用于骨痛治疗的放射性核素

介绍了用于骨疼痛治疗的放射性核素89Sr、153Sm、186Re、188Re和117Snm,评述了这些核素的生产以及在骨疼痛治疗中的应用,并对每个核素的优缺点进行了讨论。     

Considerations in the selection of radiopharmaceuticals for palliation of bone pain from metastatic osseous lesions.

Bone pain is a common complication for terminal patients with bone metastases from prostate, lung, breast, and other malignancies. A multidisciplinary approach in treating bone pain is generally required, 1 which includes a combination of analgesic drug therapy, radiation therapy, hormonal therapy, and chemotherapy. Over the years, treatment of bone pain using bone-seeking radiopharmaceuticals has been explored extensively. Pharmaceuticals labeled with energetic 1-particle emitters such as 32p, 89Sr, 153Sm, and 186Re, in addition to the low-energy electron emitter 117mSn, have been studied for this purpose. Bone-marrow toxicity as a consequence of chronic irradiation by the energetic , particles is a general problem associated with this form of treatment. It is therefore desirable to identify radiochemicals that minimize the dose to the bone marrow and at the same time deliver therapeutic doses to the bone. Methods: New S values (mean absorbed dose per unit cumulated activity) for target regions of human bone and marrow were used to ascertain the capacity of various radiochemicals to deliver a high bone dose while minimizing the marrow dose. The relative dosimetric advantage of a given radiopharmaceutical compared with a reference radiochemical was quantitated as a dosimetric relative advantage factor (RAF). Several radionuclides that emit energetic 1 particles (32p, 89Sr, 153Sm, 186Re, and 177Lu) and radionuclides that emit low-energy electrons or beta particles (169Er, 117mSn, and 33p) were evaluated. For these calculations, ratios of the cumulated activity in the bone relative to cumulated activity in the marrow alpha equal to 10 and 100 were used. Results: When the radiopharmaceutical was assumed to be uniformly distributed in the endosteum and alpha was taken as 100 for both the reference and test radiochemicals, the RAF values compared with the reference radionuclide 32p were 1.0, 1.2, 1.4, 1.6, 1.7, 1.9, and 2.0 for 89Sr, 186Re, 153Sm, 177Lu, 169Er, 117mSn, and 33P, respectively. In contrast, when the radiopharmaceutical is assumed to be uniformly distributed in the bone volume, the RAF values for these 7 radionuclides were 1.1, 1.5, 2.4, 3.2, 4.5, 5.1, and 6.5, respectively. CONCLUSION: These results suggest that low-energy electron emitters such as 117mSn and 33P are more likely to deliver a therapeutic dose to the bone while sparing the bone marrow than are energetic beta emitters such as 32p and 89Sr. Therefore, radiochemicals tagged with low-energy electron or beta emitters are the radiopharmaceuticals of choice for treatment of painful metastatic disease in bone.     

Radioprotection and environmental pollution by the use of the radionuclides 89Sr, 186Re, and 153Sm for pain palliation in metastatic bone diseases. Related calculations

Due to the fact that the existing commercial analgesic drugs are not able to reduce effectively the pain caused by the metastatic bone disease, the use of radiopharmaceuticals with avidity to selectively localize in the metastatic skeletal sites, such as strondium-89 chloride (89Sr-Cl2), rhenium-186-hydroxy ethylene diphosphonate (186Re-HEDP), and samarium-153-ethylene diamine tetramethylene (153Sm-EDTMP), is widely accepted. However this medical application may be dangerous for the occupied personnel and more for general public, if radioactive waste is not properly disposed. In the following article we try to estimate the degree and the significance of that risk. For that reason we discuss the physical properties of these radionuclides and their distribution in the body of the patient. We conclude that 89Sr is not harmful for the physician, the attending personnel or those who live with the patient, because it radiates beta-radiation, while its gamma-radiation is negligeable. The radionuclides 186Re and 153Sm besides beta-radiation, also emit a perceptible amount of gamma-radiation. It has been shown that the exposure to gamma-radiation from these radionuclides of the physician, the attending personnel or those who live with the patient is very low as compared to the internationally accepted radioprotection limits. However the environmental contamination per treatment by either of these three radionuclides is not negligeable in comparison to the national and international accepted limits. Patients that are not in good clinical condition may pose an additional contamination danger to those attending them. For limiting radiocontamination, the annual number of treatments by the above three previous radionuclides, should be considered according to the ALARA principle in relation with the correct handling of these patients, and also considering the fundamentals of radioprotection.     

