Journal of Gerontology 1978, Vol. 33, No. 2, 204-212
Effect of Sodium Fluoride, Inorganic Phosphate, and Oxymetholone Therapies in Osteoporosis: A Six-Year Progress Report1
Elderly osteoporotic males treated with sodium fluoride or inorganic phosphate for 4 years plus 2 years of follow-up observations exhibited a mean but not significant decrease in the rate of bone mass loss in comparison with those receiving oxymetholone or a placebo. No hip fractures occurred in the patients who received fluoride, while 11 hip fractures occurred in the patients in the phosphate, oxymetholone, and control groups. Because the densitometric trends and fracture incidence are impressive, the progress of all subjects will be followed for an additional 4 years.
STEOPOROSIS is not only the most common metabolic disease but is also the O principal cause of morbidity among uncounted millions of elderly persons. It has, in the past, been considered to occur inevitably with aging. In this reported study, three compounds used in previous programs (and found to be conducive to improved bone quality in disuse osteoporosis among young, bedfast children) have been administered in an attempt to reverse bone mineral loss and reduce fracture incidence among osteoporotic, geriatric males (Keele & Vose, 1969,1971). METHODS
In October 1970, 180 males 50 years of age and older who had exhibited evidence of skeletal mineral loss by quantitative x-ray densitometry began participation in a longterm therapy program. The participants resided in a home for the mentally retarded in Texas, and none had metabolic, renal, cardiac, liver, or chromosomal disease. Forty-five were treated with sodium fluoride, 45 were treated with inorganic phosphate, and 45 were
•Supported by Grant AM 15979 from the National Institute of Arthritis, Metabolism, and Digestive Diseases, USPHS, and by grants from Hoyt Laboratories (Division of Colgate-Palmolive) and Parke Davis & Co. 'Reseach Institute, Texas Woman's Univ., Denton 76204. 'Diagnostic and Evaluation Center, Univ. of Texas Southwestern Medical School at Dallas 7S235.
204
treated with oxymetholone, an anabolic steroid; while 45 acted as nontreated controls and received a placebo. The subjects were randomly subdivided according to bone density and age into three groups. The mean group ages ranged from 57.4 to 58.4 (see Table 7). Group I received sodium fluoride (Hoyt Labs Osteo-FTrolecaps) as follows: 1. Body weight less than 135 lbs 20 mg fluoride ion/day 2. Body weight 135-175 lbs 30 mg fluoride ion/day 3. Body weight more than 175 lbs — 4 0 mg fluoride ion/day Group II received potassium phosphate (Hoyt Labs Hyper-Phos-K) at a dosage of 1,000 mg phosphate/day. Group III received oxymetholone (ParkeDavis Adroyd) as follows: 1. Body weight less than 135 lbs 7.5 mg/day 2. Body weight 135-175 lbs 10.0 mg/day 3. Body weight more than 175 lbs 12.5 mg/day Group IV received 5 ml of placebo (Emerson Labs Syrpalta) daily. All subjects were given physical and laboratory examinations initially and were reexamined as the study progressed. Renal
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
George P. Vose, MS,2 Doman K. Keele, MD,3 Alice M. Milner, PhD,2 Richard Rawley, BS, 2 Ted L. Roach,2 and Edgar E. Sprinkle III, MS2
THERAPIES IN OSTEOPOROSIS
acid, calcium, phosphorus, and iron were recorded. After obtaining totals for all nutrients , daily averages were calculated for comparison with the Recommended Dietary Allowance. All were met and many, such as calcium, iron, protein, and ascorbic acid, were exceeded by 50% or more (Maier, 1971). While the precise intake of nutrients was not quantitated for each individual, all subjects normally ate at least the amount to provide the RDAof the listed nutrients. Laboratory tests. — Periodic measurements of kidney function were made. These included serum urea-nitrogen, serum creatinine, and routine urinalyses. Other parameters included blood hemoglobin, SGOT, total serum acid and alkaline phosphatases, serum inorganic phosphorus and, in the fluoride-treated patients and the controls, serum inorganic fluoride. Definition of bone density norms. — At the outset of the study in 1970 the patients were classified into bone density grades in accordance with limited standards of normalcy available at that