Systematic review of raloxifene in postmenopausal Japanese women with osteoporosis or low bone mass (osteopenia)

Figures & data

Figure 1 Flow diagram of literature-search results. Databases were Medline via PubMed and Embase. Searches were limited to human species and publications from 1980 onwards.

Abbreviation: BMD, bone mineral density.

Table 1 Study and participant characteristics

Authors	Enrolled, n	Therapy and dose, n	Mean (SD) age, years	Study period, weeks	Disease definition	Objective
Randomized controlled trials
Morii et al^Citation35	302a	RLX 60 mg/day, 92a RLX 120 mg/day, 95a Placebo, 97a	65 (6)b 65 (6)b 64 (7)	52	L-BMD ≤2.5 SD of YAM and Japanese diagnostic criteriac	Assess safety and efficacy of RLX (double-blind, placebo-controlled)
Iwamoto et al^Citation31	122	RLX 60 mg/day, 61 ALN 5 mg/day, 61	69 (7) 70 (8)	52	Japanese diagnostic criteriad	Compare effects of RLX and ALN on L-BMD, bone turnover, and lipid metabolism
Majima et al^Citation33	60	RLX 60 mg/day, 32 RLX 60 mg + ALF 1 μg/day, 28	72 (9)e 70 (11)e	52	L-BMD ≤2.5 SD of YAM and Japanese diagnostic criteriad	Assess efficacy of RLX + ALF on BMD and bone turnover
Gorai et al^Citation29	137	RLX 60 mg/day, 45 ALF 1 μg/day, 44 RLX 60 mg + ALF 1 μg/day, 48	64 (7) 65 (7) 65 (8)	52	L-BMD ≤2.5 SD of YAM (osteoporosis) or 2.5 SD <L-BMD ≤2.0 SD of YAM (osteopenia)d	Assess adherence to RLX, ALF, and RLX + ALF
Hayashi et al^Citation34	46	RLX 60 mg/day, 16 HRT, 16 Control, 14f	71 (3) 72 (3) 73 (3)	52	L-BMD ≤2.0 SD of YAM	Compare atheroprotective and osteoprotective effects of RLX and HRT when switching from HRT to RLX (age-matched controlsf)
Gorai et al^Citation32	170	RLX 60 mg/day, 42g ALF 1 μg/day, 46g RLX 60 mg + ALF 1 μg/day, 45g	64 (7) 65 (7) 65 (7)	104	L-BMD ≤2.5 SD of YAM (osteoporosis) or 2.5 SD <L-BMD ≤2.0 SD of YAM (osteopenia)d	Assess efficacy of RLX + ALF on BMD and bone turnover and effect of RLX on serum PTH
Ando et al^Citation30	39	RLX 60 mg/day am, 20 RLX 60 mg/day pm, 19	77 (10)h 78 (7)h	52	Japanese Guidelines for the Prevention and Treatment of Osteoporosisi	Assess effects of RLX dosing time on coagulation, fibrinolysis, and bone turnover
Observational studies
Majima et al^Citation36	50	RLX 60 mg/day, 50	72 (10)	52	L-BMD ≤2.5 SD of YAM and Japanese diagnostic criteriad	Assess effects of RLX on bone turnover, BMD, and lipid metabolism
Majima et al^Citation37	68	RLX 60 mg/day, 68	70 (9)j	52	L-BMD ≤2.5 SD of YAM and Japanese diagnostic criteriad	Assess associations between baseline bone turnover and BMD and their changes 52 weeks after treatment
Majima et al^Citation38	73	RLX 60 mg/day, 73	70 (9)k	52	L-BMD ≤2.5 SD of YAM and Japanese diagnostic criteriad	Assess associations between short-term reduction in bone turnover and BMD changes
Urushihara et al^Citation41	7,557	RLX 60 mg/day, 6,970l	70 (9)m	52n	NR	Compare risks of stroke and stroke death between RLX and general female population
Takada et al^Citation24	198	RLX 60 mg/day, 198	63 (8)	104	Japanese diagnostic criteriad	Clarify effects of RLX on proximal femoral geometry
Iikuni et al^Citation40	7,557	RLX 60 mg/day, 6,967 (safety)l RLX 60 mg/day, 2,784 (efficacy)l	70 (9) 70 (9)	156	Japanese diagnostic criteriad	Assess effectiveness and safety of long-term RLX use
Takada et al^Citation39	45	RLX 60 mg/day, 45	67 (5)	52	Japanese diagnostic criteriad	Assess correlations between bone turnover and proximal femur geometry
Yoh et al^Citation42	536	RLX 60 mg/day, 506l	71 (9)	24	Japanese diagnostic criteriad	Assess effect of RLX on QOL and pain

