Forearm bone mineral density and fracture incidence in postmenopausal women with osteoporosis: results from the ACTIVExtend phase 3 trial.

Abaloparatide increased ultradistal radius bone mineral density (BMD) in the Abaloparatide Comparator Trial in Vertebral Endpoints (ACTIVE) trial. Over the subsequent 24 months in ACTIVExtend, ultradistal radius BMD gains were maintained with alendronate. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. INTRODUCTION: Abaloparatide (ABL) increased femoral neck, total hip, and lumbar spine bone mineral density (BMD) in postmenopausal women with osteoporosis and decreased the risk of vertebral and nonvertebral fractures in ACTIVE. Effects on fracture risk and BMD were maintained subsequently with alendronate (ALN) in ACTIVExtend. In a prespecified subanalysis of ACTIVE, ABL also increased BMD at the ultradistal radius. Our objective was to determine the efficacy of ABL followed by ALN vs placebo (PBO) followed by ALN on forearm BMD and fracture risk over 43 months in ACTIVExtend. METHODS: Ultradistal and 1/3 radius BMD (ACTIVE baseline to month 43) were measured (ABL/ALN, n = 213; PBO/ALN, n = 233). Wrist fracture rates were estimated for the ACTIVExtend intent-to-treat population (ABL/ALN, n = 558; PBO/ALN, n = 581) by Kaplan-Meier (KM) method. RESULTS: At cumulative month 25, mean increase from ACTIVE baseline in ultradistal radius BMD was 1.1% (standard error, 0.49%) with ABL/ALN vs - 0.8% (0.43%) with PBO/ALN (P < 0.01). BMD increases with ABL were maintained with ALN through month 43 in ACTIVExtend. BMD decreases at the 1/3 radius in ACTIVE (similar with ABL and PBO) were maintained through 24 months of ALN treatment in ACTIVExtend. Wrist fractures over 43 months occurred in 15 women with ABL/ALN (KM estimate, 2.8%) and 20 with PBO/ALN (KM estimate, 3.6%) (HR = 0.77, 95% CI 0.39, 1.50; P = not significant). CONCLUSION: Ultradistal radius BMD gains following treatment with ABL in ACTIVE were maintained over 24 months of ALN treatment in ACTIVExtend. Conversely, 1/3 radius BMD remained stable during ALN treatment in ACTIVExtend after decreasing during ACTIVE. TRIAL REGISTRATION: ClinicalTrials.gov : NCT01657162 submitted July 31, 2012.

Rush Fracture Liaison Service for capturing "missed opportunities" to treat osteoporosis in patients with fragility fractures.

In spite of being a public health problem of pandemic proportions, osteoporosis continues to be underdiagnosed and undertreated especially in older adults with fragility fractures. Confirmation of this hypothesis resulted in the development of a novel Fracture Liaison Service (Rush FLS). Results of the first 12 months of operation revealed that patients with confirmed fragility fracture do not have a timely diagnosis at fracture occurrence or treatment of their disease. The Rush FLS is an effective fracture liaison model. INTRODUCTION: Determining the prevalence of undiagnosed and untreated osteoporosis in fragility fracture patients, either admitted to an academic tertiary care center or treated and discharged from the center's emergency department to be followed in the endocrinology bone clinic, using an innovative, educational, low-cost, physician-run Fracture Liaison Service (FLS). METHODS: An automated alert was integrated into the electronic medical record at Rush University Medical Center (RUMC), triggered by historical and/or acute fracture(s) in patients 50 years or older, in patients that were either admitted to the hospital or in patients evaluated in the emergency department and discharged to be followed in the endocrinology bone clinic. We report the results of the first 12 months of operation in patients admitted to the hospital. RESULTS: First acute fragility fracture(s) were identified in 36% (80/223), only historical fragility fracture(s) in 28% (63/223) and both acute and historical fragility fracture(s) in 36% (80/223). The cumulative subgroup with historical fragility fractures with/without new fractures included 67% (96/143) without a previous diagnosis of osteoporosis. First acute fragility fracture group included 83.8% (67/80) without a previous diagnosis of osteoporosis. Rush FLS "captured missed opportunities" in 73.1% (163/223) of previously undiagnosed and 77.1% (172/223) of previously untreated osteoporosis patients. Dual-energy x-ray absorptiometry (DXA) prior to FLS consult was confirmed in 30% (67/223). Vitamin D deficiency (25-hydroxy vitamin D < 20 ng/ml) in 41.9% (78/186) including undetectable levels in 16.6% (31/186) and secondary hyperparathyroidism in 43.3% (78/180) were the most common laboratory confirmed secondary etiologies for bone loss. CONCLUSIONS: This study reported undiagnosed, uninvestigated, and untreated osteoporosis in the majority of fragility fracture patients seen by the Rush FLS in the first 12 months of operation.

