In this retrospective study of 69,215 patients from primary care clinics throughout a large academic health system, we observed a high prevalence of CKD, but low rates of testing or treatment for associated metabolic bone disease. Although a documented diagnosis of kidney disease did increase the likelihood of targeted testing and treatment, the majority of CKD patients remained untested and untreated with recommended therapies. While the goal of the study was not to determine whether the presence of CKD was independently associated with bisphosphonate use, bisphosphonate therapy was not significantly lower among CKD versus non-CKD patients as would be expected given their relative contraindication in CKD. These results suggest that CKD and its associated mineral disorders are under-recognized, under-diagnosed and under-treated, which may result in increased cost and decreased quality of care.28
When clinicians consider bisphosphonate therapy for presumed osteoporosis, a thorough evaluation for potential causes of metabolic bone disease, including CKD, is warranted. Furthermore, the finding of bone loss could serve as a gateway to earlier diagnosis and tailored therapy of CKD itself.
The pathogenesis of disordered mineral metabolism in CKD involves inadequate renal conversion of 25-hydroxyvitamin D to its active hormonal form, 1,25-dihydroxyvitamin D, which may be further exacerbated by concomitant nutritional deficiency of 25-hydroxyvitamin D.29
Deficiencies in the vitamin D axis impair dietary calcium absorption and release the parathyroid glands from feedback inhibition.14
Impaired phosphorus excretion and decreased expression of the calcium sensing receptor in the parathyroid glands also promote increased PTH levels.11,30
The resultant secondary hyperparathyroidism helps maintain normocalcemia by accelerating bone resorption that decreases bone mineral density in a pattern that can be radiographically indistinguishable from osteoporosis.7
Bone biopsy studies confirm that histological abnormalities in bone turnover, mineralization and volume begin early in CKD.31
Although their contraindication in CKD stems more from a lack of safety data rather than proven toxicity, the efficacy and rationale for bisphosphonates are uncertain when there is untreated vitamin D deficiency or hyperparathyroidism,16,17
which are core mechanisms of bone loss in CKD. While one meta-analysis suggested that risedronate reduced fractures in CKD patients,32
long-term, dedicated safety and efficacy studies are lacking. Given recent concern over increased fracture rates because of excessive suppression of bone remodeling among long-term bisphosphonates users,33–36
particular caution may be warranted in CKD, as decreased renal clearance can markedly increase the half-life of these drugs.
Despite these concerns, prescription of bisphosphonates was common in patients with CKD; even in the subset with CKD stage 4 (eGFR 15–29 ml/min/1.72 m2
), bisphosphonate use was no less prevalent than in the non-CKD population. The latter finding is especially noteworthy given that CKD stage 4 is usually clinically evident. Thus, the similar rates of therapy in stage 4 and the overall population strongly suggest a lack of awareness of the contraindications and potential toxicities of these agents in advanced CKD. Furthermore, patients with CKD were nearly seven times more likely to receive a bisphosphonate than active vitamin D. The infrequency of vitamin D therapy even among those found to have secondary hyperparathyroidism suggests providers were unaware of the potentially important role of this treatment in patients with CKD. Indeed, while vitamin D agents are recommended to treat vitamin D deficiency and secondary hyperparathyroidism in patients with pre-dialysis CKD, recent pharmaco-epidemiological studies suggest a potential survival benefit of therapy.37,38
Collectively, these results suggest important gaps in understanding the potential risks and benefits of specific treatments for disordered mineral metabolism in CKD.
This large-scale study of real-world clinical practice was enabled by the presence of an institution-wide EMR. Despite the breadth of available data, this approach is accompanied by certain limitations. Data regarding care received outside the institution were unavailable; hence, it is possible that we underestimated the frequency of diagnostic testing and therapy. Nevertheless, the focus of this study was the role of PCPs, all of whom were based in the single institution encompassed by the EMR. In addition, we did include prescriptions for active vitamin D and phosphate binders from other providers, acknowledging that PCPs may co-manage CKD patients with nephrologists. It is also possible that the low rates of diagnosis, targeted laboratory testing and treatment were the result of documentation failure rather than deficits in clinical care. However, given that these rates were extremely low, it is unlikely that the conclusions of the study would be dramatically altered by perfect documentation.
Defining CKD based on a single creatinine test used to calculate eGFR is another potential limitation. Although our study design ensured that PCPs had access to at least one measure of renal function before the observation period, it could be argued that we overestimated the prevalence of CKD.39
Indeed, some individuals labeled as having CKD might actually have had only a transient reduction in GFR, and others might have had a sustained, age-dependent reduction in GFR without any other objective evidence of kidney disease. It is important to note however, that despite these limitations, an eGFR <60 ml/min/1.73 m2
has been independently associated with increased future risk of major cardiovascular events and mortality.3
Furthermore, evidence of disordered mineral metabolism, either hypocalcemia, hyperphosphatemia or hyperparathyroidism, was present in 76% of patients we identified as having CKD who were tested, and the results were qualitatively similar even when we excluded patients with eGFR of 45–60 ml/min/1.73 m2
, the population most likely to include false-positive screens for CKD. Indeed, the limited precision of eGFR should promote, rather than obviate, the need for confirmatory testing of disordered mineral metabolism. Despite this, we found rates of such testing to be low.
Recommendations to screen for vitamin D deficiency in the evaluation for osteoporosis are inconsistent. Kaiser Permanente’s osteoporosis/fracture prevention clinical practice guidelines recommend testing and repletion of 25-hydroxyvitamin D to a level of ≥30 ng/ml before initiation of bisphosphonates.40
Guidelines from the National Osteoporosis Foundation recommend considering testing for vitamin D insufficiency and obtaining calcium and creatinine levels prior to treating with bisphosphonates.41
However, many guidelines do not include routine screening for vitamin D levels in osteoporosis. If some PCPs in our study tested 25-hydroxyvitamin D levels as part of an evaluation for osteoporosis, this suggests that even fewer patients received the testing for CKD-related bone disease, further strengthening our findings.
An explicit goal of this report was not to criticize the care of exceptionally busy PCPs. Instead, we aimed to explore the obstacles in the primary care setting that prevent the appropriate diagnosis and treatment of one of the main complications of CKD. While bisphosphonates may have been deliberately used in some CKD patients after careful weighing of potential risks and benefits, their frequent use in CKD, along with infrequent targeted laboratory testing, suggests underlying knowledge deficits. These may include under-appreciation of underlying CKD, of CKD as a cause of bone loss, of recommended testing and treatment for disordered mineral metabolism in CKD or of the contraindication of bisphosphonates in advanced CKD. Indeed, other studies similarly found significant knowledge deficits in CKD diagnosis and management, even among recently trained physicians.42
Interventions to fill these gaps might include automatic eGFR reporting, automated clinical reminders to prompt clinicians to consider appropriate metabolic bone disease testing for all patients in whom bisphosphonates are being considered and CKD-specific diagnostic testing for those with eGFR <60 ml/min/1.73 m2
. Publication of additional reviews on CKD management in the general medical literature43
is also needed to increase awareness among PCPs. Ultimately, these interventions could pave the way for improved care of CKD and its various complications.