Amgen (United States)

OBJECTIVE: The 1987 American College of Rheumatology (ACR; formerly, the American Rheumatism Association) classification criteria for rheumatoid arthritis (RA) have been criticized for their lack of sensitivity in early disease. This work was undertaken to develop new classification criteria for RA. METHODS: A joint working group from the ACR and the European League Against Rheumatism developed, in 3 phases, a new approach to classifying RA. The work focused on identifying, among patients newly presenting with undifferentiated inflammatory synovitis, factors that best discriminated between those who were and those who were not at high risk for persistent and/or erosive disease--this being the appropriate current paradigm underlying the disease construct "rheumatoid arthritis." RESULTS: In the new criteria set, classification as "definite RA" is based on the confirmed presence of synovitis in at least 1 joint, absence of an alternative diagnosis that better explains the synovitis, and achievement of a total score of 6 or greater (of a possible 10) from the individual scores in 4 domains: number and site of involved joints (score range 0-5), serologic abnormality (score range 0-3), elevated acute-phase response (score range 0-1), and symptom duration (2 levels; range 0-1). CONCLUSION: This new classification system redefines the current paradigm of RA by focusing on features at earlier stages of disease that are associated with persistent and/or erosive disease, rather than defining the disease by its late-stage features. This will refocus attention on the important need for earlier diagnosis and institution of effective disease-suppressing therapy to prevent or minimize the occurrence of the undesirable sequelae that currently comprise the paradigm underlying the disease construct "rheumatoid arthritis."

BACKGROUND: Evolocumab is a monoclonal antibody that inhibits proprotein convertase subtilisin-kexin type 9 (PCSK9) and lowers low-density lipoprotein (LDL) cholesterol levels by approximately 60%. Whether it prevents cardiovascular events is uncertain. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 27,564 patients with atherosclerotic cardiovascular disease and LDL cholesterol levels of 70 mg per deciliter (1.8 mmol per liter) or higher who were receiving statin therapy. Patients were randomly assigned to receive evolocumab (either 140 mg every 2 weeks or 420 mg monthly) or matching placebo as subcutaneous injections. The primary efficacy end point was the composite of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina, or coronary revascularization. The key secondary efficacy end point was the composite of cardiovascular death, myocardial infarction, or stroke. The median duration of follow-up was 2.2 years. RESULTS: At 48 weeks, the least-squares mean percentage reduction in LDL cholesterol levels with evolocumab, as compared with placebo, was 59%, from a median baseline value of 92 mg per deciliter (2.4 mmol per liter) to 30 mg per deciliter (0.78 mmol per liter) (P<0.001). Relative to placebo, evolocumab treatment significantly reduced the risk of the primary end point (1344 patients [9.8%] vs. 1563 patients [11.3%]; hazard ratio, 0.85; 95% confidence interval [CI], 0.79 to 0.92; P<0.001) and the key secondary end point (816 [5.9%] vs. 1013 [7.4%]; hazard ratio, 0.80; 95% CI, 0.73 to 0.88; P<0.001). The results were consistent across key subgroups, including the subgroup of patients in the lowest quartile for baseline LDL cholesterol levels (median, 74 mg per deciliter [1.9 mmol per liter]). There was no significant difference between the study groups with regard to adverse events (including new-onset diabetes and neurocognitive events), with the exception of injection-site reactions, which were more common with evolocumab (2.1% vs. 1.6%). CONCLUSIONS: In our trial, inhibition of PCSK9 with evolocumab on a background of statin therapy lowered LDL cholesterol levels to a median of 30 mg per deciliter (0.78 mmol per liter) and reduced the risk of cardiovascular events. These findings show that patients with atherosclerotic cardiovascular disease benefit from lowering of LDL cholesterol levels below current targets. (Funded by Amgen; FOURIER ClinicalTrials.gov number, NCT01764633 .).

