Strontium [⁸⁹Sr]-chloride, samarium-153-ethylenediamine tetra methylene phosphonic acid [¹⁵³Sm]-EDTMP and rhenium-186-hydroxyethylidine diphosphonic acid [¹⁸⁶Re]-HEDP are approved in Europe for bone pain palliation in patients with bone metastases. [³²P] orthophosphate is used in several other countries. ⁸⁹Sr is a calcium analogue and is incorporated into the newly formed hydroxyapatite of the bone matrix. ¹⁵³Sm-EDTMP and ¹⁸⁶Re-HEDP are radiolabelled bisphosphonates and are adsorbed onto the hydroxyapatite surface of metabolically active bone by the same mechanism as Technetium [^99mTc]-labelled bisphosphonates used for diagnostic bone scintigraphy.

Selective uptake depends on the degree of metabolic (i.e. osteoblastic) response elicited in normal bone by the presence of metastatic tissue. Increased bone turnover leads to enhanced incorporation of bone seeking radiopharmaceuticals at metastatic sites by comparison with normal bone and can therefore deliver a high, targeted local radiation dose. Skeletal uptake of the radiolabelled bisphosphonates ¹⁸⁶Re-HEDP or ¹⁵³Sm-EDTMP is in the order of 22 and 48 % of administered activity, respectively (Brenner et al. 2001). The effective half life of ⁸⁹Sr in bone metastases is > 90 days, compared with 14 days in normal bone (Blake et al. 1986) (Table 2).

³²P as sodium phosphate is no longer approved in many countries because of documented myelotoxicity associated with therapeutic administration. More recently, a clinical trial comparing ⁸⁹Sr and ³²P in patients suffering from painful bone metastases from bone metastases reported slightly higher toxicity in the ³²P group but comparable efficacy in terms of pain palliation (Fettich et al. 2003). Further research will be necessary to confirm these results particularly in heavily pretreated patients who may have limited bone marrow reserve.

Clinical trials are in progress evaluating the therapeutic potential of other radionuclides for bone pain palliation. These include: tin [^117mSn]-DTPA, sodium [³³P]-phosphate, rhenium[¹⁸⁸Re]-HEDP, lutetium [¹⁷⁷Lu]-EDTMP and radium [²²³ Ra]-chloride.

In addition to clinical variables such as skeletal metastatic burden, disease distribution and prior treatment, myelosuppression resulting from systemic bone seeking radiopharmaceutical therapy reflects effective half life, particle energy and particle range of the radionuclide used in. Reversible Grade 2 and 3 haematological toxicity was demonstrated in 25.5 % of all patients and in 38.7 % of retreated patients using ¹⁸⁶Re-HEDP (deKlerk 1995). The use of low-energy beta-emitting radionuclides would be expected to deliver a high absorbed dose to the bone surface but negligible dose to the haematopoietic bone marrow (Bouchet et al. 2000). Theoretical dose calculations predict a three- to sixfold advantage in terms of myelotoxicity risk were ³³P to be substituted for ³²P, for example (Goddu et al. 2000).

To reduce myelotoxicity, the therapeutic potential of conversion electron emitting radiolabels such as ^117mSn-DTPA has been reported. Conversion electrons ejected during the decay of this nuclide have a 1.7–5.5 times lower energy than beta-particles conventionally used for systemic treatment for pain palliation (Hillegonds et al. 2007). But the limiting factor of this compound used in a phase I/II clinical study was not the radiation dose to the marrow but the high amount of DTPA in the current formulation in a 20-fold molar excess over tin (Srivastava 2004). More recently, a new 1:1 chelate was synthesised (Srivastava et al. 2002). Because only few data were published about therapy of cancer patients with ^117mSn-DTPA, there is insufficient evidence for recommending this agent now. (Program in evidence-based care—a cancer care Ontario program. Radiopharmaceuticals for the palliation of painful bone metastases. Practical Guideline Report 14–1 (June 2004)).

Estimates of absorbed radiation dose delivered to osteoblastic bone metastases vary widely, ranging from 6 to 61 cGy/MBq for ⁸⁹Sr, 1,000–14,000 cGy from a standard treatment activity of 1295 MBq ¹⁸⁶Re HEDP and a mean dose of 87 Gy from 2,590 MBq ¹⁵³Sm-EDTMP. A dose of 54 mGy/MBq was reported using ^117mSn-DTPA (see next chapter) with bone uptake ranging from 34 to 83 % of injected activity (Atkins et al. 1995).

