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.

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.

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.

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.

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.

Bone strength: the whole is greater than the sum of its parts.

OBJECTIVE: To summarize the current knowledge regarding the various determinants of bone strength. METHODS: Relevant English-language articles acquired from Medline from 1966 up to January 2005 were reviewed. Searches included the keywords bone AND 1 of the following: strength, remodeling, microcrack, structur*, mineralization, collagen, organic, crystallinity, osteocyte, porosity, diameter, anisotropy, stress risers, or connectivity. Abstracts from applicable conference proceedings were also reviewed for pertinent information. RESULTS: Bone strength is determined from both its material and its structural properties. Material properties such as its degree of mineralization, crystallinity, collagen characteristics, and osteocyte viability have substantial impacts on bone strength. Structural properties such as the diameter and thickness of the cortices, the porosity of the cortical shell, the connectivity and anisotropy of the trabecular network, the thickness of trabeculae, and the presence of trabecular stress risers and microcracks impact bone strength in diverse manners. Remodeling activity either directly or indirectly impacts all of these processes. CONCLUSIONS: Bone strength is dependent on numerous, interrelated factors. Remodeling activity has a direct impact on almost all of the components of bone strength and requires further investigation as to its impact on these factors in isolation and in unison.

Application of the 1994 WHO classification to populations other than postmenopausal Caucasian women: the 2005 ISCD Official Positions.

In 2003, the International Society for Clinical Densitometry (ISCD) developed Official Positions regarding the applicability of the World Health Organization (WHO) classification of bone mineral density to populations other than postmenopausal women. However, these prior Official Positions do not fully address bone mineral density reporting in females prior to menopause, men, and non-whites. During the 2005 ISCD Position Development Conference, members of the ISCD Expert Panel in conjunction with the ISCD Scientific Advisory Committee re-addressed these topics and, based upon stringent reviews of best available data, developed ISCD Official Positions that provide greater specificity and clarification with respect to the following: (1) the utility of the term 'osteopenia'; (2) utilization of T- and Z-scores for bone mineral density reporting; (3) when to apply the WHO densitometric classification; and (4) which normative database(s) should be used for non-white individuals. Briefly, the term "osteopenia" is retained, but 'low bone mass' or 'low bone density' is preferred. Z-scores, not T-scores, are preferred in females prior to menopause and males under age 50. In these individuals, a Z-score of -2.0 or lower is defined as "below the expected range for age" and a Z-score above -2.0 is "within the expected range for age." T-scores are preferred and the WHO classification is applicable for postmenopausal women and men age 50 and older. These Official Positions, rationale and evidence are discussed in the following report.

Standards for performing DXA in individuals with secondary causes of osteoporosis.

This document addresses skeletal health assessment in individuals with secondary causes of osteoporosis. Recommendations are based on consensus of the Canadian Panel of the International Society for Clinical Densitometry and invited international experts. Bone mineral density (BMD) testing in these populations is performed in conjunction with careful evaluation of the disease state contributing to bone loss and increased fragility fracture risk, as well as assessment of other contributing risk factors for fracture. The presence of secondary causes of bone loss may further increase the risk of fracture independently of BMD and may necessitate earlier pharmacologic intervention. Dual-energy X-ray absorptiometry is indicated in the initial workup of secondary causes of osteoporosis. The BMD fracture risk relationship is not known for individuals with chronic renal failure (CRF). The BMD testing in this population may be normal in the presence of skeletal fragility, and quantitative bone histomorphometry is better at evaluating skeletal status than BMD in CRF. Dual-energy X-ray absorptiometry is a valuable tool in assessing skeletal health in individuals with secondary causes of osteoporosis.

Fracture Incidence in Adult Kidney Transplant Recipients.

