Intravenous Bisphosphonate Treatment Research Articles

Acceptability and engagement amongst patients on oral and intravenous bisphosphonates for the treatment of osteoporosis in older adults.

Osteoporosis is common in older adults leading to fragility fractures at enormous individual and economic cost. Improving long-term adherence with bisphosphonate treatments reduces fracture risk, but adherence rates for first-line oral bisphosphonate alendronate remains low. Although alternative treatment regimens, including annual intravenous infusions are available, patient acceptability remains unclear. Therefore, understanding patients' acceptability and engagement in different bisphosphonate regimens is important to ensure optimal treatment benefits. Semi-structured interviews were conducted with 78 patients with a mean age of 69.9years, who had taken or received bisphosphonates for osteoporosis within the last 24months. Data analysis included iterative categorisation and used the theoretical framework of acceptability (TFA) to compare the acceptability of treatments regimens. Treatment acceptability and engagement were influenced by the extent to which patients understood the prescribed treatment, and evidence of the treatment working. Acceptability and engagement were compromised when treatment was perceived as burdensome, personal costs were incurred, and patients' values were incompatible with the regimen. The balancing of these factors contributed to patients' ability to cope with the treatment and their emotional responses. Intravenous treatment was generally perceived as easier to understand, more effective, less burdensome with fewer opportunity costs, and a preferable regimen compared with oral bisphosphonates. Annual intravenous zoledronate bisphosphonate treatment was generally more acceptable to patients, perceived as more straightforward to engage in, although a small portion of patients on oral bisphosphonates were satisfied with treatment. Further research is needed to identify how acceptability and engagement can be optimised.

Multicenter Study of Pain in Osteogenesis Imperfecta

<h3>Research Objectives</h3> To investigate the frequency and type of pain by disease severity and the treatment of pain in individuals with osteogenesis imperfecta (OI), a genetic disorder and member of the rare disease family. <h3>Design</h3> Cross-sectional analysis. <h3>Setting</h3> Subjects were enrolled in a longitudinal multicenter study of OI. <h3>Participants</h3> The study included 558 individuals with a clinical or molecular diagnosis of OI, classified as OI type I (44%), type III (20%), type IV (27%), and other (9%). Median age was 12.4 years (0.0 - 67.2 years). <h3>Interventions</h3> N/A. <h3>Main Outcome Measures</h3> Rare Diseases Clinical Research Network, Brittle Bone Disorders Consortium: Clinical Assessment Instrument: presence, type of pain and pharmacological treatment used for pain relief. <h3>Results</h3> 62% of subjects reported pain (25% acute; 26% chronic; 11% acute & chronic). Acute pain did not change significantly across age groups (p=0.13), but the frequency of chronic pain increased with age, being highest in adults (p < 0.01). Acute pain was significantly more frequent in OI type III when compared with OI type I (p < 0.05). The prevalence of chronic pain did not vary significantly (p=0.69) across OI types. Pain was identified as a limitation to walking by 38% of individuals. Bisphosphonates (BPs) were the pharmacological treatment most frequently used (54% BP; 13% NSAIDs; 28% No treatment). Those with OI types III and IV receiving intravenous BPs treatment had less chronic pain compared with non-treated peers (p < 0.01). <h3>Conclusions</h3> A majority of individuals with OI experience pain. Chronic pain increases with age across all disease types while acute pain is more frequent in OI type III. The study underscores the need for additional research to address causes of pain, treatment effectiveness, and the impact of pain on mobility for individuals with OI. <h3>Author(s) Disclosuress</h3> The study was supported by 1) BBDC (1U54AR068069), a part of the NCATS RDCRN. BBDC is funded through ORDR, NCATS, NIAMS, NIDCR, and NICHD, 2) HHS/NIDILRR 90ARHF0006-01, 3) OREC at Marquette University, and 4) Shriners Hospitals for Children.

Clinical and demographic aspects of Paget disease of bone: A multicentric study from Turkey.

