Effect of intravenous pamidronate on bone markers and local bone mineral density in fibrous dysplasia

Bisphosphonates have proven to be effective in patients with fibrous dysplasia of the bone (FD) as shown by their effect on bone pain, markers of bone turnover, or radiological changes. The aim of this study was to evaluate the usefulness of measuring bone mineral density (BMD) of affected bones to assess the efficacy of bisphosphonate treatment. Seven patients (mean age 26 years) received courses of 180 mg intravenous infusion of pamidronate every 6 months (60 mg/day during 3 days). Clinical symptoms, serum alkaline phosphatase, and urinary C-terminal cross-linking telopeptide of type I collagen were assessed every 3 months. BMD of total skeleton and X-rays of FD areas (FDa) were performed at baseline and at 12 months. BMD of FDa was compared with the contralateral side (CL) using the region of interest program on the total skeleton scan. BMD of total skeleton was normal at baseline. Average BMD of FDa was -11.4% compared with CL, a significantly greater difference than that observed between the left and right sides in healthy controls, -0.7% (P < 0.02). At 12 months bone pain diminished in all patients. Bone turnover markers decreased. Mean total skeleton BMD increased 3.3% (P < 0.02). Subregions of the total skeleton scan presenting FD lesions augmented: arms +9.6% (P < 0.02), legs +4.2%, and pelvis +3.5% (P < 0.05). The increase in mean BMD of FDa was +6.8% compared with +2.6% in CL. No changes were observed on the X-ray. These results indicate that simultaneous determination of markers of bone turnover and BMD of FDa is useful in short-term follow-up to determine the efficacy of intravenous pamidronate.     

Bone turnover in children and adolescents with McCune-Albright syndrome treated with pamidronate for bone fibrous dysplasia

Bone fibrous dysplasia is one of the main features of McCune-Albright syndrome, a rare genetic condition caused by constitutive activating mutations of Gs-protein and defined by skin dysplasia, bone fibrous dysplasia, and autonomous multiple endocrinopathies. Raised serum alkaline phosphatase (ALP) and urinary hydroxyproline levels indicating bone metabolic hyperactivity have been reported in these patients. Encouraging therapeutic results have been achieved, mainly in adults, with pamidronate, an aminobisphosphonate. In this study we investigate newer bone metabolic indices in a cohort of 11 children and adolescents treated with pamidronate. Tenfold increases of bone ALP and urinary pyridinoline cross-links were found and osteocalcin levels were twofold higher compared with reference values. After treatment, significant decreases in bone ALP and cross-links (Wilcoxon test P < 0.06) were found. Bone mineral density (BMD) significantly increased during treatment. There were signs of radiological healing as thickening of the cortical bone was found in some cases.     

Surgical reconstruction of fibrous dysplasia of bone in long-term follow-up

PURPOSE: To examine how different operative measures influence the surgical outcome in patients with fibrous dysplasia of bone. METHODS: 118 dysplastic fibrous lesions of bone were surgically treated and reviewed in 70 patients between 1983 to 1993 (eleven years) with a median follow-up of six and a half years. Surgery consisted of intralesional curettage in 93 and marginal en bloc resection in 25 lesions. Bony defects were reconstructed with autogenous iliac crest graft in 55 lesions, with autogenous fibula graft in 9, with homologous bone chips in 28, and 5 times with a homologous fibula graft from the bone bank. In 33 lesions the entire defect was filled with polymethylmethacrylate. Osteosynthesis was performed in 41 patients. RESULTS: Recurrences requiring surgical revision were observed in 26 of 74 primary lesions (= 35% overall recurrence rate) at a mean 123.6 weeks postoperatively. The most frequent primary and recurrence location was the proximal femur (85% revision rate). 69% of all recurrences occurred under the age of 20. After intralesional curettage the reoperation rate was 32% and after marginal resection 8%. After reconstruction with autogenous iliac crest graft recurrence rate was 36%, after autogenous fibula graft 55%, after homologous bone chips 18%, after polymethylmethacrylate 9% and allograft fibula reconstruction showed no recurrences. A combined stable osteosynthesis bridging the fibrous osseous defect significantly reduced the revision rate to 3% (p = 0.01). CONCLUSION: Intralesional curettage and reconstruction with autogenous iliac crest graft in fibrous dysplasia of bone leads to a high recurrence rate. Reconstruction with cortical grafts or bone chips from the bone bank, if necessary in combination with a durable osteosynthesis in mechanically demanding locations, or solely bone cement in mechanically less demanding areas, reduces the revision rate in patients with monoostotic and polyostotic fibrous dysplasia.     

