Calcif Tissue Int DOI 10.1007/s00223-013-9829-0
ORIGINAL RESEARCH
Clinical and Radiological Observations in a Case Series of 26 Patients with Fibrous Dysplasia Malissa Dawn Thomsen • Lars Rejnmark
Received: 6 May 2013 / Accepted: 24 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Fibrous dysplasia (FD) is a rare disease caused by a sporadic postzygotic missense mutation that leads to abnormal fibroblast proliferation, defective osteoblast differentiation, and increased bone resorption. It may affect one or several bones. Both the mono-ostotic and polyostotic types may be associated with hyperfunctional endocrinopathies and hyperpigmentation of the skin (cafe´-au-lait spots) in the so-called McCune–Albright syndrome (MAS). Due to its rarity, only a few case series are available, making it difficult for most clinicians to judge the severity of the disease. To improve our knowledge of FD, we reviewed all cases of FD treated at our department of endocrinology. Among 26 patients, 17 (65 %) had polyostotic FD, with four being diagnosed with MAS. Patients with polyostotic FD were diagnosed at an earlier age (median 13, range 0.5–64 years) than patients with the mono-ostotic form (median 21, 1–70 years). Craniofacial bones were affected in 80 % of cases, and 66 % complained of bone pain at the affected site, with no difference between patients with monoand polyostotic FD. Two patients with mono-ostotic and three with polyostotic FD had cranial nerve impairments. Fourteen underwent, at least, one surgery, six (67 %) with mono-ostotic and eight (47 %) with polyostotic FD. Most received treatment with bisphosphonates, but therapy did not result in any clear relief of symptoms or radiological improvements. In conclusion, bone pain is common in patients with FD. The severity of the disease depends on
The authors have stated that they have no conflict of interest. M. D. Thomsen (&) L. Rejnmark Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, Tage Hansens Gade 2, 8000 Aarhus C, Denmark e-mail: [email protected]
affected bones as mono-ostotic may be as debilitating as polyostotic FD. In our case series, bisphosphonate treatment did not show clear beneficial effects. Keywords Bisphosphonate Osteoclast McCune– Albright syndrome Focal bone lesion Fibrous dysplasia
Introduction Fibrous dysplasia (FD) is a rare benign skeletal disorder characterized by abnormal fibroblast proliferation and defective osteoblast differentiation resulting in replacement of cancellous bone and marrow with fibrous connective tissue. FD can present itself in either a mono-ostotic form, with involvement of one bone site, or a polyostotic form that includes multiple bone sites. FD has a predilection for certain bones including the femur, tibia, ribs, pelvis, and craniofacial bones. FD may also be associated with hyperfunctional endocrinopathies (e.g., preterm puberty or hyperthyroidism) and hyperpigmentation of the skin (cafe´au-lait spots) in the so-called McCune–Albright syndrome (MAS) [1, 2]. FD and MAS are caused by a sporadic postzygotic missense mutation in the somatic cells at the GNAS complex locus located on chromosome 20q13. This gene codes for the a-subunit of the stimulatory G protein belonging to hormone receptors. The mutation results in a constitutive activation of adenylyl cyclase and overproduction of cAMP in osteogenic cells [3]. The increase in cAMP leads to defects in osteoblast differentiation and proliferation of osteoblast progenitors and a subsequent production of abnormal bone in a fibrous stroma. The dysplastic stromal cells produce IL-6, causing hyperactivity of osteoclastic cells, resulting in increased bone resorption [1].
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M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
The estimated prevalence of FD is 1/30,000 [4]. Variable results have been reported on the occurrence of monoostotic compared to polyostotic FD lesions. Some investigators have found the mono-ostotic form to be five to six times as prevalent as polyostotic FD [4, 5], whereas others have reported polyostotic FD to be at least as (and often more) prevalent as mono-ostotic FD [6–8]. It is not uncommon for FD to be a silent disease, and some patients are asymptomatic; but when symptoms are present, they most often include bone pain, headache, bone deformities and asymmetry of the face, proptosis, diplopia, and pathological fractures, the latter especially during childhood. More serious symptoms include optic neuropathy, blindness, deafness, vestibular dysfunction, and seldom facial nerve palsy. Radiologically FD lesions have a lytic appearance and are characterized by thinning of the cortex with a ‘‘ground glass’’ matrix and can be confirmed by a biopsy of the bone lesions. To assess the extent of FD and the number of FD lesions, scintigraphy/isotopic bone scans are normally used, whereas computed tomography (CT) and magnetic resonance imagining (MRI) are used to characterize the precise involvement of bone. Due to an increased bone turnover in FD lesions, biochemical markers of bone turnover are in some cases elevated. Moreover, hypophosphatemia may be present due to an increased secretion of fibroblast growth factor (FGF-23) from the dysplastic tissue [9]. It has been reported that approximately 50 % of patients with MAS and polyostotic FD have phosphate wasting to some degree. An elevated serum FGF-23 has been found to correlate with the mass of osteogenic cells within the FD lesions and the degree of bone involvement assessed by serum and urine markers of bone metabolism [10]. Hypophosphatemia due to the renal phosphate wasting may contribute to mineralization defects, which ultimately can lead to osteomalacia, rickets, and bone pain with deformities [11, 12]. This could possibly be the reason that some patients with FD experience pronounced bone pain [13]. There is no cure or spontaneous resolution of FD, but not all patients are in a condition that requires treatment. Surgery may be indicated if a tumor mass is large and causes compression of adjacent tissue with nerve constriction, pain, or cosmetic discomfort. Bisphosphonates are often used as medical treatment as they have been suggested to reduce the increased rate of bone resorption at the affected sites. However, due to the rarity of the disease, only a few published studies are available. In order to improve our understanding of FD, we performed a systematic review of medical records from patients with FD treated at our department in the past 10 years. Symptoms and findings in patients with mono-ostotic and polyostotic FD were compared.
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Subjects and Methods Using the electronic patient register at our university hospital, we identified all patients diagnosed with FD within the past 10 years at our Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark. The search was based on medical charts assigned under the ICD-10 codes for mono-ostotic FD (M85.0) or polyostotic FD (Q78.1). Case status was adjudicated by review of the individual patient charts with extraction of information using a prespecified data-collection sheet. We collected data on gender, age, symptoms, and findings at presentation as well as radiographic methods used to diagnose the disease. In addition, we retrieved data on which treatment patients had received as well as symptoms and biochemical findings following treatment. Moreover, changes in radiological findings in response to treatment were recorded for patients for whom a radiological follow-up had been performed. In order to determine disease regression or progression we, in addition to the radiological findings, collected data on loss of mobility, deformity, pain increase or decrease, and vision and/or hearing loss or worsening. The study was approved by the Danish data protection agency, and informed consent was obtained from all patients. Biochemistry Plasma concentrations of calcium, phosphate, and albumin were measured by standard laboratory methods. Total plasma calcium levels were corrected for individual variations in albumin according to the following formula: plasma calcium, adjusted (mmol/L) = plasma calcium, total (mmol/L) ? 0.00086 9 [650—plasma albumin (lmol/L)]. Alkaline phosphatase (ALP) was measured spectrophotometrically using an automated instrument (Hitachi 917; Roche Diagnostics, Mannheim, Germany). Until December 2010, bone-specific alkaline phosphatase (BSAP) was measured after lectin precipitation (Boehringer Mannheim, Mannheim, Germany) and thereafter using an immunoassay (METRA BAP EIA kit; Quidel, San Diego, CA) with a Spectra II ELISA Reader (PerkinElmer Life and Analytical Sciences, Boston, MA) [14]. Due to this change in biochemical methods, results are reported as the proportion of studied patients with levels above the upper limit of the reference interval according to the methods used. Using a Spectra II ELISA reader, plasma 25-hydroxyvitamin D (25OHD) levels were measured by an enzyme immunoassay (OCTEIA; Immunodiagnostic Systems, Boldon, UK) until November 2005 and thereafter by isotope dilution liquid chromatography-tandem mass spectrometry by a method adapted from Maunsell et al. [15]. As the level of measurements for the two methods did not differ to any
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
major degree, we did not adjust for differences in methods used. Plasma levels of intact parathyroid hormone (PTH) were measured using a second-generation electrochemiluminescence immunoassay on an automated instrument (Cobas 6000, Roche Diagnostics).
present in 11 (42 %) patients, with a higher prevalence in the group of patients with mono-ostotic FD (n = 6, 67 %) compared to patients with polyostotic affections (n = 5, 29 %). Only, one patient (patient 2) had FD diagnosed as a random finding and had no symptoms or clinical signs.
Statistics
Radiological Findings
We assessed differences between study groups using Fisher’s exact test for categorical variables and a twosample t test or Mann–Whitney U test for continuous variables, as appropriate. Descriptive statistics are presented as medians with interquartile ranges (25–75 % percentile) or numbers with percentages. A two-sided p \ 0.05 was considered statistically significant. The calculations were performed using the OpenOffice.Org calculator program and PASW Statistics v. 20 (IBM, formerly SPSS, Chicago, IL).
Table 3 shows the distribution of skeletal effects as assessed by radiological imaging. The bones of the calvaria (frontal, occipital, sphenoidal, ethmoidal, mastoid, and temporal bones) and/or the facial bones (zygomatic, maxillary, and mandibular bones) were affected in most of the patients (81 %), with an equal proportion of patients having mono-ostotic and polyostotic FD. All four patients with a mandibular bone effect had a polyostotic manifestation of the disease (Table 3). Moreover, the ribs, spine, and pelvic bones, as well as the upper extremities, were only affected in patients with polyostotic FD. Similarly, effects on the bones of the lower extremities were most common in patients with polyostotic affections (Table 3). Only one of the nine patients with mono-ostotic FD had a noncraniofacial bone effect (patient 8). Two patients were diagnosed purely on radiological findings, whereas 24 patients (92 %) had a biopsy performed. However, in five of the patients who had a biopsy performed, the histopathological evaluation of the biopsy was no longer available for review at the time of this survey. Figure 1 is an example of how FD can present itself radiologically. It is a CT scan of the head from one of the patients used in our study.
