Incidence of atypical nontraumatic diaphyseal fractures of the femur

Bisphosphonates reduce the rate of osteoporotic fractures in clinical trials and community practice. “Atypical” nontraumatic fractures of the diaphyseal (subtrochanteric or shaft) part of the femur have been observed in patients taking bisphosphonates. We calculated the incidence of these fractures within a defined population and examined the incidence rates according to duration of bisphosphonate use. We identified all femur fractures from January 1, 2007 until December 31, 2011 in 1,835,116 patients older than 45 years who were enrolled in the Healthy Bones Program at Kaiser Southern California, an integrated health care provider. Potential atypical fractures were identified by diagnostic or procedure codes and adjudicated by examination of radiographs. Bisphosphonate exposure was derived from internal pharmacy records. The results showed that 142 patients had atypical fractures; of these, 128 had bisphosphonate exposure. There was no significant correlation between duration of use (5.5 ± 3.4 years) and age (69.3 ± 8.6 years) or bone density (T‐score ?2.1 ± 1.0). There were 188,814 patients who had used bisphosphonates. The age‐adjusted incidence rates for an atypical fracture were 1.78/100,000/year (95% confidence interval [CI], 1.5–2.0) with exposure from 0.1 to 1.9 years, and increased to 113.1/100,000/year (95% CI, 69.3–156.8) with exposure from 8 to 9.9 years. We conclude that the incidence of atypical fractures of the femur increases with longer duration of bisphosphonate use. The rate is much lower than the expected rate of devastating hip fractures in elderly osteoporotic patients. Patients at risk for osteoporotic fractures should not be discouraged from initiating bisphosphonates, because clinical trials have documented that these medicines can substantially reduce the incidence of typical hip fractures. The increased risk of atypical fractures should be taken into consideration when continuing bisphosphonates beyond 5 years. © 2012 American Society for Bone and Mineral Research.     

Bone Turnover in Bone Biopsies of Patients with Low-Energy Cortical Fractures Receiving Bisphosphonates: A Case Series

Recent reports of long-term bisphosphonate-treated patients developing cortical fractures have raised concerns that such fractures may relate to excessive suppression of bone turnover after prolonged use of these drugs. To evaluate the bone histology of patients presenting with cortical fractures after bisphosphonate therapy, we conducted a retrospective analysis of patients treated at Washington University Bone Health Program presenting with a history of low-energy cortical fractures (femoral shaft, pelvis, rib, metatarsal, and ankle), who had received bisphosphonates for at least two consecutive years and had undergone bone biopsy. Fifteen of 54 patients who underwent bone biopsy between November 2004 and March 2007 met the criteria. Of these, 10 patients had findings of suppressed trabecular bone remodeling, as demonstrated by lack of double tetracycline labels. There were no significant differences in bone density, clinical features, and biochemical features between those with suppressed turnover and the other five subjects with normal remodeling. However, the low-turnover group had received bisphosphonates (primarily alendronate) for a significantly longer duration (6.5 ± 0.6 vs. 3.9 ± 0.8 years, P = 0.02). Thus, about two-thirds of patients presenting with cortical fractures while on long-term treatment with bisphosphonates had suppressed turnover. Since the prevalence of such histological findings in nonfracture patients remains unknown, the impact of suppressed bone turnover on the development of cortical fractures cannot be determined. Considering the widespread use of bisphosphonates, it appears that the overall risk of cortical fractures is low. However, there may be a subset of as yet unidentified patients who could be predisposed to this complication.     

