The postmenopausal decline in estrogen reflects follicular depletion and age-related changes in granulosa-cell function and intraovarian signaling. The central feature of ovarian ageing is the irreversible reduction of the primordial follicular pool. As the number of follicles decreases to a critical threshold (<1,000), the level of estradiol (E2) secreted by the granulosa cells declines precipitously, and the serum E2 concentration in postmenopausal women is usually less than 20 pg/ml (22). Granulosa cells are the main functional unit of estrogen synthesis. Using single-nuclei multi-omics analyses, Jin et al (21) found that the abundance of granulosa cells in human aging ovaries was reduced compared with that in young ovaries and that the expression of apoptosis-related genes in granulosa cells was increased. Further studies revealed that this is mainly due to CCAAT/enhancer-binding protein delta (CEBPD)-mediated regulation of senescence genes (21) and mechanistic target of rapamycin (mTOR) signaling (23) leading to an ovarian-specific senescence pathway. In addition to a decrease in granulosa cell number, aging also leads to granulosa cell dysfunction and impaired estrogen synthesis. In a single-cell study of goat ovarian aging, Xu et al (24) identified pseudotime-dependent changes in hydroxysteroid 17-beta dehydrogenase 1 (HSD17B1) expression in granulosa cells. These findings suggest altered steroidogenic regulation but do not establish HSD17B1 as a causal driver of estrogen decline in human menopause. The expression level of circular RNA DDX10 (circDDX10) gradually decreased with age, inhibiting the expression of factors related to steroid hormone synthesis in ovarian granulosa cells, leading to insufficient estrogen secretion in the aged ovary (25). Aging also alters cellular communication, with FSH and growth differentiation factor (GDF) signaling depleted in aged granulosa cells and oocytes, reducing the ovarian regulatory effects of gonadotropins (21). New research found that changes in ovarian follicular fluid (FF) cytokine profiles and hormone profiles during the natural human physiological cycle are age-related and independent of endogenous gonadotropin regulation, with interleukin (IL)-2 and IL-12 in FF correlating with E2 and estrone (E1) in FF in young women (26).

Hormonal changes in menopausal women include a decrease in estrogen and a corresponding change in FSH. Elevated FSH concentrations during the menopausal transition were documented as early as 1975 (27). This phenomenon is highly correlated with the decrease in estrogen during menopause (28). Follicular depletion reduces ovarian estrogen and inhibin feedback to the hypothalamic-pituitary system, thereby increasing pituitary FSH secretion (28,29). Epidemiological analyses indicate that hormonal shifts characterized by declining E2 and elevated FSH are strongly associated with reduced BMD and increased risk of osteopenia and osteoporosis in postmenopausal populations (30).

OT is a neuropeptide primarily produced by neurons in the hypothalamus. Lower circulating OT concentrations have been reported in some postmenopausal populations (31). The underlying mechanisms for this decline may include changes in sexual activity, decreased vagal activity, and lower levels of estrogen (32).

PTH concentrations may increase with aging and disturbances in calcium and vitamin D homeostasis, but secondary hyperparathyroidism is not an inevitable consequence of menopause (33). Eastell et al (33) found a 35% increase in PTH with age by collecting blood and testing serum PTH in 51 healthy women between the ages of 26 and 88 years (P<0.02).

CT inhibits osteoclast-mediated bone resorption, but the pattern and skeletal significance of circulating CT changes after menopause remain less well established than those of estrogen deficiency. Age-related changes in thyroid C cells have been reported in male rats, and estrogen-responsive CT secretion has been demonstrated in fish; these findings cannot be directly extrapolated to postmenopausal women (34,35). Accordingly, a consistent menopause-related decline in CT should not be assumed.

Vitamin D synthesis and metabolism can be used to regulate calcium, phosphorus, and bone metabolism, with regulation of the efficiency of intestinal calcium absorption by its active form, 1,25-dihydroxyvitamin D [1,25(OH)₂D], being the most important function (36). A cross-sectional National Health and Nutrition Examination Survey (NHANES) analysis examined associations between vitamin D status and menopausal timing, but it did not establish that vitamin D deficiency causes earlier menopause (37). Vitamin D status remains relevant to calcium homeostasis and skeletal health after menopause (38). Unfortunately, vitamin D deficiency is very common in menopausal women. Vitamin D deficiency in menopausal women may have several contributing factors. First, aging reduces 7-dehydrocholesterol (7-DHC), the precursor for vitamin D₃ synthesis (39). Reduced sun exposure may contribute to low vitamin D status, although exposure patterns vary among populations (40). In addition, vitamin D transport relies on vitamin D binding protein (DBP) and albumin, whose levels can be influenced by the lower estrogen levels typical of menopause (41). The detailed mechanisms underlying the various hormonal changes that occur in postmenopausal women are shown in Fig. 1.

