Intranasal Calcitonin Research Articles

Lumbar spinal stenosis: a brief review of the nonsurgical management

The purpose of this brief narrative review is to summarize the evidence derived from randomized controlled trials pertaining to the nonsurgical treatment of lumbar spinal stenosis (LSS). The MEDLINE (January 1950 to the fourth week of January 2010) and EMBASE (January 1980 to 2009, week 53) databases, the MESH term "spinal stenosis", and the key words, "vertebral canal stenosis" and "neurogenic claudication", were searched. Results were limited to randomized controlled trials (RCTs) conducted on human subjects, written in English, and published in peer-reviewed journals. Only RCTs pertaining to nonsurgical treatment were considered. Studies comparing conservative and surgical management or different surgical techniques were not included in the review. The search criteria yielded 13 RCTs. The average enrolment was 54 subjects per study. Blinded assessment and sample size justification were provided in 85% and 39% of RCTs, respectively. The available evidence suggests that parenteral calcitonin, but not intranasal calcitonin, can transiently decrease pain in patients with LSS. In the setting of epidural blocks, local anesthetics can improve pain and function, but the benefits seem short-lived. The available evidence does not support the addition of steroids to local anesthetic agents. Based on the limited evidence, passive physical therapy seems to provide minimal benefits in LSS. The optimal regimen for active physiotherapy remains unknown. Although benefits have been reported with gabapentin, limaprost, methylcobalamin, and epidural adhesiolysis, further trials are required to validate these findings. Because of their variable quality, published RCTs can provide only limited evidence to formulate recommendations pertaining to the nonsurgical treatment of LSS. In this narrative review, no study was excluded based on factors such as sample size justification, statistical power, blinding, definition of intervention allocation, or clinical outcomes. This aspect may represent a limitation as it may serve to overemphasize evidence derived from "weaker" trials. Further well-designed RCTs are warranted.

HORMONE REPLACEMENT THERAPY AND CALCITONIN IN WOMEN WITH BONE MASS LOSS

Aim: Determining if the combined use of hormone replacement therapy and calcitonin influences on bone mass loss in postmenopausal women. Design: We studied for 24 months 45 women who were 44 to 67 years old at base line, were within 1 and 12 years of menopause, and had a bone mineral density at the lumbar spine between 150 mg/cc and 80 mg/cc measured by the QBMAP systemwith a spiral CT Picker PQ-S densitometer at L2, L3, L4 and L5. 22 women were assigned to transdermal therapy with 50 (g/day of 17(-oestradiol on a intermitent cyclic regimen (28 out of 35 days) combined with 100 mg/day of micronized progesterone, and 23 were treated with the same hormone replacement therapy plus 200 UI of intranasal calcitonin. The SPSS programme was used for statiscal analysis. Results: The characteristics of the women recruited for both groups were similar. Mean mineral bone density at the lumbar spine was between 1 and 3 DS below the mean value for 30 years old normal premenopausal women. After treatment no difference statistically significant was found among the groups with and without calcitonin as for the bone mineral density at the lumbar spine. The calcitonin group felt minus pain. Conclusion: It is necessary to carry out a wider study but it seems that the 200 UI calcitonin contribute advantages when it is combined with hormone replacement therapy to decrease the bone mass loss in postmenopausal women at least at lumbar spine.

Central giant cell lesion of the jaw: Nonsurgical treatment with calcitonin nasal spray

The aim was to evaluate the effectiveness of the long-term administration of intranasal calcitonin spray for the treatment of central giant cell granuloma (CGCG) in a retrospective case study. The medical files of 5 patients (4 male, 1 female; ages 8-66 years) with CGCG of the jaws treated with calcitonin nasal spray 200 U/spray once or twice daily were reviewed for lesion-related parameters, outcome, and adverse effects of therapy. Three lesions were located in the mandibular body and ramus region and 2 in the anterior maxilla. Mean lesion size on radiography was 3.2 x 2.3 cm. The duration of calcitonin treatment was 9-60 months (mean 28 months). All the lesions considerably decreased in size with a high degree of calcification. There were no recurrences. Calcitonin nasal spray appears to be safe and effective for the treatment of CGCG and might be considered an alternative to surgery. Further controlled studies are needed to corroborate these findings.

