Can we compare serum sclerostin results obtained with different assays in hemodialysis patients?

PURPOSE: Sclerostin, secreted by osteocytes, plays a key role in antagonizing bone formation. Recent studies, which seldom include chronic kidney disease (CKD) patients, have reported on the association of sclerostin and mortality, with contradictory results. The assay-linked variability may contribute to these discrepant results. METHODS: We have compared sclerostin results obtained with two assays (TECO and Biomedica) in a cohort of 91 CKD patients undergoing hemodialysis. RESULTS: We found a strong correlation (r = 0.870, p < 0.0001) between the serum sclerostin concentrations measured by the two assays. Bland-Altman plot shows that, although there was a partial agreement between the assays, differences found for individual values (-0.27 ± 0.54; ranging from -1.3 to 0.8 ng/ml) were quite unpredictable. By using TECO, there was a significant relationship between serum sclerostin, and calcitonin (r = 0.224), IL-6 (r = 0.251) and FGF23 (r = 0.331) levels while no correlation was found with PTH or total alkaline phosphatase. Regarding Biomedica, there was a significant correlation with calcitonin (r = 0.260), and ß2 microglobulin (r = 0.210), but no correlation with PTH or total alkaline phosphatase. Overall, 25.3% among the patients had different classifications as to normal or high values, according to the manufacturer. CONCLUSION: Sclerostin levels should be interpreted with caution, as they can vary widely according to the assay used. Further studies are clearly needed before considering sclerostin as a true marker of mortality. Moreover, we do not know at present which serum sclerostin levels should be regarded as either normal or potentially dangerous in patients with CKD.

Teriparatide and bone turnover and formation in a hemodialysis patient with low-turnover bone disease: a case report.

Teriparatide, a recombinant form of parathyroid hormone, is an anabolic agent approved for use in women and men with osteoporosis. However, it is not well studied in people with chronic kidney disease (CKD). We report on a patient with stage 5 CKD treated with dialysis who presented to our clinic with multiple fractures, including bilateral nondisplaced pelvic fractures resulting in chronic pain and interfering with the patient's ability to work. Bone histomorphometry demonstrated low-turnover bone disease, and he was treated with 20µg of teriparatide (subcutaneous injection) every morning for 24 months. Within 6 months of initiating therapy, the patient's pain resolved and he was able to resume work. Serum calcium and phosphate levels remained within reference ranges throughout his treatment, and he sustained no further fractures. During 24 months of treatment, bone mineral density was maintained at the lumbar spine, and there was an increase of 4% at the femoral neck and total hip. A second transiliac bone biopsy demonstrated improvements in static and dynamic parameters of bone formation. In our patient, 24-month treatment with teriparatide was safe and effective; however, larger studies are needed to determine the efficacy of teriparatide in the dialysis-dependent CKD population.

Bone imaging and fracture risk assessment in kidney disease.

Fractures are more common and are associated with greater morbidity and morality in patients with kidney disease than in members of the general population. Thus, it is troubling that in chronic kidney disease (CKD) patients there has been a paradoxical increase in fracture rates over the past 20 years compared to the general population. Increased fracture incidence in CKD patients may be driven in part by the lack of screening for fracture risk. In the general population, dual energy X-ray absorptiometry (DXA) is the clinical standard to stratify fracture risk, and its use has contributed to decreases in fracture incidence. In contrast, in CKD, fracture risk screening with DXA has been uncommon due to its unclear efficacy in predicting fracture and its inability to predict type of renal osteodystrophy. Recently, several prospective studies conducted in patients across the spectrum of kidney disease have demonstrated that bone mineral density measured by DXA predicts future fracture risk and that clinically relevant information regarding fracture risk is provided by application of the World Health Organization cutoffs for osteopenia and osteoporosis to DXA measures. Furthermore, novel high-resolution imaging tools, such as high-resolution peripheral quantitative computed tomography (HR-pQCT), have been used to elucidate the effects of kidney disease on cortical and trabecular microarchitecture and bone strength and to identify potential targets for strategies that protect against fractures. This review will discuss the updated epidemiology of fractures in CKD, fracture risk screening by DXA, and the utility of state-of-the art imaging methods to uncover the effects of kidney disease on the skeleton.

