Management of proximal femoral shaft fractures in osteopetrosis: a case series using internal fixation

Osteopetrosis is a group of rare sclerosing bone dysplasias. Orthopedic concerns in osteopetrosis are principally related to the characteristic brittle "marble bone" in which fractures may be easily induced by relatively low-energy mechanisms. Femoral fractures are common in this patient population, and management presents a unique technical challenge. While osteopetrotic bone may be penetrated with a drill bit, the drill bit flutes are immediately filled with bone. This renders the drill ineffective, and generation of significant frictional heat can result in breakage of the drill. This case series describes the long-term management of nine osteopetrotic femoral fractures in three patients. The difficulties encountered in these cases prompted the development of a safe and efficacious technique for intramedullary fixation of these fractures.     

Metachronous bilateral subtrochanteric fracture of femur in an osteopetrotic bone: A case report with technical note

Osteopetrosis is a rare inherited skeletal disorder characterized by increased density. The increased fragility of such dense bone results in a greater incidence of fractures, especially around hip and proximal femur. The surgical treatment of such fractures is difficult due to hard but brittle structure of bone. Herein we report a case of bilateral subtrochanteric fracture in an osteopetrotic patient. It was fixed using a dynamic hip screw with plate.     

Conservative management of bilateral femoral neck fractures in a child with autosomal dominant osteopetrosis

Management of minimally displaced femoral neck fractures in paediatric patients with autosomal dominant osteopetrosis (ADO) remains unclear as only small numbers have been reported. There are no detailed reports on successful conservative treatment. Common causes of failure in this particular area include non-union and development of coxa vara. Although there are no quantitative studies, case reports have influenced most authors to recommend operative treatment. It is well recognised that operative treatment of osteopetrotic bone is challenging. Problems arise intraoperatively due to the bone hardness, and postoperatively due to altered biomechanics and defective remodelling. This case of a child with ADO who suffered two asynchronous compression-side stress fractures in the femoral neck demonstrates that non-operative management can be satisfactory. After 8 weeks with partial weight-bearing the fractures were stable. At the latest follow-up 2.5 and 4 years after the fractures the patient presented with an excellent clinical and radiological outcome. There was no development of coxa vara.     

Total hip arthroplasty in osteopetrosis. A report of two cases.

Two patients, mother and daughter, had major hip joint problems related to osteopetrosis consisting of (1) subtrochanteric femoral fractures including delayed union, septic nonunion, and failed intramedullary fixation; and (2) coxa vara with symptomatic osteoarthrosis. Total hip arthroplasty (THA) was performed on three hips of these two patients, and the patients were followed for more than three years. One patient continues to ambulate without pain or the need for external support, and the potential for ambulation was established for the second patient, compromised only by her poor motivation. The greatest challenge in all these surgical procedures was the creation of an intramedullary canal in osteopetrotic bone without a semblance of an intramedullary canal. The bone ends presented a solid white amorphous appearance, indistinguishable from the cortex. Great care was required to avoid shattering this brittle bone, also during drilling and reaming. Preoperative assessment of the medullary canals is mandatory. Variations in the intramedullary canals present great difficulties in osteotomizing, reaming, and drilling osteopetrotic bone. However, subtrochanteric femoral fracture can be treated by cemented THA in patients with osteopetrosis.     

“Challenges in the management of fractures in osteopetrosis”! Review of literature and technical tips learned from long-term management of seven patients

Osteopetrosis is a metabolic disorder with diminished bone resorption due to osteoclastic abnormality. It causes hard and brittle marble bone which fractures easily. Most of these fractures can be treated conservatively. Operative intervention when needed presents with unique technical challenges. While osteopetrotic hard bone may be penetrated with a drill bit; high friction and prolonged drilling can make the drill bit blunt. The heat generated can cause bone necrosis and break the drill bit. Besides this, brittleness of bones can cause intra-operative fractures. Due to the difficulties during the operation, the operative time may be prolonged thereby increasing the risk of post-operative infection. There is also a risk of delay in consolidation and non-union owning to impaired bone remodelling.We present an account of seven patients treated for various fracture related problems occurring throughout their life due to this disease. Difficulties encountered during their treatment prompted us to present some general management principles.     

