The present study revealed significant elevation of bone turnover marker levels in women undergone hysterectomy with bilateral oophorectomy who did not receive
estrogen treatment. Despite a short period, asymptomatic but significantly high bone resorption process was occurred within 3 months after surgeries. In normal reproductive period, bone resorption and formation were modulated and balanced by circulating estrogen levels. Estrogen activates synthesis of osteoprotegerin (OPG), the decoy antibodies which neutralizes the receptor activator of NF-ĸB ligand (RANKL), and inhibits RANK expression (receptor of RANKL). Responses to estrogen results in inhibition of differentiation and activation of the osteoclasts. Moreover, estrogen modulates the proinflammatory cytokines such as IL-1, IL-6, TNF-α and PGE2 which reduces the pool of osteoclasts precursors. The minor estrogenic mechanism on bone is regulates TGF-β expression results in apoptosis of osteoclasts.(25) According to all mechanism mentioned above, estrogen deprivation is a major detrimental factor on bone physiology.
Surgical removal of both ovaries in women before the time of menopause leads to abrupt declination of circulating estrogen levels.(6) From a previous study, the bone turnover markers measured before and after surgical menopause procedure were elevated as soon as a month after surgery. These serum bone turnover levels were continuously elevated at 6 months after surgery. Furthermore, they found a significant negative correlation between the bone turnover markers levels and lumbar spine bone mineral density (BMD) at preoperative and 6 months after surgery. (14) In another study, bone resorption and formation markers were elevated at 3 months after surgical menopause procedure. However, the bone markers levels declined to the baseline levels after menopausal hormone prescription for 3 months. (23) Although there were several studies found that surgical menopausal women seem to have higher bone loss rate than age-matched natural menopause women in a short term period,(15, 27)there is no high-quality data demonstrated the long term bone loss and fracture risk differences between types of menopause.
Traditionally routine salpingo-oophorectomy at the time of hysterectomy should be revisited, especially in pre and perimenopausal women. Because the lifetime risk of developing ovarian cancer in the general population is only 1 in 70 or 1.4%, (27) physicians should make sure that their counseling about risks and benefits is based on current evidence. The reduction of ovarian cancer risk, avoid possible morbidities and future surgery of ovarian disease are the major potential benefits of salpingo-oophorectomy. However, these potential benefits must be balanced with the consequences of premature loss of circulating estrogen including, bone loss, hot flushes, cognitive impairment, sexual desire loss, and long-term survival rate.(27)
This study emphasized this concept. The detrimental bone effects began in surgically induced menopausal women in only 3 months after surgery. In case of women who did not receive MHT, further bone loss, potential risk of osteoporosis, and possible risk of fractures should be concerned. In the present study, we gave patients as much as possible information about risks and benefits of salpingo-oophorectomy at the time of hysterectomy. Based primarily on patient autonomy, the decisions to do salpingo-oophorectomy were made by participants with additional information from physicians.
In our cohort, twenty-seven out of 48 women did not receive MHT for treating menopausal symptoms and bone loss prevention. In other words, more than haft of women in our cohort lost their bone significantly at 3 months after surgery. Prudent clinical evaluation, life-style modification for bone health, and follow-up for bone density and/ or quality measurement should be considered in these women. In our experiences as a medical school center in Thailand, we found that around 30–40% of advanced age premenopausal and perimenopausal women accepted and made decision to remove their ovaries at the time of hysterectomy for benign gynecological conditions. However, bone measurement was offered only in a minority of these patients.
As the primary outcome in the present study, the median serum CTX levels at 12 weeks after surgical menopause procedure were statistically different between the two groups (p-value < 0.001), Table 2. The 55% lower of median serum CTX level than in the no treatment group is not only statistically significant, but is significantly clinical meaning. In other words, abnormal bone resorption from acute estrogen deprivation could be inhibited by early administration with moderate dose estrogen. Moreover, additional data in this study showed that both of bone resorptive and formative markers levels after surgical menopause were not significant differences from the baseline levels among women in hormone treatment group (before and after treatment comparison within group, Table 3).
