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Abstract

Up to 70% of menopausal women report musculoskeletal (MSK) pain during and after the time of menopause. This observation suggests oestrogen deficiency may play a role in the development of MSK pain and conditions which cause it. Therefore, we hypothesise that hormone replacement therapy (HRT) will improve these symptoms; however, there is currently no guidance on the use of HRT for such symptoms. This review aims to synthesise current evidence on the associations between HRT and chronic MSK pain in menopausal women, to help guide clinical practice. MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, Cochrane and Web of Science databases were searched from their inception to October 2024. The search initially identified 30,739 studies from which 57 studies, including a total 3,958,702 participants, were included. MSK outcomes were grouped into generalised MSK pain, osteoarthritis (OA), rheumatoid arthritis (RA), gout and carpel tunnel syndrome (CTS). Pooled analysis found no significant effect of ever HRT use versus never HRT use on generalised MSK pain (RR 1.00, 95% CI 0.96–1.04). For OA and RA outcomes significant heterogeneity between studies restricted our ability to undertake pooled analysis. Narrative synthesis of these outcomes revealed conflicting results on the effect of HRT on these conditions. This systematic review and meta-analysis demonstrates the substantial heterogeneity within this field and highlights the need for bespoke studies investigating the effect of HRT on MSK pain to draw any firm conclusions to guide clinical practice.

Keywords

association hormone replacement therapy HRT menopause osteoarthritis OA rheumatoid arthritis RA gout carpel tunnel syndrome CTS musculoskeletal MSK

Introduction

Menopause, defined clinically as the permanent cessation of menstruation due to the loss of follicular function, is a universal experience for women living beyond midlife.¹ The associated decline in oestrogen levels results in a plethora of symptoms including hot flushes, mood changes, cognitive dysfunction, sleep disturbance, fatigue, reduced libido and musculoskeletal (MSK) pain. While vasomotor symptoms (hot flushes and night sweats) have traditionally been regarded as the hallmark features of menopause, recent evidence suggests MSK pain is nearly as prevalent, affecting over 70% of women at the peak of menopause.²

Emerging research indicates strong sex-based disparity in MSK disorders, with women experiencing higher rates of arthralgia and arthritis than men.³ These differences become particularly pronounced during the menopausal transition, suggesting a potential link between oestrogen deficiency and the development and progression of such conditions. For example, the incidence of osteoarthritis (OA) rises exponentially in women over men at the age of menopause.^4,5 Furthermore, oestrogen is known to exert anti-inflammatory and immunosuppressive effects, hence associations with new onset inflammatory conditions such as rheumatoid arthritis (RA) during and after menopause.⁶ However, not all pain experienced during the menopause can be directly attributed to oestrogen deficiency. Joint and muscle pains can be related with fatigue, mood, sleep disturbance, and elevated Body Mass Index. The menopause is therefore likely to trigger and drive chronic pain syndromes.

MSK pain represents a substantial burden on both individual wellbeing and the economy. The global prevalence of OA among postmenopausal women has increased 1.3-fold in three decades⁷ and MSK pain remains one of the most frequent reasons for primary care consultations.⁸ Despite this, there are no comprehensive systematic reviews and meta-analyses examining the use of HRT for MSK symptoms in menopausal women.

The uptake of HRT has increased in recent years, perhaps due to increased awareness of menopause and associated campaigns. Currently the National Institute for Health and Care Excellence (NICE) only recommends HRT for the treatment of vasomotor symptoms, depression and altered sexual function.⁹ However, anecdotal reports and preliminary studies suggest that HRT may be beneficial for the MSK complaints,^4,10,11 although such evidence is conflicting.^12–14

The high prevalence, complex aetiology, and substantial personal and societal costs of MSK pain in menopausal women highlights the need to evaluate whether HRT may offer meaningful therapeutic benefit to these women. This review aims to synthesise current evidence on the associations between HRT and chronic MSK pain in menopausal women.

Methods

This systematic review and meta-analysis was registered with the International Prospective Register of Systematic Reviews (PROSPERO) database (CRD42023467911) and is reported in accordance with Preferred Reporting Items for Systematic Review and Meta-analyses (PRISMA) 2020 guidelines.¹⁵

Search strategy

A systematic search, developed with input from information specialists, of seven databases (MEDLINE, EMBASE, AMED, CINAHL, PsycINFO, Cochrane and Web of Science) from their inception to October 2024 was conducted. Searches utilised text word searching in the title, abstract and key words, along with database subject headings. The detailed search strategy for each database can be found in the supplemental materials. The search was extended by screening reference lists of existing systematic reviews related to this topic. There were no restrictions on study setting or language, and interpreters were utilised where possible. This search was conducted in tandem with another sister review exploring the prevalence and experience of MSK pain in menopausal women.

Study selection

Results were imported into Endnote X9 (https://endnote.com/) where duplicates were removed. Remaining unique references were uploaded to Rayyan software (https://www.rayyan.ai/cite/) to complete the screening process.

Title, abstract and full text screening were conducted independently by two reviewers (from RO, PA, AC, SR, VW, CB). Discordance between reviewers was resolved by team discussion or a third reviewer. Studies included reported the effects of non-contraceptive hormone replacement on outcomes relating to MSK pain in menopausal women. Observational studies specifically reporting outcomes relating to chronic and painful MSK conditions because of untreated menopause were excluded and analysed separately in a sister review. Studies were excluded if the intervention was an alternative menopause therapy, there was no full text available or no translation to English available. Secondary evidence, conference abstracts and unpublished studies were excluded.

Data extraction

Data extraction was conducted by one reviewer and independently verified by a second reviewer. Any disagreements were resolved through discussion and, if necessary, adjudication by a third reviewer. Data was extracted into a pre-piloted table, including author, year of publication, setting (country and healthcare setting), study design, study aim, funding, sample size, age, definition of menopause, painful condition and definition, details of comparator group, outcome measure(s) including measurement tools, duration of follow-up and measures of association.

