Long-Term Treatment With Calcitriol A. Caniggia,
in Postmenopausal
R. Nuti, F. Lore, G. Martini,
V. Turchetti,
Osteoporosis
and G. Righi
In order to assess the long-term effects of calcitriol treatment in postmenopausal osteoporotic patients, 1.0 Mg/d of calcitriol was administered in two divided doses for 1 to 8 years to 270 women with symptomatic, histologically proven postmenopausal osteoporosis. No calcium supplementation was given. Clinically, the treatment resulted in substantial relief from pain, with improvement of ambulancy. Intestinal calcium absorption, which was lower than normal at baseline, increased significantly and remained higher than the baseline value as long as calcitriol wes administered. Urinary calcium absorption also increased, but hypercalcemia occurred, exceptionally and transiently, in only a few patients. Urinary hydroxyproline excretion did not increase, indicating that hypercalciuria was not of resorptive origin. Total-body density, determined by dual-photon total-body absorptiometry in 56 patients, showed an increase after 18 to 24 months of therapy in most cases. The occurrence of nontraumatic, clinically relevant fractures decreased noticeably as compared with the period preceding calcitriol treatment. No change occurred in renal function, and no renal stones developed. Celcitriol was an effective and safe treatment of postmenopausal osteoporosis. 0 1990 by W. B. Saunders Company.
0
STEOPOROSIS is defined as a decrease in bone mass below the level required for the mechanical function of the skeleton, with normal mineralization of the remaining bone. It occurs most commonly in primary form, particularly in postmenopausal women. Its main clinical features are bone pain, dorsal kyphosis, and nontraumatic fractures. In the last few decades, postmenopausal osteoporosis has emerged as an increasing medical and social problem. As the life expectancy of women in Western countries is continuing to lengthen, most can expect to spend a third of their lives after menopause. The prevalence of osteoporosis, with consequent fractures related to bone thinning, has increased along with the rise in the aged population. Despite the considerable attention that osteoporosis is currently receiving from medical researchers, disagreement remains as to the pathogenesis of the disease. Nonetheless, it is unreservedly accepted that osteoporosis must be due to an imbalance between the rates of bone formation and resorption and that this imbalance is associated with a negative calcium balance occurring as a consequence of postmenopausal estrogen deficiency. The calcium deficiency model of osteoporosis remains the most credible explanatory model, and, in our view, the main determinant of calcium deficiency is malabsorption of this mineral.’ An impressive number of treatments have been proposed for postmenopausal osteoporosis, and this, in itself, is an indication that no single treatment is entirely satisfactory. We believe that, in this context, too little attention has been paid to the potential therapeutic role of 1,25dihydroxyvitamin D, (1,25-(OH),D,), despite the fact that some convincing findings suggest a primary role for this vitamin D metabolite in the pathophysiology of postmenopausal osteoporosis. In this regard, it has been established that 1,25-(OH&D is the main or possibly sole determinant of intestinal calcium transport2; that synthesis of 1,25-(OH),D is stimulated by estrogens3-‘; and that its serum concentrations are reduced in postmenopausal osteoporotic women.6-9 Ten years ago, we began a long-term study of the effects of 1,25-(OH),D, (calcitriol) treatment at physiological doses, without calcium supplementation, in women with postmenopausal osteoporosis. Such an approach was based on encouraging results obtained in short-term studies,” as well as on the pathophysiological hypothesis that negative calcium Merabolism,Vol39,
No 4. Suppl 1 (April), 1990: pp 43-49
balance in postmenopausal osteoporosis is due to impairment of intestinal calcium transport resulting from reduced 1,25(OH),D synthesis associated with impaired activity of renal 250HD-la-hydroxylase no longer stimulated by estrogens. Positive results obtained in previous studies”*‘2 led us to proceed with this kind of therapy. At the present time, we have by far the largest experience with calcitriol therapy in the world, in terms of both the number of patients treated and the duration of treatment, It may be. noted that the trial reported herein was not designed as a placebo-controlled study because we considered it unethical to deprive a group of patients for a long period without a potentially effective treatment. MATERIALS AND METHODS