The timing of hormone initiation might be an important issue. In our study, hormone therapy was initiated around 2 weeks after surgery. In contrast, the women from Peris P, et al study. (23) started hormone therapy at 3 months post-surgery. The differences between our results and Peris P, et al. finding are at least in part due to the timing of menopausal hormone initiation. It should be noted that, sixteen out of the total 48 women in our study had moderate to severe hot flushes as early as 2 weeks after oophorectomy. Hence, MHT could be considered as soon as possible in women who has MHT indication. The benefit of MHT in this condition is not only for improving the quality of life but also protecting accelerated bone loss. However, some clinicians may concern about the risk of venous thrombosis with MHT in early postoperative period, especially in cases of obesity, metabolic syndrome, and advanced age patients. To minimize the thrombosis risk in these patients, transdermal estrogen administration with optimum dose is preferred.
In term of treatment effects, we showed that early administration of 2 milligrams of oral estradiol valerate significantly suppressed bone remodeling process. However, conclusion cannot be done for all oral MHT products in the market. Many available products around the world are 1 milligram of estradiol plus variety of progestins. Both the lower dose of other estradiol products and estrogenic counter-action of various progestins may dramatically affect the bone outcomes.
There are incongruences in data interpretation and recommendations of estrogen therapy and bone, especially for postmenopausal osteoporosis. In the age group 50–60 years or within 10 years after menopause (the window of opportunity concept), the benefits of MHT are most likely to outweigh any risk and can be considered as first-line therapy in postmenopausal osteoporosis, based on the International Menopause Society (IMS) recommendations on women’s midlife health and menopause hormone therapy.(28) On the contrary, the North American papers, the American Association of Clinical Endocrinologists/American College of Endocrinology Clinical Practice Guidelines (AACE/ ACE) for Diagnosis and Treatment of Postmenopausal Osteoporosis 2020 stated that estrogen was never specifically approved for postmenopausal osteoporosis. Estrogen is only approved by the US FDA for prevention of postmenopausal osteoporosis and should only be used for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered to be appropriate. (29)
Finally, due to possible effects of participant age on baseline bone turnover marker levels, we made additional analysis of the correlation between age and bone turnover markers. However, there was no significant correlation between the serum CTX and age at surgical menopause in both hormone treatment and no treatment group, r = 0.28 p-value = 0.22, and r = 0.14 and p-value = 0.56, respectively. In the same way, there were no significant correlations between serum P1NP and age at surgical menopause in both hormone treatment and no treatment group, r = -0.01 p-value = 0.97 and r = 0.08 p- value = 0.72, respectively.
There were many strengths and limitations of this study. This was a prospective trial that enrolled pre and perimenopausal women at the time before the surgically induced menopause. Participants were separately assigned into the hormonal and no treatment group based on currently approved MHT indications. In term of outcome measurements, we chose serum CTX and P1NP as outcomes according to the recommendation from IOF and IFCC. However, there are many limitations of bone turnover markers interpretation in clinical practices. The biologically interobserver variation, analytic reliability, and poorly defined abnormal cut point levels are issues of concern in clinical utility. Moreover, the changes of the bone turnover markers are only representative of bone metabolism, it cannot be used for diagnosing osteoporosis. Dual-energy X-ray absorptiometry for bone density measurement is the standard method for using in both clinical practice and the majority of osteoporosis researches. Nowadays, bone turnover markers are primarily be used for patient with poor responders, nonadherence to therapy patient identification, (30) and can be used as one of the indicators to restart of treatment after the bisphosphonate drug holiday period. (31)
On other hands, this is a nonrandomized trial so we could not match the baseline prognostic factors between the two groups. The serum vitamin D level, which may affect to bone turnover was not be measured in this study, but calcium carbonate 1000 milligrams per day and vitamin D2 (ergocalciferol) 20,000 unit per week were prescribed to all participants in this study.