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Sustained-Release Sodium Fluoride in the Treatment of the Elderly With Established Osteoporosis
Craig D. Rubin, MD;
Charles Y. C. Pak, MD;
Beverley Adams-Huet, MS;
Harry K. Genant, MD;
Jiao Li, MD;
D. Sudhaker Rao, MD
Arch Intern Med. 2001;161:2325-2333.
ABSTRACT
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Background We ascertained the safety and efficacy of fluoride in augmenting spinal
bone mass and reducing spinal fractures in older women with established osteoporosis.
We compared a combination of sustained-release sodium fluoride, calcium citrate,
and cholecalciferol (SR-NaF group) with calcium and cholecalciferol alone
(control group).
Methods Eighty-five ambulatory women aged 65 years or older with 1 or more nontraumatic
vertebral compression fractures were enrolled in a 42-month randomized, double-blind,
placebo-controlled trial. Primary outcome measures were vertebral fracture
rate, bone mass, and safety.
Results The vertebral fracture rate determined by means of computer assistance
in the SR-NaF group was significantly lower than that in the control group
(relative risk [RR], 0.32; 95% confidence interval [CI], 0.14-0.73; P = .007). Results of visual adjudicated inspection also
confirmed a significant reduction in fracture rate (RR, 0.40; 95% CI, 0.17-0.95; P = .04). Bone mineral density in L2 through L4 increased
significantly from baseline in the SR-NaF group by 5.4% (95% CI, 2.7%-8.2%; P<.001), and by 3.2% in the control group (95% CI, 0.8%-5.6%; P = .01). The between-group differences in bone mineral
density were not significant. The femoral neck and total hip bone mineral
density remained stable in the SR-NaF group and was not significantly different
from that of the control group. There were no significant differences in adverse
effects between groups.
Conclusion The SR-NaF group significantly decreased the risk for vertebral fractures
and increased spinal bone mass without reducing bone mass at the femoral neck
and total hip.
INTRODUCTION
OSTEOPOROSIS is a common and morbid problem whose impact on public health
will increase as the population ages.1-2
The pathophysiology of osteoporosis in the late postmenopausal period is believed
to be related to senescent changes in osteoblastic function resulting in a
decline in bone formation.3-5
In addition, bone turnover may increase with aging.6-7
The latter appears in part because of impaired calcium absorption resulting
in secondary hyperparathyroidism.8 In this
way, calcium homeostasis is maintained at the expense of bone mass. The adequate
provision of calcium and vitamin D can suppress parathyroid function and reduce
bone turnover.9-10 Calcium and
cholecalciferol (vitamin D) supplementation in older patients has been shown
to decrease risk for fracture.11-13
During the past decade, new pharmacological interventions have become available
to treat osteoporosis.14-17
These agents are directed primarily toward the inhibition of osteoclastic
activity, thereby reducing bone resorption and turnover.18
At present, there are no approved anabolic or bone-forming agents available
for treating osteoporosis. Such therapies influence bone mass through the
stimulation of osteoblastic activity, resulting in increased bone mass. Sodium
fluoride is known to stimulate bone formation.19-20
When administered in low doses,21-24
bone mass is increased and risk for vertebral fractures is reduced in patients
with osteoporosis. However, uncertainty remains about the efficacy and safety
of sodium fluoride.25-26 In studies
of patients with osteoporosis treated with continuous25-26
and/or high-dose26 sodium fluoride, the risk
for vertebral fractures was unchanged compared with that of controls, despite
increases in spinal bone mass in the sodium fluoride–treated group.
In addition, increased numbers of nonvertebral fractures in sodium fluoride–treated
patients raised concern about impaired bone quality and reduced bone strength.26 Moreover, serious adverse effects have been associated
with sodium fluoride. In particular, gastrointestinal (GI) tract problems
such as gastritis and acute lower-extremity pain syndromes have been reported.25-26 The former is believed to be related
to the conversion of sodium fluoride to hydrofluoric acid in the stomach;
the latter, to excessive bone remodeling, resulting in weaker bone and causing
microfractures.27-28
Because age-related bone loss is due to decreased bone formation and
altered calcium metabolism, we postulated that an appropriate therapeutic
intervention for treating age-related osteoporosis would incorporate an anabolic
agent to stimulate osteoblastic activity and adequate calcium and cholecalciferol
to blunt secondary hyperparathyroidism and to reduce mobilization of calcium
from the skeleton.
