Summary
Burkard and colleagues investigate the influence of onset of menopause and of HRT use on the incidence of hand osteoarthritis (hOA), one of the most common forms of arthritis[1]. This is an epidemiological study in primary care electronic healthcare records from the well-established UK Clinical Practice Research Datalink (CPRD). All women turning 45 were identified and followed for up to 20 years, searching for codes and dates for hOA, menopause and any HRT use. The authors used careful design: 4 controls for every case, adjusting statistically for confounding factors, and also stratifying the results based on timing of current or past HRT use, including the effects of HRT cessation. Key findings were that menopause was a risk for hOA (OR 1.42, CI 1.29-1.57) and the highest proportion of cases of hOA were in the year after menopause, with incidence dropping with increasing time. 55% of cases developed their hOA within four years after menopause. Current users of HRT who started their HRT within 3 months of menopause were relatively protected from incident hOA compared with HRT never users (OR 0.72; CI 0.55-0.96). Cessation of HRT tended to increase incident hOA for the first 18 months; however an overall association of HRT with hOA in women became non-significant if being post-menopausal was considered (OR 0.98, 0.85-1.14).
Commentary
It has long been observed that osteoarthritis starts at the time of menopause in some women [2-4]. However clear evidence for true association or causation has been lacking to date. The close association for about half of women demonstrated here between a new diagnosis of hOA and onset of menopause increases the likelihood of this being a true association, at least for some women. A spike in incidence of hOA around the age of 50, the typical age of menopause, had already shown at population level by the co-authors [5]. This study adds by relating menopause to disease onset at an individual level. An identifiable subgroup with ‘perimenopausal onset’ of hOA would have implications for both our understanding and management of the disease. Effects of female sex hormone deficiency on disease pathogenesis, pain experience or local inflammation could all modulate disease presentation and its severity. A limitation, even in this large, longitudinal dataset, is the sensitivity and specificity of coding of conditions under investigation. 3440 hOA cases were identified of 438, 674 (i.e. 0.78% of women over 45). This is despite using broad inclusions, including hand pain (which could represent a variety of conditions) and subsequent any site OA, attempting to increase sensitivity. According to Versus Arthritis, ~12% of women age 45-64 in UK would be expected to have symptomatic hOA [6]. This apparent under-ascertainment could lead to significant bias affecting findings. Similarly, date of menopause is more likely documented when around the time of other presenting conditions (listed in only 25% of cases and 19% controls), potentially introducing further bias. hOA diagnosis not being coded sufficiently in the UK is arguably another key finding here; this reduces our ability to document its true impact, plan care and carry out high-quality research. There are prior conflicting reports on the effects of HRT on hOA, with some studies suggesting HRT increases its prevalence [7]. Women often seek HRT for a number of reasons, including musculoskeletal symptoms, which could lead to such apparent positive associations; menopause itself and age are also confounders, properly accounted for here. The study highlights why one must not oversimplify; stratification demonstrates that those starting early HRT are in fact protected from hOA, but that this protection is lost further post-menopause, particularly in past users. There are no data on whether the trend to increased risk on stopping HRT was after abrupt cessation or weaning in these 29 cases – this phenomenon has also been observed clinically [8]. What is not clear is whether those developing hOA after HRT cessation were always destined to develop the disease, with HRT perhaps just postponing its onset, or whether new disease is triggered by this manoeuvre. This would seem of critical importance. Half of women will have musculoskeletal symptoms of menopause, but these are often largely neglected [4]. This study shines a light on our need to better understand the interaction between musculoskeletal symptoms, arthritis, menopause and HRT. While the findings in no way support a change in practice to use of HRT, they do suggest that in an area of high unmet clinical need, further mechanistic and clinical studies seeking to understand this association better are called for.
Fiona E Watt
Associate Professor, Kennedy Institute of Rheumatology, NDORMS, University of Oxford Honorary Consultant Rheumatologist, Oxford University Hospitals NHS Trust
References
- Burkard T, Rauch M, Spoendlin J, Prieto-Alhambra D, Jick SS, Meier CR. Risk of hand osteoarthritis in new users of hormone replacement therapy: A nested case-control analysis. Maturitas. 2020 Feb;132:17-23.
https://www.ncbi.nlm.nih.gov/pubmed/31883658 - Cecil RL, Archer BH. Arthritis of the menopause: A study of fifty cases. Journal of the American Medical Association, 1925. 84(2): p. 75-79.
https://jamanetwork.com/journals/jama/article-abstract/1151859 - Watt FE. Hand osteoarthritis, menopause and menopausal hormone therapy. Maturitas. 2016 Jan;83:13-8.
https://www.ncbi.nlm.nih.gov/pubmed/26471929 - Watt FE. Musculoskeletal pain and menopause. Post Reprod Health. 2018 Mar;24(1):34-43.
https://www.ncbi.nlm.nih.gov/pubmed/29412042 - Prieto-Alhambra D, Judge A, Javaid MK, Cooper C, Diez-Perez A, Arden NK. Incidence and risk factors for clinically diagnosed knee, hip and hand osteoarthritis: influences of age, gender and osteoarthritis affecting other joints. Ann Rheum Dis. 2014 Sep;73(9):1659-64.
https://www.ncbi.nlm.nih.gov/pubmed/23744977 - Arthritis Research UK, Osteoarthritis in General Practice: Data and Perspectives. 2013, University of Keele.
https://www.bl.uk/collection-items/osteoarthritis-in-general-practice-data-and-perspectives - Sowers MF, Hochberg M, Crabbe JP, Muhich A, Crutchfield M, Updike S. Association of bone mineral density and sex hormone levels with osteoarthritis of the hand and knee in premenopausal women. Am J Epidemiol. 1996 Jan 1;143(1):38-47.
https://www.ncbi.nlm.nih.gov/pubmed/8533745 - Watt FE, Carlisle K, Kennedy D, Vincent TN. Menopause and hormone replacement therapy are important aetiological factors in hand osteoarthritis: results from a cross-sectional study in secondary care. Maturitas, Volume 81, Issue 1, 128
https://doi.org/10.1016/j.maturitas.2015.02.092
