Open Access

Bone density as a marker for local response to radiotherapy of spinal bone metastases in women with breast cancer: a retrospective analysis

  • Robert Foerster1,
  • Christian Eisele1,
  • Thomas Bruckner2,
  • Tilman Bostel1,
  • Ingmar Schlampp1,
  • Robert Wolf1,
  • Juergen Debus1 and
  • Harald Rief1Email author
Radiation Oncology201510:62

https://doi.org/10.1186/s13014-015-0368-x

Received: 12 February 2015

Accepted: 24 February 2015

Published: 7 March 2015

Abstract

Background

We designed this study to quantify the effects of radiotherapy (RT) on bone density as a local response in spinal bone metastases of women with breast cancer and, secondly, to establish bone density as an accurate and reproducible marker for assessment of local response to RT in spinal bone metastases.

Methods

We retrospectively assessed 135 osteolytic spinal metastases in 115 women with metastatic breast cancer treated at our department between January 2000 and January 2012. Primary endpoint was to compare bone density in the bone metastases before, 3 months after and 6 months after RT. Bone density was measured in Hounsfield units (HU) in computed tomography scans. We calculated mean values in HU and the standard deviation (SD) as a measurement of bone density before, 3 months and 6 months after RT. T-test was used for statistical analysis of difference in bone density as well as for univariate analysis of prognostic factors for difference in bone density 3 and 6 months after RT.

Results

Mean bone density was 194.8 HU ± SD 123.0 at baseline. Bone density increased significantly by a mean of 145.8 HU ± SD 139.4 after 3 months (p = .0001) and by 250.3 HU ± SD 147.1 after 6 months (p < .0001). Women receiving bisphosphonates showed a tendency towards higher increase in bone density in the metastases after 3 months (152.6 HU ± SD 141.9 vs. 76.0 HU ± SD 86.1; p = .069) and pathological fractures before RT were associated with a significantly higher increase in bone density after 3 months (202.3 HU ± SD 161.9 vs. 130.3 HU ± SD 129.2; p = .013). Concomitant chemotherapy (ChT) or endocrine therapy (ET), hormone receptor status, performance score, applied overall RT dose and prescription of a surgical corset did not correlate with a difference in bone density after RT.

Conclusions

Bone density measurement in HU is a practicable and reproducible method for assessment of local RT response in osteolytic metastases in breast cancer. Our analysis demonstrated an excellent local response within metastases after palliative RT.

Keywords

Bone densityBone metastasesBreast cancerRadiotherapyLocal response

Background

The bone is the most common site for metastases in women with breast cancer [1]. Bone metastases of the spinal column are a major cause of morbidity and reduced quality of life due to severe pain, pathological fractures, spinal cord compression and hypercalcemia [2,3]. Bone metastases require a multimodal treatment approach including radiotherapy (RT), minimal invasive surgery and systemic treatments such as bisphosphonates [4]. RT is the most common treatment method [5,6], and its indications are typically pain, instability or neurological symptoms due to spinal cord compression [7]. The simultaneous delivery of RT and bisphosphonates may be beneficial for re-ossification of the bone affected by osseous metastases [8-10]. Previously we were able to show that RT is capable of promoting re-ossification leading to increased stability of spinal bone metastases [11-13]. Secondly, in a recent trial we were able to show that the quantification of bone density within metastases was an accurate and practicable method to evaluate local response after RT [14]. The aim of our current analysis was to quantify the effects of RT on bone density in the metastatic bone in breast cancer patients with spinal bone metastases and to establish bone density as a marker for assessment of local response to RT.

Methods

We retrospectively assessed 135 osteolytic metastases of the thoracic and lumbar vertebral column treated with RT at our department between January 2000 and January 2012. The spinal bone metastases were found in 115 women with metastatic breast cancer. Patients’ data were collected from the local cancer registry. Median age was 60 years (range 32–88) and median Karnofsky performance status (KPS) was 80% at first presentation. Seventy-six patients (56.3%) had more than one spinal bone metastasis. Cases characteristics are shown in Table 1. The cases selected for this study were those with available minimum follow-up computed tomography (CT) scans for 3 months after RT. For patients that underwent RT for several regions, each irradiated region was regarded separately as an individual case and in each region only the metastasis with the highest degree of instability according to Taneichi et al. was included in our study [15]. The primary endpoint of this study was to compare bone density in the irradiated metastasis before RT and 3 months as well as 6 months after RT. Additionally we performed a reference measurement of the bone density in the neighboring irradiated vertebral body which was not affected by bone metastases. Most patients were treated additionally with bisphosphonates during RT (91.1%), which represents a major bias for the assessment of treatment response in the metastasis. Therefore, a bone density measurement of uninvolved vertebral bodies was executed to detect the increase by a systemic treatment. Bone density was assessed in Hounsfield units (HU) by manual region of interest (ROI) setting of the whole vertebral body for uninvolved bone and within metastases for involved bone (Figure 1). The study was approved by the university’s ethical committee (# S-513/2012).
Table 1

