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Background
The National Osteoporosis Foundation Consensus Development Conference (2003) defined osteoporosis as a disease characterized by low bone mass and micro-architectural deterioration of bone tissue, leading to enhanced bone fragility and increased risk of hip, spine, and wrist fractures. Osteoporosis is the most common bone disease in humans. Approximately 10 million Americans (80 % of them women) suffer from osteoporosis. For post-menopausal women, age, Asian or Hispanic heritage, cortisone use, family or personal history of fracture, as well as smoking have been associated with significantly increased likelihood of osteoporosis; while African American heritage, estrogen or diuretic use, exercise, as well as higher body mass index (BMI) have been associated with significantly decreased likelihood of osteoporosis (Siris et al, 2001). Furthermore, Wu and colleagues (2002) reported that any fracture (unrelated to motor vehicle accidents) sustained between the ages of 20 and 50 years is associated with increased risk of fractures after the age of 50 years in women. Although osteoporosis is usually considered a disease of women, up to 20 % of vertebral fractures and 30 % of hip fractures occur in men. Risk factors for osteoporotic fractures in men include corticosteroid therapy, diseases that predispose to low bone mass, high alcohol consumption, low BMI, physical inactivity, and smoking (Eastell et al, 1998). However, the exact mechanism of bone loss remains unknown in primary male osteoporosis (Legrand et al, 2001).
Calcitonin is a 32-amino acid peptide hormone secreted by the para-follicular cells of the thyroid gland in mammals and by the ultimo-branchial gland of birds and fishes. Its direct actions on the osteoclast are responsible for its physiological effects as a hypocalcemic agent and a potent inhibitor of bone resorption.
A joint meeting of the FDA's Reproductive Health Drugs and the Drug Safety Committee and its Risk Management Advisory Committee concluded that calcitonin salmon should no longer be used by women because there is little evidence it works and it may actually increase the risk of cancer. The committee members voted 12-9 that the risks of calcitonin exceed the benefits when used to treat osteoporosis. The combined FDA advisory panel also voted 20-1 that companies developing biotech versions of the salmon hormone must conduct trials to substantiate that their calcitonin products reduce the risk of fracture. The committees' concerns about safety and efficacy were based on data detailed in a that FDA reviewers released as background material for the meeting. The briefing document stated: "Intervention to reduce the risk of fracture is the standard for treatment of postmenopausal osteoporosis. Despite three fracture trials conducted, there remain significant questions regarding calcitonin salmon’s effectiveness in reducing fractures in postmenopausal women. This lack of effectiveness when combined with the potential for a cancer risk associated with calcitonin salmon therapy raises concerns about the overall risk and benefit assessment for calcitonin salmon products in the treatment of postmenopausal osteoporosis.
In 2012, the European Medicines Agency recommended against using calcitonin salmon long-term, after a research review showed a slight higher increase of cancer among patients who had used the drug for an extensive length of time to treat osteoporosis. Health Canada issued a statement warning of an increased risk of cancer with long-term use of calcitonin salmon products.
Lewiecki (2009) stated that adequate intake of calcium and vitamin D is recommended as baseline therapy for osteoporosis prevention and treatment. Available pharmacological agents for the management of post-menopausal osteoporosis include oral bisphosphonates, which are generally considered first-line therapy for patients with osteoporosis, but their use may be limited by gastrointestinal side effects. Other agents include calcitonin-salmon, hormone therapy, human recombinant parathyroid hormone (PTH) teriparatide (1-34 PTH), the selective estrogen-receptor modulator (SERM) raloxifene, and strontium ranelate, and rank ligand inhibitors (e.g., denosumab).. Emerging therapies for post-menopausal osteoporosis include novel SERMs (e.g., arzoxifene, bazedoxifene, lasofoxifene, ospemifene).
