Summarize the pathogenesis of adynamic bone disease.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
How to diagnose adynamic bone disease in patients with CKD?
How to prevent adynamic bone disease in patients with CKD?
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
After reading the article, do you think adynamic bone is always a disease?
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Cardiovascular complication
Increase fracture risk What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Normal mineralization and low bone volume decrease osteoblast and osteoclast.
Strength:
– The gold standard.
– Based on TMV score it assists identification of the metabolic bone state.
Drawbacks:
Limited experience
High cost
Patient acceptability
Lack of cutoffs How to diagnose adynamic bone disease in patients with CKD?
Diagnosis of ABD
– Normal or low iPTH
– Normal ALP
– Bone biopsy is a definite tool, but it is indicated when diagnosis could not be established with serum biomarkers. How to prevent adynamic bone disease in patients with CKD?
– Prevent over-suppression of PTH by injudicious use of vit D analogs, calcium-based phosphorus binders, and calcimimetics.
– In treatment of secondary, tertiary hyperparathyroidism, subtotal rather than total parathyroidectomy to avoid ABD.
– Not to start parathyroid suppression early in early CKD stages not.
– Frequent monitoring of iPTH, ALP or BALP while on treatment Criticize the use of romosozumab as osteoanabolic in patients with CKD.
It is a humanized monoclonal sclerostin that acts as an anabolic and antiresorptive for bone. Limited studies on advanced CKD patients. Concern about its safety regarding increased vascular calcification. However, a one-year study demonstrated its safety. After reading the article, do you think adynamic bone is always a disease?
Still unknown whether it is an adaptive mechanism to guard against bone resorption.
The pathogenesis of adynamic bone disease is multifactorial which include iatrogenic related with genetics? and low levels of circulating bone anabolic factors the circulating cytokines (IL -1,IL-6 AND TNF α) there are multiple risk factors also include diabetes, malnutrition, which common in ckd patients .and associated with high incidence of LBT
OVER USE OF CALCIUM AND VITAMIN D the detrimental effects of adynamic bone diseases on the patient’s health A dynamic bone disease ensues poor skeletal health , fragility of bone and diminished ability to restore damaged bone and can result in brittle bone which increases the fractures.. the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy bone biopsy with mineralized bone histology is a key to detecting different types of ROD .
Thin osteoid is the main feature differentiating ADB from the other LBT subgroup ‘‘osteomalacia’’.
Patients with ADB, bone histomorphometry, discover low bone turnover with the reduced number of both osteoblasts and osteoclasts, low bone volume coupled with normal mineralization.
Laboratory: TAP, BSAP, intact P1NP, and DKK-1 and bone resorption markers TRAP5b
iPTH
Radiological: DXA, QCT: there may be normal or decreased BMD. MRI:
Bone biopsy:
What are the detrimental effect of adynamic bone disease on patient health?
Adynamic Bone Disease can cause poor skeletal health, bone fragility and diminshed ability to restore damaged bone. Secondary mineralisaton as result of delayed bone remodellign can in long term lead to bone fractures. PTH has u shaped mortality curve and LBT being linked with low PTH means ABD. Various studies including DOPS show that ABD is associated with increased risk of mortality. ADB is linked to vascular calcification as bone cannot buffer extra calcium load which is linked to increased mortality and cardiovascular mortality.
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Features
low osteoblast,low osteoclast
low bone volume with normal mineralisation
thin osteoid
strength
most precise
give information about mineralisation ,volume and turnover
drawback- patient do not want to do it, high cost, complication discrepancy in diagnostic cut off
How to diagnose adynamic bone disease in CKD
Laboratory: decrease bone formation markers (TAP, BSAP, intact P1NP, and DKK-1) and bone resorption markers (TRAP5b) with increased sclerostin. iPTH <150 pg/ml has a sensitivity of 68.6% and a specificity of 61.2%.
Radiological: DXA, QCT: there may be normal or decreased BMD. MRI: assess bone microarchitecture.
Bone biopsy: bone histomorphometry decreased turnover, normal mineralization and decreased or normal bone volume.
How to prevent adynamic bone disease in patients with CKD?
Avoiding oversuppressing PTH by monitoring bone markers of formation and resorption
Controlling inflammation and addressing malnutrition
Avoiding Aluminiun Exposure
Criticize the use of romosozumab as osteoanabolic in patients with CKD. Romosozumab, sclerostin humanized monoclonal antibody, acts as an anabolic and anti- resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited and there was a cardiovascular concern that might be related to increased vascular calcification with its usage tho some studies show otherwise. in summary this area needs RCT
After reading the article, do you think adynamic bone is always a disease?
It can be a disease but it could also be an adaptation or evolution to progression to HBTo prevent bone loss
Summarise the pathogenesis of adynamic bone disease
It is complex and multifactorial and can be classed into iatrogenic factors, patient factors.
The pathophysiology of ABD relates to low circulating levels of bone anabolic factors like IGF1 and increased expression of bone turnover inhibitory factors such as sclerostin and dkk1 . it supresses bone formation via WNT/B-catenin signalling. Indoxyl sulphate a uraemic toxin has been linked to ABD and inhibits osteoclast function and differentiation. Inflammatory cytokines can also inhibit both bone forming and resorbing cells.
Factors that contribute to increase calcium load for example high calcium dialysate , Vitamin D sterols , calcium binders cause decrease PTH and therefore decrease bone formation as well as parathyroidectomy
Ageing, Diabetes Mellitus and malnutrition are risk factors for ABD
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab, sclerostin-humanized monoclonal antibody, acts as an anabolic and anti-resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited, as there was a cardiovascular concern that might be related to increased vascular calcification with its usage .Miller et al. reported on its efficacy in patients with mild to moderate CKD .Moreover, two recent studies demonstrated one-year romosozumab cardiovascular safety in Japanese HD patients.
How to prevent adynamic bone disease in patients with CKD?
Despite the underlying complex pathophysiology of ADB, its management is based mainly on the avoidance of risk factors associated with reduction of bone turnover, such as aluminum exposure, over-suppression of PTH secretion due to calcium overload, administration of high doses of vitamin D analogs, and/or calcimimetics. Moreover, factors that may contribute to PTH resistance, such as hyperphosphatemia, malnutrition, inflammation, and progression of CKD, among others, should also be targeted
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Bone biopsy with mineralized-bone histology is the cornerstone to detecting different types of ROD .Classification is mainly based on the turnover/mineralization/volume (TMV) system .Turnover represents the process of skeletal remodeling, attained by both bone resorption and formation. It is assessed using bone-formation rate, activation frequency, and the number of osteoclasts and osteoblasts. Mineralization reflects the calcification of bone collagen and is assessed using osteoid volume, osteoid thickness, and dynamic, tetracycline-based evaluation of mineralization lag time and osteoid-maturation time. Lastly is volume, which reflects the amount of bone per unit .In patients with ADB, bone histomorphometry reveals LBT with a reduced number of both osteoblasts and osteoclasts and low bone volume coupled with normal mineralization .Of note, the presence of a thin osteoid is the main feature differentiating ADB from the other LBT-subgroup ‘‘osteomalacia’’ .Interestingly, a different variant of ADB, characterized by low bone-formation rate in association with high osteoclastic resorption, was described. This variant might be a transitional phase between LBT and HBT .Additionally, Misof et al. reported that bone- mineralization density distribution increases and the lacunar size of the osteocytes decreases in patients with ADB. This novel tool might be helpful to discriminate hyperparathyroid bone from ADB .
Although bone biopsy is the most precise tool to assess metabolic bone disease, it has some limitations, including high cost, lack of expertise, and limited patient acceptability .Moreover, the wide discrepancy of the diagnostic cutoffs has led to significant differences in the classification of bone turnover .Selection bias, age, gender, and ethnicity, in addition to the definition of normal-range differences, might explain the inconsistencies. Ultimately, it is better to unify the used cutoffs in order to properly estimate the prevalence and type of ROD to improve therapeutic decisions
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Adynamic bone results in poor skeletal health, bone fragility, and diminished ability to
restore damaged bone .A crucial aspect of delayed remodeling is that it promotes more secondary mineralization, making the bone stiffer/tougher .However, in the long term, over-mineralization can induce brittle bone that increases the risk of atypical fractures .Moreover, suppression of bone turnover may cause microcracks, which are difficult to heal in the presence of low bone formation .The uncoupling of bone turnover with a relative predominance of resorption may also contribute to bone loss in patients with ADB and CKD .
Several studies have reported a J- or U-shaped association between PTH levels and mortality in patients on dialysis from different geographic areas .Several studies concluded that low PTH levels, indicative of LBT, were associated with a higher risk of mortality.
A Korean study reported that serum PTH < 150 pg/mL was an independent risk factor for infection-related mortality, compared to the target range of PTH 150–300 pg/mL in incident dialysis patients .In the CORES study, which included 16,173 Latin American HD patients, once again PTH < 150 pg/mL was associated with all-cause and cardiovascular mortality.
Summarize the pathogenesis of adynamic bone disease.
The pathophysiology of ADB is certainly multifactorial ,comprising patient-related and iatrogenic factors on a predisposed genetic background. A state of imbalance between the low circulating levels of bone anabolic factors (e.g., insulin-like growth factor (IGF)-I) and the increased expression of bone-turnover–inhibitory factors, such as sclerostin and Dickkopf-related protein-1 (Dkk-1), largely predominates. This imbalance ultimately suppresses bone formation through repression of WNT/β-catenin signaling .Moreover, uremic toxins may play a role in this setting. Uremic toxins are compounds that accumulate in the body as renal function declines, adversely affecting the function of multiple organs and systems. Indoxyl sulfate, a protein-bound uremic toxin (PBUT) generated by the gut microbiome from the metabolism of tryptophan, has been linked to LBT .Experimental evidence suggests that the gut-derived toxin indoxyl sulfate aggravates LBT and inhibits osteoclast function and differentiation; however, further clinical studies would be more conclusive .Of note, the circulating cytokines, for instance interleukin-1 (IL-1), IL-6, and tumor necrosis factor α (TNFα), have been supposed to directly impair bone-forming and -resorbing cells .
Patients on PD are more vulnerable to ADB due to high dialysate-calcium concentration and possibly increased glucose load .Aging, diabetes mellitus, malnutrition, and alcoholism have all been shown to be risk factors for the development of ADB .Aluminum overload resulting from contamination of HD water and non- judicious use of aluminum-containing phosphate binders represented a major culprit a few decades ago .In the 1980s, aluminum intoxication was the most prevalent cause of LBT in patients on dialysis .Aluminum significantly decreases both osteoclast and osteoblast activities and causes defective mineralization.
Imbalance state between the low circulating levels of bone anabolic factors, (insulin-like GF-1) and the increased expression of bone-turnover-inhibitory factors, (sclerostin, and Dkk-1).
This imbalance leads to an impression of bone formation through repression of WNT/B-catenin signaling.
Uremic toxins, (indoxyl sulfate) are linked to LBT and inhibit osteoclast function and differentiation.
Circulating cytokines, IL-6, and TNF impaired bone-forming and resorption cells.
Risk factors
a) PD. b) Older age. c) DM. d) Malnutrition-inflammation complex syndrome. e) Aluminum overload in HD. f) Vigrous use of oral Calcium, and vitD, high dialysate-Ca, and parathyroidectomy. g) Gonadal dysfunction. h) Hypothyroidism, (resistance to the bone-stimulating effect of PTH). i) Low vitD level, (suppress VDR expression). Impact of LBT on patient’s health
Poor skeletal health, bone fragility, and disrupted ability to restore damaged bone.
Overmineralization leads to brittle bone which can lead to atypical fractures.
Suppression of bone turnover leads to microcracks which have been difficult to be healed in the presence of low bone formation.
LBT patients had an 8-fold higher risk of fracture.
Lower PTH levels associated with ABD are associated with higher mortality and infection-related mortality rate.
Bone biopsy
Classification of ABD is mainly based on Turnover/mineralization/volume.
Turnover represents the skeletal remodeling and the results of both bone resorption and formation.
Mineralization reflects bone calcification and is assessed by bone osteoid (volume, thickness), and dynamic, tetracycline-based evaluation of mineralization.
In ABD bone histomorphometry reveals
a) LBT. b) Reduce the number of both osteoclasts and osteoblasts.
c) Low bone volume. e) Normal minelaization. f) Thin osteoid, (the main difference between ABD and LBT-subgroup) g) ABD variant may be related to the transition from HBT and LBT. h) Bone mineralization density distribution increases and the lacunar size of the osteocytes decreases.
Limitation
a) High cost. b) Lack of expertise. c) Limited patient accessibility.
d) Wide discrepancy of the diagnostic cut-off led to significant differences in the classification of bone turnover. e) Selection bias. f) Age, g) Gender. h) Ethnicity. i) Different normal ranges. Diagnosis of ABD in CKDI
Bone turnover markers provide a mild-to-moderate precision evaluation of bone health in CKD.
PTH; iPTH widely used biomarker for CKD-MBD monitoring, LBT is considered when iPTH < 150 (sensitivity 68.6% and specificity 61.2%), however the target (2-9-fold upper limit of normal does not exclude LBT).
Bone formation biomarkers;
a) BSAP, a biomarker of osteoid formation. b) Procollagen type 1 N-terminal (P1NP) and procollagen type 1 C-terminal propeptide (P1CP) are indicators of collagen synthesis rate, (P1NP is more sensitive). c) Bone-derived osteocalcin, (limited use in advance CKD). e) Sclerostin and Dkk-1; are soluble inhibitors of the Wnt-signaling pathway (the main promotor of bone formation) and the study showed a significant association between sclerostin and Dkk-1 and ABD.
