1. Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies: First in 1915 it was postulated that it OFS due to parathyroid gland overactivity In 1937 Albright releated this to high po4 and low calcium. Term of ROD was coined in 1940 Very early also rule f function nephron loss and vit D deficiency with histological osteomalcia was discussed
Which improved with better water recently using light microscopy or imaging techniques with a progressive move from X-ray and histologic aspects of ROD early it was thought uremic bone mainly passive organ suffering which changed recently where they act as endocrine organ playing active role in the cardiovascular, metabolic and bone abnormalities with progression of CKD stages 2.Explain the pathogenesis and contributing factors of ADB in patients with CKD
there are allot of factors include the uremic toxins, PTH resistant, PTH receptor hyporesponsiveness, PTh receptor downregulation, hyperphosphatemia , high (FGF-23), aluminum intoxication, DM,corticosteroid use, PD modality. bisphosphonate therapy. Use of active Vitamin D and calcium containing phosphate binders 3.Describe changes of bone related parameters with progression of chronic kidney disease. high PTh increase bone resprption high FGF23 increase bone formation high sclerostin, low vit D, decrease bone formation and mineralization.. metabolic acidosis decrease bone formation and mineralization with stimulation of resorption the progressive increase in s pth ,tAP,P1NP TRAP -5B, Fgf23, uremic toxins 4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD. PTH and ALP. (High PTH and ALP are predictive for high turnover) -Serum 25 OH Vitamin D , in osteomalacia -high sclerostin levels associated with higher fracture risk in patients with osteoporosis and type 2 diabetes Imaging: BMD by dual energy X ray absorptiometry (DXA) cannot tell the diffrence between diffrent types of ROD but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD. Quantitative CT provides more precise information but is costly and associated with exposition to high radiation .
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
bone biomarker include
PTH. VIT D S CALCIUM,Osteoprotegerin, and sclerostin FGF23, TRAP 5b IMAGING : BMD by dual-energy X-ray absorptiometry (DXA). xrays .
QCT which gives more clear information.
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies:
in earlier studies dedicated to renal osteodystrophy was done in patients ESRD which is the long term of exposure of uremic milieu with complex of major disturbances of mineral and endocrine metabolism
in recent years there is a number of studies using either light microscopy or imaging techniques in ckd patients furthermore in the nephrology community there is a progressive move from Xray and histologic aspects of renal bone disease.
The early times the perception of uremic bone was mainly that of passive organ suffering these has changed recently and found out and endocrine organ is playing in active role in the cardiovascular complications, and metabolic abnormalities along with the progression of CKD.
2.Explain the pathogenesis and contributing factors of ADB in patients with CKD
The pathogenesis is complex and there are allot of factors contributing which include the uremic toxins, hyperparathyroidism, (FGF-23) levels, malnutrition resistance of PTH aluminum overload. long term of bisphosphonate therapy. 3.Describe changes of bone related parameters with progression of chronic kidney disease.
it includes rapid change of s calcium phosphorus and magnesium levels.
metabolic acidosis and metabolic alkalosis.
the progressive increase in s pth ,tAP,P1NP TRAP -5B, Fgf23, uremic toxins and
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Adynamic bone disease is the most common form of renal osteodystrophy in patients with early stages of CKD, while osteomalacia and mixed renal osteodystrophy are more common in later stages of CKD. Histomorphometric studies have also shown that bone formation rate and mineralization lag time are generally lower in early CKD stages compared to later stages. Moreover, ethnic differences have been observed in bone histomorphometry findings, with African American patients showing higher bone formation rates and lower bone mineralization lag times than Caucasian patients.
2. Explain the pathogenesis and contributing factors of ADB in patients with CKD.
The pathogenesis of Adynamic Bone Disease (ADB) in patients with Chronic Kidney Disease (CKD) is complex and multifactorial. Several factors may contribute to the occurrence of ADB in CKD patients, including abnormalities in mineral and endocrine metabolism, medical treatment, age, gender and ethnicity, physical activity, and dietary intake. Changes in mineral and endocrine metabolism, such as disturbances in calcium, phosphorus, and magnesium balance; metabolic acidosis; and increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) levels, are associated with the development of ADB. These changes can lead to resistance to the action of PTH, as well as other mechanisms, resulting in low bone turnover. Medical treatment can also contribute to the occurrence of ADB, as drugs such as corticosteroids and immunosuppressive agents can have a major negative effect on the bone. Other factors include advanced age, diabetes mellitus, metabolic acidosis, malnutrition, alcoholism, and the long-term use of anti-resorptive therapies such as bisphosphonates. In addition, aluminum overload, genetic factors, and hypoparathyroidism can also favor the development of ADB.
3. Describe changes of bone related parameters with progression of chronic kidney disease.
These changes include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or less frequently-metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized under the term “uremic toxins”; decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of aKlotho.
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
Bone biomarkers and imaging techniques are important tools for diagnosing and assessing the prognosis of patients with CKD-MBD. Bone biomarkers, such as collagen-based biomarkers, PTH, tAP, bAP, FGF23, osteocalcin, osteoprotegerin, and sclerostin, are important for assessing bone turnover and mineralization, as well as assessing the severity of CKD-MBD. Imaging techniques, such as bone histomorphometry, bone mineral density (BMD) scans, and dual-energy X-ray absorptiometry (DXA), are useful for diagnosing and assessing the prognosis of CKD-MBD. The diagnostic value of bone biomarkers and imaging techniques in CKD-MBD is mainly related to the assessment of bone health. Bone biomarkers are useful for assessing bone turnover and mineralization, as well as assessing the severity of CKD-MBD. Imaging techniques provide a more comprehensive assessment of bone health by allowing for the visualization of bone structure, density, and mineralization. The prognostic value of bone biomarkers and imaging techniques in CKD-MBD is mainly related to the ability to predict fractures, bone loss, and mineralization lag time. Studies have shown that certain bone biomarkers, such as PTH and tAP, are associated with an increased risk of fracture in CKD-MBD patients. Imaging techniques can also be used to predict bone loss and mineralization lag time, as well as the risk of fracture. In summary, bone biomarkers and imaging techniques are important diagnostic and prognostic tools for patients with CKD-MBD. They allow for the assessment of bone health, as well as the prediction of fractures, bone loss, and mineralization lag time.
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
As early as in 1976, Malluche et alperformed a bone histomorphometry study in 50 German patients with various stages of CKD, ages 20 to 61 years, 19 males and 31 females. Their creatinine clearance (glomerular filtration rate) values ranged from 80 to 6 ml/min per 1.73 m2, that is, CKD stages 2 to 5 according to present nomenclature. The bone biopsies of patients with incipient CKD exhibited evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid(an early expression of osteitis fibrosa, was increasing with decreasing glomerular filtration rate). In 1996, Coen et al reported findings of a cross- sectional, retrospective bone histomorphometry study in 76 unselected Italian CKD patients on conservative treatment, ages 18 to 72 years, 44 males and 32 females, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl and a mean SD creatinine clearance of 20 12 ml/min per 1.73 m2.Those with adynamic bone disease. Based on these findings the authors postulated that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodys- trophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD. In 2014, Barreto et alproceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy and exhibited an inverse association between bone formation rate and coronary artery calcification. The most striking finding was that patients with CKD stages 2 and 3 had remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time. In contrast, patients with CKD stages 4 and 5 had higher values of osteoid volume, osteoblast surface, and bone formation rate, and in addition higher osteoclast surface, fibrosis,volume, and a trend toward lower mineralization lag time.
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone is predominantly defined by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and mini- mal marrow fibrosis.Their patients also had lower serum intact PTH levels than those with other types of renal osteodystrophy.
It is mainly attributed to overtreatment of secondary hyperparathyroidism with PTH-lowering agents or relative or absolute hypoparathyroidism following surgical parathyroidectomy, aluminum overload , overtreatment with vitamin D (or its derivative calcidiol), a subsequent increase in serum calcitriol, and excessive lowering of serum PTH.
Other factors favoring the occurrence of low- turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, and alcoholism.
Describe changes of bone related parameters with progression of chronic kidney disease.
They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin;variable increases in advanced glycation end products (AGEs),oxidative stress markers including advanced oxidation protein products,and protein carbamylation products;increases in numerous other compounds summarized under the term “uremic toxins”;decreases in serum concen- trations of 25 OH vitamin D and 1,25 diOH vitamin D;and decreases in serum and or tissue concentrations of a Klotho.
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The predictive value of the circulating levels of PTH and tAP or bAP for bone turnover is limited.In particular, it remains impossible to discriminate normal from moderately low or moderately high bone turnover in patients with CKD without proceeding to a bone biopsy.
Bone-derived collagen-based biomarkers were not found to be useful in predicting histo- morphometry, fractures, and bone mineral density (BMD).
However, a recent study from Japan showed that high serum tAP levels were independently associated with the incidence of hip fracture and also with mortality in patients on long-term hemodialysis therapy.
Another approach could consist in the use of bAP iso- formsor other, yet unknown bone-derived biomarkers that could allow better discrimination in the future.
Serum 25 OH vitamin D measurement allows detection of vitamin D insufficiency and deficiency. Very low levels may be associated with osteomalacia.
A possible diagnostic value of serum FGF23 in the differential diagnosis of high versus low bone turnover and normal versus abnormal mineralization has been suggested but need further studies to confirm.
Increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes, respectively.No such link has been reported so far in patients with CKD. The relation of serum sclerostin with bone for- mation and bone mass remains unclear.
X ray examination may allow detection of osteomalacia when Looser–Milkman zones are present. X-ray signs of osteitisfibrosa such as subperiosteal bone resorption, salt and pepper aspect of the skull, rugger jersey features of the spine, and cystic lesions characteristic of brown tumors are only observed in severe forms of the disease.
BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodys- trophy but is probably useful in the diagnosis of bone lossand the prediction of fractures in CKD.
Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure.
1.Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies. At early stages ADB is predominant in most of bone biopsies ,ADB ismainly due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and uremic toxins .
2.Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease is a low bone turnover mostly occurs early in a significant proportion of patients with chronic kidney disease. The pathogenesis was low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis. The contributing factors initial predominance of bone turnover inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency , diabetes and uremic toxins contribute to ABD. The increasing use of active Vitamin D in the subsequent decade was an etiological factor in the pathogenesis of ABD. Oral treatment with aluminum containing phosphate binders was a contributing factor. Other risk factor for ABD include advanced age, diabetes , metabolic acidosis, and alcoholism. 3.Describe changes of bone related parameters with progression of chronic kidney disease. They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized under the term “uremic toxins”; decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of aKlotho. FGF23 processing appears to change with CKD progression. Although circulating FGF23 undergoes cleavage in patients with normal kidney function and in those with mild CKD, most circulating FGF23 in dialysis patients is in its full-length formThey may undergo oxidation, AGE-transformation, or carbamylation, which also may greatly alter biologic activity .
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The biocehmical diagnosis of diffrent types of ROD is mainly based on PTH and AP. (High PTH and AP are predictive for high turnover)
-Serum 25 OH Vitamin D , benefits in osteomalacia
-increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes respectivly.
Imaging:
BMD by dual energy X ray absorptiometry (DXA) cannot tell the diffrence between diffrent types of ROD but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD.
Quantitative CT provides more precise information but is costly and associated with exposition to high radiation .
a) Evidence of excess PTH. b) Prevalence of woven osteoid. c) Osteitis fibrosa, even in the early stages of CKD. d) Osteoclastic resorption was abnormally high when eGFR < 50, and endosteal fibrosis if eGFR < 30. e) Evidence of mineralization defect, (osteomalacia), in many patients.
Not proven by this study that osteomalacia precede osteitis fibrosa.
There was an early stimulatory effect of PTH in the skeleton, evident by the accumulation of empty resorption cavities as well as the appearance of woven osteoid.
Coen et al, in 1996
Retrospective, bone histomorphometry in 76 Italian CKD patients.
Aged 18 to 72 years old.
44 were males and 32 were females.
Cr level (1.2 to 11.4 mg/dl).
The mean +/- SD CrCl of 20 +/-12 ml/min per 1.73m2.
Cause of CKD (chronic GN 43), (TIN 16), (PKD 7), (others 9).
None had received steroids for the last 12 months.
None had received anticoagulant and anticonvulsive medication NSAIDs at the time of the biopsy.
None was prescribed vitD, calcitriol, or aluminum-containing Pi binder.
The finding was
a) Normal bone in 10 patients. b) ABD in 9 patients, (-ve for aluminum staining), in early CKD stages. c) Mild mixed osteodystrophy in 26 patients. d) Predominant osteomalacia in 7 patients ( in more advance CKD). e) Advanced mixed osteodystrophy in 22 patients.
f) Predominant hyperparathyroidism I 2 patients. Barreto et al; In 2014
Cross-sectional study, in CKD S 2 to 5.
49 patients included.
Mean age 52 years, (66% are males, and 49% are females) of caucasian ethnicity.
60% had normal serum 25 OH vitD level >/ 30 ng/ml, and only 10% had vitD deficiency </15 ng/ml.
Bone histomorphometry finding
a) CKD S2,3 had a remarkably low bone formation, with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time. b) CKD S4, 5 had higher osteoiod volume, and bone formation rate, higher osteoclast surface, fibrosis, and lower mineralization lag time. c) No bone aluminum staining. d) None received Ca-based Pi binder, vitD derivatives. e) No malnutrition was reported in any case.
They concluded that there is a direct relation between serum intact PTH and bone formation, osteoid volume, osteoblast surface, and bone fibrosis.
The pathogenesis and contributing factors of ADB in patients with CKD. Pathophysiology and factors associated or contributed to ABD
Heavy aluminium contamination of tap water used for HD.
Use of aluminium containing Pi binder.
Vigrous use of active vitD.
Steroids and immunosuppressants.