Vascular calcification in patients with nondialysis CKD over 3 years.

BACKGROUND AND OBJECTIVES: Vascular calcification (VC) is common in CKD, but little is known about its prognostic effect on patients with nondialysis CKD. The prevalence of VC and its ability to predict death, time to hospitalization, and renal progression were assessed. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The Study of Mineral and Bone Disorders in CKD in Spain is a prospective, observational, 3-year follow-up study of 742 patients with nondialysis CKD stages 3-5 from 39 centers in Spain from April to May 2009. VC was assessed using Adragao (AS; x-ray pelvis and hands) and Kauppila (KS; x-ray lateral lumbar spine) scores from 572 and 568 patients, respectively. The primary end point was death. Secondary outcomes were hospital admissions and appearance of a combined renal end point (beginning of dialysis or drop >30% in eGFR). Factors related to VC were assessed by logistic regression analysis. Survival analysis was assessed by Cox proportional models. RESULTS: VC was present in 79% of patients and prominent in 47% (AS≥3 or KS>6). Age (odds ratio [OR], 1.05; 95% confidence interval [95% CI], 1.02 to 1.07; P<0.001), phosphorous (OR, 1.68; 95% CI, 1.28 to 2.20; P<0.001), and diabetes (OR, 2.11; 95% CI, 1.32 to 3.35; P=0.002) were independently related to AS≥3. After a median follow-up of 35 months (interquartile range=17-36), there were 70 deaths (10%). After multivariate adjustment for age, smoking, diabetes, comorbidity, renal function, and level of phosphorous, AS≥3 but not KS>6 was independently associated with all-cause (hazard ratio [HR], 2.07; 95% CI, 1.07 to 4.01; P=0.03) and cardiovascular (HR, 3.46; 95% CI, 1.27 to 9.45; P=0.02) mortality as well as a shorter hospitalization event-free period (HR, 1.14; 95% CI, 1.06 to 1.22; P<0.001). VC did not predict renal progression. CONCLUSIONS: VC is highly prevalent in patients with CKD. VC assessment using AS independently predicts death and time to hospitalization. Therefore, it could be a useful index to identify patients with CKD at high risk of death and morbidity as previously reported in patients on dialysis.

The clinical characteristics of patients with hip fractures in typical locations and atypical femoral fractures.

UNLABELLED: The pathophysiology of atypical fractures is unknown. We compared characteristics of patients with atypical femoral fractures and hip fractures in typical locations of the femur. Patients with atypical fracture reported a longer duration of use of bisphosphonates, had higher body mass index, and higher total hip bone mineral density. Further studies are needed. INTRODUCTION: This study aims to describe the characteristics of patients with typical and atypical fractures of the femur assessed in a tertiary care osteoporosis center. METHODS: We abstracted clinical, laboratory, and radiographic data on subjects with a history of a low-impact fracture at the femur and/or hip (confirmed by review of radiograph and/or radiology report) from January 2008 to October 2011. Available radiographs were reviewed and fracture categorized as typical or atypical by a radiologist blinded to the original diagnosis. RESULTS: Radiology reports were available for 72 subjects: 40 hip fractures in typical locations (typical fracture), 16 atypical femoral fracture (atypical fracture), and 16 were excluded. While both those with typical and atypical fractures reported taking bisphosphonates at the time of fracture, duration of use was longer with atypical fractures (104.2±42.0 months) compared with typical (71.1±62.8 months) (p=0.04). Body mass index (BMI) was higher in patients with atypical fractures (26.2±3.2 kg/m2) than in those with typical (23.1±4.3 kg/m2) (p=0.006). Total bone mineral density (BMD) was higher in patients with atypical fracture (0.795±0.102) versus typical (0.686±0.130) (p=0.003) Previous history of cancer was reported by 7 of 16 patients with atypical and 7 of 40 patients with typical fracture (p=0.04). CONCLUSIONS: Compared to those with typical fractures, patients with atypical fracture report a longer duration of use of bisphosphonates, higher BMI, and higher total hip BMD. Future studies should examine if these differences contribute to the pathophysiology of atypical fractures.

