0021-972X/91/7304-1111$03.00/0 Journal of Clinical Endocrinology and Metabolism Copyright© 1991 by The Endocrine Society
Vol. 73, No. 5 Printed in U.S.A.
1,25-Dihydroxyvitamin D 3 and Muscle Strength in the Elderly: A Randomized Controlled Trial* DEBORAH GRADY, BERNARD HALLORAN, STEVE CUMMINGS, SUZANNE LEVEILLE, LAUREN WELLS, DENNIS BLACK, AND NANCY BYL Departments of Epidemiology (D.G., S.C., D.B.) and Medicine (D.G., B.H., S.C., N.B.), Veterans Administration Medical Center, University of California School of Medicine (D.G., B.H., S.L., L. W.), San Francisco, California 94121
day or identical placebo for 6 months. Leg muscle strength of the quadriceps was measured with an isokinetic dynamometer. There was no difference between the two groups at 1 week, 1 month, or 6 months of treatment in any of the measures of muscle strength. We conclude that oral administration of 0.5 fig l,25-(OH)2D3/day does not improve muscle strength in older persons. Further research is needed to determine the etiology of the decline in muscle strength associated with aging. (J Clin Endocrinol Metab 73: 1111-1117, 1991)
ABSTRACT. An unexplained loss of muscle strength occurs with aging. Vitamin D deficiency can cause myopathy and administration of 1,25-dihydroxyvitamin D3 [1,25-(OH2)D3] to persons with low serum concentrations can improve strength. To test the hypothesis that the weakness associated with aging is in part due to inadequate serum concentrations of [1,25(OH2)D3], we conducted a randomized, controlled, double blinded trial in 98 men and women volunteers over 69 yr old. Treatment consisted of 0.25 ng 1,25-(OH)2D3, orally, twice per
shown to improve muscle strength measured by simple functional tests (11, 28). To test the hypothesis that the weakness associated with aging is in part due to inadequate levels of 1,25-(OH)2D3, we conducted a randomized, controlled, double blinded trial in 98 elderly subjects.
f I ^HERE is strong evidence that 1,25-dihydroxyviX tamin D3 [1,25-(OH)2D3], the most biologically active form of vitamin D, influences muscle function (114). Receptors for 1,25-(OH)2D3 have been demonstrated in cultured human muscle cells (13,14). Decreased muscle strength (usually characterized by proximal muscle atrophy and a selective loss of type II muscle fibers) is a well documented symptom of vitamin D deficiency (1-9, 12) and administration of 1,25-(OH)2D3 to patients with 1,25-(OH)2D3 deficiency restores muscle strength (6, 811). An unexplained decrease in muscle strength occurs with increasing age (15-20). Several studies indicate that the serum concentration of 1,25-(OH)2D3 also decreases with increasing age (21-24). Since production of 1,25(OH)2D3 occurs in the kidney, it has been suggested that the decrease in serum 1,25-(OH)2D3 in the elderly may be due to an age-related decline in renal function (2426). The sensitivity of target tissues to 1,25-(OH)2D3 may also decrease with increasing age (27). Treatment with 1,25-(OH)2D3 in uncontrolled studies of elderly persons without evidence of vitamin D deficiency has been
Materials and Methods
Received February 19,1991. Address all correspondence and requests for reprints to: Deborah Grady, M.D., M.P.H., Department of Epidemiology and Medicine, University of California, Veterans Administration Medical Center (111A1), 4150 Clement Street, San Francisco, California 94121. * This work was supported by Grant R01-AG-07477-02 from the NIA.
Subjects were ambulatory men and women volunteers over 69 yr old. To protect subjects with conditions thought to potentiate hypercalcemia or hypercalcuria, exclusion criteria included serum calcium levels of 2.57 mmol/L or more (>10.6 mg/dL), urinary calcium levels of 7.28 mmol/day or more (>300 mg/24 h); creatinine clearance less than 0.42 mmol/s (25 mL/ min); history of hypercalcemia, nephrolithiasis, seizure disorder, or hyperparathyroidism; treatment with calcium, vitamin D, or thiazide diuretics; and average calcium intake greater than 1000 mg/day. We also excluded subjects with any condition that would prohibit following simple instructions or performing the strength tests. The first 15 subjects enrolled were found to have an average creatinine clearance of 1.4 mmol/s (84 mL/min). Since the ability to hydroxylate 25-hydroxyvitamin D3 (25OHD3) to 1,25-(OH)2D3 parallels glomerular filtration rate (29-31), we subsequently excluded subjects with creatinine clearances above 1.33 mL/s (80 mL/min). At entry into the study, each subject completed questionnaires to ascertain demographic information, medical conditions, medications, usual physical activity (average joules expended per day in exercise), and average daily dietary calcium intake. Baseline laboratory testing included serum calcium,
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GRADY ET AL.