To study the effect of this strategy, we conducted a randomized, double-blind,
controlled trial comparing the safety and efficacy of an anabolic agent in
the form of sustained-released sodium fluoride combined with calcium citrate
and cholecalciferol with those of calcium and cholecalciferol alone in elderly
women with established age-related osteoporosis. We herein report the results
of this study.
SUBJECTS AND METHODS
SUBJECTS
Women aged 65 years or older with at least 1 nontraumatic vertebral
compression fracture were recruited by means of newspaper advertisements for
the study. The protocol was approved by the Institutional Review Board of
the University of Texas Southwestern Medical Center at Dallas. Patient recruitment,
study design, and conduct of the trial were performed by one of us (C.D.R.),
with nursing, dietary assessment, basic laboratory, and statistical support
by staff of the General Clinical Research Center at the University of Texas
Southwestern Medical Center. Additional support included special laboratory
analysis and fracture determination as described herein.29
Prospective subjects underwent initial screening and evaluation for
the purpose of verifying the presence of established osteoporosis and to exclude
secondary causes of osteoporosis. A thorough medical history was obtained.
Subjects were excluded from participation if they had a history of active
peptic ulcer disease, nephrolithiasis, primary hyperparathyroidism, inflammatory
bowel disease, or long-term use of oral steroids or phenytoin sodium. Because
of historical concern regarding the possibility of increased risk for hip
fractures with sodium fluoride therapy, patients with a history of hip fracture
were excluded. Patients were also excluded if they had taken a bone active
agent within the past year (eg, calcitonin, bisphosphonate) or ever (sodium
fluoride). Routine screening laboratory studies included a complete blood
cell count; measurement of electrolyte, glucose, creatinine, liver enzyme,
thyrotropin, and parathyroid hormone (PTH) levels; serum protein electrophoresis;
and routine urinalysis. Dietary calcium intake was estimated by a registered
dietitian using a food frequency questionnaire.
The protocol specifically attempted to recruit a cohort of women representative
of a typical outpatient population of older women with osteoporosis. Therefore,
patients commonly had multiple medical problems and complaints. For example,
patients with a history of GI tract complaints, musculoskeletal complaints,
concurrent use of aspirin or anti-inflammatory medications, or use of agents
to treat GI tract disorders were included. Patients with musculoskeletal complaints
were carefully asked the location, severity, and character of complaints to
monitor for potentially new or worsening symptoms during the study. In addition,
because estrogen is commonly used and recommended for a variety of reasons
in a typical population of postmenopausal women, current estrogen use (stable
dose for at least the past year) was allowed, but patients were stratified
to ensure equal distribution between groups.
A baseline lateral thoracic and lumbar x-ray film was obtained to confirm
the presence of at least 1 vertebral compression fracture from T4 through
L5, defined as at least a 20% reduction in anterior, middle, or posterior
vertebral height in the absence of significant trauma. There was no bone mineral
density (BMD) requirement for study entry.
RANDOMIZATION AND TREATMENT SCHEME
Once patients met entry criteria, they were randomly assigned to receive
sustained-release sodium fluoride, 25 mg (Neosten; Mission Pharmacal Company,
San Antonio, Tex) (SR-NaF group), or a placebo of identical appearance taken
in the morning and at bedtime (control group). Both groups received calcium
with cholecalciferol (Citracal with Vitamin D; Mission Pharmacal Company)
in 3 divided doses (total dose, 945 mg of elemental calcium citrate and 600
IU of cholecalciferol daily). To ensure a balanced distribution of prognostic
variables between groups, patients were dynamically randomized to the SR-NaF
or control group with the use of biased-coin minimization30
to stratify on the basis of age, baseline L2 through L4 BMD, prevalent fractures,
and estrogen use. The clinical investigators, General Clinical Research Center
personnel with patient contact, and patients were unaware of subject randomization
and assignment throughout the study. Independent research personnel performed
the randomization and had no other study participation. Treatment was given
for 3 cycles, each cycle consisting of a 12-month administration of sustained-release
sodium fluride or placebo followed by a 2-month period free of study medication.
The intermittent format of administration was devised to help ensure adequate
mineralization of newly formed bone and to avoid the accumulation of toxic
fluoride levels in the bone.31 Calcium and
cholecalciferol were given continuously for 42 months.