Risk of bias assessment

Risk of bias was assessed by two investigators using the Joanna Briggs Institute critical appraisal tool (https://jbi.global/critical-appraisal-tools) appropriate for the study type. Results of the checklists were used to categorise studies as high (<50%), moderate (50–70%) or low (>70%) risk of bias. Studies were not excluded based on quality assessment.

Synthesis of results

Studies were grouped into those that reported generalised joint and muscle pain, knee OA, hip OA, hand OA, RA, gout and carpal tunnel syndrome (CTS). A narrative synthesis was carried out for all groups of studies, with meta-analysis to estimate the pooled effect of HRT on specific painful MSK conditions, where meaningful.

Statistical analysis

We performed a meta-analysis of randomised controlled trials to estimate pooled risk ratios (RRs) for positive outcomes in two groups using the meta package in R. Between-study variance was estimated with restricted maximum-likelihood, and both common-effect and random-effects models were fitted. Heterogeneity was assessed with I², τ², and Cochran’s Q test, and results were presented in forest plots with study-level RRs, 95% confidence intervals, and weights. All analyses were done using R programming software version 4.5.1.

Results

Characteristics of the included studies

The results of the literature search up to final search are illustrated in Figure 1. The search identified 30,739 studies, of which 57 studies met the inclusion criteria, including a total 3,958,702 participants. Of the 57 studies included, 13 were randomised controlled trials (RCTs), 17 cross-sectional studies, 15 cohort studies, and 12 case control studies (Table 1).

Figure 1.

PRISMA Diagram. WHO, World Health Organization.

Table 1.

Summary of study characteristics.

Geographical region
Europe	26
North America	17
Asia	8
Oceania	3
South America	2
Africa	1
Total participants
1–50	2
50–100	7
100–1000	18
1,001–10,000	11
10,001–100,000	12
100,001–500,000	5
500,001–1,000,000	0
>1,000,000	2
Study design
Randomised control trial	13
Cross-sectional	17
Cohort	15
Case control	12
Painful condition
Generalised musculoskeletal pain	20
Knee osteoarthritis	17
Hip osteoarthritis	8
Hand osteoarthritis	5
Rheumatoid arthritis	12
Gout	1
Carpal tunnel syndrome	1

Association between HRT and generalised MSK pain

Twenty studies reported on association between HRT and generalised MSK (Table 2).^11,16–34 Eight studies reported significantly decreased MSK pain in HRT users compared to non-HRT users.^{11,16,18,19,27,28,30,34} Ten studies reported no effect of HRT on generalised joint and muscle pain.^{17,20,21,25,26,29,31–33} Three studies reported increased MSK pain in HRT users compared to non-HRT users.^22–24

Table 2.

Characteristics of studies investigating the association between HRT and generalised MSK pain.