phosphorus, creatinine, and vitamin D metabolites [25OHD and 1,25-(OH)2D] and 24-h urinary calcium, creatinine, and creatinine clearance. Isokinetic muscle strength of the knee flexor and extensor muscles was measured using an isokinetic dynamometer (Cybex 340, Lumex Corp., Ronkonkoma, NY) by a single physical therapist who had no knowledge of the treatment status of the subjects. The isokinetic dynamometer is an electromechanical device with a lever arm containing a transducer that measures force as torque when the subject pushes or pulls on the lever arm and a goniometer that measures joint angle. With the subject seated comfortably, and the torso and thigh secured with straps, the dynamometer axis was aligned with the anatomical axis of the right knee joint and the lever arm attached to the right lower leg with a shin strap. The left knee was measured in subjects with abnormalities of the right knee. After standardized practice sessions, the subject was asked to fold the arms across the chest and maximally push and pull the leg attached to the lever arm. Peak torque in flexion and extention of the knee at joint speeds of 90, 120, and 180% (dps) was measured using a standardized protocol. We also measured total work (torque multiplied by the time during which the torque is sustained) in flexion and extension of the knee at a joint speed of 120 dps. All measurements are corrected for the effect of gravity on the leg and foot by weighing the leg, foot, and lever arm together and subtracting or adding the appropriate calculated torque at each angle of measurement. Measurements were expressed in Newton-meters (n-m) of torque. Dynomometer settings were recorded and replicated exactly during subsequent testing. The test-retest correlation coefficient for various standard loads on the Cybex 340 isokinetic dynamometer exceeds 0.99 (31, 32). Grip strength was measured in the right hand using a grip dynamometer (Smedley Grip Dynamometer, J. A. Preston, Co., Clifton, NJ). The average of two measurements of grip strength, recorded to the nearest half kilogram of force, was used for analysis. Treatment consisted of 0.25 ng 1,25-(OH)2D3 or identical placebo (provided by Hoffman-LaRoche, Nutley, NJ) taken orally twice per day at breakfast and dinner for 6 months. The amount of 1,25-(OH)2D3 in randomly selected capsules was confirmed by direct assay. Subjects were evaluated at 1, 2,4, 8, 12,18, and 24 weeks of treatment to maintain compliance and ascertain side-effects. At these visits, serum calcium and creatinine and 24-h urinary calcium, creatinine, and creatinine clearance were measured, and subjects were asked about perceived adverse effects. The number of capsules taken daily was reduced from two to one if the serum calcium exceeded 2.57 mmol/L (10.5 mg/dL), 24-h urinary calcium exceeded 7.28 mmol/day (300 mg/24 h), or corrected creatinine clearance decreased by more than 20% from baseline. Muscle strength was retested, and vitamin D metabolites were remeasured at 1, 4, and 24 weeks of treatment. Compliance with study medication was estimated with capsule counts at each follow-up visit. Calcium, phosphorus, and creatinine were measured using automated analysis. Serum 25OHD (32) and 1,25-(OH)2D (33) were measured after chromatographic purification using the method of Reinhardt et al. (33). We described the characteristics of our study population,
JCE & M • 1991 Vol73«No5
muscle strength, and serum values by calculating means and SD. The relationship of age and sex to muscle strength was assessed using separate linear models in men and women. The association of age, sex, calcium intake, creatinine clearance, and muscle strength with serum vitamin D levels was assessed using simple linear regression analyses. Statistical significance of differences between treatment groups was assessed with an unpaired t test of change in muscle strength. All analyses were performed using the Statistical Analysis System (SAS) software. Results The median age of the 98 subjects was 79.1 yr (range, 70-97 yr). All but 5 of the subjects were white. The study population included 45 men (46%) and 53 women (54%). Fifty subjects were assigned to receive 1,25-(OH)2D3, and 48 to receive placebo capsules. At baseline, there were no significant differences between the treatment groups in age, sex, body weight, muscle strength, physical activity level, daily calcium intake, serum calcium, serum phosphorus, 24-h urinary calcium, creatinine clearance, or serum vitamin D levels (Table 1). Subjects in both groups took more than 95% of the assigned medication. One subject [assigned to treatment with 1,25-(OH)2D3] died following surgery for gastric cancer during the second month of the study. A second subject (assigned to placebo) suffered a stroke during the third month of the TABLE 1. Characteristics of study subjects by treatment group Baseline characteristics Age (yr) Sex (% male) BW (kg) Muscle strength Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Hand grip (kg) Physical activity (joules/week) Calcium intake (mmol/24 h) Laboratory values Serum calcium (mmol/L) Urinary calcium (mmol/day) Serum phosphorus (mmol/L) Creatinine clearance (mL/s-1.73 m2) Serum vitamin D levels 25OHD (nmol/L) 1,25-(OH)2D (pmol/L)
1,25-(OH)2D3 (n = 50)
Placebo (n = 48)
79.4 (5.4) 53.3 (0.1) 70.1 (12.0)
78.9 (5.4) 46.7 (0.1) 71.3 (14.3)
7.6 (2.7) 7.0 (2.4) 5.5 (2.0) 50.1 (19.7)
7.5 (2.5) 7.0 (2.5) 5.5 (2.1) 50.6 (19.2)
4.0 (1.4) 4.1 (1.4) 3.4 (1.4) 27.1 (12.1) 3.2 (1.1) 7716.9 (6193.9) 14.4 (7.1)
4.1 (1.6) 4.2 (1.5) 3.4 (1.4) 27.9 (12.8) 3.0 (1.1) 8925.8 (7411.5) 14.2 (5.5)
2.3 (0.1) 2.2 (1.4) 1.0 (0.1) 1.1 (0.3)
2.3 (0.1) 2.4 (1.4) 1.1 (0.2) 1.0 (0.3)
60.4 (35.3) 85.6 (33.7)
65.7 (51.4) 83.6 (31.2)
Values given are means; the SD is in parentheses.
