Nasal Calcitonin Research Articles

Comparison of the effects of vitamin D and nasal calcitonin spray with nasal calcitonin spray on postoperative abdominal pain: A randomised controlled trial

BackgroundPostoperative pain control is critical after abdominal surgery. primary researches suggest that vitamin D and nasal calcitonin spray may have an effect in reducing postoperative pain. ObjectiveThis study aims to compare postoperative abdominal pain, in patients who received a combination of Nasocalcin spray and vitamin D to those who received Nasocalcin spray. MethodsIn this double-blind randomized clinical trial, 34 patient candidates for abdominal surgery were selected. They were randomly divided into 2 groups (group A (N = 17) received vitamin D and Nasocalcin spray, and group B (N = 17) received Nasocalcin spray). The drugs have been administered to patients 1 h before surgery. Equivalent amounts of Nasocalcin and intramuscular distilled water were administered to the calcitonin group. after the surgery Patients’' pain levels were measured using a visual analog scale (VAS) after they had gained full consciousness and 6, 12, and 24 h after surgery. the amount of narcotics injected in the first 24 h after surgery was monitored and compared between the two groups. ResultsThere was no significant relation between the groups in terms of age (p = 0.98), gender distribution (p = 0.1), surgery duration (p = 0.35), and pain scores after surgery (p = 0.67). In comparison to group B, at 6 h (p = 0.007), 12 h (p = 0.001), and 24 h (p = 0.003), group A reported significantly less pain. There was a significant reduction in total narcotic injected (p = 0.003) in group A. ConclusionsPreoperative administration of vitamin D with nasal calcitonin spray improved postoperative pain control compared to nasal calcitonin. This non-opioid drug combination represents a preemptive medication for enhanced recovery after abdominal surgery.

The effects of calcitonin on quality of life in hypothyroid patients – A pilot study

IntroductionHypothyroidism is a very common endocrine disorder routinely treated with levothyroxine replacement therapy. Despite treatment to biochemical euthyroidism, some individuals continue to have hypothyroidism-related symptoms. Many individuals with hypothyroidism also have low levels of calcitonin. Our aim was to evaluate the effects of calcitonin treatment on quality of life in hypothyroid individuals treated with levothyroxine. MethodsAdult, hypothyroid individuals were treated with nasal calcitonin spray, 200 international units daily for 6 weeks. Participants completed a modified City of Hope Quality of Life questionnaire prior to initiating calcitonin and after completing 6 weeks of therapy. Perception of quality-of-life benefit with calcitonin was also assessed. ResultsImprovements in quality-of-life scores with calcitonin treatment from 184.77 to 148.44 (p = 0.342) were not statistically significant. Also, only one individual perceived any benefit with calcitonin therapy. ConclusionTreatment with nasal calcitonin spray in individuals with hypothyroidism on levothyroxine replacement therapy did not result in quality-of-life benefit.

Three-Month Randomized Clinical Trial of Nasal Calcitonin in Adults with X-linked Hypophosphatemia.

Previous work has demonstrated that a single subcutaneous dose of salmon calcitonin leads to a transient decline in circulating levels of FGF23 in patients with X-linked hypophosphatemia (XLH). Since the calcitonin receptor is expressed on osteocytes, this raises the possibility that interdicting signals through that receptor could modulate circulating levels of FGF23 in XLH. In the present study, 21 subjects with XLH were randomly assigned to receive either placebo nasal spray or 400IU of nasal salmon calcitonin daily for three months. On the first and last day of the study, serial measurements of FGF23, 1,25-dihydroxyvitamin D, and TmP/GFR were made over 27h. At the beginning of Visit 2 (the first day of month 2) and the beginning of Visit 3 (the first day of month 3), single, first-morning, fasting measurements of these same parameters were made before the next administered dose of study drug. Following the initial or final dose of study drug, there were no differences in area under the curve, based on treatment assignment, for the three principal outcome variables. Similarly, there were no differences in the fasting measures taken at the beginning of Visit 2 or Visit 3 compared to the fasting values on either day 2 of Visit 1 or the fasting values on day 2 of Visit 4. There were also no significant changes over time in serum phosphorus, serum calcium, circulating levels of PTH, CTx, or P1NP. The reasons why nasal salmon calcitonin did not recapitulate the findings with subcutaneously administered drug may relate to the kinetics of drug delivery, the bioavailability of drug or peak drug dose achieved. It remains possible, however, that other means of altering calcitonin receptor signaling may still provide an opportunity for regulating FGF23 production.

Effects of Nasal Calcitonin vs. Oral Gabapentin on Pain and Symptoms of Lumbar Spinal Stenosis: A Clinical Trial Study.

