Calcitonin.

Calcitonin is FDA approved for the treatment of postmenopausal osteoporosis but not for prevention. The preferred delivery system is nasal. Nasal calcitonin is safe and well tolerated. The vertebral fracture efficacy of calcitonin is less robust than the two approved bisphosphonates (alendronate and risedronate) but is similar to raloxifene in the treatment of established osteoporosis. Calcitonin has not been demonstrated to reduce hip fracture risk, although a post-hoc pooled analysis suggests potential effectiveness of nasal calcitonin. Calcitonin produces small increments in bone mass of the spine and modestly reduces bone turnover in women with osteoporosis. Calcitonin may have analgesic benefit in patients with acute painful vertebral fractures. Treatment with calcitonin should be considered for older women with osteoporosis with painful vertebral fractures and for women who fail to respond to or cannot tolerate bisphosphonates. Calcitonin may also be indicated for women who are unable to take bisphosphonates because of impaired renal function.     

Calcitonin treatment for osteoporosis

It has been reported that calcitonin reduces incidence of fracture in patients with osteoporosis. Calcitonin appears to have a small effect on bone density and a modest effect on the risk of fractures. Because of the analgesic effect, calcitonin is frequently used in osteoporotic patients with back pain.     

Discontinuous calcitonin treatment of established osteoporosis--effects of withdrawal of treatment

PURPOSE: The purpose of this study was to examine the effects of discontinuous treatments with intranasal salmon calcitonin on bone and calcium metabolism in postmenopausal women and to establish the effects of withdrawing treatment. PATIENTS AND METHODS: This report presents data from 26 postmenopausal women with established osteoporosis (forearm fracture) 12 months after withdrawal of a 1-year double-blind, placebo-controlled therapy with intranasal calcitonin. The women then resumed treatment with calcitonin 200 IU plus calcium 500 mg daily in an open design for an additional 1-year period. A control group of 19 age-matched women (no forearm fracture) did not receive any treatment. RESULTS: At the end of the 3 years, the control group had lost significantly more bone in the forearm (single photon absorptiometry) and spine (dual photon absorptiometry) than had the group treated with intranasal calcitonin for 2 years, whereas the group receiving calcitonin for 1 year had intermediate values. During the year of withdrawal, the rate of bone loss was similar in the women who had received calcitonin and those who had received placebo. Calcitonin was especially effective in women with initially high bone turnover and low bone mass. The bone response in the spine could, furthermore, be estimated by the changes in bone turnover. CONCLUSION: Discontinuous treatment with intranasal calcitonin affects bone and calcium metabolism in established osteoporosis. In women with high-turnover osteoporosis, therapy results in a net gain of bone in both the peripheral and axial skeleton. Response to treatment may be monitored by changes in bone turnover.     

Meta-analyses of therapies for postmenopausal osteoporosis. VI. Meta-analysis of calcitonin for the treatment of postmenopausal osteoporosis

OBJECTIVE: To review the effect of calcitonin on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 2000 and examined citations of relevant articles and the proceedings of international osteoporosis meetings. We contacted osteoporosis investigators to identify additional studies and primary authors for unpublished data. STUDY SELECTION: We included 30 studies that randomized women to calcitonin or an alternative (placebo or calcium and/or vitamin D) and measured bone density or fracture incidence for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: Calcitonin reduced the incidence of vertebral fractures, with a pooled relative risk (RR) of 0.46 [95% confidence interval (CI) 0.25-0.87, P = 0.02, n = 1404, 4 trials]. However, the RR from the one relatively large randomized controlled trial (RCT) was 0.79 (95% CI 0.62-1.00, P = 0.05, n = 1108). For nonvertebral fractures, the pooled RR was 0.52 (95% CI 0.22-1.23, P = 0.14, n = 1481, 3 trials). Once again, the single large trial showed a less impressive effect than the smaller trials (RR 0.80, 95% CI 0.59-1.09, P = 0.16, n = 1245). For bone density of the lumbar spine, the pooled weekly dose of 250 to 2800 IU per week resulted in significant increase in the weighted mean difference (WMD) of 3.74 (2.04-5.43, P < 0.01, n = 2260, 24 trials). The combined forearm showed a similar effect, with a WMD of 3.02 (95% CI 0.98-5.07, P < 0.01, n = 468, 9 trials). At the femoral neck, the pooled weighted mean difference showed a nonsignificant trend toward benefit, WMD 3.80 (95% CI -0.32-7.91, P = 0.07, 9 trials, n = 513). Methodologically weaker studies tended to show greater effects on bone density, and the lumbar spine results suggested the possibility of publication bias. CONCLUSIONS: Calcitonin likely increases bone density in postmenopausal women predominantly at the lumbar spine and forearm for weekly doses of greater than 250 IU, although the true effect may be smaller than the pooled estimate would suggest. Calcitonin likely reduces the risk of vertebral fracture; its effect on nonvertebral fracture remains uncertain.     

