- Fibrous Dysplasia
- What causes fibrous dysplasia?
- What are the symptoms of fibrous dysplasia?
- How is fibrous dysplasia diagnosed?
- How is fibrous dysplasia treated?
- Key points about fibrous dysplasia
- POLYOSTOTIC FIBROUS DYSPLASIA IN ONE OF NEGRO TWIN GIRLS
- JCI -FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting
- Fibrous Dysplasia Market Research Report- Forecast to 2023 | MRFR
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Fibrous dysplasia is a chronic problem in which scar- tissue grows in place of normal bone. It often results in one or more, of the following:
- Bone deformity
- Brittle bones
- Uneven growth of bones
Any bone can be affected. More than one bone can be affected at any one time. When multiple bones are affected, it is not unusual for them to all be on one side of the body. However, fibrous dysplasia does not spread from one bone to another. The most commonly affected bones include the following:
- Facial bones
- Shinbone (tibia)
- Thighbone (femur)
- Upper arm bone (humerus)
- Vertebrae in the spine
Some people develop hormonal problems and a condition called McCune-Albright syndrome. McCune-Albright syndrome is another form of fibrous dysplasia. It causes different symptoms, such as early onset of puberty and skin spots, called café-au-lait spots.
Fibrous dysplasia usually occurs in children ages 3 to 15. It is sometimes not diagnosed until adulthood. It is found equally in men and women.
What causes fibrous dysplasia?
The exact cause of fibrous dysplasia is not known. It is believed to be due to a chemical defect in a specific bone protein. This defect may be due to a gene mutation present at birth, although the condition is not known to be passed down in families.
What are the symptoms of fibrous dysplasia?
The following are the most common symptoms for fibrous dysplasia. However, each person may experience symptoms differently. Symptoms may include:
- A waddling walk
- Bone deformity
- Bone fractures
- Bone pain (which happens when the fibrous tissue expands in the bone)
- Scoliosis (a sideways curve of the spine)
The symptoms of fibrous dysplasia may look other medical problems. Always talk with your healthcare provider for a diagnosis.
How is fibrous dysplasia diagnosed?
In addition to a complete medical history and physical exam, other tests may include:
- Biopsy. A test in which tissue samples are removed from the body and looked at under a microscope. It can help determine if cancer or other abnormal cells are present. It can also be done to remove tissue from the affected bone.
- Bone scan. Your doctor may order a bone scan to look for additional lesions throughout your entire skeleton. During this test, a very small amount of radioactive dye is injected into the body by IV.
- Lab tests. When fibrous dysplasia lesions are actively growing, blood and urine tests may show elevated levels of the certain enzymes and amino acids in the body.
- Other imaging tests. Your healthcare provider may order an MRI or CT scan to further evaluate the affected bones.
- X-ray. A diagnostic test that makes images of internal tissues, bones, and organs onto film.
How is fibrous dysplasia treated?
Specific treatment for fibrous dysplasia will be determined by your healthcare provider :
- Your age, overall health, and medical history
- Extent of the disease
- Your tolerance for specific medicines, procedures, or therapies
- Expectations for the course of the disease
- Your opinion or preference
Surgical treatment may include the following procedures:
- Placement of a rod down the shaft of the bone
- Removal of affected bone, followed by bone grafting
- Removal of bone wedge
Other treatment may include:
- Pain management
- Physical therapy
Key points about fibrous dysplasia
Fibrous dysplasia is a chronic disorder in which scar- tissue grows in place of normal bone. Any bone can be affected.
- Fibrous dysplasia usually occurs in children ages 3 to 15, but it sometimes is not diagnosed until adulthood.
- The exact cause of fibrous dysplasia is not known, but it is not passed down through families.
- Symptoms may include bone pain and deformity, a waddling walk, and scoliosis.
- Treatment may include surgery, medicines, pain management, or physical therapy.
POLYOSTOTIC FIBROUS DYSPLASIA IN ONE OF NEGRO TWIN GIRLS
Interest in cystic lesions of bone was greatly stimulated by the successful removal of a parathyroid adenoma by Mandl1in 1925. Since that time generalized osteitis fibrosa cystica of von Recklinghausen has been recognized as due to adenoma or hypertrophy of the parathyroid glands.