Notes:

a A total of 302 participants were randomized, but only 284 participants were started on the study drug

b n=90 for the RLX60 group and n=93 for the RLX120 group

c as reported by Morii et al³⁵

d Orimo et al⁴³

e n=22 for the RLX group and n=20 for the RLX + ALF group

f control patients (age-matched) did not receive placebo medication, but did receive vitamin D (0.5 μg/day)

g n values are for the modified intent-to-treat population; of the 170 participants who provided consent, 169 were randomized and 133 received treatment; the 36 participants who were randomized but did not receive treatment either withdrew their consent or dropped out of the study

h n=18 for the RLX am group and n=17 for the RLX pm group

i Committee of Japanese Guidelines for the Prevention and Treatment of Osteoporosis¹⁹

j n=58

k n=63

l participants eligible for analysis

m n=6,963

n median follow-up was 366 days.

Abbreviations: ALF, alfacalcidol; ALN, alendronate; BMD, bone mineral density; ELD, eldecalcitol; HRT, hormone-replacement therapy (estriol 1 mg/day and medroxyprogesterone 1.25 mg/day); L-BMD, lumbar spine BMD; NR, not reported; PTH, parathyroid hormone; QOL, quality of life; RLX, raloxifene; SD, standard deviation; YAM, young average mean.

Table 2 Studies reporting mean (SD) percentage change in bone mineral density or mean (SD) bone mineral density (g/cm²) of the lumbar spine, femoral neck, total hip, or total neck after 52 weeks of RLX treatmenta

Authors	Therapy	Lumbar spine % or g/cm^2	Femoral neck % or g/cm^2	Total hip % or g/cm^2	Total neck % or g/cm^2
Randomized controlled trials
Morii et al^Citation35	RLX	+2.9 (NR)***,b	NM	NM	NM
Iwamoto et al^Citation31	RLX ALN	+2.4 (NR)** +8.0 (NR)**	NM NM	NM NM	NM NM
Majima et al^Citation33	RLX RLX + ALF	+6.3 (5.8)** +4.9 (7.7)**	+0.8 (6.3) +3.0 (17.4)	NM NM	+2.1 (5.3) +1.8 (7.9)
Gorai et al^Citation29	RLX ALF RLX + ALF	+3.0 (NR)* +0.7 (NR) +4.6 (NR)*	NM NM NM	NR (NR) NR (NR) +2.0 (NR)	NM NM NM
Gorai et al^Citation32	RLX ALF RLX + ALF	+2.9 (4.3)** −0.3 (4.4) +4.1 (3.5)***	NM NM NM	+1.6 (3.5)* −0.1 (3.8) +1.2 (4.1)	NM NM NM
Observational studies
Majima et al^Citation36	RLX	0.67 (0.14), 0.72 (0.13)**	0.54 (0.10), 0.56 (0.10)	NM	0.60 (0.12), 0.61 (0.13)
Majima et al^Citation37	RLX	0.67 (0.12), 0.70 (0.12)**	0.55 (0.10), 0.55 (0.10)	NM	NM
Majima et al^Citation38	RLX	0.67 (0.12), 0.70 (0.12)**	0.55 (0.09), 0.55 (0.09)	NM	0.60 (0.11), 0.61 (0.12)
Iikuni et al^Citation40	RLX	+2.9 (NR)***	NM	NM	NM

Notes:

* P<0.05,

** P<0.01, and

*** P<0.001 indicate significant differences from baseline

a data from two studies reporting bone mineral density (BMD) findings were not included in this table because BMD findings were of other regions in the hip;^24,39

b patients received either RLX 60 mg/day or RLX 120 mg/day, n=183.

Abbreviations: ALF, alfacalcidol; ALN, alendronate; NM, not measured; NR, not reported; RLX, raloxifene; SD, standard deviation.

