Metabolic
Effects of Synthetic Calcitriol (Rocaltrol@) in the Treatment of Postmenopausal Osteoporosis J.C. Gallagher
The long-term safety and efficacy of synthetic 1,25(OH),D, (celcitriol; Rocaltrol@) in the treatment of women with type 1 osteoporosis is being assessed in a randomized trial. Patients were allocated in double-blind fashion to 1,2S-(OH&D, or matching placebo. Initially, the calcium intake was adjusted to 1,000 mg/d. The study protocol called for increasing the dose of 1.25(OH&D, until patients developed either hypercalcemia or hypercalciuria. However, in order to maintain a higher dose of cakitriol on a long-term basis, the calcium intake had to be reduced to 600 mg/d in those receiving calcitriol; if that was not successful in eliminating hypercelcemia and hypercalciurie. then the dose of 1.25(OHI,D, was reduced as necessary. During the hypercalcemic phase, the indices of bone resorption decreased significantly, demonstrating that calcium absorption is solely responsible for hypercalcemia. The maintenance dose was established after 8 to 10 weeks, and the 24-hour urine calcium and creatinine clearance remained constant throughout the remainder of the study period. On a calcium intake of 000 mg/d, the long-term maintenance dose of 1.25~IOH),D, averaged 0.676 pg/d. Long-term therapy on an average dose of 0.675 fig/d was not associated with nephrotoxicity. 0 1990 by W.B. Saunders Company.
0
STEOPOROSIS occurring in middle-aged and older people has been classified into two major categories.‘** Type I osteoporosis is found in a subset of postmenopausal women (about 10% to 15%), usually between the menopause and age 70 years, and is characterized by an accelerated loss of trabecular bone, often resulting in fractures of the vertebral bodies and distal forearm. Pathophysiologically, postmenopausal type I osteoporosis is considered to result from estrogen deficiency and perhaps other factors, which lead to increased bone loss and decreased parathyroid hormone (PTH) secretion3; the latter results in decreased production of 1,25-(OH),D followed by decreased calcium absorption.4 Senile or type II osteoporosis occurs in a larger proportion of women (about 30% to 40%) and in men over the age of 75 years; it is characterized by fractures of skeletal sites that contain both cortical and trabecular bone. In these individuals, circulating levels of PTH tend to be higher than normal,3 although decreased circulating levels of 1,25-(OH),D are also seen as a manifestation of the aging kidney. In an ongoing study, we are examining the long-term safety and efficacy of synthetic 1,25-(OH),D, (calcitriol; Rocaltrol@) in the treatment of women with type I osteoporosis. When comparing results among centers, it is important to realize that other studies may include a mixture of type I and type II patients, thus generating varying results. PATIENTS AND METHODS
Fifty patients with postmenopausal type I osteoporosis of unknown etiology and a history of two or more fractures were entered into this trial (protocol 2294). The diagnosis was confirmed by histomorphometry, thus excluding osteomalacia. Most patients (95%) were previously untreated. The patients were randomly allocated in a double-blind fashion to 1,25-(OH),D, (Rocaltrol’) (24 patients) or matching placebo (26 patients). Calcium intake was adjusted to 1,000 mg/d; in approximately 75% of the patients, this involved adding 250 mg elemental calcium administered as calcium carbonate. The study protocol called for initially increasing the dose of 1,25-(OH),D1 until patients developed either hypercalcemia (> 11.O mg/mL) or hypercalciuria (urine calcium ~350 mg). Then, in order to establish a safe, long-term maintenance dose, the calcium intake was first reduced to 600 mg/d; if that was not successful in eliminating hypercalcemia Metabolism, Vol39,
No
4,
Suppl 1 (April), 1990: pp 27-29
and hypercalciuria, then the dose of 1,25-(OH),D, was reduced incrementally by 0.25~pg doses as necessary. We used dual-photon absorptiometry, which employes gadolinium 153 as the isotope, to measure spine density and total body calcium. Measurement of total body calcium is more precise (coefficient of variation [CV], approximately 1%) than spine density (CV, approximately 3%). Pretreatment comparison of the placebo and 1,25-(OH),D, groups showed that both were similar with regard to age (70.5 v 69.1, respectively), years since menopause (23 v 23), weight, total body calcium (650 g v 680 g), and spine density (0.89 v 0.86 g/cm’). It should be noted that all patients had developed spinal osteoporosis with associated fractures several years before entering the study; thus, the average at which patients presented with their first fracture was approximately 62 or 63 years, which is characteristic of type I osteoporosis. RESULTS