Therapies for symptomatic primary osteoporosis

There is no universally accepted pharmacologic treatment for primary symptomatic osteoporosis. However, three agents discussed in this review show varying degrees of promise. Calcitonin increases bone density and has the added benefit of analgesic properties. Etidronate disodium, a diphosphonate approved for symptomatic Paget's disease, has been shown to increase bone density and decrease fractures in osteoporosis. Sodium fluoride, although an effective stimulator of bone growth in low turnover osteoporosis, has been associated with toxicity and increased fractures.     

Role of bisphosphonates and calcitonin in the prevention and treatment of osteoporosis

Bisphosphonates have been shown to increase bone mineral density in patients with established osteoporosis as well as those with osteopenia. The evidence conclusively shows a reduction in fracture rates in patients on the more potent nitrogen containing bisphosphonates. Indeed, significant vertebral fracture rate reduction has been demonstrated after only 1 year of therapy. Alendronate, a second-generation bisphosphonate, and risedronate, a third-generation bisphosphonate, are first line medications for the treatment of osteoporosis given their efficacy in preventing both vertebral and non-vertebral fractures. There is evidence that vertebral fractures may be prevented by intermittent cyclic therapy with etidronate. All three have been shown to increase bone mineral density in the spine, with alendronate and risedronate producing significant increases in hip bone density. Calcitonin has demonstrated the ability to reduce vertebral fracture rates with minimal changes in bone density. Calcitonin is also beneficial in reducing the bone pain associated with fractures.     

Calcitonin for prevention and treatment of postmenopausal osteoporosis

Prolonged calcitonin administration (intramuscular, subcutaneous, or intranasal) can prevent postmenopausal trabecular bone loss. Nasal administration constitutes a particularly attractive option for women who cannot tolerate or benefit from estrogen replacement therapy. The optimal schedule of administration still has to be precised, but 100 U/day of nasal calcitonin, combined with calcium supplements, can currently be recommended. Interrupted regimens are maybe favourable. Calcitonin can also prevent further bone loss in established osteoporosis particularly if bone turnover is increased. The anti-fracture efficacy of calcitonin is suggested by different types of studies but has not been formally demonstrated. Lastly, its analgesic efficacy in cases of painful vertebral compression fractures has been demonstrated in controlled studies.     

Denosumab for joints and bones

Denosumab is an investigational, fully human monoclonal antibody with a high affinity and specificity for receptor activator of nuclear factor κ B ligand (RANKL), a cytokine member of the tumor necrosis factor family. RANKL, an essential mediator of osteoclast formation, function, and survival, plays a major role in the pathogenesis of postmenopausal osteoporosis, structural damage in rheumatoid arthritis, and bone loss associated with other skeletal disorders. Denosumab suppresses bone turnover by inhibiting the action of RANKL on osteoclasts. Denosumab reduces bone turnover and increases bone mineral density in postmenopausal women with low bone mineral density, reduces fracture risk in women with postmenopausal osteoporosis, and inhibits structural damage in patients with rheumatoid arthritis when added to ongoing methotrexate treatment. It is generally well tolerated, with a good safety profile. Adverse and serious adverse events, including infections and malignancy, are similar in patients treated with denosumab or placebo.     