Results We identified a total of 28 patients, of whom two were excluded because they did not have FD. Consequently, only the remaining 26 patients were used in the study. The clinical course of each of the patients is shown in Table 1. Of the 26 patients who were diagnosed with FD, 17 (65 %) had polyostotic affections, whereas 9 (35 %) had mono-ostotic FD. The median age at time of diagnosis was 16.5 years (range 6 months–70 years). Patients with polyostotic affections were diagnosed at a younger age than those with mono-ostotic FD (Table 2). Sixteen (62 %) of the patients were females. The proportion of males and females did not differ significantly between patients with mono- and polyostotic FD (Table 2). Four (15 %) patients were diagnosed with MAS (patients 17, 18, 22, and 25 in Table 1) due to polyostotic FD and cafe´-au-lait spots, among whom two had endocrine abnormalities in terms of either hyperthyroidism (patient 17) or precocious puberty (patient 18). Symptoms That Lead to a Diagnosis At time of diagnosis, 17 patients (65 %) reported pain in the area affected by FD (Table 2). Five patients (19 %) had neurological deficiencies due to their FD in terms of visual impairment (patients 4, 16, and 24), impaired hearing (patient 5), or facial nerve palsy (patient 15). Three patients (12 %) presented with a pathological fracture (patients 7, 8, and 17), and one patient (patient 13) had symptoms of chronic sinusitis which was explained by FD. Craniofacial deformities in terms of a clinical bump on the head or a protrusion on the maxillary or mandibular bone were
Surgical Treatment Fourteen (54 %) underwent, at least, one surgery after being diagnosed with FD, six (67 %) from the monoostotic group and eight (47 %) from the polyostotic group (p = 0.43). These surgeries included craniotomy, nerve decompression, osteosynthesis, osteotomy, and functional endoscopic sinus surgery (Table 1). The patient (13) who had the functional endoscopic sinus surgery suffered a quick recurrence with nuisance symptoms including pressure on her right eye and will most likely need resurgery within the near future. Among the patients with neurological impairment, the patient (5) with impaired hearing, due to blockage of the ear canal, had a complete restoration of his hearing following surgical intervention. Among the three patients with impaired vision, two have had surgery. One patient (16) had optic nerve decompression performed, which restored his vision. The other patient (4) had optic nerve decompression performed twice. This patient has severe FD with major facial deformities causing exophthalmos, putting strain on both
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Sex/age at diagnosis (years)
M/51
M/37
M/64
M/17
M/15
F/1
F/7
F/21
M/70
F/1
F/13
F/16
F/20
M/35
M/31
F/39
Patient ID
1
123
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Mono
Poly
Mono
Mono
Poly
Poly
Mono
Mono
Mono
Poly
Poly
Poly
Mono
Poly
Poly
Poly
Type
Right frontal bone and right and left sphenoidal bones Left sphenoidal sinus
Left frontal bone and sinus
Frontal bones including orbitae and sinuses Right maxillary bone and sinus
Femoral bones
Left parietal bone
Right maxilla bone
Right femoral bone
Femoral and pelvic bones
Left frontal, zygomatic, sphenoidal, parietal, and maxilla bones and mandible
Base of skull and mastoid bone including left ear canal
Left maxilla bone, including orbita
Pelvis, femoral and tibial bones
Frontal and parietal bones, left humeral, ulnar, and radial bone, 11th rib Mandible and maxilla bones, including right orbita
Affected bone
Table 1 Characteristics of studied patients with fibrous dysplasia
Visual impairment and pain
Facial nerve palsy and pain
Craniofacial deformity and pain
Chronic sinusitis
Craniofacial deformity
Pain
Craniofacial deformity and periorbital edema Craniofacial deformity
Pain and subtrochanteric fracture
Pain and femoral neck fracture
Craniofacial deformity and pain
Impaired hearing
Craniofacial deformity, pain, visual impairment and exophthalmos
Bone pain
Random finding
Craniofacial deformity
Symptoms/clinical findings at time of diagnosis
Yes
No
Yes
Yes
NA
Yes
Yes
NA
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Biopsy verified
BF, decompression of optic nerve
BF
BF
BF ? endoscopic sinus surgery
BF
BF
No treatment
BF
BF, osteosynthesis of fractured bones
BFm osteosynthesis of fractured bones
BF
BF, 2 surgeries in left ear canal
BF, 2 surgeries: craniotomy and decompression of optic nerves
BF
BF
BF, cranial plastic surgery
Treatment
RSU, normal vision after surgery
RSU
Slight progression in sinus frontalis
Relapse and in need of new surgery
RSU
RSU, alleviation of bone pain after treatment
Continued increased bone metabolism in parietal bone
NA
No alleviation of pain
Pain-free 6 months following treatment, pain-free in year 2010
Decreased activity in frontal bone
Normal hearing after surgery
RSU, following surgery: loss of vision in the left eye and impaired vision in the right eye
Slight regression of FD lesions (on scintigraphy) after treatment
Cranial discomfort after surgery, progression (CT scan) in fontal bone NA
Outcome
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
F/2
F/0.5
F/10
F/21
F/10
F/4
M/15
M/21
F/3
F/38
17
18
19
20
21
22
23
24
25
26
Mono
Poly/MAS
Poly
Poly
Poly/MAS
Poly
Mono
Poly
Poly/MAS
Poly/MAS
Type
Right parietal bone
Right femoral and tibial bones; pelvis, ribs, and spine; maxilla and occipital bones
Frontal, temporal, sphenoidal, ethmoidal, maxilla bones and mandible
Right frontal, temporal, sphenoidal and maxilla bones
Femoral, occipital, and frontal bones
Left orbit, parietal and occipital bones
Right frontal bone
Left frontal, sphenoidal, temporal, zygomatic bones involving the orbit
Left lower and upper extremities, pelvis
Mandible, left femoral and tibial bones and pelvis
Affected bone
Craniofacial deformity and pain
Discovered because of a limp when 4 years old, pain
Visual impairment
Craniofacial deformity and pain
Pain
Pain
Craniofacial deformity and pain
Craniofacial deformity and pain, exophthalmos.
Vaginal discharge at 6 months
Pain and femoral neck fracture, hyperthyroidism
Symptoms/clinical findings at time of diagnosis
Yes
Yes
Yes
Yes
NA
NA
Yes
Yes
NA
Yes
Biopsy verified
Cosmetic surgery (removal of bump)
BF, plastic surgery twice, 12 surgeries in right upper extremity
BF, decompression of optic nerve
BF, twice bone resection
No treatment
BF
BF, cosmetic surgery
BF
BF, back surgery
BF, surgery to correct the deformed shin and femoral bones
Treatment
RSU
RSU, no bone pain
RSU
RSU, fewer headaches with decreased use of analgesics
–
RSU
RSU
Increased bone metabolism but same extent of FD at followup scintigraphy
Deformed skeleton because of FD
RSU
Outcome
M male, F female, P polyostotic affection, M mono-ostotic, MAS McCune–Albright syndrome, BF IV bisphosphonate, NA not available, RSU radiological status unchanged
Sex/age at diagnosis (years)
Patient ID
Table 1 continued
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
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M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia Table 2 Clinical characteristics and distribution of skeletal effects according to radiological findings in all patients and stratified by whether the disease had a mono- or polyostotic-form
Age at diagnosis, yearsa
All (n = 26)
Mono-ostotic (n = 9)
Polyostotic (n = 17)
16.5 (0.5–70)
21 (1–70)
13 (0.5–64)
10 (38) 16 (62)
3 (33) 6 (67)
7 (41) 10 (59)
5 (19)
2 (22)
3 (18)
Gender Males, n (%) Females, n (%) Symptomsb Neurological, n (%) Impaired hearing, n (%)
1 (4)
Visual impairment, n (%)
3 (12)
Facial nerve palsy, n (%)
1 (4)
Chronic sinusitis, n (%) Bone pain at affected site(s), n (%)
0 2 (22) 0
1 (4)
1 (11)
17 (65)
6 (67)
1 (6) 1 (6) 1 (6) 0 11 (65)
Clinical findings (skeletal deformities/fractures) Craniofacial deformity (%)
11 (42)
6 (67)
5 (29)
Exophthalmos (%)
2 (8)
1 (11)
1 (6)
Deformities of femora (%)
1 (4)
History of fracture (%)
6 (23)
1 (11)
5 (29)
14 (54) 23 (89)
6 (67) 7 (78)
8 (47) 16 (94)
0
1 (6)
Treatment Surgery, n (%) Bisphosphonates, n (%)
None of the shown indices differed significantly between patients with mono- and polyostotic fibrous dysplasia. Mono-ostotic fibrous dysplasia involves only a single bone, or adjacent bones, like both the upper and lower jaw, whereas the polyostotic form involves more than one skeletal site a
Median with range Note that total number of symptoms/affected bone sites may not sum up to number of patients as patients with the polyostotic type may be counted in each group
b
optic nerves and compromising vision. The first surgery had a successful outcome. However, the patient had a rapid relapse and needed resurgery. Following the second operation, he was blind in the left eye and had severely impaired vision in his right eye. Medical Treatment Medical treatment modalities are visualized in Fig. 2. Drug, dosage, and treatment length are listed by each patient identification number (according to Table 1) including age at initiation of treatment. Overall, 23 (89 %) patients received treatment with bisphosphonates with a median treatment length of 4 years (range 3–276 months) at the time of follow-up. The median age at the time of initiation of treatment with bisphosphonates was 29 (range 4–70) years. As shown in Fig. 2, the types of bisphosphonates prescribed changed during follow-up. At the end of follow-up, most patients were on treatment with a highpotency intravenous bisphosphonate, i.e., zoledronic acid. The three patients who did not receive treatment with bisphosphonates either refused or were not eligible; one
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refused due to the potential side effects linked to bisphosphonate treatment (patient 22), while two (patients 10 and 26) were not offered treatment according to a clinical judgment. Following treatment, three patients (patients 7, 11, and 23) reported pain relief. One patient with FD in the bones of the face and skull (patient 23) had periodic relief from headache and consequently a decrease in the use of analgesics. The other two had FD in the femoral bone (patients 7 and 11) and reported a decrease in bone pain after infusion with a bisphosphonate. In contrast, one patient (patient 1) reported a feeling of growth in the FD-affected bones in the months following treatment with bisphosphonates. Three patients (patients 17, 18 and 25) sustained fractures after treatment initiation with bisphosphonates. All three were females and had polyostotic FD and MAS. They had also suffered multiple fractures in FD-affected bones before initiation of treatment. Patient 17, who has received bisphosphonates for 12 years, had her most recent fracture 10 years ago. Patient 18 has severe and debilitating FD and has suffered from multiple fractures both before and after her treatment initiation in 1987. Patient 25 had two fractures in 2001 and none since.
