Key words
osteoporosis - osteopenia - postmenopause - end-stage renal disease - raloxifene
Introduction
Osteoporosis is a systemic disorder characterized by reduced bone mineral density
(BMD) and altered skeletal microarchitecture, leading to increased bone fragility
with subsequent increased risk for fracture. According to the new diagnostic
criteria for osteoporosis recommended by the National Bone Health Alliance (NBHA),
30–50% of women over 50 years old have osteoporosis worldwide [1]
[2].
These women have a 15–20% lifetime risk of hip fracture and a
50% risk of any osteoporotic fracture [3]. Preclinical studies have suggested that the deficiency of estrogen
could accelerate the progress of postmenopausal osteoporosis through multiple
mechanisms [4]
[5]
[6]. For instance, hypoxia
inducible factor 1 alpha (HIF1α), an essential factor for osteoclast
activation, could be induced and accumulated under menopausal condition. On the
contrary, genetic inactivation or pharmacological inhibition of HIF1α in
osteoclasts alleviated postmenopausal bone loss [4]. Moreover, estrogen deficiency was associated with an enhanced
inflammatory milieu that was correlated with bone inflammation and osteoporosis
[5]
[7]. In vitro experiments further revealed that bone cell mineralization
and apoptosis were altered upon estrogen withdrawal [6]
[8].
Patients with chronic kidney disease (CKD) often develop CKD-mineral bone disorders
(CKD-MBD) due to secondary hyperparathyroidism. These patients might have
high-turnover bone diseases such as osteitis fibrosa, low-turnover bone diseases
such as osteomalacia or adynamic bone disease, and mixed forms [9]
[10].
Both high and low bone turnover in CKD-MBD patients are associated with increased
risk of fracture and mortality [11].
Epidemiologic studies suggested that patients with CKD had higher risk of developing
fractures [12]
[13], and that this risk was increased in those with end-stage renal
disease (ESRD) who required maintenance dialysis [14]
[15]. The risk of hip
and/or vertebral fractures was further increased in postmenopausal women
with the deterioration of kidney function [16]
[17]. The mainstays of therapy
for CKD-MBD include dietary phosphorus restriction, phosphate binders, dialysis,
calcimimetics with calcitriol or vitamin D analogs, and parathyroidectomy, which aim
to restore the balance between calcium, parathyroid hormone (PTH), phosphorus and
vitamin D [18]
[19].
Osteoporosis intertwined with CKD-related bone disorders makes the clinical picture
more complicated in postmenopausal uremic patients. Although antiresorptive
medications including bisphosphonates and selective estrogen receptor modulators
(SERMs) are widely used and well-tolerated in the general population, they are
actually labeled with warnings for use or contraindicated in patients with severe
CKD [20]. Besides, some of the agents may be
suitable only in patients without low turnover or adynamic bone disease [21]. Consequently, the Kidney Disease Improving
Global Outcomes (KDIGO) 2017 CKD-MBD Update Work Group recommended that clinicians
should be aware of the specific side effects of conventional antiresorptive
therapies for osteoporosis as they might exacerbate low bone turnover in patients
with ESRD [22]. Therefore, SERMs such as
raloxifene and bazedoxifene should be administered with extreme caution in
postmenopausal uremic patients without definite bone biopsy results.
Although the role of SERMs in treating osteoporosis have been studied in
postmenopausal women [23]
[24], randomized controlled trials regarding the
safety and efficacy of SERMs in the management of postmenopausal ESRD patients are
scarce. A recent post-hoc analysis suggested that raloxifene therapy might be safe
and renoprotective in postmenopausal women with osteoporosis and mild to moderate
CKD (to CKD stage 3) [25]. However, an
in-depth analysis about the benefit of raloxifene, in the treatment of osteoporosis
among ESRD patients or those who require maintenance dialysis, is lacking.
The aim of the present review was to summarize the published literature about the
safety and efficacy of raloxifene in postmenopausal osteoporotic patients with
ESRD.
Materials and Methods
This meta-analysis is reported in line with the Assessing the Methodological Quality
of Systematic Reviews (AMSTAR) and the Preferred Reporting Items for Systematic
Reviews and Meta-Analyses Statement (PRISMA) recommendations [26].
Search strategy
PubMed, Springer, CNKI (Chinese National Knowledge Infrastructure) and Wanfang
Database were searched with one or a combination of the following terms:
raloxifene, selective estrogen receptor modulator, osteopenia, osteoporosis,
postmenopausal, chronic kidney disease, end-stage renal disease, uremia,
peritoneal dialysis, and hemodialysis. In addition, the relevant references and
cited papers were searched manually to identify additional studies meeting the
inclusion criteria.
