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Hormonal replacement therapy (HRT) andosteoporosisRelated Summaries

Hormonal replacement therapy (HRT)OsteoporosisCalcium and vitamin D for treatment and prevention of osteoporosis

Overview

hormone replacement therapy (HRT) prevents bone loss (increases bone mineral density) (level 3[lacking direct] evidence) and fractures in randomized trials but risks of longshyterm use mayoutweigh benefitslargest randomized trial of estrogenprogestin combination therapy (Womens Health Initiative[WHI] with 16608 patients) showed reduction in hip fractures (NNT 2000 per year) vertebralfractures (NNT 1429 per year) and osteoporotic fractures (NNT 228 per year)estrogen alone may reduce fracture rates but increases risk for stroke and possibly venousthromboembolism (level 2 [midshylevel] evidence)systematic reviews of randomized trials before WHI trial found HRT associated with reduced riskfor

nonvertebral fractures but only significant for women lt 60 years oldvertebral fractures

observational studies find association between longshyterm HRT use and reduced fracturesfracture risk reduction may require use of HRT for at least 5 yearsfracture risk reduction appears to diminish rapidly after cessation of HRT

alendronate (Fosamax) 10 mg orally once daily prevents bone density loss after discontinuation ofHRT

see Hormonal replacement therapy (HRT) for overview of HRT

Evidence From Randomized Trials

Womens Health Initiative Trial (WHI)

longshyterm use of HRT associated with more risks than benefits in healthy postmenopausalwomen (level 2 [midshylevel] evidence)

based on randomized trial with early terminationWomens Health Initiative (WHI) is largest randomized trial of HRT stopped early due torisks exceeding benefits

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16608 postmenopausal women aged 50shy79 years with intact uterus were randomized toHRT (equine estrogens 0625 mgmedroxyprogesterone acetate 25 mg [Prempro]) vsplacebo orally once daily for mean 52 years (range 35shy85 years)few women had cardiovascular disease at baseline (16shy19 had history of myocardialinfarction 28shy29 had history of angina 11shy15 had history of CABG or percutaneouscoronary intervention 07shy1 had history of stroke)discontinuation of study drug occurred in 42 HRT and 38 placebo patients whileaddition of HRT through personal clinician was started in 62 HRT and 107 placebopatients intentionshytoshytreat analysis was performed so results likely underestimate perprotocol resultsno differences in overall mortality or endometrial cancerresults reported as annualized percentages (event rates per year of therapy)

number needed to harm (NNH) or treat for benefit (NNT) reported as number treatedwith HRT for 1 yearcomparing HRT vs placebo (for adverse outcomes more common with HRT)

coronary heart disease events 037 vs 03 (P lt 005 NNH 1428)differences related to nonfatal myocardial infarctionsstroke 029 vs 021 (p lt 005 NNH 1250)invasive breast cancer 038 vs 03 (p lt 005 NNH 1250)venous thromboembolic event 034 vs 016 (p lt 005 NNH 555)pulmonary embolism 016 vs 008 (p lt 005 NNH 1250)absolute excess in risk 17 vs 151 (p lt 005 NNH 526) based on globalindex of death coronary heart disease event stroke pulmonary embolismbreast cancer endometrial cancer colorectal cancer or hip fracture

comparing HRT vs placebo (for adverse outcomes less common with HRT thanplacebo)

colorectal cancer 01 vs 016 (p lt 005 NNT 1667)hip fracture 01 vs 015 (p lt 005 NNT 2000)vertebral fracture 009 vs 015 (p lt 005 NNT 1429)any osteoporotic fracture 147 vs 191 (p lt 005 NNT 228)