Osteoprotegerin and fractures in men and women with chronic kidney disease.

Fractures are common in men and women with chronic kidney disease (CKD) but the best tool to identify those at high risk is unknown. Increased circulating osteoprotegerin(OPG) is associated with fractures in postmenopausal women. We determined if serum OPG was associated with prevalent fractures (self-reported low trauma fractures since 40 years of age and/or prevalent vertebral fractures identified by radiographs) in men (n = 97) and women (n = 67) with stage 3­5 CKD. Analyses were performed unadjusted and adjusted for stage of CKD. Results are expressed as mean ± standard deviation(SD), and as odds ratio (OR) per SD increase in OPG with 95 % confidence intervals (CI). The mean age was 62.7 ± 16.3 years, and mean weight was 78.9 ± 18.7 kg. Compared to those without fractures, those with fractures(n = 55) were older (p < 0.01). Serum OPG increased as kidney function decreased, and OPG was higher in those with fractures compared to those without (9.42 ± 4.08 vs 8.06 ± 3.11 pmol/L, p = 0.02). After adjusting for stage of CKD, increased OPG was associated with an increased fracture risk (OR 1.13, 95 % CI 1.02­1.25); however, OPG did not discriminate fracture status well (area under the receiver operating characteristic curve 0.61, 95 % CI 0.52­0.70). OPG is associated with fractures in men and women with stage 3­5 CKD; however, the ability of OPG to discriminate fracture status is poor and cannot be used in isolation to assess fracture risk. Further studies should examine the ability of OPG in combination with other risk factors to better discriminate fracture status in men and women with CKD.

Tumour induced osteomalacia due to a sinonasal hemangiopericytoma: A case report.

Tumour induced osteomalacia (TIO) is a rare and often unrecognized cause of hypophosphatemia. We report on a case of TIO due to a hemangiopericytoma originating from the left nasal sinus. The patient was a 55-year-old male with a 3-year history of left hip pain and an undisplaced left hip fracture. Biochemical testing demonstrated low levels of serum phosphate and serum 1,25-dihydroxyvitamin D, and an elevated level of fibroblast growth factor 23. Octreotide scanning demonstrated uptake in the left nasal sinus area and a computed tomography scan revealed a left nasal sinus mass. The patient underwent surgical resection of the mass and histology was consistent with a sinonasal hemangiopericytoma. His serum phosphate levels normalized almost immediately after surgery and he had complete resolution of hip pain. Our case highlights the importance of considering TIO when assessing patients with low serum phosphate.

Bone and kidney disease: diagnostic and therapeutic implications.

Fractures are common in patients with chronic kidney disease (CKD), but the diagnosis and treatment of bone disease in CKD are difficult due to the multiple etiologies of bone disease in these patients. Noninvasive imaging, including bone mineral density by dual energy x-ray absorptiometry, can be useful in diagnosing osteoporosis in predialysis CKD; however, consensus on the diagnosis of osteoporosis among those with advanced CKD-particularly stage 5 CKD patients on dialysis-is lacking. Treatments approved for osteoporosis in postmenopausal women may be used in patients with stage 1 to 3 CKD. Furthermore, post-hoc analyses show efficacy and safety of oral bisphosphonates, raloxifene, and denosumab in stage 4 CKD for short-term treatment. However, treatment decisions are more difficult in stage 5 CKD. Bone biopsy may be required, and most treatments, if used, would be off label. Overall, the diagnosis and treatment of bone disease in patients with CKD require further research.

Effects of denosumab on fracture and bone mineral density by level of kidney function.

