The aim of this prospective study [1] was to develop a risk score, based on putative risk factors in current guidelines, which can be used to identify women at high risk of fractures in general practice. The study sample included 4157 women >60 y of age (mean ± SD: 74.1 ± 9.1 yr), with a median follow-up of 8.9 y of the Rotterdam Study (ERGO), and 762 women >65 y of age (mean ± SD: 76.0 ± 6.7.y), with a median follow-up of 6.0 y of the Longitudinal Aging Study Amsterdam (LASA). Potential risk factors were those proposed in risk scores of three recent guidelines on osteoporosis: age, family history of fractures, prior fracture, low body weight/body mass index (BMI), serious immobility, rheumatoid arthritis, current smoking, alcohol consumption >2 units daily, prevalent vertebral fracture, and systemic corticosteroid use.

Five-year absolute risk of hip fracture was 3.9% in the Rotterdam Study and 3.1% in LASA, and 10-y absolute risk of hip fracture was 8.4% in the Rotterdam Study. Using Cox regression analysis, age (70–79 and 80+ versus <60–69) and four other risk factors were included in the risk profiles of hip fractures and fragility fractures: any prior fracture after age 50, body weight <64 kg, use of a walking aid as a proxy measure of serious immobility, and current smoking. Estimated 10-y absolute risk of hip fracture ranged from 1.4% in women, age 60–69 years, without any of these predictors to 29% in women, >80 y of age, having two or more positive risk factors.

A simple risk score can satisfactorily identify older women at high risk of osteoporotic fractures in general practice. Future studies are needed to validate this score.

1. Pluijm SMF et al. J Bone Miner Res. 2009;24:768–774.

Age-related osteoporosis is characterized by low bone mass, poor bone quality, and impaired osteoblastogenesis. Recently, the Hutchinson-Gilford progeria syndrome (HGPS), a disease of accelerated aging and premature osteoporosis, has been linked to mutations in the gene encoding for the nuclear lamina protein lamin A/C. Here [1], the authors tested the hypothesis that inhibition of lamin A/C in osteoblastic lineage cells impairs osteoblastogenesis and accelerates osteoclastogenesis. Lamin A/C was knockeddown with small interfering (si)RNA molecules in human bone marrow stromal cells (BMSCs) differentiating toward osteoblasts.

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Loss- and gain-of-function mutations in the broadly expressed gene LDL receptor-related protein 5 (Lrp5) affect bone formation, causing osteoporosis and high bone mass, respectively. Although Lrp5 is viewed as a Wnt coreceptor, osteoblast-specific disruption of β-catenin does not affect bone formation.

Instead, the authors of this study [1] show here that Lrp5 inhibits expression of tryptophan hydroxylase 1 (Tph1), the rate-limiting biosynthetic enzyme for serotonin in enterochromaffin cells of the duodenum. Accordingly, decreasing serotonin blood levels normalizes bone formation and bone mass in Lrp5-deficient mice, and gut- but not osteoblast-specific Lrp5 inactivation decreases bone formation in a β-catenin-independent manner. Moreover, gut-specific activation of Lrp5, or inactivation of Tph1, increases bone mass and prevents ovariectomy-induced bone loss. Serotonin acts on osteoblasts through the Htr1b receptor and CREB to inhibit their proliferation.

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The leptin regulation of bone remodeling, has been documented through studies of loss-of-function mutations of this hormone or of its receptor in mice and humans (see Osteoscoop Newsletter N°14, 15, 34, 37). However, unanswered questions remain. For instance, it has been assumed but not formally demonstrated that this regulation occurs through neuronal means. Likewise, it has not been possible until now to dissociate the influence leptin exerts on appetite and energy expenditure from this function.