Severe malignant osteopetrosis caused by a GL gene mutation.

Infantile malignant autosomal recessive osteopetrosis is a genetically heterogeneous disease caused by the inability of OCLs to resorb and remodel bone, resulting in generalized osteosclerosis and obliteration of marrow spaces and cranial foramina. The classical clinical features are pathological fractures, visual impairment, and bone marrow failure. Two human genes have been described as the cause of this form of osteopetrosis: the T-cell immune-regulator-1 (TCIRG1) gene, which is mutated in >50% of the patients, and the chloride channel 7 (ClCN7) gene, which accounts for approximately 10% of cases. We report the clinical, radiographic, and histopathologic findings of the first human osteopetrosis case caused by a mutation in the grey-lethal (GL) gene. The patient, a 9-day-old male infant, presented with a very severe osteopetrotic phenotype including substantial hepatosplenomegaly since birth, cytopenia, and progressive major liver failure. Skeletal radiographs revealed a generalized increase in bone density with loss of corticomedullary differentiation. Histopathologic bone examination showed the typical osteopetrotic changes, with absence of resorptive activity, and osteoclasts, slightly decreased in number, with evident morphological alterations.     

Mineral and matrix alterations in the bones of incisors-absent (ia/ia) osteopetrotic rats

Summary The bones of incisors-absent (ia/ia) osteopetrotic rats differ from those of their normal littermates (ia/+) in histologic and radiographic appearance and in mechanical properties. This study examined how the mineral and matrices of osteopetrotic metaphyses and calvaria differed from normal controls. Bones of 11-day-old and 52-day-old osteopetrotic animals had higher ash (mineral) contents that age-matched controls; osteopetrotic metaphyses had elevated hexosamine contents, indicative of the persistence of cartilage. Calcium acidic phospholipid phosphate complexes, involved in initiation of hydroxyapatite formationin vivo andin vitro, were significantly reduced in content in all osteopetrotic bones. These results suggest that in the osteopetrotic rat, where osteoclast activity is defective, new mineral formation is reduced and replaced by accretion of mineral on existing crystals. Fractionation of osteopetrotic bone particles by density centrifugation demonstrated that the osteopetrotic bone was much more mineralized than that of age-matched controls. X-ray diffraction analysis of the mineralized fractions indicated a lack of growth of mineral crystals during maturation of the osteopetrotic animals. The absence of remodeling was apparent from the elevated Ca:P ratios of the highly mineralized osteopetrotic bone fractions, and from the high hexosamine content of these dense fractions. These observations may explain some of the unusual mechanical properties of osteopetrotic bone.     

Posterior spinal instrumentation and fusion of a neuromuscular scoliosis in a patient with autosomal dominant osteopetrosis

STUDY DESIGN: A case report of a patient with autosomal dominant osteopetrosis and neuromuscular scoliosis who required surgical instrumentation and fusion of her spine. OBJECTIVE: To illustrate the surgical technique and long-term outcome in this rare form of spinal deformity. SUMMARY OF BACKGROUND DATA: Osteopetrosis is a group of rare skeletal dysplasias characterized clinically by skeletal osteosclerosis that is classically described in appearance as "marble bone." Despite the ubiquitous involvement of the vertebra, clinical manifestations of spinal involvement are uncommon. We present the case of an osteopetrotic patient with neuromuscular scoliosis who required surgical correction of her progressive deformity. There are no prior reports in the literature concerning operative or nonoperative management of scoliosis in this patient population. METHODS: The surgical technique utilized as well as the patient's response to surgical management of her scoliosis is presented with 5 year follow-up. RESULTS: The patient underwent a successful T4 to L1 posterior spine fusion and instrumentation using Luque rods, sublaminar wires and allograft bone augmentation. At 5 years following her index procedure, she is clinically and radiographically fused. CONCLUSION: Patients with osteopetrosis present unique surgical challenges during surgical correction of spinal deformities. The use of segmental sublaminar wires with 1/4-inch rods and crosslinks afforded stable fixation despite poor bone quality. Allograft bone combined with postoperative bracing resulted in a well-maintained correction and a solid fusion. Five year follow-up and continued radiographic evidence of stable fusion indicate that the presented approach can lead to a successful outcome in the osteopetrotic patient population.     

