Fibrous dysplasia is a rare, mosaic skeletal disorder in which normal bone is replaced by fibro-osseous tissue. Disease activity typically peaks during childhood and diminishes by adulthood, and the extent and severity of skeletal involvement generally correlate with accelerated bone turnover. The patient had been diagnosed with mild polyostotic fibrous dysplasia 19 years before the new imaging findings.

Her history of precocious menarche at eight years of age later led clinicians to revise the diagnosis to fibrous dysplasia associated with McCune–Albright syndrome, abbreviated FD/MAS. Another defining feature of the patient’s medical history was permanent hypoparathyroidism. At age 31, she underwent total thyroidectomy for papillary thyroid cancer, and the operation was complicated by permanent hypoparathyroidism.

This condition became an important part of the case analysis because the measured bone-turnover markers did not follow the pattern generally associated with polyostotic fibrous dysplasia. During follow-up, 18F-sodium fluoride positron-emission tomography combined with computed tomography, or 18F-NaF PET/CT, identified rib lesions that had not been evident on an 18F-fluorodeoxyglucose PET/CT examination performed 19 years earlier when fibrous dysplasia was diagnosed. All of the newly detected skeletal foci showed morphological features consistent with fibrous dysplasia on the CT component of the NaF scan.

The report documents lesions recognized after a prolonged imaging interval; it does not establish when they arose or whether they represent renewed disease activity. Clinical and diagnostic checks did not offer an obvious alternative explanation for the rib findings. The patient had no clinical evidence of rib trauma and no biochemical or structural evidence of recurrent thyroid cancer.

The evidence therefore supports classifying the detected rib sites as additional skeletal manifestations consistent with fibrous dysplasia, while leaving open broader questions about their biological course in this adult case. Genetic testing supported the underlying diagnosis. Following target enrichment, next-generation sequencing of DNA extracted from the dysplastic right iliac bone identified the causal Arg201Cys variant in the GNAS gene.

The molecular result, combined with the earlier history of precocious puberty, established the revised classification as FD/MAS. Because the report concerns one person, however, the genetic finding characterizes this case rather than defining a general pattern for all adults with fibrous dysplasia. The most notable laboratory feature was the contrast among several bone-turnover indicators.

In polyostotic fibrous dysplasia, elevated markers would be expected in light of the association between skeletal involvement and accelerated bone turnover. In this patient, serum osteocalcin and alkaline phosphatase remained within their normal ranges. Procollagen type 1 N-terminal propeptide was the only marker reported as persistently elevated, staying three to four times above the upper limit of normal.

Authors suggested that this atypical profile could reflect the combined effects of FD/MAS and suppressed skeletal remodeling associated with hypoparathyroidism. That explanation remains a possibility rather than a demonstrated causal result. As a case report, the study offers a detailed clinical snapshot rather than a population-level estimate or controlled comparison.

Its scope is limited to one 42-year-old woman with mild polyostotic FD/MAS, permanent hypoparathyroidism, and additional rib foci detected on interval imaging. The authors’ principal conclusion is that skeletal lesions can become detectable in an adult case despite expected quiescence and that bone-turnover markers may display an unusual combination of normal and elevated results in the presence of FD/MAS and permanent hypoparathyroidism.

Subject of Research: Newly detected rib lesions and altered bone-turnover markers in adult fibrous dysplasia/McCune–Albright syndrome with hypoparathyroidism

Article Title: Adult fibrous dysplasia/McCune–Albright syndrome with hypoparathyroidism: additional skeletal lesions and an unusual bone turnover profile

Article References: Zajíčková, K., Včelák, J., Kuklíková, V., Černý, V., & Zogala, D. (2026). Adult fibrous dysplasia/McCune–Albright syndrome with hypoparathyroidism: additional skeletal lesions and an unusual bone turnover profile. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02687-z

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02687-z

Keywords: fibrous dysplasia, McCune–Albright syndrome, hypoparathyroidism, rib lesions, bone turnover, PET/CT, GNAS variant, osteocalcin, procollagen type 1 N-terminal propeptide, Adult, fibrous, dysplasia

