK) in 2017, and this is expected to rise as our population ages [10]. Despite their availability, utilisation of effective osteoporosis medications has declined further from already suboptimal levels in recent years [12].

While experts agree that the long-term goal of osteoporosis treatment is the prevention of new fractures [4], several knowledge gaps currently exist, including how to best manage patients at very high/imminent risk of fragility fracture and avoid the loss of independence, reduced quality of life and increased mortality that often follows a fracture [13, 14]. There is little international consensus on specific, measurable, short-term osteoporosis treatment goals [4, 15], nor current sequential treatment recommendations that aim to reduce or prevent fragility fractures by targeting at-risk patients [15‐17]. Treatment goals differ from clinically relevant treatment targets, which are biological markers that are highly correlated with the desired clinical outcome and can be used by physicians and patients to monitor treatment progress.

A T2T strategy in osteoporosis could help to address the unmet needs in fracture management by identifying a suitable treatment target, individualizing the initial treatment choice and guiding shared decision-making. Given the low treatment adherence rates in osteoporosis [18, 19], a T2T approach could increase patient engagement, improving adherence and therefore outcomes [17, 20, 21]. In 2018, a Spanish expert panel established the applicability of a T2T strategy for osteoporosis, including therapeutic objectives, patient follow-up, treatment failure criteria and appropriate treatment use [20]. The American Society for Bone and Mineral Research-US National Osteoporosis Foundation (ASBMR-NOF) working group also supports a T2T approach in osteoporosis and recommends several principles to guide treatment selection and monitoring, for example, considering more potent initial treatment in patients with high risk of fracture [4]. Clinical measures that could potentially be used as a target include bone mineral density (BMD) T-score, fracture risk assessment tool (FRAX) score, bone turnover markers (BTMs) and the absence of new fractures [4, 15, 20].

In this study, a modified Delphi approach was conducted to develop consensus among European experts on best practice for the management of fragility fractures and to determine whether a T2T strategy would be appropriate for osteoporosis patients with a fragility fracture.

This study establishes opinion among European experts regarding the use of a T2T strategy in osteoporosis and provides further support for this type of approach in patients with a history of fragility fracture. The expert panel agreed that the most important management goals for patients with a fragility fracture are the recovery of pre-fracture functional level and the reduction of subsequent fracture risk and that a T2T strategy is applicable and could be beneficial to patients with a history of fragility fracture. According to the expert panel, BMD is currently the most clinically appropriate treatment target as it is the most accessible clinical measure of bone strength. This panel focused on patients with a prior fragility fracture as many patients do not realise that they have osteoporosis and are at risk until they experience their first symptomatic fracture [9, 22], after which point use of a target BMD during treatment decisions becomes more applicable. However, logic follows that a T2T approach may also be suitable in patients with low BMD and no history of fracture, if these patients are identified early enough after developing osteoporosis. Targeting BMD may support the main goals experts established for these patients: recovery of pre-fracture functional level and reduced fracture risk. Improving BMD would decrease the risk of fractures, dramatically impacting patient ADLs and improving quality of life.

While all 13 statements reached consensus within the three voting rounds, those related to specific treatment targets for T2T in osteoporosis (Statements 10–13) reached a lower level of agreement than Statements 1–9, which consistently achieved ≥ 90% agreement. Statements relating to the targeted BMD T-score, the timepoint to assess the target achievement and the frequency of BMD monitoring reached 75–83% agreement. When asked to select a specific BMD T-score, there was no agreement and the expert panel discussed the need for individualised targets, since these values are likely to differ between patients depending on various circumstances: BMD T-score at the beginning of treatment and the presence of other risk factors for future fracture (independent from BMD) are two demonstrative examples. Recent data from some clinical trials suggest that, regardless of age or previous vertebral fracture(s), a patient will remain at high risk of future fracture until a total hip BMD T-score of − 1.5 is reached [23, 24]. Therefore, while individualised targets are likely necessary, it is possible that a BMD T-score target of − 1.5 may be appropriate for many, though would still need to be individualised based on the patient’s BMD at the start of therapy. Even with bone-forming agents (which provide optimal outcomes in severe osteoporosis), BMD can only be increased to a certain extent, so in the management of osteoporosis, it seems reasonable to consider both patient and clinician expectations. In fact, T2T guidelines in rheumatology incorporate physician- and patient-shared decision-making as part of the strategy, involving disease risks, treatment risks and benefits, treatment targets and a management plan [2]. It is unknown whether collaborative shared decision-making is feasible in a T2T approach in osteoporosis; this is an area for future research. It may be more difficult in osteoporosis partly due to the known discrepancies between how patients and practitioners perceive fracture risk [25, 26]. A previous study in RA patients found that patients’ willingness to change is directly associated with their disease activity scores [27], but this seems difficult to leverage in a disease like osteoporosis in which patients may not have yet experienced a fracture or have no complaints of back pain (as associated with vertebral fractures). The ethos of shared decision-making to ensure patients have an active role in treatment choice would remain the same, however [28], and would therefore not leave the patient at the mercy of the treating physician alone.

The results reported here are consistent with the outcomes of the Spanish Delphi panel and ASBMR-NOF working group [4, 20]. Both groups concluded that a T2T approach is applicable in osteoporosis and set the therapeutic objectives as absence of new fractures, including those that do not present clinically, increase in BMD and reduction in FRAX risk score [4, 20]. In order to integrate the occurrence of morphometric vertebral fractures into a T2T strategy, it will be necessary to improve diagnoses of these fractures in order to accurately assess progress towards the treatment goal. Further research in this area is needed.

Previous studies have demonstrated that both BMD and FRAX can predict risk of future fragility fractures and that BMD improvements on treatment are associated with reduced fracture risk [23, 29‐31]. While the Spanish experts and the ASBMR-NOF working group established specific target BMD T-scores (> − 2.5 for lumbar spine or total hip and > − 2.5 or > − 2.0 for the femoral neck) [4, 20], this panel was unable to reach agreement on this topic. Additionally, while consensus on BMD monitoring frequency was not reached in this study, every ‘2–3 years’ received the most votes. This is aligned with the outcomes of the Spanish Delphi panel, which suggest that the treatment failure criteria should be failure to achieve the target BMD T-score or occurrence of a new fracture within 2–3 years [20]. Here, panellists were asked in round 1 which treatment target would be the most appropriate. Since there was a strong consensus for BMD, this was the focus throughout the following surveys, and therefore, other possible targets were not discussed in the following rounds (e.g. FRAX score, BTMs, absence of fractures). Although there was great agreement among panellists that there is a need for clinical guidelines on how to select or sequence osteoporosis treatment in patients with a fragility fracture in a T2T strategy, they did not discuss the optimal treatment strategy in every clinical scenario (Statement 9). The importance of treatment sequence has been addressed in previous literature [32, 33], and would be a good topic for future consensus.

A European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Diseases (ESCEO) working group also highlighted the importance of establishing an international consensus on intervention thresholds and a universally accepted definition of treatment failure [15]. However, the results of this Delphi panel indicate that the individualisation of treatment selection, goals and monitoring frequency should be considered in the management of fragility fracture patients.

This study provides strong support among European experts for the value of a T2T strategy in osteoporosis. Although recovery of pre-fracture functional level and a reduction of fracture risk are the main goals, BMD seems an appropriate treatment target, echoing similar findings from Spain and the USA. Although BMD T-score cut-off and assessment timeframes remain undefined, individualisation of treatment and establishing an achievable target in each patient will likely help to close the gap in osteoporosis. Further research is needed to better establish guidelines on BMD monitoring, treatment failure, treatment sequence and the duration of pharmacological treatment.