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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 5 1535-1541
Copyright © 1998 by The Endocrine Society

Original Studies

Renal Tubular Reabsorption of Phosphate Is Positively Related to the Extent of Bone Metastatic Load in Patients with Prostate Cancer1

Nicolas Buchs, Jean-Philippe Bonjour and René Rizzoli

Division of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital, 1211 Geneva 14, Switzerland

Address all correspondence and requests for reprints to: Dr. René Rizzoli, Division of Bone Diseases, Department of Internal Medicine, University Hospital, 1211 Geneva 14, Switzerland. E-mail: rizzoli{at}cmu.unige.ch


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
Osteolytic metastases are often associated with decreased renal tubular reabsorption of phosphate. There is, however, no specific data on phosphate metabolism in metastases from prostatic cancer, which are generally osteoblastic. The aim of the present study was to investigate renal handling of inorganic phosphate (Pi) in prostatic cancer, in patients without or with skeletal metastases of various extents. Forty-eight patients were the subjects of this study. There were 39 with malignant disease, of whom 27 had bony metastases. Nine other patients had benign prostate hyperplasia. Biochemical indexes of prostatic tumor, renal tubular reabsorption of calcium and Pi, biochemical markers of bone remodeling, and relevant calciotropic hormones were measured and analyzed in relation to the extent of skeletal metastases, as assessed by bone scintigraphy. A higher bone metastatic load was associated with significantly greater prostate-specific antigen and prostatic acid phosphatase levels (P < 0.05), increased levels of biochemical markers of bone formation (P < 0.05) and resorption (P < 0.001), higher maximal renal tubular reabsorption of Pi (TmPi/GFR; P < 0.05), and higher urinary cAMP excretion (P < 0.05). Nine patients among those with bone metastases (n = 27) had higher TmPi/GFR than metastasis-free patients. These had a greater value of osteocalcin (P < 0.001). Also, 8 of these had relatively more extensive skeletal metastatic load. In patients with prostatic cancer, high skeletal metastatic load was accompanied by increased TmPi/GFR despite higher urinary cAMP excretion, which is supposed to reduce the TmPi/GFR. These results support the hypothesis that renal tubular reabsorption of Pi is capable of adaptation to meet demands for minerals in the face of enhanced bone formation.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
INORGANIC phosphate (Pi) homeostasis is regulated by constant fluxes of entry and exit through different organs. Pi enters the extracellular space by the gastrointestinal tract, by release from soft tissues and from bones; it leaves the extracellular compartment through renal excretion and deposition into bones (mineral) and/or into cells (1, 2). The renal tubular reabsorption of Pi (TmPi/GFR) is the principal regulator of the extracellular Pi concentration (1, 2, 3). This transport is firstly influenced by PTH (1) and PTH-related protein (PTHrP) (4), which is the major mediator of the humoral hypercalcemia of malignancy (5, 6) and which shares the same surface receptor with PTH (7). Secondly, Pi transport is also controlled by insulin-like growth factor I (IGF-I) (8). Beside these hormonal influences, TmPi/GFR is greatly affected by extracellular calcium levels and by the supply and demand for Pi, mechanisms that hitherto have not been defined (9, 10, 11).

Skeletal involvement by tumors is generally osteolytic and seldom osteoblastic in nature. Even without invading bones, malignant disease can affect calcium and Pi metabolism, by secreting factors into the bloodstream that not only affect the proliferation and activity of osteoclasts and osteoblasts but also alter the renal handling of calcium and Pi (12, 13, 14). Hypercalcemia is a common feature of osteolytic metastatic disease (12). Although hypercalcemia in these cases is due to enhanced net bone resorption, increased renal tubular reabsorption of calcium has an important role in its pathogenesis (15, 16). Indeed, many patients with cancer and hypercalcemia present with biological characteristics akin to primary hyperparathyroidism, which is ascribed to PTHrP (6, 12, 14), with increased bone resorption, enhanced renal tubular reabsorption of calcium, and decreased TmPi/GFR.