Interpretation and use of FRAX in clinical practice.

UNLABELLED: The introduction of the WHO FRAX® algorithms has facilitated the assessment of fracture risk on the basis of fracture probability. Its use in fracture risk prediction has strengths, but also limitations of which the clinician should be aware and are the focus of this review INTRODUCTION: The International Osteoporosis Foundation (IOF) and the International Society for Clinical Densitometry (ISCD) appointed a joint Task Force to develop resource documents in order to make recommendations on how to improve FRAX and better inform clinicians who use FRAX. The Task Force met in November 2010 for 3 days to discuss these topics which form the focus of this review. METHODS: This study reviews the resource documents and joint position statements of ISCD and IOF. RESULTS: Details on the clinical risk factors currently used in FRAX are provided, and the reasons for the exclusion of others are provided. Recommendations are made for the development of surrogate models where country-specific FRAX models are not available. CONCLUSIONS: The wish list of clinicians for the modulation of FRAX is large, but in many instances, these wishes cannot presently be fulfilled; however, an explanation and understanding of the reasons may be helpful in translating the information provided by FRAX into clinical practice.

Osteoporosis care at risk in the United States.

Osteoporotic fractures are associated with significant morbidity, mortality, and healthcare expenses. The United States (US) Surgeon General has described osteoporosis as a major public health concern that is underdiagnosed and undertreated. US federal agencies have established funding for bone density testing and put methodologies in place to monitor physician performance in the care of patients with osteoporosis. The US Centers for Medicare and Medicaid Services (CMS) has established bone density testing as a key preventive medical service and encouraged patients to have this test when first enrolling in Medicare. However, recent CMS actions have reduced reimbursement for dual-energy X-ray absorptiometry (DXA) to levels that are below the cost of providing this service at many facilities. As a consequence, it is likely that the number of DXA facilities in the US will decrease, thereby limiting patient access to an important diagnostic service and resulting in fewer patients being diagnosed and treated to reduce fracture risk. Unless there is a reversal of continuing reimbursement cuts for DXA, it is projected that future fracture rates will increase; the cost to Medicare for fracture-related care will be far greater than the savings in the cost of DXA services and medications to reduce fracture risk.

Special report on the 2007 adult and pediatric Position Development Conferences of the International Society for Clinical Densitometry.

The International Society for Clinical Densitometry (ISCD) conducts Position Development Conferences (PDCs) for the purpose of establishing standards and guidelines in the field of bone densitometry. Topics for consideration are selected according to clinical relevance, a perceived need for standardization, and the likelihood of achieving agreement. Questions regarding nomenclature, indications, acquisition, analysis, quality control, interpretation, and reporting of bone density tests for each topic area are assigned to task forces for a comprehensive review of the scientific literature. The findings of the review and recommendations are then presented to an international panel of experts at the PDC. The expert panel votes on potential Official Positions for appropriateness, necessity, quality of the evidence, strength of the recommendation, and applicability (worldwide or variable according to local requirements). Recommendations that are approved by the ISCD Board of Directors become Official Positions. The first Pediatric PDC was 20-21 June 2007 in Montreal, QC, Canada. The most recent Adult PDC was held 20-22 July 2007, in Lansdowne, VA, USA. This Special Report summarizes the methodology of the ISCD PDCs and presents selected Official Positions of general interest.

Implications of absolute fracture risk assessment for osteoporosis practice guidelines in the USA.

