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Serum Parathyroid Hormone-Related Protein Levels and Response to Bisphosphonate Treatment in Hypercalcemia of Malignancy

Division of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital (R.R.), CH-1211 Geneva 14, Switzerland; the Department of Internal Medicine, University Hospital (D.T.), CH-1011 Lausanne, Switzerland; the Department of Surgery, University Hospital (N.B.), Manchester M209BX, United Kingdom; the Department of Medicine and Medical Oncology, Wilhelminenspital (M.P.), A-1160 Vienna, Austria; Roche Diagnostics GmbH (Z.H., H.J.H., F.R.), D-68305 Mannheim, Germany; Hospital Rohrbach (C.M.), D-69126 Heidelberg, Germany; Centre R. Huguenin (M.T.-H.), F-92210 Saint-Cloud, France; City Hospital (E.U.S.), D-34125 Kassel, Germany; Centre O. Lambret (M.D.), F-59020 Lille, France; Canton Hospital (B.T.), CH-9007 St. Gallen, Switzerland; University Hospital (M.R.C.), D-54219 Tuebingen, Germany; Institut Bergonié (H.E.), F-33076 Bordeaux, France; and Institut J. Bordet (J.J.B.), B-1000 Brussels, Belgium

Address all correspondence and requests for reprints to: Dr. R. Rizzoli, M.D., Division of Bone Diseases, World Health Organization Collaborating Center for Osteoporosis and Bone Diseases, Department of Internal Medicine, University Hospital, 1211 Geneva 14, Switzerland. E-mail: rizzoli{at}cmu.unige.ch

The pathogenesis of hypercalcemia of malignancy comprises increased net bone resorption and enhanced renal tubular reabsorption of calcium (Ca). To evaluate the prevalence of an increased renal tubular reabsorption of Ca index [tubular reabsorption of calcium index (TRCaI)] in cancer patients with hypercalcemia and of elevated circulating levels of PTH-related protein (PTHrP), which is recognized as a major mediator of this syndrome, we investigated 315 well rehydrated patients, aged 58.1 ± 0.7 yr (mean ± SEM), with hypercalcemia [albumin-corrected plasma Ca (pCa), >2.7 mmol/L] secondary to histologically proven malignancy. Changes in pCa and, therefore, various Ca filtered loads were obtained by different degrees of bone resorption inhibition achieved with a single infusion of the bisphosphonate ibandronate, given at various doses on a randomized, double blind basis. PTHrP was determined at baseline in 147 of the patients and 7 days after bisphosphonate therapy in 73. Before ibandronate therapy, pCa was 3.36 ± 0.02 mmol/L, mean TRCaI was increased at 3.09 ± 0.03 mmol/L glomerular filtration rate (GFR; normal, 2.40–2.90), and 65% of patients had TRCaI above 2.90 mmol/L GFR. Mean serum PTHrP levels were 4.9 ± 0.5 pmol/L (normal, <2.5) and values above the normal range were found in 53% of the patients (76% in lung and upper respiratory tract malignancies). By 7 days after the infusion of ibandronate, a decrease in pCa of 0.69 ± 0.03 mmol/L (20.0 ± 0.7%; P < 0.001) and in bone resorption [mean change in fasting urinary Ca, 0.09 ± 0.04 mmol/L GFR (47.6 ± 8.6%; P < 0.001) and 14.4 ± 1.7 nmol/mmol (27.6 ± 10.6%; P < 0.01) in deoxypyridinoline] was observed. TRCaI was slightly lowered by 0.30 ± 0.09 mmol/L GFR. Mean changes in PTHrP, 1,25-dihydroxyvitamin D₃, and PTH were +0.7 ± 0.4 (P = NS), +27.6 ± 3.0 (P < 0.001), and +2.9 ± 0.8 (P < 0.005) pmol/L, respectively. After ibandronate treatment, the relative risk of relapsing hypercalcemia was particularly increased (3.43-fold) in lung and upper respiratory tract malignancies. These results obtained in a large cohort of patients indicate a significant prevalence of an increased renal tubular reabsorption of calcium index in hypercalcemia of malignancy and a substantial proportion of patients with detectable PTHrP.

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