Cases characteristics

Age

  

Median

60 years

 

Range

32-88 years

 
 

n

%

Karnofsky performance status

30-70%

40

29.6%

80-90%

95

70.3%

Histology

  

Invasive ductal

107

79.3%

Invasive lobular

28

20.7%

Receptor status positivity

 

ER (N = 34)

28

82.4%

PgR (N = 50)

40

80.0%

HER2 (N = 135)

39

28.9%

Site

  

Thoracic

99

73.3%

Lumbar

36

26.7%

Number of bone metastases

 

Solitary

59

43.7%

Multiple

76

56.3%

Treatment indications

 

Pain

69

51.1%

Instability

44

32.6%

Pathological fracture

 

Before RT

29

21.5%

After RT

8

5.9%

Surgical corset

  

During RT

82

60.7%

Figure 1

Osteolytic thoracic spinal metastasis (A) before RT and (B) 3 months after RT as a basis for bone density measurement in HU by manual ROI setting.

Radiotherapy

RT was planned as virtual simulation based on planning CT imaging and was delivered over a dorsal 6 MV photon filed. The planning target volume (PTV) covered the affected vertebral bodies as well as the ones directly above and below. Median prescribed total dose was 30.0 Gy in 3.0 Gy single fractions. Treatment characteristics are shown in Table 2.
Table 2

Treatment of cases

 

n

%

Radiotherapy (RT) (N = 133)

  

10 × 3 Gy

77

57.9%

14 × 2.5 Gy

20

15.1%

20 × 2 Gy

34

25.6%

Others

2

1.5%

Systemic therapy prior to RT

  

Chemotherapy

46

34.1%

Endocrine therapy

47

34.8%

Bisphosphonates

51

37.8%

Systemic therapy after RT

  

Chemotherapy

72

53.3%

Endocrine therapy (N = 30)

26

86.7%

Bisphosphonates

123

91.1.%

Statistical analysis

We calculated mean values in HU and the standard deviation (SD) as a measurement for bone density before as well as 3 and 6 months after RT. Regarding statistical analysis of difference in bone density as well as for univariate analysis of prognostic factors for difference in bone density at 3 and at 6 months after RT we calculated the equality of variances and used the t-test. As possible prognostic factors we investigated systemic therapy (chemotherapy (ChT) and endocrine therapy (ET)) before/after RT, bisphosphonates after RT, treatment indications (pain, stability), prescription of a surgical corset, irradiated area (lumbar vs. thoracic), number of metastases (1 vs. >1), prescribed overall RT dose, pathological fractures before/after RT and hormone receptor status (estrogen (ER), progesterone (PgR), Her-2/neu (HER2)). A p-value ≤ 0.05 was considered statistically significant. All statistical analyses were performed with SAS software 9.1 (SAS Institute, Cary, NC, USA).

Results

The mean calculated size of the metastases was 431.3 mm2 ± SD 313.5 and the mean bone density in the metastases was 194.8 HU ± SD 123.0 at initial assessment. Three months after RT we observed a mean bone density of 340 HU ± SD 179.2 and after 6 months a mean bone density of 433.1 HU ± SD 172.6 in the metastases. Whereas mean bone density in the irradiated unaffected neighboring vertebral bodies was 235.9 HU ± SD 143.4 before RT, 228.6 HU ± SD 143.2 after 3 months and 250.3 HU ± SD 147.1 after 6 months. Bone density increased significantly in the metastases during follow-up after RT. At 3 months the bone density had increased by a mean of 145.8 HU ± SD 139.4 (p < .0001) and after 6 months by a mean of 238.0 HU ± SD 149.2 (p < .0001). The bone density in the irradiated unaffected neighboring vertebral bodies used for reference measurements did not change significantly during follow-up after RT. After 3 months we found a slight decrease by a mean of −7.3 HU ± SD 60.4 (p = .162) and after 6 months, with a mean decrease of −0.1 HU ± SD 70.1 (p = .993), there was practically no change in bone density observable (Table 3).
Table 3