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia Table 3 Skeletal effects according to radiological findings in all patients and stratified by whether the disease had a mono- or polyostotic form All (n = 26)
Mono-ostotic (n = 9)
Polyostotic (n = 17)
Skeletal sites affecteda Head, n (%)
21 (81)
8 (89)
13 (77)
Calvaria, n (%)
16 (62)
5 (56)
11 (65)
Mandible, n (%)
4 (15)
0 (0)
4 (24)
Facial bones, n (%)
8 (31)
3 (33)
5 (29)
6 (23)
0 (0)
6 (35) 2 (12)
Ribs, spine, pelvis, n (%) Ribs, n (%)
2 (8)
0 (0)
Spine, n (%)
1 (4)
0 (0)
1 (6)
Pelvis, n (%)
5 (19)
0 (0)
5 (29)
Upper extremities, n (%)
2 (8)
0 (0)
2 (12)
Lower extremities, n (%)
8 (31)
1 (11)
7 (41)
Femoral bone, n (%)
8 (31)
1 (11)
7 (41)
Tibial bone, n (%)
4 (15)
0 (0)
4 (24)
None of the shown indices differed significantly between patients with mono- and ployostotic fibrous dysplasia. Mono-ostotic fibrous dysplasia involves only a single bone, or adjacent bones, like both the upper and lower jaw, whereas the polyostotic form involves more than one skeletal site
Fig. 1 Transverse computed tomography showing a massive lytic fibrous dysplasia lesion in the orbit and maxillary bone. Facial deformity and protrusion of the eye are also visualized
a
Note that the total number of patients may not sum up to number of affected bone sites as patients with the polyostotic type may be counted in each group of bones affected
Radiological Findings Following Medical Treatment Within the group of patients receiving medical treatment (n = 23), radiological follow-up was performed in 18 (78 %). Follow-up imaging was done using bone scintigraphy in 10 patients, MRI scans in five patients, and CT scans in three patients at follow-up. A regression of the FD lesions was found in two patients (patients 3 and 6), while three patients showed signs of progression (patients 1, 14, and 19). In the remaining 13 patients, 11 had an unchanged status of their FD compared to previous radiological examinations, which was performed a median of 54 months (range 3 months to 19 years) following initiation of medical therapy. In two patients with a follow-up radiological examination, the initial examination was no longer available and changes could therefore not be evaluated. Both of the two patients showing regression had radiological follow-up performed by bone scintigraphy. Patient 3 had a scintigraphy from 2011 showing ‘‘slight regression’’ of the FD lesions compared with a scintigraphy performed in 2006. Patient 6 had a scintigraphy from 2006 that, compared with one from 1999, showed ‘‘less activity but the same propagation’’ in the FD-affected area. Among the three patients who had progression, two had radiological follow-up performed by CT scans showing
‘‘increased lytic changes’’ (patient 1) and ‘‘slight progression’’ (patient 14) as evaluated 3 and 9 years, respectively, following the initial CT scan (Table 1). Patient 19 had a scintigraphy from 2010 that showed ‘‘increased bone metabolism but same extent of FD’’ compared to a scintigraphy from 2001. The five patients on medical treatment who did not have any radiological follow-up examinations performed (patients 2, 7, 8, 9, and 13) were all diagnosed recently and had received treatment for only a few years. Among the three patients not receiving medical treatment, two (patients 10 and 22) were diagnosed 32 and 61 years ago, respectively. Patient 10 had a CT scan and scintigraphy performed in 2010 showing ‘‘increased bone metabolism in known tumor,’’ but there was no mention of whether the lesion had progressed compared with earlier examinations. The second patient had a CT scan done in 2001, also with no mention of status compared with earlier examinations. Finally, patient 26, who did not receive medical treatment, was newly diagnosed and has not yet had any radiological follow-up examinations. Biochemical Findings Table 4 sums up the biochemical findings. Four patients (15 %) had hypophosphatemia at time of diagnosis (patients 2, 3, 12, and 22). Following bisphosphonate therapy, another four (patients 1, 11, 19, and 20) had plasma phosphate levels below the lower limit of the
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M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia Age (years) at treatment start
Patient ID 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1
x x x (year 1983) x x (year 1952) x x x x (year 1969) x (year 1964) x X (year 1975) x x x x X (year 1980) x x x X (year 1980) x x x x x 1987
1989
1991
x: year of diagnosis
1993
1995
1997
1999
2001
2003
2005
2007
2009
2011
7 37 17 16 26 10 20 35 48 62 35 20 17 14 70 23 17 21 32 18 64 37 53 29 years
Zoledronic acid IV 5 mg.
Ibandronat IV 3-6 mg.
Alendronate, oral, 70 mg/week
Clodronate, oral, 400 mg.
Pamidronat IV 15-60 mg.
Etidronate, oral, 200 mg x 2
Fig. 2 Medical treatment with bisphosphonates in patients with fibrous dysplasia. Patient ID is as shown in Table 1
Table 4 Biochemical characteristics at time of diagnosis and at time of follow-up: median with interquartile range
Total alkaline phosphatase, n (%)a Bone-specific alkaline phosphatase, n (%)
a
Reference range
Time of diagnosis
Time of follow-up
p
NA
10 (38)
5 (19)
–
NA
5 (19)
6 (22)
–
Phosphate (mmol/L)
0.76–1.41
1.07 (0.91–1.22)
0.87 (0.83–1.02)
0.02
Calcium-total (mmol/L)
2.25–2.55
2.44 (2.37–2.46)
2.36 (2.25–2.37)
0.08
Calcium-total, albumin-adjusted (mmol/L)
2.22–2.52
2.43 (2.34–2.49)
2.41 (2.29–2.48)
0.11
Ionized calcium (mmol/L)
1.18–1.32
1.23 (1.21–1.25)
1.25 (1.25–1.26)
0.21
25-Hydroxyvitamin D (nmol/L)
45–150
46 (36–82)
70 (58–94)
0.06
PTH (pmol/L)
1.6–6.9
4.4 (3.0–5.7)
4.0 (3.6–4.9)
0.4
a
Number (%) of patients with levels above the upper limit of the reference range
reference interval. All except one patient (patient 20) with hypophosphatemia had a polyostotic manifestation of the disease. On average, plasma phosphate levels were significantly lower at follow-up compared with levels at time of diagnosis (Table 4). Ten patients (38 %; patients 1, 4, 5, 6, 8, 18, 19, 21, 22, and 25) had a plasma level of total ALP above the upper limit of the reference interval at the time of diagnosis, among whom two (patients 4 and 8) had mono-ostotic FD and eight had polyostotic effects (p = 0.40). At follow-up, five (19 %) patients (patients 6, 18, 19, 22, and 25) had total ALP levels above the upper reference limit. All had a polyostotic manifestation of the disease and had elevated ALP levels at time of diagnosis. Only one of the patients
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(patient 22) with elevated ALP levels at both times of measurement did not receive medical treatment in between. BSAP levels were elevated in five (19 %) patients at time of diagnosis, among whom one (patient 4) had monoostotic FD and four (patients 19, 22, 23, and 26) had polyostotic FD (p = 0.63). Following treatment, BSAP levels were above the upper limit of the reference interval in six patients (patients 1, 6, 17, 18, 22, and 26). All six patients had polyostotic FD, and two of them (patients 22 and 26) also had elevated levels prior to medical treatment. Otherwise, biochemical analyses showed results within the reference range of analyzed indices. Neither calcium nor PTH levels were changed at follow-up compared with time of diagnosis. Plasma 25OHD levels increased from a
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
median of 46–70 nmol/L, most likely due to initiation of use of vitamin D supplements in the studied subjects.