The bone seeking alpha-particle emitter Radium-223 is predicted to deliver a high radiation absorbed dose to the bone surface with sparing of the bone marrow compartment. Following intravenous administration, skeletal uptake peaks within 1 h of injection with no subsequent redistribution. Phase I and II studies confirm low temporary myelosuppression approximately 4 weeks post treatment, but this rarely exceeds WHO Grade I/II even at high activities [200 kBqkg⁻¹] in heavily pretreated patients (Nilsson et al. 2007).

The mechanism and radiobiology of pain reduction using unsealed source therapy is not understood. A direct radiation effect on neuronal tissue seems unlikely due to the well-known, high radiation resistance of peripheral neurons. It is more conceivable that radiation to cells and tissues surrounding the metastasis promotes cell signalling changes resulting in modulation of both pain reception and transmission. Possible target cells are likely to include macrophages, mast cells, thrombocytes, lymphocytes and endothelial cells which influence secretion of pain mediators such as ATP, histamine, PGE, IL-1 and -2, leukotrienes and substance P.

When the side effects of high dose analgesics become intolerable and significantly compromise quality of life, even if pain control is adequate.

Strontium [⁸⁹Sr]-Chloride and Rhenium [¹⁸⁶Re]-HEDP are approved for pain palliation in patients with bone metastases from prostate cancer, Samarium [¹⁵³Sm]-EDTMP may also be used in patients suffering from osteoblastic metastases of other tumour types. The activity of ¹⁵³Sm-EDTMP is adjusted for the patient’s body weight (37 MBq/kg), whereas ⁸⁹Sr-Chloride and ^`86Re-HEDP are prescribed as standardised activities [150 and 1295 MBq, respectively].

A prerequisite for radionuclide treatment of metastatic bone pain is the demonstration of focal abnormal skeletal uptake on conventional ^99mTc phosphate bone scintigraphy corresponding to known pain sites. Patients should have reasonable bone marrow reserve, as evidenced by (near) normal blood counts. The γ emission of Re-186 and Sm-153 is useful for early posttherapy imaging to confirm selective tracer uptake and appropriate targeting.

Due to the delay between treatment administration and onset of pain relief, which may take 1 week in case of ¹⁵³Sm-EDTMP or ¹⁸⁶Re-HEDP and up to 4 weeks using ⁸⁹Sr, patients should have a life expectancy of at least 3 months. Absolute contraindications to radionuclide therapy include pregnancy, breast-feeding and severe bone marrow depression, indicated by platelets < 60,000 /μl or leucopenia < 2,400 /μl (Fischer 1999). Acute spinal cord compression, disseminated intravascular coagulation and impaired renal function (urea > 12 mmol/l or creatinine > 150 mmol/l) are regarded as additional contraindications in German, European and American guidelines for pain palliation treatment.

Patients with urinary incontinence should be catheterised prior to treatment to mitigate the risk of radioactive urine contamination. Specialist referral is advised where bones are considered at risk of pathological fracture. To allow time for bone marrow recovery and avoid unpredictable cumulative toxicity, unsealed source treatment should be delayed for 6–8 weeks after completion of chemotherapy. It is recommended that further chemotherapy be deferred for at least 8–12 weeks, depending on the radiopharmaceutical used. A 2–3 month delay is recommended after large-field radiation therapy.

Concomitant treatment with modern bisphosphonates, which are characterised by very low effective levels, does not interfere with the uptake of bone-seeking radionuclides (Lau et al. 2001; McEwan 1994; Marcus et al. 2002). This is contrary to former concerns, regarding the classical drugs Clodronate or Etidronate. Focal abnormal uptake should, however, be confirmed in every patient by pretherapeutic bone imaging (see Fig. 1) as described and correlated with the localisation of pain.

Following appropriate oral hydration, bone-seeking radiopharmaceutical treatment is administered intravenously via a peripheral cannula, usually in an outpatient setting, depending on local legislation. Prior to discharge, the uptake and distribution of activity Re-186-HEDP or Sm-153-EDTMP can be documented by whole body scanning 3 h post injection (see Fig. 2). Renal excretion of the unbound fraction of the radionuclide is very rapid; 45 % of the unbound activity is already excreted 5 h after injection of Re-186-HEDP, 71 % within 3 days (Maxon et al. 1988) compared with, 53 % of the unbound Sm-153-EDTMP excreted via the kidneys within 8 h after injection (Singh et al. 1989).