Bioidentical Hormones Prevent Arthritis

A Patient with Post-Menopausal Osteo-arthritis

Mary, a 53 year old post-menopausal mom had a chief complaint of arthritis in her fingers.  On physical exam, the appearance is typical for osteoarthritis with Heberden’s nodes. This was confirmed with X-rays. Laboratory testing for rheumatoid arthritis was negative. Mary was then started on a menopausal hormone replacement program including estrogen, progesterone, testosterone and DHEA, all in a topical skin oil. Mary was instructed to rub the skin oil directly into the painful finger joints. Six weeks later during a telephone follow up call,  Mary reports her arthritis pain has greatly improved.

Above header image: Poster showing a woman standing beside a bike with a brick road in the background. The poster explains that of physical activity helps the pain of arthritis. Image Courtesy of wikimedia commons. FlickR and author: NIH . (Public Domain)

Estrogen Deficiency Causes Degenerative Osteoarthritis

OsteoarthritisjeffreydachmdDegenerative osteoarthritis is common in post-menopausal women resulting in deformity, swelling and pain in finger joints and knee joints.  Recent medical research shows that menopausal estrogen deficiency is the direct cause of osteo-arthritis. Menopausal hormone replacement with estrogen prevents osteoarthritis, and may partially reverse some of the symptoms.

Above left image: Heberden’s Arthritis, Physical Exam with typical changes of osteoarthritis of the finger joints, courtesy of wikimedia commons Author Drahreg01

Osteo-arthritis and Estrogen Replacement

In 1998, Dr. David T. Felson reviewed menopasual arthtritis finding osteoarthritis increases dramatically in women after menopausal age of 50 years.   Medical studies of post menopausal women using hormone replacement users report reduced osteoarthritis when compared to women who are not using hormone replacement, thus suggesting a role for menopausal estrogen replacement for the prevention of osteoarthritis in post-menopausal women. (16)

In 2009,  Dr. Herrero- Beaumont from Spain reviewed the medical literature from 1952 to 2008 and found three causes for osteoarthritis, one being estrogen deficiency.(1)

Causes of Osteoarthritis : 1) Genetic  2) Menopause-related Estrogen deficiency and 3) Aging

In 2009, Dr Herrero Beaumont writes:

There is now increasing evidence that estrogens influence the activity of joint tissues through complex molecular pathways that act at multiple levels. (2)

Estrogen Replacement Reduces Osteoarthritis of the HIP by 43%

HipReplacementJeffreyDachMDIn 1996, Drs. Michael C Nevitt and Harry Genant at the University of California, San Francisco examined 4,366 post-menopausal  women over the age of 65. Hip X-Rays were used to assess osteoarthritis of the hip joint. The authors found that women who took oral estrogen had a 38% reduced risk osteoarthritis (OA) of the hip.  Women who used estrogen for 10 years or longer had a 43% reduction in OA of the hip.  The authors concluded that:

Postmenopausal estrogen replacement therapy may protect against OsteoArthritis (OA) of the hip. (3) Note: Harry Genant MD, who was a radiology icon, passed away in 2021.

Framingham Study – Arthritis of the Knee Reduced by 60%

In 1998, Dr. Yuqing Zhang of Boston University School of Medicine published the Framingham Study on Arthritis of the Knee. Dr. Zhang examined whether estrogen replacement therapy (ERT) prevents worsening of radiographic knee osteoarthritis (OA) in elderly women, following 551 post-menopausal women (over the age of 63) for 8 years with  serial knee X-Rays, looking for worsening of osteoarthritis over time.  The authors found a 60% decrease in osteo-arthritis in the estrogen users compared to non-users.(4)

Above left image: Hip replacement could be prevented by Estrogen Replacement, image courtesy of wikimedia commons. Public Domain Image work of NIH.

Women’s Health Initiative WHI- Lower Incidence of Joint Replacements

Data from the Womens Health Initiative Study published in 2006 showed that women receiving Premarin-alone (oral estrogen from a horse) had 12% lower rates for joint replacement for osteoarthritis.(5)

Above Image: Left Image shows severe joint space narrowing from Osteoarthritis of Knee. Right image is less severe. (White Arrows). Courtesy of wikimedia commons, author: Harrygouvas at Greek Wikipedia. CC 3.0.

Genetic Causes of Arthritis – Disturbed Estrogen Metabolism

A study was in the 2010 Journal of Osteoarthritis Cartilage by Dr Riancho from Spain explored the association of genetic abnormalities with severe osteoarthritis (OA) in 3147 patient who were compared to 2,381 normal controls. The authors examined two abnormal genes which reduce estrogen activity.  These are the gene for the Aromatase Enzyme, and the gene for the estrogen receptor (ER-Alpha), and their association with severe osteoarthritis (OA). Women with unfavorable genotypes (a mutation) had 60% increased risk for knee arthritis.  The authors conclude:

Common genetic variations of the aromatase and ER genes are associated with the risk of severe OA of the large joints of the lower limb in a sex-specific manner. These results are consistent with the hypothesis that estrogen activity may influence the development of large-joint OA. (6) 

Thus, the genetic studies indicate the importance of estrogen in preserving joint cartilage and preventing osteoarthritis.

Cellular Mechanisms of Estrogen on Cartilage

Dr Tanko from Denmark summarized three decades of medical research in an article published in 2008 in Climacteric stating:

Estrogen receptors have been identified in articular chondrocytes from various animals and humans.”  …. “The effects of estrogen on articular cartilage further corroborate the due consideration of estrogen therapy for maintaining not only bone but also cartilage health in postmenopausal women.(8)

Animal Studies – Estrogen Replacement in Monkeys Prevents Arthritis

A study published in Arthritis Rheumatism 2002 by Dr Ham from the University of Minnesota examined estrogen replacement therapy on the severity of osteoarthritis of the knee joint in postmenopausal female monkeys (after surgical removal of the ovaries).(7)

After three years of estrogen treatment using Premarin the monkeys were sacrificed and knee joints examined under the microscope.  The authors found that cartilage lesions of osteoarthritis were significantly less severe in the animals given estrogen replacement  compared with those in the control group. The authors conclude:

These results demonstrate that long-term estrogen replacement significantly reduces the severity of osteoarthritis. (7)

Ovarectomized Mice Treated with Estrogen

A 2006 study by Tanko from Denmark published in Arthritis Rheumatism found that estrogen prevented joint and cartilage degradation in an animal model with mice.   The authors found that  treatment of the animals with estrogen prevents collagen deterioration with the greatest benefits for prompt initiation of hormone replacement after menopause.  Estrogen protected the cartilage cells, the chondrocytes. from deterioration.. (9)

Pig Studies

Similarly in pigs, researchers found estrogen prevents cartilage degradation.  Published by Claassen from Germany in 2002 Annals of Anatomy, their study investigated how estrogen deficiency affects the articular cartilage.   When they examined animals with estrogen deficiency, they found the articular cartilage underwent degradation, similar to changes of aging .(10)

Electron Microscope Study
Estrogen Deficiency Induced Arthritis in the Guinea Pig