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1,25-(OH)2D3 AND STRENGTH
study and was unable to complete the protocol. Six subjects who were taking 1,25-(OH)2D3 required a reduction in dosage from two capsules (0.25 fig twice a day) to one capsule per day (0.25 ng daily) due to 24-h urinary calcium levels greater than 7.28 mmol/day (300 mg/24 h). Two subjects required a reduction from two capsules to one capsule per day [one taking 1,25-(OH)2D3, one taking placebo] due to reductions in creatinine clearance of more than 20% compared to baseline values. As expected, muscle strength at baseline was lower in older subjects and in women compared to men (Fig. 1). Based on simple linear regression modeling, muscle strength (peak torque in extension of the knee at a joint speed of 120 dps) declined by 1.6%/yr past age 69 yr in both men and women [0.10 ft-lb/yr of age in women (P = 0.01) and 0.17 ft-lb/yr of age in men (P = 0.003)]. Based on a multiple linear regression model including both age and sex as predictors of muscle strength (peak torque in extension of the knee at a joint speed of 120 dps), women were 38% weaker than men. Even after adjustment for body mass index (by addition of body mass index to the multiple linear regression model), women were still 36% weaker than men. Baseline mean serum 1,25-(OH)2D was 84.6 pmol/L, slightly lower than the mean of 89.7 pmol/L (37.3 pg/ mL) found in our laboratory in men and women less than 40 y old (n = 33). In the age range of our subjects, serum 1,25-(OH)2D did not decline with increasing age in men or women (Fig. 2). There were no significant differences in serum 25OHD or 1,25-(OH)2D by age, sex, daily calcium intake, or muscle strength (Table 2). Serum levels of both 25OHD and 1,25-(OH)2D decreased with decreasing creatinine clearance [P = 0.24 for 25OHD
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and P = 0.06 for 1,25-(OH)2D]. The change in muscle strength in the 1,25-(OH)2D3 and placebo groups at 1 week, 1 month, and 6 months of treatment is shown in Table 3. After 6 months of therapy, none of the measures of muscle strength in the 1,25(OH)2D3-treated subjects had improved by more than 5%, and similar changes were noted in the placebotreated subjects. There were no significant differences in any measure of change in muscle strength comparing the 1,25-(OH)2D3 and placebo-treated groups. To determine whether treatment with 1,25-(OH)2D3 improved muscle strength in certain subgroups, change in muscle strength was compared by age (70-74, 75-79, 80-84, and 85+ yr), sex, creatinine clearance (1.3 mmol/s or 80 mL/min), baseline muscle strength (leg extension peak torque at joint speed of 120 dps by quartiles), and baseline serum 1,25-(OH)2D (94 mmol/L or 40 pg/mL). There were no significant improvements in strength in any subgroup comparing the 1,25-(OH)2D3 and placebo groups (Table 4). After treatment with 1,25-(OH)2D3, serum calcium and urinary calcium were significantly increased (Table 5), demonstrating the effect of treatment with 1,25-(OH)2D3 on calcium metabolism. Serum 1,25-(OH)2D was only moderately increased after treatment. Discussion Using the isokinetic dynamometer as a very reliable measure of leg muscle strength, we found a 1.6% decline in strength per yr of age in persons over 69 yr old.
FIG. 1. Baseline muscle strength by age and sex (peak torque in leg extension at 120 dps).
9
Age (years)
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GRADY ET AL.
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JCE & M • 1991 Vol73«No5
FIG. 2. Baseline serum 1,25-(OH)2D by age and sex.
Age (years)
TABLE 2. Baseline serum 25OHD and 1,25-(OH)2D, and age, sex, calcium intake, creatinine clearance, and muscle strength Serum vitamin D
Age (yr) 70-74 75-79 80-84 85+ Sex Male Female Calcium intake (mmol/24 h) 19.4 Creatinine clearance (mL/s-1.73 m2) 1.3 Muscle strength (n-m) Leg extension Peak torque, 120 dps 5.0
25OHD (nmol/L)
1,25-(OH)2D (pmol/L)
56.4 (16.7) 69.1 (45.0) 64.3 (56.0) 49.0 (24.2)
91.2 (34.7) 87.3 (34.7) 81.5 (31.0) 76.3 (28.9)
68.7 (56.9) 58.2 (27.8)
78.2 (30.8) 90.1 (33.0)
61.2 (46.6) 64.7 (47.9) 61.4 (27.9)
89.8 (32.1) 81.7 (34.1) 88.0 (28.4)
51.4 (21.6) 65.2 (51.1) 68.4 (24.4)
69.5 (25.1) 86.7 (34.6) 96.5 (23.2)
60.6 (32.0) 72.0 (48.2) 49.1 (18.7) 71.8 (62.2)
82.7 (27.4) 86.1 (32.5) 83.8 (30.3) 85.9 (39.9)
51.8 (24.0) 59.1 (22.8) 76.9 (66.2) 62.5 (45.4)
79.2 (37.3) 91.3 (30.6) 87.8 (22.7) 78.2 (37.8)
Values given are means; the SD is in parentheses.
Multiple investigators have reported that elderly persons are significantly weaker than young or middle-aged persons (15-17,34), and our findings emphasize that muscle strength continues to decrease, even in the very elderly. While inactivity or chronic illness might account for some of the muscle weakness associated with aging (35, 36), longitudinal studies indicate that even healthy active elderly persons suffer an unexplained loss of muscle strength with aging. We theorized that inadequate levels of 1,25-(OH)2D in elderly persons might account for some of this loss of muscle strength. This study was designed to determine whether treatment with oral 1,25-(OH)2D3 at a dose of 0.5 ng daily would increase muscle strength in persons over 69 yr old. We found no improvement in any measure of muscle strength in the group treated with 1,25(OH)2D3 compared to the placebo-treated group. There are at least three possible explanations for our failure to show an improvement in muscle strength after treatment with 1,25-(OH)2D3. First, our study subjects were independent ambulatory elderly volunteers. While our findings are generalizable to this large elderly population, we have not shown that treatment with 1,25(OH)2D3 would be similarly ineffective in ill institutionalized elderly. Despite advanced age and diminished renal function, serum 1,25-(OH)2D in our subjects was relatively normal. Persons with 1,25-(OH)2D deficiency who develop a proximal muscle weakness generally demonstrate serum 1,25-(OH)2D levels below 12 pmol/L (5 pg/ mL). In our vitamin D-treated subjects, mean baseline serum 1,25-(OH)2D was 84.6 pmol/L (35.2 pg/mL). While this value is slightly lower than that found in our laboratory in young adults (89.7 pmol/L or 37.3 pg/mL), it is not as low as that found in older persons in several