BACKGROUND: It remains uncertain whether kidney transplant recipients are a high-risk group for fracture. METHODS: We conducted a cohort study using Ontario, Canada health care databases to estimate the 3-, 5- and 10-year cumulative incidence of nonvertebral fracture (proximal humerus, forearm, hip) in adult kidney transplant recipients between 1994 and 2009, stratifying by sex and age (<50 versus ≥50 years) at transplant. We also assessed the 3-year cumulative incidence of all fracture locations (excluding skull, toes, and fingers) and falls, 10-year cumulative incidence of hip fracture alone, and nonvertebral fracture incidence in recipients compared to nontransplant reference groups matched on age, sex, and cohort entry year. We studied 4821 recipients (median age, 50 years). RESULTS: Among the age and sex strata, female recipients aged 50 years or older had the highest 3-year cumulative incidence of nonvertebral fracture (3.1%; 95% confidence interval [95% CI], 2.1-4.4%). Recipients had a higher 3-year cumulative incidence of nonvertebral fracture (1.6%; 95% CI, 1.3-2.0%) compared to the general population with no previous nonvertebral fracture (0.5%; 95% CI, 0.4-0.6%; P < 0.0001) and nondialysis chronic kidney disease (1.1%; 95% CI, 0.9-1.2%; P = 0.03), but a lower fracture incidence than the general population with a previous nonvertebral fracture (2.3%; 95% CI, 1.9-2.8%; P = 0.007). The 10-year cumulative incidence of hip fracture in all recipients was 1.7% (≥3% defined as high risk in clinical guidelines). CONCLUSIONS: Kidney transplant recipients may have a lower fracture risk than previously suggested in the literature. Results inform our understanding of fracture incidence after kidney transplantation and how it compares to nontransplant populations.

Frequency of bone mineral density testing in adult kidney transplant recipients from Ontario, Canada: a population-based cohort study.

BACKGROUND: We lack consensus on the clinical value, frequency, and timing of bone mineral density (BMD) testing in kidney transplant recipients. This study sought to determine practice patterns in BMD testing across kidney transplant centres in Ontario, Canada, and to compare the frequency of testing in kidney transplant recipients to non-transplant reference groups. METHODS: Using healthcare databases from Ontario, Canada we conducted a population-based cohort study of adult kidney transplant recipients who received a transplant from 1994-2009. We used logistic regression to determine if there was a statistically significant difference across transplant centres in the decision to perform at least one BMD test after transplantation, adjusting for covariates that may influence a physician's decision to order a BMD test. We used the McNemar's test to compare the number of recipients who had at least one BMD test to non-transplant reference groups (matching on age, sex, and date of cohort entry). RESULTS: In the first 3 years after transplant, 4821 kidney transplant recipients underwent 4802 BMD tests (median 1 test per recipient, range 0 to 6 tests), costing $600,000 (2014 CAD equivalent dollars). Across the six centres, the proportion of recipients receiving at least one BMD test varied widely (ranging from 15.6 to 92.1 %; P < 0.001). Over half (58 %) of the recipients received at least one BMD test post-transplant, a value higher than two non-transplant reference groups (general population with a previous non-vertebral fracture [hip, forearm, proximal humerus], 13.8 %; general population with no previous non-vertebral fracture, 8.5 %; P value <0.001 for each of the comparisons). CONCLUSIONS: There is substantial practice variability in BMD testing after transplant. New high-quality information is needed to inform the utility, optimal timing, and frequency of BMD testing in kidney transplant recipients.