A guinea pig study by Dr Dai from China was published in the Chinese medical literature in 2005 (11)  The authors used the scanning electron microscope (SEM) and transmission electron microscope (TEM) to analyze cartilage degeneration in joints after ovariectomy (surgical removal of the ovaries), a form of castration which produces estrogen deficiency in the animals.  The authors looked at estrogen receptors and serum levels of estrogen.  They indeed found estrogen receptors (ER) in the cartilage of the guinea pigs.  They also found joint cartilage degeneration detected by electron microscopy at 6 weeks, and more severe degeneration at 12 weeks (post-ovarectomy) compared to controls.  The authors conclude:

Bilateral ovariectomy in the guinea pig leads to severe osteoarthritis. (11)

Ovarectomized  Sheep Treated With Estradiol Implants

A study published in 1997 in Osteoarthritis Cartilage by Dr  Turner from Colorado State University looked at estrogen replacement with estradiol implants in ovarectomized sheep.(12)   After twelve months, the articular cartilage from the knee joints were carefully evaluated.  Ovarectomy, with its attendant estrogen deficiency had a significant deleterious effect on articular cartilage.   Treatment with estradiol, a bioidentical hormone, reversed these deleterious effects, and maintained structural integrity of the joints.  (12)

Another sheep study published in 2005 in Osteoarthritis Cartilage by Dr MA Cake from Australia examined the effect of estrogen depletion (ovariectomy) on articular cartilage of the joints, and the production nitric oxide synthase (iNOS). At 26 weeks after removal of the ovaries, the joints were studied histologicaly, and amounts for nitric oxide studied. In the estrogen deficient animals, cartilage thickness was reduced, along with arthritic changes and up-regulated nitric oxide production. The authors conclude:

estrogen depletion caused regional thinning of femoro-tibial cartilage, with biomechanical and histological changes suggestive of a disturbance in proteoglycan and collagen. (13)

Animal Model Summary Paper

In 2008, Dr Sniekers of the Netherlands summarized all preceding animal studies in a report published in Osteoarthritis Cartilage.  The author noted that the prevalence of osteoarthritis increases dramatically in women after the age of 50 with onset of menopausal estrogen deficiency.  Animal models are useful to evaluate this.  The author found 11 of 14 animal studies showed that ovarectomy (surgically induced estrogen deficiency) resulted in cartilage damage,  indicating considerable evidence for a relation between cartilage degeneration and estrogen deficiency (induced by ovarectomy) in animals. (14)

By 2023, there are 38 animal studies in menopausal animal models showing estrogen treatment ameliorates osteoarthritis. Overall, cartilage outcomes were worse in post-menopausal animals compared to controls. This was evidenced by measurements of cartilage histological scoring, cartilage thickness, type II collagen, and c-terminal cross-linked telopeptide. Another finding is that earlier initiation and higher doses of estrogen produced greater improvement in cartilage health. In 2023, Dr. G. Gilmore writes:

Thirty-eight manuscripts were eligible for inclusion. The most common menopause model used was ovariectomy (92%), and most animals were young at the time of menopause induction (86%)…Cartilage outcomes were worse in post-menopausal animals compared to age-matched, non-menopausal animals, as evidenced by cartilage histological scoring [0.75, 1.72], cartilage thickness [−4.96, −0.96], type II collagen [−4.87, −0.56], and c-terminal cross-linked telopeptide of type II collagen (CTX-II) [2.43, 5.79] (95% CI of Effect Size (+greater in menopause, −greater in non-menopause)). Moreover, modeling suggests that cartilage health may be improved with early initiation and higher doses of estrogen treatment. (26)

Inducing Estrogen Deficiency with Aromatase Inhibitors

The use of aromatase inhibitor drugs (exemestane, letrazole, etc.) to induce estrogen deficency is a common treatment of women with breast cancer. One of the adverse side effects is joint pain and osteoarthritis. Block estrogen with a drug, and women report joint pain. Again, this is supportive for the role of estrogen in maintaining cartilage health. (37-45)

We Still Have Our Doubts !

In spite of the overwhelming evidence presented above, there is still some confusion in the medical literature about the role of estrogen in post-menopausal osteoarthritis. For example, in 2023, Dr. Uyen-sa Nguyen writes in the European Journal of Rheumatology that the evidence of a protective effect of estrogen in osteoarthritis is still inconclusive, and obesity and aging may be more relevant causative factors:

Although several studies show that hormone replacement therapy has the potential to be protective of OA [osteoarthritis] for some joints, there are studies that showed no protective effect or even adverse effect. Taken together, the evidence for the protective effect of estrogen therapy depends on OA joint, OA outcome, and study design. Although this area has been studied for decades, more exclusively since the 1990s, there is a lack of high-quality experimental research in this topic. The lack of definitive conclusion on whether estrogen can play a role in the development in OA of either the knee, hip, spine, or hand is often in part due to the noncomparability of studies existing within the literature. Differences in diagnostic criteria, imaging modalities, populations studied, study designs, and outcome measures, as well as random error, have all contributed to inconclusive evidence. Future research on the role of estrogen in OA is needed, particularly as global demographic shifts in increasing overweight/obesity prevalence and ageing populations may contribute to widening OA-related health inequalities. (28)

I agree that obesity and aging are additional causative factors in the estoarthritis story. However, regarding the role of estrogen deficiency as causative for osteoarthritis, the evidence is so overwhelming, holding the contrary viewpoint that evidence is inconclusive and we really do not know is one of the errors of modern medicine. The current massive medical literature on the subject is more than enough evidence to justify the conclusion that estrogen deficiency is a major cause of postmenopausal osteoarthritis, and treatment with estrogen ameliorates it. The benefits of estrogen in the post-menopausal women suffering from arthritis pain is blatantly obvious to any clinician treating these patients.

Other Treatments for Osteoarthritis

Obesity and aging both play a role in the etiology of osteoarthitis. In this regards, for the obese patient, weight loss may be the best treatment for them. Aging associated nutritional deficiencies may be addressed with any number of dietary and herbal supplements such as glucosamine, chondroitin, and MSM (Methylsulfonylmethane), hydrolyzed collagen and hyaluronic acid. In 2021, Dr. Alessandro Colletti writes:

Among the most used nutraceuticals in OA, chondroitin sulphate, glucosamine sulphate, collagen, hyaluronic acid, and methylsulfonylmethane were shown to be impressive in the improvement of clinical symptoms and in decreasing inflammatory indices in subjects with OA. (47)

Anti-inflammatory drugs such as NSAIDs are commonly prescribed by mainstream medicine. However, although they provide prompt pain relief, NSAIDs and steroid injections may actually accelerate joint destruction. Anti-inflammatory  supplements are be safer without the gastro-intestinal adverse effects of NSAIDs. These include Curcumin, Boswellia, Chinese Skullcap, Ginger, Artemisinin, Ginseng, etc.  Other treatments include PEMF (pulsed electromagnetic field) therapy and Low Level Laser therapy, both showing considerable benefits for osteoarthritis. A more recent mainstream orthopedic treatment is Platelet-Rich Plasma (PRP) injections which stimulates healing of the joint. (18-23) (29-36) (46)

Conclusion: There is now overwhelming evidence from both animal and human studies that estrogen deficiency induces cartilage damage and osteoarthritis, and treatment with estrogen is both prevention and treatment. Estrogen induces cartilage regeneration with amelioration of post-menopausal joint pain.