Calcitonin's role as a therapeutic option for glucocorticoid-induced osteoporosis (GIO) has not been established. Reviews on GIO did not mention calcitonin as a treatment option. De Nijs (2008) stated that pharmacotherapy for prevention of GIO is needed depending on the age and gender of the patient and sometimes BMI at the start of treatment, dosage of glucocorticoid, and expected duration of glucocorticoid treatment. Bisphosphonates seem to be the first choice of pharmacological intervention for prevention and treatment of GIO. There is no evidence that one specific bisphosphonate is superior to another bisphosphonate due to a lack of head-to-head studies on GIO. Calcium and vitamin D3 supplementation are considered as important support for prevention and treatment of GIO. Silverman and Lane (2009) noted that bone loss that accompanies glucocorticoid use is rapid, and early treatment with bone-sparing agents can prevent bone loss and reduce fracture risk. Several randomized controlled clinical trials have found prevention and treatment of GIO with bisphosphonates, and recently the treatment of GIO with teriparatide, to be effective. Compston (2010) stated that bisphosphonates are the front-line choice for prevention of fracture in glucocorticoid-treated patients, with teriparatide as the second-line option; calcium and vitamin D supplements should be co-prescribed in the majority of individuals. Future guidelines for the management of GIO should include recently approved interventions (e.g., teriparatide and zoledronate).
Furthermore, the Spanish Society of Internal Medicine's guidelines for the prevention and treatment of GIO (Sosa Henríquez et al, 2008) stated that treatment must be prescribed to any patient who is receiving glucocorticoids or is going to receive them at doses greater than 7.5 mg/day for more than 3 months and 5 mg/day if the patient is a post-menopausal woman or has suffered from previous fragility fractures. Alendronate and risedronate are the mainstays for the management of patients with GIO, accompanied with calcium and vitamin D supplements; in very ill patients, PTH can be used.
Calcitonin has also been reported to be beneficial in the treatment of Paget’s disease of the bone (osteitis deformans) and hypercalcemia. Paget disease of the bone is a disorder of uncertain etiology characterized by abnormal and accelerated bone formation and resorption in one or more bones. In most patients, only small areas of bone are involved, and the disease is asymptomatic. In a small number of patients, however, the abnormal bone may lead to bone deformity, cranial and spinal nerve entrapment, or spinal cord compression. Furthermore, the increased vascularity of the abnormal bone may result in high-output congestive heart failure. The effectiveness of calcitonin has been shown mainly in patients with moderate-to-severe disease characterized by polyostotic involvement with elevated serum alkaline phosphatase and urinary hydroxyproline excretion. Whyte (2006) noted that medications for Paget's disease include various bisphosphonates and calcitonin-salmon injection. The use of latter for Paget's disease has been largely supplanted by the use of the former, although treatment with calcitonin-salmon remains an option if bisphosphonates are not tolerated or contraindicated. Furthermore, Saura (2007) stated that according to the Japanese guidelines for diagnosis and management of Paget's disease of the bone, calcitonin and etidronate are approved therapeutic agents for this condition and surgery is indicated for associated orthopedic problems (e.g., bone deformity, malignant soft-tissue tumor, osteosarcoma, and unstable fractures) in these patients.
Calcitonin injection has also been demonstrated to reduce elevated serum calcium of patients with carcinoma, multiple myeloma or primary hyper-parathyroidism. In a review on drugs used in pediatric bone and calcium disorders, Cheung (2009) noted that hypercalcemia is treated initially with hyperhydration and diuretics, but may require more specific treatment with either bisphosphonates or calcitonin. Several newer drugs have either recently been introduced or are under consideration. These include bone morphogenic protein 2, calcimimetics (cinacalcet), calciolytic drugs, cathepsin K inhibitor, rank ligand inhibitors (denusomab and osteoprotegerin), and sclerostin.
Assadi (2009) stated that primary hyperparathyroidism and malignancy are responsible for greater than 90 % of all cases of hypercalcemia. Compared with the hypercalcemia of malignancy, hyperparathyroidism tends to be associated with lower serum calcium levels (less than 12 mg/dL) and a longer duration of hypercalcemia (more than 6 months). The hypercalcemic symptoms are usually fewer and subtle. Hyperparathyroidism tends to cause kidney calculi, hyperchloremic metabolic acidosis, and the characteristics of metabolic bone disease osteitis fibrosa cystica, but no anemia. In contrast, hypercalcemia of malignancy is typically rapid in onset, with higher serum calcium levels, and more severe symptoms. Patients so affected show marked anemia, but they never have kidney calculi or metabolic acidosis. Parathyroid hormone assay is the most useful test for differentiating hyperparathyroidism from malignancy and other causes of hypercalcemia. In hyperparathyroidism, serum PTH levels will be elevated. In other cases, high serum calcium concentration usually results in suppression of PTH. Treatment of hypercalcemia should commence with hydration; loop diuretics may be needed in patients with renal insufficiency or heart failure to prevent fluid over-load. Calcitonin is administered for the immediate short-term management of severe symptomatic hypercalcemia. For long-term control of severe or symptomatic hypercalcemia, the addition of bisphosphonates is typically required. Among intravenous bisphosphonates, pamidronate and zoledronic acid are the agents of choice.