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1,25-(OH)2D3 AND STRENGTH TABLE 3. Change in muscle strength at 1 week, 1 month, and 6 months of treatment in 1,25-(OH)2D3 and placebo groups Change in strength
1 Week Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Grip strength (kg) 1 Month Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Grip strength (kg) 6 Months Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Grip strength (kg)
1,25(OH)2D3 (n = 50)
Placebo (n = 48)
Difference"
P»
0.06 (1.2) -0.01 (0.8) -0.03 (0.7) 0.38 (6.7)
0.20 (1.1) 0.08 (0.7) -0.05 (0.6) 1.1 (6.5)
-0.14 -0.09 0.02 -0.72
0.55 0.58 0.93 0.59
0.40 (0.6) 0.10 (0.6) 0.13 (0.8) 0.55 (4.4)
0.47 (0.5) 0.22 (0.5) 0.31 (0.6) 1.19 (3.9)
-0.07 -0.12 -0.18 -0.64
0.550.30 0.23 0.45
0.37 (1.1) 0.26 (0.9) 0.12 (0.8) 3.32 (7.1)
0.34 (0.8) 0.15 (0.7) 0.10 (0.6) 1.48 (5.8)
0.03 0.11 0.02 1.84
0.89 0.53 0.88 0.17
0.58 (0.6) 0.22 (0.6) 0.32 (0.9) 1.97 (4.6)
0.67 (0.8) 0.24 (0.5) 0.40 (0.6) 2.10 (5.5)
-0.09 0.02 -0.08 -0.13
0.52 0.85 0.56 0.90
0.44 (1.1) 0.25 (0.8) 0.09 (0.7) 2.43 (6.4)
0.35 (0.8) 0.16 (0.7) -0.04 (0.8) 1.21 (6.6)
0.09 0.09 0.13 1.22
0.66 0.58 0.44 0.37
0.41 (0.8) 0.09 (0.6) 0.26 (0.8) 0.77 (5.1) 0.64 (1.9)
0.38 (0.8) 0.10 (0.6) 0.28 (0.7) 1.10 (5.0) 1.51 (2.4)
-0.03 -0.01 0.02 -0.33 -0.87
0.86 0.93 0.88 0.75 0.06
Values given are means; the SD is in parentheses. Difference in change in muscle strength [change in 1,25-(OH)2D3 group minus change in placebo group] in Newton-meters. 6 P value from two-sample t test comparing the change in muscle strength in the two treatment groups.
0
other studies (21, 22, 24, 37, 38). More recent reports have suggested that serum 1,25-(OH)2D is normal in healthy elderly, but declines with declining functional status (39-41), rather than with increasing age. In the age range of our subjects, we found no decline in serum 1,25-(OH)2D with aging. Perhaps treatment with might improve muscle strength among institutionalized elderly with very poor functional status and low levels of serum 1,25-(OH)2D. However, even among the subset of our patients with baseline 1,25-(OH)2D less than 50 pmol/L (20 pg/mL), there was no improvement in muscle strength after treatment. Second, the dose of 1,25-(OH)2D3 employed in this study may not have been adequate to improve muscle strength. After 6 months of treatment with 0.5 fig 1,25-
(OH)2D3 daily, serum levels of 1,25-(OH)2D increased from 85.6 pmol/L (35.6 pg/mL) to 95.4 pmol/L (39.7 pg/ mL). This dose of 1,25-(OH)2D3 has been shown to be effective in producing increased calcium uptake in the intestine and increased serum and urinary calcium, but higher doses or a larger increase in serum 1,25-(OH)2D might be required to affect skin (42), bone (43), or muscle. Larger doses of 1,25-(OH)2D3, however, are generally associated with significant hypercalcuria and hypercalcemia in older persons. Seven of our 50 vitamin D-treated subjects (14%) required a reduction in dosage. In a recent study designed to maximize the dose of oral 1,25-(OH)2D3 (given as 0.25 ng twice a day) in postmenopausal women, the mean tolerated dose was 0.62 ng daily, even with dietary calcium restricted to less than 600 mg daily (43).
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GRADY ET AL.
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TABLE 4. Change in muscle strength after 6 months of treatment by age, sex, and baseline creatinine clearance, muscle strength, and serum 1,25-(OH)2D Change in strength" llTiO1*£kTlf*4
1,25-(OH)2D; 3 Placebo
/I Here net
Age (yr) -0.18 (0.8) 0.23 (0.6) 70-74 0.44 (0.8) 0.18 (0.7) 75-79 80-84 0.31 (0.8) -0.11 (0.6) 85+ 0.14 (0.9) 0.67 (0.8) Sex Male 0.44 (1.0) 0.18 (0.8) 0.06 (0.6) 0.15 (0.6) Female Baseline creatinine clearance (mL/s-1.73 m 2) 1.3 Baseline muscle strength Leg extension (n-m) 8.4 0.34 (0.9) -0.12 (0.7) Baseline total 1,25-(OH)2D (pmol/L) 94
0.12 (1.0)
0.36 (0.8)
0.30 (0.8)
0.10 (0.7)
0.22 (0.7)
0.30 (0.7)
»* P C
-0.41 0.26 0.42 -0.53
0.21 0.40 0.11 0.33
0.26 -0.09
0.34 0.62
-0.03 0.18 -0.19
0.94 0.37 0.40
-0.20 0.18 -0.12 0.46
0.45 0.61 0.72 0.23
0.47 -0.24 0.20 -0.08
0.33 0.65 0.48 0.75
Values given are means; the SD is in parentheses. Peak torque during leg extension at joint speed of 120 degrees per s. 6 Difference in change in muscle strength [change in 1,25-(OH)2D3 group minus change in placebo group]. C P value from a two-sample t test of the change in muscle strength in the two treatment groups. 0
TABLE 5. Change in serum 1,25-(OH)2D, calcium, and phosphorus and urinary calcium after treatment Treatment group
Serum 1,25-(OH)2D (pmol/L) Baseline Mean follow-upc Serum calcium (mmol/L) Baseline Mean follow-up Urinary calcium (mmol/24 h) Baseline Mean follow-up
11 ifO1*OY1 {*£ r Jlllciclllt *
±
l,25-(OH) 2 Dji
Placebo
85.6 (33.7) 95.5 (28.8)
83.6 (31.2) 86.3 (22.8)
2.0 9.2
0.77 0.09
2.26 (0.1) 2.30 (0.1)
2.28 (0.1) 2.25 (0.1)
0.02 0.05
0.40 0.003
2.22 (1.4) 4.03 (2.0)
2.42 (1.4)
0.20 1.60
0.51
Vol. 73, No. 5 Printed in U.S.A.