Using NHANES data (1999-2002), Liu et al (80) analyzed serum FSH associations with lumbar spine and femoral neck BMD in women aged 35-60. They found a significant non-linear inverse association between serum FSH and lumbar spine BMD exclusively in postmenopausal women (P for non-linearity=0.013), and a comparable link between FSH and osteoporosis risk (P=0.05) (80). Zheng et al (81) identified follitropin subunit beta among proteins with high importance in a multivariable predictive model. Predictive importance does not establish a causal skeletal effect of circulating FSH. Mechanistically, FSH binds to the FSH receptor (FSHR) and activates G protein/CCAAT/enhancer-binding protein β signaling in adipocytes, which promotes heat shock protein 90α (HSP90α) secretion. Increased extracellular HSP90α subsequently enhances osteoclast activity and may contribute to increased bone resorption (82). Although observational and genetic analyses support an association between elevated FSH and bone loss, direct human interventional evidence is still lacking. Most mechanistic evidence remains experimental; therefore, the causal skeletal effect of elevated FSH in humans has not yet been established and requires further longitudinal and interventional validation.

Indeed, OT receptors are widely present on bone tissue and OT regulates bone remodeling by binding to OT receptors on osteoblasts and osteoclasts (83). In normal conditions, E2 triggers the mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) pathway and OT receptor expression in osteoblasts, boosting OT production. OT then upregulates BMP2 and activating transcription factor 4 promoting osteoblast differentiation and function and forming a synergistic feed-forward loop (15). Reduced estrogen signaling may weaken this feed-forward loop, although its contribution to skeletal outcomes after menopause remains to be established (15). OT has distinct effects on osteoclast formation and mature cell resorptive activity. In experimental models, OT promotes osteoclastogenesis directly and indirectly, including through increased RANKL and reduced OPG expression in osteoblasts. Conversely, OT can suppress resorption by mature osteoclasts through intracellular Ca²⁺ release and nitric oxide synthesis (84). These stage- and cell-dependent effects help explain why changes in osteoclast number do not necessarily translate into equivalent changes in bone resorption; the net therapeutic effect in postmenopausal women remains unproven.

In human studies, Du et al (85) linked OT to bone mass (β=0.59, P=0.044) and after age adjustment, to osteoporosis risk (OR: 0.75; 95% CI: 0.63-0.98; P=0.019) in a cross-sectional study of healthy community dwelling postmenopausal women aged 50-90. In an ovariectomized rat model, OT attenuated bone loss and altered bone-turnover markers and OPG/RANKL mRNA expression (86). Thus, current human evidence supports an association between OT and skeletal status but does not yet establish the therapeutic efficacy of OT supplementation.

PTH is a key regulator of bone remodeling and exhibits context-dependent effects on skeletal homeostasis. At the cellular level, PTH promotes bone formation by enhancing osteoblast precursor differentiation, inhibiting osteoblast apoptosis, and suppressing sclerostin production, a negative regulator of bone formation (87). However, prolonged elevation of PTH can shift bone remodeling toward resorption by stimulating osteoblast- and osteocyte-derived RANKL expression and reducing OPG production, thereby promoting osteoclast differentiation. By contrast, intermittent PTH stimulation used in anabolic therapies preferentially enhances osteoblast activity and bone formation (16). In experimental models, PTH reduced miR-19a/b expression, while antagonizing miR-19a/b increased its target TG-interacting factor 1 (Tgif1) and augmented PTH-induced bone gain (88). Apart from the direct effects of PTH, genetic polymorphisms in the patient's own PTH and PTH 1 receptor (PTHR1) genes also influence susceptibility to osteoporosis in menopausal women. By analyzing case-control genetic associations in a cohort of South Indian women, Fernandez et al (89) revealed lower heel BMD in women with osteoporosis who had the BstBI-AA recessive genotype. On the other hand, Abdi et al (90) selected Arab women as their subjects and discovered that the PTHR1 single-nucleotide polymorphism rs1138518 C/T genotype serves as a risk factor for osteoporosis in postmenopausal women. Furthermore, it was observed that the C/T and T/T genotypes are associated with different outcomes in 25-hydroxyvitamin D [25(OH)D] levels, suggesting that PTHR1 rs1138518 may play a regulatory role in modulating 25(OH)D levels (90). These population-specific genetic associations require replication and do not establish a functional mechanism or a clinically validated prediction tool.

