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1.
Can Bisphosphonates Prevent Recurrent Fragility Fractures? A Systematic Review and Meta-Analysis of Randomized Controlled Trials.
Lee, SY, Jung, SH, Lee, SU, Ha, YC, Lim, JY
Journal of the American Medical Directors Association. 2018;(5):384-390.e1
Abstract
OBJECTIVES Although a few trials have explored whether bisphosphonates (BPs) prevented recurrent fragility fractures (FFs), little is known about the secondary preventative effects of BPs. Thus, we performed a meta-analysis to examine the effects of BPs on prevention of subsequent fractures, mortality, and on bone metabolic and functional parameters related to FF. We compared BP and control groups. DESIGN A meta-analysis of randomized controlled trials was conducted. SETTING AND PARTICIPANTS Twelve randomized controlled trials that included 5670 participants investigating the effects of BPs following FF were retrieved from PubMed, Embase, and the Cochrane Library. MEASURES We performed a pairwise meta-analysis using fixed- and random-effects models. RESULTS BPs exhibited significant secondary preventative effects after FF compared with controls [overall standardized mean difference = 0.766; 95% confidence interval (CI) 0.493-1.038; P < .001]. The risks of subsequent fracture (odds ratio = 0.499; 95% CI 0.418-0.596; P < .001) and mortality (odds ratio = 0.662; 95% CI 0.511-0.858; P = .002) decreased in the BP groups. Bone mineral density, bone turnover marker levels, pain at the fracture site, and health-related quality of life also differed significantly between the groups. CONCLUSIONS/IMPLICATIONS Our meta-analysis revealed that BPs administered after FF potentially prevented subsequent fractures and reduced mortality. Positive effects in terms of pain, quality of life, and increased bone mineral density and bone metabolism were also verified regardless of the fracture sites and the administration types (oral or intravenous). Therefore, more active BPs use is recommended to prevent recurrent fragility fractures. LEVEL OF EVIDENCE Level I, meta-analysis.
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2.
Clinical characteristics and bisphosphonates treatment of rare pregnancy- and lactation-associated osteoporosis.
Li, LJ, Zhang, J, Gao, P, Lv, F, Song, YW, Chang, XY, Zhao, DC, Wang, O, Jiang, Y, Xing, XP, et al
Clinical rheumatology. 2018;(11):3141-3150
Abstract
Pregnancy- and lactation-associated osteoporosis (PLO) is a rare disorder with poorly known etiology, pathophysiology, and therapy. We aimed to investigate the clinical characteristics of PLO and evaluate the effectiveness and safety of bisphosphonates on it. A total of 12 patients were diagnosed with PLO on the basis of medical history, bone mineral density (BMD), and/or fragility fractures during pregnancy and lactation. We investigated the clinical, biochemical, and radiological characteristics of patients. We assessed the effects of alendronate or zoledronic acid through observing the changes of bone turnover biomarkers and BMD during the treatment. Secondary osteoporosis was excluded by comprehensive differential diagnosis. The mean age of these patients was 31 ± 5 years old. All of these patients presented severe back pain. Multiple vertebral compression fractures (VCFs) were found in 10 patients, and the median (P25th, P75th) number of compressed vertebra was 3 (3, 5). Ten patients had vitamin D insufficiency or deficiency. Serum level of bone resorption marker (β-CTX with mean of 0.68 ± 0.41 ng/ml) was moderately higher than the normal range. BMD at lumbar spine, femoral neck, and total hip were low as 0.894 ± 0.153 g/cm2, 0.728 ± 0.090 g/cm2, and 0.728 ± 0.080 g/cm2, respectively. Either alendronate or zoledronic acid could effectively relieve bone pain, reduce β-CTX level, and increase BMD. PLO is a rare type of osteoporosis, which was characterized by increased bone resorption and decreased BMD, even VCFs. Bisphosphonate therapy was well tolerated and effective in management of PLO, but needed to be further verified in randomized controlled trial.