The development of noninvasive methods to detect and monitor tumors continues to be a major challenge in oncology. We used digital polymerase chain reaction-based technologies to evaluate the ability of circulating tumor DNA (ctDNA) to detect tumors in 640 patients with various cancer types. We found that ctDNA was detectable in >75% of patients with advanced pancreatic, ovarian, colorectal, bladder, gastroesophageal, breast, melanoma, hepatocellular, and head and neck cancers, but in less than 50% of primary brain, renal, prostate, or thyroid cancers. In patients with localized tumors, ctDNA was detected in 73, 57, 48, and 50% of patients with colorectal cancer, gastroesophageal cancer, pancreatic cancer, and breast adenocarcinoma, respectively. ctDNA was often present in patients without detectable circulating tumor cells, suggesting that these two biomarkers are distinct entities. In a separate panel of 206 patients with metastatic colorectal cancers, we showed that the sensitivity of ctDNA for detection of clinically relevant KRAS gene mutations was 87.2% and its specificity was 99.2%. Finally, we assessed whether ctDNA could provide clues into the mechanisms underlying resistance to epidermal growth factor receptor blockade in 24 patients who objectively responded to therapy but subsequently relapsed. Twenty-three (96%) of these patients developed one or more mutations in genes involved in the mitogen-activated protein kinase pathway. Together, these data suggest that ctDNA is a broadly applicable, sensitive, and specific biomarker that can be used for a variety of clinical and research purposes in patients with multiple different types of cancer.

C57BL/6J mice with a mutation in the obese (ob) gene are obese, diabetic, and exhibit reduced activity, metabolism, and body temperature. Daily intraperitoneal injection of these mice with recombinant OB protein lowered their body weight, percent body fat, food intake, and serum concentrations of glucose and insulin. In addition, metabolic rate, body temperature, and activity levels were increased by this treatment. None of these parameters was altered beyond the level observed in lean controls, suggesting that the OB protein normalized the metabolic status of the ob/ob mice. Lean animals injected with OB protein maintained a smaller weight loss throughout the 28-day study and showed no changes in any of the metabolic parameters. These data suggest that the OB protein regulates body weight and fat deposition through effects on metabolism and appetite.

Cerebral deposition of amyloid beta peptide (Abeta) is an early and critical feature of Alzheimer's disease. Abeta generation depends on proteolytic cleavage of the amyloid precursor protein (APP) by two unknown proteases: beta-secretase and gamma-secretase. These proteases are prime therapeutic targets. A transmembrane aspartic protease with all the known characteristics of beta-secretase was cloned and characterized. Overexpression of this protease, termed BACE (for beta-site APP-cleaving enzyme) increased the amount of beta-secretase cleavage products, and these were cleaved exactly and only at known beta-secretase positions. Antisense inhibition of endogenous BACE messenger RNA decreased the amount of beta-secretase cleavage products, and purified BACE protein cleaved APP-derived substrates with the same sequence specificity as beta-secretase. Finally, the expression pattern and subcellular localization of BACE were consistent with that expected for beta-secretase. Future development of BACE inhibitors may prove beneficial for the treatment of Alzheimer's disease.

BACKGROUND: Denosumab is a fully human monoclonal antibody to the receptor activator of nuclear factor-kappaB ligand (RANKL) that blocks its binding to RANK, inhibiting the development and activity of osteoclasts, decreasing bone resorption, and increasing bone density. Given its unique actions, denosumab may be useful in the treatment of osteoporosis. METHODS: We enrolled 7868 women between the ages of 60 and 90 years who had a bone mineral density T score of less than -2.5 but not less than -4.0 at the lumbar spine or total hip. Subjects were randomly assigned to receive either 60 mg of denosumab or placebo subcutaneously every 6 months for 36 months. The primary end point was new vertebral fracture. Secondary end points included nonvertebral and hip fractures. RESULTS: As compared with placebo, denosumab reduced the risk of new radiographic vertebral fracture, with a cumulative incidence of 2.3% in the denosumab group, versus 7.2% in the placebo group (risk ratio, 0.32; 95% confidence interval [CI], 0.26 to 0.41; P<0.001)--a relative decrease of 68%. Denosumab reduced the risk of hip fracture, with a cumulative incidence of 0.7% in the denosumab group, versus 1.2% in the placebo group (hazard ratio, 0.60; 95% CI, 0.37 to 0.97; P=0.04)--a relative decrease of 40%. Denosumab also reduced the risk of nonvertebral fracture, with a cumulative incidence of 6.5% in the denosumab group, versus 8.0% in the placebo group (hazard ratio, 0.80; 95% CI, 0.67 to 0.95; P=0.01)--a relative decrease of 20%. There was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia, and there were no cases of osteonecrosis of the jaw and no adverse reactions to the injection of denosumab. CONCLUSIONS: Denosumab given subcutaneously twice yearly for 36 months was associated with a reduction in the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis. (ClinicalTrials.gov number, NCT00089791.)