Tumor of the prostate is the commonest cancer to produce osteoblastic metastases (>90% of bone metastases are osteoblastic). This can affect a large part of the skeleton with extensive new bone formation (17, 18, 19). Factors known to influence renal Pi transport, such as IGF-I, transforming growth factor-ß, and PTHrP (8, 20, 21, 22), have been detected in prostatic cancer cell lines and human prostatic tumor tissues (13, 23, 24, 25, 26). Plasma TGFß has even been shown to be elevated in patients with invasive prostatic cancer (27).

Whether prostatic cancer with osteoblastic metastases could be associated with modification of renal tubular handling of Pi is an important issue that has yet to be settled. Therefore, we conducted a study with the aim of investigating the relationship between the renal handling of phosphate and osteoblastic metastatic extent in prostatic cancer.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects

The study protocol was approved by the ethics committee of the Department of Surgery of the Geneva Faculty of Medicine, and informed consent was obtained from all subjects.

Thirty-nine patients with prostatic carcinoma (age, 73.5 ± 1.4 yr; mean ± SEM) and 9 with benign prostatic hyperplasia (BPH; age, 69.8 ± 1.4 yr) were enrolled. All patients with cancer had a prostatic biopsy and tissue diagnosis of adenocarcinoma. Bone involvement and its extent were evaluated by an imaging technique, using a technetium-99-labeled methylene bisphosphonate bone scan. When bone metastases were suspected, a further confirmation was obtained with standard radiography, computerized tomography, and/or magnetic resonance imaging. Among the subjects with prostatic cancer, 27 had proven bone metastases (age, 74.7 ± 1.6 yr), whereas 12 (age, 70.7 ± 2.7 yr) had none detectable. The 9 patients with BPH had no previous history of malignancy, and the biopsy specimen did not reveal any evidence of cancer. Forty of the 48 patients had no previous treatment for prostatic disease. Five subjects with skeletal metastases had undergone orchidectomy 4–56 months before the study (23 ± 4.7 months), and 2 had received previous hormonal therapy (cyproterone acetate for 3 months, flutamide for 8 months). One patient with prostatic carcinoma without bone secondaries had hormone therapy 3 months before the study (buserelin acetate). Four patients were receiving levothyroxine for hypothyroidism (between 0.05–0.15 mg/day; 3 in the malignant group and 1 in the BPH group). Forty-five of 48 subjects were independent enough to be hospitalized for only a short period (3–5 days). The other 3 were hospitalized for a longer period because of a pathological fracture of femur in 1 and poor general condition in 2. Three of our patients were included in the study despite their hypercalcemia, which was related to primary hyperparathyroidism.

Biochemical survey

In all patients, fasting plasma levels of protein-adjusted calcium (adjusted Ca = Ca/[(protein/160) + 0.55]), Pi, alkaline phosphatase, creatinine, protein, and urinary calcium, creatinine, and hydroxyproline were determined by standard laboratory methods. In addition, the following tests were performed: intact PTH using a two-site chemiluminescent immunometric assay (Immulite, Diagnostic Products Corp., Los Angeles, CA); osteocalcin employing an immunoradiometric assay (CIS-Bio, Gif-sur-Yvette, France); 25-hydroxyvitamin D (calcifediol), and 1,25-dihydroxyvitamin D (calcitriol) using a RIA and a protein binding assay, respectively (Incstar Corp., Stillwater, MN); prostate-specific antigen (PSA) and prostatic acid phosphatase employing RIA (Immulite, Diagnostic Products Corp.); and IGF-I by RIA (Nichols Institute, San Juan Capistrano, CA), after separation from binding proteins using acid-ethanol extraction and cryoprecipitation (28).

A sample of urine from the second micturition in the morning (fasting urine) was taken to determine pyridinoline and deoxypyridinoline by detecting fluorescence emission after acid hydrolysis and separation with reverse phase isocratic high performance liquid chromatography (Bio-Rad system, Munich, Germany) as well as cAMP (Immunotech, Marseille, France).