High serum sclerostin level.
Low bone turn over.
Resistant action to PTH.
Reduce calcitriol level.
Sex hormone deficiency .
DM.
Uremic toxins, (regression of osteocyte Wnt/B-catenin signaling and increased expression of Wnt antagonist.
Changes of bone related parameters with progression of chronic kidney disease.
Metabolic acidosis
a) Decrease bone formation, and mineralization. b) Increase bone resorption.
Hyperparathyroidism
a) Incraese bone formation and resorption. b) Normal bone mineralization.
High steocalcin
a) Increase bone formation. b) Normal mineralization.
High osteoprotegerin
a) Incraese bone formation. b) decrease bone resorption.
High sclerostin
a) Decrease bone formation.
Low 25OH vitD
a) Decrease bone resorption and mineralization.
Low 1,25 diOH vitD
a) increase bone formation and resorption.
Low Klotho
a) Increase bone formation and resorption. Diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
Serum concentration of PTH and tAP or bAP (limited predictive value).
Bone-derived collagen-based biomarker, (not useful in prediction of histomorphometry, fracture, and BMD.
tAP level recently by KDIGO found to be indepently associated with the incidence of hip fracture and mortality in HD patients.
Serum 25 OH vitD; deficiency associated with osteomalacia.
FGF23; not yet well established to be used for discrimination between High/Low/mormal bone turn over.
High serum sclerostin; associated with high risk of fracture.
X-ray; signs of oteitis fibrosa observed only in sever forms.
DXA cannot discriminate between different types of osteodystrophy, but useful in diagnosing bone loss, and the prediction of fracture in the CKD.
thanks dr Kamal for your excellent comprehensive effort
in addition, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
1- Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Pathogenesis: ADB ismainly due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/ b-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4.
2- Describe changes of bone related parameters with progression of chronic kidney disease:
Bone structure, static & dynamic aspects Early CKD: Low bone formation rates, Low osteoid voulme, Low osteoblast surface, High mineralization lag time Advanced CKD: Osteomalacia, High value of osteoid volume, osteoblast surface, & bone formation rate, High osteoclast surface, fibrosis volume, Low mineralization lag time Increased expression of bone protein: Sclerostin, FGF-23, PTH, Osteoprotegerin, Osteocalcin, Dentin matrix protein 1(DMP1). Matrix extracellular phosphoglycoprotein (MEPE) Decreased expression other proteins: Renal Klotho, VDRA
3- Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD:\
Biomarkers:
1.PTH & Alkaline phosphatase (tAPT, bAPT): The predictive value for the diagnosis bone turn over is limited 2.Vitamin D level: Help in the diagnosis of osteomalacia 3.FGF23: Need further studies 4.Slerostin: The role is still unclear B.Bone derived-collagen biomarkers
1.PINP for bone formation
2.TRAP-5b for bone resorption
Imaging:
1.X-ray: It is only significant in advanced1.e., subperiosteal bone resorption, salt& pepper skull appearance, Rugger Jersey features of the spine, cystic changes. 2.DXA scan: For BMD & osteoporosis 3.Quantitative Computed Tomography (QCT): More sensitive & specific, The problem is the cost & radiation exposure
4- Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies:
The earlier
Iwasaki-Ishizu et al.,(2005) and Ferrera et al.,(2013)
low bone turn over in rats with CKD 3 -4.
The follow up period was 8 weeks
the intervention was total parathroidectomy + physiologic PTH infusion.
Nikolov et al., & Sabbagh et al.,
where the showed evidence of high turn over bone disease (increase in bone formation rates, mineralization, and osteoclast activity) in Mouse model with CKD 3-4
follow up period of 10 to 20 weeks respectively.
They were no therapeutic intervention given
The recent
T rrly CKD (stage-2)
follow up peroid of 12 weeks.
He reported low bone turn over( decrease in bone formation rates > bone resorption rate, low trabecular volume & thickness) .
thanks dr Mahmoud for your comprehensive answers
jCompare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Malluche et al. performed a bone histomorphometry study in 50 patients, CKD stages 2 to 5The bone biopsies revealed evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid. These findings were compatible with an early stimulatory effect of PTH in the skeleton.
In 1996, Coen et al.47 reported findings of a cross sectional, retrospective bone histomorphometry study in 76 unselected CKD patients on conservative treatment, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl. The study reported that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
2014, Barreto et al.61 proceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy. Notably, The most striking finding was that patients with early CKD exhibited remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time.
1-Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies
The research on the various types of renal osteodystrophy has primarily focused on patients with ESRD. Osteitis fibrosa and mixed uremic osteodystrophy were thought to be the most common types, with osteomalacia being uncommon.The predominance of these two types of renal osteodystrophy was certainly true for patients with ESRD in the 1960s and early 1970s, and in the 1980s, at least in many parts of the world. This new disease was characterized by unusual types of osteomalacia or adynamic bone disease was present especially in early of disease and found by bone biopsy.
.
2-Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease is a low bone turnover mostly occurs early in a significant proportion of patients with chronic kidney disease.the pathogenesis was low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis.The contributing factors initial predominance of bone turnover inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency , diabetes and uremic toxins contribute to ABD. The increasing use of active Vitamin D in the subsequent decade was an etiological factor in the pathogenesis of ABD. Oral treatment with aluminium containing phosphate binders was a contributing factor. Other risk factor for ABD include advanced age, diabetes , metabolic acidosis, and alcoholism.
3-Describe changes of bone related parameters with progression of chronic kidney disease.
Changes in serum calcium, phosphorus, and magnesium levels occur progressively and depend on the type of nephropathy, CKD stage and other factors.Metabolic acidosis or alkalosis may occur, with acidosis being more common.
Serum or tissue concentrations of various bone markers may increase progressively, including PTH, AP, TRAP-5b, FGF23, osteocalcin, osteoprotegerin and sclerostin.increases in advanced glycation end products and oxidative stress have been observed, as well as the accumulation of uremic toxins.
serum concentrations of vitamin D may decrease progressively, as well as aKlotho.
4-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD. The most commonly used parameters as diagnostic and prognostic are PTH and alkaline phosphatase,calcium and phosphorus but their clinical value is limited especially in differentiation between normal and mild low or high bone turnover. VIT D level: can help in diagnosis of osteomalacia wih very low level. imaging studies include :- a-X-ray in osteomalacia, and subperiosteal bone resorption, salt&pepper skull finding, rugger jeresy fracture of the spine, and cystic lesoin in the skull in osteitis fibrosa DXA can differentaite between types of renal ostedystrophy quantitative CT
thanks dr Rabab for your great effort
1-Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Malluche et al. performed a bone histomorphometry study in 50 patients, CKD stages 2 to 5The bone biopsies revealed evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid. These findings were compatible with an early stimulatory effect of PTH in the skeleton.
In 1996, Coen et al.47 reported findings of a cross sectional, retrospective bone histomorphometry study in 76 unselected CKD patients on conservative treatment, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl. The study reported that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
2014, Barreto et al.61 proceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy. Notably, The most striking finding was that patients with early CKD exhibited remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time.
3-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
while addressing predictors of bone loss, Malluche etal reported that QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis
in harmony, West etal reported that decreased BMD by QCT was associated with increased risk of low-trauma clinical fractures.
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
In clinical practice, the biochemical diagnosis of the different types of renal osteodystrophy is mainly based on serum concentrations of PTH and alkaline phosphatases, either tAP or bAP. However, the predictive value of the circulating levels of PTH and tAP or bAP for bone turnover is limited.In particular, it remains impossible to discriminate normal from moderately low or moderately high bone turnover in patients with CKD without proceeding to a bone biopsy.
Bone-derived collagen-based biomarkers were not found to be useful in predicting histo- morphometry, fractures, and bone mineral density (BMD) in an analysis made by the Kidney Disease: Improving Global Outcomes group in 2009.
a recent study from Japan showed that high serum tAP levels were independently associated with the incidence of hip fracture and also with mortality in patients on long-term hemodialysis therapy.
Serum 25 OH vitamin D measurement allows detection of vitamin D insufficiency and deficiency. Very low levels may be associated with osteomalacia.
A possible diagnostic value of serum FGF23 in the differential diagnosis of high versus low bone turnover and normal versus abnormal mineralization has been suggested.
Increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes, respectively.
The noninvasive diagnosis of early changes in bone structure by imaging techniques is extremely limited.
X-Ray examination may allow detection of osteomalacia when Looser–Milkman zones are present. X-ray signs of osteitis fibrosa such as subperiosteal bone resorption, salt and pepper aspect of the skull, rugger jersey features of the spine, and cystic lesions characteristic of brown tumors are only observed in severe forms of the disease.
BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodystrophy but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD.
Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure.
Perhaps combinations of collagen-based biomarkers with imaging techniques might be most useful for fracture prediction.
They found that the highest tertiles of bone formation marker P1NP and resorption marker TRAP-5b were associated with prevalent fracture. In addition, the combination of the highest tertile of s-P1NP or TRAP-5b with femoral neck t-score assessed by DXA improved fracture discrimination over the t-score alone.
Describe changes of bone related parameters with progression of chronic kidney disease.
They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin;variable increases in advanced glycation end products (AGEs),oxidative stress markers including advanced oxidation protein products,and protein carbamylation products;increases in numerous other compounds summarized under the term “uremic toxins”;decreases in serum concen- trations of 25 OH vitamin D and 1,25 diOH vitamin D;and decreases in serum and or tissue concentrations of aKlotho.FGF23 processing appears to change with CKD progression. Although circulating FGF23 undergoes cleavage in patients with normal kidney function and in those with mild CKD,most circulating FGF23 in dialysis patients is in its full-length form.It remains to be seen whether CKD-associated alterations in mineral and endocrine metabolism or other factors are responsible for this change in FGF23 catabolism. The serum levels of secreted frizzled- related protein 4 (sFRP4) do not change with the progression of CKD or the development of hyperphosphatemia.Finally, the role of circulating Dickkopf-1 (Dkk1) is still uncertain, with either no changesor a slight decreaseof mean serum values in patients with CKD.
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
In 1996, Coen et al.reported findings of a cross- sectional, retrospective bone histomorphometry study in 76 unselected Italian CKD patients on conservative treatment. The main findings were normal bone in 10 patients, low-turnover, adynamic bone disease in 9 (all negative for histochemical aluminum staining), mild mixed osteodystrophy in 26, predominant osteomalacia in 7, advanced mixed osteodystrophy in 22, and predominant hyperparathyroidism in 2 .
patients with adynamic bone disease had a less severe degree of CKD than the other subgroups, with intact PTH values above the upper normal limit, and normal serum calcium.
Osteomalacia was found in patients with more advanced CKD stages, together with a tendency toward hypocalcemia and more severe metabolic acidosis.
Based on these findings the authors postulated that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
Adynamic bone is predominantly defined by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis.The true prevalence of the adynamic bone condition in CKD is unknown because of a lack of consensus in its definition and diagnosis, with a reported prevalence range of 5% to 50% in dialysis patients.
The patients also had lower serum intact PTH levels than those with other types of renal osteodystrophy, and they were receiving calcium carbonate treatment for the control of hyperphosphatemia. Adynamic bone disease in patients with CKD was mainly attributed by them and others to overtreatment of secondary hyperpara- thyroidism with PTH-lowering agents or relative or absolute hypoparathyroidism following surgical parathyroidectomy.
Cohen-Solal et al.suggested that in the absence of aluminum overload this type of renal osteodystrophy might be due to overtreatment with vitamin D (or its derivative calcidiol), a subsequent increase in serum calcitriol, and excessive lowering of serum PTH. Since circulating PTH levels have generally been found to be higher than normal even in CKD patients with adynamic bone disease, albeit to a lesser extent than in CKD patients with osteitis fibrosa or mixed bone disease,resistance to the skeletal action of PTH is another possible explanation,due to PTH/PTHrp receptor downregulation in CKD or other causes.
In the past, oral treatment with aluminum-containing phosphate binders was considered to be another culprit .Although clearly involved in a minority of patients—including the very young,those with inflammatory bowel disease, and those ingesting high amounts of fruits or being on citrate treatment,the importance of oral aluminum overload in individuals with CKD not yet on dialysis has probably been overestimated. Other factors favoring the occurrence of low- turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, and alcoholism.
thanks dr Asmaa for your omprehensive answers
moreover, uremi toins also play important role in the pathogenesis of ADB THROUGH inhibition of Wnt/b-catenin signaling ad stimulaton of receptor activator of nuclear factor-kB ligand (RANKL).
Finally, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
The first description of osteitis fibrosa cystica by Davies in 19151 and the discovery by Bauer and his colleagues of its association with parathyroid gland
overactivity in 1930.
Albright’s group postulated in 1937 that phosphate retention and concomitant blood calcium lowering in patients with chronic kidney disease (CKD) might cause parathyroid hyperplasia and renal osteitis fibrosa.
The term renal osteodystrophy was coined in the 1940s.
The subsequent elegant studies by Bricker and Slatopolsky et al. led to the “trade-off hypothesis.” It suggests that in the setting of CKD the progressive loss of functioning nephrons brings into play a number of compensatory mechanisms, including an increase in parathyroid hormone (PTH) secretion in response to the progressive inability of the kidneys to excrete appropriate amounts of phosphate, delaying the occurrence of hyperphosphatemia.
This therapy led to the common belief that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy observed as nephropathies progress from early to more advanced stages of CKD.
the situation changed dramatically in the 1980s, at least in many regions of the world, as a consequence of aluminum intoxication. This new disease was mainly, although not exclusively, observed in patients undergoing long-term hemodialysis treatment.
Another possible etiologic factor in the pathogenesis of adynamic bone disease was the increasingly vigorous use of active vitamin D sterols and analogs in the subsequent decade.
The term CKD-MBD, a systemic disorder due to CKD that is manifested by either 1 or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and vascular or other soft tissue calcification, then developed.