CT suppresses osteoclast-mediated bone resorption, which can be reflected by reduced urinary hydroxyproline excretion (91). For osteoclasts, CT rapidly disrupts the osteoclast ruffled border, inhibits osteoclast motility and promotes detachment from bone (18). Although CT has a well-established role in regulating osteoclasts, its effects on osteoblasts remain debated. Naot et al (92) reported the absence of CT receptors in osteoblasts, whereas Farley et al (93) demonstrated CT-mediated promotion of osteoblast proliferation. By contrast, Cornish et al (94) showed no increase in mineralized bone area following CT treatment in mice. These studies examined different models and endpoints, including receptor expression, cell proliferation and mineralized bone area, which are not interchangeable measures of a direct osteoanabolic effect. This discrepancy may arise from differences in CT concentrations and incubation durations between studies, highlighting the need for concentration- and time-dependent gradient experiments to characterize CT effects on osteoblasts. Several investigations indicate that CT primarily acts by inhibiting osteoclast activity, thereby altering the coupling signals between osteoclasts and osteoblasts rather than directly stimulating osteoblast proliferation (92).

However, although CT has well-established inhibitory effects on osteoclast-mediated bone resorption, its clinical efficacy in the treatment of osteoporosis in humans appears to be relatively limited. Randomized controlled trials (RCTs) have shown that intranasal salmon CT (sCT) can reduce the risk of vertebral fractures, but it does not significantly decrease the incidence of non-vertebral or hip fractures (95). Accordingly, most current clinical guidelines no longer recommend CT as a first-line therapy for PMO. These findings suggest that although CT plays an important role in the regulation of bone metabolism, its clinical utility in the treatment of osteoporosis remains limited and warrants further investigation. Clarifying the cellular targets and signaling mechanisms of CT will be important for determining its therapeutic relevance in PMO.

Vitamin D, a fat-soluble vitamin, is crucial for bone metabolism as it enhances intestinal calcium absorption. Chen et al (96) investigated the association between vitamin D levels and BMD, bone turnover markers (BTMs), as well as PTH in 8,532 Chinese postmenopausal women. Vitamin D deficiency or insufficiency was present in ~81% of the study population (96). In osteoporotic patients, higher vitamin D levels were positively correlated with BMD at all measured sites and negatively correlated with BTMs, including β-C-terminal telopeptide of type I collagen (β-CTX) and OCN, as well as with PTH levels (96). In line with this result, the study by Al-Rawaf et al (97) also identified vitamin D as a key predictor of osteoporosis in postmenopausal women. Current evidence links vitamin D to osteoporosis through three key mechanisms: Regulation of calcium-phosphorus homeostasis (17), immune-mediated modulation of pro-inflammatory cytokine production (17), and vitamin D receptor gene polymorphisms that influence susceptibility to the disease (98). Selected skeletal actions of FSH, OT, PTH, CT and vitamin D are summarized in Fig. 3. The regulatory effects of different hormones and their receptors on postmenopausal bone loss are summarized in Table I.

To integrate the aforementioned hormone-specific evidence, postmenopausal endocrine remodeling can be considered at three analytically distinct but interacting levels. At the upstream level, ovarian aging and the loss of estrogenic feedback establish the endocrine context of menopause. At an intermediate level, alterations involving FSH, the PTH-vitamin D axis, OT and CT modify systemic and local skeletal regulation. At the effector level, these endocrine signals converge on the basic multicellular unit, osteoimmune pathways, calcium homeostasis, and the gut-bone axis, ultimately disturbing osteoblast-osteoclast coupling and favoring net bone loss. This hierarchy should be regarded as an integrative conceptual framework rather than a strictly linear cascade, because several components are linked through feedback loops and the strength of evidence differs among individual pathways. Within this framework, the decline in estrogen is widely regarded as the key endocrine event. Under physiological conditions, estrogen provides negative feedback to the pituitary and helps regulate gonadotropin secretion. With progressive ovarian insufficiency and the accompanying fall in estrogen levels, this feedback regulation becomes attenuated, leading to a pronounced rise in FSH (99). As a result, in the postmenopausal state, reduced estrogen and elevated FSH may jointly influence bone cells and favor a shift in bone remodeling toward increased bone resorption.