Reference shy JAMA 2002 Jul 17288(3)321editorial can be found in JAMA 2002 Jul 17288(3)366 commentary can be found in BMJ2008 May 10336(7652)1033 (commentary can be found in BMJ 2008 May24336(7654)1148)considerable commentary can be found in JAMA 2002 Dec 11288(22)2819 CMAJ 2002Aug 20167(4)377 fullshytext ACP J Club 2002 SepshyOct137(2)41 J Fam Pract 2002Oct51(10)821 Evid Based Nurs 2003 Jan6(1)20 Can Fam Physician 2003 Feb49157Curr Rheumatol Rep 2003 Feb5(1)43 JAMA 2003 Dec 24290(24)3193 JAMA 2003 Jun25289(24)3241 JAMA 2004 Aug 11292(6)683 JAMA 2005 Mar 16293(11)1322JAMA 2006 Jul 19296(3)280 S Afr Med J 2003 Aug93(8)554 Evid Based Med 2008Oct13(5)142editorial commentary can be found in BMJ 2002 Jul 20325(7356)113 fullshytext (correctioncan be found in BMJ 2002 Aug 24325(7361)435) BMJ 2002 Nov 2325(7371)1036 fullshytext BMJ 2002 Nov 23325(7374)1243 fullshytextHRT did not have clinically meaningful effect on healthshyrelated quality of life in WHItrial (N Engl J Med 2003 May 8348(19)1839) editorial can be found in N Engl J Med2003 May 8348(19)1835 commentary can be found in ACP J Club 2003 NovshyDec139(3)60 Am Fam Physician 2004 Jan 1569(2)423 N Engl J Med 2004 Feb5350(6)622

estrogen alone (compared to placebo) may reduce fracture rates but increases risk for stroke

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and possibly venous thromboembolism (level 2 [midshylevel] evidence)based on randomized trial with early termination10739 postmenopausal women aged 50shy79 years with prior hysterectomy randomized toconjugated equine estrogen 0625 mg (Premarin) vs placebo orally daily for mean of almost7 yearsstudy stopped early by NIH since there was no benefit in primary outcome of reducingcardiovascular diseasecomparing estrogen vs placebo groups

333 vs 367 had coronary heart disease death or myocardial infarction (notsignificant)298 vs 217 had stroke (NNH 123)190 vs 144 had venous thromboembolism (NNH 217 but not quite statisticallysignificant)177 vs 228 had invasive breast cancer (NNT 196 but not quite statisticallysignificant)115 vs 107 had colorectal cancer (not significant)072 vs 118 had hip fracture (NNT 217)073 vs 118 had vertebral fracture (NNT 222)7 vs 752 had any fracture (NNT 192)548 vs 532 overall mortality (not significant)13 vs 13 had any of the above outcomes (except only counting hip fracturesinstead of vertebral or any fractures)

Reference shy JAMA 2004 Apr 14291(14)1701 editorial can be found in JAMA 2004 Apr14291(14)1769 NIH News Release 2004 Mar 2 commentary can be found in JAMA 2004Aug 11292(6)683 summary can be found in Am Fam Physician 2005 Jan 1571(2)371

HERS trial

HRT does not appear to prevent fractures in postmenopausal womenbased on randomized trial2763 postmenopausal women with coronary disease and intact uterus randomized to HRT(conjugated equine estrogens 0625 mg plus medroxyprogesterone acetate 25 mg) vsplacebo orally once daily for mean 41 yearsfewer than 15 had osteoporosis based on bone densitycomparing HRT vs placebo

fracture rates 263 vs 28 per 1000 personshyyears (p = 061)no difference in average height loss 106 vs 121 lost gt 2 cm in height (notsignificant)

Reference shy Heart and Estrogenprogestin Replacement Study (HERS) trial (Am J Med 2001Apr 15110(6)442) commentary can be found in J Fam Pract 2001 Nov50(11)926

Systematic reviews

hormone replacement therapy associated with reduced risk for fracturesbased on 2 systematic reviews conducted before Womens Health Initiative trial hormone replacement therapy associated with reduced risk for nonvertebral fractures

based on in systematic review and metashyanalysis of 22 randomized trials with 8774womenrisk ratio 073 (95 CI 056shy094)

