Adverse effects of drugs on the esophagus

Given the function of the esophagus to transport orally ingested solids and liquids into the stomach there are several medications with adverse effect on esophageal structures and function. Various pharmacologic agents can induce esophageal injury, promote gastroesophageal reflux by decreasing lower esophageal sphincter tone or affect esophageal perception and motility. The risks of bisphosphonates, doxycycline, ferrous sulfate, ascorbic acid, aspirin/NSAIDs and chemotherapeutic agents to induce esophageal lesions have been documented in case reports and short series. In addition to direct mucosal injury, many commonly used medications including nitroglycerins, anticholinergics, beta-adrenergic agonists, aminophyllines, and benzodiazepines promote/facilitate gastroesophageal reflux by reducing lower esophageal sphincter pressure. Additional evidence accumulates on the adverse effects of various medications on esophageal motility and perception. The treatment of medication-induced esophageal lesions includes (1) identifying and discontinuing the causative medication, (2) promoting healing of esophageal injury by decreasing esophageal acid exposure or coating already existing esophageal lesions, (3) eventual use of protective compounds.

[Bone metastasis in prostate cancer]

Bone metastasis and skeletal complications have a devastating impact on the quality of life and are a major cause of morbidity in prostate cancer patients. In addition to established bone-targeted therapies, new drugs such as endothelin A receptor antagonists, MET and VEGFR-2 antagonists or radiopharmaceuticals are in the focus of development. The standard care in prostate cancer patients with bone metastases to prevent skeletal-related events (SRE) are bisphosphonates. Denosumab, a human monoclonal antibody against RANKL, appeared to be superior to zoledronic acid for prevention of SRE and has been shown to prolong bone metastases-free survival. In contrast to zoledronic acid, denosumab clearance is not dependent on kidney function and can be administered subcutaneously. Similar rates of toxicity were observed for both substances; however, long-term data for denosumab are limited.

Biphosphonate-associated osteonecrosis of the maxilla. Case report and review of the literature

In recent years, a growing number of reports in the literature have linked osteonecrosis of the jaw bones with intravenously administered bisphosphonates prescribed for the treatment of hypercalcemia of malignancy due to bone lesions of multiple myeloma or bone metastases in patients with breast or prostate cancer. Furthermore, an association between chronic oral bisphosphonate use in patients with osteoporosis or Paget's disease, and bone necrosis in the mandible or maxilla has been demonstrated in numerous case reports and case series in the last couple of years. Therapeutically, osteonecrosis of the jaws seems to be difficult to treat surgically, often resulting in a recurring or even progressing lesion. In the present case report of a bisphosphonate-associated osteonecrosis of the maxilla in a patient with osteoporosis, the current literature will be discussed, and open research questions and potential problems for our daily dental practice routine will be addressed.

Glucocorticosteroid-induced spinal osteoporosis: scientific update on pathophysiology and treatment

Glucocorticosteroid-induced spinal osteoporosis (GIOP) is the most frequent of all secondary types of osteoporosis. The understanding of the pathophysiology of glucocorticoid (GC) induced bone loss is of crucial importance for appropriate treatment and prevention of debilitating fractures that occur predominantly in the spine. GIOP results from depressed bone formation due to lower activity and higher death rate of osteoblasts on the one hand, and from increase bone resorption due to prolonged lifespan of osteoclasts on the other. In addition, calcium/phosphate metabolism may be disturbed through GC effects on gut, kidney, parathyroid glands and gonads. Therefore, therapeutic agents aim at restoring balanced bone cell activity by directly decreasing apoptosis rate of osteoblasts (e.g., cyclical parathyroid hormone) or by increasing apoptosis rate of osteoclasts (e.g., bisphosphonates). Other therapeutical efforts aim at maintaining/restoring calcium/phosphate homeostasis: improving intestinal calcium absorption (using calcium supplementation, vitamin D and derivates) and avoiding increased urinary calcium loss (using thiazides) prevent or counteract a secondary hyperparthyroidism. Bisphosphonates, particularly the aminobisphosphonates risedronate and alendronate, have been shown to protect patients on GCs from (further) bone loss to reduce vertebral fracture risk. Calcitonin may be of interest in situation where bisphosphonates are contraindicated or not applicable and in cases where acute pain due to vertebral fracture has to be manage. The intermittent administration of 1-34-parathormone may be an appealing treatment alternative, based on its documented anabolic effects on bone resulting from the reduction of osteoblastic apoptosis. Calcium and vitamin D should be a systematic adjunctive measure to any drug treatment for GIOP. Based on currently available evidence, fluoride, androgens, estrogens (opposed or unopposed) cannot be recommended for the prevention and treatment of GIOP. However, substitution of gonadal hormones may be indicated if GC-induced hypogonadism is present and leads to clinical symptoms. Data using the SERM raloxifene to treat or prevent GIOP are lacking, as are data using the promising bone anabolic agent strontium ranelate. Kyphoplasty performed in appropriately selected osteoporotic patients with painful vertebral fractures is a promising addition to current medical treatment.

