U.S. Food and Drug Administration (FDA)-Approved Indications

Limitations of Use:

Compendial Use

Calcitonin salmon for injection is available as the brand, Miacalcin (Mylan Institutional LLC), or as a generic formulation (Leucadia Pharmaceuticals). Calcitonin is a polypeptide hormone secreted by the parafollicular cells of the thyroid gland in mammals and by the ultimobranchial gland of birds and fish. Calcitonin salmon for injection is a synthetic polypeptide of 32 amino acids in the same linear sequence that is found in calcitonin of salmon origin. Calcitonin salmon is a calcitonin receptor agonist, which acts primarily on bone, but direct renal effects and actions on the gastrointestinal tract are also recognized. The actions of calcitonin on bone and its role in normal human bone physiology are still not completely elucidated, although calcitonin receptors have been discovered in osteoclasts and osteoblasts (Mylan, 2021).

Labeled warnings and precautions for calcitonin salmon include serious hypersensitivity reactions such as fatal anaphylaxis, hypocalcemia, and malignancy. A meta-analysis of 21 clinical trials suggests an increased risk of overall malignancies in calcitonin salmon-treated patients. Circulating antibodies to calcitonin salmon may develop, and may cause loss of response to treatment. The most common advers reaction are nausea with or without vomiting (10%), injection site inflammation (10%), and flushing of the face or hands (2% to 5%) (Mylan, 2021).

Hypercalcemia

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 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.

Osteoporotic Vertebral Fracture

The American Academy of Orthopaedic Surgeons' guideline on the treatment of symptomatic osteoporotic spinal compression fractures 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 (AAOS, 2010; Esses et al, 2011).

Boucher and colleagues (2020) noted that acutely painful osteoporotic vertebral compression fractures are associated with hospitalization and mortality in older adults. Calcitonin may be an alternative to opioid or non-opioid analgesia for treating acute compression fracture pain in emergency and primary care settings. These investigators summarized pain, function, and adverse events (AEs) associated with calcitonin. They searched Medline, Embase, the Cochrane Library, clinical trials registries, and reference lists of included studies. Eligible studies examined the effect of synthetic calcitonins (salmon, eel, and human) on pain scores in adults greater than or equal to 60 years of age with a recent atraumatic compression fracture. Two reviewers screened studies, extracted data, and allocated bias in duplicate. A random effects meta-analysis evaluated standard mean difference (SMD) and heterogeneity (I2). Of 1,198 articles screened, 11 were included (9 in the meta-analysis). Treatment lasted from 14 days to 6 months. Pain was lower in the salmon calcitonin group (100 to 200 IU IM or NAS, daily) than the control group with high certainty of evidence at week 1 (SMD, -1.54; 95 % CI: -2.02 to -1.06; I2 = 52 %), representing a number needed to treat of 2. The analgesic efficacy of salmon calcitonin at 4 weeks was unclear due to substantial heterogeneity. There was low certainty evidence that calcitonin did not increase the overall risk of AEs, including nausea and vomiting (RR, 2.10; 95 % CI: 0.87 to 5.08; I2 = 47 %). The authors concluded that calcitonin was beneficial and appeared to be safe for the treatment of acute pain associated with compression fractures. Moreover, these researchers stated that further studies may improve the certainty of evidence.

Furthermore, an UpToDate review on “Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment” (Rosen and Walega, 2020) states that “Oral analgesics are first-line therapy for the relief of acute pain due to vertebral compression fractures. The choice of initial agent depends upon the severity of the pain. Acetaminophen, ibuprofen, or naproxen is often sufficient for initial management in patients with mild pain. Opioids and/or calcitonin are options for when the patient reports inadequate analgesia with initial medications or when pain is moderate to severe … For patients with mild to moderate pain who do not have adequate pain relief with oral analgesics, we suggest adding nasal calcitonin (Grade 2B). Calcitonin is typically given for a 2- to 4-week course or until the patient is able to get started on a more effective osteoporosis treatment regimen”.

An UpToDate review on "Calcitonin in the prevention and treatment of osteoporosis" (Rosen, 2022) states that "calcitonin has a beneficial short-term effect on acute pain relief in patients who have sustained a vertebral fracture. In this setting, calcitonin could be used in the short term (until the pain has abated), and then the patient should be switched to an osteoporosis therapy that more effectively prevents subsequent fracture".

Paget’s Disease of Bone

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.

Postmenopausal Osteoporosis

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).

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).

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.

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.

