Abstract

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Several studies have shown that bisphosphonates are useful in alleviating chronic pain in patients with fibrous dysplasia,but further studies are necessary to confirm these promising results. Being the most potent bisphosphonate we treated one patient of distal femur fibrous dysplasia with Zoledronic acid and would like to share our experience as a case report. 52 years old male patient presented in out-patient department complaining of pain and swelling of left thigh lower aspect for approximately eight months. An open biopsy was performed and diagnosis of fibrous dysplasia was confirmed. Due to location of lesion and financial restraints patient was treated with intravenous Zoledronic acid. There was significant functional improvement and reduction of alkaline phosphatase level to normal within a period of six months. Hence it was considered to report this case as it may add up to the available data of usage of Zoledronic acid in treating fibrous dysplasia.

Introduction

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Fibrous dysplasia is a developmental anomaly of bone-forming mesenchyme that manifests as a defect in osteoblastic differentiation and maturation.¹ The term fibrous dysplasia was suggested by Lichtenstein and Jaffe in 1942. The etiology of this abnormal growth process is related to a mutation in the gene that encodes the subunit of a stimulatory G protein (Gsα) located on chromosome 20.² Mechanical quality of bones is decreased. As a consequence, bones are fragile and patients have an increased risk of developing deformities, pain and pathological fractures. Abnormalities may involve 1 bone in the monostotic form (70% of cases) or many bones in the polyostotic form (30% of cases). The polyostotic form is occasionally associated with precocious puberty and cafe-au-lait skin lesions (McCune-Albright syndrome) or with myxomas of skeletal muscle (Mazabraud syndrome).

Fibrous dysplasia can occur anywhere but is usually found in the proximal femur, tibia, humerus, ribs, and craniofacial bones in decreasing order of incidence. Usually, fibrous dysplasia presents clinically in children and adolescents, with a median onset age of 8 years. Most cases manifest themselves before the age of 30 years. Monostotic fibrous dysplasia may be completely asymptomatic and is often an incidental finding on x-ray. Patients usually seek medical care because of either painful swelling and deformity or a pathologic fracture through a weakened bone. Asymptomatic patients do not need treatment. Surgical treatment of fibrous dysplasia is indicated in the prevention or treatment of fractures or major deformity.³ Several studies have shown that bisphosphonates are useful in alleviating chronic pain in patients with fibrous dysplasia.^{4, 5}  Zoledronic acid is the most potent bisphosphonate that has been studied in clinical trials to date.⁶  Being the most potent bisphosphonate we treated one patient of distal femur fibrous dysplasia with Zoledronic acid and would like to share our experience as a case report.

Case Report(s)

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52 years old male patient presented with complaints of pain and swelling of left thigh lower aspect for approximately eight months. Patient noted progressive swelling which was of insidious onset and gradually increased in size. Patient also developed dull aching continuous pain, aggravated by activities and relieved by rest and analgesics. Patient a tailor by occupation had significant restriction of day to day activities like sitting cross legged, squatting, etc. There was no history of trauma or fever. No other co-morbidities like diabetes, hypertension present.               &n bsp;    

On examination general physical profile was normal with no relevant findings. Local examination revealed a diffuse, ill-defined, hard, globular swelling involving entire left distal femur. Surface was smooth, hard in consistency with ill-defined borders. Skin over the swelling was normal. There was no localized lymphadenopathy and distal neuro-vascular deficit. Laboratory investigations revealed significant elevation of alkaline phosphatase. Clinically parosteal osteosarcoma and chondrosarcoma were the differential diagnosis. Radiography, CT scan and MRI were done and both reports suggested fibrous dysplasia. So an open biopsy was performed to confirm the diagnosis. The report came out to be fibrous dysplasia. No evidence of malignancy was noted. Routine haematological and biochemical investigations and oral examination were done. Pre-existing hypocalcaemia and altered renal function were ruled out.