Discussion Although FD may be a silent disease, our data emphasize that the clinical picture of the disease shows large variability as some patients are asymptomatic whereas others are severely affected with the disease showing a debilitating course. One could assume that polyostotic compared to mono-ostotic FD has a more severe course, but we found no clear connection between the type of FD and the severity. What determines the severity of FD is multifactorial and particularly depends on the location and extent of the FD lesions; but also individual characteristics such as endocrinopathies, fractures, and malignant transformation, although rare, play an important prognostic role [16]. We also found that the time of diagnosis does seem to have some predictive value of the prognosis; the earlier the diagnosis is made, the more debilitating the disease. The location of the lesions is of major importance for the prognosis as those with FD in the skull and facial bones have an increased risk of neurological symptoms or growth into vital structures. In our survey we found that involvement of the bones of the skull and face was frequent: in eight out of nine of those with mono-ostotic FD and in 12 out of 15 of those with a polyostotic manifestation. Affected Bones Previously, mono-ostotic FD was considered to be much more common than the polyostotic form [4]. However, in agreement with our findings, a number of more recent reports have suggested that polyostotic FD affects more patients than the mono-ostotic form [5, 6, 8, 17]. Implementation of better radiological methods with a more careful evaluation of patients may explain this discrepancy. Most previous studies on FD have been published by groups of specialists who treated FD at specific skeletal sites, such as the craniofacial or long bones [5, 18–20]. Only few data are available on the distribution of FD lesions at different skeletal sites. Apparently, several previous surveys have found involvement of the craniofacial bones to be less frequent than in our group of studied patients. Summarizing data from five individuals reports, including a total of 155 cases with mono-ostotic FD, Edgerton et al. [21] reported involvement of the craniofacial bones in 30 % of the patients, whereas 32 % had a lesion at the lower extremities, 6 % at the upper extremities, and 32 % at the vertebrae or ribs. Similarly, in a report based on data from the radiologic archives of the Armed Forces Institute of Pathology, USA, including 501 cases of
radiologically proven and histologically verified FD (85 % mono-ostotic), involvement of the craniofacial bone was only present in 22 (5 %) of the cases with mono-ostotic FD [4]. In a more recent survey including 58 patients treated with bisphosphonates, among whom 38 % had monoostotic FD and 62 % polyostotic FD (n = 7 with MAS), the craniofacial bones were involved in 43 % of the patients, whereas 62 % had involvement of the femoral and 45 % of the tibial bone [6]. Moreover, in a European multicenter study on FD promoted by the European Pediatric Orthopedic Society, only one of 23 cases with monoostotic FD was reported to have a craniofacial effect [5]. Our data suggest that the craniofacial bones are involved more often than suggested by these previous reports as we found craniofacial effects in 81 % of our studied patients with a similar proportion in the mono-ostotic and polyostotic groups. To a certain extent, our data on involvement of the craniofacial bones in polyostotic FD agree with a recent survey by Chapurlat et al. [7] showing FD lesions of the head in 86 % of the adults studied, among whom most had polyostotic FD. Moreover, the report by Chapurlat et al. [7] showed involvement of the lower extremities in approximately 90 % of the cases, which also agrees with our findings as all four patients with MAS within our group of patients had lesions in the lower extremities. In contrast, involvement of the spine was less common in our cohort than previously reported. In our group of patients, only one (4 %) had a spine lesion, while the spine was affected in 20 % (n = 11) of the cases in a survey including 56 patients among whom 23 had mono-ostotic effects, 9 had polyostotic effects, and 24 had polyostotic FD with MAS [8]. In our group of patients, effects on the mandibular bone, ribs, spine, pelvis, and bones of the upper extremities were only observed in patients with polyostotic FD. In contrast, mono-ostotic FD affected only the head and lower extremities. Accordingly, our data suggest that FD, depending on which type, may have a predilection of location in the skeleton. More data should be collected on the skeletal distribution of FD, based on patients. Severity of Disease Need for surgery may be used as a measure of the severity of the disease. Within our group of patients, more patients with mono-ostotic FD (n = 6, 67 %) than polyostotic FD (n = 8, 47 %) needed surgery. This was attributable to the high prevalence of craniofacial effects in the group of patients with mono-ostotic FD as this location is particularly troubling because of the close proximity to the brain and facial nerves including the eyes. Therefore, it is not surprising that more than half of these patient needed at least one surgery in order to decrease or prevent disease sequelae. Based on our findings, the severity, and thus the
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prognosis, cannot be determined by the type of FD. It does, however, appear to be a bad prognostic factor to have MAS. Among the four patients with MAS, all were diagnosed during early childhood (before the age of 4 years) and suffered multiple pathological fractures resulting in deformities of the bones. Additionally, three of them have undergone several surgeries due to their debilitating disease. Other studies have found that the proportion of the skeleton involved was a predictor of functional outcome and mobility [22]. Previously, pain caused by FD was considered often to dissolve with age. However, recent studies have shown a higher prevalence and severity of pain in adults than in children and that the pain experienced by the patients is unrelated to the burden of the disease [7, 23]. Our findings support this notion as two-thirds of our (mainly adult) patients reported pain at their FD lesions. Moreover, pain was as common in patients with mono-ostotic as in those with polyostotic FD, supporting the notion that the burden of the disease in terms of number of skeletal effects is not of major importance to the severity of the disease. But once again it must be emphasized that the severity of FD is multifactorial. Medical Treatment Therapy with bisphosphonates has been suggested to cause pain relief and to have a healing effect on bone lesions. In some studies, treatment with pamidronate, alendronate, and zoledronic acid has been shown to fill in osteolytic lesions and decrease the rate of bone resorption with an improved local bone mass density at the site of the FD lesions [6, 24– 27]. However, other studies have not shown such effects; and in the studies showing effects, it seems that only approximately half of the patients responded to treatment [22, 28, 29]. In one of the largest studies, including 58 patients treated with pamidronate for a median of 50 months (range 1–11 years), half of the participants had radiological improvements in terms of filling of osteolytic lesions and/or cortical thickening [6]. Moreover, pain intensity was reduced by 41 % following the first course of pamidronate and by 69 % after several treatment cycles [6]. Similarly, although most case series have reported a reduced pain score in response to bisphosphonates, the findings have in general been mixed in terms of the proportion of patients responding to treatment [6, 24, 30–33]. Of note, no randomized controlled clinical trial has been completed thus far. Results from published studies are therefore limited by lack of a control group. Findings may (at least in part) be due to natural variations in the course of the disease including an effect of regression to the mean. In some patients, treatment may have been initiated at a point of time when symptoms were ‘‘above’’ average and the
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findings of an apparent effect of medical treatment may more or less be due to spontaneous variations in the course of the disease. However, based on the studies showing potential beneficial effects of treatment with bisphosphonates, most patients treated at our department were offered bisphosphonate therapy. The clinical workup on these patients as presented in this report, nevertheless, does not support a general beneficial effect of bisphosphonates. Only three patients were found to have a clear decrease in bone pain following treatment, and according to the radiological evaluations, only two patients had regression of their disease, whereas three patients experienced a progression following treatment. Both patients showing regression had their radiological follow-up measurements performed by bone scintigraphy. Although scintigraphy is useful in detecting early lesions and polyostotic involvement, one should be aware of false-negative results. Depending on which type of lesion (ground glass or cystic), silent lesions have been found to make up as much as 7–14 % of the total number of lesions [34]. Explanations for this could be that some of the lesions with time become quiescent. Another theory is that the active osteoblasts are destroyed, resulting in no increased uptake of the radiopharmaceutical agent. The scan provides a functional view of the current skeletal metabolic activity, but scintigraphy shows no pathological activity and does not rule out disease. Accordingly, CT scans are more applicable as they reveal the full extent of a lesion including intraosseous and extraosseous involvements independent of the bones’ metabolic activity. This is especially useful with FD involving the face, sinuses, and skull. Because CT scans reveal the full extent of a lesion, this would be a good choice when comparing the effects of a treatment. However, considering that the type of lesion may change with age from a homogeneous ‘‘ground glass’’ appearance to a lytic appearance, this does not necessarily represent a worsening of the disease [35, 36]. Controlled trials are warranted to improve our understanding of whether patients with FD may benefit from medical treatment with antiresorptives. In a recent study, treatment with denosumab showed promising results, which also need to be investigated further [37]. Biochemical Findings Although renal phosphate wasting is quite common in patients with FD, actual hypophosphatemia is not a frequent finding [9]. Interestingly, nephrogenous cAMP has been reported to be normal in patients with FD, suggesting that the postzygotic activating mutation of the GNAS1 gene does not by itself cause phosphate wasting [10]. Rather, the low plasma phosphate levels are caused by increased plasma levels of FGF-23 secreted by the dysplastic tissue
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
[38]. Elevated plasma FGF-23 levels have been found to correlate with the mass of osteogenic cells within the FD lesions and the degree of bone involvement assessed by serum and urine markers of bone metabolism [38, 39]. In accordance with this notion, all except one of our patients with hypophosphatemia had a polyostotic manifestation of the disease. Unfortunately, measurement of FGF-23 levels was not a part of the clinical evaluation of our patients. However, low phosphate levels were not that common, and none of our studied patients needed treatment with oral phosphate supplements. The lower mean level of plasma phosphate at follow-up compared with the initial measurements may represent a variable course of the disease or an effect of treatment with bisphosphonates [40]. Additionally, measurements of urinary phosphorus levels in order to calculate TmP/GFR would have been of interest. Our findings of elevated plasma levels of ALP agree with previous findings. The fact that levels remained elevated at follow-up in approximately half of the patients despite treatments may indicate that the bisphosphonates used did not sufficiently suppress the FD lesions. Limitations to Study Our analyses are prone to bias which may apply to data collected retrospectively from patient hospital charts, including lack of objective measures of pain. However, by extracting information based on a prespecified collection sheet, we aimed to systemize available data in order to improve our understanding of the disease. Most likely, our survey is not as prone to referral bias as reports from specialized surgical departments as patients are referred to us for medical treatment independently of the skeletal site of their FD lesion. In most of the patents included, the diagnosis was confirmed by a positive lesion biopsy (n = 19). Only two patients did not have the diagnosis confirmed by a biopsy, whereas the specific result of the biopsy was unavailable in five patients. We do believe that the biopsy from these five patients, most likely, did have a histological pattern compatible with FD as their diagnosis was not changed following the biopsy.
Conclusion Polyostotic FD is at least as common as the mono-ostotic form. Patients with MAS are more severely affected than patients with only bone involvement, but the site of bone involvement is of most importance to the severity of the disease. Whether a patient has the mono-ostotic or polyostotic type does not per se determine the disease severity. Treatment with bisphosphonates may alleviate pain in some patients, but treatment response is ambiguous; and
our clinical workup on the effect of bisphosphonate therapy did not show a clear reduction in skeletal destruction. Whether or not bisphosphonates slow the disease progression or help to limit skeletal damage needs to be determined in controlled trials.
