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We report a case of melorheostosis, a rare bone disorder characterised by mesodermal dysplasia, and its successful and prolonged treatment with the intravenous bisphosphonate zoledronic acid. The middle-aged man presented with pain and swelling of his tibia, which was diagnosed by imaging and bone biopsy as being due to melorheostosis. There was early symptom control after a single infusion of intravenous zoledronic acid. Prolonged symptom relief was accompanied by long-term suppression of the bone resorption marker β cross-laps. We suggest that melorheostosis can be treated with intravenous zoledronic acid and that treatment can be monitored by the use of a specific bone resorption marker.
Melorheostosis is a rare disorder characterised by mesodermal dysplasia of bone first described by Leri and Joanny in 1922. There are now more than 200 case reports in the literature. It derives from the Greek melos = limb and rheos = flow due to the classic radiological appearance of ‘flowing hyperosteosis’ resembling hardened wax that has dripped down the side of a candle. Involvement tends to be asymmetrical and most frequently involves the lower limbs but rarely the trunk, spine, skull and facial bones.1,2 Melorheostosis occurs sporadically with equal sex distribution and is thought to be secondary to a segmentary embryogenetic defect. It is associated with vascular malformations, soft tissue masses adjacent to the affected bone and scleroderma of the overlying skin.3,4 Melorheostosis has also been associated with tumours, including osteogenic sarcoma, malignant fibrous histiocytoma and dermoid tumours.5,6 It often has an insidious onset in early adult life. Symptoms include pain, oedema and limitation of joint movement. Pain is often more common in adults because of subperiostial bone formation. Skin changes may be seen in up to 17% of cases and include hyperpigmentation of overlying skin and scleroderma.1 Bone biochemistry is usually normal. Histology is non-specific, but can be useful in excluding malignancy. Isotope bone scanning demonstrates marked increased uptake at the site(s) of involvement. Treatment options have remained rather limited and include surgical interventions such as tendon lengthening, excision of soft tissue masses, release of joint contractures and occasionally amputation. There have been a few case reports documenting the use of bisphosphonates7–9 but we report for the first time the successful and prolonged benefit of intravenous zoledronic acid in the symptomatic treatment of melorheostosis.
A 59-year-old man with chronic schizophrenia presented to accident and emergency at Aberdeen Royal Infirmary in 2003 with right foot pain following a right ankle injury 10 days earlier. He incidentally described a long history of pain and swelling in his right leg. Examination revealed a firm non-tender bony swelling over the proximal third of the right tibia.
Routine blood tests revealed a normocytic anaemia and a moderately elevated C-reactive protein of 60 mg/L (normal <10 mg/L). Liver function tests, including alkaline phosphatise, were all within normal limits.
Plain radiographs of the right lower limb demonstrated a periosteal pattern of hyperostosis with a flowing candle wax configuration affecting the anterior tibial cortex, with endosteal sclerosis also noted in the medial cuniform, neck of 1st metatarsal and neck of the 1st proximal phalanx of the right foot consistent with melorheostosis (figure 1).
Isotope bone scintigraphy, which was performed using 99m Tc-MDP and standard protocols, demonstrated increased uptake in the right proximal tibial shaft, both ankles and feet, with slight uptake in the right femoral shaft.
Bone biopsy revealed densely stained irregular cement lines with disorganisation of the bony trabeculae. Focally the bone appeared sclerotic with little osteoblastic proliferation.
In this case, x-rays showed the classical appearance of melorheostosis and the isotope bone scan, although not pathognomonic, showed changes in keeping with such a diagnosis. Milder manifestations of the disease may show only focal bone involvement. In these cases it may be harder to differentiate between myositis ossificans or a periosteal osteosarcoma.
Myositis ossificans is a benign condition in which heterotropic bone forms within soft tissue, usually within a few weeks of trauma.10 Although this patient reported an ankle injury 10 days prior to presenting, his main complaint was of a several year history of pain and bony swelling over his right tibia. Early x-rays in myositis ossificans are often normal, or show soft tissue swelling only, followed later by calcification and ossification of the soft tissue lesion. If the lesion is juxtacortical, a periosteal reaction may be seen, although this is unlike the extensive periosteal hyperostosis seen in this case. Isotope bone scanning shows intense uptake within the soft tissue rather than the bony uptake seen in this case.10
Periosteal sarcoma has a more insidious onset, arising from the surface of bone with a tendency to encircle it. X-rays often show a broad-based soft tissue mass attached to the cortex, with cortical thickening. Isotope bone scanning shows non-specific intense uptake in the periosteal area.11 Although neither the x-ray or isotope bone scan appearances in this case were in keeping with a perisosteal sarcoma, there have been case reports of melorheostosis occurring in association with osteogenic sarcoma and bone biopsy was performed to exclude the possibility of malignancy.
The patient did not receive any treatment at that point and was discharged from the care of the orthopaedic team. He was subsequently referred to the Rheumatology Department in 2006 with increasing pain, temperature and size of the lesion in his right tibia.
Alkaline phosphatase remained normal. Serum markers of bone turnover were measured using the Elecsys 2010 auto-analyser (Roche Diagnostics Ltd, Burgess Hill, UK). This has a manufactures CV of <5% across the working range of the assay. A bone formation marker, procollagen type 1 N-propeptide (P1NP), and resorption marker, C-terminal telopeptides of type 1 collagen (β cross-laps), were within the normal range as reported by the manufacturer; however, this is perhaps unsurprising given that only a relatively small amount of bone was affected by melorheostosis. However, β cross-laps were relatively higher than the bone formation marker P1NP, suggesting that bone resorption was predominant.