An UpToDate review on "Calcitonin in the prevention and treatment of osteoporosis" (Rosen, 2022) states that calcitonin is not used as first-line therapy for osteoporosis because "more effective drugs are available for prevention of bone loss and reduction of fracture risk, and there is some potential risk".

Other Indications

Behcet's disease

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.

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.

Bone Pain Due to Malignancy

Complex Regional Pain Syndrome

Diabetic Neuropathy / Neuropathic Pain

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.

Glucocorticoid-Induced Osteoporosis

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.

Inflammatory Bowel Disease and Low Bone Mineral Density

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.

Lumbar Facet Joint Osteoarthritis

Guo and colleagues (2019) examined the effects of sCT and celecoxib (CLX) on cartilage, subchondral bone and tactile allodynia in a rat model of lumbar facet joint (FJ) osteo-arthritis (OA). A total of 40 male Sprague-Dawley rats (3-month old) were randomly divided into 4 groups: 30 received surgical collagenase (type II) injections in the right L3 to L6 facet joints followed by 8 weeks of treatment with normal saline, CLX or sCT, and the other 10 received sham surgery. Tactile allodynia, changes of cartilage and subchondral bone of the L4 to L5 FJs, and serum biomarkers were analyzed for all rats. Both sCT and CLX ameliorated cartilage lesions, significantly increased aggrecan expression and decreased caspase-3 expression. sCT also decreased the expression of a disintegrin and metalloproteinase with thrombospondin motifs 4 (ADAMTS-4). According to the micro-computed tomography (micro-CT) analysis, sCT significantly improved micro-architecture parameters of subchondral bone and micro-CT score; and inhibited articular process hypertrophy. CLX showed better anti-hyperalgesic effects than sCT on days 3 and 7 post-operatively despite no statistical differences, whereas sCT possessed better analgesic effects than CLX on days 42 and 56. In addition, the sCT treatment reduced the elevated cartilage oligomeric matrix protein (COMP) concentration in rats injected with collagenase (type II). The authors concluded that both sCT and CLX exerted preventive effects on FJ OA caused by collagenase (type II), but sCT showed more protective effects, especially on maintaining cartilage metabolism, restraining the deterioration of the subchondral bone microarchitecture and tactile allodynia, and reducing serum COMP concentrations.

Neurogenic Claudication

Osteoarthritis

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.

Regional Migratory Osteoporosis

Regional migratory osteoporosis (RMO) is a migrating arthralgia of the weight-bearing joints of the lower limb that mainly affects middle-aged men. Its etiology is unknown. Aguilera and colleagues (1994) reported 2 cases of RMO. One was a 41-year old man, with the classical form, presenting with successive episodes of painful osteoporosis lasting for 5 months at the hip, knee and distal epiphysis of the right metatarsophalangeal joints. The second case was a 40-year old woman presenting with an unusual disseminated form, lasting for 30 months, with successive and simultaneous episodes of poly-articular and costal painful osteoporosis. An increased bone fraction of serum alkaline phosphatases and urine hydroxyproline/creatinine and calcium/creatinine ratios were detected. Imaging showed localized peri-articular or costal osteoporosis. Bone biopsies disclosed a severe osteopenia with accelerated bone reabsorption. Bone scintigraphy precociously detected location, migration and evolution of lesions. Patients were treated with subcutaneous calcitonin, 100 U/day during 1 month and on alternative days posteriorly; this treatment alleviated pain but did not prevent the appearance of new crisis. The authors concluded that these findings suggested that regional migratory osteoporosis presentation may range from oligo-articular to disseminated forms and that calcitonin has a precocious and persistent analgesic effect.

Straten and associates (2009) reported the first case of RMO in a patient with ankylosing spondylitis (AS). This middle-aged man suffered from an acute onset of knee pain that increased on weight-bearing, followed by ankle pain. The diagnosis of RMO was confirmed using magnetic resonance imaging (MRI), after exclusion of other causes of knee pain. MRI revealed a large area of bone marrow edema without a zone of demarcation or subchondral fracture with a demonstration of shifting marrow edema on the follow-up MRI scan from the medial femur condyl to the tibia plateau lateral and then to the distal tibia epiphysis. Treatment with the bisphosphonate ibandronate, however, was unsuccessful. RMO is characterized clinically by migrating arthralgia of the weight-bearing joints of the lower limbs, mainly in middle-aged men. Although the etiology is unknown, the pathophysiology of RMO appeared to be closely related to transient osteoporosis of the hip (TOH), which has been considered a reversible stage of avascular necrosis of the hip (AVN). There is no causal treatment for RMO. Avoidance of weight-bearing and use of analgesics are effective in reducing symptoms. The combination of RMO and AS yielded diagnostic difficulties, as the clinical picture and the marrow edema seen on MRI could be attributed to several AS-related causes such as enthesitis, early stadium of arthritis, osteonecrosis, or sterile osteomyelitis.