Bone resorption biomarker;
a) Carboxy-terminal crosslinking telopeptide of type 1 collagen (CTX), is the reference bone resorption marker (limited use in CKD). b) Titerate-resistant acid phosphatase 5 b (TRAP5b), a higher level associated with after rating of cortical-bone loss, bone resorption, and bone histomorphometry parameter.
c) The receptor activator of nuclear factor-kB (RANK)/receptor activator of nuclear factor-kB ligand (RANKL)/osteoprotegerin (OPG) system is responsible for the fine integration between osteoblast and osteoclast.
SIBLING (small integrin-binding ligand N-linked glycoprotein) and SIRT1 (sirtuin 1) proteins are regulatory proteins in bone remodeling and mineralization.
Radiology
a) DXA (dual-energy X-ray Absorptiometry scan; with several limitations, (confounded results due to soft-tissue calcifications and osteoarthritis, but helpful to evaluate the bone microarchitecture which reflects the bone quality and strength. b) QCT; discriminates trabecular from cortical bone, but it failed to identify the bone-turnover activity and the ROD type. c) HR-pQCT; assess cortical and trabecular bone and microarchitecture. d) PET scan; bone tracer used in the assessment of bone turnover and osteoblast activity, bone formation rate, osteoblast, osteoclast, and mineralization surfaces, (sensitivity 76% and specificity 78%). e) MRI; a significant association between MRI and trabecular thickness and separation as well as mineralization and turnover parameters.
Bone biopsy.
Prevention of ABD in CKD
Avoid overtreatment of 2ndary hyperparathyroidism by vitD analogs and calcimimetics.
Avoid calcium overload.
Use of low dialysate calcium.
Antiresorptive; (bisphosphonates).
Alondorante and denosumab; increase bone density and decrease fracture rate.
Blocking inflammatory cytokines.
Measures to reduce uremic toxins.
Teriparatide; bone anabolic, reduce fracture risk.
Abaloparatide; stimulate bone formation, and proved osteo-anabolic in osteoporosis.
Romosozumab, a sclerostin-humonaized monoclonal antibody, act as bone anablic and anti-resorptive.(risk of cardiovascular calcification).
Romosozumab
Is a sclerostin-humonized monoclonal antibody.
Has an anabloic properties.
Limited study in advance CKD.
Miller et al and Sato et al Studies; ABD improvement at 1 year, in lumbar spines, total hip and femur neck.
Concern about the risk of cardiovascular calcification, although in one Japanese study showed its safety for use during one year.
ABD is it a always a disease ABD is an imbalance in bone metabolism and it may be an overlapped with high and low turn over, an some times it is a transitional features between low and high turnover. Balancing treatment after specific diagnosis to avoid overtreatment and dynamic disease. ABD is a syndrome with different factors and effectors, so careful handling and managing alteration is vial in stabilizing the restoring metabolic disturbance Newer Monoclonal antibodies has a promising in supporting bone strength and reduce fracture incidence
Summarize the pathogenesis of adynamic bone disease. The pathophysiology of ADB is certainly multifactorial (Figure 1), comprising patient-related and iatrogenic factors on a predisposed genetic background A state of imbalance between the low circulating levels of bone anabolic factors (e.g., insulin-like growth factor (IGF)-I) and the increased expression of bone-turnover–inhibitory factors, such as sclerostin and Dickkopf-related protein-1 (Dkk-1), largely predominates This imbalance suppresses bone formation through repression of WNT/β-catenin signaling. Moreover, Indoxyl sulfate, a protein-bound uremic toxin.Ithas been
linked to ADB. The circulating cytokines, for instance interleukin-1 (IL-1), IL-6, and tumor necrosis factor α (TNFα), have been supposed to directly impair bone-forming and -resorbing cells. Patients on PD are more vulnerable to ADB due to high dialysate calcium concentration and possibly increased glucose load. Ageing, diabetes mellitus, malnutrition and alcoholism have all been shown as risk factors for the development of ADB. in addition, aluminum significantly decreases both osteoclast and osteoblast activities and causes defective mineralization. Vigorous use of oral calcium and vitamin D sterols to control secondary hyperparathyroidism, the high dialysate calcium concentrations, and surgical parathyroidectomy induced hypoparathyroidism has extensively contributed to the growing prevalence of ADB.
What are the detrimental effects of adynamic bone diseases on the patient’s health? Adynamic bone results in poor skeletal health, bone fragility and diminished ability to restore damaged bone. Delayed remodeling promotes more secondary mineralization, making the bone stiffer. However, in the long term, over mineralization can induce a brittle bone that increases the risk of atypical fractures. Moreover, bone turnover suppression may cause microcracks which are difficult to heal in presence of low bone formation. The uncoupling of bone turnover with a relative predominance of resorption may also contribute to bone loss in patients with ADB and CKD. There are reports about J- or U-shaped association between PTH levels and mortality. In addition, there is possible association between ADB and VC in CKD What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
In patients with ADB, bone histomorphometry reveals low bone turnover with reduced number of both osteoblasts and osteoclasts, low bone volume coupled with normal mineralization. The presence of thin osteoid is the main feature differentiating ADB from the other LBT subgroup ‘‘osteomalacia’’.
Bone biopsy is the gold standard test to assess metabolic bone disease as its classification is mainly based on turnover/mineralization/volume system. Turnover represents the process of skeletal remodelling, attained by both bone resorption and formation. It is assessed using bone formation rate, activation frequency, osteoclasts, and osteoblasts number. Mineralization reflects calcification of bone collagen and is assessed using osteoid volume, osteoid thickness as well as dynamic, tetracycline-based evaluation of mineralization lag time and osteoid maturation time. Lastly, volume which reflects the amount of bone per unit. On the other hand, it has some limitations including high cost, lack of expertise and limited patient acceptability. Moreover, the wide discrepancy of the diagnostic cutoffs led to significant differences in the classification of bone turnover. Selection bias, age, gender, ethnicity, in addition to definition of normal range differences might explain the inconsistencies.
How to diagnose adynamic bone disease in patients with CKD?
Laboratory: Decrease bone formation markers (TAP, BSAP, intact P1NP, and DKK-1) and bone resorption markers (TRAP5b) with increased sclerostin. iPTH <150 pg/ml has a sensitivity of 68.6% and a specificity of 61.2%.
Radiological: DXA, QCT: there may be normal or decreased BMD. MRI: assess bone microarchitecture.
Bone biopsy: bone histomorphometry decreased turnover, normal mineralization and decreased or normal bone volume
How to prevent adynamic bone disease in patients with CKD? By avoiding risk factors associated with reduction of bone turnover, such as aluminum exposure, oversuppression of PTH secretion by using calcium supplements, high doses of vitamin D analogs and/or calcimimetics, in addition tofactors that may contribute to PTH resistance, such as hyperphosphatemia, malnutrition, inflammation, and progression of CKD. Criticize the use of romosozumab as osteoanabolic in patients with CKD. Romosozumab, sclerostin humanized monoclonal antibody, acts as an anabolic and anti- resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited as there was a cardiovascular concern that might be related to increased vascular calcification with its usage. However, some recent studies demonstrated one-year romosozumab cardiovascular safety in HD patients. After reading the article, do you think adynamic bone is always a disease? I think it is still unknown if all cases of ADB are maladaptive, or it can be adaptive/compensatory in certain situations. It is not very well-known if all forms of ADB are truly pathological, and likewise milder degrees of ADB could be a compensatory mechanism to guard against bone loss.
Summarize the pathogenesis of adynamic bone disease.
It is multifactorial comprising patient-related and iatrogenic factors with genetic background. A state of imbalance between the low circulating levels of bone anabolic factors and the increased expression of bone turnover–inhibitory factors (sclerostin, and Dickkopf-related protein-1) largely predominates. This imbalance suppresses bone formation through repression of WNT/β-catenin signaling. Moreover, indoxyl sulfate (uremic toxin) has been linked to ADB. In addition, the circulating cytokines such as IL-1, IL-6, and TNFα have been supposed to directly impair the bone forming and resorbing cells. Patients on PD are more vulnerable to ADB due to high dialysate calcium concentration and possibly increased glucose load. Ageing, diabetes mellitus, malnutrition and alcoholism have all been shown as risk factors for the development of ADB. in addition, aluminum significantly decreases both osteoclast and osteoblast activities and causes defective mineralization. Vigorous use of oral calcium and vitamin D sterols to control secondary hyperparathyroidism, the high dialysate calcium concentrations, and surgical parathyroidectomy induced hypoparathyroidism has extensively contributed to the growing prevalence of ADB.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Adynamic bone results in poor skeletal health, bone fragility and diminished ability to restore damaged bone. Delayed remodeling promotes more secondary mineralization, making the bone stiffer. However, in the long term, over mineralization can induce a brittle bone that increases the risk of atypical fractures. Moreover, bone turnover suppression may cause microcracks which are difficult to heal in presence of low bone formation. The uncoupling of bone turnover with a relative predominance of resorption may also contribute to bone loss in patients with ADB and CKD. There are reports about J- or U-shaped association between PTH levels and mortality. In addition, there is possible association between ADB and VC in CKD.
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
In patients with ADB, bone histomorphometry reveals low bone turnover with reduced number of both osteoblasts and osteoclasts, low bone volume coupled with normal mineralization. The presence of thin osteoid is the main feature differentiating ADB from the other LBT subgroup ‘‘osteomalacia’’.
Bone biopsy is the gold standard test to assess metabolic bone disease as its classification is mainly based on turnover/mineralization/volume system. Turnover represents the process of skeletal remodelling, attained by both bone resorption and formation. It is assessed using bone formation rate, activation frequency, osteoclasts, and osteoblasts number. Mineralization reflects calcification of bone collagen and is assessed using osteoid volume, osteoid thickness as well as dynamic, tetracycline-based evaluation of mineralization lag time and osteoid maturation time. Lastly, volume which reflects the amount of bone per unit. On the other hand, it has some limitations including high cost, lack of expertise and limited patient acceptability. Moreover, the wide discrepancy of the diagnostic cutoffs led to significant differences in the classification of bone turnover. Selection bias, age, gender, ethnicity, in addition to definition of normal range differences might explain the inconsistencies.
How to diagnose adynamic bone disease in patients with CKD?
Laboratory: Decrease bone formation markers (TAP, BSAP, intact P1NP, and DKK-1) and bone resorption markers (TRAP5b) with increased sclerostin. iPTH <150 pg/ml has a sensitivity of 68.6% and a specificity of 61.2%.
Radiological: DXA, QCT: there may be normal or decreased BMD. MRI: assess bone microarchitecture.
Bone biopsy: bone histomorphometry decreased turnover, normal mineralization and decreased or normal bone volume.
How to prevent adynamic bone disease in patients with CKD?
By avoiding risk factors associated with reduction of bone turnover, such as aluminum exposure, oversuppression of PTH secretion by using calcium supplements, high doses of vitamin D analogs and/or calcimimetics, in addition tofactors that may contribute to PTH resistance, such as hyperphosphatemia, malnutrition, inflammation, and progression of CKD.
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab, sclerostin humanized monoclonal antibody, acts as an anabolic and anti- resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited as there was a cardiovascular concern that might be related to increased vascular calcification with its usage. However, some recent studies demonstrated one-year romosozumab cardiovascular safety in HD patients.
After reading the article, do you think adynamic bone is always a disease?
I think it is still unknown if all cases of ADB are maladaptive, or it can be adaptive/compensatory in certain situations. It is not very well-known if all forms of ADB are truly pathological, and likewise milder degrees of ADB could be a compensatory mechanism to guard against bone loss.
Summarise the pathogenesis of the adynamic bone disease.
ABD happens due to loss of osteoblast activity under the action of loss of anabolic hormone.
it is found to happen early in CKD stages 2 to 3 with an increase the sclerotin level which inhibits the osteoblast and bone formation.
a uraemic toxin is also implicated through the indoxyl sulphate produced from the metabolism of tryptophan by gut microbiota, causing a decrease in bone-forming and resorting activity.
t is found that PD patient has high rate of ABD due to high Ca dialysate and high glucose .
DM decrease the bone quality and increase the risk of fracture. Advanced glucose end products interfere with osteoblast and osteoclast activity. ABD is related to medication which has been used for cKD patients, like high Ca load and used of calcimimetic medication, which lead to PTH suppression .
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy? normal miniralization with reduce bone volume and no osteoblast and osteoclast activity .
The drawbacks of bone biobsy include ihigh cost, lack of expertise, and limited patient acceptability.
