Calcitonin in the prevention and treatment of osteoporosis

INTRODUCTION — Osteoporosis is a disorder of bone characterized by reduced mineral density and bone mass (see "Pathogenesis of osteoporosis"). Multiple therapeutic regimens have been designed to prevent and treat osteoporosis in adults by inhibiting bone resorption and/or increasing bone formation. The efficacy of calcitonin in the prevention and treatment of osteoporosis will be reviewed here. We do not use calcitonin as first-line therapy, because more effective drugs are available for prevention of bone loss and reduction of fracture risk. (See "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

CONCERNS ABOUT THE USE OF CALCITONIN — Calcitonin is a peptide composed of 32 amino acids that binds to osteoclasts and inhibits bone resorption [1,2]. The main concern about treatment with calcitonin, however, is that more effective drugs (eg, bisphosphonates) are available for the prevention of bone loss and reduction of fracture risk [3-5]. For this reason, we typically do not use calcitonin to treat osteoporosis, unless pain from an acute osteoporotic fracture is a problem. 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. (See "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment", section on 'Calcitonin' and "Overview of the management of low bone mass and osteoporosis in postmenopausal women" and "Bisphosphonate therapy for the treatment of osteoporosis".)

Another concern is that the long-term use of calcitonin for osteoporosis has been associated with an increase in cancer rates [6]. The European Medicines Agency (EMA) reviewed data provided by the companies who manufacture calcitonin-containing medications, postmarketing safety data, and randomized trials, and it reported that a higher proportion of patients treated with calcitonin-containing medications for long periods of time developed cancer (various types including basal cell carcinoma) than patients taking placebo [6]. The increases in cancer rates were small and ranged from 0.7 to 2.4 percent for oral and nasal formulations, respectively. Because calcitonin is a weak osteoporosis drug and there are more effective drugs to prevent bone loss and fracture, the EMA concluded that the benefits of calcitonin do not outweigh the risks for the treatment of osteoporosis. However, the EMA has taken no formal action based on these concerns.

A US Food and Drug Administration (FDA) advisory panel initiated an internal review of all calcitonin trials after a safety signal for prostate cancer was noted in clinical trials of oral calcitonin, a formulation under development. In a meta-analysis of 20 trials (17 nasal spray, 3 oral), the risk of malignancy was higher in the calcitonin-treated group (4.2 versus 2.9 percent with placebo, odds ratio [OR] 1.4, 95% CI 1.1-1.7) [7]. The meta-analysis was limited by heterogeneity and by high dropout rates in some of the trials, making it difficult to establish direct causality. Nevertheless, the FDA advisory panel similarly concluded that the benefits of calcitonin do not outweigh its potential risks as an osteoporosis drug [7]. If there is a need for calcitonin, its use should be limited to <6 months.

Other adverse effects of calcitonin include hypersensitivity reactions (bronchospasm, swelling of the tongue or throat, anaphylaxis), hypocalcemia, nasal adverse reactions (rhinitis, epistaxis), and the formation of antibodies to calcitonin [8]. In clinical trials of nasal calcitonin in postmenopausal women, the most common adverse effects were rhinitis and epistaxis, occurring in 12 and 4 percent, respectively.

PREPARATIONS AND ROUTE OF ADMINISTRATION — Calcitonins from many species are effective in humans, but salmon calcitonin is the one most widely used. It is highly potent in humans because of its high affinity (40 times that of human calcitonin) for the human calcitonin receptor and its slow rate of clearance [1]. The only other calcitonin used clinically is human calcitonin, which is less potent but also less antigenic than salmon calcitonin. Most clinical trials of calcitonin have used salmon calcitonin, but human calcitonin is as effective [9].

Calcitonin is available in the United States for administration by the subcutaneous, intramuscular, and intranasal routes [1,10-15]. The bioavailability of nasal salmon calcitonin is approximately 25 percent that of intramuscular calcitonin; thus, the biological effect of 50 international units of intramuscular salmon calcitonin is equivalent to that of 200 international units of nasal salmon calcitonin [16]. There are also several other differences between the different preparations:

●The absorption of the nasal dose is delayed compared with the parenteral route [16].

●The administration of salmon calcitonin is frequently associated with side effects such as nausea, vomiting, and flushing; these side effects are much less common with the nasal route [1,17].

●Nasal salmon calcitonin may provide more effective analgesia than parenteral salmon calcitonin. (See 'Bone pain' below.)

Thus, the convenience and freedom from side effects make nasal salmon calcitonin the preferred route of administration in patients who can tolerate and cooperate with intranasal administration.