Researchers at the University of Veterinary Medicine in Vienna, working with the Agricultural Research and Education Center Raumberg-Gumpenstein in Austria, followed 66 Fleckvieh, Holstein-Friesian, and New Zealand Friesian cows and heifers through 85 calvings between November 2022 and March 2024. Blood samples were collected at a dense series of time points: roughly 21, 14, and 7 days before the expected calving date, just hours before and after parturition, and then at 1, 3, 7, and 14 days postpartum. From each sample, the team measured serum total calcium alongside a panel of osteoimmunological markers, proteins and enzymes that reflect the ongoing dialogue between the immune system and bone tissue.

The central focus was the RANK/RANKL/OPG signaling system, a triad of molecules from the tumor necrosis factor superfamily that governs bone remodeling. RANK ligand, produced by osteoblasts and activated T cells, binds to the RANK receptor on osteoclast precursor cells and drives their differentiation into mature bone-resorbing cells. Osteoprotegerin acts as a soluble decoy receptor, neutralizing RANKL and thereby restraining osteoclast formation. This regulatory axis responds to hormonal and cytokine signals, including interleukin-6, tumor necrosis factor-alpha, and interleukin-17, which are known to shift during the inflammatory events of pregnancy and calving. Because parturition itself is an inflammatory process, involving detachment and expulsion of the fetal membranes, the researchers reasoned that immune activation around calving might perturb bone turnover and influence systemic calcium availability.

To track bone resorption directly, the team measured C-terminal cross-linked telopeptide of type I collagen, or CTX-I, a fragment released when type I collagen is degraded, widely accepted as a sensitive marker of osteoclastic activity in both human and veterinary medicine. They also measured osteocalcin, a marker of osteoblast formation activity, and alkaline phosphatase, an enzyme long used in human medicine to evaluate bone diseases such as osteomalacia and Paget’s disease. After calving, cows were retrospectively classified by their serum calcium concentrations as normocalcemic, above 2.20 millimoles per liter; subclinical hypocalcemic, between 1.80 and 2.20; or low-calcium, below 1.80 millimoles per liter.

The distribution of calcium status revealed how widespread the problem is even in a well-managed research herd. Of the 85 calvings, only about 39 percent remained normocalcemic, while 54 percent fell into the subclinical hypocalcemic range and 7 percent into the low-calcium category. Notably, the burden fell disproportionately on older animals: among cows in their fourth or later lactation, 18 of 27 calvings were subclinical and 5 were frankly low-calcium, whereas most heifers maintained normal calcium concentrations.

CTX-I emerged as the standout marker. Its concentrations rose after parturition, peaked in early lactation, and then gradually declined, consistent with a transient stimulation of bone resorption to meet the demands of lactation. Crucially, first-lactation animals showed significantly higher CTX-I concentrations than multiparous cows at every examination time, and cows that went on to develop low calcium had the lowest CTX-I concentrations at nearly all time points, with significant differences from normocalcemic cows stretching from two weeks before calving through two weeks after. The interpretation is striking: cows that could not mobilize calcium from their skeletons effectively were the ones that became hypocalcemic, and their impaired resorptive capacity was visible in the blood before calving.

The predictive power was quantified using receiver operating characteristic analysis, which evaluates how well a biomarker separates two groups across all possible threshold values. Prepartum CTX-I achieved area under the curve values between 0.75 and 0.90, with Youden indices between 0.75 and 0.82 at several time points. At 14 days before calving, a cut-off of 0.17 nanograms per milliliter yielded 100 percent specificity and roughly 81 percent sensitivity for identifying cows that would later become hypocalcemic. In practical terms, a single blood test in late gestation could flag most at-risk cows while essentially never falsely accusing a cow that would remain healthy. Alkaline phosphatase showed moderate predictive value before calving, and RANK, whose concentrations declined in all parity groups before calving and then remained low, was more useful for tracking postpartum regulatory processes than for prepartum prediction. No reliable models could be built for osteocalcin, RANKL, or osteoprotegerin, likely because RANKL and OPG act predominantly within the local bone microenvironment and are not fully reflected in circulating concentrations.