Rheumatoid Arthritis

Katri and colleagues (2019) noted that pain is a debilitating symptom of rheumatoid arthritis (RA), caused by joint inflammation and cartilage and bone destruction. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to treat pain and inflammation in RA, but are not disease-modifying and do not prevent joint destruction when administered alone. KBPs (Key Bioscience peptides) are synthetic peptides based on sCT and are expected to inhibit bone resorption and to be chondro-protective. These investigators examined if combining a standard of care NSAID (naproxen) with a KBP resulted in improvement in pain scores, as well as disease activity and structural damage in a rat model of RA. Collagen-induced arthritis (CIA) was induced in 40 female Lewis rats by immunization with porcine type II collagen; 10 rats were given sham injections. CIA rats were treated with KBP and/or naproxen. Health scores and joint scores were evaluated daily. Mechanical and cold allodynia tests and burrowing tests were used to assess pain-like behaviors. Blood samples were collected for biomarker testing, and paws were collected for histology and micro-CT. Naproxen monotherapy increased the time until humane end-points was reached, and improved health score, pain assessments, and trabecular thickness, while KBP monotherapy did not result in improvements. Combination therapy had improved efficacy over naproxen monotherapy; combination therapy resulted in improved health scores, and importantly reduced mechanical and cold allodynia assessment. Furthermore, protection of articular cartilage structure and preservation of bone structure and bone volume were also observed. The authors concluded that the findings of this study showed that combining KBP and naproxen may be a relevant therapeutic strategy for RA, resulting in improvements to the overall health, pain, inflammation, and joint structure.

Transient Osteoporosis

Arayssi and colleagues (2003) stated that TOH is a rare clinical disorder of unknown etiology characterized by hip pain and functional disability that resolve spontaneously in 6 to 24 months. These investigators reported 2 patients with TOH during pregnancy who had rapid resolution of their illness with the use of calcitonin. They reviewed the literature on TOH with special emphasis on its treatment. A Medline search of studies published from 1966 to 2002 was performed to review the therapeutic options for TOH and their effect on the natural history of the disease. These 2 patients developed hip pain during pregnancy with classical changes of TOH on MRI. Both patients received calcitonin, 1 during pregnancy and 1 post-partum with resolution of their symptoms within 6 to 9 weeks. Previous reports in the literature of treatment of TOH showed that anti-resorptive agents (bisphosphonates and calcitonin) had shortened the duration of the illness compared with the natural history of the disease. The authors concluded that TOH is an under-recognized entity associated with pain and disability; and the use of anti-resorptive agents may be of help in reducing the duration of the disease.

Laktasic-Zerjavic and co-workers (2007) reported on a case of TOH during pregnancy that was rapidly resolved with the use of calcitonin. An accurate diagnosis was made 2 months after the onset of symptoms (4 weeks post-partum) based on findings in the form of bone marrow edema of the right hip by MRI. The patient received calcitonin for 8 weeks and the beneficial effect was observed after 3 weeks of therapy with full resolution of symptoms after 8 weeks of therapy (4 months after onset of symptoms). The authors suggested that the use of calcitonin may be considered as a therapeutic intervention to shorten the disease duration.

Treatment-Refractory Phantom Limb Pain

In a case-report, Turek and Wigton (2012) described the use of calcitonin to relieve severe, treatment-refractory phantom limb pain (PLP). After an above-knee leg amputation, a 29-year old pregnant woman (at 8 weeks gestation) reported severe PLP (consistent scores of 9 or 10 on a 10-point pain severity scale). The pain persisted for more than 2 weeks and was not relieved by multiple regimens of opioid and non-opioid medications, including extremely high doses of intravenous fentanyl. On post-amputation day 16, a 30-min intravenous infusion of 200 IU of calcitonin (salmon) was administered; the woman reported transient excruciating pain during the final 5 mins of the infusion. There was little overall change in her pain status over the next 3 days. On post-infusion day 4, the patient reported reductions in the frequency and severity of PLP episodes, and a trend of improved PLP symptom control was noted over the next 48 hours, allowing the pain management team to begin tapering some medication dosages and thus reduce the woman's overall narcotic exposure. The patient was discharged to a nursing facility several weeks later with relatively stable pain (scores of less than7) on a regimen of carbamazepine, gabapentin, and oxycodone. She eventually delivered a healthy full-term baby. The authors concluded that reduction in the frequency of PLP attacks and a lessening of pain intensity were observed after administration of calcitonin (salmon) by intravenous infusion in a pregnant patient. Calcitonin therapy was not associated with any apparent long-term adverse effects to the patient or infant. This finding from a single case study needs to be validated by well-designed studies.

