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

Abstract

ContextDenosumab is a potent antiresorptive agent that reduces fractures in postmenopausal women with osteoporosis.ObjectiveDetermine effects of up to 10 years of denosumab on bone histology, remodeling, and matrix mineralization characteristics.Design and SettingInternational, multicenter, randomized, double-blind trial [Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM)] with a long-term open-label extension.PatientsPostmenopausal women with osteoporosis (92 women in FREEDOM, 46 in extension) who provided iliac bone biopsies, including 11 who provided biopsies at multiple time points.InterventionsFREEDOM 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.OutcomesBone histology, histomorphometry, matrix mineralization.ResultsTen-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.ConclusionsDenosumab 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.

Reduction of Cortical Bone Turnover and Erosion Depth After 2 and 3 Years of Denosumab: Iliac Bone Histomorphometry in the FREEDOM Trial

“…Histomorphometric studies performed on transiliac bone biopsies in women with postmenopausal osteoporosis have shown a marked reduction in bone remodeling, both resorption and formation, in cancellous bone after 2 and 3 years of denosumab . This decreased cancellous bone turnover is maintained after an extension of the treatment up to 5 and 10 years . The analysis of bone biopsies obtained approximately 2 years after discontinuation of denosumab treatment confirmed that these effects are reversible, which is consistent with the known mechanism of action of denosumab.…”

“…(9) This decreased cancellous bone turnover is maintained after an extension of the treatment up to 5 and 10 years. (10,11) The analysis of bone biopsies obtained approximately 2 years after discontinuation of denosumab treatment confirmed that these effects are reversible, (12) which is consistent with the known mechanism of action of denosumab.…”

“…(13,23) In contrast to alendronate, which reduces bone resorption after osteoclasts resorb bone tissue containing bisphosphonate, denosumab rapidly inhibits osteoclast differentiation. Fewer newly eroded sites appear with denosumab, which, associated with the re-filling of the preexisting resorption cavities and the increased matrix mineralization, (11) results in a greater gain in BMD. (13,23) An increase in cortical thickness with denosumab treatment has been observed in the distal tibia and radius assessed by HR-pQCT.…”

Treatments of osteoporosis increase bone material strength index in patients with low bone mass

“…It may, therefore, be that BMSi measurements capture the observed increases in MM by antiresorptive therapies. Notably, prolongation of treatment with bisphosphonate, as in the FLEX study with alendronate, is not associated with continuous increase in MM [36] indicating that the amount of mineral taken up by the matrix in non-pathological mineralisation is limited, or self-regulated; this finding is similar to the observed plateau of bone matrix mineralisation between 5 and 10 years treatment of patients with osteoporosis with denosumab [37] and may explain the lack of further increases in BMSi values when these reach normal levels shown in our study.…”

Identification of osteoclast-osteoblast coupling factors in humans reveals links between bone and energy metabolism

“…Thus, although both drugs inhibit bone resorption, long-term bisphosphonate therapy is associated with little or no reduction in the number of osteoclasts, but with abnormal appearing osteoclasts that include giant, hypernucleated, detached osteoclasts 45 . By contrast, DMAb markedly reduces osteoclast numbers on all bone surfaces 46 . As such, bisphosphonates and DMAb may have differing effects on osteoclast DPP4 production, and this possibility warrants further investigation.…”