Management of Bone Metastases  
[Including Vertebral Metastases]

compiled/written by doctordee
June 2002


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Links
Introduction
Detection
Bisphosphonates


Surgery -- Long Bones
Surgery -- Vertebral
Ablation
Radio Frequency Ablation [RFA]  
Cryoablation

Embolization
	Chemoembolization
	Radioisotope embolization
Radiation
RadioIsotopes 
 
RadioTherapy  
 
Injections Into Tumors
Percutaneous Vertebroplasty
Percutaneous Intratumoral Injection Therapy   
Cytotoxic Injections [alcohol, chemotherapy agents, radioisotopes]
Hyperthermia
Other Systemic Treatment
	Chemotherapy	
	Hormonal


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PubMed/Medline Search-Click below:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20metastases%20treatment
This will give you the first page of 20 citations on the subject.  By using their toolbar, you can put limits on the search, obtain the complete set of abstracts for the search, increase to 200 citations OR abstracts per page, as well sort by date or author.

Furthermore, PubMed/Medline searches give you the site where the research or technique is done.  If you are considering undergoing a specialized procedure, a recent publication can give you a place that does it, as well as information about their results.

The Coleman Article [Management of Bone Metastases]-Click below:
http://theoncologist.alphamedpress.org/cgi/content/full/5/6/463
Coleman, R., The Oncologist, Vol. 5, No. 6, 463-470, December 2000 (c) 2000 AlphaMed Press 
[This is not a comprehensive article, but it does give some valuable information.]

Other useful links:

http://www.bonetumor.org

http://www.oncolink.com/
 
Pubmed All References - metastases and spine
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=metastases%20spine

Spinal Cord Tumor Information 
http://www.tbts.org/sctumors.htm

Lesions of the Spine  
http://www.cid.ch/TEACH/Db-te26.html
  
Proton Beam and Stereotactics - Can be used on Cervical Spine 
http://www.va.gov/hac/champva/policy/cvapmchap2/1c2s30.13.pdf
 
IMRT. There are a number of new techniques like stereotactic radiotherapy or Intensity Modulated Radiation Therapy that may be used.  
http://www.varian.com/onc/imr000.html
 
USC Neurosurgery Department
http://uscneurosurgery.com/
 
 
 
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INTRODUCTION

 "Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. ... The prognosis of these patients is generally poor and the treatment is primarily palliative: the intention is to relieve pain, prevent fractures, maintain activity and, if possible, to prolong survival. Besides analgesics the therapeutic options include local treatment with radiotherapy and/or surgery, and systemic treatment using chemotherapy, endocrine therapy, radioisotopes as well as bisphosphonates. Social and psychological supportive care is also very important. Radiotherapy plays an important role, but the other modalities such as bisphosphonates may also offer the same level of palliation, but their definite role has not been as clearly defined." http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9142968 &dopt=Abstract  
Nielsen OS.  Palliative treatment of bone metastases. Acta Oncol 1996;35 Suppl 5:58-60  PMID: 9142968 

Bone develops as a result of a balance between the bone cells that break down bone [osteoclasts] and the bone cells that build up bone [osteoblasts].  Tumor metastases in bone develop from interactions between the bone cells and the tumor cells, destroying the bone's ability to bear loads, initially in disruption of the bone structure and microfractures, but finally in total loss of bone integrity.  

Complications from bone metastases include bone pain, fractures, hypercalcemia [too high level of calcium in the blood, which causes weakness and can create kidney failure], and compression of the spinal cord.  Bone metastases can massively impair quality of life, and can themselves cause death.

Surgery, Radiation, and now Bisphosphonates are the current first line treatments of choice for stabilization, pain, and hypercalcemia respectively.  

Rib fractures and the collapse of vertebrae are most common.  Vertebral collapse results in loss of height, but if multiple and severe, in humpback and curved spine, which has a further effect in restriction of lung capacity.  The most disability, however, is caused by the fracture of a long bone or compression of the spinal cord.

Surgical intervention is the treatment of choice for unstable vertebrae or neurologic deficit, with the excision of the tumorous bone and stabilization of the spine. Surgery, Radiation, and now Bisphosphonates are the current first line treatments of choice for stabilization, pain, and hypercalcemia respectively.  
There are other treatment options available for those who cannot undergo surgery, of invaluable use in preventing, controlling, eradicating, or palliating metastatic bone tumors.  [And probably, whatever other treatment modality they choose, patients with bony LMS lesions should probably be on Bisphosphonates.   Ed.]

