Effects of treatment with fluoride on bone mineral density and fracture risk - A meta-analysis

Article (PDF Available)inOsteoporosis International 19(3):257-68 · March 2008with124 Reads
DOI: 10.1007/s00198-007-0437-6 · Source: PubMed
Abstract
Fluoride has fallen into discredit due to the absence of an anti-fracture effect. However, in this meta-analysis, a fracture reducing potential was seen at low fluoride doses [< or =20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride)]: OR = 0.3, 95% CI: 0.1-0.9 for vertebral and OR = 0.5, 95% CI: 0.3-0.8 for non-vertebral fractures. Fluoride is incorporated into bone mineral and has an anabolic effect. However, the biomechanical competence of the newly formed bone may be reduced. A systematic search of PubMed, Embase, and ISI web of science yielded 2,028 references. Twenty-five eligible studies were identified. Spine BMD increased 7.9%, 95% CI: 5.4-10.5%, and hip BMD 2.1%, 95% CI: 0.9-3.4%. A meta-regression showed increasing spine BMD with increasing treatment duration (5.04 +/- 2.16%/year of treatment). Overall there was no significant effect on the risk of vertebral (OR = 0.8, 95% CI: 0.5-1.5) or non-vertebral fracture (OR = 0.8, 95% CI: 0.5-1.4). With a daily dose of < or =20 mg fluoride equivalents (152 mg monofluorophosphate/44 mg sodium fluoride), there was a statistically significant reduction in vertebral (OR = 0.3, 95% CI: 0.1-0.9) and non-vertebral (OR = 0.5, 95% CI: 0.3-0.8) fracture risk. With a daily dose >20 mg fluoride equivalents, there was no significant reduction in vertebral (OR = 1.3, 95% CI: 0.8-2.0) and non-vertebral (OR = 1.5, 95% CI: 0.8-2.8) fracture risk. Fluoride treatment increases spine and hip BMD, depending on treatment duration. Overall there was no effect on hip or spine fracture risk. However, in subgroup analyses a low fluoride dose (< or =20 mg/day of fluoride equivalents) was associated with a significant reduction in fracture risk.

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ORIGINAL ARTICLE
Effects of treatment with fluoride on bone mineral density
and fracture risk - a meta-analysis
P. Vestergaard & N. R. Jorgensen & P. Schwarz &
L. Mosekilde
Received: 17 March 2007 / Accepted: 9 July 2007
#
International Osteoporosis Foundation and National Osteoporosis Foundation 2007
Abstract
Summary Fluoride has fallen into discredit due to the
absence of an anti-fracture effect. However, in this meta-
analysis, a fracture reducing potential was seen at low
fluoride doses [20 mg fluoride equivalents (152 mg
monofluorophosphate/ 44 mg sodium fluoride)]: OR=0.3,
95% CI: 0.10.9 for vertebral and OR=0.5, 95% CI: 0.3
0.8 for non-vertebral fractures.
Introduction Fluoride is incorporated into bone mineral and
has an anabolic effect. However, the biomechanical
competence of the newly formed bone may be reduced.
Methods A systematic search of PubMed, Embase, and ISI
web of science yielded 2,028 references.
Results Twenty-five eligible studies were identified. Spine
BMD increased 7.9%, 95% CI: 5.410.5%, and hip BMD
2.1%, 95% CI: 0.93.4%. A meta-regression showed
increasing spine BMD with increasing treatment duration
(5.04±2.16%/year of treatment). Overall there was no
significant effect on the risk of vertebral (OR=0.8, 95%
CI: 0.51.5) or non-vertebral fracture (OR =0.8, 95% CI:
0.51.4). With a daily dose of 20 mg fluoride equivalents
(152 mg monofluorophosphate/44 mg sodium fluoride),
there was a statistically significant reduct ion in vertebral
(OR=0.3, 95% CI: 0.10.9) and non-vertebral (OR=0.5,
95% CI: 0.30.8) fracture risk. With a daily dose >20 mg
fluoride equivalents, there was no significant reduction in
vertebral (OR=1.3, 95% CI: 0.82.0) and non-vertebral
(OR=1.5, 95% CI: 0.82.8) fracture risk.
Conclusions Fluoride treatment increases spine and hip
BMD, depending on treatment duration. Overall there was
no effect on hip or spine fracture risk. However, in
subgroup analyses a low fluoride dose (20 mg/day of
fluoride equivalents) was as sociated with a significant
reduction in fracture risk.
Keywords Fluoride
.
Fracture
.
Meta-analysis
.
Meta-regression
.
Monofluorophosphate
.
Sodium fluoride
Fluoride has fallen into discredit as treat ment for osteopo-
rosis due to lack of anti-fracture effect in meta-analyses and
side effects [1]. However, with the advent of strontium
ranelate [2], a new treatment principle also based on
incorporation of a mineral into bone has emerged. Although
considerable differences exist between strontium and
fluoride, they are both incorporated into the crystal
structure of bone. New insight into the effects of such
drugs may, therefore, be obtained through analysis of
existing data on fluoride.