Author, date, country [ref]	Study design	Sample size	Outcome measure	HRT type	Results	Risk of bias
Chlebowski, 2013, USA¹⁶	RCT	10,739	Presence joint pain (yes, no)	Daily oral conjugated equine oestrogen vs placebo	1 year: 76.3% vs 79.2%, p < .001	Medium
					3 years: 74.2% vs 79.8%, p = .03
					6 years: 79.1% vs 83.2%, p = .11
			Severity of joint pain (1 mild, 2 moderate, 3 severe)		1 year: 1.16 ± 0.87 vs 1.22 ± 0.88, p < .001
					3 years: 1.21 ± 0.95 vs 1.31 ± 0.92, p = .09
					6 years: 1.29 ± 0.93 vs 1.35 ± 0.89, p = .35
Anartea, 1998, Spain¹⁷	RCT	73	Joint and muscle pain (Kupperman index)	Transdermal cyclical HRT	HRT vs HRT + psychological treatment at 26 weeks	Medium
Anartea, 1998, Spain¹⁷	RCT	73	Joint and muscle pain (Kupperman index)	Transdermal cyclical HRT	1.45 ± 1.04 vs 1.77 ± 0.95, p = .1855	Medium
Haines, 2005, Asia¹⁸	RCT	1028	Self-reported improvement in ‘body or joints aches and pains’	0.625 mg oestrogen + 2.5 mg MPA vs 0.45 mg oestrogen + 1.5 mg MPA vs 0.3 mg oestrogen + 1.5 mg MPA	1 month: 45.6%, 48.2% and 39.5%, no p value	Medium
Haines, 2005, Asia¹⁸	RCT	1028			6 months: 65.3%, 63.8% and 61.7%, no p value	Medium
Barnabei, 2005, USA¹⁹	RCT	16,608	Self-reported improvement in ‘joint pain or stiffness’	0.625 mg of conjugated equine oestrogens (CEE) + 2.5 mg of medroxyprogesterone vs placebo	1 year: 47.10% vs 38.4%, p < .001	Low
			Self-reported improvement in ‘joint pain or stiffness’		3 years: 41.8% vs 27.5%, p = .11
			Self-reported improvement in ‘general aches and pains’		1 year: 49.3% vs 43.8%, p = .002
			Self-reported improvement in ‘general aches and pains’		3 years: 50.0% vs 42.6%, p = .43
			Self-reported improvement in ‘lower back pain’		1 year: 44.4% vs 42.3%, p = .26
			Self-reported improvement in ‘lower back pain’		3 years: 40.4% vs 52.2%, p = .24
			Self-reported improvement in ‘neck pain’		1 year: 52.0% vs 49.5%, p = .3
			Self-reported improvement in ‘neck pain’		3 years: 52.8% vs 48.3% p = .72
Elfituria, 2005, Libya²⁰	RCT	100	Self-reported joint pain (1 mild, 2 moderate, 3 severe)	2.5 mg Livial (Tibilone) PO vs. 2/10 mg PO femoston PO (2 mg 17-oestradiol combined with 10 mg dydrogesterone)	3 months: 0.06 ± 0.24 vs 0.18 ± 0.44, p < .001	Low
					6 months: 0 ± 0 vs 0.02 ± 0.18, p < .001
					9 months: 0 ± 0 vs 0 ± 0, p < .001
Brunner, 2010, USA²¹	RCT	10,739	Self-reported joint pain	Oral conjugated equine oestrogen 0.625 mg OD vs placebo	1 year: RR 0.98 (0.93–1.03) vs RR 1.0	Low
Brunner, 2010, USA²¹	RCT	10,739	Self-reported joint pain	Oral conjugated equine oestrogen 0.625 mg OD vs placebo	7 years: RR 1.08 (0.96–1.22) vs RR 1.0	Low
Wijnhoven, 2006, Netherlands²²	Cross-sectional	11,428	Chronic lower back pain (self-reported)	Oestrogen	Never use: OR 1.0	Medium
			Chronic lower back pain (self-reported)		Ever use: OR 1.33 (1.02–1.77)
			Chronic upper extremity pain (self-reported)		Never use: OR 1.0
			Chronic upper extremity pain (self-reported)		Ever use: OR 1.09 (0.89–1.34)
Bryhilsden, 1998, Sweden²³	Cross-sectional	1103	Presence of self-reported back pain	Any HRT	Ever vs never HRT	Low
			Presence of self-reported back pain		48.2% vs 41.5%, p < .05
			Severity of self-reported back pain (mild vs moderate vs severe)		Ever vs never HRT
					Mild pain: 11.4% vs 13.2%, p > .05
					Moderate pain: 29.8% vs 23.3%, p > .05
					Severe pain: 4.7% vs 3.8%, p > .05
Heuch, 2023, Norway²⁴	Cohort	6007	Chronic lower back pain (self-reported)	Any HRT	Never HRT: RR 1.0	Low
					Current HRT: RR 1.3 (1.14–1.47)
					Previous HRT: 1.06 (0.86–1.31)
Nekora-Azak, 2008, Turkey²⁵	Cross-sectional	180	Pain in pre-auricular area in patients with temporomandibular disorder	Any HRT	Current use HRT: 22%	Low
Nekora-Azak, 2008, Turkey²⁵	Cross-sectional	180		Any HRT	Not current use HRT: 12.4%, p = .087	Low
Lora, 2016, Brazil²⁶	Cross-sectional	281	Prevalence of temporomandibular disorder (TMD) with pain	Any HRT	Ever use vs never HRT use	Low
Lora, 2016, Brazil²⁶	Cross-sectional	281	Prevalence of temporomandibular disorder (TMD) with pain	Any HRT	57.14% vs 42.86%, p > .05	Low
Cowan, 2022, Australia²⁷	RCT	132	Pain (Victorian Institute of Sport Questionnaire – gluteal tendinopathy, VISA-G) in greater trochanteric pain syndrome	Transdermal HRT	12 weeks: −12.94 (−8.99 to −16.88, p < .001)	Low
Cowan, 2022, Australia²⁷	RCT	132		Transdermal HRT	52 weeks: −16.99 (−13.05 to −20.94, p < .001)	Low
Park, 2017, Korea²⁸	Cross-sectional	4265	Radiographic spinal OA	Any HRT	Never HRT: OR 1.0	Low
Park, 2017, Korea²⁸	Cross-sectional	4265	Radiographic spinal OA	Any HRT	>1 year HRT: OR 0.717 (0.527–0.976)	Low
Parazzini, 2003, Italy¹¹	Cross-sectional	42,464	Self-reported physician diagnosed OA	Any HRT	Never HRT: OR 1.0	Low
Parazzini, 2003, Italy¹¹	Cross-sectional	42,464	Self-reported physician diagnosed OA	Any HRT	Ever HRT: OR 0.73 (0.69–0.78)	Low
Samanta, 1993, UK²⁹	Case control	690	Nodal generalised OA (radiographic + clinical diagnosis)	Any HRT	Never HRT: OR 1.0	Low
			Nodal generalised OA (radiographic + clinical diagnosis)		Ever HRT: OR 0.59 (0.19–1.89)
			Non-nodal periarticular large joint OA (radiographic + clinical diagnosis)		Never HRT: OR 1.0
					Ever HRT: OR 0.31 (0.07–1.35)
Mutlu, 2017, Turkey³⁰	Cohort	92	Pain (visual analogue scale, VAS) in sternoclavicular joint arthritis	HRT vs. placebo	1 month: 4.9 ± 2.5 vs 5.1 ± 2.6, p = .587	Medium
					3 months: 2.8 ± 1.5 vs 5.1 ± 1.1, p = .021
					6 months: 1.2 ± 0.8 vs 4.4 ± 2.1, p = .026
					9 months: 0.8 ± 0.7 vs 3.2 ± 0.7, p = .011
					12 months: 0.5 ± 0.3 vs 0.9 ± 0.2, p = .676
Stening, 2010, Sweden³¹	RCT	29	Pain thresholds in fibromyalgia, in the:	Transdermal oestrogen 50 mg/day	HRT vs placebo at 28 weeks:	Low
			Trapezius		198 ± 92 vs 176 ± 59, p > .05
			Lateral epicondyle		147 ± 61 vs 130 ± 32, p > .05
			Gluteal region		244 ± 96 vs 245 ± 63, p < .05
			Knee pad		180 ± 100 vs 178 ± 48, p > .05
Erb, 2000, Germany³²	Cross-sectional	475	Radiographic diagnosed OA	Any HRT	Never HRT: OR 1.0	Low
					HRT < 5 years: OR 0.64 (0.23–1.83)
					HRT > 5 years: OR 0.72 (0.27–1.9)
					Ever HRT: OR 0.68 (0.33–1.42)
Oliveria, 1996, USA³³	Nested case control	60	Radiographically diagnosed hand, hip and knee OA	Any HRT	Never HRT: OR 1.0	Low
					Current HRT: OR 1.4 (0.6–3.3)
					Long-term HRT: OR 1.0 (0.4–2.8)
					Ever HRT: OR 1.5 (0.7–3.4)
					Past HRT: OR 0.7 (0.3–1.9)
Dias, 2023, Brazil³⁴	Case control	69	Pain (VAS) in fibromyalgia	Transdermal oestrogen 0.6 mg ± 100 mg oral progesterone vs placebo	HRT before vs after 12 weeks	Medium
			Fibromyalgia severity score		8 (IQR 6.25–9.75) vs 8 (IQR 5.00–8.00), p = .025
			Fibromyalgia severity score		19 ± 4.6 vs 12.1 ± 4.9, p < .0001

Meta-analysis was conducted including all studies which evaluated MSK pain as a binary (yes/no) variable. Pooled analysis indicates a statistically significant reduction in MSK pain in HRT users versus never HRT users using the common-effects model (RR = 0.95, 95% CI 0.92–0.98) but not when using the random-effects model (RR = 0.76, 95% CI 0.56–1.03). The plot indicates a high heterogeneity among the studies (I² = 90%, p < .01) suggesting most of the variation in the study results are due to the differences between the studies rather than by random chance (Figure 2).