Lumbar spinal stenosis (LSS) is a chronic and prevalent disease that occurs in 10.8% of the general population, mostly in old age. We designed the first clinical trial study to compare the effects of administering the nasal salmon calcitonin spray and gabapentin in patients with LSS. In this clinical trial, 90 patients with symptoms of neurogenic claudication and magnetic resonance imaging-proven LSS were randomly assigned to nasal salmon calcitonin, gabapentin, or placebo treatments for eight weeks (30 participants in each group). This was followed by a washout period of four weeks. After three months of study and after four weeks off the prescription, mean values of Oswestry Disability Index in the calcitonin, gabapentin, and control groups were 23 ± 12.05, 32 ± 16.08, and 38 ± 22.09, respectively (P ≤ 0.05, calcitonin group vs. gabapentin group, and P ≤ 0. 001, calcitonin group vs. control group with respect to pretreatment scores). Thus, three months after the treatment, although most of the patients in the control group had a satisfactory period of improvement, the improvement in the calcitonin group was more than the other two groups with a significant difference (P ≤ 0.05 when compared to gabapentin group and P ≤ 0.01 when compared to placebo group). We revealed that the 200 International Unit (IU) and nasal calcitonin spray daily are more effective compared to 300 mg gabapentin three times per day and the placebo effect for eight weeks of treatment of symptoms of patients with LSS.

Effect of Nasal Calcitonin on the Health-Related Quality of Life in Postmenopause Women Affected With Low Bone Density.

Background:Physical activity and mental health could be affected by osteoporosis and various therapeutic options such as calcitonin may influence Quality Of Life (QOL) of these patients with Low Bone Density (LBD).Objectives:This study aimed to evaluate the effect of nasal calcitonin on QOL in post menopause women with LBD.Patients and Methods:This clinical trial study was performed on one hundred and fifteen menopause women with LBD less than 1 SD in Bone Mineral Densitometry (BMD) referred to Baqiyatallah Hospital in Tehran, Iran, during 2009 - 2010. They were assigned to receive 200 IU calcitonin nasal spray along with calcium (1000 mg) and vitamin D (400 IU) for 6 months. Quality of life was assessed by Short-Form 36 (SF-36) questionnaire (Persian-validated version).Results:The mean age (± SD) of the participants was 58.75 ± 8.15 years. Intranasal spray of calcitonin increased QOL scores significantly (88.05 ± 15.63 vs. 92.15 ± 13.22, P value = 0.000). Bone mineral density of spine was increased from 0.834 ± 0.11 to 0.12 ± 0.852 and this difference in BMD of lumbar spine was statistically significant (P value: 0.003) but not significant in femur’s BMD (P value = 0.061). In comparison with BMD indexes, The QOL scores especially Mental Health domain changes had only a significant correlation with the changes of total T score in BMD (P = 0.031, Coefficient Correlation = 0.248).Conclusions:It seems that nasal spray of calcitonin can effectively improve QOL of women with LBD and QOL changes were not influenced by clinical or para-clinical alteration. Mental health domain must be more considered in further studies as a predicting domain for Health-Related Quality of Life (HR-QOL) changes.

Nonuremic calciphylaxis precipitated by teriparatide [rhPTH(1–34)] therapy in the setting of chronic warfarin and glucocorticoid treatment

Calciphylaxis occurs rarely in the absence of end stage renal disease. Predisposing factors for nonuremic calciphylaxis (NUC) include hyperparathyroidism, coagulopathies, connective tissue disease, liver disease, glucocorticoid use, and malignancy. Warfarin can facilitate vascular calcification by reducing vitamin K-dependent carboxylation of matrix-Gla proteins. An 86-year-old Caucasian woman with a history of polymyalgia rheumatica, two spontaneous deep venous thromboses (DVTs) and multiple fractures was treated with calcium, vitamin D, prednisone, and warfarin. The patient's low bone density was treated initially with estrogen, then oral bisphosphonate, which was discontinued due to upper gastrointestinal symptoms. Nasal calcitonin was initiated. After 10 years of calcitonin treatment, she was changed to teriparatide. Two months after initiating teriparatide, she developed lower extremity edema and painful erythematous nodular lesions on her calves bilaterally, that progressed to necrotic ulcers despite antibiotic therapy. Biopsy of the lesions showed calcification in the media of small blood vessels and subcutaneous fat with fat necrosis, consistent with calciphylaxis. Teriparatide was discontinued. Aggressive wound care, antibiotics, and intravenous zoledronic acid were initiated. With cessation of teriparatide therapy and intensive wound care, the patient's lesions resolved over 8 months. We report the first case of NUC precipitated by teriparatide therapy. Our patient had multiple underlying predisposing factors including a connective tissue disorder, glucocorticoid therapy, warfarin use, and possible underlying coagulopathy given her history of multiple DVTs. In such patients, alternative osteoporosis therapies may be preferred.