According to this definition, renal osteo- dystrophy is an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by bone histomorphometry.
this question actually targets the bone biopsy studies
Malluche et al. performed a bone histomorphometry study in 50 patients, CKD stages 2 to 5The bone biopsies revealed evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid. These findings were compatible with an early stimulatory effect of PTH in the skeleton.
In 1996, Coen et al.47 reported findings of a cross sectional, retrospective bone histomorphometry study in 76 unselected CKD patients on conservative treatment, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl. The study reported that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
2014, Barreto et al.61 proceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy. Notably, the most striking finding was that patients with early CKD exhibited remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time.
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD
the most commonly used parameters are PTH and alkaline phosphatase, but their clinical value is limited especially in differentiation between normal and mild low or high bone turnover.2- 25(oH) VIT D: can help in diagnosis of osteomalacia wih very low level3- value of FGF-23 measurement is still questionable
imaging studies include :-
a-X-ray, LOOSER-MILKMAN zones in osteomalacia, and subperiosteal bone resorption, aslt&pepper skull finding, rugger jeresy fracture of the spine, and cystic lesoin in the skull in osteitis fibrosa
b-DXA can differentaite between types of renal ostedystrophy
c- quantitative CT
thanks dr Ahmed
while addressing predictors of bone loss, Malluche etal reported that QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis
in harmony, West etal reported that decreased BMD by QCT was associated with increased risk of low-trauma clinical fractures.
1-. Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies. 2. Explain the pathogenesis and contributing factors of ADB in patients with CKD. 3. Describe changes of bone related parameters with progression of chronic kidney disease. 4. Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD. THE DISTRIBUTION OF ROD TYPES classified AS TMV 1- TURNOVER OF BONE —Normal –low( adynamic turnover) —high turnover 2- MINERALIZATION — bone marker level as ca -pi- pth-vitd -mag – . 3- VOLUM —high or low density Turn over means the balance between activity of osteoclast and osteoblast activity In earlier study as In1976, Malluche et al the authors were unable to recognize a correlation between the nature of renal disease and the severity of histologic lesions. They concluded that despite the absence of frankly increased numbers of osteoclasts, the accumulation of empty resorption cavities as well as the appearance of woven osteoid even in early CKD stages was compatible with an early stimulatory effect of PTH in the skeleton in 1996, Coen et al. patients with adynamic bone disease had a less severe degree of CKD than the other subgroups, with intact PTH values above the upper normal limit, and normal serum calcium. Osteomalacia was found in patients with more advanced CKD stages, together with a tendency toward hypocalcemia and more severe metabolic acidosis. A GFR of 20 ml/min was indicative of a demarcation line between the patients with osteomalacia and those with adynamic bone disease. Based on these findings the authors postulated that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, whichappears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD. The 2 reports above appear to be contradictory, at least in part, especially with respect to the prevalence of osteomalacia and adynamic bone disease in CKD patients not yet on dialysis. Reports by other research groups of that time do not allow further clarification of this issue. Thus Dahl et al. reported that osteomalacia was extremely rare in the predialysis stage, while Mora Palma et al. found a high percentage of cases with osteomalacia, mainly in association with chronic tubulointerstitial nephritis and prevailing metabolic acidosis. The types of underlying nephropathy responsible for a more or less rapid progression of CKD and accompanying metabolic and endocrine abnormalities probably explain these differences in prevalence. Whether oral intake of aluminum-containing phosphate binders has contributed to the osteomalacia in at least some of these patients is unclear. Finally, different diagnostic criteria used to define osteomalacia may also account for the observed difference. Adynamic bone is predominantly defined by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis. The true prevalence of the adynamic bone condition in CKD is unknown because of a lack of consensus in its definition and diagnosis, with a reported prevalence range of 5% to 50% in dialysis patients. In patients with advanced CKD Hutchison et al. and Hernandez et al. observed a prevalence of 28% and 30%, respectively, thus higher than Coen et al. Their patients also had lower serum intact PTH levels than those with other types of renal osteodystrophy, and they were receiving calcium carbonate treatment for the control of hyperphosphatemia Adynamic bone disease in patients with CKD was mainly attributed by them and others to overtreatment of secondary hyperparathyroidism with PTH-lowering agents or relative or absolute hypoparathyroidism following surgical parathyroidectomy IN RECENT STUDIES AS In 2014, Barreto et al. The observation by Barreto et al. of a high prevalence of low-turnover, adynamic bone disease in early stages of CKD is in agreement with the findings reported by Coen et al. nearly 2 decades earlier. Thus, in contrast to common belief, high bone turnover is not necessarily a continuous process starting with the very onset of CKD, in direct association with a progressive increase in serum PTH. It rather seems that in early CKD stages low bone turnover prevails in a large number of patients Findings from recent studies Experimental studies in animals with CKD indicating the presence of low bone turnover at early stages (especially stage 2) of CKD Fang et al., 2014 Ferreira et al., 2013 Under experimental conditions of CKD with normal parathyroid status or with insulin resistance and the metabolic syndrome, low-turnover bone disease will develop initially, whereas in the presence of overt hyperparathyroidism, high-turnover bone disease will prevail and in low-density lipoprotein receptor knockout mice with the metabolic syndrome the superimposition of mild CKD (stage 2) led to a further aggravation of low-turnover bone diseas the various forms of renal osteodystrophy that are observed with the progression of CKD in human patients depend on many other factors as sex hormone deficiency, reduced calcitriol production, diabetes, increased synthesis of Wnt pathway inhibitors, and uremic toxins accumulating in early stages of CKD. Uremic toxins contribute to skeletal resistance to PTH and calcitriol and a decrease in calcitriol synthesis in early CKD, and to repression of Wnt/b-catenin signaling within osteocytes in conjunction with increased expression or circulating levels of Wnt pathway antagonists such as sclerostin, Dkk1, and sFRP4, together with increased osteoclast activity such as receptor activator of nuclearfactor-kB ligand (RANKL) Conclusion clinical and experimental evidence has been accumulating in favor of the development of low-turnover bone disease in early stages of CKD, as a result of resistance to the action of PTH and several other mechanisms. the role of uremictoxins such as indoxyl sulfate and of a repression of the osteocyte ,Wnt/b-catenin signaling pathway in the initial stage of renal osteodystrophy diagnostic and prognostic value of bone biomarkers and imaging techniques in patients withCKD-MBD.
1- biochemical marker used are –serum concentrations of PTH and alkaline phosphatases, either tAP or bAP. Plus bone biopsy also serum 25 OH vit D and FGF-23 — serum sclerostin increase levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes, respectively. No such link has been reported so far in patients with CKD. The relation of serum sclerostin with bone formation and bone mass remains unclear 2- imaging X-ray examination allow detection of osteomalacia when Looser–Milkman zones are present. X-ray signs of osteitis fibrosa such as subperiosteal bone resorption, salt and pepper aspect of the skull, rugger jersey features of the spine, and cystic lesions characteristic of brown tumors are only observed in severe forms of the disease ## Bone Mineral Density (BMD) by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodystrophy but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD. ###Quantitative computed tomography (QCT) provides more precise information but is expensive
thanks dr Elsayed for your effort
you have a missed question
Describe changes of bone related parameters with progression of chronic kidney disease.
increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin
decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of α-Klotho.
no change secreted frizzled related protein 4 (sFRP4) & Dickkopf-1 (Dkk1)
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
-Renal osteodystrophy is a change in bone morphology in CKD Patients
-Osteitis fibrosa and mixed osteodystrophy were thought to be the most common types in the past.
-Unusual types of osteomalacia or adynamic bone disease were reported in 1980s.
-Recent studies shows that adynamic bone disease with low bone turnover occurs early in a significant number of patient then later
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease with low turnover occurs early in a significant proportion of patients with chronic kidney disease. The initial predominance of bone turnover inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency , diabetes and uremic toxins contribute to ABD. The increasing use of active Vitamin D in the subsequent decade was an etiological factor in the pathogenesis of ABD. Oral treatment with aluminium containing phosphate binders was a contributing factor. Other risk factor for ABD include advanced age, diabetes , metabolic acidosis, and alcoholism.
Describe changes of bone related parameters with progression of chronic kidney disease.
Changes in serum calcium, phosphorus, and magnesium levels occur progressively and depend on the type of nephropathy, CKD stage and other factors.
-Metabolic acidosis or alkalosis may occur, with acidosis being more common.
Serum or tissue concentrations of various bone markers may increase progressively, including PTH, AP, TRAP-5b, FGF23, osteocalcin, osteoprotegerin and sclerostin.
-increases in advanced glycation end products and oxidative stress markeers have been observed, as well as the accumulation of uremic toxins.
-serum concentrations of vitamin D may decrease progressively, as well as aKlotho.
-FGF23 processing changes with CKD progression, with most circulating FGF23 in dialysis patients being in its full length form
-Secreted frizzled related protein 4(sFRP4) levels do not change with the progression of CKD or the development of hyperphosphatemia
-The role of DKK1 in bone realted CKD is still uncertain.
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The biocehmical diagnosis of diffrent types of ROD is mainly based on PTH and AP. (High PTH and AP are predictive for high turnover)
-Serum 25 OH Vitamin D , benefits in osteomalacia
-increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes respectivly.
Imaging:
BMD by dual energy X ray absorptiometry (DXA) cannot tell the diffrence between diffrent types of ROD but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD.
Quantitative CT provides more precise information but is costly and associated with exposition to high radiation .
thanks dr Nour for your excellent effort
3-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
while addressing predictors of bone loss, Malluche etal reported that QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis
in harmony, West etal reported that decreased BMD by QCT was associated with increased risk of low-trauma clinical fractures.
2- pathogenesis of ADB
in addition, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
**Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
It is commonly known that osteitis fibrosa cystica and mixed osteodystrophy are the most common form of renal osteodystrophy in patients with CKD, which is a high turnover bone disease due to hyperparathyroidism while the mixed type is caused by vitamin D deficiency that cause mineralization defects. More recent studies show adynamic bone disease which is a low turn over bone disease occur in the early stages of ckd in significant number of patients, then later on high turnover bone disease occur when the PTH start to increase when it overcome the peripheral PTH resistance and the inhibitory factors on bone formation.
**Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease characterized by low or absent bone formation, thin osteid seams, decrease osteoblast and osteoclast and minimal bone fibrosis, it occurs due to overtreatment of secondary hyperparathyroidism by PTH lowering agents or hypoparathyroidism after parathyroidectomy.
Risk factors are :
Advanced age, DM, immunosuppressive drugs, malnutrition, aluminum overload, genetic factors, long term antiresorptive drugs (biphosphonate), alcoholism, metabolic acidosis, hypoparathyroidism, resistant to PTH.
**Describe changes of bone related parameters with progression of chronic kidney disease.
S. Ca, phosphorous and Mg increase or decrease depending on type of nephropathology and ckd stage
Metabolic acidosis
Progressive increase in PTH
Total or bone specific alkaline phosphotase procollagen type 1 N terminal propeptides tarterate resistance acid phosphotase 5b
High FGF23
High Osteocalcin
High Osteopotegrin
Sclerotin
Advanced glycation end product
Advanced oxidation protein products
Protein carbamylation products. Decrease 1,25 OH and 25 OH vitamin D
Decrease klotho
**Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
PTH, alkaline phosphotase total or bone specific alkaline phosphotase for diagnosis of different types of renal osteodystrophy
S. 25 OH vitamin D to detect deficiency which is related to osteomalacia.
FGF23 level in high and low turnover, and in normal and abnormal mineralization
S. Sclerostin which increase when there is a high risk of fracture in patient with osteoporosis and in type 2DM.
TRAP – 5b detect bone loss in ckd.
X ray helps in diagnosis of osteomalacia when there is looser zone, and in osteitis fibrosa and features of hyperparathyroidism like subperiosteal resorption, rugger jersey appearance, salt and pepper in the skull and brown tumor.
DXA scan for diagnosis of bone mineral density and presence of osteoporosis and bone loss.
Quantitative CT for detection of bone loss and fractures but is expensive and high radiation.
thanks dr Israa for your great effort
2- the pathogenesis of ADB
Moreover, uremic toxins also play important role in the pathogenesis of ADB through the following mechanisms:
• skeletal resistance to PTH and calcitriol
• decrease in calcitriol synthesis
• repression of Wnt/b-catenin signaling within osteocytes
• increased expression or circulating levels of Wnt pathway antagonists such as sclerostin, Dkk1, and sFRP4,
• increased osteoclast activity such as receptor activator of nuclear factor-kB ligand (RANKL).
Finally, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
1.Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
For the diagnosis of the various types of renal osteodystrophy, bone biopsy remains the gold standard. Renal osteodystrophy is a change in bone morphology in CKD patients. It is one of the skeletal components of the systemic disorder CKD-MBD that can be quantified using bone histomorphometry. For decades, research on the various types of renal osteodystrophy has primarily focused on patients with ESRD. Osteitis fibrosa and mixed uremic osteodystrophy were thought to be the most common types, with osteomalacia being uncommon.
The predominance of these two types of renal osteodystrophy was certainly true for patients with ESRD in the 1960s and early 1970s, and in the 1980s, at least in many parts of the world. This new disease was characterized by unusual types of osteomalacia or adynamic bone disease. 2.Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease with low bone turnover occurs early in a significant proportion of patients. This could be due to the initial predominance of bone turnover-inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency, diabetes, and uremic toxins. The increasing use of active vitamin D in the subsequent decade was an etiologic factor in the pathogenesis of adynamic bone disease. There is significant overlap between the end of the aluminum epidemic and the excessive use of active vitamin D compounds. the prevalence of this drug induced disease has declined rapidly as a result of improved dialysis water purification and a decrease in the prescription of aluminum-containing phosphate chelators. ADB is characterized primarily by low or absent bone formation, thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis. Because of a lack of agreement in its definition and diagnosis, the true prevalence of the adynamic bone condition in CKD is unknown, with a reported prevalence range of 5% to 50% in dialysis patients.