Bone mineral density response to long-term bisphosphonate therapy in fibrous dysplasia.

Fibrous dysplasia of bone is a rare disease related to a genetic mutation in which bone formation at osseous sites is altered. In the last few years, bisphosphonates have become one of the choice drugs to treat this disease. A 26-yr-old woman presented after 6 wk of spontaneous right leg pain owing to a fissure fracture of the right femoral neck. She reported precocious puberty at the age of 2, with diagnosis of McCune-Albright syndrome. Radioisotope bone scanning, radiographic, biochemical, and densitometric studies were performed. Treatment with bisphosphonates was started because bone turnover biochemical markers were abnormal. Oral olpadronate followed by iv pamidronate substantially decreased bone resorption. Bone mineral density (BMD) of total skeleton and subareas was assessed by dual X-ray absorptiometry (DXA) throughout the 5 yr of treatment. At the end of this period, BMD of the total skeleton had increased 6.2%. However, BMD of the areas most affected by fibrous dysplasia, the legs and pelvis, had increased 12.7 and 11%, respectively. Region of interest analysis of individual bones of the legs performed with the total skeleton scan revealed that BMD of the areas most affected by fibrous dysplasia was lower than that of the less affected contralateral bones. During the first 3 yr, treatment with bisphosphonates substantially increased BMD of the right femur and tibia (22 and 28%, respectively). After that, values seemed to stabilize. DXA evaluation of the total skeleton and its subareas was useful to evaluate the efficacy of bisphosphonate treatment. Moreover, the plateau observed in BMD values after 3 yr of treatment suggests that treatment could have been discontinued when the densitometric values stabilized.     

Bisphosphonates and bone remodeling: effectiveness in Paget's disease, fibrous dysplasia and osteoporosis

Paget's disease of bone, bone fibrous dysplasia and osteoporosis are characterized by abnormal bone remodeling, and frequently imply intervention of orthopedists. Recent significant medical therapeutics improvements have been obtained with the use of bisphosphonates. Theses drugs decrease bone remodeling. In Paget's disease, bisphosphonates relieve bone pain, allow lytic areas refilling and decrease complications risk with normal bone formation. In fibrous dysplasia, bone pain is alleviated, osteolytic areas are refilled and cortices are widened. In postmenopausal osteoporosis, bisphosphonates increase bone mineral density, and reduce very significantly the subsequent risk of vertebral, femoral and lower forearm fractures. Bisphosphonates are a breakthrough in Paget's disease of bone, fibrous dysplasia of bone and osteoporosis.     

Rapid biochemical response to denosumab in fibrous dysplasia of bone: report of two cases

We report on the clinical and biochemical outcomes in two adult patients with active polyostotic fibrous dysplasia (FD) treated with the RANK-L inhibitor, denosumab, following unsatisfactory responses to prior long-term bisphosphonate therapy. A 44-year-old female (case 1) who had received a cumulative dose of 20 mg zoledronic acid over 2.5 years and a 48-year-old male (case 2) who had received a cumulative dose of 45 mg zoledronic acid over 8 years both experienced minimal reductions in pain scores and markers of bone turnover. Following initiation of denosumab 60 mg sc, changes in bone pain, bone turnover [assessed by serum amino-terminal propeptide of type I collagen (PINP) and urinary deoxypyridinoline] were monitored over a period of 20 and 8 months, respectively. Following administration of denosumab, both patients demonstrated a rapid and pronounced biochemical response: Within 4–7 weeks, bone turnover markers fell to levels within the respective reference range, and one patient reported a reduction in pain. Treatment with denosumab was well tolerated. However, transient asymptomatic hypocalcaemia and/or hypophosphatemia associated with a transient two to threefold increase in serum PTH levels was observed in both patients. Dosing intervals for denosumab varied significantly between the two patients, depending on disease activity at baseline. Denosumab appears to be effective in reducing bone turnover in adult patients with active FD. However, caution should be exercised, and patients should be monitored carefully as significant fluctuations in biochemical and hormonal indices can occur.     

