The three-year incidence of fracture in chronic kidney disease.

Knowing a person's fracture risk according to their kidney function, gender, and age may influence clinical management and decision-making. Using healthcare databases from Ontario, Canada, we conducted a cohort study of 679,114 adults of 40 years and over (mean age 62 years) stratified at cohort entry by estimated glomerular filtration rate ((eGFR) 60 and over, 45-59, 30-44, 15-29, and under 15 ml/min per 1.73 m(2)), gender, and age (40-65 and over 65 years). The primary outcome was the 3-year cumulative incidence of fracture (proportion of adults who fractured (hip, forearm, pelvis, or proximal humerus) at least once within 3-years of follow-up). Additional analyses examined the fracture incidence per 1000 person-years, hip fracture alone, stratification by prior fracture, stratification by eGFR and proteinuria, and 3-year cumulative incidence of falls with hospitalization. The 3-year cumulative incidence of fracture significantly increased in a graded manner in adults with a lower eGFR for both genders and both age groups. The 3-year cumulative incidence of fracture in women over 65 years of age across the 5 eGFR groups were 4.3%, 5.8%, 6.5%, 7.8%, and 9.6%, respectively. Corresponding estimates for men over 65 years were 1.6%, 2.0%, 2.7%, 3.8%, and 5.0%, respectively. Similar graded relationships were found for falls with hospitalization and additional analyses. Thus, many adults with chronic kidney disease will fall and fracture. Results can be used for prognostication and guidance of sample size requirements for fracture prevention trials.

Appropriate osteoporosis treatment by family physicians in response to FRAX vs CAROC reporting: results from a randomized controlled trial.

Canadian guidelines recommend either the FRAX or the Canadian Association of Radiologists and Osteoporosis Canada (CAROC) fracture risk assessment tools to report 10-yr fracture risk as low (<10%), moderate (10%-20%) or high (>20%). It is unknown whether one reporting system is more effective in helping family physicians (FPs) identify individuals who require treatment. Individuals ≥50 yr old with a distal radius fracture and no previous osteoporosis diagnosis or treatment were recruited. Participants underwent a dual-energy x-ray absorptiometry scan and answered questions about fracture risk factors. Participants' FPs were randomized to receive either a FRAX report or the standard CAROC-derived bone mineral density report currently used by the institution. Only the FRAX report included statements regarding treatment recommendations. Within 3 mo, all participants were asked about follow-up care by their FP, and treatment recommendations were compared with an osteoporosis specialist. Sixty participants were enrolled (31 to FRAX and 29 to CAROC). Kappa statistics of agreement in treatment recommendation were 0.64 for FRAX and 0.32 for bone mineral density. The FRAX report was preferred by FPs and resulted in better postfracture follow-up and treatment that agreed more closely with a specialist. Either the clear statement of fracture risk or the specific statement of treatment recommendations on the FRAX report may have supported FPs to make better treatment decisions.

Bisphosphonates for treatment of osteoporosis: expected benefits, potential harms, and drug holidays.

OBJECTIVE: To outline the efficacy and risks of bisphosphonate therapy for the management of osteoporosis and describe which patients might be eligible for bisphosphonate "drug holiday." QUALITY OF EVIDENCE: MEDLINE (PubMed, through December 31, 2012) was used to identify relevant publications for inclusion. Most of the evidence cited is level II evidence (non-randomized, cohort, and other comparisons trials). MAIN MESSAGE: The antifracture efficacy of approved first-line bisphosphonates has been proven in randomized controlled clinical trials. However, with more extensive and prolonged clinical use of bisphosphonates, associations have been reported between their administration and the occurrence of rare, but serious, adverse events. Osteonecrosis of the jaw and atypical subtrochanteric and diaphyseal femur fractures might be related to the use of bisphosphonates in osteoporosis, but they are exceedingly rare and they often occur with other comorbidities or concomitant medication use. Drug holidays should only be considered in low-risk patients and in select patients at moderate risk of fracture after 3 to 5 years of therapy. CONCLUSION: When bisphosphonates are prescribed to patients at high risk of fracture, their antifracture benefits considerably outweigh their potential for harm. For patients taking bisphosphonates for 3 to 5 years, reassess the need for ongoing therapy.