Effects of Dosage Adjustments on Urine/Serum Calcium
The action of 1,25-(OH),D, occurs initially on calcium absorption and 24-hour urine calcium excretion. As the dose of 1,25-(OH),D, is increased from 0.5 Mg/d to 0.75 pug/d, to 1.Opg/d and, occasionally, 2.0 rg/d, there is a corresponding sharp increase in 24-hour urine calcium (Fig 1). However, the amount of calcium absorbed depends not only on the Rocaltrolg dose, but also the calcium intake. Reducing the daily calcium intake from 1,000 mg to 600 mg results in a lower 24-hour urine calcium excretion as shown in Fig 1. It should be noted that the slope of mean 24-hour urine calcium/calcium intake on dose shifts to the right. Thus, reducing the calcium intake allows the use of a larger dose of Rocaltrol@. The optimal long-term maintenance dose of 1,25-(OH),D, was established after eight to 10 weeks, and the 24-hour urine calcium remained fairly constant throughout the remainder of the study period. From the Bone Metabolism Unit, Creighton University Medical Center, Saint Joseph’s Hospital, Omaha, NE. Address reprint requests to J.C. Gallagher, MD, Bone Metabolism Unit, Creighton University Medical Center, Saint Joseph’s Hospital, 601 N 30th St, Omaha, NE 68131. a 1990 by W.B. Saunders Company. 0026-0495/90/3904-1006%3.00/O 27
J.C. GALLAGHER
28
l 0
greater than 10.5 mg/mL were observed after reaching the maintenance dose in week 10. Hypercalcemia usually occurred on doses greater than 0.75 Mg/d, and urine calcium exceeded 300 mg/24 hours in approximately 50% of cases during maintenance therapy, but did not exceed 350 mg/24 hours; this nearly always could be explained by some variation in calcium intake. Moderate hypercalcemia during the dose titration phase was associated with a temporary increase in serum creatinine, but there were no long-term significant differences in serum creatinine or creatinine
1000 mg Ca. Intake 600 mg Ca. Intake
260 220
.25
50
.75
1.0
1.25
12c
Dose1,2W-W3 W
Alkaline Phosphatase Fig 1. Mean 24-hour urine calcium excretion on a l.DW mg calcium intake (0) and mean 24-hour urine calcium excretion on 600 mg calcium intake (0) on different doses of ltS(OHI,D,. Reducing the calcium intake allows the use of a larger dose of 1.25(OH),D,.
As the patients became hypercalcemic, they also developed a slight increase in serum creatinine. After establishment of the long-term maintenance dose of 1,25-(OH&D,, which averaged 0.67 pg/d in this study, the serum calcium remained fairly constant, and the serum creatinine also returned to normal and remained constant. During the initial hypercalcemic phase, the 24-hour urine hydroxyproline excretion (OHPr/Cr)-a parameter that measures bone resorption-decreased significantly in the patients receiving 1,25-(OH),D, (Fig 2). Also, there was a concomitant reduction in serum alkaline phosphatase. These observations suggest that the mechanism of hypercalcemia involves increased calcium absorption and not increased bone resorption. As the dose of 1,25-(OH),D, was reduced, serum calcium returned to normal and parameters of bone turnover returned to pretreatment levels.
11c
1oc -I zi s
60
70
60
2
6
3
9
12
Months 120
Urine OHPr/Cr
110
Effects on Creatinine Clearance
Because the dose of 1,25-(OH),D, was increased to the point of toxicity, creatinine clearance was measured in each patient on multiple occasions, weekly for the first 12 weeks and then monthly for the remainder of the study period. There was a transient decrease in creatinine clearance during the initial period of hypercalcemia, but subsequently it returned to baseline (Fig 3). No significant difference between placebo and 1,25-(OH),D, was observed in creatinine clearance or serum creatinine.
90
100 i
m \o 0
90
a0
DISCUSSION 70
bone loss occurred in the placebo group, despite the fact that the calcium intake was increased from a mean baseline of approximately 700 mg/d to 1,000 mg/d. In contrast, there has been no significant bone loss in patients treated with 1,25-(OH),D,. On a calcium intake of 600 mg/d, the long-term maintenance dose of 1,25-(OH),D, averaged 0.675 Fg/d, and long-term therapy on this dosage was not associated with toxicity. No serum calcium values Significant
6t
I
I
I
0
2
3
I
I
6
I
I
9
I
I
12
Months Fig 2. During the dose titration with 1,26(OH),D,. hypercalcemia in months 2 to 3 was accompanied by a reduction in bone turnover. (0). placebo; IO), 1,26(OH),D,.