The parity findings carry their own biological weight. The consistently lower CTX-I concentrations in older cows suggest an age-related decline in bone remodeling, echoing human studies showing that osteoclast precursors become less responsive to RANKL stimulation with age. This diminished capacity to activate osteoclast-mediated calcium mobilization offers a mechanistic explanation for why older cows are far more susceptible to milk fever: when the sudden calcium drain of lactation begins, their skeletons simply cannot respond as vigorously as those of younger animals. Markers of bone formation, by contrast, showed far less pronounced age-related variation, indicating that the parity effect is concentrated on the resorptive side of skeletal metabolism.

The authors are careful to frame the findings appropriately. The low-calcium group contained only six calvings, limiting statistical power, and the study was conducted under specific herd and management conditions without controlled nutritional factors, which are known to influence calcium metabolism. The commercial ELISA kits used may introduce analytical variability, and the observational design precludes causal inference. The proposed cut-off values require validation in independent cohorts before any clinical application, and the researchers explicitly caution that biomarker screening should complement, not replace, established herd-level prevention strategies such as dietary calcium management around calving.

Even with those caveats, the study opens a genuinely new window on an old problem. Milk fever has been managed for decades through nutritional strategies, yet individual risk prediction has remained crude. The demonstration that a bone resorption marker measured weeks before calving can identify cows destined for hypocalcemia suggests that the disease process begins long before the calcium crash, rooted in the skeleton’s diminished ability to respond. If validated at scale, CTX-I testing in late gestation could allow farmers and veterinarians to target preventive interventions precisely at the cows that need them most, turning a metabolic emergency into a manageable prediction problem.

Subject of Research: Osteoimmunological biomarkers for predicting periparturient hypocalcemia in dairy cows

Article Title: Periparturient changes in osteoimmunological markers and their association with hypocalcemia in dairy cows

Article References: Gleissenberger, J., Gleissenberger, M., Becker, S., Schraml, M., Eingang, D., Khol, J. L., & Wittek, T. (2026). Periparturient changes in osteoimmunological markers and their association with hypocalcemia in dairy cows. Journal of Veterinary Internal Medicine, 40(5), Article aalag244. https://doi.org/10.1093/jvimsj/aalag244

Image Credits: AI Generated

DOI: 10.1093/jvimsj/aalag244

Keywords: dairy cows, hypocalcemia, bone resorption, CTX-I, RANK/RANKL/OPG, osteocalcin, alkaline phosphatase, transition period, milk fever, osteoimmunology, biomarkers, veterinary medicine

The research team, led by Xiaotian Huang, Jiaoyang Zheng, Yiwen Wang and Hao Chen of the Health Management Center at the Second Affiliated Hospital of Naval Medical University, confronted a methodological problem that has plagued earlier work in this field. Most previous studies comparing bone metabolism in diabetic patients with and without osteoporosis used comparison groups that could be contaminated by antiresorptive drugs. Patients labeled as having diabetes without osteoporosis may in fact have been receiving medications such as bisphosphonates or denosumab for other reasons, including bone metastases from cancer, and those drugs profoundly alter the very biomarkers researchers were trying to compare. The team therefore excluded anyone with bone metastasis and drew its comparison group exclusively from patients with no record of antiresorptive therapy.

The scale of the dataset gives the findings unusual weight. The researchers screened electronic health records of hospitalized patients with type 2 diabetes treated between 2021 and 2024, identifying 461 patients with a documented diagnosis of both diabetes and osteoporosis. From a pool of 21,181 patients with diabetes but no osteoporosis and no antiresorptive drug exposure, they selected a matched comparison group of 1,383 individuals using propensity score matching at a one-to-three ratio. Matching was performed on age and sex, which the authors describe as the two strongest confounders of bone metabolism given the data available. The procedure worked as intended: after matching, the standardized mean difference for both variables was exactly zero, with the combined cohort averaging 69.3 years of age and 15.2 percent male.

