Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials

Black, Dennis M.; Bauer, Douglas C.; Vittinghoff, Eric; Lui, Li‐Yung; Grauer, Andreas; Marín, Fernando; Khosla, Sundeep; Papp, Anne E. de; Mitlak, Bruce; Cauley, Jane A.; McCulloch, Charles E.; Eastell, Richard; Bouxsein, Mary L.

doi:10.1016/s2213-8587(20)30159-5

Cited by 142 publications

(105 citation statements)

References 62 publications

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“…4 In the general population, vitamin D replacement in individuals who have deficiency is associated with improved BMD, 5 which is associated with reduced risk of fractures. 6 That said, there is surprisingly very little information regarding the prevalence of vitamin D deficiency (VDD) in CCS, and whether this is associated with reduced BMD. This knowledge gap has hindered the development of risk-based screening guidelines for VDD in long-term CCS.…”

Section: Introductionmentioning

confidence: 99%

Prevalence and risk factors for vitamin D deficiency in long‐term childhood cancer survivors

Bhandari

Teh

Herrera

et al. 2021

Pediatric Blood & Cancer

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Background: Childhood cancer survivors (CCS) have increased risk of developing chronic health conditions, including musculoskeletal disorders. Little is known regarding vitamin D deficiency (VDD, <20 ng/ml) and its association with bone mineral density (BMD) in long-term CCS. We evaluated the prevalence and risk factors for VDD in a large, diverse population of long-term CCS, and examined the association between VDD and BMD in patients who underwent guideline-recommended dual-energy X-ray absorptiometry (DXA) screening. Methods: This cross-sectional study included 446 consecutive CCS seen from March 2018 to September 2020. Univariate analyses examined associations between CCS demographics, socioeconomic status, and treatment exposures and VDD. Multivariable logistic regressions identified factors associated with odds of VDD and reduced BMD.Results: Median age at evaluation was 27.5 years (range 7-67 years); median time from completing therapy was 14.2 years (range 2-65 years). Fifty percent were female, and 45% were Hispanic. Twenty-four percent had VDD. In multivariable analysis, overweight and obese BMI were associated with VDD (overweight: OR 1.78, 95% CI 1.03-3.07, p = 0.04; obese: OR 2.40, 95% CI 1.39-4.13, p < 0.01; reference: normal/underweight), as was Hispanic or black race/ethnicity (OR 2.40, 95% CI 1.41-4.09, p < 0.01; reference: non-Hispanic white). In the 118 CCS with DXA results, VDD was independently associated with reduced BMD (OR 3.58, 95%CI 1.33-9.59, p = 0.01).Conclusions: CCS have a high prevalence of VDD. High BMI and Hispanic or black race/ethnicity were associated with VDD. Survivors with VDD had a greater than threefold risk of reduced BMD. Risk-based screening may facilitate timely interventions to mitigate VDD and improve BMD in CCS.

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Section: Introductionmentioning

confidence: 99%

Prevalence and risk factors for vitamin D deficiency in long‐term childhood cancer survivors

Bhandari

Teh

Herrera

et al. 2021

Pediatric Blood & Cancer

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“…The independence of fracture prevention from BMD change with potent antiresorptive therapy is also suggested by the comparable antifracture efficacies of zoledronate and denosumab in their respective phase 3 osteoporosis trials, although the latter had greater effects on BMD. ( 13,14 ) Although BMD change is related to efficacy across all osteoporosis medications, ( 15 ) this difference has not been demonstrated within the potent antiresorptive group. ( 16 ) The suggestion that an achieved T ‐score of −1.5 to −2.0 represents optimal fracture prevention also needs to be interpreted cautiously.…”

Section: Discussionmentioning

confidence: 99%

Predictors of Fracture in Older Women With Osteopenic Hip Bone Mineral Density Treated With Zoledronate

