To our knowledge, this is the first expert consensus regarding the applicability of a T2T strategy for osteoporosis in clinical practice. The results of Spanish consensus on T2T strategy for osteoporosis using Delphi methodology are presented. The study results reflect data not only from pivotal studies but also from post-authorization studies and, above all, the clinical experience of experts.
A treating strategy with which to achieve a well-predefined goal is a feature of different areas of medicine. T2T strategy has thus been widely applied in the fields of diabetes , hypertension , hypercholesterolemia , and rheumatoid arthritis [22, 23]. In osteoporosis, it has also recently become a matter of interest. Its role in this context remains controversial. T2T is an attractive approach for application in order to avoid the perpetuation of treatment and possible adverse effects, provided that the desired goal is achieved. The problem begins when a measurable and sensitive tool is required to assess the achievement of the final objective. Capturing the change in fracture risk associated with treatment is not easy. Strong evidence is needed to confirm that selecting and switching treatment reduces fracture risk more effectively than the current standard of care .
Since we have treatments to modify the bone-remodeling process, the ultimate objective has always been the reduction of fragility fractures . Given that two new issues have appeared in the field of osteoporosis, the need to establish a therapeutic goal has become evident . Some treatments, such as anti-sclerostin or denosumab, have demonstrated a high increase in BMD after short periods of treatment, with most patients reaching normal range T-score values when evaluated by dual-energy X-ray absorptiometry (DXA) measurements [24, 25].
Until now, however, the measurable goal has never been attempted, and when it was attained, debate centered upon whether the treatment should be stopped, changed, or at least reconsidered, given that fragility fractures could reappear if some treatments were discontinued. We have therefore analyzed the current thinking of Spanish experts in bone metabolism, on the basis of two perspectives: the wish or desire for occurrence and the prognosis or belief that, upon consideration of the field and resources, this will be put into practice within a 5-year period.
Wide consensus arose when experts were asked about the feasibility of establishing a well-defined objective in osteoporosis. Almost all participants agreed on the possibility of applying T2T strategy in clinical practice in osteoporosis. Consensus usually arises in Delphi methodology when agreement or disagreement ranges from 50 to 80% . In this case, agreement exceeded 95%, which could indicate that Spanish physicians have a strong desire to have a T2T for osteoporosis management.
There was consensus that the parameters used as therapeutic objectives in the context of the T2T strategy in osteoporosis should be the absence of new fractures, a specific BMD value, and, at a lower level, BTM and fracture-risk reduction measured by FRAX. Many physicians do not have access to BTM and the use of FRAX is not general practice. Consequently, its implementation as a target is less feasible.
FRAX does not seem to be a good tool for measuring the reduction in fracture risk achieved with treatments. However, 75.9% of the experts would wish a therapeutic objective of a 10-year risk of fracture measured with a tool such as FRAX. Furthermore, 84% of them predicted that FRAX, probably with certain adjustments, will become a useful tool for a T2T strategy in osteoporosis. With regard to this hypothetical situation, Leslie et al.  demonstrated in the Manitoba cohort population that the increase in FRAX score over time after therapy was lessened, albeit not prevented. Actually, this hypothetical situation is almost impossible in the real life. In fact, Leslie et al.  demonstrated in the follow-up of Manitoba cohort that a small percentage of patients, even with a medication possession rate >0.8, achieved reduction in major fracture probability of 4% or higher. Therefore, we believe that the result of the question regarding FRAX reduction, even though it could be used as the principal parameter for defining an adequate therapeutic objective, is more a wish than a reality. It might reflect the desire of having in the future a tool more linked to a reduction of the risk in patients on treatment.
Consensus was established regarding the utility of BMD as a principal parameter for defining an adequate therapeutic objective. In line with that, it was established that BMD should be measured using a tangible absolute value, or as a predetermined difference between two values. Scores higher than −2.5 SD for spine T-score were the only tangible absolute values, for which there was consensus for both perspectives. As far as femoral neck T-score value is concerned, there was consensus that scores of over −2.5 or −2.0 SD, which are almost the same threshold values for osteopenia and osteoporosis in the WHO definition , should be established as a therapeutic objective. The FLEX study  showed that the T score −2.5 was the optimal point to be achieved in order to prevent new nonvertebral fractures. Moreover, the results suggested that there was no advantage in continuing with alendronate. In our study, a T score of −2.0 was included on the basis of the FREEDOM study . The results of the FREEDOM study suggested that the reduction of nonvertebral fracture risk associated with denosumab was influenced by the hip BMD achieved with initial therapy .