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Jeffrey Dach MD
7450 Griffin Road, Suite 190
Davie, Fl 33314

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Links and References

1) Herrero-Beaumont, Gabriel, et al. “Primary osteoarthritis no longer primary: three subsets with distinct etiological, clinical, and therapeutic characteristics.Seminars in arthritis and rheumatism. Vol. 39. No. 2. WB Saunders, 2009.

Osteoarthritis (OA) has been historically divided into primary and secondary. Primary OA has been defined as an idiopathic condition developing in previously undamaged joints in the absence of an obvious causative mechanism. During the last few years a large amount of evidence has provided new insights into the biochemistry and molecular biology of cartilage, subchondral bone, and other articular tissues, which suggest distinct etiopathogenetic mechanisms in some forms of primary OA. OBJECTIVE: To propose an etiopathogenic classification of primary OA in the light of the significant progress in the understanding of the disease.

METHODS: A review of the literature was performed by searching the Medline and PubMed databases from 1952 to November 2008 using the following keywords: genetic alteration, heritability, estrogen, menopause, and aging either alone or in various combinations with joint, cartilage, subchondral bone, synovium, ligaments, muscle, tendons, OA, and osteoporosis.

RESULTS: Numerous studies have shown that genetic alterations, menopause-related estrogen deficiency, and aging play crucial roles in the molecular pathophysiological events involved in the process of cartilage and joint damage and thus in development of OA.

We propose classifying primary OA into 3 distinct although interrelated subsets:
type I OA, genetically determined;
type II OA, estrogen hormone dependent;
and type III OA, aging related.

CONCLUSIONS: The 3 proposed subsets of OA display distinct etiological, clinical, and therapeutic characteristics and should therefore no longer be considered to be “Primary OA.”

2) Roman-Blas, Jorge A., et al. “Osteoarthritis associated with estrogen deficiency.” Arthritis research & therapy 11 (2009): 1-14.

Osteoarthritis (OA) affects all articular tissues and finally leads to joint failure. Although articular tissues have long been considered unresponsive to estrogens or their deficiency, there is now increasing evidence that estrogens influence the activity of joint tissues through complex molecular pathways that act at multiple levels.

3) Nevitt, Michael C., et al. “Association of estrogen replacement therapy with the risk of osteoarthritis of the hip in elderly white women.” Archives of internal medicine 156.18 (1996): 2073-2080.

Abstract OBJECTIVE: To determine whether postmenopausal estrogen replacement therapy is associated with a reduced risk of radiographic findings of osteoarthritis (OA) of the hip. DESIGN: Cross-sectional study.

SUBJECTS: White women (N = 4366; age, > or = 65 years) who were participants in a cohort study of osteoporotic fractures.

MEASUREMENTS AND METHODS: Radiographs of the pelvis that were obtained in all subjects were assessed for radiographic features of OA of the hip on a summary scale of 0 (none) to 4 (severe OA). Postmenopausal estrogen use was assessed by interview. The association of current and past oral estrogen use with OA of the hip was analyzed by using logistic regression, adjusting for potential confounding variables (eg, indicators of osteoporosis and correlates of estrogen use).

RESULTS: Five hundred thirty-nine women (12.3%) had mild or greater radiographic findings of OA of the hip in at least 1 hip, and 214 women (4.9%) had moderate to severe findings; 17% and 24% of the women were current and past users of oral estrogen, respectively. Women who were currently using oral estrogen had a significantly reduced risk of any OA of the hip (adjusted odds ratio [OR], 0.62; 95% confidence interval [CI], 0.49-0.86) and moderate to severe manifestation of disease (OR, 0.54; 95% CI, 0.33-0.88). Current users who had taken estrogen for 10 years or longer had a greater reduction in the risk of any OA of the hip (OR, 0.57; 95% CI, 0.40-0.82) compared with that of users for less than 10 years (OR, 0.75; 95% CI, 0.47-1.24). Current estrogen use for 10 years or longer was associated with a nonsignificant trend for a reduced risk of moderate to severe symptomatic disease (OR, 0.59; 95% CI, 0.28-1.29).

CONCLUSION: Postmenopausal estrogen replacement therapy may protect against OA of the hip in elderly white women.


Zhang, Yuqing, et al. “Estrogen replacement therapy and worsening of radiographic knee osteoarthritis: the Framingham Study.” Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 41.10 (1998): 1867-1873.

Abstract OBJECTIVE: To examine whether estrogen replacement therapy (ERT) prevents worsening of radiographic knee osteoarthritis (OA) in elderly women. METHODS: A total of 551 women ages 63-91 years (mean age 71) in the Framingham Study were followed up from biennial examination 18 (1983-1985) to examination 22 (1992-1993). Data on postmenopausal ERT were obtained every 2 years. Subjects were classified into 3 groups according to their estrogen use at biennial examination 18: never users (n = 349), past users (n = 162), and current users (n = 40). Women received anteroposterior weight-bearing knee radiographs at examinations 18 and 22. Using the Kellgren and Lawrence criteria, global radiographic knee OA was assessed, (grade range 0-4) and individual radiographic features, such as osteophytes and joint space narrowing, were scored from 0 to 3. Worsening was defined as either development of radiographic OA that was not present at baseline (incident OA) or progression of baseline radiographic OA by > or =1 Kellgren and Lawrence grade (progressive OA). Potential confounding factors included age, body mass index, weight change, smoking, knee injury, physical activity level, and bone mineral density at the femoral neck. RESULTS: During 8 years of followup, 17.4% of knee radiographic scores worsened by 1 grade and 5.8% by 2 or 3 grades among never users of ERT.

Among current estrogen users, only 11.7% of knee radiographic scores worsened by 1 grade and none worsened by more than 1 grade. After adjusting for age and other potential confounding factors, the relative risk of incident radiographic knee OA in comparison with never users of estrogen was 0.8 (95% confidence interval [95% CI] 0.5-1.4) in past users and 0.4 (95% CI 0.1-3.0) in current users. Current use of estrogen also showed a trend toward decreased risk of progressive knee OA compared with never use (odds ratio [OR] 0.5, 95% CI 0.1-2.9). When both incident and progressive radiographic knee OA cases were combined, current ERT use had a 60% decreased risk compared with never use (OR 0.4, 95% CI 0.1-1.5).

5) Cirillo, Dominic J., et al. “Effect of hormone therapy on risk of hip and knee joint replacement in the Women’s Health Initiative.” Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 54.10 (2006): 3194-3204.

To determine the effect of hormone therapy on arthroplasty rates.