MISE EN CONTEXTE: À ce jour, il n'existe aucun consensus sur la pertinence, au plan clinique, de demander une analyse de la densité minérale osseuse (DMO) chez les receveurs d'une greffe de rein, non plus que sur la fréquence ni le moment opportun pour y soumettre les patients après leur intervention. OBJECTIFS DE L'ÉTUDE: L'étude avait pour but d'établir un schéma de pratique pour la mesure de la DMO dans plusieurs centres de transplantation rénale en Ontario, au Canada. On a également voulu comparer la fréquence de ces analyses chez les patients ayant reçu une greffe rénale par rapport à un groupe de référence constitué de patients non transplantés. CADRE ET TYPE D'ÉTUDE: Il s'agit d'une étude rétrospective par cohorte représentative de la population, qui s'est tenue dans six centres de transplantation rénale en Ontario, au Canada. PATIENTS: Il s'agit d'une cohorte de patients ayant reçu une greffe du rein entre 1994 et 2009. MESURES: Les renseignements sur la fréquence, le coût total et les variations dans le nombre d'analyses de la DMO pour une période couvrant les trois années suivant la greffe ont été compilés dans chacun des six centres. La fréquence des analyses de la DMO chez les patients greffés a été comparée à la fréquence de ces mêmes tests pratiqués chez les sujets de groupes témoins, apparentés sur les plans de l'âge, du sexe et de la date de leur admission dans la cohorte, mais n'ayant pas subi une greffe du rein. MÉTHODE: L'analyse par régression logistique a été utilisée pour établir la présence de différences significatives du point de vue statistique entre les six centres de transplantation en regard de la décision d'effectuer au moins un test de DMO à la suite d'une greffe rénale. L'analyse a tenu compte des covariables qui pouvaient influencer les médecins traitants au moment de décider de procéder ou non à un test de DMO sur leurs patients greffés. Le test McNemar a été utilisé pour comparer le nombre de patients greffés ayant été soumis à une analyse de leur DMO par rapport au groupe témoin. RÉSULTATS: À l'intérieur d'une période de trois ans suivant leur transplantation, un total de 4802 analyses de DMO ont été demandées parmi les 4821 patients greffés du rein répertoriés dans les six centres participant à l'étude. La valeur médiane se situait à un test par patient sur une échelle allant de 0 à 6 tests par patient. Le coût total évalué pour ces 4802 analyses de DMO était de 600 000 CDN en 2014. La proportion de receveurs de greffe ayant été soumis à une analyse de leur DMO a fluctué considérablement d'un centre de transplantation à l'autre, avec des pourcentages variant de 15,6 % à 92,1 % (P < 0,001). Dans l'ensemble, on a analysé la DMO de plus de la moitié (58 %) des patients greffés au moins une fois après leur intervention. Ce résultat s'est avéré plus élevé que les pourcentages mesurés dans deux des groupes témoins non transplantés (valeur de P < 0,001 pour chaque cas) : un premier groupe constitué de gens qui avaient subi une fracture non vertébrale (hanche, avant-bras ou humérus proximal) par le passé (13,8 %) et un second groupe constitué de gens de la population générale n'ayant pas subi de fractures (8,5 %). LIMITES DE L'ÉTUDE: Les renseignements concernant les médicaments d'ordonnance administrés aux participants étaient incomplets et les valeurs de DMO étaient manquantes dans plusieurs cas. De plus, le faible taux de fractures subies par les participants ne permet pas d'établir une relation entre la valeur de DMO mesurée et le risque de fractures. CONCLUSIONS: Une variabilité importante a été constatée dans la pratique d'analyses de la DMO à la suite d'une transplantation rénale. Davantage de données sont nécessaires pour discuter de la pertinence d'effectuer ce test chez les receveurs de greffe rénale, ainsi que pour établir le moment opportun et la fréquence à laquelle les y soumettre après l'intervention.

Risk factors for fracture in adult kidney transplant recipients.

AIM: To determine the general and transplant-specific risk factors for fractures in kidney transplant recipients. METHODS: We conducted a cohort study of all adults who received a kidney-only transplant (n = 2723) in Ontario, Canada between 2002 and 2009. We used multivariable Cox proportional hazards regression to determine general and transplant-specific risk factors for major fractures (proximal humerus, forearm, hip, and clinical vertebral). The final model was established using the backward elimination strategy, selecting risk factors with a P-value ≤ 0.2 and forcing recipient age and sex into the model. We also assessed risk factors for other fracture locations (excluding major fractures, and fractures involving the skull, hands or feet). RESULTS: There were 132 major fractures in the follow-up (8.1 fractures per 1000 person-years). General risk factors associated with a greater risk of major fracture were older recipient age [adjusted hazard ratio (aHR) per 5-year increase 1.11, 95%CI: 1.03-1.19] and female sex (aHR = 1.81, 95%CI: 1.28-2.57). Transplant-specific risk factors associated with a greater risk of fracture included older donor age (5-year increase) (aHR = 1.09, 95%CI: 1.02-1.17) and end-stage renal disease (ESRD) caused by diabetes (aHR = 1.72, 95%CI: 1.09-2.72) or cystic kidney disease (aHR = 1.73, 95%CI: 1.08-2.78) (compared to glomerulonephritis as the reference cause). Risk factors across the two fracture locations were not consistent (major fracture locations vs other). Specifically, general risk factors associated with an increased risk of other fractures were diabetes and a fall with hospitalization prior to transplantation, while length of time on dialysis, and renal vascular disease and other causes of ESRD were the transplant-specific risk factors associated with a greater risk of other fractures. CONCLUSION: Both general and transplant-specific risk factors were associated with a higher risk of fractures in kidney transplant recipients. Results can be used for clinical prognostication.