Salmon Calcitonin Use and Associated Cancer Risk

To evaluate the strength of evidence supporting a possible association between salmon calcitonin (SCT) use and cancer incidence. Searches of MEDLINE/PubMed, MEDLINE/OVID, and EMBASE (January 1973 to September 2013) were performed using the key search terms salmon calcitonin, humans, nasal calcitonin, and (for EMBASE only) randomized controlled trial. We also performed a manual review of data reviewed by the US Food and Drug Administration (FDA) committee in 2013. All articles identified from the data sources were evaluated and all information deemed relevant was included for this review. Intranasal and injectable SCT are FDA-approved for the treatment of postmenopausal osteoporosis. After a safety signal suggested a possible link between SCT use and prostate cancer, the European Medicines Agency and FDA regulatory agencies conducted analyses of SCT randomized controlled trial data to assess cancer-related adverse events and to readdress the approval status of SCT. Eighteen studies were found that compared nasal or oral SCT and placebo. In 15 of the 18 studies, the percentage of malignancy was greater in the SCT arm. The studies varied in quality, outcomes, and length. Most of the studies had poor-quality methods to assess new cancer cases. Current evidence may suggest an association between SCT use and cancer incidence based on studies with poor-quality cancer assessment methods. However, considering the lack of demonstrated efficacy of SCT to reduce fractures, clinicians should consider discontinuing its use for osteoporosis treatment regardless of the FDA's final approval decision.

Pregnancy‐associated osteoporosis presenting severe vertebral fractures

The syndrome of pregnancy-associated osteoporosis (PAO) is a rare disorder which occurs either in late pregnancy or early post-partum period leading to fragility fracture(s), most commonly in the vertebral bodies. We presented two cases with PAO who had compression fractures at multiple levels involving five vertebrae in one case and 10 vertebrae in the other. Their spinal bone mineral density values were below -2.5 standard deviations. Anti-osteoporotic treatments with nasal calcitonin 400 IU/day, vitamin D 300.000 IU single dose, calcium 1000 mg/day, vitamin D 880 IU/day were initiated. In one case, kyphoplasty was performed by a spinal surgeon. In addition to a thoracolumbosacral orthosis, a rehabilitation program including muscle strengthening, range of motion, relaxation and weight-bearing exercises was started for both cases. These cases emphasize that all pregnant women with complaints of back/lumbar pain should be carefully evaluated.

A double‐blind, placebo‐controlled study of adjunctive calcitonin nasal spray in acute refractory mania

Calcitonin, a neuropeptide, has been shown in preliminary double-blind trials to reduce agitation in patients with acute mania. Given that it has effects similar to those of lithium and anticonvulsants on modulation of second-messenger signaling pathways and stabilization of neuronal membranes, this study examined the efficacy of calcitonin nasal spray in treating acute manic symptoms in patients with treatment-resistant mania using a double-blind, placebo-controlled design. A total of 46 hospitalized patients experiencing either a manic or a mixed episode, who were refractory to treatment with adequate doses of either a mood stabilizer or an antipsychotic, or a mood stabilizer/antipsychotic combination, and had a score of ≥16 on the Young Mania Rating Scale (YMRS), were randomized to receive adjunctive nasal calcitonin 200 IU (n = 24) or saline (n = 22) spray for three weeks. The primary efficacy measure was the change in YMRS scores using the last observation carried forward (LOCF) method. The clinical and demographic characteristics were similar between the groups. Patients had a mean YMRS score of 26 in the placebo group and a mean score of 25 in the calcitonin group. There were no significant differences in YMRS scores or percentage responders at three weeks between patients who received calcitonin and those who received placebo. There were also no significant differences in change scores on any other scales. Few patients experienced any adverse events. This study does not support the use of nasal calcitonin in the treatment of treatment-resistant mania.

The Pathogenesis, Treatment and Prevention of Osteoporosis in Men

Testosterone stimulates longitudinal and appositional growth during childhood, whereas estrogen induces epiphysial closure. During adulthood, testosterone continues to stimulate periosteal growth, whereas estrogen is important for the maintenance of trabecular bone mass and structure. In males, testosterone is aromatized to estradiol. Both free and bioavailable plasma levels of testosterone and estradiol decrease with age in males, and fracture risk is associated with low estradiol levels. Testosterone may increase muscle mass and prevent fractures related to falls. Younger hypogonadal males should be treated with testosterone to attain peak bone mass and increase bone mineral density (BMD). Older hypogonadal males should be treated in cases of osteoporosis, reduced muscle strength and increased risk of falling. Secondary hyperparathyroidism caused by calcium and vitamin D insufficiency may reduce bone mass and strength and increase fracture risk and should be avoided. Since calcium supplementation has been associated with an increased risk of cardiovascular complications and renal stones, the dose should be tailored to the habitual daily calcium intake. Lifestyle-related risk factors (smoking, alcohol consumption, lack of physical activity and low body weight) should be addressed. The antifracture efficacy of antiresorptive and anabolic treatment for osteoporosis has not been documented in larger randomized controlled studies. However, changes in BMD and bone markers suggest similar effects in males and females of bisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid), nasal calcitonin, denosumab and teriparatide (parathyroid hormone [1-34]). The antiresorptive drugs should be used in males with BMD T-score less than -2.5 and one or more risk factors, or with hip and vertebral fractures. It seems appropriate to recommend a higher cut-off T-score (e.g. less than -1.0 standard deviation [SD]) in glucocorticoid-induced osteoporosis and in patients receiving androgen deprivation therapy because of the fast initial bone loss. Anabolic treatment should be used in more severe spinal fracture cases, including glucocorticoid-induced osteoporosis.

