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1.  Eleven years of experience with bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I 
We report the 11-year follow-up of a man with osteogenesis imperfecta type I who was treated with bisphosphonates and alfacalcidol. A 36-year-old Japanese man with osteogenesis imperfecta type I who had frequently experienced painful fragility fractures consulted our clinic because of chronic back pain. The patient had multiple morphometric vertebral fractures and a low bone mineral density (BMD) at the lumbar spine. The patient was treated with cyclical etidronate 200 mg, for 2 weeks every 3 months, plus alfacalcidol 1 μg daily, for 2 years; and alendronate 5 mg daily or 35 mg weekly, plus alfacalcidol 1 μg daily for 9 years. After 11 years of treatment, BMD at the lumbar spine increased by 6.4%, following a 20.3% reduction in serum alkaline phosphatase. Serum calcium, phosphorus, and intact parathyroid hormone levels remained within the normal ranges. Three clinical fractures occurred at two ribs and the metacarpus, and two morphometric vertebral fractures occurred at the thoracic spine during the 11-year treatment period, but the patient experienced no adverse effects. Thus, the present case report shows the long-term outcome and safety of bisphosphonate plus alfacalcidol treatment in a man with osteogenesis imperfecta type I.
PMCID: PMC3534324  PMID: 23293527
etidronate; alendronate; fragility fracture; bone mineral density; osteogenesis imperfecta
2.  Spontaneous Incomplete transverse subtrochanteric femoral fracture with cortical thickening possibly secondary to risedronate use: a case report 
Osteoporosis is an asymptomatic disease characterized by bone weakening and predisposition to fragility (insufficiency) fractures and can have devastating effects on individual life and great financial impact on the economy. Bisphosphonates are used worldwide for the primary and secondary prevention of osteoporotic fractures. However, increasing evidence raises concern that bisphosphonates can be associated with atypical fractures.
Case presentation
A 65-year-old Caucasian woman on long-term steroid treatment for polymyalgia rheumatica was admitted with severe and constant pain in the right hip, radiating to the right knee. She had a history of steroid-induced osteoporosis, for which she was started on risedronate four years earlier. She had no history of trauma. Her blood results were unremarkable. Her X-rays confirmed that she had an incomplete right subtrochanteric femoral fracture. A bone scan confirmed the diagnosis and also ruled out any other associated fractures. Our patient successfully underwent internal nail fixation of the fracture. She was reviewed by a rheumatology team, which stopped the risedronate. She was started on treatment with denosumab injection.
Previous case series have reported that long-term bisphosphonate use is associated with atypical fractures of the femur, and certain criteria have been established to help identify such rare fractures. Delayed union or non-union is expected in such fractures following definitive orthopedic treatment because of the long half life of bisphosphonates. In this case report, we try to raise questions related to this important subject, like the duration and safety of bisphosphonate use and the alternative medications used in osteoporosis in this rare condition. We consider this case report not only interesting but also important and unusual because it is about a patient who developed a potentially rare and serious side effect of long-term bisphosphonate use, estimated to affect 2.3 in every 10,000 patients, and who presented with a pelvic X-ray that showed the characteristic features of atypical fractures secondary to risedronate use. In addition, most of the documented cases have been associated with many years of bisphosphonate use whereas our patient had been on risedronate for only four years.
PMCID: PMC3459800  PMID: 22943389
3.  Changing pattern of femoral fractures in osteogenesis imperfecta with prolonged use of bisphosphonates 
Osteogenesis imperfecta (OI) has been treated with bisphosphonates for many years, with some clear clinical benefits. In adults, there are reports of a new pattern of atraumatic subtrochanteric fractures with bisphosphonate treatment. This study assesses if bisphosphonate treatment leads to an altered pattern of femoral fractures.
Retrospective review of imaging for a cohort of 176 bisphosphonate-treated OI patients to identify the locations of femoral fractures over a two-year period, as compared to a historical control group managed pre-bisphosphonates.
Sixteen femoral fractures were identified in this time period in the bisphosphonate-treated group. All but two were within the subtrochanteric region. In comparison, the historical group—composed of 26 femoral fractures—had a more widespread fracture pattern, with the most frequent location being the mid-diaphysis. Many of the subtrochanteric fractures in the treatment group occurred with minimal trauma.
It appears that concerns over the treatment of the adult osteoporotic population with bisphosphonates are amplified and mirrored in OI. It is possible that the high bending moments in the proximal femur together with altered mechanical properties of cortical bone secondary to the use of this group of drugs increase the risk of this type of injury, which warrants further modification of surgical management of the femur.