Oral treatment with aluminum-containing phosphate binders was a contributing factor. Other risk factors for ADB include advanced age, diabetes, metabolic acidosis, and alcoholism. 3.Describe changes of bone related parameters with progression of chronic kidney disease. Changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on the underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), Increases in procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized as “uremic toxins. The processing of FGF23 appears to change as CKD progresses. Although circulating FGF23 is cleaved in patients with normal kidney function and mild CKD, the majority of FGF23 in dialysis patients is in its full-length form. They may be oxidized, AGE-transformed, or carbamylated, all of which can significantly alter biologic activity.
4-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD
Biomarkers
1.PTH & Alkaline phosphatase (tAPT, bAPT)
Limited predictive value unless PTH AND ALP are both very high
2.Vitamin D level
Of benefit in Osteomalacia Dx
3.FGF23
Doubtful
4.Sclerostin
Need futher Clarification
6.PINP for bone formation 7.TRAP-5b for bone resorption C.Imaging 1.X-ray
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Bone and mineral disorders seen in patients with chronic kidney disease results from a spectrum of disorders which includes abnormal concentrations of serum calcium, phosphate, magnesium as well as disorders of your parathyroid hormone, fibroblast growth factor 23 and vitamin D metabolism.
The spectrum of skeletal abnormalities seen in renal osteodystrophy includes the following:
Osteitis fibrosa, which is a manifestation of hyperparathyroidism and is characterised by increased osteoclast and osteoblast activity. It is also described as being a high turnover bone disease
Osteomalacia, is a manifestation of defective mineralisation of the newlyformed bone and the bone turnover is decreased
Adynamic bone disease, is also associated with very low bone turnover
Osteopenia and osteoporosis
Mixed Renal Osteodystorphy
Bone biopsy the gold standard method of determining the type of bone disease found in patients with chronic kidney disease
Osteitis fibrosa and mixed renal osteodystrophy was the most common bone disease that was documented in the past in patients with chronic kidney disease, and this has changed recently and it was shown that the low turnover bone disease, of which adynamic bone disease is more common has come afore
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease is characterised by low or absent bone formation in conjunction with thin osteoid seams, decrease hilarity and minimal bone marrow fibrosis-thus a lack of bone activity which involves osteoblast and osteoclasts
The principal mechanisms which underlies the development of adynamic bone disease can be categorised into either over suppression of your parathyroid hormone release or the use of calcium mimetic agents
Contributing factors:
Treatment-related: All the factors listed below results in a reduced reduction of parathyroid hormone release:
Calcium load with a present in the dialysate or by means of supplementation
Vitamin D agonists
Calcimimetics
Aluminium load
Biphosphatase
Parathyroidectomy
Chronic kidney disease related: all these factors result in parathyroid hormone resistance
Hyperphosphataemia
Calcitriol deficiency
Magnesium deficiency
Metabolic acidosis
Oxidative stress
Uraemic toxins
Malnutrition
Diabetes
Increased age
Describe changes of bone related parameters with progression of chronic kidney disease.
As the kidney function worsens in the glomerular filtration rate declines, the kidney needs to work harder to excrete phosphate
Fibroblast growth factor 23 is a hormone regulates phosphate excretion
Fibroblast growth factor 23 is made by bones, and regulates phosphate excretion by the kidney. Fibroblast growth factorreceptors in the renal tubules to block the reabsorption of folded phosphate, thereby increasing the phosphate excretion
When glomerular filtration rate falls even slightly the kidney signals the bone to make more FGF 23, and it has been noted that the FGF 23 goes up at a relatively early stage during the development of chronic kidney disease
FGF 23 reduces the activity of one alpha hydroxylase which is an enzyme that converts 25 hydroxy vitamin D to the active 1,25 dihydroxy vitamin D. The inhibition of vitamin D activation by FGF 23 is consistent with the role of FGF 23 in responding to an increased phosphate burden
1,25 dihydroxy vitamin D interacts with vitamin D receptors which is located in the gut to increase the enteric absorption of phosphate and calcium, thus blocking the activation of 25 hydroxy vitamin D to 1,25 dihydroxy vitamin D and thus reduce the phosphate load which comes from the.
At the onset of stage II chronic kidney disease we see that the FGF 23 increases and this is followed by the hyperphosphataemia and hyperparathyroidism
At the onset of stage II chronic kidney disease with the changes mentioned above is also a marked decline in the levels of 1,25 dihydroxy vitamin D
At the onset of chronic kidney disease there is also a linear decline in the Klotho levels
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
Presently the biochemical diagnosis of the different types of renal osteodystrophy is mainly based on serum concentrations of your parathyroid hormone as well as alkaline phosphatase
The use of serum 25 hydroxy vitamin D measurement only allows the detection of either vitamin D insufficiency or deficiency, and it is well known that very low levels of 25 hydroxy vitamin D can result in the development of osteomalacia
FGF 23 has been postulated to help in differentiating low and high turnover bone disease however further studies need to be done to confirm this
Xrays has been used especially in patients with osteitis fibrosa, but has also been used in patients with osteomalacia-of which both condition has characteristic radiological signs
Dual energy x-ray absorptiometry has been used in the general population especially to diagnose osteopenia and osteoporosis. In the chronic kidney disease population this modality cannot differentiate between the different types of renal osteodystrophy but can predict possible fractures in these patients
Quantitative computed tomography seems to be more precise but is much more expensive
1.Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Bone biopsy remains the gold standard for the diagnosis of the different types of renal osteodystrophy.Renal osteodystrophy is an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by bone histomorphometry.For decades the study of the different types of renal osteodystrophy has mainly focused on patients with ESRD. Osteitis fibrosa and mixed uremic osteodystrophy were considered to be the predominant types, with osteomalacia being of low prevalence.The predominance of these 2 forms of renal osteodystrophy was certainly true for patients with ESRD in the 1960s and early 1970s, in the 1980s, at least in many regions of the world, This new disease was observed characterized by peculiar types of osteomalacia or adynamic bone disease,and often accompanied by microcytic anemia and encephalopathy.2.Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients.This could be due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxinsEtiologic factor in the pathogenesis of adynamic bone disease was the increasingly vigorous use of active vitamin D sterols and analogs in the subsequent decade,. With considerable overlap between the tail end of the aluminum epidemic and the overzealous use of active vitamin D compounds. Fortunately, the incidence of this “iatrogenic” disease has rapidly waned as a consequence of better dialysis water purification and the declining prescription of aluminum-containing phosphate chelators to patients with CKD. Adynamic bone is predominantly defined by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis. The true prevalence of the adynamic bone condition in CKD is unknown because of a lack of consensus in its definition and diagnosis, with a reported prevalence range of 5% to 50% in dialysis patients.. In patients with advanced CKD Hutchison et al. and Hernandez et al. observed a prevalence of 28% and 30%. Renal osteodystrophy might be due to overtreatment with vitamin D (or its derivative calcidiol), a subsequent increase in serum calcitriol, and excessive lowering of serum PTH. Since circulating PTH levels have generally been found to be higher than normal even in CKD patients with adynamic bone disease, albeit to a lesser extent than in CKD patients with osteitis fibrosa or mixed bone disease, resistance to the skeletal action of PTH is another possible explanation, due to PTH/PTHrp receptor downregulation in CKD or other causes. In the past, oral treatment with aluminum-containing phosphate binders was considered to be another culprit. Other factors favoring the occurrence of low turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, and alcoholism.
3.Describe changes of bone related parameters with progression of chronic kidney disease.
They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized under the term “uremic toxins”; decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of aKlotho. FGF23 processing appears to change with CKD progression. Although circulating FGF23 undergoes cleavage in patients with normal kidney function and in those with mild CKD, most circulating FGF23 in dialysis patients is in its full-length formThey may undergo oxidation, AGE-transformation, or carbamylation, which also may greatly alter biologic activity
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The biochemical diagnosis of the different types of renal osteodystrophy is mainly based on serum concentrations of PTH and alkaline phosphatases, either tAP or bAP. A recent study from Japan showed that high serum tAP levels were independently associated with the incidence of hip fracture and also with mortality in patients on long-term hemodialysis therapySerum 25 OH vitamin D measurement allows detection of vitamin D insufficiency and deficiency. Very low levels may be associated with osteomalacia. A possible diagnostic value of serum FGF23 in the differential diagnosis of high versus low bone turnover and normal versus abnormal mineralization has been suggestedIncreased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetesThe noninvasive diagnosis of early changes in bone structure by imaging techniques is extremely limited. X-ray examination may allow detection of osteomalacia when Looser–Milkman zones are present. X-ray signs of osteitis fibrosa such as subperiosteal bone resorption, salt and pepper aspect of the skull, rugger jersey features of the spine, and cystic lesions characteristic of brown tumors are only observed in severe forms of the disease.BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodystrophy but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD. Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis. Note, however, that bone strength as indirectly assessed by BMD and QCT, although being generally considered as the most important factor for fracture risk, is certainly not the only one in the occurrence of fractures in patients with CKD. Increased fragility, muscle weakness, and fall risk also play important roles.They found that the highest tertiles of bone formation marker P1NP and,resorption marker TRAP-5b were associated with prevalent fracture.
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
loss of nephron mass function lead to hyperparathyroidism due to phosphate retention.
with progression of renal disease . renal osteodystrophy occur characterized by :mineral bone disease as
adynamic bone disease, osteitis fibrosa cystica , Osteomalacia.
CKD-MBD, characterized by lab abnormalities, bone turnover and vascular and soft tissue calcification.
Bone biopsy and histomorphometry is the best for diagnosis of ROD .
2-Explain the pathogenesis and contributing factors of ADB in patients with CKD. factors are :
overcorrection of secondary hyperparathyroidism with PTH-lowering medications .
Aluminum overload ,Metabolic acidosis and Nutritional status
3-Describe changes of bone related parameters with progression of chronic kidney disease. with progression of renal disease:
increase
phosphorus
PTH
Osteoprotegerin
Osteocalcin
FGF-23
Dentin matrix protein 1(DMP1)
decrease : Renal Klotho .vit D ,S.Ca
with low bone mineralization and bone volume .higher fracture risk in patients with osteoporosis .
4-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
DXA scan diagnosis of bone loss and the prediction of fractures in CKD
computed tomography (QCT) .more specific
Serum PTH and bone alkaline phosphatases, used to diagnose renal osteodystrophy.
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
earlier: trade-off hypothesis: in CKD, the gradual loss of working nephrons triggers a number of compensatory mechanisms, such as an increase in parathyroid hormone (PTH) secretion in response to the kidneys’ inability to get rid of enough phosphate, which delays the onset of hyperphosphatemia.
osteitis fibrosa , osteomalacia, or adynamic bone disease, and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy, observed as nephropathies progress
CKD-MBD, a systemic disorder caused by CKD, is characterized by abnormalities in calcium, phosphorus, PTH, vitamin D, bone turnover, mineralization, volume, linear growth, or strength, and vascular or other soft tissue calcification. Renal osteodystrophy is a CKD-related morphological change in the bones. Bone histomorphometry quantifies the skeletal component of CKD-MBD.
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Little bone formation, narrow osteoid seams, diminished cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis characterize adynamic bone.
They treated hyperphosphatemia with calcium carbonate and had lower serum intact PTH levels than other renal osteodystrophies.
They believed that overtreatment of secondary hyperparathyroidism with PTH-lowering medications or relative or absolute hypoparathyroidism after surgical parathyroidectomy caused adynamic bone disease in CKD patients.
In the absence of aluminum overload, Cohen-Solal et al hypothesized that overtreatment with vitamin D (or its product calcidiol) may raise blood calcitriol and reduce serum PTH, causing renal osteodystrophy.
Factors favoring the occurrence of low-turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, vegetarian protein diets, physical activity, and alcoholism.Drugs such as corticosteroids and immunosuppressive agents given to patients with various types of renal disease may exert major negative effects on the bone.
Describe changes in bone-related parameters with the progression of chronic kidney disease.
Early CKD increases skeletal sclerostin expression. despite normal blood PTH levels, and ESRD increases it to a lesser extent despite increasing serum PTH. Dentin matrix protein 1 (DMP1), a member of the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, suppresses bone FGF23 expression, but its osteocytic expression was elevated in early CKD patients despite high osteocytic FGF23 production. Hence, DMP1 is unlikely to initiate bone FGF23 expression in CKD.
Pereira et al. recently examined the skeletal expression of FGF23, DMP1, and matrix extracellular phospho glycoprotein (MEPE) in 32 pediatric and young adult patients with CKD stages 2 to 5 using immunohistochemistry. All phases of CKD have higher bone FGF23 and DMP1 expression than controls.
Predialysis CKD and dialysis patients had similar bone FGF23 and DMP1 expression. CKD and controls expressed MEPE similarly. While all 3 proteins are expressed in osteocytes, their expression patterns vary greatly. CKD progression may increase phosphate load and bone DMP1 and FGF23 expression. Bone volume negatively correlated with bone MEPE expression.
These data suggest that FGF23 and DMP1 affect bone mineralization and MEPE bone volume. This theory needs additional research. Nevertheless, the rise in bone FGF23 and DMP1 expression implies early CKD-related osteocyte dysfunction.
Explain the diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
-BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodystrophy but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD. Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure.
-Serum PTH and alkaline phosphatases, (tAP or bAP) are used to biochemically diagnose renal osteodystrophy. Nevertheless, PTH and tAP/bAP levels do not predict bone turnover well.
-Serum FGF23 may help distinguish between high and low-bone turnover and normal and abnormal mineralization. This finding requires additional research.
-Increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes, respectively. No such link has been reported so far in patients with CKD. The relation of serum sclerostin with bone formation and bone mass remains unclear
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
The recent studies were done Fang et al., 2014 on Mouse in early CKD (stage-2) with a follow up peroid of 12 weeks. He reported low bone turn over( decrease in bone formation rates > bone resorption rate, low trabecular volume & thickness) . The therapeutic intervention was high fat diet.
The earlier studies involved different investigators, Iwasaki-Ishizu et al.,(2005) and Ferrera et al.,(2013) demonstrated low bone turn over in rats with CKD 3 -4. The follow up period was 8 weeks and the intervention was total parathroidectomy plus physiologic PTH infusion. These are in contrast to Nikolov et al., & Sabbagh et al., where the showed evidence of high turn over bone disease (increase in bone formation rates, mineralization, and osteoclast activity) in Mouse model with CKD 3-4 after follow up period of 10 to 20 weeks respectively. They were no therapeutic intervention given
Explain the pathogenesis and contributing factors of ADB in patients with CKD. Pathogenesis
ADB ismainly due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/ b-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4.
Risk factors Endogeneous, patient-related factors
Age
sex
Ethnicity/genetic factors
Exogenous factors
Nutritional status
Phyiscal activity
Drugs-vitamin D supplementation, immune suppressive agents
Toxins e.g alcohol
Other factors
Peritoneal dialysis
High dialysate Ca
Aluminum overload
Metabolic acidosis
Parathyroid surgery
Describe changes of bone related parameters with progression of chronic kidney disease. Bone structure, static & dynamic aspects Early CKD
Low bone formation rates
Low osteoid voulme
Low osteoblast surface
High mineralization lag time
Advanced CKD
Osteomalacia
High value of osteoid volume, osteoblast surface, & bone formation rate
High osteoclast surface, fibrosis volume
Low mineralization lag time
Increased expression of bone protein
Sclerostin
FGF-23
PTH
Osteoprotegerin
Osteocalcin
Dentin matrix protein 1(DMP1)
Matrix extracellular phosphoglycoprotein (MEPE)
Decreased expression other proteins
Renal Klotho
VDRA
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD A.Biomarkers 1.PTH & Alkaline phosphatase (tAPT, bAPT)
The predictive value for the diagnosis bone turn over is limited
2.Vitamin D level
Help in the diagnosis of osteomalacia
3.FGF23
Need further studies
4.Slerostin
The role is still unclear
B.Bone derived-collagen biomarkers
1.PINP for bone formation
2.TRAP-5b for bone resorption C.Imaging 1.X-ray
It is only significant in advanced1.e., subperiosteal bone resorption, salt& pepper skull appearance, Rugger Jersey features of the spine, cystic changes.
1. Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies:
First in 1915 it was postulated that it OFS due to parathyroid gland overactivity
In 1937 Albright releated this to high po4 and low calcium.
Term of ROD was coined in 1940
Very early also rule f function nephron loss and vit D deficiency with histological osteomalcia was discussed
Which improved with better water
recently using light microscopy or imaging techniques with a progressive move from X-ray and histologic aspects of ROD
early it was thought uremic bone mainly passive organ suffering which changed recently where they act as endocrine organ playing active role in the cardiovascular, metabolic and bone abnormalities with progression of CKD stages
2.Explain the pathogenesis and contributing factors of ADB in patients with CKD
there are allot of factors include the uremic toxins, PTH resistant, PTH receptor hyporesponsiveness, PTh receptor downregulation, hyperphosphatemia , high (FGF-23), aluminum intoxication, DM,corticosteroid use, PD modality. bisphosphonate therapy. Use of active Vitamin D and calcium containing phosphate binders
3.Describe changes of bone related parameters with progression of chronic kidney disease.
high PTh increase bone resprption
high FGF23 increase bone formation
high sclerostin, low vit D, decrease bone formation and mineralization..
metabolic acidosis decrease bone formation and mineralization with stimulation of resorption
the progressive increase in s pth ,tAP,P1NP TRAP -5B, Fgf23, uremic toxins
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
PTH and ALP. (High PTH and ALP are predictive for high turnover)
-Serum 25 OH Vitamin D , in osteomalacia
-high sclerostin levels associated with higher fracture risk in patients with osteoporosis and type 2 diabetes
Imaging:
BMD by dual energy X ray absorptiometry (DXA) cannot tell the diffrence between diffrent types of ROD but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD.
Quantitative CT provides more precise information but is costly and associated with exposition to high radiation .
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
bone biomarker include
PTH. VIT D S CALCIUM,Osteoprotegerin, and sclerostin
FGF23, TRAP 5b
IMAGING :
BMD by dual-energy X-ray absorptiometry (DXA).
xrays .
QCT which gives more clear information.
in earlier studies dedicated to renal osteodystrophy was done in patients ESRD which is the long term of exposure of uremic milieu with complex of major disturbances of mineral and endocrine metabolism
in recent years there is a number of studies using either light microscopy or imaging techniques in ckd patients furthermore in the nephrology community there is a progressive move from Xray and histologic aspects of renal bone disease.
The early times the perception of uremic bone was mainly that of passive organ suffering these has changed recently and found out and endocrine organ is playing in active role in the cardiovascular complications, and metabolic abnormalities along with the progression of CKD.
2.Explain the pathogenesis and contributing factors of ADB in patients with CKD
The pathogenesis is complex and there are allot of factors contributing which include the uremic toxins, hyperparathyroidism, (FGF-23) levels, malnutrition resistance of PTH aluminum overload. long term of bisphosphonate therapy.
3.Describe changes of bone related parameters with progression of chronic kidney disease.
it includes rapid change of s calcium phosphorus and magnesium levels.
metabolic acidosis and metabolic alkalosis.
the progressive increase in s pth ,tAP,P1NP TRAP -5B, Fgf23, uremic toxins and
Adynamic bone disease is the most common form of renal osteodystrophy in patients with early stages of CKD, while osteomalacia and mixed renal osteodystrophy are more common in later stages of CKD. Histomorphometric studies have also shown that bone formation rate and mineralization lag time are generally lower in early CKD stages compared to later stages. Moreover, ethnic differences have been observed in bone histomorphometry findings, with African American patients showing higher bone formation rates and lower bone mineralization lag times than Caucasian patients.
2. Explain the pathogenesis and contributing factors of ADB in patients with CKD.
The pathogenesis of Adynamic Bone Disease (ADB) in patients with Chronic Kidney Disease (CKD) is complex and multifactorial. Several factors may contribute to the occurrence of ADB in CKD patients, including abnormalities in mineral and endocrine metabolism, medical treatment, age, gender and ethnicity, physical activity, and dietary intake. Changes in mineral and endocrine metabolism, such as disturbances in calcium, phosphorus, and magnesium balance; metabolic acidosis; and increases in parathyroid hormone (PTH) and fibroblast growth factor-23 (FGF-23) levels, are associated with the development of ADB. These changes can lead to resistance to the action of PTH, as well as other mechanisms, resulting in low bone turnover. Medical treatment can also contribute to the occurrence of ADB, as drugs such as corticosteroids and immunosuppressive agents can have a major negative effect on the bone. Other factors include advanced age, diabetes mellitus, metabolic acidosis, malnutrition, alcoholism, and the long-term use of anti-resorptive therapies such as bisphosphonates. In addition, aluminum overload, genetic factors, and hypoparathyroidism can also favor the development of ADB.
3. Describe changes of bone related parameters with progression of chronic kidney disease.
These changes include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or less frequently-metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized under the term “uremic toxins”; decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of aKlotho.
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
Bone biomarkers and imaging techniques are important tools for diagnosing and assessing the prognosis of patients with CKD-MBD. Bone biomarkers, such as collagen-based biomarkers, PTH, tAP, bAP, FGF23, osteocalcin, osteoprotegerin, and sclerostin, are important for assessing bone turnover and mineralization, as well as assessing the severity of CKD-MBD.
Imaging techniques, such as bone histomorphometry, bone mineral density (BMD) scans, and dual-energy X-ray absorptiometry (DXA), are useful for diagnosing and assessing the prognosis of CKD-MBD.
The diagnostic value of bone biomarkers and imaging techniques in CKD-MBD is mainly related to the assessment of bone health.
Bone biomarkers are useful for assessing bone turnover and mineralization, as well as assessing the severity of CKD-MBD.
Imaging techniques provide a more comprehensive assessment of bone health by allowing for the visualization of bone structure, density, and mineralization. The prognostic value of bone biomarkers and imaging techniques in CKD-MBD is mainly related to the ability to predict fractures, bone loss, and mineralization lag time.
Studies have shown that certain bone biomarkers, such as PTH and tAP, are associated with an increased risk of fracture in CKD-MBD patients. Imaging techniques can also be used to predict bone loss and mineralization lag time, as well as the risk of fracture.
In summary, bone biomarkers and imaging techniques are important diagnostic and prognostic tools for patients with CKD-MBD. They allow for the assessment of bone health, as well as the prediction of fractures, bone loss, and mineralization lag time.
As early as in 1976, Malluche et al performed a bone histomorphometry study in 50 German patients with various stages of CKD, ages 20 to 61 years, 19 males and 31 females. Their creatinine clearance (glomerular filtration rate) values ranged from 80 to 6 ml/min per 1.73 m2, that is, CKD stages 2 to 5 according to present nomenclature. The bone biopsies of patients with incipient CKD exhibited evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid(an early expression of osteitis fibrosa, was increasing with decreasing glomerular filtration rate).
In 1996, Coen et al reported findings of a cross- sectional, retrospective bone histomorphometry study in 76 unselected Italian CKD patients on conservative treatment, ages 18 to 72 years, 44 males and 32 females, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl and a mean
SD creatinine clearance of 20
12 ml/min per 1.73 m2.Those with adynamic bone disease. Based on these findings the authors postulated that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodys- trophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.In 2014, Barreto et al proceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy and exhibited an inverse association between bone formation rate and coronary artery calcification. The most striking finding was that patients with CKD stages 2 and 3 had remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time. In contrast, patients with CKD stages 4 and 5 had higher values of osteoid volume, osteoblast surface, and bone formation rate, and in addition higher osteoclast surface, fibrosis,volume, and a trend toward lower mineralization lag time.
Adynamic bone is predominantly defined by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and mini- mal marrow fibrosis. Their patients also had lower serum intact PTH levels than those with other types of renal osteodystrophy.
It is mainly attributed to overtreatment of secondary hyperparathyroidism with PTH-lowering agents or relative or absolute hypoparathyroidism following surgical parathyroidectomy, aluminum overload , overtreatment with vitamin D (or its derivative calcidiol), a subsequent increase in serum calcitriol, and excessive lowering of serum PTH.
Other factors favoring the occurrence of low- turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, and alcoholism.
They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products,and protein carbamylation products;increases in numerous other compounds summarized under the term “uremic toxins”; decreases in serum concen- trations of 25 OH vitamin D and 1,25 diOH vitamin D;and decreases in serum and or tissue concentrations of a Klotho.
The predictive value of the circulating levels of PTH and tAP or bAP for bone turnover is limited. In particular, it remains impossible to discriminate normal from moderately low or moderately high bone turnover in patients with CKD without proceeding to a bone biopsy.
Bone-derived collagen-based biomarkers were not found to be useful in predicting histo- morphometry, fractures, and bone mineral density (BMD).
However, a recent study from Japan showed that high serum tAP levels were independently associated with the incidence of hip fracture and also with mortality in patients on long-term hemodialysis therapy.
Another approach could consist in the use of bAP iso- forms or other, yet unknown bone-derived biomarkers that could allow better discrimination in the future.
Serum 25 OH vitamin D measurement allows detection of vitamin D insufficiency and deficiency. Very low levels may be associated with osteomalacia.
A possible diagnostic value of serum FGF23 in the differential diagnosis of high versus low bone turnover and normal versus abnormal mineralization has been suggested but need further studies to confirm.
Increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes, respectively. No such link has been reported so far in patients with CKD. The relation of serum sclerostin with bone for- mation and bone mass remains unclear.
X ray examination may allow detection of osteomalacia when Looser–Milkman zones are present. X-ray signs of osteitisfibrosa such as subperiosteal bone resorption, salt and pepper aspect of the skull, rugger jersey features of the spine, and cystic lesions characteristic of brown tumors are only observed in severe forms of the disease.
BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodys- trophy but is probably useful in the diagnosis of bone lossand the prediction of fractures in CKD.
Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure.
1.Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
At early stages ADB is predominant in most of bone biopsies ,ADB is mainly due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and uremic toxins .
2.Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease is a low bone turnover mostly occurs early in a significant proportion of patients with chronic kidney disease. The pathogenesis was low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis. The contributing factors initial predominance of bone turnover inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency , diabetes and uremic toxins contribute to ABD. The increasing use of active Vitamin D in the subsequent decade was an etiological factor in the pathogenesis of ABD. Oral treatment with aluminum containing phosphate binders was a contributing factor. Other risk factor for ABD include advanced age, diabetes , metabolic acidosis, and alcoholism.
3.Describe changes of bone related parameters with progression of chronic kidney disease.
They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized under the term “uremic toxins”; decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of aKlotho. FGF23 processing appears to change with CKD progression. Although circulating FGF23 undergoes cleavage in patients with normal kidney function and in those with mild CKD, most circulating FGF23 in dialysis patients is in its full-length formThey may undergo oxidation, AGE-transformation, or carbamylation, which also may greatly alter biologic activity .
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The biocehmical diagnosis of diffrent types of ROD is mainly based on PTH and AP. (High PTH and AP are predictive for high turnover)
-Serum 25 OH Vitamin D , benefits in osteomalacia
-increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes respectivly.
Imaging:
BMD by dual energy X ray absorptiometry (DXA) cannot tell the diffrence between diffrent types of ROD but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD.