Oral bisphosphonate use in the elderly is not associated with acute kidney injury.

Intravenous bisphosphonates can cause acute kidney injury; however, this risk was not found with oral bisphosphonates in randomized clinical trials with restrictive eligibility criteria. In order to provide complementary safety data, we studied the risk of acute kidney injury in a population-based cohort of 122,727 patients aged 66 years and older discharged from hospital following a new fragility fracture and no history of bisphosphonate use in the prior year. Bisphosphonate treatment was identified within 120 days after discharge and event rates were measured from 90 days of therapy initiation. The primary outcome was hospitalization with acute kidney injury with secondary outcomes of new nephrology consultation and, in a subset of patients with laboratory values, acute kidney injury was defined as an increase in serum creatinine. We identified 18,286 bisphosphonate users and 104,441 non-users with a mean age of 81 years. Of 5772 patients with laboratory values, 40% had chronic kidney disease (eGFR <60 ml/min per 1.73 m(2)). Overall, there was no statistically significant difference in the risk of acute kidney injury among bisphosphonate users compared to non-users (adjusted odds ratio 1.03), and no significant differences in other outcomes or in subgroups of patients with baseline chronic kidney disease. Thus, in this older population-based cohort, oral bisphosphonate use was not associated with acute kidney injury.

Bone and mineral metabolism and fibroblast growth factor 23 levels after kidney donation.

BACKGROUND: Living kidney donation offers a unique setting to study changes in phosphate and vitamin D homeostasis attributable to mild isolated decreases in estimated glomerular filtration rate (eGFR). STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 198 living kidney donors and 98 nondonor controls from 9 transplant centers across 3 countries. For donors, median time after donation was 5.3 years. At assessment, donors had a lower eGFR than controls (73 vs 98 mL/min/1.73 m(2)). PREDICTOR: Living kidney donation (mildly decreased eGFR). OUTCOMES: Biochemical markers of chronic kidney disease-mineral and bone disorder. MEASUREMENTS: Serum creatinine, total serum calcium, serum and urine inorganic phosphate, plasma intact parathyroid hormone, serum calcidiol and calcitriol, renal fractional excretion of inorganic phosphate, and intact serum fibroblast growth factor 23 (FGF-23). RESULTS: Serum FGF-23 levels were significantly higher in donors (38.1 vs 29.7 pg/mL; P < 0.001). For every 10-mL/min/1.73 m(2) decrease in eGFR, FGF-23 level was higher by 3.2 (95% CI, 2.0-4.4) pg/mL. Compared with controls, donors showed higher renal tubular fractional excretion of inorganic phosphate (17.8% vs 12.3%; P < 0.001), lower serum phosphate (0.97 vs 1.02 mmol/L; P = 0.03), and lower serum calcitriol values (63 vs 77 pmol/L; P < 0.001). Serum calcium levels were not significantly different between the 2 groups. Plasma intact parathyroid hormone levels were significantly higher in donors (5.7 vs 5.0 pmol/L; P = 0.03), but were not correlated with FGF-23 or calcitriol levels. LIMITATIONS: Enrollment of a small proportion of past donors at participating centers; assessment of only postdonation values; unable to assess seasonal variation or other temporal patterns in biochemical markers; assessment of kidney function was based on eGFR, not measured GFR. CONCLUSIONS: The FGF-23 pathway may be activated in living kidney donors who show early biochemical changes compatible with chronic kidney disease-mineral and bone disorder. Whether these changes influence bone mineral density and fracture rates warrants consideration.

Fracture risk in living kidney donors: a matched cohort study.