Ratios of the concentrations of calcium, hydroxyproline, pyridinoline, and deoxypyridinoline over the concentration of creatinine in the fasting urinary sample were taken as a reflection of bone resorption. A tubular reabsorption of calcium index was calculated using a nomogram relating fasting urinary calcium excretion per U glomerular filtration rate and protein-adjusted plasma calcium (15). The maximal TmPi/GFR was measured according to the method of Bijvoet et al. (3).

Imaging methods

A bone scintigram was recorded at least 2 h after the injection of 99technetium-methylene bisphosphonate. The total bone metastatic load (TML), i.e. number and size of the metastatic lesions, was graded using the scoring method and stratification into five groups proposed by Soloway et al. (extent of disease score) (29).

The patients were classified into two groups. The first one included Soloway’s scores of 0 and 1, corresponding to less than six malignant bone lesions. The second included scores of 2–4, corresponding to six or more lesions.

Statistical analysis

Results are expressed as the mean ± SEM. The significance of differences between groups was assessed using nonparametric tests (Mann-Whitney rank test or Kruskall-Wallis test). Correlations between TmPi/GFR and TML, as determined by Soloway’s score, were analyzed using a Spearman rank regression. Statistical significance was achieved at P < 0.05.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Patient characteristics

Body mass indexes were within normal range and not statistically different between subjects with prostatic carcinoma with or without bone metastases (Table 1Go). Most patients were independent and fully capable of walking. The duration of the disease was shorter in subjects with carcinoma without skeletal metastases than in those with benign prostate hyperplasia or metastatic carcinoma to bone (BPH vs. carcinoma without bone metastases, P < 0.005). Distribution of bone metastases on bone scan was as follows. Pelvis was involved in 93%, spine was involved in 89%, and ribs were involved in 74%; 4% had a superbone scan, as defined as a diffuse symmetrical uptake of 99technetium-methylene bisphosphonate without visualization of the kidneys. In subjects with bone metastases, levels of tumor markers (PSA and prostatic acid phosphatase) were significantly higher than those in the other groups (P < 0.001).


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  		Table 1. Patient characteristics

 
Calcium-phosphate metabolism (Table 2Go)

The plasma total protein level was lower in patients with cancer than in those with benign disease (P < 0.005). Plasma IGF-I, taken as an index of nutritional status (30), tended to be lower in those with bone metastases (P = 0.07). It was also lower in patients with bone metastases than in those without such metastases (combined BPH and localized carcinoma, P < 0.05). The trend toward a higher plasma protein-adjusted calcium in subjects with bone metastases compared to those with BPH did not reach statistical significance (P = 0.06). Urinary cAMP was significantly increased in patients with bone metastases compared to that in patients with BPH (P < 0.05) or localized carcinoma (P < 0.005). Biochemical markers of bone remodeling were similar in patients with BPH and in cancer patients without bone metastases. Compared with combined BPH and cancer without bone metastases, bone formation markers, such as osteocalcin (P < 0.05) and alkaline phosphatase (P < 0.005), were significantly higher when bone metastases were present. Bone resorption markers, such as urinary hydroxyproline/creatinine (P < 0.001), deoxypyridinoline/creatinine (P < 0.001), and pyridinoline/creatinine (P < 0.001) ratios, were increased in patients with bone metastases. However, there was no difference in the level of fasting urinary calcium excretion, which represents the net flux of calcium between mineral accretion and resorption.


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  		Table 2. Calcium-phosphate metabolism in patients with prostate carcinoma or BPH

 
Relation between bone turnover and TmPi/GFR levels

TmPi/GFR was similar in patients with prostate carcinoma and BPH (Table 2Go). However, patients with bone metastases had a much wider range of values than those with either prostate cancer without skeletal involvement or BPH (Fig. 1Go). Thus, subjects with bone metastases were grouped according to their levels of TmPi/GFR (TmPi/GFR < or >=1.07 mmol/L GFR), with a cut-off point at the 75% percentile, corresponding to the mode of the distribution. The relationship between bone remodeling and TmPi/GFR levels was then examined. Osteocalcin was significantly higher (P < 0.005) in patients with a TmPi/GFR of 1.07 or more than in subjects with a TmPi/GFR below 1.07 mmol/L GFR (Fig. 2Go). In the former group, urinary calcium/creatinine excretion was slightly lower (P = 0.05; Fig. 3Go). In both subgroups of patients with bone metastases, hydroxyproline/creatinine, pyridinoline/creatinine, and deoxypyridinoline/creatinine ratios were similar, whatever the TmPi/GFR (Fig. 3Go). These findings were compatible with a somewhat higher bone formation rate in patients with a higher TmPi/GFR.