PMCID: PMC3303010  PMID: 23450103
Osteogenesis imperfecta; Bisphosphonates
4.  Predictors of atypical femoral fractures during long term bisphosphonate therapy: A case series & review of literature 
Background & objectives:
Bisphosphonates (BPs) are the most widely prescribed medicines for the treatment of osteoporosis because of their efficacy and favourable safety profile. There have been, several reports on an increased incidence of atypical femoral fractures after long term treatment with BPs. The objective of this study was to evaluate the clinical presentation including prodromal symptoms, skeletal radiograph findings, type and duration of BPs received and treatment outcome of patients who developed atypical femoral fractures during bisphosphonate therapy.
In this retrospective study, eight patients with atypical femoral fractures were analysed based on clinical features, biochemical and radiological investigations.
Of the eight patients, who sustained atypical femoral fractures, six were on alendronate and two were on zoledronate therapy before the fractures. In addition to BPs, two patients were on long term corticosteroid therapy for rheumatoid arthritis and Addison's disease. Three patients had bilateral atypical femoral fractures. Except one, all of them had prodromal symptoms prior to fracture. Skeletal radiograph showed cortical thickening, pointed (beaking of) cortical margin and transverse fracture in meta-diaphyseal location. Serum calcium, phosphate, alkaline phosphatase (ALP) and intact parathyroid hormone (iPTH) concentrations were within the reference range in all patients.
Interpretation & conclusions:
Long term bisphosphonate therapy may increase the risk of atypical femoral fractures. Presence of prodromal pain, thickened cortex with cortical beaking may be an early clue for predicting the atypical fractures. High risk patients need periodical skeletal survey and a close follow up for early detection of cases.
PMCID: PMC4181159  PMID: 25222777
Atypical; bisphosphonates; femoral shaft; fracture; subtrochanteric
5.  Two years’ experience with denosumab for children with Osteogenesis imperfecta type VI 
Osteogenesis imperfecta (OI) is a hereditary disease causing reduced bone mass, increased fracture rate, long bone deformities and vertebral compressions. Additional non skeletal findings are caused by impaired collagen function and include hyperlaxity of joints and blue sclera. Most OI cases are caused by dominant mutations in COL1A1/2 affecting bone formation. During the last years, recessive forms of OI have been identified, mostly affecting posttranslational modification of collagen. In 2011, mutations in SERPINF1 were identified as the molecular cause of OI type VI, and thereby a novel pathophysiology of the disease was elucidated. The subgroup of patients with OI type VI are affected by an increased bone resorption, leading to the same symptoms as observed in patients with an impaired bone formation. Severely affected children are currently treated with intravenous bisphosphonates regardless of the underlying mutation and pathophysiology. Patients with OI type VI are known to have a poor response to such a bisphosphonate treatment.
Deciphering the genetic cause of OI type VI in our 4 patients (three children and one adolescent) led to an immediate translational approach in the form of a treatment with the monoclonal RANKL antibody Denosumab (1 mg/kg body weight every 12 weeks).
Short-term biochemical response to this treatment was reported previously. We now present the results after 2 years of treatment and demonstrate a long term benefit as well as an increase of bone mineral density, a normalization of vertebral shape, an increase of mobility, and a reduced fracture rate.
This report presents the first two-year data of denosumab treatment in patients with Osteogenesis imperfecta type VI and in Osteogenesis imperfecta in general as an effective and apparently safe treatment option.
PMCID: PMC4180531  PMID: 25257953
Osteogenesis imperfecta VI; SERPINF1; RANKL Antibody; Denosumab; Bone mineral density
6.  Intravenous pamidronate treatment of infants with severe osteogenesis imperfecta 
Archives of Disease in Childhood  2006;92(4):332-338.
Children with the severe forms of osteogenesis imperfecta have in several studies been treated with intravenous pamidronate, but there are only few reports of the effect of early treatment.
To evaluate the effect of treatment started in infancy.
In a prospective observational study, with a historic control group, intravenous disodium pamidronate (APD) was given as monthly infusions to 11 children with osteogenesis imperfecta aged 3–13 (median 3.6) months, who had severe osteogenesis imperfecta with congenital bowing of the femora and vertebral compression fractures.
During treatment of children aged between 3 and 6 (median 4.5) years, dual‐energy x ray absorptiometry measurements of the lumbar spine showed a gradual increase in bone density. Bone metabolism parameters in serum (alkaline phosphatase, osteocalcin, procollagen 1 carboxy‐terminal peptide, collagen 1 teleopeptide) and in urine (deoxypyridinoline) indicated a decrease in bone turnover. An improvement of mobility was seen and at the latest recording, at the age of 3.3–6.5 (median 4.8) years, the children could all walk. Vertebral remodelling was seen, with increased vertebral height, and no child developed scoliosis, kyphosis or basilar impression. All children required femoral intramedullar rods for fractures, and five needed tibial rodding for extreme curvatures that prevented functional standing and walking. No adverse effects were seen on growth, fracture healing or blood chemistry.
