Fibrous Dysplasia of bone (FD) is a common clinical tumor-like lesion characterized by the formation of fibrous tissue and woven bone in areas of normal bone, resulting in bone fragility, various deformities and susceptibility to fracture. Simple scraping and bone grafting is a common clinical method, but the amount of bone grafting is large and prone to pathological fractures and has a certain recurrence rate. Current basic research has confirmed [1] that osteoclasts are activated and cause bone destruction in the tissues of patients with osteochondrodysplasia. Therefore, inhibition of osteoclast overactivity is a target for the treatment of this disease, and diphosphonates are the most important group of drugs available for the clinical treatment of osteoclast-mediated diseases characterized by bone resorption [2]. The effectiveness of this class of drugs in the treatment of abnormal bone fibrous proliferation disorders has been reported abroad [3], but has not been reported in China. From June 2008 to March 2010, we prospectively observed eight patients with osteochondrodysplasia with the treatment of bisphosphonates in order to further clarify the therapeutic effect of this drug. Yu Xiu-chun, Department of Orthopedics, General Hospital of Jinan Military Region
Materials and methods
I. General data
From June 2008 to March 2010, a total of 8 patients with abnormal bone fiber proliferation disease were included in this study (6 patients had a history of surgery and were diagnosed by pathology, and 2 patients had no history of surgery and were diagnosed by clinical and imaging manifestations). There were 2 males and 6 females; ages ranged from 8 to 59 years, with a mean age of 27.6 years. Site of onset: 7 cases with multiple and 1 case with single lesions. The clinical data are detailed in Table 1.
II. Methods
1.Pharmacological treatment
According to the foreign literature, the treatment regimen consists of intravenous pamidronate disodium and oral alendronate tablets [4]. In adults, 60 mg of pamidronate disodium was applied once for more than 4 hours, and in children, 1 mg/kg per drip for 3 days, every 3 months, for 1 to 2 years depending on the development of the disease; in between the application of pamidronate disodium, 10 mg/day of alendronate tablets were administered orally. In one patient with a single lesion on the left tibia, oral alendronate tablets 10mg/day alone was administered for 1 year.
2.Surgical treatment
In the three patients who presented with pathological fractures, two had closed reduction and external fixation, and one had incisional reduction, local implantation of artificial bone and internal fixation, all without tumor scraping, and postoperative systemic diphosphonate drug treatment. In the other 3 patients who had scraping and implantation, 2 patients had recurrence after surgery and were not operated, and were treated with diphosphonates alone; 1 patient had proximal femur deformity after surgery, and was treated with diphosphonates after osteotomy and orthopedics.
3.Effective observation
(1) Pain The patients’ bone pain grading and activity improvement were observed before treatment and at the end of the treatment course. The degree of bone pain grading: according to WHO grading standard: Grade 0: no pain; Grade I: pain but tolerable, and can live normally, sleep is not disturbed; Grade II: pain is obvious, not tolerable, requires analgesics, sleep is disturbed; Grade III: pain is severe and not tolerable, requires analgesics, sleep is seriously disturbed. Evaluation criteria of pain relief efficacy: effective: pain grading standard decreased by two grades; effective: pain grading standard decreased by one grade; ineffective: pain grading standard did not decrease or increased.
(2) Bone metabolic indexes.
Carboxy-terminal telopeptide of type I collagen (ICTP): 7 patients were tested before and after treatment by radioimmunoassay, with normal reference values of 0.158-0.442ug/L and intra-batch variation coefficient of 6.2% and inter-batch variation coefficient of 7.9%.
Osteocalcin (OC): 7 patients were tested before and after treatment, using radioimmunoassay, with normal reference values of 0-0ug/ L, intra-batch variation coefficient of 3.2% and inter-batch variation coefficient of 5.8%.
(3) X-ray performance
X-ray films of the lesions were routinely taken before and after treatment to observe whether the extent of osteolysis was reduced, whether the bone cortex was thickened, and whether the pathological fractures were healed.
4.Statistical processing
Firstly, each bone conversion biochemical index was tested for normality, showing that ICTP and OC values were normally distributed and expressed as x±s. Paired t-test was used to compare the same patients before and after treatment. Statistical processing was performed using SPSS 12.0 software.
Results
1. Bone pain relief and improvement of activity function: patients’ bone pain was significantly relieved after the application of diphosphonates, and the bone pain score decreased from grade 3 to grade 1 in one case and from grade 2 to grade 0 in two cases; 2 cases decreased from grade 1 to grade 0; and one case decreased from grade 2 to grade 1. The activity function improved significantly.
