Skeletal Radiol (1991) 20:363-367

Skeletal Radiology

Upper humeral cortical thickness as an indicator of osteopenia: diagnostic significance in solitary myeloma of bone Alan Jackson, Ph.D., M.R.C.P., F.R.C.R. 1 and J. Howard Scarffe, M.D., F.R.C.P. 2

1 Department of Diagnostic Radiology, Stopford Medical School, University of Manchester 2 Cancer Research Campaign, Department of Medical Oncology, The Christie Hospital & Holt Radium Institute, Manchester, UK

Abstract. Solitary myeloma of bone is a form of plasma cell tumor, histologically indistinguishable from multiple myeloma but characterised by a single bony focus of disease. Most patients respond to local radiotherapy (median survival 10-12 years); however, many (> 30%) rapidly develop multiple myeloma (median survival 2-4 years). Currently, no criteria exist for identifying these high-risk patients at the time of diagnosis.

We have assessed the prognostic value of clinical fea- tures at presentation in 32 patients with solitary myelo- ma of bone. Only osteopenia at presentation (P< 0.000003) and immunoparesis (P<0.00002) proved to be independent, significant prognosticators of decreased survival. Exclusion of patients with osteopenia or im- munoparesis at presentation identified a group with an 80%-90% chance of surviving 10 years. Patients with either risk factor had a median survival of only 27 months.

Osteopenia was assessed using measurements of com- bined cortical thickness in the upper humerus. This site has not previously been used, and normal values are presented for a control group (n = 413).

Key words: Radiogrammetry - Osteopenia - Solitary myeloma - Solitary plasmacytoma

Solitary myeloma of bone is a localised plasma cell tu- mor histologically indistinguishable from multiple mye- loma. It is solitary at presentation, may show a curative response to local radiotherapy [1, 2], and is not associat- ed with renal failure, hypercalcemia, and anemia, which are common humoral effects of multiple myeloma [2].

A significant proportion of patients with solitary myeloma (25% 65%) will remain disease-free for long periods following radiotherapy with a reported median

Address reprint requests to: Dr. A. Jackson, Department of Diag- nostic Radiology, Stopford Medical School, University of Man- chester, Oxford Road, Manchester M13 9PT, UK

survival of 10-12 years [1, 9] compared with a median survival of only 3-5 years for patients with low cell mass multiple myeloma [13, 14]. Many patients with solitary myeloma will subsequently develop multiple myeloma; most do so within 3 years of diagnosis, and progression at this stage is associated with an unfavorable prognosis [2, 7, 9, 10, 21]. If these high-risk patients could be identified at diagnosis, the use of systemic chemotherapy might be expected to improve overall survival.

The primary aim of this study was to identify features which might predict prognosis in solitary myeloma. Dur- ing this study, generalised osteopenia based on subjective criteria was found to be strongly associated with the prognosis. Quantitative assessment of bone mineraliza- tion was performed by measuring the thickness of corti- cal bone from plain radiographs. The restricted skeletal survey used in this study did not include any site for which normal values are available; a separate study was therefore performed to provide normal values for corti- cal thickness in the upper humeral shaft.

Materials and methods

Between 1974 and 1984 32 patients referred to the Christie Hospital fulfilled the criteria for the diagnosis of solitary myeloma (Table 1). The diagnosis was confirmed histologically and bone marrow aspi- ration performed in all cases. Biochemical and hematological as- sessment (Table 2) was carried out at diagnosis and at regular inter- vals during the follow-up period. Radiological assessment at pre- sentation consisted of a modified skeletal survey including chest, lateral skull, upper humeri, dorsolumbar spine, pelvis, and upper

Table 1. Criteria for diagnosis of solitary myeloma of bone (after [21)

1. Histologically proven plasmacytoma of bone 2. No excess of plasma cells in bone marrow aspirate 3. X-ray evidence of only one or two solitary lesions at diagnosis 4. No anemia 5. No hypercalcemia 6. No impairment of renal function

�9 1991 International Skeletal Society

364 A. Jackson and J.H. Scarffe: Upper humeral cortical thickness in osteopenia

Table 2. Presenting features examined for prognostic significance

Age Sex Axial vs. nonaxial origin Myeloma protein at presentation Bence Jones proteinuria at presentation Osteopenia Immunoparesis Erythrocyte sedimentation rate Serum calcium Alkaline phosphatase White cell count Absolute neutrophil count Absolute lymphocyte count Platelet count Use of adjuvant chemotherapy Radiotherapy dose equivalent

femora. The skeletal survey was repeated annually. The develop- ment of multiple myeloma was diagnosed according to the criteria of the Chronic Leukaemia and Myeloma Task Force of the Nation- al Cancer Institute [8].

All patients were treated with local radiotherapy at diagnosis. Surgical debulking was performed at the time of biopsy in several cases, but total excision of the tumor was never achieved. An inter- im analysis in 1983 showed evidence of dissemination in 75% of patients; it was therefore decided that all patients diagnosed after this date would receive adjuvant chemotherapy.

Radiogrammetric technique. Presentation radiographs were re- viewed, and the presence of osteopenia was assessed by measure- ment of the combined cortical thickness of the upper humeral shaft. The site of measurement was chosen by analysis of 35 male controls aged 30-39 years (Fig. 1). Measurements of combined cortical thickness (CCT) were made at seven equidistant points ( ~ G , Fig. 1) in each patient. Point B was located at the level at which the medial and lateral humeral cortices first become parallel; point F was located at the upper aspect of the deltoid tuberosity where the lateral humeral cortex can be seen to widen significantly.

