Calcif Tissue Int (1992) 51:184-188

Calcified Tissue International 9 1992 Springer-Verlag New York Inc.

Rectal Salmon Calcitonin for the Treatment of Postmenopausal Osteoporosis Kirsten Overgaard, Marc Allan Hansen, Karen-Lisbeth Dirksen, and Claus Christiansen Department of Clinical Chemistry, Glostrnp Hospital, University of Copenhagen, DK-2600 Glostrnp, Denmark Received December 13, 1991, and in revised form March 5, 1992

Summary. In a 2-year study, we examined bone mass and calcium metabolism in 36 elderly women with moderate osteoporosis. The study period comprised 1 year of observation, during which the women received no treatment affecting calcium metabolism, and 1 year of treatment, during which all participants received daily salmon calcitonin (sCT) 100 IU rectally and calcium 500 mg. During the observational period a significant bone loss of 1.5% was seen in the forearm (P < 0.01), whereas the spinal bone mass was virtually unchanged. After institution of treatment, the bone loss was arrested in the forearm and a significant increase of about 2% was seen in the spine (P < 0.01). The net effect of treatment revealed a positive outcome in both bone compartments (1.9% and 2.9%, P < 0.05-0.01). Correspondingly, the parameters of bone turnover (serum alkaline phosphatase, plasma bone Gla protein, and fasting urinary hydroxyproline/creatinine) did not change during the observational period, but significantly declined, 10-30%, during sCT treatment (P < 0.01-0.001). Tolerance was generally good, although in one woman, anoscopy revealed irritative changes in the rectal mucosa. We conclude that, given rectally, sCT is well absorbed and well tolerated and that it has a beneficial effect on calcium metabolism in moderately osteoporotic women. Key words: Rectal salmon calcitonin - Treatment - Osteoporosis - Bone mineral content.

Osteoporosis is a major cause of morbidity and mortality, and is a tremendous burden on medical resources. It affects millions of people worldwide and will become an even greater problem in the future, as so much of the world population survives into old age. Osteoporosis can be prevented, but it is not yet certain whether it can be effectively treated once it has been diagnosed. Calcitonin is a hormone related to calcium homeostasis. Its main target organ is the skeleton, in which it inhibits osteoclastic bone resorption. The main indications for its clinical use are Paget's disease of the bone [1, 2], hypercalcemic conditions [3, 4], and osteoporosis [5, 6]. It has also been reported to have an analgesic effect in various painful conditions [7, 8]. Injectable calcitonin has been authorized for the treatment of established osteoporosis in the United States [9], but in order to facilitate self-administration and to make long-term treatment more convenient, new galenic forms, like an intranasal spray and

suppositories, have been developed. Tolerance studies have shown that the frequency of side effects is lower with the intranasal and rectal forms than with the injectable form [10, 11]. Recent studies have suggested that intranasal salmon calcitonin (sCT) may be useful for the treatment of established osteoporosis [6, 12, 13] and in the prevention of postmenopausal bone loss [14, 15]. The rectal administration form, however, has not been extensively examined, and studies of both efficacy and tolerance remain to be performed. The aim of the present study was to examine the longterm effect of rectal calcitonin on bone and calcium metabolism in women with moderate osteoporosis and to assess tolerance. As different responses to sCT have been observed in bone compartments with different proportions of trabecular and cortical bone, the annual bone loss was examined in two different bone compartments prior to the initiation of the treatment.

Materials and Methods Subjects and Study Design Subjects were recruited by questionnaire sent to all women aged 68-72 years in six municipalities near Glostrnp Hospital. A total of 2009 questionnaires were sent out and 1522 were returned [16]. In all, 788 women fulfilled the primary selection criteria, that is, they were not immobilized, had never suffered from coronary infarction, stroke, or malignancy, and were not taking sex hormones or other drugs known to influence calcium metabolism. These women were invited to participate in a medical screening, which included examination of calcium metabolism; 512 attended. Of these, 105 women had a bone mineral content of the distal forearm (BMCarm) of 1 SD or less below the mean value for normal premenopausal women (Z-score above - 1). Another 71 women showed no signs of diseases known to affect calcium metabolism and had moderate osteoporosis as defined by a forearm Z-score of - 1 to - 2 and were invited to participate in a 2-year study: 1 year of observation without medication that affects calcium metabolism, followed by 1 year of treatment with rectal sCT. Thirty-six women (50.7%) agreed. The treatment consisted of rectal sCT (100 IU) administered every day in the morning or immediately after evacuation of the bowel (in case this followed a regular pattern) and a daily supplement of calcium 500 mg. Visits were scheduled at the end of the observation year and every 3 months during the treatment period. Anoscopy was performed annually and whenever clinically relevant. Informed consent was obtained from all the participants according to Helsinki Declaration II, and the protocol was approved by the local Ethics Committee.

