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Abstract Context Intravenous zoledronate prevents bone loss and reduces fracture risk in older adults but the optimal dosing strategy required to achieve each outcome is not known. Objective To assess the effect of very infrequent zoledronate therapy on bone mineral density (BMD) and markers of bone turnover. Design and participants An average of 5.5 years after randomization to either a single dose of 5 mg of zoledronateor placebo, 33 of the original cohort of 50 older women with osteopenia entered a 5-year open-label extension study. Setting Academic research center Intervention A 5-mg dose of intravenous zoledronate was administered to all participants. Main outcome measures BMD and bone turnover were measured annually, generating data over almost 11 years in women who received 5 mg of zoledronate at 0 and 5.5 years (ZZ, n = 16), or placebo at baseline and 5 mg of zoledronate at 5.5 years (PZ, n = 17). Results After redosing, BMD in ZZ remained stable, while BMD in PZ increased. At 11 years, changes from baseline BMD in ZZ and PZ were 3.8% (95% confidence interval (CI) 1.1,6.5) and 2.9% (0.3,5.5) at the lumbar spine (P = .61), 0.9% (–1.7,3.5) and –2.8% (–5.3,–0.3) at the total hip (P = .006), and 0.4% (–0.8,1.6) and –0.4% (–1.3,0.5) at the total body (P = .14). Bone turnover markers were similar in the PZ and ZZ groups throughout the 5 years after redosing. Conclusions These results suggest that zoledronate 5 mg administered at a 5.5-year interval prevents bone loss over almost 11 years. Clinical trials to investigate whether very infrequent treatment with zoledronate reduces fracture risk are justified.

Purpose The phase III DATA study compared 6 and 3 years of adjuvant anastrozole following 2–3 years of tamoxifen in postmenopausal breast cancer patients. This pre-planned side-study assessed the relationship between a reduced bone mineral density (BMD) and distant recurrence-free survival (DRFS), and evaluated the effect of bisphosphonates on DRFS. Methods We selected all patients with a BMD measurement within 3 years after randomisation (landmark) without any DRFS events. Kaplan–Meier methods and Cox proportional hazards models were used for analyses. Results Of 1860 eligible patients, 1142 had a DEXA scan before the landmark. The BMD was normal in 436 (38.2%) and showed osteopenia in 565 (49.5%) and osteoporosis in 141 (12.3%) patients. After a median follow-up of 5.0 years from the landmark, neither osteopenia nor osteoporosis (compared with normal BMD) were associated with DRFS in both the 6-year [osteopenia HR 0.82 (95% CI 0.45–1.49), osteoporosis HR 1.10 (95% CI 0.26–4.67)] and the 3-year arm [osteopenia HR 0.75 (95% CI 0.40–1.42), osteoporosis HR 1.86 (95% CI 0.43–8.01)]. Moreover, bisphosphonate use did not impact DRFS. Conclusion No association was observed between a reduced BMD and DRFS. Neither did we observe an impact of bisphosphonates on DRFS.

Summary This cross-sectional study involves randomly selected men aged 50 to 99 years and postmenopausal women. Either central fat mass or peripheral fat mass were associated to osteoporosis or osteopenia independently from fat-free body mass and other confounding factors. Introduction Obesity and osteoporosis are public health problems that probably share common pathophysiological mechanisms. The question if body fat mass, central or peripheral, is protective or harmful for osteoporosis or osteopenia is not completely resolved. This study aims to investigate the association between osteoporosis or osteopenia, and fat body mass (central and peripheral) independently from fat-free body mass, in men aged 50 to 99 years old and postmenopausal women randomly selected in the community. Methods This is a cross-sectional investigation with a random sample of registered population in Niterói Family Doctor Program (FDP), State of Rio de Janeiro, Brazil. Bone mineral density (BMD) and fat-free mass were assessed by dual X-ray absorptiometry (DXA). Results There was statistically significant bivariate association between bone loss with gender, age, skin color, alcohol consumption at risk dose, use of thiazide, fat-free body mass, and fat body mass (central and peripheral). In the multiple analysis of fat-free body mass, central and peripheral fat body mass showed an independent and protective effect on the presence of osteoporosis or osteopenia ( p value <0.001). Conclusion Since both obesity and osteoporosis are public health problems worldwide, strategies aimed at preventing both conditions should be encouraged during aging.

