Hormonal Stabilization of the Bone-Metabolic Environment: Implications for Anterior Cruciate Ligament Integrity and Bone-Graft Integration

GRAPHICAL ABSTRACT

The female musculoskeletal system functions as a highly dynamic metabolic environment rather than a static anatomical frame. A critical challenge in sports medicine remains the disproportional incidence of anterior cruciate ligament (ACL) injuries in female athletes, which occurs at rates reaching up to eightfold those observed in their male counterparts. While biomechanical factors are traditionally emphasized, research increasingly highlights an underlying “hormonal window” of vulnerability during the menstrual cycle.[1] Bone and soft tissue operate as interlinked endocrine organs. The surge of 17β-estradiol during the late follicular phase serves as a potent proteolytic trigger that alters the structural integrity of the ACL. Furthermore, the hormone relaxin plays a synergistic role in this metabolic flux; by binding to specific receptors on the ACL, relaxin facilitates the degradation of the collagenous extracellular matrix, significantly increasing joint laxity and subsequent injury risk.[2] In this communication, it is argued that the orthopedic community must bridge the gap between surgical technique and endocrine health by implementing targeted prevention strategies. It is being investigated exactly how oral contraceptive therapy (OCT) can serve as a “metabolic stabilizer” to mitigate these hormonal surges, thereby improving both primary injury prevention and post-surgical graft prognosis.

Menstrual cycle and ACL rupture incidence

The ACL rupture might be the best investigated of all sex associated sport injuries. Thus, many studies have investigated if the occurrence of ACL ruptures is related to the hormonal status and hence changes between the follicular, ovulatory and luteal phase of the menstrual cycle. Several reviews and meta-analyses have since concluded that there is a decreased relative risk of an ACL tear in the luteal phase and that female athletes are more predisposed to ACL ruptures during the preovulatory phase of the menstrual cycle. The finding that there is an association of ACL ruptures with the preovulatory phase, as detected in a study describing the prevalence of ACL ruptures along the menstrual cycle during skiing, might allow some general recommendations such as “Female skiers should take special care during this period”.[3]

The collagen-metabolic axis: estrogen as a proteolytic trigger

The human ACL is populated with estrogen receptors. When estrogen levels spike during ovulation, it triggers a cascade of collagen remodeling that affects mechanical properties. A time delay of 2 to 3 days could be identified between the estrogen surges and increases in knee laxity, indicating towards the days that present the highest risk of injury due to ligaments being unable to tolerate normal loads. To expand on this, specific to cruciate ligament stability, increasing estrogen concentrations are coupled with reduced tensile stress and linear stiffness.[4]

The RANKL/OPG pathway and bone-graft integration

The success of an ACL reconstruction depends on “ligamentization” and successful integration into the bone tunnels. During this period, the initially disorganized collagen fibers and extracellular matrix undergo maturation and reorganization to form a structure that closely resembles a native ligament.[5] This is a highly metabolic process governed by the receptor activator of nuclear factor-κB ligand (RANKL)/osteoprotegerin (OPG) pathway, as well as changes in bone morphogenetic protein (BMP)-2 and BMP-7, which are involved in osteogenesis and osteoblast differentiation. For example, in this study deduced by Starlinger et al. [6], age and sex greatly influenced preoperative serum levels of OPG and soluble RANKL (sRANKL), but differences were even more pronounced during fracture healing. Statistical significance was observed for overall serum levels of OPG (P=0.001) and sRANKL (P<0.001) in older men and women (age greater than 50 years). Interestingly, OPG levels increased over time in older women but decreased over time in older men. The data demonstrated that nonosteogenic factors, most significantly age and female sex, have a major impact on sRANKL and OPG levels which, due to the hormonal changes women experience throught their lives.[6]

Molecular mechanisms of laxity

Estrogen binds to these receptors on ACL fibroblasts, stimulating the expression of matrix metalloproteinases (MMPs), particularly MMP-1, MMP-3, and MMP-13, along with other metalloproteinases. These enzymes are responsible for the degradation of type I collagen, the primary structural component of the ligament. In naturally cycling women, this leads to a transient decrease in ligamentous stiffness. Without cytokine stimulation, the secretion of MMP-1 was significantly reduced by 50 pg/mL of 17β-estradiol (in immunoblot by a median of 12.3%, P=0.007; in enzyme-linked immunosorbent assay (ELISA) by a median of 18.4%, P=0.001), and 500 pg/mL (in immunoblot by a median of 23.1%, P=0.001; in ELISA by a median of 21.0%, P=0.001). [7] Clinical studies demonstrating the changes in the stability of the knee have indicated a significantly higher incidence of genu recurvatum and general joint laxity during the late follicular and ovulatory phases.[8]

