Adynamic bone disease associated with chronic kidney disease

INTRODUCTION — Disorders of mineral and bone metabolism are common sequelae of chronic kidney disease (CKD). Traditionally, these disorders were collectively termed renal osteodystrophy. However, disorders of bone and mineral metabolism in progressive CKD are frequently associated with cardiovascular abnormalities, and bone is now recognized as an endocrine organ that plays an active role in the various metabolic abnormalities and in the cardiovascular complications commonly encountered in patients with CKD [1]. Consequently, a work group convened by Kidney Disease: Improving Global Outcomes (KDIGO) recommended that the term renal osteodystrophy be used exclusively to define CKD-associated bone histologic lesions, including osteitis fibrosa cystica, adynamic bone disease, osteomalacia, and mixed uremic osteodystrophy. KDIGO also recommended the term chronic kidney disease-mineral and bone disorder (CKD-MBD) be used to describe the much broader systemic disorder resulting from CKD [2,3] that may manifest as one or more of the following:

●Abnormalities of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D metabolism

●Abnormalities in bone turnover, mineralization, volume linear growth, or strength

●Vascular or other soft-tissue calcification

Adynamic bone disease is a major form of renal osteodystrophy in patients on dialysis, particularly those with diabetes [4-12]. The disease is characterized by low bone turnover in conjunction with thin osteoid seams, decreased cellularity, and minimal bone marrow fibrosis, all in the absence of aluminum overload [13].

This topic reviews adynamic bone disease in patients with CKD. An overview of CKD-MBD is provided elsewhere:

●(See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)".)

The treatment of hyperphosphatemia and of secondary hyperparathyroidism in patients with nondialysis CKD and in patients with end-stage kidney disease is discussed elsewhere:

●(See "Management of hyperphosphatemia in adults with chronic kidney disease".)

●(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

●(See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

●(See "Refractory hyperparathyroidism and indications for parathyroidectomy in adult patients on dialysis".)

The use of bone biopsy to establish a specific diagnosis is discussed elsewhere:

●(See "Evaluation of renal osteodystrophy".)

EPIDEMIOLOGY — Adynamic bone disease is the most common form of renal osteodystrophy observed in patients on dialysis, particularly those with diabetes [4-12,14].

Over the last few decades, the prevalence of adynamic bone disease has increased relative to other forms of renal osteodystrophy, with variations in prevalence based in part upon geographic region [5,6,15,16].

Most of the earlier studies on bone disease were conducted in patients with end-stage kidney disease. To understand the development and progression of bone disease in earlier stages of CKD, an increasing number of studies on bone disease in this population were conducted. A Kidney Disease: Improving Global Outcomes (KDIGO) work group reviewed bone histology studies that were carried out between 1983 and 2006 and found that the prevalence of adynamic bone disease was 18 percent in CKD stages 3 to 5, 19 percent in patients on hemodialysis, and 50 percent in patients on peritoneal dialysis [2]. Subsequent bone biopsy studies reported a higher prevalence of adynamic bone disease among patients on hemodialysis (58 and 59 percent) [17,18]. These and other studies [7,14,15,19-22] suggest that adynamic bone disease has largely replaced osteomalacia as a frequently occurring type of renal osteodystrophy, and is now more common than osteitis fibrosa cystica [8,11].

Suggested risk factors for adynamic bone disease include the use of calcium-containing phosphate binders [14,15], high-dialysate calcium [23], and the use of active vitamin D analogs [24,25]. Other possible risk factors include increased age, diabetes, and parathyroidectomy [16].

The increased prevalence of adynamic bone disease may thus reflect multiple factors, including changes in patients' demographics (older and increased numbers of patients with diabetes), malnutrition, inflammation, hypoalbuminemia, and changes in therapeutic strategies, such as the increased and earlier use of vitamin D analogs and calcium-containing phosphate binders and differences in dialysis techniques [8].

It is possible, however, that the spectrum of bone lesions seen in patients on dialysis may change yet again in the future, particularly given the increasing use of non–calcium-containing phosphate binders and calcimimetic agents. In addition, the tendency for targeting a higher parathyroid hormone (PTH) level, as recommended by KDIGO, which recommends target PTH levels at two to nine times the upper limit of normal, may also result in resurgence of the formerly predominant bone lesions of osteitis fibrosa cystica [26,27].

●(See "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

●(See "Management of secondary hyperparathyroidism in adult patients on dialysis".)

