Emerging treatments and current strategies for mineral, vascular, and bone disorders in chronic kidney disease

Abstract

Progressive loss of kidney function in chronic kidney disease and end-stage kidney disease leads to distinct pathological changes in mineral and bone metabolism. Historically, the management of these patients focused on lowering their serum phosphate, parathyroid hormone, and normalizing serum calcium. However, persistently high morbidity and mortality of these patients from cardiovascular diseases and after bone fractures call for more specific therapies. Here, we summarize established and emerging therapies for managing the three main domains of mineral bone disorder in patients with advanced chronic kidney disease and end-stage kidney disease: Control of mineral imbalance, management of vascular disease or other soft tissue calcifications, and management of bone disorders.

Key Words: Chronic kidney disease; End-stage kidney disease; Mineral bone disorder; Parathyroid hormone; Cardiovascular disease

Core Tip: Patients with advanced chronic kidney disease and end-stage kidney disease experience disproportionally high morbidity and mortality compared to the general population, particularly from cardiovascular disease and following bone fractures. Recent data indicate that this phenomenon is due to kidney disease-induced alterations in the fundamental biological pathways. Herein, we review established and emerging therapies for the management of mineral bone disorder, vascular and tissue calcifications, and bone pathology.

INTRODUCTION

Nearly 1.3 million adults in the United States have advanced kidney disease, defined as an estimated glomerular filtration rate (eGFR) below 30 mL/minute/1.73 m²[1]. An additional 550000 adults are living with end-stage kidney disease (ESKD) requiring maintenance dialysis[2]. Reduced kidney function in these patients leads to a range of pathological changes in mineral metabolism termed mineral and bone disorder (MBD)[3]. The management of MBD historically focused on bringing phosphate and calcium levels towards the normal range and addressing the abnormalities in parathyroid hormone (PTH). Indeed, high serum phosphate in patients with ESKD is associated with increased risk of all-cause[4,5] and cardiovascular (CV) mortality[6,7], as well as bone fractures[5]. Elevated calcium levels are also associated with increased mortality across all stages of kidney disease, but particularly so in ESKD[7,8].

However, it has been established that the morbidity and mortality from vascular and bone disease remain exceedingly high despite treatment of these parameters in patients with advanced chronic kidney disease (CKD) and ESKD. In 2024, the United States Renal Data System reported that the rate of mortality from CV disease was 55.9% in patients with ESKD vs 33% in the general population[2,9,10]. Bone disease is another parameter disproportionately affecting patients with advanced CKD and ESKD of all ages. Alarmingly, the risk of fracturing a bone in a 40-year-old patient receiving dialysis is 100 times higher compared with a 40-year-old in the general population[11]. Moreover, if a patient with ESKD requiring dialysis sustains a major fracture, this doubles their personal risk of mortality[12]. These data highlight the need for a deeper understanding of the distinct pathological changes in patients with advanced CKD and ESKD and the need for more targeted therapies.

While management of high phosphate and PTH levels continues to be the mainstay of bone mineral disorder in patients with ESKD, several novel targets have been discovered, such as αKlotho and fibroblast growth factor 23 (FGF23). Serum levels of FGF23 rise as early as CKD stage 2 (eGFR 60-90 mL/minute/1.73 m²). FGF23 is produced mainly by osteoblasts and osteocytes and works to reduce serum phosphate by inhibiting phosphate transporters in the proximal renal tubule and by inhibiting the expression of 1-alpha hydroxylase. In patients with advanced CKD, the increased level of FGF23 is associated with left ventricular hypertrophy and the heightened risk of vascular calcifications, CV events, and mortality[13-15]. In ESKD, FGF23 levels can rise as high as 1000-fold above the normal level[16] and correlate with increased CV mortality[17]. Thus, it was hypothesized that lowering FGF23 level could improve MBD-associated complications in patients with CKD. However, using an FGF23-neutralizing antibody led to hypercalcemia, hyperphosphatemia, increased aortic calcifications, and increased mortality in rodent models even though there were some improvements in bone parameters[18].