The fluoride anion can substitute for hydroxyl in
hydroxyapatite crystals and thereby change the crystalline
structure of the bone tissue [3]. The fluoride content in
fluoridated hydroxyapati te increases osteoblast cell attach-
ment, prolifera tion and differentiation in ROS17/2.8 rat
osteosarcoma cells [4]. Fluoride also stimulates bone
Osteoporos Int
DOI 10.1007/s00198-007-0437-6
P. Vestergaard (*)
:
L. Mosekilde
The Osteoporosis Clinic,
Department of Endocrinology and Metabolism C,
Aarhus University Hospital Aarhus Amtssygehus,
Tage Hansens Gade 2,
8000 Aarhus C, Denmark
e-mail: p-vest@post4.tele.dk
N. R. Jorgensen
Department of Clinical Biochemistry,
Hvidovre Hospital,
Hvidovre, Denmark
N. R. Jorgensen
:
P. Schwarz
Research Center of Aging and Osteoporosis,
Department of Geriatrics, Glostrup University Hospital,
Glostrup, Denmark
formation at cellular [5, 6], tissue [7] and organ levels [8],
leading to a positive balance per remodelling cycle [7], an
increase in trabecular bone volume [7, 9] and trabecular
connectivity [10], and a positive overall calcium balance [8]
in osteoporotic patients. However, mineralisation is often
impaired with excessive osteoid formation and incomplete
mineralisation [7, 9], and at higher doses the fluorotic
bone may be a mixture of pre-existing lamellar bone and
newly formed woven bone [11]. Furthermore, biomechan-
ical testing of iliac crest bone biopsies indicates a decreased
mechanical strength after 5 years of fluoride treatment [12].
A previous meta-analysis (search date January 1998, 11
randomised controlled trials, 702 receiving intervention,
727 placebo) [1] showed a significant increase in lumbar
spine bone mineral density (BMD) of 8.1% at 2 years and
16.1% at 4 years of fluoride treat ment. The increase in hip
BMD was not significant, whereas forearm BMD decreased
significantly by -1.7% and -3.3% at 2 and 4 years,
respectively. The relative risk of new vertebral fractures
was u nchanged at 2 and 4 years. The risk of non-vertebral
fractures was unchanged after 2 years, but increased
significantly by 1.85% after 4 years. Fluoride treat ment
may be complicated by gastrointestinal side effects and
lower extremity pain syndrome with occasional stress
fractures [1 , 13].
The aim of the present meta-analysis was to explore the
effect of fluoride as sodium fluoride, monofluorophosphate
(MFP) or slow-release fluoride (SRF) on bone mineral
density, fracture risk and side effects with special attention
to the effect of dose, duration and formulation. We used the
following research questions:
1) Does fluoride treatment alone or in combination with
calcium, vitamin D or an antiresorptive drug increase
spine or hip BMD compared with calcium, vitamin D
or an antiresorptive drug?
2) Does fluoride treatment alone or in combination with
calcium, vitamin D or an antiresorptive drug reduce the
risk of vertebral or non-vertebral fractures compared
with calcium, vitamin D or an antiresorptive drug?
3) Were there differences in the effect of fluoride on BMD
or fracture risk that could be attributed to fluoride
formulation, dose or treatment duration?
4) What were the adverse effects of fluoride treatmen t?
Material and methods
PubMed (1951 and onwards), Embase (1974 and onwards),
and ISI web of science (1945 and onwards) were searched
using the MESH terms fluoride AND (bone mineral
OR fracture). The search date was September 20, 2006.
This search yielded 2,028 references.
The inclusion criteria were randomised clinical trials
(RCT) with fracture occurrence or changes in bone mineral
density (BMD) as outcome and using all formulations of
fluoride [sodium fluoride (NaF), slow-release fluoride
(SRF) or monofluorophosphate (MFP)] as exposure in at
least one treatment arm. The other treatment arm(s) could
include place bo, calci um and/or vitamin D or other
antiresorptive drugs (hormone replacement therapy or
etidronate were used in some trials). BMD had to be
measured at the lumbar spine or the femoral neck on
contemporary DEXA-scanners (Hologic, Norland, Lunar,
Sophos etc.). Spine fractures had to be verified on X-rays.
Studies on both females and males >18 years of age were
eligible along with studies on secondary osteoporosis and
glucocorticoid-induced osteoporosis. Exclusion criteria
were non-randomised trials and trial duration of less than
6 months. A total of 25 studies were included in the final
analysis.
There are some discrepancies between the present meta-
analysis and the prior meta-analysis from 1998 [1, 14]. We
included 25 RCTs (1,281 patients on fluoride and 1,067
controls, 2,348 in total) in the present study compared with
11 RCTs (1,429 patients) in total in the prior analysis. We
excluded one study included in the previous meta-analysis
[1], as it was not random ised [15]. A further two studies
were not included in the present meta-analysis as they
reported BMC and not BMD data and did not provide
fracture data [16, 17].
The data extracted consisted of number of patients with
one or more vertebral or non-vertebral fractures during
follow-up, lumbar spine and hip areal BMD. Data on
forearm BMD were not included, as only a few studies
provided data on forearm BMD, with differences between
the studies in the region of the radius analys ed.