EFFICACY

Osteoporosis prevention — The perimenopausal acceleration of bone loss is due to increased bone resorption. This has led to studies of the efficacy of calcitonin in preventing postmenopausal bone loss since it inhibits bone resorption. In one study, for example, 52 postmenopausal women were randomly assigned to treatment with either 100 international units nasal salmon calcitonin or placebo; all subjects received calcium supplementation. Over two years, mean spinal bone mineral density (BMD) increased by 2.5 percent in the calcitonin group and decreased by 5.7 percent in the placebo group (figure 1) [11]. In comparison, whole body and forearm BMD did not differ between the placebo group and the calcitonin group. Other studies have shown similar results using both human [9] and salmon [12,18] calcitonin by both the subcutaneous and intranasal routes [1]. In a two-year extension study of a randomized trial, nasal calcitonin maintained efficacy in preventing perimenopausal bone loss at the lumbar spine after as long as five years of continuous use (figure 2) [10].

Osteoporosis treatment — Calcitonin may be effective in the treatment of established osteoporosis, but it is less effective than other available agents. In one study of calcitonin in osteoporosis, 208 older osteopenic women were treated with calcium and either intranasal placebo, 50, 100, or 200 international units of salmon calcitonin daily for two years. Mean spine BMD was increased by salmon calcitonin in a dose-dependent fashion, with a maximum effect at 200 international units daily. Salmon calcitonin was also associated with a significantly lower fracture rate than placebo [13], a finding that has been confirmed by others (figure 3) [19].

The largest trial of calcitonin for treatment of osteoporosis was a five-year trial in 1255 women with a lumbar spine T-score of <-2 and at least one vertebral fracture who were randomly assigned to either placebo or 100, 200, or 400 international units of intranasal calcitonin per day (figure 4) [20]. There was a small increase in spine BMD (1 to 1.5 percent) in all groups. The risk of vertebral fracture was significantly lower than placebo only in the group taking 200 international units per day, and the risk of nonvertebral fractures was significantly lower than placebo only in the group taking 100 international units per day. Thus, the beneficial effect of nasal calcitonin on vertebral BMD and vertebral fracture risk was small, inconsistent, and not dose dependent.

Bone histology is normal in subjects with osteoporosis treated with calcitonin for two years [21].

There are conflicting data on the effect of calcitonin on sites other than the spine. Two studies found that calcitonin had no beneficial effect outside the spine [13,18], but other studies have shown improvement [15,19,21-23]. The above studies were mostly conducted in postmenopausal women.

Calcitonin is less effective for the treatment of postmenopausal osteoporosis than bisphosphonates. As an example, in a placebo-controlled, randomized trial of alendronate (10 mg per day) versus intranasal calcitonin (200 international units per day) for 12 months, BMD of the hip and spine increased significantly more in the alendronate group than in the calcitonin group [3].

Bone pain — Calcitonin has a beneficial short-term effect on acute pain relief in patients who have sustained a vertebral fracture. The ability of calcitonin to relieve pain may represent a truly distinguishing feature from other drugs used in the treatment of osteoporosis. Why pain relief occurs is not well understood; one possibility is a rise in endorphin levels induced by calcitonin [16]. (See "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment", section on 'Calcitonin'.)

The ability of calcitonin to relieve pain is illustrated by the findings of a meta-analysis of 10 trials comparing calcitonin (nasal or parenteral) with placebo in patients with acute (onset <10 days) or chronic (>3 months) pain due to an osteoporotic compression fracture [24]. After one week of treatment, there was a significant improvement in pain score at rest (three trials, 196 patients) and with activity (four trials, 228 patients) in patients receiving calcitonin for acute pain (mean difference for resting pain -3.39, 95% CI -4.02 to -2.76, using a visual analog scale from 0 to 10). There was also significant improvement in pain score two, three, and four weeks after starting treatment. In contrast, calcitonin was not effective for patients with chronic pain. The meta-analysis was limited by the small number of patients and heterogeneity of results. There were insufficient data to assess differences related to the route of calcitonin administration.

The benefits of calcitonin on bone pain have been noted with use of either parental or nasal calcitonin [25-28]. In one study, nasal calcitonin relieved pain more effectively than parenteral calcitonin (figure 5) [26], but this observation needs confirmation.

SUMMARY AND RECOMMENDATIONS

●Concern about the use of calcitonin for osteoporosis – We do not use calcitonin 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. (See 'Concerns about the use of calcitonin' above and "Overview of the management of low bone mass and osteoporosis in postmenopausal women".)

Calcitonin increases spine bone density and may decrease vertebral fracture risk. There are conflicting data on the effect of calcitonin on sites other than the spine. (See 'Osteoporosis treatment' above.)

●Short-term use to treat bone pain from acute vertebral fracture – 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. (See 'Bone pain' above and "Bisphosphonate therapy for the treatment of osteoporosis" and "Osteoporotic thoracolumbar vertebral compression fractures: Clinical manifestations and treatment", section on 'Calcitonin'.)