FGF23 requires its co-factor αKlotho in order to bind FGF receptors in the kidneys. αKlotho is produced by the kidney tubules, and its production decreases in parallel with the decrease in the number of functional tubules in CKD and aging. A cohort study following 10069 adults for one year showed that participants with the lowest level of αKlotho (< 666 pg/mL) had a 31% increased all-cause and heart disease-related mortality compared to adults with α-Klotho > 985 pg/mL[19]. This was similar to the finding of a meta-analysis of six cohort studies, which included patients with CKD[20]. In experimental models, overexpression of αKlotho can attenuate vascular and kidney damage and delay aging[21-23]. Although there are no therapeutics that can directly upregulate αKlotho in humans, several medications like sevelamer and paricalcitol may indirectly increase its levels[24,25]. Modulation of αKlotho holds promise as a novel therapeutic avenue for the management of CKD.

KIDNEYS, PHOSPHATE, AND BEYOND

In 2013, a landmark study by Block et al[7] examined laboratory abnormalities of 26221 patients with ESKD treated with hemodialysis. In this study, serum levels of phosphate, calcium, and PTH were weighed against the probability of death or CV hospitalization. Elevated serum phosphate or calcium above the upper limit of normal correlated with an increased risk of mortality and CV hospitalizations, particularly when concurrent elevation in PTH was present[7].

In healthy individuals, a normal serum phosphate level represents a balance between oral intake and intestinal absorption on one hand, and excretion through urinary and fecal routes on the other. Historically, the main approaches to reducing serum phosphate have been through limiting the oral intake of phosphate-rich foods. An average dietary intake of phosphate is 800-1000 mg daily, approximately 70% of which is absorbed into the blood[26]. The degree of intestinal absorption approaches 100% for inorganic phosphate added to processed foods to increase their shelf life or enhance their texture[27]. In contrast, plant-based phosphate has significantly lower bioavailability as it is mainly included in proteins[28]. Urinary excretion of phosphate is enhanced by PTH and FGF23, which are upregulated in advanced CKD and can promote phosphate excretion by the kidneys with eGFR as low as 3 mL/minute/1.73 m²[29].

After kidney function declines and renal replacement therapy is initiated, approximately 800 mg of phosphate is removed during a 4-hour session of in-center hemodialysis, resulting in 2400 mg of weekly phosphate removal. In contrast, peritoneal dialysis removes roughly 300 mg of phosphate per session. This compounds to 2100 mg of phosphate removal when the patient is performing peritoneal dialysis daily[28]. Given regular dietary intake of phosphate at 1000 mg daily and a 70% absorption, this leaves patients requiring renal replacement therapy with a positive balance of 2000-3000 mg of phosphate weekly, thus necessitating phosphate removal through the gastrointestinal (GI) tract. These medications can be subdivided into several categories (Table 1, Figure 1)[30-39].

Figure 1 Schematic representation of phosphate handling and systemic effects in chronic kidney disease. Metal-based and resin-based phosphate binders act within the intestinal lumen to limit phosphate absorption. Persistent hyperphosphatemia contributes to vascular calcification, bone disorders, and cardiovascular complications (created in BioRender). NHE3: Sodium/hydrogen exchanger isoform 3; PTH: Parathyroid hormone.

Table 1 Phosphate management in advanced chronic kidney disease and end-stage kidney disease.

