Osteopenia in the Patient With Cancer.

Key Words: Cancer, Osteopenia, Physical therapy.

[Croarkin E. Osteopenia in the patient with cancer. Phys Ther. 1999;79:196-201.]

Osteopenia commonly occurs in elderly women and women who are postmenopausal. This condition, however, can occur in either sex at any age. It can go undiagnosed until injury or an osteoporotic fracture is sustained.[1] Therapists who prescribe progressive mobility and strengthening programs, therefore, should understand the risk factors for osteopenia. The purpose of this article is to examine the etiology of osteopenia and the predisposition that patients with cancer have toward osteopenia. Bone growth, remodeling, and osteopenia development are described. Given the scope of this article, only the most common interventions for cancer are discussed.

During adolescence, people accumulate bone mass. Maintenance of bone mass becomes very important between the ages of 20 and 50 years, and bone loss is associated with decreases in estrogen between the ages of 50 and 65 years.[2] After the age of 65 years, bone loss occurs due to age-related factors, which vary with genetics, hormones, or environmental issues.[2] Consequently, adult bone mass is mainly dependent on 2 factors: (1) the acquisition of peak bone mass between the ages of 15 and 25 years and (2) age-related bone loss.[2] This lifelong pattern of alteration in bone mass overlies smaller cyclic changes in bone mass or density, which are mediated by intrinsic osteoclastic and osteoblastic cell activity or extrinsic forces on bone structure.

The osteoblastic and osteoclastic cycle remodels bone and takes approximately 100 days to complete.[1] Osteoclastic cells reabsorb bony material and leave abandoned cells. Osteoblastic cells then reform bone by depositing bony material into osteoclast cell cavities. The material becomes mineralized, and bone structure is formed. Nearly 25% of trabecular or cancellous bone, which composes vertebrae, the distal radius, and parts of the femur, is resorbed each year.[2] This resorption rate is more frequent for trabecular or cancellous bone than for cortical or compact bone, which predominately makes up long bones. This process occurs because trabecular bone has a greater surface area-to-volume ratio. Cortical bone remodeling is thought to be 8-fold lower than that of trabecular bone.[2] For this process to continue, metabolic and hormonal homeostasis needs to be maintained, and bone must be challenged by mechanical stress.

Bone becomes stronger as it adapts to mechanical stress (eg, muscle pulling, weight bearing), as described by Wolff's law.[3] For example, when a bone is curved due to muscular pull or tension, more bone is deposited on the concave aspect than on the convex side. Frost[4] described a process in which bone structure experiences microscopic damage from various forms of normal loading and is remodeled or repaired in a natural process of skeletal adaptation. He noted that bone loading needed to occur at a level "greater than normally experienced" to increase bone growth. When the load exceeds the bone's ability to repair, however, the structure is weakened.[4] Thus, bone strength can be affected either by an alteration in the osteoblastic and osteoclastic cycle or by insufficient or excessive loads on the bone. Nevertheless, when bone resorption exceeds bone formation, osteopenia occur.

A World Health Organization panel of experts has defined osteopenia as bone mineral density between -1 and -2.5 standard deviations from the young adult mean. Osteoporosis has been defined as bone mineral density below -2.5 standard deviations from the young adult mean.[5] Bone density generally is measured by dual-energy x-ray absorptiometry (DXA).[5] Occasionally, photon absorptiometry or computed tomography are cited in research reports. These 2 methods of bone measurement are not as widely used because of costs, length of time to perform, or lack of accuracy.[2] Photon absorptiometry and computed tomography, therefore, will not be discussed in this article. Broadband ultrasound attenuation or quantitative ultrasound is a relatively new, radiation-free method of measuring calcaneal bone structure. Nejh et al[6] described bone structure as bone connectivity (degree of trabecular strut connection), porosity, and anisotropy (orientation of struts).