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  		Figure 1. Renal tubular reabsorption of Pi (TmPi/GFR) in patients with BPH (n = 9), prostate cancer without bone metastases (n = 12), or prostate cancer with bone metastases (n = 27).

 


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  		Figure 2. Relation between biochemical markers of bone formation and TmPi/GFR. Results are the mean ± SEM. TmPi/GFR was 0.87 ± 0.05, 0.77 ± 0.05, and 1.26 ± 0.07 mmol/L GFR in BPH and carcinoma without metastases, in carcinoma with bone metastases and TmPi/GFR below 1.07, and 1.07 or more, respectively. *, P < 0.05; **, P < 0.01; ***, P < 0.001 (compared with patients with BPH or with prostate carcinoma free of detectable bone metastases). ##, P < 0.005 (compared with patients with prostate cancer with bone metastases and TmPi/GFR below 1.07 mmol/L GFR).

 


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  		Figure 3. Relation between biochemical markers of bone resorption and TmPi/GFR. Results are the mean ± SEM. TmPi/GFR values in the three groups are presented in Fig. 2Go. **, P < 0.005; ***, P < 0.001 (compared with patients with BPH or prostate carcinoma free of detectable bone metastases).

 
Patients with TmPi/GFR of 1.07 mmol/L GFR or more had serum PTH and urinary cAMP excretion similar to those in patients free of bone metastases (prostatic cancer without bone secondaries or BPH), making reduced PTH levels or function unlikely to account for their TmPi/GFR values. In contrast, patients with bone metastases and a TmPi/GFR below 1.07 mmol/L GFR had a trend toward higher plasma calcium as well as a higher level of PTH and a greater urinary cAMP excretion (P < 0.005) than those free of bone metastases (Table 3Go). This was also the case for the bone resorption markers hydroxyproline, pyridinoline, and deoxypyridinoline (P < 0.005, P < 0.001, and P < 0.005, respectively; Fig. 3Go). In the subgroup with bone metastases and TmPi/GFR below 1.07 mmol/L GFR, biochemical features of primary hyperparathyroidism were found in three cases.


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  		Table 3. Calcium-phosphate metabolism in relation to renal tubular reabsorption of Pi in patients with prostate carcinoma

 
Relation between TML and TmPi/GFR

Eight of 9 patients with prostatic cancer and a TmPi/GFR of 1.07 mmol/L GFR or more had more than 6 bone metastases [Soloway score (extent of disease score), >=2] compared to 11 of 18 in the subgroup with TmPi/GFR below 1.07. Thus, to evaluate the relation between phosphate metabolism and bone metastases (presence and number of metastases), data for the 38 subjects with prostate cancer were analyzed according to their TMLs. This group was subdivided into 2 subgroups. The first (subgroup A, n = 19) had a metastatic Soloway score less than 2, and the second (subgroup B, n = 19) had a Soloway score of 2 or more (Table 4Go). Biochemical markers reflecting bone formation were significantly higher in subgroup B (P < 0.05 for osteocalcin, P < 0.001 for alkaline phosphatase, and P < 0.005 for bone-specific alkaline phosphatase) than in subgroup A (Fig. 4Go). Pyridinium cross-links and urinary hydroxyproline/creatinine ratios were significantly increased in patients with a higher TML (P < 0.001; Fig. 5Go). However, there was no correlation between fasting urinary calcium excretion and the number of bone metastases. Plasma phosphate levels and TmPi/GFR were significantly higher in subgroup B [1.16 ± 0.07 vs. 1.00 ± 0.05 mmol/L (P < 0.05) and 1.00 ± 0.06 vs. 0.85 ± 0.07 mmol/L GFR (P < 0.05), respectively]. TmPi/GFR was positively correlated to TML (r = 0.33; P = 0.04 when all patients were considered, and r = 0.40; P = 0.04 when only patients with detectable bone metastases were analyzed; Fig. 6Go). This indicated that 11–16% of the variance could be explained by TML. PTH levels were not different in the 2 subgroups, but the urinary cAMP was just above the normal range and significantly higher in those in subgroup B than in subjects in subgroup A (50.4 ± 3.1 vs. 43.2 ± 4.2 mmol/L GFR; P < 0.05). The relation between TmPi/GFR, and PTH and TML, as independent variables, was then examined in a multiple regression model. TmPi/GFR was negatively correlated to PTH (P = 0.005), but for TML, the significance was attenuated (P = 0.08). IGF-I was reduced in patients in subgroup B (P = 0.05). Plasma calcium, creatinine, 25-hydroxyvitamin D, 1,25-dihydroxyvitamin D, and tubular reabsorption of calcium were similar in the 2 subgroups.