Calcitonin Salmon Nasal Spray

Overgaard et al (1995) performed a sub-analysis of results from a randomized, double-blind, placebo-controlled, parallel-group, 2-year study to evaluate the response of individual patients to therapy with 200 IU/day calcitonin salmon nasal spray compared with placebo in post-menopausal women who had low bone mass. All patients received 500 mg/day of oral supplemental calcium. A response to therapy was defined as an increase from baseline in lumbar vertebral BMD, measured by use of dual-energy x-ray absorptiometry, at the end of 2 years of treatment. Of 41 valid completers (i.e., patients who met the entry criteria, were compliant with the protocol, and completed the study) treated with calcitonin salmon nasal spray, 31 (76 %) responded positively to treatment. Of 40 valid completers who received placebo, 25 (63 %) lost bone mass (p = 0.001 between groups). The relative risk of bone loss for patients receiving calcitonin salmon nasal spray was 0.19 (95 % CI: 0.07 to 0.50), representing an 81 % risk reduction. The authors concluded that this sub-analysis demonstrated that the benefits of calcitonin salmon nasal spray therapy were seen in the majority of women studied. They stated that calcitonin salmon nasal spray represented an effective therapeutic alternative for osteoporotic women more than 5 years post-menopause who reject or cannot tolerate estrogens or for whom estrogens are contraindicated.

Plosker and McTavish (1996) stated that intra-nasal salcatonin (salmon calcitonin) inhibits osteoclastic bone resorption and is approximately 40 to 50 times more potent than human calcitonin. In most randomized trials in which intra-nasal salcatonin (usually 50 to 200 IU/day plus oral calcium supplements) was administered for 1 to 5 years to post-menopausal women for prevention of osteoporosis, BMD or content of the lumbar spine increased by approximately 1 to 3 % from baseline. In contrast, post-menopausal women receiving only oral calcium supplements typically had reductions in BMD or content of about 3 to 6 %. The difference between treatment groups was statistically significant in essentially all studies. Although changes in BMD or content were broadly similar in studies of post-menopausal women with established osteoporosis to those in post-menopausal women receiving therapy for prevention of the disease, studies in women with established osteoporosis did not usually demonstrated statistically significant differences between treatment groups. Also in post-menopausal women with established osteoporosis, intra-nasal salcatonin reduced pain and/or analgesic consumption in some trials and, in a limited number of studies of relatively short duration (i.e., less than or equal to 2 years), the incidence of osteoporotic fractures. A large multi-center 5-year study with adequate statistical power to confirm the effect of intra-nasal salcatonin on reducing osteoporotic fracture rates in post-menopausal women is currently under way. The intra-nasal formulation of salcatonin offered a more convenient and better tolerated alternative to the parenteral formulation of the drug which is administered by regular subcutaneous or intra-muscular injections. Adverse events associated with the intra-nasal formulation are generally mild and transient, usually involving local reactions such as nasal discomfort, rhinorrhea or rhinitis. The authors concluded that for post-menopausal women unable or unwilling to tolerate long-term hormone replacement therapy, intra-nasal salcatonin is an attractive alternative for the management of osteoporosis.

