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Chronic treatment of Paget's disease of bone with synthetic human calcitonin.

Twelve patients with Paget's disease of bone were treated with synthetic human calcitonin for seven to 26 months (mean 15.3 months). This group included six patients who had previous therapy. Eleven of the 12 patients experienced relief of the symptoms associated with Paget's disease. The initial therapy of synthetic human calcitonin 0.5-1.0 mg subcutaneously was administered daily until the alkaline phosphatase had declined to a plateau response; the dose was then decreased to thrice weekly. The major biochemical findings were a 47 percent fall in serum alkaline phosphatase and a comparable decline in 24-hour urinary hydroxyproline. Two subjects discontinued therapy because of side effects; persistent nausea and vomiting in one and a cutaneous allergic reaction in the other. Other side effects were minor. Preliminary results suggest that some patients will maintain the same biochemical response on the reduced dose but that this is not predictable by pre-treatment data. We conclude that synthetic human calcitonin is a safe and effective treatment for Paget's disease of bone. Preliminary results suggest that the dose and frequency of administration of this agent must be individualized.

literature documenting its efficacy, particularly since 1977 when a more purified preparation became available [101.
Here we report the results of long-term treatment (7-26 months) with human calcitonin in 12 patients with PD. Of particular interest are the results in eight subjects who had undergone previous treatment, including seven who had received SCT. In addition, preliminary results of studies evaluating the lowest effective dose are presented.

MATERIALS AND METHODS Patient Population
Twelve patients with previously diagnosed PD were included in the study. Initially, because of the limited supply of HCT, only patients who had allergy to or side effects from SCT were admitted. However, starting with patient 5, the admission criteria were liberalized to include anyone with PD who volunteered to be included in the protocol. Table 1 summarizes the frequency of signs and symptoms related to PD in the twelve subjects. Table 2 contains pertinent clinical data and information about previous therapies for each of the twelve patients. Pre-and Post-Treatment Evaluation All patients were admitted to the Clinical Research Center, Yale-New Haven Hospital, for baseline evaluation before initiation of HCT therapy. The eight subjects who had completed more than nine months of treatment were readmitted for post-treatment evaluation.
The following baseline analyses were performed while fasting: complete blood count with differential, serum electrolytes, BUN, magnesium, calcium, phosphorus, creatinine, uric acid, alkaline phosphatase, acid phosphatase, total protein, fasting blood glucose, total and direct bilirubin, SGOT, 5' nucleotidase, thyroid indices, PTH, and protein electrophoresis. The diet contained 400 mg calcium, 800 mg phosphorus, 1.0 gm/kg protein, and was low in gelatin.
At least two 24-hour urine collections were assayed for calcium, phosphorus, creatinine, and hydroxyproline. Selected skeletal films and a bone scan were performed during each inpatient evaluation. Yearly audiograms were performed using standard technique.  On the last day of the hospitalization, calcitonin treatment was initiated.

Follow-Up Outpatient Visits
Every 6-8 weeks, subjects were seen and evaluated for subjective (pain relief, side effects of medication, etc.) and objective improvement. The latter included blood samples for calcium, phosphorus, alkaline phosphatase, creatinine, and parathyroid hormone (PTH). Twenty-four-hour urine collections for calcium, phosphorus, creatinine, and hydroxyproline were done every 3-4 months.

Analyses
All laboratory analyses were done in the clinical chemistry laboratory of Yale-New Haven Hospital except for immunoreactive PTH; this was sent to Nichols Institute, San Pedro, California.
Serum and urine calcium were measured by atomic absorption spectrophotometry. Alkaline phosphatase was determined by the revised method of Mc-Comb and Bowers [11]. Phosphorus was estimated by a continuous flow method. Hydroxyproline was measured by the method of Parekh and Jung [12].

Calcitonin Administration
The treatment period covered by this report ranged from 7 to 26 months (mean 15.3 months). The dose of HCT administered ranged from 0.5 mg three times weekly to 1.0 mg daily. Ten subjects were started on 0.5 mg subcutaneously daily and two (patients 5 and 6) 1.0 mg daily because of severe complications of Paget's disease (two recent fractures and intense pain, respectively). In eight patients the dose of HCT was changed during the course of the study. Decreases from 0.5 mg daily to 0.5 or 1.0 mg three times per week were made after the patient had a plateau in the clinical and/or biochemical response. Patients 8 and 11 had their doses increased from 0.5 to 1.0 mg daily because of persistent symptoms, and patient 2 was increased from 0.5 to 1.0 mg daily because of partial biochemical rebound (without worsening of symptoms); he was later decreased to 1.0 mg thrice weekly.