CALCITRIOL
FOR POSTMENOPAUSAL
29
OSTEOPOROSIS
80 i a $? 70 -
I
I
I
I
I
I
I
I
I
8
123456
I
)
12
Months Fig 3. Twenty-four-hour urine creatinine clearance (mL/minI on 1.26(OH),O, (0) or placebo (0). During the titration phase in months 2 and 3 hypercalcemia was accompanied by a transient decrease in creatinine clearance, which later returned to normal.
clearance. Provided the 24-hour urine calcium is kept below 300 to 320 mg, there appears to be no evidence yet of long-term nephrotoxicity. It should be noted that the “window of efficacy” for 1,25-(OH),D, in terms of dose is quite narrow on a free
calcium intake. In earlier studies, we found that administration of doses of 0.25 to 0.40 fig/d in some osteoporotic patients did not always increase calcium absorption and urine calcium excretion.’ At 0.5 pg/d, there is a 100% response, and at 0.75 Fg/d there is a “hyperresponse,” with associated toxicity in 30% of patients. In an earlier pilot study where the calcium intake was restricted to less than 500 mg/d, we assessed the effect of 2.0 Mg/d of 1,25-(OH),D, on bone in a group of eight patients.6 The increases observed in serum calcium, urinary calcium, and PTH were all within the normal range. In addition, there was a significant increase in levels of serum osteocalcin at this high dose. Bone biopsies showed that bone formation rates, calculated from double-tetracycline labeling, increased substantially in these patients at 6 weeks. At 6 months, after the patients had been crossed-over to a calcium supplement of 1,500 mg/d there was a decrease in bone formation. These results suggest that a higher dose of 1,25-(OH),D, is more effective in stimulating bone formation. The latter may be an important end point in treatment. Other studies using synthetic calcitriol (Rocaltrola) in study designs similar to the present one have shown different results. In a study by Aloia et al,’ significant increases in total body calcium and spine density were observed on an average daily dose of 0.8 bg of Rocaltrol”. On the other hand, Ott and Chestnut,8 using a lower average daily dose of 0.4 pg, observed no increase in bone density; however, neither did they see a decrease in bone density. Japanese studies of other analogues of vitamin D such as la(OH)D, have shown significant increases in bone density and decreases in fracture rates.‘.”
REFERENCES
1. Albright F: Osteoporosis. Ann Intern Med 27:861-882, 1947 2. Riggs BL, Melton LJ: Evidence for two distinct syndromes involutional osteoporosis. Am J Med 75899-901, 1983 3. Gallagher JC, Riggs BL, Jerpbak CM, et al: The effect of age on serum immunoreactive parathyroid hormone in normal and osteoporotic women. J Lab Clin Med 95:373-385, 1980 4. Gallagher JC, Riggs BL, Eisman J, et al: Intestinal calcium absorption and serum vitamin D metabolites in normal and osteoporotic patients. Effect of age and dietary calcium. J Clin Invest 64729-736, 1979 5. Gallagher JC, Riggs BL, Deluca HF: Effects of calcitriol in osteoporosis in DeLuca HF, Parfitt AM, Jee C, et al (eds): Recent Advances in Osteoporosis. Baltimore, MD, University Park, 1981, pp 215-224 6. Gallagher JC, Reeker R: A comparison between high dose
calcitriol and calcium supplements in osteoporosis, in Norman AW, Schaefer K, Grigoleit HG, et al (eds): Vitamin D, Chemical, Biochemical and Clinical Update. Berlin, 1985 7. Aloia JF, Vaswani A, Yeh J, et al: Calcitriol in the treatment of postmenopausal osteoporosis. Am J Med 84:401-408,1988 8. Ott SM, Chestnut CH: Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med:267-274, 1989 9. Shiraki M, Orimo H, Ito H, et al: Long-term treatment of postmenopausal osteoporosis with active vitamin D, l-alphahydroxycholecalciferol and 1, 24-dihydroxycholecalciferol. Endocrinol Jpn 32:305-3 15, 1985 10. Orimo H, Shiraki M, Hayashi R, et al: Reduced occurrence of vertebral crush fractures in senile osteoporosis treated with 1 alpha(vitamin D,. Bone Min 3:47-52, 1987
Effects of Synthetic Calcitriol (Rocaltrol@) in the Treatment of Postmenopausal Osteoporosis J.C. Gallagher