BACKGROUND: Chronic kidney disease increases the risk of bone fragility fractures (osteoporotic fractures). Living kidney donors lose 50% of their renal mass and show changes in calcium homeostasis. We studied whether living kidney donation increases the risk of fragility fracture. DESIGN: Retrospective matched-cohort study. SETTING & PARTICIPANTS: We reviewed the medical charts of all 2,015 adults in Ontario, Canada, who donated a kidney between 1992 and 2009 (surgeries performed across 5 transplant programs). We linked this information to health care databases and randomly selected 20,150 matched nondonors from the healthiest portion of the general population. Median age was 43 (95% CI, 24-50) years at study enrollment. Donors and nondonors were then followed up for a median of 6.6 years and a maximum of 17.7 years. PREDICTOR: Living donor nephrectomy. OUTCOMES: The primary outcome was lower- and upper-extremity fragility fractures. Individuals who reached 66 years or older in follow-up had bisphosphonate prescriptions recorded. RESULTS: The rate of fragility fracture was no higher in donors compared with nondonors (16.4 vs 18.7 events/10,000 person-years; rate ratio, 0.88; 95% CI, 0.58-1.32). Results were similar in multiple additional analyses. There was little difference in the proportion of older adults in follow-up who received a bisphosphonate prescription (17.1% vs 15.2%; P = 0.4). LIMITATIONS: These are interim results. Ongoing surveillance of this and other donor cohorts is warranted to be sure an association does not manifest with longer follow-up. CONCLUSIONS: To date, there is no evidence of increased fragility fracture risk in living kidney donors. Our results meet an information need and are reassuring for the safety of the practice.

Reducing the risk of re-fracture in the dialysis population: is it time to consider therapy with PTH analogues?

Dialysis patients are at high risk for fracture, with published rates in excess of a 20% probability of fracture over the next 10 years of dialysis. Unfortunately, there is no accepted methodology for quantifying this risk in advance of the first fracture; conventional bone densitometry performs unreliably in this role, in contrast to its utility in elderly patients with osteoporosis. The KDIGO clinical guidelines emphasize the importance of bone turnover in the development of renal osteodystrophy with high bone turnover strongly associated with uncontrolled secondary hyperparathyroidism, and adynamic bone disease (ABD) defined as a very low bone turnover state associated with functional hypoparathyroidism. It is likely that fractures occur in association with both extremes of uremic bone turnover, in addition to the known risk factors for developing osteoporosis prior to an individual developing end-stage renal failure. No systematic evidence has been forthcoming on therapy to reduce the risk of re-fracture after a dialysis patient presents with a first fracture. Anti-resorptive therapy might be effective in high turnover uremic bone disease and has been demonstrably effective in reducing fracture risk in osteoporotic patients, but there is only post hoc evidence that cinacalcet might reduce the incidence of fractures, and almost no evidence on outcomes from the use of bisphosphonates in dialysis patients. Fractures associated with ABD present a particular challenge. Although aluminum intoxication has been an important cause of skeletal fracturing in the past, this is a rare event today, when nonaluminum containing dietary phosphate binders are routinely prescribed. We suggest that the use of an anabolic agent would be a more plausible approach to the management of ABD (rather than anti-resorptive agents) and propose that a "proof-of-concept" trial with a PTH analogue such as teriparatide should be considered for these patients.

Parathyroid hormone and teriparatide for the treatment of osteoporosis: a review of the evidence and suggested guidelines for its use.

All therapies currently recommended for the management of osteoporosis act mainly to inhibit bone resorption and reduce bone remodeling. PTH and its analog, teriparatide [recombinant human PTH(1-34)], represent a new class of anabolic therapies for the treatment of severe osteoporosis, having the potential to improve skeletal microarchitecture. Significant reductions in both vertebral and appendicular fracture rates have been demonstrated in the phase III trial of teriparatide, involving elderly women with at least one prevalent vertebral fracture before the onset of therapy. However, there is as yet no evidence that the antifracture efficacy of PTH will be superior to the bisphosphonates, whereas cost-utility estimates suggest that teriparatide is significantly more expensive. Teriparatide should be considered as treatment for postmenopausal women and men with severe osteoporosis, as well as for patients with established glucocorticoid-induced osteoporosis who require long-term steroid treatment. Teriparatide should also be considered for the management of individuals at particularly high risk for fractures, including subjects who are younger than age 65 and who have particularly low bone mineral density measurements (T scores < or = 3.5). Teriparatide therapy is not recommended for more than 2 yr, based, in part, on the induction of osteosarcoma in a rat model of carcinogenicity. Total daily calcium intake from both supplements and dietary sources should be limited to 1500 mg together with adequate vitamin D intake (< or =1000 U/d). Monitoring of serum calcium may be safely limited to measurement after 1 month of treatment; mild hypercalcemia may be treated by withdrawing dietary calcium supplements, reducing the dosing frequency of PTH, or both. At present, concurrent therapy with antiresorptive therapy, particularly bisphosphonates, should be avoided, although sequential therapy with such agents may consolidate the beneficial effects upon the skeleton after PTH is discontinued.