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  		Table 4. Calcium-phosphate metabolism in relation to bone metastatic load

 


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  		Figure 4. Relation between biochemical markers of bone formation and bone metastatic load, as assessed by isotopic bone scintigraphy (Soloway score), in patients with prostate cancer. A score less than 2 was defined by less than six bone metastases, and a score of 2 or higher was defined by six or more bone metastases. Results are the mean ± SEM. *, P < 0.05; **, P < 0.005; ***, P < 0.001.

 


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  		Figure 5. Relation between biochemical markers of bone resorption and bone metastatic load, as assessed by isotopic bone scintigraphy (Soloway score), in patients with prostate cancer. Results are the mean ± SEM. ***, P < 0.001.

 


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  		Figure 6. Correlation between TmPi/GFR and TML. In a Spearman rank regression analysis, the regression coefficient was 0.33 (P = 0.04) when all patients were considered and 0.40 (P = 0.04) when only patients with detectable metastases were analyzed.

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
Considering the incidence of prostatic cancer and its propensity towards osteoblastic metastases, it is important to gain an understanding of phosphate metabolism, particularly the handling of Pi by the kidneys in such lesions.

At first sight the analysis of results of our study suggested that the mean TmPi/GFR was not different in patients with BPH and those with cancer (with or without skeletal lesions). Several factors might be responsible for this apparent lack of difference. For instance, urinary cAMP, which is a reflection of PTH and PTHrP action, was significantly higher and above the normal range in subjects with skeletal involvement by tumor. As PTH and PTHrP decrease TmPi/GFR (4), an increase in urinary cAMP might alter or even mask the effect of other conditions that could be associated with increased TmPi/GFR. Indeed, PTHrP is expressed by human prostate cancer tissue (31) and prostate cancer cell lines (24), where it might play a role in the expansion of prostate cancer by acting in an autocrine fashion (24). In our patients with cancer, IGF-I, which can increase the TmPi/GFR (8), tended to be lower in those with bone metastases than in others with no detectable skeletal involvement (P = 0.07). There was, however, statistically lower IGF-I in cancer patients with bone metastases than in the combined group of cancer patients with no metastases and those with BPH (P < 0.05). This might reflect a poorer nutritional status in relation to active cancer disease (30). It is relevant to emphasize the possible role of IGF-I in both TmPi/GFR regulation and cancer of the prostate. IGF-I, IGF-I receptors, and IGF-binding proteins are produced in vitro by several prostate cell lines and are present in prostate tissue (32). Furthermore, PSA is an IGF-binding protein protease (33), possibly increasing the bioavailability of IGF-I. Four patients in our series with bone metastases had hypothyroidism and were receiving insufficient T4 replacement. As an excess of thyroid hormones is also related to an elevated TmPi/GFR (34, 35), insufficiently treated hypothyroidism, as was the case in these patients, could have also altered or masked any increase in TmPi/GFR.

