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1.  Insights into Nutritional and Inflammatory Aspects of Low Parathyroid Hormone in Dialysis Patients 
In people with advanced chronic kidney disease (CKD), secondary hyperparathyroidism is associated with high-turnover bone disease. A low serum PTH may not necessarily be due to hypodynamic bone but another facet of the malnutrition-inflammation cachexia-syndrome (MICS). A recent 5-year cohort study in 748 stable hemodialysis outpatients showed that after removing the confounding by the MICS, the moderately low PTH in 100 to 150 p/ml range was associated with the greatest survival. Survival data from Japanese dialysis patients show similar survival advantages of lower PTH range. Low serum PTH appears associated with markers of protein-energy wasting and inflammation, and this association may confound the relationship between serum PTH and alkaline phosphatase. PTH stimulates lipogenesis through influx of calcium into the adipocytes. PTH secretion is suppressed by interleukin-1 beta and interleukin-6, which are pro-inflammatory cytokines associated with poor outcome in dialysis patients. These cytokines inhibits PTH secretion in cultured parathyroid tissue slices. In this article we review the association of a low serum PTH with the MICS in CKD patients and suggest avoiding over-interpretation of low serum PTH as an indicator of low-turnover bone disease.
doi:10.1053/j.jrn.2010.10.006
PMCID: PMC3032422  PMID: 21195929
Parathyroid hormone (PTH); adynamic bone disease; malnutrition-inflammation complex; alkaline phosphatase; cytokines
2.  Applicability of fibroblast growth factor 23 for evaluation of risk of vertebral fracture and chronic kidney disease-mineral bone disease in elderly chronic kidney disease patients 
BMC Nephrology  2012;13:122.
Background
Elderly patients with chronic kidney disease (CKD) are usually at a high risk of fractures due to both osteoporosis and CKD-mineral bone disease (MBD). A new marker is needed to prevent fractures and control CKD-MBD from the early to advanced stages of CKD. In the early stage of CKD, fibroblast growth factor 23 (FGF23) level increases before parathyroid hormone (PTH) and phosphate levels increase, and steadily increases with the progression of kidney disease. It has been reported that FGF23 is related to the overall fracture risk. We investigated the usefulness of FGF23 as a marker for evaluating the risk of vertebral fracture and CKD-MBD in elderly CKD patients.
Methods
One hundred and five elderly predialysis CKD patients who had never been treated for osteoporosis and had never used calcium supplements, vitamin D supplements, or phosphate binders were enrolled in this cross-sectional study in Tokyo, Japan. We investigated the prevalence of vertebral fracture and measured serum calcium, phosphate, 1,25(OH)2 vitamin D [1,25(OH)2D], intact PTH, FGF23, alkaline phosphatase, and urinary N-terminal telopeptide levels. Then, we examined the relationship between the level of FGF23 and those of bone-metabolism-related markers and identified markers associated with vertebral fractures in elderly CKD patients.
Results
The background features of the patients were as follows: female, 32.4%; diabetes mellitus, 39.0%; average age (standard deviation), 73.2 (7.7) years; and estimated glomerular filtration rate (eGFR), 45.7 (24.1) ml/min/1.73 m2. Adjusted multivariate regression analysis showed that the natural logarithm value of FGF23 level [ln(FGF23)] was positively associated with body mass index (p = 0.002), serum phosphate level (p = 0.0001), and negatively with eGFR (p = 0.0006). Multivariate logistic regression analysis showed that vertebral fracture was independently associated with ln(FGF23) (adjusted odds ratio, 4.44; 95% confidence interval, 1.13-17.46). A receiver-operating-characteristic curve of ln(FGF23) showed that the optimal cutoff level of FGF23 indicative of vertebral fracture was 56.8 pg/ml (sensitivity, 0.82; specificity, 0.63).
Conclusions
FGF23 level was independently associated with the levels of bone-metabolism-related markers and vertebral fracture. FGF23 is a new candidate marker for detecting abnormalities of bone metabolism and vertebral fracture in elderly CKD patients.
doi:10.1186/1471-2369-13-122
PMCID: PMC3506497  PMID: 23013306
CKD; Fracture; FGF23; CKD-MBD; Phosphate; PTH; Geriatrics
3.  Calciotropic Hormones and the Risk of Hip and Non-Spine Fractures in Older Adults: The Health ABC Study 
The effects of vitamin D and parathyroid hormone (PTH) levels on incident fracture remains uncertain. To test the hypothesis that increasing serum 25-hydroxyvitamin D (25(OH)D) and decreasing PTH levels are associated with decreased risk of hip and any non-spine fracture we conducted a prospective cohort study among 2614 community-dwelling white and black participants, aged ≥70 years, from the Health, Aging and Body Composition (Health ABC) study. Serum and plasma samples were drawn at year 2 which formed the baseline for this analysis. Serum 25(OH)D and intact PTH (1-84) were measured using radioimmunoassay with DiaSorin reagents and EDTA plasma with a two-site immunoradiometric assay kit, respectively. Incident fractures (hip and any non-spine) were assessed after year 2, every 6 months, by self-report and validated by radiology reports. The median (IQR) follow-up times for hip and any non-spine fractures were 6.4 (6.1–6.5) and 6.4 (5.5–6.5) years, respectively. Cox proportional hazards regression was used to estimate the hazard ratios (HR) with 95% confidence intervals (CI) for fracture. There were 84 hip and 247 non-spine fractures that occurred over the follow-up period. The multivariable adjusted HRs (95% CIs) of hip fracture for participants in the lowest (≤17.78 ng/ml), second (17.79-24.36 ng/ml) and third quartile (24.37-31.94 ng/ml) of 25(OH)D were 1.92 (0.97-3.83), 0.75 (0.32-1.72) and 1.86 (1.00-3.45), respectively; compared with participants in the highest 25(OH)D quartile (>31.94 ng/ml) (p-trend=0.217). Additional adjustment for IL-6 (p-value=0.107), PTH (p-value=0.124) and hip aBMD (p-value=0.137) attenuated HRs of hip fracture in the lowest quartile by 16.3%, 17.4%, and 26.1%, respectively. There was no evidence of an association between 25(OH)D and any non-spine fractures, or between PTH and hip or any non-spine fractures. We found limited evidence to support an association between calciotropic hormones and hip and non-spine fractures in older men and women.
doi:10.1002/jbmr.1545
PMCID: PMC3541828  PMID: 22228250
serum 25-hydroxyvitamin D; parathyroid hormone; hip fractures; non-spine fractures
4.  Efficacy of Clodronate in Local and Systemic Osteoporosis 
Clodronate belongs to the first generation of the large biphosphonate family of drugs (the non-nitrogen ones), and from the earliest studies, conducted in the ’70s, it distinguished itself from etidronate, a powerful antiresorptive drug that acts at osteoclastic level but, however, causes an osteomalacic bone mineralisation deficit clearly evident on histomorphometry. Common experience and several clinical and biological studies have shown that clodronate exerts an antalgic effect not only in fracture patients but also in those affected by osteoarthrosis or athritis. The drug, therefore, can usefully be included in the treatment regimen of rheumatic patients, also on account of its symptomatic effects. Clodronate in small doses (2 mg) also appears to exert protective effects on cartilage (an intra-articular formulation is indeed to be introduced), while at doses 10–100 times higher it undoubtedly has anti-inflammatory effects and, more specifically, antimacrophage and anticytokine effects (IL-1, IL-6, TNF-alpha, PGE). These effects are amplified by the incorporation of clodronate into monolayer liposomes. The drug may therefore be considered a coadjuvant in the treatment of arthritis originating from strong osteoclast activation induced by increased levels of cytokines and by an increased RANKL/OPG ratio. It is clear that clodronate can act both upstream, on cytokines, and downstream, on the osteoclast effector function.
At local level, the anti-inflammatory and antimacrophage effect is likely at the basis of the capacity of the drug to stablilise a prosthesis, as observed at knee and at hip level.
Its impact on algodystrophic pathology, with clear reduction of bone marrow oedema as from the third month of parenteral treatment, is well known. This may also be true, albeit in the absence of adequate literature, of treatment of osteonecrosis in the first two stages, especially if it is parcellar, as seen at subchondral level in osteoarthrosis.
At systemic level, there are essentially three published studies demonstrating the anti-fracture effect of the drug: two by McCloskey, published in 2004 and 2007 in J Bone Miner Res, and our study on the prevention of fractures in corticosteroid-induced osteoporosis.
They are all controlled studies, the first two double-blind, and ours an open, controlled study.
McCloskey’s studies used 800 mg of clodronate/day per os for three years, whereas we used 100 mg of clodronate /week i.m. for four weeks.
In McCloskey’s 2004 study, 593 patients (women and men with osteoporosis or vertebral fracture), were randomised to 500 mg calcium without vitamin D or to calcium plus clodronate. Vertebral fractures were the primary endpoint.
