Article Text

Download PDFPDF

Targeting sclerostin as potential treatment of osteoporosis
  1. Socrates E Papapoulos
  1. Correspondence to Professor Socrates E Papapoulos, Department of Endocrinology and Metabolic Diseases, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands, m.v.iken{at}lumc.nl

Abstract

In recent years, study of rare bone diseases has led to the identification of signalling pathways that regulate bone formation and provided targets for the development of novel therapeutic agents to stimulate bone formation in patients with osteoporosis. Studies of two bone sclerosing dysplasias, sclerosteosis and van Buchem disease led to the identification of sclerostin, a negative regulator of bone formation. Sclerostin binds to LRP5/6 and inhibits Wnt signalling, but its precise molecular mechanism of action is not yet known. Its expression is restricted in the skeleton to osteocytes and is modified by mechanical loading and parathyroid hormone treatment. Sclerostin deficiency reproduces the findings of the human diseases in mice, while sclerostin excess leads to bone loss and reduced bone strength. An antibody to sclerostin increased bone formation dramatically at all bone envelopes in ovariectomised rats and intact monkeys, without affecting bone resorption and improved bone strength. In initial human studies, a single injection of the antibody to postmenopausal women increased serum P1NP and transiently decreased serum CTX. Clinical phase II studies with this antibody are currently underway.

Statistics from Altmetric.com

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.

Osteoporosis and its treatments

Osteoporotic fractures are common, their incidence increases with age, and are associated with considerable morbidity, deterioration of the quality of life of affected individuals and mortality. During the past 15 years, interventions to reduce the risk of osteoporotic fractures have been systematically investigated and a number of these were shown in randomised controlled clinical studies to significantly reduce the incidence of fractures and are currently used in clinical practice. While these interventions have significantly improved the management of patients with osteoporosis, there are still unmet needs requiring a broader range of therapeutic agents. In particular, there is a need for agents that can replace already lost bone and can drastically reduce the risk of non-vertebral fractures, the most common fragility fractures.

The strength of bone depends on its mass and its structural and material composition.1,,3 All these components of bone strength are affected by bone remodelling, the process responsible for bone renewal throughout adult life. The whole skeleton is renewed on average every 10 years in an orderly fashion by temporary anatomic structures called basic multicellular units (BMUs). Each BMU comprises a team of osteoclasts in the front and a team of osteoblasts in the back, supported by blood vessels, nerves and connective tissue. Osteoclasts resorb bone, while osteoblasts move to the resorbed area and lay down a new bone matrix that subsequently mineralises, a process known as coupling. The balance between the supply of new cells and their lifespan is critical for the maintenance of bone homoeostasis and is disturbed in bone diseases.

In osteoporosis, a prolonged lifespan of osteoclasts and a shortened life span of osteoblasts induce an imbalance between bone resorption and bone formation.4 An increased rate of activation of BMUs, as generally occurs after the menopause, will amplify this negative balance leading to increased rates of bone loss.5 In addition, these changes lead to increased number and depth of resorption cavities, perforation of trabecular plates and loss of trabecular elements of cancellous bone as well as thinning and porosity of cortical bone.6 The increased rates of bone remodelling reduce the degree of mineralisation of the bone matrix and the amount of collagen, and may also impair its maturation and crosslinking.3 The net outcome of all these changes is decreased bone strength and increased bone fragility. This pathophysiological background of osteoporosis forms the basis of our current rationale for developing therapeutic agents for the treatment of the disease, which are distinguished into inhibitors of bone resorption and bone turnover and stimulators of bone formation. The majority of available agents reduce bone resorption (eg calcitonin, oestrogens, selective oestrogen receptor modulators, tibolone, bisphosphonates and denosumab) while only parathyroid hormone (PTH) peptides have been shown to stimulate bone formation. The effect of another agent used in the treatment of osteoporosis, strontium ranelate, on bone remodelling has not yet been clarified.

Antiresorptive agents reduce the rate of bone resorption followed by a decrease in the rate of bone formation due to the coupling between these two processes and after about 6 months a new equilibrium between resorption and formation is achieved at a lower rate of bone remodelling (figure 1A). These changes are associated with modest increases in bone mineral density (BMD) and maintenance or some improvement of structural and material properties of bone leading to reduction in bone fragility. Of these agents, bisphosphonates are currently the most widely used antiosteoporotic treatments.7 With the approval of the most potent antiresorptive agent, the RANKL inhibitor denosumab, the possibility of further developments of this class of agents is exhausted.8 However, animal and human genetics have indicated that coupling between bone resorption and bone formation may not always be complete, leading to investigation of other targets in osteoclasts. One of these is cathepsin-K, a cystine protease abundantly expressed in osteoclasts, which is responsible for the degradation of the organic matrix of bone (mainly collagen), the second step of bone resorption. Inhibition of cathepsin-K reduces bone resorption without, however, affecting the integrity of osteoclasts. Phase II studies with such an inhibitor (odanacatib) showed a decrease in bone resorption with relatively less inhibition of bone formation (figure 1B) and very encouraging results on mineral density of cortical bone.9 A large phase III clinical trial with odanacatib is currently underway.10 However, all treatments targeting the osteoclasts cannot stimulate bone formation underlining the need for bone-forming agents.