BIOCHEMICAL MEASUREMENTS
At baseline and 3, 6, 9, 12, and 14 months of each cycle, a multisystem
screening of serum (SMA-20; Smith-Kline Laboratory, Dallas, Tex); complete
blood cell count; reticulocyte count; levels of serum fluoride (ion-specific
electrode), 24-hour urinary calcium (using atomic-absorption spectrophotometry),
and 24-hour urinary N-telopeptide (using an enzyme-linked immunosorbent assay;
Ostex International, Inc, Seattle, Wash); and presence of occult blood in
feces were measured. In addition, at baseline and 6, 12, and 14 months of
each cycle, we tested for levels of serum PTH (whole-molecule immunoradiometric
assay using a kit from Nichols Institute, San Juan Capistrano, Calif), serum
bone-specific alkaline phosphatase (BSAP) (Metra Biosystems, Mountain View,
Calif), and serum osteocalcin (using an immunoradiometric assay; Immutopics,
Inc, San Clemente, Calif). Levels of 25-hydroxyvitamin D and 1,25-dihydroxyvitamin
D were determined at baseline and every 12 months as previously described.32-34
BONE MASS MEASUREMENTS
Bone mineral density of the L2 through L4 lumbar spine, femoral neck,
and total hip were measured by means of dual-energy x-ray absorptiometry using
a scanner (Hologic QDR-2000; Hologic, Waltham, Mass) at baseline and 6 and
12 months of each cycle. The coefficient of variation, based on manufacturer-supplied
information for measurement of L2 through L4 and hip BMD, was 1%.
FRACTURE DETERMINATION
Lateral spine films were obtained annually to detect new or recurrent
fractures. Incident fractures occurring at all cycles were determined by means
of computer-assisted analysis in Dallas (quantitative morphometry [QM-Dallas]).
Fracture quantitation by means of the QM-Dallas technique used a digitizing
board and computer program to measure vertebral heights and area.35 Six landmarks were placed to outline the anterior,
middle, and posterior height of T4 through L5 from lateral thoracic and lumbar
films obained at the end of each 12-month treatment cycle. The analysis was
performed by a single trained technician with no patient contact and who was
unaware of treatment assignment. The intraobserver precision was 1.5%. A computer
program calculated the change in each vertebral height and area, after correcting
for magnification error between cycles. A reduction in height of more than
20% and in area of at least 10% from baseline defined a new fracture.36
In addition, the first and final films (pretreatment and last cycle)
were examined by using the following methods (72 subjects). Quantitative morphometry
was also determined by external analysis (performed bh H.K.G. and J. L. [San
Francisco (SM) group]) using their own software, but with the same fracture
criteria as QM in Dallas. Radiographs were visually inspected for qualitative
determination of incident fractures independently by an external expert (D.S.R.)
and an internal expert (Khashayar Sakhaee, MD). No specific definition of
a fracture was given to the reviewers. The reviewers were asked to assess
baseline and final radiographs to identify vertebral fractures that had newly
appeared or worsened from baseline, and that they believed to be permanent
deformations. All experts were unaware of group assignment and measurements
from the QM-Dallas data.
A planned fracture analysis was used to evaluate "discordant" vertebrae
findings between results of the Dallas group and QM-SF group. For first and
last films, a consensus reading from Dallas was defined by an agreement of
2 of 3 analyses (QM-Dallas and both independent visual reviews). The results
of this consensus reading from Dallas were compared with the QM-SF findings,
and vertebrae with differing fracture status were identified from each patient.
The discordant vertebrae findings so identified were examined visually by
the SF investigators. The results of their joint visual reading replaced the
discordant fracture status of vertebrae to yield the adjudicated result of
the Dallas and SF groups.
There was good to excellent agreement between the QM-Dallas and other
techniques to assess incident fractures (Sakhaee visual,  = 0.83; D.S.R.
visual, = 0.74; QM-SF unadjusted, = 0.73; SF adjudicated,
= 0.84).
SAFETY EVALUATION
Subjects underwent evaluation for adverse effects every 3 months. Subjects
were specifically queried regarding the development of any new or worsening
GI tract or musculoskeletal symptoms using a questionnaire. Subjects were
questioned about the presence of lower extremity discomfort, including shin
pain. Stool specimens were obtained every 3 months to test for fecal occult
blood.
