Bisphosphonate-treated Patients Research Articles

Adverse Effects of Bisphosphonates

Use of bisphosphonates has been growing steadily in the last decade. This follows the introduction of simpler dosing regimes, the availability of lower-priced generics, and concerns about the safety of hormone-replacement therapy. Bisphosphonates have a relatively good safety record and are tolerated by the majority of patients, but serious adverse events have been recorded in some cases. Only the most common of adverse effects are robustly observable in clinical trials. In general, studies were not powered to detect effects that were lower in incidence than fractures. This review of adverse events in bisphosphonate-treated patients was based on published information from case reports, case series, claims databases, national databases, surveys, adverse event reporting databases, and single or pooled clinical trials. The most common acute adverse events with bisphosphonates for osteoporosis are gastrointestinal discomfort and acute influenza-like illness. Renal complications are very rare with oral bisphosphonates and rare with i.v. bisphosphonates when used appropriately. Based on our current knowledge, skeletal events in the form of osteonecrosis of the jaw and atypical fragility fractures are rare compared with the risk of osteoporotic fractures, at least in patients with the same risk of fractures as those in the phase III trials. It is biologically plausible that atypical fragility fractures could follow from suppression of bone remodeling, but high-quality studies proving causality are lacking. Physicians are advised to critically reassess BMD and risk profile after 3-5 years of therapy to avoid treatment in patients at low risk.

Individualized Therapy to Prevent Bone Mineral Density Loss after Kidney and Kidney-Pancreas Transplantation

Most patients who undergo kidney or kidney-pancreas transplantation have renal osteodystrophy, and immediately after transplantation bone mineral density (BMD) commonly falls. Together, these abnormalities predispose to an increased fracture incidence. Bisphosphonate or calcitriol therapy can preserve BMD after transplantation, but although bisphosphonates may be more effective, they pose potential risks for adynamic bone. A total of 153 kidney (61%) and kidney-pancreas (39%) transplant recipients were allocated to bisphosphonate (62%) or calcitriol (38%) therapy using an algorithm that incorporated BMD, prevalent vertebral fracture, biomarkers of bone turnover, and risk factor assessment. Patients received cholecalciferol and calcium as appropriate and were followed for 12 mo. Patients who were treated with bisphosphonates had lower BMD at the lumbar spine and femoral neck and longer time on dialysis. Age and gender were similar between the groups. At 12 mo, bisphosphonate-treated patients had significant BMD increases at the lumber spine and femoral neck and a negative trend at the wrist. Patients who were allocated to calcitriol, who were assessed to have lower baseline fracture risk, had no significant change in BMD at any site. At 1 yr, mean levels of bone turnover marker and intact parathyroid hormone normalized in both groups. Incident fracture rates did not differ significantly. With targeted treatment, BMD levels were stable or improved and bone turnover markers normalized. This algorithm provides a guide to targeting therapy after transplantation that avoids BMD loss and may reduce suppression of bone turnover.

Osteonecrosis of the Jaw Correlated to Bisphosphonate Therapy in Non-oncologic Patients: Clinicopathological Features of 24 Patients

Osteonecrosis of the jaws (ONJ) is a well known side effect of bisphosphonate therapies in patients with multiple myeloma or other malignancies. Its real incidence is still undetermined, and only few cases of ONJ in patients taking bisphosphonates for non-oncologic diseases have been reported. It was postulated that the clinical features, predisposing factors, and treatment outcome of this subset of patients might be different from those of oncologic patients. Over a 4 year period, a total of 102 bisphosphonate-treated patients affected by ONJ were identified. Among these, 24 patients underwent bisphosphonate therapy for non-neoplastic disease and their profile was analyzed. In this study cohort, bisphosphonates had been administered mainly for postmenopausal osteoporosis (20/24 patients, 83.3%), the duration of therapy until presentation of ONJ ranging from 11 to 40 months and the most common triggering event being dentoalveolar surgery. All patients were nonsmokers; 6 manifested multiple ONJ lesions and only 3 of them had possible comorbidities. Surgical debridement was performed in 19 patients for a total of 22 lesions, which were individually considered in the followup. The latter showed complete remission of ONJ in 21/22 lesions. Although it might be considered a rare condition in non-oncologic patients, ONJ is a harmful side effect of bisphosphonate therapies. Clinicians must be aware of this entity, inform patients of the risks related to dental surgery, and possibly undertake adequate preventive measures.