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ORIGINAL RESEARCH
Clinical and Radiological Observations in a Case Series of 26 Patients with Fibrous Dysplasia Malissa Dawn Thomsen • Lars Rejnmark
Received: 6 May 2013 / Accepted: 24 October 2013 Ó Springer Science+Business Media New York 2013
Abstract Fibrous dysplasia (FD) is a rare disease caused by a sporadic postzygotic missense mutation that leads to abnormal fibroblast proliferation, defective osteoblast differentiation, and increased bone resorption. It may affect one or several bones. Both the mono-ostotic and polyostotic types may be associated with hyperfunctional endocrinopathies and hyperpigmentation of the skin (cafe´-au-lait spots) in the so-called McCune–Albright syndrome (MAS). Due to its rarity, only a few case series are available, making it difficult for most clinicians to judge the severity of the disease. To improve our knowledge of FD, we reviewed all cases of FD treated at our department of endocrinology. Among 26 patients, 17 (65 %) had polyostotic FD, with four being diagnosed with MAS. Patients with polyostotic FD were diagnosed at an earlier age (median 13, range 0.5–64 years) than patients with the mono-ostotic form (median 21, 1–70 years). Craniofacial bones were affected in 80 % of cases, and 66 % complained of bone pain at the affected site, with no difference between patients with monoand polyostotic FD. Two patients with mono-ostotic and three with polyostotic FD had cranial nerve impairments. Fourteen underwent, at least, one surgery, six (67 %) with mono-ostotic and eight (47 %) with polyostotic FD. Most received treatment with bisphosphonates, but therapy did not result in any clear relief of symptoms or radiological improvements. In conclusion, bone pain is common in patients with FD. The severity of the disease depends on
The authors have stated that they have no conflict of interest. M. D. Thomsen (&) L. Rejnmark Department of Endocrinology and Internal Medicine (MEA), Aarhus University Hospital, Tage Hansens Gade 2, 8000 Aarhus C, Denmark e-mail: [email protected]
affected bones as mono-ostotic may be as debilitating as polyostotic FD. In our case series, bisphosphonate treatment did not show clear beneficial effects. Keywords Bisphosphonate Osteoclast McCune– Albright syndrome Focal bone lesion Fibrous dysplasia
Introduction Fibrous dysplasia (FD) is a rare benign skeletal disorder characterized by abnormal fibroblast proliferation and defective osteoblast differentiation resulting in replacement of cancellous bone and marrow with fibrous connective tissue. FD can present itself in either a mono-ostotic form, with involvement of one bone site, or a polyostotic form that includes multiple bone sites. FD has a predilection for certain bones including the femur, tibia, ribs, pelvis, and craniofacial bones. FD may also be associated with hyperfunctional endocrinopathies (e.g., preterm puberty or hyperthyroidism) and hyperpigmentation of the skin (cafe´au-lait spots) in the so-called McCune–Albright syndrome (MAS) [1, 2]. FD and MAS are caused by a sporadic postzygotic missense mutation in the somatic cells at the GNAS complex locus located on chromosome 20q13. This gene codes for the a-subunit of the stimulatory G protein belonging to hormone receptors. The mutation results in a constitutive activation of adenylyl cyclase and overproduction of cAMP in osteogenic cells [3]. The increase in cAMP leads to defects in osteoblast differentiation and proliferation of osteoblast progenitors and a subsequent production of abnormal bone in a fibrous stroma. The dysplastic stromal cells produce IL-6, causing hyperactivity of osteoclastic cells, resulting in increased bone resorption [1].
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The estimated prevalence of FD is 1/30,000 [4]. Variable results have been reported on the occurrence of monoostotic compared to polyostotic FD lesions. Some investigators have found the mono-ostotic form to be five to six times as prevalent as polyostotic FD [4, 5], whereas others have reported polyostotic FD to be at least as (and often more) prevalent as mono-ostotic FD [6–8]. It is not uncommon for FD to be a silent disease, and some patients are asymptomatic; but when symptoms are present, they most often include bone pain, headache, bone deformities and asymmetry of the face, proptosis, diplopia, and pathological fractures, the latter especially during childhood. More serious symptoms include optic neuropathy, blindness, deafness, vestibular dysfunction, and seldom facial nerve palsy. Radiologically FD lesions have a lytic appearance and are characterized by thinning of the cortex with a ‘‘ground glass’’ matrix and can be confirmed by a biopsy of the bone lesions. To assess the extent of FD and the number of FD lesions, scintigraphy/isotopic bone scans are normally used, whereas computed tomography (CT) and magnetic resonance imagining (MRI) are used to characterize the precise involvement of bone. Due to an increased bone turnover in FD lesions, biochemical markers of bone turnover are in some cases elevated. Moreover, hypophosphatemia may be present due to an increased secretion of fibroblast growth factor (FGF-23) from the dysplastic tissue [9]. It has been reported that approximately 50 % of patients with MAS and polyostotic FD have phosphate wasting to some degree. An elevated serum FGF-23 has been found to correlate with the mass of osteogenic cells within the FD lesions and the degree of bone involvement assessed by serum and urine markers of bone metabolism [10]. Hypophosphatemia due to the renal phosphate wasting may contribute to mineralization defects, which ultimately can lead to osteomalacia, rickets, and bone pain with deformities [11, 12]. This could possibly be the reason that some patients with FD experience pronounced bone pain [13]. There is no cure or spontaneous resolution of FD, but not all patients are in a condition that requires treatment. Surgery may be indicated if a tumor mass is large and causes compression of adjacent tissue with nerve constriction, pain, or cosmetic discomfort. Bisphosphonates are often used as medical treatment as they have been suggested to reduce the increased rate of bone resorption at the affected sites. However, due to the rarity of the disease, only a few published studies are available. In order to improve our understanding of FD, we performed a systematic review of medical records from patients with FD treated at our department in the past 10 years. Symptoms and findings in patients with mono-ostotic and polyostotic FD were compared.
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Subjects and Methods Using the electronic patient register at our university hospital, we identified all patients diagnosed with FD within the past 10 years at our Department of Endocrinology and Internal Medicine, Aarhus University Hospital, Denmark. The search was based on medical charts assigned under the ICD-10 codes for mono-ostotic FD (M85.0) or polyostotic FD (Q78.1). Case status was adjudicated by review of the individual patient charts with extraction of information using a prespecified data-collection sheet. We collected data on gender, age, symptoms, and findings at presentation as well as radiographic methods used to diagnose the disease. In addition, we retrieved data on which treatment patients had received as well as symptoms and biochemical findings following treatment. Moreover, changes in radiological findings in response to treatment were recorded for patients for whom a radiological follow-up had been performed. In order to determine disease regression or progression we, in addition to the radiological findings, collected data on loss of mobility, deformity, pain increase or decrease, and vision and/or hearing loss or worsening. The study was approved by the Danish data protection agency, and informed consent was obtained from all patients. Biochemistry Plasma concentrations of calcium, phosphate, and albumin were measured by standard laboratory methods. Total plasma calcium levels were corrected for individual variations in albumin according to the following formula: plasma calcium, adjusted (mmol/L) = plasma calcium, total (mmol/L) ? 0.00086 9 [650—plasma albumin (lmol/L)]. Alkaline phosphatase (ALP) was measured spectrophotometrically using an automated instrument (Hitachi 917; Roche Diagnostics, Mannheim, Germany). Until December 2010, bone-specific alkaline phosphatase (BSAP) was measured after lectin precipitation (Boehringer Mannheim, Mannheim, Germany) and thereafter using an immunoassay (METRA BAP EIA kit; Quidel, San Diego, CA) with a Spectra II ELISA Reader (PerkinElmer Life and Analytical Sciences, Boston, MA) [14]. Due to this change in biochemical methods, results are reported as the proportion of studied patients with levels above the upper limit of the reference interval according to the methods used. Using a Spectra II ELISA reader, plasma 25-hydroxyvitamin D (25OHD) levels were measured by an enzyme immunoassay (OCTEIA; Immunodiagnostic Systems, Boldon, UK) until November 2005 and thereafter by isotope dilution liquid chromatography-tandem mass spectrometry by a method adapted from Maunsell et al. [15]. As the level of measurements for the two methods did not differ to any
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
major degree, we did not adjust for differences in methods used. Plasma levels of intact parathyroid hormone (PTH) were measured using a second-generation electrochemiluminescence immunoassay on an automated instrument (Cobas 6000, Roche Diagnostics).
present in 11 (42 %) patients, with a higher prevalence in the group of patients with mono-ostotic FD (n = 6, 67 %) compared to patients with polyostotic affections (n = 5, 29 %). Only, one patient (patient 2) had FD diagnosed as a random finding and had no symptoms or clinical signs.
Statistics
Radiological Findings
We assessed differences between study groups using Fisher’s exact test for categorical variables and a twosample t test or Mann–Whitney U test for continuous variables, as appropriate. Descriptive statistics are presented as medians with interquartile ranges (25–75 % percentile) or numbers with percentages. A two-sided p \ 0.05 was considered statistically significant. The calculations were performed using the OpenOffice.Org calculator program and PASW Statistics v. 20 (IBM, formerly SPSS, Chicago, IL).
Table 3 shows the distribution of skeletal effects as assessed by radiological imaging. The bones of the calvaria (frontal, occipital, sphenoidal, ethmoidal, mastoid, and temporal bones) and/or the facial bones (zygomatic, maxillary, and mandibular bones) were affected in most of the patients (81 %), with an equal proportion of patients having mono-ostotic and polyostotic FD. All four patients with a mandibular bone effect had a polyostotic manifestation of the disease (Table 3). Moreover, the ribs, spine, and pelvic bones, as well as the upper extremities, were only affected in patients with polyostotic FD. Similarly, effects on the bones of the lower extremities were most common in patients with polyostotic affections (Table 3). Only one of the nine patients with mono-ostotic FD had a noncraniofacial bone effect (patient 8). Two patients were diagnosed purely on radiological findings, whereas 24 patients (92 %) had a biopsy performed. However, in five of the patients who had a biopsy performed, the histopathological evaluation of the biopsy was no longer available for review at the time of this survey. Figure 1 is an example of how FD can present itself radiologically. It is a CT scan of the head from one of the patients used in our study.