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results not significant in women gt 60 years oldReference shy JAMA 2001 Jun 13285(22)2891 commentary can be found in JAMA2001 Nov 7286(17)2096editorial noting that stronger evidence suggests greater benefit with bisphosphonatescan be found in JAMA 2001 Jun 13285(22)2909conclusions are not firm due to design problems of underlying studies (J Watch 2001Jul 1521(14)112)

hormone replacement therapy associated with reduced risk for vertebral fracturesbased on systematic review and metashyanalysis of 13 randomized trialscomparing hormone replacement therapy vs control in 6723 patients 12 vs 196vertebral fracture incidence (NNT 132)Reference shy BMC Musculoskeletal Disorders 2001 Nov 627 fullshytext

evidence does not support use of hormone replacement in women with primary biliarycirrhosis and risks include increased adverse events (level 2 [midshylevel] evidence)

based on Cochrane review with limited evidencesystematic review of 2 randomized trials comparing hormone replacement for osteoporosisvs placebo or no intervention in 49 women with primary biliary cirrhosishormone replacement did not significantly improve lumbar spine or proximal femur bonemineral densityno deaths reported 2 fractures reported (both in placebo group of 1 trial) but results notsignificanthormone replacement associated with increased adverse events in analysis of 2 trials with 49patients

risk ratio (RR) 526 (95 CI 126shy2204)NNH 1shy48 with 8 adverse event rate in placebo or no intervention group

hormone replacement associated with increased withdrawals due to adverse events inanalysis of 2 trials with 49 patients

RR 526 (95 CI 126shy2204)NNH 1shy48 with 8 adverse event rate in placebo or no intervention group

Reference shy Cochrane Database Syst Rev 2011 Dec 7(12)CD009146

Transdermal Estrogen

transdermal estrogen may reduce vertebral fractures (level 2 [midshylevel] evidence)based on small randomized trial75 postmenopausal women aged 47shy75 years with osteoporosis and vertebral fracture wererandomized to transdermal 17 betashyestradiol 01 mg for days 1shy21 and oralmedroxyprogesterone acetate for days 11shy21 vs placebo for 28shyday cycles for 1 yearabout 18 HRT vs 31 placebo patients had new vertebral fracturesReference shy Ann Intern Med 1992 Jul 1117(1)1

transdermal estrogen prevents postmenopausal bone loss based on trial of 175 women gt 40 whohad hysterectomy or oophorectomy randomized to transdermal estradiol 0025shy01 mgday vsplacebo for 2 years (Obstet Gynecol 1999 Sep94330 in Am Fam Physician 2000 Feb 161(3)838)

Effects on Bone Mineral Density

oral estradiol may increase lumbar bone mineral density (BMD) in postmenopausal womenwith osteoporosis (level 3 [lacking direct] evidence)

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based on randomized trial with high dropout rate and without clinical outcomes309 women aged 45shy75 years with osteoporosis after natural menopause or bilateraloophorectomy were randomized to estradiol 05 mgday vs 1 mgday vs placebo orally for104 weeksall women given calcium 500 mg and vitamin D3 200 units patients given levonorgestrel 40mcg if requiredwomen in placebo group switched to estradiol 1 mg after 52 weeks for ethical reasons241 women (78) completed the trialboth estradiol groups associated with significant increase in lumbar BMD at 52 weeks vsplacebo (p lt 0001 for each treatment group vs placebo)estradiol 1 mg associated with significantly greater increases than estradiol 05 mg at 104weeks (p lt 0008)adverse events reported in 893Reference shy Climacteric 2010 Feb13(1)72DynaMed commentary shyshy ethical reasons for switching women in placebo group toestradiol 1 mg after 52 weeks unclear from fullshytext