In addition, alterations in estrogen levels also disturb the balance among calcium-regulating hormones. Reduced calcium absorption and low vitamin D status may contribute to compensatory PTH elevation, particularly with aging (33,100,101). At the same time, vitamin D metabolism is influenced by both aging and changes in estrogen status. Insufficient vitamin D further impairs intestinal calcium absorption and stimulates compensatory PTH secretion, forming a vitamin D-PTH regulatory loop that ultimately contributes to accelerated bone loss (100,101). At the cellular level, PTH and 1,25(OH)₂D₃ can also increase RANKL expression in osteoblasts, thereby linking hormonal changes to osteoblast-osteoclast communication within the BMU. Vitamin D-related signaling can further stimulate osteoblast-derived VEGF, providing a link between bone formation and vascular regulation (43). Beyond the classical endocrine axes, several neuroendocrine factors also participate in this regulatory network. For instance, estrogen has been shown to regulate the synthesis of OT and the expression of its receptor. Consequently, the postmenopausal decline in estrogen may indirectly weaken the protective effects of OT on bone tissue (102). These interactions illustrate how distinct endocrine changes can converge on shared skeletal regulatory pathways. However, the strength of supporting evidence differs among individual pathways; the major hormone-related findings are therefore summarized according to their evidence types in Table II.

In 2002, the WHI found that the use of combined conjugated equine estrogen and medroxyprogesterone acetate regimens, aimed at improving osteoporosis, led to an elevated risk of cardiovascular events and an increased risk of breast cancer (12). This puts the use of HRT in the limelight. In fact, HRT components are primarily estrogens and/or progestins and are primarily used to treat perimenopausal and early menopausal vasomotor symptoms. Systemic hormone therapy may prevent bone loss in appropriately selected postmenopausal women, with formulation, route, and duration individualized according to menopausal symptoms and the benefit-risk profile (103). Stevenson et al (104) employed two HRT regimens. The first regimen consisted of 1 mg of 17β-estradiol and either 5 or 10 mg of dydrogesterone administered daily for 14 consecutive days, with a 28-day cycle. The second regimen involved 2 mg of 17β-estradiol and either 10 or 20 mg of dydrogesterone given daily for 14 consecutive days, also with a 28-day cycle. They found that, compared with baseline, HRT significantly increased total disc height in both the 1-mg E2 group (0.16±0.65 cm, P=0.015) and the 2-mg E2 group (0.21±0.86 cm, P=0.006). However, between-group differences were not statistically significant, and this analysis did not directly establish a reduction in fracture risk (104). Gamsjaeger et al (105) administered a combination of 2 mg E2 and 1 mg norethindrone acetate to postmenopausal women over a two-year period. They observed that HRT with this regimen altered osteoid composition and mineralization-related characteristics (105). The 2022 North American Menopause Society (NAMS) position statement emphasizes that the benefit-risk profile of HRT is generally more favorable in healthy women younger than 60 years or within 10 years of menopause onset (103). By contrast, initiation at an older age or more than 10 years after menopause is associated with higher absolute risks of coronary heart disease, stroke and venous thromboembolism. Risk also varies according to the route and regimen of treatment. Oral estrogen is associated with a higher risk of venous thromboembolism than transdermal estrogen, although direct comparative RCT evidence remains limited. Breast cancer risk also differs according to the type and duration of hormone therapy (106-108). Systemic HRT is generally avoided in women with estrogen-sensitive malignancies, unexplained vaginal bleeding, active liver disease, previous venous thromboembolism, or established cardiovascular disease. Therefore, treatment should be individualized according to age, time since menopause, route of administration, and baseline risk profile (103).