[The hungry bone syndrome--an update]

The Hungry Bone Syndrome (HBS) represents an important cause of prolonged hypocalcemia after parathyreoidectomy (PTX) due to primary, secondary or tertiary hyperparathyreoidism. The sudden postoperative withdrawal of parathyroid hormone (PTH) induces a stop in osteoclastic bone resorption without affecting the osteoblastic activity. Consequently, an increased bone uptake of calcium, phosphate and magnesium is observed. Risk factors for the development of HBS include: Large parathyroid adenomas, age > 60 years, high preoperative levels of serum PTH, calcium and alkaline phosphatase. In these patients a careful monitoring of clinical symptoms of hypocalcemia as well as the laboratory parameters are warranted during the immediate postoperative period. Treatment with oral calcium, and especially in patients with renal failure, additionally active vitamin D should be started as soon as possible after PTX. In severe cases of HBS, the administration of intravenous calcium is necessary. The duration of therapy is governed by symptoms and severity of the HBS and may last for up to 12 or more months. While prevention of HBS in high risk patients includes preoperative Vitamin D, the role of bisphosphonates has yet to be established.

[Diagnosis, treatment and follow up of prostata cancer]

Prostate cancer is the most frequent diagnosed malignancy in men with an increasing incidence. In well informed men between the age of 50 and 70 years screening should be offered when requested. Not every newly diagnosed prostate cancer requires immediate treatment. Curative treatment should be offered to men with a minimal life expectancy of 10 years. In men older than 50-75 years, therefore further screening is not necessary due to a lack of a therapeutic consequence. Curative treatment options enclose as the gold standard surgical removal, i.e. open radical prostatectomy with pelvic lymph node dissection, and radio-oncologic treatments, be it percutaneous radiation therapy, brachytherapies or a combination thereof. Palliative treatment options are mainly hormonal treatment (medical or surgical androgen deprivation), local radiation, treatment with bisphosphonates, chemotherapy and surgical desobstruction of the prostate. Regular follow up allows for early detection of recurrences and an active treatment concept.

Renal safety of annual zoledronic acid infusions in osteoporotic postmenopausal women

Intravenous bisphosphonates reduce fracture risk but have been associated in rare cases with deteriorating renal-function in cancer patients. The renal effects of zoledronic acid were assessed in osteoporotic postmenopausal women from 27 countries who received three annual infusions of zoledronic acid or a placebo in a randomized, double-blind trial. Serum creatinine, estimated creatinine clearance and urinary protein were measured before and after at least one infusion in a predefined renal safety cohort of 5035 equally divided patients. This group was compared to 7714 patients whose parameters were measured annually. Significantly more transient pre- to post-infusion increases in serum creatinine occurred in zoledronic acid than placebo-treated patients with significant elevations, relative to pre-infusion, only in the second year. All 31 zoledronic acid and 8 of 10 patients on placebo recovered their pre-infusion serum creatinine value within 12 months. No differences in mean changes in serum creatinine, estimated creatinine clearance or adverse renal events were found. We found that transient changes in renal function can occur following an annual zoledronic acid infusion but, in the long term, renal function was not different from control patients.