PATHOGENESIS — Adynamic bone disease is characterized by low or absent bone formation in conjunction with thin osteoid seams, decreased cellularity, and minimal bone marrow fibrosis. This means that bone turnover is markedly reduced, and there is a lack of bone cell activity (both osteoblasts and osteoclasts). In contrast to osteomalacia, both the rate of collagen synthesis by osteoblasts and its subsequent mineralization are subnormal; thus, there is no increase in osteoid formation, as seen in osteomalacia. (See "Overview of chronic kidney disease-mineral and bone disorder (CKD-MBD)", section on 'Abnormalities in bone turnover, mineralization, volume linear growth, or strength'.)

A principal factor underlying adynamic bone disease is oversuppression of the parathyroid glands by medication (eg, vitamin D analogs, calcium-based phosphate binders, and/or calcimimetic agents) or parathyroidectomy [13,16,24,28-30]. However, resistance to PTH actions on bone also may contribute to the development of adynamic bone disease [31,32].

The role of calcium-containing phosphate binders is suggested by the following studies:

●In an animal model, adynamic bone was reversed with the administration of the non–calcium-based phosphate binder, sevelamer [33].

●A prospective bone biopsy study in 119 patients on hemodialysis compared the effects of calcium-based phosphate binders on bone histology with those of sevelamer. At the end of one year of treatment with either phosphate binder, a second bone biopsy was performed. The results showed no statistically significant differences in bone turnover or mineralization in patients treated with sevelamer compared with those treated with calcium carbonate, but bone formation increased and trabecular architecture improved only with sevelamer [14].

Calcimimetics (eg, cinacalcet) indirectly suppress PTH secretion by activating the calcium-sensing receptor (CaSR) on the parathyroid glands, leading to reduced bone turnover. Thus, excessive PTH inhibition by these agents may lead to adynamic bone disease as suggested by the following studies:

●A multicenter, single-arm, open-label trial evaluated the skeletal response to cinacalcet in 77 adult patients on dialysis with secondary hyperparathyroidism [34]. Bone biopsies were performed at baseline and after 6 to 12 months of cinacalcet treatment. In addition to reducing PTH levels, treatment with cinacalcet for at least six months decreased rates of bone formation and lowered several biochemical markers of high-turnover bone disease toward normal; two patients had adynamic bone disease at the end of the study with a PTH level below 150 pg/mL.

●In a double-blind, placebo-controlled trial, 32 patients on dialysis with secondary hyperparathyroidism (intact PTH ≥300 pg/mL) were randomly assigned to cinacalcet or placebo along with vitamin D and/or phosphate binder therapy; bone biopsies were performed at baseline and after one year of treatment [35]. Treatment with cinacalcet lowered PTH levels and reduced bone turnover in most patients on dialysis. Adynamic bone was observed in three patients receiving cinacalcet; in two of these, PTH levels were persistently low (<100 pg/mL).

However, bone cells also express the CaSR, and one experimental study suggests that calcimimetics have a direct anabolic action on bone that may reduce the risk of adynamic bone disease [36]. Whether the effect of cinacalcet, an allosteric modulator, on bone turnover is different from that of etelcalcetide, a direct activator of the CaSR, is unknown.

Although PTH levels in patients with adynamic bone disease are low, they tend to be higher than the upper limit of normal in the healthy population. This indicates that resistance to the bone stimulatory effects of PTH may play an even larger role since ‘normal’ PTH concentrations have been shown to be inadequate for maintaining bone turnover in CKD [31,32].

Although excessive suppression of PTH is implicated in most cases, some patients treated with intermittent calcitriol develop adynamic bone disease despite persistent hyperparathyroidism [24]. (See "Management of hyperphosphatemia in adults with chronic kidney disease".)

Most studies on renal osteodystrophy, including adynamic bone disease, have been conducted in patients with end-stage kidney disease. However, growing evidence suggests that adynamic bone disease may start in the early stages of CKD in a significant proportion of patients. In one study, patients with CKD stages 2 and 3 had lower bone formation rates, osteoid volume, and osteoblast surface than patients with stages 4 and 5 CKD and more prolonged mineralization lag time [20]. In this study, there was a positive association between levels of indoxyl sulfate, a uremic toxin, and abnormal bone formation rate, osteoid volume, osteoblast surface, and bone fibrosis volume. Thus, uremic toxins may induce low bone turnover in earlier stages of CKD when PTH levels are modestly elevated but resistance to its action is already present.

