Advances in Pharmacological Approaches for Skeletal Dysplasias: A Comprehensive Review

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Skeletal dysplasias (SD), also known as osteochondrodysplasia, are a group of rare, heterogeneous disorders characterized by significant skeletal involvement (1) with cartilage and bone growth abnormalities resulting in abnormal bone length, shape or density. Although individually rare, with 436 entities recognized so-far (1), SD have an overall prevalence of at least 1 per 5,000 births (2). Clinical manifestations are heterogeneous, involving growth, bone shape, or bone density, reflecting the complexity of etiopathogenetic mechanism. There are very few cures for skeletal dysplasia and therapy is largely supportive at present.

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The last decades were marked by the identification of a large number of genes responsible for skeletal dysplasia leading to better understanding of cellular and biological pathways involved in skeletogenesis. Functional studies in cellular and animal models have also allowed the development of novel perspectives in treatment of SD. Currently, several clinical trials are ongoing and some new drugs are available for patients. Here, we will overview some of the most recent achievements, focusing mainly on pharmacological approaches in osteogenesisimperfecta, achondroplasia, fibrodysplasiaossificansprogressiva, pseudoachondroplasia, metaphysealdysplasiaSchmid type and enzyme therapies in hypophosphatasia and Morquio A.

Physiopathology of skeletal dysplasia

The skeleton is a complex organ formed through two mechanisms, with endochondral ossification and intramembranous ossification responsible for the formation of long bones and flat bones respectively. While mesenchymal cells differentiate directly into osteoblasts in intramembranous ossification, in endochondral ossification they differentiate into chondrocytes which undergo a tightly regulated process of proliferation, hypertrophy, and transdifferentiation into osteoblasts with production of the mature bone matrix (3). Chondrocytes synthesize extracellular matrix (ECM) components such as collagen, proteoglycans and glycoproteins (4).

Bone homeostasis results from two coupled processes, bone resorption and bone formation performed by osteoclasts and osteoblasts respectively. In addition, osteocytes are key actors in the remodeling process by regulating both action and recruitment in osteoclasts and osteoblasts. An imbalance between the two processes results in significant bone loss or gain (5).

Bone ossification and bone remodeling are subtly regulated by several signaling pathways such as Indian Hedgehog (IHH), parathyroid hormone–related peptide (PTHrP), fibroblast growth factor (FGF), C-type natriuretic peptide (CNP), Transforming growth factor beta (TGF-β), bone morphogenetic protein (BMP), Notch, and WNT signaling pathways (6–9).

Defects in bone ossification, homeostasis or in one of these signaling pathways are responsible for numerous SD with a wide spectrum of features such as short stature, bone fragility or ectopicossifications. The better understanding of ossification processes and bone homeostasis provides specific targets for therapeutic approaches

Osteogenesisimperfecta: Not a unique strategy!

Osteogenesisimperfecta (OI) is the most common bone fragility disorder, affecting 1 in 10 000 to 20 000 births (10) with a broad spectrum of clinical severity from antenatal lethal form to moderate adult disorder (11). Clinical and radiological features are low-impact bone fractures, osteopenia, bowing long bones, vertebral compressions or growth deficiency (12). Individuals with OI also commonly exhibit dentinogenesisimperfecta. This generalized connective-tissue disorder can also include joint laxity, muscle weakness, fatigue, blue sclerae, hearing loss, decreased pulmonary function, and cardiac valvular regurgitation (12). The original classification by Silence described four subtypes; (I) typically mild non-deforming OI with blue sclerae; (II) perinatally lethal OI; (III) progressively deforming disease; (IV) common variable disease with normal sclera (13).

About 85-90% of cases are related to dominant mutations in the COL1A1 or COL1A2 genes (14) coding for the α1(I) and α2(I) chains of type I collagen, the most abundant protein of ECM in bones, also present in ligaments, tendons, dentin, sclera, and skin. Since 2006, advances in genetic analysis allowed the identification of new genes related in OI. These genes, mainly recessive, are implicated in collagen folding or post-translational modifications or in osteoblast differentiation and function (15,16).

Patients with OI are managed by calcium and vitamin D supplements, physiotherapy, and surgery. Oral and venous bisphosphonates are the main pharmacological interventions in OI (17). New therapeutic strategies are currently being investigated, such as pharmacological strategies with antiresorptive drugs or stimulating ossification agents and mesenchymal cell transplantation.