Figure 2.

The pooled results of the relationship between HRT and MSK pain. RR = risk ratio.

To reduce heterogenicity, a sensitivity analysis was conducted using just RCTs (I² = 51%, p = .07). Pooled analysis indicated no benefit in MSK pain in HRT users versus never users according to the random-effects model (RR 0.98, 95% CI 0.95–1.02) (Figure 3).

Figure 3.

The pooled results of the relationship between HRT and MSK pain using RCTs only.

Association between HRT and knee osteoarthritis

Seventeen studies reported the association between HRT and knee OA (Table 3).^{4,10,12–14,35–46} Six studies reported the association between HRT and the incidence of knee arthroplasty for OA.^{4,12–14,35,36} Of which, four studies reported a positive association between current HRT use and knee arthroplasty.^12–14,36 Lui et al. (2009) reported an increased risk of knee arthroplasty for all durations of HRT use, with the duration of HRT negatively associated with an increased RR (p = .02 for trend). One study, Cirillo et al. (2006), reported no association between the use of oestrogen (HR 0.87, 0.71–1.07) or oestrogen + progesterone (HR 0.91, 0.72–1.15) on knee arthroplasty. Eun et al. (2022), reported a negative association between HRT use and knee arthroplasty for HRT users up to 5 years. After 5 years they found no association between HRT and knee arthroplasty.

Table 3.

Characteristics of studies investigating the association between HRT and knee OA.

Author, date, country [ref]	Study design	Sample size	Outcome measure	HRT type	Results	Risk of bias
Cirillo, 2006, USA³⁵	Nested RCT	26,321	Knee arthroplasty	Oral oestrogen 0.625 mg +/− progesterone 2.5 mg	Placebo: HR 1.0	Low
					Oestrogen: HR 0.87 (0.71–1.07)
					Oestrogen + progesterone: HR 0.91 (0.72–1.15)
Eun, 2022, Korea⁴	Cohort	1,134,680	Knee arthroplasty	Any HRT	Never HRT: HR 1.0	Low
					HRT <2 years: HR 0.77 (0.75–0.79)
					HRT 2–5 years: HR 0.78 (0.75–0.82)
					HRT >5 years: HR 0.98 (0.93–1.1.03)
Liu, 2009, UK¹⁴	Cohort	1,306,081	Knee arthroplasty	Any HRT	Never HRT: RR 1.0	Low
					Current HRT: RR 1.58 (1.48–1.69)
					HRT <5 years: RR 1.52 (1.37–1.68)
					HRT 5–9 years: RR 1.52 (1.39–1.66)
					HRT > 10 years: RR 1.72 (1.56–1.89)
					Past HRT: RR 1.39 (1.29–1.49)
Hussain, 2018, Australia³⁶	RCT	22,289	Knee arthroplasty	Any HRT	Never HRT: OR 1.0	Low
					Current HRT: OR 1.37 (1.14–1.64)
					Past HRT: 0.99 (0.79–1.25)
					HRT <1 year: OR 1.12 (0.91–1.39)
					HRT > 1 year: OR 1.3 (0.99–1.72)
Sandmark, 1999, Sweden¹²	Case control	584	Knee arthroplasty	Any oestrogen	Never or <1 year: RR 1.0	Low
Sandmark, 1999, Sweden¹²	Case control	584	Knee arthroplasty	Any oestrogen	>1 year: RR 1.8 (1.2–2.6)	Low
Hellevik, 2017, Norway¹³	Cohort	30,289	Knee arthroplasty	Any HRT	Never HRT: HR 1.0	Low
					Current HRT: HR 1.36 (1.02–1.82)
					Past HRT: HR 1.45 (1.1–1.9)
Zhang, 1998, USA³⁷	Cohort	551	Radiographically diagnosed knee OA	Any HRT	Never HRT: OR 1.0	Low
					Current HRT: OR 0.4 (0.1–3.0)
					Past HRT: OR 0.8 (0.5–1.4)
Jung, 2018, Korea¹⁰	Cross-sectional	4766	Radiographically diagnosed knee OA	Any HRT	HRT use <12 months: OR 1	Low
Jung, 2018, Korea¹⁰	Cross-sectional	4766	Radiographically diagnosed knee OA	Any HRT	HRT use > 12 months: OR 0.59 (0.45–0.78)	Low
Spector, 1997, UK³⁸	Cross-sectional	606	Radiographic knee OA - presence of knee osteophytes	Any HRT	Never or <12 months: OR 1.0	Low
					Current > 12 months: OR 0.31 (0.11–0.93)
					Ever: OR 0.8 (0.43–1.49)
			Radiographic knee OA - presence of knee narrowing GDI 1+		Never or <12 months: OR 1.0
					Current > 12 months: OR 0.7 (0.41–1.22)
					Ever: OR 1.21 (0.81–1.81)
			Radiographic knee OA - presence of knee narrowing GDI 2+		Never or <12 months: OR 1.0
					Current > 12 months: OR 0.41 (0.05–3.15)
					Ever: OR 1.0 (0.34–2.96)
Hannan, 1990, USA³⁹	Cohort	831	Radiographically diagnosed knee OA	Any HRT	Never users: OR 1.0	Low
Hannan, 1990, USA³⁹	Cohort	831	Radiographically diagnosed knee OA	Any HRT	Ever users: OR 0.74 (0.53–1.04)	Low
Cicuttini, 1997, UK⁴⁰	Cross-sectional	325	Radiographically diagnosed knee OA	Oestrogen	Never or < 6 months: OR 1.0	Low
Cicuttini, 1997, UK⁴⁰	Cross-sectional	325	Radiographically diagnosed knee OA	Oestrogen	Ever > 6 months: OR 0.82 (0.42–1.62)	Low
Hart, 1999, UK⁴¹	Case control	830	Radiographic knee OA – osteophyte presence	Any HRT	Current HRT: OR 0.41 (0.12–1.42)	Low
			Radiographic knee OA – osteophyte presence		Ever HRT: OR 0.73 (0.32–1.67)
			Radiographic knee OA – joint space narrowing		Current HRT: OR 1.88 (0.86–4.11)
			Radiographic knee OA – joint space narrowing		Ever HRT: OR 1.17 (0.59–2.33)
Von Muhlen, 2002, USA⁴²	Cross-sectional	1001	Clinically diagnosed knee OA	Any HRT	HRT < 12 months or never: OR 1.0	Low
Von Muhlen, 2002, USA⁴²	Cross-sectional	1001	Clinically diagnosed knee OA	Any HRT	HRT > 12 months: OR 1.05 (1.03–1.07)	Low
Kim, 2022, Korea⁴³	Cross-sectional	4099	Knee pain in knee OA	Any HRT	HRT > 12 months use vs <12 months use or never	Low
Kim, 2022, Korea⁴³	Cross-sectional	4099	Knee pain in knee OA	Any HRT	22.27% vs 24.77%, p = .634	Low
Zhou, 2018, China⁴⁴	Cross-sectional	7510	Self-reported knee pain	Any HRT	Never HRT: OR 1.0	Low
			Self-reported knee pain	Any HRT	Ever HRT: OR 1.59 (1.23–2.06)
			Radiographically diagnosed knee OA	Any HRT	Never HRT: OR 1.0
			Radiographically diagnosed knee OA	Any HRT	Ever HRT: OR 1.79 (1.21–2.65)
Carbone, 2004, USA⁴⁵	Cohort	818	Radiographic knee OA – bone attrition	Any oestrogen	Current oestrogen: OR 0.36 (0.17–0.79)	Low
			Radiographic knee OA – bone attrition		Not current oestrogen: OR 1.0
			Radiographic knee OA – osteophyte presence		Current oestrogen: OR 0.94 (0.33–2.63)
			Radiographic knee OA – osteophyte presence		Not current oestrogen: OR 1.0
			Radiographic knee OA – bone marrow abnormalities		Current oestrogen: OR 0.48 (0.23–1)
			Radiographic knee OA – bone marrow abnormalities		Not current oestrogen: OR 1.0
			Radiographic knee OA – cartilage lesion		Current oestrogen: OR 1.5 (0.48–4.64)
			Radiographic knee OA – cartilage lesion		Not current oestrogen: OR 1.0
			Pain (WOMAC score) in radiographic knee OA		Current oestrogen vs not current oestrogen
			Pain (WOMAC score) in radiographic knee OA		2.9 ± 4.4 vs 3.3 ± 4.5, p > .05
Nevitt, 2001, USA⁴⁶	RCT	969	Severity of pain (assessed using WOMAC)	Oral 0.625 mg conjugated oestrogen + 2.5 mg of medroxyprogesterone acetate vs placebo	HRT vs placebo	Low
Nevitt, 2001, USA⁴⁶	RCT	969	Severity of pain (assessed using WOMAC)		5.9 ± 3.9 vs 6.1 ± 3.8, p > .05	Low