The long-term safety and efficacy of synthetic 1,25(OH),D, (celcitriol; Rocaltrol@) in the treatment of women with type 1 osteoporosis is being assessed in a randomized trial. Patients were allocated in double-blind fashion to 1,2S-(OH&D, or matching placebo. Initially, the calcium intake was adjusted to 1,000 mg/d. The study protocol called for increasing the dose of 1.25(OH&D, until patients developed either hypercalcemia or hypercalciuria. However, in order to maintain a higher dose of cakitriol on a long-term basis, the calcium intake had to be reduced to 600 mg/d in those receiving calcitriol; if that was not successful in eliminating hypercelcemia and hypercalciurie. then the dose of 1.25(OHI,D, was reduced as necessary. During the hypercalcemic phase, the indices of bone resorption decreased significantly, demonstrating that calcium absorption is solely responsible for hypercalcemia. The maintenance dose was established after 8 to 10 weeks, and the 24-hour urine calcium and creatinine clearance remained constant throughout the remainder of the study period. On a calcium intake of 000 mg/d, the long-term maintenance dose of 1.25~IOH),D, averaged 0.676 pg/d. Long-term therapy on an average dose of 0.675 fig/d was not associated with nephrotoxicity. 0 1990 by W.B. Saunders Company.
0
STEOPOROSIS occurring in middle-aged and older people has been classified into two major categories.‘** Type I osteoporosis is found in a subset of postmenopausal women (about 10% to 15%), usually between the menopause and age 70 years, and is characterized by an accelerated loss of trabecular bone, often resulting in fractures of the vertebral bodies and distal forearm. Pathophysiologically, postmenopausal type I osteoporosis is considered to result from estrogen deficiency and perhaps other factors, which lead to increased bone loss and decreased parathyroid hormone (PTH) secretion3; the latter results in decreased production of 1,25-(OH),D followed by decreased calcium absorption.4 Senile or type II osteoporosis occurs in a larger proportion of women (about 30% to 40%) and in men over the age of 75 years; it is characterized by fractures of skeletal sites that contain both cortical and trabecular bone. In these individuals, circulating levels of PTH tend to be higher than normal,3 although decreased circulating levels of 1,25-(OH),D are also seen as a manifestation of the aging kidney. In an ongoing study, we are examining the long-term safety and efficacy of synthetic 1,25-(OH),D, (calcitriol; Rocaltrol@) in the treatment of women with type I osteoporosis. When comparing results among centers, it is important to realize that other studies may include a mixture of type I and type II patients, thus generating varying results. PATIENTS AND METHODS
Fifty patients with postmenopausal type I osteoporosis of unknown etiology and a history of two or more fractures were entered into this trial (protocol 2294). The diagnosis was confirmed by histomorphometry, thus excluding osteomalacia. Most patients (95%) were previously untreated. The patients were randomly allocated in a double-blind fashion to 1,25-(OH),D, (Rocaltrol’) (24 patients) or matching placebo (26 patients). Calcium intake was adjusted to 1,000 mg/d; in approximately 75% of the patients, this involved adding 250 mg elemental calcium administered as calcium carbonate. The study protocol called for initially increasing the dose of 1,25-(OH),D1 until patients developed either hypercalcemia (> 11.O mg/mL) or hypercalciuria (urine calcium ~350 mg). Then, in order to establish a safe, long-term maintenance dose, the calcium intake was first reduced to 600 mg/d; if that was not successful in eliminating hypercalcemia Metabolism, Vol39,
No
4,
Suppl 1 (April), 1990: pp 27-29
and hypercalciuria, then the dose of 1,25-(OH),D, was reduced incrementally by 0.25~pg doses as necessary. We used dual-photon absorptiometry, which employes gadolinium 153 as the isotope, to measure spine density and total body calcium. Measurement of total body calcium is more precise (coefficient of variation [CV], approximately 1%) than spine density (CV, approximately 3%). Pretreatment comparison of the placebo and 1,25-(OH),D, groups showed that both were similar with regard to age (70.5 v 69.1, respectively), years since menopause (23 v 23), weight, total body calcium (650 g v 680 g), and spine density (0.89 v 0.86 g/cm’). It should be noted that all patients had developed spinal osteoporosis with associated fractures several years before entering the study; thus, the average at which patients presented with their first fracture was approximately 62 or 63 years, which is characteristic of type I osteoporosis. RESULTS