Nephronophthisis-like nephritis associated with fibrous dysplasia of bone

Nephronophthisis is a chronic tubulointerstitial nephritis with autosomal recessive inheritance whose evolution to end-stage renal disease is insidious but constant. Fibrous dysplasia of bone is characterized by focal replacement of normal bone and marrow with abnormal bone and fibrous tissue. We report on a young boy initially diagnosed with fibrous dysplasia of bone, who underwent renal investigation because of treatment with pamidronate. He presented with mild proteinuria (albuminuria/creatininuria 19 mg/mmol) and decreased glomerular filtration rate (GFR) (79 ml/min per 1.73 m(2) body surface area) leading to kidney biopsy, which showed nephronophthisis-like lesions, but neither NPHP1 gene deletion nor UMOD (uromodulin) mutation were identified. No association between fibrous dysplasia of bone and nephronophthisis has yet been described. Nephronophthisis-like nephritis associated with fibrous dysplasia of bone might represent a possible new syndrome in the nephronophthisis and medullary cystic kidney disease complex. However, a fortuitous association between these two conditions is also possible.     

Long-term treatment of osteoporotic women with bisphosphonates does not impair the response to subsequently administered intravenous pamidronate

Summary

We addressed the question whether the response of osteoporotic patients to bisphosphonate treatment is reduced with time. Bisphosphonate-treated women with postmenopausal or glucocorticoid-induced osteoporosis showed adequate and consistent changes of bone markers to subsequently administered intravenous pamidronate. Response of osteoporotic patients to bisphosphonates is not impaired during their long-term administration.

Introduction

Inadequate response to bisphosphonate treatment has been described in patients with Paget’s disease of bone but has not been addressed in osteoporosis although treatment failure is a clinically relevant problem.

Methods

Twenty one women with postmenopausal osteoporosis (PMO) aged 68?±?8.2 years and 14 women with glucocorticoid-induced osteoporosis (GIOP) aged 65?±?10 years were treated with tri-monthly intravenous infusions of 45 mg of pamidronate for 1 year. All patients had been previously treated with bisphosphonates (alendronate, risedronate, pamidronate) for a mean period of 6.2 years (range, 1.3–14 years). Blood samples were taken for measurement of the bone resorption marker C-terminal crosslinking telopeptide of type I collagen (CTX-I) on days?1 and 4 and of the bone formation marker procollagen type I N propeptide, (P1NP) on day?1 of every tri-monthly treatment course.

Results

With each treatment course there was a significant decrease in serum CTX-I on day?4 and an increase to baseline values 3 months after each infusion in both PMO (mean values, day?1: 291.33?±?160.78 pg/ml vs. day?4: 131?±?91.7 pg/ml, p?<?0.001) and GIOP (day?1: 219.3?±?114.8 pg/ml vs. day?4: 98.8?±?51.6 pg/ml, p?<?0.001). Serum P1NP remained stable during the whole year of treatment.

Conclusions

Long-term bisphosphonate treatment of women with either PMO or GIOP does not impair the response to subsequently administered intravenous pamidronate suggesting that inadequate response to long-term bisphosphonate treatment is not responsible for treatment failure.     

Mazabraud's syndrome: intramuscular myxoma associated with fibrous dysplasia of bone

A 53 year old male with a large swelling on the medial aspect of his right thigh was referred with a presumptive diagnosis of soft tissue sarcoma. However, biopsy revealed intramuscular myxoma and X-rays and CT scans suggested fibrous dysplasia of adjacent bone. Angiography had shown an expanded, hypervascular, intramedullary lesion in the femur, and a large avascular soft tissue mass lying medially in the distal thigh. Fibrous dysplasia of the femur was confirmed on bone biopsy. Subsequently one large and two smaller intramuscular myxomata were excised, with an uneventful postoperative course. This case illustrates Mazabraud's syndrome: the rare association between benign intramuscular myxoma and fibrous dysplasia of bone.     