Bisphosphonates and atrial fibrillation: Bayesian meta-analyses of randomized controlled trials and observational studies

BackgroundOccurrence of atrial fibrillation (AF) amongst bisphosphonate users has been increasingly reported but results are conflicting. We performed a Bayesian meta-analysis to address the possible association between the occurrence of AF and bisphosphonate use and estimated the posterior probability of development of AF with bisphosphonate use.MethodsRandomized controlled trials (RCTs) evaluating the efficacy and safety of bisphosphonates for treating and preventing osteoporosis, and observational studies investigating the incidence of AF amongst bisphosphonate users, were searched in electronic databases. We pooled the effect size with Bayesian meta-analysis for odds ratio (OR) and calculated its posterior probability of development of AF in bisphosphonate users for RCTs and observational studies, reported with the 95% credible interval (CI).ResultsOf 1751 potentially relevant citations initially retrieved, 4 RCTs and 2 reports of RCTs, and 3 observational studies were included for this meta-analysis. On pooling the RCTs, there was a non-significantly higher risk of overall (OR 1.184, 95% CI 0.837-1.656) and serious AF (OR 1.590, 95% CI 0.613-3.751) in bisphosphonate-treated patients. Combining data of observational studies also revealed a non-significantly higher risk of AF in bisphosphonate users (OR 1.251, 95% CI 0.980-1.732). Using Bayesian meta-analysis based on the effect size of observational studies as the prior, the posterior probability of OR>1.2 in the development of AF amongst bisphosphonate users in the RCTs was 0.484. Egger's regression demonstrated no notable publication bias in all the analyses.ConclusionThe current meta-analysis revealed no evidence of a higher risk of AF associated with bisphosphonate use. Nevertheless, based on Bayesian meta-analysis with the effect size of the observational studies as the prior, the posterior probabilities of development of AF was found to be 0.484 if the risk of AF was estimated to be more than 20%. The results of the current meta-analysis thus offer clinicians the practical probability of development of AF in patients who take bisphosphonates for the treatment of bone loss and corticosteroid induced osteoporosis.

Effects of Yearly Zoledronic Acid 5 mg on Bone Turnover Markers and Relation of PINP With Fracture Reduction in Postmenopausal Women With Osteoporosis

In patients with osteoporosis treated with antiresorptive agents, reduction in bone turnover explains much of the observed fracture risk reduction. Lower levels of bone turnover markers (BTMs) appear to be associated with a lower risk of fracture in bisphosphonate-treated patients. BTMs were measured in a subset of subjects in the HORIZON Pivotal Fracture Trial. Annual infusions of zoledronic acid 5 mg significantly reduced BTMs: median decrease of 50% for beta-C-terminal telopeptides of type 1 collagen (beta-CTX), 30% for bone alkaline phosphatase (ALP), and 56% for procollagen type 1 amino-terminal propeptide (PINP). The mean level of BTMs decreased in treated patients but remained within the premenopausal range before the next injection. The percentage of zoledronic acid-treated patients with values below the premenopausal reference range at all time points was 1.7%, 17.8%, and 19% for bone ALP, CTX, and PINP, respectively. The third injection of zoledronic acid resulted in 60% reduction of beta-CTX within 9-11 days, followed by a gradual increase, indicating the persistence of osteoclastic bone resorption. The association between changes in BTMs and fracture incidence was assessed in 1132 patients who had PINP measurements at baseline and 1 yr. There was no association between low PINP levels at 1 yr and increased fracture incidence. In summary, (1) annual injections of zoledronic acid reduced BTMs in the premenopausal range, with a significant response persisting after the third infusion; and (2) low levels of PINP were not associated with increased fracture risk.