Entered into this study were 270 women with symptomatic postmenopausal osteoporosis, age 49 to 78 years (mean age, 63 years). A rigid selection of cases was performed. Inclusion Criteria Criteria for admission were back pain and difficulty in walking; a radiographic finding of vertebral translucency with one or more nontraumatic vertebral fractures; decreased bone mineral density in comparison with age-matched nonosteoporotic women; a typical histologic pattern of osteoporosis as determined by microscopic inspection biopsy specimens of undecalcified bone from the iliac crest; impaired intestinal radiocalcium transport; normal renal function; normal values of serum calcium, phosphate, and alkaline phosphatase, and normal 24-hour urinary calcium, phosphate, and hydroxyproline excretion. Exclusion Criteria Criteria for exclusion consisted of renal disease; heart failure or major respiratory insufficiency; endocrine disease; disease of the alimentary tract, liver, or biliary ducts; osteomalacia or mixed osteoporosis-osteomalacia (ruled out by iliac crest biopsy); primary
From the Institute of Clinical Medicine, University of Siena, Italy. Address reprint requests to Professor Angelo Caniggia, Clinica Medica Universita di Siena, Piazzetta della Selva 7, 53100 Siena, Italy. @ 1990 by W.B. Saunders Company. 0026-0495/90/3904-1002$3.00/O 43
44
or secondary neoplastic bone disease; spondyloarthritis; and longterm treatment with glucoactive corticosteroids, anticonvulsants, or heparin. Dosage and Duration Patients were administered calcitriol at an oral dose of 0.5 rg twice a day without calcium supplementation, and at no time was treatment discontinued. No other drug was given (including analgesics). The patients were allowed to continue their usual diet. The estimated intake of calcium and vitamin D was 580 f 120 Mgand 0.5 + 0.2 peg, respectively. All 270 patients in this study were treated for at least 1 year, 181 for at least 2 years, 117 for 3 years, 70 for 4 years, 42 for 5 years, 24 for 6 years, 13 for 7 years, and four for 8 years. Chemistries Blood samples and 24-hour urine were collected for the determination of the following parameters: plasma and urinary calcium (atomic absorption spectrophotometry; Perkin-Elmer model 2280, Norwalk, CT); and serum and urinary phophate, serum alkaline phosphatase, and urinary hydroxyproline (standard methods). To assess renal function, urinalysis, blood urea nitrogen (BUN), serum creatinine, and 24-hour creatinine clearance were performed by standard methods. Fractional radiocalcium absorption was measured as follows: 10 &I of radiocalcium was administered orally in 80 mg of CaCl, used as a nonradioactive carrier; and plasma radioactivity was assessed for 4 hours, with the circulating fraction of the dose (fx) calculated according to the method of Marshall and Nordin.” Normal range in our laboratory is 0.170 to 0.270. The urine cAMP/creatinine ratio was determined as a parathyroid function index (Radiochemical Centre, Amersham, UK). The aforementioned parameters were usually determined before treatment, every other month during the first year of therapy, and every 4 to 6 months thereafter. A control group of 103 healthy age-matched women was used for comparisons concerning the baseline values of the above parameters. Skeletal Assessments Serum osteocalcin was evaluated in 72 patients before and after 1 year of calcitriol treatment and in 32 age-matched control women, using an assay kit (ImmunoNuclear, Stillwater, MN). Single-photon absorptiometry (241Am source) was used at the beginning of the study to evaluate the bone mineral content at the distal forearm. The results obtained with this technique have been published elsewhere.14 In the last 2 years, bone mineral density of the entire skeleton was measured by dual-photon absorptiometry (Lunar DP4, Madison, WI). The presence of two separate photon energies from 153 Gd (peaks at 44 and 100 KeV) avoids the need for a uniform soft tissue thickness surrounding the bone. This technique, which is completely devoid of repositioning problems, enabled us to measure bone density and bone mineral content of the whole skeleton. The variation coefficient for total-body density estimated in our department in 25 patients was found to be as low as 0.66%.15 Total-body density was measured after 12 months of calcitriol treatment in 31 patients, after 18 months in 17 patients, and after 24 months in eight patients. Total-body density was also assessed before and after a l-year period in a control group of seven untreated postmenopausal ostcoporotic women (age 55 to 68 years). X-ray films of the spine and abdomen were obtained yearly for detection of new fractures and renal stones.