For binary outcomes, such as fractures, we calculated a
weighted risk estimate based on odds ratios (OR) calculated
from the crude data in the studies. A x
2
test for heterogeneity
was applied. We chose a random effects model for hetero-
geneous outcomes and a fixed effects model for homogenous
outcomes [18]. In the case of homogeneity, the results were
not affected by a shift to the random effects models (data not
shown). For continuous outcomes, such as BMD, we
calculated the weighted mean difference (WMD). Tests for
heterogeneity were performed [18]. We performed tests for
publication bias using funnel plots, and if heterogeneity
seemed present additional tests using Eggersregression
method and correction for potential bias using the Trim and
Fill method were performed. We used review manager 4.2.7.
from the Cochrane collaboration for statistical analysis http://
cc-ims.net/RevMan/download.htm.
ORs were compared directly: following logarithmic
transformation the numbers were then compared by the
t-test. This method allowed comparison of the OR for
Osteoporos Int
Table 1 Characteristics of studies
Drug Study Inclusion criteria Duration Jadad
score
Ref
MFP 150 mg (19.8 mg F
) + calcium 1 g + vitamin D 800 IU placebo + calcium
1 g and vitamin D 800 IU
RCT Inflammatory bowel disease, spine T-score<1, normal
serum 25-hydroxy-vitamin D, median age 35 years
12
month
5[27]
NaF 40 mg (18.1 mg F
) RCT Rheumatoid arthritis 18
month
5[28]
NaF 40 mg (18.1 mg F
) RCT Rheumatoid arthritis 18
month
4[29]
HRT + calcium 1 g MFP 20 mg + calcium 1 g HRT+ MFP 20 mg + calcium 1 g
placebo + calcium 1 g
RCT Postmenopausal women 6070 years,
forearm T-score<1
24
month
4[30]
MFP 20 mg + calcium 600 mg RT Postmenopausal women 4359 years,
spine T-score<1
24
month
3[31]
Etidronate 400 mg/14 days each 3 month + calcium 11.5 g+ vitamin D 266 μg /14 days
NaF 50 mg (22.6 mg F
)+ calcium 11.5 g+ vitamin D 266 μg/14 days
RT Primary biliary cirrhosis 24
month
3[32]
NaF 50 mg (22.6 mg F
) + calcium 1 g etidronate 400 mg/day for 14 days each
3 month + calcium 1 g
RT Postmenopausal women 4877 years,
at least 1 fracture
36
month
3[33]
MFP 200 mg (26.4 mg F
) + calcium 1 g placebo + calcium 1 g RCT Prednisolone 7 mg/day for 1 year,
men 1865 years, premenopausal
women >18 years, no fractures
24
month
5[34]
NaF 60 mg (27.1 mg F
) + calcium 11.2 g NaF 60 mg
(27.1 mg F
) + HRT + calcium 11.2 g
RT Caucasian women <80 years, 1 spine fracture, no
hip fractures
27
month
3[35]
NaF 30 mg (13.6 mg F
) + calcium 1 g RCT Women 1 spine fracture 36
month
2[36]
NaF 75 mg (33.9 mg F
) + calcium 1.5 g RCT Postmenopausal women 4575 years 1
spine fracture
48
month
5[37]
NaF 50 mg (22.6 mg F
) + etidronate 400 mg/day for 14 days each 3 month + calcium>0.5 g
placebo + etidronate 400 mg/day for 14 days each 3 month + calcium>0.5 g
RCT Corticosteroid treated subjects 7.5 mg prednisolone/
day
24
month
5[38]
NaF 50 mg (22.6 mg F
) RCT Corticosteroid-treated subjects 24
month
5[39]
MFP 13.2 mg (13.2 mg F
) RCT Glucocorticoid treated 12
month
5[40]
NaF 50 mg (22.6 mg F
) + calcium 1 g + vitamin D 800 IU Calcium + vitamin D (n=93),
calcitonin + placebo (n= 85), calcitonin + calcium (n=12), calcium + placebo (n=17),
etidronate + placebo (n=2)
RT Subjects with osteoporosis 24
month
3[41]
NaF 50 mg (22.6 mg F
) MFP 150 mg (19.8 mg F
) MFP 200 mg (26.4 mg F
) Placebo RCT Caucasian women aged 4776 years
with postmenopausal osteoporosis
24
month
5[42]
NaF 50 mg (22.6 mg F
) + calcium 0.8 g placebo + calcium 0.8 g RCT 1 spine fracture 56
month
5[43]
MFP 152 mg (20 mg F
) + calcium 1 g placebo + calcium 1 g RCT Postmenopausal osteoporosis,
spine T-score <2.5
48
month
5[44]
NaF 75 mg (33.9 mg F
) + calcium 1.5 g calcium 1,500 mg RCT Postmenopausal women 5075 years with
osteoporosis
48
month
5[23]
Osteoporos Int
different treatments [19]. The meta-regression analysis was
performed using a random effects meta-regression model
with weights based on the standard errors from the studies
[20, 21].
Results
Table 1 shows baseline characteristics of the included
studies. There were substantial differences in study dura-
tion, type of fluoride formulation and dose used, combina-
tion regimens, and underlying disease of the patients
treated.
Effects on BMD
Table 2 shows the effects on BMD. For all studies
combined spine BMD increased by 7.9%, 95% CI: 5.4
10.5%, and hip BMD by 2.1%, 95% CI: 0.93.4% (p<
0.01). The estimates were highly heterogeneous (p<0.01).
The increase in spine BMD was significantly higher than
the increase in hip BMD (p<0.05).