time. More recent contractual work between Texas Woman's University and the National Center for Health Statistics during the 4-year period from July, 1971 through June, 1975 is providing the normal limits of bone density-for-age of the U.S. population. Preliminary figures from the survey and from previous examinations of civil service employees reported by Vose and Engel (1973) are available at this time. When our study was planned in 1969 and initiated in 1970, normal density of the human phalanx was not precisely known, and our original demarking limits were based on a relatively small sample. On the basis of our current findings in the National Health Survey involving several thousand people, we are now aware that some participants in the program did not have abnormally low bone density. In reclassifying the patients in view of the new standards, among all four groups (fluoride, phosphate, oxymetholone, and controls) 19% were considered "normal," while 41% had what we have termed "mild" osteoporosis, 37% had "moderate" osteoporosis, and 3% had "marked" osteoporosis. The "x-ray aluminum equivalency" value of .240 has been accepted as normal-for-age phalanx density for males within the age range of our subjects. "Mild" osteoporosis denotes
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
studies included periodic urinalyses and determinations of serum urea nitrogen and creatinine were conducted on all patients. Serum fluoride was monitored on all patients receiving fluoride treatment and dosages adjusted so that the level was maintained below 15JUM. Patients receiving oxymetholone were monitored for prostatic cancer by prostate digital examinations semi-annually and serum acid phosphatase tests bimonthly, and were monitored for liver disease by SGOT and serum alkaline phosphatase analyses throughout the study. Ophthalmological examinations. — Ophthalmological examinations by slit-lamp observation were made of the phosphatetreated patients and the controls. Bone mineral measurements. — Patients who were selected for the study were radiographed initially and at 6-week intervals for bone quality determination. Radiographs were made of the left hand at each test date for routine x-ray densitometry of phalanx V-2 (middle digit of the small finger), which was selected as the bone to be monitored because in an earlier investigation (Goldsmith et al., 1971) it was found that the mineral content of that bone correlated best with diagnosed vertebral osteoporosis (p < .001 at the phalanx V-2 site vs/7 < .05 at the distal radius, but N.S. at the os calis). The photometric computing apparatus used by this laboratory has been described previously (Mack et al., 1959; Vose, 1969; Vose & Keele, 1970). The instrument consists essentially of a modified Knorr-Albers microdensitometer interfaced with a digital computer (D.E.C. PDP-8) connected to the output of the scanning unit through an amplifier and incorporated with teletype readout. The instrument is capable of reproducibility within 1%, and the overall technique error is considered to be less than 5%. Dietary assessment. — Institutional diets were planned in 3-mo cycles by a nutritionist and evaluated according to the Recommended Dietary Allowance of the U.S. National Research Council. Provisions were made to adapt the menu for special diets and for patients with masticulatory problems. The complete diet was assessed according to nutritive composition of foods listed in the USDA Handbook no. 8. Protein, calories, vitamin D, thiamine, riboflavin, ascorbic
205
206
VOSE, KEELE, MILNER, RAWLEY, ROACH, AND SPRINKLE
Table 1. Bone Density at Time Zero (Initial Intercept of Regression Slope) for Patients in Each Treatment Group and the Controls. Al. Equiv. Range
Fluoride
Group Phosphate Oxymetholone
.24t) .258 .261 and above (SD = .O16) (SD = .O17) n = 11 n= 7
Controls
.253 (SD = .009) n=7
.272 (SD = .O17) n= 9
.221 .213 (SD = .010) (SD = .OO7) n =13 n= 15
.217 (SD=.O12) n = 18
.222 (SD = .011) n = 20
.199 .181 .174 and below (§D = .011) (SD = .O2O) n = 23 n = 21
.178 (SD=.O17) n = 20
.176 (SD = .O17) n=16
.200-.239
Fig. 1. Computer print-out of regression slope of bone density (x-ray aluminum equivalency) vs duration of treatment of a control subject as determined by method of least squares.