Against this carefully balanced backdrop, the team compared a panel of serum biomarkers that together sketch the state of bone remodeling and mineral metabolism. Parathyroid hormone, or PTH, stood out immediately. Patients with both diabetes and osteoporosis had a mean PTH concentration of 40.3 nanograms per liter, compared with 52.0 nanograms per liter in the matched diabetes-only group, a relative reduction of 22.6 percent that was highly statistically significant and carried a moderate effect size, with Cohen’s d of minus 0.434. Yet the authors are careful to frame this correctly: the median values in both groups fell within the laboratory reference range of 15 to 65 nanograms per liter, meaning the difference represents a shift within the normal spectrum rather than outright hormone deficiency.

The rest of the biomarker panel told a quieter story. Serum calcium was statistically higher in the osteoporosis group, at 2.21 versus 2.20 millimoles per liter, but the authors themselves flag that an absolute difference of one hundredth of a millimole per liter is unlikely to carry any clinical meaning. Bone turnover markers, the dynamic readouts of skeletal remodeling, showed no significant differences at all. Beta-C-terminal telopeptide of type I collagen, known as beta-CTX, a marker of bone resorption, was essentially identical between groups at 0.38 nanograms per milliliter. Osteocalcin, a marker of bone formation produced by osteoblasts, averaged 12.0 versus 11.0 nanograms per milliliter, a difference that did not reach statistical significance. Even 25-hydroxyvitamin D, the storage form of vitamin D that constrains PTH secretion, was statistically indistinguishable at 24.7 versus 22.8 nanograms per milliliter.

One secondary analysis added a layer of physiological nuance. In the diabetes-only group, glycated hemoglobin, or HbA1c, the standard measure of long-term blood sugar control, showed a moderate negative correlation with osteocalcin, with a correlation coefficient of minus 0.456. This relationship is well described in the literature: osteoblasts and the skeleton participate in energy metabolism, and poor glycemic control appears to suppress osteocalcin. In the combined diabetes and osteoporosis group, however, the correlation was much weaker, at minus 0.206, though still statistically significant. The attenuation suggests that in patients whose skeletons are already compromised by osteoporosis, the glucose-osteocalcin axis may be distorted or dominated by other forces, although a cross-sectional design cannot determine which way the causality runs.

What could explain suppressed PTH in patients whose bones are demonstrably weaker? The authors discuss two candidate mechanisms, both of which they emphasize remain unproven. The first involves altered sensitivity of the calcium-sensing receptor, or CaSR, the molecular thermostat on parathyroid cells that tunes hormone release according to circulating calcium. Advanced glycation end products, the sugar-damaged proteins that accumulate in diabetes, are one plausible influence on receptor behavior, and a shift in CaSR set-point could hold PTH lower even at normal calcium levels. The second is the concept of functional hypoparathyroidism, in which the glands are structurally intact but fail to mount an adequate hormonal response. Either mechanism would matter clinically, because PTH helps maintain bone remodeling balance, and an inappropriately low level could theoretically contribute to the skeletal fragility that defines diabetic bone disease.

The study’s limitations are candidly stated and worth understanding, because they define exactly what the finding does and does not prove. The entire population consisted of patients with type 2 diabetes, so the data cannot establish whether diabetes itself alters bone turnover relative to people without diabetes. Osteoporosis classification relied on diagnostic codes in the electronic health record rather than uniform dual-energy X-ray absorptiometry confirmation for every participant, and estimated glomerular filtration rate data were not incorporated into the analysis, even though declining kidney function is a well-known driver of elevated PTH and could confound the comparison. The design is cross-sectional, capturing a single moment in time, so it can document association but never causation. The authors call for future studies with confirmed bone mineral density measurements, renal function data, and longitudinal follow-up to test the CaSR and functional hypoparathyroidism hypotheses directly.

Why does this matter beyond the statistics? Diabetes doubles the burden of fracture in ways that bone mineral density scans often fail to capture, a phenomenon researchers call diabetic bone disease, in which the skeleton may look adequate on imaging but behaves as fragile tissue under stress. If suppressed PTH proves to be a genuine and mechanistically meaningful feature of this condition, it could eventually serve as a biomarker for identifying diabetic patients at heightened skeletal risk, or even suggest therapeutic angles, since PTH analogs such as teriparatide are already used to build bone in osteoporosis. The Shanghai team’s contribution is methodological as much as biological: by scrubbing antiresorptive drug confounders from the comparison group and matching rigorously on age and sex, they have produced one of the cleaner snapshots to date of bone metabolism in the diabetes-osteoporosis overlap, and the picture they captured, a 22.6 percent PTH reduction against an otherwise unremarkable panel, is a lead worth chasing.

