The present investigation showed a significant elevation of bone turnover markers in surgically menopausal women who did not receive estrogen treatment. Despite a short period, an asymptomatic but significantly high bone resorption process occurred within 3 months after surgery.

Bone remodeling consists of two opposing activities: resorption of old bone by osteoclasts and formation of new bone by osteoblasts. The functions of bone remodeling are replacing old bone, regulating calcium homeostasis, acidbase balance, and releasing growth factors embedded in bone. The bone remodeling process is tightly coupled in time and area at the bone basic multicellular unit (BMU) level [25]. Bone turnover markers release into the bloodstream during the bone remodeling process and provide dynamic information regarding skeletal status.

During bone resorption, collagen is degraded by osteoclasts. CTX, a non-helical fragment of type I collagen-containing cross-linking regions, is released by cathepsin K, an osteoclast-specific protease. The native form of CTX undergoes spontaneous isomerization, which is attributed to protein aging [26]. They circulate in the blood and are partly excreted in the urine. Bone resorption displays circadian variation. CTX shows the highest diurnal amplitude among the BTMs with a peak at 05.00h and a nadir at 14.00h. Consumption of breakfast reduces serum CTX by 40% [25]. The secretion of the glucagon-like peptide probably mediates this effect of feeding [27]. Therefore, blood for its measurement must be collected in the fasting status in the morning (between 7 and 10 am). It is inadvisable for some patients (such as those with diabetes) in clinical practice and restricts clinic attendance to morning appointments.

Surgical removal of both ovaries in women before menopause leads to an abrupt declination of circulating estrogen levels [6]. From a previous study, serum CTX was elevated as soon as a month after surgery. Serum CTX levels were continuously elevated until 6 months after surgery. Furthermore, they found a significant negative correlation between 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 raised 3 months after the surgical menopause procedure. However, bone markers levels declined to the baseline levels after menopausal hormone prescription for 3 months [23].

In terms of bone formation marker, we selected serum P1NP as the outcome measurement according to the IOF recommendation. Osteoid, composed of type I collagen, is formed in the early phase of bone formation. Procollagen is a trimer of two 1 and one 2 chain. The PINP is cleaved from procollagen molecule before an assembly of type I collagen molecules into fibers [28]. Although type I collagen is not specific to the bone, most circulating PINP originates from it. P1NP is released into circulation and offers several clinical advantages, including low circadian variation and stability at room temperature. Moreover, P1NP levels are not significantly influenced by dietary intake, and, consequently, patients do not need to be fasting [27]. In a previous study, serum P1NP levels were inversely associated with BMD for the lumbar spine, total hip, and femoral neck even after controlling for age, BMI, and years since menopause. P1NP level was significantly higher in postmenopausal women with osteoporosis compared to those with average bone mass. However, in clinical practice, its low specificity does not warrant utility in osteoporosis diagnosis [29].

Estrogen is essential for the maintenance of sufficient bone mass in reproductive age. Bone resorption and formation were modulated and balanced by circulating estrogen levels. Estrogen activates the synthesis of osteoprotegerin (OPG), the decoy antibodies which neutralize the receptor activator of NF-B ligand (RANKL) and inhibits RANK expression (receptor of RANKL). Responses to estrogen result in inhibition of differentiation and activation of the osteoclasts. Furthermore, estrogen modulates proinflammatory cytokines such as IL-1, IL-6, TNF-, and PGE2, reducing the pool of osteoclast precursors. The minor estrogenic mechanism on bone is regulated TGF- expression results in apoptosis of osteoclasts [30]. According to all mechanisms mentioned above, estrogen deprivation is a major detrimental factor on bone physiology. Besides, many studies demonstrated the positive effects of menopausal hormone treatment on bone turnover markers, BMD, and fracture prevention in postmenopausal women [31,32,33,34].

