Volume 12, Number 10, 1997
Blackwell Science, Inc.
1997 American Society for Bone and Mineral Research

Long-Term Effects of Intravenous Pamidronate in Fibrous Dysplasia of Bone ROLAND D. CHAPURLAT,1 PIERRE D. DELMAS,1,2 DANIEL LIENS,1 and PIERRE J. MEUNIER1 Fibrous dysplasia of bone (FD) is a rare disorder characterized by proliferation of fibrous tissue in bone marrow
leading to osteolytic lesions. It causes bone pain and fractures. To date the only treatment is orthopedic.
Histological and biochemical similarities between FD and Paget's bone disease related to increased osteoclastic
resorption led us to propose treatment with the bisphosphonate pamidronate. The aim of the study was to assess
the long-term effects of intravenous pamidronate in FD. In this open label phase III study, 20 patients with FD (11
males and 9 females; mean age 31 years) received courses of 180 mg of intravenous pamidronate every 6 months
(60 mg/day during 3 days by infusion). The mean duration of follow-up was 39 months (range 18 – 64). Severity of
bone pain, number of painful skeletal sites per patient, X-rays of all involved areas, serum alkaline phosphatase,
fasting urinary hydroxyproline, and urinary type I collagen C-telopeptide were assessed every 6 months. The
severity of bone pain and the number of painful sites appeared to be significantly reduced. All biochemical markers
of bone remodeling were substantially lowered. We observed a radiographic response in nine patients with refilling
of osteolytic lesions. A mineralization defect proven by bone biopsy was observed in one case. Four patients
sustained bone stress lines, but no fracture occurred. We suggest that intravenous pamidronate alleviates bone
pain, reduces the rate of bone turnover assessed by biochemical markers, and improves radiological lesions of FD.
Few side effects were observed. (J Bone Miner Res 1997;12:1746–1752)

disability. Sarcomatous transformation of FD is rare andoften occurs after radiation therapy.(7) FIBROUS DYSPLASIA of bone (FD) is a skeletal disorder RadiologicalsignsofFDconsistmainlyoflyticandcystic characterized by extensive proliferation of fibrous tissue lesions, with reduction of cortical thickness, and sometimes in bone marrow, leading to osteolytic lesions, fractures, and widening of the diaphysis. Radioisotope bone scans usually deformations.(1) It represents about 2.5% of bone disorders disclose increased uptake of isotope in affected areas. This and 7% of benign bone tumors.(2) Initial symptoms most feature is useful for defining the skeletal distribution of often present during childhood or adolescence as bone pain lesions.(8) Computed tomography (CT) and magnetic reso- and repeated fractures. The other usual clinical findings are nance imaging (MRI) can be used for differential diagnosis bone deformity and neurologic compression, especially with malignancies.(9,10) when the facial bones or the skull are involved.(3,4) FD may FD is a congenital disease, due to a somatic activating be limited to a single bone (monostotic form) or may mutation of the gene of the a subunit of the G-protein involve several bones (polyostotic form). Monostotic forms resulting in a mosaic population of normal and mutant are often asymptomatic.(5) The McCune-Albright syndrome tissues,(11) with an increase in cyclic adenosine monophos- is a polyostotic form of FD associated with melanotic cuta- phate (cAMP) formation. This activating mutation can be neous macules and endocrine abnormalities, including pre- found in bone cells(12,13) and in the endocrine tumors of the cocious puberty.(6) Recurrent fractures can cause severe McCune-Albright syndrome.(11,14) There is also an in- 1Department of Rheumatology and Bone Diseases, Hoˆpital Edouard Herriot, Lyon, France.
2Institut National de la Sante´ et de la Recherche Me´dicale (INSERM), Lyon, France.