For now, the practical takeaway for clinicians is one of calibrated caution. Both groups’ median PTH values sat comfortably within the normal range, bone turnover markers did not differ, and the calcium difference was trivially small, so no immediate change in screening or treatment practice follows from this single study. What the research does deliver is a sharpened hypothesis and a template for testing it. As the authors conclude, the mechanisms involving altered calcium-sensing receptor sensitivity or functional hypoparathyroidism remain unproven and require direct investigation. Given that hundreds of millions of people worldwide live with type 2 diabetes and that fragility fractures carry enormous costs in mortality and independence, even a modest hormonal clue about why diabetic bones fail deserves the longitudinal, density-confirmed follow-up studies the researchers now propose.

Subject of Research: Parathyroid hormone and calcium homeostasis in type 2 diabetes patients with osteoporosis

Article Title: Parathyroid hormone suppression and calcium homeostasis shift in type 2 diabetes with osteoporosis: a propensity score-matched cross-sectional study

Article References: Huang, X., Zheng, J., Wang, Y., & Chen, H. (2026). Parathyroid hormone suppression and calcium homeostasis shift in type 2 diabetes with osteoporosis: a propensity score-matched cross-sectional study. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02549-8

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02549-8

Keywords: type 2 diabetes, osteoporosis, parathyroid hormone, bone turnover markers, calcium homeostasis, propensity score matching, cross-sectional study, vitamin D, osteocalcin, beta-CTX, calcium-sensing receptor, diabetic bone disease

The hemoglobin glycation index, usually abbreviated HGI, is calculated by comparing the HbA1c value actually measured in a patient’s blood with the HbA1c value that would be predicted from that patient’s fasting plasma glucose. HbA1c reflects the percentage of hemoglobin molecules that have been chemically modified by glucose over the roughly two-to-three-month lifespan of red blood cells. Because individuals differ in how readily glucose binds to their hemoglobin, two patients with identical average glucose can show different HbA1c readings. The index captures this individual discrepancy: a positive value means the measured HbA1c runs higher than expected for the observed glucose, a phenomenon sometimes described as high glycators, while a negative value indicates the opposite tendency.

To investigate whether this glycation fingerprint matters for bone, the researchers retrospectively analyzed 757 hospitalized patients with type 2 diabetes who had undergone dual-energy X-ray absorptiometry, the standard technique for measuring bone mineral density, between January and December 2023. Dual-energy X-ray absorptiometry works by scanning the skeleton with X-ray beams at two different energy levels and calculating how much of each beam is absorbed by bone tissue, yielding a precise estimate of mineral content. Lumbar osteoporosis was defined using the T-score, which compares a patient’s bone density at the first through fourth lumbar vertebrae with the average density of a healthy young adult. A T-score of negative 2.5 or lower meets the conventional threshold for osteoporosis.

The results were unambiguous in direction. Overall, 208 of the 757 participants, or 27.5 percent, had lumbar osteoporosis. When the researchers divided the cohort into tertiles, three groups of equal size ranked by HGI, the prevalence of lumbar osteoporosis climbed steadily across the groups, from 15.8 percent in the lowest tertile to 28.6 percent in the middle tertile and 38.1 percent in the highest. In other words, patients whose hemoglobin showed the greatest degree of glycation relative to their measured glucose levels were more than twice as likely to have osteoporotic lumbar spines as those in the lowest group.

Because simple prevalence comparisons can be distorted by age, sex, body weight, kidney function and other confounders, the team turned to logistic regression, a statistical technique that models the probability of a binary outcome, here the presence or absence of osteoporosis, as a function of multiple explanatory variables. In the fully adjusted primary model, which included 687 participants with complete data, each one-unit increase in HGI was associated with 34 percent higher odds of lumbar osteoporosis, with an odds ratio of 1.342 and a 95 percent confidence interval running from 1.168 to 1.546, a result that was highly statistically significant. The confidence interval indicates that, given the data, the true effect very likely lies well above the null value of 1.0, meaning no association.