Bone density (HU) in metastases and in irradiated uninvolved bone

 

Mean

SD

Mean difference

SD

p-value

Bone metastases

     

Before RT

194.8

123.0

   

After 3 months

340.6

179.2

145.8

139.4

p < .0001

After 6 months

433.1

172.6

238.0

149.2

p < .0001

Irradiated uninvolved bone

     

Before RT

235.9

143.4

   

After 3 months

228.6

143.2

−7.3

−1.41

p = .162

After 6 months

250.3

147.1

−0.1

−0.01

p = .993

Increase in bone density of the metastases seemed to be associated with the prescription of bisphosphonates. While women receiving bisphosphonates had a mean increase in bone density of 152.59 HU ± SD 141.99 in the metastases after 3 months, patients without bisphosphonates only had a mean increase in bone density of 76.03 HU ± SD 86.6 (p = .069) in the metastases 3 months following RT. Additionally we found that women with pathological fractures before RT (21.5%) had a significantly higher increase in bone density after 3 months than those which presented without fractures at initial assessment (202.3 HU ± SD 161.88 vs. 130.33 HU ± SD 129.23; p = .013). These differences were no longer detectable 6 months after RT. All other investigated potentially prognostic factors, especially concomitant ChT or ET, hormone receptor status, KPS, applied overall dose as well as the prescription of a surgical corset, did not significantly correlate with an increase or decrease in bone density after RT (Table 4).
Table 4

Univariate analysis of prognostic factors for difference in bone density in HU

 

After 3 months

After 6 months

 

n

Mean

SD

p-value

n

Mean

SD

p-value

Bisphosphonates after RT

   

p = .069

   

p = .162

Yes

123

152.6

141.9

 

76

245.8

151.5

 

No

12

76.0

86.1

 

9

171.9

114.4

 

Pathological fracture before RT

   

p = .013

   

p = .801

Yes

29

202.3

161.9

 

21

230.8

141.7

 

No

106

130.3

129.2

 

64

240.3

152.6

 

Pathological fracture after RT

   

p = .399

   

p = .399

Yes

8

186.3

133.6

 

8

280.5

135.3

 

No

127

143.2

139.9

 

77

233.5

150.7

 

Chemotherapy before RT

   

p = .946

   

p = .991

Yes

46

144.7

135.3

 

23

238.3

172.9

 

No

89

146.4

148.6

 

62

237.8

140.9

 

Chemotherapy after RT

   

p = .741

   

p = .547

Yes

72

149.5

130.9

 

45

247.2

144.9

 

No

63

141.5

149.5

 

40

227.5

154.9

 

Endocrine therapy before RT

   

p = .211

   

p = .133

Yes

47

125.2

137.3

 

25

200.2

136.1

 

No

88

156.8

140.1

 

60

253.7

152.6

 

Endocrine therapy after RT

   

p = .536

   

p = .657

Yes

26

121.9

98.1

 

17

196.3

143.6

 

No

4

87.8

125.4

 

2

250.0

316.8

 

Pain as indication for RT

   

p = .822

   

p = .963

Yes

69

148.5

141.5

 

46

238.7

143.3

 

No

66

143.0

138.3

 

39

237.1

157.7

 

Instability as indication for RT

   

p = .479

   

p = .554

Yes

91

139.9

133.9

 

57

231.2

141.9

 

No

44

158.1

150.9

 

28

251.7

164.8

 

Surgical corset

   

p = .358

   

p = .213

Yes

82

136.9

134.9

 

52

221.8

144.6

 

No

53

159.6

146.3

 

33

263.4

154.9

 

Spine

   

p = .437

   

p = .858

Thoracic

99

150.7

149.1

 

65

239.6

155.9

 

Lumbar

36

132.3

109.2

 

20

232.7

128.1

 

Number of metastases

   

p = .983

   

p = .382

1

59

146.1

132.4

 

35

254.9

158.2

 

>1

76

145.6

145.5

 

50

226.1

142.9

 

Overall dose

   

p = .886

   

p = .654

<=30 Gy

79

145.1

130.9

 

57

229.6

143.8

 

>30 Gy

54

141.6

150.8

 

26

245.6

162.9

 