When we analyzed the results according to the magnitude of the TmPi/GFR, the level of plasma osteocalcin, which is known to be elevated in prostatic cancer with skeletal involvement (36, 37), was also significantly higher in patients with a higher TmPi/GFR than in those with a lower TmPi/GFR. We also found that the mean alkaline phosphatase level was greater in those with a high TmPi/GFR, although this did not reach statistical significance, possibly because of the wide distribution of values. In contrast, selective markers of bone resorption were similar in magnitude regardless of TmPi/GFR levels, whereas fasting urinary calcium excretion was lower in patients with a higher TmPi/GFR. As fasting urinary calcium excretion represents the difference between bone calcium fluxes of accretion and resorption and hence a reflection of net bone calcium balance, it follows that the trend toward a lower value might be interpreted as a tendency to a more positive calcium bone balance.

When we looked at the renal handling of Pi in relation to TML, evaluated by bone scintigram, we found that a greater TML was associated with a higher TmPi/GFR. This finding could not be accounted for by alterations in renal function, lower PTH levels (or activity), and/or higher IGF-I levels. In fact, a greater TML was accompanied by increased urinary cAMP excretion and lower IGF-I levels. However, these observations do not rule out the possibility of other circulating factors, which are known to be produced by prostate cancer and to influence renal Pi, being implicated in this mechanism. Therefore, these results indicated some correlation between TmPi/GFR and bone formation. TmPi/GFR, which is a main controller of Pi homeostasis, can adapt to changes in Pi needs through a powerful mechanism hitherto not fully elucidated. For instance, Pi and TmPi/GFR have been described to be higher in young growing rats as well as in children (10, 38). This difference in renal Pi reabsorption, which is also fully expressed in the absence of PTH (10), can be interpreted as an appropriate response to a greater need of Pi for bone mineralization. Another example is that of tumoral calcinosis, a disorder of unknown origin, characterized by extensive deposits of calcium phosphate in soft tissues, which is associated with enhanced TmPi/GFR without lowering of serum PTH (39). This might yet be regarded as a response to an inadequate increased requirement for metastatic calcifications. Furthermore, in cases of reduced demand for Pi, such as in rats treated with high doses of etidronate (a bisphosphonate that at higher doses reduces bone mineralization) (9) or in oncogenic osteomalacia (40), decreased TmPi/GFR has been described. Extensive osteoblastic metastases, such as those that occur in prostatic cancer, are potential situations in which there are enhanced needs for phosphate. Thus, the higher TmPi/GFR in patients with extensive skeletal metastases, as shown in the present study, might represent another situation in which TmPi/GFR is influenced by a putative message delivered by bone.

In conclusion, this study shows that in patients with cancer of the prostate and important osteoblastic metastatic lesions (i.e. high TML), there is an increase in TmPi/GFR. This is akin to the increase in TmPi/GFR observed during growth, which is another situation where there is active bone formation. There might be a link between bone formation and adaptation of the kidneys to the handling of Pi in response to skeletal needs. The nature of this link, however, is unclear. In this context and in cases of osteoblatic metastases of prostatic cancer, some unknown factors might be produced by the metastatic tumor cells or bone cells themselves that alter the ability of the renal tubule to reabsorb Pi, according to the need. Nevertheless, neither PTH nor IGF-I seems to be responsible for this phenomenon.


   Acknowledgments
 
We are indebted to Prof. P. Graber, M.D.; Dr. G. Venzi, M.D.; and the medical team of the Geneva University Hospital Urology Clinic for allowing us to investigate their patients. We thank Dr. L. Vadas, Ph.D., and N. Mensi, Ph.D., for the biochemical determinations, and the Division of Nuclear Medicine for the bone scintigrams.


   Footnotes
 
1 This work was supported by the Swiss National Research Foundation (Grant 32–32411.91). Back

Received August 26, 1997.

Revised November 7, 1997.

Revised December 31, 1997.

Accepted January 15, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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 Cancer Epidemiol. Biomarkers Prev.Home page
G. G. Schwartz
Prostate Cancer, Serum Parathyroid Hormone, and the Progression of Skeletal Metastases
Cancer Epidemiol. Biomarkers Prev., March 1, 2008; 17(3): 478 - 483.
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