Paget disease of bone (PDB) is a metabolic bone disease that has been rarely reported in the Eastern countries. This study aimed to evaluate the clinical and demographic characteristics of patients with PDB followed up at endocrinology clinics in Turkey. An invitation was sent to tertiary endocrinology clinics to complete a survey on the demographic, clinical, radiological, and laboratory parameters, as well as treatment modalities of patients with PDB. This study enrolled clinically and radiologically proven 185 patients with PDB from 18 endocrinology centers based in 10 cities of Turkey. This cohort of PDB had female preponderance (women/men: 105/80) with a mean age, during diagnosis, of 57±10 years. Most of the patients (59.6%) were symptomatic at diagnosis. Bone pain and headache were the predominant clinical symptoms. Polyostotic disease was observed in 67.5% (n=125) of patients. Frequently affected bones were skull (41.6%), pelvis (53.5%), spine (41%), and femur (25.4%). Moreover, 17 patients with skull involvement had hearing loss. Mean serum alkaline phosphatase (ALP) level (552±652 IU/L; range: 280-5762 IU/L) was over the normal reference cutoff with normal serum calcium levels. Intravenous bisphosphonates (zoledronic acid, 5 mg; pamidronate, 60-90 mg) were the most used drugs (75%) for the treatment of PDB. Most of the patients (87.1%) treated with intravenous bisphosphonates responded well, with a decrease in serum ALP level (117±114 IU/L) in the 12th month of therapy. Furthermore, 16 patients relapsed after the second year of therapy; 3 patients did not respond to the initial intravenous bisphosphonate treatment. The patients with PDB followed up by endocrinology clinics of Turkey exhibited polyostotic disease with classical clinical, radiological, and biochemical features and women's predominance with good response to intravenous bisphosphonate therapy.

Characteristics of patients with osteonecrosis of the jaw with oral versus intravenous bisphosphonate treatment

PurposeThis retrospective study was aimed to evaluate the clinical characteristics and treatment outcomes in patients with osteonecrosis of the jaw who were receiving oral versus intravenous (IV) bisphosphonate (BP).Materials and methodsThis retrospective study enrolled subjects who had been diagnosed with medication-related osteonecrosis of the jaw (MRONJ) during the period from July 2010 to June 2014. Information regarding the following demographic and clinical characteristics was collected: demographic data, administration route and type of BP, duration of BP medication, primary disease, number of involved sites, location of the lesion, number of surgeries, outcome of treatments, and laboratory test. All the patients were divided into oral and IV BP groups; and the between-group differences were compared.ResultsTotal 278 patients were divided into two groups as per the route of BP administration. The proportion of oral BP-related MRONJ group were more dominant over IV BP group (oral BP, n = 251; IV BP, n = 27). In the IV BP group, the average dosing duration (31.4 months) was significantly shorter than that in the oral BP group (53.1 months) (P < 0.001). The average number of involved sites in the oral BP group (1.21 ± 0.48) was smaller than that in the IV BP group (1.63 ± 0.84) (P < 0.001). The average number of surgeries was higher in the IV BP group (1.65 ± 0.95) as compared to that in the oral BP group (0.98 ± 0.73) (P < 0.001). Outcome after the surgery for MRONJ after IV BP was poor than oral BP group.ConclusionIV administration of BP causes greater inhibition of bone remodeling and could lead more severe inflammation. Therefore, even if the duration of IV administration of BP is shorter than that of oral BP, the extent of the lesion could be more extensive. Therefore, the result suggests that the MRONJ after IV BP for cancer patients needs to be considered as different characteristics to oral BP group for osteoporosis patents.

Pre-medical dental evaluation and treatment of oral infection – a survey study among hospital-affiliated dentists in Sweden

Objective To examine how hospital-affiliated dentists assess risk and evaluate oral foci of infection in patients facing certain medical treatments, and whether the nature of upcoming medical treatment affects the choice of dental intervention. Materials and methods A survey comprising six clinical cases (50 teeth) was sent to hospital-affiliated dentists in Sweden. A treatment option for the affected tooth/teeth in each case was selected whether the patient was facing heart valve surgery, chemotherapy, radiation therapy, intravenous bisphosphonate treatment, solid organ transplantation or was diagnosed with endocarditis. Results Consensus in choice of dental treatment was high in 62%, moderate in 32% and low in 6% of the assessments. High variability of choice of treatment was seen for eight teeth whereas the remaining 42 teeth often received the same therapy regardless of medical issue. Chemotherapy and radiotherapy were thought to entail the highest risk for oral infectious sequelae with a risk ranging from 1% to 100%. Conclusion Pre-medical dental evaluations and recommended treatments are often uniform with the exception of the management of asymptomatic root canal treated teeth with persisting apical radiolucency and heavily decayed molars. In many instances, dental diagnosis has a greater impact on choice of treatment than the underlying medical issue and associated implications thereof.

