INTRODUCTION
Chronic kidney disease (CKD) is common in the US; indeed, an estimated 37 million American adults live with CKD [1]. Individuals with CKD have disproportionately high rates of cardiovascular disease, progression to end-stage kidney disease requiring renal replacement therapy, and death [2–5]. Additionally, CKD is frequently associated with disorders of bone and mineral metabolism including abnormal metabolism of calcium, phosphorus, parathyroid hormone (PTH), or vitamin D; as well as abnormalities in bone mineralization, turnover, volume, linear growth, and strength [6].
In recent randomized controlled clinical trials, medications within the sodium-glucose cotransporter (SGLT) 2 inhibitors (SGLT2i) class have shown improvements in adverse cardiovascular and kidney outcomes among individuals with CKD [7▪▪,8,9▪▪,10â–ª]. For instance, in the CREDENCE (Canagliflozin and Renal Events in Diabetes with Established Nephropathy Clinical Evaluation) trial, canagliflozin was associated with a reduction in the risks of kidney failure and cardiovascular events among participants with type 2 diabetes and CKD [8]. Likewise, in the DAPA-CKD (Dapagliflozin and Prevention of Adverse Outcomes in Chronic Kidney Disease) trial, the SGLT2i dapagliflozin demonstrated similar results among individuals with CKD, regardless of the presence of diabetes mellitus [9▪▪]. With respect to safety, common adverse effects of SGLT2i include diabetic ketoacidosis, volume depletion, and genital and urinary tract infections [8,9▪▪,10â–ª]. Extant data suggest that SGLT2i may affect bone and mineral metabolism via alterations in renal phosphate reabsorption, increased calcium excretion, as well as increased bone turnover and decreased bone mineral density (BMD). In this review, we discuss recent evidence on the safety of SGLT2i with respect to bone and mineral metabolism in people with CKD. Furthermore, potential underlying mechanisms and clinical implications are reviewed.Â
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MECHANISMS OF ACTION OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS
In the nephron, the SGLT2 are primarily expressed on the apical membrane of the early (S1 and S2 segments) proximal tubules with the sodium-glucose cotransporter 1 (SGLT1) being in the late proximal tubule (S3 segment). In healthy individuals, SGLT2 mediates about 97% of glucose reabsorption in the kidney, while the remaining 3% is handled by SGLT1. SGLT2i act by blocking SGLT2, thereby enhancing the urinary excretion of glucose and sodium [11]. Thus, SGLT2i induce glycosuria and result in the reduction of plasma glucose levels and glycated hemoglobin. Additionally, the ensuing osmotic diuresis may lower blood pressure [11].
EFFECT OF CHRONIC KIDNEY DISEASE ON BONE AND MINERAL METABOLISM
The abnormalities of bone and mineral metabolism in CKD are part of a broader systemic disorder referred to as CKD-mineral and bone disorder. In this section, we present a brief description of the most common disturbances noted in this clinical entity. A more comprehensive review of this syndrome has been conducted elsewhere [12].
Decreased synthesis of 1,25-dihydroxyvitamin D
The kidney is the principal site for 1,25-dihydroxyvitamin D production. In CKD, fibroblast growth factor-23 (FGF-23) causes a rise in PTH and a decline in 1,25-dihydroxyvitamin D. This contributes to the onset of secondary hyperparathyroidism [12]. The levels of 1,25-dihydroxyvitamin D appear to decline slowly in the course of CKD. It would be expected that the increased PTH levels would maintain the levels of 1,25-dihydroxyvitamin D close to normal via a compensatory increase in the activity of 1-α-hydroxylase in the kidney. However, this is not the case since prior data have shown an inability of PTH to increase the levels of 1,25-dihydroxyvitamin D in individuals with early CKD. This suggests that other factors may contribute to the limited ability of the kidney to augment 1,25-dihydroxyvitamin D production in CKD. Such factors include the inhibition of 1-α-hydroxylase by phosphate retention and the accumulation of FGF-23 which also limits the production of 1,25-dihydroxyvitamin D [13]. Other factors have been described but are outside the scope of this review [12].
Intrinsic alterations in the parathyroid gland
In CKD, several disturbances occur that lead to intrinsic alterations within the parathyroid glands. Hypocalcemia is normally a powerful trigger for PTH secretion and parathyroid growth. This appears to be facilitated by calcium-sensing receptors [14,15]. Prior studies have shown that the expression of calcium-sensing receptors is reduced in the hyperplastic parathyroid glands of patients with CKD [14,15]. This in turn augments PTH secretion via a negative feedback loop. Another mechanism is related to reduced levels of calcitriol. Calcitriol receptors are present in the parathyroids. Studies conducted both in vitro and in vivo have shown that calcitriol decreases PTH secretion at the transcription level [16,17], increases the intestinal absorption of calcium, upregulates the expression of parathyroid vitamin D receptors, and alters the expression of calcium-sensing receptors [12]. Thus, when calcitriol levels are reduced, as in patients with CKD, the expression of vitamin D receptor in the parathyroid is reduced and hyperplasia develops in the parathyroid glands [18].