Recurrent aneurysmal bone cyst of the mandibular condyle with soft tissue extension

The case of a 17- year-old female patient with a destructive aneurysmal bone cyst of the right mandibular condyle is presented. Surgery revealed an eggshell thin, partly perforated remaining condylar cortex with extension of the lesion into the surrounding soft tissues. Condylar resection with curettage of the adjacent soft tissues and recurrence prophylaxis with intranasal calcitonin for 1 week could not prevent recurrence after 6 months. In a second operation the ascending mandibular ramus was partly resected and immediately reconstructed with a newly developed alloplastic condylar head add-on system. This time the lesion was intraoperatively completely surrounded by solid cortical bone.

Pharmacotherapy options for complex regional pain syndrome

Complex regional pain syndrome is a painful disorder of unclear etiology, typically involving the distal part of one limb, represented by spontaneous and evoked pain as well as autonomic, motor and trophic abnormalities. It can be incapacitating and severely affect function and quality of life. Although full-blown complex regional pain syndrome can be diagnosed easily, less fulminate forms of the syndrome often remain undiagnosed. Controlled trials have demonstrated that a short course of oral corticosteroids, intranasal or intramuscular calcitonin, intravenous bisphosphonates, free-radical scavengers, gabapentin, regional intravenous sympathetic blocks with bretylium and spinal cord stimulation or physical therapy and occupational therapy can be efficacious for complex regional pain syndrome. Nonetheless, the management of this syndrome is difficult because currently available drugs and technologies do not provide adequate pain relief for a considerable percentage of sufferers. The present review focuses primarily on the pharmacotherapy of complex regional pain syndrome and describes briefly the epidemiology, pathogenesis and clinical manifestations of the syndrome.

Osteoporosis: non-hormonal treatment

Significant progress has been achieved in osteoporosis treatment, in terms of agents with novel mechanisms of action, of new schedules of administration, and of long-term treatment safety demonstration.Alendronate, ibandronate, intranasal calcitonin, parathyroid hormones, raloxifene, risedronate, hormone replacement therapy, strontium ranelate and zoledronate decrease the risk of vertebral fracture. Alendronate, risedronate, strontium ranelate and zoledronate reduce the risk of hip fracture in women with osteoporosis, hormone replacement therapy in postmenopausal women, and calcium and vitamin D in institutionalized patients.In two meta-analyses, the combination of calcium and vitamin D was able to reduce the risk of falling, and hip fracture risk was decreased (>700 IU/day). Two subsequently published large trials were unable to detect any antifracture effect. PTH(1–84) reduces the risk of new vertebral fracture. There is no indication that combining PTH with a bone resorption inhibitor has any additional benefit to either drug alone. Strontium ranelate is a new agent for the treatment of osteoporosis, with antifracture efficacy whatever the severity of osteoporosis. An extension of the phase 3 trials up to 5 years has shown sustained antifracture efficacy. The humanized monoclonal antibody to the receptor activator of nuclear factor-κB ligand (RANKL) denosumab causes a rapid, high-magnitude, dose-dependent inhibition of bone resorption. Spine, hip and forearm bone mineral density increased, to an extent slightly higher than with the weekly administration of 70 mg alendronate.

The effects of daily alendronate, daily calcitonin and alendronate every other day on bone mineral density in osteoporotic men

Objectives. Biphosphonates have been widely used in the treatment of osteoporosis, but there is not enough data on their use in men. The aim of this study is to investigate the effects of twelve months' treatment with daily 10 mg alendronate, every other day 10 mg alendronate and daily 200 IU calcitonin on bone mineral density (BMD) in men with osteoporosis.Materials and methods. 46 men with osteoporosis were randomly allocated to three groups: 15 patients in the first group received daily 10 mg alendronate and calcium (1000 mg/day), 14 patients in the second group used every other day 10 mg alendronate and calcium and 17 patients in the third group were given intranasal salmon calcitonin and calcium. At the baseline, sixth and twelfth months, BMD was measured at lumbar spine (L2–4), femoral neck and Ward's triangle zone by means of dual energy X-ray absorptiometry (LUNAR).Results. In daily and every other day alendronate and calcitonin groups there was a significant increase in BMD at lumbar spine (p = 0.004, p = 0.001, p = 0.04), but no difference at the femoral neck (p > 0.05) at the end of twelve months. When the groups were compared with each other, no significant differences in BMD levels at lumbar spine, femoral neck and Ward's triangle were found (p > 0.05).