Effect of teriparatide on pregnancy and lactation-associated osteoporosis with multiple vertebral fractures

Pregnancy and lactation-associated osteoporosis (PLO) is very rare, but it can cause severe vertebral compression fractures with disabling back pain. PLO patients have commonly been treated with antiresorptive agents against high bone turnover. There are, however, some concerns regarding the use of bisphosphonates: (1) PLO occurs during the first pregnancy with a high possibility of recurrence during the second pregnancy, (2) long-term outcomes of bisphosphonates in PLO are lacking, and (3) there is a possibility of bisphosphonates accumulated in the bones crossing the placenta. Therefore, alternative therapies must be considered. We analyzed the effect of teriparatide (TPTD), the human recombinant parathyroid hormone (1-34), for 18?months in three women with PLO. Multiple vertebral fractures with severe back pain appeared within 6?months after their first childbirth. Two of them had a family history of osteoporosis. Lactation was discontinued immediately after diagnosis of PLO. Calcium carbonate, cholecalciferol, and TPTD were prescribed. The back pain immediately resolved. Bone mineral density (BMD) increased by 14.5-25.0% (mean 19.5%) at the lumbar spine and by 9.5-16.7% (mean 13.1%) at the femoral neck, after 18?months of treatment. The final Z scores in these PLO patients were nearly normalized. Two women had a second baby without any complication. BMD significantly improved after 18 months of treatment with TPTD without further fractures. In conclusion, TPTD should be considered to avoid long-term morbidity in young patients with PLO and is highly encouraged for use in PLO patients with multiple vertebral fractures.     

Atypical fractures associated with bisphosphonate use post-renal transplantation

Bone disease is a major cause of morbidity post renal transplantation. The authors present a case of adynamic bone disease and atypical fractures associated with the use of bisphosphonates following renal transplantation. The uncertain role of parathyroidectomy and bone mineral density scans is also reviewed.     

Evaluation and management of bone disease and fractures post transplant

Bone disease is common in recipients of kidney, liver, heart, and lung transplants and results in fractures in 20–40% of patients, a rate much higher than expected for age. Fractures occur because of the presence of bone disease as well as other factors such as neuropathy, poor balance, inactivity, and low body or muscle mass. Major contributors to bone disease include both preexisting bone disease and bone loss post transplant, which is greatest in the first 6–12 months when steroid doses are highest. Bone disease in kidney transplant recipients should be considered different from that which occurs in other solid organ transplant recipients for several reasons including the presence of renal osteodystrophy, which contributes to low bone mineral density in these patients; the location of fractures (more common in the legs and feet in these patients than in spine and hips as in other solid organ recipients); and the potential danger in using bisphosphonate therapy, which may cause more harm than good in kidney transplant recipients with low bone turnover.Evaluation in all patients should preferably occur in the pretransplant period or early post transplant and should include assessment of fracture risk as well as metabolic factors that can contribute to bone disease. Bone mineral density measurement is recommended in all patients even if its predictive value for fracture risk in the transplant population is unproven.Management of bone disease should be directed toward decreasing fracture risk as well as improving bone density. Pharmacologic and nonpharmacologic treatment strategies are discussed in this review. Although there have been many studies describing a beneficial effect of bisphosphonates and vitamin D analogues on bone density, none have been powered to detect a decrease in fracture rate.     

Bisphosphonate Use in Acute and Chronic Spinal Cord Injury: A Systematic Review

Background/Objective: Bone density loss occurs rapidly after traumatic spinal cord injury (SCI) and is associated with low-energy fractures below the level of injury, commonly occurring around the knee. Bisphosphonates have been tested as potential agents to prevent bone loss after SCI, but no guidelines exist for clinical use of bisphosphonates in these patients. The objective of this study was to systematically review and evaluate evidence quality in studies of bisphosphonate use in patients with post-treatment follow-up of sublesional bone mineral density.

Methods: Literature search in MEDLINE/PubMed and ISI database using key words bisphosphonates, spinal cord injury, quadriplegia, paraplegia, and tetraplegia.

Results: The search identified 6 experimental studies and 1 quasi-experimental study of bisphosphonate therapy in patients with acute and chronic SCI. The studies were small and of fair or poor quality, and none included fracture outcomes. Mild attenuation of bone density loss with acute administration of bisphosphonates after SCI was found at some measurement sites but was not always maintained during follow-up.

Conclusions: Data were insufficient to recommend routine use of bisphosphonates for fracture prevention in these patients. Current studies are limited by heterogeneity of patient populations and outcome measures. Uniform bone density measurement sites with rigorous quality control and compliance monitoring are needed to improve reliability of outcomes. Future studies should address specific populations (acute or chronic SCI) and should assess fracture outcomes.     