Research nurses performed pill counts of code pills (sodium fluoride
or placebo) during each follow-up visit. Calcium tablets were not counted.
STATISTICAL ANALYSIS
Baseline characteristics were summarized using descriptive statistics.
Because some patients had multiple vertebral fractures, differences in vertebral
fracture rates between the control and SR-NaF groups were assessed using correlated
binary regression models with generalized estimating equations.37
The correlated binary regression method was applied to the incident fracture
data from pretreatment to the last cycle obtained by means of QM-Dallas, adjudicated-Dallas,
and SF methods. Covariates such as estrogen use and initial BMD were assessed
in these models. In addition, incident fracture data at all cycles obtained
by means of the QM-Dallas method were analyzed using Cox proportional hazards
models for analysis of multiple failure times with the marginal approach of
Wei et al38 and Lin.39
The number needed to treat was calculated as the reciprocal of the absolute
risk reduction.40
Results of bone densitometry were assessed using repeated-measures analysis
of variance and change from baseline with the use of paired t tests. Biochemical measurements were assessed using repeated-measures
analysis of variance. Adverse events were compared between groups using the
Fisher exact test.
Statistical analysis was performed at the General Clinical Research
Center using commercially available software (SAS version 8.0; SAS Institute,
Cary, NC). We used SAS macros written by Terry Therneau, PhD, of Mayo Clinic,
Rochester, Minn, for Cox regression analysis of multivariate failure times.
RESULTS
BASELINE PRESENTATION
The mean age of study participants was 73 years, with approximately
26 years since menopause. Baseline characteristics were similar in the SR-NaF
and control groups (Table 1).
Eighty-five subjects were randomized, of whom 13 withdrew in the first 6 months
before completing the first cycle. None of these early withdrawals were due
to study-related adverse events. Nine of the 13 early withdrawals failed to
return for the first follow-up visit at 3 months. Two patients (1 from each
group) had hip fractures within a month of beginning treatment. Lack of interest
and transportation problems were the most common reason for the early withdrawals.
Seventy-two subjects (85%) completed at least 1 cycle of therapy (14 months).
Sixty-five subjects (76%) completed all 3 cycles (42 months). The mean (±SD)
duration of treatment was 2.9 ± 0.4 cycles for the SR-NaF and control
groups.
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Table 1. Baseline Characteristics of Randomized Patients*
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FRACTURE DATA
The analysis of spinal fracture data during the 3 treatment cycles by
means of correlated binary regression showed a 68% rate reduction of new or
recurrent fracture in the SR-NaF group compared with the control group, when
fractures were quantitated by means of the QM-Dallas technique (relative risk
[RR], 0.32; 95% confidence interval [CI], 0.14-0.73; P
= .007). A 60% reduction in the fracture rate in the SR-NaF group was seen
(Table 2) when fractures were
detected by means of the adjudicated Dallas and SF techniques (RR, 0.40; 95%
CI, 0.17-0.95; P = .04). When an analysis was performed
for the number needed to treat, 8 patients needed to be treated to prevent
1 vertebral fracture by means of the QM-Dallas technique, and 9 patients by
means of the adjudicated-Dallas and -SF techniques.
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Table 2. Vertebral Fractures*
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For spinal fractures detected by means of QM-Dallas technique from all
cycles of treatment, the multivariate Cox model showed a significantly lower
relapse rate in the SR-NaF group compared with that in the control group (RR,
0.31; 95% CI, 0.13-0.73; P = .007).
Estrogen use was not a significant covariate (RR, 0.97; P = .96) for fracture in assessing fracture risk. In addition, there
were no differences between estrogen users and nonusers in baseline demographic
or clinical characteristics.
There were no differences in the number of nonvertebral fractures between
groups. One hip fracture occurred in each group (in addition to 2 early withdrawals).
Seven nonvertebral fractures occurred in each group. These included 1 wrist,
1 metacarpal, 1 humeral, 1 femur, and 3 toe fractures in the SR-NaF group,
and 2 patellar, 3 rib, 1 wrist, and 1 toe fracture in the control group.
BMD DATA
After 3 treatment cycles, L2 through L4 BMD increased by 5.4% (95% CI,
2.7%-8.2%; P<.001) in the SR-NaF group and by
3.2% (95% CI, 0.8%-5.6%; P = .01) in the control
group. There were no significant differences between groups (95% CI, -1.2%
to 5.8%). In both groups, BMD was maintained at the femoral neck and total
hip (Figure 1).
