Rapid biochemical response to denosumab in fibrous dysplasia of bone

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Dec 6, 2013 - initiation of denosumab 60 mg sc, changes in bone pain, bone turnover [assessed by serum amino-terminal propeptide of type I collagen ...
Osteoporos Int (2014) 25:777–782 DOI 10.1007/s00198-013-2585-1

CASE REPORT

Rapid biochemical response to denosumab in fibrous dysplasia of bone: report of two cases K. Ganda & M. J. Seibel

Received: 25 July 2013 / Accepted: 18 November 2013 / Published online: 6 December 2013 # International Osteoporosis Foundation and National Osteoporosis Foundation 2013

Abstract We report on the clinical and biochemical outcomes in two adult patients with active polyostotic fibrous dysplasia (FD) treated with the RANK-L inhibitor, denosumab, following unsatisfactory responses to prior long-term bisphosphonate therapy. A 44-year-old female (case 1) who had received a cumulative dose of 20 mg zoledronic acid over 2.5 years and a 48-year-old male (case 2) who had received a cumulative dose of 45 mg zoledronic acid over 8 years both experienced minimal reductions in pain scores and markers of bone turnover. Following initiation of denosumab 60 mg sc, changes in bone pain, bone turnover [assessed by serum amino-terminal propeptide of type I collagen (PINP) and urinary deoxypyridinoline] were monitored over a period of 20 and 8 months, respectively. Following administration of denosumab, both patients demonstrated a rapid and pronounced biochemical response: Within 4–7 weeks, bone turnover markers fell to levels within the respective reference range, and one patient reported a reduction in pain. Treatment with denosumab was well tolerated. However, transient asymptomatic hypocalcaemia and/or hypophosphatemia associated with a transient two to threefold increase in serum PTH levels was observed in both patients. Dosing intervals for denosumab varied significantly between the two patients, depending on disease activity K. Ganda : M. J. Seibel Department of Endocrinology and Metabolism, Concord Hospital, Level 6 Concord Hospital Medical Centre, Hospital Road, Concord, NSW 2139, Australia K. Ganda (*) : M. J. Seibel Bone Research Program, ANZAC Research Institute, The University of Sydney, Concord, NSW 2139, Australia e-mail: [email protected]

at baseline. Denosumab appears to be effective in reducing bone turnover in adult patients with active FD. However, caution should be exercised, and patients should be monitored carefully as significant fluctuations in biochemical and hormonal indices can occur. Keywords Bone turnover markers . Denosumab . Fibrous dysplasia . Response . Therapy

Introduction Fibrous dysplasia of bone (FD) is a nonheritable genetic disorder characterized by excessive formation of fibrous tissue in the bone marrow and destruction of normal bone in conjunction with abnormal bone formation and increased osteoclast activity [1–3]. The pathogenesis involves a postzygotic mutation in the gene encoding for the alphasubunit of stimulatory G-protein [4] resulting in constitutive activation of G-protein-coupled receptors in osteoblasts. Clinical manifestations range from simple monostotic FD to the triad of polyostotic fibrous dysplasia, endocrine abnormalities, and café-au-lait skin hyperpigmentation referred to as McCune–Albright Syndrome [5, 6]. Patients with FD may present with bone pain, fragility fracture, deformity, neurological compromise, or with incidental x-ray findings [1]. Bisphosphonates reduce pain and bone turnover in FD [7–13]. To our knowledge, denosumab treatment for FD has only been described in one case report in 2012—a 9-year-old boy with a rapidly expanding fibrous dysplastic lesion of the femur [14]. After a poor response to intravenous bisphosphonate therapy, monthly denosumab was initiated, resulting in significant improvements in pain and bone turnover.

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Bisphosphonates inhibit osteoclastic bone resorption by inducing apoptosis in actively resorbing osteoclasts [15, 16]. Denosumab, in contrast, is a fully human monoclonal antibody, which binds to receptor activator of nuclear factor kappa-B ligand (RANK-L), thereby inhibiting osteoclast recruitment, differentiation, and activation [17]. In this case report, we describe for the first time, the use of denosumab in two adult patients with polyostotic FD who had a poor response to prior bisphosphonate treatment but responded rapidly to denosumab therapy.

Case 1 A 44-year-old woman was referred in May 2009 for treatment of polyostotic FD. A craniofacial deformity was present since childhood, requiring multiple reconstructions of the left maxillary bone. The patient complained of longstanding bilateral hip pain (7/10 on an analog scale), which was the indication for antiresorptive treatment. Puberty occurred at 12 years of age. On examination, a left maxillary deformity and left facial café-au-lait hyperpigmentation were noted. There were no other skeletal deformities or focal tenderness. Hip, knee, and spine movements were normal. Her blood pressure was 110/70, BMI 20.4 kg/m2 (height 159 cm). There were no features to suggest hyperthyroidism, acromegaly, or Cushing’s syndrome. Initial investigations in May 2009 revealed normal renal function, serum calcium, and phosphate. Her 25-OH-vitamin D level was deficient at 35 nmol/L (>75). Bone turnover was accelerated with serum amino-terminal collagen type I propeptide (PINP) at 134 μg/L (