Outcome of Surgical Treatment for Complicated Humeral Shaft Fractures in Elderly Adults with Osteoporosis

Although the majority of humeral shaft fractures sustained by elderly adults with osteoporosis can be successfully managed nonoperatively,1-3 at the First Orthopedic Clinic, Medical School, Aristotle University of Thessaloniki, “G. Papanikolaou” Hospital (Thessaloniki, Greece), excellent results have been achieved with the selection of surgical treatment for different types of humeral shaft fractures in a cohort of such individuals. Over a 27-year period (1984–2011), 182 elderly adults with osteoporosis (mean age 66.5, range 57–87; 142 female (mean T-score 3.89), 40 male (mean T-score 3.13); 190 humeral shaft fractures; classification according to Arbeitsgemeinschaft für Osteosynthesefragen Association for the Study of Internal Fixation: AO 12 were treated using internal fixation. Fracture classification was performed according to AO principles.4 The indications were 73 patients with multiple fractures, 51 fractures with coexisting primary radial nerve injury, 12 Goustillo Grade I or II, eight bilateral and 50 insufficient reductions after conservative treatment; 115 fractures were located at the middle third, 32 at the upper third, and 43 at the lower third of the humeral bone; 73 were comminuted (AO 12 C and AO 12 B), 95 transverse (AO 12 A3), eight oblique (AO 12 A2) and 15 spiral (AO 12 A1). A standard anterolateral approach (Thompson and Henry) was performed, and the radial nerve was routinely identified and exposed. Fracture stabilization was mainly performed using a 4-mm self-compressing dynamic compression plate (DCP) (114 cases) and a low-contact (LC) DCP (76 cases) with 4.5-mm cortical screws. In 54 of these cases, compression lag screws were applied. A Y-shaped DCP plate was used in eight cases. Autologous iliac crest grafts were used in 30 cases because of the lack of medial cortex integrity. The addition of cement in the drill holes for extra purchase was selected intraoperatively in 12 cases. All patients received a modification of their osteoporosis treatment by addition of nasal calcitonin in doses of 100 IU per day until fracture union. Patients were asked to attend the outpatient fracture clinic at 4, 8, and 26 weeks; 1 year; and then yearly or on an as-need basis. Patient follow-up in 158 patients was 7 to 24 years (mean 13.6 years). Twenty-four patients did not complete the follow-up and were excluded from the analysis. Fracture healing interval was 3 to 6 months in 153 fractures (92.73%). Nonunion occurred in 12 fractures (7.27%), and new fixation was implemented with more-rigid plating and grafts, with favorable outcome in all cases. Postoperative infection reported in four patients was treated successfully. Cumulative results are reported in Table 1. Two patients developed neurapraxia of the ipsilateral radial nerve after surgical treatment, with nerve functionality restored in a few days without any final functional deficit. Of the 51 patients with preoperative nerve function deficit, two experienced injury to the brachial plexus (no progress noted), whereas the remaining 49 patients experienced radial nerve injury solely. No macroscopic damage of the nerve was observed in 47 patients. A splint for keeping the wrist and fingers in slight extension was suggested postoperatively, and all patients were rehabilitated for a mean of 10 weeks. Full dissection of the radial nerve was observed in one patient, and nerve suturing could not be performed. During the final follow-up, elbow range of motion was very good in 146 patients (153 fractures, 92.7%), whereas an elbow extensor deficit of 10º was recorded in four patients (four fractures, 24.2%). There was no reported motor dysfunction in the ipsilateral shoulder. Nonunion occurred in 12 fractures (7.3%). Thus, results were satisfactory in 146 cases (153 fractures, 92.7%) and unsatisfactory in 12 cases (7.3%). These patients developed mechanical failure of the plate osteosynthesis and fracture pseudarthrosis. The success percentage of functional rehabilitation reaches 92.7% and is similar to the results of other researchers who have used the same technique3, 5 in patients without osteoporosis. Surgical treatment of humeral shaft fractures based on the principles of stable internal fixation has good results in elderly adults with osteoporosis, but it should be chosen only in cases in which there is absolute indication for surgery. Conflict of Interest: The editor in chief has reviewed the conflict of interest checklist provided by the authors and has determined that the authors have no financial or any other kind of personal conflicts with this paper. Author Contributions: Thomas Pagonis: Study concept and design, acquisition of subjects and data, analysis and interpretation of data, and preparation of manuscript and one of the operating surgeons. Kostantinos Ditisos and Georgios Petsatodis: Acquisition of subjects and data and two of the operating surgeons. Anastasios Christodoulou: Analysis of data and one of the operating surgeons. Sponsor's Role: There was no sponsor for this study.