CANIGGIA
ET AL
The rate of fracture occurrence during calcitriol treatment was compared with that of the period between menopause and the initiation of calcitriol therapy and was expressed as the number of fractures per 100 patients per year. Only vertebral collapses easily distinguishable on x-ray film (and generally accompanied by sudden acute pain) were considered. Statistical Analyses Statistical analyses were based on the determination of probability density functions,16 according to the equation: fx =
1
- 1 (x - u2)
&YzY
262
The significance of differences and paired Student’s t tests.
.
was evaluated
by ANOVA
RESULTS
Before the start of treatment, intestinal radiocalcium absorption, expressed as fractional calcium absorption (fx) values, was significantly lower than the normal range (fx = 0.128 f 0.02). Within 2 months, calcitriol treatment promoted a significant increase in fractional calcium absorption (fx), as indicated by the changes in mean values and probability density functions (Fig 1). The normalization of intestinal calcium transport persisted throughout the treatment (for 1 to 7 years or more), as long as calcitriol was administered (Fig 2). Fasting plasma calcium did not differ from normal controls in basal conditions. During the study, the mean values averaged slightly higher (Fig 2); differences were statistically significant only during the first years of treatment (Table 1). Hypercalcemia was observed exceptionally (14 cases) and transiently; however, in no patient did treatment need to be discontinued. The 24-hour urinary calcium excretion showed baseline levels lower in osteoporotic women (152 mg/24 h + 68) than in controls (187 mg/24 h -c 90). Within 2 months, calcitriol promoted a significant increase in urinary calcium (Fig 1); hypercalciuria was constantly present throughout the treatment (Fig 2, Table 1). At baseline, no significant correlation was found between fractional calcium absorption and urinary calcium excretion (r = .05, NS). Calcitriol treatment promoted a statistically significant correlation between these two parameters as long as the study was continued (eg, after 2 years r = .308, P < .OOl). A similar correlation, though of lower statistical significance, was observed between fasting plasma calcium and urinary calcium. The 24-hour urinary hydroxyproline excretion at baseline did not differ from that of controls and did not change significantly during long-term calcitriol treatment (Table 1), whereas the ratio of calcium/hydroxyproline in urine increased substantially (Fig 2). A statistically significant correlation was found between 24-hour urinary calcium and 24-hour urinary hydroxyproline at baseline (r = .246; P < .OOl); during calcitriol treatment these two parameters were no longer correlated (Fig 2). Plasma phosphate showed only slight changes during
LONG-TERM CALCITRIOL TREATMENT
45
0.3
f-
___________ --_ ___-________ 0.2 __-_- _ ____ _-_ _______-____ x It. i-t0.1
0
2
4
6
6
10
12
0.07
0.27
MONTHS
0.47
FX
500
400
Changes in intestinal Fig 1. radiocalcium absorption (FX) (P < .flDll and 24-hour urinary calcium excretion ICau) If < .DDl) during the first yeer of cakitriol treatment expressed as mean f SD (left) and probebility density function6 fright). ----, Barral vaiues: -, 2- to 12-month treatment values.
calcitriol excretion Before averaged matched
f Y P :”
300 I 200 1
L
100
0
tl-
L 0
2
4
6
MONTHS
treatment, whereas the 24-hour urinary phosphate increased significantly (Table 1). the initiation of treatment, serum osteocalcin levels lower in our subjects than in a group of agenonosteoporotic women (3.8 ng/mL * 1.1 and 6.8
6
10
12
-4
-1
2
Cm
5
6
11 (X 1001
mg/24h
ng/mL * 2.0, respectively, P < .Ol). One year of calcitriol therapy promoted a significant increase (4.5 ng/mL + 1.4, P < .OOl). No changes in renal function occurred during long-term
calcitriol treatment, as demonstrated
by the normal values
Fig 2. Changes in intestinal radiocalcium absorption (FX) (P < CD1 1, plarma calcium (Cal (P < .Ol). 24-hour urinary calcium (Cau) (P-c .oOlL and 24 hour urinary cakiumlhydroxproIke ratio fCa/HOPl (P < .DDl). expressed as probability den&y functions before and during oaloitriol treatment. ----, Basal values: -, l- to &year treatment values.