Surgical intervention, external beam radiotherapy, and systemic endocrine and chemotherapy treatments have been the classical methods of treatment of metastases to bone.  However, the opportunities for improving the management of metastatic bone disease have never been greater. Recent developments have occurred in all aspects of cancer management with improvements in skeletal imaging, reconstructive orthopedic surgery, and radiotherapy-particularly through the development of bone-seeking 
radiopharmaceuticals, new endocrine and cytotoxic treatments, and an increasing use of bisphosphonates to prevent and treat skeletal complications, as well as embolization, radio frequency ablation, percutaneous alcohol injection, percutaneous vertebroplasty, and new specific molecules based on cellular signaling mechanisms. 

        "Multimodal therapy of tumor patients with osseous metastases is an interdisciplinary task. 
        The surgical treatment requires optimal integration, in terms of timing and extent of the procedure, into the 
        overall treatment plan. In addition to surgery, modern therapeutic 
        approaches include systemic chemotherapeutic, hormonal and immunological 
        therapy, radiotherapy, and other drug therapy (i.e. bisphosphonates). We 
        use classical stabilization methods with plates and bone cement or 
        intramedullary nailing and also new implants with angular stability like 
        an internal fixator and modular endoprothesis systems in operative 
        therapy. Such stabilizing systems allow bridging of tumor defects in 
        almost all parts of the skeleton. The ultimate goal of any treatment and 
        especially of operative intervention is a mobile patient with little or 
        no pain and a good quality of life."  [10]

Surgery, Palliative Radiation, and now Bisphosphonates are the current first line treatments of choice for stabilization, pain, and hypercalcemia respectively.  It is this compiler's choice to include many possible treatment modalities, for situations where the usual and usually available modalities might not be effective.  Chemotherapy is best saved for inoperable metastases that are potentially life threatening, such as lung, liver, or brain.  

10: Haas NP, Melcher I, Peine R. Metastases compromising physical stability Chirurg 1999 Dec;70(12):1415-21         


Increasing Incidence of Vertebral Metastases
After survival time was prolonged because of the advent of doxorubicin, sarcoma patients started showing an increased incidence of brain metastases, as patients lived long enough for these metastases to seed and grow. [For more information on this, see the Brain Metastasis section of Metastatic Disease on this website.]
Coincident with improved overall cancer palliation during the past 2 decades has been an increasing incidence of clinically apparent bone metastases. Likewise, as survival time for LMS continues to increase, but without a cure and without effective control over tumor seeding and growth, the incidence of metastatic LMS to the spine might also increase.
References:
Fukutomi M, Yokota M, et.al. Increased incidence of bone metastases in hepatocellular carcinoma. Eur J Gastroenterol Hepatol 2001 Sep;13(9):1083-8
Harrington KD, Orthopedic surgical management of skeletal complications of malignancy. Cancer 1997 Oct 15;80(8 Suppl):1614-27



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DETECTION OF BONY METASTASES


Of 277 soft tissue sarcoma [STS] patients, 10% had metastases within an average period of 18.6 months from diagnosis.. The regional bones close to the primary tumour were affected in 46% of the patients with bony mets, and the axial bones in 64%.  STS metastatic bony lesions showed predominantly lytic changes, and approximately half of the lesions progressed to pathological fractures. [6]
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&list_uids=9250736&dopt=Abstract


By Symptoms:  pain or fracture or neurologic deficit.

By Blood Tests:  elevated alkaline phosphatase, elevated bone isoenzyme of alkaline phosphatase, hypercalcemia [blood calcium levels too high].  Current research is aimed at trying to find good blood test markers that indicate bone resorption, and to differentiate metabolic from tumoral problems if possible.   Hopefully techniques would be developed that would allow evaluation of bone tumor response to treatment by a simple blood test.

By Imaging Techniques:
The main imaging techniques used to diagnose bone tumors are conventional radiography, CT, MRI, and isotope bone scan. Angiography is rarely used, but is helpful when a preoperative selective embolization is needed, or when complex vertebral surgery or vascular surgery is planned.

By Xrays:  lytic lesions, usually, 'holes' in bones.  For a lytic lesion to show on Xray, 50% of the bone matrix must be destroyed.  Xrays will not show early stage disease.  Conventional radiography is the screening examination of choice and is sufficient in several benign lesions not requiring treatment. Supplementary imaging studies are usually needed when radiographic findings are questionable and/or the lesion requires treatment. 