the initial data point has resulted in recalculations of patient assignment using the time-zero intercept of the regression slope instead of the recorded time-zero value, which is considered to be a more accurate procedure. RESULTS
Fracture incidence. — At the present 6-year point, 11 hip fractures have occurred in the 146 remaining patients of the 180 who originally started the program. All of the fractures have occurred in the control, oxymetholone, and phosphate subjects, and chi-square and Fisher's Exact Test indicate that neither the oxymetholone nor phosphate subjects were significantly different from the controls in regard to fracture incidence. It is interesting to note that, while not statistically significant, no hip fractures have occurred in the fluoridetreated patients during the 4-year treatment period and nearly 2 years of follow-up observations. By chi-square analysis of fractures among patients who did not receive fluoride vs those patients on fluoride therapy, the probability of this occurrence is p < 0.10. Admittedly, the tenability of this analysis is
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
those individuals with bone density values between .200 and .239; "moderate" osteoporosis indicates those subjects within the range of .150 and .199; and "marked" osteoporosis includes patients with densities of less than .150. Because the latter group is quite small among our total subjects (3%) it has been combined with the . 199 and below group. Assignment of participants into bone density classes. — In assessing the trends in bone mineral change during the program, radiographs were made of the left hand at 6-week intervals. The bone density analyzer used at Texas Woman's University equates the x-ray absorbence by bone with that of a standard aluminum wedge placed adjacent to the small finger during exposure and yields "bone density" in terms of "x-ray aluminum equivalency." To measure bone density changes, a plot was made of aluminum equivalency values for each test point and the best straight line fit of the points was determined by computer utilizing the method of Least Squares, and the intercept of the slope with the bone density coordinate was used as the phalanx density at time zero. The time zero intercepts for the four groups are shown in Table 1. Fig. 1 is an example of a computer printout of data points and the Least Squares fit of the regression slope. Grouping of the patients was based on photometric evaluations of radiographs made approximately 9 mo before the initiation of treatment. Fig. 1 indicates that an experimental error produces a scatter of individual data points above and below the regression line. The original, inappropriate matching based on
THERAPIES IN OSTEOPOROSIS
Table 2. Hip Fracture Occurrence in Each Treatment Group (Transcervical or Subtrochanteric).
207
MODEKATE/MARKED OSTEOPOROSIS
s
•6
z „
i-g
3 29 +4 J-
< E >• E
Control
Patient No.
Age at Fracture Occurrence (Years)
20 164
52 60
.195 .261
-13.3% + 19.5%
40 106 117 135 165 172
52 72 60 60 54 58
.209 .175 .252 .130 .160 .210
-6.0% -16.6% + 14.3% -66.2% -27.3% -0.4%
25 43 175
60 59 57
.214 .151 .180
-0.1% -43.7% -21.7%
2^
^ r l de
'
^
* 1 'l '''-
••
.1.
•2
_
*E 0 S E CHANGE ALENCY |
Group
Bone Density at Fracture OccurDifference rence from Normal(A.E.)a for-Age
"
Hhnsn.'iaie
r
-2 • 4
H>
gg u
0.
1
1
Fluoride
Oxymetholone 3
Fig. 2. Mean percentage of changes in x-ray aluminum equivalency of phalanx V-2 during the treatment program for subjects with moderate/marked osteoporosis.
and -5.8% for the controls and oxymetholone subjects. In viewing the trends among the patients with initially "moderate/marked" osteoquestionable, since the majority of patients porosis only — those subjects most in need of not receiving fluoride were receiving either therapeutic assistance — the group mean oxymetholone or phosphate with the remote increases were impressive (although not possibility that those compounds were con- significant) at +3.5% and +0.9% for the ducive to fracturing. Of the 11 hip fractures, fluoride and phosphate patients, respectively. 