CANIGGIA ET AL
46
Table 1. Metabolic
fx Ca
(mg/d)
24-hcwCau
Img)
Pbw/b) 24-howPuImg~
Parameters
of Bone Metabolism
Before and During Calcitriol Treatment
Basal (II = 270)
In = 270)
In - 161)
7-w
3n In = 1171
4v In = 70)
5v In = 42)
6yr In - 24)
7w In = 13)
Byr In = 4)
0.126 f 0.028
0.206 * 0.053t
0.215 * 0.053t
0.214 t O.OSlt
0.218 f O.OSOt
0.203 r 0.043t
0.200 + 0.046t
0.199 * 0.03lt
0.219 * 0.026*
9.6 * 0.6
9.6 * 0.q
9.8 + 0.6t
9.7 * 0.q
9.7 * 0.4'
9.8 * 0.5
9.6 f 0.6
9.9 zt0.6
9.8 * 0.1
316 f 131t
336 f 14Ot
314 * 133t
319 * 122t
309 * 124t
304 * 131t
311 * 153t
330 * 489
1Yr
152 +66 3.7 * 0.6
3.6 * 0.5
3.7 * 0.5
3.7 * 0.5
3.7 * 0.5
3.7 * 0.4
3.7 * 0.7
669 i 212
793 * 245t
626 * 292t
803 * 257t
854 * 264t
682 * 326t
662 * 350t
24-hourHOP lmg)
26 f 12
25 * 13
26i14
CAMPICI
3.2 f 1.3
2.9 * 1.3
2.9 * 1.3.
25*11 3.2 * 1.5
26 A 14 2.7 * 1.2
29*13 2.8 * 1.4
29*14 3.1 * 1.4
3.9 zt0.6 l.C",Z+436 30*13 3.2 * 1.9
3.7 t 0.5 683 t234 31 * 13 3.5 * 1.5
Abtmviations:lx.. radiocalcium sbsaptim:Ca,pbmscakium: Cm, urinary calcium: P,plasma phawhate:Pu.winmy phosphate; HOP, hydroxpdine;Cr. ueatinine. lf< .05. tP
in Postmenopausal
R. Nuti, F. Lore, G. Martini,
V. Turchetti,
Osteoporosis
and G. Righi
In order to assess the long-term effects of calcitriol treatment in postmenopausal osteoporotic patients, 1.0 Mg/d of calcitriol was administered in two divided doses for 1 to 8 years to 270 women with symptomatic, histologically proven postmenopausal osteoporosis. No calcium supplementation was given. Clinically, the treatment resulted in substantial relief from pain, with improvement of ambulancy. Intestinal calcium absorption, which was lower than normal at baseline, increased significantly and remained higher than the baseline value as long as calcitriol wes administered. Urinary calcium absorption also increased, but hypercalcemia occurred, exceptionally and transiently, in only a few patients. Urinary hydroxyproline excretion did not increase, indicating that hypercalciuria was not of resorptive origin. Total-body density, determined by dual-photon total-body absorptiometry in 56 patients, showed an increase after 18 to 24 months of therapy in most cases. The occurrence of nontraumatic, clinically relevant fractures decreased noticeably as compared with the period preceding calcitriol treatment. No change occurred in renal function, and no renal stones developed. Celcitriol was an effective and safe treatment of postmenopausal osteoporosis. 0 1990 by W. B. Saunders Company.
