Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression

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

doi:10.1002/jbmr.3355

Cited by 58 publications

(45 citation statements)

References 33 publications

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“…Reductions in bone resorption biomarkers associated with subsequent increases in bone mineral density (BMD) are characteristic of antiresorptive therapies for osteoporosis . When bone is resorbed, degradation products of type I collagen are released and can be measured in the serum and/or urine.…”

Section: Introductionsupporting

confidence: 68%

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Stone

McCrea

Witter

et al. 2019

Brit J Clinical Pharma

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Cathepsin K (CatK) is a cysteine protease abundantly expressed by osteoclasts and localized in the lysosomes and resorption lacunae of these cells. CatK is the principal enzyme responsible for the degradation of bone collagen. Odanacatib is a selective, reversible inhibitor of CatK at subnanomolar potency. The pharmacokinetics of odanacatib have been extensively studied and are similar in young healthy men, postmenopausal women and elderly men, and were qualitatively similar throughout Phase 1 development and in-patient studies. Following 3 weeks of 50 mg once weekly dosing the geometric mean area under the curve from 0 to 168 hours was 41.1 μM h, the concentration at 168 hours was 126 nM and the harmonic mean apparent terminal half-life was 84.8 hr. Odanacatib exposure increased in a less than dose proportional manner due to solubility limited absorption. It is estimated that approximately 70% of the absorbed dose of odanacatib is eliminated via metabolism, 20% is excreted as unchanged drug in the bile or faeces, and 10% is excreted as unchanged drug in the urine. The systemic clearance was low (approximately 13 mL/min). Odanacatib decreases the degradation of bone matrix proteins and reduces the efficiency of bone resorption with target engagement confirmed by a robust decrease in serum C-telopeptides of type 1 collagen (approximately 60%), urinary aminoterminal crosslinked telopeptides of type 1 collagen to creatinine ratio (approximately 50%) and total urine deoxypyridinoline/Cr (approximately 30%), with an increase in serum cross-linked carboxy-terminal telopeptide of type 1 collagen (approximately 55%). The 50-mg weekly dosing regimen evaluated in Phase 3 achieved near maximal reduction in bone resorption throughout the treatment period. The extensive clinical programme for odanacatib, together with more limited clinical experience with other CatK inhibitors (balicatib and ONO-5334), provides important insights into the clinical pharmacology of CatK inhibition and the potential role of CatK in bone turnover and mineral homeostasis. Key findings include the ability of this mechanism to: (i) provide sustained reductions in resorption markers, increases in bone mineral density, and demonstrated fracture risk reduction; (ii) be associated with relative formationsparing effects such that sustained resorption reduction is achieved without accompanying meaningful reductions in bone formation; and (iii) lead to increases in osteoclast number as well as other osteoclast activity (including build-up of CatK enzyme), which may yield transient increases in resorption following treatment discontinuation and the potential for nonmonotonic responses at subtherapeutic doses.

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Section: Introductionsupporting

confidence: 68%

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Stone

McCrea

Witter

et al. 2019

Brit J Clinical Pharma

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“…As part of the Foundation for NIH's Bone Quality Project, we are in the process of collecting patient‐level data from most of the randomized controlled trials of osteoporosis drugs. We have already used this data to relate changes in bone turnover markers to fracture risk reduction . A reanalysis of these primary data for BMD should allow us to address several of the limitations inherent in working only with published data.…”

Section: Discussionmentioning

confidence: 99%

“…We have already used this data to relate changes in bone turnover markers to fracture risk reduction. (32) A reanalysis of these primary data for BMD should allow us to address several of the limitations inherent in working only with published data. For example, we will be able to have a more consistent definition of nonvertebral fracture, a fixed duration of follow-up, and standard statistical analysis.…”

Section: Discussionmentioning

confidence: 99%

Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials

Bouxsein

Eastell

Lui

et al. 2019

Journal of Bone and Mineral Research

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154

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Meta‐analyses conducted >15 years ago reported that improvements in bone mineral density (BMD) were associated with reduction in vertebral and nonvertebral fractures in osteoporosis trials. Numerous studies have been conducted since then, incorporating new therapies with different mechanisms of action and enrolling many more subjects. To extend these prior analyses, we conducted a meta‐regression of 38 placebo‐controlled trials of 19 therapeutic agents to determine the association between improvements in BMD and reductions in fracture risk. We used a linear model to examine the relationship between mean percent difference in BMD change between treatment and placebo groups and the logarithm of the relative risk. We found that greater improvements in BMD were strongly associated with greater reductions in vertebral and hip fractures but not nonvertebral fractures. For vertebral fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.56, 0.54, and 0.63, respectively (p ≤ 0.0002). For a 2% or 6% improvement in total hip BMD, we might expect a 28% or 66% reduction, respectively, in vertebral fracture risk. For hip fracture, the r2 values for total hip, femoral neck, and lumbar spine BMD change were 0.48 (p = 0.01), 0.42 (p = 0.02), and 0.22 (ns), respectively. For a 2% or 6% improvement in total hip BMD, we might expect a 16% or 40% reduction in hip fracture risk. In conclusion, our results extend prior observations that larger improvements in dual‐energy X‐ray absorptiometry (DXA)‐based BMD are associated with greater reductions in fracture risk, particularly for vertebral and hip fractures. Although these results cannot be directly applied to predict the treatment benefit in an individual patient, they provide compelling evidence that improvements in BMD with osteoporosis therapies may be useful surrogate endpoints for fracture in trials of new therapeutic agents. © 2019 American Society for Bone and Mineral Research.