GDI = gate deviation index.

Eight studies reported the association between HRT and radiographic knee OA.^{10,37–41,44,45} Zhou et al. (2018) reported a positive association between ever use of HRT and radiographic diagnosed knee OA (OR 1.79, 1.21–2.65). Four studies found no association between HRT use and radiographic knee OA.^39–41,47 Two studies reported a negative association between HRT use and bone attrition⁴⁵ and osteophyte presence³⁸ but otherwise no association between HRT and other X-ray features including joint space narrowing, bone marrow abnormalities and cartilage lesions. One study found a negative association between HRT use and radiographic knee OA.¹⁰

One study⁴² reported on clinical diagnosis of knee OA and found a mild positive association between use of HRT >12 months compared to <12 months or never (OR 1.05, 1.03–1.07).

Four studies reported the association between knee pain in participants with known knee OA and HRT use. Three studies found no association between HRT use and reported knee pain in knee OA.^43,45,46 One study, Zhou et al. (2018), found a positive association between self-reported knee pain and ever use of HRT (OR 1.59, 1.23–2.06).

Association between HRT and hip osteoarthritis

Eight studies reported on association between HRT and Hip OA (Table 4).^{4,13,14,35,42,48–50} Six studies reported the association between HRT and incidence of hip arthroplasty for OA.^{4,13,14,35,48,49} Lui et al. (2009) reported an increased risk of hip arthroplasty for current (RR 1.38, 1.3–1.46) and previous (RR 1.13, 1.06–2.1) HRT use and found duration of HRT was negatively associated with increased RR (p = .02 for trend). Eun et al. (2022) reported a positive association between hip arthroplasty in HRT users > 5 years (HR 1.33, 1.02–1.72) but no association for HRT durations shorter than this. Hellevik et al. (2017) found a positive association between current users of HRT and hip arthroplasty (HR 1.32, 1.05–1.66) but no association in past users. Three studies reported no association between HRT use and hip arthroplasty.^35,48,49

Table 4.

Characteristics of studies investigating the association between HRT and hip OA.