The incidences of osteoporosis and chronic kidney disease (CKD) both increase with increasing age, yet there is a paucity of data on treatments for osteoporosis in the setting of impaired kidney function. We examined the efficacy and safety of denosumab (DMAb) among subjects participating in the Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) Study. We estimated creatinine clearance (eGFR) using Cockcroft-Gault and classified levels of kidney function using the modified National Kidney Foundation classification of CKD. We examined incident fracture rates; changes in bone mineral density (BMD), serum calcium, and creatinine; and the incidence of adverse events after 36 months of follow-up in subjects receiving DMAb or placebo, stratified by level of kidney function. We used a subgroup interaction term to determine if there were differences in treatment effect by eGFR. Most (93%) women were white, and the mean age was 72.3 ± 5.2 years; 73 women had an eGFR of 15 to 29 mL/min; 2817, between 30 to 59 mL/min; 4069, between 60 to 89 mL/min, and 842 had an eGFR of 90 mL/min or greater. None had stage 5 CKD. Fracture risk reduction and changes in BMD at all sites were in favor of DMAb. The test for treatment by subgroup interaction was not statistically significant, indicating that treatment efficacy did not differ by kidney function. Changes in creatinine and calcium and the incidence of adverse events were similar between groups and did not differ by level of kidney function. It is concluded that DMAb is effective at reducing fracture risk and is not associated with an increase in adverse events among patients with impaired kidney function.

Lasofoxifene in osteoporosis and its place in therapy.

Selective estrogen-receptor modulators (SERMs), which have estrogen-like effects on bone and "antiestrogen effects" on other tissues, have been in development for osteoporosis prevention and treatment in postmenopausal women as a safer alternative to long-term estrogen. We conducted a literature review of the skeletal and extraskeletal effects of lasofoxifene, a new generation SERM approved by the European Commission for osteoporosis treatment. Published data on the effects of lasofoxifene are based on 23 clinical pharmacology studies with over 10,000 participants from 17 phase 2 and 3 randomized controlled trials (RCTs). In RCTs, lasofoxifene decreases bone turnover markers (BTMs), increases bone mineral density (BMD) at the spine and hip, and decreases the incidence of vertebral and nonvertebral nonhip fractures compared with placebo. Compared with raloxifene, lasofoxifene gave greater decreases in BTMs, and greater increases in lumbar spine BMD. Lasofoxifene also decreased the risk of breast cancer, major coronary heart disease events, and stroke, but-similar to raloxifene-there was an increased risk of venous thromboembolism. In one trial, endometrial hypertrophy and uterine polyps were more common with lasofoxifene than with placebo, but endometrial cancer and hyperplasia were not. Lasofoxifene is probably most appropriate for use among women in their early or middle menopausal years (age 55-65) who have, or are at risk of developing, osteoporosis and in particular vertebral fractures. At the time of publication, lasofoxifene is not approved for use by the US Food and Drug Administration, and as such is not used in North America.

Fracture Risk Assessment in Chronic Kidney Disease, Prospective Testing Under Real World Environments (FRACTURE): a prospective study.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased risk of fracture. Decreased bone mass and disruption of microarchitecture occur early in the course of CKD and worsens with the progressive decline in renal function so that at the time of initiation of dialysis at least 50% of patients have had a fracture. Despite the excess fracture risk, and the associated increases in morbidity and mortality, little is known about the factors that are associated with an increase in fracture risk. Our study aims to identify prognostic factors for bone loss and fractures in patients with stages 3 to 5 CKD. METHODS: This prospective study aims to enroll two hundred and sixty men and women with stages 3 to 5 CKD. Subjects will be followed for 24 months and we will examine the ability of: 1) bone mineral density by dual x-ray absorptiometry at the spine, hip, and radius; 2) volumetric bone density by high resolution peripheral quantitated computed tomography at the radius and tibia; 3) serum markers of bone turnover; 4) bone formation rate by bone biopsy; and 5) muscle strength and balance to predict spine and non-spine fractures, identified by self-report and/or vertebral morphometry. All measurements will be obtained at baseline, at 12 and at 24 months with the exception of bone biopsy, which will be measured once at 12 months. Subjects will be contacted every 4 months to determine if there have been incident fractures or falls. DISCUSSION: This study is one of the first that aims to identify risk factors for fracture in early stage CKD patients. Ultimately, by identifying risk factors for fracture and targeting treatments in this group-before the initiation of renal replacement therapy--we will reduce the burden of disease due to fractures among patients with CKD.

Effects of calcium on cardiovascular events in patients with kidney disease and in a healthy population.