Intranasal Calcitonin in the Treatment of Acute Charcot Neuroosteoarthropathy

Charcot neuroosteoarthropathy (CNO) can lead to disruption of the bone architecture of the foot (1). Increased osteoclastic activity is believed to be responsible for the bone destruction in CNO (2). Previous studies showed COOH-terminal telopeptide region of type 1 collagen (1CTP) and bone-specific alkaline phosphatase (BALP) as useful markers of bone turnover in patients with CNO (3–5). Presently, only bisphosphonates have been demonstrated to have some benefit in patients with CNO (6). However, bisphosphonates may have potential disadvantages in that they decrease bone remodeling and are contraindicated in patients with renal insufficiency (7). Our previous study (8) showed positive effects of calcitonin on bone resorption in patients with acute CNO. In this study, we set out to assess the effect of calcitonin on bone metabolism and disease activity during a 6-month treatment with intranasal calcitonin in acute CNO. Thirty-two consecutive patients with acute CNO were entered into the study. Subjects were recruited from our diabetic foot clinic during a 17-month period and were followed up for 6 months. The study was approved by the local ethics committee, and all participants gave written informed consent. Acute CNO was defined by clinical signs: warm, swollen foot and skin temperatures ≥2°C at the site of maximum deformity of the affected foot compared with a similar site on the contralateral foot (infrared thermometer) and confirmed by plain X-ray and three-phase technetium bone scan (9). The presence of diabetic neuropathy was determined by measurement of vibration perception …

Management of age-related osteoporosis and prevention of associated fractures

Osteoporosis and related fractures are a significant concern for the global community. As the population continues to age, morbidity and mortality from fractures due to low bone mineral density (BMD) will likely continue to increase. Efforts should be made to screen those at risk for osteoporosis, identify and address various risk factors for falls and associated fractures, ensure adequate calcium and vitamin D intake, and institute pharmacological therapy to increase BMD when indicated. Agents which increase BMD and have been shown to decrease fractures, particularly at the hip, should be considered preferentially over those for which only BMD data are available. Drugs which have been shown to decrease the risk of age-related osteoporotic fractures include oral bisphosphonates (alendronate, ibandronate, and risedronate), intranasal calcitonin, estrogen receptor stimulators (eg, estrogen, selective estrogen receptor modulators [raloxifene]), parathyroid hormone (teriparatide), sodium fluoride, and strontium ranelate. Data are beginning to emerge supporting various combination therapies (eg, bisphosphonate plus an estrogen receptor stimulator), though more data are needed to identify combinations which are most effective and confer added fracture protection. In addition, further research is needed to identify ideal regimens in special populations such as nursing home patients and men.

The effectiveness of calcitonin on chronic back pain and daily activities in postmenopausal women with osteoporosis

The aim of this study was to investigate the effect of nasal calcitonin on chronic back pain and disability attributed to osteoporosis. The study design involved three groups of osteoporotic postmenopausal women suffering from chronic back pain. Group I consisted of 40 women with vertebral fractures, group II of 30 women with degenerative disorders and group III of 40 patients with non specific chronic back pain and without abnormality on plain X-rays. Pain intensity was measured using a numerical rating scale (NRS) and disability due to back pain was measured using the Oswestry disability questionnaire. The patients were randomly assigned to receive, for three months, either 200 IU intranasal salmon calcitonin and 1,000 mg of oral calcium daily (groups IA, IIA, IIIA) or 1,000 mg of oral calcium daily (groups IB, IIB, IIIB). Repeated measures ANOVA showed that there were no significant time, group or interaction effects for pain intensity and disability in any of the groups studied. Mean Oswestry and NRS scores were reduced during the follow-up period in the groups IA, IIIA, but the differences between the two time points were not statistically significant. Intranasal calcitonin has no effect on chronic back pain intensity and functional capacity of osteoporotic women regardless of the presence of fractures, degenerative disorders or chronic back pain of non-specific etiology.