Bauer et al[7] have shown that this method can be used to strongly predict the occurrence of fractures in older women. Broadband ultrasound attenuation is less established because there are no standards on which to base estimates of its accuracy.[5] Dual-energy x-ray absorptiometry does have established methods for determining accuracy and, therefore, is considered the gold standard of bone mineral density.[5]

The Table lists 2 categories of acquired osteopenia: (1) type I, or primary osteopenia, and (2) type II, or secondary osteopenia. Primary osteopenia occurs idiopathically or is caused by a lack of hormonal balance.[1] Its most common form is postmenopausal osteoporosis. This type of osteopenia is associated with accelerated loss of trabecular bone and, therefore, mainly vertebral fractures. (2) Secondary osteoporosis has an identifiable cause and involves both trabecular and cortical bone. There are many factors that predispose people to osteopenia. The focus of this review will be limited to specific etiologies that can occur with treatment for cancer.

Table.
Etiologies of Types of Osteopenia(a)

Type I                             Type II
(Primary Osteopenia)               (Secondary Osteopenia)

Menopause                          Immobilazation/disuse
Hereditary                         Nutritional imbalances
Idiopathic (ie, premenopausal)     Drug-induced
Radiotherapy                       Malignancies

(a) Adapted and reprinted with permission from Sinaki.[1]

Osteopenia Relative to Treatment for Cancer

Among the interventions available to oncologists, the most common are surgical, pharmacological, and radiological treatments or combinations of these treatments. When evaluating the effect of surgical intervention on bone health, the site of the surgical procedure is an important factor. If cancerous bone is excised, depending on the amount and location, there can be a direct effect of mechanical weakening of bone. Weight bearing through the bone and use of the respective extremity may be restricted, if not contraindicated. If a surgical intervention causes an interruption in hormonal status or nutritional uptake, there can be indirect effects. Consider the following 2 hypothetical cases.

Case 1

A 45-year-old woman develops ovarian cancer. If an oophorectomy is performed, menopause is surgically induced and estrogen levels will be reduced similar to if she underwent menopause naturally.[8] In postmenopausal (ie, type I) osteopenia, the reduction in estrogen levels plays a role in bone demineralization.[8] The role of estrogen in bone health has yet to be clearly defined. Osteoclasts are thought to become less responsive to circulating parathyroid hormone as estrogen levels decrease.[1] Bone demineralization occurs rapidly in the first 5 to 7 years after menopause. About 5% to 10% of trabecular bone is lost in the first 2 years postmenopause.[8] Thus, women who are postmenopausal and even women who are perimenopausal are often predisposed to bone softening prior to the cancer diagnosis and intervention.[1]

Case 2

A 65-year-old man develops colon cancer and, during the surgical treatment for the disease, the tumor and a portion of the digestive system are removed. If a large enough portion of the digestive system is removed, the patient can experience deficiencies in nutrient uptake. Minerals and vitamins are essential for healthy bone structure. Calcium deposition, the cornerstone of the bone matrix, is regulated mainly by vitamin D.[1] Thus, both vitamin D and calcium play a critical role in maintaining a strong bony matrix, and recently there has been interest in the involvement of minerals and micronutrients, such as potassium, magnesium, and fiber, in bone formation.[5] Additionally, if pain is intense, the patient's participation in exercise may be poor. In this example, pain can be general abdominal pain, pain secondary to bony metastatic disease, or pain caused by weight bearing on weakened bone structure.[9] The lack of weight-bearing exercise, such as ambulation, may reduce bone remodeling activity. Bone mineral density has been shown to decrease by approximately 0.9% in young adults after 1 week of bed rest.[10] In this case, osteopenia can be considered type II or secondary osteopenia.