Calcium and salmon calcitonin in treatment of osteoporosis.

Calcitonin has been considered of therapeutic value in osteoporosis because of its effects in tissue culture. In the whole animal, however, the predominant result seems to be hypocalcemia, which might be expected to have the opposite effect of stimulating parathyroid hormone secretion and therefore resorption of bone. Indeed, in a short term study of 3- and 4-month duration in osteoporotic women, this was found to be so. A combination of calcium and calcitonin was therefore considered a more promising therapeutic alternative for this disease. Calcium was given to 26 patients, alone or with vitamin D, for a period of 15 months, and the effects on serum and urine calcium and phosphorus and on bone resorption and formation were evaluated. Calcium and vitamin D decreased serum parathyroid hormone levels, reduced bone resorption, and increased urinary calcium. The addition of calcitonin to the calcium and vitamin D did not seem to change these effects. Neither form of treatment resulted in change of bone mass. Calcium, with or without vitamin D supplements, may prevent the development of osteoporosis, but it seems unlikely that calcitonin has any additional desirable effect in the disease.     

Drug therapy for osteoporosis associated with rheumatoid arthritis (calcitonin)

Calcitonin (CT) inhibits osteoclastic bone resorption and also exhibits long-lasting analgestic action, probably mediating through intrinsic serotonin and opioid peptides. The injection form of eel and salmon CT is only available in Japan. There are a few RCT data regarding the effect of CT on osteoporosis associated with RA, the previous studies have shown its effectiveness in terms of maintaining or increasing bone mineral density in RA patients with or without corticosteroid therapy. RA patients with high turnover osteoporosis and back pain might be a good indication of CT therapy.     

Treatment of osteoporosis and Paget's disease

Osteoporosis is a major public health problem. In women, the estimated lifetime risks of hip and vertebral fractures are 15% and 25%, respectively. The development of accurate and reproducible methods of assessing bone mineral density has enabled identification of persons at risk of fracture and assessment of response to treatment. Estrogen replacement therapy is effective in the prophylaxis of postmenopausal osteoporosis, and is the only therapy with well-proven antifracture efficacy. Fluoride can dramatically increase bone density, although a recent large, controlled study has demonstrated no effect on vertebral fractures. Bisphosphonates are emerging as a likely effective therapy for both idiopathic and glucocorticoid-induced osteoporosis. Calcium, vitamin D, calcitonin, and anabolic steroids may still have a role. Parathyroid hormone is a promising development that will need further study. Paget's disease is also common, affecting more than 3% of people over 40 years old. Calcitonin is an established therapy, although the bisphosphonates are a promising alternative.     

Corticosteroid-Induced Osteoporosis

Corticosteroid-induced osteoporosis is the leading cause of secondary osteoporosis and a significant cause of morbidity in both men and women. Long-term use of even low-dose corticosteroids has been associated with increased risk of bone loss. Recent large randomized controlled trials have generated new knowledge on treatment strategies for patients with corticosteroid-induced osteoporosis. However, the majority of individuals receiving corticosteroids are not receiving prophylaxis for osteoporosis. Calcium and vitamin D should be recommended to patients initiating therapy with corticosteroids (and should be adequate for those receiving corticosteroids for less than 3 months). For those receiving corticosteroids for greater than 3 months, bisphosphonates are the therapy of choice, with both alendronate (alendronic acid) and risedronate (risedronic acid) approved by the US FDA for use in this indication. Calcitonin can be considered a second-line agent and should be reserved for patients who are intolerant of bisphosphonates or who are experiencing pain from a vertebral fracture. Hormone replacement therapy or testosterone therapy may be offered to those individuals on long-term corticosteroid treatment who are hypogonadal. Teriparatide (recombinant human parathyroid hormone 1-34) shows promise as a future anabolic agent for the prevention and treatment of patients with corticosteroid-induced osteoporosis.     

