Bone Resorption and Constipation Predict Higher Tenapanor Dose Requirements in Dialysis Patients with Hyperphosphatemia
核心洞察
A pooled analysis of three clinical trials identified higher serum TRACP-5b (搜索) levels and lower Bristol Stool Form Scale scores as independent predictors of requiring higher tenapanor doses in dialysis patients with hyperphosphatemia (搜索).
Elevated TRACP-5b (搜索), a marker of bone resorption, suggests that greater bone-derived phosphorus release may attenuate tenapanor's phosphorus-lowering effect, necessitating dose escalation.
Patients prone to constipation were more likely to tolerate higher tenapanor doses, likely due to the drug's osmotic, stool-softening mechanism of action.
A pooled analysis of data from three clinical trials has identified patient characteristics that predict the need for higher doses of tenapanor hydrochloride (tenapanor) in dialysis patients with hyperphosphatemia (搜索). The study, published in PLoS One, found that higher serum TRACP-5b (搜索) levels and lower Bristol Stool Form Scale (BSFS) scores independently predicted the requirement for higher tenapanor doses, offering clinicians a potential framework for individualized dosing of this recently launched therapy.
Tenapanor, a novel therapeutic agent for hyperphosphatemia (搜索) in dialysis patients, was launched in the USA in 2023 and in Japan in 2024. Unlike conventional phosphate binders (PBs), which bind dietary phosphorus in the gastrointestinal tract, tenapanor selectively inhibits the sodium/hydrogen exchanger isoform 3 (搜索) (NHE3) expressed on the apical membrane of intestinal epithelial cells, thereby reducing paracellular phosphorus absorption.
Clinical Context and Unmet Need
In hemodialysis (HD) patients, the loss of urinary phosphate excretion makes dialysis alone insufficient to eliminate excess phosphorus, often resulting in hyperphosphatemia (搜索). This condition contributes to the development and progression of cardiovascular calcification and secondary hyperparathyroidism, which are associated with increased risks of all-cause mortality, cardiovascular mortality, and fractures.
For many years, phosphate binders have been the only approved pharmacological treatment for hyperphosphatemia (搜索). However, PBs are often associated with adverse effects, the use of two or more PBs in combination, and the requirement for frequent daily dosing. They also substantially contribute to high pill burden, which leads to decreased medication adherence and poor phosphorus control.
The dosing regimen approved in Japan recommends initiating tenapanor at 5 mg twice daily, with titration to 10, 20, or 30 mg twice daily based on clinical response (serum phosphorus levels) and tolerability, with dose increases made at intervals of at least one week. However, tenapanor is frequently associated with gastrointestinal (GI) side effects, such as diarrhea, soft stools, and increased stool frequency, which may make patients reluctant to escalate the dose in real-world clinical practice.
Study Design and Key Findings
The investigators conducted a pooled analysis of data from three clinical trials to identify patient background factors that necessitate and enable the use of higher tenapanor doses. Multivariate analysis identified higher serum TRACP-5b (搜索) levels and lower BSFS scores as independent predictors of requiring higher tenapanor doses.
TRACP-5b (搜索) is a reliable marker of bone resorption in dialysis patients. Elevated levels reflect increased osteoclast number and activity, often seen in high-turnover bone disease, particularly secondary hyperparathyroidism. Notably, parathyroid hormone (a bone formation marker) showed no univariate association with tenapanor dose, whereas TRACP-5b (a bone resorption marker) did. In addition, baseline levels of bone-specific alkaline phosphatase, reflecting osteoblast activity, and procollagen type 1 N-terminal propeptide, reflecting collagen production, were largely comparable between the low-dose and high-dose groups.
"Taken together, these findings support the notion that bone resorption, rather than bone formation, is more closely associated with tenapanor dose requirements," the authors wrote. Mechanistically, approximately 85% of total body phosphorus is stored in bone as hydroxyapatite, and osteoclast-mediated resorption releases phosphorus into the circulation. While calcimimetics lower serum phosphorus levels by reducing this bone-derived phosphorus flux via suppression of parathyroid hormone, tenapanor acts by inhibiting intestinal phosphorus absorption and does not directly affect bone resorption. Therefore, patients with greater phosphorus release from bone, reflected by higher TRACP-5b (搜索) levels, may require higher tenapanor doses to achieve target serum phosphorus levels.