Figure 1

Schematic presentation of changes of bone remodelling during treatment with antiosteoporotic agents. (A) Antiresorptive agents (eg, bisphosphonates, denosumab); (B) cathepsin-K inhibition (eg, odanacatib); (C) parathyroid hormone; (D) theoretical example of anabolic treatment.

The first, and only available agent that can stimulate bone formation is PTH (the 1–34 fragment, teriparatide and the 1–84 whole molecule) given by daily subcutaneous injections. PTH stimulates bone formation, which after about 1 month of treatment is followed by stimulation of bone resorption. These effects are mirrored in the changes of biochemical markers of bone turnover during treatment with daily injections of PTH, which are characterised by early increases in serum P1NP values followed by increases in serum CTX values (figure 1C). PTH increases cancellous and endocortical bone formation but has a limited, if any, effect on periosteal bone formation and increases cortical porosity. In addition, most of the bone forming activity of PTH occurs at sites that were already undergoing bone remodelling rather than at quiescent surfaces.11 Finally, the effect of PTH on bone remodelling is transient, a steady state is not obtained, consistent with a decrease in the response with time. Thus, although PTH has added a new option in the management of osteoporosis and demonstrated that pharmacological stimulation of bone formation is possible, it cannot be considered a pure anabolic therapeutic agent.

Sclerostin expression and mechanism of action

The need for a genuine anabolic treatment raises the question whether stimulation of bone formation can be achieved at all skeletal envelopes without a concomitant increase in bone resorption (figure 1D). Human and animal genetics have indicated that this may be feasible. In particular, the recognition of the pivotal role of Wnt signalling pathway in bone formation provided a number of potential targets for the development of new pharmaceuticals.12 For clinical use, however, treatments should modify the expression of target molecules but also need to have bone specificity to avoid potential effects on other organs in the body. Extracellular, secreted molecules expressed predominantly in bone tissue present, therefore, the most attractive targets of new treatments. One such target is sclerostin, a protein produced exclusively in the skeleton by osteocytes, which is a negative regulator of bone formation.13 Inhibition of sclerostin is currently being explored as a potential anabolic treatment of osteoporosis.14

Sclerosteosis and van Buchem disease are two rare sclerosing bone disorders, included in the group of craniotubular hyperostoses, which were first described in the 1950s as distinct clinical entities with closely related phenotypes. Sclerosteosis has been mainly diagnosed among Afrikaners in South Africa while most of the patients with van Buchem disease come from a small fishing village in the Netherlands. The skeletal manifestations of both diseases result from endosteal hyperostosis, are characterised by progressive generalised bone overgrowth and thickening and are most pronounced in the mandible and the skull (figure 2). Patients have characteristic enlargement of the jaw and the facial bones leading to facial distortion, increased intracranial pressure and entrapment of cranial nerves, often associated with facial palsy, hearing loss and loss of smell.15 Compared with patients with van Buchem disease, patients with sclerosteosis have a more severe phenotype and usually have malformations of the hands (eg, syndactyly). Genetic analysis revealed that the two conditions have different defects localised in the same gene called SOST, which is located on chromosome 17q12–21 and encodes the protein sclerostin. Six mutations of the SOST gene, three nonsense, two altering the splicing of the gene and one missense, have been identified so far in patients with sclerosteosis.15 16 No mutations of the SOST gene were present in patients with van Buchem disease but a 52 kb deletion downstream of the SOST gene was identified. This deleted region harbours an enhancement element that drives the expression of the SOST gene, explaining the similarities between the two conditions. The reported mutations in SOST and the deletion found in patients with van Buchem disease result in the absence of expression of sclerostin while the reported missense mutation leads to complete loss of function of sclerostin.

Figure 2

(A) A patient with sclerosteosis with characteristic enlargement of the mandible and the skull and facial palsy. Reproduced from van Bezooijen RL, Papapoulos SE, Hamdy NAT, et al. In: Bilezikian JP, Raisz LG, Martin JP, eds. Principles of Bone Biology. San Diego, California, USA: Academic Press 2008:139–52. (B) Increased thickness of the skull of a patient with sclerosteosis.