Quantitative CT provides more precise information but is costly and associated with exposition to high radiation .
The distribution of ROD types was reported in earlier versus recent bone biopsy studies.
Malluche et al, In 1976
a) Evidence of excess PTH.
b) Prevalence of woven osteoid.
c) Osteitis fibrosa, even in the early stages of CKD.
d) Osteoclastic resorption was abnormally high when eGFR < 50, and endosteal fibrosis if eGFR < 30.
e) Evidence of mineralization defect, (osteomalacia), in many patients.
Coen et al, in 1996
a) Normal bone in 10 patients.
b) ABD in 9 patients, (-ve for aluminum staining), in early CKD stages.
c) Mild mixed osteodystrophy in 26 patients.
d) Predominant osteomalacia in 7 patients ( in more advance CKD).
e) Advanced mixed osteodystrophy in 22 patients.
f) Predominant hyperparathyroidism I 2 patients.
Barreto et al; In 2014
a) CKD S2,3 had a remarkably low bone formation, with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time.
b) CKD S4, 5 had higher osteoiod volume, and bone formation rate, higher osteoclast surface, fibrosis, and lower mineralization lag time.
c) No bone aluminum staining.
d) None received Ca-based Pi binder, vitD derivatives.
e) No malnutrition was reported in any case.
The pathogenesis and contributing factors of ADB in patients with CKD.
Pathophysiology and factors associated or contributed to ABD
Changes of bone related parameters with progression of chronic kidney disease.
a) Decrease bone formation, and mineralization.
b) Increase bone resorption.
a) Incraese bone formation and resorption.
b) Normal bone mineralization.
a) Increase bone formation.
b) Normal mineralization.
a) Incraese bone formation.
b) decrease bone resorption.
a) Decrease bone formation.
a) Decrease bone resorption and mineralization.
a) increase bone formation and resorption.
a) Increase bone formation and resorption.
Diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
thanks dr Kamal for your excellent comprehensive effort
in addition, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
1- Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Pathogenesis: ADB is mainly due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxins leading to repression of osteocyte Wnt/ b-catenin signaling and increased expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP4.
Risk factors
Endogeneous, patient-related factors: Age, sex, Ethnicity/genetic factors
Exogenous factors: Nutritional status, Phyiscal activity, Drugs-vitamin D supplementation, immune suppressive agent, Toxins e.g alcohol
+ Peritoneal dialysis, High dialysate Ca, Aluminum overload, Metabolic acidosis, Parathyroid surgery.
2- Describe changes of bone related parameters with progression of chronic kidney disease:
Bone structure, static & dynamic aspects
Early CKD: Low bone formation rates, Low osteoid voulme, Low osteoblast surface, High mineralization lag time
Advanced CKD: Osteomalacia, High value of osteoid volume, osteoblast surface, & bone formation rate, High osteoclast surface, fibrosis volume, Low mineralization lag time
Increased expression of bone protein: Sclerostin, FGF-23, PTH, Osteoprotegerin, Osteocalcin, Dentin matrix protein 1(DMP1). Matrix extracellular phosphoglycoprotein (MEPE)
Decreased expression other proteins: Renal Klotho, VDRA
3- Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD:\
Biomarkers:
1.PTH & Alkaline phosphatase (tAPT, bAPT): The predictive value for the diagnosis bone turn over is limited
2.Vitamin D level: Help in the diagnosis of osteomalacia
3.FGF23: Need further studies
4.Slerostin: The role is still unclear
B.Bone derived-collagen biomarkers
1.PINP for bone formation
2.TRAP-5b for bone resorption
Imaging:
1.X-ray: It is only significant in advanced1.e., subperiosteal bone resorption, salt& pepper skull appearance, Rugger Jersey features of the spine, cystic changes.
2.DXA scan: For BMD & osteoporosis
3.Quantitative Computed Tomography (QCT): More sensitive & specific, The problem is the cost & radiation exposure
4- Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies:
thanks dr Mahmoud for your comprehensive answers
jCompare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Malluche et al. performed a bone histomorphometry study in 50 patients, CKD stages 2 to 5The bone biopsies revealed evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid. These findings were compatible with an early stimulatory effect of PTH in the skeleton.
In 1996, Coen et al.47 reported findings of a cross sectional, retrospective bone histomorphometry study in 76 unselected CKD patients on conservative treatment, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl. The study reported that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
2014, Barreto et al.61 proceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy. Notably, The most striking finding was that patients with early CKD exhibited remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time.
1-Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies
The research on the various types of renal osteodystrophy has primarily focused on patients with ESRD. Osteitis fibrosa and mixed uremic osteodystrophy were thought to be the most common types, with osteomalacia being uncommon.The predominance of these two types of renal osteodystrophy was certainly true for patients with ESRD in the 1960s and early 1970s, and in the 1980s, at least in many parts of the world. This new disease was characterized by unusual types of osteomalacia or adynamic bone disease was present especially in early of disease and found by bone biopsy.
.
2-Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease is a low bone turnover mostly occurs early in a significant proportion of patients with chronic kidney disease.the pathogenesis was low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis.The contributing factors initial predominance of bone turnover inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency , diabetes and uremic toxins contribute to ABD. The increasing use of active Vitamin D in the subsequent decade was an etiological factor in the pathogenesis of ABD. Oral treatment with aluminium containing phosphate binders was a contributing factor. Other risk factor for ABD include advanced age, diabetes , metabolic acidosis, and alcoholism.
3-Describe changes of bone related parameters with progression of chronic kidney disease.
Changes in serum calcium, phosphorus, and magnesium levels occur progressively and depend on the type of nephropathy, CKD stage and other factors.Metabolic acidosis or alkalosis may occur, with acidosis being more common.
Serum or tissue concentrations of various bone markers may increase progressively, including PTH, AP, TRAP-5b, FGF23, osteocalcin, osteoprotegerin and sclerostin.increases in advanced glycation end products and oxidative stress have been observed, as well as the accumulation of uremic toxins.
serum concentrations of vitamin D may decrease progressively, as well as aKlotho.
4-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The most commonly used parameters as diagnostic and prognostic are PTH and alkaline phosphatase,calcium and phosphorus but their clinical value is limited especially in differentiation between normal and mild low or high bone turnover. VIT D level: can help in diagnosis of osteomalacia wih very low level.
imaging studies include :-
a-X-ray in osteomalacia, and subperiosteal bone resorption, salt&pepper skull finding, rugger jeresy fracture of the spine, and cystic lesoin in the skull in osteitis fibrosa
DXA can differentaite between types of renal ostedystrophy
quantitative CT
thanks dr Rabab for your great effort
1-Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Malluche et al. performed a bone histomorphometry study in 50 patients, CKD stages 2 to 5The bone biopsies revealed evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid. These findings were compatible with an early stimulatory effect of PTH in the skeleton.
In 1996, Coen et al.47 reported findings of a cross sectional, retrospective bone histomorphometry study in 76 unselected CKD patients on conservative treatment, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl. The study reported that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
2014, Barreto et al.61 proceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy. Notably, The most striking finding was that patients with early CKD exhibited remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time.
3-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
while addressing predictors of bone loss, Malluche etal reported that QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis
in harmony, West etal reported that decreased BMD by QCT was associated with increased risk of low-trauma clinical fractures.
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
In clinical practice, the biochemical diagnosis of the different types of renal osteodystrophy is mainly based on serum concentrations of PTH and alkaline phosphatases, either tAP or bAP. However, the predictive value of the circulating levels of PTH and tAP or bAP for bone turnover is limited.In particular, it remains impossible to discriminate normal from moderately low or moderately high bone turnover in patients with CKD without proceeding to a bone biopsy.
Bone-derived collagen-based biomarkers were not found to be useful in predicting histo- morphometry, fractures, and bone mineral density (BMD) in an analysis made by the Kidney Disease: Improving Global Outcomes group in 2009.
a recent study from Japan showed that high serum tAP levels were independently associated with the incidence of hip fracture and also with mortality in patients on long-term hemodialysis therapy.
Serum 25 OH vitamin D measurement allows detection of vitamin D insufficiency and deficiency. Very low levels may be associated with osteomalacia.
A possible diagnostic value of serum FGF23 in the differential diagnosis of high versus low bone turnover and normal versus abnormal mineralization has been suggested.
Increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes, respectively.
The noninvasive diagnosis of early changes in bone structure by imaging techniques is extremely limited.
X-Ray examination may allow detection of osteomalacia when Looser–Milkman zones are present. X-ray signs of osteitis fibrosa such as subperiosteal bone resorption, salt and pepper aspect of the skull, rugger jersey features of the spine, and cystic lesions characteristic of brown tumors are only observed in severe forms of the disease.
BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodystrophy but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD.
Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure.
Perhaps combinations of collagen-based biomarkers with imaging techniques might be most useful for fracture prediction.
They found that the highest tertiles of bone formation marker P1NP and resorption marker TRAP-5b were associated with prevalent fracture. In addition, the combination of the highest tertile of s-P1NP or TRAP-5b with femoral neck t-score assessed by DXA improved fracture discrimination over the t-score alone.
Describe changes of bone related parameters with progression of chronic kidney disease.
They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin;variable increases in advanced glycation end products (AGEs),oxidative stress markers including advanced oxidation protein products,and protein carbamylation products;increases in numerous other compounds summarized under the term “uremic toxins”;decreases in serum concen- trations of 25 OH vitamin D and 1,25 diOH vitamin D;and decreases in serum and or tissue concentrations of aKlotho.FGF23 processing appears to change with CKD progression. Although circulating FGF23 undergoes cleavage in patients with normal kidney function and in those with mild CKD,most circulating FGF23 in dialysis patients is in its full-length form.It remains to be seen whether CKD-associated alterations in mineral and endocrine metabolism or other factors are responsible for this change in FGF23 catabolism. The serum levels of secreted frizzled- related protein 4 (sFRP4) do not change with the progression of CKD or the development of hyperphosphatemia.Finally, the role of circulating Dickkopf-1 (Dkk1) is still uncertain, with either no changesor a slight decreaseof mean serum values in patients with CKD.
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
In 1996, Coen et al.reported findings of a cross- sectional, retrospective bone histomorphometry study in 76 unselected Italian CKD patients on conservative treatment. The main findings were normal bone in 10 patients, low-turnover, adynamic bone disease in 9 (all negative for histochemical aluminum staining), mild mixed osteodystrophy in 26, predominant osteomalacia in 7, advanced mixed osteodystrophy in 22, and predominant hyperparathyroidism in 2 .
patients with adynamic bone disease had a less severe degree of CKD than the other subgroups, with intact PTH values above the upper normal limit, and normal serum calcium.
Osteomalacia was found in patients with more advanced CKD stages, together with a tendency toward hypocalcemia and more severe metabolic acidosis.
Based on these findings the authors postulated that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
Adynamic bone is predominantly defined by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis.The true prevalence of the adynamic bone condition in CKD is unknown because of a lack of consensus in its definition and diagnosis, with a reported prevalence range of 5% to 50% in dialysis patients.
The patients also had lower serum intact PTH levels than those with other types of renal osteodystrophy, and they were receiving calcium carbonate treatment for the control of hyperphosphatemia. Adynamic bone disease in patients with CKD was mainly attributed by them and others to overtreatment of secondary hyperpara- thyroidism with PTH-lowering agents or relative or absolute hypoparathyroidism following surgical parathyroidectomy.
Cohen-Solal et al.suggested that in the absence of aluminum overload this type of renal osteodystrophy might be due to overtreatment with vitamin D (or its derivative calcidiol), a subsequent increase in serum calcitriol, and excessive lowering of serum PTH. Since circulating PTH levels have generally been found to be higher than normal even in CKD patients with adynamic bone disease, albeit to a lesser extent than in CKD patients with osteitis fibrosa or mixed bone disease,resistance to the skeletal action of PTH is another possible explanation,due to PTH/PTHrp receptor downregulation in CKD or other causes.
In the past, oral treatment with aluminum-containing phosphate binders was considered to be another culprit .Although clearly involved in a minority of patients—including the very young,those with inflammatory bowel disease, and those ingesting high amounts of fruits or being on citrate treatment,the importance of oral aluminum overload in individuals with CKD not yet on dialysis has probably been overestimated. Other factors favoring the occurrence of low- turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, and alcoholism.
thanks dr Asmaa for your omprehensive answers
moreover, uremi toins also play important role in the pathogenesis of ADB THROUGH inhibition of Wnt/b-catenin signaling ad stimulaton of receptor activator of nuclear factor-kB ligand (RANKL).
Finally, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
The first description of osteitis fibrosa cystica by Davies in 19151 and the discovery by Bauer and his colleagues of its association with parathyroid gland
overactivity in 1930.
Albright’s group postulated in 1937 that phosphate retention and concomitant blood calcium lowering in patients with chronic kidney disease (CKD) might cause parathyroid hyperplasia and renal osteitis fibrosa.
The term renal osteodystrophy was coined in the 1940s.
The subsequent elegant studies by Bricker and Slatopolsky et al. led to the “trade-off hypothesis.” It suggests that in the setting of CKD the progressive loss of functioning nephrons brings into play a number of compensatory mechanisms, including an increase in parathyroid hormone (PTH) secretion in response to the progressive inability of the kidneys to excrete appropriate amounts of phosphate, delaying the occurrence of hyperphosphatemia.
This therapy led to the common belief that osteitis fibrosa and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy observed as nephropathies progress from early to more advanced stages of CKD.
the situation changed dramatically in the 1980s, at least in many regions of the world, as a consequence of aluminum intoxication. This new disease was mainly, although not exclusively, observed in patients undergoing long-term hemodialysis treatment.
Another possible etiologic factor in the pathogenesis of adynamic bone disease was the increasingly vigorous use of active vitamin D sterols and analogs in the subsequent decade.