Skeletal Resistance to the actions of parathyroid hormone
A reduced response to the action of PTH has been described in CKD [19,20]. Indeed, a decreased calcemic response to the infusion of PTH as well as a delayed recovery from induced hypocalcemia in patients with CKD have been reported [21]. This phenomenon has been attributed to a number of mechanisms including phosphate retention, lower levels of calcitriol, downregulation of the PTH receptors, and the possible actions of PTH fragments that may blunt the calcemic actions of PTH.
EFFECTS OF SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS ON MARKERS OF PHOSPHATE HOMEOSTASIS
In the proximal tubule, phosphate reabsorption is mostly controlled by PTH, FGF-23, and α-klotho [22]. This is mediated by the sodium/phosphate cotransporters Npt2a and Npt2c [22]. It is well known that people with CKD have a high propensity to develop abnormalities in phosphate homeostasis and may display, depending on the CKD stage, elevated PTH and FGF-23 levels, and hyperphosphatemia [23]. Early studies of the effect of SGLT inhibition of proximal tubule reabsorption of certain metabolites had already indicated a role of SGLT inhibition on phosphate excretion. Indeed, the administration of phloridzin, a nonselective SGLT inhibitor, to 5 healthy adults was associated with a decrease in phosphate clearance and a 4-fold decrease in the fractional excretion of phosphate [24]. Several studies of SGLT2i have indicated that this medication class may increase serum phosphate levels [25], generating the hypothesis that these medications may affect bone and mineral homeostasis.
Studies in animal models have shown some alterations in bone and mineral metabolism. Indeed, in two studies of DBA/2J male mice, mice treated with canagliflozin had increased calciuria coupled with a rise in the serum levels of FGF-23 and PTH [26,27]. Changes in gene expression of renal CYP27B1 (a key factor in vitamin D metabolism), and sodium-dependent phosphate transporter 2A (which regulates renal phosphate excretion) were also observed [26,27]. In both studies, canagliflozin led to increased levels of serum type I collagen (CTX), [26,27]. With respect to bone microarchitecture, bone strength in femur and vertebra of canagliflozin-treated mice were significantly impaired [26,27]. In male Wistar rats and KKAy mice treated with tofogliflozin, no changes were noted in the bone mass by microcomputed tomography after 8 weeks [28].
Table 1 and Fig. 1 summarize the effects of selected SGLT2i on markers of phosphate homeostasis.
Table 1 -
Effects of SGLT2i on markers of phosphate homeostasis
| SGLT2i |
Effects on serum levels of markers of phosphate metabolism |
| Canagliflozin |
Increased levels of serum phosphate by 16%, FGF-23 by 20%, and PTH by 25%; decreased serum 1,25-hydroxyvitamin D levels by 10% [29]. |
| Dapagliflozin |
Increased levels of serum phosphate by 9%, FGF-23 by 19%, and PTH by 16%; decreased levels of 1,25-hydroxyvitamin D by 12% [30]. |
| Empagliflozin |
Increased levels of serum phosphate, PTH and FGF-23; decreased levels of 1,25-dihydroxyvitamin D [31â–ª]. |
FGF-23, fibroblast growth factor-23; PTH, parathyroid hormone; SGLT2i, sodium-glucose cotransporter 2 inhibitors.
FIGURE 1: Effects of SGLT2 Inhibitors on markers of phosphate homeostasis (A) and bone turnover (B). SGLT2, sodium-glucose cotransporter 2.
Canagliflozin
In a small placebo-controlled randomized crossover study of 25 healthy adults, treatment with canagliflozin administration was associated with increased levels of serum phosphate by 16%, plasma FGF-23 by 20%, and plasma PTH by 25%. The increased renal tubular reabsorption of phosphate was noted within 2–4 h after the administration of canagliflozin. Peak levels of FGF-23 were noted about 12 h after the peak serum phosphorus level. Canagliflozin also decreased levels of 1,25-dihydroxyvitamin D by 10% [29]. The augmentation of plasma FGF-23 levels correlated with an increase in serum phosphate level; while the reduction in 1,25-dihydroxyvitamin D correlated with an increase in plasma FGF-23 level.
Dapagliflozin
A double-blind, randomized, crossover trial evaluated the effects of dapagliflozin on circulating markers of phosphate homeostasis among 31 adults with type 2 diabetes with early-stage diabetic kidney disease. Compared to placebo, dapagliflozin was associated with increased levels of serum phosphate by 9%, plasma PTH by 16%, and plasma FGF-23 by 19%. Dapagliflozin decreased the levels of 1,25-dihydroxyvitamin D by 12% [30]. These changes persisted over the 6-week study period.
Empagliflozin
In a double-blind placebo-controlled, randomized, clinical trial of 42 adults with type 2 diabetes, after 3 days, treatment with empagliflozin was associated with increased levels of serum phosphate, PTH and FGF-23, and decreased levels of 1,25-dihydroxyvitamin D [31â–ª]. These effects were transient and no longer present after 3 months of treatment. Empagliflozin did not affect urinary calcium and phosphate levels after 3 days or 3 months of treatment.
SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS AND BONE TURNOVER MARKERS
An important determinant of bone quality is bone turnover, or the process of resorption (by osteoclasts) followed by replacement with new bone (by osteoblasts). CKD is known to be associated with abnormalities of bone turnover. Abnormalities of bone turnover may be associated with a higher fracture risk in individuals with CKD [32]. Some effects of SGLT2i on markers of bone turnover have been described (Fig. 1). In animal studies, canagliflozin-treated diabetic mice had a significant increase in the serum concentrations of cross-linked C-terminal telopeptides of CTX, suggesting an intensification of bone resorption [26]. Canagliflozin has also been shown to alter bone turnover markers in human studies. Indeed, in a randomized double-blind placebo-controlled study, treatment with canagliflozin was associated with a decrease in total hip BMD over 104 weeks, but not at other measured sites (femoral neck, lumbar spine, or distal forearm); no significant changes in bone strength were observed; at week 52, canagliflozin was associated with an increase in collagen type 1 β-carboxy-telopeptide, an increase in osteocalcin, and, in women, a decrease in estradiol [33]. In another randomized double-blind placebo-controlled study, dapagliflozin was not associated with any significant changes in serum levels of procollagen type 1 N-terminal propeptide, CTX or BMD over a 50-week period [34].
SODIUM-GLUCOSE COTRANSPORTER 2 INHIBITORS AND RISK OF FRACTURES
Studies of the association of SGLT2i and fracture risk among patients with CKD are scant and have shown conflicting results. In a randomized, double-blind, placebo trial of 252 patients with type 2 diabetes and moderate renal impairment, 13 patients receiving dapagliflozin experienced bone fractures while no fracture was observed among those in the placebo arm over the course of 104 weeks [35]. In the CREDENCE trial, the risk of fracture was not significantly different among participants in the canagliflozin arm (67/2200) compared to those in the placebo arm (68/2197) [8]. Similar results were noted in the DAPA-CKD trial with the risk of fracture being 4% in the dapagliflozin arm (85 out of 2149 participants) compared to 3.2% in the placebo arm (69 out of 2149 participants) [9▪▪]. Likewise, in the EMPA-KIDNEY study, the risk of fracture was 4% (133/3304) in the empagliflozin arm vs. 3.7% (123/3,305) in the placebo arm (hazard ratio 1.08, 95% CI 0.84–1.38) [7▪▪].
A recent meta-analysis examined the association of SGLT2i and the risk of fracture in individuals with diabetic kidney disease. The included studies were Canagliflozin Cardiovascular Assessment Study Program [36], CREDENCE [8], Empagliflozin Cardiovascular Outcome Event Trial in Type 2 diabetes Mellitus Patients [37], and SCORED (Effect of Sotagliflozin on Cardiovascular and Renal Events in Patients with Type 2 Diabetes and Moderate Renal Impairment Who Are at Cardiovascular Risk) [38▪]. No significant association was observed between SGLT2i and the risk of bone fracture among individuals with CKD (Relative risk 1.00, 95% CI 0.84–1.20) [9▪▪].
CONCLUSION
In conclusion, SGLT2i are an emerging class of antidiabetic medications with beneficial effects on adverse cardiovascular and kidney outcomes in various populations including those with CKD with and without diabetes. Individuals with CKD tend to have several abnormalities of mineral metabolism including decreased 1,25-dihydroxyvitamin D, increased PTH and higher FGF-23 levels [12]. CKD is associated with suboptimal bone health as well as a higher risk of fracture [39]. The uptake of SGLT2i is steadily increasing among patients with CKD [40], as major professional organizations are recommending the use of this medication class in this patient population [41].
Mechanistic studies have shown that SGLT2i increase renal phosphate reabsorption resulting in increased FGF-23 and PTH levels and a decrease in 1,25-dihydroxyvitamin D level. However, it is possible that these changes in mineral metabolism are transient and go away after a few months. With respect to the association between SGLT2i and the risk of fractures among individuals with CKD, current data suggest a lack of association in this population. However, in the elderly who were underrepresented in the clinical studies, no conclusion can be drawn. More research is needed to evaluate the effect of SGLT2i on fracture among patients with CKD who are at the extreme of the FGF-23/1,25-dihydroxyvitamin D/PTH distribution as those individuals would be expected to have greater baseline risk of experiencing fracture. While we await more research to be conducted, we recommend that potential adverse effects of SGLT2i on bone health be considered in susceptible individuals such as elderly patients with CKD, the routine evaluation of vitamin D and PTH levels and the correction of vitamin D deficiency before and after initiation of SGLT2i.
Acknowledgements
None.
Financial support and sponsorship
Dr Paik is supported by an R01 grant AR075117 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases. Dr Patorno is supported by a career development grant K08AG055670 from the National Institute on Aging, the Patient-Centered Outcomes Research Institute (DB-2020C2-20326), the Food and Drug Administration (5U01FD007213), and an investigator-initiated grant by Boehringer Engelheim.
Conflicts of interest
There are no conflicts of interest.
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
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