Table 3 Studies reporting mean (SD) percentage change in or mean (SD) concentrations for biochemical markers of bone turnover after 52 weeks of RLX treatment

Authors	Therapy	Serum BAP (% or U/L)	CTx (% or μg/L)	NTx (% or nmol BCE/L)
Randomized controlled trials
Morii et al^Citation35,a,b	RLX RLX (120 mg/day)	NR (NR)*** NR (NR)***	NR (NR)***,c NR (NR)***,c	NR (NR)***,c NR (NR)***,c
Iwamoto et al^Citation31	ALN RLX	−18 (NR)***,d −10 (NR)***,d	NM NM	−45 (NR)***,c,e −35 (NR)***,c,e
Majima et al^Citation33	RLX RLX + ALF	−20 (37)* −20 (29)**	NM NM	−29 (20)**,f −25 (17)**,f
Gorai et al^Citation29,g	RLX ALF RLX + ALF	−22 (NR) NR (NR) −37 (NR)	−37 (NR)c NR (NR)c −42 (NR)c	NR (NR)c NR (NR)c −35 (NR)c
Gorai et al^Citation32,a	RLX ALF RLX + ALF	NR (NR)* NR (NR) NR (NR)***	NR (NR)***,c NR (NR) NR (NR)***,c	NR (NR)***,c NR (NR) NR (NR)***,c
Ando et al^Citation30,g,h	All RLX am RLX pm	−32 (−43 to −22)i −26 (−39 to −13)i −38 (−55 to −21)i	NM NM NM	NM NM NM
Observational studies
Majima et al^Citation36	RLX	33 (16), 24 (9)**	NM	19 (6), 14 (3)**,f
Majima et al^Citation37	RLX	33 (17), 23 (9)**	NM	19 (5), 14 (3)**,f
Majima et al^Citation38	RLX	33 (16), 24 (9)**	NM	20 (5), 14 (3)**,f
Iikuni et al^Citation40,a,j	RLX	NR (NR)***	NM	NR (NR)***,c
Takada et al^Citation39,g	RLX	NM	NM	−13.5 (NR)f,k

Notes:

* P<0.05,

** P<0.01, and

*** P<0.001 indicate significant differences from baseline

a study presented data of biochemical markers of bone turnover in figures, but did not report specific values in the figure or results text

b osteocalcin levels were also measured in this study; statistically significant (P<0.001) reductions from weeks 0 to 52 were reported

c urinary levels tested

d serum alkaline phosphatase levels were measured

e mean (SD) percentage change for NTx is from week 0 to week 12

f serum levels tested

g authors did not specify the value of statistical significance for bone biochemical marker reductions

h tartrate-resistant acid phosphatase levels were also measured in this study; the mean (95% CI) percentage change from week 0 to 52 was −27 (−33 to −21) mU/dL for all postmenopausal women, −31 (−40 to −22) mU/dL for the RLX am group, and −23 (−32 to −14) mU/dL for the RLX pm group

i values are means (95% CI)

j urinary deoxypyridinoline levels were also measured in this study; statistically significant (P<0.001) reductions from week 0 to 52 were reported

k values are medians; median percentage change for NTx is from week 0 to week 26.

Abbreviations: ALF, alfacalcidol; ALN, alendronate; BAP, bone-specific alkaline phosphatase; BCE, bone collagen equivalents; CTx, type 1 collagen C-telopeptide; NM, not measured; NR, not reported; NTx, type 1 collagen N-telopeptide; RLX, raloxifene 60 mg/day; SD, standard deviation; CI, confidence interval.

Table 4 Studies reporting mean (SD) percentage change in blood–lipid parameters or mean (SD) blood–lipid parameters after 52 weeks of RLX treatment

Authors	Therapy	Total cholesterol % or mg/dL	Triglycerides % or mg/dL	HDL-cholesterol % or mg/dL	LDL-cholesterol % or mg/dL
Randomized controlled trials
Morii et al^Citation35	RLX RLX (120 mg/day)	NR (NR)*,a NR (NR)*,a	NR (NR) NR (NR)	NR (NR) NR (NR)	NR (NR)*,a NR (NR)*,a
Iwamoto et al^Citation31	RLX ALN	−3.9 (NR)** −2.1 (NR)	+7.4 (NR) −3.4 (NR)	+5.1 (NR) −0.4 (NR)	−7.7 (NR)*** +0.4 (NR)
Majima et al^Citation33	RLX RLX + ALF	202 (39), 184 (30)** 210 (29), 199 (28)*	133 (74), 125 (58) 144 (58), 124 (72)	57 (14), 53 (11) 57 (15), 56 (15)	119 (38), 106 (24) 125 (30), 118 (27)
Hayashi et al^Citation34	RLX HRT Control	NR (NR), NR (NR) NR (NR), NR (NR) NR (NR), NR (NR)	95 (24), 86 (11) 96 (25), 97 (18) 97 (21), 95 (21)	56 (6), 64 (7)* 57 (5), 56 (8) 57 (5), 56 (6)	113 (14), 102 (15) 112 (11), 114 (13) 119 (11), 125 (9)
Observational studies
Majima et al^Citation36	RLX	204 (32), 192 (31)**	123 (66), 122 (63)	55 (13), 54 (11)	125 (33), 113 (27)*

Notes:

* P<0.05,

** P<0.01, and

*** P<0.001 indicate significant differences from baseline;

a statistical significance is for differences between placebo and RLX groups at week 52.