Effects of calcitonin on knee osteoarthritis and quality of life

There has been a recent interest in calcitonin as a potential treatment for osteoarthritis, based on its metabolic activities in both bone turnover and cartilage. The aim of this study was to evaluate the effects of nasal form calcitonin on knee osteoarthritis and quality of life in women who receive calcitonin treatment for postmenopausal osteoporosis. Two hundred and twenty postmenopausal women, aged between 55 and 65 years with knee pain and knee osteoarthritis, graded II-III by using Kellgren-Lawrence radiographic scoring system, were included. Western Ontario and McMaster Universities (WOMAC) osteoarthritis index, the quality of life questionnaire of the European Foundation for Osteoporosis (QALEFFO-41) and visual analog scale were used for the algofunctional assessments. Need of rescue analgesic was recorded. Pain (P < 0.001), stiffness (P < 0.05), functional capability (P < 0.05) and total score of WOMAC (P < 0.05) revealed statistically significant improvements after 3 months of the treatment and remained consistent throughout 1 year of the treatment period. Participants experienced significant reductions in WOMAC perceptions of pain (-53 %), joint stiffness (-44 %) and limitations in physical function (-49 %) at the end of 1 year of calcitonin treatment. Need of rescue analgesic intake was reported to have decreased approximately by 60 % at the end of the 1-year treatment period. QUALEFFO_41 scores improved: 37.6 (baseline), 30.9 (3 months), 28.0 (6 months) and 24.4 (1 year). In conclusion, nasal calcitonin treatment provided dual action on osteoporosis and osteoarthritis with significant improvements in quality of life and algofunctional results in knee osteoarthritis.

A phase 3 trial of the efficacy and safety of oral recombinant calcitonin: The oral calcitonin in postmenopausal osteoporosis (ORACAL) trial

The Oral Calcitonin in Postmenopausal Osteoporosis (ORACAL) study was a randomized, double-blind, double-dummy, active- and placebo-controlled, multiple-dose, phase 3 study to assess the efficacy and safety of oral recombinant calcitonin for treatment of postmenopausal osteoporosis. A total of 565 women age 46 to 86 (mean 66.5) years were randomized (4:3:2) to receive oral recombinant salmon calcitonin (rsCT) tablets (0.2 mg/d) plus placebo nasal spray, synthetic salmon calcitonin (ssCT) nasal spray (200 IU/d) plus placebo tablets, or placebo (placebo tablets plus placebo nasal spray), respectively for 48 weeks. All women received calcium (≥1000 mg/d) and vitamin D (800 IU/d). Women randomized to oral rsCT had a mean ± SD percent increase from baseline in lumbar spine bone mineral density (BMD) (1.5% ± 3.2%) that was greater than those randomized to ssCT nasal spray (0.78% ± 2.9%) or placebo (0.5% ± 3.2%). Lumbar spine BMD change in those receiving nasal calcitonin did not differ from placebo. Oral rsCT treatment also resulted in greater improvements in trochanteric and total proximal femur BMD than ssCT nasal spray. Reductions in bone resorption markers with oral rsCT were greater than those observed in ssCT nasal spray or placebo recipients. Approximately 80% of subjects in each treatment group experienced an adverse event, the majority of which were mild or moderate in intensity. Gastrointestinal system adverse events were reported by nearly one-half of women in all treatment groups and were the principal reason for premature withdrawals. Less than 10% of women experienced a serious adverse event and no deaths occurred. Overall, oral rsCT was superior to nasal ssCT and placebo for increasing BMD and reducing bone turnover. Oral rsCT was safe and as well tolerated as ssCT nasal spray or placebo. Oral calcitonin may provide an additional treatment alternative for women with postmenopausal osteoporosis.

Evidence to Inform Decision Makers in Thailand: A Cost-Effectiveness Analysis of Screening and Treatment Strategies for Postmenopausal Osteoporosis

Objectives To assess value for money of providing systematic screening for osteoporosis among postmenopausal women and medical treatments for those diagnosed with osteoporosis as evidence-based decision making for the revision of the National List of Essential Medicines. Methods Decision analytic models were constructed, using a societal perspective, to assess the cost per quality-adjusted life-years (QALYs) gained from systematic screening using the Osteoporosis Self-Assessment Tool and dual-energy X-ray absorptiometry or dual-energy X-ray absorptiometry alone compared with no screening. Alendronate, risedronate, raloxifene, and nasal calcitonin were economically evaluated to determine a treatment of choice for the prevention of osteoporosis-related fractures. Most input parameters were obtained from literature reviews, and systematic reviews and meta-analyses, if available. The service costs and related household expenses were based on the Thai setting. Probabilistic and one-way sensitivity analyses were used to incorporate the impact of parameter uncertainty. Results The Osteoporosis Self-Assessment Tool and sequential dual-energy X-ray absorptiometry provided better value for money for osteoporosis screening among young age groups (<60 years old). Although there was no significant difference in cost per QALY for older age groups, alendronate provided the lowest incremental cost-effectiveness ratio while nasal calcitonin presented the highest incremental cost-effectiveness ratio. It was shown that providing medication for a secondary prevention yielded a much higher cost per QALY gained compared with providing medication for a primary prevention. Conclusions Given the benchmark set at 100,000 Thai baht per QALY gained, providing systematic screening and treatment for osteoporosis was cost-ineffective in the Thai setting.