As regards the antifracture effect, there emerged a 46% reduction in vertebral fractures in the clodronate versus the control group. The reduction was 40% in patients with post-menopausal osteoporosis and a remarkable 65% in patients with secondary osteoporosis. There was also a 73% reduction in the incidence of vertebral fractures in subjects who did not previously have fractures and a reduction of 41% in those who already had fractures. This study recorded a 30% reduction in non-vertebral fractures, which was not statistically significant. In the 2007 study, McCloskey investigated 5600 women over the age of 75 years who, on invitation to take part in the study, had consented. The patients were randomised in a double-blind manner to receive either clodronate 800 mg/day or inert placebo. Clinical and densitometric monitoring lasted three years. The primary endpoint was reduction of fractures of all types.
The sample presented some interesting features, given that no densitometric criteria had been applied in the enrolment stage: only 1 woman in 5 was osteoporotic; furthermore, subjects with other problems were excluded, and this was reflected in the fact that mortality at the end of the three years was half the expected level, and fracture episodes, too, were 50% lower than the expected level. This clearly had repercussions on the statistical power of this study.
The important finding emerging from this study is that the overall antifracture effect is present both in osteoporotic subjects (−29.5%), and in normal and osteopenic subjects (−22.5%).
As regards corticosteroid-induced osteoporosis there exist several studies that investigate bone mass, but our 2003 study published in Bone is the only one to take vertebral fractures as an endpoint and also absolutely the only one to test, using this endpoint, the 100 mg i.m. formulation.
It was a study on prevention of corticosteroid-induced osteoporosis. Indeed, the subjects (160 patients with arthritis) had started cortiscosteroid therapy within the previous 100 days. They were randomised to receive clodronate + calcium and vitamin D or only calcium and vitamin D. Each year, DXA scans, US measurement of the heel and DXA morphometry were carried out. The results showed maintenance of bone mass in the patients receiving clodronate (which was the objective, given that these were osteopenic or normal patients) while mineral loss was marked in the controls. The US heel measurements were in line with the DXA data.
An around 40% reduction in fractures overall was recorded, while multiple fractures were reduced by 75%.
Finally, in recent years the cost/benefit question has started to be raised, especially after the birth of algorithms like FRAX, which allow the selection of patients at increased ten-year fracture risk, and of pharmaco-economic models that make it possible to calculate FRAX-based intervention thresholds on the basis of drug and monitoring costs, antifracture efficacy, quality of life, and the amount that a community can or wishes to spend. In this regard, a subanalysis of patients from the McCloskey study (3974 patients aged over 65), showed that clodronate is more effective in patients with a higher FRAX-calculated fracture risk. Furthermore, another study, by Kanis, has shown that for a drug costing 100 pounds/year (very similar to the cost of clodronate), the “cost-effective” threshold for intervention is around 7–10%.
PMCID: PMC3213787
5.  Impact of mineral and bone disorder on healthcare resource use and associated costs in the European Fresenius medical care dialysis population: a retrospective cohort study 
BMC Nephrology  2012;13:140.
Background
Secondary hyperparathyroidism (SHPT) is associated with mortality in patients with chronic kidney disease (CKD), but the economic consequences of SHPT have not been adequately studied in the European population. We assessed the relationship between SHPT parameters (intact parathyroid hormone [iPTH], calcium, and phosphate) and hospitalisations, medication use, and associated costs among CKD patients in Europe.
Methods
The analysis of this retrospective cohort study used records of randomly selected patients who underwent haemodialysis between January 1, 2005 and December 31, 2006 at participating European Fresenius Medical Care facilities in 10 countries. Patients had ≥ 1 iPTH value recorded, and ≥ 1 month of follow-up after a 3-month baseline period during which SHPT parameters were assessed. Time at risk was post-baseline until death, successful renal transplantation, loss to follow-up, or the end of follow-up. Outcomes included cost per patient-month, rates of hospitalisations (cardiovascular disease [CVD], fractures, and parathyroidectomy [PTX]), and use of SHPT-, diabetes-, and CVD-related medications. National costs were applied to hospitalisations and medication use. Generalised linear models compared costs across strata of iPTH, total calcium, and phosphate, adjusting for baseline covariates.
Results
There were 6369 patients included in the analysis. Mean ± SD person-time at risk was 13.1 ± 6.4 months. Patients with iPTH > 600 pg/mL had a higher hospitalisation rate than those with lower iPTH. Hospitalisation rates varied little across calcium and phosphate levels. SHPT-related medication use varied with iPTH, calcium, and phosphate. After adjusting for demographic and clinical variables, patients with baseline iPTH > 600 pg/mL had 41% (95% CI: 25%, 59%) higher monthly total healthcare costs compared with those with iPTH in the K/DOQI target range (150–300 pg/mL). Patients with baseline phosphate and total calcium levels above target ranges (1.13–1.78 mmol/L and 2.10–2.37 mmol/L, respectively) had 38% (95% CI: 27%, 50%) and 8% (95% CI: 0%, 17%) higher adjusted monthly costs, respectively. Adjusted costs were 25% (95% CI: 18%, 32%) lower among patients with baseline phosphate levels below the target range. Results were consistent in sensitivity analyses.
Conclusions
These data suggest that elevated SHPT parameters increase the economic burden of CKD in Europe.
doi:10.1186/1471-2369-13-140
PMCID: PMC3504570  PMID: 23106934
6.  PTH 1–84: bone rebuilding as a target for the therapy of severe osteoporosis 
Summary
Osteoporotic fractures, especially in elderly people, represent a health concern as they are associated with increased morbidity and mortality together with an increased economic burden for the society. During the past 20 years a great effort has been done in order to reduce the risk of fracture and many drugs are now available for this purpose, but osteoporosis is still regarded as an inevitable consequences of the aging process. Osteoporotic fractures occur most frequently in the spine and hip and with lower frequency in the wrist, pelvis, and upper arm. They are associated with significant morbidity and those of the hip and spine are also associated with excess mortality. The correct diagnosis and the adequate treatment of osteoporosis can reduce fracture risk. Together with well known anti-resorptive agents (like bisphosphonates, oestrogen and selective oestrogen receptor modulators) in the past few years anabolic therapy with parathyroid hormone (PTH) has become available for the treatment of severe osteoporosis. Human recombinant intact parathyroid hormone (PTH 1–84) and human recombinant PTH peptide 1–34 (Teriparatide) belong to this group of agents.
This paper will review PTH actions together with the anabolic effect of PTH 1–84 both in reducing fracture risk and in promoting fracture healing. Although in primary hyperparathyroidism bone catabolism prevails on bone anabolism, PTH remains a potent stimulator of osteoblasts and its anabolic properties can be seen when it is given at a low dosage and intermittently. Intermittent PTH can stimulate bone formation to a greater extent and earlier than bone resorption, thus creating the so called “anabolic window”.
The TOP study demonstrated that PTH 1–84 is able to reduce the risk of a new fracture in patients with prevalent vertebral fractures, but the same effect was also seen on the incidence of the first fracture in women without fractures at baseline. Moreover PTH produced a continuous increase of bone mineral density, particularly in the cancellous bone. A positive effect of PTH has been described also on fracture healing, consisting both by a shortened time for fracture repair and by an improving of all the parameters of callus formation and development. Although most of the evidence has been obtained in animals some recent studies in humans confirmed, at least in part, these findings. In elderly patients with osteoporosis and fractures PTH treatment may reduce the healing time, improve clinical outcomes and reduce the time of immobilization together with the risk of complications.
PMCID: PMC3392676  PMID: 22783333
human recombinant intact parathyroid hormone; PTH 1–84; osteoporotic fractures; fracture risk reduction; fracture healing
7.  Chronic kidney disease and bone fracture: a growing concern 
Kidney international  2008;74(6):721-731.