9 subjects had below-normal bone densities at The control subjects in the same bone density fracture occurrence while 2 subjects had classification exhibited a mean bone density above-normal densities (see Table 2). loss of-4.3%, and the oxymetholone group had Bone mineral changes by densitometry. — a mean loss of-5.7%. (The foregoing changes Bone density within the total skeleton normally represent terminal values for all patients decreases at a mean rate of about 1% per year, averaged, regardless of whether or not the which is approximately the same as that entire 208-week treatment period was we have observed among the control subjects completed.) in this study. The mean percentage of loss Analysis of covariance was conducted on among control subjects (regardless of early the percentage of change in x-ray aluminum termination or full-period completion) in all equivalency of phalanx V-2 for subjects in bone density classifications combined was each of three levels of bone density. Signifi-3.3% in 4 years. Fig. 2 depicts that the mean cant differences between the fluoride and percentage of loss in the control subjects phosphate treated patients vs their controls with "moderate/marked" osteoporosis was were observed only when all classes of initial perhaps a bit greater at -4.3% during the bone density were combined (p < 0.02 and 4-year period. p < 0.05, respectively). This information is The patients treated with fluoride and given in Table 3. When the subjects were phosphate exhibited trends in bone density subdivided into the three initial bone density losses which were less marked than in the levels, however, none of the groups exhibited controls when all four bone density classes impressive differences by covariance analysis were combined. The losses in bone density even though the conspicuous differences in over the 4-year period for subjects in all regression slopes shown in Fig. 2 were evident. four bone density classes combined were It is recognized that pairwise comparisons in -0.2% and -1.7% for the fluoride and phosphate this manner may be overly liberal, but the trend patients, respectively, in contrast with -3.3% is interesting. a
A . E . = X-ray aluminum equivalency
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
Phosphate
208
VOSE, KEELE, MILNER, RAWLEY, ROACH, AND SPRINKLE
Table 3. Co variance Analysis of Variance of Percentage of Change in X-Ray Aluminum Equivalency of Phalanx V-2 for all Subjects Combined and for Subjects in Each of Four Levels of Bone Density. Fluoride vs Controls All Subjects Combined Nonosteoporotic (.240 and above)
Oxymetholone vs Controls
Oxymetholone
-0.060
-0.033
-0.035
-0.082
Nonosteoporotic (.240 and above)
-0.089
-0.044
-0.048
-0.103
F = 4.368** F = 0.003
F = 2.750 F = 0.189
F = 0.465
F = 0.257
F = 2.731
Mild osteoporosis (.200-.239)
-0.045
-0.058
-0.049
-0.079
F= 3.631
F = 1.287
F = 0.718
Moderate/marked osteoporosis (.199 and below)
-0.047
0.004
-0.008
-0.063
Table 4. Mean Percentage of Change by Treatment and by Bone Density Grade Within Treatments. Controls Fluoride Phosphate Oxymetholone -3.5
-1.8
-2.6
-6.9
All subjects combined (unweighted)
Nonosteoporotic (.240 and above)
-4.7
-3.3
-3.7
-8.3
-5.0
Mild osteoporosis (.200-.239)
-2.3
-4.6
-4.2
-5.8
-4.2
Moderate/marked osteoporosis (.199 and below)
All Subjects Combined (unweighted)
Phosphate
F = 5.969* F = 0.448
•Significant atp
Effect of Sodium Fluoride, Inorganic Phosphate, and Oxymetholone Therapies in Osteoporosis: A Six-Year Progress Report1
Elderly osteoporotic males treated with sodium fluoride or inorganic phosphate for 4 years plus 2 years of follow-up observations exhibited a mean but not significant decrease in the rate of bone mass loss in comparison with those receiving oxymetholone or a placebo. No hip fractures occurred in the patients who received fluoride, while 11 hip fractures occurred in the patients in the phosphate, oxymetholone, and control groups. Because the densitometric trends and fracture incidence are impressive, the progress of all subjects will be followed for an additional 4 years.
STEOPOROSIS is not only the most common metabolic disease but is also the O principal cause of morbidity among uncounted millions of elderly persons. It has, in the past, been considered to occur inevitably with aging. In this reported study, three compounds used in previous programs (and found to be conducive to improved bone quality in disuse osteoporosis among young, bedfast children) have been administered in an attempt to reverse bone mineral loss and reduce fracture incidence among osteoporotic, geriatric males (Keele & Vose, 1969,1971). METHODS
In October 1970, 180 males 50 years of age and older who had exhibited evidence of skeletal mineral loss by quantitative x-ray densitometry began participation in a longterm therapy program. The participants resided in a home for the mentally retarded in Texas, and none had metabolic, renal, cardiac, liver, or chromosomal disease. Forty-five were treated with sodium fluoride, 45 were treated with inorganic phosphate, and 45 were
•Supported by Grant AM 15979 from the National Institute of Arthritis, Metabolism, and Digestive Diseases, USPHS, and by grants from Hoyt Laboratories (Division of Colgate-Palmolive) and Parke Davis & Co. 'Reseach Institute, Texas Woman's Univ., Denton 76204. 'Diagnostic and Evaluation Center, Univ. of Texas Southwestern Medical School at Dallas 7S235.