The patient was given an infusion of 5mg of intravenous Zoledronic acid as an infusion after adequate hydration. After 24 hours he developed myalgia, polyarthralgia and mild fever which persisted for 72 hours and then subsided. The patient was put on regular 3 month follow up and was also restricted from activities that can stress distal femur significantly like running, jumping, sitting cross legged, squatting etc. He was advised to use a walking stick in the opposite hand for three month period. After 6 month and after one year evaluation there was significant functional improvement and reduction in pain. The alkaline phosphatase value normalized and is maintained in normal range till now. He was given another dose of 5mg of intravenous Zoledronic acid as an infusion one year later and now after an approximate two year follow-up he is having significant reduction in pain, better functional abilities and a normal alkaline phosphatase level. There is no increase in size of lesion as noted by limb girth measurements. There is neither a decrease in size of lesion. A CT scan performed at the end of one and a half years showed no significant filling of the lytic lesions or increase in cortical thickness at distal femur.

Discussion

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Bisphosphonate treatment of polyostotic and monostotic fibrous dysplasia (FD) has been reported to reduce pain and fracture rate of affected areas. Some reports of bisphosphonate treatment of FD lesions suggest that reduction in size and filling in of bony defects can occur in adults and children while others report no improvement in lesion size.⁷ Treatment regimens had included pamidronate and alendronate but not zoledronic acid. It was decided to use Zoledronic acid, the most potent bisphosphonate described for treating a case of fibrous dysplasia where surgical treatment is thought to increase morbidity of the patient.

Zoledronic acid is a member of the class of nitrogen containing bisphosphonates, and is a potent inhibitor of bone resorption. Zoledronic acid binds with high affinity to calcium phosphate bone mineral hydroxyapatite, localizing primarily at areas of high bone turnover. The drug becomes released during bone resorption and is subsequently internalized by osteoclasts. It acts primarily by inhibiting the mevalonate pathway in osteoclasts via farnesyl diphosphate synthase inhibition, resulting in the prevention of downstream protein prenylation, ⁸ with subsequent inhibition of osteoclast mediated bone resorption and osteoclast formation and the induction of osteoclast apoptosis.

The patient described here is a 52 years old active male patient. Although the lesion is diagnosed in younger age group, mono-ostotic lesion may present late. The lesion had been reported in a 68 years old patient and it was concluded that in some patients widespread bone lesions remained totally silent and unrecognized until as late as the seventh decade. The lesion presented here occupies distal femoral epiphyseal region and therefore caused a diagnostic dilemma due to its location. Parosteal osteosarcoma and chondrosarcoma were the differentials and were excluded by histopathological examination. On reviewing literature fibrous dysplasia after puberty had been reported to appear in the epiphyseal area, although lesions are usually in the diaphysis extending towards metaphysis.⁹

There are no clear treatment guidelines, and thus the orthopaedic surgeon has to make treatment decisions on a case-by-case basis. The surgical treatment options available are curettage and bone grafting and if more radical procedure is required, resection and reconstruction with custom made prosthesis or osteo-allografts. Curettage and Cancellous or cortical bone grafting did not appear to have any advantage in the treatment of symptomatic lesions. All grafts resorbed with persistence of the lesion. At the time of the latest follow up evaluation, no lesion had been eradicated or had decreased in size.¹⁰  The other treatment options had limitations like affordability, availability of allograft or prosthesis, morbidity associated with the procedure as well as the active lifestyle of the patient which may lead onto early failure.

Response to therapy was monitored by serial measurements of  alkaline phosphatase levels and assessment of  Medical Outcomes Study 36-item Short-Form General Health Survey (SF-36), which assesses eight aspects of health status: general and mental health, physical and social functioning, physical and emotional roles, pain and vitality; scores on each scale can range from 0 (worst) to 100 (best). Alkaline phosphatase level normalized within 6 months of treatment and the physical component summary score of the Medical Outcomes Study 36-item Short-Form General Health Survey, a measure of quality of life, increased significantly from baseline at 6 months. Pain score also improved significantly. Alkaline phosphatase level remained normal in these two years as well as the SF – 36 remained significantly improved.