UNLABELLED: Application of the WHO fracture prediction algorithm in conjunction with an updated US economic analysis indicates that osteoporosis treatment is cost-effective in patients with fragility fractures or osteoporosis, in older individuals at average risk and in younger persons with additional clinical risk factors for fracture, supporting existing practice recommendations. INTRODUCTION: The new WHO fracture prediction algorithm was combined with an updated economic analysis to evaluate existing NOF guidance for osteoporosis prevention and treatment. METHODS: The WHO fracture prediction algorithm was calibrated to the US population using national age-, sex- and race-specific death rates and age- and sex-specific hip fracture incidence rates from the largely white population of Olmsted County, MN. Fracture incidence for other races was estimated by ratios to white women and men. The WHO algorithm estimated the probability (%) of a hip fracture (or a major osteoporotic fracture) over 10 years, given specific age, gender, race and clinical profiles. The updated economic model suggested that osteoporosis treatment was cost-effective when the 10-year probability of hip fracture reached 3%. RESULTS: It is cost-effective to treat patients with a fragility fracture and those with osteoporosis by WHO criteria, as well as older individuals at average risk and osteopenic patients with additional risk factors. However, the estimated 10-year fracture probability was lower in men and nonwhite women compared to postmenopausal white women. CONCLUSIONS: This analysis generally endorsed existing clinical practice recommendations, but specific treatment decisions must be individualized. An estimate of the patient's 10-year fracture risk should facilitate shared decision-making.

Cost-effective osteoporosis treatment thresholds: the United States perspective.

UNLABELLED: A United States-specific cost-effectiveness analysis, which incorporated the cost and health consequences of clinical fractures of the hip, spine, forearm, shoulder, rib, pelvis and lower leg, was undertaken to identify the 10-year hip fracture probability required for osteoporosis treatment to be cost-effective for cohorts defined by age, sex, and race/ethnicity. A 3% 10-year risk of hip fracture was generally required for osteoporosis treatment to cost less than $60,000 per QALY gained. INTRODUCTION: Rapid growth of the elderly United States population will result in so many at risk of osteoporosis that economically efficient approaches to osteoporosis care warrant consideration. METHODS: A Markov-cohort model of annual United States age-specific incidence of clinical hip, spine, forearm, shoulder, rib, pelvis and lower leg fractures, costs (2005 US dollars), and quality-adjusted life years (QALYs) was used to assess the cost-effectiveness of osteoporosis treatment ($600/yr drug cost for 5 years with 35% fracture reduction) by gender and race/ethnicity groups. To determine the 10-year hip fracture probability at which treatment became cost-effective, average annual age-specific probabilities for all fractures were multiplied by a relative risk (RR) that was systematically varied from 0 to 10 until a cost of $60,000 per QALY gained was observed for treatment relative to no intervention. RESULTS: Osteoporosis treatment was cost-effective when the 10-year hip fracture probability reached approximately 3%. Although the RR at which treatment became cost-effective varied markedly between genders and by race/ethnicity, the absolute 10-year hip fracture probability at which intervention became cost-effective was similar across race/ethnicity groups, but tended to be slightly higher for men than for women. CONCLUSIONS: Application of the WHO risk prediction algorithm to identify individuals with a 3% 10-year hip fracture probability may facilitate efficient osteoporosis treatment.

A chimeric mammalian transactivator based on the lac repressor that is regulated by temperature and isopropyl beta-D-thiogalactopyranoside.

LAP267 is a lacI activator protein (LAP) containing an insertion of the transcriptional activation domain of the herpes simplex virus virion protein 16 within the inducer-binding and dimerization domain of the lac repressor protein. LAP267 strongly induces expression in a conditional manner from a minimal simian virus 40 early promoter linked to lac operator sequences. LAP267 is temperature-sensitive, activating expression at 32 degrees C but not at 39.5 degrees C. It is allosterically regulated in a manner opposite that of wild-type lac repressor, in that LAP267 activity is rescued at the nonpermissive temperature by isopropyl beta-D-thiogalactopyranoside (IPTG). Stable mouse cell lines containing both the LAP267 gene and a LAP-inducible chloramphenicol acetyltransferase (CAT) reporter gene were readily established and exhibited up to a 1200-fold increase in CAT activity within 24 hr upon addition of IPTG. Thus, LAP267 is a powerful inducible switch in mammalian cells, imparting a regulatory stringency similar to that observed with lac repressor in Escherichia coli.