骨靶向放射性核素治疗肺癌骨转移疼痛的研究进展

肺癌骨转移是肿瘤晚期的常见并发症,患者由于严重的疼痛往往导致生活质量下降,且易出现与骨骼相关的不良事件,如病理性骨折、脊髓压迫和高钙血症等。针对轻、中度骨转移引起的疼痛可以采用常规止痛、镇痛和外部照射放疗。但在全身多处转移和疼痛严重的情况下,以上3种方法的疗效都不好,且不良反应严重。而某些放射性核素能够特异性地被活性增高的成骨细胞摄取,并且能较长时间滞留于骨组织中。因此,使用一些新型骨靶向放射性核素,如89Sr、153Sm和186Re等进行系统性的治疗成为新型方式,为肺癌骨转移疼痛的治疗提供了更多的靶点和安全有效的手段。     

Nuclear medicine in diagnosis and therapy of bone and joint diseases

Concerning bone and joint diseases therapy of rheumatic synovitis (= radiosynoviorthesis) was introduced in 1952 before clinically relevant diagnostic procedures were developed. Radionuclides of Sr and later on 99mTc phosphonates then started the wide use of bone scintigraphy since > 30 years. The diagnostic methods have an excellent sensitivity for detection of local abnormalities of bone metabolism, the specificity of such studies, however, is low. Modifications of the technique (3-phase-bone-scintigraphy, pinhole collimators, ROI-technique), increasing knowledge of pathological scan patterns and introduction of other radionuclide studies (67Ga, 201Tl, inflammation scans with 99mTc-leukocytes or 99mTc-HIG) as well as 18FDG-PET have increased the specificity significantly in recent years and improvements of imaging systems (SPECT) also increased the accuracy of diagnostic methods in diseases of bone and joints. Therapy of such diseases has made considerable progress: inflamed, swollen joints can effectively be treated with 90Y-, 186Re, 169Er-colloids or with 165Dy-particles by radiosynoviorthesis. Severe pain due to disseminated bone metastases of cancer or polyarthritis can be controlled by radionuclide therapy with 89Sr, 153Sm-EDTMP, 186Re- or 188Re-HEDP and possibly 117mSn-DTPA with an acceptable risk of myelodepression. Possibilities, technical details and limitations of radionuclide applications for diagnostic and therapeutic purposes must be considered if optimal benefit for individual patients should be achieved. Overall Nuclear Medicine can become an essential element in management of bone and joint diseases. The relationship of Nuclear Medicine to bone and joint pathology is peculiar: In 1952 treatment of rheumatic synovitis by radiosynoviorthesis with 198Au Colloid was started by Fellinger and Schmid before diagnostic approaches to bone pathology existed. Bone scintigraphy was introduced only in 1961 using 85Sr but obviously the unfavourable radiation characteristics of this radionuclide limited it's broad application and 87mSr did not improve this situation. Only when 99mTc phosphonates were developed by Subramanian the importance of bone scintigraphy became apparent: The excellent imaging properties of these radiotracers showed, that abnormal bone metabolism could be visualized even before morphological alterations in the skeleton become visible on radiographies or even CT-scans. Moreover, proposals made earlier to use 32P or 89Sr for palliation of pain in patients with disseminated skeletal metastases were picked up again and led also to other radiopharmaceuticals (186Re-HEDP, 153Sm-EDTMP, 117mSn-DTPA) which are applied today for the same purpose with very good success. Therefore Nuclear Medicine today has a broad program for diagnostic and therapeutic approaches to diseases of bone and joints. In bone scanning the high sensitivity led to inclusion of this method for routine staging and re-staging programs in a variety of cancer forms which have a trend to develop bone metastases (e.g. breast, lung, prostate, melanoma) but the low specificity of abnormal patterns on such scans can impair the diagnostic value of the technique. To increase specificity and to define inflammatory lesions, radiotracers used for "inflammation scanning" were introduced such as labeled granulocytes, 99mTc Human Immunoglobulin and others but also a simple modification of bone scanning--triple phase bone scintigraphy--was used. Recently the excellent properties of 18F for PET of the skeleton were rediscovered again and emission CT scanning--possibly with overlay with transmission CT or MRT pictures--can enhance the diagnostic impact of radionuclide bone studies.     