BACKGROUND AND OBJECTIVES: Cardiovascular disease (CVD) is the largest contributor to all-cause mortality in patients with end stage renal disease (ESRD). Accelerated vascular calcification is a key risk factor for CVD in these patients. The etiology of vascular calcification and the specific role calcium supplementation may play in accelerating calcification have not been fully elucidated. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We summarize published data that report on the association between calcium supplementation, vascular calcification, and CVD in patients with and without ESRD. RESULTS: The majority of randomized, controlled trials in patients with ESRD suggest that calcium supplementation--in the form of calcium-based phosphate binders--leads to a progression of vascular calcification. However, studies showing that calcium-based phosphate binders increase cardiovascular mortality are lacking in patients with ESRD. In contrast, one randomized trial in healthy postmenopausal women reported that, compared with those not receiving calcium supplementation, women who take supplements are at an increased risk for cardiovascular events. CONCLUSIONS: Given the potential for harm with calcium supplementation in healthy postmenopausal women and the evidence that calcium-based phosphate binders are associated with adverse intermediate outcomes in patients with ESRD, calcium-either as a phosphate binder or as a supplement--should be prescribed with caution.

The presence of both an energy deficiency and estrogen deficiency exacerbate alterations of bone metabolism in exercising women.

BACKGROUND: Bone loss in amenorrheic athletes has been attributed to energy deficiency-related suppression of bone formation, but not increased resorption despite hypoestrogenism. OBJECTIVE: To assess the independent and combined effects of energy deficiency and estrogen deficiency on bone turnover markers in exercising women. DESIGN: PINP, osteocalcin, U-CTX-I, TT3, leptin, and ghrelin were measured repeatedly, and bone mineral density (BMD) was measured once in 44 exercising women. Resting energy expenditure (REE) was used to determine energy status (deficient or replete) and was corroborated with measures of metabolic hormones. Daily levels of urinary estrone and pregnanediol glucuronides (E1G, PdG), were assessed to determine menstrual and estrogen status. Volunteers were then retrospectively categorized into 4 groups: 1) Energy Replete+Estrogen Replete (EnR+E2R), (n=22), 2) Energy Replete+Estrogen Deficient (EnR+E2D), (n=7), 3) Energy Deficient+Estrogen Replete (EnD+E2R), (n=7), and 4) Energy Deficient+Estrogen Deficient (EnD+E2D), (n=8). RESULTS: The groups were similar (p>0.05) with respect to age (24.05+/-1.75 yrs), weight (57.7+/-2.2 kg), and BMI (21.05+/-0.7 kg/m2). By design, REE/FFM (p=0.028) and REE:pREE (p<0.001) were lower in the EnD vs. EnR group, and the E2D group had a lower REE:pREE (p=0.005) compared to the E2R group. The EnD+E2D group had suppressed PINP (p=0.034), and elevated U-CTX-I (p=0.052) and ghrelin (p=0.028) levels compared to the other groups. These same women also had convincing evidence of energy conservation, including TT3 levels that were 29% lower (p=0.057) and ghrelin levels that were 44% higher (p=0.028) than that observed in the other groups. Energy deficiency was associated with suppressed osteocalcin, and TT3 (p<0.05), whereas estrogen deficiency was associated with decreased E1G (p<0.02), and lower L2-L4 BMD (p=0.033). Leptin was significant in predicting markers of bone formation, but not markers of bone resorption. CONCLUSIONS: When the energy status of exercising women was adequate (replete), there were no apparent perturbations of bone formation or resorption, regardless of estrogen status. Estrogen deficiency in exercising women, in the presence of an energy deficiency, was associated with bone loss and involved suppressed bone formation and increased bone resorption. These findings underscore the importance of avoiding energy deficiency, which is associated with hypoestrogenism, to avoid bone health problems.

Effective initiation of osteoporosis diagnosis and treatment for patients with a fragility fracture in an orthopaedic environment.