Bisphosphonates for the treatment of fibrous dysplasia of bone

Fibrous dysplasia of bone (FD) is a rare congenital bone disease, due to a somatic mutation of GNAS. This mutation results in a defect of osteoblast differentiation and mineralization and also an increase in bone resorption by large active osteoclasts. Bone pain is present in half of patients and is the main determinant of quality of life of patients with FD. Bisphosphonates are known to reduce bone pain and reduce the risk of fracture in patients with bone metastases or Paget's disease. Bisphosphonates may have similar effects in FD. In this article, we have reviewed the therapeutic potential of bisphosphonates to reduce bone pain due to FD, improve bone strength and reduce the occurrence of fracture. We have reviewed 234 articles examining the effect of bisphosphonates on FD/McCune Albright Syndrome with no date limit, in PubMed and selected the articles with highest quality of methodology. Pamidronate therapy significantly decreased bone pain and bone resorption (urinary NTX, urinary and serum CTX). Pamidronate may improve radiological lesions of FD patients (filling of osteolytic lesion and/or cortical thickening). This data with intravenous pamidronate, however, has been obtained from observational studies and no randomized controlled trial is available. Randomized placebo-controlled trials of oral bisphosphonates (alendronate or risedronate) have failed to demonstrate a significant decrease in bone pain over placebo. Several studies including one randomized controlled trial have shown an increase in bone mineral density (BMD) at FD sites with oral and intravenous bisphosphonate treatment. No effect on occurrence of fracture has been reported. In conclusion, intravenous bisphosphonates may be proposed to treat persistent, moderate to severe bone pain of FD, e.g., according to the guidelines from the FD/MAS International Consortium. Oral bisphosphonates should not be used in this indication.

Dental consideration and management of cancer patients before initiation of IV bisphosphonates

Purpose Osteonecrosis of the jaw (ONJ) related to intravenous bisphosphonates (IVBP) is characterized by exposed necrotic bone in the maxillofacial region in patients who have received or are receiving treatment with IVBP and have no history of radiation therapy of the jaws.1 The risk of complication of using IVBP for oncologic purposes can be reduced with effective management of cancer patients. Therefore, it is imperative for practitioners to follow patient-specific guidelines for the dental management of patients who will be treated with IVBP. The purpose of this article was to provide a patient-specific, individualized approach for the dental management of patients before initiation of IVBP to prevent ONJ. This guideline will focus on 3 separate factors: the cancer, the patient, and the dentition. Methods A systematic literature review was conducted via PubMed using the following medical subject headings and terms: “bisphosphonates,” “avascular necrosis,” “bisphosphonate-related osteonecrosis of the jaw,” and “medication-related osteonecrosis of the jaw.” We then cross-referenced the same terms with the terms “multiple myeloma (MM),” “breast cancer,” “prostate cancer,” “jaw disease,” and “metastatic cancer” to identify publications that can provide evidence to develop pretreatment dental guidelines in cancer patients treated with IVBP. Articles were reviewed as a result of the PubMed literature search. The cancer types evaluated included breast cancer, prostate cancer, and MM. Relevant studies regarding patient- and dentition-related factors and their relation to IVBP treatment of the said cancers, survival, or comorbidities were evaluated. Results Upon review of articles, 137 articles met our inclusion criteria. No association was found between development of ONJ and the primary tumor site. The hazard of developing ONJ was significantly higher in patients who received zoledronic acid alone compared to those who received pamidronate alone or in combination with zoledronic acid. Our review also concluded that time of exposure to IVBP is strongly associated with development of ONJ, with exposure beyond 4 years of IVBP treatment increasing the incidence of ONJ significantly.2 Our literature search indicated that the risk of development of ONJ after IVBP treatment in cancer patient is also dose dependent, with higher doses being associated with higher risk of ONJ. This suggests that not only does the type of IVBP treatment positively correlate with the likelihood of developing ONJ, the dose and duration of IVBP therapy is also a significant factor. Our analysis identified several unique patient characteristics, including motivation, presence of a support system, socioeconomic status, nutrition, and race, which have all been found to affect the outcomes of IVBP therapy. Dental disease and available supportive dental management was found to significantly impact treatment and quality of life in this patient population. Conclusion Complications from IVBP treatment in cancer patients can have a lifelong impact on quality of life. Dentists and oral and maxillofacial surgeons can play a major role in preventing and minimizing these complications. The cancer, the patient, and the dentition should be analyzed thoroughly to assemble an effective pre-IVBP dental treatment plan. A pre-IVBP extraction-based dental treatment plan is warranted for patients with history of noncompliance, limited financial means, lack of motivation, and presence of tooth factors that decrease the prognosis of dentition. Use of zoledronic acid, IVBP for extended period of 4+ years, and dosage of 22.6 doses or higher are associated with significantly higher chance of developing ONJ and a more aggressive dental treatment (e.g., extraction vs restoration) should be utilized in treatment of these patients.