However, the occurrence of other cystic bone lesions, either generalized or localized, without obvious abnormality of calcium and phosphorus metabolism, has been noted with increasing frequency and has aroused considerable speculation as to the nature of this condition or variety of conditions.
In 1937 Albright, Butler, Hampton and Smith2called attention to a syndrome characterized…
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JCI -FGF-23 in fibrous dysplasia of bone and its relationship to renal phosphate wasting
Patients and samples. Forty-nine FD/MAS patients (age range 4–58 years) were enrolled in Institutional Review Board–approved (IRB-approved) studies of FD/MAS at the National Institutes of Health and gave written informed consent for the studies.
Diagnosis of FD/MAS was confirmed clinical history, radiographic findings, histopathological findings, and mutation analysis of the GNAS1 gene. Due to known effects of bisphosphonate treatment on markers of bone turnover, patients receiving bisphosphonates were not included in this cohort.
Sera and urine specimens were collected while patients were inpatients and on a hospital diet consisting of the following nutrients: calcium (850 mg; range 690–1,066 mg), phosphorus (1,312 mg; range 1,065–1,744 mg); potassium (3,596 mg; range 3,107–4,595 mg), and sodium (5,111 mg; range 4,282–6,412 mg).
Sera and urine specimens from all 49 patients were used for FGF-23, phosphate, and maximum rate of reabsorption of phosphate relative to the GFR (TmP/GFR) determinations. Sera from 283 normal control subjects (age range 1–84 years) were collected under an IRB-approved protocol at Indiana University.
Biopsy specimens from the FD-involved iliac crest from five patients (two nonphosphaturic and three phosphaturic) were used for in situ hybridization analysis as detailed below.
Normal controls included one iliac crest specimen taken from the uninvolved bone of a FD patient, two normal iliac crest samples from non-FD patients, and one sample of fracture callus. Cell cultures were established from FD tissue of five patients (three nonphosphaturic and two phosphaturic) and normal bone of three age-matched normal controls as detailed below.
GNAS1 mutation analysis. Mutations were determined in genomic DNA (gDNA) isolated from either tissue or cells using the standard protocol of the DNeasy Tissue Kit (QIAGEN Inc., Valencia, California, USA).
Purified gDNA (200–500 ng) was amplified using either standard primers for direct DNA sequencing or using a protein nucleic acid– based (PNA-based) primer, which blocks amplification of the normal allele.
Amplification for direct sequencing used 1 μg of the forward primer: 5′-TGACTATGTGCCGAGCGA-3′ (exon 7), and the reverse primer: 5′-AACCATGATCTCTGTTATATAA-3′ (intron G) (GenBank Accession no. M21142.1, bases 272–289 and 521–542, respectively) in a 100-μl reaction.
Samples were heated to 94°C for 15 minutes, then cycled 35 times at 94°C for 60 seconds, 55°C for 30 seconds, and 72°C for 60 seconds, and terminated for 7 minutes at 72°C.
To block amplification of the wild-type allele, a PNA-based primer that blocks amplification of the normal allele was used as reported previously (25). PCR products were purified using the QiAmp PCR purification kit (QIAGEN Inc.) and sequenced with a dRhodamine dye-terminator cycle sequencing with Ampli Taq and the Perkin-Elmer Applied Biosystems 377 automated sequencer (Palo Alto, California, USA).
In situ hybridization. A 755-bp sequence within the human FGF-23 cloned into the pcDNA3.1(+) plasmid (8) was inserted into pBluescript plasmid vector (Invitrogen Life Technologies, Carlsbad, California, USA) and used as template for transcription of digoxigenin-labeled RNA probes.
The fragment, excised with EcoRI and BamHI restriction enzymes (New England Biolabs Inc., Beverly, Massachusetts, USA), was purified by 0.8% agarose gel and a QIAquik Gel Extraction Kit (QIAGEN Inc.), and then subcloned into pBluescript vector.
RNA probes were synthesized using the DIG RNA Labeling Kit (Boehringer Mannheim GmbH, Mannheim, Germany), according to the manufacturer’s instructions. BamHI and T7 RNA polymerase and EcoRI and T3 RNA polymerase were used to synthesize the antisense probe and sense probes, respectively.
Limited alkaline hydrolysis was used to generate fragments of both probes.