Studying the role of microcracks in the pathophysiology of BRONJ

There has been a speculation about the potential role of microdamage in the pathophysiology of bisphosphonaterelated osteonecrosis of the jaw (BRONJ) since the condition was first described five years ago. Much of the speculation is fueled by studies showing that treatment with bisphosphonates causes significant reductions in bone turnover and is associated with significant accumulation of microdamage at multiple bone sites [1–6]. In a recent paper, Hoefert et al. [7] report that microdamage exists in just over 50% of bone tissue samples collected from patients with BRONJ and conclude that microdamage “ could be af irst step in the pathogenesis of bisphosphonate-related ONJ.” Given the importance of trying to understand the pathogenesis of BRONJ, Hoefert and colleagues are commended for attempting to study the role of microdamage accumulation in this condition. However, there are several aspects of this study that are important to consider when evaluating the conclusions. Hoefert and colleagues studied bone tissue samples from patients who had been diagnosed with BRONJ, as well as from patients who had various other conditions (radiationinduced osteonecrosis, osteomyelitis, bisphosphonatetreated patients without osteonecrosis of the jaw, and individuals with osteoporosis who were untreated). Bone samples were collected during routine oral surgeries such as extractions, resections, or removal of the sequestra. The evaluation of the tissue was focused on microdamage, which the authors assessed using scanning electron microscopy. They found that 54% of the samples from patients

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.

Bone Scintigraphy and SPECT/CT of Bisphosphonate-Induced Osteonecrosis of the Jaw

Endovenous bisphosphonate therapy seems associated with osteonecrosis of the jaw. The aim of this study was to evaluate the additional diagnostic value of hybrid SPECT/CT in 99mTc-methylene diphosphonate 3-phase bone scintigraphy of osteonecrosis of the jaw in bisphosphonate-treated patients. We studied 15 patients (12 women and 3 men) with extraoral tumors affected by lytic bone metastases and multiple myeloma. All patients were previously treated with intravenous bisphosphonates (zoledronic acid) for 1-3 y, were negative for dental disease at clinical examination, and had suspected osteonecrosis of the jaw. All 15 patients underwent panoramic x-ray orthopantomography, CT or MRI (or both), microbiologic examination, 3-phase bone scintigraphy, and SPECT/CT of the maxillary region. Three-phase bone-scintigraphy showed increased perfusion and an increased blood pool in 9 of 12 and 10 of 12 patients, respectively; at the metabolic phase, SPECT was positive in all patients and showed abnormal hyperactivity in the maxilla of 2 patients, in the mandible of 9 patients, and in both the mandible and the maxilla of 4 patients. Hybrid SPECT/CT was of particular value in 8 of 15 patients, allowing discrimination of the osteonecrotic core from nearby hyperactivity due to viable bone. Whole-body scintigraphy showed remote and multiple metastases in all patients. Orthopantomography showed nonspecific bone rarefaction in all patients but was not able to aid diagnosis of osteonecrosis of the jaw. CT and MRI showed anomalies in all symptomatic patients: CT was helpful in evaluating both cortical and trabecular bone aspects, and MRI was able to detect soft-tissue involvement but not cortical bone destruction. In appropriately selected oncology patients treated with bisphosphonates, an increased uptake of 99mTc-methylene diphosphonate in maxillary bones may suggest probable osteonecrosis of the jaw. In such cases, SPECT/CT may be of value in increasing the diagnostic accuracy of bone scanning, providing a precise functional anatomic correlation for the definition of the extent of disease.