A critical question for any study involving HbA1c is whether the index is merely re-describing what HbA1c or fasting glucose already reveal. To address this, the researchers performed sensitivity analyses in which they additionally adjusted for HbA1c itself and, separately, for fasting plasma glucose. The association survived both tests. With additional adjustment for HbA1c, the odds ratio was 1.251, with a confidence interval of 1.039 to 1.507 and a P value of 0.018. With additional adjustment for fasting glucose, the odds ratio was 1.337, with a confidence interval of 1.164 to 1.540 and a P value below 0.001. This pattern suggests that HGI carries information about bone health that is not redundant with either component used to compute it.

The team also examined bone density as a continuous outcome rather than a binary diagnosis. Higher HGI was associated with a lower T-score across the first through fourth lumbar vertebrae, with a standardized coefficient of negative 0.134 and a confidence interval of negative 0.236 to negative 0.031, statistically significant at P equal to 0.011. Restricted cubic spline models, which allow the relationship between exposure and outcome to bend flexibly rather than being forced into a straight line, were used to probe for nonlinearity in the association. Together, these secondary analyses reinforced the primary finding that the glycation index tracks with progressively weaker lumbar bone density.

Perhaps the most intriguing results came from the exploratory analysis of bone turnover markers, molecules released into the bloodstream during the constant remodeling of skeletal tissue. Osteocalcin, a protein secreted by osteoblasts, the cells that build new bone, serves as a marker of bone formation. PINP, a fragment of type I collagen propeptide, marks the synthesis of new bone matrix, while beta-CTX, a collagen degradation product, reflects bone resorption by osteoclasts. In this cohort, higher HGI was inversely associated with osteocalcin, with a coefficient of negative 0.057 and a confidence interval of negative 0.103 to negative 0.011, statistically significant at P equal to 0.016. Associations with PINP and beta-CTX did not reach statistical significance. The authors are careful to characterize the osteocalcin finding as modest and exploratory, but it hints at a possible mechanism: chronic non-enzymatic glycation of bone matrix proteins, including osteocalcin itself, may impair bone quality even when the quantity of mineral looks adequate on a scan.

This mechanistic hypothesis fits a broader picture that bone scientists have been assembling for years. In diabetes, skeletal fragility is thought to arise less from low bone mass and more from degraded bone material properties. Glucose can attach to collagen and other matrix proteins without the help of enzymes, forming advanced glycation end-products that stiffen collagen fibers and make bone more brittle under stress, even though the tissue appears denser on absorptiometry. A hemoglobin glycation index that runs high may flag patients whose tissues are more exposed to this process, offering a window into bone quality that bone mineral density measurements alone cannot provide. The inverse link with osteocalcin, a formation marker, could indicate suppressed or altered bone-building activity in high-glycating patients, though the cross-sectional data cannot establish which comes first.

The researchers are equally clear about the limits of their work. Because the study is cross-sectional, capturing a single moment in time, it demonstrates association rather than causation; it cannot show whether a high glycation index precedes bone loss or merely accompanies it. The cohort consisted of hospitalized patients, a group that may differ systematically from the broader population of people with type 2 diabetes, and the authors note the absence of formal discrimination or reclassification analyses, meaning the study did not test whether adding HGI to existing models actually improves the prediction of osteoporosis beyond HbA1c. Still, the findings open a compelling line of inquiry for a disease in which fractures carry enormous costs in mobility, independence and mortality. If future longitudinal studies confirm that the hemoglobin glycation index identifies patients at skeletal risk that standard glucose metrics miss, this inexpensive calculation, derivable from two routine blood tests, could become a practical tool for flagging which of the hundreds of millions of people worldwide living with type 2 diabetes need their bones watched as closely as their blood sugar.