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Figure 1. Bone mineral density for lumbar
spine, femoral neck, and total hip. Data are given as mean (±SEM) percentage
of change from baseline. SR-NaF indicates sustained-release sodium fluoride;
asterisk, P<.05 compared with baseline; dagger, P<.01 compared with baseline; and double dagger, P<.001 compared with baseline.
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BIOCHEMICAL VARIABLES OF BONE METABOLISM
Serum and urinary variables of bone metabolism for the 12-month visit
of each cycle are reported in Table 3.
Urinary N-telopeptide levels, reflecting bone resorption, declined in the
control group and were maintained in the SR-NaF group. Urinary hydroxyproline
levels followed a similar trend. Urinary calcium levels increased in both
groups but to a lesser degree in the SR-NaF group.
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Table 3. Serum and Urinary Biochemical Findings After Treatment With
Placebo or Sustained-Release Sodium Fluoridea
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The SR-NaF group showed significant increases in markers of bone formation
compared with the control group. The BSAP response was significantly higher
in the SR-NaF group than in the control group (P
= .009). Differences in BSAP response were not significant in samples measured
at the end of the 2-month period free of study medication, but once sodium
fluoride therapy was reinitiated, levels increased significantly in the SR-NaF
group. Levels of serum osteocalcin during treatment were also significantly
higher (P = .01) in the SR-NaF group compared with
the control group (Figure 2).
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Figure 2. Measurement of biochemical markers
during the 42-month study. Data are given as mean (±SEM). PTH indicates
parathyroid hormone; BSAP, bone-specific alkaline phosphatase; BCE, bone collagen
equivalents; and SR-NaF, sustained-release sodium fluoride. Months 12 to 14,
26 to 28, and 40 to 42 represent 2-month periods free of study medication.
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Serum PTH levels tended to decline similarly in both groups, but this
trend was significant in the SR-NaF group (P = .045)
and was borderline (P = .12) in the control group.
Serum levels of 25-dihydroxyvitamin D increased significantly in both groups
compared with baseline (P<.01) and were not different
between groups. Levels of 1,25-dihydroxyvitamin D tended to fall in both groups.
Serum calcium and phosphorus levels remained stable and without significant
differences between groups during the 3-year study.
SAFETY
There were no differences observed in GI tract and musculoskeletal adverse
effects between the SR-NaF and control groups. No subject withdrew from the
study because of adverse effects.
Occult blood in stool was identified in 7 patients: 4 in the SR-NaF
group and 3 in the control group. In the SR-NaF group, occult GI tract bleeding
developed in 1 patient who was also receiving a nonsteroidal anti-inflammatory
drug. Endoscopy disclosed peptic erosions. The nonsteroidal anti-inflammatory
drug therapy was discontinued and histamine2 blockers were prescribed.
Patient enrollment continued (blinding was maintained). Erosion healing was
documented by subsequent endoscopy findings. The subject completed the study
with no recurrence of occult GI tract blood loss. One patient receiving hormone
replacement therapy was menstruating during a single follow-up, with subsequent
negative findings for occult blood in stools, and 1 patient had positive findings
during a hemorrhoidal flare. One patient dropped out after 2 months in the
study because of bright red blood in the rectum (undocumented) and "too hectic
a personal schedule to participate in the study." In the control group, 1
patient was menstruating while receiving hormone replacement therapy, 1 patient
experienced hemorrhoidal flare, and a gastric ulcer developed in 1 patient.
Adverse effects previously associated with higher doses of sodium fluoride
therapy were absent.26 The prevalence of any
history of musculoskeletal complaint in both groups was high. Complaints of
at least 1 intermittent musculoskeletal problem of a chronic nature at enrollment
were made by 95% (42/44) of the SR-NaF group and 98% (40/41) of the control
group. Specifically, no symptoms developed suggestive of acute lower extremity
pain syndromes. Although bone scans were available to assess for microfractures
and/or to evaluate acute lower extremity pain, neither were indicated.
The number of adverse effects in the GI tract was similar between groups.
At baseline, 70% of patients in the SR-NaF group and 51% in the control group
had noted at least 1 chronic GI tract complaint. A new episode of transient
dyspepsia was reported sometime during the 42-month trial in 14 subjects (32%)
in the SR-NaF group and 14 (34%) in the control group.