Atraumatic Teeth Extraction in Bisphosphonate-Treated Patients

The purpose of this study was to suggest an alternative technique for atraumatic teeth extraction that would prevent bone exposure and the associated complication of osteonecrosis of the jaws in bisphosphonate (BP)-treated patients, without terminating the treatment. A total of 10 patients treated with BPs for multiple myeloma, metastatic breast cancer, and osteoporosis, requiring dental extractions of nontreatable teeth, were included in this study. The extractions were performed by means of orthodontic elastics placed around the roots, causing slow and gradual exfoliation of the teeth. The technique was applied to 21 roots of 15 teeth. A total of 19 roots exfoliated spontaneously. Two roots had to be removed with minimal manipulation by forceps. The mean time required for exfoliation was 5.8 weeks. All sockets showed soft tissue secondary healing and there were no signs of inflammation or exposed bone during the 9-month follow-up. Atraumatic extraction by use of elastics is a safe technique that may be used in BP-treated patients to prevent osteonecrosis of the jaws.

Effects of bisphosphonates on tooth eruption in children with osteogenesis imperfecta

Bisphosphonates are currently used in the therapy of osteogenesis imperfecta (OI) to decrease the bone fragility observed in OI patients. Bisphosphonate therapy delays tooth eruption in rats. The aim of this study was to determine whether or not bisphosphonate therapy delays tooth eruption in children. The clinical emergence of teeth was observed and the calculated dental age and the number of delayed teeth were determined for 33 OI patients treated with bisphosphonates and for strictly gender- and age-matched controls. There were significant differences between bisphosphonate-treated patients and controls for calculated dental age and number of delayed teeth. Bisphosphonate therapy was associated with a mean delay of 1.67 yr in tooth eruption in children with OI.

Increase in Bone Mass After Correction of Vitamin D Insufficiency in Bisphosphonate-Treated Patients

Increase in Bone Mass After Correction of Vitamin D Insufficiency in Bisphosphonate-Treated Patients

Increase in Bone Mass After Correction of Vitamin D Insufficiency in Bisphosphonate-Treated Patients

To assess the relative contribution of vitamin D insufficiency to loss of bone mineral density (BMD) in patients taking bisphosphonates. Patients were eligible for inclusion if they had osteoporosis or osteopenia and demonstrated a decline in BMD during the preceding year while taking stable doses of alendronate or risedronate, plus supplemental calcium and vitamin D. Patients with previously known secondary causes of osteoporosis were excluded from the study. Eligible patients underwent prospective measurement of bilateral hip and lumbar spine BMD by dual-energy x-ray absorptiometry, serum 25-hydroxyvitamin D (25-OHD), 1,25-dihydroxyvitamin D, intact parathyroid hormone, osteocalcin, and thyroid-stimulating hormone (thyrotropin), and urinary calcium:creatinine ratio. Annual BMD was assessed in 175 previously bisphosphonate-responsive patients with low BMD. Of the 175 patients, 136 (78%) had either a significant interval increase or no change in BMD, whereas 39 (22%) had a significant decrease. Of the 39 patients who lost BMD, 20 (51%) had vitamin D insufficiency (25-OHD <30 ng/mL). After a single course of orally administered vitamin D2 (500,000 IU during a 5-week period), the 25-OHD level returned to normal in 17 of the 20 vitamin D-insufficient patients and was associated with significant (P<.02) 3.0% and 2.7% increases in BMD at the lumbar spine and the femoral neck, respectively. Failure to normalize the serum 25-OHD level was associated with further loss of BMD. Vitamin D insufficiency was the most frequently identified cause of bone loss in patients with declining BMD during bisphosphonate therapy. Correction of vitamin D insufficiency in these patients led to a significant rebound in BMD.