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3.
Pharmacological interventions for the prevention of insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults.
van den Blink, QU, Garcez, K, Henson, CC, Davidson, SE, Higham, CE
The Cochrane database of systematic reviews. 2018;(4):CD010604
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Abstract
BACKGROUND Pelvic radiotherapy is a treatment delivered to an estimated 150,000 to 300,000 people annually across high-income countries. Fractures due to normal stresses on weakened bone due to radiotherapy are termed insufficiency fractures. Pelvic radiotherapy-related interruption of the blood supply to the hip is termed avascular necrosis and is another recognised complication. The reported incidences of insufficiency fractures are 2.7% to 89% and risk of developing avascular necrosis is 0.5%. These complications lead to significant morbidity in terms of pain, immobility and consequently risk of infections, pressure sores and mortality. OBJECTIVES To assess the effects of pharmacological interventions for preventing insufficiency fractures and avascular necrosis in adults over 18 years of age undergoing pelvic radiotherapy. SEARCH METHODS We performed electronic literature searches in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase and DARE to 19 April 2017. We also searched trial registries. Further relevant studies were identified through handsearching of citation lists of included studies. SELECTION CRITERIA Randomised controlled trials (RCTs) or non RCTs with concurrent comparison groups including quasi-RCTs, cluster RCTs, prospective cohort studies and case series of 30 or more participants were screened. We included studies assessing the effect of pharmacological interventions in adults over 18 years of age undergoing radical pelvic radiotherapy as part of anticancer treatment for a primary pelvic malignancy. We excluded studies involving radiotherapy for bone metastases. We assessed use of pharmacological interventions at any stage before or during pelvic radiotherapy. Interventions included calcium or vitamin D (or both) supplementation, bisphosphonates, selective oestrogen receptor modulators, hormone replacement therapy (oestrogen or testosterone), denosumab and calcitonin. DATA COLLECTION AND ANALYSIS Two review authors independently assessed trial quality and extracted data. We contacted study authors to obtain missing data. Data were to be pooled using the random-effects model if study comparisons were similar, otherwise results were to be reported narratively. MAIN RESULTS We included two RCTs (1167 participants). The first RCT compared zoledronic acid with placebo in 96 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.The second RCT had four treatment arms, two of which evaluated zoledronic acid plus adjuvant androgen suppression compared with androgen suppression only in 1071 men undergoing pelvic radiotherapy for non-metastatic prostate cancer.Both studies were at a moderate to high risk of bias and all evidence was judged to be of very low certainty.The studies provided no evidence on the primary outcomes of the review and provided limited data in relation to secondary outcomes, such that meta-analyses were not possible. Both studies focused on interventions to improve bone health in relation to androgen deprivation rather than radiation-related insufficiency fractures and avascular necrosis. Few fractures were described in each study and those described were not specific to insufficiency fractures secondary to radiotherapy. Both studies reported that zoledronic acid in addition to androgen deprivation and pelvic radiotherapy led to improvements in BMD; however, the changes in BMD were measured and reported differently. There was no available evidence regarding adverse effects. AUTHORS' CONCLUSIONS The evidence relating to interventions to prevent insufficiency fractures and avascular necrosis associated with pelvic radiotherapy in adults is of very low certainty. This review highlights the need for prospective clinical trials using interventions prior to and during radiotherapy to prevent radiation-related bone morbidity, insufficiency fractures and avascular necrosis. Future trials could involve prospective assessment of bone health including BMD and bone turnover markers prior to pelvic radiotherapy. The interventions for investigation could begin as radiotherapy commences and remain ongoing for 12 to 24 months. Bone turnover markers and BMD could be used as surrogate markers for bone health in addition to radiographic imaging to report on presence of insufficiency fractures and development of avascular necrosis. Clinical assessments and patient reported outcomes would help to identify any associated adverse effects of treatment and quality of life outcomes.