APD is an efficient symptomatic treatment for infants with severe osteogenesis imperfecta, but additional orthopaedic surgery is often needed. Early treatment may prevent scoliosis and basilar impression. Long‐term follow‐up is important.
PMCID: PMC2083683  PMID: 17114205
7.  Is It a Simple Stress Fracture or Bisphosphonate-related Atypical Fracture? 
Journal of Bone Metabolism  2012;19(2):129-132.
A number of reports regarding atypical fractures of the femur have raised questions concerning the possible correlation between long-term bisphosphonate treatment and the occurrence of insufficiency fractures in the proximal femur. However, clinically, it is often confused whether is it a fatigue fracture because of implant induced stress concentration or a bisphosphonate-related atypical fracture, especially in a patient with a subtrochanteric fracture who receive bisphosphonate therapy after open reduction and internal fixation, such as dynamic hip screw (DHS) fixation for previous ipsilateral femoral neck or intertrochanteric fracture. The authors experienced a case of a progressive femoral insufficiency fracture in a woman who had been on Fosamax (Alendronic acid with Vitamin D; Merck & Co. Inc, NJ, USA) therapy for four years after ipsilateral femoral neck fracture treated with a two hole DHS system. Despite a high suspicion of an insufficiency femoral subtrochanteric fracture by bone scan, the occult fracture progressed to a displaced femoral subtrochanteric fracture one year after. The fracture site was fixed with a 6 hole DHS plate, and six months after reoperation the patient had no symptoms and the fracture site had united without any complication.
PMCID: PMC3780922  PMID: 24524043
Bisphosphonate; Early diagnosis; Femoral fractures; Fractures stress; Osteoporosis
8.  Subtrochanteric fractures after long-term treatment with bisphosphonates: a European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis, and International Osteoporosis Foundation Working Group Report 
Osteoporosis International  2010;22(2):373-390.
This paper reviews the evidence for an association between atypical subtrochanteric fractures and long-term bisphosphonate use. Clinical case reports/reviews and case–control studies report this association, but retrospective phase III trial analyses show no increased risk. Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is yet unproven.
A Working Group of the European Society on Clinical and Economic Aspects of Osteoporosis and Osteoarthritis and the International Osteoporosis Foundation has reviewed the evidence for a causal association between subtrochanteric fractures and long-term treatment with bisphosphonates, with the aim of identifying areas for further research and providing recommendations for physicians.
A PubMed search of literature from 1994 to May 2010 was performed using key search terms, and articles pertinent to subtrochanteric fractures following bisphosphonate use were analysed.
Several clinical case reports and case reviews report a possible association between atypical fractures at the subtrochanteric region of the femur in bisphosphonate-treated patients. Common features of these ‘atypical’ fractures include prodromal pain, occurrence with minimal/no trauma, a thickened diaphyseal cortex and transverse fracture pattern. Some small case–control studies report the same association, but a large register-based study and retrospective analyses of phase III trials of bisphosphonates do not show an increased risk of subtrochanteric fractures with bisphosphonate use. The number of atypical subtrochanteric fractures in association with bisphosphonates is an estimated one per 1,000 per year. It is recommended that physicians remain vigilant in assessing their patients treated with bisphosphonates for the treatment or prevention of osteoporosis and advise patients of the potential risks.
Bisphosphonate use may be associated with atypical subtrochanteric fractures, but the case is unproven and requires further research. Were the case to be proven, the risk–benefit ratio still remains favourable for use of bisphosphonates to prevent fractures.
PMCID: PMC3020314  PMID: 21085935
Atypical; Bisphosphonate; Femur; Low trauma; Osteoporosis; Subtrochanteric
9.  Rotatory atlanto-axial dislocation in an infant with osteogenesis imperfecta 
European Spine Journal  2008;18(Suppl 2):168-171.
This is a case report of a 15-month-old patient with osteogenesis imperfecta (OI) who sustained atlanto-axial dislocation. Our objective is to report a unique case of traumatic atlanto-axial subluxation in a child with osteogenesis imperfecta associated with bilateral femoral fractures. The management is discussed. Atlanto-axial dislocation occurring with associated osteogenesis imperfecta is very rare. There have been no previous reported cases. A 15-month-old girl with osteogenesis imperfecta sustained a traumatic atlanto-axial dislocation. The child was followed-up through presentation, diagnosis, management and post-discharge. The initial diagnosis was confirmed with a CT scan. The patient was treated conservatively with a halo-traction for 4 weeks followed by a halo jacket for a further 4 weeks. Both appliances were fitted under general anaesthetic. An anatomical reduction was achieved. There was no neurological deficit at any stage. The child has had a successful outcome. She is asymptomatic with a full range of movement at the atlanto-axial joints at 9 months. In conclusion, this paper records our management of this rare problem.