The Effect of Prior Bisphosphonate Exposure on the Treatment Response to Teriparatide in Clinical Practice

Our objective was to determine the effect of prior bisphosphonate exposure on the treatment response to teriparatide. All patients started on teriparatide in our hospital are entered into a database. All patients who had at least 12 months' treatment were identified. Patients were divided into two groups depending on whether or not they had prior bisphosphonate exposure, and the response to teriparatide was compared using procollagen of type 1 N-terminal propeptide (P1NP) and bone mineral density (BMD). Fifty-two patients had been treated for at least 12 months, 38 with prior bisphosphonate exposure and 14 without. The mean duration of bisphosphonate treatment was 67 months, discontinued a mean of 1 month previously. P1NP increased significantly at 3 and 6 months in both groups. However, those without previous bisphosphonate treatment had a higher baseline P1NP (49 vs. 30 microg/L, P<0.01), and this remained higher at 3 months (109 vs. 71 microg/L, P=0.10) and 6 months (183 vs. 126 microg/L, P=0.06), although the difference was not significant. In the prior bisphosphonate and bisphosphonate naive groups, respectively, the change in spinal BMD was 9.0% and 7.8% (P=0.54) at 12 months and 9.8% and 6.1% (P=0.30) at 18 months. The respective change in hip BMD was 1.0% and -0.3% (P=0.36) at 12 months and 2.8% and 1.3% (P=0.44) at 18 months. There was a trend toward a smaller but still significant increase in P1NP in response to teriparatide in bisphosphonate-treated patients. Although this suggests a blunting of the anabolic effects, in our clinic population this did not result in a reduction in BMD gain.

Randomized Active-Controlled Phase II Study of Denosumab Efficacy and Safety in Patients With Breast Cancer-Related Bone Metastases

Denosumab, a fully human monoclonal antibody to receptor activator of nuclear factor-kappaB ligand, suppresses bone resorption. In this study, we evaluated the efficacy and safety of five dosing regimens of denosumab in patients with breast cancer-related bone metastases not previously treated with intravenous bisphosphonates (IV BPs). Eligible women (n = 255) with breast cancer-related bone metastases were stratified by type of antineoplastic therapy received and randomly assigned to one of six cohorts (five denosumab cohorts [blinded to dose and frequency]; one open-label IV BP cohort). Denosumab was administered subcutaneously every 4 weeks (30, 120, or 180 mg) or every 12 weeks (60 or 180 mg). The primary end point was percentage of change in the bone turnover marker urine N-telopeptide corrected for urine creatinine (uNTx/Cr) from baseline to study week 13. The percentage of patients achieving more than 65% uNTx/Cr reduction, time to more than 65% uNTx/Cr reduction, patients experiencing one or more on-study skeletal-related events (SRE), and safety were also evaluated. At study week 13, the median percent reduction in uNTx/Cr was 71% for the pooled denosumab groups and 79% for the IV BP group. Overall, 74% of denosumab-treated patients (157 of 211) achieved a more than 65% reduction in uNTx/Cr compared with 63% of bisphosphonate-treated patients (27 of 43). On-study SREs were experienced by 9% of denosumab-treated patients (20 of 211) versus 16% of bisphosphonate-treated patients (seven of 43). No serious or fatal adverse events related to denosumab occurred. Subcutaneous denosumab may be similar to IV BPs in suppressing bone turnover and reducing SRE risk. The safety profile was consistent with an advanced breast cancer population receiving systemic therapy.

Bisphosphonate Therapy for Reduced Bone Mineral Density in Children with Chronic Graft-versus-Host Disease

