The therapeutic approach to bone disease in CKD is based on its specific type. As such, this Guideline encompasses 3 parts: Guideline 13A deals with high-turnover and mixed bone disease; Guideline 13B with osteomalacia; and Guideline 13C with adynamic bone disease.
GUIDELINE 13C. ADYNAMIC BONE DISEASE
13C.1 Adynamic bone disease in stage 5 CKD (as determined either by bone biopsy or intact PTH <100 pg/ml [11.0 pmol/L]) should be treated by allowing plasma levels of intact PTH to rise in order to increase bone turnover. (OPINION)
13C.1a This can be accomplished by decreasing doses of calcium-based phosphate binders and vitamin D or eliminating such therapy. (OPINION)
Adynamic bone disease has become increasingly frequent since it has become possible to suppress PTH with calcium and potent vitamin D analogs. In certain dialysis centers, it has become the most common bone disorder. The degree to which it increases morbidity and mortality is unknown, but the limited available data increasingly raise concerns about these issues. The main concerns are related to the inability of bone to contribute to mineral homeostasis in the absence of kidney function and the risk of hip fracture.
With the use of high-dose calcium salts for phosphate binding, and more frequent and aggressive vitamin D treatment, adynamic bone lesions have become increasingly common in histological studies. Typically associated with low PTH levels, the disease has been ascribed to oversuppression of PTH, either with the aggressive use of vitamin D, chronic positive calcium balance, or following parathyroidectomy. It is also seen in association with aging and diabetes, 2 conditions known to predispose to osteoporosis in the general population. Data on bone mass (bone densitometry) and on fracture in dialysis patients increasingly suggest that the adynamic lesion is not without clinical consequences.
While low blood levels of intact PTH strongly suggest the presence of adynamic bone, a high PTH level does not exclude this possibility. Histological studies have found adynamic bone despite PTH values well above 400 pg/mL (44.0 pmol/L). This may be related to limitations of the PTH assay due to accumulation of inhibitory PTH fragments. Thus, bone biopsy may be required to establish or rule out the diagnosis of adynamic bone disease even when the level of PTH is at or above target levels.
Accumulating data suggest that the adynamic histology is not benign. A 4-fold increase in hip fracture risk has been found in the dialysis population compared to the general population. Age, duration of dialysis, female sex, and diabetes appear to confer an increased risk for fracture. In 1 study, an increased risk of hip fracture occurred in dialysis patients with lower PTH levels. An increased risk of vertebral collapse fracture has been found in association with a reduced DEXA measurement and low PTH values. An unanswered question is how adynamic bone lesions and osteoporosis are related. Many of the risk factors noted for adynamic bone disease also predispose to osteoporosis in the general population. In addition, low bone turnover is seen in the majority of osteoporotic subjects who do not have kidney disease. Finally, the aging of the dialysis population results in a population that would be expected to be at high risk for osteoporosis. While osteodystrophy and osteoporosis have generally been defined as distinct entities, they are likely to exist together in kidney failure (Stage 5). Recent advances in treatment of osteoporosis, which utilize PTH administration to stimulate bone formation, further strengthen this association.
The relatively inert, adynamic bone does not modulate calcium and phosphate levels appropriately. With this regulatory function impaired, calcium is neither released from nor taken up by the bone normally. One result is that minimal calcium loading often leads to marked hypercalcemia. In addition, with the failure of the bone to accrue calcium, other tissues become vulnerable to its accumulation in the form of metastatic calcification, with calciphylaxis being the most dreaded result. Curiously, early descriptions of calciphylaxis in dialysis patients noted its association with hyperparathyroidism and parathyroidectomy was often curative. More recently, such patients have had low PTH levels and, when assessed, bone biopsy evidence of adynamic histology. Treatment of this condition has been particularly frustrating, but measures to improve bone turnover appear promising.
Calcium kinetic studies clearly show that in patients with adynamic bone disease, decreased calcium accretion with similar intestinal calcium absorption occurs as in patients with high bone turnover. This predisposes the patients to hypercalcemia and risks of calcification. There are no controlled studies on treatment of adynamic bone disease, though its consequences are troublesome. Recommendations on therapy can be based only on the current understanding of the pathogenetic mechanisms of the bone abnormalities.
Bone densitometry and its relationship to fracture has only begun to be defined in end-stage kidney disease patients, though data continue to suggest that bone density is reduced and it is clear that fracture rates are markedly increased. In the general population, there is a strong association between decreased bone density and fractures, both of which are improved by current therapies. The most recently described therapy for osteoporosis, intermittent bolus PTH infusions, is extremely effective in regards to both these outcomes. It seems very possible that these and other measures used in osteoporosis may be of benefit to patients with adynamic bone disease.
Much of the data described above suggest a relationship between low PTH, bone mass, and low bone turnover in the dialysis population with fracture as a foreseeable outcome. Similar data and outcomes are noted in osteoporosis. Correction of these factors clearly improves the outcome in that disorder. However, there are no fracture or bone mass intervention trials in dialysis patients.
Adynamic bone is treated by increasing bone turnover through an increase in PTH. This can best be accomplished by lowering doses of calcium-based phosphate binders and vitamin D or entirely eliminating such therapy. The lowering of dialysate calcium (1.0 to 2.0 mEq/L) has also been suggested as a possible approach. The 1 published study of this therapy (in peritoneal dialysis patients) did lead to a substantial increase in the number of patients with marked PTH elevation; however, this approach must be considered experimental at this point.
The long-term safety of lower dialysate calcium concentration for treatment of adynamic bone disease, that is the risk of development of osteoporosis, needs to be carefully studied. Moreover, agents with a potential to increase bone turnover (eg, PTH) or newer vitamin D analogs need to be studied as candidates for treatment of adynamic bone disease. Manipulation of the calcium receptor with either calcilytics (which stimulate PTH release) or calcimimetics (which suppress PTH, but increase the amplitude of PTH cycling) may also become important therapeutic agents. Trials with some of these approaches are already underway, while others are planned for the future.