Compliance Offprint requests to: K. Overgaard

Of the 36 women who agreed to participate, 25 (69.4%) completed

K. Overgaard et al.: Rectal Salmon Calcitonin

185

Table 1. Gross morphology and initial values (mean • 1 SEM) of bone mass measurements and biochemical parameters in 70-year-old women and normal ranges for healthy premenopausal women (mean (95% confidence intervals))

Height (cm) Weight (kg) BMCarm (U) BMD~pin~ (g/cm2) sCalcium/Protein(mmol/g) sAlkaline phosphatase (U/liter) pBone Gla protein (ng/ml) FU hydroxyproline/Creatinine (mmol/mol)

70-year-old women with a forearm Z-score of - 1 to - 2 (n = 71)

Entered 2-year study (n = 36)

Completed treatment period (n = 25)

160 68 34.4 0.922 2.36

• 1 • 1 • 0.018 b'd 20.01

160 67 34.5 0.923 2.36

• 1 • 2 • 0.4 -+ 0.024 ---0.01

160 65 34.6 0.938 2.35

-+ 1 • 2 • 0.6 • 0.033 • 0.02

175 10.1

--- 8~'a • 0.60

181 11.1

• 9 • 0.9

164 11.8

13.2

• 0,4 c

14.1

• 0,7

13.6

• 0.2 b'd

70-year-old women with a forearm Z-score above - 1 (n = 105)

Normal ranges for healthy premenopausal women (n = 351)

--

--

-40.5 -+ 0.3 1.009 • 0.015 2.35 -+ 0.01

-40.9 (32.3-49.5) 1.091 (0.847-1.335) 2.31 (2.15-2.48)

• 7 • 1.2

155 10.0

• 4 • 0.5

118 7.0

(68-205) (2.5-19.5)

• 0.9

13.2

• 0.3

11.3

(5.9-21.6)

Differences between groups were tested by Student's t test for unpaired data a = p < 0.05; b = p < 0.001 ; compared with 70-year-old women with a forearm Z-score above - 1 c = p < 0.05; d = p < 0.001 compared with healthy premenopausal women

the 2-year study. Of those who dropped out, 6 women did so at 3 months and 5 women between 6 and 9 months. Five women dropped out because of systemic reactions to the treatment, that is, dizziness and nausea (n = 2), headache (2), and flushing (1); and two women dropped out because of local reactions, that is, changes in bowel movement patterns (looser and more frequent stools). Another 2 women dropped out because of symptoms unrelated to treatment: low back pain (n = 1) and low abdominal pain (1). One woman dropped out for personal reasons and another died suddenly from acute heart failure.

Measurements of Bone Mass BMCarm w a s measured by single photon absorptiometry with a 125I

source (3.7 GBq) with photopeak at 27 KeV (Osteometer AS, model DT-100) [17]. B C M ~ , is determined as the mean of six scans 4 mm apart just proximal to the site where the distance between the ulna and the radius is 8 ram. The long-term in vivo precision of this method is 1% in our laboratory [17]. The bone mineral density of the lumbar spine (BMDs~,i~) was measured by dual-energy X-ray absorptiometry (Hologic, Inc., Waltham, MA, model QDR-1000 TM) [18]. This system uses a highly collimated dicromatic X-ray source (70 and 140 KVP). The bone mineral content (BMC) is expressed in g after internal calibration and BMD is calculated as the BMC divided by the area of interest (g/cm2) from L 2 to L4, including the intervertebral discs.

Measurements of Bone Turnover Blood samples were taken and urine was collected in the morning, after overnight fasting and abstinence from tobacco. Serum alkaline phosphatase (sAP) was measured enzymatically according to Scandinavian recommendations [ 19] with a coefficient of variation of 5%. Plasma bone Gla protein (pBGP) was measured by radioimmunoassay with intra- and interassay variations of less than 7% and 12% [20]. These parameters are indicators of bone formation. Fasting urinary hydroxyproline was measured by spectrophotometry [21] and corrected for creatinine excretion (FuHpr/Cr). The intra- and interassay variations of FuHpr were about 10% and 13%, an indicator of bone resorption. To eliminate the interassay variations of both pBGP and FuHpr, samples from each woman were measured in the same assays. Frozen at -20~ both parameters keep constant over a period of 24 months. Other variables were measured by routine procedures. Serum calcium was corrected to a

protein concentration of 70 g/liter and according to a protein-binding of 40% [22].