creased expression of the proto-oncogene c-fos, presumably TABLE 1. DISTRIBUTION OF BONE LESIONS OF FD a consequence of raised adenylate cyclase activity in abnor-mal cells.(12) This increased expression of c-fos appears to Number of patients be specific to FD.(12) Pregnancy has been implicated in exacerbation of FD perhaps because of estrogen receptors in the fibrous tis- sue.(15) Bone lesions include collagen fibers randomly dis- tributed, synthetized by fibroblasts that can originate by metaplasia of osteogenic cells.(16) These incompletely dif- ferentiated osteoblasts produce within connective tissue ir- regular islands of woven bone with no evidence for later replacement by mature lamellar bone. Osteocalcin has been discovered in several types of FD cells, confirming their osteogenic lineage.(17) Increased rates of bone resorption can be noted and may be due to elevated secretion of interleukin-6 (IL-6) by bone cells.(18) To date, orthopedic surgery has been the only treatment of FD and consists of preventive measures (curettage, bone grafting, internal fixation of long bones) and management of fractures.(19) Calcitonin, mithramycin, and etidronatehave been tried in a few cases of FD with poor results.(20,21)Use of antiresorptive drugs has been proposed because ofthe evidence for increased osteoclastic bone resorption, mine the sites of the disease but not to assess the efficacy of mediated by the presence of numerous and large osteoclasts the treatment. There was a total number of 145 sites of FD at the interface between marrow fibrous areas and bone in our 20 patients, with a mean of 7.25 per patient (range surfaces (with similarities with Paget's disease of bone) and 1–25). There were 65 lesions involving limbs, with 14 pa- by the increase of fasting urinary hydroxyproline.(1,4,6) tients having one or more sites in the lower limbs (40 We have assessed the long-term effects of intravenous lesions). Before treatment, 13 patients were suffering from pamidronate, a second generation bisphosphonate which is bone pain. Painful sites were sites of FD.
a potent inhibitor of bone resorption, in 20 patients withFD. We have reported preliminary findings on the short- term effects of pamidronate in nine patients in 1994.(22) Pamidronate was given by intravenous infusion over 3 days with a total dose of 180 mg/course (60 mg/day), i.e., MATERIALS AND METHODS
one course consists of a complete 3-day package. The drug was administered in normal saline or glucose solution (1l/day), as a 4-h infusion on 3 consecutive days. During the Twenty patients have been followed up in an open label study period, patients received supplements of calcium study design, 9 females and 11 males, for a mean duration (1000 mg/day) and vitamin D (800 –1200 IU) or D (600 – of 39 months (range 18 – 64, SD 5 16.72, 65 years follow- 900 IU) to prevent potential vitamin D deficiency and up) after the first course of treatment. The mean age at secondary hyperparathyroidism induced by the bisphospho- diagnosis was 18 (range 1.5– 46). The mean age at onset of nate. For the two patients who were 13 years old at the treatment was 31 (range 13– 69); 18 patients were mature beginning of treatment, the dose of pamidronate was adults, and 2 were 13 years old at the beginning of treat- adapted to their weight (1 mg/kg/day). Patients received a ment. We chose to perform a study without a control group course of treatment every 6 months, during the first 18 because FD is a very uncommon and heterogeneous dis- months, and subsequently every 12 months.
ease. No improvement of FD has been experienced by ourpatients before treatment, and for 12 of them the period Measurement and follow-up before diagnostic and treatment was over 4 years.
Two patients had monostotic form. The distribution of Each patient was examined every 6 months. Biochemical FD lesions in our patients is presented in Table 1. One measurements were performed, and X-rays of involved sites woman had McCune-Albright syndrome, with precocious were taken at each visit.
puberty at age 8 and characteristic melanotic skin macules.
We used a pain scale to assess the severity of bone pain: Thirteen patients had sustained one or several fractures 0 for no painful site, 1 for low, 2 for moderate, 3 for before treatment with pamidronate. Pathological confirma- medium, and 4 for severe. When patients had several pain- tion of FD was available for eight patients. For the other 12 ful sites, the most painful was chosen to evaluate the effect patients, FD was diagnosed with radiographs, because of of treatment. We also assessed the number of painful sites characteristic lesions. X-rays were taken for each localiza- per patient before and after each course of treatment. We tion in all patients, and bone scans were performed in 14 defined the clinical response as follows: complete response patients at baseline. These bone scans were used to deter- if the pain intensity dropped from 4, 3, 2, or 1 to 0, with a CHAPURLAT ET AL.
Evolution of severity of bone pain with treatment. Comparison of painscores at each visit with baseline values(Wilcoxon match pairs test).
Evolution of the number of painful localizations with treatment.