By Bone Isotope Scan: will show areas of increased bone activity-including inflammation, arthritis, and infection. It can be thus useful to depict lesion quiescence or activity and to stage any tumor that can metastasize to the skeleton. Bone scan is also helpful to show bone lesions when they are not visible on plain radiographs and can indicate the tumor response to preoperative chemotherapy. 

By MRI scan:  MRI is the scan of choice for depicting any bone tumor.  MRI beautifully shows the different tissues and compartments and it is particularly sensitive in depicting fat. Moreover, it can be repeated many times, even in pregnant women, because it needs no ionizing radiations and iodinated contrast; it is also free of artifacts in the patients with orthopedic devices that are usually nonferromagnetic. However, the execution of an adequate MRI requires experience and knowledge of bone pathologic conditions. 
While Bone Isotope Scans and PET scans are useful adjuncts to indicate strong suspicious of metastases to bone, it is the MRI which is the definitive examination to give clear delineation of the bone tumor and its extent.  No imaging method is without its difficulties, however, and sometimes the MRI cannot distinguish between different types of lesions; one notable situation is between a hemangioma [a noncancerous tumor of twisted blood vessels] and some neoplasms [often also highly vascular].  [Repeatedly on the LMS ACOR List, the MRI has shown the bone mets, despite negative Xrays and negative bone scans.  The scan of choice for detecting bone tumors is MRI.  Ed.]

By PET scan:  will show areas of increased metabolic rate, in bone and other organs, including inflammation, arthritis, and infection.  It is a new technique, and its specificity and reliability are still open to interpretation.  

By CT scan: CT best shows mineralized tissues and pulmonary metastases. It is also frequently used as a guide for needle biopsies. Not a good choice for bone studies. 



References: 
1. Campanacci M, Mercuri M, Gasbarrini A, Campanacci L. The value of imaging in the diagnosis and treatment of bone tumors Eur J Radiol 1998 May;27 Suppl 1:S116-22  
2. Krappel FA, Bauer E, Harland U. Efficacy of MRI--whole spine image in diagnosis of vertebral metastases--results of a prospective study. Z Orthop Ihre Grenzgeb 2001 Jan-Feb;139(1):19-25 
3. Woitge HW, Pecherstorfer M,  et.al.   Novel serum markers of bone resorption: clinical assessment and comparison with established urinary indices. J Bone Miner Res 1999 May;14(5):792-801
4. Griffith JF, Kumta SM.  Clinics in diagnostic imaging (25). Aggressive vertebral haemangioma. Singapore Med J 1997 May;38(5):226-30 
5. Savelli G, Maffioli L, Maccauro M, De Deckere E, Bombardieri E., Bone scintigraphy and the added value of SPECT (single photon emission tomography) in detecting skeletal lesions. Q J Nucl Med 2001 Mar;45(1):27-37
6. Yoshikawa H, Ueda T, Mori S, Araki N, Kuratsu S, Uchida A, Ochi T. Skeletal metastases from soft-tissue sarcomas. Incidence, patterns, and radiological features. J Bone Joint Surg Br 1997 Jul;79(4):548-52  PMID: 9250736 [PubMed - indexed for MEDLINE] 


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BISPHOSPHONATES


Usually bone metastases are lytic lesions, ones in which the bone is destroyed and replaced with tumor tissue. Lytic lesions imply an increase in osteoclastic bone cell activity.  Tumor cells within the bone marrow space can secrete substances [paracrine factors] that stimulate osteoclast function, resulting in osteolysis [bone destruction].  Also, bone cells can release cytokines and growth factors, which might can encourage tumor growth.

Bisphosphonates, a class of drugs that inhibit osteoclast activity, are useful in preventing and/or inhibiting the growth and symptoms of lytic bone metastases, as well as preventing and treating generalized osteoporosis [sometimes caused by chemotherapy agents] in cancer patients.