Medication	Mechanism of action	Comments	Effect on GI system	Effect on cardiovascular system	Effect on bone	Ref.
Metal-based phosphate binders
Aluminum hydroxide	Formation of insoluble complexes with phosphate in GI tract prevents absorption of dietary phosphate	Use not recommended	Constipation, delayed gastric emptying	Anemia, accelerated dementia	Accumulation in the bone and bone pain	Slatopolsky et al[30], Drüeke[34]
Calcium carbonate, calcium acetate		Inexpensive. Calcium is absorbed systemically	Neutralizes gastric acid, increases GI motility	Hypercalcemia. Accelerated vascular calcifications, increased mortality with long-term use	No increase in fractures	Block et al[31], Di Iorio et al[32], Di Iorio et al[33]
Lanthanum carbonate		Chewable	Good GI tolerance	No improvement in mortality	No increase in bone fractures	Hutchison et al[35], Toussaint et al[36]
Ferric citrate, sucroferric oxyhydroxide		Lower pill burden. Decreased the need for erythropoiesis stimulating agents	Diarrhea, constipation, nausea, abdominal pain, and discolored stool	Additional iron delivery may help with management of heart failure but no high-quality data	No high-quality data	Pennoyer et al[37], Block et al[38], Vervloet et al[39]
Resin-based phosphate binders
Sevelamer carbonate, sevelamer hydrochloride	Formation of insoluble complexes with dietary phosphate	High pill burden, large size of tablets	Constipation, nausea	Decreased vascular calcifications compared to Ca-based binders	No increase in fractures	Di Iorio et al[32], Di Iorio et al[33]

GI: Gastrointestinal.

Metal-based phosphate binders

Aluminum hydroxide and aluminum chloride were first used in the 1970s due to their ability to bind dietary phosphate in the GI tract (Table 1)[30-39]. The efficacy and early popularity of these binders resulted in patients with ESKD ingesting over 100 mg of aluminum daily. Unfortunately, aluminum-based binders have a high level of systemic absorption and rely heavily on renal clearance for elimination. Subsequently, growing data on aluminum accumulation and toxicity (anemia, bone pain, dementia) in ESKD patients led to an eventual cessation of use of this class of medications.

Calcium-based phosphate binders such as calcium carbonate and calcium acetate are inexpensive and easily accessible. Unfortunately, these binders were shown to accelerate vascular calcifications in patients with eGFR 20-45 mL/minute/1.73 m² vs calcium-free binders such as sevelamer or lanthanum carbonate[31]. In patients with ESKD, this resulted in higher CV mortality when calcium carbonate was used as compared to sevelamer[32,33].

Lanthanum carbonate has been used for phosphate binding in the United States since 2005. It has good GI tolerance, minimal absorption from GI tract (0.06%-0.1%), forms an insoluble complex with dietary phosphate without affecting gastric emptying, and its excess is eliminated through the hepatobiliary system[34,35]. However, there are theoretical concerns that lanthanum’s chemical similarity to aluminum can lead to accumulation in bone and other tissues with prolonged use. To this end, a 10-year post-marketing safety data showed that the use of lanthanum carbonate did not increase bone fractures or mortality in ESKD patients[35]. In 138 participants with an eGFR of 15-44 mL/minute/1.73 m², administration of lanthanum carbonate for 96 weeks showed no difference in terms of abdominal aortic calcification, pulse wave velocity, serum phosphate, or FGF23 levels vs 140 participants receiving placebo[36].

Iron-based phosphate binders, ferric citrate and sucroferric oxyhydroxide, are the newest medications of this class. They hold a promise of improving serum iron levels in addition to correcting hyperphosphatemia. Ferric citrate has similar efficacy in terms of phosphate lowering as a resin-based phosphate binder sevelamer or calcium carbonate but was also able to increase mean hemoglobin levels from 10.4 g/dL to 11.4 g/dL over a 16-week period[37]. Main side effects were GI: (1) Diarrhea; (2) Constipation; (3) Nausea; (4) Abdominal pain; and (5) Discolored stool. In 203 patients with advanced CKD with eGFR < 20 mL/minute/1.73 m², ferric citrate administration was associated with a decreased rate of hospitalizations and a lower composite outcome of death, transition to dialysis, or transplantation[38]. A recent meta-analysis of 8 studies confirmed the role of ferric citrate in management of both anemia and hyperphosphatemia in patients with advanced CKD, but mortality or hospitalizations were not evaluated in all included studies[40]. A prospective cohort study of 1365 patients taking sucroferric oxyhydroxide confirmed its safety and efficacy in reducing serum phosphate in ESKD patients on hemodialysis or peritoneal dialysis while reducing their daily pill burden vs sevelamer, at an average of 2.3 pills/day vs 8.7 pills/day, respectively[39]. Currently, there is no definitive data on CV or all-cause mortality or bone fracture for patients treated with iron-based phosphate binders compared to other binders.