Inclusion and exclusion criteria
The inclusion criteria were: (1) original research papers written in English; (2)
the study participants were human; (3) randomized controlled trials (RCTs) or
prospective studies with control or placebo groups; (4) studies of
perimenopausal/postmenopausal patients diagnosed with
osteopenia/osteoporosis[27]
[28]; (5) studies of
patients with CKD stage 5 with or without maintenance dialysis; and (6) studies
with a follow-up period of at least 6 months.
The exclusion criteria were: (1) retrospective studies, case reports, reviews, in
vitro studies, and animal studies; (2) studies consisting of patients with CKD
not reaching CKD stage 5; (3) studies in which patients were also treated with
any other drugs intended for the treatment of osteopenia/osteoporosis
except for vitamin D and calcium salts; and (4) studies with a lack of relevant
outcome data.
Outcomes and outcome measurements
(1) Safety profile: Possible side effects of raloxifene listed in the articles
included breast cancer, cervical carcinoma, thrombosis, thromboembolism,
cerebral and myocardial infarction. All the included studies investigated these
potential adverse effects.
(2) Bone mineral density (BMD): Two studies provided relevant data on lumbar
spine or femoral neck BMD by employing dual energy X-ray absorptiometry (DEXA)
[29]
[30]. Data regarding the speed of the sound (SOS) in the calcaneus
region, which was thought to be positively correlated with the lumbar BMD in the
general population and used to estimate the bone density of participants, could
be obtained from one study [27].
(3) Bone metabolism markers: One study reported the serum level of N-terminal
cross-linking telopeptide of type I collagen (NTx) and another one specified
serum alkaline phosphatase (ALP) in the follow-up [27]
[30]. Three studies provided exact data on calcium, PTH and phosphorus
[27]
[30]
[31]. Information regarding
bone alkaline phosphatase (BAP) could be obtained from two studies [27]
[31].
Data extraction and the assessment of risk of bias
All data were extracted independently by two reviewers using a paper data
extraction form. The accuracy of the extracted data was further confirmed by a
third author. The extracted information included: author and year of
publication, study design, participants, interventions and follow-ups, treatment
outcomes and key conclusions. For continuous data, we extracted the mean value
and converted standard error of the mean (SEM) to standard deviation (SD). Two
raters independently assessed the methodological quality of the included studies
in accordance with the Cochrane Collaboration guidelines [32]. We assessed the risk of bias from the
following six aspects: sequence generation, allocation concealment, blinding of
participants and personnel, blinding of outcome assessment, incomplete outcome
data and selective outcome reporting.
Statistical analysis
We performed the analysis using R program (version 3.4.4) and Review Manager
Version 5.2. We used mean differences (MD) to estimate continuous variables with
95% confidence interval (CI). A p-value of<0.05 was considered
statistically significant. Heterogeneity among the studies was assessed with the
inconsistency factor (I2). I2>50% or
p<0.10 was considered to indicate significant heterogeneity. Whenever
I2 was<50%, the fixed-effects model results were
used; otherwise, the random-effects model results were used.
Results
Study selection
A PRISMA flowchart of the selection process is shown in [Fig. 1]. After discarding the duplicate
studies and screening, 10 studies were selected for full-text examination. One
study was excluded because there was no placebo/control group [33]. One study was excluded because
patients had normal baseline kidney functions [34]. One retrospective study was also excluded [35]. Two studies were excluded because of
insufficient data [36]
[37]. Five studies fulfilled the inclusion
criteria and were ultimately included in this analysis [27]
[29]
[30]
[31]
[38].
Fig. 1 Flowchart of paper selection.
Characteristics and risk of bias of the included studies
In total, 121 patients were included in the raloxifene group, and 123 patients
were enrolled in the placebo/control group. The median duration of treatment was
12 months. The follow-up period ranged from 8–12 months. The PICOS
approach was used to summarize the characteristics of the included studies
([Table 1]
). An assessment of
the risk of bias using Cochrane Collaboration’s tool is shown in [Fig. 2a, b].
Fig. 2
a: Risk of bias graph; b: Risk of bias summary.
Table 1 Summary of characteristics of the included
studies.
|
Author, year [Ref]
|
Study design
|
Participants
|
Interventions/follow-up
|
Outcomes
|
Key findings
|
|
Hernandez et al. 2003 [29]
|
Prospective, blind, placebo-controlled, and randomized
study.