The term CKD-MBD, a systemic disorder due to CKD that is manifested by either 1 or a combination of the following: abnormalities of calcium, phosphorus, PTH, or vitamin D metabolism; abnormalities in bone turnover, mineralization, volume, linear growth, or strength; and vascular or other soft tissue calcification, then developed.
According to this definition, renal osteo- dystrophy is an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by bone histomorphometry.
this question actually targets the bone biopsy studies
Malluche et al. performed a bone histomorphometry study in 50 patients, CKD stages 2 to 5The bone biopsies revealed evidence of PTH excess, with empty osteoclastic lacunae and woven osteoid. These findings were compatible with an early stimulatory effect of PTH in the skeleton.
In 1996, Coen et al.47 reported findings of a cross sectional, retrospective bone histomorphometry study in 76 unselected CKD patients on conservative treatment, with serum creatinine levels ranging from 1.2 to 11.4 mg/dl. The study reported that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, which appears with the development of skeletal resistance to PTH. It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
2014, Barreto et al.61 proceeded to a post hoc analysis of a previously reported cross-sectional study in patients with CKD stages 2 to 5 who had undergone a bone biopsy. Notably, the most striking finding was that patients with early CKD exhibited remarkably low bone formation rates with low osteoid volume, low osteoblast surface, and greatly prolonged mineralization lag time.
Explain diagnostic and prognostic value of bone biomarkers
and imaging techniques in patients with CKD-MBD
the most commonly used parameters are PTH and alkaline phosphatase, but their clinical value is limited especially in differentiation between normal and mild low or high bone turnover.2- 25(oH) VIT D: can help in diagnosis of osteomalacia wih very low level3- value of FGF-23 measurement is still questionable
imaging studies include :-
a-X-ray, LOOSER-MILKMAN zones in osteomalacia, and subperiosteal bone resorption, aslt&pepper skull finding, rugger jeresy fracture of the spine, and cystic lesoin in the skull in osteitis fibrosa
b-DXA can differentaite between types of renal ostedystrophy
c- quantitative CT
thanks dr Ahmed
while addressing predictors of bone loss, Malluche etal reported that QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis
in harmony, West etal reported that decreased BMD by QCT was associated with increased risk of low-trauma clinical fractures.
1-. Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
2. Explain the pathogenesis and contributing factors of ADB in
patients with CKD.
3. Describe changes of bone related parameters with
progression of chronic kidney disease.
4. Explain diagnostic and prognostic value of bone biomarkers
and imaging techniques in patients with CKD-MBD.
THE DISTRIBUTION OF ROD TYPES classified AS TMV
1- TURNOVER OF BONE
—Normal
–low( adynamic turnover)
—high turnover
2- MINERALIZATION
— bone marker level as ca -pi- pth-vitd -mag – .
3- VOLUM
—high or low density
Turn over means the
balance between activity of osteoclast and osteoblast activity
In earlier study as
In1976, Malluche et al
the authors were unable to recognize a correlation between the nature of renal disease and the severity of histologic lesions. They concluded that despite the absence of frankly increased numbers of osteoclasts, the accumulation of empty resorption cavities as well as the appearance of woven osteoid even in early CKD stages was compatible with an early stimulatory effect of PTH in the skeleton
in 1996, Coen et al.
patients with adynamic bone disease had a less severe degree of CKD than the other subgroups, with intact PTH values above the upper normal limit, and normal
serum calcium.
Osteomalacia was found in patients with more advanced CKD
stages, together with a tendency toward hypocalcemia and more severe metabolic
acidosis.
A GFR of 20 ml/min was indicative of a demarcation line between the patients with osteomalacia and those with adynamic bone disease. Based on these findings the authors postulated that adynamic bone disease in patients with mild to moderate CKD corresponds to a form of renal osteodystrophy separate from osteomalacia, whichappears with the development of skeletal resistance to PTH.
It might represent a transient stage on the way toward hyperparathyroid bone disease of increasing severity with the progression of CKD.
The 2 reports above appear to be contradictory, at least in part, especially with respect to the prevalence of osteomalacia and adynamic bone disease in CKD patients not yet on dialysis. Reports by other research groups of that time do not allow further clarification of this issue.
Thus Dahl et al. reported that osteomalacia was extremely rare in the predialysis stage, while Mora Palma et al. found a high percentage of cases with osteomalacia, mainly in association with chronic tubulointerstitial nephritis and prevailing metabolic acidosis.
The types of underlying nephropathy responsible for a more or less rapid progression of CKD
and accompanying metabolic and endocrine abnormalities probably explain these
differences in prevalence. Whether oral intake of aluminum-containing phosphate
binders has contributed to the osteomalacia in at least some of these patients
is unclear.
Finally, different
diagnostic criteria used to define osteomalacia may also account for the observed
difference.
Adynamic bone
is predominantly defined by low or absent bone formation in conjunction with
thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and
minimal marrow fibrosis.
The true prevalence
of the adynamic bone condition in CKD is unknown because of a lack of consensus
in its definition and diagnosis, with a reported prevalence range of 5% to 50%
in dialysis patients.
In patients
with advanced CKD Hutchison et al. and Hernandez et al. observed a prevalence
of 28% and 30%, respectively, thus higher than Coen et al. Their patients also
had lower serum intact PTH levels than those with other types of renal
osteodystrophy, and they were receiving calcium carbonate treatment for the
control of hyperphosphatemia
Adynamic bone disease
in patients with CKD was mainly attributed by them and others to overtreatment
of secondary hyperparathyroidism with PTH-lowering agents or relative or
absolute hypoparathyroidism following surgical parathyroidectomy
IN RECENT STUDIES AS
In 2014, Barreto et
al.
The observation by
Barreto et al. of a high prevalence of low-turnover, adynamic bone disease in
early stages of CKD is in agreement with the findings reported by Coen et al.
nearly 2 decades earlier. Thus, in contrast to common belief, high bone
turnover is not necessarily a continuous process starting with the very onset
of CKD, in direct association with a progressive increase in serum PTH. It
rather seems that in early CKD stages low bone turnover prevails in a large
number of patients
Findings from recent
studies
Experimental
studies in animals with CKD indicating the presence of low bone turnover at
early stages (especially stage 2) of CKD
Fang et al.,
2014 Ferreira et al., 2013
Under
experimental conditions of CKD with normal parathyroid status or with insulin
resistance and the metabolic syndrome, low-turnover bone disease will develop
initially,
whereas in the
presence of overt hyperparathyroidism, high-turnover bone disease will prevail
and in low-density
lipoprotein receptor knockout mice with the metabolic syndrome the
superimposition of mild CKD (stage 2) led to a further aggravation of
low-turnover bone diseas
the various forms of
renal osteodystrophy that are observed with the progression of CKD in human
patients depend on many other factors as sex hormone deficiency, reduced calcitriol
production, diabetes, increased synthesis of Wnt pathway inhibitors, and uremic
toxins accumulating in early stages of CKD.
Uremic toxins contribute to skeletal resistance to PTH and calcitriol and a decrease in calcitriol synthesis in early CKD, and to repression of Wnt/b-catenin signaling within osteocytes in conjunction with increased expression or circulating levels of Wnt pathway antagonists such as sclerostin, Dkk1, and sFRP4, together with increased osteoclast activity such as receptor activator of nuclearfactor-kB ligand (RANKL)
Conclusion
clinical and experimental evidence has been accumulating in favor of the development of low-turnover bone disease in early stages of CKD, as a result of resistance to the action of PTH and several other mechanisms.
the role of uremictoxins such as indoxyl sulfate and of a repression of the osteocyte ,Wnt/b-catenin signaling pathway in the initial stage of renal osteodystrophy
diagnostic and prognostic value of bone biomarkers and imaging techniques in patients withCKD-MBD.
1- biochemical marker used are
–serum
concentrations of PTH and alkaline phosphatases, either tAP or bAP.
Plus bone biopsy
also serum 25 OH vit D and FGF-23
— serum sclerostin
increase levels were found to be associated with higher fracture risk in
patients with osteoporosis and type 2 diabetes, respectively. No such link has
been reported so far in patients with CKD. The relation of serum sclerostin
with bone formation and bone mass remains unclear
2- imaging
X-ray examination
allow detection of osteomalacia when Looser–Milkman zones are present.
X-ray signs of
osteitis fibrosa such as subperiosteal bone resorption, salt and pepper aspect
of the skull, rugger jersey features of the spine, and cystic lesions
characteristic of brown tumors are only observed in severe forms of the disease
## Bone Mineral
Density (BMD) by dual-energy X-ray absorptiometry
(DXA) cannot
discriminate between the different types of renal osteodystrophy but is
probably useful in the diagnosis of bone loss and the prediction of fractures
in CKD.
###Quantitative
computed tomography (QCT) provides more precise information but is expensive
thanks dr Elsayed for your effort
you have a missed question
Describe changes of bone related parameters with progression of chronic kidney disease.
increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin
decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of α-Klotho.
no change secreted frizzled related protein 4 (sFRP4) & Dickkopf-1 (Dkk1)
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
-Renal osteodystrophy is a change in bone morphology in CKD Patients
-Osteitis fibrosa and mixed osteodystrophy were thought to be the most common types in the past.
-Unusual types of osteomalacia or adynamic bone disease were reported in 1980s.
-Recent studies shows that adynamic bone disease with low bone turnover occurs early in a significant number of patient then later
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease with low turnover occurs early in a significant proportion of patients with chronic kidney disease. The initial predominance of bone turnover inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency , diabetes and uremic toxins contribute to ABD. The increasing use of active Vitamin D in the subsequent decade was an etiological factor in the pathogenesis of ABD. Oral treatment with aluminium containing phosphate binders was a contributing factor. Other risk factor for ABD include advanced age, diabetes , metabolic acidosis, and alcoholism.
Describe changes of bone related parameters with progression of chronic kidney disease.
Changes in serum calcium, phosphorus, and magnesium levels occur progressively and depend on the type of nephropathy, CKD stage and other factors.
-Metabolic acidosis or alkalosis may occur, with acidosis being more common.
Serum or tissue concentrations of various bone markers may increase progressively, including PTH, AP, TRAP-5b, FGF23, osteocalcin, osteoprotegerin and sclerostin.
-increases in advanced glycation end products and oxidative stress markeers have been observed, as well as the accumulation of uremic toxins.
-serum concentrations of vitamin D may decrease progressively, as well as aKlotho.
-FGF23 processing changes with CKD progression, with most circulating FGF23 in dialysis patients being in its full length form
-Secreted frizzled related protein 4(sFRP4) levels do not change with the progression of CKD or the development of hyperphosphatemia
-The role of DKK1 in bone realted CKD is still uncertain.
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The biocehmical diagnosis of diffrent types of ROD is mainly based on PTH and AP. (High PTH and AP are predictive for high turnover)
-Serum 25 OH Vitamin D , benefits in osteomalacia
-increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes respectivly.
Imaging:
BMD by dual energy X ray absorptiometry (DXA) cannot tell the diffrence between diffrent types of ROD but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD.
Quantitative CT provides more precise information but is costly and associated with exposition to high radiation .
thanks dr Nour for your excellent effort
3-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
while addressing predictors of bone loss, Malluche etal reported that QCT identified prospectively more bone loss at the hip than DXA. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis
in harmony, West etal reported that decreased BMD by QCT was associated with increased risk of low-trauma clinical fractures.
2- pathogenesis of ADB
in addition, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
**Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
It is commonly known that osteitis fibrosa cystica and mixed osteodystrophy are the most common form of renal osteodystrophy in patients with CKD, which is a high turnover bone disease due to hyperparathyroidism while the mixed type is caused by vitamin D deficiency that cause mineralization defects. More recent studies show adynamic bone disease which is a low turn over bone disease occur in the early stages of ckd in significant number of patients, then later on high turnover bone disease occur when the PTH start to increase when it overcome the peripheral PTH resistance and the inhibitory factors on bone formation.
**Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease characterized by low or absent bone formation, thin osteid seams, decrease osteoblast and osteoclast and minimal bone fibrosis, it occurs due to overtreatment of secondary hyperparathyroidism by PTH lowering agents or hypoparathyroidism after parathyroidectomy.
Risk factors are :
Advanced age, DM, immunosuppressive drugs, malnutrition, aluminum overload, genetic factors, long term antiresorptive drugs (biphosphonate), alcoholism, metabolic acidosis, hypoparathyroidism, resistant to PTH.
**Describe changes of bone related parameters with progression of chronic kidney disease.
S. Ca, phosphorous and Mg increase or decrease depending on type of nephropathology and ckd stage
Metabolic acidosis
Progressive increase in PTH
Total or bone specific alkaline phosphotase procollagen type 1 N terminal propeptides tarterate resistance acid phosphotase 5b
High FGF23
High Osteocalcin
High Osteopotegrin
Sclerotin
Advanced glycation end product
Advanced oxidation protein products
Protein carbamylation products. Decrease 1,25 OH and 25 OH vitamin D
Decrease klotho
**Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
PTH, alkaline phosphotase total or bone specific alkaline phosphotase for diagnosis of different types of renal osteodystrophy
S. 25 OH vitamin D to detect deficiency which is related to osteomalacia.
FGF23 level in high and low turnover, and in normal and abnormal mineralization
S. Sclerostin which increase when there is a high risk of fracture in patient with osteoporosis and in type 2DM.
TRAP – 5b detect bone loss in ckd.
X ray helps in diagnosis of osteomalacia when there is looser zone, and in osteitis fibrosa and features of hyperparathyroidism like subperiosteal resorption, rugger jersey appearance, salt and pepper in the skull and brown tumor.
DXA scan for diagnosis of bone mineral density and presence of osteoporosis and bone loss.