The possible OCT intervention

By delivering a steady dose of synthetic ethinyl estradiol and progestin, OCT suppresses endogenous hormonal peaks. This “flattens” the metabolic profile of the ligament throughout the cycle. Based on the data of Moriceau et al. [9], OCT decreased the laxity of the ACL, making the anterior tibial translation weaker and decreasing the levels of relaxin, which appears to decrease the possibility of an ACL tear.[9] Without the ovulatory spike, MMP activity remains baseline and the structural stiffness of the ACL is maintained consistently. For the orthopedic surgeon, this translates to a patient with a more predictable and stable joint profile during and after surgery. In a recent study performed by Fry et al. [10], the 2,120,628 female patients in the systemic hormonal contraceptive use group had a lower incidence of ACL injury (0.079%; 95% confidence interval [CI], 0.075%–0.083%) than the 12,766,138 female patients in the noncontraceptive use group (0.12%; 95% CI, 0.118%–0.121%).

The pro-anabolic environment of OCT

OCT has been associated with a more favorable OPG to RANKL ratio. In women using oral contraceptives, OPG serum levels were significantly higher (2.71 +/− 1.42 pmol/L) compared to nonusers (1.35 +/− 1.02 pmol/L; P=0.0003), whereas free (P=0.55) and total (P=0.24) sRANKL serum levels did not differ between both groups. This resulted in an increased OPG/free sRANKL OPG acts as a decoy receptor, binding to RANKL and preventing it from activating osteoclasts. By maintaining a stable, pro-anabolic environment, OCT may facilitate reduced tunnel widening by minimizing peri-tunnel bone resorption.[11]

The role of estrogen on muscle, tendon and ligament health

While the ovulatory spike is detrimental to ligaments, baseline estrogen is inherently anti-inflammatory and muscle-protective. Beyond the known relationship between estrogen and bone, it directly affects the structure and function of other musculoskeletal tissues such as muscle, tendon, and ligament. Meta-analysis covered by Chidi-Ogbolu and Baar [12] make it clear that estrogen improves muscle proteostasis and increases collagen content. For example, in professional soccer, women suffer 54% fewer muscle strains than their male counterparts. The majority of the benefit results from decreases in groin (83% fewer) and hamstring (36% fewer) pulls. A decrease in tendon stiffness could also leave the tendon less prone to injury. However, the benefits on bone and muscle come at the cost of decreased connective tissue stiffness. Evolutionarily, this makes sense since laxer joints and better repair following injury facilitate childbirth and recovery afterwards. As more women participate in sports, it is clear that these physiological effects of estrogen contribute to decreases in power and performance and make women more prone for catastrophic ligament injury.[12]

Strengths and limitations of the study

Strengths

This proposal bridges the gap between surgical technique and endocrine biology, offering a systemic approach to a traditionally mechanical problem. It utilizes large-scale clinical data and molecular evidence to support hormonal stabilization.

Limitations

The recommendation for OCT must be balanced against individual patient contraindications for hormonal therapy. Additionally, while the “hormonal window” is well-defined, individual variability in cycle length and hormone concentration requires personalized assessment.

The disproportionate incidence of ACL injuries in female athletes might present a biological consequence of a “hormonal window” of vulnerability. Estrogen and relaxin surges during the late follicular and ovulatory phases act as proteolytic triggers, stimulating MMPs that degrade Type I collagen and increase joint laxity. Furthermore, the RANKL/OPG pathway, which governs graft “ligamentization” and bone-tunnel integration, remains sensitive to these cyclic fluctuations.

OCT serves as a critical “metabolic stabilizer” by suppressing these hormonal peaks and promoting a consistent, pro-anabolic environment. This stabilization leads to a more predictable joint profile and a significantly lower incidence of ACL injuries among users. Ultimately, the orthopedic community must bridge the gap between surgical technique and endocrine health to optimize injury prevention and post-surgical outcomes.