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Postmenopausal Osteoporosis: A Clinical Review.
Watts, NB
Journal of women's health (2002). 2018;(9):1093-1096
Abstract
In postmenopausal women, osteoporotic fractures are more common than stroke, myocardial infarction, and breast cancer combined, and fractures can be costly and result in disability or death. Because there are no signs or symptoms of osteoporosis other than fracture, risk assessment is necessary to identify those at higher risk for clinical events. For women, a clinical fracture risk assessment (FRAX) is appropriate at menopause. Bone mineral density (BMD) measurement is recommended for women at age 65, and earlier for those who have risk factors. Adequate calcium, vitamin D, and weight-bearing exercise are important for bone health at all ages, and those at high risk for fracture based on BMD or FRAX should be offered medical therapy to reduce fracture risk after an appropriate medical evaluation. Bisphosphonates can accumulate in bone, so after a period of treatment, lower risk patients may be offered a period off drug therapy. However, the effects of denosumab are not sustained when treatment is discontinued, so there is no "drug holiday" with denosumab. Anabolic therapy can be offered to those with higher risk for fracture. Although rare safety concerns regarding atypical femoral fracture and osteonecrosis of the jaw have received prominent attention, for patients who are appropriately treated according to National Osteoporosis Foundation guidelines, the benefit of hip fracture risk reduction far outweighs the risk of these uncommon side effects. Accurate information for patients and shared decision-making are important for acceptance and persistent with appropriate treatment.
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Update on the Comprehensive Approach to Fragility Fractures.
Cohn, MR, Gianakos, AL, Grueter, K, Rosen, N, Cong, GT, Lane, JM
Journal of orthopaedic trauma. 2018;(9):480-490
Abstract
The prevention and treatment of fragility fractures continuously evolve. Adequate fracture care should involve treating the fracture itself and the underlying bone disease. Although effective treatments of osteoporosis are available, a large proportion of patients with fragility fractures are not prescribed antiosteoporotic medications after their injury. Recent advances in diagnostic tools, medications, and implementation of Fracture Liaison Services allow for more effective and comprehensive treatment or fragility fractures. In the Fracture Liaison Service model, a physician and physician extenders coordinate care. This includes a thorough medical and surgical history, metabolic bone disease laboratory testing, dual-energy x-ray absorptiometry screening, treatment, and long-term follow-up. Treatment options include nonpharmacologic treatment with calcium and vitamin D and antiresorptive and anabolic agents. Antiresorptive agents such as bisphosphonates and denosumab are first-line treatments for osteoporosis and anabolic agents such as teriparatide are effective in reducing bone density loss and have implications in fracture healing. In addition, new anabolic agents including antisclerostin antibodies and parathyroid hormone-related protein show promise as potential treatments to increase bone density.
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Medical Management of Otosclerosis.
de Oliveira Penido, N, de Oliveira Vicente, A
Otolaryngologic clinics of North America. 2018;(2):441-452
Abstract
Otosclerosis/otospongiosis is a primary osteodystrophy of the otic capsule that affects genetically predisposed individuals and leads to progressive hearing loss. Diagnosis is usually clinical, based on the findings of anamnesis, physical examination, and audiometric evaluation. However, high-resolution computed tomography scan and MRI have played an important role in the diagnosis and therapeutic approach of otosclerosis and in assisting in the differential diagnosis. The therapeutic approach is aimed at preventing, or at least minimizing, disease progression while attempting to restore hearing. The use of sodium fluoride and bisphosphonates can be an important adjunct, perhaps even primary treatment, in managing active lesions.
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Bone-targeted therapies to reduce skeletal morbidity in prostate cancer.