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Activation of osteoclasts and their acidification-dependent resorption of bone is thought to maintain proper serum calcium levels. In a recent study [1], the authors show that osteoclast dysfunction alone does not generally affect calcium homeostasis. Indeed, mice deficient in Src, encoding a tyrosine kinase critical for osteoclast activity, show signs of osteopetrosis, but without hypocalcemia or defects in bone mineralization. Mice deficient in a gastrin receptor that affects acid secretion by parietal cells have the expected defects in gastric acidification but also secondary hyperparathyroidism and osteoporosis and modest hypocalcemia.
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Src family kinases (SFKs) are nonreceptor tyrosine kinases that are promiscuous in their impact on events such as growth, differentiation, cytoskeletal organization, and survival. One member of this family, c-Src kinase, is a rate-limiting activator of osteoclast function and Src inhibitors are therefore candidate antiosteoporosis drugs. By affecting M-CSF-induced signaling, c-Src is central to osteoclast activity, but not differentiation. The authors of a recent study [1] found that Lyn, another member of Src family kinases is, in contrast, a negative regulator of osteoclastic bone resorption.

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Low-density lipoprotein receptor–related protein 5 (Lrp5) is a membrane protein acting as a coreceptor in canonical Wnt signaling. Lrp5 increases osteoblast proliferation, differentiation, and function. The purpose of a recent study [1] was to use Lrp5-deficient mice to evaluate the potential role of this gene in mediating the bone anabolic effects of parathyroid hormone (PTH).

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Genetic studies in humans and mice have shown that the secreted protein sclerostin, synthesized by osteocytes, is a key negative regulator of bone formation, although the magnitude and extent of sclerostin’s role in the control of bone formation in the aging skeleton is still unclear. To study this unexplored area of sclerostin biology and to assess the pharmacologic effects of sclerostin inhibition, the authors of a recent study [1] used a cell culture model of bone formation to identify a sclerostin neutralizing monoclonal antibody (Scl-AbII) for testing in an aged ovariectomized rat model of postmenopausal osteoporosis.

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Estrogens are key hormones in bone remodeling. Estrogen deficiency in postmenopausal women frequently leads to osteoporosis, the most common skeletal disorder. Osteoporotic bone loss is the result of high bone turnover in which bone resorption outpaces bone formation. This imbalance can be ameliorated with bioavailable estrogens. Estrogens primarily act by regulating gene transcription via estrogen receptors (ERα, ERα). In mice, though ERα appears to be the major estrogen receptor, neither bone loss nor high bone turnover is detectable in ERα knock-out females. This unexpected maintenance of bone mass in female mutants is presumed to be due to unphysiologically elevated levels of other osteoprotective hormones, like androgens. Systemic defects in the hypothalamus caused by ER inactivation appear to impair the negative feedback system of hormone production. This leads to an excess in estrogen precursors, notably androgens. Thus, irrespective of the accumulating clinical and basic research data on the osteoprotective actions of estrogens, the molecular basis of this osteoprotection in females remains elusive. In this study [1], the authors report a critical role for ERα in mediating estrogen-dependent bone maintenance in female mice.

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Bone modeling and remodeling are responsible for the construction of the skeleton during growth and its maintenance during adulthood. Bone remodeling involves the removal of a quantum of bone from a surface followed by the formation of new bone within the cavity created. Remodeling is carried out at spatially discrete foci by teams of cells that form the basic multicellular unit (BMU). The number of BMUs and the relative amounts of bone resorbed and formed within individual BMUs determine bone turnover. Assessment of remodeling balance and rate is achieved using static and dynamic histomorphometry. Estimation of remodeling balance requires measurement of the volume of bone formed (wall width) and resorbed (erosion depth) within individual BMUs. Measurement of erosion depth at completion of the resorptive phase of a remodeling cycle is problematic, imposing limitations on the accurate assessment of BMU balance. Remodeling rate is often expressed as the activation frequency, which represents the probability that a new remodeling cycle will be initiated at any point on the bone surface. Activation frequency represents the bone formation rate at surface level divided by the wall width. The histomorphometric derivation of activation frequency assumes that the remodeling rate is dependent on the duration of the remodeling cycle and the amount of bone formed in individual remodeling units. This implies that remodeling balance and remodeling rate are coregulated. A recent study [1] tested this assumption in normal human adult cancellous bone. Relationships between indices of bone formation at the basic multicellular unit (BMU) level (wall width and mineral apposition rate) and indices of remodeling rate (mineralizing perimeter and osteoid perimeter) were examined in iliac crest biopsies obtained from 57 healthy adults (24 men) 19 to 80 y of age.

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