PMCID: PMC2899552  PMID: 18762995
Atlanto-axial dislocation; Osteogenesis imperfecta; Bilateral femoral fractures; Halo-traction; Conservative treatment
10.  An unusual case of atrophic mandible fracture in a patient with osteogenesis imperfecta and on oral bisphosphonate therapy: Case report 
The Saudi Dental Journal  2014;26(2):68-73.
Fractures of severely atrophic (height < 10 mm) edentulous mandibles are infrequent and challenging to manage. Factors such as sclerotic bone and decreased vascularity combined with systemic diseases complicate the management of such fractures. Osteogenesis imperfecta (OI) is a heterogeneous group of inherited disorders of type I collagen metabolism. Patients with OI characteristically present with histories of long bone fractures, deformities, blue sclerae, and opalescent dentin. However, fractures of the facial skeleton are rare. Bisphosphonate therapy has been proven to effectively reduce the fracture risk in patients with OI. The purpose of this clinical report is to present an unusual case of spontaneous fracture of the atrophic mandible in a patient with OI. Despite open reduction and internal fixation (ORIF) with miniplate osteosynthesis, the patient developed a second fracture at a screw placement site distal to the first fracture. The patient was successfully treated with ORIF using locking reconstruction plates fixed in the symphyseal and angle regions. Bone healing following ORIF was normal, and no clinical sign of osteonecrosis as a result of bisphosphonate therapy was observed. Patients with OI can present with spontaneous fractures of already weakened mandibles. Although such fractures can be managed with care using established protocols, further research is required to examine the effects of concomitant medication, such as bisphosphonates.
PMCID: PMC4229676  PMID: 25408599
Atrophic mandible; Mandible fracture; Osteogenesis imperfecta; Bisphosphonates
11.  Severe Osteogenesis Imperfecta Caused by a Small In-Frame Deletion in CRTAP 
Mutations of proteins involved in posttranslational modification of collagen type I can cause osteogenesis imperfecta inherited in a recessive pattern. The CRTAP protein is part of a heterotrimeric complex (together with prolyl-3-hydroxylase-1 [P3H1] and cyclophilin B) that 3-hydroxylates the alpha 1 chain of collagen type I at proline residue 986 and plays a collagen chaperon role. CRTAP mutations usually cause severe osteogenesis imperfecta. We report a patient with osteogenesis imperfecta and a homozygous in-frame deletion in CRTAP and a severe form of osteogenesis imperfecta. The girl was born with markedly deformed long bones. Despite intravenous bisphosphonate treatment, she developed multiple vertebral compression fractures and severe scoliosis and at 4 years of age was able to sit only with support. Although CRTAP transcript levels were normal in the patient’s fibroblasts, protein levels of both CRTAP and P3H1 were severely reduced. The degree of 3-hydroxylation at proline residue 986 was also decreased. This report characterizes a patient with a CRTAP small in-frame deletion. We are unaware of prior reports of this finding. We suggest that this deletion affects crucial amino acids that are important for the interaction and/or stabilization of CRTAP and P3H1.
PMCID: PMC3957185  PMID: 21964860
Recessive osteogenesis imperfecta; CRTAP; 3-hydroxylation complex; P3H1
12.  Systematic review of effectiveness of bisphosphonates in treatment of low bone mineral density and fragility fractures in juvenile idiopathic arthritis 
Archives of Disease in Childhood  2006;91(9):753-761.
To evaluate the currently available evidence for the effectiveness of bisphosphonates in children with low bone mineral density (BMD) and fragility fractures associated with juvenile idiopathic arthritis (JIA), and the safety of bisphosphonates in JIA and other conditions.
Literature databases were searched using a structured search strategy. The effectiveness review included any studies of children with JIA treated with bisphosphonates. The safety review also included studies of osteogenesis imperfecta. Quantitative data analysis was not undertaken because of the heterogeneity of the studies; findings were summarised using tables and narrative synthesis.
Ninety four studies were identified. Sixteen studies (78 JIA children) were included in the effectiveness review: one randomised controlled trial, three controlled cohort studies, 11 case series, and one case report. At baseline, children had low BMD below the expected values for age and sex matched children. In all studies, treatment with bisphosphonates increased BMD compared with baseline: the mean percentage increase in spine BMD ranged from 4.5% to 19.1%. Overall, studies were heterogeneous and of variable quality. A total of 59 papers were included in the safety review; treatment durations were up to three years. The most common side effect was a flu‐like reaction with intravenous treatment. This occurred during the first infusion and was transient; the symptoms were managed with paracetamol and did not occur during subsequent cycles.
Bisphosphonates are a promising treatment for low BMD and fragility fractures in children with JIA. However, the quality of the current evidence is variable and better studies are needed to more clearly assess their role.
PMCID: PMC2082926  PMID: 16690698
juvenile idiopathic arthritis; bisphosphonates; systematic review; fragility fractures
13.  Oral bisphosphonates are associated with increased risk of subtrochanteric and diaphyseal fractures in elderly women: a nested case–control study 
BMJ Open  2013;3(1):e002091.