2. Changes in bone metabolic indexes: The mean values of blood OC and ICTP before treatment were 223.10±124.77 ug/L and 1.74±0.90 ug/L in 7 patients, respectively; the mean values after treatment were 168.81±97.15 ug/L and 1.21±0.48 ug/L, respectively, which were higher than the normal reference values. After paired t-test, serum OC was significantly reduced after treatment (P=0.03), which was statistically significant. There was no significant change in serum ICTP after treatment (P=0.059).
3, X-ray changes: X-ray films of 8 patients after drug treatment showed varying degrees of bone volume increase, osteolysis area reduction, and bone cortex thickening (Figure 1, 2). 3 patients who developed pathological fractures showed blurred fracture lines, continuous bone cortex, and fracture healing on average 4 months after surgery (Figure 3).
4. adverse drug reactions: 2 cases had fever of 37.3~38.5 ℃ on the next day after the first drip of pamidronate disodium, which gradually subsided after the administration of dexamethasone injection 5 mg in 500 ml of 0.9% saline. 2 patients developed upper gastrointestinal symptoms such as acid reflux and heartburn after oral administration of alendronate, which disappeared after discontinuation of the drug. 8 patients had liver function, blood biochemistry, and peripheral blood leukocytes and erythrocytes checked before and after the administration of the drug. The liver function, blood biochemistry and peripheral blood leukocyte, red blood cell and platelet counts of the eight patients were checked before and after the administration of the drug, and no abnormalities were found.
Discussion
1. Treatment of osteochondrodysplasia and drug selection
The etiology of osteochondrodysplasia is not very clear. Most people believe that it is an abnormal bone development, that is, during embryonic development, normal bone tissue and bone marrow tissue are replaced by a large amount of abnormally proliferating fibrous tissue, causing the normal bone tissue to be dissolved. Others believe that the bone is not mature, but rather stagnates at the weaving stage, allowing infantile tissue in the fibrous matrix to replace normal bone tissue, preventing it from forming normal bone trabeculae. For patients with a single occurrence and a small extent of erosion, they can be treated by scraping and inactivating bone grafting. However, for patients with multiple occurrences, extensive lesions or postoperative recurrence, and the presence of pathological fractures, clinical treatment is very difficult, and if treated by scraping and inactivation osteotomy alone, a large number of bone grafting is required, which is prone to pathological fractures and has a certain recurrence rate.
The mutation theory, which is widely accepted, has found that in most patients with osteochondrodysplasia, there are mutations in the active site of the Gsα (G protein present on the cell membrane, i.e., coupling protein) gene, resulting in enhanced adenylate cyclase activity and increased intracellular cyclic adenosine phosphate and interleukin-6, which induce a large amount of abnormal fibrous tissue proliferation, while cyclic adenosine phosphate and interleukin-6 activates osteoclasts, causing bone destruction. Inhibition of osteoclast overactivity is the key to the treatment of this disease, and diphosphonates are the most important group of drugs available for the treatment of osteoclast-mediated diseases characterized by bone resorption.
Pamidronate disodium and alendronate sodium are second-generation bisphosphonate agents, which have selective adsorption effects on bone tissue, leading to morphological changes in osteoclasts by preventing the dissolution of hydroxyapatite, thus directly and strongly inhibiting osteoclast activity and controlling bone destruction: it can also inhibit various mediators, such as inhibiting acid production, controlling prostaglandin synthesis and lysosome release, thereby indirectly reducing osteoclast activity. This indirectly reduces the activity of osteoclasts and inhibits bone resorption to reduce pain. These drugs have a strong adsorption of calcium and bone minerals, which are mainly distributed in the bone without affecting the normal metabolism of minerals in bone tissue. Among them, disodium pamidronate has a strong inhibitory effect on bone resorption, and most of it is deposited in bone after entering the body, with a half-life of up to 300 d in bone, and a long maintenance time for a single dose, which is convenient for clinical use. Since 1994, when Liens et al [3] first reported the definite effect of intravenous pamidronate disodium in the treatment of abnormal bone fibrous proliferation disorder, diphosphonates have been widely used. chapurlat et al [5] treated 58 patients with bulk FD with intravenous pamidronate disodium, with a mean follow-up of 50 months, including 12 patients with a follow-up of more than 8 years. The authors found a significant reduction in pain and a significant decrease in bone conversion biochemical parameters after treatment in 44 patients with pain, and an increase in bone mineral density in all 12 patients with hip FD. Muriel et al [6] performed a mean follow-up of 6.9 years in 7 patients who had been on pamidronate disodium for more than 3 years, and all patients had a reduction in bone pain and an increase in bone mineral density, with no new pathological fractures and a good treatment outcome. Lane et al [4] applied oral alendronate tablets and intravenous pamidronate disodium to six patients with abnormal bone fiber proliferation disorder, and the authors concluded that the combination of the two diphosphonates provided significant pain relief, increased bone mineral density, and prevented pathological fractures. In this prospective study, eight patients were treated with intravenous pamidronate disodium (120-180 mg) every 3 months and oral alendronate tablets 10 mg/day during this period. 7 patients had significant reduction in bone pain after 3 months, and 5 of them had disappeared. 3 patients with pathological fractures were operated and administered with bisphosphonates, and the fracture line was blurred, the bone cortex was continuous, and the fracture healed at an average of 4 months after surgery. In one patient with recurrence after scraping bone grafting, no surgical treatment was given and oral alendronate tablets of 10 mg/day were administered for 12 months, and the bone in the original destruction area in the medullary cavity was significantly sclerotic on re-examination. 8 patients did not develop pathological fractures after the application of bisphosphonates.