lowshydose estrogen prevents bone losslowshydose estrogen prevents bone loss compared to placebo and modestly less gainscompared with highshydose estrogen (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes822 healthy postmenopausal women aged 40shy65 were randomized to 1 of 8 treatmentgroups with varying combinations of placebo conjugated equine estrogens (03 045or 0625 mgday) and medroxyprogesterone acetate (15 or 25 mgday) for 2 years allwomen given calcium carbonate (Caltrate) 600 mg once dailyall active treatment groups had significant increases in spine and hip bone mineraldensity (BMD) all active treatment groups except lowest estrogen dose withoutprogestin had significant increase in total body bone mineral content placebo grouphad significant losses in all these measuresgains in spine BMD were significantly higher with highshydose estrogen compared withlowshydose estrogen but differences small compared to differences with placeboReference shy JAMA 2002 May 22shy29287(20)2668

lowshydose estrogen prevented bone loss as well as higher doses in randomized trial of almost600 women comparing estradiol 1 mg vs 2 mg for over 2 years (Osteoporosis International200112251 in BMJ 2001 Jun 16322(7300)1498)micronized 17shybetashyestradiol 025 mgday increased bone density compared to placebo in 3shyyear randomized trial of 167 women gt 65 years old study too small to evaluate fracture data(JAMA 2003 Aug 27290(8)1042)

ultrashylowshydose transdermal estrogenultrashylowshydose transdermal estrogen increases bone mineral density in postmenopausalwomen (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes417 postmenopausal women aged 60shy80 years with intact uterus and zshyscore shy2 orhigher were randomized to unopposed transdermal estradiol 0014 mgday vs placebofor 2 yearsall women received calcium and vitamin Dcomparing transdermal estradiol vs placebo

lumbar BMD increased 26 vs 06 (p lt 0001)mean total hip BMD increased 04 vs decreased 08 (p lt 0001)endometrial hyperplasia in 05 vs 0

Reference shy Obstet Gynecol 2004 Sep104(3)443 commentary can be found in Am

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Fam Physician 2005 Aug 172(3)513ultrashylowshydose transdermal estrogen may be similar to raloxifene for effect on bonemineral density in postmenopausal women (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes500 postmenopausal women with osteopenia randomized to microdose 17shybetashyestradiol (0014 mgday) transdermally vs raloxifene 60 mgday orally for 2 years66shy70 completed trialno significant differences comparing estrogen vs raloxifene

lumbar spine bone mineral density increased by 24 vs 3no bone loss in lumbar spine in 773 vs 805no histological evidence of endometrial stimulation in 99 vs 100mean dense area in breast mammograms 198 vs 19

Reference shy Menopause 2009 MayshyJun16(3)559

dehydroepiandrosterone (DHEA) supplementation in combination with calcium andvitamin D associated with increased lumbar spine bone mineral density (BMD) in olderwomen

based on randomized trial113 patients aged 65shy75 years taking vitamin D 16 mcg daily and calcium 700 mg dailyrandomized to additional supplementation with oral DHEA 50 mg daily vs placebo in year1 all patients took openshylabel DHEA 50 mg daily in year 2in men no significant difference among groups in

BMD measuresbone turnover makers

in women increase in lumbar spine BMDin DHEA group compared with placebo group at 12 months (p = 003)from baseline at 24 months in those on DHEA for 24 months (p lt 0001)from baseline at 24 months in those crossed over from placebo (p = 0006)

Reference shy Am J Clin Nutr 2009 May89(5)1459 fullshytextcombined hormone replacement therapy (HRT) and bisphosphonate therapy may increase bonemineral density more than monotherapies in postmenopausal women

estrogen plus alendronate more effective than estrogen alone for increasing BMD inwomen taking HRT ge 1 year (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes428 postmenopausal women with osteoporosis who had been taking HRT for ge 1 yearcontinued HRT and were randomized to alendronate 10 mg vs placebo orally oncedaily for 12 monthscomparing HRT plus alendronate vs HRT alone at 12 months

mean increase in BMD at lumbar spine 36 vs 1 (p lt 0001)mean increase in BMD at hip 27 vs 05 (p lt 0001)

difference at femoral neck not significant (p = 007)no significant differences in adverse effectsReference shy J Clin Endocrinol Metab 1999 Sep84(9)3076 fullshytextDynaMed commentary shyshy study too small and too short to assess fracture rates

estrogen plus alendronate more effective than either monotherapy for increasing BMDin postmenopausal women after hysterectomy (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes425 postmenopausal women with osteoporosis who had all undergone hysterectomyand were not receiving HRT were randomized to 1 of 4 groups for 2 years

alendronate 10 mg orally once dailyconjugated equine estrogen 0625 mg orally once daily