METHODS: We examined data from the Women’s Health Initiative placebo-controlled, double-blind, randomized trials. Community-dwelling women ages 50-79 years were enrolled at 40 US clinics. Women with prior arthroplasty were excluded, yielding a sample size of 26,321 subjects. Women who had had hysterectomies (n = 10,272) were randomly assigned to receive 0.625 mg/day conjugated equine estrogens (n = 5,076), or placebo (n = 5,196), with a mean followup of 7.1 years. Those who had not had hysterectomies (n = 16,049) were randomly assigned to receive estrogen plus progestin (n = 8,240), given as 0.625 mg/day conjugated equine estrogens plus 2.5 mg/day medroxyprogesterone acetate, or placebo (n = 7,809), with a mean followup of 5.6 years. Participants reported hospitalizations, and arthroplasties were identified by procedure codes. Arthroplasties due to hip fracture were censored. Cox proportional hazards regression was used to assess hazard ratios (HRs) and 95% confidence intervals (95% CIs) using intent-to-treat methods and outcome of time to first procedure.

RESULTS: In the estrogen-alone trial, women receiving hormone therapy had significantly lower rates of any arthroplasty (HR 0.84 [95% CI 0.70- 1.00], P = 0.05).

CONCLUSION: These data suggest that hormone therapy may influence joint health, but this observed decrease in risk may be limited to unopposed estrogen and may possibly be more important in hip than in knee osteoarthritis.

GENETIC CAUSES OF Osteoarthritis

6) Riancho, Jose A., et al. “Common variations in estrogen-related genes are associated with severe large-joint osteoarthritis: a multicenter genetic and functional study.” Osteoarthritis and Cartilage 18.7 (2010): 927-933.

OBJECTIVE: Several lines of evidence suggest that estrogens influence the development of osteoarthritis (OA). The aim of this study was to explore the association of two common polymorphisms within the aromatase (CYP19A1) and estrogen receptor (ER) alpha (ESR1) genes with severe OA of the lower limbs.

METHODS: The rs1062033 (CYP19A1) and rs2234693 (ESR1) single nucleotide polymorphisms were genotyped in 5528 individuals (3147 patients with severe hip or knee OA, and 2381 controls) from four centres in Spain and the United Kingdom. Gene expression was measured in femoral bone samples from a group of patients.

RESULTS: In the global analysis, both polymorphisms were associated with OA, but there was a significant sex interaction. The GG genotype at rs1062033 was associated with an increased risk of knee OA in women [odds ratio (OR) 1.23; P=0.04]. The CC genotype at rs2234693 tended to be associated with reduced OA risk in women (OR 0.76, P=0.028, for knee OA; OR=0.84, P=0.076 for hip OA), but with increased risk of hip OA in men (OR 1.28; P=0.029). Women with unfavourable genotypes at both loci had an OR of 1.61 for knee OA (P=0.006). The rs1062033 genotype associated with higher OA risk was also associated with reduced expression of the aromatase gene in bone.

CONCLUSIONS: Common genetic variations of the aromatase and ER genes are associated with the risk of severe OA of the large joints of the lower limb in a sex-specific manner. These results are consistent with the hypothesis that estrogen activity may influence the development of large-joint OA.

Estrogen Replacement in Ovarectomized Monkeys Prevents OA

7) Ham, Kimberley D., et al. “Effects of long‐term estrogen replacement therapy on osteoarthritis severity in cynomolgus monkeys.” Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 46.7 (2002): 1956-1964.

OBJECTIVE: To determine the effects of long-term estrogen replacement therapy (ERT) on the severity of osteoarthritis (OA) of the knee joint in surgically postmenopausal (bilaterally ovariectomized) female monkeys. A secondary aim was to evaluate the effect of soy phytoestrogen (SPE) treatment on the severity of OA.

METHODS: Feral adult female cynomolgus macaques were ovariectomized bilaterally and then randomly divided into 3 age- and weight-matched treatment groups. For 3 years, the first group received ERT with conjugated equine estrogens, the second group received SPE, and the third group received no treatment (controls). At necropsy, histologic lesions of OA were graded, and the area and thickness of cartilage and subchondral bone were measured. The data were summarized by principal components analysis, and the resulting factors and individual variables were compared using analysis of variance and analysis of covariance (age and weight as covariates).

RESULTS: Cartilage lesions of OA were significantly less severe in the animals given ERT compared with those in the control group. This treatment effect remained significant when adjusted for age and weight. The factor representing subchondral bone was significantly higher, but the number of osteophytes was lower, in the ERT group compared with the control group. SPE treatment had no significant effect on cartilage or bone lesions of OA.

CONCLUSION: These results demonstrate that long-term ERT significantly reduces the severity of OA lesions in this animal model.

8) Tanko, L. B., et al. “An update review of cellular mechanisms conferring the indirect and direct effects of estrogen on articular cartilage.” Climacteric 11.1 (2008): 4-16.

OBJECTIVE: To review cellular mechanisms that have been proposed to mediate the indirect and direct effects of estrogen on articular cartilage, and to outline the remaining clinical questions that need to be clarified before utilizing the beneficial effects of estrogen for the prevention of osteoarthritis in early postmenopausal women.

DESIGN: Summary of original research papers and reviews listed in Pubmed (1980-2007).

RESULTS: Estrogen receptors have been identified in articular chondrocytes from various animals and humans. Molecular studies showed that estrogen can elicit genomic and rapid non-genomic effects on various cell types, including chondrocytes, and the latter effects are only inducible in females. In addition to direct effects, estrogen can also affect the homeostasis of articular cartilage by modulating the expression/production of different molecules such as various growth factors, inflammatory cytokines, matrix metalloproteinases, and reactive oxygen species. Moreover, in vivo observation argues for the notion that inhibition of subchondral bone turnover is also part of the mechanisms by which estrogen (and antiresorptive agents in general) can protect against joint degradation. Published studies undertaken at cellular, tissue, and in vivo levels illustrate that the effect of estrogen on cartilage may depend on the dose applied, the administration route, the time of initiation, and whether it is combined with a progestin.

CONCLUSIONS: The herein reviewed direct and indirect effects of estrogen on articular cartilage further corroborate the due consideration of estrogen therapy for maintaining not only bone but also cartilage health in postmenopausal women. Future studies in postmenopausal women are needed to clarify whether the efficacy of estrogen therapy can be further optimized by using other forms of estrogen, other progestins, or by initiating the therapy in the peri- or early postmenopausal period.

Animal Studies

9) Oestergaard, Svetlana, et al. “Effects of ovariectomy and estrogen therapy on type II collagen degradation and structural integrity of articular cartilage in rats: implications of the time of initiation.” Arthritis & Rheumatism: Official Journal of the American College of Rheumatology 54.8 (2006): 2441-2451.

Abstract OBJECTIVE: To investigate how the time of initiation influences the effects of estrogen therapy on type II collagen (CII) turnover and the structural integrity of articular cartilage in ovariectomized rats and to determine whether estrogen exerts direct effects on the catabolic function of chondrocytes ex vivo.

METHODS: A total of 46 Sprague-Dawley rats were distributed into 1 of the following treatment groups:
1) ovariectomy,
2) ovariectomy plus early estrogen therapy,
3) ovariectomy plus delayed estrogen therapy, or
4) sham operation.