To evaluate the association between bisphosphonate use and the risk of atypical femoral fractures among women aged 65 or older.
Nested case–control study.
General practice research database in Spain.
Use of oral bisphosphonates before the occurrence of atypical fractures among cases or the corresponding index date among controls. Bisphosphonate use was categorised as ever versus never users. Ever users were divided according to the total time since first prescription.
Main outcome measures
Cases were defined as women aged 65 years or older with a first diagnosis of subtrochanteric or diaphyseal fracture, recorded in the BIFAP database between 1 January 2005 and 31 December 2008, and with at least 1 year of follow-up before the index date. For each case, five age-matched and calendar-year-matched controls without a history of hip or atypical fracture were randomly selected from the database.
Statistical analysis
OR of atypical femoral fracture by bisphosphonate use was determined using conditional logistic regression. Models were adjusted for comorbidities and use of other medications.
The analysis included 44 cases and 220 matched controls (mean age, 82 years). Ever use of bisphosphonates was more frequent in cases than controls (29.6% vs 10.5%). In multivariate analyses, OR (95% CI) of atypical femoral fracture was 4.30 (1.55 to 11.9) in ever versus never users of bisphosphonates. The risk increased with long-term use, with an OR of 9.46 (2.17 to 41.3) comparing those using bisphosphonates over 3 years versus no users (p for trend=0.01).
Bisphosphonate use was associated with an increased risk of subtrochanteric or diaphyseal fractures in elderly women in a low fracture risk population, with a higher risk among long-term bisphosphonate users.
PMCID: PMC3563115  PMID: 23370011
Clinical Pharmacology; Epidemiology; Primary Care
14.  Alendronate Treatment of Brtl Osteogenesis Imperfecta Mouse Improves Femoral Geometry and Load Response before Fracture but Decreases Predicted Material Properties and has Detrimental Effects on Osteoblasts and Bone Formation 
Long courses of bisphosphonates are widely administered to children with osteogenesis imperfecta (OI), although bisphosphonates do not block mutant collagen secretion and may affect bone matrix composition or structure. The Brtl mouse has a glycine substitution in col1a1, and is ideal for modeling the effects of bisphosphonate in classical OI. We treated Brtl and wild-type mice with alendronate (0.219 mg/kg/wk sq) for 6 or 12 weeks and compared treated and untreated femora of both genotypes. Mutant and wild-type bone had similar responses to Aln treatment. Femoral areal BMD and cortical vBMD increased significantly after 12 weeks, but femoral length and growth curves were unaltered. Alendronate improved Brtl diaphyseal cortical thickness and trabecular number after 6 weeks, and cross-sectional shape after 12 weeks. Mechanically, Aln significantly increased stiffness in wild-type femora, and load to fracture in both genotypes after 12 weeks. However, predicted material strength and elastic modulus were negatively impacted by 12 week Aln in both genotypes, and metaphyseal remnants of mineralized cartilage also increased. Brtl femoral brittleness was unimproved. Brtl osteoclast and osteoblast surface were unchanged by treatment. However, decreased MAR and BFR/BS and the flattened morphology of Brtl osteoblasts suggested that Aln impaired osteoblast function and matrix synthesis. We conclude that alendronate treatment improves Brtl femoral geometry and load to fracture, but decreases bone matrix synthesis and predicted material modulus and strength, with striking retention of mineralized cartilage. Beneficial and detrimental changes appear concomitantly. Limiting cumulative bisphosphonate exposure of OI bone will minimize detrimental effects.
PMCID: PMC2672204  PMID: 19113917
Brtl Mouse; Bisphosphonates; Osteogenesis Imperfecta; Biomechanics; Histomorphometry; Bone Quality
15.  Management pitfalls of fractured neck of femur in osteogenesis imperfecta 
Fractured neck of femur in osteogenesis imperfecta is rarely reported. Its management is always difficult because of bone fragility and the outcome is not well known. We, therefore, aimed to study the management pitfalls in this group of patients.
We retrospectively reviewed five cases of fractured neck of femur in four patients treated in our hospital between 2006 and 2009. The demographic data, mode of injury, fracture configuration, treatment, complications, clinical and radiological outcome were reviewed.
According to the Sillence classification, one patient was type I, two were type III and one was type IV. There were two children (aged 8 and 15 years) and two adults (aged 21 and 22 years), with the 8 year-old girl suffering from hip fracture on different sides in two accidents. All five hip fractures were the result of low-energy injury and were associated with other fractures. Two undisplaced fractures required intra-operative fluoroscopic confirmation to demonstrate movement at the fracture site. The interval between the injury and fixation ranged from 6 h to 3 days. One hip required secondary surgery to openly reduce the fracture due to inadequate primary fixation and reduction. Two hips were fixed with paediatric dynamic hip screws and three hips were fixed with cannulated screws. All patients were immobilised in hip spica for 6 weeks. The average follow-up was 4 years (3–5 years). All patients had satisfactory union and none of them developed radiological evidence of avascular necrosis at the latest follow-up. All patients returned to their pre-injury functional level.