Statistical Analysis To express the serial bone mass measurements over the 2-year period, all subsequent measurements were expressed in percent of the screening values. The 2-year serial measurements of BMCarrn and BMD~pine were analyzed according to the concept described by Matthews et al. [23]. This concept suggests serial measurements to be analyzed by a two-step method that uses summary measures. In the first stage, rate of change or area under the curve should be calculated for each subject. In the second stage, the summary measures should be tested by simple statistical techniques as though they were raw data. The individual rates of change during calcitonin treatment were calculated by linear regression (aBMCtreat) , and the difference between 0% and the intercept expressed the net effect of treatment (ActBMC). No effect of treatment corresponded to an intercept of 0%. The net effect was calculated by extrapolation to an assumed bone loss during the second year if no treatment were given. The summary measures were compared to zero by t-test analysis. For the measurements of bone turnover, the changes over the observational period were expressed as a percentage of the screening values. The maximum changes during the treatment period were expressed in percent of the pretreatment values. The changes within groups were tested by Student's t test for paired data. The differences between groups were tested by Student's t test for unpaired data, that is, differences between the study population and healthy premenopausal women and age-matched women with a forearm Z-score above - 1, and between those women who completed the treatment study and those who did not.

Results

Table 1 gives the d e s c r i p t i v e data, baseline values o f b o n e m a s s , and b i o c h e m i c a l p a r a m e t e r s for the entire s t u d y p o p ulation and the w o m e n c o m p l e t i n g the 2-year study. T h e data indicate that the w o m e n w h o a g r e e d to p a r t i c i p a t e w e r e well m a t c h e d w i t h t h o s e w h o did n o t , and t h a t t h e values w e r e similar w h e t h e r or not the w o m e n w h o left the s t u d y w e r e included. F o r c o m p a r i s o n , the table gives the c o r r e s p o n d i n g data for a g e - m a t c h e d p o s t m e n o p a u s a l w o m e n with a f o r e a r m Z - s c o r e a b o v e - 1 and the n o r m a l r a n g e s for

K. Overgaard et al.: Rectal Salmon Calcitonin

186

BMOarm %

BMCarrn %

4 p ffi 0 . 0 2

T

2

0

9

A c~ BMC -2

-4

I

I

1

I

BMDspine %

BMD spine %

4

p = 0.01

G ....................

A ~ BMD -2

-4

Fig. 1. Percentage changes in bone mineral 1

I

I

0

12

18,

{

Treatment

{

Observation

content of the distal forearm (BMC~m) and bone mineral density of the lumbar spine (BMDspine) during the 2-year period (left), and responses to calcitonin treatment in the two bone compartments (right). Values are mean +- 2 SEM. P values are for net effect to treatment tested by t-test analysis [23].

I

24 months I

healthy premenopausal women. The study population had a significantly lower bone mass in both the forearm and the spine compared with age-matched women and healthy premenopausal women. Correspondingly, the indicators of bone turnover (sAP, pBGP, FuHpr/Cr) were significantly higher than in the premenopausal women. The levels of sAP were also significantly higher than in the age-matched women with a forearm Z-score above - 1. Figure 1 illustrates the percentage changes (mean +- 2 SEM) in bone mass measurements (left). During the observational period, a significant bone loss of 1.5% was seen in the forearm (P < 0.01), whereas the spinal bone mass was virtually unchanged. After initiation of treatment, further bone loss was prevented in the forearm ( + 0.4%) ( o t B M C t r e a t ) and a significant increase of 2.4% was seen in the spine (P < 0.01). The net effect of treatment (AetBMC) was positive in both bone compartments (P = 0.02-0.01) (right). Figure 2 visualizes the percentage changes (mean --- 2 SEM) in the parameters of bone turnover (left). No changes were seen during the observational period whereas calcitonin treatment decreased bone turnover significantly (P < 0.05--0.001). F o r sAP and FuHpr/Cr, the maximum changes occurred between 6 and 9 months after the start of treatment and then the responses leveled off. The differences between the responses occurring during the observational and treatment periods were statistically significant for sAP and pBGP (P < 0.01-0.001). During treatment, there were no significant changes in the safety variables, that is, blood pressure, serum creatinine, serum aspartate aminotransferase activity (ASAT), serum calcium per protein, fasting serum glucose, blood hemoglobin, and leucocyte count (data not shown). Tolerance was generally good. F o u r t e e n participants (39%) experi-

enced either systemic adverse reactions, such as dizziness and nausea, headache, and flushing, or local adverse reactions, such as looser and more frequent stools and perianal irritation. In one woman, anoscopy revealed irritative changes in the rectal mucosa.