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both treatmentsdouble placebo

combined alendronate and estrogen more effective than either monotherapy which wasmore effective than placebo in increasing BMD at lumbar spine and femoral neckno differences between 3 treatment groups in total body BMDReference shy J Clin Endocrinol Metab 2000 Feb85(2)720 fullshytextDynaMed commentary shyshy study too small to evaluate fracture rates

HRT plus alendronate improved BMD more than alendronate alone which was moreeffective than HRT alone (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes373 postmenopausal women aged 65shy90 years randomized to 1 of 4 groups for 3 years

conjugated equine estrogen 0625 mgday (HRT)alendronate 10 mgdayHRT plus alendronateplacebo

HRT plus alendronate HRT alone and alendronate alone each improved BMD at thehip femoral neck and trochanterBMD at all femoral and vertebral sites increased significantly more in HRT plusalendronate group than either monotherapy group (p lt 005)hip BMD increased significantly more in alendronate alone group than in HRT alonegroup (42 vs 3 p lt 005)Reference shy JAMA 2003 May 21289(19)2525 fullshytext correction can be found inJAMA 2007 Feb 7297(5)470

addition of alendronate to estradiol may increase bone mineral density (level 3 [lackingdirect] evidence)

based on randomized trial without clinical outcomes150 women with surgical menopause randomized to 1 of 3 groups for 2 years

estradiol 2 mg plus alendronate 5 mg once dailyestradiol 2 mg plus alendronate 10 mg once dailyestradiol 2 mg plus placebo once daily

both estradiol plus alendronate groups associated with significantly increased BMD atlumbar spine trochanter and femoral neckReference shy J Clin Endocrinol Metab 2002 Apr87(4)1502 fullshytext

addition of alendronate to hormone replacement therapy may not increase bonemineral density in Korean postmenopausal women (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes139 postmenopausal women in Korea who had low bone mineral density (BMD) afterhormone replacement therapy (HRT) for ge 1 year randomized to continued HRT plusalendronate 10 mgday vs placebo for 1 yearcomparing alendronate vs placebo

mean change in lumbar spine BMD 37 vs 43 (not significant)mean change in total hip BMD 22 vs 32 (not significant)

Reference shy Menopause 2013 Jul20(7)761addition of risedronate to daily hormone therapy may increase bone density (level 3[lacking direct] evidence)

based on randomized trial with high dropout rate and without clinical outcomes524 postmenopausal women randomized to conjugated equine estrogens 0625 mgplus risedronate 5 mg (risedronate plus HRT) vs conjugated equine estrogens alone(HRT alone) for 12 monthsall patients received 1 g elemental calcium daily patients with 25shyhydroxyvitamin D

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levels lt 399 nmolL (16 ngmL) received oral vitamin D le 500 unitsday76 HRT only group and 71 risedronate plus HRT group completed trialat 12 months risedronate plus HRT associated with increased bone density in thefemoral neck and midshaft radiusno significant differences in bone density at lumbar spine femoral trochanter or distalradiusReference shy J Clin Endocrinol Metab 2001 May86(5)1890 fullshytext

combined HRT and etidronate may increase bone mineral density (BMD) compared tomonotherapy but effect on fracture rates unclear (level 3 [lacking direct] evidence)

based on small randomized trial without clinical outcomes72 postmenopausal women with osteoporosis and 1shy4 thoracic vertebral compressionfractures randomized to 1 of 4 groups for 4 years