A meta-regression showed an increase in spine BMD
with increasing treatment duration (5.04±2.16%/year of
treatment), while there was no effect of fluoride formulation
(sodium fluoride, monofluorophosphate or combinations of
fluoride with other drugs, p=0.83) or fluoride dose (0.20±
0.35%/mg F equivalents, p=0.57). A meta-regression of hip
BMD showed no effect of treatment duration, dose or type
of fluoride.
Effects on fractures
Overall, there was no statistically significant effect of
fluoride treatment on the risk of vertebral (OR=0.8, 95%
CI: 0.51.5, test for heterogeneity: p<0.01) or non-vertebral
fracture risk (OR=0.8, 95% CI: 0.51.4, test for heteroge-
neity: p<0.01) in a meta-analysis (Table 3).
A meta-regression was performed for odds ratio for
fracture risk versus (1) treatment type (one of the three
alternatives: a) sodium fluoride vs. calcium with or without
vitamin D (nine studies) or ant iresorptive drug (two
studies), b) m onofluo rophosp hate vs. calcium with or
without vitamin D (10 studies), or c) any type of fluoride
combined with an antiresorptive drug (HRT in one case,
etidronate in two studies) vs. antiresorptive drug alone (two
studies) or calcium (one study), (2) treatment duration, and
(3) daily dose of fluoride equivalents.
The meta-regression showed that for vertebral fracture
risk there was a non-significant trend towards a lower
fracture risk reduction with fluoride combined with anti-
resorptive drugs compared to sodium fluoride or mono-
Table 1 (continued)
Drug Study Inclusion criteria Duration Jadad
score
Ref
MFP 114 mg (15 mg F
) + calcium 1 g placebo + Ca 1 g RT Men with idiopathic osteoporosis 36
month
3[45]
MFP 20 mg + calcium 1 g placebo + calcium 1 g RT Postmenopausal osteoporosis 36
month
3[46]
MFP 152 mg (20 mg F
) + etidronate 400 mg/day for 14 days each 3 month + calcium 1.2 g +
vitamin D 800 IU etidronate 400 mg/day for 14 days each 3 month+ calcium 1.2 g+ vitamin D
800 IU
RT Postmenopausal osteoporosis, 3 spine fractures,
spine T-score <3
36
month
3[47]
MFP 200 mg (26.4 mg F
)+ calcium 1 g placebo+ calcium 1 g RCT Men or women 5070 years, spine T-score <2, no
vertebral fractures
24
month
5[48]
NaF 50 mg (22.6 mg F
) + calcium 0.5 g + vitamin D 1,000 IU calcium 500 mg + vitamin D 1,000
IU
RT Crohns disease 12
month
3[49]
NaF 50 mg (22.6 mg F
) + calcium 0.8 g + vitamin D 1,000 IU Ibandronate i.v. 1 mg/3 month +
calcium 0.8 g + vitamin D 1,000 IU calcium 0.8 g + vitamin D 1,000 IU
RT Crohns disease 27
month
3[50]
RCT: Randomised placebo-controlled trial, RT: randomised not-blinded trial. Jadad score: a quality assessment score [51]. MFP: monofluorophosphate, NaF: sodium fluoride, HRT: hormone
replacement therapy, F
: fluoride equivalents.
Osteoporos Int
Table 2 BMD changes
Reference Spine Hip
Treatment Control Weight
(%)
Weighted mean difference
in % and 95% CI
Treatment Control Weight
(%)
Weighted mean difference
in % and 95% CI
N Δ% N Δ% N Δ% N Δ%
MFP 150 mg (19.8 mg F) [27] 45 4.8±6.7 49 3.2±4.9 4.4 1.6 (0.8 to 4.0) 45 2.7±10.7 49 0.8±5.6 5.7 1.9 (1.6 to 5.4)
NaF 40 mg (18.1 mg F) [28] 19 5.2±8.3 19 1.0±4.8 4.1 6.2 (1.9 to 10.5)
NaF 50 mg [29] 15 4.0±5.4 16 1.0±4.8 4.2 5.0 (1.4 to 8.6)
[30] 24 0.0±4.4
MFP 20 mg 25 4.4±5.5 4.4 4.4 (1.6 to 7.2)
HRT+ MFP 20 mg 25 21.8±15.5 3.6 21.8 (15.5 to 28.1)
MFP 20 mg [31] 30 5.0±10.3 30 1.2±10.1 3.9 6.2 (1.0 to 11.4)
NaF 50 mg (22.6 mg F) [32]161.9±10.0 16 0.5±4.4 4.5 2.4 (4.6 to 0.2) 16 1.4±12 16 0.3±18 1.2 1.1 (11.7 to 9.5)