Summarize the pathogenesis of adynamic bone disease
The pathophysiology of ADB is multifactorial ), comprising patient-related and iatrogenic factors on a predisposed genetic background. A state of imbalance between the low circulating levels of bone anabolic factors (e.g., insulin-like growth factor (IGF)-I) and the increased expression of bone-turnover–inhibitory factors, such as sclerostin and Dickkopf-related protein-1 (Dkk-1), largely predominates. This imbalance ultimately suppresses bone formation through repression of WNT/β-catenin signaling . Moreover, uremic toxins may play a role in this setting. Uremic toxins are compounds that accumulate in the body as renal function declines, adversely affecting the function of multiple organs and systems. Indoxyl sulfate, a protein-bound uremic toxin (PBUT) generated by the gut microbiome from the metabolism of tryptophan, has been linked to LBT [15]. Experimental evidence suggests that the gut-derived toxin indoxyl sulfate aggravates LBT and inhibits osteoclast function and differentiation; however, further clinical studies would be more conclusive [31–33]. Of note, the circulating cytokines, for instance interleukin-1 (IL-1), IL-6, and tumor necrosis factor α
diagnosis ob ADBD
laboratory
iPTH
bone turnover
bone spisfic ALP
bone biopsy
==================
how to prevent ABD
1-avoid exposure to aluminum exposure
2=avoid oversuppression of PTH by VDRA and calcimimetics
**How to diagnose adynamic bone disease in patients with CKD?
Laboratory tests : bone turnover markers eg bone formation markers like total alkaline phosphotase and bone specific alkaline phosphotase especially Bsap, procollagen type 1 N terminal pro-peptide and procollagen type 1 C terminal pro-peptide which are indicators of collagen synthesis especially P1NP bone derived osteocalcin but is of limited value in advanced CKD
Sclerostin and DKK1 which are inhibitor of bone formation
Bone resorption markers :type 1 collagen in normal population but it is use is limited in Ckd, tartrate resistant acid phosphotase 5 b used in ckd
Intact PTH when less than 150pg/ml so consider LBT
DXA normal or low BMD advantages is available and low cost but cannot differentiate between cortical and trabecular bone
Quantitative CT scan can differentiate between cortical and trabecular bone
MRI can diagnose microarchicture and correlate well with histomorphometric TMV parameters
PET scan florin 18 sodium fluoride for assessment of bone turnover and osteoblast function
Bone biopsy which is the gold standard for Diagnosis of ADB to assess bone turnover, mineralization and volume
Microcomputer tomography is 3D high resolution modality use small bone sample used in children with ESKD
Fourier transform infrared spectroscopy which is a tool used in analyzing mineral quality and bone matrix properties in bone biopsy Specimen
**How to prevent adynamic bone disease in patients with CKD?
Avoidance of risk factor associated with the decrease of bone turnover such as oversuppresion of pth from overdone of calcium or excessive use of vitamin D analogs or calcimimetic and from aluminum toxicity
Or factors that lead to PTH resistance like malnutrition, hyperphosphatemia, inflammation and progression of ckd
**Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Is a Sclerostin humanized monoclonal antibody has anabolic and antiresorptive activity so lead to improvement in BMD of the hip and spine in ckd but. Cardio-vascular concern
**After reading the article, do you think adynamic bone is always a disease?
Is a difficult question to be answered, as it has multifactorial causes and depends on the duration af ckd and underlying cause,
It is a state of loss of ability of bone to remodule, can return it is activity when the effect removed but it is also associated with many complications and increase risk of VC and mortality.
**Summarize the pathogenesis of adynamic bone disease.
The pathogenesis is multifactorial in which there is imbalance between low bone forming factors eg IGF 1 and increase expressions of bone inhibitory factors eg sclerostin and DKK-1 this will suppress bone formation through repression of WNT/B catinen Signalling.
Uremic toxins like indoxyl sulphate produced from metabolism of tryptophan by gut microbiota, cause decrease in bone forming and resorting activity.
PD patient at risk of ADB from high Calcium content and High glucose, in addition to the age, gender and alcoholic,will decrease bone formation. Aluminum toxicity from water in dialysate or aluminum phosphate binders will decrease osteoblast and osteoclast activity
Gonadal dysfunction in which decrease testosterone in men and estradiol in women cause decrease bone activity and affect bone health
Inflammatory cytokines like IL1, IL6 and TNF-alpha will decrease bone forming and resorting cells. Malnutrition and malnutrition – inflammation complex affect on bone health and quality and increase catabolic state and bone loss.
Parathyroidectomy causes increase incidence of ADB and VC.
DM decrease bone quality and increase risk of fracture. Advanced glucose end products interfere with osteoblast and osteoclast activity.
Low vitamin D level causes suppressed vitamin D receptors expressions
**What are the detrimental effects of adynamic bone diseases on the patient’s health?
It lead to poor skeletal health, increase bone fragility and inability to restore damaged bone. Delayed remodeling will increase secondary mineralization and making bone stiffer and tougher and lead to a typical fracture, in addition to that suppression of bone turnover lead to micocracks that are difficult to heal in the presence of low bone formation. Bone loss increase with low trabecular bone volume and increase risk of fracture.
Studies show J or U shape association between PTH and mortality as ADB may increase risk of all causes and cardiovascular mortality in addition to increase risk of VC
**What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
It based on turnover /mineralization /volume
Turnover represent skeletal remodeling and bone formation and resorption activity which represented by the number of osteoclast and osteoblast, bone formation rate and activation frequency
Mineralization represents calcification of bone collagen and assessed using osteoid volume, osteoid thickness and dynamic, TC based evaluation of mineralization lag time and osteoid maturation time.
Volume represents amount of bone per unit
In ADB bone show low number of osteoclast and osteoblast, low bone volume and normal mineralization.
The presence of thin osteoid is the main feature that differentiate ADB from osteomalacia.
Drawbacks :high cost, lack of expertise, limited patient acceptability, wide discrepancy of the diagnostic cutoff, selection bias, age, gender and ethnicity, definition of no range difference may explain the inconsistencies.
1-Summarize the pathogenesis of adynamic bone disease.
ABD is characterized by an imbalance in the circulation of bone anabolic factors such as insulin-like growth factor and an increase in the levels of DKK and Sclerostin,Indoxol sulfate, a uremic toxin, inhibits bone formation by inhibiting osteoclast differentiation.
TNFalpha, IL-6, and IL-1 are inflammatory factors that inhibit bone formation.
Because of the low albumin, high calcium, and high glucose load,
PTH suppression caused by medications such as vitamin D , Calcimemetics, and parathyroidectomy.
Vitamin D Receptors are essential for bone health because they inhibit osteoblast apoptosis and promote osteoblast differentiation.
2-What are the detrimental effects of adynamic bone diseases on the patient’s health?
Poor skeletal health, Bone fragility, Diminished ability to restore damaged bone,and delayed bone remodeling and increased risk of all cause & cardiovascular mortality dueto vascular calcification.
3-What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease
Normal mineralization and low bone volume decreased osteoblasts and osteoclasts activity and presence of thin osteoid is primarily used to distinguish ABD from osteomalacia.
what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Strength s point accuracy in providing a precise assessment of metabolic bone disease.
The drawbacks of bone biobsy include ihigh cost, lack of expertise, and limited patient acceptability.
4-How to diagnose adynamic bone disease in patients with CKD?
Lab as Bone turnover marker : low bone formation -low tAP, low bAP, low intact P1NP high sclerostin.
Low Bone resorption: low TRAP5b.
Low iPTH :<150 pg/ml.
Radiology DXA scan, MRI: Assess bone microarchitecture.
Bone biopsy is the gold standard low turnover, normal mineralization, low or normal bone volume.
5-How to prevent adynamic bone disease in patients with CKD?
Avoid over-suppression of PTH by vitamin D & calcimimetics
Avoid Ca overload ,Avoid malnutrition–inflammation, improve uremic toxins via improve adequecy of dialysis reduce intestinal generation of toxins.
6-Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Unfortunately arelimited studies in CKD
And increased incidence of cardiovascular calcification
7-After reading the article, do you think adynamic bone is always a disease?
Yes I think so
Summarize the pathogenesis of adynamic bone disease. a combination of many factors will lead to icrease bone turnover inhibitory factors and decrease anabolic factors, cumulating into regression of WNT/B catenin signaling and suppression of bone formation.these factors include:1- patient age, 2-DM,3- alcoholism,4-aluminium through HD water or aluminium containing phosphate binder, 5- uremic toxins eg indoxyl sulfate inhibit osteoclast functio and differentiation, 6- malnutrition-inflammation complex: creates negative protein balance, increased proinflammatory markers,and catabolic state favoring suppression of bone formationa and increased bone resorption, 7- gonadal dysfunction impairs bone formation,8- last but not least is hypoparathyroidism and pth hyporesponsiveness status.
What are the detrimental effects of adynamic bone diseases on the patient’s health? 1-LBT is assosciated with poor skeletal health ch.ch by bone fragility,decrease ability to restore damaged bone, delayed remodelling and excess mineralization, making bone more stiffer, but overtime the bone becomes brittle.
2-ABD is assosciated with vascular calcification, due diminished buffering of the bone.
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease, decreased number of osteoblast and osteoclast, low bone volume and normal mineralization
drawbacks of bone biopsy
high cost, lack of expertise, and limited acceptability, no clear cutoffs.
How to diagnose adynamic bone disease in patients with CKD? lab, radiolagy and bone biopsy
lab includes 1- bone resorption markers, 2-bone formation markers, 3- PTH 1- bone resorption markers: CTX is the invesigation of choice in normal population, but of limited value in CKD as it is renal excreted, 2- BONE formation markers: a- total and bone specific alkaline phosphatase, b-procollagen type I N-terminal and c-terminal. c- sclerostin and DKK-1: their level increase in LBT 3- PTH: with level less than 150. LBT should be considered
radiology includes
a- DXA nd quantitative computed tomography, but soft tissue calcification may interfer with DXA
b- high resolution periperal quantitative computed tomography: evaluate microarchitecture c-PET scan: there is significant correlation between floride activity and histomorphometric parameters d-MRI: CAN evaluate microarchitecture
3- bone biopsy is the gold standard for diagnosis of LBT
How to prevent adynamic bone disease in patients with CKD? 1- avoid aluminum toxicity, limit use of aluminum based phosphate binder and check aluminium in HD water 2- avoid of suppression of parathyroid gland: a- careful use of vit D and calcimimetics, b- frequent monitoring of PTH 3- Avoidance of calcium overload: a- use of non- calcium based phosphate binder, b- use of low calcium dialysate in PD 4- uremic toxins a- improve adequecy of dialysis b-reduce intestinal generation of toxins. 5- correction of malnutrition-inflammatory syndrome: improvement of nutritonal status and inflammatory profile can improve bone turnover 6- antiresorptive: eg bisphosphonate should be prescribed a case by case
# Summarize the pathogenesis of adynamic bone disease.
Adynamic bone disease the 1st description since 1980
Also called ablastic bone disease due to very low remodeling and reduce number of osteoblast and reduced amount of osteoid
Also characterized by low bone turn over
without osteoid accumulation i.e decrease bone matrix
Studies show increase prevalence ABD in CKD stage 3-4 more than CKD stag 5
Many risk factors for ABD
AS low PTH ,, Aluminum toxicity ,, aging ,, peritoneal dialysis ,, DM ,, over treated of SHPTH and anti-resorptive agent
The main cause and pathogenesis of ABD and proposed mechanism of decrease bone formation . In pt. with CKD is decreased osteoblastic activity or differentiation or proliferation as follow 1-low serum vit D >>>>decrease osteoblast differentiation and decrease life span of osteoblast 2-metabolic acidosis and high phosphate >>>>>suppression of 1,(25 )2 vit D production 3- uremic toxins decrease vit D , VDR and decrease osteoblast proliferation 4- hypogonadism and aging >>>decrease osteoblast life span 5- malnutrional and DM >>>>>decrease IGF and decrease vit D >> decrease osteoblast proliferation 6- high serum IL , IL 6 TNF >>>>decrease osteoblast life span
# What are the detrimental effects of adynamic bone diseases on the patient’s health?
The ABD poor impact on bone health ,poor skeletal health , bone fragility
Fracture risk
Vascular calcification
THE study show ABD associated with worse outcome in CKD
U -shaped association between PTH level and mortality as PTH level <150 pg/ml and > 500pg/ml
Increased hazards risk for both , all causes of cardiovascular mortality In dr alhusseni study conclusion that low bone turn over and vascular calcification are predominant in early stage of CKD
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
How to diagnose adynamic bone disease in patients with CKD?
Start by bone marker
PTH
Calcium
Pi
Another marker added as b alp ( bone specific alp) PINP —-TRAP Sb BONE biopsy followed histomorphometry analysis is the golden standard method for diagnosis Histological finding – few or no osteoblast – Minimal or no peritrabecular fibrosis – Bone volum normal or low , bone microarchitecture disrupted – Bone formation is substantially diminished – Both the rate of collagen synthesis and the subsequent mineralization are subnormal How to prevent adynamic bone disease in patients with CKD?
Avoid calcium over load
1- stop ca contain phosphate binder and replaced w non calcium non al. containing phosphate binder
2- What are the detrimental effects of adynamic bone diseases on the patient’s health?
Poor skeletal health, Bone fragility, Diminished ability to restore damaged bone, Increased risk of all cause & cardiovascular mortality (CORES study), Increased risk of infection-related mortality (Korean study), Vascular calcification (London et al.).
3- What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and Bone biopsy findings:
T = Reduced number of both osteoblasts & osteoclasts
M = Normal minerilzation, thin osteoid
V = Low volume Normal
4- what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Strength of bone biopsy: The most precise tool .
Drawbacks: Cost, Lack of expertise, Limited patient acceptability, lack of standardization
5- How to diagnose adynamic bone disease in patients with CKD?
6- How to prevent adynamic bone disease in patients with CKD?
Avoid over-suppression of PTH by vitamin D & calcimimetics
Avoid Ca overload and keep daily intake in the range of 800 to 1000 mg/dl
Avoid high dialysate Ca of 1.75 mmol/l
Avoid anti-resorptive therapy in dialysis patients
Avoid malnutrition–inflammation
Strategies to decrease intestinal production or increase removal of protein bound uremic toxins e.g ., AST-120 in animal studies, oral charcoal adsorbant, additive charcoal in dialysate, mixed-matrix membrane hollow fibers, and use of binding competitors in conjuction with conventional HD
Future direction ; antagonist of arl hydrocarbon receptor, a ligand-activated transcription factor that controls the toxic consequences of uremic toxins
7- Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Studies in advanced CKD are limited
May be associated with increased risk of vascular calcification and cardiovascular concerns, However, data from Japan showed at least one-year cardiovascular safety
8- After reading the article, do you think adynamic bone is always a disease?
Summarize the pathogenesis of adynamic bone disease.