Comparison of pain scores at each visitwith baseline values (Wilcoxon matchpairs test).
number of painful localizations which fell to 0; and partial worsening without any new treatment, among patients who response if there is a decrease of the intensity of pain or of present a response.
the number of painful localizations. We defined radio-graphic response as a decrease in the area of one (or several) lytic lesion(s) and/or as a thickening of bone cortex.
Laboratory tests were performed before treatment and Biochemical data at each visit were compared with base- during the follow-up period (every 6 months) for each line values, expressed in percentage of variation, using the patient, including serum calcium, phosphate, total alkaline Wilcoxon matched pairs test. Pain was assessed by compar- phosphatase (ALP), and fasting urinary excretion of hy- ing the data at each visit with the baseline values (for the droxyproline and calcium, by standard laboratory methods severity using the pain scale and for the number of painful in our department (colorimetric assays). We also measured, sites) with the Wilcoxon matched pairs test.
in a subgroup of patients, serum intact parathyroid hor-mone (PTH) by immunochemoluminometric assay (N:28.5 6 11.2 ng/ml), serum 25-hydroxyvitamin D (25(OH)D) (D and D isomers together) by competitive binding-pro- Clinical effects tein assay (N: 28.1 6 11 ng/ml). Urinary peptides of cross-linking domains of collagen I, also called CTX (CrossLaps Before the first treatment, 13 patients complained of Osteometer, Copenhagen, Denmark), a sensitive and spe- bone pain. The mean severity at baseline was 2.8 on our cific marker of bone resorption,(23) were measured after a pain scale. Pain severity was significantly reduced (using the pamidronate course in 10 patients (12 courses). Urine pyr- Wilcoxon test) after 6, 12, 18, 24, 30, and 36 months (Fig. 1).
idinoline was also measured in seven patients, with an The mean number of painful sites per patient at baseline immunoassay (Pyrilinks, Metra Biosystems, Mountain was 2.9 (range 0 – 4; SD 1.67), corresponding to a total View, CA, U.S.A.). We defined the biological response as number of painful localizations of 41 in our 20 patients. The follows: partial response if serum ALP and/or fasting uri- number of painful localizations was significantly reduced nary hydroxyproline decreased at least 30%, and complete (Wilcoxon test) after 6, 12, 18, 24, and 30 months (Fig. 2).
response if serum ALP and/or fasting urinary hydroxypro- The clinical response in these 13 patients was complete in 8 line returned to within normal values. We defined the of them and partial in 5 of them.
relapse as clinical and/or radiological and/or biological There was a relapse in 8 patients out of 13, but we

(A) Before treatment, 1994. (B) After treatment, 1995. Radiographic as-pect (A) before and (B) after threecourses of pamidronate: filling of a lyticarea.
(A) Before treatment, 1989.
(B) After treatment, 1995. Radiographicaspect (A) before and (B) after 10courses of pamidronate: filling of a lyticarea and thickening of a cortice.
obtained a response to a new course of pamidronate in all on Figs. 3A, 3B, 4A, and 4B. Seven out of the nine patients of them. Children, the two monostotic patients, and the who had a radiographic response had painful sites, and all McCune-Albright patient did not respond differently.
of them presented a clinical response.
No patient sustained a complete fracture. Four patients developed a stress line during the period of treatment.
These stress lines appeared in a dysplasic area of femur.
Radiological changes were evident in nine patients, con- Complete healing was achieved for three patients within 6 sisting in a progressive filling of osteolytic areas and in weeks of ceased weight bearing. For one of these patients cortical thickening. No obvious changes were observed in (age 13 at the beginning of treatment), the line has occurred the other 11 patients. There was neither spreading of pre- after 7 months of treatment, on a great trochanter, and has vious lesions nor appearance of new bone lesions during the increased with time, resulting in a varus of the femoral period of therapy in all patients. Among these nine patients, neck. It was necessary to undertake a surgical correction.
two had monostotic FD. A mean of 15 months (range 6 –25)was necessary to achieve a clear improvement in the radio-graphic aspect. The mean age of these patients was 32 years (range 19 –59 years). There were four females and fivemales. These characteristics were similar to those of the During the treatment period, repeated infusions of pamidr- total sample. Examples of radiological changes are shown onate led to a marked decrease of serum ALP and of urinary CHAPURLAT ET AL.
