From disease to treatment: from rare skeletal disorders to treatments for osteoporosis

Abstract

During the past 15 years there has been an expansion of our knowledge of the cellular and molecular mechanisms regulating bone remodeling that identified new signaling pathways fundamental for bone renewal as well as previously unknown interactions between bone cells. Central for these developments have been studies of rare bone disorders. These findings, in turn, have led to new treatment paradigms for osteoporosis some of which are at late stages of clinical development. In this article, we review three rare skeletal disorders with case descriptions, pycnodysostosis and the craniotubular hyperostoses sclerosteosis and van Buchem disease that led to the development of cathepsin K and sclerostin inhibitors, respectively, for the treatment of osteoporosis.

Keywords: Cathepsin K; Osteoporosis; Pycnodystostosis; Sclerosteosis; Sclerostin; Van Buchem disease.

Fig. 1

Pycnodysostosis: a Open sutures; b Acro-osteolysis; c Iliac crest bone biopsy showing cortical (Ct) and trabecular osteosclerosis (from [11]); d High magnification of an iliac crest bone biopsy showing an osteoclast adjacent to a resorption lacuna filled with unmineralized matrix (from [12]); SEM images of odanacatib-treated osteoclast culture on dentine slides: e Control, showing a deep resorption pit; f Treated, showing discrete, small, shallow resorption pits (from [87])

Fig. 2

Percent changes of biochemical markers in serum of women treated with odanacatib 50 mg once weekly for 5 years. Open bars baseline; Closed bars 5 years (from [5])

Fig. 3

Sclerosteosis: a Enlarged skull and mandible with facial palsy; b Syndactyly; c Biopsy of compact bone with high numbers of osteoblasts and osteoid van Buchem disease: d Typical features with facial palsy; e Petrous part of temporal bone and acoustic meatus (arrows) of a normal skull (upper) and of a skull of a patient (lower); note the increased thickening and the narrowing of the meatus (from [88]); f Increased bone formation in a biopsy from compact bone

Fig. 4

Schematic representation of sclerostin actions. Osteocyte-produced sclerostin inhibits the proliferation, differentiation and survival of osteoblasts and reduces bone formation; it stimulates also the production of RANKL by neighboring osteocytes and bone resorption. In osteoblasts, sclerostin binds to LRP5/6 and inhibits the Wnt signaling pathway, an action facilitated by LRP4. Production of sclerostin is decreased by mechanical loading, PTH, estrogens and other factors (from [67])

Fig. 5

Percent changes of lumbar spine and total hip BMD during treatment of women with low bone mass with romosozumab (ROMO) 210 mg once-monthly sc, teriparatide (TPTD) 20 μg daily sc, alendronate (ALN) 70 mg once-weekly orally, or placebo (from [83])

Fig. 6

Schematic representation of changes in levels of serum biochemical markers of bone formation (P1NP) and bone resorption (CTX) during treatment with subcutaneous injections of either teriparatide (TPTD, 20 μg daily) or romosozumab (ROMO, 210 mg once monthly) for 1 year (from [86])