1,25-Dihydroxyvitamin D 3 and Muscle Strength in the Elderly: A Randomized Controlled Trial* DEBORAH GRADY, BERNARD HALLORAN, STEVE CUMMINGS, SUZANNE LEVEILLE, LAUREN WELLS, DENNIS BLACK, AND NANCY BYL Departments of Epidemiology (D.G., S.C., D.B.) and Medicine (D.G., B.H., S.C., N.B.), Veterans Administration Medical Center, University of California School of Medicine (D.G., B.H., S.L., L. W.), San Francisco, California 94121
day or identical placebo for 6 months. Leg muscle strength of the quadriceps was measured with an isokinetic dynamometer. There was no difference between the two groups at 1 week, 1 month, or 6 months of treatment in any of the measures of muscle strength. We conclude that oral administration of 0.5 fig l,25-(OH)2D3/day does not improve muscle strength in older persons. Further research is needed to determine the etiology of the decline in muscle strength associated with aging. (J Clin Endocrinol Metab 73: 1111-1117, 1991)
ABSTRACT. An unexplained loss of muscle strength occurs with aging. Vitamin D deficiency can cause myopathy and administration of 1,25-dihydroxyvitamin D3 [1,25-(OH2)D3] to persons with low serum concentrations can improve strength. To test the hypothesis that the weakness associated with aging is in part due to inadequate serum concentrations of [1,25(OH2)D3], we conducted a randomized, controlled, double blinded trial in 98 men and women volunteers over 69 yr old. Treatment consisted of 0.25 ng 1,25-(OH)2D3, orally, twice per
shown to improve muscle strength measured by simple functional tests (11, 28). To test the hypothesis that the weakness associated with aging is in part due to inadequate levels of 1,25-(OH)2D3, we conducted a randomized, controlled, double blinded trial in 98 elderly subjects.
f I ^HERE is strong evidence that 1,25-dihydroxyviX tamin D3 [1,25-(OH)2D3], the most biologically active form of vitamin D, influences muscle function (114). Receptors for 1,25-(OH)2D3 have been demonstrated in cultured human muscle cells (13,14). Decreased muscle strength (usually characterized by proximal muscle atrophy and a selective loss of type II muscle fibers) is a well documented symptom of vitamin D deficiency (1-9, 12) and administration of 1,25-(OH)2D3 to patients with 1,25-(OH)2D3 deficiency restores muscle strength (6, 811). An unexplained decrease in muscle strength occurs with increasing age (15-20). Several studies indicate that the serum concentration of 1,25-(OH)2D3 also decreases with increasing age (21-24). Since production of 1,25(OH)2D3 occurs in the kidney, it has been suggested that the decrease in serum 1,25-(OH)2D3 in the elderly may be due to an age-related decline in renal function (2426). The sensitivity of target tissues to 1,25-(OH)2D3 may also decrease with increasing age (27). Treatment with 1,25-(OH)2D3 in uncontrolled studies of elderly persons without evidence of vitamin D deficiency has been
Materials and Methods
Received February 19,1991. Address all correspondence and requests for reprints to: Deborah Grady, M.D., M.P.H., Department of Epidemiology and Medicine, University of California, Veterans Administration Medical Center (111A1), 4150 Clement Street, San Francisco, California 94121. * This work was supported by Grant R01-AG-07477-02 from the NIA.
Subjects were ambulatory men and women volunteers over 69 yr old. To protect subjects with conditions thought to potentiate hypercalcemia or hypercalcuria, exclusion criteria included serum calcium levels of 2.57 mmol/L or more (>10.6 mg/dL), urinary calcium levels of 7.28 mmol/day or more (>300 mg/24 h); creatinine clearance less than 0.42 mmol/s (25 mL/ min); history of hypercalcemia, nephrolithiasis, seizure disorder, or hyperparathyroidism; treatment with calcium, vitamin D, or thiazide diuretics; and average calcium intake greater than 1000 mg/day. We also excluded subjects with any condition that would prohibit following simple instructions or performing the strength tests. The first 15 subjects enrolled were found to have an average creatinine clearance of 1.4 mmol/s (84 mL/min). Since the ability to hydroxylate 25-hydroxyvitamin D3 (25OHD3) to 1,25-(OH)2D3 parallels glomerular filtration rate (29-31), we subsequently excluded subjects with creatinine clearances above 1.33 mL/s (80 mL/min). At entry into the study, each subject completed questionnaires to ascertain demographic information, medical conditions, medications, usual physical activity (average joules expended per day in exercise), and average daily dietary calcium intake. Baseline laboratory testing included serum calcium,
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GRADY ET AL.