Compliance, determined by pill count at each visit, found that patients
in the SR-NaF group were compliant 73% of the time compared with 71% for the
controls.
Seven patients withdrew after completing 1 cycle: 4 were in the SR-NaF
group and 3 in the control group. Causes of withdrawal were hip fracture in
1 patient in the SR-NaF group, gastric ulcer in 1 patient in the control group,
emphysema and suspected lung cancer in a patient with a smoking history in
the control group, death due to natural causes in 1 patient in the control
group, use of other bone active agents or steroids in 2 patients in the SR-NaF
group, and failure to return in 1 patient in the SR-NaF group. Another control
group patient had a hip fracture at the end of the study but completed the
study. One patient in each group had an esophageal ulcer, but both completed
the study.
COMMENT
Our findings show that the combination therapy consisting of sustained-release
sodium fluoride, calcium, and cholecalciferol in older women with established
osteoporosis significantly reduced the risk for subsequent vertebral fractures
compared with cholecalciferol and calcium therapy alone. The reduction in
vertebral fracture rate and increased vertebral BMD occurred without reducing
bone mass at the hip or increasing nonvertebral fractures. The redistribution
of bone mass from other sites to the spine has been a commonly held concern
regarding sodium fluoride therapy.26
Increases in biochemical markers of bone formation in the SR-NaF group
suggest that the mechanism of fracture reduction was stimulation of bone remodeling
and bone formation. These findings support achievement of reductions in vertebral
fracture risk by combining a formation-stimulating and/or antiresorptive agent.41
Lumbar BMD increased significantly compared with baseline in both groups,
but between-group differences were not significant. Furthermore, the increase
in BMD was not as large as in a previously reported trial using sustained-release
sodium fluoride.23 There may be multiple reasons
for this finding. First, spinal BMD measurements are commonly difficult to
assess in older patients because of degenerative spinal changes that present
technical difficulties in assessing spinal BMD. A review of L2 through L4
spinal films found 14 subjects with severe scoliosis, aortic calcifications,
severely collapsed vertebrae, or sclerotic degenerative arthritis. The clarity
of individual radiographs at baseline was not used as a consideration for
study entry. That is, a single vertebral compression was required for entry,
but other qualitative radiographic aspects were not considered. Although this
method has limitations for BMD and fracture analysis, the study was designed
to enroll a typical ambulatory population of elderly patients. To exclude
older patients because of degenerative spinal changes could have hindered
this goal.
Second, the lack of a difference in BMD between groups may be related
to the dose of calcium and cholecalciferol given to all subjects. Both groups
received substantially higher doses of calcium and cholecalciferol than in
most clinical studies of osteoporosis, including an earlier study by Pak et
al23 using sustained-release sodium fluoride.
Indeed, the doses used are consistent with recommendations made by the Institute
of Medicine's Food and Nutrition Board in 1997, which recommended 600 IU of
cholecalciferol for persons older than 70 years, and the 1994 Consensus Development
Panel for Optimal Calcium Intake of the National Institutes of Health, which
recommended 1500 mg/d for estrogen-deficient, postmenopausal women. Although
the dose of calcium and cholecalciferol for the study protocol was selected
before current recommendations, the importance of calcium and cholecalciferol
in older patients has been demonstrated in a number of studies.11-13,42
Levels of 25-hydroxyvitamin D increased significantly in both groups,
supporting a pharmacologic effect of cholecalciferol supplementation. However,
the rise was small, and 25-hydroxyvitamn D levels remained within the normal
range. Surprisingly, 1,25-dihydroxyvitamin D levels fell in both groups. The
mechanism of the fall in 1,25-dihydroxyvitamin D level is not clear. Cholecalciferol
toxicity has been shown to inhibit renal 1 -hydroxylase activity.43 The subtle decline in PTH level seems a possible
but unlikely explanation for the fall in 1,25-dihydroxyvitamin D levels. Weisinger
et al44 reported that 1,25-dihydroxyvitamin
D levels are regulated by calcium independently of serum PTH in rats. Whether
the decline in PTH levels or influence of supplemental calcium independently
played a role in reducing 1,25-dihydroxyvitamin D levels in this study is
speculative and would require further investigation.