Susceptibility to fracture is increased across the spectrum of chronic kidney disease (CKD). Moreover, fracture in patients with end-stage kidney disease (ESKD) results in significant excess mortality. The incidence and prevalence of CKD and ESKD are predicted to increase markedly over the coming decades in conjunction with the aging of the population. Given the high prevalence of both osteoporosis and CKD in older adults, it is of the utmost public health relevance to be able to assess fracture risk in this population. Dual-energy X-ray absorptiometry (DXA), which provides an areal measurement of bone mineral density (aBMD), is the clinical standard to predict fracture in individuals with postmenopausal or age-related osteoporosis. Unfortunately, DXA does not discriminate fracture status in patients with ESKD. This may be, in part, because excess parathyroid hormone (PTH) secretion may accompany declining kidney function. Chronic exposure to high PTH levels preferentially causes cortical bone loss, which may be partially offset by periosteal expansion. DXA can neither reliably detect changes in bone volume nor distinguish between trabecular and cortical bone. In addition, DXA measurements may be low, normal, or high in each of the major forms of renal osteodystrophy (ROD). Moreover, postmenopausal or age-related osteoporosis may also affect patients with CKD and ESKD. Currently, transiliac crest bone biopsy is the gold standard to diagnose ROD and osteoporosis in patients with significant kidney dysfunction. However, bone biopsy is an invasive procedure that requires time-consuming analyses. Therefore, there is great interest in developing non-invasive high-resolution imaging techniques that can improve fracture risk prediction for patients with CKD. In this paper, we review studies of fracture risk in the setting of ESKD and CKD, the pathophysiology of increased fracture risk in patients with kidney dysfunction, the utility of various imaging modalities in predicting fracture across the spectrum of CKD, and studies evaluating the use of bisphosphonates in patients with CKD.
doi:10.1038/ki.2008.264
PMCID: PMC4139042  PMID: 18563052
chronic kidney disease; renal osteodystrophy; fracture; bone imaging
8.  Estimated GFR and Risk of Hip Fracture in Older Men: Comparison of Associations Using Cystatin C and Creatinine 
Background
Higher serum cystatin C is associated with an increased risk of hip fracture in postmenopausal white women, but there is a paucity of data in men. Whether an estimated GFR (eGFR) based on cystatin C (eGFRcys) is superior in predicting hip fracture risk to an eGFR based on creatinine (eGFRcr) or the combination (eGFRcr-cys) is also uncertain.
Study Design
Nested case-cohort.
Setting & Participants
Participants enrolled in the Osteoporotic Fractures in Men (MrOS) Study (5,994 men aged ≥65 years from six U.S. centers) including a random subcohort of 1602 men and 168 men with incident hip fractures (51 of whom were in the subcohort).
Predictor
eGFRcys, eGFRcr and eGFRcr-cys computed using the CKD-EPI equations and expressed in categories of <60, 60–74, and ≥75 mL/min/l.73 m2 (referent group).
Outcome
Incident hip fracture ascertained by participant contacts every 4 months and confirmed with radiographic reports.
Results
Median eGFRcys was 72.9 (IQR, 60.5–85.7) mL/min/1.73 m2. In unadjusted models, all measures of eGFR were associated with increased hip fracture risk. However, after adjustment for age, race, site and BMI, the association of lower eGFRcys (but not lower eGFRcr or lower eGFRcr-cys) with higher hip fracture risk remained: for <60 vs. ≥75 mL/min/l.73 m2, HRs were 1.96 [95% CI, 1.25–3.09], 0.84 [95% CI, 0.52–1.37], and 1.08 [95% CI, 0.66–1.77] for eGFRcys, eGFRcr, and eGFRcr-cys, respectively. Similarly, after adjustment for age, race, site and BMI, eGFR of <60 ml/min/1.73 m2 defined by eGFRcys but not eGFRcr or eGFRcr-cys, was associated with higher hip fracture risk. The association between eGFRcys and hip fracture was not explained by levels of calcitropic hormones or inflammatory markers, but the relationship was attenuated and no longer reached significance (for <60 vs. ≥75 mL/min/l.73 m2: HR, 1.43; 95% CI, 0.88–2.34) after consideration of additional clinical risk factors and bone mineral density.
Limitations
Findings not generalizable other populations; residual confounding may exist.
Conclusions
Older community-dwelling men with lower eGFRcys have an increased risk of hip fracture that is explained in large part by greater burden of risk factors among men with lower eGFRcys. In contrast, lower eGFRcr or lower eGFRcr-cys were not associated with a higher age-adjusted hip fracture risk.
doi:10.1053/j.ajkd.2013.05.022
PMCID: PMC3833961  PMID: 23890927
kidney function; cystatin C; creatinine; hip fracture; elderly; men
9.  The high prevalence of chronic kidney disease-mineral bone disorders: A hospital-based cross-sectional study 
Indian Journal of Nephrology  2012;22(4):285-291.
Mineral bone disorder (MBD) is an important complication of chronic kidney disease (CKD). However, there are limited data on the pattern of MBD in Indian CKD population. The aim of this study was to describe spectrum of MBD in patients with CKD in our center. This was a hospital-based cross-sectional observational study. Patients with stage 4 and 5 CKD were included in this study. Those receiving calcium supplement, vitamin D or its analogues, and calcimimetic were excluded. Serum/plasma levels of creatinine, albumin, calcium, phosphate, total alkaline phosphatase (TAP), intact parathormone (iPTH), and 25-OH vitaminD (25-vitD) were measured. Radiological survey of bones was carried out in all cases, and echocardiography done in selected patients. Statistical analysis was done using Sigmaplot 10.0 software. A total of 150 patients (114 males, 36 females) were included in this study. Mean age was 45.67±16.96 years. CKD stage 4 and 5D were found in 26% (n=39) and 74% (n=111) of study population, respectively. The most common underlying native kidney diseases in patients of CKD 4 and 5D were diabetic nephropathy (41.03%) and CGN (41.44%), respectively. Median (first quartile, third quartile) values for serum levels of corrected calcium (cCa), phosphate, cCaXPO4 product, TAP, plasma iPTH, and 25-vitD in stage 4 CKD were 8.36 (7.79, 8.91) mg/dL, 4.9 (3.92, 6.4) mg/dL, 41.11 (34.01, 53.81) mg2/dL2, 97 (76.5, 184.25) IU/L, 231 (124.5, 430.75) pg/mL, and 12 (6.98, 23.55) ng/mL, respectively; and in stage 5D CKD were 8.36 (7.66, 8.95) mg/dL, 5.7 (4.23, 6.95) mg/dL, 46.5 (37.16, 54.47) mg2/dL2, 180 (114.5, 276.25) IU/L, 288 (169.75, 625.0) pg/mL, and 18.4 (10.0, 26.4) ng/mL, respectively. Prevalence of hypocalcemia (56.41% vs. 54.95%), hyperphosphatemia (64.10% vs. 70.27%), and hyperparathyroidism (84.62% vs. 88.29%) was not different between patients with CKD 4 and 5D. However, iPTH level outside the target range and increased TAP level were significantly (P<0.001) more common in CKD stage 5D. Multiple logistic regression analysis for hyperparathyroidism revealed significant inverse correlation with cCa in CKD 5D. There were no significant differences in vitamin D status and prevalence of valvular calcification between CKD stage 4 and 5D. X-ray revealed renal osteodystrophy in 8 (5.33%) patients, while it was normal in 118 (78.67%) patients. Secondary hyperparathyroidism, hyperphosphatemia, hypocalcemia, increased TAP, and 25-OH vitamin D deficiency and insufficiency were quite common in CKD 4 and 5 patients. The commonest type of MBD in CKD 4 and 5D was secondary hyperparathyroidism.
doi:10.4103/0971-4065.101249
PMCID: PMC3495351  PMID: 23162273
Chronic kidney disease; hyperparathyroidism; hyperphosphatemia; hypocalcemia; mineral bone disorder
10.  Inflammatory Markers and the Risk of Hip Fracture: The Women's Health Initiative 
Journal of Bone and Mineral Research  2012;27(5):1167-1176.
Cytokines play a major role in bone remodeling in vitro and in animal models, with evidence supporting the involvement of inflammatory markers in the pathogenesis of osteoporosis. However, less is known about the longitudinal association of inflammatory markers with hip fracture. We tested whether high receptor levels of pro-inflammatory cytokines are associated with an increased risk of hip fracture in older women. We used a nested case-control study design from the Women's Health Initiative Observational Study (WHI-OS) and selected 400 cases with physician adjudicated incident hip fractures and 400 age, race, and date of blood draw matched controls. Participants were chosen from 39,795 postmenopausal women without previous hip fractures, not using estrogens or other bone-active therapies. Incident hip fractures (median follow-up 7.1 years) were verified by review of radiographs and confirmed by blinded central adjudicators. Hip fractures with a pathological cause were excluded. In multivariable models, the risk of hip fracture for subjects with the highest levels of inflammatory markers (quartile 4) compared with those with lower levels (quartiles 1, 2, and 3) was 1.43 (95% CI, 0.98 to 2.07) for IL-6 SR and 1.41 (95% CI, 0.97 to 2.05) for TNF SR1 and 1.57 (95% CI, 1.09 to 2.25) for TNF SR2. In subjects with all three markers in the highest quartile, the risk ratio of fracture was 2.27 (95% CI to 1.04 to 4.93) in comparison with subjects with 0 or 1 elevated marker(s) (p trend = 0.042). Elevated levels of inflammatory markers for all 3 cytokine soluble receptors were associated with an increased risk of hip fractures in older women. Future clinical trials should test whether interventions to decrease inflammatory marker levels reduces hip fractures.
doi:10.1002/jbmr.1559
PMCID: PMC3361578  PMID: 22392817
Inflammation; hip fractures; cytokines; women; osteoporosis; nested case-control
11.  Osteogenic Protein-1 for Long Bone Nonunion 
Executive Summary
Objective
To assess the efficacy of osteogenic protein-1 (OP-1) for long bone nonunion.