0
STEOPOROSIS is defined as a decrease in bone mass below the level required for the mechanical function of the skeleton, with normal mineralization of the remaining bone. It occurs most commonly in primary form, particularly in postmenopausal women. Its main clinical features are bone pain, dorsal kyphosis, and nontraumatic fractures. In the last few decades, postmenopausal osteoporosis has emerged as an increasing medical and social problem. As the life expectancy of women in Western countries is continuing to lengthen, most can expect to spend a third of their lives after menopause. The prevalence of osteoporosis, with consequent fractures related to bone thinning, has increased along with the rise in the aged population. Despite the considerable attention that osteoporosis is currently receiving from medical researchers, disagreement remains as to the pathogenesis of the disease. Nonetheless, it is unreservedly accepted that osteoporosis must be due to an imbalance between the rates of bone formation and resorption and that this imbalance is associated with a negative calcium balance occurring as a consequence of postmenopausal estrogen deficiency. The calcium deficiency model of osteoporosis remains the most credible explanatory model, and, in our view, the main determinant of calcium deficiency is malabsorption of this mineral.’ An impressive number of treatments have been proposed for postmenopausal osteoporosis, and this, in itself, is an indication that no single treatment is entirely satisfactory. We believe that, in this context, too little attention has been paid to the potential therapeutic role of 1,25dihydroxyvitamin D, (1,25-(OH),D,), despite the fact that some convincing findings suggest a primary role for this vitamin D metabolite in the pathophysiology of postmenopausal osteoporosis. In this regard, it has been established that 1,25-(OH&D is the main or possibly sole determinant of intestinal calcium transport2; that synthesis of 1,25-(OH),D is stimulated by estrogens3-‘; and that its serum concentrations are reduced in postmenopausal osteoporotic women.6-9 Ten years ago, we began a long-term study of the effects of 1,25-(OH),D, (calcitriol) treatment at physiological doses, without calcium supplementation, in women with postmenopausal osteoporosis. Such an approach was based on encouraging results obtained in short-term studies,” as well as on the pathophysiological hypothesis that negative calcium Merabolism,Vol39,
No 4. Suppl 1 (April), 1990: pp 43-49
balance in postmenopausal osteoporosis is due to impairment of intestinal calcium transport resulting from reduced 1,25(OH),D synthesis associated with impaired activity of renal 250HD-la-hydroxylase no longer stimulated by estrogens. Positive results obtained in previous studies”*‘2 led us to proceed with this kind of therapy. At the present time, we have by far the largest experience with calcitriol therapy in the world, in terms of both the number of patients treated and the duration of treatment, It may be. noted that the trial reported herein was not designed as a placebo-controlled study because we considered it unethical to deprive a group of patients for a long period without a potentially effective treatment. MATERIALS AND METHODS
Entered into this study were 270 women with symptomatic postmenopausal osteoporosis, age 49 to 78 years (mean age, 63 years). A rigid selection of cases was performed. Inclusion Criteria Criteria for admission were back pain and difficulty in walking; a radiographic finding of vertebral translucency with one or more nontraumatic vertebral fractures; decreased bone mineral density in comparison with age-matched nonosteoporotic women; a typical histologic pattern of osteoporosis as determined by microscopic inspection biopsy specimens of undecalcified bone from the iliac crest; impaired intestinal radiocalcium transport; normal renal function; normal values of serum calcium, phosphate, and alkaline phosphatase, and normal 24-hour urinary calcium, phosphate, and hydroxyproline excretion. Exclusion Criteria Criteria for exclusion consisted of renal disease; heart failure or major respiratory insufficiency; endocrine disease; disease of the alimentary tract, liver, or biliary ducts; osteomalacia or mixed osteoporosis-osteomalacia (ruled out by iliac crest biopsy); primary
From the Institute of Clinical Medicine, University of Siena, Italy. Address reprint requests to Professor Angelo Caniggia, Clinica Medica Universita di Siena, Piazzetta della Selva 7, 53100 Siena, Italy. @ 1990 by W.B. Saunders Company. 0026-0495/90/3904-1002$3.00/O 43
44
or secondary neoplastic bone disease; spondyloarthritis; and longterm treatment with glucoactive corticosteroids, anticonvulsants, or heparin. Dosage and Duration Patients were administered calcitriol at an oral dose of 0.5 rg twice a day without calcium supplementation, and at no time was treatment discontinued. No other drug was given (including analgesics). The patients were allowed to continue their usual diet. The estimated intake of calcium and vitamin D was 580 f 120 Mgand 0.5 + 0.2 peg, respectively. All 270 patients in this study were treated for at least 1 year, 181 for at least 2 years, 117 for 3 years, 70 for 4 years, 42 for 5 years, 24 for 6 years, 13 for 7 years, and four for 8 years. Chemistries Blood samples and 24-hour urine were collected for the determination of the following parameters: plasma and urinary calcium (atomic absorption spectrophotometry; Perkin-Elmer model 2280, Norwalk, CT); and serum and urinary phophate, serum alkaline phosphatase, and urinary hydroxyproline (standard methods). To