Calcitonin is also being used in the treatment of various conditions/diseases/disorders such as Behcet's disease, bone pain, complex regional pain syndrome, diabetic neuropathy, osteoarthritis, osteogenic sarcoma, renal osteodystrophy, and spinal stenosis, as well as prevention of osteoporosis following organ and bone marrow transplantations. However, its effectiveness for these indications has not been established.
Calcitonin has been employed, however without much success, in the treatment of osteogenic sarcoma and renal osteodystrophy (AHFS, 2001). In a Cochrane review, Martinez-Zapata et al (2006) evaluated the effectiveness of calcitonin in controlling metastatic bone pain and reducing bone complications (fractures, hypercalcemia, and nerve compression) in patients with bone metastases. Electronic searches were performed in Medline (1966 to 2005), Embase (1974 to 2005), the Cochrane Central Register of Controlled Trials (Issue 2, 2005), specialized registers of the Cochrane Cancer Network and of the Cochrane Pain, Palliative and Supportive Care Group. Registers of clinical trials in progress were also searched. Studies were included if they were randomized, double-blind, clinical trials of patients with metastatic bone pain, treated with calcitonin, where the major outcome measure was pain, assessed at 4 weeks or longer. Study selection and data extraction were performed by 2 independent review authors. Only 2 studies (n = 90) were eligible for inclusion in the review and therefore meta-analysis of the data was not possible. Intention-to-treat analysis was performed by imputing all missing values as adverse outcomes. Of the 2 small studies included in the review, 1 study showed a non-significant effect of calcitonin in the number of patients with total pain reduction (relative risk [RR] 2.50; 95 % confidence interval [CI]: 0.55 to 11.41). The second study provided no evidence that calcitonin reduced analgesia consumption (RR 1.05; 95 % CI: 0.90 to 1.21) in patients with painful bone metastases. There was no evidence that calcitonin was effective in controlling complications due to bone metastases; and for improving quality of life or patients' survival. Although not statistically significant, a greater number of adverse effects were observed in the groups given calcitonin in the 2 included studies (RR 3.35, (5 % CI: 0.72 to 15.66). The authors concluded that the limited evidence currently available does not support the use of calcitonin to control pain from bone metastases.
In a review on diabetic neuropathy, Vinik (1999) stated that no definitive treatment is available for painful diabetic neuropathy. Several medications have been used, among them antiepileptic drugs, calcitonin, dextromethorphan, local anesthetics, non-steroidal anti-inflammatory drugs, phenothiazines, and tricyclic antidepressants. Moreover, calcitonin was not mentioned as a therapeutic option in recent reviews on management of neuropathic pain. Gilron and colleagues (2006) noted that pharmacotherapy includes gabapentin, mixed serotonin-norepinephrine reuptake inhibitors, opioids, pregabalin, topical lidocaine, tramadol, and tricyclic antidepressants. Baron (2009) stated that the medical management of neuropathic pain consists of 5 main classes of oral medication (anticonvulsants with calcium-modulating actions, anticonvulsants with sodium-blocking action, antidepressants with reuptake blocking effect, opioids, and tramadol) and several categories of topical medications for patients with cutaneous allodynia and hyperalgesia (e.g., capsaicin and local anesthetics).