ABD is characterized by an imbalance in the circulation of bone anabolic factors such as insulin-like growth factor and an increase in the levels of DKK and Sclerostin. The suppression of the Wnt/Beta Catonin pathway is the mechanism of action. Indoxol sulfate, a uremic toxin, inhibits bone formation by inhibiting osteoclast differentiation. TNFalpha, IL-6, and IL-1 are inflammatory factors that inhibit bone formation. Because of the low albumin, high calcium, and high glucose load, peritoneal dialysis may aggravate ABD ABD was previously linked to HD Water contamination with aluminum. nowadays, the main cause of ABD is PTH suppression caused by medications such as vitamin D , Calcimemetics, and parathyroidectomy. Malnutrition (low albumin level) exacerbates ABD- Estrogen and testosterone levels are known to affect bone health. Vitamin D Receptors are essential for bone health because they inhibit osteoblast apoptosis and promote osteoblast differentiation. There will be more osteoblast apoptosis in the presence of low Vitamin D, which will impact bone health and increase the risk of fracture. Furthermore, diabetic patients are at a higher risk of overall fracture.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
*Calciphylaxis *Fractures *Arteriosclerosis *Increased incidences of CVDs and increased mortality
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
-Normal mineralization and low bone volume; -decreased osteoblasts and osteoclasts. -The presence of thin osteoid is primarily used to distinguish ABD from osteomalacia. The gold standard for distinguishing between different types of ROD is a bone biopsy with a tetracycline label. High cost, lack of experience and expertise, and limited patient acceptability are some of the limitations.
How to diagnose adynamic bone disease in patients with CKD?
Bone turnover marker: poor bone formation – low tAP, low bAP, and low intact P1NP and high sclerostin in the laboratory. Bone resorption is poor: TRAP5b is low. Low iPTH:150 pg/ml sensitivity and specificity are 68% and 61%, respectively. DXA: BMD is normal or reduced. Cannot distinguish between cortical and trabecular bone, but QCT can. Evaluate bone microarchitecture using MRI. Correlation with parameters of the TMV. PET: 18F fluoride activity is poor. Bone biopsy: Low turnover, normal mineralization, and low or normal bone volume, as measured by histomorphometry.
How to prevent adynamic bone disease in patients with CKD?
Prevention based on avoiding risk factors such as aluminum exposure, excessive suppression, (PTH), calcium overload and administration of high doses of vitamin D and calcimimetics. Moreover, factors contributing to PTH resistance should be tackled ( like hyperphosphatemia, malnutrition, inflammation and progression of CKD)
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
*Limited studies in CKD *Linked to increased incidence of CVD *May be safe for one year (Japanese Study)
After reading the article, do you think adynamic bone is always a disease?
ABD is not pathologically significant in all patients, but should be constantly observed because it may be a precursor to osteitis fibrosa/high-turnover bone disease, and it could be a compensatory response.
Summarize the pathogenesis of adynamic bone disease.
The imbalance between low circulating levels of bone anabolic factors and increased expression of bone-turnover-inhibitory factors predominates, suppressing the bone formation and WNT/ß-catenin signaling.
Uremic toxins, such as indoxyl sulfate, aggravate low bone turnover and inhibit osteoclast function and differentiation.
Cytokines, such as IL-1, IL-6, and tumor necrosis factor a (TNFa) have been suggested to directly impair bone forming and resorbing cells.
Patients on peritoneal dialysis are more vulnerable to ADB due to high dialysate-ca concentration and increased glucose load. Aging, diabetes mellitus, malnutrition, and alcoholism are risk factors.
Aluminum overload resulting from contamination of hemodialysis water and non-judicious use of aluminum-containing phosphate binders can contribute.
Parathyroidectomy has been shown to cause a shift in bone turnover from high to low
Treatment with cinacalcet and calcitriol therapies can also precipitate hypoparathyroidism.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
ADB can lead to poor skeletal health, bone fragility, and diminished ability to restore damaged bone. it is also related to Calciphylaxis and vascular calcification accelerating the risk of cardiovascular calcifications
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Bone biopsy is the gold standard for diagnosing adynamic bone disease (ADB), and it is the cornerstone for detecting different types of renal osteodystrophy (ROD). Characteristic findings in bone biopsy results for diagnosing ADB include decreased or absent bone formation, low cellularity of both osteoblasts and osteoclasts, thin osteoid seams, and minimal or no peritrabecular or marrow fibrosis.
The strengths of Bone biopsy:The strengths of bone biopsy in diagnosing ROD include its accuracy in providing a precise assessment of metabolic bone disease.
The drawbacks of bone biopsy: The drawbacks include its high cost, lack of expertise, and limited patient acceptability.
How to diagnose adynamic bone disease in patients with CKD?
The diagnosis of adynamic bone disease (ADB) in patients with CKD requires a combination of clinical, laboratory, imaging, and histomorphometric studies.
Clinical evaluation should include a review of an individual’s risk factors for ADB. Laboratory tests that evaluate bone turnover, such as bone-specific alkaline phosphatase (BSAP) and tartrate-resistant acid phosphatase 5b (TRAP 5b), can help to determine the bone turnover status of an individual.
iPTH cutoff of <150 pg/mL for diagnosis of ADB
Imaging studies, such as dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), can help to assess bone mineral density (BMD). Histomorphometry: is the gold standard for diagnosing ADB.
Fourier-transform infrared spectroscopy (FTIR) and positron emission tomography (PET) can also provide information on bone quality.
Finally, magnetic resonance imaging (MRI) can be used to assess bone microarchitecture.
How to prevent adynamic bone disease in patients with CKD?
Prevention and treatment of ADB in CKD involve avoiding risk factors associated with the reduction of bone turnover, such as aluminum exposure, over suppression of PTH secretion due to calcium overload, administration of high doses of vitamin D analogs, and/or calcimimetics. Additionally, management strategies such as improving nutritional status and reducing inflammation may help increase bone turnover. Additionally, bisphosphonates may be considered for use in patients with CKD on a case-by-case basis, taking into consideration bone turnover. Finally, antiresorptive medications may be used, although studies evaluating the efficacy and safety of antiresorptives in patients with advanced CKD are needed.
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab is not suitable for use as an osteoanabolic agent in patients with CKD due to the;
Limited studies in patients with advanced CKD,
Lack of long term efficacy data
Possible cardiovascular concerns related to its usage.
There is a risk of rebound associated fractures after discontinuation of romosozumab and other anti-resorptive medications, which can be particularly concerning in CKD patients due to their higher fracture risk.
There is evidence of abnormal calcium homeostasis in patients with CKD, which could affect the efficacy of romosozumab.
After reading the article, do you think adynamic bone is always a disease?
No, I do not think adynamic bone is always a disease. While it can be a sign of pathology, it can also represent an adaptive process to suppress bone resorption and further bone loss. Further research and evaluation are needed to determine if adynamic bone is a true disease or if it is a symptom of another underlying condition.
Summarize the pathogenesis of adynamic bone disease.
ADB’s pathogenesis is multifaceted, including genetic predisposition, and patient-related and iatrogenic variables. Low levels of bone anabolic hormones like insulin-like growth factor (IGF)-I and enhanced expression of bone-turnover–inhibitory proteins like sclerostin and Dickkopf-related protein-1 (Dkk-1) prevail. This imbalance inhibits bone formation through WNT/β-catenin signaling. Furthermore, uremic poisons may contribute. When renal function diminishes, uremic toxins build up in the body, harming many organs and systems. Indoxyl sulfate, a protein-bound uremic toxin (PBUT) produced by the gut microbiota from tryptophan metabolism, is associated with LBT. The gut-derived toxin indoxyl sulfate aggravates LBT and inhibits osteoclast activity and development, although further clinical trials are needed. Circulating cytokines such as IL-1, IL-6, and TNFα are thought to directly damage bone-forming and -resorbing cells.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Calciphylaxis
coronary arterial calcification
all-cause and cardiovascular mortality
Increase incidence of infection
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
ADB patients had LBT with fewer osteoblasts and osteoclasts, poor bone volume, and normal mineralization. The key difference between ADB and the other LBT-subgroup “osteomalacia” is a thin osteoid. ADB with poor bone-formation rate and strong osteoclastic resorption was reported. This variety may be an LBT-to-HBT transition.
THE DRAWBACKS: including high cost, lack of expertise, and limited patient acceptability. Moreover, the wide discrepancy of the diagnostic cutoffs has led to significant differences in the classification of bone turnover.
STRENGTH:
An accurate method for determining whether or not a patient has a metabolic bone disease.
How to diagnose adynamic bone disease in patients with CKD?
The diagnosis mainly relies on a bone biopsy, gold standard, and reduced bone formation and bone-resorption markers.
PTH Despite its limitations, intact or bio-intact PTH is the most widely used biomarker for CKD–MBD monitoring. LBT should be considered when iPTH is < 150 pg/mL in patients with advanced CKD.
Bone-Formation Biomarkers
Both blood total and bone-specific alkaline phosphatase (TAP, BSAP) are indicators for osteoid development, whereas BSAP better distinguishes bone turnover status in dialysis patients.
P1NP and P1CP indicate collagen production. In CKD patients, only intact P1NP is trustworthy since it is unaffected by GFR or dialysis.
Bone-Resorption Biomarkers
CTX, the reference bone-resorption marker in normal people, is really excreted in CKD patients. Nevertheless, tartrate-resistant acid phosphatase 5 b (TRAP5b) is unaffected by renal function or dialysis, and larger levels were associated with quicker cortical-bone loss.
Radiology
Dual-Energy X-ray Absorptiometry (DXA) Scan and Quantitative Computed
Tomography (QCT, MRI assess bone microarchitecture, PET; decreased 18F-fluride activity
How to prevent adynamic bone disease in patients with CKD?
The management involves avoiding risk factors that reduce bone turnover, such as aluminum exposure, over suppression of PTH production owing to calcium overload, excessive doses of vitamin D analogs, and/or calcimimetics. Hyperphosphatemia, malnutrition, inflammation, and CKD development may all cause PTH resistance, thus, these should be addressed.
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab studies in patients with advanced CKD are limited, as there was a cardiovascular concern that might be related to increased vascular calcification with its usage
limited studies in CKD patients.
After reading the article, do you think adynamic bone is always a disease?
Yes, I think it is a disease and needs early intervention to avoid more progression and complications.
A state of imbalance of low ciruclating level of bone anabolic factor like insulin like growth factor and increase of level of DKK and Sklerostin. The mechanism of action is through Wnt/Beta Catonin pathway suppression.
Uremic toxin like indoxyl sulfate suppress bone formation through inhibiting osteoclast differentiation.
Inflammatory factor like TNFalpha , IL6 und IL 1 inhibit bone formation
Peritoneal dialysis is a factor that may aggravate LBD because of low albumin, high calcium and high glucose load.
In the past the contamination of HD Water with aluminium was linked with ABD.
The main key factor that induce ABD is the oversuppression of PTH through medication like overuse of Vit D , Calciummimetics , parathyreoidectomy
Malnutrition (low albumin level) aggravate ABD- Japanese study over 15 000 HD PAtient with PTH < 60 and low albumin.
Decreased Estrogen and testesterone are well known to impact bone health.
Vitamin D Receptor are important in maintaing bone health, they block osteoblast apoptosis and promote osteoblast differentiation. In the presence of low Vitamin D , there will more osteoblast apoptosis what impact bone health and increase the risk of
fracture. Furthermore , patients with Diabetes mellitus have high risk of overall fracture.
2. Detrimental effects are increased cardiovascular calcification, increase risk of fracture, increase mortality.
Increased calcification around joints, lobular calcification masses like tumoral calcification.
Increased risk of calciphylaxis. Uncontrolled parathyroidismus is not a key determinant of calciphylaxis.
-Barreto demonstrated association between ABD and Coronary artery calcification.
3.characteristic finding in bone biopsy are low bone turnover, normal mineralization and low bone volume.
-reduced osteoblasts and osteoclasts.
-the presence of thin osteoid is used mainly for differential from osteomalacia.
Bone biopsy with tetracycline label is considered the gold standard to differentiate between different types of ROD.
Limitations include: high cost, lack of experience and expertise, limited patient acceptability.
4.diagnosis of ABD in patients with CKD: Laboratory finding:
Bone turnover marker : low bone formation -low tAP, low bAP, low intact P1NP high sclerostin.
Low Bone resorption: low TRAP5b.
Low iPTH :<150 pg/ml sensitivity and specificity respectively 68% and 61%.
Radiology
DXA: Normal or decreased BMD. Low dose radiation.but it cannot differentiate between
Cannot differentiate between cortical and trabecular bone but QCT can differentiate.
MRI: Assess bone microarchitecture. Correlation with TMV parameters.
PET: low 18F fluoride activity.
Bone biopsy
Histomorphometry: low turnover, normal mineralization, low or normal bone volume.
FTIR: increased mineral to matrix ratio. Bigger crystal size.
MikroCT: exvivo images of bone sample:
-ABD(increased BMD)
-Osteomalacia(decreased BMD)
5.Prevention based on the avoidance of risk factors like aluminum exposure, over suppression of PTH due to calcium overload, and due to administration of high dose vitamin D, and calcimimetics.moreover factors that contribute to PTH resistance should also be targeted( like hyperphosphatemia, malnutrition, inflammation and progression of CKD)
6. Romosozumab is a monoclonal antibodies against sclerostin -there is safety concerns because of linkage to increased vascular calcification in animals
7. I think signs of mild low turnover bone disease might be adaptive especially in early stage CKD but furthermore aggrevation of low turnover bone disease till the level of adynamic bone is a disease that obviously associated with CVC, all cause mortality, calciphylaxis..
The pathogenesis of ABD is multifactorial, and results from an imbalance between the low circulating levels of bone anabolic factors, and the increased expression of bone-turnover inhibitory factors – which results in the repression WNT-pathway
Uremic toxins of which Indoxyl sulfate(which originates from Tryptophan) inhibits osteoclast function and differentiation – also plays a role!
PD patients are more prone to develop ABD due to high Calcium dialysate and high glucose exposure
other disease specific conditions that contribute to PTH hyporesponsiveness, includes:
malnutrition
alcoholism
Inflammation(IL-1, IL-6, TNF), AGE’s
magnesium deficiency
gonadal dysfunction
calcitriol deficiency
hyperphosphatemia diabetes mellitus
therapy related factors which results in PTH suppresion, includes:
calcium loading
parathyroidectomy
vitamin D agonists
calcimimetics
What are the detrimental effects of adynamic bone diseases on the patient’s health?