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“…The results of our study were negative, possibly due to the lack of a nonosteoporosis group for statistical contrast. ALP is of great significance to the judgment regarding OF healing in older women when metabolic bone diseases caused by primary hyperparathyroidism are excluded 22 for vertebral compression fractures, it is also strongly recommended that the efficacy of drug therapy be monitored 29 .…”

Section: Analysis Of the Levels Of Alkaline Phosphatase Calcium Andmentioning

confidence: 99%

Bone Turnover Markers and Bone Mineral Density to Predict Osteoporotic Fractures in Older Women: A Retrospective Comparative Study

Zheng

Chen

et al. 2019

Orthopaedic Surgery

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Objective To investigate the clinical significance of the detection of bone mineral density (BMD) and bone turnover markers (BTM) in older women with osteoporosis, and to compare their predictive power for osteoporotic fractures (OF). Methods In this retrospective study, 96 patients with OF and 107 patients with osteoporosis who were hospitalized in the Department of Orthopedics at the First Affiliated Hospital of Chengdu Medical College were examined from October 2017 to February 2019. All selected patients were divided into either the fracture group (96 cases, 47.3%) or the non‐fracture group (107 cases, 52.7%). BMD was measured by dual‐energy X‐ray absorptiometry (DXA). BTM were detected by electrochemical luminescence: aminoterminal propeptide of type I procollagen (PINP), β‐cross‐linked C‐telopeptide of type I collagen (β‐CTX), and molecular fragment of osteocalcin N terminal (N‐MID). Bone metabolism‐related indicators were detected, including alkaline phosphatase (ALP), calcium (Ca), and phosphorus (P). Independent‐samples t‐tests were used to compare the measurement data between the two groups, one‐way ANOVA to compare the gaps between groups, and binary logistic regression to analyze the correlation of BMD and BTM with OF. Results There were no significant differences in age, weight, height, body mass index, age, and time of menopause between the two groups. There were a total of 71 cases (35.0%) in group A (60–70 years), 80 cases (39.4%) in group B (71–80 years), and 52 cases (25.6%) in group C (81–90 years). The fracture group was compared with the non‐fracture group for BMD in the lumbar (0.75 ± 0.05 vs 0.88 ± 0.13, 0.75 ± 0.16 vs 0.87 ± 0.09, 0.74 ± 0.21 vs 0.87 ± 0.12 g/cm2; P < 0.05), BMD in the hip (0.62 ± 0.16 vs 0.74 ± 0.14, 0.61 ± 0.15 vs 0.73 ± 0.0, 0.58 ± 0.13 vs 0.73 ± 0.08 g/cm2; P < 0.05), PINP (83.7 ± 5.7 vs 74.8 ± 5.0, 80.7 ± 4.1 vs 72.1 ± 5.1, 81.2 ± 7.0 vs 68.7 ± 6.3 ng/mL, P < 0.05), and β‐CTX (829.7 ± 91.5 vs 798.8 ± 52.2, 848.1 ± 71.2 vs 812.4 ± 79.0, 867.3 ± 53.1 vs 849.1 ± 67.2 pg./mL, P < 0.05). N‐MID (19.0 ± 6.7 vs 21.3 ± 9.7, 16.2 ± 7.0 vs 18.0 ± 5.3 ng/mL, P < 0.05) in the fracture cases was lower than in the non‐fracture cases for groups B and C, and there was statistical significance. Among the fracture cases, PINP in group A was higher than in group B and C, and β‐CTX in group C was higher than in group A and B (P < 0.05). There was no significant difference in the ALP, P, and Ca between the two groups (P > 0.05). Binary logistic regression analysis showed that for BMD in the lumbar and hip, β‐CTX and OF were significantly correlated (respectively, odds ratio [OR] = −4.182, 95% confidence interval [CI] 1.672–3.448; OR = 6.929, 95% CI 2.586–12.106; OR = 7.572, 95% CI 1.441–3.059), and the differences were statistically significant. PINP and N‐MID were correlated with OF (respectively, OR = 4.213, 95% CI 0.978–1.005; OR = 2.510, 95% CI 1.070–1.134, P > 0.05), the difference was not statistically significant. Conclusion Osteoporotic older women, with lower bone density and hig...

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Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Anti-Resorptive Drugs: A Meta-Regression

Cited by 58 publications

References 33 publications

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Clinical and translational pharmacology of the cathepsin K inhibitor odanacatib studied for osteoporosis

Change in Bone Density and Reduction in Fracture Risk: A Meta-Regression of Published Trials

Bone Turnover Markers and Bone Mineral Density to Predict Osteoporotic Fractures in Older Women: A Retrospective Comparative Study

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