Clinical and experimental studies have also shown that, in the initial stage of bone disease associated with kidney function impairment, uremic toxins lead to repression of osteocyte Wnt/beta-catenin signaling and increase expression of Wnt antagonists such as sclerostin, Dickkopf-1, and sFRP-4 [37-40].

CLINICAL FEATURES — Many patients with adynamic bone disease are asymptomatic, although some patients develop bone pain [41]. However, these patients are at increased risk of fractures (likely due to an impaired ability to repair microdamage) and hypercalcemia [16,28].

Vascular calcification, which may be observed on imaging studies [16,28], has been associated with increased mortality. This issue is discussed elsewhere. (See "Vascular calcification in chronic kidney disease", section on 'Clinical significance'.)

Bone pain — Most patients are asymptomatic at the time of presentation. However, pain is the predominant symptom among patients with adynamic bone disease [42]. Pain results from low bone turnover, which in turn leads to an impaired ability to repair microdamage.

Fractures — Fractures are more common among patients with adynamic bone disease compared with the general population. In a review of >1000 patients on dialysis, the incidence of hip fracture was 13.9 per 1000 patient-years and, compared with the general population, 14 and 17 times greater for males and females with end-stage kidney disease, respectively [43]. Although bone disease was not verified by biopsy in this study, multivariate analysis revealed that a plasma parathyroid hormone (PTH) value of <195 pg/dL, a value likely to be associated with adynamic bone disease, predicted fracture risk.

A second observational study including >9000 patients on dialysis from the United States Renal Data System (USRDS) Dialysis Morbidity and Mortality Study (DMMS) Waves 1 to 4 identified a weak, U-shaped association between PTH concentration and risk for vertebral and hip fractures, with the lowest risk observed around a PTH concentration of 300 pg/mL (ng/L) [44]. Similar results were reported in a third study, which found that patients with serum PTH levels in the lowest tertile had a 2.4-fold greater risk for vertebral fractures than those with levels in the middle tertile and a 1.6-fold greater risk than those with PTH levels in the highest tertile [45].

The higher risk of fractures may be in part related to altered microstructural properties in the bone of patients with adynamic bone disease that reduce bone strength. A study of bone specimens from 35 patients on dialysis (18 with low bone turnover and 17 with high bone turnover) and 12 healthy volunteers with normal kidney function found that cancellous or trabecular bone volume in bone with low turnover was 17 and 35 percent less than that in bone with normal and high turnover, respectively [46]. In addition, trabecular thickness in bone with low turnover was 20 and 33 percent less than that in bone with normal and high turnover, respectively.

Hypercalcemia — Patients with adynamic bone disease may develop hypercalcemia [47]. The rise in plasma calcium is due, in part, to a marked reduction in the bone uptake of calcium after a calcium load, as with calcium carbonate to treat hyperphosphatemia [47].

Vascular calcification — Adynamic bone disease may predispose patients to vascular calcification. In one study in patients on hemodialysis, an association was observed between low bone turnover and vascular calcification [48]. In another study in patients on dialysis, there was a significant interaction between the dose of calcium-containing phosphate binders and bone activity such that calcium load had a significantly greater impact on aortic calcification and stiffness in patients with adynamic bone disease when compared with patients with active bone disease [49]. The clinical consequences of vascular calcification are discussed elsewhere. (See "Vascular calcification in chronic kidney disease", section on 'Clinical significance'.)

DIAGNOSIS — Patients with adynamic bone disease are frequently asymptomatic, and, therefore, clinicians must have a high degree of suspicion of the diagnosis. Bone biopsy remains the gold standard for diagnosing adynamic bone disease. However, bone biopsies are rarely performed, because they are invasive and there is insufficient expertise in their interpretation at most academic centers. For most patients, we, and most other clinicians, use serum parathyroid hormone (PTH) and bone-specific alkaline phosphatase (BSAP) as surrogate biomarkers of adynamic bone disease and other forms of CKD-associated metabolic bone disease, although these markers have limited sensitivity and specificity to correctly classify bone disease in an individual patient with CKD [17]. We do not routinely measure other biochemical markers of bone turnover (eg, serum C-telopeptide crosslink [CTX]) or obtain bone imaging studies (eg, radiography, dual-energy X-ray absorptiometry [DXA]), as these tests do not reliably distinguish among the various types of CKD-associated bone lesions [50]. (See "Evaluation of renal osteodystrophy".)