Recent studies continue to refine the evidence base for hormone therapy in PMO. A reanalysis of the WHI randomized trials reported fracture-risk reductions across baseline risk strata (109). Separately, a 2025 nested case-control study examined fracture risk after discontinuation of menopausal hormone therapy (110). Additionally, emerging evidence suggests that combining HRT with structured exercise can further enhance BMD (111). Contemporary analyses also highlight that the risk profile of HRT varies with formulation and route, with observational evidence suggesting lower venous thromboembolic risk with transdermal than oral estrogen (108,112). In summary, the individual benefit risk balance of HRT hinges on the type, dose and duration of HRT, along with each woman's unique characteristics. Further studies are required to investigate these variables comprehensively.

Beyond the aforementioned HRT and non-HRT pharmacological treatments, non-pharmacological approaches play a crucial role in preventing and ameliorating PMO. Lifestyle measures include smoking cessation, avoidance of excessive alcohol intake, adequate nutrition, and weight-bearing, resistance, and balance exercise adapted to individual fracture risk and physical capacity (4,128). In addition to its effects on skeletal loading, regular exercise can help preserve muscle function and physical performance, which are important components of fall and fracture prevention (4). An updated systematic review and meta-analysis of 80 controlled studies involving 5,581 postmenopausal women further demonstrated beneficial effects of exercise on BMD at the lumbar spine, femoral neck and total hip (128). Besides lifestyle modifications, adequate calcium and vitamin D intake is also advantageous. Calcium and vitamin D intake should follow applicable guidance and individual assessment. For example, the Bone Health and Osteoporosis Foundation recommends a total calcium intake of 1,200 mg/day for women aged 51 years or older and vitamin D supplementation of 800-1,000 IU/day when needed (4). Treatment of established vitamin D deficiency should be individualized rather than equated with routine maintenance supplementation. Together, these lifestyle and nutritional measures should be considered integral components of comprehensive osteoporosis management and are generally used alongside pharmacological therapy in women at elevated fracture risk (4). The representative mechanisms, clinical efficacy, and key limitations of current therapeutic strategies for PMO are summarized in Table III.

Despite their established clinical utility, current therapeutic strategies are constrained by patient-specific safety considerations, limitations of long-term treatment, discontinuation-related effects, or incomplete applicability across different risk groups. Together with increasing recognition of the broader endocrine remodeling that accompanies menopause, these limitations provide a rationale for exploring complementary strategies that target additional hormone-related pathways and mechanisms of bone loss.

As aforementioned, HRT is effective in preventing and alleviating PMO, but the long-term use of estrogen- and progestin-based regimens may be associated with adverse effects. This has prompted increasing interest in natural bioactive compounds as potential complementary strategies for modulating bone remodeling. Some natural bioactive compounds have been reported to exert both pro-anabolic and antiresorptive effects by supporting osteoblast function and suppressing osteoclast activity, with additional mechanisms involving estrogen-like, anti-inflammatory, antioxidant and bone signaling effects (129). Recent experimental evidence supports this dual regulatory concept. In 2024, a formononetin-derived phytoestrogen was shown to promote osteoblast formation through BMP/Smad signaling while simultaneously inhibiting RANKL-induced osteoclastogenesis through regulation of the RANK/RANKL/OPG axis in vitro and in an ovariectomized mouse model (130). Additionally, several ER-targeted plant-derived compounds have also shown potential osteoprotective effects. Chen et al (131) generated a PMO rat model through ovariectomy. Subsequently, upon administering Secoisolariciresinol diglucoside (SDG) to the rats, it was observed that SDG regulated the expression of E2 and ER. This regulation led to a reduction in injury and inflammation, and an improvement in bone formation indices (131). Hyperoside, a flavonoid constituent of Cuscutae Semen, has shown osteoprotective effects in OVX mice through the ERα/integrin β3 (ITGβ3) signaling pathway (132). Siwu decoction (SWD), composed of Rehmannia glutinosa (Gaertn.) DC., Angelica sinensis (Oliv.) Diels, Paeonia lactiflora Pall., and Ligusticum striatum DC., has been investigated for its potential effects on PMO. Network pharmacology identified the ER/phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) pathway as a potential mechanism, which was subsequently examined in both in vivo and in vitro experiments (133). Although the aforementioned specific ER-targeted plant-derived compounds are supported predominantly by preclinical evidence, the clinical evidence is not uniform across all classes of phytoestrogens. A 2024 systematic review and meta-analysis of 63 RCTs reported that isoflavone interventions were associated with improvements in BMD at the lumbar spine, femoral neck and distal radius in postmenopausal women (134). However, these findings cannot be directly extrapolated to compounds such as SDG, hyperoside, or SWD, for which robust randomized clinical evidence and long-term safety data remain limited.