Clinical Need
Although most fractures heal within a normal period, about 5% to 10% do not heal and are classified as delayed or nonunion fractures. Nonunion and segmental bone loss after fracture, reconstructive surgery, or lesion excision can present complex orthopedic problems, and the multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life.
Many factors contribute to the pathogenesis of a delayed union or nonunion fractures, including deficiencies of calcium, vitamin D, or vitamin C, and side effects of medications such as anticoagulants, steroids, some anti-inflammatory drugs, and radiation. It has been shown that smoking interferes with bone repair in several ways.
Incidence of Nonunion and Delayed Union Cases
An estimated 5% to 10% of fractures do not heal properly and go on to delayed union or nonunion. If this overall estimate of incidence were applied to the Ontario population1, the estimated number of delayed union or nonunion in the province would be between 3,863 and 7,725.
Treatment of Nonunion Cases
The treatment of nonunion cases is a challenge to orthopedic surgeons. However, the basic principle behind treatment is to provide both mechanical and biological support to the nonunion site.
Fracture stabilization and immobilization is frequently used with the other treatment modalities that provide biological support to the fractured bone. Biological support includes materials that could be served as a source of osteogenic cells (osteogenesis), a stimulator of mesenchymal cells (osteoinduction), or a scaffold-like structure (osteoconduction).
The capacity to heal a fracture is a latent potential of the stromal stem cells, which synthesize new bone. This process has been defined as osteogenesis. Activation of the stem cells to initiate osteogenic response and to differentiate into bone-forming osteoblasts is called osteoinduction. These 2 properties accelerate the rate of fracture healing or reactivate the ineffective healing process. Osteoconduction occurs when passive structures facilitate the migration of osteoprogenitor cells, the perivascular tissue, and capillaries into these structures.
Bone Grafts and Bone Graft Substitutes
Bone graft and bone graft substitutes have one or more of the following components:
Undifferentiated stem cells
Growth factors
Structural lattice
Undifferentiated stem cells are unspecialized, multipotential cells that can differentiate into a variety of specialized cells. They can also replicate themselves. The role of stem cells is to maintain and repair the tissue in which they are residing. A single stem cell can generate all cell types of that tissue. Bone marrow is a source of at least 2 kinds of stem cells. Hematopoietic stem cells that form all types of blood cells, and bone marrow stromal stem cells that have osteogenic properties and can generate bone, cartilage, and fibrous tissue.
Bone marrow has been used to stimulate bone formation in bone defects and cases of nonunion fractures. Bone marrow can be aspirated from the iliac crest and injected percutaneously with fluoroscopic guidance into the site of the nonunion fracture. The effectiveness of this technique depends on the number and activity of stem cells in the aspirated bone marrow. It may be possible to increase the proliferation and speed differentiation of stem cells by exposing them to growth factor or by combining them with collagen.
Many growth factors and cytokines induced in response to injury are believed to have a considerable role in the process of repair. Of the many bone growth factors studied, bone morphogenetics (BMPs) have generated the greatest attention because of their osteoinductive potential. The BMPs that have been most widely studied for their ability to induce bone regeneration in humans include BMP-2 and BMP-7 (osteogenic protein). Human osteogenic protein-1 (OP-1) has been cloned and produced with recombinant technology and is free from the risk of infection or allergic reaction.
The structural lattice is osteoconductive; it supports the ingrowth of developing capillaries and perivascular tissues. Three distinct groups of structural lattice have been identified: collagen, calcium sulphate, and calcium phosphate. These materials can be used to replace a lost segment of bone.
Grafts Used for Nonunion
Autologous bone graft is generally considered the gold standard and the best material for grafting because it contains several elements that are critical in promoting bone formation, including osteoprogenitor cells, the matrix, and bone morphogenetic proteins. The osteoconductive property of cancellous autograft is related to the porosity of bone. The highly porous, scaffold-like structure of the graft allows host osteoblasts and host osteoprogenitor cells to migrate easily into the area of the defect and to begin regeneration of bone. Sources of cancellous bone are the iliac crest, the distal femur, the greater trochanter, and the proximal tibia. However, harvesting the autologous bone graft is associated with postoperative pain at the donor site, potential injury to the surrounding arteries, nerves, and tissues, and the risk of infection. Thus the development of synthetic materials with osteoconductive and osteoinductive properties that can eliminate the need for harvesting has become a major goal of orthopedic research.
Allograft is the graft of tissue between individuals who are of the same species but are of a disparate genotype. Allograft has osteoconductive and limited osteoinductive properties. Demineralized bone matrix (DBM) is human cortical and cancellous allograft. These products are prepared by acid extraction of allograft bone, resulting in the loss of most of the mineralized component while collagen and noncollagenous proteins, including growth factors, are retained. Figures 1 to 5 demonstrate the osteogenic, osteoinduction, and osteoconduction properties of autologous bone graft, allograft, OP-1, bone graft substitutes, and bone marrow.
Autologous Bone Graft
Osteogenic Protein-1
Allograft bone and Demineralized Bone Matrix
Bone Graft Substitutes
Autologous Bone Marrow Graft
New Technology Being Reviewed: Osteogenic Protein-1
Health Canada issued a Class IV licence for OP-1 in June 2004 (licence number 36320). The manufacturer of OP-1 is Stryker Biotech (Hapkinton, MA).
The United States Food and Drug Administration (FDA) issued a humanitarian device exemption for the application of the OP-1 implant as an “alternative to autograft in recalcitrant long bone nonunions where use of autograft is unfeasible and alternative treatments have failed.” Regulatory agencies in Europe, Australia, and New Zealand have permitted the use of this implant in specific cases, such as in tibial nonunions, or in more general cases, such as in long bone nonunions.
According to the manufacturer, OP-1 is indicated for the treatment of long bone nonunions. It is contraindicated in the patient has a hypersensitivity to the active substance or collagen, and it should not be applied at the site of a resected tumour that is at or near the defect or fracture. Finally, it should not be used in patients who are skeletally immature (< 18 years of age), or if there is no radiological evidence of closure of epiphysis.
Review Strategy
Objective
To summarize the safety profile and effectiveness of OP-1 in the treatment of cases of long bone nonunion and bone defects
To compare the effectiveness and cost effectiveness of OP-1 in the treatment of long bone nonunions and bone defects with the alternative technologies, particularly the gold standard autologous bone graft.
Literature Search
International Network of Agencies for Health Technology Assessments (INAHTA), the Cochrane Database of Systematic Reviews and the CCTR (formerly Cochrane Controlled Trials Register) were searched for health technology assessments. MEDLINE, EMBASE, Medline In Process and Other Non-Indexed Citations were searched from January 1, 1996 to January 27, 2004 for studies on OP-1. The search was limited to English-language articles and human studies. The search yielded 47 citations. Three studies met inclusion criteria (2 RCTs and 1 Ontario-based study presented at an international conference.
Summary of Findings
Friedlaender et al. conducted a prospective, randomized, partially blinded clinical trial on the treatment tibial nonunions with OP-1. Tibial nonunions were chosen for this study because of their high frequency, challenging treatment requirements, and substantial morbidity. All of the nonunions were at least 9 months old and had shown no progress toward healing over the previous 3 months. The patients were randomized to receive either treatment with autologous bone grafting or treatment with OP-1 in a type-1 collagen carrier. Both groups received reduction and fixation with an intramedullary rod. Table 1 summarizes the clinical outcomes of this study.
Outcomes in a Randomized Clinical Trial on Tibial Nonunions: Osteogenic Protein-1 versus Autologous Bone Grafting
Clinical success was defined as full weight-bearing, loss of severe pain at the fracture site on weight-bearing, and no further surgical treatment to enhance fracture repair.
The results of this study demonstrated that recombinant OP-1 is associated with substantial clinical and radiographic success for the treatment of tibial nonunions when used with intramedullary rod fixation. No adverse event related to sensitization was reported. Five per cent of the patients in the OP-1 group had circulating antibodies against type 1 collagen. Only 10% of the patients had a low level of anti-OP-1 antibodies, and all effects were transient. Furthermore, the success rate with the OP-1 implant was comparable with those achieved with autograft at 9 and 24 months follow-up. Eighty-two per cent of patients were successful at 24 months follow-up in both groups.
Statistically significant increased blood loss in the group treated with the autograft was observed (P = .049). Patients treated with autograft had longer operation and hospitalization times. All patients in the autograft group had pain at the donor site after surgery, and more than 80% judged their postoperative pain as moderate or severe. At their 6-month visit, 20% of the patients in the autograft group had persistent pain, mild or moderate in nature, at the donor site. This number fell to 13% at 12 months.
