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Autosomal Dominant Osteopetrosis Revisited: Lessons from Recent Studies

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Autosomal Dominant Osteopetrosis Revisited: Lessons from Recent Studies European Journal of Endocrinology (2013) 169 R39–R57 ISSN 0804-4643 REVIEW GENETICS IN ENDOCRINOLOGY Autosomal dominant osteopetrosis revisited: lessons from recent studies Jens Bollerslev1,2, Kim Henriksen3, Morten Frost Nielsen4,5, Kim Brixen4,5 and Wim Van Hul6 1Section of Specialized Endocrinology, Medical Clinic B, Rikshospitalet, Oslo University Hospital, N-0027 Oslo, Norway, 2Faculty of Medicine, University of Oslo, N-0027 Oslo, Norway, 3Nordic Bioscience AS, Herlev Bygade 207, Herlev, Denmark, 4Department of Endocrinology and Metabolism, Odense University Hospital, Odense, Denmark, 5University of Southern Denmark, Odense, Denmark and 6Department of Medical Genetics, University of Antwerp, Antwerp, Belgium (Correspondence should be addressed to J Bollerslev at Section of Specialized Endocrinology, Medical Clinic B, Rikshospitalet, Oslo University Hospital; Email: [email protected]) Abstract Systematic studies of autosomal dominant osteopetrosis (ADO) were followed by the identification of underlying mutations giving unique possibilities to perform translational studies. What was previously designated ADO1 turned out to be a high bone mass phenotype caused by a missense mutation in the first propeller of LRP5, a region of importance for binding inhibitory proteins. Thereby, ADO1 cannot be regarded as a classical form of osteopetrosis but must now be considered a disease of LRP5 activation. ADO (Albers-Scho¨nberg disease, or previously ADO2) is characterized by increased number of osteoclasts and a defect in the chloride transport system (ClC-7) of importance for acidification of the resorption lacuna (a form of Chloride Channel 7 Deficiency Osteopetrosis). Ex vivo studies of osteoclasts from ADO have shown that cells do form normally but have reduced resorption capacity and an expanded life span. Bone formation seems normal despite decreased osteoclast function. Uncoupling of formation from resorption makes ADO of interest for new strategies for treatment of osteoporosis. Recent studies have integrated bone metabolism in whole-body energy homeostasis. Patients with ADO may have decreased insulin levels indicating importance beyond bone metabolism. There seems to be a paradigm shift in the treatment of osteoporosis. Targeting ClC-7 might introduce a new principle of dual action. Drugs affecting ClC-7 could be antiresorptive, still allowing ongoing bone formation. Inversely, drugs affecting the inhibitory site of LRP5 might stimulate bone formation and inhibit resorption. Thereby, these studies have highlighted several intriguing treatment possibilities, employing novel modes of action, which could provide benefits to the treatment of osteoporosis. European Journal of Endocrinology 169 R39–R57 Introduction heritable forms varied. Intermediate forms with rela- tively mild course but a recessive mode of inheritance The concept of osteopetrosis was introduced in the were identified. In one of these, the patients presented 1920s to describe patients with radio-opaque bones and basal ganglia calcifications and renal tubular acidosis, universal osteosclerosis. The disease corresponded to and this syndrome was subsequently found to be caused marble bone disease (1) first described in 1904 by the by carbonic anhydrase deficiency (4, 5, 6, 7). With German radiologist Albers-Scho¨nberg (2). He described these observations, malfunctioning bone resorption was a man with multiple fractures and a radiographic introduced as a common pathogenic factor in osteo- osteosclerosis characterized by increased cortical thick- petrosis, and at least in the intermediate forms, this ness and reduced marrow space. It became clear that was demonstrated in the beginning of the 1980s to osteopetrosis could be seen in families, and based on be due to an acidification defect across the osteoclast mode of inheritance, Johnston et al. (1968) (3) cell membrane (5), see section on Genetic studies iden- suggested two different forms: a benign form designated tifying CLCN7. autosomal dominant osteopetrosis (ADO) and a malig- Osteopetrosis was described as a heterogeneous group nant form seen in childhood and inherited in an of diseases related to defective bone resorption (3). autosomal recessive manner, termed autosomal reces- However, also within ADO, a systematic search for the sive osteopetrosis (ARO). However, other forms were disease revealed radiographic heterogeneity (8). Based described during the following years, and moreover, it on several families with ADO from the county of Funen, became clear that the clinical presentation of each of the Denmark, in the mid-1980s, we described two distinct q 2013 European Society of Endocrinology DOI: 