CN80 - Prevention of dental complications in patients with multiple myeloma (MM) receiving bisphosphonates treatment

BackgroundThanks to the new therapeutic strategies, the patients with MM live longer, but with complex chronic disease and with a diversity of supportive treatments that are increasingly complex. The bisphosphonates are important part of these therapeutic options for them. The aim of this study is to describe four clinical cases presenting dental complications and to define the prevention actions they needed. MethodsA series of cases study. Sample 4 cases with MM patients in treatment with bisphosphonates attended by Functional Unit during 6 months in 2018. Variables recruited were dental complications, nurses’ activities, clinical implications and type of treatment received. ResultsFrom October-2018 to March-2019, a total of 32 patients with MM have been received intravenous bisphosphonates treatment. Four of them (12.5%) have presented dental complications that are following: Two patients (♂ 68 years old and ♀ 68) have needed a 6 months of bisphosphonates interruption to have a dental extraction One patient (♂ 51 years) has delayed 15 days his autologous stem cell transplantation due to dental extraction with infection One patient (♂ 69 years) has delayed one month his autologous stem cell because of a dental fistula that needed surgical intervention Preventive nurses’ measures included: dental assessment prior to bisphosphonate initiation so that any invasive dental procedures could be completed prior to initiation the therapy. It is crucial to include prevention in the health system to avoid increasing financial toxicity for patients & families. ConclusionsAll the patients with dental complications affected and delayed the planned treatment. A preventive approach with oral care before and during treatment with bisphosphonates can minimize the occurrence of complications associated with treatment and avoid interruptions since extractions are contraindicated and endodontic treatment should be performed under conditions that ensure no trauma to bone tissue. Nurses should be aware that MM patient treatment depends not only on anti-myeloma treatments but, also on supportive measures to improve their quality of life and avoid complications. Legal entity responsible for the studyCesca Llopis. FundingHas not received any funding. DisclosureAll authors have declared no conflicts of interest.

Intravenous bisphosphonate treatment in severe infantile hypercalcemia associated with Williams Syndrome

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Pain and quality of life of children and adolescents with osteogenesis imperfecta over a bisphosphonate treatment cycle.

Children and adolescents with OI experience mild, yet complex pain localized across several body areas. There is little fluctuation in the pain intensity and functioning of children with OI undergoing bisphosphonate treatment. What is Known: • Acute and chronic musculoskeletal pain remains a major issue in OI. • Pain has a negative impact on quality of life. What is New: • New and unpublished methods and findings describing the pain and quality of life of children and adolescents with OI over one intravenous bisphosphonate treatment cycle from a child- and parental-proxy perspective. • Children and adolescents with OI experience pain intensity that is mild, yet complex in quality and localized across several body areas.

An open-label, prospective, observational study of the efficacy of bisphosphonate therapy for painful osteoid osteoma.