Chronic idiopathic hyperphosphatasia: normalization of bone turnover with cyclical intravenous pamidronate therapy

Chronic idiopathic hyperphosphatasia (CIH), or juvenile Paget disease, is a rare disorder characterized by increased bone turnover and progressive enlargement of bones. We report a girl, 6 1/2 years old, with a history of three fractures, short stature, delayed eruption of teeth, and poor hair growth. She had a waddling gait, bone deformities, kyphoscoliosis, hyperlordosis, genu valgum and curvature of her limbs. She also had progressive hearing loss but other cranial nerves were unaffected. Laboratory studies indicated high bone turnover: serum alkaline phosphatase: 4047 IU/l (normal value: 150-550), urinary hydroxyproline: 1205 mg/g creatinine (n.v.: 60-160), and urinary CrossLaps: 4360 microg/mmol creatinine (n.v.: 450-2100). Radiographs demonstrated generalized skeletal involvement with osteoectasia (expansion) of long bones, diffuse sclerosis, cotton wool appearance of the skull, absence of mastoid pneumatization, and crushed dorsal and lumbar vertebrae. Iliac crest biopsy was compatible with CIH. Cyclical intravenous pamidronate (1 mg/kg/day during 3 h, 3 consecutive days at 2- to 3-month intervals) was administered during 2 years with oral calcium 500 mg and vitamin D 1000 IU/day. Oral pamidronate was added after 11 months of i.v. therapy. Treatment-induced remarkable clinical and radiographic improvement with normalization of bone markers of osteoblastic and osteoclastic activity, including bone alkaline phosphatase, urinary hydroxyproline, and urinary CrossLaps.     

带骨膜腓骨治疗桡骨骨纤维异常增殖症严重骨缺损1例

骨纤维异常增殖症是以病理纤维增殖为基础的良性病变,早在1891年Von Reck inghcuson首先发现本病,直到1942年L ichtenste in与Teffe才正式命名为骨纤维异常增殖症[1]。本病可单发或多发,多发者治疗较困难。在处理骨缺损上方法比较多,笔者曾治疗1例单发于桡骨中上段的骨纤维异常     

股骨纤维结构不良伴重度内翻畸形的外科治疗

[目的]探索一种治疗股骨纤维结构不良伴重度髋或及股内翻畸形的有效外科方法。[方法]自2000年8月~2005年7月共收治13例14个股骨纤维结构不良伴重度髋或及股内翻畸形患者,均采用股骨单处或双处外翻截骨矫形、病灶刮除、打压植骨、重建钉内固定治疗。[结果]所有病人随访8~41个月(平均21个月)。X线显示,14个股内翻畸形股骨力线几乎完全矫正;髋内翻畸形的颈干角由术前平均75°(55°~100°)矫正为术后120°(95°~130°);股骨相对长度由术前平均短缩3.4 cm(2.0~4.5 cm),矫正后延长2.8 cm(1.8~3.6 cm);14个股骨共19处截骨面均达骨性愈合。所有患者植骨区于术后3个月均有不同程度的吸收,术后10~14个月最明显。术前4例患者扶双拐行走,2例扶单杖行走,5例病理性骨折不能行走,2例不扶杖跛行;术后11例患者不扶拐行走,2例扶单杖行走。11例患者疼痛消失,2例疼痛明显减轻。所有患者无感染、畸形进展及再骨折。[结论](1)该治疗方法能够有效的矫正股骨畸形,恢复股骨生物力学力线,改善患肢功能;(2)能有效的去除病变,防止复发;(3)股骨髓腔内大量打压式植骨是促进骨愈合及防止病理性骨折的关键。     

Orthopedic management in children with fibrous dysplasia of bone]

The method and results of treatment in 9 children with fibrous dysplasia of bone and 3 children with Albright syndrome are presented. Curettage and filling of the defect with autologous and/or lyophilized grafts failed in all 5 attempted cases. Due to pathological fracture or deformity Rush nailing combined with multilevel osteotomies has been performed within 5 femoral bones and 4 tibial bones. Healing was undisturbed, neither fracture nor deformity recurred. Valgus osteotomy has been done in 2 children with pseudoarthrosis of the femoral neck. In one case osteotomy healed, in another bony union is not completed yet but the neck-shaft angle remained unchanged. In authors' opinion curettage and grafting proved ineffective; Rush nailing rendered good results in both fracture and deformity treatment.     