FSH-targeted approaches have been investigated experimentally, although the direct skeletal contribution of FSH in humans remains unresolved (135). In 2022, Gera et al (136) developed a humanized epitope specific FSH blocking antibody, designated as MS-Hu6. They reported on the efficacy of MS-Hu6 in preventing and treating osteoporosis in mice, along with safety parameters from monkey experiments. These preclinical findings support further evaluation of MS-Hu6 for the treatment of PMO. Ning et al (137) reported that knockdown of the long non-coding RNA designated MRF enhanced BMSC osteogenic differentiation and bone-defect repair through FSHR-associated cyclic adenosine monophosphate (cAMP)/protein kinase A (PKA)/cAMP response element-binding protein signaling. This identifies MRF as an experimental regulatory target, but it does not establish that MRF inhibition is equivalent to systemic FSH blockade or that it is an effective treatment for PMO. Although preclinical studies of the FSH-blocking antibody MS-Hu6 have shown both preventive and therapeutic effects in animal models, its translation to humans requires further investigation. Key issues, including long-term safety, immunogenicity, optimal dosing and cost-effectiveness, remain unresolved. The cited study provides preclinical evidence and does not establish antifracture efficacy or long-term safety in humans (136).

Lower circulating OT concentrations have been associated with skeletal outcomes in some postmenopausal populations (85). Exogenous OT supplementation has been shown to exert anti-osteoporotic effects in OVX rats (86). A 2022 study in senescent female rats further examined the effects of OT on bone remodeling (138). Although animal studies have shown osteoprotective effects of OT, human evidence remains largely observational. A recent systematic review similarly found that intervention evidence is dominated by animal studies, whereas human studies mainly report associations between circulating OT and skeletal outcomes; clinical trials are still needed to establish therapeutic efficacy and optimal dosing (139). Well-designed, large-scale RCTs are therefore needed to clarify the appropriate dose, long-term safety, and its efficacy compared with established anti-osteoporotic treatments.

Anabolic treatment is generally followed by antiresorptive therapy to preserve skeletal gains (115). Treatment duration should follow agent-specific and jurisdiction-specific recommendations; teriparatide use beyond two years is reserved under US labeling for patients who remain at or return to high fracture risk (116). This clinical context provides the impetus for the current studies, which aim to investigate the advantages of PTH combination therapy in postmenopausal women with osteoporosis. Wei et al (140) reported that, following six months of treatment of patients with PMO with teriparatide alone or a combination of teriparatide and zoledronic acid, visual analogue scale (VAS) scores, along with serum levels of osteopontin (OPN) and C-terminal telopeptide of type I collagen (S-CTX), were significantly lower in the combination-treatment group compared with the teriparatide-monotherapy group (VAS: P=0.001; OPN: P<0.001; S-CTX: P<0.001) (140). Compared with vitamin K2 alone, combined recombinant human PTH (1-34) [rhPTH(1-34)] and vitamin K2 improved BMD and selected bone-turnover markers in a small, randomized study (141). This comparison does not establish the additional benefit of vitamin K2 over PTH monotherapy. These results should not be interpreted as established superiority for fracture prevention without adequately powered comparative trials.

sCT, a peptide hormone, exhibits clinical efficacy in inhibiting osteoclast activity, thereby regulating bone metabolism. A meta-analysis reported changes in selected biochemical outcomes with intranasal sCT but did not establish clear superiority for BMD outcomes or for combination treatment over conventional therapy alone (142). Furthermore, sCT is susceptible to rapid degradation, attributed to its short half-life and inherent instability. This characteristic substantially restricts its clinical utility. Zhang et al (143) engineered a microsphere formulation for encapsulating sCT. This innovation has achieved a decrease in the dosing frequency and an extension of the sustained-release duration, suggesting that this formulation may improve sCT delivery for PMO treatment (143). Formulation improvements do not establish superior antifracture efficacy. CT has a limited role in contemporary osteoporosis management and is generally considered only when more effective alternatives are unsuitable (115).