To assess the efficacy of bisphosphonate therapy on bone pain in patients with osteoid osteoma (OO) (main objective), and to describe bisphosphonate-induced changes in nidus mineralisation and regional bone-marrow oedema (BMO). A prospective, observational study was conducted from 2011 to 2014. Patients with risk factors for complications of percutaneous or surgical ablation or recurrence after ablation, were offered once monthly intravenous bisphosphonate treatment until significant pain alleviation was achieved. We included 23 patients. The first two patients received pamidronate and the next 21 zoledronic acid (mean, 2.95 infusions per patient). Bisphosphonate therapy was successful in 19 patients (83%), whose mean pain visual analogue scale score decreased by 76.7%; this pain-relieving effect persisted in 17 patients (74%) with a mean follow-up time of 36 months. Computed tomography (CT) demonstrated a mean nidus density increase of 177.7% (p = 0.001). By magnetic resonance imaging (MRI), mean decreases were 38.4% for BMO surface area and 30.3% for signal intensity (p = 0.001 and p = 0.000, respectively). In 17/23 patients with painful OO managed conservatively with bisphosphonates, long-term final success was achieved. Bisphosphonates may accelerate the spontaneous healing of OO. • 19/23 patients with OO managed with bisphosphonates experienced significant pain relief • Pain relief was sustained in 17/23 patients, mean follow-up of 36 months • CT demonstrated a significant increase in nidus mineralisation • MRI demonstrated a significant decrease in bone marrow oedema • Bisphosphonate therapy may accelerate the spontaneous healing of OO.

Long-term follow-up in osteogenesis imperfecta type VI.

Osteogenesis imperfecta (OI) type VI is an ultra-rare bone fragility disorder caused by recessive mutations in SERPINF1. Here, we describe long-term outcomes in OI type VI and compare the clinical phenotypes caused by different types of SERPINF1 mutations. This study includes a retrospective chart review of 13 individuals with OI type VI. In the absence of therapy, lumbar spine areal bone mineral density (BMD) did not increase during childhood and longitudinal growth seemed to stall after the age of 6 to 8years. The phenotype was similar between individuals with different types of SERPINF1 mutations. Intravenous bisphosphonate treatment was associated with an increase in lumbar spine areal BMD and some reshaping of compressed vertebral bodies. Patients who had started bisphosphonate treatment early (before the age of 6years) were taller than patients who had received bisphosphonate treatment later during their growing years. Lower extremity fractures were frequent despite bisphosphonate treatment and scoliosis was present in all patients who had reached the final height. Most patients had restricted mobility. In four patients, intravenous bisphosphonate treatment was eventually substituted by subcutaneous injections of denosumab, without clear changes in the clinical picture. Patients with OI type VI who received intravenous bisphosphonate treatment during growth had an increase in lumbar spine areal BMD, a higher final height z-score, and presented some reshaping of vertebral bodies. More effective treatment modalities are clearly required in OI type VI.

The effect of low-dose intravenous bisphosphonate treatment on osteoporosis in children with quadriplegic cerebral palsy.

PurposeQuadriplegic children with cerebral palsy are more susceptible to osteoporosis because of various risk factors that interfere with bone metabolism. Pamidronate is effective for pediatric osteoporosis, but there are no guidelines for optimal dosage or duration of treatment in quadriplegic children with osteoporosis. We aimed to evaluate the efficacy of low-dose pamidronate treatment in these patients.MethodsTen quadriplegic patients on antiepileptic drugs (6 male, 4 female patients; mean age, 10.9±5.76 years), with osteoporosis and gross motor function classification system level V, were treated with pamidronate (0.5–1.0 mg/kg/day, 2 consecutive days) every 3–4 months in a single institution. The patients received oral supplements of calcium and vitamin D before and during treatment. The lumbar spine bone mineral density (BMD) z score and biochemical markers of bone metabolism were measured regularly during treatment.ResultsThe main underlying disorder was perinatal hypoxic brain damage (40%, 4 of 10). The mean cumulative dose of pamidronate was 4.49±2.22 mg/kg/yr, and the mean treatment period was 10.8±3.32 months. The BMD z score of the lumbar spine showed a significant increase from −4.22±1.24 before treatment to −2.61±1.69 during treatment (P=0.008). Alkaline phosphatase decreased during treatmentn (P=0.037). Significant adverse drug reactions and new fractures were not reported.ConclusionLow-dose pamidronate treatment for quadriplegic children with cerebral palsy increased lumbar BMD and reduced the incidence of fracture.

Bisphosphonate therapy for osteogenesis imperfecta.