NaF 50 mg (22.6 mg F) [33] 55 8.5±17.8 63 3.6±6.3 3.9 4.9 (0.1 to 9.9) 55 1.7±10.4 63 0.4±7.1 6.1 1.3 (2.0 to 4.6)
26.4 mg F [34] 15 8.8±12.4 13 0.5±7.2 3.3 8.3 (0.9 to 15.7)
[35] 31 9.5±7.8 31 2.5±6.7
NaF 60 mg (27.1 mg F) 34 3.0±8.3 4.2 6.5 (10.4 to 2.6) 34 3.6±7.0 5.9 1.1 ( 4.4 to 2.2)
NaF 60 mg (27.1 mg F)+ HRT 17 16.5±11.1 3.7 7.0 (1.1 to 13.0) 17 0.4±6.2 5.3 2.1 (1.7 to 5.9)
NaF 50 mg (22.6 mg F) [38] 23 9.3±16.8 24 0.3±6.4 3.3 9.0 (1.7 to 16.3) 23 2.5±10.6 24 4.0±6.4 3.8 1.5 (3.5 to 6.5)
NaF 50 mg (22.6 mg F) [39] 20 2.2±6.7 24 3.0±4.9 4.2 5.2 (1.7 to 8.7) 20 3.8±5.4 24 3.0±4.9 6.4 0.8 (3.9 to 2.3)
MFP 13.2 mg [40 ] 8 3.7±6.5 7 1.7±2.0 4.0 2.0 (2.7 to 6.7) 8 0.4±3.4 7 0.5±2.0 6.8 0.1 (2.8 to 2.7)
[42] 146 2.4±19.3 146 0.6±15.7
NaF 50 mg (22.6 mg F) 73 9.3±26.5 3.4 6.9 (0.1 to 13.7) 73 2.2±22.2 3.3 2.8 (2.9 to 8.5)
MFP 150 mg (19.8 mg F) 68 9.8±23.9 3.5 7.4 (0.9 to 13.9) 68 0.7±22.3 3.1 1.3 (4.6 to 7.2)
MFP 200 mg (26.4 mg F) 67 13.6±36.0 2.9 11.2 (2.0 to 20.4) 67 0.7±25.4 2.6 1.3 (5.3 to 7.9)
MFP 20 mg [44] 100 10.0±15 100 0.4±7 4.3 10.4 (7.2 to 13.6) 100 1.8±1.0 100 0.7±7.0 9.2 1.1 (0.3 to 2.5)
NaF 75 mg [23] 101 38.4±55.1 101 0.0±14.0 2.4 38.4 (27.3 to 49.5) 101 7.8±29.5 101 0.0±24.6 2.2 7.8 (0.3 to 15.3)
MFP 15 mg [45] 30 8.9±6.0 30 2.4±3.8 4.4 11.3 (8.8 to 13.8) 30 1.9±3.8 30 1.4±1.1 9.2 3.3 (1.9 to 4.7)
[46]331.6±2.9 33 6.3±1.7
Intermittent MFP 20 mg 31 12.6±9.5 4.2 14.2 (10.7 to 17.7) 31 2.3±6.7 7.5 8.6 (6.2 to 11.0)
Continuous MFP 20 mg 30 19.5±18.6 3.4 15.7 (8.8 to 22.6) 30 1.8±4.5 8.7 4.5 (2.8 to 6.2)
MFP 20 mg [47] 26 13.9±7.6 26 3.8±4.6 4.3 10.1 (6.7 to 13.5) 26 4.1±2.0 26 2.3±3.1 9.2 1.8 (0.4 to 3.2)
MFP 200 mg (26.4 mg F) [48] 35 14.3±11.8 41 3.3±6.4 4.1 11.0 (6.6 to 15.4)
NaF 50 mg [49] 18 10.2±13.2 15 2.2±11.1 3.1 12.4 (4.1 to 20.7)
[50] 12 2.6±3.5 4.3 3.2 (0.0 to 6.4 12 0.3±8.0 3.8 0.7 (5.8 to 4.4)
NaF 50 mg (22.6 mg F) 28 5.8±6.9 28 0.4±6.3
Heterogeneity Effect Heterogeneity Effect
Combined 954 820 P<0.01 P<0.01 7.9 (5.4 to 10.5) 772 662 P<0.01
P<0.01 2.1 (0.9 to 3.4)
MFP: monofluorophosphate, NaF: Sodium fluoride, HRT: hormone replacement therapy, F
: Fluoride equivalents, N : number of participants, Δ%: % increase in BMD
Osteoporos Int
fluorophosphate (p=0.07), i.e., for fluoride combined with
an antiresorptive drug (etidronate or HRT), the OR for
vertebral fracture risk tended to be increased (theoretical ln
(OR)=1.98) compared to sodium fluoride (ln(OR)=1.32) or
monofluorophosphate (ln(RO)=0.66). In the meta-regres-
sion there was a trend towards an increase in odds ratio for
fracture risk with increasing fluoride dose (Δln(OR): 0.09±
0.05/mg fluoride, p=0.088, i.e., would OR theoretically
increase by a factor of e
0.09
=1,094, i.e., from e.g. 1.00 to
1.094 with each mg more of fluoride equivalents), while
there was no effect of treatment duration ( Δln(OR): 0.00±
0.03/month of treatment). The theoretical cut point of
fluoride dose below whic h there was a reduction in
vertebral fracture risk was 21.2 mg of fluoride equivalents
per day (Fig. 1).
For non-vertebral fracture risk the meta-regression
showed no effect of type of fluoride (p=0.93), while there
was a highly significant increase in odds ratio for fracture
risk with increasing fluoride dose (Δln(OR): 0.14±0.03/mg
F, p<0.01). There was no effect of treatment duration (Δln
(OR): 0.0±0.02/month of treatment, p=0.79). The theoret-
ical cut point of fluoride dose below which there was a
reduction on non-vertebral fracture risk was 26.3 mg of
fluoride equivalents per day (Fig. 1).
These results were confirmed in a subgroup analysis.
