The research was motivated by a biological hypothesis that has been gaining traction over the past two decades: the existence of a bone-pancreas-testis axis. Osteocalcin, secreted by osteoblasts during bone remodeling, is not merely a marker of skeletal turnover. Animal studies have shown that the undercarboxylated, hormonally active form of osteocalcin stimulates insulin secretion by pancreatic beta cells and enhances insulin sensitivity in peripheral tissues. In parallel, osteocalcin appears to influence testosterone biosynthesis, acting on Leydig cells in the testes to promote production of the male sex hormone. Testosterone, in turn, supports bone mass in men by regulating osteoblast and osteoclast activity. If this feedback loop operates in humans as it does in mice, then a metabolic disturbance such as prediabetes could, in principle, ripple through the entire axis — altering insulin, sex hormones, and bone quality simultaneously.

To test that idea, the team recruited 65 men with prediabetes and compared them with 66 healthy controls who were carefully matched for age and body mass index, two variables that independently influence both glucose metabolism and skeletal health. Matching for BMI was a critical design choice, because adiposity confounds nearly every hormone measured in the study: fat tissue aromatizes testosterone into estrogen, drives chronic low-grade inflammation, and mechanically loads the skeleton in ways that stimulate bone formation. By holding age and BMI constant across groups, the investigators could more cleanly isolate the effects of dysglycemia itself. Blood samples were drawn to quantify serum insulin, osteocalcin, interleukin 6, C-reactive protein, follicle-stimulating hormone, luteinizing hormone, total testosterone, and dehydroepiandrosterone sulfate, a weaker adrenal androgen that serves as a precursor for sex steroid synthesis.

Bone status was assessed with dual-energy X-ray absorptiometry, the workhorse technology of clinical osteoporosis evaluation, at four sites: the lumbar vertebrae, the neck of the left femur, the total hip, and — less conventionally — the lumbar spine trabecular bone score, abbreviated LS TBS. The trabecular bone score is a textural analysis of standard DXA images that estimates the microarchitectural integrity of cancellous bone, the spongy, honeycombed tissue that fills the interior of vertebrae and bears much of the spine’s load. Unlike areal bone mineral density, which measures how much mineral is packed into a scanned area, TBS captures how that mineral is organized. Two spines with identical density can differ sharply in trabecular connectivity, and the one with degraded microarchitecture fractures more easily. This distinction proved to be the crux of the new findings.

The hormonal results were unambiguous. Prediabetic men had significantly lower total testosterone than their normoglycemic counterparts, a difference that reached statistical significance at p equals 0.030, and markedly lower osteocalcin, at p equals 0.004. The osteocalcin finding is particularly intriguing given the hormone’s proposed role in glucose regulation: reduced osteocalcin in a prediabetic population fits the circular logic of the bone-pancreas axis, in which impaired insulin signaling suppresses osteoblast activity, lowering osteocalcin output, which in turn may further weaken insulin secretion and sensitivity. The researchers also measured two inflammatory markers, interleukin 6 and C-reactive protein, because chronic inflammation is a recognized suppressor of osteoblast function and a plausible mechanistic bridge between metabolic dysfunction and skeletal deterioration.

Yet when the investigators examined the relationships among these hormones, the expected connections did not all materialize. Total testosterone showed no significant association with fasting insulin levels or with the homeostasis model assessment-estimated insulin resistance index, the widely used HOMA-IR calculation derived from fasting glucose and insulin. However, testosterone was inversely related to the metabolic score for insulin resistance, or METS-IR, a newer surrogate index that incorporates body mass index, fasting glucose, and triglycerides rather than insulin measurements. The divergence between the two indices is itself informative: METS-IR was designed to capture insulin resistance in settings where insulin assays are unavailable, and it weights adiposity and lipid metabolism more heavily. An inverse testosterone-METS-IR relationship in prediabetic men suggests that the hormone tracks with broader metabolic dysfunction rather than with insulin concentration per se, though the cross-sectional design of the study cannot establish which direction any causality might run.

The skeletal findings told a story of apparent paradox. At the conventional DXA sites — lumbar spine, femoral neck, and total hip — bone mineral density was statistically similar between the prediabetic and control groups. On the surface, this suggests that prediabetes spares the skeleton. But the trabecular bone score told a different tale: prediabetic men had significantly lower LS TBS than their normoglycemic peers, indicating degraded trabecular microarchitecture despite preserved density. Moreover, within the prediabetic group, interleukin 6 levels correlated negatively with LS TBS, meaning that men with higher circulating concentrations of this pro-inflammatory cytokine tended to have worse trabecular texture scores. This aligns with a growing body of evidence that inflammation erodes bone quality through mechanisms that density measurements do not capture, including increased osteoclast activation and disruption of the coupling between bone resorption and formation.

One further result underscored the dominant role of body composition in male skeletal health: within the prediabetic group, BMI was significantly associated with bone density. Heavier men carried denser bones, a mechanical effect of load-bearing that is among the most robust findings in osteology. But BMI’s protective association with density may coexist with harm to quality, since visceral adiposity fuels the inflammatory milieu implicated in the TBS reductions. The study’s authors are appropriately cautious in interpreting these patterns. They conclude that despite lower testosterone and osteocalcin, bone density in prediabetic men resembles that of controls, yet trabecular bone score is reduced — and they explicitly state that the potential influence of sex hormones and metabolic abnormalities on bone density or quality in this population remains uncertain and warrants further research.

The clinical implications, if confirmed, could be consequential. Prediabetes affects an estimated hundreds of millions of adults worldwide, and men with the condition may currently be reassured by normal DXA density readings that overlook microarchitectural decline. TBS is already integrated into fracture-risk assessment tools in many clinics, and the new findings suggest it may add value specifically in metabolically compromised patients whose density scans appear reassuring. Longitudinal studies will be needed to determine whether prediabetic men with low TBS actually sustain more fragility fractures, and whether interventions that improve insulin sensitivity — exercise, weight management, or pharmacotherapy — simultaneously restore osteocalcin, testosterone, and trabecular integrity. For now, the study adds a compelling piece to the puzzle of how metabolism and skeleton converse, and a reminder that the most important changes in bone health may be the ones standard scans cannot see.

Subject of Research: The relationship between sex hormones, osteocalcin, and bone parameters in men with prediabetes

Article Title: Sex hormones and osteocalcin levels in relation to bone parameters: a study on male subjects with prediabetes

Article References: Karimi, F., Jeddi, M., & Behdadnia, A. (2026). Sex hormones and osteocalcin levels in relation to bone parameters: a study on male subjects with prediabetes. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02598-z

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02598-z

Keywords: prediabetes, osteocalcin, testosterone, bone density, trabecular bone score, insulin resistance, METS-IR, interleukin-6, bone-pancreas-testis axis, dual-energy X-ray absorptiometry, endocrinology, men's health