All biopsy specimens were fixed in freshly prepared phosphate-buffered 4% formaldehyde for 24 hours. After washing in PBS, samples were decalcified in buffered EDTA and paraffin embedded.
Additional specimens were embedded in poly-methyl methacrylate (MMA), as described previously (26), and undecalcified sections obtained from MMA blocks were stained with von Kossa stain. Deparaffinized sections were digested with 20 μg/ml proteinase K (Invitrogen Life Technologies) in 10 mM Tris-HCl, 1 mM EDTA, pH 8.0, at 37°C for 20 minutes, washed in 0.
1 M glycine (Invitrogen Life Technologies), then PBS, and preincubated with mRNA in situ hybridization solution (DAKO Corp., Carpinteria, California, USA) at 50°C for 2 hours. Sense and anti-sense RNA probes were diluted in hybridization solution at a final concentration of 5 ng/μl.
After hybridization at 55°C overnight, sections were washed as follows: 4× SSC (four times for 5 minutes), 2× SSC (two times for 5 minutes), 1× SSC (once for 10 minutes), 0.5× SSC (once for 10 minutes) at room temperature, and 0.2× SSC plus 0.2% BSA (Sigma-Aldrich, St. Louis, Missouri, USA) twice for 20 minutes at 60°C.
Hybridization was detected using alkaline phosphatase–conjugated antidigoxygenin (Boehringer Mannheim GmbH) with p-nitroblue tetrazolium chloride and 5-bromo-4-chloro-3-indolyl-phosphate p-toluidine salt (Boehringer Mannheim GmbH), as described previously (28).
Deparaffinized sections were incubated for immunohistochemistry using Ab’s against alkaline phosphatase (LF-47), osteonectin (BON-1), osteopontin (LF-123), osteocalcin (LF-32), and bone sialoprotein (LF-83), kindly provided by Larry W.
Fisher (National Committee for Clinical Laboratory Studies, NIH, Department of Health and Human Services, Bethesda, Maryland, USA) (29). All antisera were used in an indirect immunoperoxidase protocol as described previously (30).
Isolation of human bone marrow stromal cells. Marrow stromal cell cultures were established as described previously (31). Briefly, cells were released by scraping bone marrow into nutrient medium consisting of α-MEM (Biofluids Inc., Rockville, Maryland, USA), 20% S (Life Technologies Inc.
, Gaithersburg, Maryland, USA), penicillin, streptomycin, and glutamine (Biofluids Inc.). Single cell suspensions were plated in 75-mm2 flasks (0.02 × 105–1.
7 × 105 nucleated cells/cm2) to generate multicolony-derived strains (by passaging all colonies together at day 10) or in Petri dishes (104 nucleated cells/100 mm2) to generate single colony–derived strains.
The medium used was the same as above, which supports proliferation rather than differentiation of stromal progenitors, as described previously (32). After 10–14 days, individual colonies were isolated using cloning cylinders and trypsin release and expanded in cell number (32).
After mutation analysis of gDNA by direct DNA sequencing, individual clonal lines were identified as normal or mutant. Multiple mutant clonal strains from each sample were combined to derive 100% mutant strains. Cell strains at the third passage were used for RT-PCR and ELISA analysis of FGF-23 production.
Isolation of human trabecular bone cells. Human trabecular bone (HTB) cells (osteoblast- cells) derived from normal and FD bone specimens were established in culture under IRB-approved procedures as described previously (33).
Briefly, fragments of trabecular bone were minced to the consistency of sand, washed extensively, and treated with bacterial collagenase (250 U/ml collagenase P; Boehringer Mannheim GmbH) to remove all soft tissue and associated cells. The collagenase-treated fragments were placed in low-calcium (0.
02mM) nutrient medium containing a 50:50 mixture of DMEM/Ham’s F-12 K with 10% S, glutamine, penicillin, and streptomycin. Cells grew from the fragments starting at 1–2 weeks and were passaged after reaching confluence at approximately 4 weeks. Cells were plated in the same medium, but with normal levels of calcium (1.
8 mM), for analysis of FGF-23 expression. These cells have been shown previously to have all characteristics of osteoblast- cells (33).