Dorff, TB, Agarwal, N
Asian journal of andrology. 2018;(3):215-220
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Abstract
Bone metastases are the main driver of morbidity and mortality in advanced prostate cancer. Targeting the bone microenvironment, a key player in the pathogenesis of bone metastasis, has become one of the mainstays of therapy in men with advanced prostate cancer. This review will evaluate the data supporting the use of bone-targeted therapy, including (1) bisphosphonates such as zoledronic acid, which directly target osteoclasts, (2) denosumab, a receptor activator of nuclear factor-kappa B (RANK) ligand inhibitor, which targets a key component of bone stromal interaction, and (3) radium-223, an alpha-emitting calcium mimetic, which hones to the metabolically active areas of osteoblastic metastasis and induces double-strand breaks in the DNA. Denosumab has shown enhanced delay in skeletal-related events compared to zoledronic acid in patients with metastatic castration-resistant prostate cancer (mCRPC). Data are mixed with regard to pain control as a primary measure of efficacy. New data call into question dosing frequency, with quarterly dosing strategy potentially achieving similar effect compared to monthly dosing for zoledronic acid. In the case of radium-223, there are data for both pain palliation and improved overall survival in mCRPC. Further studies are needed to optimize timing and combination strategies for bone-targeted therapies. Ongoing studies will explore the impact of combining bone-targeted therapy with investigational therapeutic agents such as immunotherapy, for advanced prostate cancer. Future studies should strive to develop biomarkers of response, in order to improve efficacy and cost-effectiveness of these agents.
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Altered microRNA expression profile in the peripheral lymphoid compartment of multiple myeloma patients with bisphosphonate-induced osteonecrosis of the jaw.
Musolino, C, Oteri, G, Allegra, A, Mania, M, D'Ascola, A, Avenoso, A, Innao, V, Allegra, AG, Campo, S
Annals of hematology. 2018;(7):1259-1269
Abstract
Bisphosphonates are formidable inhibitors of osteoclast-mediated bone resorption employed for therapy of multiple myeloma (MM) subjects with osteolytic lesions. Osteonecrosis of the jaw (ONJ) is an uncommon drug-induced adverse event of these agents. MicroRNAs (miRNAs) are a group of small, noncoding RNAs nucleotides, which are essential post-transcriptional controllers of gene expression. They have a central role in the normal bone development. The goal of our study was to investigate 18 miRNAs, whose targets were previously validated and described in MM subjects without ONJ, in peripheral lymphocytes of MM subjects with bisphosphonate-induced ONJ. Utilizing reverse transcription quantitative polymerase chain reaction, we evaluated miRNAs in five healthy subjects and in five MM patients with ONJ. Our experimental data revealed that a diverse miRNA signature for ONJ subjects emerged with respect to control subjects. Using the filter for in silico analysis, among the 18 miRNAs, we recognized 14 dysregulated miRNAs. All these miRNAs were significantly over-expressed in patients vs controls (MIR-16-1, MIR-21, MIR-23A, MIR-28, MIR-101-1, MIR-124-1, MIR-129, MIR-139, MIR-145, MIR-149, MIR-202, MIR-221, MIR-424, MIR-520). Among them, six were strongly upregulated (fourfold upregulated and more). These miRNAs target numerous pathways and genes implicated in calcium ion binding, bone resorption, mineralization of bone matrix, and differentiation and maintenance of bone tissue. A modified microRNA expression profile after zoledronate therapy could participate to the onset of ONJ. Targeting these miRNAs could provide a new opportunity for the prevention or treatment of ONJ.
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Prevalence and incidence of osteoporotic fractures in patients on long-term glucocorticoid treatment for rheumatic diseases: the Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) study.