assess renal function, urinalysis, blood urea nitrogen (BUN), serum creatinine, and 24-hour creatinine clearance were performed by standard methods. Fractional radiocalcium absorption was measured as follows: 10 &I of radiocalcium was administered orally in 80 mg of CaCl, used as a nonradioactive carrier; and plasma radioactivity was assessed for 4 hours, with the circulating fraction of the dose (fx) calculated according to the method of Marshall and Nordin.” Normal range in our laboratory is 0.170 to 0.270. The urine cAMP/creatinine ratio was determined as a parathyroid function index (Radiochemical Centre, Amersham, UK). The aforementioned parameters were usually determined before treatment, every other month during the first year of therapy, and every 4 to 6 months thereafter. A control group of 103 healthy age-matched women was used for comparisons concerning the baseline values of the above parameters. Skeletal Assessments Serum osteocalcin was evaluated in 72 patients before and after 1 year of calcitriol treatment and in 32 age-matched control women, using an assay kit (ImmunoNuclear, Stillwater, MN). Single-photon absorptiometry (241Am source) was used at the beginning of the study to evaluate the bone mineral content at the distal forearm. The results obtained with this technique have been published elsewhere.14 In the last 2 years, bone mineral density of the entire skeleton was measured by dual-photon absorptiometry (Lunar DP4, Madison, WI). The presence of two separate photon energies from 153 Gd (peaks at 44 and 100 KeV) avoids the need for a uniform soft tissue thickness surrounding the bone. This technique, which is completely devoid of repositioning problems, enabled us to measure bone density and bone mineral content of the whole skeleton. The variation coefficient for total-body density estimated in our department in 25 patients was found to be as low as 0.66%.15 Total-body density was measured after 12 months of calcitriol treatment in 31 patients, after 18 months in 17 patients, and after 24 months in eight patients. Total-body density was also assessed before and after a l-year period in a control group of seven untreated postmenopausal ostcoporotic women (age 55 to 68 years). X-ray films of the spine and abdomen were obtained yearly for detection of new fractures and renal stones.
CANIGGIA
ET AL
The rate of fracture occurrence during calcitriol treatment was compared with that of the period between menopause and the initiation of calcitriol therapy and was expressed as the number of fractures per 100 patients per year. Only vertebral collapses easily distinguishable on x-ray film (and generally accompanied by sudden acute pain) were considered. Statistical Analyses Statistical analyses were based on the determination of probability density functions,16 according to the equation: fx =
1
- 1 (x - u2)
&YzY
262
The significance of differences and paired Student’s t tests.
.
was evaluated
by ANOVA
RESULTS
Before the start of treatment, intestinal radiocalcium absorption, expressed as fractional calcium absorption (fx) values, was significantly lower than the normal range (fx = 0.128 f 0.02). Within 2 months, calcitriol treatment promoted a significant increase in fractional calcium absorption (fx), as indicated by the changes in mean values and probability density functions (Fig 1). The normalization of intestinal calcium transport persisted throughout the treatment (for 1 to 7 years or more), as long as calcitriol was administered (Fig 2). Fasting plasma calcium did not differ from normal controls in basal conditions. During the study, the mean values averaged slightly higher (Fig 2); differences were statistically significant only during the first years of treatment (Table 1). Hypercalcemia was observed exceptionally (14 cases) and transiently; however, in no patient did treatment need to be discontinued. The 24-hour urinary calcium excretion showed baseline levels lower in osteoporotic women (152 mg/24 h + 68) than in controls (187 mg/24 h -c 90). Within 2 months, calcitriol promoted a significant increase in urinary calcium (Fig 1); hypercalciuria was constantly present throughout the treatment (Fig 2, Table 1). At baseline, no significant correlation was found between fractional calcium absorption and urinary calcium excretion (r = .05, NS). Calcitriol treatment promoted a statistically significant correlation between these two parameters as long as the study was continued (eg, after 2 years r = .308, P < .OOl). A similar correlation, though of lower statistical significance, was observed between fasting plasma calcium and urinary calcium. The 24-hour urinary hydroxyproline excretion at baseline did not differ from that of controls and did not change significantly during long-term calcitriol treatment (Table 1), whereas the ratio of calcium/hydroxyproline in urine increased substantially (Fig 2). A statistically significant correlation was found between 24-hour urinary calcium and 24-hour urinary hydroxyproline at baseline (r = .246; P < .OOl); during calcitriol treatment these two parameters were no longer correlated (Fig 2). Plasma phosphate showed only slight changes during
LONG-TERM CALCITRIOL TREATMENT
45
0.3
f-
___________ --_ ___-________ 0.2 __-_- _ ____ _-_ _______-____ x It. i-t0.1
0
2
4
6
6
10
12
0.07
0.27
MONTHS
0.47
FX
500
400
Changes in intestinal Fig 1. radiocalcium absorption (FX) (P < .flDll and 24-hour urinary calcium excretion ICau) If < .DDl) during the first yeer of cakitriol treatment expressed as mean f SD (left) and probebility density function6 fright). ----, Barral vaiues: -, 2- to 12-month treatment values.