Cartilage turnover was estimated by measuring the serum levels of C-telopeptide of type II collagen (CTX-II). Cartilage lesions at week 9 were quantified using a published scoring technique. The presence of the CTX-II epitope in articular cartilage was assessed by immunohistochemistry. The effects of estrogen (1 -100 nM) on chondrocytes were investigated in bovine cartilage explants subjected to catabolic cytokines (tumor necrosis factor alpha [TNFalpha] and oncostatin M [OSM]).

RESULTS: In ovariectomized rats, estrogen therapy evoked significant decreases in serum CTX-II independently of the time of initiation; yet, delayed initiation resulted in diminished efficacy in terms of preventing cartilage lesions. CTX-II fragments were present in articular cartilage, colocalizing with early lesions at the cartilage surface. In untreated animals, the early relative increases in serum CTX-II were proportional to the severity of cartilage lesions at week 9 (r = 0.73, P < 0.01). Estrogen significantly and dose- dependently countered CTX-II release from TNFalpha plus OSM-stimulated cartilage explants ex vivo.

CONCLUSION: Our results suggest that estrogen counters the acceleration of CII degradation and related structural alterations, and these benefits can be maximized by early initiation after menopause. The protective effect of estrogen seems to involve direct inhibition of the catabolic function of chondrocytes.

10) Claassen, Horst, et al. “The effect of estrogens and dietary calcium deficiency on the extracellular matrix of articular cartilage in Göttingen miniature pigs.” Annals of Anatomy-Anatomischer Anzeiger 184.2 (2002): 141-148.

Abstract Clinical observations have suggested that estrogens are involved in the pathogenesis of postmenopausal osteoarthritis (OA). However, positive and negative associations between the incidence of OA and serum estrogen concentrations have been reported.

In contrast to this, osteoporosis is regarded as a disease with a strong estrogen-dependent component. Moreover, there is an interaction between estrogen and calcium deficiency: calcium supplementation potentiates the effect of estrogen therapy. The present study was designed to investigate how estrogen deficiency affects the articular cartilage depending on calcium supply. The distribution of different types of glycosaminoglycans and collagens can be used as an indicator for extracellular matrix changes induced by estrogen deficiency. Different levels of dietary calcium were therefore fed to intact and ovariectomized Göttingen miniature pigs for one year before articular cartilage was harvested. The histochemical staining for heavy sulfated glycosaminoglycans in the extracellular matrix of ovariectomized miniature pigs, especially of those fed with a low calcium diet, was stronger in comparison to intact animals. In intact animals type II-collagen was immunodetected in all zones of unmineralized and mineralized articular cartilage, while immunostaining for this protein was negative to weak in the deep radiated fiber zone of ovariectomized minipigs.

These results suggest that the synthesis of heavy sulfated glycosaminoglycans and immunohistochemically detectable type II-collagen is possibly influenced by estrogen deficiency.

In conclusion, under estrogen deficiency, the extracellular matrix of articular cartilage underwent similar changes to those observed in physiologically aging cartilage where keratan sulfate is increased as a heavy sulfated glycosaminoglycan.

11) Guofeng, Dai, et al. “The relationship of the expression of estrogen receptor in cartilage cell and osteoarthritis induced by bilateral ovariectomy in guinea pig.” Journal of Huazhong University of Science and Technology [Medical Sciences] 25 (2005): 683-686.

Abstract To investigate the estrogen receptor (ER) expression in cartilage cell in the development of osteoarthritis induced by bilateral ovariectomy in guinea pig and to find their relationship. 30 two-month-old female guinea pigs were randomly divided into two groups (n = 15 each): sham operation (control) group and ovariectomized group (OVX);

Scanning electron microscope (SEM) and transmission electron microscope (TEM) were obtained to analysis the cartilage degeneration of the hind limb knee joint after 6 and 12 weeks of ovariectomy. Dextran-Coated-Charcoal (DCC) was taken to quantitively detect the expression of ER. The serum levels of estrogen and gestone were detected by immune contest assay.

The results showed that ER do exist in the cartilages of the guinea pigs, with higher expression in the control group than in OVX group at the same time point (P < 0.05). It was increased also at 12 th week after operation than that of preoperation. The blood serum levels of estrogen and gestone showed a similar tendency to the expression of ER. Joint cartilage degeneration detected by SEM and TEM could be found at 6 th week, but severe degenerative lesions at 12 th week in the OVX group compared with the control group (P < 0.01).

The data suggested that bilateral ovariectomy in guinea pig lead to severe osteoarthritis which might be related to the lower serum level of estrogen and the downregulation of the expression of ER in the cartilage also.

12) Turner, A. Simon, et al. “Biochemical effects of estrogen on articular cartilage in ovariectomized sheep.” Osteoarthritis and Cartilage 5.1 (1997): 63-69.

Abstract Cartilage is a sex-hormone-sensitive tissue but the role of estrogen in the pathogenesis of osteoarthritis (OA) remains controversial. In this study, intrinsic material properties and thickness of articular cartilage of the knee joint of ovariectomized (OVX) and estrogen-treated sheep were measured. Skeletally mature ewes (N = 36, same breed, same housing 4-5 years old) were divided into; sham treated (n = 9), OVX (N = 13), OVX plus one estradiol implant (OVXE; N = 10) and OVX plus two estradiol implants (OVX2E; N = 4).

Twelve months following sham procedure or OVX, sheep were euthanized and articular cartilage from a total of 216 points in the left femorotibial (knee) joints was tested for aggregate modulus, Poisson’s ratio, permeability, thickness and shear modulus (six sites per sheep). When all of the sites in each knee were grouped together, OVX had a significant effect on articular cartilage. The sham cartilage of all sites grouped together had a larger aggregate modulus (P = 0.001) and a larger shear modulus (P = 0.054) than the OVX tissue. No statistically significant differences were seen for permeability and thickness between OVX, sham, OVXE and OVX2E. Differences existed in biomechanical properties at the different sites that were tested. Overall, no one location tended to be lowest or highest for all variables. This biomechanical study suggests that OVX may have a detrimental effect on the intrinsic material properties of the articular cartilage of the knee, even though the cartilage of the OVX animals appeared normal.

Treatment with estradiol implants ameliorated these deleterious effects and may have helped maintain the tissue’s structural integrity. Our study supports epidemiological studies of OA in women after menopause. The protective effect of estrogen and it’s therapeutic effect remain to be further defined. This model may allow the relationship of estrogen and estrogen antagonists to be studied in greater detail, and may be valuable for the study of the pathogenesis and therapies of OA of postmenopausal women, particularly in its early stages.

13) Cake, Martin A., et al. “Ovariectomy alters the structural and biomechanical properties of ovine femoro-tibial articular cartilage and increases cartilage iNOS.” Osteoarthritis and cartilage 13.12 (2005): 1066-1075.