KPS

   

p = .815

   

p = .412

</=70%

40

150.1

148.1

 

23

263.4

259.9

 

>70%

95

143.9

136.4

 

62

228.5

163.7

 

Estrogen receptor status

   

p = .278

   

p = .828

Positive

28

139.9

115.2

 

19

222.5

156.6

 

Negative

6

83.8

99.3

 

2

250.0

316.8

 

Progesterone receptor status

   

p = .088

   

p = .694

Positive

40

159.9

123.5

 

25

242.7

149.5

 

Negative

10

87.8

83.4

 

4

276.5

214.5

 

Her-2/neu receptor status

   

p = .581

   

p = .379

Positive

39

156.3

118.4

 

28

220.2

108.2

 

Negative

96

141.5

147.5

 

57

246.7

165.8

 

Discussion

In previous studies we demonstrated that RT is capable of improving stability in spinal bone metastases by facilitating re-ossification [11-14]. With our current analysis we were able to quantify the re-ossification after RT by measuring the change in mean bone density on the basis of x-ray absorption in CT scans and we found that mean bone density, as a local response, increased significantly in the metastases after RT. While mean bone density in the metastases increased by 145.8 HU ± SD 139.4 after 3 months (p < .0001) and by 238.0 HU ± SD 149.2 after 6 months (p < .0001), this was not the case in the irradiated neighboring vertebrae unaffected by bone metastases. Other investigators found bone density to increase after RT as well [16,17]. Currently local response is chiefly assessed by visual judgment of sclerosis of the osteolytic lesions in CT scans, with complete response being classified as complete sclerosis of the metastasis, partial response as >50% regression of the metastasis and no response as an unchanged metastases [18]. Such an evaluation of local treatment response is very subjective and imprecise. We believe bone density measurement to be a more reliable and reproducible method for assessment and quantification of re-ossification as a local response to RT in osteolytic spinal bone metastases.

Clinical and preclinical studies suggest a benefit from combined treatment with systemic bisphosphonates concomitant to RT [19-21] since they have been shown to exhibit cytotoxic and radiosensitizing effects when combined with RT additional to their anti-bone-resorptive properties [22,23]. In our analysis there was a strong tendency towards statistical significance for increased bone density in the metastases with concomitant bisphosphonate treatment 3 months following RT (p = .069) and after 6 months the mean increase in mean bone density was still larger in patients receiving combination treatment compared to those without bisphosphonates (245.8 HU ± SD 151.5 vs. 171.9 HU ± SD 114.4). Nevertheless, the rate of bisphosphonates was high (91.1%). However, this was not the case for the irradiated bone unaffected by metastases. We believe that bisphosphonates may be capable of facilitating RT effects in bone metastases and that these patients may respond more rapidly. Other concomitant systemic treatments in the form of ChT or ET did not affect bone density in our analysis. Similarly, systemic treatment before/after RT did not influence local response in terms of stability in two earlier studies [12,13]. This is probably due to the fact that most patients in our study were already postmenopausal and did received bisphosphonates which was not the case in another previous study where ChT before RT had a negative effect on stability as a local response to RT [11]. Negative effects on bone density by aromatase inhibitors [24] and disturbances in bone remodeling by ChT [25] may have been compensated by concomitant bisphosphonate therapy, tamoxifen treatment probably had a rather bone-protective effect [26] and ChT-associated ovarian failure [27] did not play a relevant role in our cohort.

Furthermore we found that mean bone density increase after 3 months was significantly higher in patients with pathological fractures at initial assessment (p = .013) which can be explained by physiological consolidation processes with callus formation after acute fractures. Nevertheless, pathological fracture may affect the bone density in sintered vertebral body after treatment, but this bias was insignificant small in 5.9% of patients.

We found no statistically significant correlation between the remaining investigated prognostic factors and an increase or decrease in bone density after RT. Koswig and Budach found bone density after 6 months to have increased by 173% after 30 Gy in 10 fractions compared to 120% after a single fraction of 8 Gy [16]. Most women in our analysis were treated with an overall dose of 30 Gy in 3 Gy single fractions and thus we were unable to detect any differences between fractionation schedules. KPS and the prescription of a surgical corset also did not affect response to RT in terms of bone density although a higher KPS and not wearing a surgical corset should in theory be associated with more physical activity which in turn can lead to an improved stability of spinal bone metastases [11,14].