Summary We have examined the effect of oral monthly ibandronate on distal radius and tibia microarchitecture with high-resolution peripheral quantitative tomography compared with placebo, in women with osteopenia, and found that ibandronate did not significantly affect trabecular bone but improved cortical density and thickness at the tibia. Methods We have examined the effect of ibandronate on bone microarchitecture with peripheral high-resolution quantitative computed tomography (HR-pQCT) in a randomized placebo-controlled trial among 148 women with osteopenia. Patients received either oral 150 mg monthly ibandronate or placebo over 24 months. Bone microarchitecture was assessed at baseline, 6, 12, and 24 months, using HR-pQCT at the distal radius and tibia; areal bone mineral density (aBMD) was measured with DXA at the spine, hip, and radius. Results At 12 months, there was no significant difference in trabecular bone volume at the radius (the primary end point) between women on ibandronate (10.8 ± 2.5%) and placebo (10.5 ± 2.9%), p  = 0.25. There was no significant difference in other radius trabecular and cortical microarchitecture parameters at 12 and 24 months. In contrast, at the tibia, cortical vBMD in the ibandronate group was significantly greater than in the placebo group at 6, 12, and 24 months, with better cortical thickness at 6, 12, and 24 months. With ibandronate, aBMD was significantly increased at the hip and spine at 12 and 24 months but at the radius was significantly superior to placebo only at 24 months. Most of the adverse events related to ibandronate were expected with bisphosphonate use, and none of them were serious. Conclusion We conclude that 12 months of treatment with ibandronate in women with osteopenia did not affect trabecular bone microarchitecture, but improved cortical vBMD at the tibia at 12 and 24 months, and preserved cortical thickness at the tibia.

IntroductionCancer treatment-induced bone loss (CTIBL) is a long-term side effect of breast cancer therapy. Both calcitriol and weight-bearing exercise improve bone metabolism for osteoporotic patients, but are unproven in a breast cancer population. We used a novel high-dose calcitriol regimen with an individualized exercise intervention to improve bone metabolism in breast cancer survivors.MethodsWe accrued 41 subjects to this open label, 2 × 2 factorial, randomized feasibility trial. Breast cancer survivors were randomized to receive the following: (1) calcitriol (45 micrograms/week), (2) individualized exercise with progressive walking and resistance training, (3) both, or (4) a daily multivitamin (control condition) for 12 weeks. Primary outcomes included changes in biomarkers of bone formation, bone resorption, and the bone remodeling index, a composite measure of bone formation and resorption. Safety measures included clinical and biochemical adverse events. A main effect analysis was used for these endpoints.ResultsHypercalcemia was limited to three grade I cases with no grade ≥ 2 cases. Among exercisers, 100% engaged in the prescribed aerobic training and 44.4% engaged in the prescribed resistance training. Calcitriol significantly improved bone formation (Cohen’s d = 0.64; p < 0.01), resulting in a non-significant increase in the bone remodeling index (Cohen’s d = 0.21; p = 31). Exercise failed to improve any of the bone biomarkers.ConclusionsBoth calcitriol and exercise were shown to be feasible and well tolerated. Calcitriol significantly improved bone formation, resulting in a net increase of bone metabolism. Compliance with the exercise intervention was sub-optimal, which may have led to a lack of effect of exercise on bone metabolism.

The gut microbiome is a key regulator of bone health that affects postnatal skeletal development and skeletal involution. Alterations in microbiota composition and host responses to the microbiota contribute to pathological bone loss, while changes in microbiota composition that prevent, or reverse, bone loss may be achieved by nutritional supplements with prebiotics and probiotics. One mechanism whereby microbes influence organs of the body is through the production of metabolites that diffuse from the gut into the systemic circulation. Recently, short-chain fatty acids (SCFAs), which are generated by fermentation of complex carbohydrates, have emerged as key regulatory metabolites produced by the gut microbiota. This Review will focus on the effects of SCFAs on the musculoskeletal system and discuss the mechanisms whereby SCFAs regulate bone cells.

Coupling is the process that links bone resorption to bone formation in a temporally and spatially coordinated manner within the remodeling cycle. Several lines of evidence point to the critical roles of osteoclast-derived coupling factors in the regulation of osteoblast performance. Here, we used a fractionated secretomic approach and identified the axon-guidance molecule SLIT3 as a clastokine that stimulated osteoblast migration and proliferation by activating β-catenin. SLIT3 also inhibited bone resorption by suppressing osteoclast differentiation in an autocrine manner. Mice deficient in Slit3 or its receptor, Robo1, exhibited osteopenic phenotypes due to a decrease in bone formation and increase in bone resorption. Mice lacking Slit3 specifically in osteoclasts had low bone mass, whereas mice with either neuron-specific Slit3 deletion or osteoblast-specific Slit3 deletion had normal bone mass, thereby indicating the importance of SLIT3 as a local determinant of bone metabolism. In postmenopausal women, higher circulating SLIT3 levels were associated with increased bone mass. Notably, injection of a truncated recombinant SLIT3 markedly rescued bone loss after an ovariectomy. Thus, these results indicate that SLIT3 plays an osteoprotective role by synchronously stimulating bone formation and inhibiting bone resorption, making it a potential therapeutic target for metabolic bone diseases.