Chemotherapy, used in the treatment of patients with cancer, can elicit numerous undesirable side effects. These side effects can indirectly predispose patients to osteopenia by affecting appetite and thereby reducing nutrient intake. The following are 3 examples of how chemotherapy can lessen a patient's appetite. First, antineoplastic agents are able to retard or arrest the growth of cancer by impairing cell replication. Cancer cells generally replicate rapidly, and chemotherapy targets these cancer cells. Cells of the mucous membranes that line the mouth, throat, esophagus, and stomach also divide rapidly, making them susceptible to chemotherapy. This susceptibility can lead to mucositis, an inflammation of the mucous membrane, and can lead to swallowing and eating difficulties.[11] Second, emesis is common immediately following chemotherapy administration. Third, patients receiving chemotherapy frequently develop an adverse response to the smell of food or become nauseated at the sight of food. Each of these side effects can dissuade a patient from maintaining a balanced diet.

Chemotherapy can also lead to osteopenia by having a direct effect on bone. Methotrexate (MTX), an antimetabolite drug, is one example. It is commonly used in the treatment for childhood lymphocytic leukemia and osteosarcoma. In 1970, Ragab et al[12] studied 11 children who were receiving long-term MTX therapy. About 50% of the children had severe, diffuse bone pain unrelated to the diagnosis. Other researchers[13-15] provided similar confirmatory data. In 1994, Meister et al[16] examined prolonged doses versus high-cumulative doses in children with central nervous system tumors. All of the children studied developed MTX-related osteopathy. Those patients did not receive steroids in addition to MTX, nor did they have diseases with bone involvement (as do children with leukemia). Stanisavljevic and Babcock[15] reported severe fractures in association with MTX use, and many fractures healed only after MTX cessation. The incidence of MTX-induced osteopenia has decreased, as protocols using high-cumulative and prolonged doses are no longer implemented.[16]

Doxorubicin also was found to have detrimental effects on bone. Friedlaender et al[17] reported an 11.5% decrease in trabecular bone formation with doxorubicin therapy. This drug, an anticycline, inhibits the DNA replication process but at a less critical stage than MTX. When taken in conjunction with MTX, bone formation decreased by 60%.[17]

Steroids, which are commonly used to treat patients with inflammation, are also used in the treatment of patients with cancer. Prednisone, for example, is used extensively as a chemotherapeutic agent.[18] Findings suggest that glucocorticoids increase osteoclastic activity and decrease osteoblastic activity and that trabecular bone is more affected than cortical bone by steroid use.[19] The benefits of steroid use in treatment for cancer are considered to outweigh the deleterious side effects.[18] The British National Lymphoma Investigation of 1975 revealed a "striking" increase in complete remission rates with use of steroids.[18] Remission rates were reported to be 80% with use of MVPP (mustine, vincristine, procarbazine, and prednisone) compared with 44% with use of MVP (mustine, vincristine, and procarbazine) in stage IV Hodgkin disease.[18]

Radiation alone has been linked to osteopenia of the irradiated area.[20] Patients with cancer who receive high doses of radiation often sustain osteolysis and develop avascular necrosis. Howland et al[20] noted coarsening or, in severe cases, loss of the trabecular pattern and slight to moderate cortical thickening. Less common changes included diffused demineralization and lytic and sclerotic changes.[20] They described the possible relationship of bone atrophy as secondary to osteoblastic destruction. Radiation can cause bone to become hypocellular, affecting its ability to repair and inducing bone softening, especially in the first 6 to 8 weeks.[21] After radiation ceases, bone must undergo several cycles to restore normal structure and mature. Recalcification is evident in 3 to 4 months, and return of full density may take up to 6 months.[9] The bony structures that Howland et al[20] examined had no evidence of cancer infiltration, nor were they adjacent to the involved sites. For example, Howland et al studied the shoulder girdle of patients receiving radiation for carcinoma of the breast. All patients developed bony atrophic changes by the end of the third year. In general, these researchers found that changes were evident when the absorbed radiation dose ranged from 40 to 100 Gy. In comparison, T2-3 squamous cell tumors are usually treated with 70 Gy.[22]