Resin-based phosphate binders

Resin-based binders such as sevelamer carbonate and sevelamer hydrochloride are non-absorbable polymers that bind phosphate anions in GI tract without causing hypercalcemia. Similar to other phosphate binders, they have to be taken with meals and may cause GI side effects, mainly constipation and nausea. Frequently, as many as 12 tablets daily are needed to achieve adequate phosphate control in patients with ESKD.

Adherence to oral phosphate binders is a major barrier to serum phosphate control in ESKD. The large size and high number of tablets that need to be timed with meals and ensuing GI side effects are the main factors for non-compliance. The study by Van Camp et al[41] showed that only 22% of patients receiving hemodialysis were entirely adherent to their oral phosphate binders over the entire 8-week duration of the study. The patients, who were living with a partner, or had higher social support and higher physical quality of life were more likely to be adherent.

Novel therapies for hyperphosphatemia

In 2023, tenapanor was approved as a first-in-class phosphate absorption inhibitor for the management of hyperphosphatemia in adults with ESKD on maintenance dialysis[42]. Rather than directly binding to dietary phosphate, tenapanor prevents its intestinal absorption by inhibiting sodium/hydrogen exchanger isoform 3 (Figure 1). Consequent efflux of protons changes the conformations of proteins in tight junctions, leading to impaired paracellular phosphate transport[43]. As a result, tenapanor increases sodium, phosphate, and water content in the stool. Thus, it is not surprising that the main disadvantage of this medication is diarrhea, particularly in those patients who consume high levels of dietary sodium. In fact, tenapanor was originally approved for the management of constipation in patients with irritable bowel syndrome[44]. A 52-week randomized controlled trial PHREEDOM showed a reduction in serum phosphate from 7.7 mg/dL to 5.1 mg/dL[45] with an acceptable safety and tolerability profile. The specific advantages of tenapanor include minimal systemic absorption, small tablet size, and no need to be taken simultaneously with food.

VASCULAR AND SOFT TISSUE CALCIFICATIONS

More than half of all deaths in those with advanced CKD and ESKD are due to CV disease as compared to 33% among age-matched people without CKD[10,46]. It has been hypothesized that the pathological mechanisms leading to CV disease in these patients have distinct features compared to the general population. For example, traditional risk factors of diabetes, smoking, and hypertension are less likely to predict CV events in those with advanced CKD[47-49]. Furthermore, the interventions that are used to manage CV risk factors in the general population, such as aspirin, statins, and lower blood pressure goals, are less likely to decrease these risks in those with advanced CKD[50-54]. The mechanisms that have been proposed to help explain increased risk of CV morbidity and mortality in advanced CKD include an increased rate of calcification of coronary arteries and cardiac valves, leading to early vascular senescence, difficult-to-control hypertension, decreased cardiac contractility, and myocardial fibrosis.

