Suppression of Bone Resorption in Early ... - Springer Link

Calcif Tissue Int (1998) 62:379–382

© 1998 Springer-Verlag New York Inc.

Clinical Investigations Suppression of Bone Resorption in Early Postmenopausal Women by Intranasal Salmon Calcitonin in Relation to Dosage and Basal Bone Turnover B. Ongphiphadhanakul, N. Piaseu, L. Chailurkit, R. Rajatanavin Department of Medicine, Ramathibodi Hospital, Mahidol University, Rama 6 Rd., Phya Thai, Bangkok 10400, Thailand

Received: 10 March 1997 / Accepted: 14 November 1997

Abstract. In the present study, we assessed the ability of increasing doses of intranasal calcitonin to suppress urinary deoxypyridinoline cross-link (DPD), a specific biochemical marker of bone resorption, in early postmenopausal women. Subjects consisted of 30 healthy Thai women within 5 years of postmenopause, randomly assigned to 50, 100, or 200 IU of intranasal calcitonin 5 days/week for 3 months. Calcium supplementation by calcium carbonate capsules at 750 mg of elemental calcium per day was given to all subjects. Twenty four-hour urine for DPD and creatinine assays was collected at baseline, 1 month, and 3 months after treatment. All DPD values were corrected with urinary creatinine before analyses. Data were expressed as mean ± SEM. DPD decreased significantly 1 month after intranasal calcitonin treatment (P < 0.01). However, at 3 months, DPD increased when compared with the values at 1 month (P < 0.01), suggesting that there may be a reduction in the suppression of bone resorption after prolonged calcitonin therapy. Using a stepwise multiple regression model to address whether dosage and DPD at baseline influence the response to intranasal calcitonin, it was found that DPD suppression after intranasal calcitonin was not related to dosage but was strongly associated with baseline DPD (P < 0.0001). Suppression of bone resorption in early postmenopausal women by intranasal calcitonin is determined more by the state of bone turnover at baseline than the dosage of calcitonin. Key words: Salmon calcitonin — Osteoporosis — Bone turnover — Menopause — Dosage study.

Calcitonin has been reported to be effective in preventing bone loss and to decrease vertebral fractures in postmenopausal women with osteoporosis [1–3]. It acts through specific calcitonin receptors on osteoclasts [4] and this is reflected in the decrease of biochemical markers of bone resorption in subjects on calcitonin [5]. Although effective, calcitonin needed to be administered by intramuscular or

Correspondence to: B. Ongphiphadhanakul

subcutaneous injection until recently when intranasal calcitonin became available. Similar to the results from calcitonin injection, intranasal calcitonin has been shown to be effective in the retardation of bone loss and decrease in vertebral fractures in patients with osteoporosis [3]. Immediately after menopause, bone loss occurs at an accelerated rate largely because of estrogen deficiency [6–8]. Estrogen replacement is considered to be the therapeutic intervention of choice for preventing postmenopausal bone loss. However, a number of postmenopausal women are unable to take estrogen because of the side effects, especially vaginal bleeding [9]. Increased risk for endometrial cancer with unopposed estrogen has been well documented. Moreover, potential risk of breast cancer is another constraint especially in subjects with family or previous history of breast cancer. Besides estrogen, alendronate [10] and intranasal calcitonin [11–14] have been shown to be effective in the reduction of bone loss during early postmenopausal years. Appropriate doses of intranasal calcitonin for this purpose vary widely among studies—from 50 to 400 IU. The reasons for this inconsistency are unclear. Since intranasal calcitonin is relatively expensive, we attempted to find the minimal effective dose within 5 years of postmenopause by examining the dose-response relationship of intranasal calcitonin in the retardation of bone resorption. The probable effect of basal bone turnover on the response to calcitonin was also addressed. Materials and Methods Subjects consisted of 30 healthy Thai women within 5 years of postmenopause, recruited by flyers or advertisement. History taking and complete physical examination were performed on each subjects. All were considered to be healthy and were not taking medications that may affect calcium and bone metabolism. The study was approved by the ethical clearance committee on human rights related to research involving human subjects of the Faculty of Medicine, Ramathibodi Hospital, Mahidol University. The subjects were randomly assigned to self-administer 50 IU, 100 IU, or 200 IU of intranasal salmon calcitonin (Sandoz, Switzerland) 5 days/week for 3 months. Each subject also took calcium supplementation in the form of calcium carbonate capsules at a dose of 750 mg of elemental calcium per day. Twenty-four-hour urine for deoxypyridinoline cross-link (DPD) and creatinine assays were collected at baseline, 1 month, and 3 months after treatment.