Bisphosphonates

Bisphosphonates inhibit osteoclastic function, leading to a significant decrease of bone remodelling (18). Current evidence demonstrates that this treatment increases bone mineral density (BMD) in patients with OI, even though the long-term fracture reduction and improvement in quality of life still remains uncertain (19). According to the latest guidelines on the use of bisphosphonate therapy in children and adolescents, intravenous bisphosphonates should be considered for use in children with severe OI (e.g. type III), children with vertebral compression fractures or children who have had two or more long-bone fractures per year. Oral bisphosphonates should only be considered for those with mild to moderate OI in the absence of vertebral compression fractures. However, the most efficient agent, dose and frequency is still undefined (17). While pamidronate is the most frequent drug used in children younger than 2 years of age, with a dose between 9 to 12 mg/kg/year, zoledronate is used in older children with moderate to severe OI and commenced at 0.1 mg/kg/year in two divided doses (17).

Denosumab

Some patients with OI-IV without mutation in COL1A1/2 genes show a poor response to bisphosphonates, suggesting another etiopathogenic mechanism in OI. Thus, recessive mutations in the SERPINF1 gene encoding for pigment epithelium-derived factor (PEDF), were identified in few patients with OI-IV. These mutations lead to an overactivation of osteoclasts via RANK/RANKL (receptor activator of nuclear factor κB ligand) pathway, essential for the osteoclast differentiation and function (20). Denosumab, a human monoclonal antibody against RANKL, is an antiresorptive agent approved for the treatment of postmenopausal osteoporosis (21). This antibody links RANKL, preventing the interaction with its receptor, RANK, to osteoclasts and osteoclasts precursors leading to the inhibition of osteoclast formation and function, decreasing bone resorption, and increasing bone density (21).

First, subcutaneous injections of Denosumab (1 mg/kg body weight every 12 weeks) allowed the suppression of bone resorption and consequently an increase of bone mineral density in four patients with a severe phenotype of OI VI related to SERPINF1 mutations after two years of treatment (22,23). Then, several clinical trials showed an improvement of areal bone mineral density (24,25) in children and adults with OI-I related to COL1A1/2 mutations. One of the adverse effects of Denosumab is hypocalcemia, caused by the inhibition of bone resorption. Supplementation with vitamin D and calcium is recommended during this treatment.

While bisphosphonates can suppress bone resorption for several years, Denosumab has a short duration of action. Thus, hypercalcemia 7-9 weeks after denosumab injection was observed (26). This side effect could be due to the short life of Denosumab, and a reduction on the injection-interval could be sufficient to prevent it. Moreover, excess of bone resorption with a rapid decrease in bone density was also observed as soon as Denosumab is discontinued. Finally, some children developed hypercalciuria and nephrocalcinosis.

To date, the pharmacodynamics and the pharmacokinetic of anti-RANKL remain unknown. Clinical trials are still necessary to determine an efficient and safe protocol for Denosumab administration in patients with OI.

Anti-sclerostin

The Wnt/β-catenin pathway plays a major role in the regulation of bone formation and regeneration. Wntligands are glycoproteins expressed by osteocytes, which bind its receptor LRP5/6 and Frizzled to the osteoblasts and initiate a downstream intracellular signaling cascade, leading to activation of β-catenin and thus upregulation of its target gene expression which are implicated in osteoblast differentiation, proliferation, and activity. Sclerostin, encoded by the SOST gene and expressed by osteocytes and articular chondrocytes, is a monomericglycoprotein, which binds the LRP5/6 and Frizzled coreceptors leading to inhibition of Wnt/β-catenin signaling pathway and resulting in reduced osteoblastic bone formation (27).

Anti-sclerostin (Scl-Ab) is a monoclonal antibody against sclerostin. Preclinical studies demonstrated that administration of anti-sclerotin induced an enhancement of Wnt/β-catenin signaling, thereby an increase in bone formation, bone mineral density and bone strength (28) and an acceleration of bone repair (29). Likewise, Scl-Ab reduces long-bone fractures in mouse models of OI (30).

Anti-sclerostin including romosozumab, blosozumab, and BPS804, has already proved beneficial effects in patients with osteoporosis, with effects such as an increase of bone density with a reduction of fracture risk (27,31).