phosphorus, creatinine, and vitamin D metabolites [25OHD and 1,25-(OH)2D] and 24-h urinary calcium, creatinine, and creatinine clearance. Isokinetic muscle strength of the knee flexor and extensor muscles was measured using an isokinetic dynamometer (Cybex 340, Lumex Corp., Ronkonkoma, NY) by a single physical therapist who had no knowledge of the treatment status of the subjects. The isokinetic dynamometer is an electromechanical device with a lever arm containing a transducer that measures force as torque when the subject pushes or pulls on the lever arm and a goniometer that measures joint angle. With the subject seated comfortably, and the torso and thigh secured with straps, the dynamometer axis was aligned with the anatomical axis of the right knee joint and the lever arm attached to the right lower leg with a shin strap. The left knee was measured in subjects with abnormalities of the right knee. After standardized practice sessions, the subject was asked to fold the arms across the chest and maximally push and pull the leg attached to the lever arm. Peak torque in flexion and extention of the knee at joint speeds of 90, 120, and 180% (dps) was measured using a standardized protocol. We also measured total work (torque multiplied by the time during which the torque is sustained) in flexion and extension of the knee at a joint speed of 120 dps. All measurements are corrected for the effect of gravity on the leg and foot by weighing the leg, foot, and lever arm together and subtracting or adding the appropriate calculated torque at each angle of measurement. Measurements were expressed in Newton-meters (n-m) of torque. Dynomometer settings were recorded and replicated exactly during subsequent testing. The test-retest correlation coefficient for various standard loads on the Cybex 340 isokinetic dynamometer exceeds 0.99 (31, 32). Grip strength was measured in the right hand using a grip dynamometer (Smedley Grip Dynamometer, J. A. Preston, Co., Clifton, NJ). The average of two measurements of grip strength, recorded to the nearest half kilogram of force, was used for analysis. Treatment consisted of 0.25 ng 1,25-(OH)2D3 or identical placebo (provided by Hoffman-LaRoche, Nutley, NJ) taken orally twice per day at breakfast and dinner for 6 months. The amount of 1,25-(OH)2D3 in randomly selected capsules was confirmed by direct assay. Subjects were evaluated at 1, 2,4, 8, 12,18, and 24 weeks of treatment to maintain compliance and ascertain side-effects. At these visits, serum calcium and creatinine and 24-h urinary calcium, creatinine, and creatinine clearance were measured, and subjects were asked about perceived adverse effects. The number of capsules taken daily was reduced from two to one if the serum calcium exceeded 2.57 mmol/L (10.5 mg/dL), 24-h urinary calcium exceeded 7.28 mmol/day (300 mg/24 h), or corrected creatinine clearance decreased by more than 20% from baseline. Muscle strength was retested, and vitamin D metabolites were remeasured at 1, 4, and 24 weeks of treatment. Compliance with study medication was estimated with capsule counts at each follow-up visit. Calcium, phosphorus, and creatinine were measured using automated analysis. Serum 25OHD (32) and 1,25-(OH)2D (33) were measured after chromatographic purification using the method of Reinhardt et al. (33). We described the characteristics of our study population,
JCE & M • 1991 Vol73«No5
muscle strength, and serum values by calculating means and SD. The relationship of age and sex to muscle strength was assessed using separate linear models in men and women. The association of age, sex, calcium intake, creatinine clearance, and muscle strength with serum vitamin D levels was assessed using simple linear regression analyses. Statistical significance of differences between treatment groups was assessed with an unpaired t test of change in muscle strength. All analyses were performed using the Statistical Analysis System (SAS) software. Results The median age of the 98 subjects was 79.1 yr (range, 70-97 yr). All but 5 of the subjects were white. The study population included 45 men (46%) and 53 women (54%). Fifty subjects were assigned to receive 1,25-(OH)2D3, and 48 to receive placebo capsules. At baseline, there were no significant differences between the treatment groups in age, sex, body weight, muscle strength, physical activity level, daily calcium intake, serum calcium, serum phosphorus, 24-h urinary calcium, creatinine clearance, or serum vitamin D levels (Table 1). Subjects in both groups took more than 95% of the assigned medication. One subject [assigned to treatment with 1,25-(OH)2D3] died following surgery for gastric cancer during the second month of the study. A second subject (assigned to placebo) suffered a stroke during the third month of the TABLE 1. Characteristics of study subjects by treatment group Baseline characteristics Age (yr) Sex (% male) BW (kg) Muscle strength Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Hand grip (kg) Physical activity (joules/week) Calcium intake (mmol/24 h) Laboratory values Serum calcium (mmol/L) Urinary calcium (mmol/day) Serum phosphorus (mmol/L) Creatinine clearance (mL/s-1.73 m2) Serum vitamin D levels 25OHD (nmol/L) 1,25-(OH)2D (pmol/L)
1,25-(OH)2D3 (n = 50)
Placebo (n = 48)
79.4 (5.4) 53.3 (0.1) 70.1 (12.0)
78.9 (5.4) 46.7 (0.1) 71.3 (14.3)
7.6 (2.7) 7.0 (2.4) 5.5 (2.0) 50.1 (19.7)
7.5 (2.5) 7.0 (2.5) 5.5 (2.1) 50.6 (19.2)
4.0 (1.4) 4.1 (1.4) 3.4 (1.4) 27.1 (12.1) 3.2 (1.1) 7716.9 (6193.9) 14.4 (7.1)
4.1 (1.6) 4.2 (1.5) 3.4 (1.4) 27.9 (12.8) 3.0 (1.1) 8925.8 (7411.5) 14.2 (5.5)
2.3 (0.1) 2.2 (1.4) 1.0 (0.1) 1.1 (0.3)
2.3 (0.1) 2.4 (1.4) 1.1 (0.2) 1.0 (0.3)
60.4 (35.3) 85.6 (33.7)
65.7 (51.4) 83.6 (31.2)
Values given are means; the SD is in parentheses.