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B. Ongphiphadhanakul et al.: Suppression of Bone Resorption by Intranasal Calcitonin

Fig. 1. Effects of 50, 100, and 200 IU of intranasal calcitonin on DPD at 1 month and 3 months after treatment. The data were analyzed by repeated measures analysis of variance with time after treatment as the within-subject effect and the doses of intranasal calcitonin as the between-subject effect. *DPD decreased significantly at 1 month after intranasal calcitonin treatment (P < 0.01). **At 3 months, DPD increased when compared with the values at 1 month (P < 0.01). DPD was measured by ELISA (Metra Biosystems, USA). All DPD values were corrected with urinary creatinine before analyses. Repeated measure analyses of variance (ANOVA) was used to assess the difference in levels of DPD after treatment with different doses of calcitonin. Changes from basal DPD levels at different doses of calcitonin were determined by one-way ANOVA. Stepwise multiple linear regression analyses were performed to find the relationship between doses and baseline bone turnover to changes in bone resorption. Data were expressed as mean ± SEM. Results

The age and number of years since menopause were 53.4 ± 5.2 and 3.5 ± 1.6 years, respectively. Using repeated measure ANOVA to assess the change in DPD after treatment and the effects of dosage in all groups combined, it was found that DPD decreased significantly at 1 month after intranasal calcitonin treatment (P < 0.01). However, at 3 months DPD increased when compared with the values at 1 month (P < 0.01) suggesting that there may be a reduction in the suppression of bone resorption after prolonged calcitonin therapy (Fig. 1). No difference was found between DPD at 1 month and at 3 months. Figure 2A demonstrated the relationship between increased doses of intranasal calcitonin and the decrease in DPD after 1 month of treatment. With 50 IU of intranasal calcitonin, bone resorption was significantly reduced at 1 month. Increasing doses of calcitonin to 100 and 200 IU did not cause further reduction in bone resorption. Likewise, after 3 months of intranasal calcitonin, 50 IU of intranasal calcitonin significantly reduced bone resorption and no further decrease in bone resorption was observed with 100 and 200 IU of calcitonin (Fig. 2B). When considering the relationship between the degree of bone resorption at baseline and the changes in DPD after calcitonin by regression analysis, it was found that baseline DPD was strongly associated with the response to intranasal calcitonin at 1 month (r 4 −0.65, P < 0.0001) (Fig. 3A). Those with higher levels of bone resorption, as measured by biochemical markers at baseline, tend to have a better response to calcitonin. A similar relationship was observed at 3 months after treatment with intranasal calcitonin (r 4 −0.66, P < 0.0001) (Fig. 3B). Using stepwise multiple regression to look at the relative contribution of calcitonin

Fig. 2(A). Relation between increasing doses of intranasal calcitonin and the changes in DPD after 1 month of treatment. There was no significant association between doses of intranasal calcitonin and changes in DPD (50 IU, −11.1 ± 16.8%; 100 IU, −14.5 ± 11.8%; 200 IU, −28.2 ± 8.4%). (B) Relation between increasing doses of intranasal calcitonin and the changes in DPD after 3 months of treatment. There was no significant association between doses of intranasal calcitonin and changes in DPD (50 IU, 3.0 ± 20.8%; 100 IU, −2.2 ± 14.7%; 200 IU, −3.1 ± 10.4%).

doses and basal bone turnover to the suppression of bone resorption, it was found that only basal bone turnover was related to the degree of suppression of DPD at both 1 month (r 4 −0.65, P < 0.0001) and 3 months after treatment (r 4 −0.66, P < 0.0001). Discussion