Nuclear medicine of bone

Bone scintigraphy using 99mTc-labeled phosphorous compounds was found to be the most frequently ordered nuclear medicine examination in a nationwide survey in Japan, and has been used for the detection of lesions and the evaluation of disease progression and response to therapy in various skeletal diseases. In this article, we review improvement of the diagnostic sensitivity and specificity for bone metastasis of not only nuclear medicine techniques, such as planar imaging, SPECT, early flow phase imaging and quantification of bone scintigraphy, and bone marrow scintigraphy but also such recently developed methods as bone mineral measurement, and bone metabolic marker assays. In addition, radionuclide therapy of intractable bone pain due to bone metastasis is also addressed.     

放射性药物治疗肿瘤骨转移性骨痛的作用

恶性肿瘤会发生骨转移,早期发现骨转移可以预防骨相关事件的发生,改善预后.用于治疗转移性骨痛的放射性核素有5大类:89Sr、153Sm、186Re/188Re、117Sn、31P.放射性药物治疗转移性骨痛的效果较好,尤其适用于成骨性或混合型骨转移.放射性药物联合双磷酸盐药物治疗广泛转移性骨痛效果显著,优于两者的单独使用,明显改善患者生存质量.     

Assessment of 186Re chelate-conjugated bisphosphonate for the development of new radiopharmaceuticals for bones

INTRODUCTION: The preferable pharmacokinetics of rhenium-186 (186Re)-monoaminemonoamidedithiol-conjugated or 186Re-mercaptoacetyltriglycine-conjugated bisphosphonates (BPs) suggested that the molecular design would be applicable to other radionuclides such as 68Ga, 99mTc, 153Sm and 177Lu. In this study, a key factor affecting the pharmacokinetics of a chelate-conjugated BP was investigated to estimate the validity and the applicability of molecular design. METHODS: Chemically inert and well-characterized tricarbonyl[186Re][(cyclopentadienylcarbonyl amino)-acetic acid]rhenium ([186Re]CpTR-Gly) was conjugated with 3-amino-1-hydroxypropylidene-1,1-bisphosphonate and purified by high-performance liquid chromatography (HPLC) to prepare [186Re](1-{3-[tricarbonyl(cyclopentadienylcarbonyl amino)-acetylamido]-1-hydroxy-1-phosphono-propyl}-phosphonic acid)rhenium ([186Re]CpTR-Gly-APD). Plasma stability, plasma protein binding, hydroxyapatite (HA) binding and the pharmacokinetics of [186Re]CpTR-Gly-APD were compared with those of 186Re 1-hydroxyethylidene-1,1-diphosphonate (HEDP). The effect of HEDP coadministration and preadministration on the pharmacokinetics of [186Re]CpTR-Gly-APD was also determined. RESULTS: The HPLC-purified [186Re]CpTR-Gly-APD showed higher plasma stability, higher HA binding, higher bone accumulation and lower plasma protein binding than did 186Re-HEDP. However, HA binding of [186Re]CpTR-Gly-APD decreased to levels slightly higher than that of 186Re-HEDP at similar HEDP concentrations. Bone accumulation of [186Re]CpTR-Gly-APD also decreased to levels similar to that of 186Re-HEDP when [186Re]CpTR-Gly-APD was coinjected with HEDP equivalent to that in 186Re-HEDP. In contrast, HEDP pretreatment did not impair bone accumulation of the two 186Re-labeled compounds. However, a delay in blood clearance and an increase in renal radioactivity levels were observed particularly with 186Re-HEDP. CONCLUSIONS: Although 186Re-HEDP possessed HA binding and bone accumulation similar to those of [186Re]CpTR-Gly-APD, the specific activity of 186Re-labeled BPs was found to play a crucial role in bone accumulation and blood clearance. Thus, the molecular design of chelate-conjugated BP would be useful for the development of bone-seeking radiopharmaceuticals with a variety of radionuclides by selecting chelating molecules that provide high specific activities.     