The results also demonstrate significant biochemical changes in markers
of bone turnover and resorption in patients receiving only calcium citrate
and cholecalciferol. A significant decline from baseline in urinary N-telopeptide
and serum osteocalcin levels was seen in the control group, suggesting that
bone turnover was reduced and resulting in the modest increase in bone mass
at the spine and maintenance at the hip. These findings support the therapeutically
effective antiresorptive action of the calcium and cholecalciferol.11-12 The pattern of decline in markers
of bone turnover is similar to that of other antiresorptive agents.14-16,45
However, the addition of a bone-forming agent (sustained-release sodium
fluoride) to calcium and cholecalciferol mitigated the reduction in markers
of bone turnover that was seen in the control group. As opposed to a reduction
in BSAP response seen with estrogen or bisphosphonates, potent inhibitors
of bone resorption, BSAP response increased and osteocalcin levels were maintained
in the SR-NaF group. Furthermore, urinary calcium levels increased in both
groups compared with baseline but significantly less in the SR-NaF subjects
compared with controls. This finding may be related to increased calcium use
by newly formed bone. The combination of a regimen of bone-forming (sustained-release
sodium fluoride) and antiresorptive (calcium and cholecalciferol) agents proved
effective in decreasing the vertebral fracture rate in this group of high-risk
patients. Whether the addition of a more potent antiresorptive agent, such
as a bisphosphonate or estrogen, would have shown greater therapeutic efficacy
is not known but would seem to be an appropriate avenue of future investigation.
The small subgroup of patients already receiving estrogen did not appear to
influence response to therapy.
The pattern of increased markers of bone turnover and formation has
also been seen with other anabolic agents. When PTH was given with estrogen
in postmenopausal women with osteoporosis, urinary N-telopeptide and serum
osteocalcin levels transiently increased compared with an estrogen-only group.46 These findings suggest that anabolic bone agents
such as fluoride and PTH may influence bone metabolism by increasing bone
turnover via osteoblastic stimulation or recruitment, directly or indirectly.
Since bone mass increases, a new resorption-formation coupling ratio seems
to be established.
The results of this study are similar to those of an earlier study in
which sustained-release sodium fluoride and calcium were given to postmenopausal
women with established osteoporosis.23 The
present study differs from that of Pak et al23
in that all patients in this trial received supplemental cholecalciferol (600
IU vs none) and a higher amount of supplemental calcium citrate (945 mg vs
800 mg). The mean age of patients was also somewhat older (73 vs 68 years),
and they were exclusively aged 65 years or older in this trial.
Our findings support the use of sustained-release sodium fluoride with
calcium and cholecalciferol in treating older ambulatory women with established
osteoporosis. Our results suggest this combination of therapy safely reduces
the risk for vertebral fractures by stimulating new bone formation by fluoride-mediated
increased osteoblastic activity. In addition, the adequate provision of calcium
and cholecalciferol reduces bone resorption. Therefore, this combination therapy
addresses 2 fundamental abnormalities underlying the pathophysiology of age-related
osteoporosis. Our findings also support investigations in the use of combining
bone-forming and antiresorptive agents in the treatment of osteoporosis.
AUTHOR INFORMATION
Accepted for publication March 29, 2001.
This work was supported by grants K08-AG00481 and M01-RR00633 from the
National Institutes of Health, Bethesda, Md.
Presented as a poster at the annual American Geriatrics Society Meeting,
Chicago, Ill, May 1-5, 1996, and at the 19th Annual American Bone and Mineral
Research Meeting, Cincinnati, Ohio, September 10-14, 1997.
We wish to thank Ann Heard, RN, Elizabeth McDonald, RN, and the staff
of the General Clinical Research Center, Dallas, Tex, for their invaluable
assistance in performing this study; John Poindexter for data management support;
and Khashayar Sakhaee, MD, for x-ray visual determination.
Corresponding author and reprints: Craig D. Rubin, MD, Geriatrics
Section, University of Texas Southwestern Medical Center, 5323 Harry Hines
Blvd, Dallas, TX 75390-8889 (e-mail: Craig.Rubin{at}UTSouthwestern.edu).
From the Department of Internal Medicine, University of Texas Southwestern
Medical Center at Dallas (Drs Rubin and Pak and Ms Adams-Huet); the Division
of Mineral Metabolism and the Osteoporosis and Arthritis Research Group, University
of California–San Francisco (Drs Genant and Li); and Department of Internal
Medicine, Henry Ford Hospital, Detroit, Mich (Dr Rao).
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