TABLE 2. BASELINE VALUES OF BIOCHEMICAL MARKERS (nmol/mmol Cr) Data shown are means 6 SD.
intake of calcium. Four patients complained of transientstiffness and bone pain located on the dysplasic areas, whichoccurred once or twice for each of them.
After three courses of pamidronate (540 mg), our younger patient (age 13 at the beginning of treatment)suffered from unusual changes of the right knee. The thick-ness of the growth plate on the medial side of both thefemur and the tibia expanded over 18 months, reminiscentof rickets. Complete healing of these lesions was observedon X-rays 12 months after cessation of treatment. A trans-iliac bone biopsy in a bone involved by fibrous dysplasiashowed clear evidence of osteomalacia (Fig. 6). A bonebiopsy was also taken in two other adult patients. Focalmineralization defects were seen in these two adult pa-tients, but without increase in the mean osteoid seam widthnor decrease in mean calcification rate measured by bone Evolution of serum alkaline phosphatase (SAP) as histomorphometry after tetracycline double labelling.
a function of time, expressed as a percentage of variation.
Comparison of SAP at each visit with baseline values (Wil- coxon match pairs test).
We provide evidence that in FD treated with intravenous type I collagen C-telopeptide (CTX). Baseline values of all pamidronate, bone pain could be alleviated, bone turnover biochemical markers measured are shown in Table 2.
could be reduced, and radiological lesions could be im- Serum ALP was significantly lower than baseline values proved. Few reports have studied the nonsurgical treatment after 6, 12, 18, 24, 30, 42, and 48 months of treatment of FD. The existence of increased bone resorption and (Fig. 5). Urinary CTX levels were reduced after treatment remodeling activity, at least in agressive forms of FD, en- by 71%, p 5 0.002, in 10 patients (12 courses).
couraged some open therapeutic trials with calcitonin in Fasting urinary excretion of hydroxyproline was also de- order to inhibit osteoclastic resorption. Bell reported a creased, but this was significant only after 12 and 18 decrease in elevated urinary excretion of hydroxyproline in months. It was also reduced after 1, 2, and 4 courses of one patient treated with calcitonin for 16 days.(20) The same treatment. For the 11 patients in whom it was measured, we effect was obtained in a 12-year-old girl treated with elca- observed a trend for a decrease of urinary pyridinoline (not tonin for 20 weeks.(17) Morii showed a decrease of serum significant: p 5 0.4).
ALP after administration of porcine calcitonin to a patient Serum calcium, phosphate, 25 hydroxyvitamin D, and with polyostotic fibrous dysplasia.(24) But Helmstedt(25) and fasting urinary excretion of calcium remained unchanged.
Yamamoto(17) did not find any change of serum ALP levels PTH had a tendency to increase, but this was significant in their patients treated with calcitonin. No report men- only after 6 months of treatment (mean 5 74%; p 5 0.038).
tioned the effects of calcitonin on clinical symptoms orX-ray abnormalities. One study reported the effects of atreatment with disodium etidronate(26) in an 18-year-old Side effects boy suffering from a polyostotic fibrous dysplasia, who had We observed some of the side effects usually described an unsuccessful attempt with calcitonin for 3 months. He with intravenous pamidronate.(24) Transient fever occurred has been treated with etidronate 400 mg/day during a 2- in eight patients after the first infusion (maximum 38.5°C), week period. This treatment did not induce any change in but this effect did not reappear with subsequent infusions of ALP and fasting urinary excretion of hydroxyproline. Be- pamidronate. Hypocalcemia (minimum: 2.05 mmol/l) was sides, these parameters were reduced after administration regularly noted after the infusions, but was seldom symp- of mithramycin, but this effect lasted only 1 week after the tomatic (four times) and was quickly corrected by oral improvement, and this treatment was poorly tolerated.

ogeneity of FD. Thus, in the lesions of FD, which wouldcontain too many osteoclasts, fibrous tissue, and/or meta-plasic cartilage in comparison with the amount of osteo-blasts, bone resorption could not be sufficiently inhibited,and the subsequent period of enhanced bone formationwould be inadequate.
The biochemical changes induced by pamidronate in FD are consistent with a marked reduction of bone remodeling,as shown by the decrease of fasting urinary excretion ofhydroxyproline, and above all of serum ALP and urinaryCTX. Despite the intake of adjuvant calcium and vitaminD, we observed a tendency toward a rise in serum PTH.