204
treated with oxymetholone, an anabolic steroid; while 45 acted as nontreated controls and received a placebo. The subjects were randomly subdivided according to bone density and age into three groups. The mean group ages ranged from 57.4 to 58.4 (see Table 7). Group I received sodium fluoride (Hoyt Labs Osteo-FTrolecaps) as follows: 1. Body weight less than 135 lbs 20 mg fluoride ion/day 2. Body weight 135-175 lbs 30 mg fluoride ion/day 3. Body weight more than 175 lbs — 4 0 mg fluoride ion/day Group II received potassium phosphate (Hoyt Labs Hyper-Phos-K) at a dosage of 1,000 mg phosphate/day. Group III received oxymetholone (ParkeDavis Adroyd) as follows: 1. Body weight less than 135 lbs 7.5 mg/day 2. Body weight 135-175 lbs 10.0 mg/day 3. Body weight more than 175 lbs 12.5 mg/day Group IV received 5 ml of placebo (Emerson Labs Syrpalta) daily. All subjects were given physical and laboratory examinations initially and were reexamined as the study progressed. Renal
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
George P. Vose, MS,2 Doman K. Keele, MD,3 Alice M. Milner, PhD,2 Richard Rawley, BS, 2 Ted L. Roach,2 and Edgar E. Sprinkle III, MS2
THERAPIES IN OSTEOPOROSIS
acid, calcium, phosphorus, and iron were recorded. After obtaining totals for all nutrients , daily averages were calculated for comparison with the Recommended Dietary Allowance. All were met and many, such as calcium, iron, protein, and ascorbic acid, were exceeded by 50% or more (Maier, 1971). While the precise intake of nutrients was not quantitated for each individual, all subjects normally ate at least the amount to provide the RDAof the listed nutrients. Laboratory tests. — Periodic measurements of kidney function were made. These included serum urea-nitrogen, serum creatinine, and routine urinalyses. Other parameters included blood hemoglobin, SGOT, total serum acid and alkaline phosphatases, serum inorganic phosphorus and, in the fluoride-treated patients and the controls, serum inorganic fluoride. Definition of bone density norms. — At the outset of the study in 1970 the patients were classified into bone density grades in accordance with limited standards of normalcy available at that time. More recent contractual work between Texas Woman's University and the National Center for Health Statistics during the 4-year period from July, 1971 through June, 1975 is providing the normal limits of bone density-for-age of the U.S. population. Preliminary figures from the survey and from previous examinations of civil service employees reported by Vose and Engel (1973) are available at this time. When our study was planned in 1969 and initiated in 1970, normal density of the human phalanx was not precisely known, and our original demarking limits were based on a relatively small sample. On the basis of our current findings in the National Health Survey involving several thousand people, we are now aware that some participants in the program did not have abnormally low bone density. In reclassifying the patients in view of the new standards, among all four groups (fluoride, phosphate, oxymetholone, and controls) 19% were considered "normal," while 41% had what we have termed "mild" osteoporosis, 37% had "moderate" osteoporosis, and 3% had "marked" osteoporosis. The "x-ray aluminum equivalency" value of .240 has been accepted as normal-for-age phalanx density for males within the age range of our subjects. "Mild" osteoporosis denotes
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
studies included periodic urinalyses and determinations of serum urea nitrogen and creatinine were conducted on all patients. Serum fluoride was monitored on all patients receiving fluoride treatment and dosages adjusted so that the level was maintained below 15JUM. Patients receiving oxymetholone were monitored for prostatic cancer by prostate digital examinations semi-annually and serum acid phosphatase tests bimonthly, and were monitored for liver disease by SGOT and serum alkaline phosphatase analyses throughout the study. Ophthalmological examinations. — Ophthalmological examinations by slit-lamp observation were made of the phosphatetreated patients and the controls. Bone mineral measurements. — Patients who were selected for the study were radiographed initially and at 6-week intervals for bone quality determination. Radiographs were made of the left hand at each test date for routine x-ray densitometry of phalanx V-2 (middle digit of the small finger), which was selected as the bone to be monitored because in an earlier investigation (Goldsmith et al., 1971) it was found that the mineral content of that bone correlated best with diagnosed vertebral osteoporosis (p < .001 at the phalanx V-2 site vs/7 < .05 at the distal radius, but N.S. at the os calis). The photometric computing apparatus used by this laboratory