Purpose Panitumumab, a fully human antibody against the epidermal growth factor receptor (EGFR), has activity in a subset of patients with metastatic colorectal cancer (mCRC). Although activating mutations in KRAS, a small G-protein downstream of EGFR, correlate with poor response to anti-EGFR antibodies in mCRC, their role as a selection marker has not been established in randomized trials. Patients and Methods KRAS mutations were detected using polymerase chain reaction on DNA from tumor sections collected in a phase III mCRC trial comparing panitumumab monotherapy to best supportive care (BSC). We tested whether the effect of panitumumab on progression-free survival (PFS) differed by KRAS status. Results KRAS status was ascertained in 427 (92%) of 463 patients (208 panitumumab, 219 BSC). KRAS mutations were found in 43% of patients. The treatment effect on PFS in the wild-type (WT) KRAS group (hazard ratio [HR], 0.45; 95% CI: 0.34 to 0.59) was significantly greater (P &lt; .0001) than in the mutant group (HR, 0.99; 95% CI, 0.73 to 1.36). Median PFS in the WT KRAS group was 12.3 weeks for panitumumab and 7.3 weeks for BSC. Response rates to panitumumab were 17% and 0%, for the WT and mutant groups, respectively. WT KRAS patients had longer overall survival (HR, 0.67; 95% CI, 0.55 to 0.82; treatment arms combined). Consistent with longer exposure, more grade III treatment-related toxicities occurred in the WT KRAS group. No significant differences in toxicity were observed between the WT KRAS group and the overall population. Conclusion Panitumumab monotherapy efficacy in mCRC is confined to patients with WT KRAS tumors. KRAS status should be considered in selecting patients with mCRC as candidates for panitumumab monotherapy.

The discovery of various protein/receptor targets from genomic research is expanding rapidly. Along with the automation of organic synthesis and biochemical screening, this is bringing a major change in the whole field of drug discovery research. In the traditional drug discovery process, the industry tests compounds in the thousands. With automated synthesis, the number of compounds to be tested could be in the millions. This two-dimensional expansion will lead to a major demand for resources, unless the chemical libraries are made wisely. The objective of this work is to provide both quantitative and qualitative characterization of known drugs which will help to generate "drug-like" libraries. In this work we analyzed the Comprehensive Medicinal Chemistry (CMC) database and seven different subsets belonging to different classes of drug molecules. These include some central nervous system active drugs and cardiovascular, cancer, inflammation, and infection disease states. A quantitative characterization based on computed physicochemical property profiles such as log P, molar refractivity, molecular weight, and number of atoms as well as a qualitative characterization based on the occurrence of functional groups and important substructures are developed here. For the CMC database, the qualifying range (covering more than 80% of the compounds) of the calculated log P is between -0.4 and 5.6, with an average value of 2.52. For molecular weight, the qualifying range is between 160 and 480, with an average value of 357. For molar refractivity, the qualifying range is between 40 and 130, with an average value of 97. For the total number of atoms, the qualifying range is between 20 and 70, with an average value of 48. Benzene is by far the most abundant substructure in this drug database, slightly more abundant than all the heterocyclic rings combined. Nonaromatic heterocyclic rings are twice as abundant as the aromatic heterocycles. Tertiary aliphatic amines, alcoholic OH and carboxamides are the most abundant functional groups in the drug database. The effective range of physicochemical properties presented here can be used in the design of drug-like combinatorial libraries as well as in developing a more efficient corporate medicinal chemistry library.