With a daily dose of 20 mg of fluoride equivalents
(corresponding to 152 mg monofluorophosphate or 44 mg
sodium fluoride) there was a statistically significant
reduction in both vertebral (OR=0.28, 95% CI: 0.090.87,
six studies, 285 fluoride-treated patients, 308 controls, 593
patients in total) and non-vertebral (OR=OR 0.52, 95% CI:
0.280.76, 6 studies, 363 fluoride-treated patients, 405
controls, 768 patients in total) fracture risk. Figure 2 shows
Forest plots of the results. However, with a daily dose >20
mg of fluoride equivalents there was a trend towards an
overall increase in the risk of both vertebral (OR=1.26,
95% CI: 0.782.04, 11 studies) and non-vertebral (OR=
1.46, 95% CI: 0.772.76, 7 studies) fracture.
In absolute term s the fracture risk reduction was 17%,
95% CI: 233% for verteb ral and 9%, 95% CI: 217% for
non-vertebral fractures with a daily dose of 20 mg of
fluoride equivalents.
In a subgroup analysis, there was no difference in the
fracture risk reduction for vertebral and non-vertebral
fractures with sodium fluoride and monofluorophosphate.
There were too few studies to allow analysis of the
effects of supplementation with vitamin D.
Regarding other covariates, study duration (27±11 vs.
30±12 month, 2p=0.55) and Jadad quality score (3.9±1.1
vs. 4.2±1.0 points, 2p=0.49) did not differ between the
studies with a fluoride dose 20 mg/day and >20 mg/day.
The two dose groups also did not differ in the use of co-
medications (antiresorptive drugs, calcium/vitamin D or
other, p=0.5 5), disease state as evaluated by baseline
presence of fracture or not (p=0.53) or target population
(secondary vs. primary osteoporosis, p=0.72).
Vertebral fractures Non vertebral fractures
Forest plots
Funnel plots
Fig. 1 Forest plots and funnel plots for the dose groups 20 mg of fluoride equivalents per day
Osteoporos Int
Funnel plots did not reveal signs of major publication
bias, and additional analyses did not change the results
(Fig. 2).
Side effects
Table 4 shows an overview of side effects reported by the
studies. The studies differed significantly in the definition
and the reporting of side effects. Due to these differences
only a few subtypes of side effects could be subject to
analysis. The only two groups of side effects that allowed
analyses were gastrointestinal symptoms and lower extrem-
ity an d joint pain with the precaution that the definition of
these side effects varied somewhat between the studies.
For gastrointestinal symptoms, 14 studies reported data.
There was no significant difference between fluoride and
controls in the freque ncy of gastrointestinal symptoms (OR=
1.07, 95% CI: 0.741.54). The estimate was borderline
significantly heterogeneous (p=0.06).
For lower extremity pain 13 studies were available.
fluoride-treated patients had a significantly higher risk of
pain than controls (OR=2.76, 95% CI: 1.355.65). The
estimate was highly significantly heterogeneous (p<0.01).
The effect with an increased pain was the same in studies
with a dose 20 mg of fluoride (OR=4.07, 95% CI: 0.99
16.73, p for heterogeneity <0.01) and >20 mg (OR=2.34,
95% CI: 0.985.56, p for heterogeneity <0.01). A meta-
regression failed to show an effect of fluoride formulation
(p=0.40), d uration of treatment (p =0.96) or dose of
fluoride (p=0.89) on the risk of pain.
Discussion
The present study has disclosed that across the used doses
of fluoride equiva lents there is a marked and clinically
significant increase in BMD especially in the spine but also
in the hip without any reduction in vertebral or non-
Vertebral fracture Non-vertebral fracture
-3
-2,5
-2
-1,5
-1
-0,5
0
0,5
1
1,5
2
10 15 20 25 30 35
Dose (mg)
ln(RR)
-2,5
-2
-1,5
-1
-0,5
0
0,5
1
1,5
2
10 15 20 25 30 35
Dose (mg)
ln(RR)
Funnel plots for fractures
Vertebral fractures Non vertebral fractures
All studies
Fig. 2 Odds ratio for vertebral and non-vertebral fracture stratified by daily dose of fluoride equivalents. Note the logarithmic scale on the
ordinate
Osteoporos Int
Table 3 Comparison of vetebral and non-vertebral fractures
Vertebral fractures Non-vertebral fractures
