What’s New in Musculoskeletal Basic Science 2023

Recent findings related to bone loss and bone healing, among other important topics, are presented in the new JBJS Guest Editorial What’s New in Musculoskeletal Basic Science. Here, we highlight the 5 most impressive studies, as selected by author Zbigniew Gugala, MD, PhD. 

New Regulators of Bone Remodeling

A murine study investigated the relationship between changes in parathyroid hormone (PTH), an essential calcium regulator, and the subfornical organ (SFO), which is located near the third ventricle of the central neural system and regulates body fluid homeostasis¹. Serum PTH and bone mass increased following glutamatergic nerve activation in the SFO and decreased following GABAergic neuron stimulation. Guest Editorial author Dr. Gugala notes that this study “elucidates the uncontrollable serum PTH in late-stage hyperparathyroidism and its related neuropsychiatric symptoms.” 

Conditions Involving Bone Loss and Fracture Risk

Childhood cancer survivors are susceptible to bone loss and fracture risk, as demonstrated in a cross-sectional study from The Netherlands that included 1,548 adult patients with a malignancy prior to 19 years of age and surviving ≥5 years². Bone mineral density at any site, as assessed by dual x-ray absorptiometry, was low in 36.1% of patients and very low in 9.6%. Factors associated with low or very low bone mineral density were male sex, underweight status, treatment with platinum compounds, radiation therapy, hypogonadism, hyperthyroidism, low physical activity, smoking, and vitamin D deficiency.  

Using longitudinal data of 875 U.S. women from the Study of Women’s Health Across the Nation, researchers investigated the impact of leisure time physical activity on bone mineral density during the menopause transition³. Greater leisure time physical activity (assessed with use of a validated Kaiser Physical Activity Survey) during the menopause transition was directly related to better bone mineral density of the spine and hip. Even a modest amount of physical activity was associated with a reduction in bone mineral density loss. 

Factors Affecting Bone Healing

The effects of chronic mental stress on bone healing were recently examined in both patients and mice⁴. Delayed bone healing and increased expression of tyrosine hydroxylase (TH) in fracture hematoma were associated with depression, psychosocial stress, and low social functioning among patients with ankle fracture. Among mice in a chronic subordinate colony housing model, the researchers observed delayed healing following femoral osteotomy and an increase in TH+Ly6G+ neutrophils in hematoma. “The study reveals that neutrophil-derived catecholamines compromise endochondral ossification,” writes Dr. Gugala, “and supports short-term β-blocker use to mitigate the effects of chronic mental stress on bone healing.” 

Epigenetic Functions of Vitamins

According to a new study, vitamin D has a role in embryonic epigenetic immune cell programming, with vitamin D deficiency in utero associated with a predisposition to insulin resistance and type-2 diabetes later in life⁵. Type-2 diabetes was induced in vitamin D-sufficient mice following transplantation of fetal hematopoietic stem cells derived from mouse embryos with vitamin D deficiency. Further, epigenetic repression of Jarid2 and activation of the Mef2/PGC1α pathway was observed in the vitamin D-deficient hematopoietic stem cells. Similar patterns in genetic expression were demonstrated in the monocytes of vitamin D-deficient human cord blood during the clinical component of the study, which included 30 healthy pregnant women and their full-term infants. 

What’s New in Musculoskeletal Basic Science is freely available at JBJS.org. 

What’s New by Subspecialty

Each month, JBJS publishes a review of the most pertinent studies from the orthopaedic literature in a select subspecialty. To read the reports, visit the What’s New by Subspecialty collection at JBJS.org. 

Recent OrthoBuzz posts include: What’s New in Orthopaedic Rehabilitation, What’s New in Shoulder and Elbow Surgery, and What’s New in Hip Surgery. 

References 

1. Zhang L, Liu N, Shao J, Gao D, Liu Y, Zhao Y, Han C, Chen D, Wang L, Lu WW, Yang F. Bidirectional control of parathyroid hormone and bone mass by subfornical organ. Neuron. 2023 Jun 21;111(12):1914-1932.e6. 
2. van Atteveld JE, de Winter DTC, Pluimakers VG, Fiocco M, Nievelstein RAJ, Hobbelink MGG, de Vries ACH, Loonen JJ, van Dulmen-den Broeder E, van der Pal HJ, Pluijm SMF, Kremer LCM, Ronckers CM, van der Heiden-van der Loo M, Versluijs AB, Louwerens M, Bresters D, van Santen HM, Olsson DS, Hoefer I, van den Berg SAA, den Hartogh J, Tissing WJE, Neggers SJCMM, van den Heuvel-Eibrink MM; Dutch LATER study group. Risk and determinants of low and very low bone mineral density and fractures in a national cohort of Dutch adult childhood cancer survivors (DCCSS-LATER): a cross-sectional study. Lancet Diabetes Endocrinol. 2023 Jan;11(1):21-32. 
3. Greendale GA, Jackson NJ, Shieh A, Cauley JA, Karvonen-Gutierrez C, Ylitalo KR, Gabriel KP, Sternfeld B, Karlamangla AS. Leisure time physical activity and bone mineral density preservation during the menopause transition and postmenopause: a longitudinal cohort analysis from the Study of Women’s Health Across the Nation (SWAN). Lancet Reg Health Am. 2023 Mar 26;21:100481. 
4. Tschaffon-Müller MEA, Kempter E, Steppe L, Kupfer S, Kuhn MR, Gebhard F, Pankratz C, Kalbitz M, Schütze K, Gündel H, Kaleck N, Strauß G, Vacher J, Ichinose H, Weimer K, Ignatius A, Haffner-Luntzer M, Reber SO. Neutrophil-derived catecholamines mediate negative stress effects on bone. Nat Commun. 2023 Jun 5;14(1):3262. 
5. Oh J, Riek AE, Bauerle KT, Dusso A, McNerney KP, Barve RA, Darwech I, Sprague JE, Moynihan C, Zhang RM, Kutz G, Wang T, Xing X, Li D, Mrad M, Wigge NM, Castelblanco E, Collin A, Bambouskova M, Head RD, Sands MS, Bernal-Mizrachi C. Embryonic vitamin D deficiency programs hematopoietic stem cells to induce type 2 diabetes. Nat Commun. 2023 Jun 13;14(1):3278.