BACKGROUND: Fragility fractures resulting from osteoporosis are common injuries. However, the identification and treatment of osteoporosis in these high-risk patients are widely reported to be inadequate. The goals of this study were to determine how many patients receiving inpatient or outpatient treatment for a fragility fracture could be identified and enrolled in a program for osteoporosis education, investigation, and treatment and receive appropriate osteoporosis care within the program. METHODS: An Osteoporosis Exemplary Care Program was implemented to identify, educate, evaluate, refer, and treat patients considered to be at risk for osteoporosis because of a typical fragility fracture. System modifications included coordination among the orthopaedic unit, Metabolic Bone Disease Clinic, and nuclear medicine unit to provide a continuum of care for these patients. Barriers were addressed through ongoing education of physicians, staff, and patients to increase knowledge and awareness of osteoporosis. The percentages of patients previously diagnosed and treated for osteoporosis, referred for investigation of osteoporosis, treated by the orthopaedic team, and receiving appropriate attention for osteoporosis were calculated. Risk factors for osteoporosis were also assessed. RESULTS: Three hundred and forty-nine patients with a fragility fracture (221 outpatients and 128 inpatients) who met the inclusion criteria and an additional eighty-one patients with a fracture (fifty-five outpatients and twenty-six inpatients) who did not meet the inclusion criteria but were suspected by their orthopaedic surgeons of having underlying osteoporosis were enrolled in the Osteoporosis Exemplary Care Program. More than 96% (414) of these 430 patients received appropriate attention for osteoporosis. Approximately one-third (146) of the 430 patients had been diagnosed and treated for osteoporosis before the time of recruitment. Two hundred and twenty-two of the remaining patients were referred to the Metabolic Bone Disease Clinic or to their family physician for further investigation and treatment for osteoporosis. Treatment was initiated by the orthopaedic team for another twenty-three patients. Many patients had risk factors for osteoporosis in addition to the fragility fracture; these included a previous fracture (forty-nine of 187; 26%), a mother who had had a fragility fracture (forty-two of 188; 22%), or a history of smoking (105 of 188; 56%). CONCLUSIONS: In a coordinated post-fracture osteoporosis education and treatment program directed at patients with a fragility fracture and their caregivers, >95% of patients were appropriately diagnosed, treated, or referred for osteoporosis care. To accomplish this, a dedicated coordinator and the full cooperation of orthopaedic surgeons and residents, orthopaedic technologists, allied health-care professionals (nurses, physical and occupational therapists, and social workers), and administrative staff were required.

Isosorbide mononitrate increases bone formation and decreases bone resorption in postmenopausal women: a randomized trial.

UNLABELLED: NO regulates bone remodeling in cellular and animal models. We examined the effect of administering ISMO, a NO donor, on bone turnover in 144 postmenopausal women. After 3 months, women randomized to ISMO had a greater decrease in bone resorption and a greater increase in bone formation compared with placebo. NO donors may prevent postmenopausal bone loss. INTRODUCTION: NO both stimulates bone formation and inhibits bone resorption in vitro. NO donors (nitrates) are inexpensive and widely available, but their value for postmenopausal osteoporosis has never been evaluated in a randomized trial. MATERIALS AND METHODS: We randomly assigned 144 healthy postmenopausal women with a hip BMD T score between 0 and -2.5 to 5 or 20 mg/day of isosorbide mononitrate (ISMO) or placebo for 12 weeks. We measured urine N-telopeptide (NTx), a marker of bone resorption, and serum bone-specific alkaline phosphatase (BSALP), a marker of bone formation. Markers were measured immediately before randomization and after 12 weeks of treatment. We calculated the percent change in NTx and BSALP for each of the treatment groups (placebo, 5 mg ISMO, and 20 mg ISMO). Our primary outcome was the percent change in NTx and BSALP in the 5- and 20-mg ISMO groups compared with placebo. RESULTS AND CONCLUSIONS: Compared with women randomized to placebo, women randomized to 20 mg of ISMO had a 45.4% decrease in NTx (95% CI, 25.8-64.9) and a 23.3% increase (95% CI, 8.9-37.8) in BSALP. Women randomized to 5 mg of ISMO had a 36.3% decrease in NTx (95% CI, 14.8-57.8) and a 15.9% increase in BSALP (95% CI, 1.1-30.7). ISMO decreases bone resorption and increases bone formation. These findings suggest that nitrates may be useful for the prevention of postmenopausal osteoporosis.