Reference Treatment Fx/N Control Fx/N Weight (%) OR (95% CI) Treatment Fx/N Control Fx/N Weight (%) OR (95% CI)
[30] 0/24 3/24
MFP 20 mg 0/25 0.0 3/25 4.8 1.0 (0.2 to 5.3)
MFP 20 mg + HRT 1/25 1.8 3.0 (0.1 to 77.3) 1/25 3.3 0.3 (0.0 to 3.0)
NaF 50 mg [32] 2/16 0/16 1.9 5.7 (0.3 to 129) 2/16 3/16 4.1 0.6 (0.1 to 4.3)
NaF 50 mg [33] 5/55 8/63 5.7 0.7 (0.2 to 2.2) 6/55 6/63 6.5 1.2 (0.4 to 3.8)
[34] 2/15 0/13 1.9 5.0 (0.2 to 114)
[35] 3/31 6/31
NaF 60 mg 11/34 5.0 4.5 (1.1 to 17.9) 5/34 6.1 0.7 (0.2 to 2.6)
NaF 60 mg + HRT 4/17 4.3 2.9 (0.6 to 14.7) 0/17 2.4 0.1 (0.0 to 2.1)
[36] 1/25
NaF 30 mg + 1,000 mg Ca 0/25 1.8 0.3 (0.0 to 8.3)
NaF 10 mg + 1,000 mg Ca 2/25 2.7 2.1 (0.2 to 24.6)
NaF 50 mg [38] 7/23 4/24 5.0 2.2 (0.5 to 8.8) 8/23 5/24 6.1 2.0 (0.6 to 7.5)
NaF 50 mg [39] 1/20 3/24 2.8 0.4 (0.0 to 3.9) 0/22 0/22 0.0
NaF 50 mg [41] 71/180 69/136 8.0 0.6 (0.4 to 1.0)
[42] 71/146 17/146
NaF 50 mg 41/73 7.7 1.4 (0.8 to 2.4) 10/73 7.9 1.2 (0.5 to 2.8)
MFP 150 mg 32/68 7.6 0.9 (0.5 to 1.7) 6/68 7.3 0.7 (0.3 to 2.0)
MFP 200 mg 19/67 7.5 0.4 (0.2 to 0.8) 13/67 8.1 1.8 (0.8 to 4.0)
NaF 50 mg [43] 22/51 7/48 6.4 4.4 (1.7 to 11.8)
MFP 20 mg [44] 12/100 11/100 7.7 1.1 (0.5 to 2.6)
NaF 75 mg [23] 62/101 66/101 7.7 0.8 (0.5 to 1.5) 61/101 24/101 8.7 4.9 (2.7 to 9.0)
MFP 15 mg [45] 3/30 12/30 5.0 0.2 (0.0 to 0.7) 3/30 8/30 5.6 0.3 (0.1 to 1.3)
[46] 30/33 22/45
Intermittent MFP 20 mg 8/31 4.9 0.0 (0.0 to 0.2) 8/45 7.4 0.2 (0.1 to 0.6)
Continuous MFP 20 mg 12/30 5.0 0.1 (0.0 to 0.3) 13/44 7.7 0.4 (0.2 to 1.1)
MFP 20 mg [47] 3/26 9/26 4.8 0.3 (0.1 to 1.1) 6/26 10/26 6.4 0.5 (0.1 to 1.6)
MFP 200 mg [48] 2/35 1/41 2.7 2.4 (0.2 to 27.9)
Number Number Heterogeneity Pooled OR Number Number Heterogeneity Pooled OR
Pooled 310/972 284/781 P<0.01 0.8 (0.5 to 1.3) 157/771 115/628 P<0.01 0.8 (0.5 to 1.4)
MFP: monofluorophosphate, NaF: sodium fluoride, HRT: hormone replacement therapy, F
: fluoride equivalents, N: number of participants, Fx: number of subjects with at least one incident
fracture during follow-up, OR: odds ratio
Osteoporos Int
vertebral fracture risk. This supports the view that the
average quality of the newly bone formed during fluoride
treatment may be inferior [7, 12, 22, 23]. However, at low
doses a fracture risk reduction was seen.
In an unco ntrolled before -and-af ter study based on
biomechanical testing, Sogaard et al. [12] reported that a
relatively high dose of 4060 mg of sodium fluoride in
combination w ith 1.01.5 g of calcium (as calcium
Table 4 Serious adverse events reported by the studies
Study Type of adverse event Fluoride Controls
Abitbol et al. [27] Any serious adverse event 5/45 10/49
Adachi et al. [28] Gastrointestinal 7/15 12/16
Periarticular pain 7/15 3/16
Rheumatoid arthritis flare 0/15 3/16
Alexandersen [30] Joint pain, pain in extremities, heartburn
MFP 7/25 7/24
MFP+HRT 7/25
Any serious adverse event
MFP 23/25 21/24
MFP+HRT 24/25
Gambacchiani et al. [31] Transient gastralgia 7/21 6/21
Guanabens et al. [32] Left study due to gastrointestinal side effects 3/16 0/16
Guanabens et al. [33] Gastrointestinal symptoms 12/31 10/47
Lower extremity pain syndrome 7/31* 0/47?
Guaydier-Soquieres [34] Any adverse event 3/17 5/18
Gastrointestinal disorders 3/17 2/18
Lower limb pain 1/17 3/18
Hip pain 0/17 2/18
Hansson et al. [36] Any serious adverse event probably caused by treatment
Fluoride 30 mg 4/25 0/25?
Fluoride 10 mg 0/25? 0/25?
Kleerekoper et al. [37] Gastrointestinal symptoms 16/46 6/38
Osteomalacia 8/46 0/38
Mamelle et al. [41] 1 episode of osteoarticular pain 67/180 41/136
1 episode of gastrointestinal disorders 71/180 60/136
Meunier et al. [42] Lower limb pain syndrome 37/208 7/146
Digestive adverse event 123/208 87/146
Pak et al. [43] Minor gastrointestinal side effects 5/51 3/48
Minor musculoskeletal side effects 6/51 7/48
Reginster et al. [44] Lower limb pain 3/100 5/100
Riggs et al. [23 ] Any adverse event 23/101 0/101
Joint pain, swelling or plantar fascial syndrome 13/101 0/101
Gastrointestinal symptoms 9/101 0/101
Ringe et al. [45] Lower limb pain syndrome 7/30 0/30?
