Reports linking long-term use of bisphosphonates (BPs) with atypical fractures of the femur led the leadership of the American Society for Bone and Mineral Research (ASBMR) to appoint a task force to address key questions related to this problem. A multidisciplinary expert group reviewed pertinent published reports concerning atypical femur fractures, as well as preclinical studies that could provide insight into their pathogenesis. A case definition was developed so that subsequent studies report on the same condition. The task force defined major and minor features of complete and incomplete atypical femoral fractures and recommends that all major features, including their location in the subtrochanteric region and femoral shaft, transverse or short oblique orientation, minimal or no associated trauma, a medial spike when the fracture is complete, and absence of comminution, be present to designate a femoral fracture as atypical. Minor features include their association with cortical thickening, a periosteal reaction of the lateral cortex, prodromal pain, bilaterality, delayed healing, comorbid conditions, and concomitant drug exposures, including BPs, other antiresorptive agents, glucocorticoids, and proton pump inhibitors. Preclinical data evaluating the effects of BPs on collagen cross-linking and maturation, accumulation of microdamage and advanced glycation end products, mineralization, remodeling, vascularity, and angiogenesis lend biologic plausibility to a potential association with long-term BP use. Based on published and unpublished data and the widespread use of BPs, the incidence of atypical femoral fractures associated with BP therapy for osteoporosis appears to be very low, particularly compared with the number of vertebral, hip, and other fractures that are prevented by BPs. Moreover, a causal association between BPs and atypical fractures has not been established. However, recent observations suggest that the risk rises with increasing duration of exposure, and there is concern that lack of awareness and underreporting may mask the true incidence of the problem. Given the relative rarity of atypical femoral fractures, the task force recommends that specific diagnostic and procedural codes be created and that an international registry be established to facilitate studies of the clinical and genetic risk factors and optimal surgical and medical management of these fractures. Physicians and patients should be made aware of the possibility of atypical femoral fractures and of the potential for bilaterality through a change in labeling of BPs. Research directions should include development of animal models, increased surveillance, and additional epidemiologic and clinical data to establish the true incidence of and risk factors for this condition and to inform orthopedic and medical management. ß

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SummaryThe bacterial pathogen Xanthomonas campestris pv. campestris co-ordinates virulence factor production and biofilm dispersal through a diffusible signal factor (DSF)-mediated cell-cell communication mechanism. The RpfC/RpfG two-component system plays a key role in DSF signal transduction and appears to modulate downstream DSF regulon by changing intracellular content of cyclic dimeric GMP (c-di-GMP), an unusual nucleotide second messenger. Here we show that Clp, a conserved global regulator showing a strong homology to the cAMP nucleotide receptor protein Crp of Escherichia coli, is essential for DSF regulation of virulence factor production but not for biofilm dispersal. Deletion of clp in Xcc changed the transcriptional expression of 299 genes including a few encoding transcription factors. Further genetic and microarray analysis led to identification of a homologue of the transcriptional regulator Zur, and a novel TetR-type transcription factor FhrR. These two regulatory factors regulated different sets of genes within Clp regulon. These results outline a hierarchical signalling network by which DSF modulates different biological functions, and may also provide a clue on how the novel nucleotide signal can be coupled to its downstream regulatory networks.