Effects of Dosage Adjustments on Urine/Serum Calcium
The action of 1,25-(OH),D, occurs initially on calcium absorption and 24-hour urine calcium excretion. As the dose of 1,25-(OH),D, is increased from 0.5 Mg/d to 0.75 pug/d, to 1.Opg/d and, occasionally, 2.0 rg/d, there is a corresponding sharp increase in 24-hour urine calcium (Fig 1). However, the amount of calcium absorbed depends not only on the Rocaltrolg dose, but also the calcium intake. Reducing the daily calcium intake from 1,000 mg to 600 mg results in a lower 24-hour urine calcium excretion as shown in Fig 1. It should be noted that the slope of mean 24-hour urine calcium/calcium intake on dose shifts to the right. Thus, reducing the calcium intake allows the use of a larger dose of Rocaltrol@. The optimal long-term maintenance dose of 1,25-(OH),D, was established after eight to 10 weeks, and the 24-hour urine calcium remained fairly constant throughout the remainder of the study period. From the Bone Metabolism Unit, Creighton University Medical Center, Saint Joseph’s Hospital, Omaha, NE. Address reprint requests to J.C. Gallagher, MD, Bone Metabolism Unit, Creighton University Medical Center, Saint Joseph’s Hospital, 601 N 30th St, Omaha, NE 68131. a 1990 by W.B. Saunders Company. 0026-0495/90/3904-1006%3.00/O 27
J.C. GALLAGHER
28
l 0
greater than 10.5 mg/mL were observed after reaching the maintenance dose in week 10. Hypercalcemia usually occurred on doses greater than 0.75 Mg/d, and urine calcium exceeded 300 mg/24 hours in approximately 50% of cases during maintenance therapy, but did not exceed 350 mg/24 hours; this nearly always could be explained by some variation in calcium intake. Moderate hypercalcemia during the dose titration phase was associated with a temporary increase in serum creatinine, but there were no long-term significant differences in serum creatinine or creatinine
1000 mg Ca. Intake 600 mg Ca. Intake
260 220
.25
50
.75
1.0
1.25
12c
Dose1,2W-W3 W
Alkaline Phosphatase Fig 1. Mean 24-hour urine calcium excretion on a l.DW mg calcium intake (0) and mean 24-hour urine calcium excretion on 600 mg calcium intake (0) on different doses of ltS(OHI,D,. Reducing the calcium intake allows the use of a larger dose of 1.25(OH),D,.
As the patients became hypercalcemic, they also developed a slight increase in serum creatinine. After establishment of the long-term maintenance dose of 1,25-(OH&D,, which averaged 0.67 pg/d in this study, the serum calcium remained fairly constant, and the serum creatinine also returned to normal and remained constant. During the initial hypercalcemic phase, the 24-hour urine hydroxyproline excretion (OHPr/Cr)-a parameter that measures bone resorption-decreased significantly in the patients receiving 1,25-(OH),D, (Fig 2). Also, there was a concomitant reduction in serum alkaline phosphatase. These observations suggest that the mechanism of hypercalcemia involves increased calcium absorption and not increased bone resorption. As the dose of 1,25-(OH),D, was reduced, serum calcium returned to normal and parameters of bone turnover returned to pretreatment levels.
11c
1oc -I zi s
60
70
60
2
6
3
9
12
Months 120
Urine OHPr/Cr
110
Effects on Creatinine Clearance
Because the dose of 1,25-(OH),D, was increased to the point of toxicity, creatinine clearance was measured in each patient on multiple occasions, weekly for the first 12 weeks and then monthly for the remainder of the study period. There was a transient decrease in creatinine clearance during the initial period of hypercalcemia, but subsequently it returned to baseline (Fig 3). No significant difference between placebo and 1,25-(OH),D, was observed in creatinine clearance or serum creatinine.
90
100 i
m \o 0
90
a0
DISCUSSION 70
bone loss occurred in the placebo group, despite the fact that the calcium intake was increased from a mean baseline of approximately 700 mg/d to 1,000 mg/d. In contrast, there has been no significant bone loss in patients treated with 1,25-(OH),D,. On a calcium intake of 600 mg/d, the long-term maintenance dose of 1,25-(OH),D, averaged 0.675 Fg/d, and long-term therapy on this dosage was not associated with toxicity. No serum calcium values Significant
6t
I
I
I
0
2
3
I
I
6
I
I
9
I
I
12
Months Fig 2. During the dose titration with 1,26(OH),D,. hypercalcemia in months 2 to 3 was accompanied by a reduction in bone turnover. (0). placebo; IO), 1,26(OH),D,.