Discussion Previous studies have shown that sCT given intranasally affects calcium metabolism in women with established osteoporosis [6, 12, 13]. The present study indicates that this is also the case for rectally administered sCT. The effect was assessed in a representative group of elderly women with a moderate degree of osteoporosis, defined by a BMC of the distal forearm, which was, on average, 20% lower than the level of healthy premenopausal women (mean Z-score = - 1 . 6 ) . During the observational period, the women had a mean bone loss of 1.5% in the forearm and 0.4% in the spine, which is consistent with the bone loss reported for that age group [24]. Rectal therapy with sCT reversed these changes by preventing further bone loss in the forearm and increasing the bone mass in the spine. The response in bone mass was confirmed by the treatment-induced modification of bone turnover, that is, no changes during the observational period but significant declines of 10-30% during sCT therapy. Thus, in women aged 70 years, the bone turnover seems to have reached a steady state at a level high enough to cause bone loss, at least in the forearm. The continuous bone loss from the forearm and the diminished loss from the spine in this age group are in accordance with the findings of other studies, both in untreated subjects and in women treated with cal-

K. Overgaard et al.: Rectal Salmon Calcitonin

187 %

(%) sAP

Q4

-20 "k'k

-4O %

(%) pBGP 0

I

A v

l

-20

-40 2O

J-4~4 %

(%) FuHpr/Cr

-20

p = 0.07 C) I

1'2 Observation

]

lJ8

2'4 Months Treatment ]

cium [24-26]. Thus, in the earliest postmenopausal years, women lose more bone from the spine than from the forearm, but when they have passed the years of accelerated bone loss, the loss from the forearm exceeds that from the spine. As the period with accelerated bone loss lasts for about 10 years, the bone loss in 70-year-old women may be higher in the forearm. It has previously been demonstrated that sCT therapy affects the bone mass in the forearm and spine differently [13, 15] and that long-term therapy is especially effective in the spine [13]. This was confirmed by the present study, but we were also able to relate the response to the previous bone loss. This relation revealed virtually similar net outcomes in the two bone compartments, that is, forearm loss - 1 . 5 % , gain during treatment + 0.4%, spinal loss - 0.4%, gain during treatment + 2.4%. Although the extrapolation to an assumed bone loss during the second year is prone to uncertainty, the data suggest that the differences observed earlier in bone response may actually reflect differences in the turnover of the individual bone compartments. Previous studies have furthermore demonstrated that sCT is particularly effective in patients with a high-turnover osteoporosis [5, 6] and when administered in borderline doses, sCT has been shown to be effective only in bone compartments with the highest bone turnover [15]. Thus, the daily dose of sCT 100 IU given in the present study seemed adequate for the current age group.

Fig. 2. Percentage changes in serum alkaline phosphatase (sAP), plasma bone Gla protein (pBGP), and fasting urinary hydroxyproline/creatinine (FuHpr/Cr) during the 2-year period (left) and the annual responses (right). Values are mean -+ 2 SEM. ~ = P < 0.05; ~ $ + = P < 0.001 for changes during treatment tested by Student's paired t test. ** = P < 0.01; *** = P < 0.001; and P values indicate levels of differences between the two periods tested by Student's paired t test.

Injectable sCT has proved to be safe without serious side effects and with an adverse reaction rate of about 30%. However, the frequent injections are uncomfortable. Compliance during the 1 year of treatment with rectal sCT was high, although suppositories are not always well accepted by patients. Thirty-nine percent of the participants experienced either systemic or local adverse reactions. F o r comparison, data obtained in our department showed an adverse reaction rate of 23% in subjects treated with placebo calcitonin [27]. We conclude that sCT rectally administered is well absorbed and well tolerated and that it has a beneficial effect on calcium metabolism in elderly women presenting with a moderate degree of osteoporosis. Thus, sCT in suppository form constitutes a realistic candidate for treatment of moderate osteoporosis and represents an alternative to the intranasal form of administration.

Acknowledgment. We thank Sandoz Italy for the salmon calcitonin and calcium. The study was supported by Grant 12-9528 from the Danish Medical Research Council. References

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