RT-PCR. Total RNA was isolated from both fresh FD tissue and cell strains using TRIzol (Sigma-Aldrich), and cDNA was generated using random primers and the SuperScript First-Strand Synthesis System (Invitrogen Life Technologies), both according to the manufacturers’ instructions.
The target cDNA sequence was amplified using two different primer sets. In the first set the forward primer was 5′-GTGCAGCGTCTGCAGCATG-3′ (bases 185–203), and the reverse primer was 5′-CCATGCAGAGGTATCTTCTG-3′ (bases 416–435).
In the second set, the forward primer was 5′-CACTGCCATCACATACTAAC-3′ (bases 2308–2327), and the reverse primer was 5′-ATACTGCCACATGACGAG-3′ (bases 2663–2680) (GenBank Accession no. 15055547). Standard PCR reactions were performed using reagents from the Perkin Elmer Kit and 2.5 units of Platinum Taq polymerase.
After 94°C for 5 minutes, the reaction was run for 30 cycles at 94°C, 55°C, and 72°C for 45 seconds at each temperature, with a final extension at 72°C for 5 minutes, which generated a 251-bp amplification product from the first primer set, and 94°C, 49°C, 72°C for 45 seconds at each temperature, with final extension at 72°C for 5 minutes, which generated a 373-bp amplification product from the second primer set. All amplification products were verified by DNA sequencing.
ELISA analysis. Conditioned medium was generated by near-confluent cultures of normal and mutant stromal cells and HTB cells maintained in serum-free α-MEM.
Media samples were collected at 24 hours and frozen at –80°C until analysis by ELISA, using a commercially available two-site ELISA for the FGF-23 C terminus according to the manufacturer’s instructions (Immutopics International, San Clemente, California, USA).
In additional experiments, normal stromal cells and normal human osteoblast- cells were treated with serum-free medium containing 1 mM dibutyryl cAMP (Sigma-Aldrich) (28), and medium was collected 24 hours later.
Serum measurements. Sera from 49 FD patients (21 pediatric patients, younger than 18 years old; 28 adult patients, older than 18 years old) were assayed for FGF-23 activity using a commercially available two-site ELISA for the FGF-23 C terminus, according to the manufacturer’s instructions (Immutopics International).
As a control, FGF-23 was also measured in sera of normal pediatric (younger than 18 years, n = 79) and adult donors (older than 18 years, n = 204).
Statistical analysis was performed using ANOVA and the Scheffe F test; regression analysis was used to determine potential correlations between serum levels of FGF-23 and other metabolic parameters.
TmP/GFR and serum phosphate determination. Renal phosphate handling was assessed by calculating the TmP/GFR using serum samples obtained after an overnight fast and urine samples from 24-hour urine collections, using an adaptation of the technique and nomogram of Walton and Bijovet (24, 34, 35).
Patients were considered to have normal excretion of phosphate in the urine (non–phosphate wasters, NPW) or renal phosphate wasting (phosphate wasters, PW) if their value of TmP/GFR was higher or lower, respectively, than the lower limit of the age- and gender-specific normal range (36).
Twenty-four–hour urine samples were used to determine TmP/GFR after having determined that calculation of TmP/GFR using fasting second-morning voided urine specimens and aliquots from 24-hour urine samples generates virtually identical values consistently on the same side of the lower limit of the range for each patient.
Serum phosphate was determined for each patient and compared in the groups of adult and pediatric NPW and PW patients.
Assessment of disease burden. To test whether phosphate wasting and FGF-23 concentrations are correlated to disease burden, we assessed disease burden in all patients, using a validated tool that calculates the percentage of the skeleton involved with FD (Chen, C., et al., manuscript submitted for publication).
This technique takes advantage of the fact the FD is avid for 99Tc-MDP. All patients underwent 99Tc-MDP bone scintigraphy, and the scans were assessed as to the relative amount of each segment of the skeleton that incorporated the isotope.
These segments were then normalized relative to the percentage of the total skeleton that each segment represents. These values were then summed, and a value was generated that represents the amount of the skeleton involved with FD, that is, disease burden.
In addition, conventional markers of bone turnover, commonly taken as indices of disease extent and activity in FD (27, 37), were also assessed by standard commercially available techniques.