与双膦酸盐类药物相关的非典型股骨骨折的研究进展

双膦酸盐类药物是治疗骨质疏松症的常用药物之一。它们的应用大大降低了骨质疏松症相关的椎体、非椎体骨折的发生率。然而,近年来美国食品药品监督管理局发布安全警告:长期使用双膦酸盐可能导致下颌骨坏死、心房颤动、非典型股骨骨折等。最近关于长期应用双膦酸盐与非典型骨折的关系越来越受到关注。这些低能量性骨折也称为脆性骨折。其多发生于股骨转子下或股骨干。目前认为双膦酸盐可能通过长期严重地过度抑制骨转换,导致骨重塑受损,骨微损伤累积,骨脆性增加,从而诱发自发性骨折。女性、亚裔、西班牙裔人种、体重指数、长期应用糖皮质激素、长期应用双膦酸盐且无药物假期被认为是非典型股骨骨折的危险因素。美国骨与矿物质研究学会推荐非典型骨折患者应立即停用双膦酸盐类药物,并予以钙剂、维生素D及特立帕肽治疗;对于完全性骨折患者,建议行股骨全长髓内钉内固定以保护整个股骨。总之,与经典的高能量性骨折相比,非典型股骨骨折具有独特的病理生理学特点、临床表现及影像学特征等。这里我们基于近期研究及文献检索做一综述。     

Treatment of Osteoporosis with Parathyroid Hormone and Teriparatide

Nowadays osteoporosis treatment is based primarily on therapy with antiresorptive agents, like the bisphosphonates. Parathyroid hormone (Preotact) and human recombinant parathyroid hormone peptide 1–34 (Teriparatide) are relatively new for the treatment of osteoporosis and belong to the group of anabolic agents. Both agents demonstrated an increase in bone mineral density and a significant reduction in vertebral fractures in postmenopausal women with osteoporosis when given for 18–24 months. Data on nonvertebral fractures are, however, not clear-cut, and so far only bisphosphonates and strontium ranelate have been demonstrated to reduce all types of fractures and therefore remain the front-line option for treatment of osteoporosis. As the safety, tolerability, and cost of the therapy also influence the choice of therapy, Preotact and Teriparatide might be useful additions to the armamentarium for (second-line) treatment of osteoporosis. An erratum to this article can be found at     

Recovery from Severe Glucocorticoid-Induced Osteoporosis in an Adolescent Boy

An 18-yr-old boy presented with extreme back pain as the result of multiple vertebral fractures. At age 16 he had developed a tumor of the mesencephalon. A ventriculoperitoneal shunt was established surgically. One year later, he developed progressive neurologic deficits in his upper and lower limbs with an increase in the size of the tumor. He was treated by irradiation and high doses of glucocorticoids. Although the neurologic deficits progressively improved, he developed severe back pain resulting in complete immobilization for 3 mo in spite of neurologic recovery. Multiple vertebral fractures were diagnosed by X-ray. Bone density was extremely low (Z-score of -5.5 in the spine and -3.1 in the femoral neck). The patient was treated with calcium and vitamin D, calcitonin, bisphosphonates, physiotherapy, and progressive mobilization. Glucocorticoids were decreased and could be stopped as the neurologic deficits fully recovered. After 1 yr of treatment with intermittent i.v. pamidronate, bone density had increased by 40% in the spine and by 25% in the femoral neck despite growth arrest. He progressively recovered from back pain and is now, at age 20, fully ambulant, studying mechanical engineering, without neurologic sequelaes and free of glucocorticoids. Magnetic resonance imaging revealed that the tumor had disappeared. This case proves that treatment of symptomatic glucocorticoid-induced osteoporosis during puberty can be rewarding, even when multiple and invalidating vertebral fractures already exist.     