Auditory ossicle abnormalities and hearing loss in the toothless (osteopetrotic) mutation in the rat and their improvement after treatment with colony-stimulating factor-1.

Osteopetrosis describes a group of skeletal metabolic diseases of heterogeneous etiology and varied severity that produces a generalized accumulation of skeletal mass, the result of reduced bone resorption. Inherited in a variety of species including humans, the most severe forms are lethal. Among common features are progressive blindness and deafness of controversial etiologies for which there are no universally effective treatments. We have studied the auditory responsiveness and auditory ossicle quantitative histomorphology and temporal bone vasculature in the toothless (tl) rat, a lethal osteopetrotic mutation with few osteoclasts, very low bone turnover, and limited angiogenesis in the axial skeleton. Compared with normal littermates, 3-week-old mutants showed significantly reduced auditory responsiveness, a hearing loss due to abnormalities in both form and tissue composition of the stapes, and little capillary sprouting in the vascular bed of the temporal bone. Treatment of mutants with colony-stimulating factor 1 (CSF-1), known to greatly reduce sclerosis in the axial skeleton, significantly improved hearing, stapedial form and tissue composition, and angiogenesis in the temporal bone. In normal rats, the stapes consisted of 89.3% bone, 9.1% mineralized cartilage, and 0.8% porosity. In osteopetrotic rats, the stapes consisted of 48.3% bone, 35.9% mineralized cartilage, and 15.9% porosity, while after CSF-1 treatment, the bone content increased to 55.2%, cartilage was decreased to 21.7%, and porosity increased to 23.0%, respectively. This is the first demonstration of an auditory abnormality in an osteopetrotic animal mutation and shows that the hearing loss in tl rats can be significantly improved following treatment with CSF-1.     

Osteogenesis in osteopetrotic mice

Summary Ectopic bone arising in grafts of compatible normal intact bone marrow in microphthalmic osteopetrotic recipients was examined in the light microscope and was found to be unaffected by the deficiency that curtails resorption of primitive woven bone in osteopetrotic animals.     

Fracture management in pycnodysostosis: 27 years of follow-up

Pycnodysostosis is a rare hereditary disease, characterized by systemic bone sclerosis, which is often brought to the orthopedic surgeon's attention because of repeated fractures. The operative treatment of the patient with a fracture is a real challenge for the orthopedic surgeon because of the unusual problems imposed by the hard but-brittle bone characteristics of the disease. We report a 27-year follow-up of a patient treated for fractures of both femurs and tibia with intramedullary nailing. According to our experience and literature review, we recommend the use of an internal fixation, preferably intramedullary nailing as the treatment of choice for these rare cases. Once the fractures are healed, the removal of the hardware is not recommended, as these keep the bones from further fractures.     

骨质疏松性骨折围手术期的药物治疗

骨质疏松性骨折是一个全球性的骨骼健康问题,患病人群广泛且早期症状隐伏,严重危害老年人群的健康,骨折是其最严重的并发症。骨质疏松性骨折手术治疗难度大,疗效常不令人满意,因此,在积极手术治疗骨折的同时,一定要重视骨质疏松的药物治疗。骨质疏松性骨折围手术期使用抗骨吸收,以及补充活性维生素D3和钙剂,可以为骨质疏松性骨折进行各种手术准备较好的骨质基础,同时促进骨愈合,预防再次骨折的发生。本文针对骨质疏松性骨折围手术期的药物治疗进行讨论。     

Response to Denosumab Treatment for 2 Years in an Adolescent With Osteoradionecrosis