In a 1-year, prospective, open, RCT, Kaskani and colleagues (2005) examined the effect of intermittent administration of 200 IU intra-nasal salmon calcitonin and 1alpha(OH) vitamin D3 [1alpha(OH)D3] on BMD of the lumbar spine and hip as well as on the markers of bone metabolism in women with post-menopausal osteoporosis. A total of 102 randomly recruited women received either 200 IU intra-nasal salmon calcitonin (Miacalcic nasal 200) daily, 1 month on-1 month off, 0.25 mug 1alpha(OH)D3, and 500 mg elemental calcium continuously (n = 57 women) or only 0.25 mug 1alpha(OH)D3 and 500 mg calcium (n = 45 women) for a period of 1 year; BMD of the lumbar spine and hip plus biochemical markers reflecting calcium (Ca) metabolism and bone turnover [serum Ca, serum phosphorus, intact parathyroid hormone (iPTH), total and bone-specific alkaline phosphatase, osteocalcin levels, 24-h urinary Ca, morning fasting urinary Ca/creatinine, and Pyrilinks-D/creatinine ratio] were measured at the beginning of the study before treatment and after 6 and 12 months of treatment. Baseline characteristics of participants, including age, BMI, lumbar and hip BMD, and biochemical markers were similar between the 2 groups. A total of 91 patients completed the study (50 in the salmon calcitonin nasal spray group and 41 in the other group). Lumbar BMD increased significantly in the salmon calcitonin group from baseline (3.0 %, p = 0.005) and in comparison to the non-calcitonin-treated group (p = 0.009). The salmon calcitonin group also had a significant increase in femoral neck BMD compared with baseline values (3.1 %, p = 0.0005) and in comparison to the non-calcitonin-treated group (p = 0.0005) in Ward's triangle BMD (2.9 % from baseline values, p = 0.009) and in comparison to the non-calcitonin-treated group (p = 0.005) in trochanteric BMD (3.4 % from baseline values, p = 0.007) and in comparison to the non-calcitonin-treated group (p = 0.01). Urinary Ca/creatinine and Pyrilinks-D/creatinine levels were significantly decreased from baseline in the salmon calcitonin-treated group (-6.1 and -6.3 %, respectively, p = 0.001). Bone-specific alkaline phosphatase levels were also significantly decreased from baseline in the salmon calcitonin-treated group (-3.6 %, p = 0.003). In the same group, a significant decrease in iPTH serum levels compared to baseline values (-2.5 %, p = 0.005) and in comparison to the non-calcitonin-treated group (p = 0.005) was noted. The authors concluded that 1-year intermittent treatment with 200 IU intra-nasal salmon calcitonin and low doses of 1alpha(OH)D3 produced a significant effect on bone turnover and BMD in post-menopausal women with osteoporosis.

Per the Prescribing Information, Miacalcin (calcitonin-salmon) nasal spray is indicated for the treatment of post-menopausal osteoporosis in females greater than 5 years post-menopause with low bone mass relative to healthy premenopausal females. Miacalcin nasal spray should be reserved for patients who refuse or cannot tolerate estrogens or in whom estrogens are contraindicated. Use of Miacalcin nasal spray is recommended in conjunction with an adequate calcium (at least 1,000 mg elemental calcium per day) and vitamin D (400 I.U. per day) intake to retard the progressive loss of bone mass.

Intraarticular Injection for Joint Inflammation

Sladek and colleagues (2018) noted that polyelectrolyte nanoparticle constructs (NPs) comprising salmon calcitonin (sCT), chitosan (CS), and hyaluronic acid (HA) were previously established as having anti-inflammatory potential when injected via the intra-articular (i.a.) route to a mouse model. These researchers attempted to translate the formulation to a large animal model, the lipopolysaccharide (LPS)-stimulated equine model of joint inflammation. The objective was to manufacture under aseptic conditions to produce sterile pyrogen-free NPs, to confirm physicochemical characteristics, and to test toxicity and efficacy in a pilot study. Polyelectrolyte nanoparticle constructs dispersions were successfully formulated using pharmaceutical-grade source materials and were aseptically manufactured under GMP-simulated conditions in a grade A modular aseptic processing work-station. The NP formulation had no detectable pathogen or endotoxin contamination; NPs were then tested versus a lactated Ringer's solution control following single i.a. injections to the radio-carpal joints of 2 groups of 4 horses pre-treated with LPS, followed by arthrocentesis at set intervals over 1 week. There was no evidence of treatment-related toxicity over the period. While there were no differences between clinical read-outs of the NP and the control, 2 synovial fluid-derived biomarkers associated with cartilage turnover revealed a beneficial effect of NPs. The authors concluded that NPs comprising well-known materials were manufactured for an equine i.a.-injectable pilot study and yielded no NP-attributable toxicity. Evidence of NP-associated benefit at the level of secondary end-points was detected as a result of decreases in synovial fluid inflammatory biomarkers.

Appendix

Appendix A: Clinical reasons to avoid oral bisphosphonate therapy

Appendix B: WHO Fracture Risk Assessment Tool

Requires Precertification

Precertification of calcitonin salmon injection (Miacalcin) is required of participating providers and members in applicable Medicare Part B plan designs. For precertification of calcitonin-salmon injection (Miacalcin), call (866) 503-0857, or fax (844) 268-7263.

Aetna considers calcitonin salmon injection (Miacalcin or generic) medically necessary for treatment of any the following indications:

Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

Continuation of Therapy