All patients in each of the groups had at least 1 adverse event that wasn’t serious, such as fever, nausea and vomiting, leg edema, discomfort, and bruising at the operative site. The incidence of these events was similar in both groups. Serious adverse events were observed in 44% of both groups, none of which were considered related to the OP-1 implant or autograft.
On the basis of this data, the FDA issued a humanitarian device exemption for the application of OP-1 implant as an alternative to autograft in recalcitrant long bone nonunions when the use of autograft is unfeasible and alternative treatments have failed.
Study on Fibular Defects
Geesink et al. investigated the osteogenic activity of OP-1 by assessing its value in bridging fibular defects made at the time of tibial osteotomy for varus or valgus deformity of the knee. This study had 2 phases and included 12 patients in each phase. Each phase included 12 patients (6 in each group). Patients in the first phase received either DBM or were left untreated. Patients in the second phase received either OP-1 on collagen type-1 or collagen type-1 alone.
Radiological and Dual Energy X-ray Absorptiometry (DEXA) evaluation showed that in patients in whom the defect was left untreated, no formation of bone occurred. At 12 months follow-up, new bone formation with bridging occurred in 4 of the 6 patients in DMB group, and 5 of the 6 patients in OP-1 group. One patient in OP-1 group did not show any evidence of new bone formation at any point during the study.
Ontario Pilot Study
A prospective pilot study was conducted in Ontario, Canada to investigate the safety and efficacy of OP-1 for the treatment of recalcitrant long bone nonunions. The study looked at 15 patients with complex, recalcitrant, long bone nonunions whose previous treatment had failed. The investigators concluded that this bone graft substitute appears to be safe and effective in providing sufficient biological stimulation in difficult to treat nonunions. Results of a more complete study on 70 patients are ready for publication. According to the principal investigator, OP-1 was 90% effective in inducing bone formation and bone healing in this sample.
Alternative Technologies
The Medical Advisory Secretariat conducted a literature search from January 1, 2000 to February 28, 2005 to identify studies on nonunions/bone defects that had been treated with alternative technologies. A review of these studies showed that, in addition to the gold standard autologous bone marrow grafting, bone allografts, demineralized bone matrices, bone graft substitutes, and autologous bone marrow have been used for treatment of nonunions and bone defects. These studies were categorized according to the osteoinductive, osteoconductive, and osteogenesis properties of the technologies studied.
A review of these studies showed that bone allografts have been used mostly in various reconstruction procedures to restore the defect after excavating a bone lesion. Two studies investigated the effectiveness of DBM in healing fracture nonunions. Calcium phosphate and calcium sulphate have been used mostly for repair of bone defects.
Several investigators have looked at the use of autologous bone marrow for treatment of long bone nonunions. The results of these studies show that method of percutaneous bone marrow grafting is highly effective in the treatment of long bone nonunions. In a total of 301 fractures across all studies, 268 (89%) healed with a mean healing time of 2.5 to 8 months. This healing time as derived from these case series is less than the timing of the primary end point in Friedlaender’s study (9 months). Table 2 summarizes the results of these studies. Table 2 summarizes the results of these studies.
Studies that used Percutaneous Bone Marrow Grafting for Treatment of Nonunions
Economic Analysis
Based on annual estimated incidence of long-bone nonunion of 3,863 - 7,725, the annual hospitalization costs associated with this condition is between $21.2 and $42.3 million based on a unit cost of $5,477 per hospital separation. When utilized, the device, a single vial of OP-1, is approximately $5,000 and if adopted universally in Ontario, the total device costs would be in the range of $19.3 - $38.6 million annually. The physician fee for harvest, insertion of bone, or OP-1 is $193 and is $193 for autologous bone marrow transplantation. Total annual physician costs are expected to be in the range of from $0.7 million to $1.3 million per year. Expenditures associated with long-bone nonunion are unlikely to increase since incidence of long-bone nonunion is unlikely to change in the future. However, the rate of uptake of OP-1 could have a significant impact on costs if the uptake were large.
The use of OP-1 and autologous bone marrow transplantation may offset pain medication costs compared with those associated with autologous bone harvest given that the former procedures do not involve the pain associated with the bone harvest site. However, given that this pain is normally not permanent, the overall offset is likely to be small. There are likely to be smaller OHIP costs associated with OP-1 than bone-harvest procedures given that only 1, rather than 2, incisions are needed when comparing the former with the latter procedure. This offset could amount to between $0.3 million to $0.7 million annually.
No data on the cost-effectiveness of OP-1 is available.
PMCID: PMC3382627  PMID: 23074475
12.  Inflammatory and bone turnover markers in relation to PTH and vitamin D status among Saudi postmenopausal women with and without osteoporosis 
Postmenopausal osteoporosis is characterized by rapid bone loss occurring in the post-menopausal period. The bone loss predominantly involves the trabecular bone and is brought about by an imbalance between the bone remodeling process which can be influenced by factors that could cause or contribute to osteoporosis. Pro-inflammatory cytokines (Il-1β, Il-6, IL-8 and TNF-α) have been implicated in the regulation of bone cells and play a critical role in bone remodeling. They act both directly and indirectly to increase bone resorption, and/or inhibit bone formation. The aim of the study is to determine whether pro-inflammatory cytokines correlate with bone turnover markers (BTM) in a cohort of Saudi post-menopausal women with or without osteoporosis and which BTMs will correlate with PTH and Vitamin D for use in osteoporosis diagnosis. The study is composed of 100 post-menopausal patients and 100 controls aged 50 years and above. Serum concentrations of pro-inflammatory and BTMs as well as PTH and vitamin D were determined by ELISA, Luminex and electrochemiluminescence. Serum calcium, phosphorus, glucose, and lipid profile were measured by using a chemical analyzer. There was a significant increase in the levels of pro-inflammatory cytokines, PTH, CTx, and glucose. A significantly lower vitamin D and osteocalcin levels were observed in subjects with osteoporosis than those without. No significant differences were recorded in the circulating lipid profile between groups. The present study proved that the pro-inflammatory cytokines accelerate the bone loss in postmenopausal women.
PMCID: PMC4211793  PMID: 25356143
PTH; osteoporosis; Saudi women; vitamin D; bone biomarkers
13.  Inflammatory and bone turnover markers in relation to PTH and vitamin D status among saudi postmenopausal women with and without osteoporosis 
Postmenopausal osteoporosis is characterized by rapid bone loss occurring in the post-menopausal period. The bone loss predominantly involves the trabecular bone and is brought about by an imbalance between the bone remodeling process which can be influenced by factors that could cause or contribute to osteoporosis. Pro-inflammatory cytokines (Il-1β, Il-6, IL-8 and TNF-α) have been implicated in the regulation of bone cells and play a critical role in bone remodeling. They act both directly and indirectly to increase bone resorption, and/or inhibit bone formation. The aim of the study is to determine whether pro-inflammatory cytokines correlate with bone turnover markers (BTM) in a cohort of Saudi post-menopausal women with or without osteoporosis and which BTMs will correlate with PTH and Vitamin D for use in osteoporosis diagnosis. The study is composed of 100 post-menopausal patients and 100 controls aged around 50 years. Serum concentrations of pro-inflammatory and BTMs as well as PTH and vitamin D were determined by ELISA, Luminex and electrochemiluminescence. Serum calcium, phosphorus, glucose, and lipid profile were measured by using a chemical analyzer. There was a significant increase in the levels of pro-inflammatory cytokines, PTH, CTx, and glucose. A significantly lower vitamin D and osteocalcin levels were observed in subjects with osteoporosis than those without. No significant differences were recorded in the circulating lipid profile between groups. The present study proved that the pro-inflammatory cytokines accelerate the bone loss in postmenopausal women.
PMCID: PMC4238474  PMID: 25419393
Postmenopausal osteoporosis; pro-inflammatory cytokines; vitamin D; osteocalcin
14.  Intact PTH Combined With the PTH Ratio for Diagnosis of Bone Turnover in Dialysis Patients: A Diagnostic Test Study 
Background
Determination of parathyroid hormone (PTH) is the most commonly used surrogate marker for bone turnover in stage 5 chronic kidney disease patients on dialysis (CKD-5D patients). The objective of the current study was to evaluate the predictive value of various PTH measurements for identifying low or high bone turnover rate.
Study design
Diagnostic test study.
Settings & Participants
141 CKD-5D patients from 15 US hemodialysis centers.
Index Tests
Intact PTH, PTH 1–84, and PTH ratio (ratio of level of PTH 1–84 to level of large carboxy-terminal PTH fragments).
Reference Test or Outcome
Bone turnover determined by bone histomorphometry
Other Measurements
Demographic and treatment related factors, serum calcium and phosphorus.