Repeat isotope bone scan demonstrated that the intense uptake along the right tibial shaft had encroached further on the proximal metaphysis and the disease was felt to be active. After ensuring that the patient had good dental hygiene and adequate 25-hydroxy vitamin D levels, they received a single infusion of 5 mg zoledronic acid given over 30 minutes. The result was a dramatic reduction in symptoms and size of the lesion.
Markers of bone turnover have remained appropriately suppressed following treatment and the patient remains asymptomatic. Eighteen months later he has still not required any further infusions of zoledronic acid and his β cross-laps remain significantly depressed (table 1).
Isotope bone scanning was not repeated following treatment with zoledronic acid as β cross-laps and, therefore, bone resorption were significantly depressed following the infusion and we would have expected this to be reflected in decreased uptake on the isotope bone scan. In addition, the patient has significant chronic mental health issues and we did not feel it was appropriate to expose him to an additional investigation and radiation exposure, which would have provided little additional information.
Melorheostosis is often thought of as a benign sclerosing bone dysplasia, the aetiology of which remains uncertain. Lesions follow innervation of the spinal sensory nerves leading to the hypothesis by Murray and McCredie that embryonic infection of these nerves causes neural scarring and segmental bone sclerosis. Dermatomal involvement of the same sensory nerve root may be responsible for the associated cutaneous manifestations.12 Kim et al demonstrated down regulation of adhesion proteins involved in osteoblastic regulation, specifically transforming growth factor ß induced gene product, which may contribute to the development of hyperostosis and associated soft tissue abnormalities.13 Endo et al demonstrated increased collagen secretion from dermal fibroblasts overlying involved bone and suggested that cortical hyperostosis may influence proliferation of neighbouring deep dermal collagen to produce the overlying skin changes seen.14
On plain radiography, melorheostosis is classically described as periosteal hyperosteosis; however, a review of 23 cases by Freyschmidt found the most frequent appearance was an osteoma-like hyperosteosis on the endosteal surface of the bone. The lesions are typically eccentrically placed with no evidence of bony destruction.1 Isotope bone scanning reveals increased uptake in the same distribution seen on plain radiography reflecting an increase in bone metabolism.
Histology is non-specific but is useful to exclude malignancy as melorheostosis has been associated with a number of tumours, including osteogenic sarcoma. Extensive cortical sclerosis is usually seen with some areas of immature bone and active bone turnover. Small bone islands within the soft tissue have also been noted.1,2
Both periosteal and endosteal patterns of hyperosteosis were seen on plain radiography in our patient. Isotope bone scanning revealed increased uptake in the same distribution as the plain radiograph changes. Bone biopsy was performed to exclude the possibility of malignancy. It revealed changes consistent with benign bone dysplasia and small bone islands within the soft tissue consistent with melorheostosis.
Bisphosphonates are used for symptomatic control in both malignant and non-malignant diseases associated with increased bone turnover. They have been shown to decrease bone pain, slow progression of bone lesions and decrease the risk of pathological fracture.15,16 Nitrogen containing bisphosphonates inhibit osteoclast-mediated bone resportion by direct and indirect actions on osteoblasts and macrophages. Bisphosphonates also decrease bone vascularity and zoledronic acid has been shown in vitro to be a potent inhibitor of angiogenesis.17
Potential causes of bone pain in melorheostosis include increased osteoclastic bone resorption and activation of pain receptors, raised intraosseous pressure and increased vascularity secondary to hyperosteosis and soft tissue involvement around joints. Thus, bisphosphonate treatment via a number of mechanisms would be expected to reduce inflammatory bone pain and symptoms in melorheostosis. Donath et al described a case of melorheostosis with extensive bilateral disease and elevated alkaline phosphatase where the patient was treated with 30 mg of pamidronate daily for 6 days. This resulted in a rapid improvement in symptoms; however, alkaline phosphatase fell only slightly and the radionuclide bone scan appearance was unchanged.7
In this case the diagnosis of melorheostosis was made incidentally and the patient was not particularly symptomatic at initial diagnosis. Histology revealed little in the way of active bone turnover, which may have reflected the fact that the disease was relatively quiescent at that point. When the patient was referred to the Rheumatology Department in 2006 he was clearly symptomatic. Markers of bone turnover were within the normal reference range; however, only a relatively small amount of bone was affected by melorheostosis. Repeat isotope bone scan in 2006 demonstrated that the intense uptake along the right tibial shaft had encroached further on the proximal metaphysis, in keeping with an increase in disease activity.
A single infusion of 5 mg zoledronic acid given over 30 minutes resulted in a dramatic improvement in pain, temperature and size of the melorheostotic lesion and no further treatments have been required so far. Serum β cross-laps were significantly suppressed following treatment and have remained so. Zoledronic acid may decrease the frequency of disease activity as well as reducing symptoms during an active phase.
Recent guidance has been issued regarding osteonecrosis of the jaw (ONJ) and bisphosphonate treatment by the American Society for Bone and Mineral Research (ASBMR). It is recognised that ONJ is commoner, although still very rare, with intravenous compared to oral bisphosphonate treatment. It is very important to ensure patients do not require any dental extractions and have been seen recently by a dental practitioner prior to receiving intravenous bisphosphonate treatment.18
This is the first reported case of the successful use of zoledronic acid in the symptomatic treatment of melorheostosis and demonstrates the value of monitoring with a bone resorption marker.
We would like to thank Dr Sinclair Dundas, Consultant Pathologist, Aberdeen Royal Infirmary, Aberdeen, UK for reviewing the bone biopsy and his helpful comments regarding this.
Competing interests: None.
Patient consent: Patient/guardian consent was obtained for publication.