calcitriol excretion Before averaged matched
f Y P :”
300 I 200 1
L
100
0
tl-
L 0
2
4
6
MONTHS
treatment, whereas the 24-hour urinary phosphate increased significantly (Table 1). the initiation of treatment, serum osteocalcin levels lower in our subjects than in a group of agenonosteoporotic women (3.8 ng/mL * 1.1 and 6.8
6
10
12
-4
-1
2
Cm
5
6
11 (X 1001
mg/24h
ng/mL * 2.0, respectively, P < .Ol). One year of calcitriol therapy promoted a significant increase (4.5 ng/mL + 1.4, P < .OOl). No changes in renal function occurred during long-term
calcitriol treatment, as demonstrated
by the normal values
Fig 2. Changes in intestinal radiocalcium absorption (FX) (P < CD1 1, plarma calcium (Cal (P < .Ol). 24-hour urinary calcium (Cau) (P-c .oOlL and 24 hour urinary cakiumlhydroxproIke ratio fCa/HOPl (P < .DDl). expressed as probability den&y functions before and during oaloitriol treatment. ----, Basal values: -, l- to &year treatment values.
CANIGGIA ET AL
46
Table 1. Metabolic
fx Ca
(mg/d)
24-hcwCau
Img)
Pbw/b) 24-howPuImg~
Parameters
of Bone Metabolism
Before and During Calcitriol Treatment
Basal (II = 270)
In = 270)
In - 161)
7-w
3n In = 1171
4v In = 70)
5v In = 42)
6yr In - 24)
7w In = 13)
Byr In = 4)
0.126 f 0.028
0.206 * 0.053t
0.215 * 0.053t
0.214 t O.OSlt
0.218 f O.OSOt
0.203 r 0.043t
0.200 + 0.046t
0.199 * 0.03lt
0.219 * 0.026*
9.6 * 0.6
9.6 * 0.q
9.8 + 0.6t
9.7 * 0.q
9.7 * 0.4'
9.8 * 0.5
9.6 f 0.6
9.9 zt0.6
9.8 * 0.1
316 f 131t
336 f 14Ot
314 * 133t
319 * 122t
309 * 124t
304 * 131t
311 * 153t
330 * 489
1Yr
152 +66 3.7 * 0.6
3.6 * 0.5
3.7 * 0.5
3.7 * 0.5
3.7 * 0.5
3.7 * 0.4
3.7 * 0.7
669 i 212
793 * 245t
626 * 292t
803 * 257t
854 * 264t
682 * 326t
662 * 350t
24-hourHOP lmg)
26 f 12
25 * 13
26i14
CAMPICI
3.2 f 1.3
2.9 * 1.3
2.9 * 1.3.
25*11 3.2 * 1.5
26 A 14 2.7 * 1.2
29*13 2.8 * 1.4
29*14 3.1 * 1.4
3.9 zt0.6 l.C",Z+436 30*13 3.2 * 1.9
3.7 t 0.5 683 t234 31 * 13 3.5 * 1.5
Abtmviations:lx.. radiocalcium sbsaptim:Ca,pbmscakium: Cm, urinary calcium: P,plasma phawhate:Pu.winmy phosphate; HOP, hydroxpdine;Cr. ueatinine. lf< .05. tP