Abstract OBJECTIVE: To examine the effect of oestrogen depletion produced by surgical ovariectomy on the structural and biomechanical properties of ovine femoro-tibial articular cartilage (AC), and the production of inducible nitric oxide synthase (iNOS) and nitrotyrosine by these tissues. METHODS: Six aged ewes were surgically ovariectomised (OVX), while six were used as unoperated controls. Dynamic biomechanical indentation testing of tibial plateau AC was performed at 26 weeks post-op. Histological sections of medial tibial plateau and lateral tibial plateau (LTP), medial and lateral femoral condyles (MFC, LFC) and patellar AC were examined for histopathology, toluidine blue staining intensity, and patterns of collagen birefringence intensity. Immunoreactivity for iNOS and nitrotyrosine was assessed in full-thickness biopsy plugs of LFC and patellar AC, and patellar AC explants were cultured to determine in vitro NO release.

RESULTS: Phase lag was reduced overall in LTP-AC of OVX sheep (10.9+/-2.2 degrees vs 12.1+/-2.3 degrees ; P<0.0001). Cartilage thickness was reduced in the LTP of OVX sheep (P=0.0002), in association with localised changes in dynamic shear modulus. Toluidine blue staining intensity was reduced in the patella, LFC, and MFC. Histological examination revealed greater histopathology scores in the MFC of OVX animals, and altered collagen birefringence intensity plots in the LTP. Immunostaining for iNOS was increased in patella AC (P=0.008), whilst nitrotyrosine immunoreactivity was increased in patella (P=0.03) and LFC (P<0.0001) AC. NO release by patellar AC explants was also elevated.

CONCLUSIONS: Oestrogen depletion induced by OVX caused regional thinning of femoro-tibial cartilage, with biomechanical and histological changes suggestive of a disturbance in the content and/or structural organisation of the proteoglycan and collagen macromolecular assembly. The observed up-regulation of cartilage iNOS suggests a possible mechanism for these matrix changes.

ANimal Model Summary

14) Sniekers, Y. H., et al. “Animal models for osteoarthritis: the effect of ovariectomy and estrogen treatment–a systematic approach.” Osteoarthritis and cartilage 16.5 (2008): 533-541

OBJECTIVE: The prevalence of osteoarthritis (OA) increases dramatically in women after the age of 50. Animal models are used to study the effects of hormone depletion [by ovariectomy (OVX)] and estrogen treatment on OA. This review summarizes these animal studies, in order to get a better insight in the role of hormones on OA.

METHOD: The literature was systematically reviewed until May 2007. The results were divided into two parts: the effect of OVX on cartilage, and the effect of estrogen treatment on cartilage. Only studies with an appropriate control group (e.g., sham-operated) were included.

RESULTS AND DISCUSSION: Eleven out of 16 animal studies showed that OVX resulted in cartilage damage. When only studies using sexually mature animals were included, we saw that 11 out of 14 studies showed a detrimental effect, indicating considerable evidence for a relation between cartilage degeneration and OVX in mature animals. The effect of estrogen treatment was inconclusive with only 11 out of 22 animal studies reporting a beneficial effect on cartilage, whereas all six studies administering selective estrogen receptor modulators (SERMs) after OVX described protective effects. The discrepancy between the studies may be caused by the large variation in experimental set-up. We suggested a list of quality criteria for animal models since standardisation of design and outcome parameters of animal experiments may help to compare different studies and to gain better insight in the role of hormones in the osteoarthritic process.

15)  Sniekers, Yvonne H., et al. “Oestrogen is important for maintenance of cartilage and subchondral bone in a murine model of knee osteoarthritis.” Arthritis Research & Therapy 12.5 (2010): R182. This study demonstrates the significance of oestrogen for articular cartilage and subchondral bone and maintenance of healthy joints, supporting an etiological role for altered oestrogen signaling in osteoarthritis either by directly affecting cartilage or increasing susceptibility for an osteoarthritis trigger.


16) Felson, David T., and Michael C. Nevitt. “The effects of estrogen on osteoarthritis.” Current opinion in rheumatology 10.3 (1998): 269-272.

Abstract The prevalence of osteoarthritis is higher in women than men, and in women it increases dramatically in the years after menopause. These observations and others reporting a painful form of hand osteoarthritis after the menopause suggest that loss of estrogen at the time of menopause increases a woman’s risk of getting osteoarthritis. This article reviews biologic evidence for hormone sensitivity of cartilage, animal studies testing the effect of estrogen on the joints of ovariectomized animals, and human epidemiologic and clinical studies evaluating endogenous estrogen levels and estrogen replacement therapy and their relation to the occurrence of osteoarthritis. Overall the evidence for a role of estrogen in osteoarthritis is conflicting. Epidemiologic studies of women who take estrogen replacement therapy, however, consistently report that these women have a lower prevalence of osteoarthritis than women not taking estrogen, suggesting a possible therapeutic role for estrogen in osteoarthritis.

17)  Xiao, Ya-Ping, et al. “Are estrogen-related drugs new alternatives for the management of osteoarthritis?.” Arthritis Research & Therapy 18 (2016).
Taken together, evidence strongly suggests that estrogen may be involved in the development of OA.

Estrogen appears to have a potential protective effect on chondrocytes in vitro. In rabbit articular chondrocytes, 17β-estradiol has been shown to upregulate collagen type II expression by Sp1/3, Sox-9, and ERα [26]. In another study, 17β-estradiol treatment prevented injury-related cell death and glycosaminoglycan release in mature articular cartilage explants, suggesting that 17β-estradiol may be useful for treating either cartilage-related sports injuries or OA [27]. Kumagai et al. [28] also found that 17β-estradiol suppressed doxorubicin-induced apoptosis by blocking volume-sensitive Cl– current in rabbit articular chondrocytes. In cultured chondrocytes from a rat OA model, 17β-estradiol promoted chondrocyte proliferation via the PI3K/Akt pathway [29].

In the Women’s Health Initiative study [32], women receiving conjugated equine estrogens had significantly lower rates of arthroplasty, particularly hip replacement rates. In a cross-sectional study, knee MRI scans identified that women receiving estrogen had significantly less subchondral bone attrition and bone marrow edema-like abnormalities in the knee compared with nontreated women

PEMF – Pulsed Electro MAgnetic Fields

18) Fini, M., et al. “Pulsed electromagnetic fields reduce knee osteoarthritic lesion progression in the aged Dunkin Hartley guinea pig.” Journal of orthopaedic research 23.4 (2005): 899-908.

Abstract An experimental in vivo study was performed to test if the effect of Pulsed Electromagnetic Fields (PEMFs) on chondrocyte metabolism and adenosine A2a agonist activity could have a chondroprotective effect on the knee of Dunkin Hartley guinea-pigs of 12 months with spontaneously developed osteoarthritis (OA).