ABD results in poor skeletal health, bone fragility and reduced ability to restore damaged bone
Also results in vascular calcification as well calciphylaxis; and, accelerated cardiovascular disease
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Bone biopsies remains the cornerstone of diagnosing the different types of ROD
Classification is based on the TMV-criteria
Turnover(T): represents skeletal remodelling
Mineralization(M): represents calcification of bone collagen
Volume(V): reflects the amount of bone per unit
Histological findings:
Decreased or absent bone formation
Reduced number of both osteoblasts and osteoclasts
Low bone volume coupled with normal mineralization
Has a thin osteiod seem
How to diagnose adynamic bone disease in patients with CKD?
Bone biopsy remains the gold standard for diagnosing ABD
Bone Turnover markers:
PTH
Bone formation markers
TAP and BSAP
P1CP
Sclerostin(high levels is associated with ADB) and Dkk-1
Bone resorption markers
TRAP5b
Other biomarkers
SIBLING
Radiology:
DXA and QCT
DXA is influenced by other calcifications in soft tissue or vascular calcifications. Also unable to differentiate between trabecular and cortical bone
QCT is not influenced by the above-mentioned confounding factors
BOTH can be used to diagnose asymptomatic vertebral fractures and to diagnose cardiovascular calcifications
HR-pQCT
Assesses cortical and trabecular bone
PET scan
Uses Fluorine 18-Sodium fluoride tracer, and evaluates bone turnover and osteoblast function
MRI
Assesses bone microarchitecture
How to prevent adynamic bone disease in patients with CKD?
Avoid the oversuppression of PTH secretion
The use of Vit D analogues and Calcimimetics
Avoid calcium overload
Limit calcium intake
Minimize dialysate calcium use
Antiresorptive use shopuld be minimised
Manage and treat the Malnutrition-Inflammations Syndrome
Improve the clearance of Uremic Toxins
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Very little data is available on its use in patients with CD, but there has been a concern regarding the dvelopment of cardiovascular disease
After reading the article, do you think adynamic bone is always a disease?
Not all patients with ABD is of pathologiacl significance, but should be monitored closely since it could be the forerunner for osteitis fibrosa/high-turnover bone disease
1 -Summarize the pathogenesis of adynamic bone disease.
imbalance between low circulating levels of bone anabolic factors avd the increased expression of bone turnover inhibitory factors.
Genetic predisposition
Malnutrition
Gonodal dysfunction
Uremic toxins particularly indoxyl sulphate
Alumnium intoxication.
Medications e.g., calcitriol, cinacalcet
Inflamation e.g ., IL1,IL6, &TNF-a
patients on PD are high risk for ADB due to high dialysate calcium concentration.
2- What are the detrimental effects of adynamic bone diseases on the patient’s health?
Poor skeletal health
Bone fragility
Diminished ability to restore damaged bone
Increased risk of all cause & cardiovascular mortality .
Increased risk of infection-related mortality .
Vascular calcification .
3- What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
bone biopsy is the cornerstone to detecting different types of ROD.
CLASSIFICATION based on the turnover, mineralzation and volume.( TMV) system.
Reduced number of both osteoblasts & osteoclasts Normal minerilzation, thin osteoid Low volume Normal
B .Strength of bone biopsy bone biopsy is the cornerstone to detecting different types of ROD.
– C.Drawbacks
Cost
invasive techniqe
Limited patient acceptability
Discrepancies in diagnostic cut offs i.e lack of standardization
4 -How to diagnose adynamic bone disease in patients with CKD? A.Laboratory
5–How to prevent adynamic bone disease in patients with CKD?
Avoid over-suppression of PTH by vitamin D & calcimimetics
Avoid Ca overload and keep daily intake in the range of 800 to 1000 mg/dl
Avoid high dialysate Ca of 1.75 mmol/l
Avoid anti-resorptive therapy in dialysis patients
Avoid malnutrition-inflammation
Strategies to decrease intestinal production or increase removal of protein bound uremic toxins e.g ., AST-120 in animal studies, oral charcoal adsorbant, additive charcoal in dialysate, mixed-matrix membrane hollow fibers, and use of binding competitors in conjuction with conventional HD
Future direction ; antagonist of arl hydrocarbon receptor, a ligand-activated transcription factor that controls the toxic consequences of uremic toxins
6–Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Studies in advanced CKD are limited
May be associated with increased risk of vascular calcification and cardiovascular concerns
However, data from Japan showed at least one-year cardiovascular safety
7–After reading the article, do you think adynamic bone is always a disease?
,ADB might be an adaptive/compensatory response but need more studies .
-What are the detrimental effects of adynamic bone diseases on the patient’s health?
Poor skeletal health
Bone fragility
Diminished ability to restore damaged bone
Increased risk of all cause & cardiovascular mortality (CORES study)
Increased risk of infection-related mortality (Korean study)
Vascular calcification (London et al.)
-What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy? A.Bone biopsy findings
T = Reduced number of both osteoblasts & osteoclasts
M = Normal minerilzation, thin osteoid
V = Low volume Normal
B.Strength of bone biopsy
The most precise tool to assess metabolic bone disease
C.Drawbacks
Cost
Lack of expertise
Limited patient acceptability
Discrepancies in diagnostic cut offs i.e lack of standardization
-How to diagnose adynamic bone disease in patients with CKD? A.Laboratory
-How to prevent adynamic bone disease in patients with CKD?
Avoid over-suppression of PTH by vitamin D & calcimimetics
Avoid Ca overload and keep daily intake in the range of 800 to 1000 mg/dl
Avoid high dialysate Ca of 1.75 mmol/l
Avoid anti-resorptive therapy in dialysis patients
Avoid malnutrition-inflammation
Strategies to decrease intestinal production or increase removal of protein bound uremic toxins e.g ., AST-120 in animal studies, oral charcoal adsorbant, additive charcoal in dialysate, mixed-matrix membrane hollow fibers, and use of binding competitors in conjuction with conventional HD
Future direction ; antagonist of arl hydrocarbon receptor, a ligand-activated transcription factor that controls the toxic consequences of uremic toxins
-Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Studies in advanced CKD are limited
May be associated with increased risk of vascular calcification and cardiovascular concerns
However, data from Japan showed at least one-year cardiovascular safety
-After reading the article, do you think adynamic bone is always a disease?
There is a possibility that, ADB might be an adaptive/compensatory response but we need more studies to clarify this issue i.e adaptive versus maladaptive responses
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Cardiovascular complication
Increase fracture risk
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Normal mineralization and low bone volume decrease osteoblast and osteoclast.
Strength:
– The gold standard.
– Based on TMV score it assists identification of the metabolic bone state.
Drawbacks:
Limited experience
High cost
Patient acceptability
Lack of cutoffs
How to diagnose adynamic bone disease in patients with CKD?
Diagnosis of ABD
– Normal or low iPTH
– Normal ALP
– Bone biopsy is a definite tool, but it is indicated when diagnosis could not be established with serum biomarkers.
How to prevent adynamic bone disease in patients with CKD?
– Prevent over-suppression of PTH by injudicious use of vit D analogs, calcium-based phosphorus binders, and calcimimetics.
– In treatment of secondary, tertiary hyperparathyroidism, subtotal rather than total parathyroidectomy to avoid ABD.
– Not to start parathyroid suppression early in early CKD stages not.
– Frequent monitoring of iPTH, ALP or BALP while on treatment
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
It is a humanized monoclonal sclerostin that acts as an anabolic and antiresorptive for bone. Limited studies on advanced CKD patients. Concern about its safety regarding increased vascular calcification. However, a one-year study demonstrated its safety.
After reading the article, do you think adynamic bone is always a disease?
Still unknown whether it is an adaptive mechanism to guard against bone resorption.
The pathogenesis of adynamic bone disease is multifactorial which include iatrogenic related with genetics? and low levels of circulating bone anabolic factors
the circulating cytokines (IL -1,IL-6 AND TNF α) there are multiple risk factors also include diabetes, malnutrition, which common in ckd patients .and associated with high incidence of LBT
OVER USE OF CALCIUM AND VITAMIN D
the detrimental effects of adynamic bone diseases on the patient’s health
A dynamic bone disease ensues poor skeletal health , fragility of bone and diminished ability to restore damaged bone and can result in brittle bone which increases the fractures..
the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy
bone biopsy with mineralized bone histology is a key to detecting different types of ROD .
Thin osteoid is the main feature differentiating ADB from the other LBT subgroup ‘‘osteomalacia’’.
Patients with ADB, bone histomorphometry, discover low bone turnover with the reduced number of both osteoblasts and osteoclasts, low bone volume coupled with normal mineralization.
Laboratory: TAP, BSAP, intact P1NP, and DKK-1 and bone resorption markers TRAP5b
iPTH
Radiological: DXA, QCT: there may be normal or decreased BMD. MRI:
Bone biopsy:
What are the detrimental effect of adynamic bone disease on patient health?
Adynamic Bone Disease can cause poor skeletal health, bone fragility and diminshed ability to restore damaged bone. Secondary mineralisaton as result of delayed bone remodellign can in long term lead to bone fractures. PTH has u shaped mortality curve and LBT being linked with low PTH means ABD. Various studies including DOPS show that ABD is associated with increased risk of mortality. ADB is linked to vascular calcification as bone cannot buffer extra calcium load which is linked to increased mortality and cardiovascular mortality.
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Features
low osteoblast,low osteoclast
low bone volume with normal mineralisation
thin osteoid
strength
most precise
give information about mineralisation ,volume and turnover
drawback- patient do not want to do it, high cost, complication discrepancy in diagnostic cut off
How to diagnose adynamic bone disease in CKD
Laboratory: decrease bone formation markers (TAP, BSAP, intact P1NP, and DKK-1) and bone resorption markers (TRAP5b) with increased sclerostin. iPTH <150 pg/ml has a sensitivity of 68.6% and a specificity of 61.2%.
Radiological: DXA, QCT: there may be normal or decreased BMD. MRI: assess bone microarchitecture.
Bone biopsy: bone histomorphometry decreased turnover, normal mineralization and decreased or normal bone volume.
How to prevent adynamic bone disease in patients with CKD?
Avoiding oversuppressing PTH by monitoring bone markers of formation and resorption
Controlling inflammation and addressing malnutrition
Avoiding Aluminiun Exposure
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab, sclerostin humanized monoclonal antibody, acts as an anabolic and anti- resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited and there was a cardiovascular concern that might be related to increased vascular calcification with its usage tho some studies show otherwise. in summary this area needs RCT
After reading the article, do you think adynamic bone is always a disease?
It can be a disease but it could also be an adaptation or evolution to progression to HBTo prevent bone loss
Summarise the pathogenesis of adynamic bone disease
It is complex and multifactorial and can be classed into iatrogenic factors, patient factors.
The pathophysiology of ABD relates to low circulating levels of bone anabolic factors like IGF1 and increased expression of bone turnover inhibitory factors such as sclerostin and dkk1 . it supresses bone formation via WNT/B-catenin signalling. Indoxyl sulphate a uraemic toxin has been linked to ABD and inhibits osteoclast function and differentiation. Inflammatory cytokines can also inhibit both bone forming and resorbing cells.
Factors that contribute to increase calcium load for example high calcium dialysate , Vitamin D sterols , calcium binders cause decrease PTH and therefore decrease bone formation as well as parathyroidectomy
Ageing, Diabetes Mellitus and malnutrition are risk factors for ABD
After reading the article, do you think adynamic bone is always a disease?
It is still unknown whether all cases of ADB are maladaptive or whether it can be adaptive/compensatory in certain situations.
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab, sclerostin-humanized monoclonal antibody, acts as an anabolic and anti-resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited, as there was a cardiovascular concern that might be related to increased vascular calcification with its usage .Miller et al. reported on its efficacy in patients with mild to moderate CKD .Moreover, two recent studies demonstrated one-year romosozumab cardiovascular safety in Japanese HD patients.
How to prevent adynamic bone disease in patients with CKD?
Despite the underlying complex pathophysiology of ADB, its management is based mainly on the avoidance of risk factors associated with reduction of bone turnover, such as aluminum exposure, over-suppression of PTH secretion due to calcium overload, administration of high doses of vitamin D analogs, and/or calcimimetics. Moreover, factors that may contribute to PTH resistance, such as hyperphosphatemia, malnutrition, inflammation, and progression of CKD, among others, should also be targeted
How to diagnose adynamic bone disease in patients with CKD?
1- Labaratory:
iPTH (<150pg/ml)
Sensitivity 68.6%
Specifically 61.2%
BTM
Bone formation and bone resorption
2-Radiology
DEXA
HRCT
PET
3-Bone biopsy
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Bone biopsy with mineralized-bone histology is the cornerstone to detecting different types of ROD .Classification is mainly based on the turnover/mineralization/volume (TMV) system .Turnover represents the process of skeletal remodeling, attained by both bone resorption and formation. It is assessed using bone-formation rate, activation frequency, and the number of osteoclasts and osteoblasts. Mineralization reflects the calcification of bone collagen and is assessed using osteoid volume, osteoid thickness, and dynamic, tetracycline-based evaluation of mineralization lag time and osteoid-maturation time. Lastly is volume, which reflects the amount of bone per unit .In patients with ADB, bone histomorphometry reveals LBT with a reduced number of both osteoblasts and osteoclasts and low bone volume coupled with normal mineralization .Of note, the presence of a thin osteoid is the main feature differentiating ADB from the other LBT-subgroup ‘‘osteomalacia’’ .Interestingly, a different variant of ADB, characterized by low bone-formation rate in association with high osteoclastic resorption, was described. This variant might be a transitional phase between LBT and HBT .Additionally, Misof et al. reported that bone- mineralization density distribution increases and the lacunar size of the osteocytes decreases in patients with ADB. This novel tool might be helpful to discriminate hyperparathyroid bone from ADB .