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1,25-(OH)2D3 AND STRENGTH
study and was unable to complete the protocol. Six subjects who were taking 1,25-(OH)2D3 required a reduction in dosage from two capsules (0.25 fig twice a day) to one capsule per day (0.25 ng daily) due to 24-h urinary calcium levels greater than 7.28 mmol/day (300 mg/24 h). Two subjects required a reduction from two capsules to one capsule per day [one taking 1,25-(OH)2D3, one taking placebo] due to reductions in creatinine clearance of more than 20% compared to baseline values. As expected, muscle strength at baseline was lower in older subjects and in women compared to men (Fig. 1). Based on simple linear regression modeling, muscle strength (peak torque in extension of the knee at a joint speed of 120 dps) declined by 1.6%/yr past age 69 yr in both men and women [0.10 ft-lb/yr of age in women (P = 0.01) and 0.17 ft-lb/yr of age in men (P = 0.003)]. Based on a multiple linear regression model including both age and sex as predictors of muscle strength (peak torque in extension of the knee at a joint speed of 120 dps), women were 38% weaker than men. Even after adjustment for body mass index (by addition of body mass index to the multiple linear regression model), women were still 36% weaker than men. Baseline mean serum 1,25-(OH)2D was 84.6 pmol/L, slightly lower than the mean of 89.7 pmol/L (37.3 pg/ mL) found in our laboratory in men and women less than 40 y old (n = 33). In the age range of our subjects, serum 1,25-(OH)2D did not decline with increasing age in men or women (Fig. 2). There were no significant differences in serum 25OHD or 1,25-(OH)2D by age, sex, daily calcium intake, or muscle strength (Table 2). Serum levels of both 25OHD and 1,25-(OH)2D decreased with decreasing creatinine clearance [P = 0.24 for 25OHD
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and P = 0.06 for 1,25-(OH)2D]. The change in muscle strength in the 1,25-(OH)2D3 and placebo groups at 1 week, 1 month, and 6 months of treatment is shown in Table 3. After 6 months of therapy, none of the measures of muscle strength in the 1,25(OH)2D3-treated subjects had improved by more than 5%, and similar changes were noted in the placebotreated subjects. There were no significant differences in any measure of change in muscle strength comparing the 1,25-(OH)2D3 and placebo-treated groups. To determine whether treatment with 1,25-(OH)2D3 improved muscle strength in certain subgroups, change in muscle strength was compared by age (70-74, 75-79, 80-84, and 85+ yr), sex, creatinine clearance (1.3 mmol/s or 80 mL/min), baseline muscle strength (leg extension peak torque at joint speed of 120 dps by quartiles), and baseline serum 1,25-(OH)2D (94 mmol/L or 40 pg/mL). There were no significant improvements in strength in any subgroup comparing the 1,25-(OH)2D3 and placebo groups (Table 4). After treatment with 1,25-(OH)2D3, serum calcium and urinary calcium were significantly increased (Table 5), demonstrating the effect of treatment with 1,25-(OH)2D3 on calcium metabolism. Serum 1,25-(OH)2D was only moderately increased after treatment. Discussion Using the isokinetic dynamometer as a very reliable measure of leg muscle strength, we found a 1.6% decline in strength per yr of age in persons over 69 yr old.
FIG. 1. Baseline muscle strength by age and sex (peak torque in leg extension at 120 dps).
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Age (years)
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GRADY ET AL.
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JCE & M • 1991 Vol73«No5
FIG. 2. Baseline serum 1,25-(OH)2D by age and sex.
Age (years)
TABLE 2. Baseline serum 25OHD and 1,25-(OH)2D, and age, sex, calcium intake, creatinine clearance, and muscle strength Serum vitamin D
Age (yr) 70-74 75-79 80-84 85+ Sex Male Female Calcium intake (mmol/24 h) 19.4 Creatinine clearance (mL/s-1.73 m2) 1.3 Muscle strength (n-m) Leg extension Peak torque, 120 dps 5.0
25OHD (nmol/L)
1,25-(OH)2D (pmol/L)
56.4 (16.7) 69.1 (45.0) 64.3 (56.0) 49.0 (24.2)
91.2 (34.7) 87.3 (34.7) 81.5 (31.0) 76.3 (28.9)
68.7 (56.9) 58.2 (27.8)
78.2 (30.8) 90.1 (33.0)
61.2 (46.6) 64.7 (47.9) 61.4 (27.9)
89.8 (32.1) 81.7 (34.1) 88.0 (28.4)
51.4 (21.6) 65.2 (51.1) 68.4 (24.4)
69.5 (25.1) 86.7 (34.6) 96.5 (23.2)
60.6 (32.0) 72.0 (48.2) 49.1 (18.7) 71.8 (62.2)
82.7 (27.4) 86.1 (32.5) 83.8 (30.3) 85.9 (39.9)
51.8 (24.0) 59.1 (22.8) 76.9 (66.2) 62.5 (45.4)
79.2 (37.3) 91.3 (30.6) 87.8 (22.7) 78.2 (37.8)
Values given are means; the SD is in parentheses.
Multiple investigators have reported that elderly persons are significantly weaker than young or middle-aged persons (15-17,34), and our findings emphasize that muscle strength continues to decrease, even in the very elderly. While inactivity or chronic illness might account for some of the muscle weakness associated with aging (35, 36), longitudinal studies indicate that even healthy active elderly persons suffer an unexplained loss of muscle strength with aging. We theorized that inadequate levels of 1,25-(OH)2D in elderly persons might account for some of this loss of muscle strength. This study was designed to determine whether treatment with oral 1,25-(OH)2D3 at a dose of 0.5 ng daily would increase muscle strength in persons over 69 yr old. We found no improvement in any measure of muscle strength in the group treated with 1,25(OH)2D3 compared to the placebo-treated group. There are at least three possible explanations for our failure to show an improvement in muscle strength after treatment with 1,25-(OH)2D3. First, our study subjects were independent ambulatory elderly volunteers. While our findings are generalizable to this large elderly population, we have not shown that treatment with 1,25(OH)2D3 would be similarly ineffective in ill institutionalized elderly. Despite advanced age and diminished renal function, serum 1,25-(OH)2D in our subjects was relatively normal. Persons with 1,25-(OH)2D deficiency who develop a proximal muscle weakness generally demonstrate serum 1,25-(OH)2D levels below 12 pmol/L (5 pg/ mL). In our vitamin D-treated subjects, mean baseline serum 1,25-(OH)2D was 84.6 pmol/L (35.2 pg/mL). While this value is slightly lower than that found in our laboratory in young adults (89.7 pmol/L or 37.3 pg/mL), it is not as low as that found in older persons in several