Effect of once-yearly zoledronic acid 5 mg on fracture risk and change in femoral neck bone mineral density

Context: In the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg significantly reduced fracture risk. Objective: To identify factors associated with greater efficacy during ZOL 5 mg treatment. Design, Setting and Patients: Subgroup analysis (preplanned and post hoc) of a multicenter, double-blind, placebo-controlled, 36-month trial in 7765 women with postmenopausal osteoporosis. Intervention: Single infusion of ZOL 5 mg or placebo at baseline, 12 and 24 months. Main Outcome Measures: Primary endpoints: new vertebral fracture and hip fracture. Secondary endpoints: non-vertebral fracture, change in femoral neck bone mineral density (BMD). Baseline risk factor subgroups: age, BMD T-score and vertebral fracture status, total hip BMD, race, weight, geographical region, smoking, height loss, history of falls, physical activity, prior bisphosphonates, creatinine clearance, body mass index (BMI), concomitant osteoporosis medications. Results: Greater ZOL induced effects on vertebral fracture risk with younger age (treatment-by-subgroup interaction P=0.05), normal creatinine clearance (P=0.04), and BMI >/=25 kg/m(2) (P=0.02). There were no significant treatment-factor interactions for hip or non-vertebral fracture or for change in BMD. Conclusions: ZOL appeared more effective in preventing vertebral fracture in younger women, overweight/obese women and women with normal renal function. ZOL had similar effects irrespective of fracture risk factors or femoral neck BMD.

Systemic conditions and treatments as risks for implant therapy

PURPOSE: To evaluate whether systemic diseases with/without systemic medication increase the risk of implant failure and therefore diminish success and survival rates of dental implants. MATERIALS AND METHODS: A MEDLINE search was undertaken to find human studies reporting implant survival in subjects treated with osseointegrated dental implants who were diagnosed with at least one of 12 systemic diseases. RESULTS: For most conditions, no studies comparing patients with and without the condition in a controlled setting were found. For most systemic diseases there are only case reports or case series demonstrating that implant placement, integration, and function are possible in affected patients. For diabetes, heterogeneity of the material and the method of reporting data precluded a formal meta-analysis. No unequivocal tendency for subjects with diabetes to have higher failure rates emerged. The data from papers reporting on osteoporotic patients were also heterogeneous. The evidence for an association between osteoporosis and implant failure was low. Nevertheless, some reports now tend to focus on the medication used in osteoporotic patients, with oral bisphosphonates considered a potential risk factor for osteonecrosis of the jaws, rather than osteoporosis as a risk factor for implant success and survival on its own. CONCLUSIONS: The level of evidence indicative of absolute and relative contraindications for implant therapy due to systemic diseases is low. Studies comparing patients with and without the condition in a controlled setting are sparse. Especially for patients with manifest osteoporosis under an oral regime of bisphosphonates, prospective controlled studies are urgently needed.

Management of RA medications in pregnant patients

A desire for children or the presence of pregnancy limits the drug therapy options for a woman with rheumatoid arthritis. Combination therapies that include methotrexate or new drugs that have not been studied or used in pregnant patients must be excluded, even though they might be highly efficacious. With few exceptions, the reason for this exclusion is not the proven teratogenicity of the drugs, but the absence of proven safety for the fetus. Whereas methotrexate, leflunomide, abatacept and rituximab must be withdrawn before a planned pregnancy, tumor necrosis factor inhibitors and bisphosphonates can be continued until conception. Antimalarial agents, sulfasalazine, azathioprine and ciclosporin are compatible with pregnancy, and so can be administered until birth. Corticosteroids and analgesics such as paracetamol (acetaminophen) can also be used throughout pregnancy. NSAIDs can be safely administered until gestational week 32. The most important consideration when managing rheumatoid arthritis medications during pregnancy is that therapy must be tailored for the individual patient according to disease activity.