The utilization of appropriate osteoporosis medications improves following a multifaceted educational intervention: the Canadian quality circle project (CQC).

BACKGROUND: Osteoporosis is a serious but treatable condition. However, appropriate therapy utilization of the disease remains suboptimal. Thus, the objective of the study was to change physicians' therapy administration behavior in accordance with the Osteoporosis Canada 2002 guidelines. METHODS: The Project was a two year cohort study that consisted of five Quality Circle (QC) phases that included: 1) Training & Baseline Data Collection, 2) First Educational Intervention & First Follow-Up Data Collection 3) First Strategy Implementation Session, 4) Final Educational Intervention & Final Follow-up Data Collection, and 5) Final Strategy Implementation Session. A total of 340 family physicians formed 34 QCs and participated in the study. Physicians evaluated a total of 8376, 7354 and 3673 randomly selected patient charts at baseline, follow-up #1 and the final follow-up, respectively. Patients were divided into three groups; the high-risk, low-risk, and low-risk without fracture groups. The generalized estimating equations technique was utilized to model the change over time of whether physicians RESULTS: The odds of appropriate therapy was 1.29 (95% CI: 1.13, 1.46), and 1.41 (95% CI: 1.20, 1.66) in the high risk group, 1.15 (95% CI: 0.97, 1.36), and 1.16 (95% CI: 0.93, 1.44) in the low risk group, and 1.20 (95% CI: 1.01, 1.43), and 1.23 (95% CI: 0.97, 1.55) in the low risk group without fractures at follow-up #1 and the final follow-up, respectively. CONCLUSION: QCs methodology was successful in increasing physicians' appropriate use of osteoporosis medications in accordance with Osteoporosis Canada guidelines.

Optimizing care in osteoporosis: the Canadian quality circle project.

BACKGROUND: While the Osteoporosis Canada 2002 Canadian guidelines provided evidence based strategies in preventing, diagnosing, and managing this condition, publication and distribution of guidelines have not, in and of themselves, been shown to alter physicians clinical approaches. We hypothesize that primary care physicians enrolled in the Quality Circle project would change their patient management of osteoporosis in terms of awareness of osteoporosis risk factors and bone mineral density testing in accordance with the guidelines. METHODS: The project consisted of five Quality Circle phases that included: 1) Training & Baseline Data Collection, 2) First Educational Intervention & First Follow-Up Data Collection 3) First Strategy Implementation Session, 4) Final Educational Intervention & Final Follow-up Data Collection, and 5) Final Strategy Implementation Session. A total of 340 circle members formed 34 quality circles and participated in the study. The generalized estimating equations approach was used to model physician awareness of risk factors for osteoporosis and appropriate utilization of bone mineral density testing pre and post educational intervention (first year of the study). Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. RESULTS: After the 1st year of the study, physicians' certainty of their patients' risk factor status increased. Certainty varied from an OR of 1.4 (95% CI: 1.1, 1.8) for prior vertebral fracture status to 6.3 (95% CI: 2.3, 17.9) for prior hip fracture status. Furthermore, bone mineral density testing increased in high risk as compared with low risk patients (OR: 1.4; 95% CI: 1.2, 1.7). CONCLUSION: Quality Circle methodology was successful in increasing both physicians' awareness of osteoporosis risk factors and appropriate bone mineral density testing in accordance with the 2002 Canadian guidelines.

Effects of a one-month treatment with PTH(1-34) on bone formation on cancellous, endocortical, and periosteal surfaces of the human ilium.