It is encouraging that the marked biochemical effects of Zoledronic acid appeared to be accompanied by significant improvements in indexes of quality of life, physical functioning, pain, general health, vitality and emotional well being. Despite previous reports of limitation or reduction in size of fibrous dysplasia lesions, it is our experience that bisphosphonate treatment of fibrous dysplasia does not arrest the expanding nature of these lesions whilst apparently safe and providing continuing pain control. Our findings confirm the efficacy of Zoledronic acid in patients with fibrous dysplasia and add substantially to the available data by demonstrating that prolonged remission can be achieved, accompanied by improvements in quality of life. Although early results are encouraging, many questions remain about optimizing their use for fibrous dysplasia therapy. Management of FD has previously consisted of either conservative follow-up or surgery depending on disease activity and localization. Bisphosphonates may be suitable especially for lesions in which surgical treatment is particularly challenging.

Despite these promising results, FDA reports have surfaced about serious adverse effects associated with bisphosphonates which include jaw osteonecrosis, atrial fibrillation and medication-induced fractures. For suspected adverse events, including atrial fibrillation and medication-induced fractures, more data is needed before final recommendations can be made. We need to move from smaller, retrospective series to long-term studies with well-controlled data collection before indications and contraindications for bisphosphonate use can be better defined.

Abbreviations(s)

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FD: Fibrous Dysplasia

References

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1. Harris WH, Dudley HR, Barry RJ. The natural history of fibrous dysplasia. An orthopaedic, pathological, and roentgenographic study. J Bone Joint Surg Am. Mar 1962; 44-A: 207-33.
2. DiCaprio MR, Enneking WF. Fibrous Dysplasia. Pathophysiology, Evaluation, and Treatment. J Bone Joint Surg Am. 2005; 87:1848-1864.
3. McCune DJ: Osteitis fibrosa cystica: the case of a nine year old girl who also exhibits precocious puberty, multiple pigmentation of the skin and hyperthyroidism. Am J Dis Child. 1936; 52:743-747.
4. Chapurlat RD, Hugueny P, Delmas PD, Meunier PJ. Treatment of fibrous dysplasia of bone with intravenous pamidronate: long-term effectiveness and evaluation of predictors of response to treatment. Bone. 2004; Volume 35, Issue 1:235-242.
5. Liens D, Delmas PD, Meunier PJ. Long-term effects of intravenous pamidronate in fibrous dysplasia of bone. Lancet. 1994; 343:953-4.
6. Body JJ, Lortholary A, Romieu G, Vigneron AM, Ford J. A dose finding study of zoledronate in hypercalcemic cancer patients. J Bone Miner Res. 1999 Sep; 14(9): 1557-61.
7. Chan B and Zacharin M. Pamidronate treatment of polyostotic fibrous dysplasia: failure to prevent expansion of dysplastic lesions during childhood J Pediatr Endocrinol Metab 19:75-80
8. Coxon FP, Helfrich MH, van’t Hof RJ, et al. Protein geranylgeranylation is required for osteoclast formation, function, and survival: inhibition by bisphosphonates and GGTI-298. J Bone Miner Res 2000; 15:1467–76.
9.  Harris WH, Dudley HR and Barry RJ.The natural history of fibrous dysplasia: An Orthopaedic, Pathological and Roentgenographic study. J Bone Joint Surg. 1962; 44: 207 – 33.
10. Guille JT, Kumar SJ and MacEwen GD. Fibrous dysplasia of the proximal part of the femur. Long-term results of curettage and bone-grafting and mechanical realignment. J Bone Joint Surg Am. 1998 May; 80(5):648-58.

Source(s) of Funding

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No funding acquired

Competing Interests

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Nil

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