Improvement of QOL in osteoporotic patients by calcitonin treatment

Quality of life (QOL) is impaired in patients with osteoporosis, to which bodily pain greatly contributes. The presence of vertebral fractures detrimentally affects the patients' QOL in a dose-dependent manner. Calcitonin, with its potent analgesic action, markedly improves the various aspects of patients' QOL. Efficacy for the treatment of osteoporosis should be evaluated in terms of QOL also, in addition to the increase in bone mineral density and fracture prevention.     

Radiologic observations on bone resorption in Paget's disease

The diagnosis of Paget's disease of bone at its earliest osteolytic phase is difficult and requires radiographs of the highest quality. Calcitonin controls the bone resorption of uncomplicated Paget's disease but does not prevent disuse osteoporosis in normal and pagetic bones. Cessation of treatment leads to a recurrence of the osteolytic phase of the disease in some patients. Retreatment with human calcitonin arrests the bone resorption and permits bony consolidation of resorption clefts.     

Measures of bone loss in rheumatoid arthritis

Patients with rheumatoid arthritis (RA) are prone to develop osteoporosis, especially women receiving steroid hormone therapy. Inhibition of bone formation and/or excessive bone resorption may be responsible. Bone gamma-carboxyglutamic acid-containing protein (BGP), the major noncollagen protein of bone and a plasma marker of bone formation, was measured in 81 consecutive RA patients and 79 age- and sex-matched control subjects, in addition to the hormone regulators of bone metabolism, calcitonin, parathyroid hormone, and 1,25-dihydroxyvitamin D. Mean (+/- SE) BGP levels (picomoles per milliliter) were lower for RA men (1.46 +/- 0.14) and women (1.52 +/- 0.2) compared with their respective controls (2.05 +/- 0.17 for men, 2.47 +/- 0.22 for women). Women taking steroids had the lowest levels (1.13 +/- 0.22) and, in contrast to men, this value was lower than the nonsteroid-treated group. Steroid treatment appears to be a major determinant of low BGP levels; the effect of RA itself is suspected but not proved in this study. Calcitonin levels were lower in RA men as well as in all women. Diminution of BGP in these subjects supports the view that "low-dose" corticosteroid treatment may suppress bone formation, especially in women. Prevention or remediation of osteopenia may be monitored by BGP, if further studies validate this hypothesis with other measures of skeletal mass.     

Which is the better choice, estrogen or SERMs in postmenopausal women?

Hormone replacement therapy (HRT) increases the bone mineral density (BMD) and reduces the risk of vertebral and hip fractures in postmenopausal women. But, long term HRT slightly increases the risk of breast cancer. Raloxifene is a selective estrogen receptor modulator that has estrogen agonist effects in the skeleton and cardiovascular system and estrogen antagonist effects in the uterus and breast. Raloxifene effectively prevents bone loss and significantly, increases lumbar spine, hip, and total body bone mineral density, raloxifene reduces the risk of vertebral fracture. Raloxifene treatment leads to no increase in vaginal bleeding or mastaigia and to greater than 70% reduction in risk for invasive breast cancer. But raloxifene increases the hot flashes in postmenopausal women. In conclusion, HRT is optimal therapy for prevention and treatment of osteoporosis in postmenopausal women with menopausal symptoms, raloxifene is optimal therapy for prevention and treatment of osteoporosis in postmenopausal women without menopausal symptoms.     