As the primary outcome in the present study, there were no notable changes in serum CTX and P1NP levels at 12weeks in the hormone treatment group compared to baseline. In contrast, serum CTX and P1NP levels were significantly elevated among women who did not receive hormone treatment. In other words, early administration with moderate-dose estrogen could inhibit abnormal bone resorption from acute estrogen deprivation. In secondary outcomes, serum CTX and P1NP levels at 12weeks after surgical menopause procedure were statistically different between the two groups. The 55% lower median serum CTX level than in the no-treatment group is statistically and clinically significant. The timing of hormone initiation might be an essential issue. In our study, hormone therapy was initiated proximately 2 weeks after surgery. In contrast, Peris et al. study [23] started hormone therapy 3 months post-surgery. The differences between our outcomes and Peris et al.'s finding are partly 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 for improving the quality of life and protecting against accelerated bone loss. However, some clinicians may concern about the risk of venous thrombosis with MHT in the early postoperative period, especially in cases of obesity, metabolic syndrome, and advanced age patients. Transdermal estrogen administration with optimum dose is preferred to minimize the thrombosis risk in these patients.

In terms of treatment effects, we showed that early administration of 2mg of oral estradiol valerate significantly suppressed the bone remodeling process. However, a conclusion cannot be made for all oral MHT products in the market. Many available products around the world are 1mg of estradiol plus a variety of progestins. The lower dose of other estradiol products and estrogenic counter-action of various progestins may dramatically affect bone outcomes.

Each participant was evaluated and allocated to the hormone treatment group by FDA-approved MHT indication in the present study. Estradiol valerate 2mg/day was prescribed for 16 women who had moderate to severe hot flushes and five women diagnosed with early menopause at the time of surgery (age<45years). Although early menopause was associated with bone loss in general perception, there was no significant difference in bone turnover markers concentration across quartiles of patient age [29]. To the best of our knowledge, no study confirms a direct association between hot flush symptoms and bone turnover marker concentration. We attenuate selection bias risk by strictly allocating each participant to the hormone treatment group, depending on MHT indication. All participants and a physician assigned treatment did not know baseline bone turnover marker levels at the day of allocation.

Although elevation of bone turnover markers was associated with low BMD and increased risk of fractures, there are many limitations in interpreting bone turnover markers in clinical practices. The biologically interobserver variation, intra-individual variability, analytic reliability, and poorly defined abnormal cut point levels are issues of concern in clinical utility. Vitamin D levels, sunlight exposure, history of fractures over the preceding 12months, vigorous physical activity, and year should be considered and carefully considered for the interpretation of results. Moreover, the changes in the bone turnover markers are the only representative of bone metabolism; they cannot be used for diagnosing osteoporosis. Dual-energy X-ray absorptiometry for bone density measurement is the standard method used in clinical practice and osteoporosis research. Nowadays, bone turnover markers are primarily used for patients with poor responders, nonadherence to therapy patient identification [35], and can be used as indicators to restart treatment after the bisphosphonate drug holiday period [36].

There are incongruences in data interpretation and recommendations of estrogen therapy and bone, especially for postmenopausal osteoporosis. In the age group 5060years or within 10 years after menopause (the window of opportunity concept), the benefits of MHT are most likely to outweigh any risk. Based on the International Menopause Society (IMS) recommendations on women's midlife health and menopause hormone therapy, MHT can be considered first-line therapy in postmenopausal osteoporosis [37]. 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 approved explicitly for postmenopausal osteoporosis. Estrogen is only approved by the US FDA to prevent postmenopausal osteoporosis and should only be used for women at significant risk of osteoporosis and for whom non-estrogen medications are not considered appropriate [38].

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% [39], 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 significant potential benefits of salpingo-oophorectomy at the time of hysterectomy. 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 [39]. This research emphasized this concept. Forty-nine percent (20/41) of women in our cohort did not receive MHT for bothersome vasomotor symptoms and early menopause indication. These women lost their bone significantly as early as 3 months after surgery. Careful clinical evaluation, lifestyle modification for bone health, and long-term follow-up for bone density and/or quality measurement should be considered. In the present study, we gave patients as much information as possible about the 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 adequate information from physicians. In our experiences as a medical school center in Thailand, we found that 3040% of advanced age premenopausal and perimenopausal women accepted and decided 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.

Finally, due to the possible effects of participant age on baseline bone turnover marker levels, we made an 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 limitations of this study. As a nonrandomized design, we could not match the baseline prognostic factors between the two groups. This study type cannot eliminate selection bias. The randomized controlled trial to prove this hypothesis should be considered in further study. Because bone turnover markers can be involved by various factors, such as vitamin D status, sunlight exposure, vigorous physical activity, patient's medical data, and history of recent fractures should be recorded and carefully considered.

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