Gastrointestinal symptoms 7/30 9/30
Ringe et al. [46] Lower extremity pain syndrome 0/33
Intermittent MFP 20 mg 11/31
Continuous MFP 20 mg 23/30
Gastrointestinal symptoms 12/33
Intermittent MFP 20 mg 5/31
Continuous MFP 20 mg 6/30
Ringe et al. [47] Any adverse event 12/26 13/26
Sebert et al. [ 48] Any serious adverse event 18/45 14/49
Minor gastrointestinal symptoms 10/45 9/49
Lower extremity pain syndrome 5/45 2/49
Von Tirpitz et al. [49] Gastrointestinal symptoms 2/18 1/15
Lower extremity pain syndrome 0/18 0/15
Von Tirpitz et al. [50] Any adverse event 11/28 3/12
* Six had microfractures, many discontinued treatment, ? data not exactly stated, MFP: monofluorophosphate
Osteoporos Int
phosphate) and 18,000 IU/day of vitamin D for 5 years
reduced the compressive strength of iliac crest bone
biopsies by 58% when normalized for ash content. A
reduced biomechanical competence may, thus, be respon-
sible for the lower extremity stress fractures observed
during fluoride therapy [13, 24]. However, the present
meta-analysis indicates that beneficial anabolic effects may
dominate at lower doses of fluoride (20 mg/day fluoride
equivalents). Although no distinct dose effect could be demon-
strated for pain syndromes, the definition used for pain was
highly variable between studies (Table 4), and further
studies with a more precise uniform definition of lower
extremity pain is needed to elucidate if a lower fluoride dose
indeed affects pain. From the available studies, it was not
possible to evaluate the effects of vitamin D supplementation,
and vitamin D combined with a lower fluoride dose may
perhaps not increase the risk of pain syndromes.
The anti-fracture efficacy of lower doses of fluoride was
of the same magnitude a s the effect of other anabolic drugs
like PTH and, to a certain extent, strontium ranelate. Low
dose fluoride reduced vertebral fractures by 72% (OR=
0.28, 95% CI: 0.090.87) and non-vertebral fractures by
48% (OR = OR 0.52, 95% CI: 0.280.76). In comparison a
recent meta-analysis showed that PTH alone or in combi-
nation with anti-resorptive drugs reduced vertebral fractures
by 64% (RR=0.36, 95% CI: 0.280.47) and non-vertebral
fracture risk by 38% (RR=0.62, 95% CI: 0.480.82) in a
heterogeneous group of osteoporosis patients [25]. Another
meta-analysis reveal ed that strontium ranelate, which may
combine an anti-resorptive effect with an anabolic effect, in
postmenopausal women reduces vertebral fractures by 37%
(RR=0.63, 95% CI: 0.560.71) and non-vertebral fractures
by 14% (RR=0.86, 95% 0.750.98) [26]. None of the
studies have reported significant effect on hip fracture risks.
According to these figures low dose fluoride treatment may
not be inferior to PTH or strontium ranelate.
The limiting effect of fluoride use is side effects. In the
present meta-analysis, there was no difference between
treated and controls in the frequency of gastrointestinal
symptoms. However, the definition of these symptoms
varied between studies and often did not separate between
upper and lower gastrointestinal symptoms. The definition
of lower extremity pain was even more heterogeneous,
spanning from periarticular pain to stress fractures. This
syndrome occurre d nearly t hree times m ore oft en in
fluoride-treated patients than in controls. Most remarkable,
there was a t endency towards a higher risk of pain
syndrome at low fluoride dosing than at high dosing,
although the difference was not significant. This suggests
that restricting the dose of fluoride to 20 mg fluoride
equivalents may not limit this often troublesome and
prolonged side effect. However, as pointed out above,
more data are needed on side effects.
A randomised controlled trial of a low dose of fluoride
(20 mg/day fluoride equivalents, which is equal to 152
mg of MFP per day or 44 mg of NaF per day) combined
with calcium and vitamin D may be needed to finally assess
the anti-fracture effects and side effects of fluoride.
Limitations to the study
The study is a meta-analysis, i.e., the data are aggregate
data and not individual data. Fluoride may have varying
effects in the individual patients, and this would need
further evaluation in a trial of low doses. The studies included
were heterogeneous in design. Some of them included an anti-
resorptive drug, and the effects of these drugs may have
altered the effects of fluoride. The number of studies on
vitamin D supplementation was too low for analyses of the
effects of vitamin D. To this end more studies are needed.
In conclusion fluoride treatment increases BMD in the
spine and the hip depending on treatment duration. Overall
there was no effect on hip or spine fracture risk. However,
in subgroup analyses a low dose of fluoride (20 mg/day
fluoride equivalents) was associated with a reduction in risk
in spine as well as non-spine fracture risk. Daily dose is an
important issue for the anti-fracture efficacy of fluoride but
not for the occurrence of lower extre mity pain syndromes.
Acknowledgements Research librarian Ms. Edith Clausen is acknowl-
edged for skilful help with the references.
Financial support Laura og Jens Veng Christensens Foundation,
and Bagermester August H. Jensen og Hustrus Legat provided
financial support.
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Osteoporos Int
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