Clinical Observations
Ten of the twelve patients tolerated the medication well. Side effects were generally minor and were principally limited to the first one to two hours post injection. These included mild nausea (eight patients), local warmth and/or erythema at the site of injection (two patients), flushing (two patients), hyperdefecation (one patient), "chilly sensation" (one patient), and eructation (one patient). In many patients these symptoms gradually decreased or disappeared entirely during the first few weeks of therapy.
Three patients discontinued HCT therapy: subject 3 (after 9.5 months) because of significant side effects (persistent nausea and vomiting) and only modest symptomatic improvement, patient 6 (after 9 months) because of an apparent allergic (urticarial) reaction, and subject 7 because of relocation.
Eleven patients experienced symptomatic improvement, in most cases by 1-3 months after starting HCT. This consisted of the relief of bone pain and headache, a decrease in skin temperature, and/or an increase in mobility. The recent fractures in patient 5 healed normally. A few patients continued to have some pain, thought to be due to concomitant arthritis and/or far-advanced deforming PD of the lower 358 LANG ET AL. HUMAN CALCITONIN TREATMENT OF PAGET'S DISEASE extremities. No patient experienced a worsening of symptoms, and no patient sustained a fracture while on therapy. None of the nine patients who had hearing loss experienced any subjective or objective improvement. Biochemical Studies As noted in Table 2, AP was initially elevated (greater than 70 IU/dl) in 11 of the 12 patients, ranging from 102 to 2,500 with a mean of 611 698 (SD). Patient 7, who also had primary hyperparathyroidism and had been treated previously with sodium etidronate, began calcitonin therapy with a nortnal AP of 28 IU/dl. In 10 of the 11 patients with pre-treatment elevations in AP, the AP dropped to an average of 47 percent of pre-treatment values (range of 24-72 percent) (Fig. 1). In these patients, the AP gradually decreased over the first 30 weeks of treatment and then leveled off.
The individual AP data for the 10 patients are shown in Fig. 2. Three subjects reached AP values within the normal range. One patient (2) experienced a biochemical rebound. Initially he had a significant response, decreasing his AP from 2,500 to 1,630 (65.2 percent) in six months. Over the next few months it gradually rose, and, despite an increase in his dose from 0.5 mg to 1.0 mg daily, it continued to rise, peaking at 2,200. This was not accompanied by an increase in hydroxyproline excretion, and his previously mild symptoms remained unchanged. Elevation of the AP during treatment was also seen in patient 1 and patients 4 and 9, whose dose of HCT was decreased to 1.0 mg three times a week and 0.5 mg three times a week, respectively. The HCT dosage in patients 2 and 5 was decreased to 1.0 mg three times a week, and they remained unchanged both clinically and biochemically.
The degree and the rate of decline of the AP values were not related to the initial dose of HCT. However, there was a tendency for subjects with the highest AP to have the smallest percent age of decrease with treatment.
Urinary hydroxyproline (Table 1) was initially elevated in all except patient 7. Data on hydroxyproline excretion over the course of therapy was obtained for seven subjects. The mean (a SD) 24-hour excretion for these patients at the onset of therapy was 222.7 166 mg (range of 87-537.5 mg) with normal less than 45 mg. Figure 3 shows the urinary hydroxyproline vs. duration of therapy (in weeks) for seven patients, irrespective of dose. As with the AP response, the maximum decrease  Fig. 1. The dose of calcitonin is depicted for each subject by the symbols noted above. The patient numbers from Table 2 are next to the respective curve. Subjects whose post-treatment alkaline phosphase fell to the normal range are identified by an asterisk (*).
occurred after approximately 25-30 weeks of HCT therapy, with hydroxyproline excretion leveling off at an average of 47 percent of the original mean value (range of 26-60 percent). Figure 4 shows the hydroxyproline response for the individual patients. The asterisks identify three patients (4,5, and 9) whose hydroxyproline excretion fell into, or very near (9), the normal range. Two patients had rebound elevations: patient 1, from a low of 54 percent of baseline value at 28 weeks to 92 percent at 65 weeks, and patient 8, from a low of 35 percent at six weeks to 80 percent after one year. This was not accompanied by a change in symptoms or an increase in AP.
Serum levels of calcium and P04 were within normal limits for 11 of the subjects  throughout the study. Patient 7, with primary hyperparathyroidism, had a modestly elevated serum calcium and a low serum P04, neither of which changed with HCT treatment. The 24-hour urine calcium was normal in all subjects before and after HCT therapy. Other blood studies, including PTH, uric acid, BUN, bilirubin, SGOT, thyroxine, protein electrophoresis, and complete blood count with differential did not change during the treatment period. There was an excellent correlation between the X-rays and bone scans. In 100 percent of sclerotic/deformed bones on X-ray, the bone scan was positive. There was only one instance in which there was a positive scan without definite corresponding radiologic involvement. Patient 3 had increased uptake in the skull; her skull X-ray showed prominent vascular channels, indicative of uniform demineralization. This pattern is consistent with early PD given the presence of PD in other areas of the skeleton. There were no instances of diseases seen on X-ray but not by bone scan.
Seven subjects had a second set of skeletal films and bone scans taken after approximately one year of therapy. Four (patients 3,4,7,8) had no change, and three (subjects 1,2, and 5) had decreased uptake on bone scan. Only one patient (2) had a change noted on X-ray: a decrease in the size of a lytic area of his left proximal femur without a corresponding change in his bone scan.

