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Fracture risk is increased in patients with type 2 diabetes mellitus (T2DM). In addition, these patients sustain fractures despite having higher levels of areal bone mineral density, as measured by dual-energy X-ray absorptiometry, than individuals without T2DM. Thus, additional factors such as alterations in bone quality could have important roles in mediating skeletal fragility in patients with T2DM. Although the pathogenesis of increased fracture risk in T2DM is multifactorial, impairments in bone material properties and increases in cortical porosity have emerged as two key skeletal abnormalities that contribute to skeletal fragility in patients with T2DM. In addition, indices of bone formation are uniformly reduced in patients with T2DM, with evidence from mouse studies published over the past few years linking this abnormality to accelerated skeletal ageing, specifically cellular senescence. In this Review, we highlight the latest advances in our understanding of the mechanisms of skeletal fragility in patients with T2DM and suggest potential novel therapeutic approaches to address this problem.This Review outlines the pathogenesis of skeletal fragility in patients with type 2 diabetes mellitus, and discusses potential therapeutic approaches to the management of increased fracture risk in these patients. The evidence that skeletal fragility should now be included in the list of well-recognized diabetic complications is also summarized.

The endocrine hormone fibroblast growth factor 21 (FGF21) is a powerful modulator of glucose and lipid metabolism and a promising drug for type 2 diabetes. Here we identify FGF21 as a potent regulator of skeletal homeostasis. Both genetic and pharmacologic FGF21 gain of function lead to a striking decrease in bone mass. In contrast, FGF21 loss of function leads to a reciprocal high-bone-mass phenotype. Mechanistically, FGF21 inhibits osteoblastogenesis and stimulates adipogenesis from bone marrow mesenchymal stem cells by potentiating the activity of peroxisome proliferator-activated receptor γ (PPAR-γ). Consequently, FGF21 deletion prevents the deleterious bone loss side effect of the PPAR-γ agonist rosiglitazone. Therefore, FGF21 is a critical rheostat for bone turnover and a key integrator of bone and energy metabolism. These results reveal that skeletal fragility may be an undesirable consequence of chronic FGF21 administration.

Loss of skeletal integrity during ageing and disease is associated with an imbalance in the opposing actions of osteoblasts and osteoclasts 1 . Here we show that intrinsic ageing of skeletal stem cells (SSCs) 2 in mice alters signalling in the bone marrow niche and skews the differentiation of bone and blood lineages, leading to fragile bones that regenerate poorly. Functionally, aged SSCs have a decreased bone- and cartilage-forming potential but produce more stromal lineages that express high levels of pro-inflammatory and pro-resorptive cytokines. Single-cell RNA-sequencing studies link the functional loss to a diminished transcriptomic diversity of SSCs in aged mice, which thereby contributes to the transformation of the bone marrow niche. Exposure to a youthful circulation through heterochronic parabiosis or systemic reconstitution with young haematopoietic stem cells did not reverse the diminished osteochondrogenic activity of aged SSCs, or improve bone mass or skeletal healing parameters in aged mice. Conversely, the aged SSC lineage promoted osteoclastic activity and myeloid skewing by haematopoietic stem and progenitor cells, suggesting that the ageing of SSCs is a driver of haematopoietic ageing. Deficient bone regeneration in aged mice could only be returned to youthful levels by applying a combinatorial treatment of BMP2 and a CSF1 antagonist locally to fractures, which reactivated aged SSCs and simultaneously ablated the inflammatory, pro-osteoclastic milieu. Our findings provide mechanistic insights into the complex, multifactorial mechanisms that underlie skeletal ageing and offer prospects for rejuvenating the aged skeletal system. An analysis of skeletal stem cells in mice reveals that bone ageing occurs at the level of local niches affecting skeletal and haematopoietic lineage output, which may influence systemic aspects of multi-organ physiological ageing.

Introduction Biophysical stimulation is a non-invasive therapy used in orthopaedic practice to increase and enhance reparative and anabolic activities of tissue. Methods A sistematic web-based search for papers was conducted using the following titles: (1) pulsed electromagnetic field (PEMF), capacitively coupled electrical field (CCEF), low intensity pulsed ultrasound system (LIPUS) and biophysical stimulation; (2) bone cells, bone tissue, fracture, non-union, prosthesis and vertebral fracture; and (3) chondrocyte, synoviocytes, joint chondroprotection, arthroscopy and knee arthroplasty. Results Pre-clinical studies have shown that the site of interaction of biophysical stimuli is the cell membrane. Its effect on bone tissue is to increase proliferation, synthesis and release of growth factors. On articular cells, it creates a strong A 2A and A 3 adenosine-agonist effect inducing an anti-inflammatory and chondroprotective result. In treated animals, it has been shown that the mineralisation rate of newly formed bone is almost doubled, the progression of the osteoarthritic cartilage degeneration is inhibited and quality of cartilage is preserved. Biophysical stimulation has been used in the clinical setting to promote the healing of fractures and non-unions. It has been successfully used on joint pathologies for its beneficial effect on improving function in early OA and after knee surgery to limit the inflammation of periarticular tissues. Discussion The pooled result of the studies in this review revealed the efficacy of biophysical stimulation for bone healing and joint chondroprotection based on proven methodological quality. Conclusion The orthopaedic community has played a central role in the development and understanding of the importance of the physical stimuli. Biophysical stimulation requires care and precision in use if it is to ensure the success expected of it by physicians and patients.