Vranken (2009) stated that while many options are available for relieving neuropathic pain, there is no consensus on the most appropriate therapy. However, recommendations can be proposed for first-line, second-line, and third-line pharmacotherapies based on the level of evidence for the different treatment strategies. Beside opioids, the available therapies shown to be effective in managing neuropathic pain include anticonvulsants, antidepressants, ketamine, and topical treatments (e.g., capsaicin and lidocaine patch). Tricyclic antidepressants are often the first drugs selected to alleviate neuropathic pain (first-line pharmacological treatment). Although they are very effective in reducing pain in several neuropathic pain disorders, treatment may be compromised by their side effects. In patients with a history of cardiovascular disorders, glaucoma, and urine retention, gabapentine and pregabalin are emerging as first-line treatment for neuropathic pain. In addition these anti-epileptic drugs have a favorable safety profile with minimal concerns regarding drug interactions and showing no interference with hepatic enzymes. Despite the many treatment options available for relieving neuropathic pain, the most appropriate treatment strategy is only able to reduce pain in 70 % of these patients. In the remaining patients, combination therapies using 2 or more analgesics with different mechanisms of action may also offer adequate pain relief. Although combination treatment is clinical practice and may result in greater pain relief, trials regarding different combinations of analgesics are lacking. Additionally, 10 % of patients still experience intractable pain and are refractory to all forms of pharmacotherapy. If medical treatments fail, invasive therapies such as intrathecal drug administration and neurosurgical interventions may be considered.
Karsdal et al (2007) noted that several lines of evidence suggest direct anabolic effects of calcitonin on articular chondrocytes, resulting in increased proteoglycan synthesis, which may prove calcitonin to be beneficial for the prevention and treatment of osteoarthritis. Chesnut et al (2008) noted that calcitonin-salmon demonstrates clinical utility in the treatment of such metabolic bone diseases as osteoporosis and Paget's disease, and potentially in the treatment of osteoarthritis. In a review on non-surgical treatment of osteoarthritis of large joints, Wagner (2009) listed bisphosphonates, calcitonin, and interleukin-1 antagonists as experimental drugs for this condition.
The Institute for Clinical Systems Improvement's guideline on diagnosis and treatment of osteoporosis (ICSI, 2008) stated that studies demonstrate that standard calcium and vitamin D supplementation, with or without calcitonin, are unable to prevent osteoporosis following organ or bone marrow transplantation. Palmer et al (2005) evaluated the evidence available to guide targeted treatment to reduce bone disease in transplant recipients. The Cochrane CENTRAL Registry, Medline, and Embase were searched for randomized trials of interventions for bone disease after renal transplantation. Data were extracted on acute graft rejection, adverse events, bone mineral density (BMD) by means of dual-energy X-ray absorptiometry, and fracture. Analysis was performed with a random-effects model, and all results are expressed as RR with 95 % CIs. A total of 23 eligible trials (n = 1,209) were identified. No trial found a reduction in risk for fracture. Bisphosphonates (7 trials; n = 268; weighted mean difference [WMD], 7.66; 95 % CI: 4.82 to 10.50), vitamin D analogs (2 trials; n = 51; WMD, 6.13; 95 % CI: 4.97 to 7.29), and calcitonin (1 trial; n = 31; WMD, 5.00; 95 % CI: 0.88 to 9.12) favorably affected the percentage of change in BMD at the lumbar spine compared with no treatment. Bisphosphonates (4 trials; n = 149; WMD, 7.18; 95 % CI: 6.22 to 8.13) and vitamin D analogs (2 trials; n = 51; WMD, 3.73; 95 % CI: 2.71 to 4.75), but not calcitonin (1 trial; n = 31; WMD, -0.30; 95 % CI: -5.00 to 4.40), had a favorable effect on BMD measured at the femoral neck compared with no treatment. The incidence of reported toxicity was low. The authors concluded that the trials were inadequately powered to show a reduction in risk for fracture. Bisphosphonates and vitamin D have a beneficial effect on BMD at the lumbar spine and femoral neck. With increasing survival after renal transplantation, this study emphasized the importance of randomized controlled trial (RCT) evidence of interventions of bone disease after renal transplantation.
In a randomized, single-blind study, Sahin et al (2009) compared the effectiveness of physical therapy alone and in combination with calcitonin in patients with neurogenic claudication (NC). Patients with lumbar spinal canal stenosis who were diagnosed by clinical findings and magnetic resonance imaging and having NC were included. They were observed for 8 weeks and evaluated before and after treatment. Patients were randomized between the calcitonin-salmon 200 U/day + physical therapy (n = 23; group 1) and paracetamol 1,500 mg/day + physical therapy (n = 22; group 2) treatment groups. Both groups received the same physical therapy (hot pack + interferential current + short wave diathermy) and exercise protocol. The association of various clinical and functional parameters was assessed statistically by using paired and unpaired t-tests, Chi-square test and McNemar's test; p < 0.05 indicated statistical significance. Mean ages of the patients were 57.6 +/- 11.2 years and 2 54.5 +/- 10.6 years for group 1 and group 2, respectively. Before treatment, there were no significant differences between groups with respect to age, BMI, spinal axial diameter, visual analog scale (VAS), spinal mobility, functional status and walking distance (p > 0.05). After 8 weeks of treatment, both groups benefited significantly with respect to VAS, functional status and walking distance (p < 0.001). There was no statistically significant difference between groups (p > 0.05). The authors concluded that in patients with lumbar spinal stenosis who received 8 weeks of treatment, concomitant use of calcitonin with physical therapy and exercise did not have any beneficial effect on the patient's pain, functional status, lumbar mobility and walking distance.