After a pilot study, 10 animals were randomly divided into two groups: PEMF-treated group (6 h/day for 3 months) and Sham-treated group. Microradiography and histomorphometry were performed on the entire articular surface of knee joints used in evaluating chondropathy severity, cartilage thickness (CT), cartilage surface Fibrillation Index (FI), subchondral bone plate thickness (SBT) and histomorphometric characteristics of trabecular epiphyseal bone. The PEMF-treated animals showed a significant reduction of chondropathy progression in all knee examined areas (p<0.05). CT was significantly higher (p<0.001) in the medial tibia plateaus of the PEMF-treated group when compared to the Sham-treated group. The highest value of FI was observed in the medial tibia plateau of the Sham-treated group (p<0.05). Significant lower values were observed in SBT of PEMF-treated group in comparison to Sham-treated group in all knee examined areas (p<0.05).

The present study results show that PEMFs preserve the morphology of articular cartilage and slower the progression of OA lesions in the knee of aged osteoarthritic guinea pigs. The chondroprotective effect of PEMFs was demonstrated not only in the medial tibial plateau but also on the entire articular surface of the knee.

19) Fini, Milena, et al. “Effect of pulsed electromagnetic field stimulation on knee cartilage, subchondral and epyphiseal trabecular bone of aged Dunkin Hartley guinea pigs.” Biomedicine & pharmacotherapy 62.10 (2008): 709-715.

Abstract It has been demonstrated that pulsed electromagnetic field (PEMF) stimulation has a chondroprotective effect on osteoarthritis (OA) progression in the knee joints of the 12-month-old guinea pigs. The aim of the present study was to discover whether the therapeutic efficacy of PEMFs was maintained in older animals also in more severe OA lesions. PEMFs were administered daily (6 h/day for 6 months) to 15-month-old guinea pigs. The knee joints (medial and lateral tibial plateaus, medial and lateral femoral condyles) were evaluated by means of a histological/histochemical Mankin modified by Carlsson grading score and histomorphometric measurements of cartilage thickness (CT), fibrillation index (FI), subchondral bone thickness (SBT) and epiphyseal bone microarchitecture (bone volume: BV/TV; trabecular thickness: Tb.Th; trabecular number: Tb.N; trabecular separation: Tb.SP). Periarticular knee bone was also evaluated with dual X-ray absorptiometry (DXA). PEMF stimulation significantly changed the progression of OA lesions in all examined knee areas. In the most affected area of the knee joint (medial tibial plateau), significant lower histochemical score (p<0.0005), FI (p<0.005), SBT (p<0.05), BV/TV (p<0.0005), Tb.Th (p<0.05) and Tb.N (p<0.05) were observed while CT (p<0.05) and Tb.Sp (p<0.0005) were significantly higher than in SHAM-treated animals. DXA confirmed the significantly higher bone density in SHAM-treated animals.

20) Cadossi, Ruggero, et al. “Pulsed Electromagnetic Field Stimulation of Bone Healing and Joint Preservation: Cellular Mechanisms of Skeletal Response.” Journal of the American Academy of Orthopaedic Surgeons. Global research & reviews 4.5 (2020): e1900155.

In 1979, the US FDA approved PEMF as a safe and effective treatment for nonunions of bone. Since then, the use of PEMF stimulation for bone repair has grown both in the United States and in Europe. In the United States, a survey showed that 72% of hospitals offer bone repair stimulation treatments for fractures that fail to heal.

These observations suggest that PEMFs exert a proanabolic effect on the cartilage matrix and a chondroprotective effect counteracting the catabolic effects of inflammation in the joint environment. Together, these data suggest that PEMF may prevent or limit articular cartilage degradation, leading to joint preservation.

Even in the presence of severe OA lesions PEMFs maintained a significant efficacy in reducing lesion progression.

Low Level Laser for OA

21) Hegedűs, Béla, et al. “The effect of low-level laser in knee osteoarthritis: a double-blind, randomized, placebo-controlled trial.” Photomedicine and laser surgery 27.4 (2009): 577-584.

Introduction:  Low-level laser therapy (LLLT) is thought to have an analgesic effect as well as a biomodulatory effect on microcirculation. This study was designed to examine the pain-relieving effect of LLLT and possible microcirculatory changes measured by thermography in patients with knee osteoarthritis (KOA). Materials and Methods: Patients with mild or moderate KOA were randomized to receive either LLLT or placebo LLLT. Treatments were delivered twice a week over a period of 4wk with a diode laser (wavelength 830 nm, continuous wave, power 50mW) in skin contact at a dose of 6 J=point. The placebo control group was treated with an ineffective probe (power 0.5mW) of the same appearance. Before examinations and immediately, 2 wk, and 2 mo after completing the therapy, thermography was performed (bilateral comparative thermograph by AGA infrared camera); joint flexion, circumference, and pressure sensitivity were measured; and the visual analogue scale was recorded. Results: In the group treated with active LLLT, a significant improvement was found in pain (before treatment [BT]: 5.75; 2 mo after treatment : 1.18); circumference (BT: 40.45; AT: 39.86); pressure sensitivity (BT: 2.33; AT: 0.77); and flexion (BT: 105.83; AT: 122.94). In the placebo group, changes in joint flexion and pain were not significant. Thermographic measurements showed at least a 0.58C increase in temperature—and thus an improvement in circulation compared to the initial values. In the placebo group, these changes did not occur.

Conclusion: Our results show that LLLT reduces pain in KOA and improves microcirculation in the irradiated area.

22) Kahn, F., R. Liboro, and F. Saraga. “Laser therapy for the treatment of arthritic knees: a clinical study.” Mechanisms for Low-Light Therapy V. Vol. 7552. SPIE, 2010.

ABSTRACT In a follow-up clinical study to our previously published 2006 SPIE conference proceeding, we analyzed a cross-section of patients treated for a variety of knee problems that present at our Meditech Laser Rehabilitation Clinics on a daily basis. Of the 98 patients with knee pathologies included in this study, 63% presented with degenerative osteoarthritis. On average 11 treatments, each 30-45 minutes in duration, were administered for the individual patient resulting in a significant improvement rate in excess of 92%. Laser Therapy is active at both the cellular and systemic levels activating a variety of mechanisms including cartilage regeneration, DNA synthesis, improved microcirculation and an analgesic and anti-inflammatory effect.

23) Cho, Hyung-Jin, et al. “Effect of low-level laser therapy on osteoarthropathy in rabbit.” in vivo 18.5 (2004): 585-592.

Conversely, the 4-week treatment group showed chondrocyte replacement, with sometimes close to normal articular cartilage on the articular surface. These results suggest that LLLT was effective in the treatment of chemically-induced OA.


24) Liu, Y. P., et al. “Study the relevance between inflammatory factors and estradiol and their association with knee osteoarthritis in postmenopausal women.” Eur Rev Med Pharmacol Sci 22.2 (2018): 472-478.

The lack of estradiol is associated with the pathogenesis of OA in postmenopausal women, the inflammatory factors of IL-1, IL-6, TNF-α in postmenopausal increased in serum and synovial fluid may promote and aggravate the OA.

25) Pang, Huiwen, et al. “Low back pain and osteoarthritis pain: a perspective of estrogen.” Bone research 11.1 (2023): 42.

estrogen supplementation has been shown to be effective at ameliorating IVD degeneration and OA progression, indicating its potential use as a therapeutic agent for people with LBP and OA pain.