This point allows us to emphasize the importance of the Bone biopsy from the only patient with FD having adjuvant calcium and vitamin D.
developed a mineralization defect after treatment. Transil- To improve our knowledge of the disease, biochemical iac bone biopsy taken in an iliac crest with FD. Osteoma- markers of bone remodeling should be measured on a lacia proved by the existence of extended and thick osteoid monthly basis, at least at the beginning of the follow-up.
seams (in black). Typical fibrosis of marrow spaces also This would allow the studying of the kinetics of markers containing many vascular luminae. Undecalcified bone.
after a course of pamidronate on the one hand and of Goldner method staining. Magnification 503.
whether these kinetics are different among several patientson the other hand. We therefore would be able to decide Our current study is the continuation of the communica- more precisely when a new course of treatment is necessary tion about short-term effects of pamidronate in nine pa- for one given patient. This moment may be different among tients with FD.(22) Pamidronate is a potent inhibitor of different patients because the disease is perhaps more ac- bone resorption and has, like other bisphosphonates, a tive in some patients and thus more likely to relapse.
lasting effect on bone turnover.(27) It has been successfully A transient mineralization defect visible in dysplasic bone and extensively used in Paget's disease of bone,(28,29) ma- has occurred in one patient, a 13-year-old boy. In two lignant hypercalcemia,(30) lytic bone metastases,(31,32) mul- adults, focal and limited mineralization defects were seen tiple myeloma,(33) and osteoporosis.(34,35) Intravenous ad- by biopsy in noninvolved iliac bone. The growth rate of the ministration is preferred to oral intake because of the poor adolescent was not affected. The abnormal findings in the digestive tolerance (gastralgia, esophagitis) of the com- adolescent may be explained by the increased uptake of pound when it is given orally(36) and of the low intestinal pamidronate by his growth plates and by the iliac bone absorption of bisphosphonates in general.(37) The intrave- involved with FD. This has very likely increased the focal nous administration allows a rapid and prolonged intake of concentration of the compound and enhanced the inhibit- pamidronate in bone matrix. We chose a dose used in our ing effects of pamidronate on bone mineralization. Similar department and by several authors for patients with Paget's and also reversible changes on growth plates have been disease of bone.(29) induced by high daily doses of tiludronate, another bisphos- In our present study, pamidronate has led to a marked phonate, in baboons.(38) This fact suggests a cautious use of decrease in pain severity, and in the number of painful sites high doses of bisphosphonates in children and the preven- per patient, as far as an open study permits us to conclude.
tive use of calcium and vitamin D. For these three patients, Usually two courses of pamidronate were necessary to it has been possible to resume courses of pamidronate achieve the improvement. Bone pain was always alleviated without any problem.
when pamidronate was given after a relapse of bone pain.
In conclusion, intravenous pamidronate appears to have There was no difference concerning the quality of clinical potential as a nonsurgical treatment of FD, because it can response according to the location of the involved sites.
induce radiological and biochemical improvement in some The radiological survey has shown that in about half of patients and may alleviate bone pain in most affected indi- patients lytic lesions could be filled, at least in part, and that viduals. This treatment was well tolerated, but the possibil- a thickening of cortices could be obtained. This result is in ity of a mineralization defect must be monitored in young agreement with our previous report.(22) Therefore, pamid- patients. Further double-blind study is required to establish ronate may induce an increase of bone strength in sites fully the efficacy of pamidronate for FD.
affected by FD, thus reducing the fracture risk. It must benoted that there are more radiological responses in long bones of lower limbs than in upper limbs or in skull, but theinterpretation of skull X-rays is far more difficult than for We thank Dr. M. Arlot for her assistance in statistics and lower limbs. Furthermore, it is difficult to conclude about E. Gineyts for the assays of CTX.
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1997; accepted May 30, 1997.


Revista Alergia México 2014;61(Supl. 2):S117-S193. Guía Mexicana para el Diagnóstico Avalado por Colegio Mexicano de Inmunología Clínica y y el Tratamiento de la Urticaria Presidente: Dr. Miguel Medina Ávalos Colegio Mexicano de Pediatras Especialistas en Inmunología Clínica y Alergia (COMPEDIA) Presidente: José Lozano Saenz

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