Reduced bone mineral density (BMD) occurs frequently in children after hematopoietic cell transplantation (HCT), but therapy for this complication is undefined. To determine the impact of bisphosphonate therapy on reduced BMD after HCT, we compared baseline and follow-up dual energy X-ray absorptiometry (DEXA) scans of 48 patients (controls) who received calcium and vitamin D to 18 patients who also received bisphosphonate therapy. Among the controls, median annualized increase in standardized BMD (sBMD) was 10% (range, −26% to +41%), but the deviation of sBMD from normal, as indicated by the Z-score, did not improve from baseline, −2.46 (range: −5.15 to −1.16) compared to follow-up, −2.79 (range: −5.76 to +0.07). For the bisphosphonate-treated patients, the median annualized increase in sBMD was 33% (range 3% to 147%, P = .0002) and the median Z-score improved from −3.57 (range: −5.13 to −0.86) at baseline, to −1.80 (−4.89 to +0.47) at follow-up ( P = .06). The annualized median change in BMD Z-scores per year was +0.12 (−2.28 to +4.24) among the controls and +1.43 (−0.29 to +3.72) for the bisphosphonate group ( P = .0002). The greatest improvement in BMD was observed in children who received therapy with bisphosphonates.

Jaw osteonecrosis related to bisphosphonate therapy

Bisphosphonate-related osteonecrosis of the jaws (BON), first described in 2003, is gaining importance due to the increasing indication spectrum of bisphosphonate therapy [S. Takeyama, M. Ito, H. Shinoda, A novel bisphosphonate, TRK-530, for periodontitis, Bone 38 (2006) 31-31; M. Tagil, A. W-Dahl, J. Astrand, D. Little, S. Toksvig-Larsen, Decreasing the catabolic response by a single bisphosphonate infusion shortens the healing time in hemicallotasis operations, Bone 38 (2006) 84-85; E. Rodriguez, M.C. Duran, L.M. Rodriguez, R. Ros, M.R. Aleman, M. Rodriguez-Gaspar, A.M. Lopez, E. Garcia-Valdecasas, F. Santolaria, Intravenous (IV) bisphosphonates for osteopenic cancer survivor women: an alternative treatment, Bone 38 (2006) 72-73; D.G. Little, K. Ward, P. Kiely, M.C. Bellemore, J. Briody, C.T. Cowell, Bisphosphonate rescue in distraction osteogenesis: a case series, Bone 38 (2006) 80-80; R. Marx, Pamidronate (Aredia) and zoledronate (Zometa) induced avascular necrosis of the jaws: a growing epidemic, J. Oral Maxillofac. Surg. 61 (2003) 1115-1118]. BON patients suffering from varying bony defects and symptoms are extremely restricted in their quality of life. Due to a limited knowledge of the aetiology of BON efficient evidence-based treatment strategies are lacking. Until now 23 patients with bisphosphonate-related osteonecrosis have been admitted to the Department of Cranio-Maxillofacial Surgery of the University of Zurich. A complete history has been recorded. All patients underwent clinical and radiographic examination. CT scans and MRI have been performed in selected cases. All patients had in common that, before signs of BON were observed, a local traumatic incidence had occurred. All patients showed signs of infection which could be remarkably reduced by antibacterial treatment. Furthermore, the period of bisphosphonate treatment was found to be one of the significant factors causing bisphosphonate-related osteonecrosis of the jaws. The aetiology of BON appears to depend on multiple factors: period and type of bisphosphonate therapy and trauma paving the way for an invasion of pathogens. Because evidence based therapy protocols for complete remodelling of bone defect are still missing, prevention in bisphosphonate-treated patients seems to be of utmost importance. A close interdisciplinary collaboration is required.