The specific values of intact PTH and BSAP we use to distinguish among various types of renal osteodystrophy, including adynamic bone disease, and indications for bone biopsy are discussed in detail elsewhere. (See "Evaluation of renal osteodystrophy", section on 'Initial noninvasive testing for all patients' and "Evaluation of renal osteodystrophy", section on 'Bone biopsy for selected patients'.)

TREATMENT

Reversal of PTH suppression — Our initial approach to treatment of adynamic bone disease is to allow parathyroid hormone (PTH) secretion to rise [4]. This can be achieved by using non–calcium-based phosphate binders; decreasing or stopping active vitamin D analogs; and, for patients on dialysis, possibly by lowering the dialysate calcium concentration [14,51,52]. PTH goals are discussed elsewhere. (See "Management of secondary hyperparathyroidism in adult patients on dialysis", section on 'Treatment goals'.)

Most patients do not have biopsy-proven adynamic bone disease but rather have the diagnosis suggested by a persistently low PTH concentration (see "Evaluation of renal osteodystrophy", section on 'Initial noninvasive testing for all patients'). Our approach to therapy is the same for patients with biopsy-proven or suspected adynamic bone disease:

●We suggest using non–calcium-containing phosphate binders rather than calcium-containing phosphate binders. One randomized, prospective trial has suggested that the use of non–calcium-based binders may increase the bone formation rate [14]. Among 68 patients on hemodialysis who were randomly assigned to receive either sevelamer or calcium carbonate, although there were no changes in bone turnover between groups at one year, the bone formation rate per bone surface increased from baseline in the sevelamer group but not in the calcium carbonate group. (See "Management of hyperphosphatemia in adults with chronic kidney disease", section on 'Phosphate binders'.)

●We decrease or stop active vitamin D therapy (ie, calcitriol and active vitamin D analogs) to allow the serum PTH concentration to increase. The effect of reducing or stopping active vitamin D therapy on reversing adynamic bone disease in patients on dialysis remains uncertain, and there is no high-quality evidence to support this approach. However, two studies in children on peritoneal dialysis who had high-turnover bone disease at baseline showed that calcitriol decreased the bone formation rate and induced adynamic bone disease [24,25]. Similarly, in a small, randomized trial of 16 adults with nondialysis CKD (creatinine clearance of 20 to 59 mL/min) that compared the effects of calcitriol versus placebo on bone histology, calcitriol decreased bone turnover, and adynamic bone disease developed in 80 percent of calcitriol-treated patients [53].

The potential benefit on adynamic bone disease that is conferred by withdrawal of vitamin D therapy should be balanced against the survival benefits associated with vitamin D therapy that have been reported from observational studies, even in the presence of low PTH levels [54,55]. Administration of a physiologic dose of vitamin D may be appropriate, even in patients with adynamic bone disease. The optimal dose is not known and varies with the vitamin D analog that is used: In patients on dialysis, we generally give paricalcitol 1 to 2 mcg intravenously with every dialysis session. However, other clinicians stop completely all vitamin D analogs among patients with adynamic bone disease.

●In patients who are on dialysis, we use low-calcium dialysate (ie, 2 mEq/L) rather than standard dialysate (ie, 2.5 mEq/L), particularly if the PTH level remains low despite switching to non–calcium-containing phosphate binders and stopping vitamin D administration. Low-dialysate calcium concentration results in lower serum-ionized calcium and increased PTH level. This was suggested by a prospective trial including 51 patients treated with peritoneal dialysis who had biopsy-proven adynamic bone disease, in which two levels of dialysate calcium concentrations (3.25 or 2.00 mEq/L) were compared [23]. Repeat bone biopsies after 16 months showed that low-calcium dialysate led to normalization of bone formation rates as well as a 300 percent increase in PTH levels.

●The use of bisphosphonates in patients with preexisting adynamic bone disease should be discouraged in order to avoid further suppression of bone turnover. This is because bisphosphonates accumulate in bone and inhibit osteoclasts and thereby may cause or worsen adynamic bone disease [56,57]. KDIGO guidelines state that bone biopsy is warranted before treatment with antiresorptive agents in patients with CKD stages 4 to 5D who have biochemical abnormalities of CKD-MBD and low bone mineral density (BMD), with or without fragility fractures. [27].