Medical treatment of vertebral osteoporosis

Although osteoporosis is a systemic disease, vertebral fractures due to spinal bone loss are a frequent, sometimes early and often neglected complication of the disease, generally associated with considerable disability and pain. As osteoporotic vertebral fractures are an important predictor of future fracture risk, including at the hip, medical management is targeted at reducing fracture risk. A literature search for randomized, double-blind, prospective, controlled clinical studies addressing medical treatment possibilities of vertebral fractures in postmenopausal Caucasian women was performed on the leading medical databases. For each publication, the number of patients with at least one new vertebral fracture and the number of randomized patients by treatment arm was retrieved. The relative risk (RR) and the number needed to treat (NNT, i.e. the number of patients to be treated to avoid one radiological vertebral fracture over the duration of the study), together with the respective 95% confidence intervals (95%CI) were calculated for each study. Treatment of steroid-induced osteoporosis and treatment of osteoporosis in men were reviewed separately, based on the low number of publications available. Forty-five publications matched with the search criteria, allowing for analysis of 15 different substances tested regarding their anti-fracture efficacy at the vertebral level. Bisphosphonates, mainly alendronate and risedronate, were reported to have consistently reduced the risk of a vertebral fracture over up to 50 months of treatment in four (alendronate) and two (risedronate) publications. Raloxifene reduced vertebral fracture risk in one study over 36 months, which was confirmed by 48 months' follow-up data. Parathormone (PTH) showed a drastic reduction in vertebral fracture risk in early studies, while calcitonin may also be a treatment option to reduce fracture risk. For other substances published data are conflicting (calcitriol, fluoride) or insufficient to conclude about efficacy (calcium, clodronate, etidronate, hormone replacement therapy, pamidronate, strontium, tiludronate, vitamin D). The low NNTs for the leading substances (ranges: 15-64 for alendronate, 8-26 for risedronate, 23 for calcitonin and 28-31 for raloxifene) confirm that effective and efficient drug interventions for treatment and prevention of osteoporotic vertebral fractures are available. Bisphosphonates have demonstrated similar efficacy in treatment and prevention of steroid-induced and male osteoporosis as in postmenopausal osteoporosis. The selection of the appropriate drug for treatment of vertebral osteoporosis from among a bisphosphonate (alendronate or risedronate), PTH, calcitonin or raloxifene will mainly depend on the efficacy, tolerability and safety profile, together with the patient's willingness to comply with a long-term treatment. Although reduction of vertebral fracture risk is an important criterion for decision making, drugs with proven additional fracture risk reduction at all clinically relevant sites (especially at the hip) should be the preferred options.

T-786C polymorphism of the endothelial nitric oxide synthase gene and neuralgia-inducing cavitational osteonecrosis of the jaws.

OBJECTIVE: We hypothesized that, similar to idiopathic hip osteonecrosis, the T-786C mutation of the endothelial nitric oxide synthase (eNOS) gene affecting nitric oxide (NO) production was associated with neuralgia-inducing cavitational osteonecrosis of the jaws (NICO). DESIGN: In 22 NICO patients, not having taken bisphosphonates, mutations affecting NO production (eNOS T-786C, stromelysin 5A6A) were measured by polymerase chain reaction. Two healthy normal control subjects were matched per case by race and gender. RESULTS: Homozygosity for the mutant eNOS allele (TT) was present in 6 out of 22 patients (27%) with NICO compared with 0 out of 44 (0%) race and gender-matched control subjects; heterozygosity (TC) was present in 8 patients (36%) versus 15 control subjects (34%); and the wild-type normal genotype (CC) was present in 9 patients (36%) versus 29 controls (66%) (P = .0008). The mutant eNOS T-786C allele was more common in cases (20 out of 44 [45%]) than in control subjects (15 out of 88 [17%]) (P = .0005). The distribution of the stromelysin 5A6A genotype in cases did not differ from control subjects (P = .13). CONCLUSIONS: The eNOS T-786C polymorphism affecting NO production is associated with NICO, may contribute to the pathogenesis of NICO, and may open therapeutic medical approaches to treatment of NICO through provision of L-arginine, the amino-acid precursor of NO.

The Effect of 6 versus 9 Years of Zoledronic Acid Treatment in Osteoporosis: A Randomized Second Extension to the HORIZON-Pivotal Fracture Trial (PFT).