Radiotherapy, an essential component of cancer treatment, is not without risk to bone, particularly to the immature or growing skeleton. Known side effects range from post‐radiation osteitis to osteoradionecrosis. We report the case of a 14‐year‐old male patient undergoing denosumab treatment, a new antiresorptive agent, for osteoradionecrosis. The patient exhibited fractures and associated pain and functional limitations secondary to radiation for the treatment of an embryonal rhabdomyosarcoma of prostate grade III administered at age 5 years. After treatment with denosumab, the pain disappeared, bone remodeling markers dramatically declined, bone mass increased, and pathological bone scan findings resolved without adverse effects or new fractures. © 2015 American Society for Bone and Mineral Research.     

Osteoclast inhibition impairs chondrosarcoma growth and bone destruction

Because Chondrosarcoma is resistant to available chemotherapy and radiation regimens, wide resection is the mainstay in treatment, which frequently results in high morbidity and which may not prevent local recurrence. There is a clear need for improved adjuvant treatment of this malignancy. We have observed the presence of osteoclasts in the microenvironment of chondrosarcoma in human pathological specimens. We utilized the Swarm rat chondrosarcoma (SRC) model to test the hypothesis that osteoclasts affect chondrosarcoma pathogenesis. We implanted SRC tumors in tibia of Sprague‐Dawley rats and analyzed bone histologically and radiographically for bone destruction and tumor growth. At three weeks, tumors invaded local bone causing cortical disruption and trabecular resorption. Bone destruction was accompanied by increased osteoclast number and resorbed bone surface. Treatment of rats with the zoledronic acid prevented cortical destruction, inhibited trabecular resorption, and resulted in decreased tumor volume in bone. To confirm that inhibition of osteoclasts per se, and not off‐target effects of drug, was responsible for the prevention of tumor growth and bone destruction, we implanted SRC into osteopetrotic rat tibia. SRC‐induced bone destruction and tumor growth were impaired in osteopetrotic bone compared with control bone. The results from our animal model demonstrate that osteoclasts contribute to chondrosarcoma‐mediated bone destruction and tumor growth and may represent a therapeutic target in particular chondrosarcoma patients. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:1562–1571, 2014.     

Case Report of Spontaneous,Nonspinal Fractures in a Multiple Myeloma Patient on Long-term Pamidronate and Zoledronic Acid

Pamidronate and zoledronic acid are two potent intravenous bisphosphonates used in the treatment of multiple myeloma as well as osteoporosis. While the concern for heightened fracture risk in a patient on long-term bisphosphonate treatment for malignancy has been previously noted, we present the first case of spontaneous, nonspinal fractures in a patient undergoing treatment for multiple myeloma. The patient had a positive 9-year history of bisphosphonate treatment and presented with sequential subtrochanteric stress fractures of the left and right femurs. Pathological reports of fracture site biopsies demonstrate signs consistent with ametabolic bone and no malignancy. These findings point to extreme inhibition of bone turnover by bisphosphonates as the cause of this patient's morbidity. This is a single retrospective case study (level IV evidence).     

Osteoarthritis associated with osteopetrosis treated by total knee arthroplasty. Report of a case

Osteopetrosis is due to a defect in osteoclastic cell function and results in osteosclerosis and progressive obliteration of the marrow spaces. Early onset osteoarthritis is associated with osteopetrosis. The authors describe a case of early onset osteoarthritis associated with osteopetrosis treated by total knee arthroplasty. The marblelike quality of osteopetrotic bone makes surgical treatment of these patients technically challenging and requires modification of standard surgical technique.     

Femoral neck fracture in a child with autosomal dominant osteopetrosis

A child with autosomal dominant osteopetrosis had successful treatment of a femoral neck fracture by internal fixation. Drilling the pins into the femoral neck was extremely difficult. The histopathology in osteopetrotic bone provides a probable explanation for the technical difficulty seen in this case.     