Quantitative CT for detection of bone loss and fractures but is expensive and high radiation.
thanks dr Israa for your great effort
2- the pathogenesis of ADB
Moreover, uremic toxins also play important role in the pathogenesis of ADB through the following mechanisms:
• skeletal resistance to PTH and calcitriol
• decrease in calcitriol synthesis
• repression of Wnt/b-catenin signaling within osteocytes
• increased expression or circulating levels of Wnt pathway antagonists such as sclerostin, Dkk1, and sFRP4,
• increased osteoclast activity such as receptor activator of nuclear factor-kB ligand (RANKL).
Finally, the dialysis treatment modality also plays a role. It has long been known that high dialysate calcium concentrations suppress PTH levels and favor the occurrence of both adynamic bone disease and vascular calcification
1.Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
For the diagnosis of the various types of renal osteodystrophy, bone biopsy remains the gold standard. Renal osteodystrophy is a change in bone morphology in CKD patients. It is one of the skeletal components of the systemic disorder CKD-MBD that can be quantified using bone histomorphometry. For decades, research on the various types of renal osteodystrophy has primarily focused on patients with ESRD. Osteitis fibrosa and mixed uremic osteodystrophy were thought to be the most common types, with osteomalacia being uncommon.
The predominance of these two types of renal osteodystrophy was certainly true for patients with ESRD in the 1960s and early 1970s, and in the 1980s, at least in many parts of the world. This new disease was characterized by unusual types of osteomalacia or adynamic bone disease.
2.Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease with low bone turnover occurs early in a significant proportion of patients. This could be due to the initial predominance of bone turnover-inhibitory conditions such as PTH resistance, low calcitriol levels, sex hormone deficiency, diabetes, and uremic toxins. The increasing use of active vitamin D in the subsequent decade was an etiologic factor in the pathogenesis of adynamic bone disease. There is significant overlap between the end of the aluminum epidemic and the excessive use of active vitamin D compounds. the prevalence of this drug induced disease has declined rapidly as a result of improved dialysis water purification and a decrease in the prescription of aluminum-containing phosphate chelators. ADB is characterized primarily by low or absent bone formation, thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis. Because of a lack of agreement in its definition and diagnosis, the true prevalence of the adynamic bone condition in CKD is unknown, with a reported prevalence range of 5% to 50% in dialysis patients.
Oral treatment with aluminum-containing phosphate binders was a contributing factor. Other risk factors for ADB include advanced age, diabetes, metabolic acidosis, and alcoholism.
3.Describe changes of bone related parameters with progression of chronic kidney disease.
Changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on the underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), Increases in procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized as “uremic toxins.
The processing of FGF23 appears to change as CKD progresses. Although circulating FGF23 is cleaved in patients with normal kidney function and mild CKD, the majority of FGF23 in dialysis patients is in its full-length form. They may be oxidized, AGE-transformed, or carbamylated, all of which can significantly alter biologic activity.
4-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD
Biomarkers
1.PTH & Alkaline phosphatase (tAPT, bAPT)
2.Vitamin D level
3.FGF23
4.Sclerostin
6.PINP for bone formation
7.TRAP-5b for bone resorption
C.Imaging
1.X-ray
2.DXA scan
3.Quantitative Computed Tomography (QCT)
thanks dr Hassan for your comprehensive answers
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Describe changes of bone related parameters with progression of chronic kidney disease.
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
1.Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Bone biopsy remains the gold standard for the diagnosis of the different types of renal osteodystrophy.Renal osteodystrophy is an alteration of bone morphology in patients with CKD. It is one measure of the skeletal component of the systemic disorder of CKD-MBD that is quantifiable by bone histomorphometry.For decades the study of the different types of renal osteodystrophy has mainly focused on patients with ESRD. Osteitis fibrosa and mixed uremic osteodystrophy were considered to be the predominant types, with osteomalacia being of low prevalence.The predominance of these 2 forms of renal osteodystrophy was certainly true for patients with ESRD in the 1960s and early 1970s, in the 1980s, at least in many regions of the world, This new disease was observed characterized by peculiar types of osteomalacia or adynamic bone disease,and often accompanied by microcytic anemia and encephalopathy.2.Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Adynamic bone disease characterized by low bone turnover occurs first, at least in a significant proportion of patients.This could be due to the initial predominance of bone turnover–inhibitory conditions such as resistance to the action of parathyroid hormone (PTH), reduced calcitriol levels, sex hormone deficiency, diabetes, and, last but not least, uremic toxinsEtiologic factor in the pathogenesis of adynamic bone disease was the increasingly vigorous use of active vitamin D sterols and analogs in the subsequent decade,. With considerable overlap between the tail end of the aluminum epidemic and the overzealous use of active vitamin D compounds. Fortunately, the incidence of this “iatrogenic” disease has rapidly waned as a consequence of better dialysis water purification and the declining prescription of aluminum-containing phosphate chelators to patients with CKD. Adynamic bone is predominantly defined by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis. The true prevalence of the adynamic bone condition in CKD is unknown because of a lack of consensus in its definition and diagnosis, with a reported prevalence range of 5% to 50% in dialysis patients.. In patients with advanced CKD Hutchison et al. and Hernandez et al. observed a prevalence of 28% and 30%. Renal osteodystrophy might be due to overtreatment with vitamin D (or its derivative calcidiol), a subsequent increase in serum calcitriol, and excessive lowering of serum PTH. Since circulating PTH levels have generally been found to be higher than normal even in CKD patients with adynamic bone disease, albeit to a lesser extent than in CKD patients with osteitis fibrosa or mixed bone disease, resistance to the skeletal action of PTH is another possible explanation, due to PTH/PTHrp receptor downregulation in CKD or other causes. In the past, oral treatment with aluminum-containing phosphate binders was considered to be another culprit. Other factors favoring the occurrence of low turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, and alcoholism.
3.Describe changes of bone related parameters with progression of chronic kidney disease.
They include progressive changes in serum calcium, phosphorus, and magnesium levels (either increases or decreases depending on underlying type of nephropathy, CKD stage, and a variety of endogenous and exogenous factors); metabolic acidosis or—less frequently—metabolic alkalosis; a progressive increase in serum or tissue concentrations of PTH, total alkaline phosphatases (tAP) or bone-specific alkaline phosphatase (bAP), procollagen type 1 N-terminal propeptide (P1NP), tartrate-resistant acid phosphatase-5b (TRAP-5b), fibroblast growth factor 23 (FGF23), osteocalcin, osteoprotegerin, and sclerostin; variable increases in advanced glycation end products (AGEs), oxidative stress markers including advanced oxidation protein products, and protein carbamylation products; increases in numerous other compounds summarized under the term “uremic toxins”; decreases in serum concentrations of 25 OH vitamin D and 1,25 diOH vitamin D; and decreases in serum and or tissue concentrations of aKlotho. FGF23 processing appears to change with CKD progression. Although circulating FGF23 undergoes cleavage in patients with normal kidney function and in those with mild CKD, most circulating FGF23 in dialysis patients is in its full-length formThey may undergo oxidation, AGE-transformation, or carbamylation, which also may greatly alter biologic activity
4.Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
The biochemical diagnosis of the different types of renal osteodystrophy is mainly based on serum concentrations of PTH and alkaline phosphatases, either tAP or bAP. A recent study from Japan showed that high serum tAP levels were independently associated with the incidence of hip fracture and also with mortality in patients on long-term hemodialysis therapySerum 25 OH vitamin D measurement allows detection of vitamin D insufficiency and deficiency. Very low levels may be associated with osteomalacia. A possible diagnostic value of serum FGF23 in the differential diagnosis of high versus low bone turnover and normal versus abnormal mineralization has been suggestedIncreased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetesThe noninvasive diagnosis of early changes in bone structure by imaging techniques is extremely limited. X-ray examination may allow detection of osteomalacia when Looser–Milkman zones are present. X-ray signs of osteitis fibrosa such as subperiosteal bone resorption, salt and pepper aspect of the skull, rugger jersey features of the spine, and cystic lesions characteristic of brown tumors are only observed in severe forms of the disease.BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodystrophy but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD. Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure. The baseline serum biochemical parameters sclerostin and TRAP-5b were noninvasive independent predictors of bone loss in CKD patients on dialysis. Note, however, that bone strength as indirectly assessed by BMD and QCT, although being generally considered as the most important factor for fracture risk, is certainly not the only one in the occurrence of fractures in patients with CKD. Increased fragility, muscle weakness, and fall risk also play important roles.They found that the highest tertiles of bone formation marker P1NP and,resorption marker TRAP-5b were associated with prevalent fracture.
loss of nephron mass function lead to hyperparathyroidism due to phosphate retention.
with progression of renal disease .
renal osteodystrophy occur characterized by :mineral bone disease as
adynamic bone disease, osteitis fibrosa cystica , Osteomalacia.
CKD-MBD, characterized by lab abnormalities, bone turnover and vascular and soft tissue calcification.
Bone biopsy and histomorphometry is the best for diagnosis of ROD .
2-Explain the pathogenesis and contributing factors of ADB in patients with CKD.
factors are :
3-Describe changes of bone related parameters with progression of chronic kidney disease.
with progression of renal disease:
decrease : Renal Klotho .vit D ,S.Ca
with low bone mineralization and bone volume
.higher fracture risk in patients with osteoporosis .
4-Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD.
earlier: trade-off hypothesis: in CKD, the gradual loss of working nephrons triggers a number of compensatory mechanisms, such as an increase in parathyroid hormone (PTH) secretion in response to the kidneys’ inability to get rid of enough phosphate, which delays the onset of hyperphosphatemia.
osteitis fibrosa , osteomalacia, or adynamic bone disease, and mixed uremic osteodystrophy are the predominant forms of renal osteodystrophy, observed as nephropathies progress
CKD-MBD, a systemic disorder caused by CKD, is characterized by abnormalities in calcium, phosphorus, PTH, vitamin D, bone turnover, mineralization, volume, linear growth, or strength, and vascular or other soft tissue calcification. Renal osteodystrophy is a CKD-related morphological change in the bones. Bone histomorphometry quantifies the skeletal component of CKD-MBD.
Little bone formation, narrow osteoid seams, diminished cellularity (osteoblasts and osteoclasts), and minimal marrow fibrosis characterize adynamic bone.
They treated hyperphosphatemia with calcium carbonate and had lower serum intact PTH levels than other renal osteodystrophies.
They believed that overtreatment of secondary hyperparathyroidism with PTH-lowering medications or relative or absolute hypoparathyroidism after surgical parathyroidectomy caused adynamic bone disease in CKD patients.
In the absence of aluminum overload, Cohen-Solal et al hypothesized that overtreatment with vitamin D (or its product calcidiol) may raise blood calcitriol and reduce serum PTH, causing renal osteodystrophy.
Factors favoring the occurrence of low-turnover bone disease are advanced age, diabetes mellitus, metabolic acidosis, vegetarian protein diets, physical activity, and alcoholism. Drugs such as corticosteroids and immunosuppressive agents given to patients with various types of renal disease may exert major negative effects on the bone.
Early CKD increases skeletal sclerostin expression. despite normal blood PTH levels, and ESRD increases it to a lesser extent despite increasing serum PTH. Dentin matrix protein 1 (DMP1), a member of the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, suppresses bone FGF23 expression, but its osteocytic expression was elevated in early CKD patients despite high osteocytic FGF23 production. Hence, DMP1 is unlikely to initiate bone FGF23 expression in CKD.
Pereira et al. recently examined the skeletal expression of FGF23, DMP1, and matrix extracellular phospho glycoprotein (MEPE) in 32 pediatric and young adult patients with CKD stages 2 to 5 using immunohistochemistry. All phases of CKD have higher bone FGF23 and DMP1 expression than controls.
Predialysis CKD and dialysis patients had similar bone FGF23 and DMP1 expression. CKD and controls expressed MEPE similarly. While all 3 proteins are expressed in osteocytes, their expression patterns vary greatly. CKD progression may increase phosphate load and bone DMP1 and FGF23 expression. Bone volume negatively correlated with bone MEPE expression.
These data suggest that FGF23 and DMP1 affect bone mineralization and MEPE bone volume. This theory needs additional research. Nevertheless, the rise in bone FGF23 and DMP1 expression implies early CKD-related osteocyte dysfunction.
-BMD by dual-energy X-ray absorptiometry (DXA) cannot discriminate between the different types of renal osteodystrophy but is probably useful in the diagnosis of bone loss and the prediction of fractures in CKD. Quantitative computed tomography (QCT) provides more precise information but is expensive and requires high radiation exposure.
-Serum PTH and alkaline phosphatases, (tAP or bAP) are used to biochemically diagnose renal osteodystrophy. Nevertheless, PTH and tAP/bAP levels do not predict bone turnover well.
-Serum FGF23 may help distinguish between high and low-bone turnover and normal and abnormal mineralization. This finding requires additional research.
-Increased serum sclerostin levels were found to be associated with higher fracture risk in patients with osteoporosis and type 2 diabetes, respectively. No such link has been reported so far in patients with CKD. The relation of serum sclerostin with bone formation and bone mass remains unclear
Compare the distribution of ROD types reported in earlier versus recent bone biopsy studies.
Explain the pathogenesis and contributing factors of ADB in patients with CKD.
Pathogenesis
Risk factors
Endogeneous, patient-related factors
Exogenous factors
Other factors
Describe changes of bone related parameters with progression of chronic kidney disease.
Bone structure, static & dynamic aspects
Early CKD
Advanced CKD
Increased expression of bone protein
Decreased expression other proteins
Explain diagnostic and prognostic value of bone biomarkers and imaging techniques in patients with CKD-MBD
A.Biomarkers
1.PTH & Alkaline phosphatase (tAPT, bAPT)
2.Vitamin D level
3.FGF23
4.Slerostin
B.Bone derived-collagen biomarkers
1.PINP for bone formation
2.TRAP-5b for bone resorption
C.Imaging
1.X-ray
2.DXA scan
3.Quantitative Computed Tomography (QCT)