Mortality rates in ESRD are unacceptably high. Disorders of mineral metabolism (hyperphosphatemia, hypercalcemia, and secondary hyperparathyroidism) are potentially modifiable. For determining associations among disorders of mineral metabolism, mortality, and morbidity in hemodialysis patients, data on 40,538 hemodialysis patients with at least one determination of serum phosphorus and calcium during the last 3 mo of 1997 were analyzed. Unadjusted, case mix-adjusted, and multivariable-adjusted relative risks of death were calculated for categories of serum phosphorus, calcium, calcium x phosphorus product, and intact parathyroid hormone (PTH) using proportional hazards regression. Also determined was whether disorders of mineral metabolism were associated with all-cause, cardiovascular, infection-related, fracture-related, and vascular access-related hospitalization. After adjustment for case mix and laboratory variables, serum phosphorus concentrations >5.0 mg/dl were associated with an increased relative risk of death (1.07, 1.25, 1.43, 1.67, and 2.02 for serum phosphorus 5.0 to 6.0, 6.0 to 7.0, 7.0 to 8.0, 8.0 to 9.0, and >/=9.0 mg/dl). Higher adjusted serum calcium concentrations were also associated with an increased risk of death, even when examined within narrow ranges of serum phosphorus. Moderate to severe hyperparathyroidism (PTH concentrations >/=600 pg/ml) was associated with an increase in the relative risk of death, whereas more modest increases in PTH were not. When examined collectively, the population attributable risk percentage for disorders of mineral metabolism was 17.5%, owing largely to the high prevalence of hyperphosphatemia. Hyperphosphatemia and hyperparathyroidism were significantly associated with all-cause, cardiovascular, and fracture-related hospitalization. Disorders of mineral metabolism are independently associated with mortality and morbidity associated with cardiovascular disease and fracture in hemodialysis patients.

autophagic responses. Here, we critically discuss current methods of assessing autophagy and the information they can, or cannot, provide. Our ultimate goal is to encourage intellectual and technical innovation in the field.

PURPOSE: Talimogene laherparepvec (T-VEC) is a herpes simplex virus type 1-derived oncolytic immunotherapy designed to selectively replicate within tumors and produce granulocyte macrophage colony-stimulating factor (GM-CSF) to enhance systemic antitumor immune responses. T-VEC was compared with GM-CSF in patients with unresected stage IIIB to IV melanoma in a randomized open-label phase III trial. PATIENTS AND METHODS: Patients with injectable melanoma that was not surgically resectable were randomly assigned at a two-to-one ratio to intralesional T-VEC or subcutaneous GM-CSF. The primary end point was durable response rate (DRR; objective response lasting continuously ≥ 6 months) per independent assessment. Key secondary end points included overall survival (OS) and overall response rate. RESULTS: Among 436 patients randomly assigned, DRR was significantly higher with T-VEC (16.3%; 95% CI, 12.1% to 20.5%) than GM-CSF (2.1%; 95% CI, 0% to 4.5%]; odds ratio, 8.9; P < .001). Overall response rate was also higher in the T-VEC arm (26.4%; 95% CI, 21.4% to 31.5% v 5.7%; 95% CI, 1.9% to 9.5%). Median OS was 23.3 months (95% CI, 19.5 to 29.6 months) with T-VEC and 18.9 months (95% CI, 16.0 to 23.7 months) with GM-CSF (hazard ratio, 0.79; 95% CI, 0.62 to 1.00; P = .051). T-VEC efficacy was most pronounced in patients with stage IIIB, IIIC, or IVM1a disease and in patients with treatment-naive disease. The most common adverse events (AEs) with T-VEC were fatigue, chills, and pyrexia. The only grade 3 or 4 AE occurring in ≥ 2% of T-VEC-treated patients was cellulitis (2.1%). No fatal treatment-related AEs occurred. CONCLUSION: T-VEC is the first oncolytic immunotherapy to demonstrate therapeutic benefit against melanoma in a phase III clinical trial. T-VEC was well tolerated and resulted in a higher DRR (P < .001) and longer median OS (P = .051), particularly in untreated patients or those with stage IIIB, IIIC, or IVM1a disease. T-VEC represents a novel potential therapy for patients with metastatic melanoma.

Osteoprotegerin (OPG) is a secreted protein that inhibits osteoclast formation. In this study the physiological role of OPG is investigated by generating OPG-deficient mice. Adolescent and adult OPG-/- mice exhibit a decrease in total bone density characterized by severe trabecular and cortical bone porosity, marked thinning of the parietal bones of the skull, and a high incidence of fractures. These findings demonstrate that OPG is a critical regulator of postnatal bone mass. Unexpectedly, OPG-deficient mice also exhibit medial calcification of the aorta and renal arteries, suggesting that regulation of OPG, its signaling pathway, or its ligand(s) may play a role in the long observed association between osteoporosis and vascular calcification.