In a systematic review, Coronado-Zarco and colleagues (2009) examined the effectiveness of calcitonin on the treatment of NC in patients with lumbar spinal stenosis. These investigators performed a search on electronic databases that included Medline and Embase; they recovered 10 original articles, of which only 4 fulfilled the RCT criteria. These articles were reviewed independently by 6 reviewers to extract data and their quality scored by the criteria of Cochrane Handbook (with maximum score of 1.00 and minimum score of 0.33). Score quality vary in the 4 articles. Due to the great heterogenicity observed (doses, duration and frequency of calcitonin, outcome measurements, sample sizes, and selection criteria), these researchers were unable to perform a meta-analysis. Only 1 of these studies found favorable results for the use of calcitonin compared with placebo; of the 3 remaining trials, none found significant evidence between drug therapy and placebo. The authors concluded that the present data suggest that calcitonin administration in the treatment for NC has no benefit in patients with lumbar spinal stenosis. Furthermore, the North American Spine Society's guideline on diagnosis and treatment of degenerative lumbar spinal stenosis (2007) stated that there is little evidence that pharmacotherapies, including intramuscular calcitonin, intranasal calcitonin, intravenous lipo-prostaglandin E1, or methyl-cobalamin provides long-term benefit in patients with lumbar spinal stenosis.
Qin and associates (2009) noted that the treatment of Behcet's disease, a chronic, multi-system inflammatory disorder, continues to be a major therapeutic challenge. Exogenous calcitonin is thought to cross the blood-brain barrier and to accumulate slowly in the brain, inducing analgesia once sufficient receptors are occupied. Since calcitonin could antagonize resorptive and analgesic activity by competitively binding to calcitonin receptor and has been considered as a specific antagonist, these researchers postulated that the calcitonin could function as a novel agent to inhibit Behcet's disease.
Tran and associates (2010) reviewed the evidence derived from RCTs pertaining to the treatment of complex regional pain syndrome. The search criteria yielded 41 RCTs with a mean of 31.7 subjects per study. Blinded assessment and sample size justification were provided in 70.7 % and 19.5 % of RCTs, respectively. Only bisphosphonates appear to offer clear benefits for patients with complex regional pain syndrome. Improvement has been reported with dimethyl sulfoxide, epidural clonidine, intrathecal baclofen, motor imagery programs, spinal cord stimulation, and steroids, but further trials are required. The available evidence does not support the use of calcitonin, vasodilators, or sympatholytic and neuromodulative intravenous regional blockade. Clear benefits have not been reported with gabapentin, mannitol, occupational/physical therapy, and lumbar/stellate sympathetic blocks.
The American Academy of Orthopaedic Surgeons' guideline on the treatment of symptomatic osteoporotic spinal compression fractures (AAOS, 2010) recommended that patients who present with an osteoporotic spinal compression fracture on imaging with correlating clinical signs and symptoms suggesting an acute injury (0 to 5 days after identifiable event or onset of symptoms) and who are neurologically intact be treated with calcitonin for 4 weeks.
In a randomized, placebo-controlled, double-blind trial, Pappa et al (2011) examined the safety and effectiveness of intra-nasal calcitonin in improving BMD in young patients with inflammatory bowel disease (IBD) and defined additional factors that impact bone mineral accrual. A total of 63 subjects, aged 8 to 21 years, with a spinal BMD Z-score less than or equal to -1.0 S.D. measured by dual energy X-ray absorptiometry were included in this study. Subjects were randomized to 200 IU intra-nasal 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. Intra-nasal 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 2 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. The authors concluded that intra-nasal 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.
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