Fractured neck of femur is rare given the high prevalence of long bone fractures in osteogenesis imperfecta. They all have characteristic associated fractures of the extremity at the time of injury and neck of femur fractures could be easily missed. Fracture fixation is a great challenge to the orthopaedic surgeons because of the small size of the patients, poor bone quality with suboptimal imaging intra-operatively and compromised purchase of fixation devices. The choice of implants should be determined by the size of the patients and the presence of prior instrumentation close to the hip joint.
PMCID: PMC3672462  PMID: 24432078
Osteogenesis imperfecta; Fractured neck of femur; Operative challenge
16.  Atypical Femoral Fracture Combined with Osteonecrosis of Jaw During Osteoporosis Treatment with Bisphosphonate 
Journal of Bone Metabolism  2014;21(2):155-159.
Bisphosphonate, a potent anti-resorptive agent, is generally accepted as a safe, effective, well tolerated treatment for postmenopausal osteoporosis. Atypical femoral fracture (AFF) and bisphosphonate related osteonecrosis of jaw (BRONJ) are the increasing morbidities in patients treated with long term bisphosphonate. Pathogenic mechanisms of AFF and BRONJ are not fully identified and not identical. We report a case of BRONJ followed by AFF and its nonunion in a 67-year-old woman patient receiving an oral bisphosphonate during 7 years for the treatment of osteoporosis.
PMCID: PMC4075270  PMID: 25025002
Atypical femoral fracture; Bisphosphonate
17.  Prophylactic Nailing of Incomplete Atypical Femoral Fractures 
The Scientific World Journal  2013;2013:450148.
Introduction. Recent reports have described the occurrence of low-energy subtrochanteric and femoral shaft fractures associated with long-term bisphosphonate use. Although information regarding the surgical treatment of these atypical femoral fractures is increasing, it is unclear if the preventive operation is useful in incomplete fractures. This study examined the results of preventive intramedullary nailing for incomplete atypical femoral fractures. Material and Methods. A retrospective search was conducted for patients older than 50 years receiving bisphosphonate therapy, with incomplete, nondisplaced fractures in either the subtrochanteric or diaphyseal area of the femur. Seventeen patients with a total of 20 incomplete, non-displaced lesions were included. The mean duration of bisphosphonate use was 50.5 months. Eleven of the 17 (64.7%) patients had complete or incomplete fractures on the contralateral femur. All were treated with prophylactic fixation of an intramedullary (IM) nail. The minimum followup was 12 months. Results. All cases healed with a mean period of 14.3 weeks. Nineteen of the 20 cases healed with the dissolution of incomplete fractures of the lateral aspect. A complete fracture developed at the time of nailing in one patient, but it healed with callus bridging. Conclusion. IM nailing appears to be a reliable way of preventing the progress of incomplete atypical femoral fractures.
PMCID: PMC3556877  PMID: 23365544
18.  Femoral artery thrombosis after internal fixation of a transverse acetabular fracture in a patient with osteogenesis imperfecta type I 
Osteogenesis imperfecta is a genetic disorder characterized by increased susceptibility to fractures and vascular injuries due to connective tissue fragility. In this case report, we present a patient with osteogenesis imperfecta type I who sustained a transverse fracture of the right acetabulum while transferring from bed to chair. The fracture was repaired through an ilioinguinal approach. During the surgery, an iatrogenic injury to the femoral artery and vein occurred. This intraoperative complication was salvaged by immediate vascular repair. We discuss the possible causes of iatrogenic vascular injuries in patients with osteogenesis imperfecta. Orthopaedic surgeons should be aware of this potentially devastating complication in this particular patient cohort.
PMCID: PMC2262876  PMID: 18271949
19.  Spondylolisthesis caused by extreme pedicle elongation in osteogenesis imperfecta 
European Spine Journal  2007;16(10):1636-1640.
Although osteogenesis imperfecta is a well-known skeletal disorder, reports of spondylolisthesis in osteogenesis imperfecta are rare. Only very few cases of spondylolisthesis caused by elongation of lumbar pedicles have been described in the literature. Here we report three patients suffering from osteogenesis imperfecta showing a severe form of hyperlordosis caused by lumbar pedicle elongation and consecutive spondylolisthesis. Radiographs in the course of childhood and adolescence show a rapid progression of pedicle elongation and hyperlordosis with increased mechanical loads. The treatment strategy consists of physiotherapy, medical treatment with bisphosphonates, and orthopedic surgery and is preferably conservative. In the three patients reported here, one patient was treated with laminectomy and postero-lateral fusion, whereas in the other two patients surgery is currently not considered as necessary.