While bisphosphonates reduce fracture risk over 3 to 5 years, the optimal duration of treatment is uncertain. In a randomized extension study (E1) of the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly - Pivotal Fracture Trial (HORIZON-PFT), zoledronic acid (ZOL) 5 mg annually for 6 years showed maintenance of bone mineral density (BMD), decrease in morphometric vertebral fractures, and a modest reduction in bone turnover markers (BTMs) compared with discontinuation after 3 years. To investigate the longer-term efficacy and safety of ZOL, a second extension (E2) was conducted to 9 years in which women on ZOL for 6 years in E1 were randomized to either ZOL (Z9) or placebo (Z6P3) for 3 additional years. In this multicenter, randomized, double-blind study, 190 women were randomized to Z9 (n=95) and Z6P3 (n=95). The primary endpoint was change in total hip BMD at year 9 vs. year 6 in Z9 compared with Z6P3. Other secondary endpoints included fractures, BTMs, and safety. From year 6 to 9, the mean change in total hip BMD was -0.54% in Z9 vs. -1.31% in Z6P3 (difference 0.78%; 95% confidence interval [CI]: -0.37%, 1.93%; p=0.183). BTMs showed small, non-significant increases in those who discontinued after 6 years compared with those who continued for 9 years. The number of fractures was low and did not significantly differ by treatment. While generally safe, there was a small increase in cardiac arrhythmias (combined serious and non-serious) in the Z9 group but no significant imbalance in other safety parameters. The results suggest almost all patients who have received six annual ZOL infusions can stop medication for up to 3 years with apparent maintenance of benefits. This article is protected by copyright. All rights reserved.

Frequencies and risk factors for bisphosphonate-related osteonecrosis of the jaw in cancer patients: A matched case-control study

Bisphosphonates represent a unique class of drugs that effectively treat and prevent a variety of bone-related disorders including metastatic bone disease and osteoporosis. High tolerance and high efficacy rates quickly ranked bisphosphonates as the standard of care for bone-related diseases. However, in the early 2000s, case reports began to surface that linked bisphosphonates with osteonecrosis of the jaw (ONJ). Since that time, studies conducted have corroborated the linkage. However, as with most disease states, many factors can contribute to the onset of disease. The aim of this study was to determine which comorbid factors presented an increased risk for developing ONJ in cancer patients.^ Using a case-control study design, investigators used a combination of ICD-9 codes and chart review to identify confirmed cases of ONJ at The University of Texas M. D. Anderson Cancer Center (MDACC). Each case was then matched to five controls based on age, gender, race/ethnicity, and primary cancer diagnosis. Data querying and chart review provided information on variables of interest. These variables included bisphosphonate exposure, glucocorticoids exposure, smoking history, obesity, and diabetes. Statistical analysis was conducted using PASW (Predictive Analytics Software) Statistics, Version 18 (SPSS Inc., Chicago, Illinois).^ One hundred twelve (112) cases were identified as confirmed cases of ONJ. Variables were run using univariate logistic regression to determine significance (p < .05); significant variables were included in the final conditional logistic regression model. Concurrent use of bisphosphonates and glucocorticoids (OR, 18.60; CI, 8.85 to 39.12; p < .001), current smokers (OR, 2.52; CI, 1.21 to 5.25; p = .014), and presence of diabetes (OR, 1.84; CI, 1.06 to 3.20; p = .030) were found to increase the risk for developing ONJ. Obesity was not associated significantly with ONJ development.^ In this study, cancer patients that received bisphosphonates as part of their therapeutic regimen were found to have an 18-fold increase in their risk of developing ONJ. Other factors included smoking and diabetes. More studies examining the concurrent use of glucocorticoids and bisphosphonates may be able to strengthen any correlations.^

Osteonecrosis de los maxilares y bifosfonatos : revisión

La osteonecrosis de los maxilares es la necrosis y exposición del hueso de la mandíbula y el maxilar, asociada al consumo de bifosfonatos. Estos son una familia de drogas que se utiliza en el tratamiento de alteraciones óseas causadas principalmente por tumores malignos (mama y próstata) y osteoporosis. No existe irradiación previa. El hueso macroscópicamente se ve sucio avascular. El objetivo de este artículo es profundizar el conocimiento sobre los bifosfonatos, factores causales de las lesiones.