Rossini, M, Viapiana, O, Vitiello, M, Malavolta, N, La Montagna, G, Maddali Bongi, S, Di Munno, O, Nuti, R, Manzini, CU, Ferri, C, et al
Reumatismo. 2017;(1):30-39
Abstract
Osteoporosis and fractures are common and invalidating consequences of chronic glucorticoid (GC) treatment. Reliable information regarding the epidemiology of GC induced osteoporosis (GIOP) comes exclusively from the placebo group of randomized clinical trials while observational studies are generally lacking data on the real prevalence of vertebral fractures, GC dosage and primary diagnosis. The objective of this study was to evaluate the prevalence and incidence of osteoporotic fractures and to identify their major determinants (primary disease, GC dosage, bone mineral density, risk factors, specific treatment for GIOP) in a large cohort of consecutive patients aged >21 years, on chronic treatment with GC (≥5 mg prednisone - PN - equivalent) and attending rheumatology centers located all over Italy. Glucocorticoid Induced OsTeoporosis TOol (GIOTTO) is a national multicenter cross-sectional and longitudinal observational study. 553 patients suffering from Rheumatoid Arthritis (RA), Polymyalgia Rheumatica (PMR) and Connective Tissue Diseases (CTDs) and in chronic treatment with GCs were enrolled. Osteoporotic BMD values (T score <-2.5) were observed in 28%, 38% and 35% of patients with CTDs, PMR or RA at the lumbar spine, and in 18%, 29% and 26% at the femoral neck, respectively. Before GC treatment, prevalent clinical fractures were reported by 12%, 37% and 17% of patients with CTDs, PMR, or RA, respectively. New clinical fragility fractures during GC treatment were reported by 12%, 10% and 23% of CTDs, PMR and RA patients, respectively. Vertebral fractures were the prevailing type of fragility fracture. More than 30% of patients had recurrence of fracture. An average of 80% of patients were in supplementation with calcium and/or vitamin D during treatment with GCs. Respectively, 64%, 80%, and 72% of the CTDs, PMR and RA patients were on pharmacological treatment for GIOP, almost exclusively with bisphosphonates. The GIOTTO study might provide relevant contributions to clinical practice, in particular by highlighting and quantifying in real life the prevalence of GIOP and relative fractures, the frequency of the main risk factors, and the currently sub-optimal prevention. Moreover, these results emphasize the importance of the underlying rheumatic disease on the risk of GIOP associated fractures.
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Chronic Myeloid Leukemia Associated Hypercalcemia: A Case Report and Literature Review.
Toro-Tobón, D, Agosto, S, Ahmadi, S, Koops, M, Bruder, JM
The American journal of case reports. 2017;:203-207
Abstract
BACKGROUND Hypercalcemia associated with chronic myeloid leukemia (CML) is an ominous sign. Although rare, several cases have been reported and multiple pathophysiologic mechanisms have been independently proposed. We present a patient case and a literature review of the clinical presentation and mechanisms of CML-associated hypercalcemia. CASE REPORT A 58-year-old male with a past medical history of CML diagnosed six years earlier, presented to the emergency department with one week of acute confusion, disorientation, polyuria, and polydipsia. On physical examination, we observed tachycardia, altered mental status, and dehydration. Blood analysis revealed leukocytosis, thrombocytosis, and marked hypercalcemia (18.6 mg/dL). His chest CT scan showed diffuse lytic lesions and bone destruction concerning for diffuse bone marrow involvement. The patient was diagnosed with hypercalcemia in the context of a CML blast phase. Treatment with hydration, calcitonin, and zoledronic acid lead to control of his symptoms and normalization of his serum calcium levels. After discharged, the patient was maintained on palliative treatment and zoledronic acid management without new episodes of hypercalcemia. However, eight months later, the patient died. CONCLUSIONS Evidence from the literature demonstrates a highly variable clinical presentation of CML-associated hypercalcemia, commonly occurring during an accelerated or a blast phase, and associated with poor survival. Multiple mechanisms could be involved and are not exclusive of each other. Better understanding of the pathophysiologic mechanisms involved in CML-associated hypercalcemia could lead to improvement in clinical and laboratory evaluation of these patients and be the foundation for the development of better management strategies and possibly target-directed therapy to positively improve prognosis.