Osteocyte-produced sclerostin decreases bone formation by inhibiting the terminal differentiation of osteoblasts and promoting their apoptosis. Sclerostin was originally thought to be a BMP antagonist based on its amino acid sequence similarity with the DAN (differential screening-selected gene aberrative in neuroblastoma) family of secreted glycoproteins that share the ability to antagonise BMP activity. It was shown, however, that sclerostin could not antagonise all BMP responses and had a mechanism of action distinct from that described for classical BMP antagonists, decreasing bone formation by inhibiting the Wnt signalling pathway in osteoblasts.15 Sclerostin antagonises Wnt signalling and binds directly to the first YWTD-EGF repeats of LRP5 and this binding is decreased in the mutated form of LRP5, which is associated with the high bone mass phenotype. However, although sclerostin binds to LRP5/6 and antagonises Wnt signalling, it does not appear to compete with Wnt proteins for binding to these co-receptors. Sclerostin may be transported to the bone surface via the canaliculi or it may induce another signal in osteocytes, which contain Wnt signalling, that is transported to osteoblasts to inhibit bone formation. Although the mechanism of action of sclerostin to decrease bone formation involves inhibition of the Wnt signalling pathway, its precise molecular mechanism of action and factors controlling its secretion are yet to be determined. Animal studies have shown that mechanical loading and high PTH levels downregulate the expression of SOST in osteocytes and decrease the production of sclerostin, resulting in stimulation of bone formation.17 18

SOST knockout mice were shown to have similar skeletal features to those of patients with sclerosteosis, with significant increases (>50%) in bone mass at both the trabecular and cortical compartments of the lumbar spine and the hip, increased bone formation rate and bone strength.19 In contrast, transgenic mice overexpressing human SOST exhibited a low bone mass phenotype and decreased bone strength associated with decreased bone formation while bone resorption was unaffected.20

Inhibition of sclerostin

The findings of the human and animal studies led to the development of an antibody against sclerostin, which has been tested mainly in animal models. Subcutaneous administration of 25 mg/kg of this antibody twice weekly for 5 weeks to aged ovariectomised rats resulted in a dramatic increase in bone mass and improvement in strength in virtually all skeletal sites.21 Remarkably, this short-term treatment with sclerostin antibody not only reversed completely ovariectomy-induced bone loss, but it further increased bone mass and bone strength to levels greater than those of sham-operated control animals. Bone biopsies showed that bone formation markedly increased in trabecular as well as in periosteal, endocortical and intracortical surfaces, leading to increases in trabecular and cortical thickness and reduction in cortical porosity. These effects of the sclerostin antibody on the mass and quality of cortical bone, if confirmed in human studies, might have a significant clinical impact on the prevention of non-vertebral fractures. Similar results were also reported in cynomolgus monkeys after 2 months of treatment with a humanised sclerostin antibody.22 Treatment increased BMD at trabecular and cortical sites and almost doubled vertebral load to failure, indicating an increase in bone strength. Recently, treatment with a sclerostin antibody was reported to increase fracture callus density and strength in animal models of fracture healing.23 Finally, in a mouse model of chronic colitis, a short period of treatment with a sclerostin antibody completely reversed the bone loss and decline of several bone mechanical and microstructural properties associated with chronic inflammation.24

The increased bone formation induced by sclerostin antibodies was not associated with an increase in bone resorption. Instead a decrease of osteoclast surface was observed, suggesting a functional uncoupling between bone formation and bone resorption, as was also shown in the studies of SOST knockout mice. The mechanism responsible for this surprising finding has not yet been elucidated and longer-term studies are needed to examine whether this uncoupling of bone formation to bone resorption is transient or persistent. The effect of sclerostin antibodies on bone formation is reversible when treatment is stopped.

In the first human, placebo-controlled, dose-escalating study of 72 healthy men and postmenopausal women, it was shown that a single injection of a monoclonal antibody against sclerostin markedly increased bone formation markers and BMD and was well tolerated.25 Serum P1NP levels reached a peak 14–25 days after the antibody administration and returned progressively to baseline values after about 2 months. In contrast, the bone resorption marker serum CTX decreased to a minimum about 14 days after the antibody injection and returned to baseline values after about 2 months, in agreement with the uncoupling of osteoblast and osteoclast activity observed in the animal studies. Clinical phase II studies with this antibody are currently underway. Particularly relevant for further development are also studies of heterozygous carriers of sclerosteosis who were shown to have BMD values consistently higher than those of healthy individuals without any of the bone complications, owing to bone overgrowth in the skull and the mandible, of the homozygotes.26 These data suggest that titration of sclerostin activity in vivo can have a favourable effect on bone mass without the skeletal complications of sclerosteosis.

These animal and human studies show that the stimulation of bone formation by inhibition of sclerostin has distinct differences from that following PTH administration, the most important being the stimulation of bone formation at all bone envelopes and reduction of cortical porosity without an effect on osteoclastic activity. These results, if confirmed in humans over longer periods of time, indicate a new treatment paradigm that fulfils all requirements of an anabolic treatment of osteoporosis.

References

Footnotes

  • Funding This work was supported by a grant from the European Commission (HEALTH-F2-2008–201099, TALOS).

  • Competing interests The author has received consulting fees from Amgen, Merck & Co, Novartis, Procter & Gamble and Roche/GSK.

  • Provenance and peer review Not commissioned; externally peer reviewed.