An antibody that inhibits the bone-regulating protein sclerostin and effectively stimulates bone formation has been shown to increase bone mass, bone strength and resistance to fracture in experimental models of multiple myeloma.
A combination of the anti-sclerostin antibodies and the bisphosphonate zoledronic acid was also found to increase bone volume more than either agent alone.
The findings, published in Blood and presented at a recent meeting of the Australian and New Zealand Bone and Mineral Society (ANZBMS), suggest a new approach to managing the morbidity and mortality associated with bone disease in multiple myeloma.
The limbic spoke to lead researcher Dr Michelle McDonald, from the Bone Biology Division in the Garvan Institute of Medical Research.
You found anti-sclerostin antibodies increased trabecular and cortical bone thickness in both the femur and vertebra. What do we understand about the mechanisms at work?
Anti-sclerostin is a potent bone anabolic agent, known to stimulate bone formation by osteoblasts. This is achieved through neutralising the osteocyte specific protein sclerostin, which is an endogenously expressed negative regulator of bone formation.
Anti-sclerostin treatment increased the activity of bone forming osteoblasts by almost two-fold, without impacting the activity of bone resorbing osteoclasts. Therefore, anti-sclerostin treatment protected against myeloma-induced bone loss by increasing bone formation.
Bisphosphonates can prevent but can’t reverse bone loss. How have you shown that adding in anti-sclerostin antibodies might improve the standard of care for these patients?
Given the potent bone anabolic potential of anti-sclerostin and the well-known anti-resorptive activity of bisphosphonates, the combination of these two agents in our model produced a superior outcome in terms of bone volume, structure and strength when compared to either of the agents administered alone.
This combination approach addresses both the increased bone resorption and suppressed bone formation that result in the devastating bone loss in patients with myeloma.
Importantly this new approach therefore has the potential to reduce fractures and improve the quality of life in patients with myeloma.
There was a suspicion that anti-sclerostin antibodies might also promote myeloma cell proliferation. What did you find?
Evidence suggests that increased wnt signalling can stimulate the growth of tumour cells. As sclerostin is a wnt antagonist, anti-sclerostin potentially stimulates wnt signaling.
It was important, therefore, that we examined tumour growth in response to this treatment. Across all four experiments and three animal models we saw no impact of anti-sclerostin treatment on tumour growth.
We also examined this in vitro and demonstrated no direct response of the tumour cells to anti-sclerostin. As sclerostin is a protein with high specificity for osteocytes, this treatment targets the bone microenvironment specifically, with no direct impact on tumour growth.
The bone specificity of sclerostin is a promising property of this agent. Sclerostin is expressed across all individuals with myeloma; we would therefore expect that all patients would respond to this therapy in the clinic.
Anti-sclerostin antibodies have been shown to reduce fractures in postmenopausal women with osteoporosis. Does this make it easier to move your research forward quickly into clinical trials in myeloma patients?
This is certainly an advantage for the future clinical application of this agent in myeloma. The data available from these extensive clinical trials in osteoporosis provide evidence that is likely to accelerate the successful translation of our results to clinical use in myeloma.
Based on our work, anti-sclerostin alone or in combination with bisphosphonates could significantly improve bone structure, reduce fractures and, importantly, improve survival for patients with myeloma. We are hopeful that clinical trials will be underway soon.