A prominent trait of vascular disease in CKD is an accelerated deposition of calcium phosphate (hydroxyapatite crystals) within the medial layer of the blood vessel walls and cardiac valves (Figure 1). This process differs from the calcifications of the intima layer that present as calcified atherosclerotic plaques and are associated with chronic vascular inflammation. Recent studies have shown that the depositions of hydroxyapatite crystals are not sporadic but driven by osteogenic transformation of vascular smooth muscle cells[55]. This is supported by experimental models that show that exogenous phosphate levels > 6 mg/dL can trigger the osteogenic transformation of cultured vascular smooth muscle cell phenotype by promoting the expression of bone-specific markers, calcification of matrix proteins, and loss of contractility[56]. The elements involved in this process include collagen, osteopontin, Runx2/Cbfa1, and alkaline phosphatase, as well as changes in inhibitory factors, including matrix Gla protein, and osteonectin[57,58]. In patients with CKD and ESKD undergoing dialysis, the calcification of the tunica media leads to arterial stiffness, elevated systolic and decreased diastolic blood pressure, and left ventricular hypertrophy[59]. Increased calcification of cardiac valves was observed as early as stage 3 CKD in patients with a mean eGFR of 50.6 mL/minute/1.73 m² as compared to those without kidney disease[60].

Alarmingly, the extent of medial vascular calcifications in young patients with ESKD requiring dialysis mirrors that found in elderly individuals with normal kidney function. A study by Goodman et al[61] looked at 39 young patients (mean age 19 ± 7 years; age range 7-30 years), who had ESKD treated with either hemodialysis (18 patients) or peritoneal dialysis (21 patients). There was no significant difference in serum phosphate or calcium levels among these patients. What was predictive of a significantly higher coronary artery calcification score in these patients was the duration of dialysis for 14 ± 5 years vs 4 ± 0.4 years[61]. Thus, end stage kidney disease is associated with premature and accelerated vascular calcifications regardless of dialysis modality, even in young adults with ESKD.

Phosphate binders

Vascular calcifications progress faster when calcium-based phosphate binders are used in patients with moderate to advanced CKD (eGFR 20-45 mL/minute/1.73 m²)[31]. In patients with eGFR 15-30 mL/minute/1.73 m², the use of calcium carbonate for phosphate binding for over 12 months was associated with increased coronary artery calcifications and higher all-cause mortality as compared to sevelamer[32,62]. In patients with ESKD, calcium-based binders were shown to increase cardiac arrhythmias and CV mortality when used longer than 6 months[33]. A randomized controlled trial Impact of Phosphate Reduction on Vascular Endpoints in CKD found no difference of phosphate lowering on vascular endpoints when treating patients with eGFR 15-45 with lanthanum carbonate[36]. The trial that included 115 patients randomized to strict serum phosphate control (3.5-4.5 mg/dL vs 5.0-6.0 mg/dL) showed a significant reduction of coronary artery calcifications in the strictly controlled group, but there was no difference between sucroferric oxyhydroxide or lanthanum carbonate to achieve this goal[63].

Oral magnesium[64] was able to prevent vascular calcifications in a rat model of CKD (Table 2)[17,44,45,65-69]. However, in humans, when magnesium hydroxide was tested for 52 weeks as a promising agent for the prevention of vascular calcifications in participants with eGFR of 15-45 mL/minute/1.73 m², but unfortunately did not slow down coronary artery calcifications (MAGiCAL trial)[65]. Similarly, a systematic review and meta-analysis of 8 randomized controlled trials and one non-randomized controlled trial showed that magnesium supplementation during hemodialysis raised serum magnesium levels, but did not reduce vascular calcification scores[66].

Table 2 Other and novel therapies for mineral bone disorder in advanced chronic kidney disease and end-stage kidney disease.