New approvals

Azilsartan medoxomil (Edarbi) tablets have been approved by the Food and Drug Administration (FDA) for treating hypertension.1 Compared with olmesartan and valsartan, the 80-mg dose had greater 24-hour blood pressure-lowering effects, in Phase 3 clinical trials.2 It is available in 40-mg and 80-mg tablets. In addition, a new drug application (NDA) was recently filed for a tablet that combines both azilsartan and chlorthalidone. In a clinical trial presented at the American Society of Hypertension's 2010 meeting, the combination of azilsartan/chlorthalidone had better blood pressure-lowering effects than the combination of azilsartan and hydrochlorothiazide (HCTZ). After all this waiting, belimumab (Benlysta) was finally FDA-approved for treating systemic lupus erythematosus (SLE) in March 2011.3 It is a monoclonal antibody that targets B-lymphocyte stimulator protein, also known as BLyS. It is dosed via an intravenous (IV) infusion of 10 mg/kg every 2 weeks for three doses, followed by every 4-week dosing thereafter. Patients in clinical trials only had modest improvement in symptoms with the agent, but its effectiveness was significantly better than placebo. One-year response rates were 43% for belimumab-treated patients and 32% for placebo-treated patients. The drug should not be administered along with live vaccines. A medication guide will be distributed to all patients who receive this agent to inform them of the treatment risks. The last agent to be FDA-approved to treat SLE was hydroxychloroquine, in 1955. For patients with CrCl > 30 mL/min, take 150 mg orally, twice daily For patients with CrCl 15-30 mL/min, take 75 mg orally, twice daily. At a recent guideline committee meeting of the American College of Cardiology, the American Heart Association, and the Heart Rhythm Society, the committee recommended that dabigatran be used as an alternative to warfarin in patients with atrial fibrillation who do not have significant heart valve disease, do not have a prosthetic heart valve, and/or do not have advanced hepatic disease, and/or do not have severe renal failure to reduce their clot risk.6 Other similar agents are currently in the FDA pipeline for this and other similar uses.7 The QMS Everolimus Immunoassay was recently FDA-approved as the first test to monitor everolimus blood levels in renal transplant patients.8 Similar blood level tests are already available to monitor transplant patients receiving cyclosporine, tacrolimus, and/or sirolimus. The test is manufactured by Thermo Fisher Scientific (Waltham, Mass.). Voriconazole tablets were FDA-approved as a generic of Vfend in February of 2011.9 The company has 180 days of market exclusivity before other generics will be available. The liquid and IV versions of the drug are covered under a separate patent. Calcitonin, recombinant salmon oral, is currently in Phase 3 clinical trials for the treatment of postmenopausal osteoporosis.10 It was compared with synthetic salmon calcitonin nasal spray and placebo in 565 women, in a Phase 3 clinical trial. At 1 year, the recombinant oral calcitonin product was statistically significantly non-inferior to placebo and nasal calcitonin in increasing bone mineral density. CTAP101 is currently in Phase 2b clinical trials.11 It is an oral, non-hormonal, treatment for vitamin D insufficiency in patients with secondary hyperparathyroidism and stage 3 chronic kidney disease (CKD). It is currently undergoing clinical trials to evaluate its efficacy, safety, pharmacokinetics, pharmacodynamics, and tolerability. Dapagliflozin has had its NDA accepted by the FDA and the European Medicines Agency (EMA) as a new antidiabetic agent in a potentially new medication class.12 The new class is that of sodium-glucose co-transporter-2 (SGLT2) inhibitors, which target a specific location in the kidney, controlling glycemia independent of insulin pathways.12 Presently, there is limited information on using this agent in patients with renal disease. The FDA's Prescription Drug User Fee Act (PDUFA) goal date for this agent is October 28, 2011. Exenatide extended-release (Bydureon) failed to reduce average blood glucose levels in type 2 diabetics compared with liraglutide in a Phase 3 head-to-head trial known as DURATION-6.13 The fate of this agent is not yet known. The FDA declined its approval in October 2010, requesting additional data on its effect on heart rates. It is expected that Eli Lilly/Amylin will respond to the FDA's letter in the second half of this year. Lixisenatide, a once-daily glucagon-like peptide-1 (GLP-1) agonist, was shown to be as effective as twice daily exenatide in lowering HbA1c levels from baseline in type 2 diabetic patients in the 24-week GetGoal-X trial.14, 15 Additionally, lixisenatide-treated patients exhibited fewer symptomatic hypoglycemic reactions compared with exenatide-treated patients (2.5% vs. 7.9%, p < 0.05), and sixfold fewer hypoglycemic events were observed with the investigational agent compared with the FDA-approved agent (8 vs. 48 events). Patients received stepwise dose increases up to a maximum of 20 µm.