 " All bisphosphonates are characterized by a phosphorus-carbon-phosphorus (P-C-P)-containing central structure, which promotes their binding to the mineralized bone matrix, and a variable R' chain which determines the relative potency, side effects, and probably also the precise mechanism of action. Following administration, bisphosphonates bind avidly to exposed bone mineral around resorbing osteoclasts leading to very high local concentrations of bisphosphonate in the resorption lacunae (up to 1,000 µM). On release from the bone surface, bisphosphonates are internalized by the osteoclast, where they cause disruption of the biochemical processes involved in bone resorption [9]. Bisphosphonates also cause osteoclast apoptosis, with the appearance of distinctive changes in cell and nuclear morphology. Although the molecular targets responsible for promoting this apoptosis are unknown, the bisphosphonates have recently been shown to inhibit enzymes of the mevalonate pathway which are ultimately responsible for events that lead to the post-translational modification of GTP-binding proteins such as Ras. Recent studies also suggest that bisphosphonates may have direct apoptotic effects on tumor cells [10, 11]. "  [Coleman, R. The Oncologist, Vol. 5, No. 6, 463-470, December 2000 (c) 2000 AlphaMed Press ]


USE OF BISPHOSPHONATES 


Bisphosphonates for Hypercalcemia of Malignancy
Hypercalcemia is a common complication of malignancy.  Focal bone destruction by tumor cells, generalized bone destruction by substances secreted by the tumor, and impairment of kidney function may all contribute to high blood calcium levels. Intravenous bisphosphonates are now established as the treatment of choice for hypercalcemia. Seventy to ninety percent of patients will achieve normocalcemia resulting in relief of symptoms and improved quality of life [12] 


Bisphosphonates for Bone Pain
Radiotherapy is the treatment of choice for localized bone pain but many patients have widespread poorly localized, nonmechanical bone pain while others 
will experience recurrence of pain in previously irradiated skeletal sites. The bisphosphonates provide an alternative treatment approach to the management of 
these patients. [13-15].

Randomized controlled trials of intravenous pamidronate, clodronate, ibandronate, and zoledronate have all demonstrated bone tumor pain relief.  None of the oral preparations alone have been shown to reduce bone tumor pain.  Both sclerotic and lytic lesions respond to the bisphosphonates.  Bone tumor pain seems to be linked to the rate of bone resorption.   Patients with bony tumors and high rates of bone resorption respond poorly to bisphosphonates.  Following bone resorption markers will probably become important in evaluation the effects of bisphosphonate treatment.  [13, 16, 17]



Bisphosphonates as Adjunctive Therapy in Metastatic Bone Disease

Trials of bisphosphonates delayed disease progression in bone, and maintained quality of life and a reduction in pain and use of analgesics in treatment of breast cancer and multiple myeloma.  The research questions now are when to start treatment, optimal duration of treatment, and predicting those patients most likely to benefit.  Bisphosphonates may confer a small increase in survival time in the under 50 breast cancer group, and in myeloma patients receiving salvage chemotherapy. [1, 13-26]

 
"We are still lacking good data from randomized trials of the role of bisphosphonates for other tumor types affecting bone. Osteoclast stimulation is a consistent finding in all tumor types, even those associated with predominantly sclerotic metastases, and certainly acute pain relief is seen in prostate cancer. However, at the present time long-term bisphosphonate use cannot be justified outside clinical trials until more evidence from the current trials is available." [12] 

 
"At present clodronate, usually given orally, and infusions of pamidronate are the two most widely used bisphosphonates in oncology. However, a small percentage (<5%) of an oral dose of clodronate is absorbed, and for some patients the size and number of capsules required limit compliance, while infusions of pamidronate are costly, time-consuming and place additional demands on already overworked intravenous therapy units. The development of more potent bisphosphonates could be expected to simplify treatment and possibly improve the therapeutic effectiveness of bisphosphonate therapy." [12] 


"Zoledronate is the most potent bisphosphonate in clinical development, and in in vitro systems has around 100-1,000 times the potency of pamidronate." [27,28]

"Ibandronate is another highly potent amino-bisphosphonate which is licensed in Europe for the treatment of hypercalcemia of malignancy, and in late clinical 
development for both the treatment of metastatic bone disease, and the prevention and treatment of osteoporosis. "  An oral form has been developed. [14,29]


Bisphosphonates for Treatment of Osteoporosis

Many patients with cancer are at increased risk of osteoporosis. This is a problem in women with uterine LMS, for whom there questions about the safety of hormone replacement therapy.  Chemotherapy can also precipitate osteoporosis.   Osteoporosis can be treated OR prevented with bisphosphonates.  [30]