Effects of Altered Bone Remodeling and Retention of Cement Lines on Bone Quality in Osteopetrotic Aged c-Src-Deficient Mice

Cement lines represent mineralized, extracellular matrix interfacial boundaries at which bone resorption by osteoclasts is followed by bone deposition by osteoblasts. To determine the contribution of cement lines to bone quality, the osteopetrotic c-Src mouse model—where cement lines accumulate and persist as a result of defective osteoclastic resorption—was used to investigate age-related changes in structural and mechanical properties of bone having long-lasting cement lines. Cement lines of osteopetrotic bones in c-Src knockout mice progressively mineralized with age up to the level that the entire matrix of cement lines was lost by EDTA decalcification. While it was anticipated that suppressed and abnormal remodeling, together with the accumulation of cement line interfaces, would lead to defective bone quality with advancing age of the mutant mice, unexpectedly, three-point bending tests of the long bones of 1-year-old c-Src-deficient mice indicated significantly elevated strength relative to age-matched wild-type bones despite the presence of numerous de novo microcracks. Among these microcracks in the c-Src bones, there was no sign of preferential propagation or arrest of microcracks along the cement lines in either fractured or nonfractured bones of old c-Src mice. These data indicate that cement lines are not the site of a potential internal failure of bone strength in aged c-Src osteopetrotic mice and that abundant and long-lasting cement lines in these osteopetrotic bones appear to have no negative impacts on the mechanical properties of this low-turnover bone despite their progressive hypermineralization (and thus potential brittleness) with age.     

Bilateral Fractures of the Femur Diaphysis in a Patient With Rheumatoid Arthritis on Long‐Term Treatment With Alendronate: Clues to the Mechanism of Increased Bone Fragility

Unusual fractures of the femur diaphysis have been reported in patients treated with alendronate and, although no causal relationship has been established, excessive suppression of bone turnover and length of treatment with alendronate have been implicated in their pathogenesis. We report here clinical, biochemical, and radiological findings of a patient with rheumatoid arthritis and multiple risk factors for fractures who was treated with alendronate for 8 yr and developed spontaneous bilateral subtrochanteric/diaphyseal fractures. Bone biopsies obtained form the iliac crest and the femur showed decreased bone formation with histomorphometric evidence of markedly increased bone resorption at the femur. These results show for the first time that an imbalance between bone resorption and bone formation at the affected bone is associated with the occurrence of these atypical femur fractures. The cause of this imbalance is currently unknown, and further studies of the epidemiology and pathogenesis of diaphyseal femur fractures are warranted.     

Mineral density and bone strength are dissociated in long bones of rat osteopetrotic mutations.

Bone mineral density (BMD) and mechanical strength generally show strong positive correlations. However, osteopetrosis is a metabolic bone disease with increased skeletal density radiographically and increased risk of fracture. We have evaluated mechanical strength and mineral density in three osteopetrotic mutations in the rat (incisors-absent [ia/ia], osteopetrosis [op/op], and toothless [tl/tl]) to test the hypothesis that reduced bone resorption in one or more of these mutations results in weaker bones in the presence of greater mineral density and skeletal mass. Peripheral quantitative computed tomography (pQCT) was used to analyze BMD and cross-sectional geometry in the tibial diaphysis and metaphysis as well as the femoral diaphysis and femoral neck. The bending breaking force of tibial and femoral midshafts was obtained using the three-point bending test and femoral neck strength was tested by axial loading. Osteopetrotic mutants were significantly smaller than their normal littermates (NLMs) in each stock. The pQCT analysis showed that BMD and bone mineral content (BMC) were higher than or equal to NLMs in all skeletal sites measured in the osteopetrotic mutants. However, the mechanical breaking force was equal to or lower than their NLMs in all sites. The cross-sectional structure of long bone shafts was markedly different in osteopetrotic mutants, having a thin cortex and a medullary area filled with primary trabecular bone. These results indicate that osteopetrotic mutations in the rat increase bone density and decrease bone strength. The tibial diaphysis was significantly weaker in tl/tl and ia/ia mutants and the tibial metaphysis showed the greatest increase in BMD in all mutants. These data are another illustration that an increased BMD does not necessarily lead to stronger bones.