Sclerosteosis was first reported by Truswell in 1958. Consequently, Professor Herman Hamersma (1929-2020), former Professor and Head of the ENT Department at the University of Pretoria, diagnosed the first sclerosteosis case in South Africa and devoted his entire career to managing patients with this ultra-rare condition. In the following years Prof. Hamersma, Prof. Peter Beighton, Dr Jacques du Plessis and Dr Louis Hofmeyr significantly expanded on the disease genotype and phenotype, and critically, developed successful surgical procedures to manage sclerosteosis.

In 2001, two groups independently reported loss-of-function mutations in the SOST gene of sclerosteosis patients that result in loss of sclerostin (a negative regulator of bone formation) expression due to the presence of a premature stop codon in the amino terminus of the protein. Subsequently, additional sclerosteosis-related SOST mutations have been identified, all of which result in the failure to produce active sclerostin protein.

Sclerostin-deficient Sost knockout (Sost^-/-) mice developed by Li et al., exhibit increased bone mass throughout the skeleton in early life, which is sustained as mice age. This mouse model of sclerosteosis has since been used to investigate potential treatments for sclerosteosis.

Theuns Botha (father of a sclerosteosis patient), persistently approached multiple academic institutes to initiate sclerosteosis treatment research. In 2016, his perseverance paid off and research project planning was started at the University of Pretoria, South Africa, by Dr Timothy Dreyer, under supervision of Prof. Vinny Naidoo.

A collaboration between University of Pretoria (South Africa) and biopharmaceutical company UCB Pharma (UK) was initiated in 2017 whilst Dr Dreyer prepared his PhD thesis on a potential sclerosteosis treatment strategy. The subsequent research study investigated the effectiveness of sclerostin replacement therapy in a mouse model of sclerosteosis. UCB Pharma generously provided funding and use of their state-of-the-art labs in Slough, UK, providing much appreciated guidance and expertise.

This study concluded that administration of recombinant mouse sclerostin constructs partially corrected the high bone mass phenotype in Sost^-/- mice, suggesting that bone-targeting of sclerostin engineered to improve half-life was able to negatively regulate bone formation in the Sost^-/- mouse model of sclerosteosis. However, the modest efficacy suggests that sclerostin replacement may not be an optimal strategy to mitigate excessive bone formation in sclerosteosis, hence alternative approaches should be explored.

A new multi-year research project, led by the RVC, and in partnership with UCB Pharma, was initiated to further investigate potential novel therapeutic options and mechanism of disease progression in sclerosteosis. Over the following three years the team tested new potential therapeutic options in preclinical models for sclerosteosis.

Researchers reported that PORCN inhibitor (LGK974) treatment reduces bone mass in various skeletal sites that are known to be profoundly affected by sclerosteosis i.e. skull, ear as well as the spine and limbs. This is the first evidence of a therapeutic approach that effectively limits bone accrual at these skeletal sites in mice, supporting the use of this approach to alleviate the symptoms of sclerosteosis and potentially of other Wnt-related HBM conditions, such as Van Buchem disease.