UNLABELLED: Using bone histomorphometry, we found that a 1-month treatment with PTH(1-34) [hPTH(1-34)] stimulated new bone formation on cancellous, endocortical, and periosteal bone surfaces. Enhanced bone formation was associated with an increase in osteoblast apoptosis. INTRODUCTION: The precise mechanisms by which hPTH(1-34) increases bone mass and improves bone structure are unclear. Using bone histomorphometry, we studied the early effects of treating postmenopausal women with osteoporosis with hPTH(1-34). MATERIALS AND METHODS: Tetracycline-labeled iliac crest bone biopsies were obtained from 27 postmenopausal women with osteoporosis who were treated for 1 month with hPTH(1-34), 50 microg daily subcutaneously. The results were compared with tetracycline-labeled biopsies from a representative control group of 13 postmenopausal women with osteoporosis. RESULTS: The bone formation rate on the cancellous and endocortical surfaces was higher in hPTH(1-34)-treated women than in control women by factors of 4.5 and 5.0, respectively. We also showed a 4-fold increase in bone formation rate on the periosteal surface, suggesting that hPTH(1-34) has the potential to increase bone diameter in humans. On the cancellous and endocortical surfaces, the increased bone formation rate was primarily caused by stimulation of formation in ongoing remodeling units, with a modest amount of increased formation on previously quiescent surfaces. hPTH(1-34)-stimulated bone formation was associated with an increase in osteoblast apoptosis, which may reflect enhanced turnover of the osteoblast population and may contribute to the anabolic action of hPTH(1-34). CONCLUSIONS: These findings provide new insight into the cellular basis by which hPTH(1-34) improves cancellous and cortical bone architecture and geometry in patients with osteoporosis.

Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: regulation of PTH1R nuclear-cytoplasmic shuttling by importin-alpha/beta and chromosomal region maintenance 1/exportin 1.

The type 1 PTH/PTH-related peptide receptor (PTH1R) is a class B G protein-coupled receptor that demonstrates immunoreactivity in the nucleus as well as cytoplasm of target cells. Our previous studies on the PTH1R have shown that it associates with the importin family of transport regulatory proteins. To investigate the role of the importins in PTH1R nuclear import, we used small interfering (si)RNA technology to knock down the expression of importin-beta in the mouse osteoblast-like cell line, MC3T3-E1. Immunofluorescence microscopy as well as ligand blotting for PTH1R in nuclear fractions of importin-beta siRNA-treated cells demonstrated a decrease in nuclear localization of the PTH1R in comparison with control cells. Under normal culture conditions, PTH1R is present in both the nucleus and cytoplasm of cells. Serum starvation favors nuclear localization of PTH1R, whereas returning cells to serum or treatment with PTH-related peptide induced its cytoplasmic localization. To address the nuclear export of PTH1R, interactions between PTH1R and chromosomal region maintenance 1 (CRM1) were investigated. PTH1R and CRM1 coimmunoprecipitated from MC3T3-E1 cells, suggesting that CRM1 and PTH1R form a complex in vivo. After treatment with leptomycin B, a specific inhibitor of CRM1-mediated nuclear export, PTH1R accumulated in the nucleus. Taken together, our studies show that PTH1R shuttles from the nucleus to the cytoplasm under normal physiological conditions and that this nuclear-cytoplasmic transport is dependent upon importin-alpha/beta and CRM1.

Expression of PTH1R constructs in LLC-PK1 cells: protein nuclear targeting is mediated by the PTH1R NLS.