Bisphosphonates for Prevention of Bone Metastases

There have been conflicting results in clinical trials testing whether bisphosphonates prevent bone metastases. [31-33]  Proving adjuvant effectiveness for bisphosphonates will need large randomized trials. Zoledronate, clodronate, and ibandronate are currently under investigation.   Significant positive results in preventing bone metastasis, added to the known effects of bisphosphonates on protecting bone mass, would make adjuvant treatment with bisphosphonates routine. 
However, until results prove a benefit for their use, bisphosphonates  cannot be used adjuvantly except for the prevention  or treatment of osteoporosis.  [37]


"The optimum time in the course of the disease to start bisphosphonates remains uncertain, but once treatment is initiated, patients should continue to receive 
bisphosphonate treatment for as long as the skeleton is the dominant site of metastases. Bisphosphonates may also prevent, or at least delay, the development of skeletal metastases and will prevent treatment-induced osteoporosis, but their routine use in early breast cancer cannot be recommended until the completion of 
confirmatory trials."[37] 



OTHER OSTEOCLAST INHIBITORS 

 
"In recent years much has been learned about the signaling mechanisms between osteoblasts and osteoclasts and the control of bone metabolism in cancer. Osteoprotogerin (OPG) is a member of the tumor necrosis factor receptor superfamily which is a natural inhibitor of osteoclast production and activity. OPG acts as a decoy receptor binding with OPG-ligand, the natural stimulator of osteoclast maturation that is produced in large quantities by the osteoblast [34]. OPG has recently been shown to inhibit cancer-induced bone destruction and reduce skeletal pain in mice [35], and a synthetic version is now entering phase I trials in cancer patients. If the effects on bone resorption that have been seen in normal volunteer testing (Amgen-data on file) are confirmed in a cancer population, this long-acting subcutaneous preparation could be of great importance in the future. "[37]



PubMed/Medline Search for more information and references: Click on link:
http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=search&db=PubMed&term=bone%20metastases%20bisphosphonates
 

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References:  Bisphosphonates


1. Theriault RL, Lipton A, Hortobagyi GN et al. Pamidronate reduces skeletal   morbidity in women with advanced breast cancer bone lesions: a randomized,   placebo-controlled trial. Protocol 18 Aredia Breast Study Group. J Clin Oncol   1999;17:846-854.

2 Hortobagyi GN, Theriault RL, Porter L et al. Efficacy of pamidronate in   reducing skeletal complications in patients with breast cancer and lytic bone   metastases. Protocol 19 Aredia Breast Study Group. N Engl J Med   1996;335:1785-1791.[Abstract/Full Text] 
  
9 Rogers MJ, Watts DJ, Russell RG. Overview of bisphosphonates. Cancer   1997;80(suppl 8):1652-1660.[Medline] 

10  Yoneda T, Michigami T, Yi B et al. Use of bisphosphonates for the treatment of   bone metastasis in experimental animal models. Cancer Treat Rev   1999;25:293-299.[Medline] 
 
11 van der Pluijm G, Lowik C, Papapoulos S. Tumour progression and angiogenesis   in bone metastases from breast cancer: new approaches to an old problem.   Cancer Treat Rev 2000;26:11-27.

12  Coleman RE. Pamidronate disodium in the treatment and management of hypercalcaemia. Reviews in Contemporary Pharmacotherapy 1998;9:147-164

13 Body JJ, Bartl R, Burckhardt P et al. Current use of bisphosphonates in   oncology. International Bone and Cancer Study Group. J Clin Oncol   1998;16:3890-3899.[Abstract] 
  
14 Body JJ, Lichinitser MR, Diehl IE et al. Double-blind placebo controlled trial   of ibandronate in breast cancer metastatic to bone. Proc Am Soc Clin Oncol   1999;18:575a. 
  
15 Berenson JR, Lipton A, Rosen LS et al. Phase I clinical study of a new   bisphosphonate, zoledronate (CGP-42446), in patients with osteolytic bone   metastases. Blood 1998;88(suppl 1):586a. 
  
16 Vinholes JJ, Purohit OP, Abbey ME et al. Relationships between biochemical and   symptomatic response in a double-blind trial of pamidronate for metastatic   bone disease. Ann Oncol 1997;8:1243-1250.  
17 Coleman RE. Biochemical markers of malignant bone disease. In: Rubens RD,   Mundy GR, eds. Cancer and the Skeleton. London: Martin Dunitz, 2000:137-150. 
  