Recent Animal Models

26) Gilmer, G., et al. “Uncovering the “riddle of femininity” in osteoarthritis: a systematic review and meta-analysis of menopausal animal models and mathematical modeling of estrogen treatment.” Osteoarthritis and cartilage 31.4 (2023): 447-457.

Thirty-eight manuscripts were eligible for inclusion. The most common menopause model used was ovariectomy (92%), and most animals were young at the time of menopause induction (86%). Most studies did not report inclusion criteria, animal monitoring, protocol registration, or data accessibility. Cartilage outcomes were worse in post-menopausal animals compared to age-matched, non-menopausal animals, as evidenced by cartilage histological scoring [0.75, 1.72], cartilage thickness [−4.96, −0.96], type II collagen [−4.87, −0.56], and c-terminal cross-linked telopeptide of type II collagen (CTX-II) [2.43, 5.79] (95% CI of Effect Size (+greater in menopause, −greater in non-menopause)). Moreover, modeling suggests that cartilage health may be improved with early initiation and higher doses of estrogen treatment.

27) Dreier, Rita, et al. “Estradiol inhibits ER stress-induced apoptosis in chondrocytes and contributes to a reduced osteoarthritic cartilage degeneration in female mice.” Frontiers in Cell and Developmental Biology 10 (2022): 913118.

Taken together, this study demonstrates that the female sex hormone estradiol can reduce ER stress and ER stress-induced apoptosis in articular chondrocytes, thus minimizing critical events favoring osteoarthritic cartilage degeneration. Therefore, the inhibition of ER stress through a modulation of effects induced by female sex hormones appears to be attractive for OA therapy.

We Still HAve Doubts

28) Nguyen, Uyen-sa, Fiona Saunders, and Kathryn Martin. “Sex difference in OA: Should we blame estrogen?.” European Journal of Rheumatology (2023).

Studies are confusing and we dont know for sure.


Other Treatments

Kim, Hye In, et al. “Clinical effects of Korean red ginseng in postmenopausal women with hand osteoarthritis: A double-blind, randomized controlled trial.” Frontiers in Pharmacology 12 (2021): 745568.
Korean red ginseng may be an effective dietary supplement for postmenopausal women with degenerative osteoarthritis of the hand. It may relieve pain and improve antioxidative activity without the risk of endometrial thickening.

30) Chen, Jincai, Lin Huang, and Xiaofei Liao. “Protective effects of ginseng and ginsenosides in the development of osteoarthritis.” Experimental and Therapeutic Medicine 26.4 (2023): 1-12.

31) Vaishya, Raju, et al. “Current status of top 10 nutraceuticals used for Knee Osteoarthritis in India.” Journal of clinical orthopaedics and trauma 9.4 (2018): 338-348.

Boswellia, Aflapin, Chondroitin sulphate, Glucosamine sulphate, Collagen peptide, Curcumin, Fish Oil, Ginger, Green tea, and Rosehip extract.

32) Sethi, Vidhu, et al. “Potential complementary and/or synergistic effects of curcumin and boswellic acids for management of osteoarthritis.” Therapeutic Advances in Musculoskeletal Disease 14 (2022): 1759720X221124545.

33) Marana, Rosana Rodrigues, et al. “Omega 3 polyunsaturated fatty acids: Potential anti-inflammatory effect in a model of ovariectomy and temporomandibular joint arthritis induction in rats.” Archives of Oral Biology 134 (2022): 105340.

34) Ma, Long, et al. “Dihydroartemisinin attenuates osteoarthritis by inhibiting abnormal bone remodeling and angiogenesis in subchondral bone.” International Journal of Molecular Medicine 47.3 (2021): 1-1.

35) Zhong, Gang, et al. “Artemisinin ameliorates osteoarthritis by inhibiting the Wnt/β-catenin signaling pathway.” Cellular Physiology and Biochemistry 51.6 (2019): 2575-2590.

36) Jiang, Li-Bo, et al. “Dihydroartemisinin inhibits catabolism in rat chondrocytes by activating autophagy via inhibition of the NF-κB pathway.” Scientific Reports 6.1 (2016): 38979.


37) Camejo, Natalia, et al. “Arthralgia and myalgia associated with aromatase inhibitors: frequency and characterization in real-life patients.” ecancermedicalscience 18 (2024).

38) Tenti, Sara, et al. “Aromatase Inhibitors—induced musculoskeletal disorders: current knowledge on clinical and molecular aspects.” International Journal of Molecular Sciences 21.16 (2020): 5625.

39) Kim, Sara, Nan Chen, and Pankti Reid. “Current and future advances in practice: aromatase inhibitor–induced arthralgia.” Rheumatology Advances in Practice 8.2 (2024): rkae024.

40) Chien, Hsu-Chih, et al. “Aromatase inhibitors and risk of arthritis and carpal tunnel syndrome among Taiwanese women with breast cancer: a nationwide claims data analysis.” Journal of Clinical Medicine 9.2 (2020): 566.

41) Cathcart-Rake, Elizabeth, et al. “A randomized, double-blind, placebo-controlled trial of testosterone for treatment of postmenopausal women with aromatase inhibitor-induced arthralgias: Alliance study A221102.” Supportive Care in Cancer 29 (2021): 387-396.

42) Grigorian, Nelly, and Steven J. Baumrucker. “Aromatase inhibitor–associated musculoskeletal pain: An overview of pathophysiology and treatment modalities.” SAGE Open Medicine 10 (2022): 20503121221078722.

43) Baba, Ozge, Hakan Kisaoglu, and Mukaddes Kalyoncu. “Letrozole‐induced inflammatory arthritis and tendinopathy in pediatric rheumatology setting.” International Journal of Rheumatic Diseases 26.11 (2023): 2314-2316.

44) Gaudio, Agostino, et al. “Therapeutic options for the management of aromatase inhibitor-associated bone loss.” Endocrine, Metabolic & Immune Disorders-Drug Targets (Formerly Current Drug Targets-Immune, Endocrine & Metabolic Disorders) 22.3 (2022): 259-273.

45) Wang, Tao, et al. “Prevalence and correlates of joint pain among Chinese breast cancer survivors receiving aromatase inhibitor treatment.” Supportive Care in Cancer 30.11 (2022): 9279-9288.

46) Mende, Emily, Ryan J. Love, and Jody-Lynn Young. “A Comprehensive Summary of the Meta-Analyses and Systematic Reviews on Platelet-Rich Plasma Therapies for Knee Osteoarthritis.” Military Medicine (2024): usae022.

47) Colletti, Alessandro, and Arrigo FG Cicero. “Nutraceutical approach to chronic osteoarthritis: from molecular research to clinical evidence.” International Journal of Molecular Sciences 22.23 (2021): 12920.

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Bioidentical Hormones Prevent Arthritis
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Bioidentical Hormones Prevent Arthritis
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About Jeffrey Dach MD

Medical Director of TrueMedMD, a Clinic in Davie Florida specializing in Bioidentical Hormones and Natural thyroid. Office address 7450 Griffin Road Suite 190, Davie, Florida 33314 telephone 954-792-4663

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