Results
Histologically, patients presented with a broad range of bone turnover abnormalities. In White patients (n=70), the iPTH cut-off of >420 pg/ml resulted in classifying 84% of the patients correctly as high turnover. A PTH ratio <1.0 when added to an intact PTH <420 pg/ml increased the positive predictive value for low bone turnover from 74% to 90% in these patients. In Black patients (n=71), adding a PTH ratio <1.2 to an intact PTH <340pg/ml increased the positive predictive value for low bone turnover from 48% to 90%. Adding a PTH ratio >1.6 to an intact PTH between 340 and 790 pg/ml increased the positive predictive value for high bone turnover from 56% to 71%.
Limitations
Since the research protocol called for carefully controlled blood specimen handling, drawing of blood and routine specimen handling might be less stringent in clinical practice. By limiting study participation to Black and White CKD-5D patients, we cannot comment on the roles of intact PTH, PTH 1–84 and the PTH ratio in other racial/ethnic groups.
Conclusion
In Black CKD-5D patients, addition of the PTH ratio to intact PTH measurements is helpful for diagnosing low and high bone turnover. In White CKD-5D patients, it aids in the diagnosis of low bone turnover.
doi:10.1053/j.ajkd.2009.12.041
PMCID: PMC2882243  PMID: 20347512
15.  Noninvasive assessment of bone health in Indian patients with chronic kidney disease 
Indian Journal of Nephrology  2013;23(3):161-167.
Abnormalities in mineral and bone disease are common in chronic kidney disease (CKD). Evaluation of bone health requires measurement of parameters of bone turnover, mineralization, and volume. There are no data on bone health in CKD patients from India. In this cross-sectional study, we evaluated serum biomarkers of bone turnover: Bone-specific alkaline phosphatase (BAP) and total deoxypyridinoline (tDPD) along with parathyroid hormone, 25(OH) vitamin D, and bone mineral density (BMD) using dual absorption X-ray absorptiometry in a cohort of 74 treatment-naive patients with newly diagnosed stage 4 and 5 CKD (age 42 ± 14.5 years, 54 men) and 52 non-CKD volunteers (age 40.2 ± 9.3 years, 40 men). Compared to the controls, CKD subjects showed elevated intact PTH (iPTH), BAP, and tDPD and lower BMD. There was a strong correlation between iPTH and BAP (r = 0.88, P < 0.0001), iPTH and tDPD (r = 0.51, P < 0.0001), and BAP and tDPD (r = 0.46, P = 0.0004). The iPTH elevation was greater than twice the upper range of normal in 73% cases, and BAP was >40 U/L in 66% cases. The combination of these markers suggests high turnover bone disease in over 60% cases. The prevalence of osteopenia and osteoporosis was 37% and 12%, respectively. Osteoporotic subjects had higher iPTH, BAP, and tDPD, suggesting a role of high turnover in genesis of osteoporosis. Vitamin D deficiency was seen in 80%, and another 13% had insufficient levels. Vitamin D correlated inversely with BAP (r = −0.3, P = 0.009), and levels were lower in those with iPTH >300 pg/ml (P = 0.0.04). In conclusion, over 60% of newly diagnosed Indian stage 4–5 CKD patients show biochemical parameters consistent with high turnover bone disease. High turnover could contribute to the development of osteoporosis in CKD subjects. Deficiency of 25 (OH) vitamin D is widespread and seems to have a role in the genesis of renal bone disease. Studies on the effect of supplementation of native vitamin D are needed.
doi:10.4103/0971-4065.111831
PMCID: PMC3692139  PMID: 23814412
Bone mineral density; bone-specific alkaline phosphatase; chronic kidney disease; deoxypyrinolidine; parathyroid hormone; renal osteodystrophy; vitamin D
16.  Fracture Risk Assessment in Chronic Kidney Disease, Prospective Testing Under Real World Environments (FRACTURE): a prospective study 
BMC Nephrology  2010;11:17.
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.
doi:10.1186/1471-2369-11-17
PMCID: PMC2936367  PMID: 20727179
17.  Epidemiology of rib fractures in older men: Osteoporotic Fractures in Men (MrOS) prospective cohort study  
Objective To study the causes and consequences of radiologically confirmed rib fractures (seldom considered in the context of osteoporosis) in community dwelling older men.
Design Prospective cohort study (Osteoporotic Fractures in Men (MrOS) Study).
Setting and participants 5995 men aged 65 or over recruited in 2000-2 from six US sites; 99% answered mailed questionnaires about falls and fractures every four months for a mean 6.2 (SD 1.3) year follow-up.
Main outcome measures New fractures validated by radiology reports; multivariate Cox proportional hazard ratios were used to evaluate factors independently associated with time to incident rib fracture; associations between baseline rib fracture and incident hip and wrist fracture were also evaluated.
Results The incidence of rib fracture was 3.5/1000 person years, and 24% (126/522) of all incident non-spine fractures were rib fractures. Nearly half of new rib fractures (48%; n=61) followed falling from standing height or lower. Independent risk factors for an incident rib fracture were age 80 or above, low bone density, difficulty with instrumental activities of daily living, and a baseline history of rib/chest fracture. Men with a history of rib/chest fracture had at least a twofold increased risk of an incident rib fracture (adjusted hazard ratio 2.71, 95% confidence interval 1.86 to 3.95), hip fracture (2.05, 1.33 to 3.15), and wrist fracture (2.06, 1.14 to 3.70). Only 14/82 of men reported being treated with bone specific drugs after their incident rib fracture.
Conclusions Rib fracture, the most common incident clinical fracture in men, was associated with classic risk markers for osteoporosis, including old age, low hip bone mineral density, and history of fracture. A history of rib fracture predicted a more than twofold increased risk of future fracture of the rib, hip, or wrist, independent of bone density and other covariates. Rib fractures should be considered to be osteoporotic fractures in the evaluation of older men for treatment to prevent future fracture.
doi:10.1136/bmj.c1069
PMCID: PMC2839084  PMID: 20231246
18.  Correlation of vitamin D, bone mineral density and parathyroid hormone levels in adults with low bone density 
Indian Journal of Orthopaedics  2013;47(4):402-407.
Background:
Bone mineral densiy (BMD) is known to be affected by serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels. Indian data pertinent to above observation is scant. Our study aimed to investigate the relationships between serum 25-hydroxyvitamin D (25(OH) D) levels, intact parathyroid hormone (iPTH) levels and bone mineral density (BMD) in a cohort of Indian patients.
Materials and Methods:
Adults with or without fragility fractures with low BMD at the hip or lumbar spine were evaluated clinically along with laboratory investigations. T-scores of the hip and spine were derived from BMD-DEXA (dual-energy X-ray absorptiometry). Multivariate regression models were used to investigate the relationships between serum 25(OH) D, iPTH and BMD.
Results:
Total of 102 patients (male:female = 38:64) with a mean age of 62.5 ± 6.4 years were included in the study. Forty-four patients had osteopenia. Osteoporosis was present in 58 patients. The mean values for serum 25(OH) D and iPTH levels were 21.3 ± 0.5 ng/ml and 53.1 ± 22.3 pg/ml, respectively. In 84.3% of patients, serum 25(OH) D levels were below 30 ng/ml (Normal = 30-74 ng/ml), confirming vitamin D deficiency. There was no association between 25(OH) D levels and BMD at the hip or lumbar spine (P = 0.473 and 0.353, respectively). Both at the hip and lumbar spine; iPTH levels, male gender, body mass index (BMI) and age were found to be significant predictors of BMD. Patients with higher BMI had significantly lower BMD and T-score. At levels <30 ng/ml, 25(OH) D was negatively associated with iPTH (P = 0.041).
Conclusion:
Among our cohort of patients with low BMD, no direct relationship between serum 25(OH) D levels and BMD was observed. However, a negative correlation between iPTH and 25(OH) D at serum 25(OH) D concentrations <30 ng/ml. Serum iPTH levels showed a significant negative association with BMD at the hip and lumbar spine. Our findings underscore the critical role of parathyroid hormone in bone metabolism and health.
doi:10.4103/0019-5413.114932
PMCID: PMC3745696  PMID: 23960286
Bone mineral density; osteoporosis; parathyroid hormone; vitamin D
19.  Decreased cortical thickness, as estimated by a newly developed ultrasound device, as a risk for vertebral fracture in type 2 diabetes mellitus patients with eGFR of less than 60 mL/min/1.73 m2 
Osteoporosis International  2014;26:229-236.
Summary
Cortical porosity is increasingly recognized as an important risk for fracture in DM patients. The present study demonstrated that decreased cortical thickness, assessed using a newly developed quantitative ultrasonic bone densitometry, is a significant risk factor for vertebral fractures in type 2 diabetes mellitus patients with stage 3 or higher chronic kidney disease, but not in those without.
Introduction
Cortical porosity is increasingly recognized as an important risk factor for fracture in type 2 diabetes mellitus (T2DM) patients as well as in stage 3 chronic kidney disease (CKD) patients in whom serum parathyroid hormone (PTH) starts to increase. The present study aimed to clarify whether the coexistence of CKD might affect the relationship of decreased cortical thickness (CoTh) in the development of vertebral fractures (VF) in T2DM patients.