Results We identified a total of 28 patients, of whom two were excluded because they did not have FD. Consequently, only the remaining 26 patients were used in the study. The clinical course of each of the patients is shown in Table 1. Of the 26 patients who were diagnosed with FD, 17 (65 %) had polyostotic affections, whereas 9 (35 %) had mono-ostotic FD. The median age at time of diagnosis was 16.5 years (range 6 months–70 years). Patients with polyostotic affections were diagnosed at a younger age than those with mono-ostotic FD (Table 2). Sixteen (62 %) of the patients were females. The proportion of males and females did not differ significantly between patients with mono- and polyostotic FD (Table 2). Four (15 %) patients were diagnosed with MAS (patients 17, 18, 22, and 25 in Table 1) due to polyostotic FD and cafe´-au-lait spots, among whom two had endocrine abnormalities in terms of either hyperthyroidism (patient 17) or precocious puberty (patient 18). Symptoms That Lead to a Diagnosis At time of diagnosis, 17 patients (65 %) reported pain in the area affected by FD (Table 2). Five patients (19 %) had neurological deficiencies due to their FD in terms of visual impairment (patients 4, 16, and 24), impaired hearing (patient 5), or facial nerve palsy (patient 15). Three patients (12 %) presented with a pathological fracture (patients 7, 8, and 17), and one patient (patient 13) had symptoms of chronic sinusitis which was explained by FD. Craniofacial deformities in terms of a clinical bump on the head or a protrusion on the maxillary or mandibular bone were
Surgical Treatment Fourteen (54 %) underwent, at least, one surgery after being diagnosed with FD, six (67 %) from the monoostotic group and eight (47 %) from the polyostotic group (p = 0.43). These surgeries included craniotomy, nerve decompression, osteosynthesis, osteotomy, and functional endoscopic sinus surgery (Table 1). The patient (13) who had the functional endoscopic sinus surgery suffered a quick recurrence with nuisance symptoms including pressure on her right eye and will most likely need resurgery within the near future. Among the patients with neurological impairment, the patient (5) with impaired hearing, due to blockage of the ear canal, had a complete restoration of his hearing following surgical intervention. Among the three patients with impaired vision, two have had surgery. One patient (16) had optic nerve decompression performed, which restored his vision. The other patient (4) had optic nerve decompression performed twice. This patient has severe FD with major facial deformities causing exophthalmos, putting strain on both
123
Sex/age at diagnosis (years)
M/51
M/37
M/64
M/17
M/15
F/1
F/7
F/21
M/70
F/1
F/13
F/16
F/20
M/35
M/31
F/39
Patient ID
1
123
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Mono
Poly
Mono
Mono
Poly
Poly
Mono
Mono
Mono
Poly
Poly
Poly
Mono
Poly
Poly
Poly
Type
Right frontal bone and right and left sphenoidal bones Left sphenoidal sinus
Left frontal bone and sinus
Frontal bones including orbitae and sinuses Right maxillary bone and sinus
Femoral bones
Left parietal bone
Right maxilla bone
Right femoral bone
Femoral and pelvic bones
Left frontal, zygomatic, sphenoidal, parietal, and maxilla bones and mandible
Base of skull and mastoid bone including left ear canal
Left maxilla bone, including orbita
Pelvis, femoral and tibial bones
Frontal and parietal bones, left humeral, ulnar, and radial bone, 11th rib Mandible and maxilla bones, including right orbita
Affected bone
Table 1 Characteristics of studied patients with fibrous dysplasia
Visual impairment and pain
Facial nerve palsy and pain
Craniofacial deformity and pain
Chronic sinusitis
Craniofacial deformity
Pain
Craniofacial deformity and periorbital edema Craniofacial deformity
Pain and subtrochanteric fracture
Pain and femoral neck fracture
Craniofacial deformity and pain
Impaired hearing
Craniofacial deformity, pain, visual impairment and exophthalmos
Bone pain
Random finding
Craniofacial deformity
Symptoms/clinical findings at time of diagnosis
Yes
No
Yes
Yes
NA
Yes
Yes
NA
Yes
Yes
No
Yes
Yes
Yes
Yes
Yes
Biopsy verified
BF, decompression of optic nerve
BF
BF
BF ? endoscopic sinus surgery
BF
BF
No treatment
BF
BF, osteosynthesis of fractured bones
BFm osteosynthesis of fractured bones
BF
BF, 2 surgeries in left ear canal
BF, 2 surgeries: craniotomy and decompression of optic nerves
BF
BF
BF, cranial plastic surgery
Treatment
RSU, normal vision after surgery
RSU
Slight progression in sinus frontalis
Relapse and in need of new surgery
RSU
RSU, alleviation of bone pain after treatment
Continued increased bone metabolism in parietal bone
NA
No alleviation of pain
Pain-free 6 months following treatment, pain-free in year 2010
Decreased activity in frontal bone
Normal hearing after surgery
RSU, following surgery: loss of vision in the left eye and impaired vision in the right eye
Slight regression of FD lesions (on scintigraphy) after treatment
Cranial discomfort after surgery, progression (CT scan) in fontal bone NA
Outcome
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
F/2
F/0.5
F/10
F/21
F/10
F/4
M/15
M/21
F/3
F/38
17
18
19
20
21
22
23
24
25
26
Mono
Poly/MAS
Poly
Poly
Poly/MAS
Poly
Mono
Poly
Poly/MAS
Poly/MAS
Type
Right parietal bone
Right femoral and tibial bones; pelvis, ribs, and spine; maxilla and occipital bones
Frontal, temporal, sphenoidal, ethmoidal, maxilla bones and mandible
Right frontal, temporal, sphenoidal and maxilla bones
Femoral, occipital, and frontal bones
Left orbit, parietal and occipital bones
Right frontal bone
Left frontal, sphenoidal, temporal, zygomatic bones involving the orbit
Left lower and upper extremities, pelvis
Mandible, left femoral and tibial bones and pelvis
Affected bone
Craniofacial deformity and pain
Discovered because of a limp when 4 years old, pain
Visual impairment
Craniofacial deformity and pain
Pain
Pain
Craniofacial deformity and pain
Craniofacial deformity and pain, exophthalmos.
Vaginal discharge at 6 months
Pain and femoral neck fracture, hyperthyroidism
Symptoms/clinical findings at time of diagnosis
Yes
Yes
Yes
Yes
NA
NA
Yes
Yes
NA
Yes
Biopsy verified
Cosmetic surgery (removal of bump)
BF, plastic surgery twice, 12 surgeries in right upper extremity
BF, decompression of optic nerve
BF, twice bone resection
No treatment
BF
BF, cosmetic surgery
BF
BF, back surgery
BF, surgery to correct the deformed shin and femoral bones
Treatment
RSU
RSU, no bone pain
RSU
RSU, fewer headaches with decreased use of analgesics
–
RSU
RSU
Increased bone metabolism but same extent of FD at followup scintigraphy
Deformed skeleton because of FD
RSU
Outcome
M male, F female, P polyostotic affection, M mono-ostotic, MAS McCune–Albright syndrome, BF IV bisphosphonate, NA not available, RSU radiological status unchanged
Sex/age at diagnosis (years)
Patient ID
Table 1 continued
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
123
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia Table 2 Clinical characteristics and distribution of skeletal effects according to radiological findings in all patients and stratified by whether the disease had a mono- or polyostotic-form
Age at diagnosis, yearsa
All (n = 26)
Mono-ostotic (n = 9)
Polyostotic (n = 17)
16.5 (0.5–70)
21 (1–70)
13 (0.5–64)
10 (38) 16 (62)
3 (33) 6 (67)
7 (41) 10 (59)
5 (19)
2 (22)
3 (18)
Gender Males, n (%) Females, n (%) Symptomsb Neurological, n (%) Impaired hearing, n (%)
1 (4)
Visual impairment, n (%)
3 (12)
Facial nerve palsy, n (%)
1 (4)
Chronic sinusitis, n (%) Bone pain at affected site(s), n (%)
0 2 (22) 0
1 (4)
1 (11)
17 (65)
6 (67)
1 (6) 1 (6) 1 (6) 0 11 (65)
Clinical findings (skeletal deformities/fractures) Craniofacial deformity (%)
11 (42)
6 (67)
5 (29)
Exophthalmos (%)
2 (8)
1 (11)
1 (6)
Deformities of femora (%)
1 (4)
History of fracture (%)
6 (23)
1 (11)
5 (29)
14 (54) 23 (89)
6 (67) 7 (78)
8 (47) 16 (94)
0
1 (6)
Treatment Surgery, n (%) Bisphosphonates, n (%)
None of the shown indices differed significantly between patients with mono- and polyostotic fibrous dysplasia. Mono-ostotic fibrous dysplasia involves only a single bone, or adjacent bones, like both the upper and lower jaw, whereas the polyostotic form involves more than one skeletal site a
Median with range Note that total number of symptoms/affected bone sites may not sum up to number of patients as patients with the polyostotic type may be counted in each group
b
optic nerves and compromising vision. The first surgery had a successful outcome. However, the patient had a rapid relapse and needed resurgery. Following the second operation, he was blind in the left eye and had severely impaired vision in his right eye. Medical Treatment Medical treatment modalities are visualized in Fig. 2. Drug, dosage, and treatment length are listed by each patient identification number (according to Table 1) including age at initiation of treatment. Overall, 23 (89 %) patients received treatment with bisphosphonates with a median treatment length of 4 years (range 3–276 months) at the time of follow-up. The median age at the time of initiation of treatment with bisphosphonates was 29 (range 4–70) years. As shown in Fig. 2, the types of bisphosphonates prescribed changed during follow-up. At the end of follow-up, most patients were on treatment with a highpotency intravenous bisphosphonate, i.e., zoledronic acid. The three patients who did not receive treatment with bisphosphonates either refused or were not eligible; one
123
refused due to the potential side effects linked to bisphosphonate treatment (patient 22), while two (patients 10 and 26) were not offered treatment according to a clinical judgment. Following treatment, three patients (patients 7, 11, and 23) reported pain relief. One patient with FD in the bones of the face and skull (patient 23) had periodic relief from headache and consequently a decrease in the use of analgesics. The other two had FD in the femoral bone (patients 7 and 11) and reported a decrease in bone pain after infusion with a bisphosphonate. In contrast, one patient (patient 1) reported a feeling of growth in the FD-affected bones in the months following treatment with bisphosphonates. Three patients (patients 17, 18 and 25) sustained fractures after treatment initiation with bisphosphonates. All three were females and had polyostotic FD and MAS. They had also suffered multiple fractures in FD-affected bones before initiation of treatment. Patient 17, who has received bisphosphonates for 12 years, had her most recent fracture 10 years ago. Patient 18 has severe and debilitating FD and has suffered from multiple fractures both before and after her treatment initiation in 1987. Patient 25 had two fractures in 2001 and none since.