Comparison of cyclic and continuous calcitonin regimens in the treatment of postmenopausal osteoporosis

We aimed to compare and evaluate the efficacies of a continuous regimen of intranasal salmon calcitonin (SCT) and two cyclic regimens (different cyclic regimens from previous studies) based on alternating 15 days or on 10 days consecutively per month for 1 year in the treatment of postmenopausal osteoporosis. We performed an open-label, prospective, randomized clinical trial. A total of 120 postmenopausal osteoporotic participants between 50 and 65 years old were randomly assigned to one of three treatment groups. Patients in group 1 (n = 40) received continuously SCT nasal spray at a dose of 200 IU/day, plus continuously 500 mg/day elementary calcium and 0.25 microg/day 1-alpha hydroxyvitamin D3, for 1 year. Patients in group 2 (n = 40) received cyclically SCT nasal spray at a dose of 200 IU/day on alternating 15 days per month, plus continuously 500 mg/day elementary calcium and 0.25 microg/day 1-alpha hydroxyvitamin D3, for 1 year. Patients in group 3 (n = 40) received cyclically SCT nasal spray on 10 days consecutively per month (20 days/month rest), plus continuously 500 mg/day elementary calcium and 0.25 microg/day 1-alpha hydroxyvitamin D3, for 1 year. Data was evaluated by repeated analysis of variance (ANOVA). In addition, statistical differences between groups were assessed by the two-tailed Student's t test. After 1 year of the study, seven patients from group 1, eight patients from group 2 and five patients from group 3 withdrew from the study. No patient discontinued the study because of adverse drug effects. There was a statistically-significant improvement in pain intensity VAS scores at the end of the year to baseline scores in all three groups (p < 0.001). There was no significant difference in pain intensity VAS scores between groups at the end of the year (p > 0.05). Lumbar and femur neck BMD scores improved significantly at the end of treatment in all three groups (p < 0.05). There was no statistically-significant difference in BMD scores between groups at final (p > 0.05). Urinary DPD/Cre levels decreased significantly in all three groups by the end of the year (p < 0.05). There was no statistically-significant difference in urinary DPD/Cre final levels between groups (p > 0.05). According to the results of the present study, consecutive 10 days therapy with SCT, which is the first in the literature to our knowledge, is as effective as the other two regimens in the treatment of osteoporosis. Both cyclic regimens in our study (alternating 15 days and 10 consecutive days each month for 1 year) do appear to offer some advantages, especially economically and clinically, as compared to continuous treatment.

Effectiveness of Salmon Calcitonin Nasal Spray in the Treatment of Lumbar Canal Stenosis

Double-blind, randomized, placebo-controlled study to assess the effectiveness of calcitonin nasal spray on symptoms and function in patients with lumbar canal stenosis. To compare effectiveness of calcitonin administered by nasal spray with placebo in patients with clinically symptomatic lumbar canal stenosis. Lumbar canal stenosis is the most common reason for spine surgery in individuals over 65 years of age. Nonoperative approaches have been not well studied and limited primarily to physical therapy exercises. Several small trials in the past have suggested that subcutaneous and intramuscular calcitonin is an effective nonsurgical option in treating the symptoms of spinal stenosis patients. Only three trials were randomized and placebo-controlled. Fifty-five patients with clinical lumbar canal stenosis (pseudoclaudication), confirmatory MR imaging, and pain intensity index (VAS) of > or =6 were randomized to either placebo or intranasal calcitonin daily for 6 weeks, followed by an open label 6-week extension, during which all patients received active drug. Outcome parameters performed at baseline, 6 weeks, and 12 weeks, included pain intensity index, walking time and distance to pain, SF-36, and Oswestry disability index. Thirty-six patients received calcitonin, and 19 placebo. Eight (14.54%) calcitonin and 4 (7.27%) placebo patients withdrew from the study. The mean baseline pain score for calcitonin group was 7.8 and 7.5 for placebo. Comparisons at week 6 showed no statistically significant difference in the change in pain intensity (VAS) between calcitonin group (-2.9) and placebo (-2.4) (P = 0.4382) from baseline. There was no significant difference in walking time to pain (calcitonin -10.0 seconds; placebo +32.2 seconds; P = 0.5136). Walking distance to pain showed a mean improvement of +91.4 ft in the calcitonin group and +254.7 ft in the placebo group (P = 0.4948). No significant difference was observed in the SF-36 score between the treatment groups. Using a threshold of at least 50% reduction in pain from baseline to 6 weeks, 12 of 29 (41.37%) of calcitonin patients were considered responders versus 7 of 18 (38.88%) of placebo patients (P = 0.4238) In this first ever largest randomized placebo-controlled parallel group trial of nasal calcitonin in spinal stenosis, nasal calcitonin was not superior to placebo in treating the symptoms of spinal stenosis at 6 weeks. Based on this study, nasal calcitonin does not appear to have a role in nonoperative treatment of lumbar canal stenosis.