Osteoporosis is the most prevalent metabolic bone disease that affects half the women in the sixth and seventh decade of life. Osteoporosis is characterized by uncoupled bone resorption that leads to low bone mass, compromised microarchitecture and structural deterioration that increases the likelihood of fracture with minimal trauma, known as fragility fractures. Several factors contribute to osteoporosis in men and women. In women, menopause – the cessation of ovarian function, is one of the leading causes of primary osteoporosis. Over the past three decades there has been growing appreciation that the adaptive immune system plays a fundamental role in the development of postmenopausal osteoporosis, both in humans and in mouse models. In this review, we highlight recent data on the interactions between T cells and the skeletal system in the context of postmenopausal osteoporosis. Finally, we review recent studies on the interventions to ameliorate osteoporosis.

This study examined bone-biopsy specimens obtained after a 3-year, double-blind, randomized, placebo-controlled, dose-ranging trial of oral alendronate to prevent bone resorption in healthy postmenopausal women. Long-term alendronate treatment was associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that undergo protracted apoptosis. The finding of such cells, despite decreased resorption after long-term therapy with oral nitrogen-containing bisphosphonate, may have clinical implications. In healthy postmenopausal women, long-term alendronate treatment was associated with an increase in the number of osteoclasts, which include distinctive giant, hypernucleated, detached osteoclasts that undergo protracted apoptosis. Bisphosphonates are used worldwide to prevent fractures in patients with osteoporosis. 1 – 6 Treatment with these drugs decreases the rate of bone resorption and levels of biochemical markers of bone turnover and causes progressive increases in bone mineral density. The clinical efficacy of nitrogen-containing bisphosphonates is widely believed to result from their potent ability to decrease the number of osteoclasts by promoting their apoptosis. 7 – 9 Once osteoclasts become apoptotic, they are usually quickly ingested by bone marrow phagocytes. 10 However, enumeration of osteoclasts in specimens of cancellous bone (bone composed of multiple trabecular structures) obtained from patients treated with nitrogen-containing bisphosphonates shows . . .

The gut microbiota (GM) modulates the hosts metabolism and immune system. Probiotic bacteria are defined as live microorganisms which when administered in adequate amounts confer a health benefit on the host and can alter the composition of the GM. Germ-free mice have increased bone mass associated with reduced bone resorption indicating that the GM also regulates bone mass. Ovariectomy (ovx) results in bone loss associated with altered immune status. The purpose of this study was to determine if probiotic treatment protects mice from ovx-induced bone loss. Mice were treated with either a single Lactobacillus (L) strain, L. paracasei DSM13434 (L. para) or a mixture of three strains, L. paracasei DSM13434, L. plantarum DSM 15312 and DSM 15313 (L. mix) given in the drinking water during 6 weeks, starting two weeks before ovx. Both the L. para and the L. mix treatment protected mice from ovx-induced cortical bone loss and bone resorption. Cortical bone mineral content was higher in both L. para and L. mix treated ovx mice compared to vehicle (veh) treated ovx mice. Serum levels of the resorption marker C-terminal telopeptides and the urinary fractional excretion of calcium were increased by ovx in the veh treated but not in the L. para or the L. mix treated mice. Probiotic treatment reduced the expression of the two inflammatory cytokines, TNFα and IL-1β, and increased the expression of OPG, a potent inhibitor of osteoclastogenesis, in cortical bone of ovx mice. In addition, ovx decreased the frequency of regulatory T cells in bone marrow of veh treated but not probiotic treated mice. In conclusion, treatment with L. para or the L. mix prevents ovx-induced cortical bone loss. Our findings indicate that these probiotic treatments alter the immune status in bone resulting in attenuated bone resorption in ovx mice.