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia Table 3 Skeletal effects according to radiological findings in all patients and stratified by whether the disease had a mono- or polyostotic form All (n = 26)
Mono-ostotic (n = 9)
Polyostotic (n = 17)
Skeletal sites affecteda Head, n (%)
21 (81)
8 (89)
13 (77)
Calvaria, n (%)
16 (62)
5 (56)
11 (65)
Mandible, n (%)
4 (15)
0 (0)
4 (24)
Facial bones, n (%)
8 (31)
3 (33)
5 (29)
6 (23)
0 (0)
6 (35) 2 (12)
Ribs, spine, pelvis, n (%) Ribs, n (%)
2 (8)
0 (0)
Spine, n (%)
1 (4)
0 (0)
1 (6)
Pelvis, n (%)
5 (19)
0 (0)
5 (29)
Upper extremities, n (%)
2 (8)
0 (0)
2 (12)
Lower extremities, n (%)
8 (31)
1 (11)
7 (41)
Femoral bone, n (%)
8 (31)
1 (11)
7 (41)
Tibial bone, n (%)
4 (15)
0 (0)
4 (24)
None of the shown indices differed significantly between patients with mono- and ployostotic fibrous dysplasia. Mono-ostotic fibrous dysplasia involves only a single bone, or adjacent bones, like both the upper and lower jaw, whereas the polyostotic form involves more than one skeletal site
Fig. 1 Transverse computed tomography showing a massive lytic fibrous dysplasia lesion in the orbit and maxillary bone. Facial deformity and protrusion of the eye are also visualized
a
Note that the total number of patients may not sum up to number of affected bone sites as patients with the polyostotic type may be counted in each group of bones affected
Radiological Findings Following Medical Treatment Within the group of patients receiving medical treatment (n = 23), radiological follow-up was performed in 18 (78 %). Follow-up imaging was done using bone scintigraphy in 10 patients, MRI scans in five patients, and CT scans in three patients at follow-up. A regression of the FD lesions was found in two patients (patients 3 and 6), while three patients showed signs of progression (patients 1, 14, and 19). In the remaining 13 patients, 11 had an unchanged status of their FD compared to previous radiological examinations, which was performed a median of 54 months (range 3 months to 19 years) following initiation of medical therapy. In two patients with a follow-up radiological examination, the initial examination was no longer available and changes could therefore not be evaluated. Both of the two patients showing regression had radiological follow-up performed by bone scintigraphy. Patient 3 had a scintigraphy from 2011 showing ‘‘slight regression’’ of the FD lesions compared with a scintigraphy performed in 2006. Patient 6 had a scintigraphy from 2006 that, compared with one from 1999, showed ‘‘less activity but the same propagation’’ in the FD-affected area. Among the three patients who had progression, two had radiological follow-up performed by CT scans showing
‘‘increased lytic changes’’ (patient 1) and ‘‘slight progression’’ (patient 14) as evaluated 3 and 9 years, respectively, following the initial CT scan (Table 1). Patient 19 had a scintigraphy from 2010 that showed ‘‘increased bone metabolism but same extent of FD’’ compared to a scintigraphy from 2001. The five patients on medical treatment who did not have any radiological follow-up examinations performed (patients 2, 7, 8, 9, and 13) were all diagnosed recently and had received treatment for only a few years. Among the three patients not receiving medical treatment, two (patients 10 and 22) were diagnosed 32 and 61 years ago, respectively. Patient 10 had a CT scan and scintigraphy performed in 2010 showing ‘‘increased bone metabolism in known tumor,’’ but there was no mention of whether the lesion had progressed compared with earlier examinations. The second patient had a CT scan done in 2001, also with no mention of status compared with earlier examinations. Finally, patient 26, who did not receive medical treatment, was newly diagnosed and has not yet had any radiological follow-up examinations. Biochemical Findings Table 4 sums up the biochemical findings. Four patients (15 %) had hypophosphatemia at time of diagnosis (patients 2, 3, 12, and 22). Following bisphosphonate therapy, another four (patients 1, 11, 19, and 20) had plasma phosphate levels below the lower limit of the
123
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia Age (years) at treatment start
Patient ID 26 25 24 23 22 21 20 19 18 17 16 15 14 13 12 11 10 9 8 7 6 5 4 3 2 1
x x x (year 1983) x x (year 1952) x x x x (year 1969) x (year 1964) x X (year 1975) x x x x X (year 1980) x x x X (year 1980) x x x x x 1987
1989
1991
x: year of diagnosis
1993
1995
1997
1999
2001
2003
2005
2007
2009
2011
7 37 17 16 26 10 20 35 48 62 35 20 17 14 70 23 17 21 32 18 64 37 53 29 years
Zoledronic acid IV 5 mg.
Ibandronat IV 3-6 mg.
Alendronate, oral, 70 mg/week
Clodronate, oral, 400 mg.
Pamidronat IV 15-60 mg.
Etidronate, oral, 200 mg x 2
Fig. 2 Medical treatment with bisphosphonates in patients with fibrous dysplasia. Patient ID is as shown in Table 1
Table 4 Biochemical characteristics at time of diagnosis and at time of follow-up: median with interquartile range
Total alkaline phosphatase, n (%)a Bone-specific alkaline phosphatase, n (%)
a
Reference range
Time of diagnosis
Time of follow-up
p
NA
10 (38)
5 (19)
–
NA
5 (19)
6 (22)
–
Phosphate (mmol/L)
0.76–1.41
1.07 (0.91–1.22)
0.87 (0.83–1.02)
0.02
Calcium-total (mmol/L)
2.25–2.55
2.44 (2.37–2.46)
2.36 (2.25–2.37)
0.08
Calcium-total, albumin-adjusted (mmol/L)
2.22–2.52
2.43 (2.34–2.49)
2.41 (2.29–2.48)
0.11
Ionized calcium (mmol/L)
1.18–1.32
1.23 (1.21–1.25)
1.25 (1.25–1.26)
0.21
25-Hydroxyvitamin D (nmol/L)
45–150
46 (36–82)
70 (58–94)
0.06
PTH (pmol/L)
1.6–6.9
4.4 (3.0–5.7)
4.0 (3.6–4.9)
0.4
a
Number (%) of patients with levels above the upper limit of the reference range
reference interval. All except one patient (patient 20) with hypophosphatemia had a polyostotic manifestation of the disease. On average, plasma phosphate levels were significantly lower at follow-up compared with levels at time of diagnosis (Table 4). Ten patients (38 %; patients 1, 4, 5, 6, 8, 18, 19, 21, 22, and 25) had a plasma level of total ALP above the upper limit of the reference interval at the time of diagnosis, among whom two (patients 4 and 8) had mono-ostotic FD and eight had polyostotic effects (p = 0.40). At follow-up, five (19 %) patients (patients 6, 18, 19, 22, and 25) had total ALP levels above the upper reference limit. All had a polyostotic manifestation of the disease and had elevated ALP levels at time of diagnosis. Only one of the patients
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(patient 22) with elevated ALP levels at both times of measurement did not receive medical treatment in between. BSAP levels were elevated in five (19 %) patients at time of diagnosis, among whom one (patient 4) had monoostotic FD and four (patients 19, 22, 23, and 26) had polyostotic FD (p = 0.63). Following treatment, BSAP levels were above the upper limit of the reference interval in six patients (patients 1, 6, 17, 18, 22, and 26). All six patients had polyostotic FD, and two of them (patients 22 and 26) also had elevated levels prior to medical treatment. Otherwise, biochemical analyses showed results within the reference range of analyzed indices. Neither calcium nor PTH levels were changed at follow-up compared with time of diagnosis. Plasma 25OHD levels increased from a
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
median of 46–70 nmol/L, most likely due to initiation of use of vitamin D supplements in the studied subjects.