Distrofia simpática reflexa pós herpes zoster

A distrofia simpatica reflexa (DSR) e uma sindrome dolorosa pouco entendida que consiste na presenca de multiplos sinais e sintomas incluindo dor, edema, alteracoes cutâneas distroficas e disfuncao autonomica envolvendo uma ou mais extremidades. Nem sempre a DSR pos-herpes zoster e facilmente reconhecida. Poucos relatos dessa complicacao foram publicados, o que torna interessante esta descricao. Apresentamos o caso de uma mulher branca, de 65 anos de idade cujos sinais e sintomas caracteristicos de DSR no membro superior direito surgiram apos 4 semanas do aparecimento das lesoes de herpes zoster envolvendo trajeto dermatomerico. Com o diagnostico precoce e abordagem terapeutica com calcitonina nasal e fisioterapia houve melhoras funcional e algica satisfatorias em um mes de tratamento.

Bone marrow edema syndrome of the hip

Bone marrow edema syndrome (BMES) is a rare clinical condition. Its etiology is unknown and it can be seen in different locations. In the case of the hip, avascular necrosis is the main differential diagnosis. To present our experience of BMES of the hip and a review of the literature. Retrospective analysis of clinical records of patients with hip pain that met clinical, radiological, and magnetic resonance imaging criteria for BMES. Clinical outcome and clinical and radiological follow up are presented. Two men and two women (one of them pregnant) aged 42, 48, 36 and 26 years old, fulfilled criteria. Treatment included limited weight bearing, non steroidal antiinflammatory drugs, intranasal calcitonin and physical therapy. Complete remission of symptoms was observed within five to seven months. At an average follow up of 36 months, all patients presented complete function of the hip, returning to their previous activity levels, with no new episodes of BMES. It is important to be aware of this condition as part of the differential diagnosis of hip pain to avoid aggressive and unnecessary diagnostic and therapeutic procedures.

Calcitonin intranasal--unigene: Salcatonin intranasal--unigene.

An intranasal spray formulation of recombinant salmon calcitonin [salcatonin] is in development with Unigene Laboratories as therapy for postmenopausal osteoporosis. Calcitonin is an endogenous polypeptide hormone that regulates calcium and bone metabolism. It is produced by the parafollicular cells of the thyroid gland in humans and other species. Calcitonin inhibits bone loss through the suppression of osteoclast activity. Salmon calcitonin is approximately 40-50 times more potent than natural human calcitonin at inhibiting osteoclast function. It can be obtained naturally from salmon or can be synthesised with the same chemical structure. Calcitonin was originally available only as an injectable formulation, but in recent years more convenient formulations have become available. Unigene is actively seeking to license its intranasal calcitonin product in Europe and other territories outside the US. nigene licensed its intranasal calcitonin product to Upsher-Smith Laboratories in December 2002, under a $US10 million exclusive US licensing agreement. Under the terms of the agreement, Unigene received an upfront payment of $US3 million from Upsher-Smith and will be eligible to receive milestone payments and royalty payments on product sales. Unigene will be responsible for manufacturing the product at its Boonton facility in New Jersey, USA, and will sell finished calcitonin product to Upsher-Smith. Upsher-Smith will package, market and distribute the product nationwide. Unigene granted an exclusive license to Faran Laboratories in September 2003 for its intranasal calcitonin osteoporosis product in Greece. Unigene will sell the finished product to Faran, who will promote and market it throughout the country after Unigene obtains European regulatory approval and local pricing approval. Unigene will receive an upfront payment and is eligible to receive milestone payments prior to product launch. Faran will pay Unigene a fixed price for each unit of product received. Qingdao General Pharmaceutical Company was a licensee for Unigene's injectable and intranasal calcitonin products in the People's Republic of China, and Unigene had received initial payments from Qingdao General Pharmaceutical in 1996. However, in June 2000, Unigene announced that it has entered into a joint venture with Shijiazhuang Pharmaceutical Group Company for the manufacture and distribution of injectable and intranasal calcitonin for the treatment of osteoporosis in China. Unigene initially will be responsible for supplying bulk calcitonin manufactured in its production facility in New Jersey and the joint venture will be responsible for filling, packaging, promoting and marketing the products. Unigene owns 45% of the contractual joint venture. Unigene is also developing oral and injectable formulations of calcitonin. In January 2004, Unigene announced it had received an approvable letter from the US FDA to market its calcitonin intranasal spray for the treatment of osteoporosis. The letter indicates that the FDA will approve the NDA upon finalisation of the labelling and resolution of specific remaining issues, including the submission of additional information and clinical data. Unigene filed the NDA in March 2003. Using the results from a pilot study completed in the UK, Unigene filed an IND with the FDA and began clinical testing of this intranasal calcitonin in the US. Clinical studies were successfully completed by year end 2001, demonstrating significant bone marker activity and similar serum concentrations between this product and that of an existing nasal calcitonin product. The European Union's regulatory authority, the Committee for Proprietary Medicinal Products (CPMP), has confirmed the efficacy of calcitonin formulations for the treatment of postmenopausal osteoporosis and other bone disorders. The CPMP has recommended revisions to and harmonisation within the European Union of the authorised indications for calcitonin formulations. The CPMP has determined that authorised indications for intranasal calcitonin will be approved for "treatment of established post-menopausal osteoporosis in order to reduce the risk of vertebral fractures", and new prescribing information will clarify that intranasal calcitonin does not appear to reduce the number of hip fractures. These recommendations will be implemented in the near future and will eliminate discrepancies between countries and between formulations. The Chinese regulatory authorities have granted Unigene an import license for calcitonin, and Unigene and Shijiazhuang have submitted an NDA in China. If this NDA is approved, the joint venture will have up to 6 years' market exclusivity for intranasal and injectable calcitonin. Unigene was granted a US patent for the intranasal formulation of calcitonin in 2002.