Osteogenesis imperfecta is caused by a genetic defect resulting in an abnormal type I collagen bone matrix which typically results in multiple fractures with little or no trauma. Bisphosphonates are used in an attempt to increase bone mineral density and reduce these fractures in people with osteogenesis imperfecta. This is an update of a previously published Cochrane Review. To assess the effectiveness and safety of bisphosphonates in increasing bone mineral density, reducing fractures and improving clinical function in people with osteogenesis imperfecta. We searched the Cochrane Cystic Fibrosis and Genetic Disorders Group Inborn Errors of Metabolism Trials Register which comprises references identified from comprehensive electronic database searches, handsearches of journals and conference proceedings. We additionally searched PubMed and major conference proceedings.Date of the most recent search of the Cochrane Cystic Fibrosis and Genetic Disorders Group's Inborn Errors of Metabolism Register: 28 April 2016. Randomised and quasi-randomised controlled trials comparing bisphosphonates to placebo, no treatment, or comparator interventions in all types of osteogenesis imperfecta. Two authors independently extracted data and assessed the risk of bias of the included trials. Fourteen trials (819 participants) were included. Overall, the trials were mainly at a low risk of bias, although selective reporting was an issue in several of the trials. Data for oral bisphosphonates versus placebo could not be aggregated; a statistically significant difference favouring oral bisphosphonates in fracture risk reduction and number of fractures was noted in two trials. No differences were reported in the remaining three trials which commented on fracture incidence. Five trials reported data for spine bone mineral density; all found statistically significant increased lumbar spine density z scores for at least one time point studied. For intravenous bisphosphonates versus placebo, aggregated data from two trials showed no statistically significant difference for the number of participants with at least one fracture, risk ratio 0.56 (95% confidence interval 0.30 to 1.06). In the remaining trial no statistically significant difference was noted in fracture incidence. For spine bone mineral density, no statistically significant difference was noted in the aggregated data from two trials, mean difference 9.96 (95% confidence interval -2.51 to 22.43). In the remaining trial a statistically significant difference in mean per cent change in spine bone mineral density z score favoured intravenous bisphosphonates at six and 12 months. Data describing growth, bone pain, and functional outcomes after oral or intravenous bisphosphonate therapy, or both, as compared to placebo were incomplete among all studies, but do not show consistent improvements in these outcomes. Two studies compared different doses of bisphosphonates. No differences were found between doses when bone mineral density, fractures, and height or length z score were assessed. One trial compared oral versus intravenous bisphosphonates and found no differences in primary outcomes. Two studies compared the intravenous bisphosphonates zoledronic acid and pamidronate. There were no significant differences in primary outcome. However, the studies were at odds as to the relative benefit of zoledronic acid over pamidronate for lumbosacral bone mineral density at 12 months. Bisphophonates are commonly prescribed to individuals with osteogenesis imperfecta. Current evidence, albeit limited, demonstrates oral or intravenous bisphosphonates increase bone mineral density in children and adults with this condition. These were not shown to be different in their ability to increase bone mineral density. It is unclear whether oral or intravenous bisphosphonate treatment consistently decreases fractures, though multiple studies report this independently and no studies report an increased fracture rate with treatment. The studies included here do not show bisphosphonates conclusively improve clinical status (reduce pain; improve growth and functional mobility) in people with osteogenesis imperfecta. Given their current widespread and expected continued use, the optimal method, duration of therapy and long-term safety of bisphosphonate therapy require further investigation. In addition, attention should be given to long-term fracture reduction and improvement in quality of life indicators.

Intravenous pamidronate versus oral and intravenous clodronate in bone metastatic breast cancer: a randomized, open-label, non-inferiority Phase III trial.