Radioimmunotherapy of B-cell non-Hodgkin's lymphoma.

In the past decade, several new antibody-based therapies - using either radiolabelled or unlabelled monoclonal antibodies - have become available for the treatment of patients with refractory or recurrent non-Hodgkin's lymphoma (NHL). Unlabelled monoclonal antibodies (mAbs) kill lymphoma cells by activating host immune effector mechanisms, or by inducing apoptosis. These mAbs can also be used to guide radionuclides to the lymphoma. This radioimmunotherapy (RIT) has been studied with various nuclides (131I, 90Y, 67Cu and 186Re) and with various mAbs. In this review the radionuclides, methods of dosing and recent RIT studies in patients with B-cell NHL are reviewed. Most of these studies demonstrate that RIT is an effective new treatment modality for NHL.     

Teletherapy and radiopharmaceutical therapy of painful bone metastases

Bone pain from metastatic disease is most common in cancers of the breast, prostate, and lung. Despite the World Health organization algorithm for treating such pain, the outcomes are not often satisfactory. In 2005, there will be 3 radiopharmaceuticals available in the United States that can reduce or relieve bone pain caused by osteoblastic metastases with apparently equal efficacy. Phosphorus-32 as sodium phosphate, strontium-89 ( 89Sr) as the chloride, and samarium-153 lexidronam may all be given intravenously (and 32P also orally) in patients where bone scintigraphy demonstrates a metastatic lesion causing the patient's bone pain. Side effects are usually mild and include pancytopenia with leukocyte and platelet nadirs at approximately 50% of baseline, and a mild-to-moderate, but brief, increase in pain ("flare") in approximately 10% of patients. At least 1 of these radiotracers, 89Sr, has the availability to reduce the incidence of new bone metastases as well, but, given alone, none prolong life. In a few studies in which 89Sr has been combined with chemotherapy, prolongation of patient survival has been demonstrated. Many questions remain as to the optimization of use of this group of radiopharmaceuticals, including whether combinations of radiopharmaceuticals with each other, with bisphosphonates or with chemotherapy can improve the therapeutic outcomes even more.     

Comparison of 99mTc-labeled phosphate and phosphonate agents for skeletal imaging.

The use of 99mTc-labeled phosphate and phosphonate compounds in place of 18F, 85Sr, and 87Sr for bone scintigraphy has become commonplace throughout the world in a relatively short time. The labeling of polyphosphate with 99mTc 4 years ago, followed rapidly by the introduction of 99mTc-labeled pyrophosphate for skeletal imaging, must therefore be regarded as a major contribution to the practice of diagnostic nuclear medicine. The markedly reduced patient radiation exposure and concomitant increase in photon detection efficiency derived from the more favorable physical decay characteristics of 99mTc led to increased sensitivity and resolution and in turn to improved diagnostic efficacy. The subsequent clinical use of the phosphonate complex 99mTc-HEDP represented a further modification of the same basic approach. Current clinical trials with 99mTc-labeled methylene diphosphonic acid (MDP), which appears to demonstrate enhanced biologic properties for scintigraphy of the osseous structures, is the latest example in this series of refinements. This article compares the technetium-labeled agents already in clinical use and, using animal data, contrasts them with several new multifunctional phosphonates and the novel inorganic compound sodium imidodiphosphate (IDP). In addition, an attempt is made to clarify the conflicting evidence in the nuclear medicine literature regarding the relationship between polyphosphate chain length and skeletal uptake.     