Conversion of the lac repressor into an allosterically regulated transcriptional activator for mammalian cells.

A novel mammalian regulatory system was created by using the Escherichia coli lac repressor. The lac repressor was converted into a mammalian transcriptional activator by modifying the lac repressor coding region to include a nuclear localization signal from the simian virus 40 (SV40) large tumor antigen and the transcription activation domain from the herpes simplex virus type 1 virion protein 16. The lac activator protein (LAP) fusions were potent activators of several promoters containing lac operator sequences positioned either upstream or downstream of the transcription unit. A single lac operator allowed for transactivation, whereas multiple operators acted synergistically when separated by a small distance. Promoters containing 14 or 21 operator sequences were induced at least 1,000-fold in response to LAP, reaching levels of activity 20 to 30 times greater than that of the SV40 early promoter in HeLa cells. Activation was strongly inhibited by isopropyl-beta-D-thiogalactoside (IPTG), indicating that LAP retained the functions needed for allosteric regulation. LAP was bifunctional, also acting as a repressor of expression of an SV40 promoter containing an operator immediately downstream of the TATA box. Finally, genetic selection schemes were developed such that LAP-expressing cell lines can be generated at high frequency from either established or primary cells in culture.

The adenovirus E4 17-kilodalton protein complexes with the cellular transcription factor E2F, altering its DNA-binding properties and stimulating E1A-independent accumulation of E2 mRNA.

E2F is a cellular DNA-binding factor. Its binding activity is changed within adenovirus-infected cells so that it binds cooperatively to pairs of properly spaced and oriented E2F recognition sites. In the work described in this report, the conversion to cooperative binding was shown to require the adenovirus E4 17-kilodalton (kDa) polypeptide. Mutant viruses carrying alterations within the E4 17-kDa coding region failed to generate the infection-specific, cooperatively binding form of E2F. It was possible to alter E2F from uninfected cells so that it bound cooperatively by incubation with a partially purified fraction obtained from infected cells. The E4 17-kDa protein copurified with this activity and was also found to be present in a complex containing E2F. Consistent with its ability to alter the binding of E2F to its recognition sites within the E2 promoter, the E4 17-kDa polypeptide contributed to maximal expression of E2 mRNAs in some cell types. Its ability to enhance E2 transcription did not require expression of the E1A transactivator protein. These results are consistent with a model which proposes that the E4 17-kDa polypeptide binds to the cellular E2F factor, altering its binding behavior and thereby enhancing its ability to stimulate transcription.

Differential stability of two apo-isocytochromes c in the yeast Saccharomyces cerevisiae.

The yeast Saccharomyces cerevisiae contains two forms of cytochrome c, iso-1-cytochrome c and iso-2-cytochrome c, encoded by the genes CYC1 and CYC7, respectively. The amino acid sequences of these two isozymes are approximately 80% identical. Cyc3- mutants lack both holocytochromes c, because of a deficiency of cytochrome c heme lyase, the enzyme catalyzing covalent attachment of the heme group to apocytochrome c. A deficiency of heme lyase also prevents import into mitochondria. Surprisingly, apo-iso-1-cytochrome c is absent in cyc3- strains, although apo-iso-2-cytochrome c is present at approximately the same level at which holo-iso-2-cytochrome c is found in CYC3+ strains. The lack of apo-iso-1-cytochrome c is not due to a deficiency of either transcription or translation, but to rapid degradation of the protein. Apocytochromes c encoded by composite cytochrome c genes composed of the central portion of iso-2-cytochrome c flanked by amino and carboxyl regions of iso-1-cytochrome c exhibit increased stability compared with apo-iso-1-cytochrome c. A region encompassing no more than four amino acid differences between iso-1- and iso-2-cytochromes c is sufficient to partially stabilize the protein. In contrast to what is observed in vivo with the apo forms, the holo forms of the composite isocytochromes c are even less stable to thermal denaturation than iso-1-cytochrome c or iso-2-cytochrome c. Either a small region of the sequence of apo-iso-1-cytochrome c is involved in degradation of the protein, or the corresponding region in apo-iso-2-cytochrome c is preventing degradation. The differential stability of the two isocytochromes c may be part of a regulatory process that increases the proportion of iso-2-cytochrome c under certain physiological conditions.

mRNA structures influencing translation in the yeast Saccharomyces cerevisiae.