PMCID: PMC2078305  PMID: 17242874
Osteogenesis imperfecta; Spondylolisthesis; Pedicle elongation; Hyperlordosis
20.  Bilateral atypical insufficiency fractures of the proximal tibia and a unilateral distal femoral fracture associated with long-term intravenous bisphosphonate therapy: a case report 
Atypical insufficiency fractures of the femur in patients on long-term bisphosphonate therapy have been well described in recent literature. The majority of cases are associated with minimal or no trauma and occur in the subtrochanteric or diaphyseal region.
Case presentation
We describe the case of a 76-year-old British Caucasian woman who presented initially to an emergency department and then to her primary care physician with a long-standing history of bilateral knee pain after minor trauma. Plain radiographs showed subtle linear areas of sclerosis bilaterally in her proximal tibiae. Magnetic resonance imaging confirmed the presence of insufficiency fractures in these areas along with her left distal femur. There are very few reports of atypical insufficiency fractures involving the tibia in patients on long-term bisphosphonate therapy and this appears to be the only documented bilateral case involving the metaphyseal regions of the proximal tibia and distal femur.
In addition to existing literature describing atypical fractures in the proximal femur and femoral shaft, there is a need for increased awareness that these fractures can also occur in other weight-bearing areas of the skeleton. All clinicians involved in the care of patients taking long-term bisphosphonates need to be aware of the growing association between new onset lower limb pain and atypical insufficiency fractures.
PMCID: PMC3292822  PMID: 22309438
21.  Therapeutic impact of low amplitude high frequency whole body vibrations on the osteogenesis imperfecta mouse bone☆ 
Bone  2013;53(2):507-514.
Osteogenesis imperfecta (OI) is characterized by extremely brittle bone. Currently, bisphosphonate drugs allow a decrease of fracture by inhibiting bone resorption and increasing bone mass but with possible long term side effects. Whole body mechanical vibrations (WBV) treatment may offer a promising route to stimulate bone formation in OI patients as it has exhibited health benefits on both muscle and bone mass in human and animal models. The present study has investigated the effects of WBV (45 Hz, 0.3 g, 15 minutes/days, 5 days/week) in young OI (oim) and wild type female mice from 3 to 8 weeks of age. Vibration therapy resulted in a significant increase in the cortical bone area and cortical thickness in the femur and tibia diaphysis of both vibrated oim and wild type mice compared to sham controls. Trabecular bone was not affected by vibration in the wild type mice; vibrated oim mice, however, exhibited significantly higher trabecular bone volume fraction in the proximal tibia. Femoral stiffness and yield load in three point bending were greater in the vibrated wild type mice than in sham controls, most likely attributed to the increase in femur cortical cross sectional area observed in the μCT morphology analyses. The vibrated oim mice showed a trend toward improved mechanical properties, but bending data had large standard deviations and there was no significant difference between vibrated and non-vibrated oim mice. No significant difference of the bone apposition was observed in the tibial metaphyseal trabecular bone for both the oim and wild type vibrated mice by histomorphometry analyses of calcein labels. At the mid diaphysis, the cortical bone apposition was not significantly influenced by the WBV treatment in both the endosteum and periosteum of the oim vibrated mice while a significant change is observed in the endosteum of the vibrated wild type mice. As only a weak impact in bone apposition between the vibrated and sham groups is observed in the histological sections, it is possible that WBV reduced bone resorption, resulting in a relative increase in cortical thickness.
Whole body vibration appears as a potential effective and innocuous means for increasing bone formation and strength, which is particularly attractive for treating the growing skeleton of children suffering from brittle bone disease or low bone density pathologies without the long term disadvantages of current pharmacological therapies.
► Whole body vibration (WBV) therapeutic impacts on bone were investigated in young osteogenesis imperfecta mice (oim). ► WBV beneficial impact on the cortical bone morphology of both femur and tibia in the wild type and oim mice ► Bone volume fraction was improved in the proximal tibia of oim vibrated mice. ► WBV has beneficial impact on bending properties in wild type vibrated mice but only a positive trend in oim mice. ► Bone apposition is not significantly improved in the mid-tibia cortical and proximal tibia trabecular bone in the oim vibrated mice.
PMCID: PMC3590448  PMID: 23352925
Whole body vibration; Osteogenesis imperfecta disease; oim mouse model; Bone morphology; Bone formation; Bending properties
22.  Efficacy of Oral Etidronate for Skeletal Diseases in Japan 
Yonsei Medical Journal  2005;46(3):313-320.
