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Bone Metastases: Introduction
written and compiled by doctordee
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Introduction

"Bone metastases are frequently one of the first signs of disseminated disease in cancer patients. ... 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."
Nielsen OS. Palliative treatment of bone metastases. Acta Oncol 1996;35 Suppl 5:58-60
Fetch PMID: 9142968

Bone metastases are not usually directly potentially life threatening, as lung, liver or brain metastases can be. However, they can impair the quality of life significantly through pain, fractures, and disability, And they do add their bulk to the total tumor load, which does have influence on survival time.

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.

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. Multiple, severe vertebral fractures can cause 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 is the current first line treatment of choice for stabilization. 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
Useful Links

Search Pubmed for Bone Metastases Treatment

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 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]
[This is not a comprehensive article, but it does give valuable information.]
Coleman, R., The Oncologist, Vol. 5, No. 6, 463-470, December 2000 (c) 2000 AlphaMed Press

www.bonetumor.org

oncolink

Search Pubmed for All References metastases and spine

Proton Beam and Stereotactics -- Can be used on Cervical Spine

There are a number of new techniques like stereotactic radiotherapy or Intensity Modulated Radiation Therapy that may be used.
IMRT and stereotactic radiotherapy

USC Neurosurgery Department
Detection of Bone Lesions

Of 277 soft tissue sarcoma [STS] patients, approximately 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]
Fetch PMID: 9250736

Metastases of the Bones Can be Detected:

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 Xrays, CT, MRI, and isotope bone scans. Angiography is rarely used, but is helpful when a preoperative selective embolization is needed, or when complex vertebral surgery or vascular surgery is planned. MRI is the most definitive scan, and is usually done preoperatively.

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 [ regular Xrays] 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 injection; it is also free of artifacts in the patients with orthopedic devices that are usually nonferromagnetic [not responding to magnets like iron does]. 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 CT scans. The scan of choice for the most accurate imaging of 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
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 ÁM). 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


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 [too high a level of calcium in the blood]. 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]

"Zoledronate [Zometa] 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 as possible inhibitors of sarcoma and cancer cell growth
"The bisphosphonate pamidronate is a potent inhibitor of Ewing's sarcoma cell growth in vitro " "The bisphosphonate pamidronate is a potent inhibitor of human osteosarcoma cell growth in vitro." "Zoledronic acid induces antiproliferative and apoptotic effects in human pancreatic cancer cells in vitro"

LWW Articles: Enter 'pamidronate and sarcoma' in search box

BJC Article

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]

Search Pubmed for Bone Metastases and Bisphosphonates

References for this Section
Tetracyclines

Tetracycline, Doxycycline, and Minocycline are three members of the tetracycline family. Tetracyclines are used as antibiotics, and their patents have long expired, so they are available cheaply as generics. Because the medication is generic and cheap, there's less financial incentive for drug companies to fund research.

Tetracyclines migrate to and are absorbed by bone.

In order for metastases to grow in bone, the structure of the bone must be dissolved. Either osteoclasts or cancer cells secrete matrix metalloproteinases [MMPs] [enzymes that help break bone structure down.] Tetracyclines inhibit "matrix metalloproteinases", by combining with a Zinc ion at the active site on the MMP.

Additionally, Tetracyclines have shown cytostatic and cytotoxic activity against cell lines of various tumor origins.

Doxycycline was able to inhibit the activity of 72- and 92-kDa type IV collagenase secreted by bone-metastasizing cells by 79-87%. These characteristics could make tetracycline a unique candidate as a therapeutic agent to prevent bone metastases in cancer patients who have a high likelihood of developing bone metastasis.

╔xperimental evidence showing that doxycycline reduces tumor burden in a mouse model of breast cancer-derived osteolytic bone metastasis. This effect is likely due to a combination of multiple roles of doxycycline, including MMP inhibition and a negative effect on osteoclast differentiation and survival. These encouraging results have now paved the way for an ongoing trial of doxycycline in early combination therapy for breast cancer and prostate cancer patients.

Col-3, a chemically modified tetracycline, is now the subject of clinical trials in cancer patients.


Search Pubmed for Bone Metastases and Tetracycline

1. Anti-Cancer Drugs 2003; 14(10):773-778
Doxycycline and other tetracyclines in the treatment of bone metastasis
Zeina Saikali, Gurmit Singh

2. Invasion Metastasis 1997;17(6):312-22 Related Articles, Links
Use of tetracycline as an inhibitor of matrix metalloproteinase activity secreted by human bone-metastasizing cancer cells.
Duivenvoorden WC, Hirte HW, Singh G.
Fetch PMID: 9949290



compiled/written by doctordee
with thanks to Lynette and Laura
June 2002
updated December 2003


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