Estimating osteoporotic fracture risk following a wrist fracture: a tale of two systems.

UNLABELLED: The WHO fracture risk assessment (FRAX) and Canadian Association of Radiologists and Osteoporosis Canada (CAROC) tools can both be used to determine an individual's 10-year risk of osteoporotic fracture. However, these tools differ in their risk calculation. For participants <65 years with a wrist fracture, FRAX provides a lower fracture risk estimate than CAROC resulting in fewer decisions to initiate therapy. PURPOSE: The purpose of the current report is to compare fracture risk prediction rates using the CAROC and the FRAX® tools. METHODS: Individuals ≥50 years with a distal radius fracture resulting from a fall from standing height or less were recruited from a single orthopedic clinic. Participants underwent a DXA scan of their lumbar spine and hip. Femoral neck (FN) bone mineral density (BMD) and fracture risk factors were used to determine each participant's 10-year fracture risk using both fracture risk assessment tools. Participants were categorized as low (<10 %), moderate (10-20 %), or high (>20 %) risk. Stratified by age (<65 years, >65 years), the proportion of participants in each category was compared between the tools. RESULTS: Analyses included 60 participants (mean age 65.7 ± 9.6 years). In those <65 years (n = 26), the proportion of individuals at low, moderate, and high risk differed between the FRAX and CAROC tools (p < 0.0001). FRAX categorized 69 % as low (CAROC 0 %) and 3 % as high (CAROC 12 %) risk. For individuals >65 years, almost all were at least at moderate risk (FRAX 79 %, CAROC 53 %), but fewer were at high risk using FRAX (18 vs. 47 %, p < 0.0003). CONCLUSION: For participants <65 years with a wrist fracture, FRAX provides a lower estimate of 10-year fracture risk than CAROC resulting in fewer decisions to initiate therapy. However, almost all participants >65 years were at moderate or high risk under both FRAX and CAROC and should at least be considered for pharmacotherapy.

Efficacy and safety of human parathyroid hormone-(1-84) in increasing bone mineral density in postmenopausal osteoporosis.

Daily sc injections of N-terminal analogs of PTH increase bone mass and decrease fractures in osteoporotic women. We investigated the efficacy and safety of human PTH-(1-84) (full-length PTH) in the treatment of postmenopausal osteoporosis in a double-blind, placebo-controlled study. The women (n = 50-53/group) self-administered PTH (50, 75, or 100 microg) or placebo by daily sc injection for 12 months. PTH treatment induced time- and dose-related increases in lumbar spine bone mineral density (BMD). The 100-microg dose increased BMD significantly at 3 months (+2.0%) and 12 months (+7.8%). BMD underestimated the anabolic effect of PTH in lumbar spine (bone mineral content, +10.0%) because bone area increased significantly (+2.0%). A nonsignificant decrease (-0.9%) in total hip BMD occurred during the first 6 months with the 100-microg dose, but this trend reversed (+1.6%) during the second 6 months. Bone turnover markers increased during the first half of the study and were maintained at elevated levels during the second 6 months. Protocol compliance was excellent (95-98%), and treatment was generally safe and well tolerated. Dose-related incidences of transient hypercalcemia occurred, but only one patient (100-microg group) was withdrawn because of repeated hypercalcemia. Thus, full-length PTH was efficacious and safe over 12 months.