Severely obese (ob/ob) mice are deficient in the adipocyte-derived hormone leptin, which acts on the hypothalamus to control appetite and energy expenditure.1 The administration of leptin to these mice corrects their obesity by reducing their food intake and increasing their energy expenditure.2–4 These mice also have hyperinsulinemia, corticosterone excess, and infertility, which also are reversed by treatment with leptin.5 In humans, serum leptin concentrations, in general, correlate positively with indexes of obesity.6,7 We previously described two cousins with severe, early-onset obesity and undetectable serum leptin concentrations who were homozygous for a frame-shift mutation in the leptin . . .

In this randomized, prospective, open-label trial, we studied 1233 patients with congestive heart failure or ischemic heart disease who were undergoing hemodialysis at 51 centers (see the Appendix). The institutional review boards at all centers approved the protocol, and all the patients gave written, informed consent. All the patients had end-stage renal disease and were undergoing longterm hemodialysis, and they had hematocrit values of 27 to 33 percent while receiving epoetin during the four weeks before enrollment. Ninety percent of the patients received epoetin intrave-

BACKGROUND: p.G12C-mutated advanced solid tumors in a phase 1 study, and particularly promising anticancer activity was observed in a subgroup of patients with non-small-cell lung cancer (NSCLC). METHODS: p.G12C-mutated advanced NSCLC previously treated with standard therapies. The primary end point was objective response (complete or partial response) according to independent central review. Key secondary end points included duration of response, disease control (defined as complete response, partial response, or stable disease), progression-free survival, overall survival, and safety. Exploratory biomarkers were evaluated for their association with response to sotorasib therapy. RESULTS: . CONCLUSIONS: p.G12C-mutated NSCLC. (Funded by Amgen and the National Institutes of Health; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

Advancements in neural machinery have led to a wide range of algorithmic solutions for molecular property prediction. Two classes of models in particular have yielded promising results: neural networks applied to computed molecular fingerprints or expert-crafted descriptors and graph convolutional neural networks that construct a learned molecular representation by operating on the graph structure of the molecule. However, recent literature has yet to clearly determine which of these two methods is superior when generalizing to new chemical space. Furthermore, prior research has rarely examined these new models in industry research settings in comparison to existing employed models. In this paper, we benchmark models extensively on 19 public and 16 proprietary industrial data sets spanning a wide variety of chemical end points. In addition, we introduce a graph convolutional model that consistently matches or outperforms models using fixed molecular descriptors as well as previous graph neural architectures on both public and proprietary data sets. Our empirical findings indicate that while approaches based on these representations have yet to reach the level of experimental reproducibility, our proposed model nevertheless offers significant improvements over models currently used in industrial workflows.

BACKGROUND: Romosozumab, a monoclonal antibody that binds sclerostin, increases bone formation and decreases bone resorption. METHODS: We enrolled 7180 postmenopausal women who had a T score of -2.5 to -3.5 at the total hip or femoral neck. Patients were randomly assigned to receive subcutaneous injections of romosozumab (at a dose of 210 mg) or placebo monthly for 12 months; thereafter, patients in each group received denosumab for 12 months, at a dose of 60 mg, administered subcutaneously every 6 months. The coprimary end points were the cumulative incidences of new vertebral fractures at 12 months and 24 months. Secondary end points included clinical (a composite of nonvertebral and symptomatic vertebral) and nonvertebral fractures. RESULTS: At 12 months, new vertebral fractures had occurred in 16 of 3321 patients (0.5%) in the romosozumab group, as compared with 59 of 3322 (1.8%) in the placebo group (representing a 73% lower risk with romosozumab; P<0.001). Clinical fractures had occurred in 58 of 3589 patients (1.6%) in the romosozumab group, as compared with 90 of 3591 (2.5%) in the placebo group (a 36% lower risk with romosozumab; P=0.008). Nonvertebral fractures had occurred in 56 of 3589 patients (1.6%) in the romosozumab group and in 75 of 3591 (2.1%) in the placebo group (P=0.10). At 24 months, the rates of vertebral fractures were significantly lower in the romosozumab group than in the placebo group after each group made the transition to denosumab (0.6% [21 of 3325 patients] in the romosozumab group vs. 2.5% [84 of 3327] in the placebo group, a 75% lower risk with romosozumab; P<0.001). Adverse events, including instances of hyperostosis, cardiovascular events, osteoarthritis, and cancer, appeared to be balanced between the groups. One atypical femoral fracture and two cases of osteonecrosis of the jaw were observed in the romosozumab group. CONCLUSIONS: In postmenopausal women with osteoporosis, romosozumab was associated with a lower risk of vertebral fracture than placebo at 12 months and, after the transition to denosumab, at 24 months. The lower risk of clinical fracture that was seen with romosozumab was evident at 1 year. (Funded by Amgen and UCB Pharma; FRAME ClinicalTrials.gov number, NCT01575834 .).