Author, date, country [ref]	Study design	Sample size	Outcome measure	HRT type	Results	Risk of bias
Cirillo, 2006, USA³⁵	Nested RCT	26,321	Hip arthroplasty	Oral oestrogen 0.625 mg +/− progesterone 2.5 mg	Placebo: HR 1.0	Low
					Oestrogen: HR 0.73 (0.52–1.03)
					Oestrogen + progesterone: HR 1.14 (0.83–1.57)
Eun, 2022, Korea⁴	Cohort	1,134,680	Hip arthroplasty	Any HRT	Never HRT: HR 1.0	Low
					HRT <2 years: HR 0.93 (0.78–1.11)
					HRT 2–5 years: HR 0.98 (0.75–1.27)
					HRT >5 years: HR 1.33 (1.02–1.72)
Liu, 2009, UK¹⁴	Cohort	1,306,081	Hip arthroplasty	Any HRT	Never HRT: RR 1.0	Low
					Current HRT: RR 1.38 (1.3–1.46)
					HRT <5 years: RR 1.49 (1.36–1.62)
					HRT 5–9 years: RR 1.35 (1.25–1.47)
					HRT > 10 years: RR 1.26 (1.14–1.39)
					Past HRT: RR 1.13 (1.06–2.1)
Vingard, 1997, Sweden⁴⁸	Case control	503	Hip arthroplasty	Any oestrogen	Never HRT: RR 1.0	Medium
Vingard, 1997, Sweden⁴⁸	Case control	503	Hip arthroplasty	Any oestrogen	Ever HRT: RR 0.7 (0.5–1.0)	Medium
Dennison, 1998, UK⁴⁹	Case control	826	Hip arthroplasty	Any HRT	Never HRT: OR 1.0	Low
					Ever HRT: OR 1.4 (0.9–2.3)
					<5 years HRT: OR 1.7 (0.9–2.9)
					>5 years HRT: OR 0.8 (0.3–2.0)
Hellevik, 2017, Norway¹³	Cohort	30,289	Hip arthroplasty	Any HRT	Never HRT: HR 1.0	Low
					Current HRT: HR 1.32 (1.05–1.66)
					Past HRT: HR 1.12 (0.88–1.41)
Von Muhlen, 2002, USA⁴²	Cross-sectional	1001	Clinically diagnosed hip OA	Any HRT	HRT <12 months or never: OR 1.0	Low
Von Muhlen, 2002, USA⁴²	Cross-sectional	1001	Clinically diagnosed hip OA	Any HRT	HRT > 12 months: OR 1.05 (1.01–1.10)	Low
Nevitt, 1996, USA⁵⁰	Cross-sectional	4366	Radiographically diagnosed hip OA	Oral oestrogen	Never use: OR 1.0	Low
					Current use <10 years: OR 0.77 (0.48–1.23)
					Current use > 10 years: OR 0.6 (0.42–0.85)
					Past use <10 years: OR 1.19 (0.93–1.52)
					Past use > 10 years: OR 0.8 (0.54–1.18)

One study⁴² observed the relationship between HRT and clinically diagnosed hip OA. They reported postmenopausal oestrogen use >12 months is associated with an increased risk of hip OA compared to < 12 months use or never use (OR 1.05, 1.01–1.10). One study⁵⁰ observed the relationship between HRT and radiographic Hip OA. Nevitt et al. (1996) reported that current use of oral oestrogen ≥ 10 years was associated with a reduced risk of grade 2–4 hip OA (OR 0.77, 0.48–1.23). There was no association between current use of oral oestrogen < 10 years and grade 2–4 (OR 0.77, 0.48–1.23). There was no association between past use of oestrogen and hip OA.

Association between HRT and hand osteoarthritis

Five studies reported on association of HRT on hand OA (Table 5).^{38,42,51–53} Two studies reported the association between HRT use and radiographic hand OA.^38,52 Cooley et al. (2003) reported a positive association between HRT use and Heberden’s nodes in current or ever users but not in joint space narrowing and osteophytes at the distal interphalangeal (DIP) joint and carpometacarpal (CMC) joint. Whilst Spector et al. (1997) found no association between HRT use and radiographic hand OA. Two studies reported the association between HRT and clinically diagnosed hand OA. Both found a significantly increased prevalence of hand OA in HRT users compared to non-HRT users.^42,53 One study reported the association between pain in hand OA and HRT use and found no significant relationship.⁵¹

Table 5.

Characteristics of studies investigating the association between HRT and hand OA.

Author, date, country [ref]	Study design	Sample size	Outcome measure	HRT type	Results	Risk of bias
Von Muhlen, 2002, USA⁴²	Cross-sectional	1001	Clinically diagnosed hand OA	Any HRT	HRT <12 months or never: OR 1.0	Low
Von Muhlen, 2002, USA⁴²	Cross-sectional	1001	Clinically diagnosed hand OA	Any HRT	HRT > 12 months: OR 1.09 (1.06–1.11)	Low
Maheu, 2000, France⁵¹	Cross-sectional	711	Pain (VAS) in painful hand OA	Any HRT	Current HRT or within last 6 months vs no HRT	Low
			Pain (VAS) in painful hand OA		55.8 ± 14.4 vs 53.4 ± 15.6, p > .05
			Pain (VAS) in quiescent hand OA		Current HRT or within last 6 months vs no HRT
			Pain (VAS) in quiescent hand OA		16.4 ± 11.4 vs 16.3 ± 12.9, p > .05
Spector, 1997, UK³⁸	Cross-sectional	606	Radiographical DIP joint OA	Any HRT	Never or < 12 months: OR 1.0	Low
					Current > 12 months: OR 0.48 (0.17–1.42)
					Ever > 12 months: OR 0.67 (0.34–1.35)
			Radiographic carpometacarpal joint OA	Any HRT	Never or <12 months: OR 1.0	Low
					Current > 12 months: OR 0.94 (0.44–2.03)
					Ever > 12 months: OR 0.65 (0.34–1.23)
Cooley, 2003, Australia⁵²	Cross-sectional	348	Radiographic hand OA – presence of joint space narrowing and osteophytes at DIP	Any HRT	Never: OR 1.0	Low
					Current: OR 2.21 (0.88–5.51)
					Ever: OR 0.21 (0.94–4.68)
			Radiographic hand OA – presence of joint space narrowing and osteophytes at CMC		Never: OR 1.0
					Current: OR 1.6 (0.76–3.39)
					Ever: OR 1.41 (0.72–2.79)
			Radiographic hand OA – presence of Heberden’s nodes		Never: OR 1.0
					Current: OR 3.02 (1.42–6.44)
					Ever: OR 2.46 (1.34–4.49)
Burkard, 2020, UK⁵³	Nested case control	17,200	Clinically diagnosed hand OA	Any HRT	Never: OR 1.0	Low
					Current: OR 1.27 (1.07–1.5)
					Past (>180 days before index date): 1.62 (1.39–1.89)