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1,25-(OH)2D3 AND STRENGTH TABLE 3. Change in muscle strength at 1 week, 1 month, and 6 months of treatment in 1,25-(OH)2D3 and placebo groups Change in strength
1 Week Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Grip strength (kg) 1 Month Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Grip strength (kg) 6 Months Leg extension Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Leg flexion Peak torque, 90 dps (n-m) Peak torque, 120 dps (n-m) Peak torque, 180 dps (n-m) Work, 120 dps (joules) Grip strength (kg)
1,25(OH)2D3 (n = 50)
Placebo (n = 48)
Difference"
P»
0.06 (1.2) -0.01 (0.8) -0.03 (0.7) 0.38 (6.7)
0.20 (1.1) 0.08 (0.7) -0.05 (0.6) 1.1 (6.5)
-0.14 -0.09 0.02 -0.72
0.55 0.58 0.93 0.59
0.40 (0.6) 0.10 (0.6) 0.13 (0.8) 0.55 (4.4)
0.47 (0.5) 0.22 (0.5) 0.31 (0.6) 1.19 (3.9)
-0.07 -0.12 -0.18 -0.64
0.550.30 0.23 0.45
0.37 (1.1) 0.26 (0.9) 0.12 (0.8) 3.32 (7.1)
0.34 (0.8) 0.15 (0.7) 0.10 (0.6) 1.48 (5.8)
0.03 0.11 0.02 1.84
0.89 0.53 0.88 0.17
0.58 (0.6) 0.22 (0.6) 0.32 (0.9) 1.97 (4.6)
0.67 (0.8) 0.24 (0.5) 0.40 (0.6) 2.10 (5.5)
-0.09 0.02 -0.08 -0.13
0.52 0.85 0.56 0.90
0.44 (1.1) 0.25 (0.8) 0.09 (0.7) 2.43 (6.4)
0.35 (0.8) 0.16 (0.7) -0.04 (0.8) 1.21 (6.6)
0.09 0.09 0.13 1.22
0.66 0.58 0.44 0.37
0.41 (0.8) 0.09 (0.6) 0.26 (0.8) 0.77 (5.1) 0.64 (1.9)
0.38 (0.8) 0.10 (0.6) 0.28 (0.7) 1.10 (5.0) 1.51 (2.4)
-0.03 -0.01 0.02 -0.33 -0.87
0.86 0.93 0.88 0.75 0.06
Values given are means; the SD is in parentheses. Difference in change in muscle strength [change in 1,25-(OH)2D3 group minus change in placebo group] in Newton-meters. 6 P value from two-sample t test comparing the change in muscle strength in the two treatment groups.
0
other studies (21, 22, 24, 37, 38). More recent reports have suggested that serum 1,25-(OH)2D is normal in healthy elderly, but declines with declining functional status (39-41), rather than with increasing age. In the age range of our subjects, we found no decline in serum 1,25-(OH)2D with aging. Perhaps treatment with might improve muscle strength among institutionalized elderly with very poor functional status and low levels of serum 1,25-(OH)2D. However, even among the subset of our patients with baseline 1,25-(OH)2D less than 50 pmol/L (20 pg/mL), there was no improvement in muscle strength after treatment. Second, the dose of 1,25-(OH)2D3 employed in this study may not have been adequate to improve muscle strength. After 6 months of treatment with 0.5 fig 1,25-
(OH)2D3 daily, serum levels of 1,25-(OH)2D increased from 85.6 pmol/L (35.6 pg/mL) to 95.4 pmol/L (39.7 pg/ mL). This dose of 1,25-(OH)2D3 has been shown to be effective in producing increased calcium uptake in the intestine and increased serum and urinary calcium, but higher doses or a larger increase in serum 1,25-(OH)2D might be required to affect skin (42), bone (43), or muscle. Larger doses of 1,25-(OH)2D3, however, are generally associated with significant hypercalcuria and hypercalcemia in older persons. Seven of our 50 vitamin D-treated subjects (14%) required a reduction in dosage. In a recent study designed to maximize the dose of oral 1,25-(OH)2D3 (given as 0.25 ng twice a day) in postmenopausal women, the mean tolerated dose was 0.62 ng daily, even with dietary calcium restricted to less than 600 mg daily (43).
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GRADY ET AL.
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TABLE 4. Change in muscle strength after 6 months of treatment by age, sex, and baseline creatinine clearance, muscle strength, and serum 1,25-(OH)2D Change in strength" llTiO1*£kTlf*4
1,25-(OH)2D; 3 Placebo
/I Here net
Age (yr) -0.18 (0.8) 0.23 (0.6) 70-74 0.44 (0.8) 0.18 (0.7) 75-79 80-84 0.31 (0.8) -0.11 (0.6) 85+ 0.14 (0.9) 0.67 (0.8) Sex Male 0.44 (1.0) 0.18 (0.8) 0.06 (0.6) 0.15 (0.6) Female Baseline creatinine clearance (mL/s-1.73 m 2) 1.3 Baseline muscle strength Leg extension (n-m) 8.4 0.34 (0.9) -0.12 (0.7) Baseline total 1,25-(OH)2D (pmol/L) 94
0.12 (1.0)
0.36 (0.8)
0.30 (0.8)
0.10 (0.7)
0.22 (0.7)
0.30 (0.7)
»* P C
-0.41 0.26 0.42 -0.53
0.21 0.40 0.11 0.33
0.26 -0.09
0.34 0.62
-0.03 0.18 -0.19
0.94 0.37 0.40
-0.20 0.18 -0.12 0.46
0.45 0.61 0.72 0.23
0.47 -0.24 0.20 -0.08
0.33 0.65 0.48 0.75
Values given are means; the SD is in parentheses. Peak torque during leg extension at joint speed of 120 degrees per s. 6 Difference in change in muscle strength [change in 1,25-(OH)2D3 group minus change in placebo group]. C P value from a two-sample t test of the change in muscle strength in the two treatment groups. 0
TABLE 5. Change in serum 1,25-(OH)2D, calcium, and phosphorus and urinary calcium after treatment Treatment group
Serum 1,25-(OH)2D (pmol/L) Baseline Mean follow-upc Serum calcium (mmol/L) Baseline Mean follow-up Urinary calcium (mmol/24 h) Baseline Mean follow-up
11 ifO1*OY1 {*£ r Jlllciclllt *
±
l,25-(OH) 2 Dji
Placebo
85.6 (33.7) 95.5 (28.8)
83.6 (31.2) 86.3 (22.8)
2.0 9.2
0.77 0.09
2.26 (0.1) 2.30 (0.1)
2.28 (0.1) 2.25 (0.1)
0.02 0.05
0.40 0.003
2.22 (1.4) 4.03 (2.0)
2.42 (1.4)
0.20 1.60
0.51