Bisphosphonate treatment in ochronotic osteoporotic patients

In ochronotic patients, abnormalities in bone metabolism leading to increased bone loss have been reported. Therefore, we attempted antiresorptive therapy to (almost) partially reverse bone loss in four out of five osteopenic or osteoporotic ochronotic patients, two men and two women, aged 56-82 years. Each patient was treated with a 70-mg tablet of alendronate weekly and 1,000 mg/day of elemental calcium, such as gluconolactate or carbonate, throughout 24 months. Before starting therapy, and after 1 and 2 years of treatment, the bone mineral density (BMD) at the femoral subregions and at the lumbar spine was measured (in grams per square centimeter and as a T score) by dual energy X-ray absorptiometry. A 50-year-old osteopenic ochronotic man refusing the treatment underwent the same checks. The BMD was measured in all patients on the same densitometer by the same operator. The results showed a progressive decrease of the femoral subregion BMD measurements both in the bisphosphonate-treated patients and in the untreated patient. In particular, the percentage differences with respect to the basal values of the total femur BMD measurements ranged from -0.52 to -6.72% in the first year and from -5.29 to -9.05% in the second year. The lumbar spine BMD measurements provided spuriously overestimated results. Moreover, two treated patients and the untreated patient experienced fragility fractures of the femur. The study showed that osteoporosis and fragility fractures are prominent manifestations in the natural history of ochronosis. Matrix microdamage, osteocyte viability, and collagen cross-linking impairment, due to homogentisic acid and to its polymer, might be the processes involved. For this reason, the bisphosphonate therapy was ineffective.

Predictive Value of Bone Resorption and Formation Markers in Cancer Patients With Bone Metastases Receiving the Bisphosphonate Zoledronic Acid

Three large, randomized trials of patients with bone metastases recently demonstrated that zoledronic acid reduces the risk of skeletal-related events. These trials provide an opportunity for investigating the correlation between bone metabolism and clinical outcome during bisphosphonate therapy. Urinary measurements of N-telopeptide (Ntx) and serum bone alkaline phosphatase (BAP) were obtained in 1,824 bisphosphonate-treated patients-1,462 with zoledronic acid (breast, 490; prostate, 411; myeloma, 210; non-small-cell lung, 183; other, 168) and 362 with pamidronate (breast, 254; myeloma, 108). This exploratory cohort analysis grouped patients by baseline and most recent levels of Ntx as low (< 50 nmol/mmol creatinine), moderate (50 to 99 nmol/mmol creatinine), or high (> or = 100 nmol/mmol creatinine), and BAP as low (< 146 U/L) or high (> or = 146 U/L). The relative risks for negative clinical outcomes were estimated for each group using multiple-event and Cox regression models with time-varying covariates. Patients with high and moderate Ntx levels had 2-fold increases in their risk of skeletal complications and disease progression compared with patients with low Ntx levels (P < .001 for all). High Ntx levels in each solid tumor category were associated with a 4- to 6-fold increased risk of death on study, and moderate Ntx levels a 2- to 4-fold increased risk compared with low Ntx levels (P < .001 for all). Bone alkaline phosphatase also showed some correlation with risk of negative clinical outcomes. The bone resorption marker Ntx provides valuable prognostic information in patients with bone metastases receiving bisphosphonates.

Effect of Bisphosphonates on Periprosthetic Bone Mineral Density After Total Joint Arthroplasty

Periprosthetic bone loss following total joint arthroplasty may threaten the survival of the implant. Bisphosphonates are effective in reducing bone loss in conditions associated with accelerated bone turnover. To determine the current understanding of the effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty, we conducted computerized searches for randomized controlled trials evaluating the use of bisphosphonates in patients treated with primary total joint arthroplasty. We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the web site of the United Kingdom National Research Register, and the archives of the American Academy of Orthopaedic Surgeons annual meetings (1989 through 2003), and we conducted hand searches of the bibliographies of relevant articles. We assessed methodological quality and abstracted relevant data. When necessary, we contacted authors to provide additional information. Of 386 citations that were initially identified, six (five complete papers and one abstract), which included a total of 290 patients, met our inclusion criteria. Those papers showed that significantly less periprosthetic bone loss had occurred in the bisphosphonate-treated patients than in the control patients at three months (152 patients; weighted mean difference, 3.3%; 95% confidence interval, 1.9% to 4.7%; p < 0.01), six months (248 patients; weighted mean difference, 4.5%; 95% confidence interval, 1.6% to 7.4%; p < 0.001), and twelve months (197 patients; weighted mean difference, 4.2%; 95% confidence interval, 1.5% to 6.9%; p = 0.03). Bisphosphonates appeared to have a larger effect on bone loss following arthroplasties with cement than on bone loss following arthroplasties without cement (difference, 0.1%, 5%, and 5.4% at three, six, and twelve months; significant difference [p < 0.001] at one year only) and a larger effect on bone loss following total knee arthroplasties than on bone loss following total hip arthroplasties (difference, 4.1%, 11.5%, and 7.1% at three, six, and twelve months; significant difference [p < 0.001] at six months only). None of the studies related the effects of bisphosphonates on bone mineral density to clinically relevant outcomes. A meta-analysis of six randomized controlled trials suggested that bisphosphonates have a beneficial effect with regard to maintaining more periprosthetic bone mineral density than that in controls. However, the limitations of the available studies and the lack of analyses of clinically relevant outcomes (functional outcomes, revision rates, and quality of life) necessitate the planning and conduct of a sufficiently sized, methodologically sound study with clinically relevant end points. Until this has been done, the current evidence regarding the beneficial effects of bisphosphonates on periprosthetic bone after total joint arthroplasty should be interpreted with caution.