Abbreviations: ALF, alfacalcidol; ALN, alendronate; HDL, high-density lipoprotein; HRT, hormone-replacement therapy; LDL, low-density lipoprotein; NR, not reported; RLX, raloxifene 60 mg/day; SD, standard deviation.

Table 5 Adverse events (AEs)

Authors	Therapy (n)	AEs n	Serious AEs n	Death n	Other
Randomized controlled trials
Morii et al^Citation35	RLX (92) RLX (120 mg/day) (95) Placebo (97)	32 40 33	5 3 7a	0 1b 0	No significant increases in incidence of hot flushes, leg cramps, breast pain or vaginal bleeding between RLX and placebo groups; no VTE events reported
Gorai et al^Citation29,c	RLX (45) ALF (44) RLX + ALF (48)	17 11 13	NR NR NR	NR NR NR	Hot flush 1, leg cramp 2, limb cramp 2 Hot flush 1 Leg cramp 2
Observational studies
Iikuni et al^Citation40	RLX (6,967)	776d	76d	3	Stroke 12 (8 serious), VTE 11 (3 serious) Most frequent AEs: peripheral edema 45, abdominal discomfort 39, abdominal pain 33
Yoh et al^Citation42	RLX (506)	34e	1	0	Most frequent AEs: abdominal discomfort 6, peripheral edema 3

Notes:

a Seven participants reported nine serious AEs;

b death caused by anaplastic thyroid cancer; not related to RLX;

c adverse events were self-reported or observed;

d 961 AEs were reported in 775 participants, and 87 serious AEs were reported in 76 participants;

e 40 AEs were reported in 34 participants.

Abbreviations: ALF, alfacalcidol; NR, not reported; RLX, raloxifene 60 mg/day; VTE, venous thromboembolism.

Table 6 Study discontinuations

Authors	Therapy (n)	Overall n	Because of AEs n	AE type n
Randomized controlled trials
Morii et al^Citation35	RLX (92) RLX (120 mg/day) (95) Placebo (97)	13 14 10	7 8 3	NR NR NR
Iwamoto et al^Citation31	RLX (61) ALN (61)	9 11	6 8	Epigastric pain 4, liver dysfunction 1, urticaria 1 Epigastric pain 3, gastric ulcer 1, heartburn 1, liver dysfunction 1, diarrhea 1, constipation 1
Majima et al^Citation33	RLX (32) RLX + ALF (28)	10 8	2 2	Muscle pain entire body 1, leg cramps 1a Increased BP 1, leg cramps 1a
Gorai et al^Citation29	RLX (45) ALF (44) RLX + ALF (48)	NR NR NR	7 5 6	Itching paresthesia 2, limb cramp 2, leg cramp 2, alopecia areata 1 Hypercalciuria 4, hot flash 1 Digestive symptoms 3, leg cramp 2, angina attack 1
Gorai et al^Citation32	RLX (42) ALF (46) RLX + ALF (45)	NR NR NR	7 5 6	Itching paresthesia 2, limb cramp 2, leg cramp 2, alopecia areata 1 Hypercalciuria 4, hot flash 1 Digestive symptoms 3, leg cramp 2, angina attack 1
Ando et al^Citation30	RLX am (20) RLX pm (19)	4 1	3 1	Muscle pain 1, headache 1, loss of fingernails 1 Hot flush 1
Observational studies
Majima et al^Citation36	RLX (50)	16	4	Leg cramps 2, muscle pain entire body 1, increased BP 1a
Majima et al^Citation37	RLX (68)	10	2	Leg cramps 1, muscle pain entire body 1a
Majima et al^Citation38	RLX (73)	10	2	Leg cramps 1, muscle pain entire body 1a

Note:

a AEs resolved spontaneously with cessation of RLX.

Abbreviations: AEs, adverse events; ALF, alfacalcidol; ALN, alendronate; BP, blood pressure; NR, not reported; RLX, raloxifene 60 mg/day.