Subject of Research: Association between the hemoglobin glycation index and lumbar osteoporosis in patients with type 2 diabetes

Article Title: Association between hemoglobin glycation index and lumbar osteoporosis in patients with type 2 diabetes mellitus: a cross-sectional study with exploratory analysis of bone turnover markers

Article References: Chen, C., Yang, J., Jiang, X., Wang, Q., Wang, X., & Zhang, X. (2026). Association between hemoglobin glycation index and lumbar osteoporosis in patients with type 2 diabetes mellitus: a cross-sectional study with exploratory analysis of bone turnover markers. BMC Endocrine Disorders. https://doi.org/10.1186/s12902-026-02615-1

Image Credits: AI Generated

DOI: 10.1186/s12902-026-02615-1

Keywords: hemoglobin glycation index, type 2 diabetes, osteoporosis, bone mineral density, HbA1c, lumbar spine T-score, bone turnover markers, osteocalcin, dual-energy X-ray absorptiometry, advanced glycation end-products, endocrinology, metabolic bone disease

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

A new study published in Archives of Osteoporosis now offers the most detailed portrait yet of what happens to bone in the immediate aftermath of a cerebral ischemic event. In the baseline analysis of the Post-stroke Osteopathy study, a team led by researchers at the Medical University of Innsbruck in Austria combined high-resolution peripheral quantitative computed tomography, or HR-pQCT, with an extensive panel of biochemical bone markers in a cohort of acute stroke and TIA patients. According to the investigators, this is the largest cohort of ischemic stroke or TIA patients ever examined prospectively with HR-pQCT and the first study anywhere to correlate bone biomarkers with high-resolution imaging parameters in this clinical setting.

The imaging technique at the heart of the study represents a major leap beyond conventional bone assessment. Dual-energy X-ray absorptiometry, the workhorse of osteoporosis screening, measures bone mass in two dimensions and misses critical information about bone quality. HR-pQCT, by contrast, resolves the three-dimensional microarchitecture of cortical and trabecular bone at peripheral sites such as the distal radius and distal tibia with an impressive 61-micrometer voxel size and very low radiation exposure. This matters because bone strength depends not merely on how much mineral bone contains but on its morphology and microstructure, a fact convincingly established by large international consortia showing that cortical and trabecular microarchitecture independently predict fracture risk in older women and men.

In the study, 122 participants were enrolled between March 2021 and May 2022 at the University Hospital Innsbruck as a pilot sub-study of the ongoing STROKE-CARD Registry. Of these, 116 underwent baseline HR-pQCT imaging of all four extremities within days of their event, with a median age of 71.5 years and 26.7 percent women. Neurological deficits were predominantly mild, reflected by a median National Institutes of Health Stroke Scale score of 2, and scans were performed on average 5.4 days after admission. Blood samples for biomarker analysis were drawn in 62 patients a mean of 3.0 days after admission and analyzed using validated enzyme-linked immunosorbent assays for osteocalcin, C-telopeptide of crosslinked collagen type 1, sclerostin, osteoprotegerin, soluble RANKL, and periostin.

The imaging results revealed clear patterns. Women in the cohort had lower total, cortical, and trabecular volumetric bone mineral density, along with lower values for nearly every other HR-pQCT parameter, in both the upper and lower extremities. This finding mirrors what has been documented in healthy reference populations, suggesting that stroke patients retain normal sex-based differences in bone structure. Increasing age was associated with lower total and cortical volumetric bone mineral density, but intriguingly, trabecular parameters showed no relationship with age in this cohort, a dissociation the authors suggest may be linked to higher sclerostin levels in elderly patients, which correlated with stable trabecular architecture.

Lifestyle and metabolic factors left their own signatures on the skeleton. Active or former smokers had lower total and trabecular volumetric bone mineral density in the tibia but not in the radius, consistent with prior evidence that smoking exerts a particularly strong influence on the trabecular compartment. Higher body mass index was associated with greater cortical and trabecular bone areas and higher trabecular density, especially in the radius. The weaker BMI effect in the tibia, a weight-bearing bone where mechanical loading might be expected to matter most, prompted the authors to argue that BMI captures complex systemic processes rather than simple mechanical loading, with detrimental lipotoxic and metabolic pathways potentially counteracting the localized benefits of extra weight at the lower limb.