CALCITRIOL
FOR POSTMENOPAUSAL
29
OSTEOPOROSIS
80 i a $? 70 -
I
I
I
I
I
I
I
I
I
8
123456
I
)
12
Months Fig 3. Twenty-four-hour urine creatinine clearance (mL/minI on 1.26(OH),O, (0) or placebo (0). During the titration phase in months 2 and 3 hypercalcemia was accompanied by a transient decrease in creatinine clearance, which later returned to normal.
clearance. Provided the 24-hour urine calcium is kept below 300 to 320 mg, there appears to be no evidence yet of long-term nephrotoxicity. It should be noted that the “window of efficacy” for 1,25-(OH),D, in terms of dose is quite narrow on a free
calcium intake. In earlier studies, we found that administration of doses of 0.25 to 0.40 fig/d in some osteoporotic patients did not always increase calcium absorption and urine calcium excretion.’ At 0.5 pg/d, there is a 100% response, and at 0.75 Fg/d there is a “hyperresponse,” with associated toxicity in 30% of patients. In an earlier pilot study where the calcium intake was restricted to less than 500 mg/d, we assessed the effect of 2.0 Mg/d of 1,25-(OH),D, on bone in a group of eight patients.6 The increases observed in serum calcium, urinary calcium, and PTH were all within the normal range. In addition, there was a significant increase in levels of serum osteocalcin at this high dose. Bone biopsies showed that bone formation rates, calculated from double-tetracycline labeling, increased substantially in these patients at 6 weeks. At 6 months, after the patients had been crossed-over to a calcium supplement of 1,500 mg/d there was a decrease in bone formation. These results suggest that a higher dose of 1,25-(OH),D, is more effective in stimulating bone formation. The latter may be an important end point in treatment. Other studies using synthetic calcitriol (Rocaltrola) in study designs similar to the present one have shown different results. In a study by Aloia et al,’ significant increases in total body calcium and spine density were observed on an average daily dose of 0.8 bg of Rocaltrol”. On the other hand, Ott and Chestnut,8 using a lower average daily dose of 0.4 pg, observed no increase in bone density; however, neither did they see a decrease in bone density. Japanese studies of other analogues of vitamin D such as la(OH)D, have shown significant increases in bone density and decreases in fracture rates.‘.”
REFERENCES
1. Albright F: Osteoporosis. Ann Intern Med 27:861-882, 1947 2. Riggs BL, Melton LJ: Evidence for two distinct syndromes involutional osteoporosis. Am J Med 75899-901, 1983 3. Gallagher JC, Riggs BL, Jerpbak CM, et al: The effect of age on serum immunoreactive parathyroid hormone in normal and osteoporotic women. J Lab Clin Med 95:373-385, 1980 4. Gallagher JC, Riggs BL, Eisman J, et al: Intestinal calcium absorption and serum vitamin D metabolites in normal and osteoporotic patients. Effect of age and dietary calcium. J Clin Invest 64729-736, 1979 5. Gallagher JC, Riggs BL, Deluca HF: Effects of calcitriol in osteoporosis in DeLuca HF, Parfitt AM, Jee C, et al (eds): Recent Advances in Osteoporosis. Baltimore, MD, University Park, 1981, pp 215-224 6. Gallagher JC, Reeker R: A comparison between high dose
calcitriol and calcium supplements in osteoporosis, in Norman AW, Schaefer K, Grigoleit HG, et al (eds): Vitamin D, Chemical, Biochemical and Clinical Update. Berlin, 1985 7. Aloia JF, Vaswani A, Yeh J, et al: Calcitriol in the treatment of postmenopausal osteoporosis. Am J Med 84:401-408,1988 8. Ott SM, Chestnut CH: Calcitriol treatment is not effective in postmenopausal osteoporosis. Ann Intern Med:267-274, 1989 9. Shiraki M, Orimo H, Ito H, et al: Long-term treatment of postmenopausal osteoporosis with active vitamin D, l-alphahydroxycholecalciferol and 1, 24-dihydroxycholecalciferol. Endocrinol Jpn 32:305-3 15, 1985 10. Orimo H, Shiraki M, Hayashi R, et al: Reduced occurrence of vertebral crush fractures in senile osteoporosis treated with 1 alpha(vitamin D,. Bone Min 3:47-52, 1987