The current status of bone scintigraphy in malignant diseases

For the past few decades, planar bone scintigraphy has been the most frequently performed imaging study in the evaluation of metastatic bone disease. Although scintigraphic findings alone are often nonspecific for skeletal pathologies, this technique reportedly has an exquisite sensitivity. However, recently accumulated data on the efficacy of positron emission tomography with fluorine-18 fluorodeoxyglucose and fluorine-18 sodium fluoride as well as magnetic resonance imaging for evaluating skeletal metastatic disease now indicate that conventional planar bone scintigraphy is not very sensitive in the detection of metastatic bone lesions in selected malignancies. Nevertheless, bone scintigraphy still remains the primary imaging modality for evaluation of metastatic bone disease owing mainly to its cost effectiveness and wide availability. In addition, recently introduced hybrid imaging systems combining single-photon emission computed tomography and spiral computed tomography, although not widely available yet, increase considerably both the sensitivity and specificity of bone scintigraphy. This article focuses primarily on the current role of bone scintigraphy and its strengths and weaknesses in assessing different types of malignant diseases relative to other imaging modalities in selected malignancies.     

A comparative study of 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr in the treatment of painful skeletal metastases

AIM: The surface bone-seeking radiopharmaceuticals 188Re-HEDP, 186Re-HEDP and 153Sm-EDTMP, and the volume seeker 89Sr were investigated to determine the efficacy and toxicity in pain palliation of bone metastases. METHOD: The effect of treatment with 188Re-HEDP, 186Re-HEDP, 153Sm-EDTMP and 89Sr on pain symptoms, quality of life, and bone marrow function were studied. In total, 79 patients (18 with breast cancer and 61 with prostate cancer) were treated (31 patients with 188Re-HEDP, 15 patients each with 186Re-HEDP and 153Sm-EDTMP, and 18 patients with 89Sr). All patients were interviewed using standardized sets of questions before and after therapy weekly for 12 weeks. Blood counts were taken weekly for 6 weeks and after 12 weeks. RESULTS: In total, 73% of patients reported pain relief (77% after 188Re-HEDP, 67% after 186Re-HEDP 73% after 153Sm-EDTMP, and 72% after 89Sr). Fifteen percent of patients could discontinue their analgesics and were pain-free. Pain showed a decrease from 3.6+/-1.7 to a maximum of 2.2+/-1.8 at visual analogue scale in 10 steps (P<0.01). Patients described an improvement on the Karnofsky performance scale from 70+/-10% to 78+/-14% 12 weeks after treatment (P=0.15). There were eight patients with a thrombocytopenia grade I, two patients with grade II and one with grade III. The maximum nadir of platelet and leukocyte counts were observed between the 2nd to 5th week after treatment and was reversible within 12 weeks. There were no significant differences in pain palliation, Karnofsky performance status (KPS) and bone marrow toxicity between the different radionuclides (P=0.087-0.449). CONCLUSION: All radiopharmaceuticals were effective in pain palliation, without induction of severe side effects or significant differences in therapeutic efficacy or toxicity.     

Influence of the radioactive strontium (89Sr) using for nuclear medical radiation therapy upon radioactive draining-water system

PURPOSE: Strontium-89 chloride (89Sr) is a new radiopharmaceutical that provides effective pain relief for metastatic bone lesions, and is expected to be available soon in the palliative management for metastatic bone pain in Japan. Because of relatively long physical half life (50.5 days), 89Sr may affect to the radioactive draining-water system by exceeding the limits of activity concentration for radioactive drain. In this article, the influence of 89Sr use on the radioactive drainage system was simulated. METHODS: The standard tank capacity of drainage and draining frequency was determined from the results of questionnaire carried out for the nationwide medical and research institutes where radioisotope treatment are performed. On the assumption that 89Sr of 148 MBq for one therapy was used twice a week and several common radionuclides were used as the same activity as used at Chiba Cancer Center, the influence of 89Sr was estimated. The calculation was performed using the activity contamination ration into the draining-water system of each radionuclide of 0.01, which was legally determined. RESULTS: The simulation revealed that the sum of the contamination ratios of individual radionuclides exceeded a legal value of 1.0 in standard drainage with the capacity of 5 m3 and 10 m3 and draining frequency of 7 times per year. The actual contamination ratios of common radiopharmaceuticals measured at Chiba Cancer Center ranged from 1/100 to 1/1000 of the legal values. CONCLUSION: It is necessary that the legal value of activity contamination ratios into the draining-water system should be reassessed before starting 89Sr therapy.     