10.1530/EJE-13-0136 Online version via www.eje-online.org Downloaded from Bioscientifica.com at 09/24/2021 09:22:09PM via free access R40 J Bollerslev and others EUROPEAN JOURNAL OF ENDOCRINOLOGY (2013) 169 radiological forms based on plain radiographs (8). HBMT253I cohort. Bone mass in adults based on Further studies characterizing ADO at the clinical, dual-energy X-ray absorptiometry (DXA) is almost biochemical, histological, and biomechanical levels increased to the same level in patients with the bone- revealed that these types corresponded to two distinct resorptive defect (ADO) as in patients with LRP5 disorders, which we designated as ADO type 1 (ADO1) activation bone disease. Thus, ADO patients and our and ADO2 (9, 10, 11, 12, 13). These early studies were HBMT253I cohort had increased bone mineral density reviewed in 1989 (14). ADO was defined as a condition (BMD) at all skeletal sites measured. Z-scores ranged from with diffuse osteosclerosis, primarily involving the axial C2toC12 at the lumbar spine, which is mostly skeleton, but with symmetrical effects on the long bones comprised of trabecular bone, and the whole-body and with little or no modeling defects (14). Based on compartment, consisting primarily of cortical bone, bone biopsies, it was hypothesized that the pathogenesis Fig. 1, also illustrating studies by high-resolution periph- of these two forms involved defective bone resorption, eral quantitative computed tomography (CT) (20, 21, 22). directly or indirectly. Penetrance is high in ADO; however, several During the recent 20 years, investigations of asymptomatic carriers have been described (14, 20). osteopetrosis have contributed significantly to our Waguespack et al. (20) described a total of 32 obligate insight into bone biology. After the millennium, it carriers and presented data on BMD in six. In these, turned out that ADO1 was caused by an activating BMD Z-scores were modestly elevated with values mutation in LRP5 (15) and thus cannot be recognized ranging from 0 to C4(Fig. 1). The authors had the as a classical form of osteopetrosis but rather should be possibility to reevaluate six patients and one carrier regarded as a LRP5-activating bone disease, or high after more than 30 years since the original description bone mass (HBM) phenotype. Also, the disease most (3, 20). In all patients, clinical symptoms progressed, probably described by Albers-Scho¨nberg (2) turned out whereas the carrier remained asymptomatic (20). The to be a form of Chloride Channel 7 Deficiency progression of symptoms is in alignment with pro- Osteopetrosis (16). However, it should be noted that a gression of the universal osteosclerosis, as indicated by mutation in CLCN7 has not been demonstrated in up to cross-sectional studies using DXA and histomorphome- 30% of patients presenting with a clinical phenotype of try (11, 12, 20, 21, 23). ADO, indicating further heterogeneity (17, 18). Patients with ADO have typical and prevalent The aim of the present review is to give an overview of symptoms (2, 3, 10, 19, 20, 24). The typical findings clinical lessons learned by studies on large and are increased fracture frequency, delayed healing, and homogenous populations of patients with ADO and osteomyelitis, especially in the jaw (2, 10, 19, 20). The HBM. This review will discuss genetic studies leading to latter is of special interest in relation to the current the identification of the mutated genes in the original discussion of osteonecrosis of the jaw (ONJ) associated cohorts, of instrumental importance for separating the with bisphosphonates and denosumab, i.e. drugs that syndromes into an intrinsic bone-resorptive defect decrease the number and activity of osteoclasts (25, 26, (Chloride Channel 7 Deficiency Osteopetrosis (ADO)) 27, 28, 29), as will be discussed in more detail below. and a LRP5 activation disease related to the bone With the prevalent and often serious symptoms, the formative site. Moreover, we will describe subsequent term benign osteopetrosis could be questioned (19, 20). in vitro investigations on bone-resorptive cells in ADO, As an example of this, Waguespack et al. (20) found increasing the understanding of bone biology and the early-onset vision loss in one-fifth of the patients and coupling principle. Also, we will critically review recent signs of bone marrow failure in 3%. Thus, their cohort data on metabolic consequences of disturbed bone had clearly more serious symptoms than we found in resorption in ADO. Finally, perspectives from these our original studies (14). However, the findings are studies regarding treatment of other metabolic bone prone to selection bias, as patients with symptoms are diseases are outlined. For this purpose, literature was found by clinical work-up, whereas patients with sparse searched through PubMed for the key words autosomal symptoms and carriers are mostly
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