Current approach to fibrous dysplasia of bone and McCune–Albright syndrome

Fibrous dysplasia (FD) of bone is an uncommon disease caused by sporadic, congenital mutations in the cAMP regulating protein, G_sα. It is an example of somatic mosaicism in which a wide spectrum of disease is possible. Widespread skeletal involvement is often associated with varying combinations of café-au-lait skin spots, and/or endocrine dysfunction (precocious puberty, renal phosphate wasting, hyperthyroidism, and/or growth hormone excess). Unrecognized and untreated endocrine dysfunction can exacerbate the skeletal disease. The diagnosis is usually established on clinical grounds on the basis of physical examination and typical radiographic appearance. Occasionally, gene testing of affected tissue may be helpful. The skeletal sites involved with disease are established at an early age, and the complications of fracture deformity are most pronounced in childhood. Bone pain in the absence of a fracture is more common in adults, but can also be present in children. Treatment with bisphosphonates is usually effective at relieving pain, but probably has no effect on the natural history of the disease. Scoliosis, which was previously thought to be an uncommon occurrence, has been shown to be common and progressive, and as such, warrants investigation and, when necessary, surgical treatment. The surgical management of FD remains challenging. Timing and technique remain controversial, but some consensus exists in that grafting materials (of any type) usually fail and should not be a central aspect of the surgical approach. Intramedullary devices are in general superior to side plates and screws. In extremely widespread disease with very early fracture and deformity, no surgical approach will affect final functional outcome. Efforts should be made for the initiation of international collaborative studies to better define optimal surgical approaches to the treatment of this challenging disease.     

Treatment of bony fibrous dysplasia with calcium-phosphate cement: a case report

We report successful use of calcium-phosphate cement for the treatment of benign polyostotic fibrous dysplasia in a patient who had undergone several unsuccessful surgical procedures. As no autologous bone was available for further grafting, we used a bone substitute to fill two defects, one in the upper part of the humerus and the other in the radial shaft. The curettage cavity was filled with calcium-phosphate hydroxyapatite cement. The type of bone substitute was chosen for its specific properties: mineral structure similar to bone, microporosity, resistance to compression between cancellous and cortical bone, composition favorable to exchange between the crystals and the interstitial medium. Outcome was favorable early for the shoulder and later for the forearm after surgery for recurrence. Due to progress in the development of diphosphonates, indications for surgery for fibrous dysplasia have been reduced. There remains a risk of recurrence and incomplete results but bone substitute filling can be a useful alternative to autografts and complementary fixation. Calcium-phosphate cement is an easy-to-use paste-like product with interesting physicochemical and biological properties making it a leading choice for bone substitution.     

Scoliosis and spine involvement in fibrous dysplasia of bone

Few studies focused on the prevalence of scoliosis and involvement of the spine in patients with fibrous dysplasia (FD) of bone. We examined for FD involvement of the spine and scoliosis in 56 patients affected by FD of bone. Fifty patients were part of a cohort reported in a multicentric study on FD promoted by European Pediatric Orthopedic Society (EPOS) in 1999, and six were new patients. There were 30 females and 26 males (mean age 12.5 years; range 1–42 years). Twenty-three had monostotic FD, 9 polyostotic FD, and 24 McCune-Albright Syndrome (MAS). Scoliosis was observed in 11 cases of polyostotic FD and MAS (33.3%). In seven of the patients with scoliosis (63.3%) spine was involved by FD lesional tissue. FD lesions involved the thoracic or lumbar spine in all patients but one, where cervical spine was also affected. A correlation between scoliosis and either spinal (p < 0.01) or pelvic lesions (p < 0.05) and pelvic obliquity (p < 0.01) was observed. Three of the 11 patients showed familiarity for scoliosis but in 2 of them spine was involved by FD. Scoliosis and spine involvement were never detected in monostotic FD. This study indicates that in FD patients with polyostotic disease (1) the prevalences of FD involvement of the spine and scoliosis are high enough to include spine in the clinico-radiographic survey of these patients, and (2) the involvement of the spine and pelvis by FD lesions and pelvic obliquity are important determinants in the occurrence of scoliosis.