Posible beneficio de la calcitonina en el tratamiento de la otosclerosis

AbstractThis study shows the results obtained after treatment with intranasal calcitonin in 23 patients (36 ears) suffering from otosclerosis. 19,4% showed a hearing improvement upper of 10 dB. The gain was 32 dB in air conduction thresholds and 23 dB. in bone conduction. Tinnitus disappeared in 25% of cases suffering from tinnitus. Calcitonin tolerance was good, 8.7% of patients reported migraine. Authors recomnend additional studies in order to evaluate the efficacy of this drug in the treatment of otosclerosis.

Complex regional pain syndrome I (reflex sympathetic dystrophy).

Complex regional pain syndrome I (reflex sympathetic dystrophy).

Calcitonin for the long-term prevention and treatment of postmenopausal osteoporosis

Calcitonin is a powerful inhibitor of osteoclast activity that exerts a rapid, transient, and reversible inhibition of bone resorption. Prolonged administration of parenteral calcitonin, by injections of 100 IU every 1 or 2 days, can prevent postmenopausal or postovariectomy bone loss, and is also able to increase trabecular bone mass among patients presenting an established osteoporosis. Prolonged treatment with calcitonin injections is, however, difficult to maintain over the long run. In addition to the ease of administration compared with the injectable forms, nasal calcitonin is much better tolerated, the side effects being rare and generally negligible. A prolonged administration of 200 IU intranasal calcitonin acutely inhibits parameters of bone resorption and can increase lumbar spine bone mineral density (BMD) by 1.7%–3.3% after 1 year. Lower doses also appear to be efficient to prevent early postmenopausal bone loss, but the data are conflictual. The results are more consistent in patients who already suffer from established osteoporosis. The increase in lumbar spine BMD is in the order of 1%–2% after 1 year with 200 IU daily. A therapeutic benefit of calcitonin at the level of the cortical bone has been less well demonstrated than for the trabecular bone. As for other antiosteoporotic therapies, the effect of calcitonin on the reduction of fracture risk has been examined less than the beneficial effect on trabecular bone mass. Currently, there is still no prospective, placebo-controlled study with a sufficient number of patients that demonstrates that long-term parenteral calcitonin administration reduces the risk of osteoporotic fractures. The efficacy of nasal calcitonin treatment to reduce vertebral fracture rate has been best examined in the PROOF (Prevent Recurrence of Osteoporotic Fractures) study. This was a prospective 5-year, placebo-controlled, dose-response study of nasal calcitonin (100, 200, or 400 IU daily). The increase in lumbar spine BMD was modest but significant and not clearly dose dependent, as was the reduction in bone turnover. The relative risk of developing new vertebral fractures was reduced by 33% at the end of the study in the 200-IU dose group (relative risk = 0.67, 95% CI 0.47–0.97, p = 0.03). There was also a nonsignificant reduction in the risk of hip fracture in this dose group. The doses of 100 and 400 IU of calcitonin also reduced the vertebral fracture risk, but the difference did not reach the classical level of statistical significance. A possible effect of calcitonin to enhance bone quality, which cannot be assessed by routinely available methods, is currently being investigated in a prospective placebo-controlled trial that could provide a rational explanation for these effects of calcitonin on the reduction in the vertebral fracture rate without much increase in bone mass or a marked reduction in bone turnover.