Bone Biopsies
All patients in the study underwent iliac crest bone biopsies prior to treatment with HCT. Six subjects had a second biopsy performed after one year of HCT. All biopsies were characteristic of PD, and post-treatment biopsies revealed a decrease in active resorption surface in pagetic areas.

DISCUSSION
Paget's disease is a chronic condition characterized by an extremely high turnover rate of bone [14]. It has been shown that pharmacologic agents which slow bone remodeling to or toward normal are accompanied by evidence of improvement (see below) [1][2][3]8]. Of the various agents which have been shown to be effective, calcitonin has been found to be the safest [8]. Since 1967 salmon, porcine, and human calcitonin have been used in the management of PD [1][2][3]. Numerous studies have demonstrated subjective improvement, including pain relief and increased mobility in pagetic patients [8]. This has been accompanied by objective changes such as lowering of the serum AP and the urinary hydroxyproline values [1][2][3]8], radiologic regression of early PD [2], and histomorphometric evidence of normal bone formation in pagetic areas [9]. Generally, the above biochemical parameters decrease to 50 percent of pre-treatment levels after six months of CT treatment, then plateau for the duration of treatment [8]. Symptomatic relief is maintained without any further decrease in the biochemical values, which, while significantly decreased, may still be well above the normal range. The failure of the AP to fall to normal cannot necessarily be interpreted as an incomplete response because it has been shown that therapy is associated with the formation of normal lamellar bone in previously pagetic areas of bone even in the presence of elevated AP. Conversely, a fall of AP into the normal range, as is frequently seen in etidronate-treated patients, may be accompanied by increased bone pain, generalized skeletal demineralization, and an increase in the number of fractures [15]. Thus, the biochemical response does not necessarily reflect efficacy. At best, it will confirm subjective impressions, but it may be completely misleading as with some etidronate-treated patients [15].
"Resistance" to the action of SCT develops in up to 40 percent of treated patients [5][6][7][8]. This is characterized by a rebound in alkaline phosphatase and hydroxyproline levels and a re-emergence of symptoms [5][6][7][8]. At the present time, most authorities agree that this resistance is usually due to the presence of neutralizing antibodies to the non-human calcitonins [6][7][8]. HCT has been shown to be active in these patients in the presence of neutralizing antibodies to SCT [7].
The largest study of HCT came from the Hammersmith Hospital where patients with PD have undergone long-term therapy with HCT since 1969 [2,9,16]. As with SCT, significant symptomatic improvement was achieved in the majority of patients, and there was a plateau in AP and hydroxyproline to approximately 50 percent of pre-treatment values after six months of therapy [16]. The present study confirms these findings. None of the patients in the Hammersmith trial developed resistance to the medication, no antibodies to HCT were detected, and, while a few patients could be called "non-responders," clinical or biochemical relapse was uncommon [16]. It was concluded that HCT was non-immunogenic [13,16]. In our study, patient 6 developed an urticarial reaction without clinical or biochemical relapse (Fig. 2). Preliminary studies suggest that this patient was allergic to the HCT; detailed studies of her immunologic response to HCT are in progress and will be reported in detail separately. Only one patient has been reported to have developed antibodies to human calcitonin [17] and she did not have an allergic reaction or relapse of her PD [17].
Three of our patients showed some biochemical relapse while on a level or increasing dose of HCT. The AP (but not the hydroxyproline) in patient 2 began to increase gradually after almost 55 weeks of therapy and continued to rise despite an increase in HCT dose (Figs. 2 and 4). Patients 1 and 8 had rebounds in hydroxyproline without a change in AP (Figs. 2 and 4). In our hands, hydroxyproline is a less accurate indication of disease activity than serum AP levels, because urinary hydroxyproline values may vary with diet [18] and some of these measurements were made on 24-hour outpatient urine collections without strict dietary control of gelatin intake. Only patient 1 had concomitant return of pain, but this was not to pretreatment levels. None of these three patients had a significant rise in antibody titer to HCT. Alternative explanations which have been offered for the phenomenon of biochemical rebound without the development of neutralizing antibodies are 362 LANG ET AL.