Conclusions

Bone density increased significantly in the metastases during follow-up after RT, while practically no change was seen in the irradiated bone unaffected by metastases. Bone density measurement in HU is a reliable and reproducible method for assessment of local response in osteolytic metastases after RT. Concomitant bisphosphonate may protect from bone-resorptive effects induced by ChT and ET.

Declarations

Acknowledgement

We acknowledge the financial support of Deutsche Forschungsgemeinschaft and Ruprecht-Karls-Universität Heidelberg within the funding program Open Access Publishing.

Authors’ Affiliations

(1)
Department of Radiation Oncology, University Hospital Heidelberg
(2)
Department of Medical Biometry, University Hospital Heidelberg

References

  1. Lutz S, Berk L, Chang E, Chow E, Hahn C, Hoskin P, et al. Palliative radiotherapy for bone metastases: an ASTRO evidence-based guideline. Int J Radiat Oncol Biol Phys. 2011;79:965–76.View ArticlePubMedGoogle Scholar
  2. Whyne CM, Hu SS, Lotz JC. Biomechanically derived guideline equations for burst fracture risk prediction in the metastatically involved spine. J Spinal Disord Tech. 2003;16:180–5.View ArticlePubMedGoogle Scholar
  3. Janjan N, Lutz ST, Bedwinek JM, Hartsell WF, Ng A, Pieters Jr RS, et al. Therapeutic guidelines for the treatment of bone metastasis: a report from the American College of Radiology Appropriateness Criteria Expert Panel on Radiation Oncology. J Palliat Med. 2009;12:417–26.View ArticlePubMedGoogle Scholar
  4. Chow E, Zeng L, Salvo N, Dennis K, Tsao M, Lutz S. Update on the systematic review of palliative radiotherapy trials for bone metastases. Clin Oncol (R Coll Radiol). 2012;24:112–24.View ArticleGoogle Scholar
  5. Mitera G, Probyn L, Ford M, Donovan A, Rubenstein J, Finkelstein J, et al. Correlation of computed tomography imaging features with pain response in patients with spine metastases after radiation therapy. Int J Radiat Oncol Biol Phys. 2011;81:827–30.View ArticlePubMedGoogle Scholar
  6. Wu JS, Monk G, Clark T, Robinson J, Eigl BJ, Hagen N. Palliative radiotherapy improves pain and reduces functional interference in patients with painful bone metastases: a quality assurance study. Clin Oncol (R Coll Radiol). 2006;18:539–44.View ArticleGoogle Scholar
  7. Souchon R, Feyer P, Thomssen C, Fehm T, Diel I, Nitz U, et al. Clinical Recommendations of DEGRO and AGO on Preferred Standard Palliative Radiotherapy of Bone and Cerebral Metastases, Metastatic Spinal Cord Compression, and Leptomeningeal Carcinomatosis in Breast Cancer. Breast Care (Basel). 2010;5:401–7.View ArticleGoogle Scholar
  8. Oda I, Abumi K, Lu D, Shono Y, Kaneda K. Biomechanical role of the posterior elements, costovertebral joints, and rib cage in the stability of the thoracic spine. Spine (Phila Pa 1976). 1996;21:1423–9.View ArticleGoogle Scholar
  9. Oster G, Lamerato L, Glass AG, Richert-Boe KE, Lopez A, Chung K, et al. Natural history of skeletal-related events in patients with breast, lung, or prostate cancer and metastases to bone: a 15-year study in two large US health systems. Support Care Cancer. 2013;21:3279–86.View ArticlePubMedGoogle Scholar
  10. Weber MH, Burch S, Buckley J, Schmidt MH, Fehlings MG, Vrionis FD, et al. Instability and impending instability of the thoracolumbar spine in patients with spinal metastases: a systematic review. Int J Oncol. 2011;38:5–12.PubMedGoogle Scholar
  11. Foerster R, Habermehl D, Bruckner T, Bostel T, Schlampp I, Welzel T, et al. Spinal bone metastases in gynecologic malignancies: a retrospective analysis of stability, prognostic factors and survival. Radiat Oncol. 2014;9:194.View ArticlePubMed CentralPubMedGoogle Scholar
  12. Rief H, Bischof M, Bruckner T, Welzel T, Askoxylakis V, Rieken S, et al. The stability of osseous metastases of the spine in lung cancer–a retrospective analysis of 338 cases. Radiat Oncol. 2013;8:200.View ArticlePubMed CentralPubMedGoogle Scholar