The liver X receptors (LXRs) are members of the nuclear hormone receptor superfamily that are bound and activated by oxysterols. These receptors serve as sterol sensors to regulate the transcription of gene products that control intracellular cholesterol homeostasis through catabolism and transport. In this report, we describe a novel LXR target, the sterol regulatory element-binding protein-1c gene (SREBP-1c), which encodes a membrane-bound transcription factor of the basic helix-loop-helix-leucine zipper family. SREBP-1c expression was markedly increased in mouse tissues in an LXR-dependent manner by dietary cholesterol and synthetic agonists for both LXR and its heterodimer partner, the retinoid X receptor (RXR). Expression of the related gene products, SREBP-1a and SREBP-2, were not increased. Analysis of the mouse SREBP-1c gene promoter revealed an RXR/LXR DNA-binding site that is essential for this regulation. The transcriptional increase in SREBP-1c mRNA by RXR/LXR was accompanied by a similar increase in the level of the nuclear, active form of the SREBP-1c protein and an increase in fatty acid synthesis. Because this active form of SREBP-1c controls the transcription of genes involved in fatty acid biosynthesis, our results reveal a unique regulatory interplay between cholesterol and fatty acid metabolism.

BACKGROUND: . METHODS: p.G12C mutation. Patients received sotorasib orally once daily. The primary end point was safety. Key secondary end points were pharmacokinetics and objective response, as assessed according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1. RESULTS: A total of 129 patients (59 with NSCLC, 42 with colorectal cancer, and 28 with other tumors) were included in dose escalation and expansion cohorts. Patients had received a median of 3 (range, 0 to 11) previous lines of anticancer therapies for metastatic disease. No dose-limiting toxic effects or treatment-related deaths were observed. A total of 73 patients (56.6%) had treatment-related adverse events; 15 patients (11.6%) had grade 3 or 4 events. In the subgroup with NSCLC, 32.2% (19 patients) had a confirmed objective response (complete or partial response) and 88.1% (52 patients) had disease control (objective response or stable disease); the median progression-free survival was 6.3 months (range, 0.0+ to 14.9 [with + indicating that the value includes patient data that were censored at data cutoff]). In the subgroup with colorectal cancer, 7.1% (3 patients) had a confirmed response, and 73.8% (31 patients) had disease control; the median progression-free survival was 4.0 months (range, 0.0+ to 11.1+). Responses were also observed in patients with pancreatic, endometrial, and appendiceal cancers and melanoma. CONCLUSIONS: p.G12C mutation. Grade 3 or 4 treatment-related toxic effects occurred in 11.6% of the patients. (Funded by Amgen and others; CodeBreaK100 ClinicalTrials.gov number, NCT03600883.).

A receptor that mediates osteoprotegerin ligand (OPGL)-induced osteoclast differentiation and activation has been identified via genomic analysis of a primary osteoclast precursor cell cDNA library and is identical to the tumor necrosis factor receptor (TNFR) family member RANK. The RANK mRNA was highly expressed by isolated bone marrow-derived osteoclast progenitors and by mature osteoclasts in vivo. Recombinant OPGL binds specifically to RANK expressed by transfected cell lines and purified osteoclast progenitors. Transgenic mice expressing a soluble RANK-Fc fusion protein have severe osteopetrosis because of a reduction in osteoclasts, similar to OPG transgenic mice. Recombinant RANK-Fc binds with high affinity to OPGL in vitro and blocks osteoclast differentiation and activation in vitro and in vivo. Furthermore, polyclonal Ab against the RANK extracellular domain promotes osteoclastogenesis in bone marrow cultures suggesting that RANK activation mediates the effects of OPGL on the osteoclast pathway. These data indicate that OPGL-induced osteoclastogenesis is directly mediated through RANK on osteoclast precursor cells.