Monitoring the response to therapy — The best evidence for a therapeutic response in patients with adynamic bone disease is a bone biopsy. However, since a bone biopsy is not realistic for most patients, most clinicians monitor serum levels of PTH, bone-specific alkaline phosphatase (BSAP), calcium, phosphate, and 25-hydroxyvitamin D during treatment. Reversal of adynamic bone disease is suggested by a progressive increase in PTH and BSAP levels and resolution of hypercalcemia (if present). Improvement in these biochemical parameters may occur within weeks; however, treatment should be continued, since reversal of adynamic bone disease may take up to at least one year in some bone biopsy studies [14,23]. The levels of PTH and BSAP at which reversal of adynamic bone disease occurs are unknown.

Experimental therapies — The administration of PTH, such as with the anabolic agents teriparatide (PTH 1-34) and abaloparatide (PTH-related peptide [PTHrP] analogue), may benefit patients with adynamic bone disease. Both teriparatide and abaloparatide, which have been approved by the US Food and Drug Administration (FDA) for the treatment of postmenopausal osteoporosis, have not yet been approved for the treatment of adynamic bone disease. We do not routinely use teriparatide or abaloparatide in patients with CKD and adynamic bone disease.

Teriparatide directly stimulates the number of osteoblasts and osteoclasts, which may result in increased bone turnover in patients with adynamic bone disease. This agent has been tried in a total of 19 patients with biopsy-proven adynamic bone disease [58-62]. A small, prospective, open-labeled pilot study that included seven patients on hemodialysis with adynamic bone disease showed a significant increase in BMD [58]. In one patient on dialysis with low bone turnover and frequent, disabling bone pain and fractures, a six-month, daily subcutaneous injection of 20 micrograms of teriparatide lead to a resolution of bone pain and prevented further fractures [59]. A second transiliac bone biopsy demonstrated improvements in static and dynamic parameters of bone formation. Similar results were observed in two other case reports [61,62]. Larger studies are needed to demonstrate the efficacy and safety of this agent in patients with adynamic bone disease.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic kidney disease-mineral and bone disorder".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Adynamic bone disease is the most common form of renal osteodystrophy observed in patients on dialysis, particularly those with diabetes. Over the last few decades, the prevalence of adynamic bone disease has increased relative to other forms of renal osteodystrophy and has been reported to be present in as high as 59 percent in some studies. (See 'Introduction' above and 'Epidemiology' above.)

●Risk factors – Suggested risk factors for adynamic bone disease include the use of calcium-containing phosphate binders, high-dialysate calcium, and the use of active vitamin D analogs. Other possible risk factors include increased age and diabetes. (See 'Epidemiology' above.)

●Clinical features – Most patients with adynamic bone disease are asymptomatic, although some patients have bone pain. Patients with adynamic bone disease are at increased risk for fractures, hypercalcemia, and vascular calcification, which has been associated with increased mortality. (See 'Clinical features' above.)

●Diagnosis – Bone biopsy remains the gold standard for diagnosing adynamic bone disease. However, bone biopsies are rarely performed, because they are invasive and there is insufficient expertise in their interpretation at most academic centers. For most patients, we use serum parathyroid hormone (PTH) and bone-specific alkaline phosphatase as surrogate biomarkers of adynamic bone disease, although these markers have limited sensitivity and specificity to correctly classify bone disease in an individual patient with CKD. (See 'Diagnosis' above and "Evaluation of renal osteodystrophy".)

●Treatment – Adynamic bone disease (as diagnosed by bone biopsy or strongly suspected on the basis of PTH concentration or trends in PTH concentration) should be treated by allowing PTH secretion to rise. Our approach is as follows (see 'Treatment' above):

•For patients with diagnosed or suspected adynamic bone disease, we suggest using non–calcium-containing phosphate binders rather than calcium-containing phosphate binders (Grade 2C).

•For patients with diagnosed or suspected adynamic bone disease, we decrease the dose or stop calcitriol and all active vitamin D analogs to allow the serum PTH concentration to increase (Grade 2C).

•For most patients on dialysis with diagnosed or suspected adynamic bone disease, we suggest the use of low-calcium dialysate (ie, 2 mEq/L) rather than standard (ie, 2.5 mEq/L) (Grade 2C).

ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledge William L Henrich, MD, MACP, who contributed to earlier versions of this topic review.