hypophosphatemia [19], secondary hyperparathyroidism [20], and the "escape" phenomenon [21]. PTH levels were within normal limits for all of our patients throughout the treatment period, with the exception of patient 7, who also had primary hyperparathyroidism. Although calcitonin has been shown to be phosphaturic, none of the patients in our study developed hypophosphatemia, similar to the experience of most other investigators [8]. The so-called "escape" phenomenon has been demonstrated in vitro [21] but not in vivo so that we cannot assess the role of "escape" in the biochemical rebound in our subjects.
Because of the long biologic half-life of SCT, many patients will experience full benefit from as little as 1-3 doses weekly [22,23]. Since the half-life of HCT is shorter than SCT, one would expect that more frequent administration would be necessary. This was confirmed in the Hammersmith study [2,16]. However, in 1977, after most previously published studies had been completed, the manufacturer announced that HCT was being highly purified [10]. They recommended initial treatment with 0.5 mg daily, followed by maintenance with 0.5 mg two to three times weekly [10]. Therefore, we did some preliminary trials with thrice weekly therapy. Five subjects (patients 1,2,4,5, and 9) had sufficient follow-up data for assessment. Three subjects (1,4, and 9) had a modest rise in their alkaline phosphatase, and the other two had no change. Hydroxyproline values were available for two subjects (2 and 9), and there was no change. In this small group, it was not possible to predict from the severity, extent, or activity of the PD which subjects would be controlled on the three times weekly schedule. Furthermore, two of the three subjects who had a rise in AP did not have return of their previous symptoms. Patient 1, who did have partial return of his symptoms associated with the decreased dose of HCT, did not improve after reinstitution of daily therapy. These results, although preliminary, suggest that the frequency of therapy must be individualized. Radiologic regression of PD has been seen in patients with early disease after long-term HCT treatment [2]. Once sclerotic changes have occurred, however, the radiologic patterns change little, if at all, with therapy. Doyle et al. [24] demonstrated a dose-related radiologic response to long-term (10-40 months) HCT treatment. Five of 11 patients treated with 0.5 mg twice a day showed improvement, while the other six had no change. Three of 14 patients on 0.5 mg per day showed regression, four showed deterioration, and seven had no change. In 15 patients on doses of less than or equal to 0.5 mg three times per week, five deteriorated, 10 had no change, and none showed improvement. None of the patients who demonstrated radiologic regression in at least one bone showed advance of disease in other bones [24].
In our study, correlation between pre-treatment X-rays and bone scans was excellent. Seven patients had follow-up studies after one year of HCT therapy. Two subjects (3 and 7) had residual biochemical evidence of response to previous treatment (salmon calcitonin and etidronate, respectively) and thus would not be expected to show a post-HCT response on bone scan because bone turnover had already been suppressed by the prior treatment. Another subject, who was previously untreated, had no change in the bone scan. Three patients with sclerotic lesions showed improvement on bone scan without corresponding changes in their radiographic patterns. Only patient 2 had radiologic regression of disease, a decrease in the size of a lytic lesion in his left femur. This was too small an area to be picked up by his bone scan which was "hot" in the entire surrounding femur.
In conclusion, this study confirms earlier investigations demonstrating the effectiveness of HCT in the treatment of PD. The majority of symptomatic patients have 363 364 LANG ET AL. dramatic reductions in pain and increased mobility, with a minimum of side effects. There was no evidence of toxicity except for one subject who developed an apparent cutaneous allergic reaction. Only one patient had bothersome side effects (nausea) from the medication. Treatment was accompanied by a 47 percent reduction in AP and hydroxyproline values; in the few patients with mild disease, these fell into the normal range. We confirm that radiologic regression may occur in lytic areas but that in all probability sclerotic lesions will not show improvement with HCT therapy.