Other therapies	Mechanism of action	Comments	Effect on GI system	Effect on cardiovascular system	Effect on bone	Ref.
Magnesium hydroxide	Pleiotropic effects on endothelial function and inflammation	Low pill burden. Does not need to be timed with meals	Loose stool, diarrhea	No change in coronary artery calcifications	No high-quality data	Bressendorff et al[65], Zhan et al[66]
Cinacalcet	Enhances sensitivity of calcium sensing receptor in parathyroid glands	Relatively low pill burden. Can be administered every other day with hemodialysis	Nausea, emesis, diarrhea	Reduction in cardiovascular mortality and all-cause mortality	Hypocalcemia. Reduction in bone fractures in patients with end-stage kidney disease over age 65	Moe et al[17], Chertow et al[67]
Novel therapies
Tenapanor	Inhibition of sodium/hydrogen exchanger isoform 3 transporter in GI tract	Low pill burden (one tablet twice daily). Does not need to be timed with meals	Osmotic diarrhea	No high-quality data	No high-quality data	Herekar et al[44], Block et al[45]
SNF472	Selective inhibition of formation and growth of hydroxyapatite crystals	Requires intravenous administration. Can be given after hemodialysis	Mild nausea, similar rate to placebo	Decrease in coronary artery calcifications	Slight reduction in bone density	Raggi et al[68], Bushinsky et al[69]

GI: Gastrointestinal.

Calcimimetics

Cincalcet enhances the responsiveness of the calcium sensing receptors on the parathyroid gland and decreases circulating PTH and calcium levels. In patients with ESKD and disproportionally high PTH[70], cinacalcet use was associated with a lower progression of vascular calcifications (Table 2)[17,44,45,65-69]. The Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial included 2602 patients with ESKD receiving hemodialysis and studied two outcomes: The effect of cinacalcet vs placebo on the rate of mortality and CV events[17,67]. The authors found that administration of cinacalcet in patients with PTH > 300 pg/mL for 20 weeks was associated with a significant reduction in CV mortality (relative hazard = 0.66), sudden cardiac death (relative hazard = 0.57), and heart failure (relative hazard = 0.69)[17].

SNF472

Recently, a novel agent, myo-inositol hexaphosphate (SNF472), received an orphan drug designation by the United States Food and Drug Administration for the treatment of peripheral arterial disease in patients with ESKD[68]. SNF472 acts through selective inhibition of the formation and growth of hydroxyapatite crystals, one of the final steps in the development of vascular calcifications. The primary outcomes were the progression of log coronary artery calcium and aortic valve calcium score volume from baseline after 52 weeks of treatment. This is the first multicenter randomized trial to test the efficacy and safety of this novel agent in a double-blind placebo-controlled fashion. Patients treated with SNF472 experienced a slight reduction in bone mineral density at the femoral neck, but fractures were infrequent in both groups[69]. Thus, larger studies are needed to evaluate the risk of bone fractures in patients treated with SNF472.

A rare but highly morbid microvascular complication in advanced CKD is calcific uremic arteriolopathy or calciphylaxis. A CACIPHYX is a phase 3 clinical trial that will investigate the safety and efficacy of SNF472 for the treatment of calciphylaxis[71]. Sodium thiosulfate has been used off-label for the treatment of calciphylaxis. A meta-analysis of 6 studies that included 305 participants with ESKD receiving hemodialysis showed that infusions of sodium thiosulphate may attenuate progression of vascular calcifications and arterial stiffness[72]. The main side effects of sodium thiosulphate are metabolic acidosis and nausea.

BONE DISEASE

The landmark Dialysis Outcomes and Practice Patterns Study showed that among 34579 hemodialysis-dependent patients, mortality can exceed 50% within a year of fracture[73]. The patients who were more likely to sustain a fracture were older, female, and had a lower body mass index, longer duration of dialysis, and a higher comorbidity burden[73]. Even patients with moderate to advanced CKD (eGFR below 45 mL/minute/1.73 m²) are at increased risk of hip fractures compared to individuals with normal kidney function[74]. In 2024, the Current management of Secondary hyperparathyroidism: A Multicentre Observational Study group reported that in 6797 patients receiving hemodialysis, an increase in serum phosphate above 6.1 mg/dL was the laboratory abnormality most strongly associated with a 53% increased risk of bone fractures (42% in the fully adjusted model)[75]. Despite this, little is known about the management of bone disease in advanced CKD and ESKD.