  13. Schlampp I, Rieken S, Habermehl D, Bruckner T, Forster R, Debus J, et al. Stability of spinal bone metastases in breast cancer after radiotherapy: a retrospective analysis of 157 cases. Strahlenther Onkol. 2014;190:792–7.View ArticlePubMed CentralPubMedGoogle Scholar
  14. Rief H, Petersen LC, Omlor G, Akbar M, Bruckner T, Rieken S, et al. The effect of resistance training during radiotherapy on spinal bone metastases in cancer patients - A randomized trial. Radiother Oncol. 2014;112(1):133–9.View ArticlePubMedGoogle Scholar
  15. Taneichi H, Kaneda K, Takeda N, Abumi K, Satoh S. Risk factors and probability of vertebral body collapse in metastases of the thoracic and lumbar spine. Spine (Phila Pa 1976). 1997;22:239–45.View ArticleGoogle Scholar
  16. Koswig S, Budach V. Remineralization and pain relief in bone metastases after after different radiotherapy fractions (10 times 3 Gy vs. 1 time 8 Gy). A prospective study. Strahlenther Onkol. 1999;175:500–8.View ArticlePubMedGoogle Scholar
  17. Chow E, Holden L, Rubenstein J, Christakis M, Sixel K, Vidmar M, et al. Computed tomography (CT) evaluation of breast cancer patients with osteolytic bone metastases undergoing palliative radiotherapy–a feasibility study. Radiother Oncol. 2004;70:291–4.View ArticlePubMedGoogle Scholar
  18. Xie CM, Liu XW, Li H, Zhang R, Mo YX, Li JP, et al. Computed tomographic findings of skull base bony changes after radiotherapy for nasopharyngeal carcinoma: implications for local recurrence. J Otolaryngol Head Neck Surg. 2011;40:300–10.PubMedGoogle Scholar
  19. Krempien R, Huber PE, Harms W, Treiber M, Wannenmacher M, Krempien B. Combination of early bisphosphonate administration and irradiation leads to improved remineralization and restabilization of osteolytic bone metastases in an animal tumor model. Cancer. 2003;98:1318–24.View ArticlePubMedGoogle Scholar
  20. Ural AU, Avcu F, Baran Y. Bisphosphonate treatment and radiotherapy in metastatic breast cancer. Med Oncol. 2008;25:350–5.View ArticlePubMedGoogle Scholar
  21. Kouloulias V, Matsopoulos G, Kouvaris J, Dardoufas C, Bottomley A, Varela M, et al. Radiotherapy in conjunction with intravenous infusion of 180 mg of disodium pamidronate in management of osteolytic metastases from breast cancer: clinical evaluation, biochemical markers, quality of life, and monitoring of recalcification using assessments of gray-level histogram in plain radiographs. Int J Radiat Oncol Biol Phys. 2003;57:143–57.View ArticlePubMedGoogle Scholar
  22. Ural AU, Avcu F, Candir M, Guden M, Ozcan MA. In vitro synergistic cytoreductive effects of zoledronic acid and radiation on breast cancer cells. Breast Cancer Res. 2006;8:R52.View ArticlePubMed CentralPubMedGoogle Scholar
  23. Algur E, Macklis RM, Hafeli UO. Synergistic cytotoxic effects of zoledronic acid and radiation in human prostate cancer and myeloma cell lines. Int J Radiat Oncol Biol Phys. 2005;61:535–42.View ArticlePubMedGoogle Scholar
  24. Eastell R, Adams JE, Coleman RE, Howell A, Hannon RA, Cuzick J, et al. Effect of anastrozole on bone mineral density: 5-year results from the anastrozole, tamoxifen, alone or in combination trial 18233230. J Clin Oncol. 2008;26:1051–7.View ArticlePubMedGoogle Scholar
  25. Lustberg MB, Reinbolt RE, Shapiro CL. Bone health in adult cancer survivorship. J Clin Oncol. 2012;30:3665–74.View ArticlePubMedGoogle Scholar
  26. Love RR, Mazess RB, Barden HS, Epstein S, Newcomb PA, Jordan VC, et al. Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med. 1992;326:852–6.View ArticlePubMedGoogle Scholar
  27. Shapiro CL, Manola J, Leboff M. Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol. 2001;19:3306–11.PubMedGoogle Scholar

Copyright

© Foerster et al.; licensee BioMed Central. 2015

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly credited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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