Efficacy and Harms of Nasal Calcitonin in Improving Bone Density in Young Patients With Inflammatory Bowel Disease: A Randomized, Placebo-Controlled, Double-Blind Trial

There are very few published studies of agents having the potential to improve bone health in children with inflammatory bowel disease (IBD). The objective of this study was to establish the efficacy and safety of intranasal calcitonin in improving bone mineral density (BMD) in young patients with IBD and to define additional factors that impact bone mineral accrual. We conducted a randomized, placebo-controlled, double-blind clinical trial in 63 participants, ages 8-21 years, with a spinal BMD Z-score ≤ -1.0 s.d. measured by dual energy X-ray absorptiometry. Subjects were randomized to 200 IU intranasal calcitonin (n=31) or placebo (n=32) daily. All received age-appropriate calcium and vitamin D supplementation. Subsequent BMD measurements were obtained at 9 and 18 months. Intranasal calcitonin was well tolerated. Adverse event frequency was similar in both treatment groups, and such events were primarily minor, reversible, and limited to the upper respiratory tract. The BMD Z-score change documented at screening and 9 months and screening and 18 months did not differ between the two therapeutic arms. In participants with Crohn's disease, the spinal BMD Z-score improved between screening and 9 months (change in spine BMD Z-score (ΔZSBMD)(9-0)) in the calcitonin group (ΔZSBMD(9-0)(calcitonin)=0.21 (0.37), ΔZSBMD(9-0)(placebo)=-0.15 (0.5), P=0.02); however, this was only a secondary subgroup analysis. Bone mineral accrual rate during the trial did not lead to normalization of BMD Z-score in this cohort. Factors favoring higher bone mineral accrual rate were lower baseline BMD and higher baseline body mass index Z-score, improvement in height Z-score, higher serum albumin, hematocrit and iron concentration, and more hours of weekly weight-bearing activity. Factors associated with lower bone mineral accrual rate were more severe disease-as indicated by elevated inflammatory markers, need for surgery, hospitalization, and the use of immunomodulators-and higher daily caffeine intake. Intranasal calcitonin is well tolerated but does not offer a long-term advantage in youth with IBD and decreased BMD. Bone mineral accrual rate remains compromised in youth with IBD and low BMD raising concerns for long-term bone health outcomes. Improvement in nutritional status, catch-up linear growth, control of inflammation, increase in weight-bearing activity, and lower daily caffeine intake may be helpful in restoring bone density in children with IBD and low BMD.

Prescription of anti-osteoporosis drugs during 2004–2007—a nationwide register study in Norway

To assess 1-year prevalence, incidence rates and minimum refill of anti-osteoporosis drug use in Norway by age, gender and place of residence during 2004-2007. Data from patients aged > or = 40 years receiving anti-osteoporosis drugs (AOD) were retrieved from the Norwegian Prescription Database (NorPD). AOD were defined as bisphosphonates (alendronate with or without cholecalciferol, risedronate, ibandronate and etidronate with or without calcium), raloxifene, teriparatide and nasal calcitonin. The NorPD covers the total Norwegian population in ambulatory care. Key measurements were 1-year prevalence, incidence rate and minimum refill. Among Norwegian women and men > or = 40 years, 4.3 and 0.45% respectively used AOD in 2004. In 2007, the prevalence of AOD use had slightly increased to 4.6% in women and to 0.52% in men. In 2007, 90% of users were women. The use of alendronate, representing 88% of all AOD use in 2007, increased from 2004 to 2007 while the use of other bisphosphonates decreased. The counties with highest overall bisphosphonate use were the counties with the historically lowest incidence of osteoporotic fractures. The incidence rate of overall bisphosphonate use decreased from 2005 to 2007. Among those patients who were dispensed a bisphosphonate in 2005, 72% refilled at least one prescription both in 2006 and 2007. There was an increasing prevalence and a decreasing incidence of AOD use over this limited time period. There was substantial geographical variation in the prevalence of anti-osteoporosis drugs. We also observed a high minimum refill rate.