Whether sensory nerve can sense bone density or metabolic activity to control bone homeostasis is unknown. Here we found prostaglandin E2 (PGE2) secreted by osteoblastic cells activates PGE2 receptor 4 ( EP4 ) in sensory nerves to regulate bone formation by inhibiting sympathetic activity through the central nervous system. PGE2 secreted by osteoblasts increases when bone density decreases as demonstrated in osteoporotic animal models. Ablation of sensory nerves erodes the skeletal integrity. Specifically, knockout of the EP4 gene in the sensory nerves or cyclooxygenase-2 ( COX2 ) in the osteoblastic cells significantly reduces bone volume in adult mice. Sympathetic tone is increased in sensory denervation models, and propranolol, a β2-adrenergic antagonist, rescues bone loss. Furthermore, injection of SW033291, a small molecule to increase PGE2 level locally, significantly boostes bone formation, whereas the effect is obstructed in EP4 knockout mice. Thus, we show that PGE2 mediates sensory nerve to control bone homeostasis and promote regeneration. Bone is innervated, and its turnover is affected by sympathetic nerve activity. Here, the authors show that prostaglandin E2, secreted by osteoblasts, activates the EP4 receptor on sensory nerves, inhibiting sympathetic nerve activity and modulating bone formation in mice.

Background. Abacavir-lamivudine and tenofovir DF-emtricitabine fixed-dose combinations are commonly used as first-line antiretroviral therapies. However, few studies have comprehensively compared their relative safety profiles. Methods. In this European, multicenter, open-label, 96-week study, antiretroviral-naive adult subjects with human immunodeficiency virus (HIV) infection were randomized to receive either abacavir-lamivudine or tenofovir-emtricitabine with efavirenz. Primary analyses were conducted after 48 weeks of treatment. Bone mineral density (BMD), a powered secondary end point, was assessed by dual energy x-ray absorptiometry. Bone turnover markers (osteocalcin, procollagen 1 N-terminal propeptide, bone specific alkaline phosphatase, and type 1 collagen cross-linked C telopeptide [CTx]) were assessed in an exploratory analysis. Results. A total of 385 subjects were enrolled in the study. BMD loss was observed in both treatment groups, with a significant difference in the change from baseline in both total hip (abacavir-lamivudine group, −1.9%; tenofovir-emtricitabine group, −3.6%; P <; .001) and lumbar spine (abacavir-lamivudine group, −1.6%; tenofoviremtricitabine group, −2.4%; P = .036). BMD loss of ⩾6% was more common in the tenofovir-emtricitabine group (13% of the tenofovir-emtricitabine group vs 3% of the abacavir-lamivudine group had a loss of ⩾6% in the hip; 15% vs 5% had a loss of ⩾6% in the spine). Bone turnover markers increased in both treatment groups over the first 24 weeks, stabilizing or decreasing thereafter. Increases in all markers were significantly greater in the tenofovir-emtricitabine treatment group than in the abacavir-lamivudine group at week 24. All but CTx remained significantly different at week 48 (eg, osteocalcin: abacavir-lamivudine group, +8.07 mg/L; tenofoviremtricitabine group, +11.92 mg/L; P < .001). Conclusions. This study demonstrated the impact of first-line treatment regimens on bone. Greater increases in bone turnover and decreases in BMD were observed in subjects treated with tenofovir-emtricitabine than were observed in subjects treated with abacavir-lamivudine.

Key Points Osteoarthritis (OA) is a whole-joint disease in which all of the components of the joint are affected The articular cartilage, subchondral bone, and calcified cartilage form an osteochondral biocomposite that is uniquely adapted to transferring loads during weight bearing and joint motion Marked alterations in the composition, functional properties, and structure of the osteochondral tissues occur during the evolution of OA Alteration in the composition or structure of any of the individual components of the osteochondral unit can initiate OA pathology in the joint The differential capacity of bone and cartilage to adapt to the effects of local mechanical and environmental influences has an important role in the development of OA Crosstalk between chondrocytes and bone cells contributes to OA pathogenesis To develop rational therapies for OA, it is essential to have diagnostic tools to define the state of the components of the osteochondral unit In this Review, the authors summarize the changes that occur in the biocomposite formed by articular cartilage and bone during the evolution of osteoarthritis (OA). They also discuss how an improved understanding of these changes could be exploited to develop new therapies for patients with OA. In diarthrodial joints, the articular cartilage, calcified cartilage, and subchondral cortical and trabecular bone form a biocomposite — referred to as the osteochondral unit — that is uniquely adapted to the transfer of load. During the evolution of the osteoarthritic process the compositions, functional properties, and structures of these tissues undergo marked alterations. Although pathological processes might selectively target a single joint tissue, ultimately all of the components of the osteochondral unit will be affected because of their intimate association, and thus the biological and physical crosstalk among them is of great importance. The development of targeted therapies against the osteoarthritic processes in cartilage or bone will, therefore, require an understanding of the state of these joint tissues at the time of the intervention. Importantly, these interventions will not be successful unless they are applied at the early stages of disease before considerable structural and functional alterations occur in the osteochondral unit. This Review describes the changes that occur in bone and cartilage during the osteoarthritic process, and highlights strategies for how this knowledge could be applied to develop new therapeutic interventions for osteoarthritis.