EFFECT OF BISPHOSPHONATES ON PERIPROSTHETIC BONE MINERAL DENSITY AFTER TOTAL JOINT ARTHROPLASTY

Background: Periprosthetic bone loss following total joint arthroplasty may threaten the survival of the implant. Bisphosphonates are effective in reducing bone loss in conditions associated with accelerated bone turnover. To determine the current understanding of the effect of bisphosphonates on periprosthetic bone mineral density after total joint arthroplasty, we conducted computerized searches for randomized controlled trials evaluating the use of bisphosphonates in patients treated with primary total joint arthroplasty. Methods: We searched MEDLINE, EMBASE, the Cochrane Central Register of Controlled Trials, the Cochrane Database of Systematic Reviews, the web site of the United Kingdom National Research Register, and the archives of the American Academy of Orthopaedic Surgeons annual meetings (1989 through 2003), and we conducted hand searches of the bibliographies of relevant articles. We assessed methodological quality and abstracted relevant data. When necessary, we contacted authors to provide additional information. Results: Of 386 citations that were initially identified, six (five complete papers and one abstract), which included a total of 290 patients, met our inclusion criteria. Those papers showed that significantly less periprosthetic bone loss had occurred in the bisphosphonate-treated patients than in the control patients at three months (152 patients; weighted mean difference, 3.3%; 95% confidence interval, 1.9% to 4.7%; p < 0.01), six months (248 patients; weighted mean difference, 4.5%; 95% confidence interval, 1.6% to 7.4%; p < 0.001), and twelve months (197 patients; weighted mean difference, 4.2%; 95% confidence interval, 1.5% to 6.9%; p = 0.03). Bisphosphonates appeared to have a larger effect on bone loss following arthroplasties with cement than on bone loss following arthroplasties without cement (difference, 0.1%, 5%, and 5.4% at three, six, and twelve months; significant difference [p < 0.001] at one year only) and a larger effect on bone loss following total knee arthroplasties than on bone loss following total hip arthroplasties (difference, 4.1%, 11.5%, and 7.1% at three, six, and twelve months; significant difference [p < 0.001] at six months only). None of the studies related the effects of bisphosphonates on bone mineral density to clinically relevant outcomes. Conclusions: A meta-analysis of six randomized controlled trials suggested that bisphosphonates have a beneficial effect with regard to maintaining more periprosthetic bone mineral density than that in controls. However, the limitations of the available studies and the lack of analyses of clinically relevant outcomes (functional outcomes, revision rates, and quality of life) necessitate the planning and conduct of a sufficiently sized, methodologically sound study with clinically relevant end points. Until this has been done, the current evidence regarding the beneficial effects of bisphosphonates on periprosthetic bone after total joint arthroplasty should be interpreted with caution. Level of Evidence: Therapeutic Level I. See Instructions to Authors for a complete description of levels of evidence.