Methods
In this cross-sectional study, trabecular bone mineral density (TrBMD), elastic modulus of trabecular bone (EMTb), and CoTh were estimated with a new quantitative ultrasound bone densitometry in 173 T2DM patients. VFs were identified radiographically.
Results
Thirty-nine patients (22.5 %) had VF. Those with estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 (low eGFR) showed a significantly higher VF rate (32.4 %) than those with eGFR ≥60 mL/min/1.73 m2 (high eGFR, 16.2 %). Serum PTH was significantly higher with low eGFR than with high eGFR. In those with high eGFR, EMTb was significantly lower in VF(+) than VF(−). In those with low eGFR, TrBMD, EMTb, and CoTh were significantly lower in VF(+) than in VF(−). In a multivariate logistic regression analysis, EMTb was independently and significantly associated with VF in T2DM patients with a high eGFR, in contrast to those with only CoTh with VF in T2DM with low eGFR.
Conclusion
This study demonstrated CoTh as a factor independently associated with VF in T2DM patients with low eGFR and increasing serum PTH levels.
Electronic supplementary material
The online version of this article (doi:10.1007/s00198-014-2843-x) contains supplementary material, which is available to authorized users.
doi:10.1007/s00198-014-2843-x
PMCID: PMC4286635  PMID: 25187117
Bone fracture; Bone mineral density; Chronic kidney disease; Cortical thickness; Type 2 diabetes
20.  Association of Relatively Low Serum Parathyroid Hormone with Malnutrition-Inflammation Complex and Survival in Maintenance Hemodialysis Patients 
Background
Low serum parathyroid hormone (PTH) has been implicated as a primary biochemical marker of adynamic bone disease in individuals with chronic kidney disease (CKD) who undergo maintenance hemodialysis (MHD) treatment. We hypothesized that the malnutrition-inflammation complex is associated with low PTH levels in these patients and confounds the PTH-survival association.
Methods
We examined 748 stable MHD outpatients in Southern California and followed them for up to 5 years (10/2001-12/2006).
Results
In 748 MHD patients, serum PTH <150 pg/ml was more prevalent among non-Blacks and diabetics. There was no association between serum PTH and coronary artery calcification score, bone mineral density or dietary protein or calorie intake. Low serum PTH was associated with markers of protein-energy wasting and inflammation, and this association confounded the relationship between serum PTH and alkaline phosphatase. Although 5-year crude mortality rates were similar across PTH increments, after adjustment for the case-mix and surrogates of malnutrition and inflammation, a moderately low serum PTH in 100 to 150 pg/ml range was associated with the greatest survival compared to other serum PTH levels, i.e., a death hazard ratio of 0.52 (95% confidence interval: 0.29-0.92, p<0.001) compared to PTH of 300 to 600 pg/ml (reference).
Conclusions
Low serum PTH may be another facet of the malnutrition-inflammation complex in CKD, and after controlling for this confounder, a moderately low PTH in 100 to 150 pg/ml range appears associated with the greatest survival. Limitations of observational studies should be considered.
doi:10.1053/j.jrn.2009.10.006
PMCID: PMC3175364  PMID: 20199875
Parathyroid hormone (PTH); adynamic bone disease; malnutrition-inflammation complex; alkaline phosphatase; paricalcitol; cytokines
21.  Hip Fracture Incidence in Relation to Age, Menopausal Status, and Age at Menopause: Prospective Analysis 
PLoS Medicine  2009;6(11):e1000181.
Using data from the UK Million Women Study, Emily Banks and colleagues investigate the relationships between the incidence of hip fracture and a woman's age, menopausal status, and age at menopause.
Background
Bone mineral density is known to decrease rapidly after the menopause. There is limited evidence about the separate contributions of a woman's age, menopausal status and age at menopause to the incidence of hip fracture.
Methods and Findings
Over one million middle-aged women joined the UK Million Women Study in 1996–2001 providing information on their menopausal status, age at menopause, and other factors, which was updated, where possible, 3 y later. All women were registered with the UK National Health Service (NHS) and were routinely linked to information on cause-specific admissions to NHS hospitals. 561,609 women who had never used hormone replacement therapy and who provided complete information on menopausal variables (at baseline 25% were pre/perimenopausal and 75% postmenopausal) were followed up for a total of 3.4 million woman-years (an average 6.2 y per woman). During follow-up 1,676 (0.3%) were admitted to hospital with a first incident hip fracture. Among women aged 50–54 y the relative risk (RR) of hip fracture risk was significantly higher in postmenopausal than premenopausal women (adjusted RR 2.22, 95% confidence interval [CI] 1.22–4.04; p = 0.009); there were too few premenopausal women aged 55 y and over for valid comparisons. Among postmenopausal women, hip fracture incidence increased steeply with age (p<0.001), with rates being about seven times higher at age 70–74 y than at 50–54 y (incidence rates of 0.82 versus 0.11 per 100 women over 5 y). Among postmenopausal women of a given age there was no significant difference in hip fracture incidence between women whose menopause was due to bilateral oophorectomy compared to a natural menopause (adjusted RR 1.20, 95% CI 0.94–1.55; p = 0.15), and age at menopause had little, if any, effect on hip fracture incidence.
Conclusions
At around the time of the menopause, hip fracture incidence is about twice as high in postmenopausal than in premenopausal women, but this effect is short lived. Among postmenopausal women, age is by far the main determinant of hip fracture incidence and, for women of a given age, their age at menopause has, at most, a weak additional effect.
Please see later in the article for the Editors' Summary
Editors' Summary
Background
Anyone can break a hip but most hip fractures occur in elderly people. As people age, their bones gradually lose minerals and become less dense, which weakens the bones and makes them more susceptible to fracture. Because women lose bone density faster than men as they age and because women constitute the majority of the elderly, three-quarters of hip fractures occur in women. Hip fractures can cause long-term health problems and premature death. Thus, although surgical repair of a broken hip usually only requires a hospital stay of about a week, a quarter of elderly people who were living independently before their fracture have to stay in a nursing home for at least a year after their injury and a fifth of elderly people who break a hip die within the year. Most hip fractures are caused by falls. Regular exercise to improve strength and balance combined with review of medicines (to reduce side effects and interactions), regular eye examinations, and the removal of fall hazards from the home can help to prevent hip fractures in elderly people.
Why Was This Study Done?
Bone density decreases very rapidly in women immediately after menopause—the time when menstruation permanently stops—and then continues to decrease more slowly with age. Most women have their menopause in their early 50s but menopause can occur in younger women. Early menopause is thought to be a risk factor for osteoporosis (thinning of the bones) and fractures later in life but little is known about how menopause influences hip fracture risk as women age. In this prospective study (a type of study in which a group of people is followed for several years to see whether they develop a particular condition), the researchers investigate the incidence of hip fractures in relation to age, menopausal status, and age at menopause among the participants of the Million Women Study. This study, which recruited 1.3 million women aged 50–64 years who attended UK breast cancer screening clinics between 1996 and 2001, has been investigating how reproductive and lifestyle factors affect women's health.
What Did the Researchers Do and Find?
At enrollment and three years later, the study participants provided information about their menopausal status and other health and lifestyle factors likely to affect their fracture risk. From these data, the researchers identified more than half a million women who had never used hormone replacement therapy (which reduces fracture risk) and who had given complete information about their menopausal status. They then looked for statistical associations between the occurrence of a first hip fracture in these women over the next few years and their age, menopausal status, and age at menopause. Among women aged 50–54 years, postmenopausal women were twice as likely to have a hip fracture as premenopausal women. Among postmenopausal women, the incidence of hip fractures increased steeply with age and was seven times higher in 70–74-year olds than in 50–54-year olds. Women who had their menopause before age 45 had a slightly increased risk of hip fracture but any effect of age at menopause on the risk of hip fracture was small compared to the effect of age itself, and the slightly increased risk may have been due to other factors that could not be fully accounted for in the analysis.
What Do These Findings Mean?
These findings indicate that around the time of menopause, although hip fractures are rare, the risk of a fracture in postmenopausal women is twice that in premenopausal women. The findings also show that among postmenopausal women, age is the major determinant of hip fracture risk and that for women of a given age, their age at menopause has little effect on hip fracture risk. Women attending breast cancer screening clinics and completing questionnaires about their health may not be representative of the general population. Furthermore, these findings rely on women self-reporting their menopausal status accurately. Nevertheless, the results of this study suggest that clinicians advising women about hip fracture prevention should probably base their advice on the woman's age and on age-related factors such as frailty rather than on factors related to menopause. Clinicians can also now reassure elderly women who had an early menopause that their risk of hip fracture is unlikely to be higher than that of similar women who had a later menopause.
Additional Information
Please access these Web sites via the online version of this summary at http://dx.doi.org/10.1371/journal.pmed.1000181.
