Bone Health

Denosumab Reduces Bone Turnover by Inhibiting Osteoclast Formation, Activity in Cortical Bone

Roxanne Nelson, BSN, RN
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In patients with HIV, the disease process and ART may contribute to bone loss, resulting in osteopenia or osteoporosis and increased fracture risk.3,10 Proinflammatory cytokines and viral load contribute directly to reduced bone mineral density through their effects on osteoclast and osteoblast activity, inhibiting new bone formation and accelerating bone loss.3 Other risk factors for bone loss or fracture in the HIV population include low body mass index, smoking, substance abuse, glucocorticoid therapy, hypogonadism, coinfection with hepatitis B virus or hepatitis C virus, and vitamin D deficiency (affects ~90% of patients).3,11 Bone loss caused by ART emerges within 1 to 2 years after starting therapy.3,11 Tenofovir-based regimens are associated with higher rates of bone loss.3,11 Guidelines suggest avoiding tenofovir disoproxil fumarate or PI-boosting regimens in patients at high risk.3 Bisphosphonates (eg, alendronate or zoledronate) are recommended for those with HIV who have osteoporosis.3

In patients with HIV, the disease process and ART may contribute to bone loss, resulting in osteopenia or osteoporosis and increased fracture risk.3,10 Proinflammatory cytokines and viral load contribute directly to reduced bone mineral density through their effects on osteoclast and osteoblast activity, inhibiting new bone formation and accelerating bone loss.3 Other risk factors for bone loss or fracture in the HIV population include low body mass index, smoking, substance abuse, glucocorticoid therapy, hypogonadism, coinfection with hepatitis B virus or hepatitis C virus, and vitamin D deficiency (affects ~90% of patients).3,11

Bone loss caused by ART emerges within 1 to 2 years after starting therapy.3,11 Tenofovir-based regimens are associated with higher rates of bone loss.3,11 Guidelines suggest avoiding tenofovir disoproxil fumarate or PI-boosting regimens in patients at high risk.3 Bisphosphonates (eg, alendronate or zoledronate) are recommended for those with HIV who have osteoporosis.3

Denosumab inhibits osteoclast formation and activity in cortical bone, and this mechanism of action may be reflected by the reduction of erosion in both depth and surface.

Denosumab inhibits osteoclast formation and activity in cortical bone, and this mechanism of action is reflected by the reduction of erosion in both depth and surface, according to findings published in the Journal of Bone and Mineral Research.

A fully human monoclonal antibody, denosumab binds and reversibly inhibits the activity of human RANKL, which is an essential factor for osteoclast differentiation and activity. This activity in turn, mediates bone resorption. In the Fracture REduction Evaluation of Denosumab in Osteoporosis every 6 Months (FREEDOM) trial, treatment with denosumab cut the risk for vertebral, hip, and nonvertebral fractures in postmenopausal women with osteoporosis compared with placebo. 

The current study sought to evaluate the effects of denosumab vs placebo in the cortical compartment from transiliac bone biopsies that were obtained from participants of the FREEDOM trial. A total of 112 specimens were analyzed for cortical histomorphometry, including 67 that were obtained at month 24 (37 placebo, 30 denosumab) and 45 that were obtained at month 36 (25 placebo, 20 denosumab).

The results showed that endocortical osteoclast surface, eroded surface, and mean and maximum erosion depth were significantly reduced in the denosumab specimens compared with those treated with placebo at 24 months and 36 months (P <.0001 to P =.04). Endocortical wall thickness and intracortical measures (cortical porosity and cortical thickness) did not differ between groups. In addition, dynamic parameters were low with tetracycline labels in cortical bone that was observed in 13 (43%) and 10 (50%) of denosumab treated specimens at both 24 and 36 months, showed a substantial decrease in bone turnover.

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“Consistent with what was observed in cancellous bone, denosumab induced a marked reduction of resorption and formation in cortical bone, reflecting decreased bone remodeling on the endocortical surfaces and in intracortical bone,” wrote the researchers.

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Reference

Chavassieux P, Portero-Muzy N, Roux JP, et al. Reduction of cortical bone turnover and erosion depth after 2 and 3 years of denosumab: iliac bone histomorphometry in the FREEDOM trial [published online January 2, 2019]. J Bone Miner Res. doi: 10.1002/jbmr.3631

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