Withdrawal: 0%.
Two centers in
Venezuela.
|
50 postmenopausal patients on HD. Age: 62.5±8.58
years. Diagnosed with severe osteopenia or osteoporosis (T
score below–2.0 SD).
|
Group R (n=25): raloxifene,
60 mg/d.
Group P (n=25):
placebo.
Follow-up: 12 months.
|
L2-L4 lumbar spine BMD and femoral neck BMD.
Serum
lipid panel: TC, LDL-cholesterol, HDL-cholesterol,
triglycerides.
|
Drug side effects*: 0%.
An
improvement in lumbar spine BMD and a slight increase of
HDL-cholesterol in patients taking
raloxifene.
Decreased serum levels of LDL-cholesterol
and pyridinoline crosslinks in raloxifene group.
|
|
Saito et al. 2011 [31]
|
Randomized and controlled interventional
study.
Withdrawal: 0%.
Single center
in Japan.
|
47 patients on HD (6 perimenopausal and 41 postmenopausal).
Age: 63.8±13.3 years. Diagnosed with osteoporosis
(an increase of NTx and a decrease of calcaneus SOS).
|
Group R (n=21): raloxifene, 60 mg/d,
postprandial.
Group P
(n=26).
Follow-up: 12 months.
|
Lumbar BMD reflected by SOS in the calcaneus region. Serum
NTx, BAP, and iPTH, etc.
|
Drug side effects: 0%.
Treatment with
raloxifene led to a significant decline of NTx and an
improvement of BMD reflected by the increased calcaneus
SOS.
|
|
Tanaka, et al. 2011 [38]
|
Prospective controlled study. Withdrawal: 0%.
Multiple centers in Japan.
|
27 postmenopausal patients on HD. Age: 63.23±5.09
years. Patients receiving raloxifene were diagnosed with
severe osteoporosis. Patients in the control group had
similar baseline mean lumbar spine BMD levels.
|
Group R (n=17): raloxifene,
60 mg/d.
Group P
(n=10).
Vitamin D and calcium salts dosages
were not changed throughout the study period. Follow-up: 12
months.
|
BMD of the radius and lumbar spine determined by DEXA. Serum
bone metabolism markers such as calcium, phosphorus, iPTH,
ALP, BAP, NTx, etc.
|
Drug side effects: 0%.
Raloxifene treatment
improved lumbar spine BMD. It also reduced serum calcium and
increased serum iPTH. Vitamin D and calcium salts should be
added to the regimen.
|
|
Saito. et al. 2012 [27]
|
Prospective controlled study.
Withdrawal:
0%.
Single center in Japan.
|
60 postmenopausal patients on HD. Age: 66.1±10.9
years. Diagnosed with osteopenia or osteoporosis according
to the value of calcaneus SOS.
|
Group R (n=28, consisting of 14 diabetics and 14
non-diabetics): raloxifene, 60 mg/d,
postprandial.
Group P (n=32, consisting of 16
diabetics and 16 non-diabetics). Follow-up: 12 months.
|
Lumbar BMD reflected by SOS in the calcaneus. Serum calcium,
phosphorus, NTx, BAP, and iPTH, etc.
|
Drug side effects: 0%.
Raloxifene treatment
resulted in a significant decrease in NTx and an increase in
SOS in both non-diabetic and diabetic postmenopausal
patients on HD.
|
|
Haghverdi et al. 2014 [30]
|
Block-randomized, placebo-controlled trial. Withdrawal:
0%.
Single center in Iran.
|
A total number of 60 postmenopausal patients (HD,
n=51; CKD stage 5 without dialysis,
n=9).
Age: 62.8±11.77
years.
Diagnosed with severe osteopenia or
osteoporosis (T score below–2.0 SD).
|
Group R (n=30, including 4 patients without
dialysis): raloxifene, 60 mg/d. Group P
(n=30, including 5 patients without dialysis):
placebo. Follow-up: 8 months.
|
Lumbar spine and femoral neck BMD determined by DEXA. Serum
calcium, phosphorus, ALP and iPTH, etc.
|
Drug side effects: 0%.
One patient had lumbar
spine fracture in the placebo group. Raloxifene proved to be
effective in improving BMD. It had no effect on controlling
secondary hyperparathyroidism in these patients.
|
HD: Hemodialysis; BMD: Bone mineral density; TC: Total cholesterol; LDL:
Low-density lipoprotein; HDL: High-density lipoprotein; NTx: N-terminal
cross-linking telopeptide of type I collagen; SOS: Speed of sound; BAP:
Bone alkaline phosphatase; iPTH: Intact parathyroid hormone; DEXA: Dual
energy X-ray absorptiometry; ALP: Alkaline phosphatase. *
Possible side effects of raloxifene listed in the cited papers include
breast cancer, cervical carcinoma, thrombosis, thromboembolism, cerebral
and myocardial infarction.
