Increased Renal Calcium Reabsorption by Parathyroid Hormone–Related Protein Is a Causative Factor in the Development of Humoral Hypercalcemia of Malignancy Refractory to Osteoclastic Bone Resorption Inhibitors

Abstract

Purpose: Bisphosphonate and calcitonin lower blood calcium in humoral hypercalcemia of malignancy (HHM) by suppressing osteoclastic bone resorption, but repeated administration of these drugs often leads to relapse. In this study, we examined the roles of parathyroid hormoner elated protein (PTHrP) in the development of bisphosphonate-and calcitonin-refractory HHM. Experimental Design: Nude rats bearing the LC-6 JCK tumor xenograft (LC-6 rats) exhibited high bone turnover and HHM. Repeated administration of alendronate induced a sustained suppression of the bone resorption, but it caused only early and transient reduction of the blood calcium levels, leading to unresponsiveness to the drug. Because high blood levels of PTHrP were detected in the LC-6 rats, those that developed alendronate-refractory HHM were treated with an anti-PTHrP antibody. Results: Administration of anti-PTHrP antibody to animals that received repeated administration of alendronate, thereby developing alendronate-refractory HHM, resulted in an increase in fractional excretion of calcium and a marked decrease of blood calcium level. Drug-refractory HHM was also observed in animals that received another osteoclast inhibitor, an eel calcitonin analogue elcatonin. The blood calcium level decreased after the initial administration of elcatonin, but it eventually became elevated during repeated administration. Administration of the anti-PTHrP antibody, but not of alendronate, effectively reduced the blood calcium of the animals that developed elcatonin-refractory HHM. Conclusion: High levels of circulating PTHrP and the resulting augmentation of renal calcium reabsorption is one of the major causes of the emergence of osteoclast inhibitor-refractory HHM. Thus, blockage of PTHrP functions by a neutralizing antibody against PTHrP would benefit patients who develop bisphosphonate-or calcitonin-refractory HHM.Humoral hypercalcemia of malignancy (HHM) is one of the most common paraneoplastic syndromes that considerably deteriorate the quality of life of cancer patients (1). Increased bone resorption has been thought to play important roles in the development of HHM and current therapies for HHM focus rather on inhibiting the osteoclastic bone resorption. In fact, bisphosphonate drugs that interfere with the osteoclasts have become the gold standard for the treatment of HHM (2). However, there are patients who do not respond to these drugs and others often suffer relapse after repeated administration of bisphosphonate drugs. In a recent study by Body et al. (3), the percentage of patients who responded to a first dosing of pamidronate was 90%, but decreased to 80% and 70% at second and third dosings, respectively. Furthermore, the response rate to pamidronate was higher in patients with lower blood parathyroid hormone -related protein (PTHrP) levels (between 2 and 12 pg/mL) than those with higher PTHrP levels (higher than 12 pg/mL), suggesting the involvement of PTHrP in bisphosphonate-refractory HHM (4).Bisphosphonate-refractory HHM has also ...

Parathyroid Hormone-Related Protein Induces Cachectic Syndromes without Directly Modulating the Expression of Hypothalamic Feeding-Regulating Peptides

“…Consistent with previous results (24,26,27), body weight of HHM rats significantly decreased in comparison with nontumor-bearing rats after day 30 (30 days after tumor implantation) but significantly increased after HHM rats were given the antiPTHrP antibody (Fig. 1A).…”

“…As previous studies have shown, rats carrying the LC-6 xenograft display HHM and concurrent anorexia, and administration of anti-PTHrP antibody restored blood calcium, food intake, and body weight in these rats (24,26,27). Capparelli et al (35) reported that s.c. administration of osteoprotegerin improved hypercalcemia in mice bearing the Colon-26 tumor, which produced and secreted PTHrP into plasma and induced hypercalcemia; however, body weight loss and high levels of PTHrP in plasma remained.…”

Similar changes of hypothalamic feeding‐regulating peptides mRNAs and plasma leptin levels in PTHrP‐, LIF‐secreting tumors‐induced cachectic rats and adjuvant arthritic rats

“…Body weight, arthritis index, iCa and plasma leptin in Normal rats, HHM rats, SEKI rats, AA rats and 1a,25(OH) 2 D 3 rats Consistent with previous results, 19,20,22,23 the body weight of the HHM rats bearing PTHrP secreting LC-6 significantly decreased after day 30, but significantly increased after the HHM rats were given the anti-PTHrP antibody (Fig. 1a).…”

“…Rats that displayed blood ionized calcium (iCa) levels higher than 1.8 mmol/L and at least 0.5 mmol/L higher than normal (control) rats were used as the HHM rats. [20][21][22][23] Nude mice and nude rats were purchased from Charles River Japan (Yokohama, Japan) and Clea Japan (Tokyo, Japan), respectively, and kept in sterilized cages. For treatment with an anti-PTHrP mAb, the rats were given 3 mg/kg of anti-PTHrP antibody intravenously (i.v.)…”

Intensification therapy with anti-parathyroid hormone-related protein antibody plus zoledronic acid for bone metastases of small cell lung cancer cells in severe combined immunodeficient mice

“…For example, the rate of response to pamidronate was higher in patients with lower (2-12 pg/ mL) than higher (>12 pg/mL) blood PTHrP concentrations (29). In addition, the emergence of alendronate-refractory humoral hypercalcemia of malignancy was associated with high levels of circulating PTHrP (30), further suggesting that PTHrP may play a critical role in intrinsic and/or acquired resistance to bisphosphonates in bone metastases. Thus, combined treatment with of PTHrP antibody and zoledronic acid may control the progression of bone metastases.…”