Alendronate: an update of its use in osteoporosis.

Alendronate (alendronic acid) is a nitrogen-containing bisphosphonate which binds to bone surfaces and inhibits bone resorption by osteoclasts. Oral alendronate 5 or 10 mg/day produces sustained increases in bone mineral density (BMD) in postmenopausal women with or without osteoporosis, in men with primary osteoporosis and in both men and women with or without osteoporosis receiving systemic corticosteroid therapy. Histomorphometric analyses have found that alendronate does not appear to impair bone quality. Alendronate reduced the risk of radiographic vertebral fracture, clinical vertebral fracture or hip fracture by 47 to 56% in postmenopausal women who had > or = 1 existing vertebral fracture and in those with no existing vertebral fractures but who had osteoporosis. In a number of comparative trials in postmenopausal women with osteoporosis, alendronate 10 mg/day was found to be more effective at inducing sustained increases in BMD than intranasal calcitonin, and at least as effective as conjugated estrogens and raloxifene. Alendronate 70 mg administered once weekly and 35 mg twice weekly are as effective at increasing BMD as 10 mg/day in this patient group. In clinical trials, alendronate was generally well tolerated when taken as recommended. Adverse events tended to be transient and associated with the upper GI tract, most commonly including abdominal pain, nausea, dyspepsia, acid regurgitation and musculoskeletal pain. No statistically significant differences between alendronate 10 mg/day and placebo have been found in the incidence of upper GI adverse events in large clinical trials. However, postmarketing surveillance reported a low incidence of adverse events related to the oesophagus. Specific instructions aimed at reducing the risk of upper GI adverse events have been provided by the manufacturer. Alendronate is effective and generally well tolerated in the treatment of women or men with primary (including postmenopausal) or corticosteroid-induced osteoporosis and in the prevention of osteoporosis in postmenopausal women. The drug has been associated with upper GI tract adverse events, although the extent to which alendronate is responsible for these events has not been clearly established. Alendronate should be considered a treatment of choice in postmenopausal women with osteoporosis. Alendronate is also a suitable treatment option for primary osteoporosis in men and for corticosteroid-induced osteoporosis in both men and women.

Statistical Analysis for Comparing Antifracture Efficacy among Antiresorptive Agents

Objective: To develop a method that estimates and compares the antifracture efficacy [relative risk reduction (RRR) and number needed to treat (NNT)] of various antiresorptive agents when fracture trials are not available. Design, Setting and Patients: Statistical analysis using efficacy data from clinical trials of postmenopausal women with osteoporosis. Interventions: Oral alendronate 5mg, oral alfacalcidol lμg, or intranasal calcitonin 200IU daily. Methods: We used the effects on bone mineral density (BMD) in head-to-head trials together with the relationship between BMD changes and fracture risk reductions reported in published meta-analyses of antifracture trials to predict and compare RRR and NNT. Results: The predicted RRR was similar to the published values in large clinical trials, thus validating the method. With an incidence of 12% over 3 years in untreated women with pre-existing vertebral fractures (based on a large epidemiological study), the predicted NNT to prevent a new vertebral fracture was 17 for alendronate and 29 for alfacalcidol; similar results were observed for alendronate versus calcitonin. For nonvertebral fractures, the NNT was three to four times lower for alendronate, compared with alfacalcidol and calcitonin. Conclusions: There is currently insufficient evidence of antifracture efficacy from randomised trials to recommend the use of alfacalcidol or calcitonin for treating osteoporosis. Furthermore, our analyses indicate that alendronate is substantially more effective for reducing vertebral and nonvertebral fracture risk than alfacalcidol or calcitonin.