Discussion Although FD may be a silent disease, our data emphasize that the clinical picture of the disease shows large variability as some patients are asymptomatic whereas others are severely affected with the disease showing a debilitating course. One could assume that polyostotic compared to mono-ostotic FD has a more severe course, but we found no clear connection between the type of FD and the severity. What determines the severity of FD is multifactorial and particularly depends on the location and extent of the FD lesions; but also individual characteristics such as endocrinopathies, fractures, and malignant transformation, although rare, play an important prognostic role [16]. We also found that the time of diagnosis does seem to have some predictive value of the prognosis; the earlier the diagnosis is made, the more debilitating the disease. The location of the lesions is of major importance for the prognosis as those with FD in the skull and facial bones have an increased risk of neurological symptoms or growth into vital structures. In our survey we found that involvement of the bones of the skull and face was frequent: in eight out of nine of those with mono-ostotic FD and in 12 out of 15 of those with a polyostotic manifestation. Affected Bones Previously, mono-ostotic FD was considered to be much more common than the polyostotic form [4]. However, in agreement with our findings, a number of more recent reports have suggested that polyostotic FD affects more patients than the mono-ostotic form [5, 6, 8, 17]. Implementation of better radiological methods with a more careful evaluation of patients may explain this discrepancy. Most previous studies on FD have been published by groups of specialists who treated FD at specific skeletal sites, such as the craniofacial or long bones [5, 18–20]. Only few data are available on the distribution of FD lesions at different skeletal sites. Apparently, several previous surveys have found involvement of the craniofacial bones to be less frequent than in our group of studied patients. Summarizing data from five individuals reports, including a total of 155 cases with mono-ostotic FD, Edgerton et al. [21] reported involvement of the craniofacial bones in 30 % of the patients, whereas 32 % had a lesion at the lower extremities, 6 % at the upper extremities, and 32 % at the vertebrae or ribs. Similarly, in a report based on data from the radiologic archives of the Armed Forces Institute of Pathology, USA, including 501 cases of
radiologically proven and histologically verified FD (85 % mono-ostotic), involvement of the craniofacial bone was only present in 22 (5 %) of the cases with mono-ostotic FD [4]. In a more recent survey including 58 patients treated with bisphosphonates, among whom 38 % had monoostotic FD and 62 % polyostotic FD (n = 7 with MAS), the craniofacial bones were involved in 43 % of the patients, whereas 62 % had involvement of the femoral and 45 % of the tibial bone [6]. Moreover, in a European multicenter study on FD promoted by the European Pediatric Orthopedic Society, only one of 23 cases with monoostotic FD was reported to have a craniofacial effect [5]. Our data suggest that the craniofacial bones are involved more often than suggested by these previous reports as we found craniofacial effects in 81 % of our studied patients with a similar proportion in the mono-ostotic and polyostotic groups. To a certain extent, our data on involvement of the craniofacial bones in polyostotic FD agree with a recent survey by Chapurlat et al. [7] showing FD lesions of the head in 86 % of the adults studied, among whom most had polyostotic FD. Moreover, the report by Chapurlat et al. [7] showed involvement of the lower extremities in approximately 90 % of the cases, which also agrees with our findings as all four patients with MAS within our group of patients had lesions in the lower extremities. In contrast, involvement of the spine was less common in our cohort than previously reported. In our group of patients, only one (4 %) had a spine lesion, while the spine was affected in 20 % (n = 11) of the cases in a survey including 56 patients among whom 23 had mono-ostotic effects, 9 had polyostotic effects, and 24 had polyostotic FD with MAS [8]. In our group of patients, effects on the mandibular bone, ribs, spine, pelvis, and bones of the upper extremities were only observed in patients with polyostotic FD. In contrast, mono-ostotic FD affected only the head and lower extremities. Accordingly, our data suggest that FD, depending on which type, may have a predilection of location in the skeleton. More data should be collected on the skeletal distribution of FD, based on patients. Severity of Disease Need for surgery may be used as a measure of the severity of the disease. Within our group of patients, more patients with mono-ostotic FD (n = 6, 67 %) than polyostotic FD (n = 8, 47 %) needed surgery. This was attributable to the high prevalence of craniofacial effects in the group of patients with mono-ostotic FD as this location is particularly troubling because of the close proximity to the brain and facial nerves including the eyes. Therefore, it is not surprising that more than half of these patient needed at least one surgery in order to decrease or prevent disease sequelae. Based on our findings, the severity, and thus the
123
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
prognosis, cannot be determined by the type of FD. It does, however, appear to be a bad prognostic factor to have MAS. Among the four patients with MAS, all were diagnosed during early childhood (before the age of 4 years) and suffered multiple pathological fractures resulting in deformities of the bones. Additionally, three of them have undergone several surgeries due to their debilitating disease. Other studies have found that the proportion of the skeleton involved was a predictor of functional outcome and mobility [22]. Previously, pain caused by FD was considered often to dissolve with age. However, recent studies have shown a higher prevalence and severity of pain in adults than in children and that the pain experienced by the patients is unrelated to the burden of the disease [7, 23]. Our findings support this notion as two-thirds of our (mainly adult) patients reported pain at their FD lesions. Moreover, pain was as common in patients with mono-ostotic as in those with polyostotic FD, supporting the notion that the burden of the disease in terms of number of skeletal effects is not of major importance to the severity of the disease. But once again it must be emphasized that the severity of FD is multifactorial. Medical Treatment Therapy with bisphosphonates has been suggested to cause pain relief and to have a healing effect on bone lesions. In some studies, treatment with pamidronate, alendronate, and zoledronic acid has been shown to fill in osteolytic lesions and decrease the rate of bone resorption with an improved local bone mass density at the site of the FD lesions [6, 24– 27]. However, other studies have not shown such effects; and in the studies showing effects, it seems that only approximately half of the patients responded to treatment [22, 28, 29]. In one of the largest studies, including 58 patients treated with pamidronate for a median of 50 months (range 1–11 years), half of the participants had radiological improvements in terms of filling of osteolytic lesions and/or cortical thickening [6]. Moreover, pain intensity was reduced by 41 % following the first course of pamidronate and by 69 % after several treatment cycles [6]. Similarly, although most case series have reported a reduced pain score in response to bisphosphonates, the findings have in general been mixed in terms of the proportion of patients responding to treatment [6, 24, 30–33]. Of note, no randomized controlled clinical trial has been completed thus far. Results from published studies are therefore limited by lack of a control group. Findings may (at least in part) be due to natural variations in the course of the disease including an effect of regression to the mean. In some patients, treatment may have been initiated at a point of time when symptoms were ‘‘above’’ average and the
123
findings of an apparent effect of medical treatment may more or less be due to spontaneous variations in the course of the disease. However, based on the studies showing potential beneficial effects of treatment with bisphosphonates, most patients treated at our department were offered bisphosphonate therapy. The clinical workup on these patients as presented in this report, nevertheless, does not support a general beneficial effect of bisphosphonates. Only three patients were found to have a clear decrease in bone pain following treatment, and according to the radiological evaluations, only two patients had regression of their disease, whereas three patients experienced a progression following treatment. Both patients showing regression had their radiological follow-up measurements performed by bone scintigraphy. Although scintigraphy is useful in detecting early lesions and polyostotic involvement, one should be aware of false-negative results. Depending on which type of lesion (ground glass or cystic), silent lesions have been found to make up as much as 7–14 % of the total number of lesions [34]. Explanations for this could be that some of the lesions with time become quiescent. Another theory is that the active osteoblasts are destroyed, resulting in no increased uptake of the radiopharmaceutical agent. The scan provides a functional view of the current skeletal metabolic activity, but scintigraphy shows no pathological activity and does not rule out disease. Accordingly, CT scans are more applicable as they reveal the full extent of a lesion including intraosseous and extraosseous involvements independent of the bones’ metabolic activity. This is especially useful with FD involving the face, sinuses, and skull. Because CT scans reveal the full extent of a lesion, this would be a good choice when comparing the effects of a treatment. However, considering that the type of lesion may change with age from a homogeneous ‘‘ground glass’’ appearance to a lytic appearance, this does not necessarily represent a worsening of the disease [35, 36]. Controlled trials are warranted to improve our understanding of whether patients with FD may benefit from medical treatment with antiresorptives. In a recent study, treatment with denosumab showed promising results, which also need to be investigated further [37]. Biochemical Findings Although renal phosphate wasting is quite common in patients with FD, actual hypophosphatemia is not a frequent finding [9]. Interestingly, nephrogenous cAMP has been reported to be normal in patients with FD, suggesting that the postzygotic activating mutation of the GNAS1 gene does not by itself cause phosphate wasting [10]. Rather, the low plasma phosphate levels are caused by increased plasma levels of FGF-23 secreted by the dysplastic tissue
M. D. Thomsen, L. Rejnmark: Fibrous Dysplasia
[38]. Elevated plasma FGF-23 levels have been found to correlate with the mass of osteogenic cells within the FD lesions and the degree of bone involvement assessed by serum and urine markers of bone metabolism [38, 39]. In accordance with this notion, all except one of our patients with hypophosphatemia had a polyostotic manifestation of the disease. Unfortunately, measurement of FGF-23 levels was not a part of the clinical evaluation of our patients. However, low phosphate levels were not that common, and none of our studied patients needed treatment with oral phosphate supplements. The lower mean level of plasma phosphate at follow-up compared with the initial measurements may represent a variable course of the disease or an effect of treatment with bisphosphonates [40]. Additionally, measurements of urinary phosphorus levels in order to calculate TmP/GFR would have been of interest. Our findings of elevated plasma levels of ALP agree with previous findings. The fact that levels remained elevated at follow-up in approximately half of the patients despite treatments may indicate that the bisphosphonates used did not sufficiently suppress the FD lesions. Limitations to Study Our analyses are prone to bias which may apply to data collected retrospectively from patient hospital charts, including lack of objective measures of pain. However, by extracting information based on a prespecified collection sheet, we aimed to systemize available data in order to improve our understanding of the disease. Most likely, our survey is not as prone to referral bias as reports from specialized surgical departments as patients are referred to us for medical treatment independently of the skeletal site of their FD lesion. In most of the patents included, the diagnosis was confirmed by a positive lesion biopsy (n = 19). Only two patients did not have the diagnosis confirmed by a biopsy, whereas the specific result of the biopsy was unavailable in five patients. We do believe that the biopsy from these five patients, most likely, did have a histological pattern compatible with FD as their diagnosis was not changed following the biopsy.
Conclusion Polyostotic FD is at least as common as the mono-ostotic form. Patients with MAS are more severely affected than patients with only bone involvement, but the site of bone involvement is of most importance to the severity of the disease. Whether a patient has the mono-ostotic or polyostotic type does not per se determine the disease severity. Treatment with bisphosphonates may alleviate pain in some patients, but treatment response is ambiguous; and
our clinical workup on the effect of bisphosphonate therapy did not show a clear reduction in skeletal destruction. Whether or not bisphosphonates slow the disease progression or help to limit skeletal damage needs to be determined in controlled trials.
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