There was discussion regarding the T-score threshold and the site of BMD measurement. It seems that spine BMD is influenced by several artifacts such as osteophytes, vascular calcifications, and sclerosis, and such factors could bias the real results . Femoral-neck BMD, meanwhile, reflects more cortical bone, whereas total hip measures cortical and trabecular bone . The first step to establish a measurable mark for T2T strategy would therefore be to select the proper location for measuring BMD. Despite all these technical considerations, when asked about the most appropriate anatomic locations for monitoring BMD in the Delphi questionnaire, consensus was reached on lumbar zone, femoral neck, and total hip, while only femoral-neck area saw strong consensus for both perspectives (wish and prognosis).
When fracture-risk reduction was used as the main parameter for defining an adequate therapeutic objective, there was agreement that this parameter should be measured using FRAX. Like BMD, there was consensus that fracture risk reduction should be measured either using a tangible percentage or as a predetermined difference between two values. As far as the former is concerned, consensus was only achieved on the value of risk of major fractures attained to be lower than 10%. It is noteworthy that consensus was not established for the perspective of prognosis.
As regards BTM, there was consensus that they were good therapeutic indicators for determining the therapeutic objective and performing treatment follow-up. However, from the perspective of prognosis, consensus was established only on their utility in treatment follow-up.
For both perspectives, there was consensus concerning the utility of all parameters/techniques proposed for the measurement of incidence of new fractures: vertebral fracture analysis (VFA), height, conventional X-ray, major peripheral fragility fractures, or any fracture.
With regard to the optimal follow-up scheme, our results suggest that the best anatomic site for monitoring densitometry was the femoral neck, although lumbar spine obtained also a high participant wish score. In fact, this reflects the expertise of participants in the Delphi study, because it is well known that as precision and reproducibility are lower at lumbar spine, osteoarthritis and other artifacts might affect results in older people, and therefore, in these cases, femoral neck could be a better choice for measurement .
Experts reached consensus regarding the possibility of applying the T2T strategy in osteoporosis when the treatments used are oral bisphosphonates, intravenous bisphosphonates, and SERMs such as raloxifene or bazedoxifene, strontium ranelate, denosumab, teriparatide, denosumab plus teriparatide, or developing drugs. There was no consensus with regard to the perspective of prognosis when strontium ranelate was used. This result can perhaps be explained by the fact that even though the studies with strontium ranelate show a clear increase in BMD, its use has recently been restricted and there is a chance that the drug will be removed from the Spanish market.
The treatments for which the wish consensus scores were highest were denosumab and teriparatide. This result could be associated with its positive impact that has been reported in recent studies published after long-term treatment with denosumab alone [20, 33] or with combinations .
In reference to the treatment period, the experts agreed that regardless of the treatment used, once the therapeutic objective is accomplished, treatment should be stopped for a period of time, and also disagreed that treatment should be administrated indefinitely. It should be mentioned that no consensus was achieved when SERM was used. Meanwhile, in the case of teriparatide, there was also consensus on changing the treatment when, following recommendations to discontinue treatment, 18 or 24 months were achieved. Additionally, this point reflects the experience of participants, as these results are consistent with recent publications [35, 36]. BMD monitorization after target accomplishment by reversible drugs such as denosumab would require further investigation. Denosumab is characterized by reversal of effect, and is associated with a progressive increase in vertebral fracture risk rate to levels comparable with before the start of treatment. Consequently, in order to prevent new factures, as has been reported by Anastasilakis et al. , those who discontinue denosumab should switch to another therapy after the 6 months dosing interval [38, 39]. There was consensus regarding therapeutic failure upon inability to achieve a clinically significant increase of BMD for 2 or 3 years, when a new fracture was diagnosed in the subsequent 1 to 5 years, or when a significant change in BTM was not achieved in the following 6 months or 1 year.