Although bone biopsy is the most precise tool to assess metabolic bone disease, it has some limitations, including high cost, lack of expertise, and limited patient acceptability .Moreover, the wide discrepancy of the diagnostic cutoffs has led to significant differences in the classification of bone turnover .Selection bias, age, gender, and ethnicity, in addition to the definition of normal-range differences, might explain the inconsistencies. Ultimately, it is better to unify the used cutoffs in order to properly estimate the prevalence and type of ROD to improve therapeutic decisions
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Adynamic bone results in poor skeletal health, bone fragility, and diminished ability to
restore damaged bone .A crucial aspect of delayed remodeling is that it promotes more secondary mineralization, making the bone stiffer/tougher .However, in the long term, over-mineralization can induce brittle bone that increases the risk of atypical fractures .Moreover, suppression of bone turnover may cause microcracks, which are difficult to heal in the presence of low bone formation .The uncoupling of bone turnover with a relative predominance of resorption may also contribute to bone loss in patients with ADB and CKD .
Several studies have reported a J- or U-shaped association between PTH levels and mortality in patients on dialysis from different geographic areas .Several studies concluded that low PTH levels, indicative of LBT, were associated with a higher risk of mortality.
A Korean study reported that serum PTH < 150 pg/mL was an independent risk factor for infection-related mortality, compared to the target range of PTH 150–300 pg/mL in incident dialysis patients .In the CORES study, which included 16,173 Latin American HD patients, once again PTH < 150 pg/mL was associated with all-cause and cardiovascular mortality.
Summarize the pathogenesis of adynamic bone disease.
The pathophysiology of ADB is certainly multifactorial ,comprising patient-related and iatrogenic factors on a predisposed genetic background. A state of imbalance between the low circulating levels of bone anabolic factors (e.g., insulin-like growth factor (IGF)-I) and the increased expression of bone-turnover–inhibitory factors, such as sclerostin and Dickkopf-related protein-1 (Dkk-1), largely predominates. This imbalance ultimately suppresses bone formation through repression of WNT/β-catenin signaling .Moreover, uremic toxins may play a role in this setting. Uremic toxins are compounds that accumulate in the body as renal function declines, adversely affecting the function of multiple organs and systems. Indoxyl sulfate, a protein-bound uremic toxin (PBUT) generated by the gut microbiome from the metabolism of tryptophan, has been linked to LBT .Experimental evidence suggests that the gut-derived toxin indoxyl sulfate aggravates LBT and inhibits osteoclast function and differentiation; however, further clinical studies would be more conclusive .Of note, the circulating cytokines, for instance interleukin-1 (IL-1), IL-6, and tumor necrosis factor α (TNFα), have been supposed to directly impair bone-forming and -resorbing cells .
Patients on PD are more vulnerable to ADB due to high dialysate-calcium concentration and possibly increased glucose load .Aging, diabetes mellitus, malnutrition, and alcoholism have all been shown to be risk factors for the development of ADB .Aluminum overload resulting from contamination of HD water and non- judicious use of aluminum-containing phosphate binders represented a major culprit a few decades ago .In the 1980s, aluminum intoxication was the most prevalent cause of LBT in patients on dialysis .Aluminum significantly decreases both osteoclast and osteoblast activities and causes defective mineralization.
ABD
Pathogenesis
a) PD.
b) Older age.
c) DM.
d) Malnutrition-inflammation complex syndrome.
e) Aluminum overload in HD.
f) Vigrous use of oral Calcium, and vitD, high dialysate-Ca, and parathyroidectomy.
g) Gonadal dysfunction.
h) Hypothyroidism, (resistance to the bone-stimulating effect of PTH).
i) Low vitD level, (suppress VDR expression).
Impact of LBT on patient’s health
Bone biopsy
a) LBT.
b) Reduce the number of both osteoclasts and osteoblasts.
c) Low bone volume.
e) Normal minelaization.
f) Thin osteoid, (the main difference between ABD and LBT-subgroup)
g) ABD variant may be related to the transition from HBT and LBT.
h) Bone mineralization density distribution increases and the lacunar size of the osteocytes decreases.
a) High cost.
b) Lack of expertise.
c) Limited patient accessibility.
d) Wide discrepancy of the diagnostic cut-off led to significant differences in the classification of bone turnover.
e) Selection bias.
f) Age,
g) Gender.
h) Ethnicity.
i) Different normal ranges.
Diagnosis of ABD in CKDI
a) BSAP, a biomarker of osteoid formation.
b) Procollagen type 1 N-terminal (P1NP) and procollagen type 1 C-terminal propeptide (P1CP) are indicators of collagen synthesis rate, (P1NP is more sensitive).
c) Bone-derived osteocalcin, (limited use in advance CKD).
e) Sclerostin and Dkk-1; are soluble inhibitors of the Wnt-signaling pathway (the main promotor of bone formation) and the study showed a significant association between sclerostin and Dkk-1 and ABD.
a) Carboxy-terminal crosslinking telopeptide of type 1 collagen (CTX), is the reference bone resorption marker (limited use in CKD).
b) Titerate-resistant acid phosphatase 5 b (TRAP5b), a higher level associated with after rating of cortical-bone loss, bone resorption, and bone histomorphometry parameter.
c) The receptor activator of nuclear factor-kB (RANK)/receptor activator of nuclear factor-kB ligand (RANKL)/osteoprotegerin (OPG) system is responsible for the fine integration between osteoblast and osteoclast.
a) DXA (dual-energy X-ray Absorptiometry scan; with several limitations, (confounded results due to soft-tissue calcifications and osteoarthritis, but helpful to evaluate the bone microarchitecture which reflects the bone quality and strength.
b) QCT; discriminates trabecular from cortical bone, but it failed to identify the bone-turnover activity and the ROD type.
c) HR-pQCT; assess cortical and trabecular bone and microarchitecture.
d) PET scan; bone tracer used in the assessment of bone turnover and osteoblast activity, bone formation rate, osteoblast, osteoclast, and mineralization surfaces, (sensitivity 76% and specificity 78%).
e) MRI; a significant association between MRI and trabecular thickness and separation as well as mineralization and turnover parameters.
Prevention of ABD in CKD
Romosozumab
ABD is it a always a disease
ABD is an imbalance in bone metabolism and it may be an overlapped with high and low turn over, an some times it is a transitional features between low and high turnover.
Balancing treatment after specific diagnosis to avoid overtreatment and dynamic disease.
ABD is a syndrome with different factors and effectors, so careful handling and managing alteration is vial in stabilizing the restoring metabolic disturbance
Newer Monoclonal antibodies has a promising in supporting bone strength and reduce fracture incidence
Summarize the pathogenesis of adynamic bone disease.
The pathophysiology of ADB is certainly multifactorial (Figure 1), comprising
patient-related and iatrogenic factors on a predisposed genetic background
A state of imbalance between the low circulating levels of bone anabolic factors (e.g., insulin-like growth factor (IGF)-I) and the increased expression of bone-turnover–inhibitory factors, such as sclerostin and Dickkopf-related protein-1 (Dkk-1), largely predominates
This imbalance suppresses bone formation through repression of WNT/β-catenin signaling. Moreover, Indoxyl sulfate, a protein-bound uremic toxin.Ithas been
linked to ADB. The circulating cytokines, for instance interleukin-1 (IL-1), IL-6, and tumor necrosis factor α (TNFα), have been supposed to directly impair bone-forming and -resorbing cells. Patients on PD are more vulnerable to ADB due to high dialysate calcium concentration and possibly increased glucose load. Ageing, diabetes mellitus, malnutrition and alcoholism have all been shown as risk factors for the development of ADB. in addition, aluminum significantly decreases both osteoclast and osteoblast activities and causes defective mineralization. Vigorous use of oral calcium and vitamin D sterols to control secondary hyperparathyroidism, the high dialysate calcium concentrations, and surgical parathyroidectomy induced hypoparathyroidism has extensively contributed to the growing prevalence of ADB.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Adynamic bone results in poor skeletal health, bone fragility and diminished ability to restore damaged bone. Delayed remodeling promotes more secondary mineralization, making the bone stiffer. However, in the long term, over mineralization can induce a brittle bone that increases the risk of atypical fractures. Moreover, bone turnover suppression may cause microcracks which are difficult to heal in presence of low bone formation. The uncoupling of bone turnover with a relative predominance of resorption may also contribute to bone loss in patients with ADB and CKD. There are reports about J- or U-shaped association between PTH levels and mortality. In addition, there is possible association between ADB and VC in CKD
What are the characteristic findings in bone biopsy results for diagnosing
adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
In patients with ADB, bone histomorphometry reveals low bone turnover with reduced number of both osteoblasts and osteoclasts, low bone volume coupled with normal mineralization. The presence of thin osteoid is the main feature differentiating ADB from the other LBT subgroup ‘‘osteomalacia’’.
Bone biopsy is the gold standard test to assess metabolic bone disease as its classification is mainly based on turnover/mineralization/volume system. Turnover represents the process of skeletal remodelling, attained by both bone resorption and formation. It is assessed using bone formation rate, activation frequency, osteoclasts, and osteoblasts number. Mineralization reflects calcification of bone collagen and is assessed using osteoid volume, osteoid thickness as well as dynamic, tetracycline-based evaluation of mineralization lag time and osteoid maturation time. Lastly, volume which reflects the amount of bone per unit. On the other hand, it has some limitations including high cost, lack of expertise and limited patient acceptability. Moreover, the wide discrepancy of the diagnostic cutoffs led to significant differences in the classification of bone turnover. Selection bias, age, gender, ethnicity, in addition to definition of normal range differences might explain the inconsistencies.
How to diagnose adynamic bone disease in patients with CKD?
How to prevent adynamic bone disease in patients with CKD?
By avoiding risk factors associated with reduction of bone turnover, such as aluminum exposure, oversuppression of PTH secretion by using calcium supplements, high doses of vitamin D analogs and/or calcimimetics, in addition tofactors that may contribute to PTH resistance, such as hyperphosphatemia, malnutrition, inflammation, and progression of CKD.
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab, sclerostin humanized monoclonal antibody, acts as an anabolic and anti- resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited as there was a cardiovascular concern that might be related to increased vascular calcification with its usage. However, some recent studies demonstrated one-year romosozumab cardiovascular safety in HD patients.
After reading the article, do you think adynamic bone is always a disease?
I think it is still unknown if all cases of ADB are maladaptive, or it can be adaptive/compensatory in certain situations. It is not very well-known if all forms of ADB are truly pathological, and likewise milder degrees of ADB could be a compensatory mechanism to guard against bone loss.
Here are the answers of this article:
Summarize the pathogenesis of adynamic bone disease.
It is multifactorial comprising patient-related and iatrogenic factors with genetic background. A state of imbalance between the low circulating levels of bone anabolic factors and the increased expression of bone turnover–inhibitory factors (sclerostin, and Dickkopf-related protein-1) largely predominates. This imbalance suppresses bone formation through repression of WNT/β-catenin signaling. Moreover, indoxyl sulfate (uremic toxin) has been linked to ADB. In addition, the circulating cytokines such as IL-1, IL-6, and TNFα have been supposed to directly impair the bone forming and resorbing cells. Patients on PD are more vulnerable to ADB due to high dialysate calcium concentration and possibly increased glucose load. Ageing, diabetes mellitus, malnutrition and alcoholism have all been shown as risk factors for the development of ADB. in addition, aluminum significantly decreases both osteoclast and osteoblast activities and causes defective mineralization. Vigorous use of oral calcium and vitamin D sterols to control secondary hyperparathyroidism, the high dialysate calcium concentrations, and surgical parathyroidectomy induced hypoparathyroidism has extensively contributed to the growing prevalence of ADB.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
Adynamic bone results in poor skeletal health, bone fragility and diminished ability to restore damaged bone. Delayed remodeling promotes more secondary mineralization, making the bone stiffer. However, in the long term, over mineralization can induce a brittle bone that increases the risk of atypical fractures. Moreover, bone turnover suppression may cause microcracks which are difficult to heal in presence of low bone formation. The uncoupling of bone turnover with a relative predominance of resorption may also contribute to bone loss in patients with ADB and CKD. There are reports about J- or U-shaped association between PTH levels and mortality. In addition, there is possible association between ADB and VC in CKD.
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
In patients with ADB, bone histomorphometry reveals low bone turnover with reduced number of both osteoblasts and osteoclasts, low bone volume coupled with normal mineralization. The presence of thin osteoid is the main feature differentiating ADB from the other LBT subgroup ‘‘osteomalacia’’.
Bone biopsy is the gold standard test to assess metabolic bone disease as its classification is mainly based on turnover/mineralization/volume system. Turnover represents the process of skeletal remodelling, attained by both bone resorption and formation. It is assessed using bone formation rate, activation frequency, osteoclasts, and osteoblasts number. Mineralization reflects calcification of bone collagen and is assessed using osteoid volume, osteoid thickness as well as dynamic, tetracycline-based evaluation of mineralization lag time and osteoid maturation time. Lastly, volume which reflects the amount of bone per unit. On the other hand, it has some limitations including high cost, lack of expertise and limited patient acceptability. Moreover, the wide discrepancy of the diagnostic cutoffs led to significant differences in the classification of bone turnover. Selection bias, age, gender, ethnicity, in addition to definition of normal range differences might explain the inconsistencies.
How to diagnose adynamic bone disease in patients with CKD?
How to prevent adynamic bone disease in patients with CKD?
By avoiding risk factors associated with reduction of bone turnover, such as aluminum exposure, oversuppression of PTH secretion by using calcium supplements, high doses of vitamin D analogs and/or calcimimetics, in addition tofactors that may contribute to PTH resistance, such as hyperphosphatemia, malnutrition, inflammation, and progression of CKD.
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab, sclerostin humanized monoclonal antibody, acts as an anabolic and anti- resorptive concurrently. Romosozumab studies in patients with advanced CKD are limited as there was a cardiovascular concern that might be related to increased vascular calcification with its usage. However, some recent studies demonstrated one-year romosozumab cardiovascular safety in HD patients.