Osteopenia is the most common cause of scoliosis following treatment for cancer in adults.[23] Children who have received spinal irradiation are at a higher risk than adults for developing osteopenia, which can develop into scoliosis during adolescent growth spurts. This form of scoliosis is the most predominant delayed manifestation of spinal column radiation. It is found almost exclusively in patients treated for solid spinal tumors, and it is reported in 50% of patients with Wilms tumor who received abdominal radiation.[23] Children under 5 years of age who have received spinal irradiation are advised to have a radiological examination every 6 months.[23] If they are older than 5 years of age, it is recommended that they be examined every few years.[23]

Combination treatment involving the concurrent use of radiation and chemotherapy is another treatment regimen with even higher potential for inducing osseous changes. Osteopenia has been described in patients with rhabdomyosarcoma and Ewing sarcoma, where radiation is the primary treatment for cancer and chemotherapy has been used as an adjuvant treatment modality.[24] Jentzsch et al[24] noted that, of 29 patients with Ewing sarcoma who were treated with combination therapy, 9 patients had fractures. Most fractures were of the femur; all patients were treated with on average 50 Gy of radiation.[24] Patients with Hodgkin disease who are treated with combination treatment can have iatrogenic fractures not associated with the disease.[25] Of those patients studied by Timothy et al,[25] bone pain occurred, on average, 4.4 years after the diagnosis was made and 22.5 months after combined treatment initiation. In addition, he intervals between the appearance of radiological changes, the onset of bone pain, and the absence of Hodgkin disease upon femoral head excision indicated osteonecrosis not related to the disease.[25] According to Tefft et al,[26] the use of drugs such as actinomycin D, Adriamycin, and cyclophosphamide to enhance the effects of radiation has resulted in damaged bone. They noted that, with cyclic administration of these drugs, there was a reactivation of "latent radiation damage." They concluded that "concomitant and maintenance chemotherapy" enhanced the existing postradiation damage by approximately 40%.

Cancer alone can affect the health of the bone. Neoplasms that involve the cortex of the bone will stretch the periosteum, causing discomfort, and can lead to decreased weight bearing and subsequent bone softening.[9] Paget disease, or osteitis deformans, a disease of bone marked by increased bone resorption followed by excessive attempts at repair, can result in weakened bone with increased mass.[27] This disease can lead to bowed bones and stress fractures[27,28] and may coexist with myeloma, lymphoma, and metastatic bone cancer.[28] Additionally, hematological malignancies, such as multiple myeloma, are almost always associated with severe bone destruction and hypercalcemia.[29]

Hypercalcemia resulting from cancer has been linked to tumor-induced osteolysis.[30] The incidence of hypercalcemia is a result of a marked increase of osteoclast mediated bone resorption and other factors that involve the kidney and circulating parathyroid levels[29] Solid tumors without metastasis can induce the least common type of hypercalcemia. Solid tumor cells probably release a factor or hormone that stimulates bone resorption systemically. This bone resorption is called "humoral-mediated hypercalcemia."[29] Patients with solid tumors with metastasis can sustain bone destruction due to the metastatic activity in conjunction with humoral-mediated hypercalcemia. Research supports medical intervention to abate the probability of a hypercalcemic crisis in hopes of allowing patients to be discharged from the hospital in the terminal stages of cancer.[31]

Implications for Physical Therapy

Patients who are at high risk for osteopenia require health care planning that takes into account potential complications. Some patients can have more than one risk factor for both type I and type II osteopenia. The Figure illustrates the concept that there is a critical balance necessary to achieve systemic homeostasis and those factors that may alter that balance. Given the potential of long-term deleterious side effects from cancer and its treatment, therapists should be aware of the patient's diagnosis, stage of the disease, past and present medical and antineoplastic treatments. Goals should be established to educate the patient about expectations of rehabilitation, provide palliative relief from pain, restore function, and maintain quality of life. Follow-up evaluations and treatment depend on the diagnosis and age of the patient. Generally, follow-up appointments are recommended more frequently during the adolescent growth spurt. When changes in bone mineral density are suspected, a diagnostic test specific to bone mineral density, such as DXA measurement, may be warranted.