PurposePatients with metastasized breast cancer often suffer from discomfort caused by metastatic bone disease. Thus, osteoprotection is an important part of therapy in breast cancer metastasized to bone, and bisphosphonates (BPs) are a major therapeutic option. In this study, our objectives were to compare the side effects of oral versus intravenous BP treatment and to assess their clinical effectiveness.Patients and methodsIn this prospective randomized, open-label, non-inferiority trial, we enrolled breast cancer patients with at least one bone metastasis and an Eastern Cooperative Oncology Group performance status of 0–2. Patients were randomly assigned to one of the three treatment groups: A, 60 mg pamidronate intravenously q3w; B-iv, 900 mg clodronate intravenously q3w; and B-o, 2,400 mg oral clodronate daily. Assessments were performed at baseline and every 3 months thereafter.ResultsBetween 1995 and 1999, 321 patients with confirmed bone metastases from breast cancer were included in the study. At first follow-up, gastrointestinal (GI) tract side effects were most common, and adverse effects on the GI tract were more frequent in the oral treatment group (P=0.002 and P<0.001, respectively). There were no statistically significant differences among the treatment cohorts for other documented side effects (skin, serum electrolytes, urinary tract, immune system, and others). No significant differences in clinical effectiveness of BP treatment, as assessed by pain score, were detected among the groups; however, pathologic fractures were more effectively prevented by intravenous than oral BP administration (P=0.03). Noncompliance rates were similar among the study cohorts.ConclusionWe conclude that oral BP treatment is significantly associated with higher rates of adverse GI side effects. Additionally, our data indicate that intravenous BP administration is more effective than oral treatment in prevention of pathologic fractures; hence, oral administration should be considered with caution.

Fibrous Dysplasia and Medication-Related Osteonecrosis of the Jaw

Osteonecrosis of the jaw (ONJ) is an established side effect of intravenous bisphosphonates and other antiresorptive medications. Although bisphosphonates are frequently prescribed for patients with the skeletal disorder fibrous dysplasia (FD), there are no reports of ONJ in this population. This has led some to conclude that patients with FD are at low risk for the development of bisphosphonate-related ONJ. Patients were evaluated as part of a longstanding FD natural history study at the National Institutes of Health. Of 76 patients with FD who were treated with bisphosphonates, 4 developed ONJ (5.4%). Three patients developed ONJ in areas of FD-affected bone and 1 in an area of normal bone. All 4 patients had features known to be associated with ONJ in the general population, including long-term high-dose intravenous bisphosphonate treatment, periodontal and endodontic infections, and dentoalveolar surgical procedures. These cases establish ONJ as a potential complication of bisphosphonate treatment in patients with FD. The presence of established risk factors for ONJ in this group of patients with FD suggests that high-risk patients could be identified before the development of ONJ. Clinicians should use caution in prescribing bisphosphonates to patients with FD and should do so only for established indications.

Multidisciplinary Treatment of Severe Osteogenesis Imperfecta: Functional Outcomes at Skeletal Maturity

ObjectiveTo determine the functional outcomes associated with long-term multidisciplinary treatment, intravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation in children with severe osteogenesis imperfecta (OI) (diagnosed clinically as OI types III or IV). DesignRetrospective study where outcomes were measured prospectively. SettingPediatric orthopedic hospital. ParticipantsAdolescents (N=41; age range, 15–21y) with severe OI (OI type III: n=17; OI type IV: n=24) who had started therapy before the age of 6 years, had received treatment for at least 10 years, and had achieved final height. InterventionsIntravenous bisphosphonate treatment, orthopedic surgery, and rehabilitation. Main Outcome MeasurePediatric Evaluation of Disability Inventory. ResultsAt the time of the last available follow-up examination, none of the individuals diagnosed with OI type III (most severely affected group) was able to ambulate without ambulation aids, whereas 20 (83%) patients with OI type IV were able to ambulate without ambulation aids. Regarding self-care, we specifically assessed 8 skills that we deemed essential for living independently (grooming; dressing; toileting; bed, chair, toilet, tub, and car transfers). Only 6 (35%) of the youths with OI type III were able to complete all 8 items, whereas 23 (96%) individuals with OI type IV managed to perform all tasks. Teens with OI type III often needed assistance for the transfer to toilet, tub, and car and for personal hygiene and clothing management associated with toileting, usually because of limitations in upper-extremity function. ConclusionsThese observations suggest that further improvements in the functional status of the most severely affected children with OI are contingent on advances in the clinical management of upper-extremity issues.

Intravenous Bisphosphonate Therapy of Young Children With Osteogenesis Imperfecta: Skeletal Findings During Follow Up Throughout the Growing Years.