Bisphosphonate Use in Acute and Chronic Spinal Cord Injury: A Systematic Review

Background/Objective:

Bone density loss occurs rapidly after traumatic spinal cord injury (SCI) and is associated with low-energy fractures below the level of injury, commonly occurring around the knee. Bisphosphonates have been tested as potential agents to prevent bone loss after SCI, but no guidelines exist for clinical use of bisphosphonates in these patients. The objective of this study was to systematically review and evaluate evidence quality in studies of bisphosphonate use in patients with post-treatment follow-up of sublesional bone mineral density.

Methods:

Literature search in MEDLINE/PubMed and ISI database using key words bisphosphonates, spinal cord injury, quadriplegia, paraplegia, and tetraplegia.

Results:

The search identified 6 experimental studies and 1 quasi-experimental study of bisphosphonate therapy in patients with acute and chronic SCI. The studies were small and of fair or poor quality, and none included fracture outcomes. Mild attenuation of bone density loss with acute administration of bisphosphonates after SCI was found at some measurement sites but was not always maintained during follow-up.

Conclusions:

Data were insufficient to recommend routine use of bisphosphonates for fracture prevention in these patients. Current studies are limited by heterogeneity of patient populations and outcome measures. Uniform bone density measurement sites with rigorous quality control and compliance monitoring are needed to improve reliability of outcomes. Future studies should address specific populations (acute or chronic SCI) and should assess fracture outcomes.     

Multidetector-row computed tomography is useful to evaluate the therapeutic effects of bisphosphonates in glucocorticoid-induced osteoporosis

Osteoporosis is one of the major complications of glucocorticoid therapy. Osteoporosis is usually defined by the levels of bone mineral density (BMD) assessed by dual energy X-ray absorptiometry (DEXA); however, glucocorticoids often induce fractures in patients with normal BMD. Thus, novel diagnostic approaches are required. In this study, we examined whether multidetector-row computed tomography (MDCT) is useful to assess the bone status in glucocorticoid-induced osteoporosis (GIO). Because bisphosphonates have been proven to prevent bone fracture in GIO, we tried to detect the therapeutic effects of bisphosphonates in GIO by MDCT. Fifteen Japanese patients with immunoglobulin A nephropathy who had normal renal function were enrolled in this open-label randomized trial. Patients were randomly divided into three groups—calcitriol (VD), menatetrenone (VK), or bisphosphonate (Bis). Bone conditions were analyzed twice by three different methods—bone turnover markers, DEXA, and MDCT—at the start and 6 months after the start of therapy. Both bone markers and DEXA could not detect significant differences among the therapeutic groups; however, MDCT-based analyses detected the preventive effects of bisphosphonates in GIO. Compared to VD, Bis improved structural indices, such as bone volume fraction, trabecular separation, marrow star volume, and structure model index whereas the difference between VD and VK was not significant. Finite element analysis revealed that simulated fracture load in the Bis group was significantly improved. These findings suggested that MDCT-based assessment is superior to bone markers and/or DEXA in assessing the therapeutic effect of bisphosphonates on GIO.     

妊娠和哺乳相关的骨质疏松症病例分享

妊娠和哺乳相关的骨质疏松症(pregnancy and lactation-associated osteoporosis,PLO)是一种罕见的临床特殊骨质疏松症,大多数病例出现在初产妇的妊娠晚期或产后早期,但是也会发生于经产妇中.PLO患者主要表现为在妊娠晚期以及产后初期严重的下背部疼痛、身高下降和脆性骨折,尤其是椎...     

We need a break: Bisphosphonates

Bone is a dynamic tissue. It remodels, thereby maintaining serum calcium, repairing micro damage and maintaining strength. A reduction in the strength of bone leads to osteoporosis that may manifest clinically as low energy vertebral and non-vertebral fractures. The bone strength, in turn, is determined by its material, structural properties and on its remodeling potential. Commonly, osteoporosis is objectively evaluated by ‘T’ and ‘Z’ scores and these are the indicators of bone density as determined by Dexa scan; these scores correlate inversely with the fracture risk. Quite often, we forget that Dexa scan results are not the only factors determining bone strength and the association between bone density and bone strength is not fixed, and is exemplified by the example of "osteopetrosis". The same issue is happening with the prolonged use of bisphosphonates (BP's).     