has been described previously (Mack et al., 1959; Vose, 1969; Vose & Keele, 1970). The instrument consists essentially of a modified Knorr-Albers microdensitometer interfaced with a digital computer (D.E.C. PDP-8) connected to the output of the scanning unit through an amplifier and incorporated with teletype readout. The instrument is capable of reproducibility within 1%, and the overall technique error is considered to be less than 5%. Dietary assessment. — Institutional diets were planned in 3-mo cycles by a nutritionist and evaluated according to the Recommended Dietary Allowance of the U.S. National Research Council. Provisions were made to adapt the menu for special diets and for patients with masticulatory problems. The complete diet was assessed according to nutritive composition of foods listed in the USDA Handbook no. 8. Protein, calories, vitamin D, thiamine, riboflavin, ascorbic
205
206
VOSE, KEELE, MILNER, RAWLEY, ROACH, AND SPRINKLE
Table 1. Bone Density at Time Zero (Initial Intercept of Regression Slope) for Patients in Each Treatment Group and the Controls. Al. Equiv. Range
Fluoride
Group Phosphate Oxymetholone
.24t) .258 .261 and above (SD = .O16) (SD = .O17) n = 11 n= 7
Controls
.253 (SD = .009) n=7
.272 (SD = .O17) n= 9
.221 .213 (SD = .010) (SD = .OO7) n =13 n= 15
.217 (SD=.O12) n = 18
.222 (SD = .011) n = 20
.199 .181 .174 and below (§D = .011) (SD = .O2O) n = 23 n = 21
.178 (SD=.O17) n = 20
.176 (SD = .O17) n=16
.200-.239
Fig. 1. Computer print-out of regression slope of bone density (x-ray aluminum equivalency) vs duration of treatment of a control subject as determined by method of least squares.
the initial data point has resulted in recalculations of patient assignment using the time-zero intercept of the regression slope instead of the recorded time-zero value, which is considered to be a more accurate procedure. RESULTS
Fracture incidence. — At the present 6-year point, 11 hip fractures have occurred in the 146 remaining patients of the 180 who originally started the program. All of the fractures have occurred in the control, oxymetholone, and phosphate subjects, and chi-square and Fisher's Exact Test indicate that neither the oxymetholone nor phosphate subjects were significantly different from the controls in regard to fracture incidence. It is interesting to note that, while not statistically significant, no hip fractures have occurred in the fluoridetreated patients during the 4-year treatment period and nearly 2 years of follow-up observations. By chi-square analysis of fractures among patients who did not receive fluoride vs those patients on fluoride therapy, the probability of this occurrence is p < 0.10. Admittedly, the tenability of this analysis is
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
those individuals with bone density values between .200 and .239; "moderate" osteoporosis indicates those subjects within the range of .150 and .199; and "marked" osteoporosis includes patients with densities of less than .150. Because the latter group is quite small among our total subjects (3%) it has been combined with the . 199 and below group. Assignment of participants into bone density classes. — In assessing the trends in bone mineral change during the program, radiographs were made of the left hand at 6-week intervals. The bone density analyzer used at Texas Woman's University equates the x-ray absorbence by bone with that of a standard aluminum wedge placed adjacent to the small finger during exposure and yields "bone density" in terms of "x-ray aluminum equivalency." To measure bone density changes, a plot was made of aluminum equivalency values for each test point and the best straight line fit of the points was determined by computer utilizing the method of Least Squares, and the intercept of the slope with the bone density coordinate was used as the phalanx density at time zero. The time zero intercepts for the four groups are shown in Table 1. Fig. 1 is an example of a computer printout of data points and the Least Squares fit of the regression slope. Grouping of the patients was based on photometric evaluations of radiographs made approximately 9 mo before the initiation of treatment. Fig. 1 indicates that an experimental error produces a scatter of individual data points above and below the regression line. The original, inappropriate matching based on
THERAPIES IN OSTEOPOROSIS
Table 2. Hip Fracture Occurrence in Each Treatment Group (Transcervical or Subtrochanteric).
207
MODEKATE/MARKED OSTEOPOROSIS
s
•6
z „
i-g
3 29 +4 J-
< E >• E
Control
Patient No.
Age at Fracture Occurrence (Years)
20 164
52 60
.195 .261
-13.3% + 19.5%
40 106 117 135 165 172
52 72 60 60 54 58
.209 .175 .252 .130 .160 .210
-6.0% -16.6% + 14.3% -66.2% -27.3% -0.4%
25 43 175
60 59 57
.214 .151 .180
-0.1% -43.7% -21.7%
2^
^ r l de
'
^
* 1 'l '''-
••
.1.