Meta-analysis results
Safety of raloxifene in postmenopausal osteoporotic patients with
ESRD
All studies reported the incidence rate of side effects of raloxifene:
0/121 (0%) in the raloxifene group. Potential adverse
effects of raloxifene include deep vein thrombosis (DVT), venous
thromboembolism (VTE), stroke, and ischemic cardiovascular events [39]. One patient in the placebo group
had lumbar spine fracture by the end of follow-up.
Improvement of femur BMD
Data about femoral neck BMD (mg/cm2) at baseline and the
end of follow-up were reported in two articles. There was no significant
heterogeneity among the studies (p=0.70,
I2=0%), so the fixed-effects model was used for
the meta-analysis. There was no significant difference between the groups
concerning the improvement of femoral neck BMD (MD: –0.02,
95% CI: –0.04, 0.00, p=0.38) ([Fig. 3a]).
Fig. 3
a: Forest plot analyzing the effect of raloxifene on
improving femur BMD (mg/cm2); b: Forest plot
analyzing the effect of raloxifene on improving lumbar spine BMD
(mg/cm2).
Improvement of lumbar spine BMD
Data about lumbar spine BMD (mg/cm2) at baseline and the end of
follow-up were reported in two articles. There was no significant
heterogeneity among the studies (p=0.98,
I2=0%), so the fixed-effects model was applied in
the meta-analysis. There was a significant improvement of lumbar spine BMD
levels in the raloxifene group (MD: 33.88, 95% CI: 10.93, 56.84,
p=0.004) ([Fig. 3b]).
iPTH level
Data about iPTH levels (pg/ml) were reported in three articles. There
was no significant heterogeneity among the studies (p=0.53,
I2=0%), so the fixed-effects model was used
for the meta-analysis. There was no significant difference between the
groups concerning iPTH levels (MD: –12.62, 95% CI:
–35.36, 10.13, p=0.28) ([Fig. 4a]).
Fig. 4
a: Forest plot of iPTH (pg/ml); b: Forest plot of
calcium (mg/dl); c: Forest plot of phosphorus (mg/dl);
d: Forest plot of BAP (mg/dl).
Calcium level
Data about calcium levels (mg/dl) were reported in three articles. There was
a significant heterogeneity among the studies (p<0.01,
I2=84%), so the random-effects model was used for
the meta-analysis. There was no significant difference between the groups
concerning calcium levels (MD: –0.08, 95% CI: –0.61,
0.44, p=0.76) ([Fig.
4b]).
Phosphorus level
Data about phosphorus levels (mg/dl) were reported in three articles.
There was no significant heterogeneity among the studies (p=0.87,
I2=0%), so the fixed-effects model was
applied in the meta-analysis. There was no significant difference between
the groups concerning phosphorus levels (MD: 0.18, 95% CI:
–0.12, 0.48, p=0.23) ([Fig.
4c]).
BAP level
Data about BAP levels (mg/dl) were reported in two articles. There
was no significant heterogeneity among the studies (p=0.82,
I2=0%), so the fixed-effects model was
applied in the meta-analysis. There was no significant difference between
the groups concerning BAP levels (MD: –4.33, 95% CI:
–14.44, 5.79, p=0.40) ([Fig. 4d]).
Discussion
The declining level of estrogen in menopausal women put them at risk for osteoporosis
and subsequent fractures. Randomized controlled trials suggested that the
therapeutic property of estrogen in postmenopausal osteoporosis might be associated
with promoting the Wnt/β-catenin signaling pathway and reducing bone
resorption [40]
[41]. Postmenopausal women treated with hormone
therapy had lower serum levels of bone resorbing cytokines interleukin-1β
(IL-1β) and tumor necrosis factor α (TNFα) [42].
The safety and efficacy of SERMs in the treatment of osteoporosis have been well
studied in postmenopausal women without severe renal impairments. Raloxifene
treatment is associated with a 30 to 40% reduction in risk of one or more
spine fractures and with extraskeletal benefits [43]. Nevertheless, it is associated with increased risk of venous
thromboembolism, pulmonary embolism, and fatal stroke in postmenopausal women [44]
[45].