Bisphosphonates for the Prevention of Fractures in Osteogenesis Imperfecta: Meta‐Analysis of Placebo‐Controlled Trials

Bisphosphonates are widely used off‐label in the treatment of patients with osteogenesis imperfecta (OI) with the intention of reducing the risk of fracture. Although there is strong evidence that bisphosphonates increase bone mineral density in osteogenesis imperfecta, the effects on fracture occurrence have been inconsistent. The aim of this study was to gain a better insight into the effects of bisphosphonate therapy on fracture risk in patients with osteogenesis imperfecta by conducting a meta‐analysis of randomized controlled trials in which fractures were a reported endpoint. We searched Medline, Embase, and the Cochrane Central Register of Controlled Trials in which the effects of bisphosphonates on fracture risk in osteogenesis imperfecta were compared with placebo and conducted a meta‐analysis of these studies using standard methods. Heterogeneity was assessed using the I² statistic. Six eligible studies were identified involving 424 subjects with 751 patient‐years of follow‐up. The proportion of patients who experienced a fracture was not significantly reduced by bisphosphonate therapy (Relative Risk [RR] = 0.83 [95% confidence interval 0.69–1.01], p = 0.06) with no heterogeneity between studies (I² = 0). The fracture rate was reduced by bisphosphonate treatment when all studies were considered (RR = 0.71 [0.52–0.96], p = 0.02), but with considerable heterogeneity (I² = 36%) explained by one study where a small number of patients in the placebo group experienced a large number of fractures. When this study was excluded, the effects of bisphosphonates on fracture rate was not significant (RR = 0.79 [0.61–1.02], p = 0.07, I² = 0%). We conclude that the effects of bisphosphonates on fracture prevention in osteogenesis imperfecta are inconclusive. Adequately powered trials with a fracture endpoint are needed to further investigate the risks and benefits of bisphosphonates in this condition. © 2014 American Society for Bone and Mineral Research.     

Update on the use of distal radial bone density measurements in prediction of hip and Colles' fracture risk

A controversy has developed around the question as to whether bone density values from the distal radius can be used to accurately predict risk of future fractures. To address this question, two separate studies were undertaken: (a) Bone density was measured in 460 healthy ambulatory women living in retirement centers in the state of North Carolina; 83% of these women were followed for up to 60 months for occurrence of minimal trauma hip and wrist fractures. Thirty-one minimal trauma fractures were reported in our study population, representing 8% of those followed. The fracture incidence density rate showed a close inverse relationship with incremental changes in bone density at the distal site. Twenty-eight of the 31 fractures were reported in women with bone density values below the 325-mg/cm2 "at risk" value. (b) Bone density values of the distal radius and the lumbar spine from 360 women (aged 18-85 years) from the Chapel Hill area were used to analyze the error in predicting individual spinal density from the distal radial density. Although the overall correlation was high (r = 0.67) and the confidence intervals were narrow, the prediction intervals were quite wide. Thus, prediction of an individual value of spine density from the distal radius density would result in a value with a range too wide to be clinically useful. We conclude that single-photon absorptiometry appears to be a useful tool for screening normal populations of asymptomatic women for prediction of hip or Colles' fracture risk even though it has limited usefulness in prediction of spinal fracture risk or individual values for spinal density.     

Mineralization pattern of vertebral bone material following fragility fracture of the spine