Calcitonin has been shown to reduce bone loss and decrease fractures in patient with established osteoporosis in a number of studies [3, 15]. Most of these patients were well beyond menopause. Although there was evidence that increased bone turnover, which occurs after menopause, persists into late menopause in some individuals [16], there is a possibility that responses to antiresorptive therapies may differ between women in early and late postmenopausal periods. For example, calcium supplementation has been shown to reduce bone loss in late postmenopausal women [17] though it is not effective in early postmenopausal women [18]. The mechanism underlying the different responses is unclear but it is probable that the effect of estrogen deficiency on bone metabolism may be greater in the early menopausal period after which it tends to be less when a new steady state is attained. The efficacy of intranasal calcitonin in early postmenopausal periods is controversial and the effective doses of intranasal calcitonin differ among different studies, causing uncertainty in choosing the right dose in clinical practice. In the present study, we demonstrated that 50 IU of intranasal calcitonin was as effective as higher doses in


Fig. 3(A). Relation between baseline DPD and the changes in DPD after 1 month of treatment. Baseline DPD was strongly associated with the response to intranasal calcitonin at 1 month (r 4 −0.65, P < 0.0001). (B) Relation between baseline DPD and the changes in DPD after 3 months of treatment. Baseline DPD was strongly associated with the response to intranasal calcitonin at 3 months (r 4 −0.66, P < 0.0001).

reducing biochemical marker of bone resorption in recently postmenopausal Thai women. Although reduction of a marker may not necessarily be equivalent to resorption within bone, this is in concordance with the finding from a study in Caucasians where 50 IU of intranasal calcitonin was found to be as effective as higher doses in the prevention of postmenopausal bone loss [14]. We also demonstrated in the present study that the basal state of bone turnover in early postmenopausal women was related to the response in bone resorption marker such that those with higher bone turnover tended to have better response to intranasal calcitonin. This is in keeping with a subgroup analysis in elderly women which showed that those with a higher state of bone turnover responded better to calcitonin injection [19]. The variation in the basal state of bone turnover may partially explain the differences among studies in responsiveness to different doses of intranasal calcitonin. It can also be seen that the efficacy of intranasal calcitonin is less than perfect and a number of subjects did not have decreased DPD after 50 IU of intranasal calcitonin. Measuring bone resorption markers at baseline may help select patients who will be more likely to respond favorably to intranasal calcitonin. Whether the favorable change in bone resorption marker will finally lead to an equally favorable outcome in bone mass remains to be determined. At least the findings so far seem to suggest a less than perfect relationship between change in biochemical markers of bone turnover and bone mass after antiresorptive treatments such as alendronate [20] and estrogen [21]. Although calcitonin is safe and effective in the treatment

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of osteoporosis, there are still some unresolved questions related to its usage. Tachyphylaxis seems to occur with long-term calcitonin use [22]. In the present study, suppression of bone resorption marker appeared to decline at 3 months compared with the values at 1 month. Although change in DPD may not finally relate to therapeutic effects, our findings suggest that the reduction antiresorptive action of intranasal calcitonin assessed by DPD also occurs with prolonged use. The reduction in efficacy may be due to the down regulation of calcitonin receptor [23], development of calcitonin antibody, especially with salmon calcitonin [24], or some other counter-regulatory mechanisms. Although discontinuing the administration of calcitonin is believed to make one less prone to the development of tolerance, the most appropriate scheme for the administration of calcitonin is still unclear. Varying the frequency of administration such as daily, alternate day, 5 days per week, 1 month on and 1 month off schemes have been used. However, whether discontinuous regimens are more effective is open to question. At least, discontinuous regimen such as 5 days per week used in the present study still resulted in the diminution of the suppression of bone resorption after prolonged treatment. Nevertheless, treatment with calcitonin for as long as 2 years or more has been reported to maintain its effectiveness in terms of bone mass despite the known incidence of resistance [13]. In conclusion, suppression of bone resorption in early postmenopausal women by intranasal salmon calcitonin is determined more by the state of bone turnover at baseline than the dosage of calcitonin. The optimal treatment scheme for intranasal calcitonin still remains to be determined.

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