A randomized phase 2a trial demonstrated that multiple, dose-escalating, intravenous infusions of BPS804 significantly increased bone formation biomarkers, decreased bone resorption biomarkers and improved lumbar spinal bone density in adults with moderate OI (32). In the next few years, other studies are necessary to investigate further the effects of anti-sclerotin treatment in patients with OI.

Transforming growth factor β inhibition

Extracellular matrix is a reservoir of various growth factors and cytokines, such as TGF-β, a key factor of cell proliferation, lineage determination and cell differentiation, but also responsible for coupling bone resorption with formation (33). During osteoclast-mediated bone resorption, TGF- β is released from the bone matrix and induces mesenchymal stem cell (MSC) recruitment for osteoblast differentiation and new bone formation. Then, both high concentration and prolonged exposure to TGF-β prohibit further recruitment of osteoclast precursors, preventing bone resorption during the reversal phase of remodeling (33). Thus, high levels of active TGF-β have been shown in mouse models of OI (Crtap−/−s and Col1a2tm1.1Mcbr) (34) and a TGF-β neutralizing antibody improved bone mass in these models (35).

This data suggests that increased signaling of TGF- . During osteoclast-mediated bone resorption, TGF-β, released from the bone matrix, plays a key role in bone remodelling by coupling bone resorption with formation (33). High levels of active TGF-β have been shown in mouse models of OI (Crtap−/−s and Col1a2tm1.1Mcbr) (34) and a TGF-β neutralizing antibody improved bone mass in these models (35). This data suggests that increased signaling of TGF-β could be a common mechanism contributing to the OI phenotype and thus a new target for treatment in patients with OI. Nevertheless, these results seem to depend on the mouse model and therefore the effect of TGF-β inhibition may vary with the underlying genetic cause of the disorder (36). A phase I randomized study is currently testing the safety profile of fresolimumab, an antibody targeting TGF-β in moderate to advanced OI disease [ClinicalTrials.gov identifier: NCT03064074].

Mesenchymal stem cells (MSC)

While osteoclasts derive from hematopoietic stem cells, osteoblasts and chondrocytes derive from mesenchymalstroma cells (MSC). MCS are able to engraft into target tissues and to differentiate into different types of cells such as chondrocytes or osteoblasts (37,38). Moreover, MCS secrete a wide range of factors such as cytokines, chemokines, and growth factors, modifying the microenvironment and thus stimulating cell proliferation and preventing apoptosis (39). MCS also release extracellular vesicles containing lipids, microRNAs and peptides, stimulating chondrocyte proliferation in the growth plate and resulting in improved bone growth in a mouse model of OI (40).

The first studies which demonstrated MSC derived from bone marrow transplantation (BMT) were able to migrate to bone in children with OI and give rise to osteoblasts with an improvement in bone structure and function (41). These results were improved by an infusion of bone marrow-derived mesenchymal cells from the patients' original donors which engraft in bone, marrow stroma, and skin without the requirement for preparative chemotherapy in five children with OI after BMT. MSC secrete a soluble mediator that indirectly stimulates growth (42). Experiments in mouse models corroborated these observations.

Severe cases of OI are detectable during pregnancy. Pre-clinical studies of OI on mouse models showed that MSC transplanted in utero or in early neonatal life resulted in a significant reduction of bone fracture and an increased bone strength (43,44). To date, two patients with type III and type IV OI with a prenatal transplantation of allogenic human first-trimester liver-derived MSCs at 31 weeks of gestational age have been reported. Observed over several years, their clinical condition was better than expected with their mutation. Because of a decrease of the lengthwise growth and/or the increase of fracture frequency, they received several booster doses from the same donor at 8-year-old and 19-month-old, resulting in a significant clinical improvement (45,46). Indeed, although these healthy cells can survive in damaged tissue, they tend to decrease with time.

MCS transplantation is a promising treatment; nevertheless, clinical experience with MSC for OI is limited and further studies are currently ongoing. One of them, the BOOSTB4 (Boost Brittle Bones Before Birth, NCT03706482) study (a European multicenter phase I/II study), is evaluating the efficacy of prenatal and postnatal or postnatal only transplantation of fetal-derived MSCs in patients with OI type III or IV.