Key Points Bone homeostasis is dependent on the concerted actions of bone-building osteoblasts and bone-degrading osteoclasts — a process called bone remodelling. Two of the major factors that induce osteoblast differentiation and activation are: the signalling mediated by bone morphogenetic proteins via runt-related transcription factor 2; and the WNT–Frizzled–β-catenin pathway. Conversely, Dickkopf-related protein 1 (DKK1) and sclerostin inhibit osteoblast activation. Major molecules involved in osteoclast differentiation and activation include macrophage colony-stimulating factor and receptor activator of nuclear factor-κB (RANK) as well as its ligand (RANKL). Inflammation is associated with the overproduction of various cytokines, such as tumour necrosis factor, interleukin-1 (IL-1), IL-6 or IL-17. Their upregulation in the course of inflammation leads to excessive bone degradation mainly due to hyperactivation of osteoclasts, although some cytokines can also impair osteoblast function. Many diseases lead to inflammatory bone loss, including inflammatory bowel disease, chronic obstructive lung disease, cystic fibrosis, periodontitis, rheumatoid arthritis and other inflammatory diseases. Inflammatory bone loss is always systemic, and in some diseases — such as rheumatoid arthritis or periodontitis — it can also involve local bone. Therapies interfering with inflammation also affect systemic inflammatory bone loss, primarily by reducing the effects of cytokines on osteoclast activation; however, many of these treatments will not fully control inflammation. Owing to this ongoing inflammatory activity (even at low levels), bone loss will continue to accrue and therefore also requires specific targeting of bone cells. Bisphosphonates and denosumab are among the bone-targeting therapies that have been shown to be effective in treating inflammatory bone loss, but it is assumed that blockers of DKK1 and sclerostin — which are upregulated by cytokines and inhibit osteoblast repair mechanisms — are also likely to be effective. Bone continuously undergoes building and degradation — a process known as bone remodelling. This tightly controlled process can be dysregulated by chronic inflammation, and bone loss is commonly associated with inflammatory diseases. Here, Redlich and Smolen discuss the molecular mechanisms mediating the inflammatory loss of bone and present strategies and agents for therapeutic intervention. Bone is a tissue undergoing continuous building and degradation. This remodelling is a tightly regulated process that can be disturbed by many factors, particularly hormonal changes. Chronic inflammation can also perturb bone metabolism and promote increased bone loss. Inflammatory diseases can arise all over the body, including in the musculoskeletal system (for example, rheumatoid arthritis), the intestine (for example, inflammatory bowel disease), the oral cavity (for example, periodontitis) and the lung (for example, cystic fibrosis). Wherever inflammatory diseases occur, systemic effects on bone will ensue, as well as increased fracture risk. Here, we discuss the cellular and signalling pathways underlying, and strategies for therapeutically interfering with, the inflammatory loss of bone.

Vascularization is fundamental for bone formation and bone tissue homeostasis. However, in human subjects, a direct molecular relationship has not been identified between angiogenesis and agents that promote bone disease or factors related to age. Osteopenia is a condition in which bone mineral density is lower than normal, and it represents a sign of normal aging. Here we tested whether the type H vessel, which was recently identified as strongly positive for CD31 and Endomucin (CD31 hi Emcn hi ) in mice, is an important indicator of aging and osteopenia in human subjects. We found that age-dependent losses of type H vessels in human bone sections conform to the observations in aged mice. The abundance of human type H vessels and osteoprogenitors may be relevant to changes in the skeletal microarchitecture and advanced osteopenia. Furthermore, ovariectomized mice, a widely used model for postmenopausal osteoporosis, exhibited significantly reduced type H vessels accompanied by reduced osteoprogenitors, which is consistent with impaired bone microarchitecture and osteoporosis, suggesting that this feature is an indicator of bone mass independent of aging. More importantly, administration of desferrioxamine led to significantly increased bone mass via enhanced angiogenesis and increased type H vessels in ovariectomized mice. Altogether, these data represent a novel finding that type H vessels are regulated in aged and osteopenia subjects. The abundance of human type H vessels is an early marker of bone loss and represents a potential target for improving bone quality via the induction of type H vessels.

In a new study, Yingzi Yang and her colleagues show that a careful balance between Wnt and Hedgehog signaling is required to maintain proper differentiation of osteogenic precursor cells. Upon mutation of GNAS , this balance is disturbed and severe bone disease develops, including either heterotopic ossification or fibrous dysplasia. Heterotopic ossification, the pathologic formation of extraskeletal bone, occurs as a common complication of trauma or in genetic disorders and can be disabling and lethal. However, the underlying molecular mechanisms are largely unknown. Here we demonstrate that Gα s restricts bone formation to the skeleton by inhibiting Hedgehog signaling in mesenchymal progenitor cells. In progressive osseous heteroplasia, a human disease caused by null mutations in GNAS , which encodes Gα s , Hedgehog signaling is upregulated in ectopic osteoblasts and progenitor cells. In animal models, we show that genetically-mediated ectopic Hedgehog signaling is sufficient to induce heterotopic ossification, whereas inhibition of this signaling pathway by genetic or pharmacological means strongly reduces the severity of this condition. As our previous work has shown that GNAS gain-of-function mutations upregulate WNT–β-catenin signaling in osteoblast progenitor cells, resulting in their defective differentiation and fibrous dysplasia, we identify Gα s as a key regulator of proper osteoblast differentiation through its maintenance of a balance between the Wnt–β-catenin and Hedgehog pathways. Also, given the results here of the pharmacological studies in our mouse model, we propose that Hedgehog inhibitors currently used in the clinic for other conditions, such as cancer, may possibly be repurposed for treating heterotopic ossification and other diseases caused by GNAS inactivation.