no specific treatmentHRTintermittent cyclical etidronateHRT and etidronate

nonsignificant trend toward fewer vertebral fractures in all treatment groupsReference shy Am J Med 1998 Mar104(3)219

estrogen may improve bone mineral density in frail elderly (level 3 [lacking direct] evidence)based on small randomized trial without clinical outcomes67 women gt 75 years old with mild to moderate physical frailty were randomized to HRT(conjugated estrogens 0625 mg orally once daily plus medroxyprogesterone acetate 5 mgorally once daily for 13 days every 3 months) vs placebo for 9 monthscomparing HRT vs placebo

mean 43 vs 04 change in lumbar bone mineral density (BMD)mean 17 vs shy01 change in total hip BMD

Reference shy JAMA 2001 Aug 15286(7)815 commentary can be found in JAMA 2001 Nov28286(20)2544

exerciseshyassociated amenorrheaHRT does not appear to improve bone density in amenorrheic women (level 3 [lackingdirect] evidence)

based on small randomized trial without clinical outcomes24 amenorrheic ballet dancers (mean age 22 years) randomized to HRT (conjugatedequine estrogens 0625 mg for 25 daysmonth plus medroxyprogesterone acetate 10mg for 10 daysmonth) vs placebo for 2 yearsall took calcium 1250 mgdayno significant differences in mean bone mineral density at 2 years bone mineraldensity increased markedly in 5 placebo patients who resumed mensesReference shy Fertil Steril 2003 Aug80(2)398

Cessation of Hormone Therapy

cessation of HRT quickly associated with loss of protection from hip fractures (level 2 [midshylevel] evidence)

based on cohort of 140584 postmenopausal women gt 50 years old followed for 12 months269 had incident hip fracturecurrent HRT users had reduced risk for hip fracturewomen with previous HRT use did not have reduced risk even if HRT stopped withinprevious 5 yearsReference shy Obstet Gynecol 2004 Mar103(3)440 commentary can be found in J Fam Pract

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2004 Jun53(6)444 BMJ 2004 Jul 3329(7456) Am Fam Physician 2005 Jan 171(1)166 cessation of HRT quickly associated with loss of protection from any fractures (level 2 [midshylevel] evidence)

based on prospective cohort of 138738 postmenopausal women aged 50shy69 years followedfor 2shy4 yearsany type of current hormone use was associated with reduced fracture incidence protectionstarted soon after hormone therapy startedpast hormone users had no significant protection without about 1 year of hormone cessationReference shy JAMA 2004 May 12291(18)2212

cessation of estrogen does not appear to accelerate bone lossbased on followshyup study495 women who were adherent to assigned treatment in 3shyyear PostmenopausalEstrogenProgestin Interventions randomized controlled trial (PEPIshyRCT) and who hadadditional BMD measurement during PEPI Safety Followshyup Study were followed for mean3 years during and 4 years after the PEPIshyRCTdecreases in bone mineral density after cessation of HRT following randomized trial werenot significantly different than decreases in placebo groupReference shy Arch Intern Med 2002 Mar 25162(6)665

alendronate prevents bone density loss after discontinuation of hormone replacementtherapy (HRT) (level 3 [lacking direct] evidence)

based on randomized trial without clinical outcomes144 postmenopausal women with low bone mineral density (BMD) who had discontinuedHRT within 3 months were randomized to alendronate 10 mg vs placebo daily for 12months119 (83) completed the study (87 alendronate group vs 74 placebo group)comparing alendronate vs placebo for mean change in BMD at 12 months significantdifferences found in

spine (+23 vs shy32)femoral neck (+02 vs shy14)hip trochanter (+25 vs +02)total body (+1 vs shy07)

Reference shy Arch Intern Med 2003 Apr 14163(7)789

Additional Information

AHRQ comparative effectiveness review on treatment to prevent fractures in men and women withlow bone density or osteoporosis can be found at AHRQ Comparative Effectiveness Review 2012Mar53 PDF

References

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