18 Body JJ, Coleman RE., Piccart M. Use of bisphosphonates in cancer patients.   Cancer Treat Rev 1996;22:265-287.[Medline] 
  
19 Paterson AHG, Powles TJ, Kanis J et al. Double-blind controlled trial of oral  clodronate in patients with bone metastases from breast cancer. J Clin Oncol   1993;11:59-65.[Abstract] 
  
20 Lahtinen R, Laakso M, Palva I et al. Randomised, placebo controlled   multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group.   Lancet 1992;340:1049-1052.[Medline] 

21  McCloskey EV, Maclennan ICM, Drayson M et al. A randomised trial of the effect   of clodronate on skeletal morbidity in multiple myeloma. Br J Haematol   1998;100:317-325.[Medline] 
  
22 Conte PF, Mauriac L, Calabresi F et al. Delay in progression of bone   metastases treated with intravenous pamidronate: results from a multicentre   randomised controlled trial. J Clin Oncol 1996;14;2552-2559.[Abstract] 
  
23 Hultborn R, Ryden S, Gunderson S et al. Efficacy of pamidronate on skeletal   complications from breast cancer metastases. A randomised prospective double   blind placebo controlled trial. Acta Oncol 1996;35(suppl 5):73-74. 
  
24 Berenson JR, Lichtenstein A, Porter L et al. Long-term pamidronate treatment   of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol   1998;16:593-602.[Abstract] 

 25  Lipton A, Demers L, Curley E et al. Markers of bone resorption in patients   treated with pamidronate. Eur J Cancer 1998;34:2021-2026.[Medline] 
  
26 Lipton A, Theriault RL, Hortobagyi GN et al. Pamidronate prevents skeletal   complications and is effective palliative treatment in women with breast   cancer and osteolytic bone metastases: long-term results of two randomised,   placebo-controlled trials. Cancer 2000;88:1082-1090.[Medline] 
  
27 Body JJ, Lortholary A, Romieu G et al. A dose-finding study of zoledronate in   hypercalcaemic cancer patients. J Bone Miner Res 1999;14:1557-1661.[Medline] 
  
28 Major P, Lortholary A, Hon J et al. Zoledronic acid is superior to pamidronate   in the treatment of tumor-induced hypercalcamia: a pooled analysis. Proc Am   Soc Clin Oncol 2000;19:604a. 
  
29 Coleman RE, Purohit OP, Black C et al. Double-blind, randomised,   placebo-controlled study of oral ibandronate in patients with metastatic bone   disease. Ann Oncol 1999;10:311-316.[Medline] 
  
30 Saarto S, Blomqvist C, Valimaki M et al. Chemical castration induced by   adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes   rapid bone loss which is reduced by clodronate: a randomised study in   premenopausal patients. J Clin Oncol 1997;15:1341-1347.[Abstract] 
  
31 Powles TJ, Paterson AHG, Nevantaus A et al. Adjuvant clodronate reduces the  incidence of bone metastases in patients with primary operable breast cancer.   Proc Am Soc Clin Oncol 1998;17:468a. 
  
32 Diel I, Solomayer E-F, Costa SJ et al. Reduction in new metastases in breast   cancer with adjuvant clodronate treatment. N Engl J Med   1998;339:357-363.[Abstract/Full Text] 
  
33 Saarto T, Blomqvist C, Virkkunen P et al. No reduction of bone metastases with  adjuvant clodronate treatment in node-positive breast cancer patients. Proc Am   Soc Clin Oncol 1999;18:128a. 
  
34 Kong Y-Y, Yoshida H, Sarosi O et al. OPGL is a key regulator of  osteoclastogenesis, lymphocyte development and lymph-node organogenesis.   Nature 1999;397:315-323.[Medline] 
  
35 Honore P, Luger NM, Sabino AC et al. Osteoprotogerin blocks bone   cancer-induced skeletal destruction. Skeletal pain and pain-related   neurochemical re-organisation of the spinal cord. Nat Med 
  2000;6:521-528.[Medline  

36 van Holten-Verzantvoort AT, Bijvoet OLM, Cleton FJ et al. Reduced morbidity from skeletal metastases in breast cancer patients during long term bisphosphonate (APD) treatment. Lancet 1987;ii:983-985.

37. The Coleman Article [link and the citation] http://theoncologist.alphamedpress.org/cgi/content/full/5/6/463
The Oncologist, Vol. 5, No. 6, 463-470, December 2000 (c) 2000 AlphaMed Press  
Management of Bone Metastases     Robert E. Coleman   e-mail: r.e.coleman@sheffield.ac.uk.

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