Pregnancy-associated osteoporosis revisited

To the Editor, A 23-year-old female was seen due to severe back pain for 3 months after delivering her first child. On detailed questioning, she declared that her pain started during the last trimester of pregnancy and that it was worse during activities. She denied having any numbness, weakness or pain in the lower limbs. She had recently stopped breastfeeding and the medical history was otherwise noncontributory. Questioning for osteoporosis (OP) risk factors only yielded inadequate calcium intake. On physical examination, her height was 160 cm, body weight was 50 kg (BMI 19.5 kg/m). Posture analysis revealed increased dorsal kyphosis and thoracolumbar scoliosis. Thoracic vertebrae were tender to compression. Neurological evaluation was unremarkable. Plain radiographs showed compression fractures at T8–T12 and scoliosis (Fig. 1). Dual energy X-ray absorptiometry (DXA) (Hologic QDR-4500) was performed for the evaluation of bone mineral density (BMD) (Table 1). Laboratory tests (inclusing serum calcium, phosphate, alkaline phosphatase, parathyroid hormone levels and thyroid, liver and renal function tests) were all normal except decreased 25-OH vitamin D level (12.2 ng/ml = 30.45 nmol/L, N [ 20 ng/ ml). Overall, she was diagnosed to have pregnancyassociated osteoporosis (PAO). Medical treatment comprised daily intake of calcium carbonate (1,200 mg ionized calcium), 800 IU vitamin D3 and 200 IU nasal calcitonin. She was additionally prescribed analgesics, bed rest and a thoracolumbar brace at the initial stage. Thereafter, she was commenced on a physical therapy program (superficial and deep heat for the low back region; isometric strengthening exercises for the trunk muscles and scoliosis exercises). PAO is an uncommon disorder characterized by painful vertebral fractures (generally more than one) in late pregnancy or early postpartum periods [1, 2]. The incidence is estimated to be only 0.4 cases per 100,000 women whereas the number of undiagnosed cases is probably higher [3]. Despite the skepticism on its etiology and pathogenesis, the condition has been linked to insufficient calcium intake and increased mechanical stress throughout the course of pregnancy (hyperlordosis). Significant calcium transfer from the mother to the fetus and the infant (during rapid mineralization) occurs during pregnancy and lactation, theoretically placing the mother at an increased risk for OP later in life [4]. Further, it is also reflected on the maternal BMD, as a decrease of 2–4% depending on the site of measurement [5]. It is well known that peak bone mass (the basis of the latter calcium reservoir) is achieved between 20 and 30 years of age and depends on genetic disposition, gender, age at menarche, nutrition, lifestyle, level of physical activity and consumption of alcohol, tobacco and caffeine. Accordingly, the lower the peak bone mass before pregnancy is, the higher the risk of PAO development becomes [3]. In our primagravid female patient, the risks for PAO with nontraumatic vertebral fractures seemed to be poor calcium and vitamin D intake prior and throughout her pregnancy. Management of PAO is not well established but should definitely not be confined to medical treatment only. Recent studies have shown that the bone loss should improve toward normal after the delivery; however, this G. Kara L. Ozcakar F. U. Malas A. Akinci O. Basgoze Department of Physical Medicine and Rehabilitation, Hacettepe University Medical School, Ankara, Turkey e-mail: gkara2005@yahoo.com.tr

Confounder summary scores when comparing the effects of multiple drug exposures

Little information is available comparing methods to adjust for confounding when considering multiple drug exposures. We compared three analytic strategies to control for confounding based on measured variables: conventional multivariable, exposure propensity score (EPS), and disease risk score (DRS). Each method was applied to a dataset (2000-2006) recently used to examine the comparative effectiveness of four drugs. The relative effectiveness of risedronate, nasal calcitonin, and raloxifene in preventing non-vertebral fracture, were each compared to alendronate. EPSs were derived both by using multinomial logistic regression (single model EPS) and by three separate logistic regression models (separate model EPS). DRSs were derived and event rates compared using Cox proportional hazard models. DRSs derived among the entire cohort (full cohort DRS) was compared to DRSs derived only among the referent alendronate (unexposed cohort DRS). Less than 8% deviation from the base estimate (conventional multivariable) was observed applying single model EPS, separate model EPS or full cohort DRS. Applying the unexposed cohort DRS when background risk for fracture differed between comparison drug exposure cohorts resulted in -7 to + 13% deviation from our base estimate. With sufficient numbers of exposed and outcomes, either conventional multivariable, EPS or full cohort DRS may be used to adjust for confounding to compare the effects of multiple drug exposures. However, our data also suggest that unexposed cohort DRS may be problematic when background risks differ between referent and exposed groups. Further empirical and simulation studies will help to clarify the generalizability of our findings.

Trends and determinants of prescription medication use for treatment of osteoporosis

Trends in the use of different treatments for osteoporosis among the civilian, ambulatory U.S. population are described. Data from the Medical Expenditure Panel Survey (MEPS) were used to estimate osteoporosis prevalence and treatment rates among individuals ages 50 years and older who self-reported having osteoporosis. Specific pharmacologic treatments analyzed included oral and transdermal estrogen and estrogen and progesterone combination products in women, injectable and transdermal testosterone products in men, oral bisphosphonate medications, raloxifene, and nasal calcitonin. Predisposing characteristics included sex, age, education, income, and race. Required characteristics included the use of an oral corticosteroid medication, having a fracture in the current MEPS year, presently smoking, and self-report of fair or poor health status. Self-report of osteoporosis increased steadily from approximately 3.2 million patients in 1999 to 7.2 million patients in 2005. This was associated with an increase of the number of patients who used medication for the treatment of osteoporosis from 2.3 million in 1999 to 5.6 million in 2005. Although medication use increased over time, only 77% of people with osteoporosis reported using medication for the treatment of osteoporosis in the previous year. Only 25.4% of men, 55.6% of blacks, 64.2% of patients without a usual source of health care, and 66.8% of patients who reported their health as fair or poor used medication for the treatment of osteoporosis in the previous year. Although the MEPS data are based on patient self-report, the results from our study suggest that approximately one in four patients with osteoporosis did not receive prescription management for this condition.