This study demonstrates that the PTH1R NLS can target a fusion protein to the nucleus, and that this is blocked by sequences downstream of the NLS. GFP fused to the NLS showed a significant increase in nuclear targeting compared to GFP alone or GFP fused to a peptide of the same length. In previous studies, we demonstrated that the type I PTH/PTHrP receptor (PTH1R) localizes to the nucleus of cells within rat liver, kidney, uterus, ovary and gut. Similarly, nuclear localization of the PTH1R was observed in the cultured osteoblast-like cells MC3T3-E1, UMR106, ROS 17/2.8 and SaOS-2. We have identified a putative bipartite nuclear localization signal (NLS), from residues 471-488 in the protein sequence of the PTH1R. In this study, several PTH1R constructs were made in the Enhanced Green Fluorescent Protein (EGFP) expression vector (Clontech), transiently transfected into LLC-PK1 Clone 46 cells, and the resultant fusion protein expression followed by fluorescence microscopy. This particular clone of LLC-PK1 shows no biochemical response in vitro to parathyroid hormone. Constructs included the entire PTH1R sequence (PTH1R-GFP), the putative NLS fused to the C-terminus of GFP (GFP-NLS) or the NLS through to the C-terminus of the PTH1R fused to GFP (GFP-NLSCT). Deconvolution fluorescence microscopy of cells transfected with PTH1R-GFP showed abundant fluorescent signal throughout the cells with distinctly fluorescing plasma membranes. These cells also exhibited an increase in cAMP production in response to (0-10(-8) M) hPTH(1-34), with an increase in cAMP from 11 fmol/mug of protein to 101 fmol/microg. In contrast, cells transfected with the GFP-NLS construct showed significant nuclear sequestration of fluorescence as compared to GFP alone, GFP-NLSCT, or a short amino acid sequence fused to GFP (GFP-FFVAIYCFCNGEVQAEI). These results indicate that the NLS at residues 471-488 of the mature rat PTH1R is functional and plays a role in targeting the PTH1R the nucleus, also the addition of GFP to the C-terminus of the PTH1R still allows cAMP generation which will be useful for further studies.

Re-exposure to mismatched HLA class I is a significant risk factor for graft loss: multivariable analysis of 259 kidney retransplants.

BACKGROUND: Kidney retransplants carry increased immunologic risk. One possible contributor to this risk may be re-exposure to human leukocyte antigens (HLA) common to a previous donor but foreign to the recipient. Conflicting publications have assessed this risk, so to examine our experience 259 kidney retransplants were analyzed. METHODS: A retrospective cohort of retransplant patients from 1973 to 2005 with minimum 12 months follow up was examined. Using multivariable modeling, important confounders were controlled for identifying factors significantly affecting graft survival. RESULTS: Re-exposure to HLA class I (HLA-A or B) antigens, peak panel reactive antibodies and donor source were the most important determinants of allograft survival, despite a negative conventional or anti-human globulin-augmented T cell crossmatch. We failed to demonstrate that recipient re-exposure to HLA class II (HLA-DR) or positive B cell crossmatch were associated with adverse outcomes. Sample size and molecular versus serologic methods may have influenced the former, while inability to determine antibody specificities may have influenced the latter. Controlling for other variables, the adjusted risk of graft loss associated with re-exposure to HLA class I increased by 71% (P=0.006) and occurred early, consistent with recall of memory cytotoxic T lymphocyte or antibody responses. CONCLUSIONS: Kidney recipients re-exposed to mismatched HLA class I antigens appear to be at heightened risk of early graft loss. Such patients may benefit from pretransplant identification of donor specific antibodies using solid phase methods and heightened vigilance for acute rejection. Future studies may indicate whether more intensive immunosuppression for these patients is warranted.

Management of osteoporosis in men: an update and case example.

In 2002, Osteoporosis Canada published clinical practice guidelines for the diagnosis and management of osteoporosis. The current paper supplements that guideline and provides a review and synthesis of the current literature on the diagnosis and management of osteoporosis in men.

Recommendations for bone mineral density reporting in Canada: a shift to absolute fracture risk assessment.

In June 2005, new Canadian recommendations for bone mineral density (BMD) reporting in postmenopausal women and older men were published by Osteoporosis Canada (formerly the Osteoporosis Society of Canada) and the Canadian Association of Radiologists. The recommendations were developed by a multidisciplinary working group that included the Canadian Panel of the International Society for Clinical Densitometry and were reviewed and endorsed by multiple stakeholders. Previous Canadian osteoporosis guidelines advised intervention based on an individual's World Health Organization category (normal, osteopenia, or osteoporosis) as a marker of relative fracture risk. In the new approach, an individual's 10-yr absolute fracture risk, rather than BMD alone, is used for fracture risk categorization. Absolute fracture risk is determined using not only BMD results, but also age, sex, fragility fracture history, and glucocorticoid use. A procedure is presented for estimating absolute 10-yr fracture risk in untreated individuals, leading to assigning an individual to 1 of 3 absolute fracture risk categories: low risk (<10% 10-yr fracture risk), moderate risk (10-20%), and high risk (>20%). We propose that an individual's absolute fracture risk category should be the basis for deciding on treatment and frequency of BMD monitoring.

