Inherited multicentric osteolysis: case report of three siblings treated with bisphosphonate

Inherited multicentric osteolysis (IMO) is a rare familial skeletal condition characterised by osteolysis leading to bone dysplasia. Patients subsequently experience pain, dysfunction and disability. First described in 1838 by Jackson [1], IMO has been infrequently reported in international literature with synonymous names such as 'vanishing bone' syndrome, inherited osteolysis/arthritis syndromes, multicentric carpal-tarsal osteolysis, nodulosis arthropathy and osteolysis (NAO) syndrome, and Torg-Winchester syndrome [1‐3]. The heterogeneity of independent case reports of syndromes sharing similar manifestations and radiologic findings of osteolysis led to grouping by the International Skeletal Dysplasia Society into an "osteolysis" group (Table 1) [4].

The disorders grouped in this fashion still had some distinct differences in clinical features, associations, and anatomic locations. Similarities exist between these disorders in that they were familial, and that the primary pathophysiology was of abnormal osteolytic bone causing pain, dysfunction, and disability. In some cases, IMO has other additional clinical manifestations including facial dysmorphism, nephropathy, and neurologic dysfunction. None have been associated with bilateral hip dysplasia.

IMO is often initially misdiagnosed as it mimics other chronic rheumatic disorders such as juvenile idiopathic arthritis [5]. A genetic aetiology is likely, however with the precise genetic mechanisms not yet understood. Studies have shown links of some form of IMO with mutation in gene 16q12-21 which encodes matrix metalloproteinase-2 gene (MMP2). MMP2 deficiency or lack of activity is hypothesised to cause extracellular matrix breakdown, leading to disturbance in bony remodelling favouring osteolysis [1].

Bisphosphonate therapy was commenced in all three children. Bisphosphonates are agents which decrease osteoclastic activity, hence favouring bone formation [6]. Extensive literature supports bisphosphonate use in adults [7, 8]. Bisphosphonates are now used in the paediatric population to successfully treat a variety of conditions including osteoporosis and osteogenesis imperfecta. Paediatric case reports suggest that bisphosphonates may have analgesic effects, improve range of movement and function, improve BMD, and potentially improve the natural history of osteonecrosis [9‐12]. Some of these studies have shown reduced risk of fractures, but overall data to date is inconclusive. Similarly, data on risk of further surgical intervention is inconclusive.

We present a report of three siblings of a non-consanguineous Caucasian family diagnosed with a possibly unique form of IMO treated with bisphosphonates, seen in our Rheumatology Department of a tertiary paediatric hospital. Consent and permission to publish relevant information, clinical photos, and radiologic images were obtained from the parents of the three siblings.

IMO is an interesting yet rare familial osteolytic condition of largely unknown aetiology. The International Skeletal Dysplasia Society recently revised their nosology and classification guidelines in which IMO encompasses many different osteolytic syndromes. These syndromes have some overlap of clinical features but commonly share the same pathogenesis of osteolysis, with a pattern of familial inheritance. Clinical symptoms or signs usually occur early in childhood (usually 2^nd or 3^rd year of life). Findings include multiple bone and joint pain and bony "dysplasia" with associated decreased range of movement and function. Diagnosis is usually made with characteristic osteolytic changes on radiological investigations. Serologic and histologic investigations are always negative for classical inflammatory or autoimmune causes. Further investigations must always be initially performed to distinguishing IMO from differential diagnoses, including inflammatory, autoimmune, endocrine and metabolic causes. As the pathophysiology is unknown, differential diagnoses of IMO must include conditions which cause avascular necrosis. Treatment of IMO with traditional anti-inflammatory or anti-rheumatic medications appears to have little effect on pain or disease progression. Genetic testing have revealed possible associations with specific genes such as MMP2, however sibling A was tested and found not to have a mutation in MMP2. Our IMO patients may be a unique form genetically, as it is unusual that these siblings experienced decreased sensation to pain. One sibling had hip dysplasia, which is not a characteristic of the other osteolytic syndromes. In this family, mode of inheritance was thought to be autosomal recessive as no other generations were affected.

Bisphosphonates are analogues of inorganic pyrophosphate with selectivity to bone rather than other tissue. Their primary mechanism of action is to either inhibit osteoclastic activity, reduce osteoclastic recruitment, differentiation and resorptive activity, or induce apoptosis [6], thereby favouring bone formation. Evidence in paediatric use suggests potential benefits, which may include reduction in pain, increased function and range of motion, improved BMD, reduced risk of fractures, and retardation of the natural disease history.

In this case report, we have found that bisphosphonates in these children with IMO have been beneficial in improving acute pain and BMD. There was no effect on range of motion. In two siblings, there was radiologic evidence suggesting that bisphosphonates may retard the natural history or progression of the disease. We could not comment on the effects on fracture risk as one sibling developed a significant fracture post-bisphosphonate, even following an improvement in BMD. Similarly, we could not comment on whether bisphosphonates reduce the risk for further surgical intervention as one sibling required stapling to correct leg length discrepancy. Bisphosphonate therapy in these three siblings seemed safe, as reported side effects were mild and clinically insignificant. Given that the treatment options for conditions such as IMO are limited, we conclude that bisphosphonate therapy could be considered for treatment of IMO as it appears safe and has potential benefits as described above.

IMO is a rare familial condition which must be considered in children and adolescents with idiopathic osteolysis of bones affecting other members of the family. The pathophysiology is thought to be of genetic aetiology but not well understood. Reported genetic links include mutations of the MMP2 gene. IMO often mimics the symptoms of other chronic rheumatologic disorder, and is often initially misdiagnosed. It is a diagnosis of exclusion, hence investigations must be performed to rule out other diagnoses. Patients with IMO may benefit from bisphosphonate therapy. These benefits may include pain relief, decreased analgesic requirements, improved BMD, and potentially reducing new fracture or osteolytic collapse risk. Given small numbers seen in any single tertiary centre, further multi-centre studies into safety and efficacy of bisphosphonate therapy in conditions such as IMO are warranted.

Written informed consent was obtained from the patient for publication of this case report and any accompanying images. A copy of the written consent is available for review by the Editor-in-Chief of this journal.

SJL is an advanced trainee in Paediatric Rheumatology, governed under the Royal Australasian College of Physicians. CW is a consultant Orthopaedic Surgeon and a member of the Royal Australasian College of Surgery (Orthopaedics). KJM is a consultant Paediatric Rheumatologist and a member of the Royal Australasian College of Physicians.