•2
_
*E 0 S E CHANGE ALENCY |
Group
Bone Density at Fracture OccurDifference rence from Normal(A.E.)a for-Age
"
Hhnsn.'iaie
r
-2 • 4
H>
gg u
0.
1
1
Fluoride
Oxymetholone 3
Fig. 2. Mean percentage of changes in x-ray aluminum equivalency of phalanx V-2 during the treatment program for subjects with moderate/marked osteoporosis.
and -5.8% for the controls and oxymetholone subjects. In viewing the trends among the patients with initially "moderate/marked" osteoquestionable, since the majority of patients porosis only — those subjects most in need of not receiving fluoride were receiving either therapeutic assistance — the group mean oxymetholone or phosphate with the remote increases were impressive (although not possibility that those compounds were con- significant) at +3.5% and +0.9% for the ducive to fracturing. Of the 11 hip fractures, fluoride and phosphate patients, respectively. 9 subjects had below-normal bone densities at The control subjects in the same bone density fracture occurrence while 2 subjects had classification exhibited a mean bone density above-normal densities (see Table 2). loss of-4.3%, and the oxymetholone group had Bone mineral changes by densitometry. — a mean loss of-5.7%. (The foregoing changes Bone density within the total skeleton normally represent terminal values for all patients decreases at a mean rate of about 1% per year, averaged, regardless of whether or not the which is approximately the same as that entire 208-week treatment period was we have observed among the control subjects completed.) in this study. The mean percentage of loss Analysis of covariance was conducted on among control subjects (regardless of early the percentage of change in x-ray aluminum termination or full-period completion) in all equivalency of phalanx V-2 for subjects in bone density classifications combined was each of three levels of bone density. Signifi-3.3% in 4 years. Fig. 2 depicts that the mean cant differences between the fluoride and percentage of loss in the control subjects phosphate treated patients vs their controls with "moderate/marked" osteoporosis was were observed only when all classes of initial perhaps a bit greater at -4.3% during the bone density were combined (p < 0.02 and 4-year period. p < 0.05, respectively). This information is The patients treated with fluoride and given in Table 3. When the subjects were phosphate exhibited trends in bone density subdivided into the three initial bone density losses which were less marked than in the levels, however, none of the groups exhibited controls when all four bone density classes impressive differences by covariance analysis were combined. The losses in bone density even though the conspicuous differences in over the 4-year period for subjects in all regression slopes shown in Fig. 2 were evident. four bone density classes combined were It is recognized that pairwise comparisons in -0.2% and -1.7% for the fluoride and phosphate this manner may be overly liberal, but the trend patients, respectively, in contrast with -3.3% is interesting. a
A . E . = X-ray aluminum equivalency
Downloaded from http://geronj.oxfordjournals.org/ at University of Otago on July 2, 2015
Phosphate
208
VOSE, KEELE, MILNER, RAWLEY, ROACH, AND SPRINKLE
Table 3. Co variance Analysis of Variance of Percentage of Change in X-Ray Aluminum Equivalency of Phalanx V-2 for all Subjects Combined and for Subjects in Each of Four Levels of Bone Density. Fluoride vs Controls All Subjects Combined Nonosteoporotic (.240 and above)
Oxymetholone vs Controls
Oxymetholone
-0.060
-0.033
-0.035
-0.082
Nonosteoporotic (.240 and above)
-0.089
-0.044
-0.048
-0.103
F = 4.368** F = 0.003
F = 2.750 F = 0.189
F = 0.465
F = 0.257
F = 2.731
Mild osteoporosis (.200-.239)
-0.045
-0.058
-0.049
-0.079
F= 3.631
F = 1.287
F = 0.718
Moderate/marked osteoporosis (.199 and below)
-0.047
0.004
-0.008
-0.063
Table 4. Mean Percentage of Change by Treatment and by Bone Density Grade Within Treatments. Controls Fluoride Phosphate Oxymetholone -3.5
-1.8
-2.6
-6.9
All subjects combined (unweighted)
Nonosteoporotic (.240 and above)
-4.7
-3.3
-3.7
-8.3
-5.0
Mild osteoporosis (.200-.239)
-2.3
-4.6
-4.2
-5.8
-4.2
Moderate/marked osteoporosis (.199 and below)
All Subjects Combined (unweighted)
Phosphate
F = 5.969* F = 0.448
•Significant atp