2. Monitoring the efficacy of osteochondrodysplasia
Although the diagnosis of osteochondrodysplasia does not depend on bone conversion biochemical indexes, bone conversion biochemical indexes can reflect the degree of disease activity. The selection of sensitive bone turnover biochemical indexes can not only determine the patient’s response to treatment at an early stage, but also guide the selection of drug treatment dosage. Osteocalcin (OC) is a non-collagenous protein produced and secreted by osteoblasts, mostly deposited in the bone matrix, with a small portion entering the circulation. When the bone matrix is degraded, the osteocalcin in it enters the circulation. Measurement of osteocalcin in blood therefore reflects the activity of osteoblasts on the one hand, but to a greater extent the extent of bone resorption.Zacharin et al [7] administered pamidronate disodium 1 mg/kg/d intravenously for 3 days every 6 months for 2 years in 8 patients with multiple osteochondrodysplasia. Osteocalcin decreased from 35.5±5.6 μg/L to 28.4±4.1 μg/L, with a statistically significant difference. This study also showed a statistically significant decrease in serum OC after treatment (P=0.03). This indicates that the application of bisphosphonates is effective in reducing bone turnover in patients with FD.
Carboxy-terminal telopeptide of type I collagen (ICTP) is a degradation product of type I collagen, and the peptide is released into the serum intact during the degradation of type I collagen. In cases of accelerated bone destruction, serum ICTP concentrations are elevated. There are very few reports on the changes in serum ICTP after the application of bisphosphonates in patients with abnormal bone fibrous proliferation, Kitagawa et al [1] applied alendronate orally to a patient and serum ICTP remained at a low level with no change (4.1 ng/ml) after 2 years. koizumi et al [8] applied bisphosphonates to 15 patients with bone metastases from breast cancer treatment, and there was no significant change in serum ICTP after treatment. The mean values of blood ICTP before and after treatment were classified as 1.74±0.90 ug/L and 1.21±0.48 ug/L in our group of 7 patients, which were slightly higher than the normal reference values, but there was no significant change after treatment (P=0.059), which is consistent with the literature. This indicates that the search for a more effective indicator of bone resorption needs to be continued.
Dynamic imaging of the patients allowed the observation of reduced extent of osteolysis and thickening of the bone cortex at the lesion site. Chapurlat et al [9] treated 20 patients with FD with intravenous pamidronate disodium at a mean follow-up of 39 months and performed X-ray examinations of the lesion site. Chapurlat et al [5] followed up 50 patients with FD who had X-ray data and found significant improvement in 27 (54%) of them.
3. Adverse effects
Foreign studies have not found serious adverse effects with the application of bisphosphonates [5]. Adverse reactions reported with pamidronate disodium include mild to moderate transient fever, often with myalgia, with an incidence of 25-30%, usually occurring on the day of administration and often relieved by acetaminophen. Occasionally, transient asymptomatic blood leukopenia or lymphocytopenia may occur. Adverse reactions of alendronate are mainly acid reflux, heartburn, abdominal pain and other upper gastrointestinal symptoms [1], and only minor adverse reactions such as hypothermia, acid reflux and heartburn occurred in our group. The symptoms disappeared after symptomatic treatment, suggesting the good safety of the drug.
In conclusion, the results of our prospective observations indicate that the application of bisphosphonates for the treatment of abnormal bone fiber proliferation disease can reduce pain, decrease osteolytic destruction and prevent fracture risk in patients with more significant efficacy. Adverse effects are mild and transient. It is especially suitable for patients with extensive lesions and multiple lesions that are difficult to operate. Due to the limited number of cases and follow-up time in this group, the long-term efficacy of patients needs to be further studied in depth by increasing the number of cases and follow-up time.