Denosumab in Patients With Fibrous Dysplasia Previously Treated With Bisphosphonates

Bas C. J. Majoor; Socrates E. Papapoulos; P. D. Sander Dijkstra; Marta Fiocco; Neveen A. T. Hamdy; Natasha M. Appelman-Dijkstra


J Clin Endocrinol Metab. 2019;104(12):6069-6078. 

In This Article

Patients and Methods


Patients eligible for treatment with denosumab were adults with FD/MAS attending the outpatient clinic of the Center for Bone Quality of the Leiden University Medical Center who fulfilled the following criteria. First, patients had to have been treated previously with bisphosphonates with incomplete clinical and biochemical responses as defined by persistence of pain and/or failure to normalize serum values of total serum alkaline phosphatase (ALP) activity (in the absence of liver disease), and/or of serum amino-terminal propeptide of type 1 procollagen (P1NP). Patients had to be aged ≥18 years, had never been treated with denosumab, and to have no contraindications for the use of this agent (e.g., hypocalcemia, vitamin D deficiency, pregnancy, and lactation). Impending tooth extraction or localization of the disease in the proximal femur were not exclusion criteria.

In our center, management of patients with FD/MAS is conducted following an in-house standard care trajectory that includes collection of data about type and extent of disease, extent of skeletal involvement, screening for endocrinopathies, history of previous medical or surgical treatment, and evaluation of laboratory and clinical parameters of disease activity at predefined time intervals. Patients were seen on their regular three-month outpatient clinic visits during which nonfasting morning blood samples were collected for evaluation of bone and mineral metabolism and data on change in pain complaints were registered, although pain was not quantitively measured. All patients received calcium/D3 supplements as required. Patients with persistent hypophosphatemia resulting from renal phosphate wasting were treated with active vitamin D metabolites. Oral informed consent was obtained from all patients for the off-label use of denosumab (Prolia®, Amgen) and written approval for the retrospective analysis and reporting of the collected data were obtained from the medical ethics committee of the Leiden University Medical Center.


All patients included in the study had been treated previously with bisphosphonates, primarily olpadronate [(3-dimethylamino-1-hydroxypropylidene)-1,1 bisphosphonate], a nitrogen-containing bisphosphonate that is 5 to 10 times more potent than pamidronate that has been used in our center for the treatment of patients with Paget disease of bone, malignancies, and rare bone diseases.[12,19–26] The diagnosis of fibrous dysplasia was established based on clinical and radiological evaluation, with additional histological and genetic evaluation where required. The extent of bone involvement was determined by 99m-technetium bone scans using the validated skeletal bone score (SBS).[27] Serum calcium adjusted for albumin binding, phosphate, creatinine and γ-glutamyltransferase were measured by semiautomated techniques. Serum ALP activity was measured using a fully automated P800 modulator system (Roche BV, Woerden, Holland). PTH and 25-OH vitamin D (25-OHD) were measured using the Immulite 2500 assay (Siemens Diagnostics, Breda, Netherlands) and the LIAISON® 25-OH Vitamin D TOTAL assay (DiaSorin S.A./N.V., Brussels, Belgium), respectively. P1NP and the C-terminal telopeptide of type 1 collagen (CTX) were determined by the E-170 system (Roche BV). C-terminal fibroblast growth factor (FGF)-23 was measured in plasma by ELISA (Immutopics, San Clemente, CA). Normal ranges: ALP 40 to 98 IU/L, P1NP in premenopausal women and men <59 ng/mL, CTX <573 pg/mL, FGF-23 <125 pg/mL, PTH 0.7 to 8.0 pmol/L, 25-OHD 50 to 250 nmol/L. Maximal renal tubular phosphate reabsorption in relation to glomerular filtration rate was assessed in some patients from a nomogram (normal range, 0.8 to 1.42 mmol/L).[28]

Outcomes of Treatment

The primary outcomes of treatment were the stable reduction of biochemical markers of bone turnover and the decrease or disappearance of FD-related skeletal pain. Patients were followed until the last included patient had completed 12 months of treatment with denosumab (end of observation period).

Biochemical response to treatment was evaluated with percentage change of serum levels of ALP and P1NP and normalization rates were calculated (upper limit of normal ALP 98 IU/L, P1NP 59 ng/mL). Possible attributive factors on biochemical response nine months after start of treatment with denosumab, including type of FD and dosage scheme, were evaluated in a linear mixed model with a follow-up of nine months, as patients with six-month doses were switched to three-month doses after nine months of inadequate response. Pain response was assessed at each visit and response was categorized as increased, unchanged, improved. or disappeared. Potential adverse effects of denosumab treatment were registered at each visit; radiographs were only obtained during treatment when clinically indicated.

Statistical Analysis

Statistical analysis was performed using SPSS for Windows, version 23.0 (SPSS Inc., Chicago, IL). Unless otherwise stated, results are presented as median (range) or as a percentage in case of categorical data. A linear mixed model was used to assess the subtypes of FD and dose intervals as attributive factors to the response to treatment with denosumab over time. A paired sample t-test was used to compare bone turnover markers (BTMs) before starting denosumab and at the end of the observation period. Spearman correlation was used to evaluate the relation between pretreatment values and treatment outcome.