Little is known whether trabecular bone matrix mineralization is altered at the site of osteoporotic vertebral fractures. Bone mineralization density distribution (BMDD) was assessed in trabecular bone of acute, single-level compression fractures of the spine at various stages of fracture repair using quantitative backscattered electron imaging (qBEI). The grading of the repair stage was performed by histological methods. From 20 patients, who underwent either kyphoplasty (n=18) or vertebroplasty (n=2), a vertebral bone biopsy was taken prior to cement augmentation. Six patients took bisphosphonates (BP) prior to fracture. Three study groups were formed: N1=early-, N2=late-healing and B=BP treatment at late healing stage. In general, all groups had an altered BMDD when compared to historical normative reference data. Mean matrix mineralization (CaMean) was significantly (p<0.001) lower in all groups (N1: -5%, N2: -16%, and B2: -16%). In N2, CaMean was -13.1% (p<0.001) lower than N1. At this stage, deposition of new bone matrix and/or formation of woven bone are seen, which also explains the more heterogeneous matrix mineralization (CaWidth). Moreover, BP treatment (B2) led to a significant reduction in CaWidth (-28.5%, p<0.001), when compared to N2. Bone tissue from vertebrae with acute compression fractures reveals a large variation in matrix mineralization depending on the stage of repair. Bisphosphonate treatment does affect the mineralization pattern of tissue repair. The low mineralization values found in early stage of repair suggest that altered bone material properties may play a role in the occurrence of fragility fractures of the spine.     

Secondary Fracture Prevention: Consensus Clinical Recommendations from a Multistakeholder Coalition

Osteoporosis-related fractures are undertreated, due in part to misinformation about recommended approaches to patient care and discrepancies among treatment guidelines. To help bridge this gap and improve patient outcomes, the American Society for Bone and Mineral Research assembled a multistakeholder coalition to develop clinical recommendations for the optimal prevention of secondary fracture among people aged 65 years and older with a hip or vertebral fracture. The coalition developed 13 recommendations (7 primary and 6 secondary) strongly supported by the empirical literature. The coalition recommends increased communication with patients regarding fracture risk, mortality and morbidity outcomes, and fracture risk reduction. Risk assessment (including fall history) should occur at regular intervals with referral to physical and/or occupational therapy as appropriate. Oral, intravenous, and subcutaneous pharmacotherapies are efficacious and can reduce risk of future fracture. Patients need education, however, about the benefits and risks of both treatment and not receiving treatment. Oral bisphosphonates alendronate and risedronate are first-line options and are generally well tolerated; otherwise, intravenous zoledronic acid and subcutaneous denosumab can be considered. Anabolic agents are expensive but may be beneficial for selected patients at high risk. Optimal duration of pharmacotherapy is unknown but because the risk for second fractures is highest in the early post-fracture period, prompt treatment is recommended. Adequate dietary or supplemental vitamin D and calcium intake should be assured. Individuals being treated for osteoporosis should be reevaluated for fracture risk routinely, including via patient education about osteoporosis and fractures and monitoring for adverse treatment effects. Patients should be strongly encouraged to avoid tobacco, consume alcohol in moderation at most, and engage in regular exercise and fall prevention strategies. Finally, referral to endocrinologists or other osteoporosis specialists may be warranted for individuals who experience repeated fracture or bone loss and those with complicating comorbidities (eg, hyperparathyroidism, chronic kidney disease). © 2019 American Society for Bone and Mineral Research.     

Prevalence,pathogenesis, and treatment options for mastocytosis-related osteoporosis

Mastocytosis is a rare condition characterized by abnormal mast cell proliferation and a broad spectrum of manifestations, including various organs and tissues. Osteoporosis is one of the most frequent manifestations of systemic mastocytosis, particularly in adults. Osteoporosis secondary to systemic mastocytosis is a cause of unexplained low bone mineral density that should be investigated when accompanied by suspicious clinical elements. Bone involvement is often complicated by a high recurrence of fragility fractures, mainly vertebral, leading to severe disability. The mechanism of bone loss is the result of different pathways, not yet fully discovered. The main actor is the osteoclast with a relative or absolute predominance of bone resorption. Among the stimuli that drive osteoclast activity, the most important one seems to be the RANK-RANKL signaling, but also histamine and other cytokines play a significant role in the process. The central role of osteoclasts made bisphosphonates, as anti-resorptive drugs, the most rational treatment for bone involvement in systemic mastocytosis. There are a few small studies supporting this approach, with large heterogeneity of drug and administration scheme. Currently, zoledronate has the best evidence in terms of gain in bone mineral density and bone turnover suppression, two surrogate markers of anti-fracture efficacy.