Canadian Quality Circle pilot project in osteoporosis: rationale, methods, and feasibility.

UNLABELLED: PROBLEM ADDRESSED Family physicians are not adequately following the 2002 Osteoporosis Canada guidelines for providing optimal care to patients with osteoporosis. OBJECTIVE OF PROGRAM: The Canadian Quality Circle (CQC) pilot project was developed to assess the feasibility of the CQC project design and to gather information for implementing a national study of quality circles (QCs). The national study would assess whether use ofQCs could improve family physicians' adherence to the osteoporosis guidelines. PROGRAM DESCRIPTION: The pilot project enrolled 52 family physicians and involved 7 QCs. The project had 3 phases: training and baseline data collection, educational intervention and follow-up data collection, and sessions on implementing strategies for care. CONCLUSION: Findings from the pilot study showed that the CQC project was well designed and well received. Use of QCs appeared to be feasible for transferring knowledge and giving physicians an opportunity to analyze work-related problems and develop solutions to them.

Type 1 parathyroid hormone receptor (PTH1R) nuclear trafficking: association of PTH1R with importin alpha1 and beta.

Previous studies have shown that the type 1 PTH receptor (PTH1R), a class B G protein-coupled receptor, appears in the nucleus of target cells. Through immunofluorescence and deconvolution microscopy, we demonstrate that PTH1R, importin alpha(1), and importin beta are present within the nucleus and cytoplasm of osteoblast-like cell lines with the nuclear PTH1R being restricted to the nucleoplasm. Immunofluorescence studies showed that nuclear accumulation of PTH1R was associated with specific stages of the cell cycle. Using immunoprecipitation and affinity chromatography, we show that the PTH1R forms a complex with the importin family of transport molecules. Total cell protein from osteoblast-like cells was immunoprecipitated with antibodies for PTH1R, importin alpha(1), or importin beta. When the immunoprecipitates were separated and subsequently exposed to biotinylated PTH (1-84) a single band was present on the gel at 66.3 kDa, corresponding to the PTH1R. To confirm the interaction between PTH1R and both importin alpha(1) and beta, the complex was purified from total cell protein of osteoblast-like cells using a PTH-linked affinity chromatography column. Using an anti-importin alpha(1) antibody, Western blots detected importin alpha(1) at 58 kDa in the purified sample. Also, using an anti-importin beta antibody, Western blots detected importin beta at 94 kDa. These results indicate that the importins were associated with the PTH1R at the time of the purification. In conclusion, we show that the PTH1R forms a complex with the transport regulatory proteins, importin alpha(1) and importin beta, and that nuclear PTH1R is associated with the nucleoplasm.

The effects of antifracture therapies on the components of bone strength: assessment of fracture risk today and in the future.

OBJECTIVE: To summarize the current knowledge regarding the impact of the most common antifracture medications on the various determinants of bone strength. METHODS: Relevant English-language articles acquired from Medline from 1966 to January 2005 were reviewed. Searches included the keywords bone AND 1 of the following: strength, remodeling, microcrack, structure, mineralization, collagen, organic, crystallinity, osteocyte, porosity, diameter, anisotropy, stress risers, or connectivity AND alendronate, estrogen, etidronate, hormone replacement therapy, parathyroid hormone, risedronate, OR teriparatide. Abstracts from relevant conference proceedings were also reviewed for pertinent information. RESULTS: Antiresorptive therapies increase bone strength through decreasing bone turnover. This lower bone turnover results in a higher mean mineralization and decreases the number of active resorption pits within bone at any given time. These resorption pits are speculated to be areas of focal weakness and a higher number of them would, if all other things were equal, result in greater fragility. Parathyroid hormone therapy increases the rate of bone remodeling, which introduces many resorption pits, but this source of strength loss is thought to be compensated by rapid increases in bone mass. CONCLUSIONS: Both the antiresorptives, particularly bisphosphonates, and the parathyroid hormone therapy increase bone strength; however, the changes that are elicited to achieve this differ significantly.