by Divya Bajpai, MD (@divyaa24)
Disorders of mineral and bone metabolism (MBD) commence early in the course of chronic kidney disease (CKD). Kidney Disease Improving Global Outcomes (KDIGO) recommends the term CKD-MBD to describe this systemic disorder and restricts the use of the term renal osteodystrophy to define the bone histologic lesions. CKD-MBD is defined as an abnormality of one or more of the following:
A. Calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism.
B. Bone turnover, mineralization, volume linear growth, or strength.
C. Vascular or another soft-tissue calcification.
Bone turnover is an ongoing process of bone resorption which is replaced by the formation of new bone. Adynamic bone disease is characterized by a decrease in the number of bone cells (both osteoblasts and osteoclasts) associated with decreased accumulation of osteoid (osteoid volume <12% -15%), and no (or minimal) bone marrow fibrosis. It must be differentiated from another common low bone turnover disease - osteomalacia in which bone mineralization exceeds the defect in collagen synthesis by osteoblasts, resulting in increased osteoid formation.
Pathogenesis of low bone turnover in CKD
The major factor underlying adynamic bone disease (ABD) is either suppression of PTH release or resistance of PTH action on bones. The incidence of ABD has increased exponentially making it the most common form of renal osteodystrophy in dialysis patientsat present. This can be attributed to exogenous calcium loading via dialysate or via calcium-based phosphate binders but is primarily due to the evolution of effective measures to suppress PTH, like active vitamin D analogs and calcimimetics. Other possible risk factors like increased age and diabetes may also contribute to the rising incidence of ABD. Calcimimetics activate the calcium-sensing receptor (CaSR) on the parathyroid glands to suppress PTH release. In patients with chronic kidney disease, even higher than normal PTH levels are inadequate to maintain bone turnover. This is ascribed to the resistance to bone stimulatory effects of PTH due to the uremic milieu. Several mechanisms have been postulated to explain this PTH hyporesponsiveness – PTH receptor downregulation in the bone, decreased levels of bone morphogenetic proteins, increased levels of osteoprotegerin, uremic toxins, accumulation of N-terminal truncated PTH molecular species, and inhibition by inflammatory cytokines (figure 1). Due to this PTH resistance, serum PTH is not an optimal marker of bone turnover.
Clinical features and diagnosis
The majority of patients with ABD are asymptomatic; however, some may develop bone pain that results from the impaired ability to heal micro-fractures. Axial skeletal pain is a hallmark of aluminium-related ABD. These patients are at higher risk of fractures with PTH levels <195 pg/dL predicting fracture risk in a retrospective analysis. Additionally, there is a risk of developing hypercalcemia due to reduced buffering of calcium load by bones. Finally, ABD predisposes patients to vascular calcification which may add to the cardiovascular risk associated with CKD.
Documenting reduced bone formation rate (>1SD below the mean) on double-labeled bone biopsy from the anterior iliac crest remains the gold standard for the diagnosis of ABD. However, bone biopsies are invasive and their interpretation is difficult, hence they are rarely performed. Thus, surrogate markers of bone turnover like serum PTH, bone-specific alkaline phosphatase (BSAP), and serum C-telopeptide crosslink can be used. In patients on dialysis, a persistently low serum PTH (<100 pg/mL) is highly suggestive of ABD, especially in the presence of hypercalcemia. In patients not on dialysis, the progressive decreasing trend of PTH levels to less than the upper limit of normal (65 pg/ml) may reflect ABD. In the setting of unexplained hypercalcemia or bone pains and intermediate PTH levels, serum BSAP levels can be measured. Elevated BSAP levels (≥20 ng/mL) can rule out the diagnosis of ABD.
Can ABD occur in earlier stages of CKD?
ABD is common in patients on dialysis but its prevalence in earlier stages of CKD is less known. On reviewing bone histology studies from 1983 to 2006 the KDIGO Work Group found that the prevalence of ABD increased over the years and was present in up to 18% of patients with CKD stages 3 to 5.
Published in the recent issue of KI reports, the study by Husseini et al evaluates renal osteodystrophy and vascular calcification (VC) in 32 patients with CKD stages II to IV (mean eGFR = 44 ± 16 ml/min per 1.73 m2). Patients with systemic illnesses, which could potentially affect bone health, were excluded. Also, patients on treatment affecting bone metabolism (except calcium and parent vitamin D) like vitamin D analogs, bisphosphonates, calcimimetics, systemic anticoagulants, glucocorticoids, and other immunosuppressants were excluded. All patients underwent serum bone marker analysis, dual-energy X-ray absorptiometry (DXA) assessment, thoracic computed tomography for VC scoring, anterior iliac crest bone biopsy for mineralized bone histology, histomorphometry, and Fourier transform infrared spectroscopy (FTIR). Low bone turnover was found in 84% of patients. An inverse relationship was found between eGFR and bone turnover (in caucasian participants), which remained after adjustment for age and the presence of diabetes. The occurrence of low bone turnover in this cohort with moderately increased PTH levels despite the use of PTH lowering therapies indicates that secondary hyperparathyroidism is an adaptive mechanism to overcome the PTH hypo-responsiveness and maintain bone health in the early stages of CKD. With the use of FITR, they showed impaired mineral-to-matrix ratios in the early stages of CKD which correlate with reduced fracture resistance. Coronary artery calcification was found in 72% and 81% had aortic calcifications. They correlated negatively with bone formation rate and trabecular bone scores.
Visual abstract by @divyaa24
Despite being limited by the cross-sectional design and small sample size, this study employed a comprehensive evaluation of bone metabolism including an assessment of bone quality by FITR. The association of abnormal bone quality with VC in early CKD is intriguing and paves the path for future longitudinal studies. This study also underscores the need for control of risk factors and a high degree of suspicion for early diagnosis and management.