The pathological features of bone disease in CKD are accelerated cortical bone resorption, resulting in cortical thinning, increased cortical porosity, and abnormal bone mineralization and strength. The gold standard for bone density evaluation is a dual X-ray absorptiometry scan. It can distinguish between osteopenia and osteoporosis, but not between high (osteitis fibrosa cystica) and low bone turnover (adynamic bone disease), both of which are seen in advanced CKD and ESKD. The prevalence of adynamic bone disease can be as high as 18% in patients with CKD with eGFR < 60 mL/minute/1.73 m² and reaches 19% and 50% for patients with ESKD requiring hemodialysis and peritoneal dialysis, respectively[76]. Molecular markers provide limited help in drawing a distinction between high and low bone turnover. A PTH level that is higher than 9 times the upper limit of the normal range is 86% specific for high turnover disease; however, lower levels do not aid with the diagnosis of bone disease[77]. A low level of bone-specific alkaline phosphatase predicts low bone turnover (< 42 unit/L excludes adynamic bone disease) in patients with ESKD requiring dialysis[78]. The current treatments of adynamic bone disease focus on transitioning away from calcium-based phosphate binders and reducing vitamin D analogs and calcimimetics.

Several approaches have been used for the treatment of high bone turnover disease. In the general population, bone resorption is the predominant pathology resulting in osteopenia or osteoporosis. Thus, several anti-resorptive therapies such as bisphosphonates, RANK ligand inhibitors, and hormone therapies are used to promote bone strength in these patients. In patients with advanced CKD and ESKD, the use of these medications is controversial due to the exclusion of these patients from clinical trials. Moreover, since anti-resorptive therapies decrease bone turnover, it is important to exclude CKD-associated low bone turnover (adynamic bone disease).

Bisphosphonates should be used with caution in patients with advanced CKD, as they carry a potential 14% risk of kidney disease progression[78,79]. In patients with ESKD, the use of bisphosphonates is off-label. Nevertheless, several groups have reported an improvement in bone turnover in patients with ESKD and osteoporosis when alendronate or pamidronate was added to their standard therapy with a calcimimetic and a vitamin D analog[78,80]. The use of RANK ligand inhibitors such as denosumab does not appear to accelerate kidney disease[81]. It can, however, cause prolonged hypocalcemia requiring calcium supplementation for weeks to months, with more severe effects seen in patients with the lowest kidney function and ESKD. Finally, raloxifene is a selective estrogen receptor modulator, but data in advanced CKD and ESKD are limited due to the exclusion of these patients from clinical trials[82].

Cinacalcet is another therapy with the potential to reduce bone fracture risk in patients with high bone turnover seen in ESKD (Figure 1). The analysis of data from the aforementioned Evaluation of Cinacalcet HCl Therapy to Lower Cardiovascular Events trial showed that cinacalcet use reduced bone fracture risk in hemodialysis-dependent patients aged ≥ 65 years who had PTH > 300 pg/mL as compared to placebo, but this effect was blunted in younger participants[83]. Thus, despite overwhelming need, very few therapies have been studied to help increase bone strength in patients with CKD and ESKD.

CONCLUSION

Reduced kidney function in patients with advanced CKD and ESKD creates a unique spectrum of pathological changes in vascular and bone disease. While targeted treatment of hyperphosphatemia and secondary hyperparathyroidism can help correct associated biochemical abnormalities, mortality rates from vascular calcifications and following bone fractures remain disproportionately higher compared to the general population. Among recent therapeutic developments, tenapanor and SNF472 have emerged as promising Food and Drug Administration-approved therapies for the management of hyperphosphatemia and vascular calcifications while αKlotho is an interesting therapeutic target with the potential to attenuate vascular disease and aging. Further high-quality studies are needed to better prevent, diagnose and treat vascular and bone disease in patients with advanced CKD and ESKD.