Etidronate is an oral bisphosphonate compound that is known to reduce bone resorption through the inhibition of osteoclastic activity. The efficacy of etidronate for involutional (postmenopausal and senile) and glucocorticoid-induced osteoporosis, as well as that for other skeletal diseases, was reviewed in Japanese patients. Cyclical etidronate treatment (200 mg or 400 mg/day for 2 weeks about every 3 months) increases the lumbar bone mineral density (BMD) in patients with involutional osteoporosis and prevents incident vertebral fractures in patients with glucocorticoid-induced osteoporosis. The losses of the lumbar BMD in patients with liver cirrhosis and the metacarpal BMD in hemiplegic patients after stroke are prevented, and the lumbar BMD is possibly increased, preventing fragile fractures in adult patients with osteogenesis imperfecta type I. Furthermore, proximal bone resorption around the femoral stem is reduced and some complications may be prevented in patients who undergo cementless total hip arthroplasty. Oral etidronate treatment may also help to transiently relieve metastatic cancer bone pain followed by a decrease in abnormally raised bone resorption in patients with painful bone metastases from primary cancer sites, such as the lung, breast and prostate. Thus, oral etidronate treatment is suggested to be efficacious for osteoporosis, as well as other skeletal diseases associated with increased bone resorption, in Japanese patients. Randomized controlled trials needed to be conducted on a large number of patients to confirm these effects.
PMCID: PMC2815806  PMID: 15988801
Postmenopausal women; glucocorticoid; disuse; cancer bone metastasis; etidronate
23.  Systematic Review on the Incidence of Bisphosphonate Related Osteonecrosis of the Jaw in Children Diagnosed with Osteogenesis Imperfecta 
To conduct a systematic review of epidemiological literature to determine the incidence of bisphosphonate related osteonecrosis of the jaw occurring either spontaneously or after dental surgery, in children and adolescents diagnosed with osteogenesis imperfecta.
Material and Methods
MEDLINE, HMIC and EMBASE were used to search for English-language articles published from 1946 - 2013. Inclusion criteria consisted of population based studies of children and adolescents (24 years and younger) diagnosed with osteogenesis imperfecta, only studies which included a dental examination, and patients treated with intravenous bisphosphonates were included. Articles were excluded if patients had any other co-morbidity which could affect osteonecrosis of the jaw, and those which treated patients with oral bisphosphonates only.
Five studies consisting of four retrospective cohort studies and one case series were identified. Study populations ranged from 15 to 278 patients and number of subjects with osteogenesis imperfecta ranged from 15 to 221. Mean duration of intravenous bisphosphonate use ranged from 4.5 to 6.8 years. All patients were clinically examined and no patients were found to have osteonecrosis of the jaw.
There is no evidence to support hypothesis of causal relationship between bisphosphonates and osteonecrosis of the jaw in children and adolescents with osteogenesis imperfecta. More prospective studies on bisphosphonate use in osteogenesis imperfecta needs to be carried out.
PMCID: PMC3904727  PMID: 24478911
osteonecrosis; jaw; osteogenesis imperfecta; children; bisphosphonates.
24.  Propagation of Bisphosphonate-Related Femoral Stress Fractures Despite Femoral Nailing 
We report 2 cases of atypical femoral fracture displacement despite treatment with intramedullary (IM) nailing. Both patients had received more than 3 years of bisphosphonates. One patient had prophylactic fixation of an atypical femur fracture due to intractable pain. The other had undergone nailing previously for a traumatic shaft fracture. The patient then received bisphosphonate later and sustained an atypical fracture with the nail in place. Both femoral nails were slotted, cannulated stainless steel piriformis entry designs. These 2 cases are among the first reported failures of IM fixation in preventing displacement of a bisphosphonate stress fracture. We advice caution when using slotted nails in prophylaxis of atypical femur fractures because of its significantly reduced torsional stiffness compared to modern nonopen sectioned nails.
PMCID: PMC3962052  PMID: 24660094
femur fractures; bisphosphonates; atypical fractures; intramedullary nailing; case report; geriatric fractures
25.  Atypical femoral diaphyseal and subtrochanteric fractures and their association with bisphosphonates 
BMJ Case Reports  2009;2009:bcr10.2008.1073.
Antiresorptive bisphosphonate agents are the mainstay of treatment for osteoporosis in both men and postmenopausal women. However, recent studies have raised concerns about the oversuppression of bone turnover related to the long-term use of bisphosphonates. Cases of atypical femoral diaphyseal and subtrochanteric fracture were reported recently in patients on long-term alendronate, and oversuppression of bone turnover was postulated to be the cause. We retrospectively reviewed all patients with femoral diaphyseal and subtrochanteric fracture presented between July 2003 and June 2008, and identified 10 patients who reported prior bisphosphonate use. Bone formation markers of all these patients were in the low range. Although the incidence of bisphosphonate-related atypical fracture accounts for an extremely low percentage of the total number of femoral diaphyseal and subtrochanteric fractures, we observed a steady increase from 0% in 2003 to 2004 to 25% in 2007 to 2008.
PMCID: PMC3027310  PMID: 21686468

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