After reading the article, do you think adynamic bone is always a disease?
I think it is still unknown if all cases of ADB are maladaptive, or it can be adaptive/compensatory in certain situations. It is not very well-known if all forms of ADB are truly pathological, and likewise milder degrees of ADB could be a compensatory mechanism to guard against bone loss.
ABD happens due to loss of osteoblast activity under the action of loss of anabolic hormone.
it is found to happen early in CKD stages 2 to 3 with an increase the sclerotin level which inhibits the osteoblast and bone formation.
a uraemic toxin is also implicated through the indoxyl sulphate produced from the metabolism of tryptophan by gut microbiota, causing a decrease in bone-forming and resorting activity.
t is found that PD patient has high rate of ABD due to high Ca dialysate and high glucose .
DM decrease the bone quality and increase the risk of fracture. Advanced glucose end products interfere with osteoblast and osteoclast activity.
ABD is related to medication which has been used for cKD patients, like high Ca load and used of calcimimetic medication, which lead to PTH suppression .
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
normal miniralization with reduce bone volume and no osteoblast and osteoclast activity .
The drawbacks of bone biobsy include ihigh cost, lack of expertise, and limited patient acceptability.
Summarize the pathogenesis of adynamic bone disease
The pathophysiology of ADB is multifactorial ), comprising patient-related and iatrogenic factors on a predisposed genetic background. A state of imbalance between the low circulating levels of bone anabolic factors (e.g., insulin-like growth factor (IGF)-I) and the increased expression of bone-turnover–inhibitory factors, such as sclerostin and Dickkopf-related protein-1 (Dkk-1), largely predominates. This imbalance ultimately suppresses bone formation through repression of WNT/β-catenin signaling . Moreover, uremic toxins may play a role in this setting. Uremic toxins are compounds that accumulate in the body as renal function declines, adversely affecting the function of multiple organs and systems. Indoxyl sulfate, a protein-bound uremic toxin (PBUT) generated by the gut microbiome from the metabolism of tryptophan, has been linked to LBT [15]. Experimental evidence suggests that the gut-derived toxin indoxyl sulfate aggravates LBT and inhibits osteoclast function and differentiation; however, further clinical studies would be more conclusive [31–33]. Of note, the circulating cytokines, for instance interleukin-1 (IL-1), IL-6, and tumor necrosis factor α
diagnosis ob ADBD
laboratory
iPTH
bone turnover
bone spisfic ALP
bone biopsy
==================
how to prevent ABD
1-avoid exposure to aluminum exposure
2=avoid oversuppression of PTH by VDRA and calcimimetics
**How to diagnose adynamic bone disease in patients with CKD?
Laboratory tests : bone turnover markers eg bone formation markers like total alkaline phosphotase and bone specific alkaline phosphotase especially Bsap, procollagen type 1 N terminal pro-peptide and procollagen type 1 C terminal pro-peptide which are indicators of collagen synthesis especially P1NP bone derived osteocalcin but is of limited value in advanced CKD
Sclerostin and DKK1 which are inhibitor of bone formation
Bone resorption markers :type 1 collagen in normal population but it is use is limited in Ckd, tartrate resistant acid phosphotase 5 b used in ckd
Intact PTH when less than 150pg/ml so consider LBT
DXA normal or low BMD advantages is available and low cost but cannot differentiate between cortical and trabecular bone
Quantitative CT scan can differentiate between cortical and trabecular bone
MRI can diagnose microarchicture and correlate well with histomorphometric TMV parameters
PET scan florin 18 sodium fluoride for assessment of bone turnover and osteoblast function
Bone biopsy which is the gold standard for Diagnosis of ADB to assess bone turnover, mineralization and volume
Microcomputer tomography is 3D high resolution modality use small bone sample used in children with ESKD
Fourier transform infrared spectroscopy which is a tool used in analyzing mineral quality and bone matrix properties in bone biopsy Specimen
**How to prevent adynamic bone disease in patients with CKD?
Avoidance of risk factor associated with the decrease of bone turnover such as oversuppresion of pth from overdone of calcium or excessive use of vitamin D analogs or calcimimetic and from aluminum toxicity
Or factors that lead to PTH resistance like malnutrition, hyperphosphatemia, inflammation and progression of ckd
**Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Is a Sclerostin humanized monoclonal antibody has anabolic and antiresorptive activity so lead to improvement in BMD of the hip and spine in ckd but. Cardio-vascular concern
**After reading the article, do you think adynamic bone is always a disease?
Is a difficult question to be answered, as it has multifactorial causes and depends on the duration af ckd and underlying cause,
It is a state of loss of ability of bone to remodule, can return it is activity when the effect removed but it is also associated with many complications and increase risk of VC and mortality.
**Summarize the pathogenesis of adynamic bone disease.
The pathogenesis is multifactorial in which there is imbalance between low bone forming factors eg IGF 1 and increase expressions of bone inhibitory factors eg sclerostin and DKK-1 this will suppress bone formation through repression of WNT/B catinen Signalling.
Uremic toxins like indoxyl sulphate produced from metabolism of tryptophan by gut microbiota, cause decrease in bone forming and resorting activity.
PD patient at risk of ADB from high Calcium content and High glucose, in addition to the age, gender and alcoholic,will decrease bone formation. Aluminum toxicity from water in dialysate or aluminum phosphate binders will decrease osteoblast and osteoclast activity
Gonadal dysfunction in which decrease testosterone in men and estradiol in women cause decrease bone activity and affect bone health
Inflammatory cytokines like IL1, IL6 and TNF-alpha will decrease bone forming and resorting cells. Malnutrition and malnutrition – inflammation complex affect on bone health and quality and increase catabolic state and bone loss.
Parathyroidectomy causes increase incidence of ADB and VC.
DM decrease bone quality and increase risk of fracture. Advanced glucose end products interfere with osteoblast and osteoclast activity.
Low vitamin D level causes suppressed vitamin D receptors expressions
**What are the detrimental effects of adynamic bone diseases on the patient’s health?
It lead to poor skeletal health, increase bone fragility and inability to restore damaged bone. Delayed remodeling will increase secondary mineralization and making bone stiffer and tougher and lead to a typical fracture, in addition to that suppression of bone turnover lead to micocracks that are difficult to heal in the presence of low bone formation. Bone loss increase with low trabecular bone volume and increase risk of fracture.
Studies show J or U shape association between PTH and mortality as ADB may increase risk of all causes and cardiovascular mortality in addition to increase risk of VC
**What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
It based on turnover /mineralization /volume
Turnover represent skeletal remodeling and bone formation and resorption activity which represented by the number of osteoclast and osteoblast, bone formation rate and activation frequency
Mineralization represents calcification of bone collagen and assessed using osteoid volume, osteoid thickness and dynamic, TC based evaluation of mineralization lag time and osteoid maturation time.
Volume represents amount of bone per unit
In ADB bone show low number of osteoclast and osteoblast, low bone volume and normal mineralization.
The presence of thin osteoid is the main feature that differentiate ADB from osteomalacia.
Drawbacks :high cost, lack of expertise, limited patient acceptability, wide discrepancy of the diagnostic cutoff, selection bias, age, gender and ethnicity, definition of no range difference may explain the inconsistencies.
1-Summarize the pathogenesis of adynamic bone disease.
ABD is characterized by an imbalance in the circulation of bone anabolic factors such as insulin-like growth factor and an increase in the levels of DKK and Sclerostin,Indoxol sulfate, a uremic toxin, inhibits bone formation by inhibiting osteoclast differentiation.
TNFalpha, IL-6, and IL-1 are inflammatory factors that inhibit bone formation.
Because of the low albumin, high calcium, and high glucose load,
PTH suppression caused by medications such as vitamin D , Calcimemetics, and parathyroidectomy.
Vitamin D Receptors are essential for bone health because they inhibit osteoblast apoptosis and promote osteoblast differentiation.
2-What are the detrimental effects of adynamic bone diseases on the patient’s health?
Poor skeletal health, Bone fragility, Diminished ability to restore damaged bone,and delayed bone remodeling and increased risk of all cause & cardiovascular mortality dueto vascular calcification.
3-What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease
Normal mineralization and low bone volume decreased osteoblasts and osteoclasts activity and presence of thin osteoid is primarily used to distinguish ABD from osteomalacia.
what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Strength s point accuracy in providing a precise assessment of metabolic bone disease.
The drawbacks of bone biobsy include ihigh cost, lack of expertise, and limited patient acceptability.
4-How to diagnose adynamic bone disease in patients with CKD?
Lab as Bone turnover marker : low bone formation -low tAP, low bAP, low intact P1NP high sclerostin.
Low Bone resorption: low TRAP5b.
Low iPTH :<150 pg/ml.
Radiology DXA scan, MRI: Assess bone microarchitecture.
Bone biopsy is the gold standard low turnover, normal mineralization, low or normal bone volume.
5-How to prevent adynamic bone disease in patients with CKD?
Avoid over-suppression of PTH by vitamin D & calcimimetics
Avoid Ca overload ,Avoid malnutrition–inflammation, improve uremic toxins via improve adequecy of dialysis reduce intestinal generation of toxins.
6-Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Unfortunately arelimited studies in CKD
And increased incidence of cardiovascular calcification
7-After reading the article, do you think adynamic bone is always a disease?
Yes I think so
Summarize the pathogenesis of adynamic bone disease.
a combination of many factors will lead to icrease bone turnover inhibitory factors and decrease anabolic factors, cumulating into regression of WNT/B catenin signaling and suppression of bone formation.these factors include:1- patient age, 2-DM,3- alcoholism,4-aluminium through HD water or aluminium containing phosphate binder, 5- uremic toxins eg indoxyl sulfate inhibit osteoclast functio and differentiation, 6- malnutrition-inflammation complex: creates negative protein balance, increased proinflammatory markers,and catabolic state favoring suppression of bone formationa and increased bone resorption, 7- gonadal dysfunction impairs bone formation,8- last but not least is hypoparathyroidism and pth hyporesponsiveness status.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
1-LBT is assosciated with poor skeletal health ch.ch by bone fragility,decrease ability to restore damaged bone, delayed remodelling and excess mineralization, making bone more stiffer, but overtime the bone becomes brittle.
2-ABD is assosciated with vascular calcification, due diminished buffering of the bone.
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease,
decreased number of osteoblast and osteoclast, low bone volume and normal mineralization
drawbacks of bone biopsy
high cost, lack of expertise, and limited acceptability, no clear cutoffs.
How to diagnose adynamic bone disease in patients with CKD?
lab, radiolagy and bone biopsy
lab includes 1- bone resorption markers, 2-bone formation markers, 3- PTH
1- bone resorption markers: CTX is the invesigation of choice in normal population, but of limited value in CKD as it is renal excreted,
2- BONE formation markers: a- total and bone specific alkaline phosphatase, b-procollagen type I N-terminal and c-terminal. c- sclerostin and DKK-1: their level increase in LBT
3- PTH: with level less than 150. LBT should be considered
radiology includes
a- DXA nd quantitative computed tomography, but soft tissue calcification may interfer with DXA
b- high resolution periperal quantitative computed tomography: evaluate microarchitecture
c-PET scan: there is significant correlation between floride activity and histomorphometric parameters
d-MRI: CAN evaluate microarchitecture
3- bone biopsy is the gold standard for diagnosis of LBT
How to prevent adynamic bone disease in patients with CKD?
1- avoid aluminum toxicity, limit use of aluminum based phosphate binder and check aluminium in HD water
2- avoid of suppression of parathyroid gland: a- careful use of vit D and calcimimetics, b- frequent monitoring of PTH
3- Avoidance of calcium overload: a- use of non- calcium based phosphate binder, b- use of low calcium dialysate in PD
4- uremic toxins a- improve adequecy of dialysis b-reduce intestinal generation of toxins.
5- correction of malnutrition-inflammatory syndrome: improvement of nutritonal status and inflammatory profile can improve bone turnover
6- antiresorptive: eg bisphosphonate should be prescribed a case by case
# Summarize the pathogenesis of adynamic bone disease.
without osteoid accumulation i.e decrease bone matrix
The main cause and pathogenesis of ABD and proposed mechanism of decrease bone formation
. In pt. with CKD is decreased osteoblastic activity or differentiation or proliferation as follow
1-low serum vit D >>>>decrease osteoblast differentiation and decrease life span of osteoblast
2-metabolic acidosis and high phosphate >>>>>suppression of 1,(25 )2 vit D production
3- uremic toxins decrease vit D , VDR and decrease osteoblast proliferation
4- hypogonadism and aging >>>decrease osteoblast life span
5- malnutrional and DM >>>>>decrease IGF and decrease vit D >> decrease osteoblast proliferation
6- high serum IL , IL 6 TNF >>>>decrease osteoblast life span
# What are the detrimental effects of adynamic bone diseases on the patient’s health?
The ABD poor impact on bone health ,poor skeletal health , bone fragility
Increased hazards risk for both , all causes of cardiovascular mortality
In dr alhusseni study conclusion that low bone turn over and vascular calcification are predominant in early stage of CKD
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
How to diagnose adynamic bone disease in patients with CKD?
Another marker added as b alp ( bone specific alp)
PINP —-TRAP Sb
BONE biopsy followed histomorphometry analysis is the golden standard method for diagnosis
Histological finding
– few or no osteoblast
– Minimal or no peritrabecular fibrosis
– Bone volum normal or low , bone microarchitecture disrupted
– Bone formation is substantially diminished
– Both the rate of collagen synthesis and the subsequent mineralization are subnormal
How to prevent adynamic bone disease in patients with CKD?
Reduced vit D analog and Reduced or stop calcimumetic
Treat al. intoxication
DFO
1- Summarize the pathogenesis of adynamic bone disease:
2- What are the detrimental effects of adynamic bone diseases on the patient’s health?