The American Academy of Orthopaedic Surgeons has detailed information about hip fractures
The US National Institute of Arthritis and Muscoloskeletal and Skin Diseases has an interactive feature called “Check up on your bones and provides detailed information about osteoporosis, including advice on fall prevention
The US Centers for Disease Control and Prevention has a fact sheet about hip fractures among older adults
MedlinePlus has links to resources about hip fracture, osteoporosis, and menopause (in English and Spanish)
More information on the Million Women Study is available
doi:10.1371/journal.pmed.1000181
PMCID: PMC2766835  PMID: 19901981
22.  TNF signaling contributes to the development of nociceptive sensitization in a tibia fracture model of complex regional pain syndrome type I 
Pain  2007;137(3):507-519.
Tibia fracture in rats initiates a cascade of nociceptive, vascular, and bone changes resembling complex regional pain syndrome type I (CRPS I). Previous studies suggest that the pathogenesis of these changes is attributable to an exaggerated regional inflammatory response to injury. We postulated that the pro-inflammatory cytokine tumor necrosis factor alpha (TNF) might mediate the development of CRPS-like changes after fracture. RT-PCR and EIA assays were used to evaluate changes in TNF expression and content in skin, nerve, and bone after fracture. Bilateral hindpaw thickness, temperature, and nociceptive thresholds were determined, and bone microarchitecture was measured using microcomputed tomography. Lumbar spinal cord Fos immunostaining was performed for quantification of Fos positive neurons. After baseline testing the distal tibia was fractured and the hindlimb casted for 4 weeks. The rats were subcutaneously injected either with a soluble TNF receptor type 1 (sTNF-R1, 5mg/kg/d) or saline every 3 days over 28 days and then were retested at 4-weeks post-fracture. Tibia fracture chronically upregulated TNF expression and protein levels in the hindpaw skin and sciatic nerve. After fracture the rats developed hindpaw mechanical allodynia and unweighting, which were reversed by sTNF-R1 treatment. Consistent with the behavioral data, spinal Fos increased after fracture and this effect was inhibited by sTNF-R1 treatment. Collectively, these data suggest that facilitated TNF signaling in the hindlimb is an important mediator of chronic regional nociceptive sensitization after fracture, but does not contribute to the hindlimb warmth, edema, and bone loss observed in this CRPS I model.
doi:10.1016/j.pain.2007.10.013
PMCID: PMC2529181  PMID: 18035493
tibia fracture; neuropathic pain; TNF; sTNF-R1; microCT scanning; Fos immunoreactivity; complex regional pain syndrome
23.  The hormonal profile of hip fracture female patients differs from community-dwelling peers over a 1-year follow-up period 
Summary
Hormone levels were compared over a 1-year period between elderly women who had sustained a hip fracture and women of similar age and functional ability. Our study suggests progressive hormonal changes that may contribute to severe bone loss during the year following hip fracture.
Introduction
Alterations in hormones affecting the musculoskeletal system may increase risk of hip fracture or poor post-fracture recovery in postmenopausal women. Most studies lack appropriate reference groups, and thus cannot assess the extent to which these alterations are attributable to hip fracture.
Methods
Women aged ≥65 years hospitalized for an acute hip fracture (Baltimore Hip Studies, BHS-3; n = 162) were age-matched to 324 women enrolled in the Women’s Health and Aging Study I, a Baltimore-based cohort with similar functional status to the pre-fracture status of BHS-3 women. Both studies enrolled participants from 1992 to 1995. Insulin-like growth hormone-1 (IGF-1), parathyroid hormone (PTH), 1,25 dihydroxyvitamin D [1,25(OH)2D], and osteocalcin were evaluated at baseline and 2, 6, and 12 months post-fracture, and at baseline and 12 months in the comparison group. Between-group differences in trajectories of each hormone were examined.
Results
Baseline mean IGF-1 levels were significantly lower in hip fracture patients than the comparison group (75.0 vs. 110.5 µg/dL; p<0.001). Levels increased by 2 months post-fracture, but remained significantly lower than those in the comparison group throughout the 12-month follow-up (p< 0.01). Levels of PTH and osteocalcin were similar between groups at baseline, but rose during the year post-fracture to significantly differ from the comparison women (p<0.001). 1,25(OH)2D levels did not differ between the hip fracture and comparison women at any time.
Conclusions
Older women who have sustained a hip fracture have progressive changes in hormonal milieu that exceed those of women of similar health status during the year following fracture.
doi:10.1007/s00198-010-1187-4
PMCID: PMC2916079  PMID: 20204599
1,25, Dihydroxyvitamin D; Elderly; Hip fracture; Hormones; IGF-1; Osteocalcin; PTH; Women
24.  Effects of paricalcitol on calcium and phosphate metabolism and markers of bone health in patients with diabetic nephropathy: results of the VITAL study 
Nephrology Dialysis Transplantation  2013;28(9):2260-2268.
Background
Chronic kidney disease (CKD) is associated with elevations in serum phosphate, calcium–phosphorus product and bone-specific alkaline phosphatase (BAP), with attendant risks of cardiovascular and bone disorders. Active vitamin D can suppress parathyroid hormone (PTH), but may raise serum calcium and phosphate concentrations. Paricalcitol, a selective vitamin D activator, suppressed PTH in CKD patients (stages 3 and 4) with secondary hyperparathyroidism (SHPT) with minimal changes in calcium and phosphate metabolism.
Methods
The VITAL study enrolled patients with CKD stages 2–4. We examined the effect and relationship of paricalcitol to calcium and phosphate metabolism and bone markers in a post hoc analysis of VITAL. The study comprised patients with diabetic nephropathy enrolled in a double-blind, placebo-controlled, randomized trial of paricalcitol (1 or 2 μg/day). Urinary and serum calcium and phosphate, serum BAP, and intact PTH (iPTH) concentrations were measured throughout the study.
Results
Baseline demographics and calcium, phosphate, PTH (49% with iPTH <70 pg/mL), and BAP concentrations were similar between groups. A transient, modest yet significant increase in phosphate was observed for paricalcitol 2 μg/day (+0.29 mg/dL; P < 0.001). Dose-dependent increases in serum and urinary calcium were observed; however, there were few cases of hypercalcemia: one in the 1-μg/day group (1.1%) and three in the 2-μg/day group (3.2%). Significant reductions in BAP were observed that persisted for 60 days after paricalcitol discontinuation (P < 0.001 for combined paricalcitol groups versus placebo). Paricalcitol dose-dependent reductions in iPTH were observed. Paricalcitol in CKD patients (±SHPT) was associated with modest increases in calcium and phosphate.
Conclusion
Paricalcitol reduces BAP levels, which may be beneficial for reducing vascular calcification.
Trial registration
Trial is registered with ClinicalTrials.gov, number NCT00421733.
doi:10.1093/ndt/gft227
PMCID: PMC3769981  PMID: 23787544
bone-specific alkaline phosphatase; calcitriol; hypercalcemia; hyperphosphatemia; paricalcitol; vitamin D receptor activation
25.  Rapid cortical bone loss in patients with chronic kidney disease 
Chronic kidney disease (CKD) patients may have high rates of bone loss and fractures, but microarchitectural and biochemical mechanisms of bone loss in CKD patients have not been fully described. In this longitudinal study of 53 patients with CKD Stages 2-5D, we used dual energy X-ray absorptiometry (DXA), high resolution peripheral quantitative computed tomography (HRpQCT) and biochemical markers of bone metabolism to elucidate effects of CKD on the skeleton. Median follow-up was 1.5 years (Range 0.9 to 4.3 years); bone changes were annualized and compared to baseline. By DXA, there were significant declines in areal bone mineral density (BMD) of the total hip and ultradistal radius: −1.3% (95% CI: −2.1 to −0.6) and −2.4% (95% CI: −4.0 to −0.9), respectively. By HRpQCT at the distal radius, there were significant declines in cortical area, density and thickness, and increases in porosity: −2.9% (95% CI −3.7 to −2.2), −1.3% (95% CI −1.6 to −0.6), −2.8% (95% CI −3.6 to −1.9), and +4.2% (95% CI 2.0 to 6.4) respectively. Radius trabecular area increased significantly: +0.4% (95% CI 0.2 to 0.6), without significant changes in trabecular density or microarchitecture. Elevated time-averaged levels of parathyroid hormone (PTH) and bone turnover markers predicted cortical deterioration. Higher levels of serum 25-hydroxyvitamin D predicted decreases in trabecular network heterogeneity. These data suggest that significant cortical loss occurs with CKD, which is mediated by hyperparathyroidism and elevated turnover. Future investigations are required to determine whether these cortical losses can be attenuated by treatments that reduce PTH levels and remodeling rates.
doi:10.1002/jbmr.1916
PMCID: PMC3720694  PMID: 23456850
chronic kidney disease; cortical bone; renal osteodystrophy; HRpQCT; DXA

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