This interpretation is supported by the observation that serum phosphorus levels remained higher in the high-dose group than in the low-dose group throughout the study period. Clinically, TRACP-5b (搜索) measurement could help identify dialysis patients needing more intensive serum phosphorus-lowering strategies, including higher tenapanor doses or combination therapy with calcimimetics.
Role of Bowel Habits in Dose Titration
The BSFS classifies stools into seven types according to form and consistency: Types 1 and 2 indicate constipation, Types 3 and 4 represent normal stools, Type 5 consists of soft blobs with clear-cut edges, and Types 6 and 7 indicate diarrhea. Multivariate logistic regression analysis showed that patients with lower BSFS scores, reflecting a tendency toward constipation, were more likely to require higher tenapanor doses.
Tenapanor inhibits NHE3, causing sodium to accumulate in the intestinal lumen and increasing luminal osmotic pressure. This osmotic gradient drives water movement from the interstitium into the lumen, resulting in softer stools and diarrhea, which are well-recognized adverse effects of the drug. In rats, a single oral dose of tenapanor increased both ileal luminal water content and fecal sodium excretion, consistent with these clinical observations.
Univariate analysis showed that laxatives and sevelamer hydrochloride were prescribed to a significantly higher proportion of patients in the high-dose group, with the latter known to cause constipation as an adverse effect. Moreover, no significant difference was observed in the incidence of GI-related adverse drug reactions between the low-dose and high-dose groups. These findings are consistent with a recent report indicating that patients who continue tenapanor therapy are more likely to be habitual laxative users than those who discontinue it, as well as with results showing that tenapanor prescriptions are associated with reduced laxative use.
"Therefore, in patients prone to constipation, titration of tenapanor may be achieved more readily due to its osmotic, laxative-like effect," the authors noted.
Study Limitations
The authors acknowledged several limitations. As a pooled analysis of three clinical trials with differing designs, the study included both tenapanor monotherapy after PB washout and combination therapy with PBs. In the combination therapy group, serum phosphorus levels and GI-related adverse drug reactions may have been influenced by the type and dose of PBs, potentially affecting tenapanor dose adjustments. Separate analyses of the monotherapy and combination therapy trials were not feasible due to the small number of subjects.
The study included 162 HD patients and 52 peritoneal dialysis (PD) patients. However, when treated with tenapanor monotherapy, the dose, frequency of diarrhea, and frequency of soft stools were comparable between the two groups. Additionally, although one trial included a total of 16 weeks of tenapanor treatment, the primary endpoint was the change in serum phosphorus levels after 8 weeks, so only data up to Week 8 were used. Because the mean tenapanor dose at Week 16 (16.8 mg) was similar to that at Week 8 (16.4 mg), it is likely that dose escalation had been essentially completed by Week 8.
The sample size was relatively small for a pooled analysis, and the relatively large number of explanatory variables compared with the number of patients in the high-dose group raises the possibility of overfitting. The authors also noted that because dose titration was based on serum phosphorus levels and tolerability, and group classification was based on the final dose, the possibility of circular inference cannot be completely excluded, although baseline serum phosphorus was included in the multivariable analysis.
Clinical Implications
"In conclusion, patients requiring higher doses of tenapanor are characterized by either increased bone resorption or a propensity for constipation," the authors stated. "Increased bone resorption may attenuate the drug's phosphorus-lowering effect by contributing to a greater release of phosphorus from bone, whereas constipation may facilitate more aggressive dose titration owing to the drug's stool-softening properties."
Accordingly, incorporating assessments of bone turnover and bowel habits into routine clinical evaluations may help guide individualized tenapanor dosing. The authors called for further large-scale prospective studies in real-world clinical settings to validate these findings.
The study was funded by Kyowa Kirin Co., Ltd., which provided support in the form of salaries for authors Shin Tokunaga and Shinji Asada and was involved in the study design, conduct of the study, and the decision to submit the manuscript for publication. The statistical analyses were performed by an external specialized organization with no affiliation with the funder.