3- What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and Bone biopsy findings:
4- what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
5- How to diagnose adynamic bone disease in patients with CKD?
A.Laboratory: iPTH < 150 pg/ml, BTM; lowTRAP5b, low TAP, BSAT, intact PINP, Dkk1, & high sclerostin
B.Radiology: DEXA/QCT; normal or redeuced BMD. MRI; microarchitecture. PET; reduce 18F-fluride activity
C.Bone biopsy (Histomorphometry): TMV classification
6- How to prevent adynamic bone disease in patients with CKD?
7- Criticize the use of romosozumab as osteoanabolic in patients with CKD.
8- After reading the article, do you think adynamic bone is always a disease?
ABD is characterized by an imbalance in the circulation of bone anabolic factors such as insulin-like growth factor and an increase in the levels of DKK and Sclerostin. The suppression of the Wnt/Beta Catonin pathway is the mechanism of action.
Indoxol sulfate, a uremic toxin, inhibits bone formation by inhibiting osteoclast differentiation.
TNFalpha, IL-6, and IL-1 are inflammatory factors that inhibit bone formation.
Because of the low albumin, high calcium, and high glucose load, peritoneal dialysis may aggravate ABD
ABD was previously linked to HD Water contamination with aluminum.
nowadays, the main cause of ABD is PTH suppression caused by medications such as vitamin D , Calcimemetics, and parathyroidectomy.
Malnutrition (low albumin level) exacerbates ABD-
Estrogen and testosterone levels are known to affect bone health.
Vitamin D Receptors are essential for bone health because they inhibit osteoblast apoptosis and promote osteoblast differentiation. There will be more osteoblast apoptosis in the presence of low Vitamin D, which will impact bone health and increase the risk of fracture. Furthermore, diabetic patients are at a higher risk of overall fracture.
*Calciphylaxis
*Fractures
*Arteriosclerosis
*Increased incidences of CVDs and increased mortality
-Normal mineralization and low bone volume;
-decreased osteoblasts and osteoclasts.
-The presence of thin osteoid is primarily used to distinguish ABD from osteomalacia.
The gold standard for distinguishing between different types of ROD is a bone biopsy with a tetracycline label.
High cost, lack of experience and expertise, and limited patient acceptability are some of the limitations.
Bone turnover marker: poor bone formation – low tAP, low bAP, and low intact P1NP and high sclerostin in the laboratory.
Bone resorption is poor: TRAP5b is low.
Low iPTH:150 pg/ml sensitivity and specificity are 68% and 61%, respectively.
DXA: BMD is normal or reduced.
Cannot distinguish between cortical and trabecular bone, but QCT can.
Evaluate bone microarchitecture using MRI. Correlation with parameters of the TMV.
PET: 18F fluoride activity is poor.
Bone biopsy: Low turnover, normal mineralization, and low or normal bone volume, as measured by histomorphometry.
Prevention based on avoiding risk factors such as aluminum exposure, excessive suppression, (PTH), calcium overload and administration of high doses of vitamin D and calcimimetics. Moreover, factors contributing to PTH resistance should be tackled ( like hyperphosphatemia, malnutrition, inflammation and progression of CKD)
*Limited studies in CKD
*Linked to increased incidence of CVD
*May be safe for one year (Japanese Study)
ABD is not pathologically significant in all patients, but should be constantly observed because it may be a precursor to osteitis fibrosa/high-turnover bone disease, and it could be a compensatory response.
Summarize the pathogenesis of adynamic bone disease.
The imbalance between low circulating levels of bone anabolic factors and increased expression of bone-turnover-inhibitory factors predominates, suppressing the bone formation and WNT/ß-catenin signaling.
Uremic toxins, such as indoxyl sulfate, aggravate low bone turnover and inhibit osteoclast function and differentiation.
Cytokines, such as IL-1, IL-6, and tumor necrosis factor a (TNFa) have been suggested to directly impair bone forming and resorbing cells.
Patients on peritoneal dialysis are more vulnerable to ADB due to high dialysate-ca concentration and increased glucose load. Aging, diabetes mellitus, malnutrition, and alcoholism are risk factors.
Aluminum overload resulting from contamination of hemodialysis water and non-judicious use of aluminum-containing phosphate binders can contribute.
Parathyroidectomy has been shown to cause a shift in bone turnover from high to low
Treatment with cinacalcet and calcitriol therapies can also precipitate hypoparathyroidism.
What are the detrimental effects of adynamic bone diseases on the patient’s health?
ADB can lead to poor skeletal health, bone fragility, and diminished ability to restore damaged bone. it is also related to Calciphylaxis and vascular calcification accelerating the risk of cardiovascular calcifications
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
Bone biopsy is the gold standard for diagnosing adynamic bone disease (ADB), and it is the cornerstone for detecting different types of renal osteodystrophy (ROD). Characteristic findings in bone biopsy results for diagnosing ADB include decreased or absent bone formation, low cellularity of both osteoblasts and osteoclasts, thin osteoid seams, and minimal or no peritrabecular or marrow fibrosis.
The strengths of Bone biopsy: The strengths of bone biopsy in diagnosing ROD include its accuracy in providing a precise assessment of metabolic bone disease.
The drawbacks of bone biopsy: The drawbacks include its high cost, lack of expertise, and limited patient acceptability.
How to diagnose adynamic bone disease in patients with CKD?
The diagnosis of adynamic bone disease (ADB) in patients with CKD requires a combination of clinical, laboratory, imaging, and histomorphometric studies.
Clinical evaluation should include a review of an individual’s risk factors for ADB. Laboratory tests that evaluate bone turnover, such as bone-specific alkaline phosphatase (BSAP) and tartrate-resistant acid phosphatase 5b (TRAP 5b), can help to determine the bone turnover status of an individual.
iPTH cutoff of <150 pg/mL for diagnosis of ADB
Imaging studies, such as dual-energy X-ray absorptiometry (DXA) and quantitative computed tomography (QCT), can help to assess bone mineral density (BMD). Histomorphometry: is the gold standard for diagnosing ADB.
Fourier-transform infrared spectroscopy (FTIR) and positron emission tomography (PET) can also provide information on bone quality.
Finally, magnetic resonance imaging (MRI) can be used to assess bone microarchitecture.
How to prevent adynamic bone disease in patients with CKD?
Prevention and treatment of ADB in CKD involve avoiding risk factors associated with the reduction of bone turnover, such as aluminum exposure, over suppression of PTH secretion due to calcium overload, administration of high doses of vitamin D analogs, and/or calcimimetics.
Additionally, management strategies such as improving nutritional status and reducing inflammation may help increase bone turnover.
Additionally, bisphosphonates may be considered for use in patients with CKD on a case-by-case basis, taking into consideration bone turnover.
Finally, antiresorptive medications may be used, although studies evaluating the efficacy and safety of antiresorptives in patients with advanced CKD are needed.
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
Romosozumab is not suitable for use as an osteoanabolic agent in patients with CKD due to the;
After reading the article, do you think adynamic bone is always a disease?
No, I do not think adynamic bone is always a disease. While it can be a sign of pathology, it can also represent an adaptive process to suppress bone resorption and further bone loss.
Further research and evaluation are needed to determine if adynamic bone is a true disease or if it is a symptom of another underlying condition.
The diagnosis mainly relies on a bone biopsy, gold standard, and reduced bone formation and bone-resorption markers.
PTH Despite its limitations, intact or bio-intact PTH is the most widely used biomarker for CKD–MBD monitoring. LBT should be considered when iPTH is < 150 pg/mL in patients with advanced CKD.
Bone-Formation Biomarkers
Both blood total and bone-specific alkaline phosphatase (TAP, BSAP) are indicators for osteoid development, whereas BSAP better distinguishes bone turnover status in dialysis patients.
P1NP and P1CP indicate collagen production. In CKD patients, only intact P1NP is trustworthy since it is unaffected by GFR or dialysis.
Bone-Resorption Biomarkers
CTX, the reference bone-resorption marker in normal people, is really excreted in CKD patients. Nevertheless, tartrate-resistant acid phosphatase 5 b (TRAP5b) is unaffected by renal function or dialysis, and larger levels were associated with quicker cortical-bone loss.
Radiology
Dual-Energy X-ray Absorptiometry (DXA) Scan and Quantitative Computed
Tomography (QCT, MRI assess bone microarchitecture, PET; decreased 18F-fluride activity
The management involves avoiding risk factors that reduce bone turnover, such as aluminum exposure, over suppression of PTH production owing to calcium overload, excessive doses of vitamin D analogs, and/or calcimimetics. Hyperphosphatemia, malnutrition, inflammation, and CKD development may all cause PTH resistance, thus, these should be addressed.
Yes, I think it is a disease and needs early intervention to avoid more progression and complications.
A state of imbalance of low ciruclating level of bone anabolic factor like insulin like growth factor and increase of level of DKK and Sklerostin. The mechanism of action is through Wnt/Beta Catonin pathway suppression.
Uremic toxin like indoxyl sulfate suppress bone formation through inhibiting osteoclast differentiation.
Inflammatory factor like TNFalpha , IL6 und IL 1 inhibit bone formation
Peritoneal dialysis is a factor that may aggravate LBD because of low albumin, high calcium and high glucose load.
In the past the contamination of HD Water with aluminium was linked with ABD.
The main key factor that induce ABD is the oversuppression of PTH through medication like overuse of Vit D , Calciummimetics , parathyreoidectomy
Malnutrition (low albumin level) aggravate ABD- Japanese study over 15 000 HD PAtient with PTH < 60 and low albumin.
Decreased Estrogen and testesterone are well known to impact bone health.
Vitamin D Receptor are important in maintaing bone health, they block osteoblast apoptosis and promote osteoblast differentiation. In the presence of low Vitamin D , there will more osteoblast apoptosis what impact bone health and increase the risk of
fracture. Furthermore , patients with Diabetes mellitus have high risk of overall fracture.
2. Detrimental effects are increased cardiovascular calcification, increase risk of fracture, increase mortality.
Increased calcification around joints, lobular calcification masses like tumoral calcification.
Increased risk of calciphylaxis. Uncontrolled parathyroidismus is not a key determinant of calciphylaxis.
-Barreto demonstrated association between ABD and Coronary artery calcification.
3.characteristic finding in bone biopsy are low bone turnover, normal mineralization and low bone volume.
-reduced osteoblasts and osteoclasts.
-the presence of thin osteoid is used mainly for differential from osteomalacia.
Bone biopsy with tetracycline label is considered the gold standard to differentiate between different types of ROD.
Limitations include: high cost, lack of experience and expertise, limited patient acceptability.
4.diagnosis of ABD in patients with CKD:
Laboratory finding:
Bone turnover marker : low bone formation -low tAP, low bAP, low intact P1NP high sclerostin.
Low Bone resorption: low TRAP5b.
Low iPTH :<150 pg/ml sensitivity and specificity respectively 68% and 61%.
Radiology
DXA: Normal or decreased BMD. Low dose radiation.but it cannot differentiate between
Cannot differentiate between cortical and trabecular bone but QCT can differentiate.
MRI: Assess bone microarchitecture. Correlation with TMV parameters.
PET: low 18F fluoride activity.
Bone biopsy
Histomorphometry: low turnover, normal mineralization, low or normal bone volume.
FTIR: increased mineral to matrix ratio. Bigger crystal size.
MikroCT: exvivo images of bone sample:
-ABD(increased BMD)
-Osteomalacia(decreased BMD)
5.Prevention based on the avoidance of risk factors like aluminum exposure, over suppression of PTH due to calcium overload, and due to administration of high dose vitamin D, and calcimimetics.moreover factors that contribute to PTH resistance should also be targeted( like hyperphosphatemia, malnutrition, inflammation and progression of CKD)
6. Romosozumab is a monoclonal antibodies against sclerostin -there is safety concerns because of linkage to increased vascular calcification in animals
7. I think signs of mild low turnover bone disease might be adaptive especially in early stage CKD but furthermore aggrevation of low turnover bone disease till the level of adynamic bone is a disease that obviously associated with CVC, all cause mortality, calciphylaxis..
Summarise the pathogenesis of ABD:
What are the detrimental effects of adynamic bone diseases on the patient’s health?
What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
How to diagnose adynamic bone disease in patients with CKD?
How to prevent adynamic bone disease in patients with CKD?
Criticize the use of romosozumab as osteoanabolic in patients with CKD.
After reading the article, do you think adynamic bone is always a disease?
1 -Summarize the pathogenesis of adynamic bone disease.
bone biopsy is the cornerstone to detecting different types of ROD.
CLASSIFICATION based on the turnover, mineralzation and volume.( TMV) system.
Reduced number of both osteoblasts & osteoclasts
Normal minerilzation, thin osteoid
Low volume Normal
B .Strength of bone biopsy
bone biopsy is the cornerstone to detecting different types of ROD.
– C.Drawbacks
4 -How to diagnose adynamic bone disease in patients with CKD?
A.Laboratory
B.Radiology diagnose adynamic bone disease in patients with CKD?
A.Laboratory
B.Radiology
C.Bone biopsy
5–How to prevent adynamic bone disease in patients with CKD?
6–Criticize the use of romosozumab as osteoanabolic in patients with CKD.
7–After reading the article, do you think adynamic bone is always a disease?
-Summarize the pathogenesis of adynamic bone disease.
-What are the detrimental effects of adynamic bone diseases on the patient’s health?
-What are the characteristic findings in bone biopsy results for diagnosing adynamic bone disease and what are the strengths and drawbacks of bone biopsy in diagnosing renal osteodystrophy?
A.Bone biopsy findings
B.Strength of bone biopsy
C.Drawbacks
-How to diagnose adynamic bone disease in patients with CKD?
A.Laboratory
B.Radiology
C.Bone biopsy (Histomorphometry)
-How to prevent adynamic bone disease in patients with CKD?
-Criticize the use of romosozumab as osteoanabolic in patients with CKD.
-After reading the article, do you think adynamic bone is always a disease?