[Figure ILLUSTRATION OMITTED]

Summary

Osteopenia is defined as a reduction in bone mass.[1] It is commonly known to occur in elderly people or women who are postmenopausal due to hormonal imbalances. This condition, however, can result because of many other factors, such as poor nutrition, prolonged pharmacological intervention, disease, and decreased mobility. Because patients with cancer experience many of these factors, they are often predisposed to osteopenia. Currently, patients with cancer are living longer and leading more fulfilling lives after treatment. Therefore, it is imperative that therapists who are responsible for these patients understand the risk factors for osteopenia and their relevance to a patient with cancer.

Acknowledgments

I gratefully thank Charles McGarvey, PT, Paul Jarosinski, PharmD, and Maureen Leser, RD, for their guidance and editorial advice in the preparation of this article.

References

[1] Sinaki M. Osteoporosis. In: Joel A, DeLisa JB, eds. Rehabilitation Medicine: Principles and Practice. 2nd ed. Philadelphia, Pa: JB Lippincott Co; 1993:1018-1035.

[2] Rosen CJ, Kessenich CR. The pathophysiology of osteoporosis. In: Rosen CJ, ed. Current Clinical Practice -- Osteoporosis: Diagnostic and Therapeutic Principles. Totowa, NJ: Humana Press; 1996:47-64.

[3] Wolff JL, Wessinghage D, eds. Das Gesetz der Transformation der Knochen. Stuttgart, Germany: FK Schattauer Verlag GmbH; 1892.

[4] Frost HM. Suggested fundamentals and concepts in skeletal physiology. Calcif Tissue Int. 1993;52:1-4.

[5] Kanis JA, McCloskey EV, Beneton MNC, et al. Bone measurements with DXA and ultrasound: diagnostic and prognostic use. In: Papapoulos SE, Lips P, Pols HAP, et al, eds. Osteoporosis 1996: Proceedings of the 1996 World Congress on Osteoporosis. Amsterdam, the Netherlands: Elsevier Science Publishers BV; 1996:181-190.

[6] Nejh CF, Boivin CM, Langton CM. The role of ultrasound in the assessment of osteoporosis: a review. Osteoporos Int. 1997;7:7-22.

[7] Bauer DC, Gluer CC, Cauley JA, et al. Broadband ultrasound attenuation predicts fractures strongly and independently of densitometry in older women: a prospective study. Arch Intern Med. 1997;157:629-634.

[8] Cann CE, Genant HK, Ettinger B, Gordan GS. Spinal mineral loss in oophorectomized women: determination by quantitative computed tomography. JAMA. 1980;244:2056-2059.

[9] Vargo M. Orthopedic management of malignant bone lesions. Physical Medicine and Rehabilitation: State-of-the-Art Reviews. Philadelphia, Pa: Hanley & Belfus Inc; 1994;8(2).

[10] Krolner B, Tort B. Vertebral bone loss: an unheeded side effect of therapeutic bed rest. Clin Sci. 1983;64:537-540.

[11] Holtzman L, Chesney K. Rehabilitation of the leukemia/lymphoma patient. In: McGarvey CL, ed. Clinics in Physical Therapy: Physical Therapy for the Cancer Patient. New York, NY: Churchill Livingstone Inc; 1990:85-110.

[12] Ragab AH, Frech RS, Vietti TJ. Osteoporosis fractures secondary to methotrexate therapy of acute leukemia in remission. Cancer. 1970;25:580-585.

[13] O'Regan S, Melhorn DK, Newman AJ. Methotrexate-induced bone pain in childhood leukemia. Am J Dis Child. 1973; 126:489-490.