Vitamin D is a fundamental mediator of skeletal metabolism. It also has important nonskeletal actions. We hypothesized that vitamin D deficiency may play an important role in skeletal morbidity and clinical outcomes in MM. We studied 148 newly diagnosed MM patients from IntroductionSkeletal complications are a major cause of morbidity in multiple myeloma (MM). These complications include hypercalcemia due to increased bone resorption, generalized bone loss, intractable bone pain due to lytic bone destruction, and pathologic fractures at skeletal sites compromised by osteolytic lesions [1,2]. Vitamin D is a fundamental mediator of skeletal metabolism, due to its ability to stimulate the absorption of calcium and phosphate across the intestinal mucosa, and to promote bone mineralization. Vitamin D deficiency results in reduced intestinal calcium absorption and secondary hyperparathyroidism, leading to increased skeletal catabolism to maintain serum calcium levels within the normal range [3].In addition to its critical role in maintenance of skeletal homeostasis, several recent reports suggest that vitamin D modulates several other critical cellular processes, including inhibition of carcinogenesis by induction of differentiation, inhibition of proliferation and angiogenesis, and promotion of apoptosis [4]. To date, evidence of an inverse association between 25(OH)D levels and cancer risk in humans is best documented for cancers of the gastrointestinal tract with emerging evidence in prostate cancer and breast cancer [4]. Given these recognized roles of vitamin D, it is plausible that vitamin D deficiency may be both an important contributor to the spectrum of skeletal complications seen in patients with MM and an important determinant of the prognosis and progression of MM. In vitro studies, in which 1,25(OH) 2 D3 analogues demonstrate antiproliferative and proapoptotic effects in myeloma cell lines [5][6][7][8], support this hypothesis. However, human studies on the relationship between vitamin D deficiency and MM are notably lacking. The need for such studies is even more urgent considering the current ''pandemic'' of vitamin D deficiency [3]; using current recommended minimum levels for serum 25(OH)D, recent studies suggest that a high proportion of community-dwelling men and women in both tropical and temperate climates are deficient in vitamin D [9].In this study, we examined the relationship between vitamin D deficiency and the presentation of multiple myeloma at diagnosis. Our hypotheses were that vitamin D defi-

Recent population-based studies demonstrate an increased fracture risk with monoclonal gammopathy of undetermined significance (MGUS). The etiology of this increased risk remains unclear, however, because areal bone mineral density (aBMD) measurements by dualenergy x-ray absorptiometry cannot assess bone microstructural properties critical to determining bone quality and strength. To better define the skeletal effects of MGUS, we performed aBMD and high-resolution peripheral quantitative computed tomography volumetric bone mineral density (vBMD) measurements in 50 MGUS patients (20 females, 30 males; mean ؎ SEM age, 70.5 ؎ 1.4 years) and 100 matched control subjects. Relative to controls, MGUS patients had decreased aBMD at the femoral neck (P ‫؍‬ .05) and total femur (P < .05) but no differences at other sites. In contrast, highresolution peripheral quantitative computed tomography showed markedly diminished cortical thickness (P < .05) and increased endocortical area (P < .01). Average vBMD (P < .01), cortical vBMD (P < .001), and trabecular thickness (P < .01) were all significantly decreased in MGUS patients, suggestive of impaired bone formation. Serum levels of the Wnt pathway inhibitor Dickkopfrelated protein 1 (P < .001) and osteoclastactivating factor MIP-1␣ (P < .05) also were significantly elevated in MGUS patients. Our data provide the first evidence of altered bone microstructure in MGUS and suggest that cytokines elevated in osteolytic myeloma also may be associated with bone loss in MGUS. (Blood. 2011;118(25):6529-6534) IntroductionMultiple myeloma (MM) results from the clonal expansion of malignant plasma cells within the bone marrow. Bone disease is nearly universal in MM. Roughly 80% of patients develop a pathologic fracture at some point during their disease, and nearly 90% have radiographic evidence of skeletal lesions. 1 At the other end of the monoclonal gammopathy spectrum, monoclonal gammopathy of undetermined significance (MGUS) is a premalignant condition, with an ϳ 1% annual risk of progression to an MMrelated malignancy. 2 MGUS is a common finding in clinical practice, with a prevalence of ϳ 3.2% in white persons 50 years of age and older. 3 This increases with age, such that in persons older than 85 years of age, the prevalence of MGUS is ϳ 7.5%.By definition, MGUS patients lack lytic bone lesions. 3 Nonetheless, population-based studies show that MGUS is associated with a significantly increased risk of fracture, 4,5 suggesting that alterations in bone quantity, quality, or both are present even before disease progression to MM. 6 However, little is known about the skeletal phenotype of MGUS and whether abnormalities exist to explain this increased fracture risk. Indeed, even whether bone loss is increased in MGUS is a subject of debate. Thus, some studies 7,8 but not others 9,10 have reported that biochemical markers of bone resorption are increased in MGUS. Furthermore, although several studies have reported that fractures are increased in MGUS, 4,[10][11][12] some of these same s...