Unfortunately, evidence is insufficient from clinical trials assessing the safety and
efficacy of raloxifene in postmenopausal osteoporotic women with severe renal
insufficiency or those who require maintenance dialysis. Because of the altered drug
pharmacokinetics in patients with CKD, and because of the coexisting renal
osteopathy caused by CKD itself, the safety profile of raloxifene should be
carefully evaluated in those patients with ESRD. Moreover, patients with CKD are
often complicated with other severe comorbidities such as vascular calcification,
coronary artery disease, and stroke [46].
Coagulopathies such as hypercoagulability and thrombosis are commonly seen in uremic
patients on maintenance hemodialysis [47].
These issues add more uncertainties and complexities on the use of raloxifene in
patients with ESRD. The included studies in the present meta-analysis all showed
that raloxifene could be well-tolerated in uremic patients without obvious side
effects. However, we have to take into account the relatively short follow-up
duration in these studies because some potential adverse effects might not occur in
the short term [48].
The NBHA Work Group recommended that in postmenopausal women, osteoporosis be
diagnosed based on any one of the three elements: traditional BMD based T-score, or
qualified fractures, or a fracture risk assessment tool (FRAX) score [49]. The 2017 KDIGO guidelines recommended that
BMD testing be assessed in patients with CKD-MBD and/or risk factors for
osteoporosis [22]. Pooled analysis showed that
there was a significant improvement of lumbar spine BMD levels in the raloxifene
group compared with the placebo group. There was no significant difference in favor
of the raloxifene group regarding the improvement of femoral neck BMD. This result
was consistent with previous studies in which raloxifene reduced the risk of
vertebral fractures, but not nonvertebral or hip fractures in osteoporotic women
without severe renal impairments [50]
[51].
Since antiresorptive agents such as raloxifene and other SERMs might exacerbate low
bone turnover in patients with ESRD, the indications for a bone biopsy prior to
initiating antiresorptives and other osteoporosis therapies should be addressed
[22]. However, bone biopsy as the gold
standard for assessment of bone turnover is quite limited by its invasiveness and
cost [11]. The included studies in the present
meta-analysis did not provide information about whether participants had actually
undergone bone biopsy before taking raloxifene. The 2017 KDIGO guidelines
recommended monitoring serum levels of calcium, phosphorus, PTH, and ALP beginning
in CKD stage 3. In patients with advanced CKD stage, measurements of serum PTH or
BAP could be used to evaluate the underlying bone turnover [10]. There has been controversy over the role
of bone turnover markers in predicting certain clinical outcomes related to BMD
[52]
[53]
[54]. Using multiple regression
analysis, Osamu et al. found that changes of serum BAP and NTx were correlated with
the change of SOS value over one year in female dialysis patients, which indicated
that the sequential variation of bone turnover markers might be associated with the
dynamic level of BMD [31]. To further
investigate the effect of raloxifene on bone turnover markers, Osamu et al. reported
that there was a significant increase in SOS and decrease in NTx in patients treated
with raloxifene for one year [27]
[31]. However, Motoko et al. concluded that the
level of NTx did not alter significantly in the raloxifene group as compared to the
placebo group [38]. Studies by Farshid and
Motoko et al. also revealed that no statistical difference regarding serum ALP
existed between the two groups [30]
[38]. In this analysis, three studies provided
data on serum levels of calcium, phosphorus and PTH; two studies reported the bone
formation marker BAP. Pooled analysis showed no statistically significant difference
between the raloxifene group and the placebo group regarding bone metabolism
markers. Still, these data should be interpreted prudently because participants in
these studies might have taken other drugs which had effects on bone turnover
markers.
There are some limitations in our study. First, the number of included RCTs was
limited and most of the studies had a small sample size, and this could lead to an
overestimation of the efficacy of raloxifene in osteoporotic patients with ESRD.
Second, the clinical outcomes were inadequate and outcome measurements were not
uniform among the studies. Furthermore, differences in study protocols (e.g., the
type of assay used for calcium measurement, the use of albumin-adjusted calcium,
different normal ranges, etc.) might influence the interpretation of the treatment
effect of raloxifene. Another limit is that the follow-up duration of the included
studies was relatively short, which made it inappropriate to conclude that the use
of raloxifene in patients with ESRD was safe and well-tolerated.
Conclusion
The present analysis reveals that raloxifene is more effective than placebo in
improving the lumbar spine bone mineral density in postmenopausal women with
end-stage renal disease. More large randomized controlled trials are necessary to
evaluate the long-term safety of raloxifene in uremic patients.