A review of the efficacy of bone scanning in prostate and breast cancer.

Bone scintigraphy has provided valuable data in the assessment and management of neoplastic disease since being first described in the early 1960s. There have been many developments in imaging techniques and radiopharmaceuticals over the years allowing more reliable detection of metastatic spread to bone. Other imaging modalities are also evolving roles in the detection of metastatic spread including computed tomography (CT), magnetic resonance imaging (MRI), and positron emission tomography (PET). Despite this, isotope bone scans continue to have a central role in detection and surveillance of bone metastases in breast and prostate cancer. Paralleling developments in imaging there have been enormous changes in the treatment options available for cancers of the breast and prostate that have metastasised to bone. Bone specific treatments including radionuclides and bisphosphonates as well as high dose chemotherapy provide potential improvement in disease control. There is also evidence that earlier treatment of bone metastases may prolong survival. This increases the need for efficient methods of detection and monitoring of disease. In this article we discuss the efficacy of bone scintigraphy in breast and prostate cancer from the point of view of staging, systematic follow-up of asymptomatic patients, evaluation of symptomatic patients and the assessment of response to therapy.     

Preparation, stability studies and pharmacological behavior of [186Re]Re-HEDP.

99mTc-HEDP is widely used as a bone imaging agent and its Re analog [186Re]Re-HEDP is now well established as a therapeutic radiopharmaceutical for palliation of pain due to bone metastases. In the present paper, we report the work carried out for the preparation of stable 186Re-HEDP which retains RC purity up to 5 days when stored at 4 degrees C. 186Re was prepared by irradiation of natural Re metal at a flux of 3 x 10(13) neutrons/cm2/s for seven days and processed after a cooling period of four days. The specific activity of 186Re formed was approximately 35 mCi/mg. A complex with RC purity > 98% could be prepared by varying the reaction conditions. By carefully optimizing the reaction and storage conditions, a complex which was stable for over 4 days could be synthesized. Bio-distribution studies carried out in rats revealed approximately 30% bone uptake of 186Re-HEDP at 3 h postinjection which remained almost constant for 48 h, at which time there was negligible activity in other organs.     

Gamma camera imaging of osseous metastatic lesions by strontium-89 bremsstrahlung

The aim of this study was to optimise the parameters affecting the Bremsstrahlung scintigraphy of patients injected with strontium-89 chloride. The parameters considered were : (1) instrumental detection efficiency, and (2) tissue attenuation factor for ⁸⁹Sr calibrated sources, which permit quantitative evaluation of the activity in a given bone lesion. Some typical examples of in vivo ⁸⁹Sr imaging are presented to illustrate the clinical utility of the imaging procedure developed by us, which is implemented in our department for all patients treated with ⁸⁹Sr chloride. Received 7 April and in revised form 14 July 1997     

Radiopharmaceuticals for spleen and bone marrow studies

The spleen and bone marrow have important hematologic functions. Evaluation of bone marrow alone may be incomplete, unless the function of the spleen is studied also. In addition to hematologic functions, each organ has unique characteristics that may need to be evaluated in assessing its activity. The evaluation of the distribution of reticuloendothelial cells, through the phagocytosis of radioactive particles, provides the basis for most of the morphological and functional studies of these organs. During the past three decades, a variety of radioactive agents have been prepared and examined. Among them, colloids of 99mTc, heat-damaged 99mTc labeled RBCs, and the radionuclides of iron and indium, make possible the functional and morphological examination of the spleen and bone marrow by external scintigraphy.     

Optimization of radioimmunotherapy of renal cell carcinoma: labeling of monoclonal antibody cG250 with 131I, 90Y, 177Lu, or 186Re.