Reid

Horne

Mihov

et al. 2020

Journal of Bone and Mineral Research

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A recent analysis has found that during treatment with denosumab, women attaining higher bone densities (BMD) are less likely to have incident fractures. We have reexamined this important question using data from our recent trial of zoledronate in osteopenic women. One thousand women randomized to treatment with zoledronate were followed for 6 years. Of those, 122 sustained fragility fractures during follow‐up. Baseline age, nonvertebral fracture history, total hip BMD, and calculated fracture risk were all significantly different between those who had fractures during the study and those who did not. BMDs achieved during the study were higher in those without incident fractures. However, achieved BMDs were very closely related to baseline values (r = 0.93, p < 0.0001). The increase in BMD during zoledronate treatment was not different between those who had incident fractures and those who did not (0.15 < p < 0.78), and change in BMD was not predictive of fracture (univariate logistic regression analysis). Stepwise regression analysis of all baseline variables showed the best independent predictors of fracture to be age (odds ratio [OR] = 1.08, 95% confidence interval [CI] 1.04–1.13, p = 0.0003), baseline spine BMD (OR = 0.81, 95% CI 0.67–0.96, p = 0.016), and history of nonvertebral fracture (OR = 1.69, 95% CI 1.06–2.69, p = 0.028). Addition of change in BMD to this model did not improve its predictive power. If changes in BMD were included in the stepwise regression analysis of baseline variables, they did not emerge as significant predictors of fracture. It is concluded that age, fracture history, and baseline BMD determine the risk of new fractures. Differences in achieved BMD between those who do or do not fracture arise from the close relationship between baseline and achieved BMDs. These findings suggest that targeting any particular BMD during treatment is unlikely to be a useful or valid strategy. © 2020 American Society for Bone and Mineral Research (ASBMR).

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“…Taken as a whole, these data support the use of total hip T-score target of at least -2.0 and perhaps higher, at least for treatment with denosumab. Although it is not known with certainty that the same T-score targets would apply to treatment with other pharmacological agents, it is biologically plausible and supported by data from the FNIH meta-regression [16].…”

Section: Measuring Treatment Successmentioning

confidence: 98%

“…There are limitations with the use of published trial data in the FNIH meta-regression, such as inconsistency of study durations and fracture definitions. To address these limitations and further evaluate the association between BMD increase with treatment and fracture risk reduction, the FNIH Bone Quality Project conducted another meta-regression that used a unique dataset of individual patient data [16]. In this analysis, individual patient data from 91,779 participants of 23 RCTs were analyzed.…”

Section: Measuring Treatment Successmentioning

confidence: 99%

“…These include a more potent antiresorptive compound, denosumab, that increases BMD more than bisphosphonates [6][7][8], and anabolic compounds that reduce fracture risk more than bisphosphonates [9][10][11][12], with some anabolic compounds increasing BMD more than others [13,14]. These new developments, along with robust data showing that larger increases of BMD with treatment are associated with greater reductions of fracture risk [15,16] and recognition of the importance of treatment sequence [17] have increased the complexity of choosing initial osteoporosis therapy and assessing the outcomes of treatment.…”

Section: Introductionmentioning

confidence: 99%

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Operationalizing Treat-to-Target for Osteoporosis

Lewiecki

2021

Endocrinol Metab

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Treat-to-target (TTT) for osteoporosis is a concept for individualizing patient treatment decisions that focuses on achieving an acceptable level of fracture risk rather than response to treatment alone. While a response to treatment is essential in order to achieve an acceptable level of risk, it is not necessarily sufficient. Some patients have a good response to treatment yet remain at high level of fracture risk. Since there is no way to directly measure bone strength in patients treated for osteoporosis, a surrogate measurement must be used. Bone mineral density (BMD) is commonly used to select patients for treatment and has emerged as the most useful surrogate for assessing reduction of fracture risk after treatment is started. Recent large meta-regression studies have shown a robust correlation between larger increases in BMD with treatment and greater reductions in fracture risk. Application of TTT for osteoporosis involves assessing fracture risk before starting treatment and initiating treatment with an agent that is most likely to reduce fracture risk to an acceptable level, represented by a target BMD T-score, over a reasonable period of time. This review offers suggestions for implementing TTT for osteoporosis in clinical practice and managing patients who fail or succeed in reaching the target. More study is needed to fully validate the use of TTT for osteoporosis for initiating and modifying treatments to reduce fracture risk.

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Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials

Cited by 142 publications

References 62 publications

Prevalence and risk factors for vitamin D deficiency in long‐term childhood cancer survivors

Prevalence and risk factors for vitamin D deficiency in long‐term childhood cancer survivors

Predictors of Fracture in Older Women With Osteopenic Hip Bone Mineral Density Treated With Zoledronate

Operationalizing Treat-to-Target for Osteoporosis

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