Association between HRT and rheumatoid arthritis

Twelve studies reported on the association of HRT and RA (Table 6).^54–65 Ten studies examined the association between HRT use and the incidence of RA.^54–63 One study reported an increased association between ever use of HRT and RA (HR 1.46, 1.35–1.57).⁶³ They found that risk increased with every added year of HRT use by 2% (HR 1.02, 1.01–1.03). Hadizedah et al. (2024) reported ever use of HRT was positively associated with the incidence of RA HR 1.15 (1.06–1.25) but did not find a significant association between current or previous use of HRT on RA. Seven studies found no association between HRT use and the incidence of RA.^{54–56,58–61} One study found a significantly reduced risk of RA in ever users of HRT compared to never users (OR 0.22, 0.07–0.66).⁵⁷

Table 6.

Characteristics of studies investigating the association between HRT and RA.

Author, date, country [ref]	Study design	Sample size	Outcome measure	HRT type	Results	Risk of bias
Bengtsson, 2017, USA⁵⁴	Cohort	221,966	Seronegative RA	Any HRT	Never: HR 1.0	Low
					Current: HR 1.3 (0.9–1.8)
					Past: HR 0.9 (0.6–1.4)
			Seropositive RA		Never: HR 1.0
					Current: HR 1.3 (0.9–1.8)
					Past: HR 1.1 (0.8–1.5)
Spector, 1991, UK⁵⁵	Cohort	4326	RA	Any oestrogen	Never HRT: RR 1.0	Low
Spector, 1991, UK⁵⁵	Cohort	4326	RA	Any oestrogen	Ever HRT (>3 months): RR 1.62 (0.56–4.74)	Low
Walitt, 2008, USA⁵⁶	RCT	27,347	RA	0.625 mg conjugated equine oestrogen ± 2.5 mg medroxyprogesterone	Placebo: HR 1.0	Medium
Walitt, 2008, USA⁵⁶	RCT	27,347	RA		HRT: 0.74 (0.51–1.1)	Medium
Vandenbroucke, 1986, Netherlands⁵⁷	Case control	1149	RA	Any HRT	Never: OR 1.0	Low
Vandenbroucke, 1986, Netherlands⁵⁷	Case control	1149	RA	Any HRT	Ever: OR 0.22 (0.07–0.66)	Low
Hernandez-Avila, 1990, USA⁵⁸	Prosepective cohort	60,057	RA	Any oestrogen containing HRT	Never: RR 1.0	Medium
					Current: RR 1.3 (0.9–2.0)
					Past: RR 0.7 (0.5–1.2)
					Ever: RR 1.0 (0.7–1.4)
Koepsell, 1994, USA⁵⁹	Case control	727	RA	Any oestrogen or progestin	Never use: OR 1.0	Low
					Current oestrogen: OR 0.99 (0.63–1.56)
					Current progestin: OR 0.79 (0.44–1.42)
					Ever oestrogen: OR 1.06 (0.71–1.57)
					Ever progestin: OR 0.66 (0.4–1.07)
					<12 months oestrogen: RR 0.68 (0.34–1.37)
					12–59 months oestrogen: RR 1.21 (0.75–1.96)
					<60 months oestrogen: RR 0.89 (0.56–1.42)
					<12 months progestin: RR 0.34 (0.12–0.96)
					12–59 months progestin: RR 0.71 (0.39–1.31)
					<60 months progestin: RR 0.79 (0.32–1.96)
Carette, 1989, Canada⁶⁰	Case control	416	RA	Any HRT	Never HRT: OR 1.0	Low
					Current HRT: OR 0.82 (0.46–1.44)
					<10 years HRT: 0.85 (0.41–1.77)
					>10 years HRT: 0.79 (0.38–1.62)
					Past HRT: OR 0.97 (0.59–1.6)
Yuk, 2023, Korea⁶¹	Cohort	277,982	Seropositive RA	Any HRT	Any HRT: HR 1.12 (0.998–1.256)	Low
					No HRT: HR 1.0
					Oestrogen + progesterone: HR 1.116 (0.963–1.293)
					Oestrogen: HR 1.085 (0.287–1.424)
Hadizadeh, 2024, UK⁶²	Cohort	257,194	RA	Any HRT	Never HRT: HR 1.0	Low
					Any HRT: HR 1.15 (1.06–1.25)
					Current: HR 1.17 (0.87–1.58)
					Previous: HR 1.12 (1.02–1.22)
Jiang, 2024, UK⁶³	Cohort	223,526	RA	Any HRT	Never HRT: HR 1.0	Low
					Ever HRT: HR 1.46 (1.35–1.57)
					Risk per added year of HRT: HR 1.02 (HR 1.01–1.03)
MacDonald, 1994, UK⁶⁴	RCT	62	Ritchie articular index in RA	Transdermal oestrogen ± norethisterone vs placebo	Baseline: 24 vs 28, p < .05	Low
					12 weeks: 20 vs 15, p > .05
					24 weeks: 16 vs 15, p > .05
					48 weeks: 15 vs 14, p < .05 (compared to baseline)
			Pain (VAS score) in RA		Baseline: 5.0 vs 6.0, p > .05
					12 weeks: 5.3 vs 6.3, p > .05
					24 weeks: 6.0 vs 5.1, p > .05
					28 weeks: 5.0 vs 7.0, p > .05
Van Den Brink, 1993, Netherlands⁶⁵	RCT	40	Ritchie articular index in RA	2 mg oestradiol valerate (progynova) for 74 days + 200 mg progesterone (progestan) for 10 days	HRT vs placebo at 52 weeks (differences between groups compared to baseline)	Medium
			Ritchie articular index in RA		1.5 (95% CI–3.8 to 6.8), p = .56
			Thompson articular index in RA		21 (95% CI–49 to 92), p = .54
			Pain score (VAS) in RA		14 (95% CI 3 to 25), p = .01

Two studies reported pain and stiffness outcomes in patients with pre-existing RA.^64,65 Van Den Brink et al. (1993) found no effect of 1 year of HRT on joint pain, stiffness and swelling in patients with RA. MacDonald et al. (1994) found a statistically significant improvement in subjective overall wellbeing week 12 and 48 (p < .05 from baseline) and in the Ritchie articular index by week 48 of the study (p < .05 from baseline). However, neither Macdonald et al. or Van Den Brink et al. (1993) found any change in ESR levels following one year of HRT.