[14] Nesbit M, Krivit W, Heyn R, Sharp H. Acute and chronic effects of methotrexate on hepatic, pulmonary, and skeletal systems. Cancer. 1976;37:1048-1054.

[15] Stanisavljevic S, Babcock AL. Fractures in children treated with methotrexate for leukemia. Clin Orthop. 1977;125:139-144.

[16] Meister B, Gassner I, Streif W, et al. Methotrexate osteopathy in infants with tumors of the central nervous system. Med Pediatr Oncol. 1994;23:49.3-496.

[17] Friedlaender GE, Tross RB, Doganis AC, et al. Effects of chemotherapy agents on bone, I: short-term methotrexate and doxorubicin (adriamycin) treatment in a rat model. J Bone Joint Surg Am. 1984;66:602-607.

[18] Report from the British National Lymphoma Investigation. Value of prednisone in combination chemotherapy of stage IV Hodgkin's disease. BMJ. 1975;3:413-414.

[19] Bressot C, Meunier PJ, Chapuy MC, et al. Histomorphometric profile, pathophysiology and reversibility of corticosteroid-induced osteoporosis. Metab Bone Dis Relat Res. 1979;1:303-311.

[20] Howland WJ, Loeffler RK, Starchman DE, Johnson RG. Postirradiation atrophic changes of bone and related complications. Radiology. 1975; 177:677-685.

[21] Ergun H, Howland WJ. Postradiation atrophy of mature bone. CRC Crit Rev Diagn Imaging. 1980;12:225-243.

[22] Shukovsky LJ, Baeza MR, Fletcher GH. Results of irradiation in squamous cell carcinomas of the glossopalatine sulcus. Radiology. 1976; 120:405-408.

[23] Blatt J, Bleyer WA. Late effects of childhood cancer and its treatment. In: Pizzo P, Poplack D, eds. Principles and Practice of Pediatric Oncology. 3rd ed. Philadelphia, Pa: JB Lippincott Co; 1994:1003-1008.

[24] Jentzsch K, Binder H, Cramer H, et al. Leg function after radiotherapy for Ewing's sarcoma. Cancer. 1981 ;47:1267-1278.

[25] Timothy AR, Park WM, Cannell LB. Osteonecrosis in Hodgkin's disease. Br J Radiol. 1978;51:328-332.

[26] Tefft M, Lattin PB, Jereb B, et al. Acute and late effects on normal tissues following combined chemo- and radiotherapy for childhood rhabdomyosarcoma and Ewing's sarcoma. Cancer. 1976;37:1201-1217.

[27] Dorland's Illustrated Medical Dictionary. 26th ed. Philadelphia, Pa: WB Saunders Co; 1981.

[28] Norman A. The radiology of Paget's disease. In: Singer FR, Wallach S, eds. Paget's Disease of Bone: Clinical Assessment, Present and Future Therapy. Amsterdam, the Netherlands: Elsevier Science Publishers BV; 1989:1-19.

[29] Mundy GR, Martin TJ. The hypercalcemia of malignancy: pathogenesis and management. Metabolism. 1982;131:1247-1277.

[30] Body JJ. Bone metastases and tumor-induced hypercalcemia. Curr Opin Oncol. 1992;4:624-631.

[31] Ralston SH, Gallacher SJ, Patel U, et al. Cancer-associated hypercalcemia: morbidity and mortality -- clinical experience in 126 treated patients. Ann Intern Med. 1990;112:499-504.

E Croarkin, PT, is Physical Therapist, Warren G Magnuson Clinical Center, National Institutes of Health, Bldg 10, Room 6S-235, Bethesda, MD 20892-1604 (USA) ([e-mail]). She was responsible for the concept and writing of this paper.

Charles L McGarvey, PT, Chief of Physical Therapy, Warren G Magnuson Clinical Center, provided consultation on the manuscript.