Effects of Long-Term Denosumab on Bone Histomorphometry and Mineralization in Women With Postmenopausal Osteoporosis

Abstract

Context: Denosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis.

Objective: Determine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics.

Design and setting: International, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension.

Patients: Postmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points.

Interventions: FREEDOM subjects were randomized 1:1 to subcutaneous denosumab 60 mg or placebo every 6 months for 3 years. Long-term extension subjects continued receiving denosumab, open-label, for 7 additional years.

Outcomes: Bone histology, histomorphometry, matrix mineralization.

Results: Ten-year denosumab biopsies showed normal histology. Bone histomorphometry indicated normal bone structure and reduced bone remodeling after 10 years of denosumab, similar to levels after 2 and/or 3 and 5 years of denosumab. The degree of mineralization of bone was increased and mineralization heterogeneity was reduced in the denosumab years 2/3 group vs placebo. Changes in these mineralization variables progressed from years 2/3 to year 5 of denosumab, but not thereafter.

Conclusions: Denosumab for 2/3, 5, and 10 years was associated with normal histology, low bone remodeling rate, increased matrix mineralization, and lower mineralization heterogeneity compared with placebo. These variables were unchanged from year 5 to year 10. These data, in combination with the maintenance of low fracture rates for up to 10 years as previously reported with denosumab therapy, suggest that strong, prolonged remodeling inhibition does not impair bone strength.

Trial registration: ClinicalTrials.gov NCT00089791.

Figure 1.

Percentage of bone biopsies with any fluorochrome on trabecular, cortical, and trabecular or cortical bone. n, number of biopsies with any label; N, number of evaluable biopsies.

Figure 2.

Bone histomorphometry results for iliac crest bone biopsies from FREEDOM and the extension. All parameters except cortical width were obtained from cancellous bone. Data represent median and interquartile range, n = number of subjects with observed data; N = number of randomized subjects who enrolled in the bone biopsy substudy who received at least 1 dose of investigational product during FREEDOM (for the FREEDOM groups) and during extension (for the extension groups), and had at least one evaluable biopsy. *P < 0.05 vs placebo years 2/3; ^†P < 0.05 vs denosumab year 2/3; ^§P < 0.05 vs denosumab year 5, by two-sided Wilcoxon rank-sum test. BFR, bone formation rate; TV, tissue volume.

Figure 3.

Digitized microradiographs of single cortices of iliac crest bone biopsies representative of placebo (PBO) year 2 group and denosumab (DMAb) years 2, 5, and 10. Samples were selected based on cortical DMB and HI values (bottom) similar to their respective group’s median values (in parentheses). For the year 2 PBO and DMAb samples, the group median values (in parentheses) represent values for years 2 and 3 combined.

Figure 4.

DMB and HI for iliac crest bone biopsies. Note that the y-axis scales are truncated. For the box-and-whisker plots, the box’s lower bound represents the first quartile (Q1), its upper bound represents the third quartile (Q3), the line is the median, the diamond is the mean, and the circles are outliers. The gray bands with dashed lines represent the interquartile range (Q1–Q3) and median value, respectively, for the premenopausal reference group (n = 42), from which endocortical and periosteal subcompartment mineralization data were not obtained. *P < 0.05 vs placebo years 2/3, ^†P < 0.05 vs denosumab years 2/3, ^§P < 0.05 vs premenopausal reference group, by two-sided Wilcoxon rank-sum test for between-group comparisons. n = number of subjects with observed data.

Figure 5.

Additional DMB and HI results for denosumab-treated subjects. Note that the x-axis scales are truncated. (A) Results for sequential biopsies from 11 denosumab-treated subjects that provided serial bone biopsy samples. (B) DMB and HI results in total bone for subjects with and without fluorochrome labels. The box-and-whisker plots and n values are explained in the Fig 4. legend.