The mRNA sequence and structures that modify and are required for translation of iso-1-cytochrome c in the yeast Saccharomyces cerevisiae were investigated with sets of CYC1 alleles having alterations in the 5' leader region. Measurements of levels of CYC1 mRNA and iso-1-cytochrome c in strains having single copies of altered alleles with nested deletions led to the conclusion that there is no specific sequence adjacent to the AUG initiator codon required for efficient translation. However, the nucleotides preceding the AUG initiator codon at positions -1 and -3 slightly modified the efficiency of translation to an order of preference similar to that found in higher cells. In contrast to large effects observed in higher eucaryotes, the magnitude of this AUG context effect in S. cerevisiae was only two- to threefold. Furthermore, introduction of hairpin structures in the vicinity of the AUG initiator codon inhibited translation, with the degree of inhibition related to the stability and proximity of the hairpin. These results with S. cerevisiae and published findings on other organisms suggest that translation in S. cerevisiae is more sensitive to secondary structures than is translation in higher eucaryotes.

Induced heat shock mRNAs escape the nucleocytoplasmic transport block in adenovirus-infected HeLa cells.

Under conditions in which cytoplasmic accumulation of HeLa cell mRNAs has been blocked by adenovirus infection, hsp70 family mRNAs are transported from the nucleus to the cytoplasm at near normal efficiency subsequent to heat shock. Heat shock does not reverse the general virus-induced block to host cell mRNA transport. The heat shock mRNAs are translated within the cytoplasm of the infected cell but at substantially reduced efficiency compared with that of uninfected cells. Thus, the hsp70 family of mRNAs can escape the transport block but not the translational block instituted late after adenovirus infection. The beta-tubulin gene family is induced by the viral E1A gene after infection, and its mRNAs also accumulate in the cytoplasmic compartment. Given these two examples, it seems likely that the process of transcriptional induction allows the resulting mRNA to escape the viral block of transport.

Comparison of the safety and efficacy of nabumetone and aspirin in the treatment of osteoarthritis in adults.

A six-month, multicenter, double-blind study compared the efficacy and safety of two therapeutic regimens in 332 patients with osteoarthritis. The patients received either 1,000 mg of nabumetone as a single bedtime dose or 900 mg of aspirin in four divided doses. At the end of the study, patients in both treatment groups showed significant improvement from baseline for all five parameters; no statistically or clinically significant differences were observed between the groups. The safety data did reveal clinically and statistically significant differences between the groups. Aspirin-treated patients experienced a greater frequency of withdrawal from the study because of adverse experiences (34 percent versus 13 percent), a greater incidence of having at least one treatment-related adverse experience (73 percent versus 52 percent), a greater percentage of patients with at least one moderate or severe treatment-related adverse experience (47 percent versus 22 percent), and a greater percentage of patients with treatment-related adverse experiences affecting the gastrointestinal system (43 percent versus 32 percent) or the inner ear (32 percent versus 10 percent). The results of this study demonstrated that nabumetone, 1,000 mg at bedtime, is as efficacious as aspirin, 900 mg four times daily, produces fewer adverse effects, and is indicated in the treatment of osteoarthritis.

A mutation allowing an mRNA secondary structure diminishes translation of Saccharomyces cerevisiae iso-1-cytochrome c.

The CYC1-239-O mutation in the yeast Saccharomyces cerevisiae produces a -His-Leu- replacement of the normal -Ala-Gly- sequence at amino acid positions 5 and 6, which lie within a dispensable region of iso-1-cytochrome c; this mutation can accommodate the formation of a hairpin structure at the corresponding site in the mRNA. The amount of the altered protein was diminished to 20% of the wild-type level, whereas the amount of the mRNA remained normal. However, in contrast to the normal CYC1+ mRNA that is associated mainly with four to seven ribosomes, the bulk of the CYC1-239-O mRNA is associated with one to four ribosomes. These results suggest that the stable secondary structure within the translated region of the CYC1 mRNA diminishes translation by inhibiting elongation.