The biomarker correlations provided some of the most novel insights of the analysis. Sclerostin, a protein secreted by osteocytes that suppresses bone formation, showed a positive correlation with trabecular HR-pQCT parameters, including trabecular volumetric bone mineral density in both the radius and the tibia, an association never before examined in a stroke or TIA population. Higher osteoprotegerin levels were linked to lower cortical area and thickness, echoing findings from the STRAMBO study of men, which similarly showed that elevated osteoprotegerin selectively affects the cortical rather than the trabecular compartment. Osteocalcin, a marker of bone turnover, correlated negatively with total volumetric bone mineral density and cortical thickness in the radius, in line with prior studies linking higher osteocalcin to increased bone turnover and skeletal fragility.

Notably, several traditional cardiovascular risk factors failed to leave any measurable trace on the skeleton in this cohort. No correlation was found between any HR-pQCT parameter and diabetes mellitus, blood pressure, or dyslipidemia, and neither stroke severity at admission nor stroke etiology, classified according to the TOAST criteria, was associated with imaging or biomarker outcomes. When the 17 patients with TIA were excluded to focus on confirmed strokes, the findings remained unchanged, reinforcing the robustness of the observed patterns. Overall, the biochemical markers exerted more influence on bone parameters in the radius than in the tibia, an asymmetry that future longitudinal follow-up may help explain.

The authors are candid about the limitations of their work. The cohort was recruited at a single center, all participants were of European descent, women were underrepresented owing to eligibility criteria such as the exclusion of patients with known osteoporosis, and HR-pQCT measurements were confined to peripheral skeletal sites that may not fully reflect changes in the axial skeleton. The acute phase after stroke may itself perturb biomarker levels, baseline blood sampling was not feasible in all patients, and the exploratory correlation analyses, involving many comparisons without formal adjustment for multiple testing, warrant cautious interpretation. The absence of an in-house, age-matched healthy control group further means the baseline findings describe the absolute bone status of acute patients rather than stroke-specific deviations.

Even so, the study establishes a crucial foundation. By pairing the finest available in vivo images of bone microstructure with a comprehensive biochemical profile gathered within days of a cerebral ischemic event, the Innsbruck team has created the reference point against which future bone loss after stroke can be measured. The prospective design of the Post-stroke Osteopathy study, with follow-up imaging and blood sampling at 3, 6, and 12 months, promises to chart the trajectory of skeletal deterioration and to clarify whether the biomarker signals identified at baseline predict which patients will go on to suffer the devastating fractures that raise mortality and erode quality of life after stroke. If those predictions hold, routine bone microarchitecture screening and early targeted intervention could become standard components of post-stroke care.

Subject of Research: Bone microarchitecture and biomarker characteristics in patients after ischemic stroke or transient ischemic attack assessed with HR-pQCT imaging

Article Title: High-resolution peripheral quantitative computed tomography imaging and bone biomarker characteristics of patients with ischemic stroke or transient ischemic attack—baseline analysis of the Post-stroke Osteopathy study

Article References: Dejakum, B., Bereiter-Payr, J., Felicetti, S., Moelgg, K., Karisik, A., Degenhart, G., Toell, T., Boehme, C., Mayer-Suess, L., Pechlaner, R., Liphardt, A.-M., Berg, G., Schett, G., Kiechl, S., & Knoflach, M. (2026). High-resolution peripheral quantitative computed tomography imaging and bone biomarker characteristics of patients with ischemic stroke or transient ischemic attack—baseline analysis of the Post-stroke Osteopathy study. Archives of Osteoporosis, 21(1), Article 134. https://doi.org/10.1007/s11657-026-01767-w

Image Credits: AI Generated

DOI: 10.1007/s11657-026-01767-w

Keywords: ischemic stroke, transient ischemic attack, HR-pQCT, bone microarchitecture, post-stroke osteopathy, bone biomarkers, osteoporosis, fracture risk, sclerostin, osteoprotegerin, osteocalcin, volumetric bone mineral density