Cyclical intravenous bisphosphonate therapy is widely used to treat children with osteogenesis imperfecta (OI), but little is known about long-term treatment outcomes. We therefore reviewed 37 children with OI (OI type I, n = 1; OI type III, n = 14; and OI type IV, n = 22) who started intravenous bisphosphonate therapy before 5 years of age (median 2.2 years; range, 0.1 to 4.8 years), and who had a subsequent follow-up period of at least 10 years (median 14.8 years; range, 10.7 to 18.2 years), during which they had received intravenous bisphosphonate treatment (pamidronate or zoledronic acid) for at least 6 years. During the observation period, the mean lumbar spine areal bone mineral density Z-score increased from -6.6 (SD 3.1) to -3.0 (SD 1.8), and weight Z-score increased from -2.3 (SD 1.5) to -1.7 (SD 1.7) (p < 0.001 and p = 0.008). At the time of the last assessment, patients with OI type IV had significantly higher height Z-scores than a control group of patients matched for age, gender, and OI type who had not received bisphosphonates. Patients had a median of six femur fractures (range, 0 to 18) and five tibia fractures (range, 0 to 17) during the follow-up period. At baseline, 35% of vertebra were affected by compression fractures, whereas only 6% of vertebra appeared compressed at the last evaluation (p < 0.001), indicating vertebral reshaping during growth. Spinal fusion surgery was performed in 16 patients (43%). Among the 21 patients who did not have spinal fusion surgery, 13 had scoliosis with a curvature ranging from 10 to 56 degrees. In conclusion, long-term intravenous bisphosphonate therapy was associated with higher Z-scores for lumbar spine areal bone mineral density and vertebral reshaping, but long-bone fracture rates were still high and the majority of patients developed scoliosis.

The Long-Term Effects of Switching from Active Intravenous Bisphosphonate Treatment to Low-Dose Maintenance Therapy in Children with Osteogenesis Imperfecta

Background/Aims: Intravenous bisphosphonate therapy is the first-line treatment in moderate-to-severe osteogenesis imperfecta (OI), but there are varied treatment protocols with little data on long-term efficacy. This study evaluates the clinical outcomes when transitioning from active bisphosphonate treatment to maintenance therapy. Methods: A retrospective review was conducted on 17 patients before treatment, following active treatment (zoledronate 0.05 mg/kg 6-monthly or pamidronate 6-9 mg/kg/year) and after establishment on maintenance treatment for more than 2 years (zoledronate 0.025 mg/kg 6-monthly or pamidronate <4 mg/kg/year). Results: There was a significant reduction in mean fracture rate from 1.5 ± 1.1 fractures/year at baseline to 0.7 ± 0.7 fractures/year on active treatment. Z-scores for lumbar spine bone mineral density, bone mineral content, volumetric bone mineral density and bone mineral content for lean tissue mass increased during active treatment. These improvements were maintained during the period of maintenance treatment. Vertebral height improved in fractured thoracic vertebrae from pre-treatment to active therapy and improved further during maintenance treatment. Metacarpal cortical thickness and relative cortical area also increased over the treatment periods. Conclusion: Maintenance intravenous bisphosphonate therapy preserved the beneficial effects of active treatment at the doses stated above. Further studies are required to determine the optimal bisphosphonate treatment regimen in the management of children with OI.

Bisphosphonates: Clinical Applications and Adverse Events in Dentistry.

To review the mechanisms of action and clinical applications of bisphosphonate drugs, which are widely used in the management of metastatic bone cancer and systemic metabolic bone diseases, as well as the complications related to bisphosphonate treatment, emphasising the occurrence and management of bisphosphonate-related osteonecrosis of the jaws (BRONJ). A search of the medical and dental literature was conducted in Medline and Embase using a combination of the key words bisphosphonates, jaw, complications, osteonecrosis, osteoporosis and periodontal disease. A manual search of the references of the retrieved articles was also performed. BRONJ predominantly affects cancer patients being treated with high-dose intravenous bisphosphonates and is characterised by the appearance of necrotic bone in the oral cavity either spontaneously or following an invasive surgical procedure such as dental extraction. The severity of this condition warrants a thorough medical and dental history in every patient in order to identify high risk patients. It is important that dental practitioners be aware of the association between bisphosphonate treatment and osteonecrosis of the jaws. Clinicians should perform a thorough oral examination in cancer patients before they begin intravenous bisphosphonate treatment. Optimal oral hygiene and regular dental care can lower BRONJ risk. Further clinical research is necessary to unveil the full therapeutic potential of bisphosphonates, their mechanisms of action and the factors that induce unwanted side-effects.