Fibrous Dysplasia Market Research Report- Forecast to 2023 | MRFR
ID: MRFR/Pharma/3354-HCR | | Region: Global | 120 pages
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Fibrous Dysplasia Market Information: By Diagnosis (X-Rays, CT Scans, MRI, Bone Scan, Biopsy), Treatment (Medication (Bisphosphonates, Intravenous Pamidronate), Surgical), End User (Hospitals & Clinics, Research Centers) – Global Forecast Till 2023
Fibrous dysplasia is a rare and chronic bone disorder in which fibrous tissue develops in place of normal bone, weakens the affected bone, and deform or fracture it.
As per reports from The Johns Hopkins University, the exact cause of fibrous dysplasia is unknown, but it is believed to be due to a chemical irregularity in a specific bone protein.
This bone protein abnormality may arise due to a gene mutation present at birth, although it is not known to be an inherited disorder.
It often results in uneven growth of bones, pain, brittle bones, and bone deformity. In fibrous dysplasia, the most commonly affected bones includes femur (thighbone), tibia (shin bone), ribs, skull, facial bones, humerus (the bone of the upper arm), pelvis, vertebrae in the spine (less often).
The fibrous dysplasia market growth is majorly attributed to the increasing prevalence of the bone disorders. Moreover, some cases of fibrous dysplasia leads to cancer, which is ly to drive the market growth.
Currently, no cure is available for fibrous dysplasia. However, present treatment methods helps to prevent complications, such as recurrent bone fractures to help make the condition less severe.
According to reports from International Osteoporosis Foundation, Each year an estimated 1.5 million individuals suffer a fracture due to bone disease. The risk of a fracture increases with age and is more in women.
Furthermore, globalization in healthcare has increased the market growth.
Established market players in the developed countries leads the globalization by pushing new products and services into developing countries and emerging economies.
However, high cost of the current treatment methods and lack of alternative methods for the treatment of fibrous dysplasia may slow the market growth during the forecast period.
The global fibrous dysplasia market is expected to grow at a CAGR of ~6.2 % during the forecast period 2017-2023.
- Pharmaceutical Companies
- Research and Development (R&D) Companies
- Government Research Institute
- Academic Institutes and Universities
- Medical Research Laboratories
- Market Research and Consulting Service Providers
- Potential Investors
Figure: Global Fibrous Dysplasia Market, By Region Market Share, 2016 (%)
Sources: Annual reports, Press release, White paper, Company presentation
The global fibrous dysplasia market is segmented on the basis by diagnosis, by treatment, and by end user.
On the basis of diagnosis, it is segmented into X-rays, CT scans, MRI, bone scan, biopsy, and others.
On the basis of treatment, it is segmented into medications, surgical, and others. The medications is further segmented into bisphosphonates, intravenous (IV) pamidronate, calcitonin, raloxifene, and others
On the basis of the end user, it is segmented into hospitals & clinics, research centers, and others.
The Americas dominate the global fibrous dysplasia market owing to well-developed technology, increasing patient with bone disorders, high healthcare spending, and increasing government support for research & development. Furthermore, increased R&D activities and the concentration of major companies have fuelled the growth of the market in this region.
Europe holds the second position in the global fibrous dysplasia market owing to the government support for research & development and availability of funds for research. This is expected to continue to drive the European market over the forecasted period.
Asia Pacific is the fastest growing market owing to the presence of rapidly developing healthcare technology, increasing patient population, and high healthcare expenditure.
Moreover, increasing demand for new treatment methods in countries such as India is ly to emerge as the fastest growing market across the globe.
Furthermore, increasing demand for quality devices in the healthcare is projected to lead to the use of advanced equipment, which, in turn, may increase the market growth of the fibrous dysplasia in the region.
On the other hand, the Middle East & Africa holds the least share of the global fibrous dysplasia market due to limited screening, ignorance of diseases, and poor access to treatment, especially, in African region. Majority of the market of this region is held by the Middle East due to a well-developed healthcare sector and huge healthcare expenditure.
Some of key the players in the market are Novartis AG, Pfizer Inc, Amgen Inc, AVEO Pharmaceuticals Inc, Bayer AG, Bellicum Pharmaceuticals Inc, MediaPharma srl, Merck & Co., Inc, Merrimack Pharmaceuticals Inc, Oncolys BioPharma Inc, United Therapeutics Corp and others.
Sources: Annual reports, Press release, White paper, and Company presentation