MoriiHOhashiYTaketaniYEffect of raloxifene on bone mineral density and biochemical markers of bone turnover in Japanese postmenopausal women with osteoporosis: results from a randomized placebo-controlled trialOsteoporos Int2003141079380012955333

 PubMed Web of Science ®Google Scholar

IwamotoJSatoYUzawaMTakedaTMatsumotoHComparison of effects of alendronate and raloxifene on lumbar bone mineral density, bone turnover, and lipid metabolism in elderly women with osteoporosisYonsei Med J29200849111912818306478

 PubMed Web of Science ®Google Scholar

MajimaTKomatsuYShimatsuAEfficacy of combined treatment with raloxifene and alfacalcidol on bone density and biochemical markers of bone turnover in postmenopausal osteoporosisEndocr J200855112713418219181

 PubMed Web of Science ®Google Scholar

GoraiITanakaYHattoriSIwaokiYAssessment of adherence to treatment of postmenopausal osteoporosis with raloxifene and/or alfacalcidol in postmenopausal Japanese womenJ Bone Miner Metab201028217618419657590

 PubMed Web of Science ®Google Scholar

HayashiTInaKMaedaMNomuraHThe effects of selective estrogen receptor modulator treatment following hormone replacement therapy on elderly postmenopausal women with osteoporosisNitric Oxide201124419920321513812

 PubMed Web of Science ®Google Scholar

GoraiIHattoriSTanakaYIwaokiYAlfacalcidol-supplemented raloxifene therapy has greater bone-sparing effect than raloxifene-alone therapy in postmenopausal Japanese women with osteoporosis or osteopeniaJ Bone Miner Metab201230334935822130786

 PubMed Web of Science ®Google Scholar

AndoHOtodaTOokamiHDosing time-dependent effect of raloxifene on plasma plasminogen activator inhibitor-1 concentrations in post-menopausal women with osteoporosisClin Exp Pharmacol Physiol201340322723223323567

 PubMed Web of Science ®Google Scholar

MajimaTKomatsuYShimatsuAClinical significance of 1-year treatment with raloxifene on bone and lipid metabolism in Japanese postmenopausal women with osteoporosisEndocr J200754685586217917307

 PubMed Web of Science ®Google Scholar

MajimaTShimatsuAKomatsuYAssociation between baseline values of bone turnover markers and bone mineral density and their response to raloxifene treatment in Japanese postmenopausal women with osteoporosisEndocr J2008b551414818187874

 PubMed Web of Science ®Google Scholar

MajimaTShimatsuASatohNThree-month changes in bone turnover markers and bone mineral density response to raloxifene in Japanese postmenopausal women with osteoporosisJ Bone Miner Metab200826217818418301975

 PubMed Web of Science ®Google Scholar

UrushiharaHKikuchiNYamadaMYoshikiFMiyauchiARaloxifene and stroke risks in Japanese postmenopausal women with osteoporosis on postmarketing surveillanceMenopause200916597197719357545

 PubMed Web of Science ®Google Scholar

TakadaJMikiTImanishiYEffects of raloxifene treatment on the structural geometry of the proximal femur in Japanese women with osteoporosisJ Bone Miner Metab201028556156720333418

 PubMed Web of Science ®Google Scholar

IikuniNHamayaENihojimaSSafety and effectiveness profile of raloxifene in long-term, prospective, postmarketing surveillanceJ Bone Miner Metab201230667468222752125

 PubMed Web of Science ®Google Scholar

TakadaJIbaKYoshizakiTYamashitaTCorrelation between a bone resorption marker and structural geometry of the proximal femur in osteoporotic women treated with raloxifeneJ Orthop Surg (Hong Kong)201220220921322933681

 PubMedGoogle Scholar

YohKHamayaEUrushiharaHQuality of life in raloxifene-treated Japanese women with postmenopausal osteoporosis: a prospective, postmarketing observational studyCurr Med Res Opin201228111757176623035693

 PubMed Web of Science ®Google Scholar

OrimoHHayashiYFukunagaMDiagnostic criteria for primary osteoporosis: year 2000 revisionJ Bone Miner Metab200119633133711685647

 PubMed Web of Science ®Google Scholar

Committee of Japanese Guidelines for the Prevention and Treatment of OsteoporosisJapanese Guidelines for the Prevention and Treatment of OsteoporosisTokyoLife Science2011

 Google Scholar