Radioimmunotherapy (RIT) can be performed with various radionuclides. We tested the stability, biodistribution, and therapeutic efficacy of various radioimmunoconjugates ((131)I, (88/90)Y, (177)Lu, and (186)Re) of chimeric antirenal cell cancer monoclonal antibody G250 (mAb cG250) in nude mice with subcutaneous renal cell cancer (RCC) tumors. METHODS: The (88/90)Y and (177)Lu labeling procedures of cG250 conjugated with cyclic diethylenetriaminepentaacetic acid anhydride (cDTPA), isothiocyanatobenzyl-DTPA (SCN-Bz-DTPA), or 1,4,7,10-tetraazacyclododecanetetraacetic acid (DOTA) were characterized. Stability of the labeled conjugates in plasma at 37 degrees C was assessed. Biodistribution and therapeutic efficacy of labeled cG250 were compared in nude mice with SK-RC-52 human RCC xenografts. RESULTS: Both SCN-Bz-DTPA and DOTA were stable in vitro (<5% release of the radiolabel during 14 and 21 d of incubation) and in vivo (uptake in bone 相似文献   

Marrow toxicity of 33P-versus 32P-orthophosphate: implications for therapy of bone pain and bone metastases.

Several bone-seeking radiopharmaceuticals, such as 32P-orthophosphate, 89Sr-chloride, 186Re-1,1 hydroxyethylidene diphosphonate (HEDP), and 153Sm-ethylene diamine tetramethylene phosphonic acid (EDTMP), have been used to treat bone pain. The major limiting factor with this modality is bone marrow toxicity, which arises from the penetrating nature of the high-energy beta particles emitted by the radionuclides. It has been hypothesized that marrow toxicity can be reduced while maintaining therapeutic efficacy by using radionuclides that emit short-range beta particles or conversion electrons. In view of the significant clinical experience with 32P-orthophosphate, and the similarity in pain relief afforded by 32P-orthophosphate and 89Sr-chloride, this hypothesis is examined in this study using 32P- and 33P-orthophosphate in a mouse femur model. METHODS: Survival of granulocyte macrophage colony-forming cells (GM-CFCs) in femoral marrow was used as a biologic dosimeter for bone marrow. 32P- and 33P-orthophosphate were administered intravenously, and GM-CFC survival was determined as a function of time after injection and, at the nadir, as a function of injected activity. The kinetics of radioactivity in the marrow, muscle, and femoral bone were also determined. The biologic dosimeter was calibrated by assessing GM-CFC survival at its nadir after chronic irradiation of Swiss Webster mice with exponentially decreasing dose rates of gamma rays (relative biologic effectiveness equivalent to that of beta particles) from a low-dose rate 137Cs irradiator. Dose-rate decrease half-times (Td) (time required for 137Cs gamma ray dose rate to decrease by one half) of 62, 255, and 425 h and infinity were used to simulate the dose rate patterns delivered by the radiopharmaceuticals as dictated by their effective clearance half-times from the mouse femurs. These data were used to experimentally determine the mean absorbed dose to the femoral marrow per unit injected activity. Finally, a theoretical dosimetry model of the mouse femur was developed, and the absorbed doses to the femoral marrow, bone, and endosteum were calculated using the EGS4 Monte Carlo code. RESULTS: When the animals were irradiated with exponentially decreasing dose rates of 137Cs gamma rays, initial dose rates required to achieve 37% survival were 1.9, 0.98, 0.88, and 0.79 cGy/h for dose rate decrease half-times of 62, 255, and 425 h and infinity, respectively. The D37 values were 144 +/- 15, 132 +/- 12, 129 +/- 3, and 133 +/- 10 cGy, respectively, compared with a value of 103 cGy for acute irradiation. When 32P and 33P were administered, the injected activities required to achieve 37% survival were 313 and 2,820 kBq, respectively. Theoretical dosimetry calculations show that 33P offers a 3- to 6-fold therapeutic advantage over 32P, depending on the source and target regions assumed. CONCLUSION: The low-energy beta-particle emitter 33P appears to offer a substantial dosimetric advantage over energetic beta-particle emitters (e.g., 32p, 89Sr, 186Re) for irradiating bone and minimizing marrow toxicity. This suggests that low-energy beta or conversion electron emitters may offer a substantial advantage for alleviation of bone pain as well as for specifically irradiating metastatic disease in bone.