Calcitonin

Calcitonin is a 32-amino acid polypeptide secreted by the parafollicular cells of the thyroid. Effects on bone include inhibition of osteoclasts, thus preventing bone resorption, as well as increased renal calcium excretion. Salmon calcitonin is often used therapeutically because it is more potent and has a longer duration of action compared with human calcitonin. Calcitonin also possesses analgesic properties. The mechanism of its analgesic effect is unknown but is thought to involve inhibition of prostaglandins and stimulation of β-endorphins. Most of the clinical data in postmenopausal osteoporosis involves the use of salmon calciton in nasal spray. Clinical trials have demonstrated a reduction in the risk of vertebral fractures and increased bone mineral density. Studies examining nonvertebral fractures have shown mixed results, some indicating a nonsignificant risk In general, calcitonin is inferior to bisphosphonates (BPs) in reducing fracture risk. Calcitonin is effective in the treatment of osteopathic pain. It has also been used in glucocorticoid-induced osteoporosis. Parenteral calcitonin is generally associated with more frequent side effects compared with intranasal calcitonin. Injectable administration can cause flushing, tingling, nausea, and injection site and allergic reactions. Side effects with intranasal use are usually limited to local effects (nasal congestion and irritation). Recent phase I trials with a new oral dosage form show promise in terms of efficacy and tolerability for treating patients who prefer this route of administration. This review of pertinent literature on calcitonin indicates that this remains a viable, though second-or third-line, agent for osteoporotic patients who refuse or cannot tolerate other treatments (e.g., BPs, raloxifene, and estrogen).     

原发性骨质疏松症病人降钙素储备功能的改变

为进一步探讨降钙素（ＣＴ）在骨质疏松症发生中的作用，用钙负荷－降钙素兴奋试验观察２１例原发性骨质疏松症妇女ＣＴ储备功能的改变（血清ＣＴ用放射免疫分析法测定），并与４８名健康女性（其中绝经后妇女２０名）及７例骨量减少妇女进行比较。结果表明，未发生骨质疏松的健康绝经后妇女与绝经前妇女比较，血ＣＴ的基础值、峰值、升高幅度及曲线下面积均无明显差别；原发性骨质疏松症妇女以上４项指标均明显低于健康妇女，较骨量减少组妇女的血ＣＴ峰值、升高幅度亦有降低。而骨量减少组妇女与同年龄健康绝经后妇女比较，血ＣＴ的基础值和曲线下面积有所下降，但血ＣＴ峰值及升高幅度无差异。本研究未观察到绝经对ＣＴ储备功能有明显影响；骨质疏松病人的ＣＴ储备功能有降低，且降低程度与骨量丢失的程度有关，提示与骨质疏松本身似有内在联系，这种ＣＴ水平的降低可能参与了骨质疏松的发生。     

Hip fracture protection by alendronate treatment in postmenopausal women with osteoporosis: a review of the literature

Osteoporosis most commonly affects postmenopausal women, placing them at a significant risk of fractures. In particular, hip fractures are an important cause of mortality and morbidity among postmenopausal women. Anti-resorptive therapies that produce greater decreases in bone turnover markers together with greater increases in bone mineral density (BMD) are associated with greater reductions in fracture risk, especially at sites primarily composed of cortical bone such as the hip. Thus, treatment with potent anti-resorptive drugs like alendronate is a strategy for preventing hip fractures in postmenopausal women with osteoporosis. The purpose of this paper is to discuss the efficacy of alendronate against hip fractures and the mechanism for this anti-fracture efficacy in postmenopausal women with osteoporosis. A meta-analysis of randomized controlled trials has shown that alendronate reduces the risk of hip fractures by 55% in postmenopausal women with osteoporosis. According to the analyses of the Fracture Intervention Trial, each 1 standard deviation reduction in a 1-year change in bone-specific alkaline phosphatase (BSAP) is associated with 39% fewer hip fractures in alendronate-treated postmenopausal women, and those with at least 30% reduction in BSAP have a 74% lower risk of hip fractures relative to those with less than 30%. Alendronate is effective in reducing the risk of hip fractures across a spectrum of ages. The mechanism for this anti-fracture efficacy has been clarified; alendronate strongly suppresses bone turnover and subsequently increases hip BMD, decreases cortical porosity, improves parameters of hip structure geometry (cortical thickness, cross-sectional area, section modulus, and buckling ratio), and produces more uniform mineralization (increases the mean degree of mineralization of bone) in cortical bone. A once-weekly regimen of alendronate administration provides better patient compliance and persistence with the treatment than the once-daily dosing regimen, leading to greater efficacy against hip fractures. Thus, the efficacy of alendronate against hip fractures has been confirmed in postmenopausal women with osteoporosis, especially with a once-weekly dosing regimen.