Association between HRT and gout

One study reported the association between HRT and the incidence of self-reported physician diagnosed gout.⁶⁶ Hak et al. found current use of HRT was protective against gout (RR 0.81, 0.7–0.94). There was no significant effect of previous HRT use on incidence of gout RR 1.04 (0.89–1.2) or the duration of postmenopausal hormone use among current users (p = .37).

Association between HRT and carpal tunnel syndrome

One study reported the association between HRT use and the prevalence of CTS. They reported ever users of HRT had a significantly increased risk of CTS compared to never users (OR 2.72, 2.56–2.88).⁶⁷

Discussion

The aim of this systematic review and meta-analysis was to assess the association between HRT and MSK pain, to help guide clinical practice. MSK conditions assessed included OA, RA, generalised MSK pain, fibromyalgia, gout and CTS. Overall, the evidence does not demonstrate a significant effect of HRT on MSK pain.

With recent reports highlighting the increasing burden of OA on menopausal women we hoped to draw conclusion on the effect of HRT on this condition. Thirty studies investigated the association between HRT and OA, but findings were inconsistent and contradictory. This mirrors earlier systematic reviews and meta-analyses, which have reported both positive^63,66 and negative⁶⁷ associations between HRT use and OA. This may be attributable to the heterogenicity in HRT formulation and duration, as well as its complex interplay with other menopausal factors, which may act as confounders and limit the ability to draw robust and reliable conclusions.

In the subgroup analysis of generalised MSK group, including non-specific joint and muscle pain, we hypothesised that HRT would improve pain outcomes given the therapeutic benefits on mood, sleep disturbance and fatigue. A greater understanding of relevant physiological pathways including oestrogen’s modulation of inflammatory cytokines, nociceptive signally, and cartilage metabolism may help clarify these findings and should be explored in future research.

Notably, this is the first systematic review to evaluate the association between HRT and RA. With recent evidence illustrating that postmenopausal women had a 35% increased risk of developing RA compared to pre-menopausal women⁶ we hypothesised that HRT would be associated with a reduced incidence and improve symptom control in patients with established RA. However, of the 10 studies examining the effect of HRT on incidence of RA only one found a reduced incidence, whilst seven found no effect and two found HRT in fact increased the incidence of RA. One explanation for this observation is detection bias: women on HRT are more likely to be engaging regularly with healthcare services and therefore have a greater likelihood of receiving a RA diagnosis. Although some studies observed improvements in subjective wellbeing with HRT use, this was not reflected in objective markers of disease activity (e.g. platelet count, ESR or CRP)⁵⁸ further supporting that HRT may not be directly influencing disease pathophysiology to improve symptoms.

The strengths of this systematic review and meta-analysis include its comprehensive scope and large sample size, which exceed that of previous reviews in this field. However, important limitations must be acknowledged. Crude data was preferentially used to ensure consistency across studies, reduce reporting bias and improve the accuracy of pooled estimates. However, for some studies included in this review the crude data directly contradicted the adjusted data.³⁰ Therefore, known confounding variables such as obesity and age have been carried through to the results of this review and may reduce the reliability of results presented here. Furthermore, the heterogeneity in study designs, HRT uses and diagnostic methods precluded robust meta-analysis in several domains. Because of this, it was preferrable to avoid pooling data and instead divide studies into smaller groups for best evidence synthesis.

This review highlights the necessity to standardise outcome measures and control variables to facilitate pooled analysis which could be used to guide clinical practice. The most significant source of heterogeneity between studies was the inconsistent classification of HRT exposure. For example, some studies included 6–12 months of HRT use with the ‘never users’ of HRT category, whilst others classed participants as users of HRT based on a single prescription of HRT. Given that even 8 weeks of HRT use can significantly increase oestrogen levels²⁴ we recommend future studies reserve ‘never users’ of HRT for those who have never received postmenopausal HRT. Similarly, we found studies had a varied definition of menopause including the date of the last period, 6- or 12-months amenorrhoea. We would recommend menopause be standardised within all future research as date of last menstruation, as stated by the NICE guidance⁹ and the World Health Organisation.⁶⁸ Furthermore, we recommend greater consistency in defining HRT formulations (e.g. oestrogen-only, oestrogen + progesterone, and progestin) and utilising standardised diagnostic criteria or recognised symptom scores for MSK conditions.

Conclusion

Despite the large volume of literature examining the association between HRT and MSK health, it is not possible to draw any firm conclusions regarding the effect of HRT in this population. This systematic review and meta-analysis demonstrates the vast heterogeneity within this field and highlights the need for standardised studies looking at the effect of HRT on MSK pain to draw any firm conclusions.

Supplemental Material

Supplemental Material - The effect of hormone replacement therapy on musculoskeletal pain in menopausal women: A systematic review and meta-analysis

Supplemental Material for The effect of hormone replacement therapy on musculoskeletal pain in menopausal women: A systematic review and meta-analysis by Rachel Overton, Payam Amini, Adam Chew, Opeyemi Babatunde, Kayleigh Mason, Sneha Rathod, Victoria Welsh, and Claire Burton in Post Reproductive Health.

Footnotes

ORCID iDs

Rachel Overton

Adan Chew

Kayleigh J Mason

Claire Burton

Funding

The author(s) received no financial support for the research, authorship, and/or publication of this article.

Declaration of conflicting interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Contributorship

Study protocol: SR, CB, OB, RO.

Data extraction: CB, RO, PA, AC, VW.

Statistical analysis: PA, KJM.

Paper writing: RO.

Final approval of article: all authors.

Guarantor

RO.

Supplemental material

Supplemental material for this article is available online.

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