CTT (rnm)

A B C D E

I I I I I I I

~ M M a l e s 30--39yrs (n = 35) 11-

10-

9-

8-

7-

6-

5-

4-

3-

2-

1-

G

0 i i i i i 1 i

A B C D E F G

Fig. 1. Measurement points used in assessing the variation in com- bined cortical thickness (CTT) of the upper humeral shaft. Lower figure shows mean measurements and standard deviation (SD) at each point in a group of 35 male controls aged 30-39 years

Standard values for upper humeral CCT were subsequently ob- tained by measurement in 201 male and 212 female controls. All control values were taken from normal shoulder radiographs ob- tained for suspected trauma. All measurements in control patients were made at a single point equivalent to point D in Fig. 1.

Statistical technique. The prognostic significance of presenting fea- tures (Table 2) was examined using univariate (log rank) and multi- variate (Cox) tests. Comparison of the sites of humeral measure- ment used the coefficient of variation.

f

B

~t

Fig. 2. Measurement site used in the study to assess upper humeral CCT

A. Jackson and J.H. Scarffe: Upper humeral cortical thickness in osteopenia 365

CCT

(mm)

11.0-

10.0-

9.0-

8.0.

7.0-

6.0-

5.0-

4.0-

3.0 i

2'0 t 1.0

0

A

MALES

[ ] 95% Confidence Limits

(n = 201 )

11.0-

10.0-

9.0-

8.0, i

7.0~ I 6.0-

5 .0-

4 .0-

3 .0-

2 .0-

1.0-

CCT

(ram)

~ 1 , o- ql , 20 do go do r B 20

Age (Years)

FEMALES

[ ] 95% Confidence Limits

(n =212)

'A 'do' ' 30 0 70 80

Age (Years)

Hg. 3. Normal values for upper humeral CCT by age and sex. Circles represent values obtained at presentation in patients with solitary myeloma of bone. Filled cir- cles represent patients with solitary myelo- ma of bone for whom the upper humeral CCT values lay below normal for their age and sex

Results

Control group

Measurements of CCT in the initial control group of 35 male patients demonstrated minimal variation be- tween the humeral neck and the deltoid tuberosity (Fig. 1). CCT values at the five points in this region (B-F) demonstrated a coefficient of variation of 10.9%. Use of only the central point (D) resulted in a coefficient of variation between patients o f 8.5% (Fig. 2).

Measurements of the CCT of the upper humeral shaft in 212 female and 201 male controls are shown in Fig. 3 and Table 3. The standard values in female controls show the expected postmenopausal drop, and values in both sexes show widening of the confidence intervals with increasing age.

Solitary myeloma patients

A total of 32 patients (19 male and 13 female) fulfilled the diagnostic criteria for solitary myeloma. Patients ' ages ranged f rom 28 to 82 years (median 62 years). Tu- mor sites are shown in Table 4.

Median follow-up was 101 months (range 23-174 months), and median overall survival was t17 months (range 2-118 months ; Fig. 4). In all, 20/32 patients de- veloped multiple myeloma, and 13/32 died of their dis- ease.

Myeloma protein production

Serum monoclonal proteins were present in 11/32 pa- tients (IgG2 8; I g G K 1 ; IgA2 2). Bence Jones proteinuria was present in a further 2/32 patients. In 7/13 patients with myeloma proteins, there was evidence of immuno- paresis with depression of one or more immunoglobulin classes below normal ( IgG < 8.0 g/l, IgA < 1.2 g/l, IgM <

Table 3. Upper hulneral combined cortical thickness in control groups

AGE (years)

Upper humeral CCT (mm)

Females Males (mean_+ SD) (mean _+ SD)

20-29 8.4 _+ 0.66 8.7 • 0.50 30-39 8.7_+0.85 8.8_+0.57 4049 8.5_+0.76 8.5_+0.86 50 59 8.1+_0.87 8.3-t-_0.85 60-69 7.1 +_ 1.10 7.8 +_ 1.03 70-79 6.5 -t-0.96 7.8 _+ 1.16

Table 4. Distribution of solitary myeloma of bone

Site Number of cases

Axial tumors Skull t Cervical spine 1 Thoracic spine 16 ~ Lumbar spine 4 Sacrum 2

Nonaxial tumors Clavicle 2 Femur 3 Humerus 1 Sternum 1 Pelvis 1

a One patient presenting with a dorsal spine tumor also had a solitary lesion of the eighth rib

0.5 g/I). Immunoparesis was not present in any patient in whom myeloma proteins were not detected. The pres- ence of immunoparesis at presentation was related to early death (P<0 .04) but not to early development of multiple myeloma.

366 A. Jackson and J.H. Scarffe : Upper humeral cortical thickness in osteopenia

%

S U R V I V I N G

1 0 0

7 5 L . .

50 ....... [

1 E - , ]

25

0 0 3O

4

S u r v i v a l

T i m e to R e l a p s e

( n = 3 2 )

=, . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

I i I I i

6 0 9 0 1 2 0 1 5 0 1 8 0 TIME (months)

%

S U R V I V I N G

1 0 0 -

7 5

5 0

2 5

0 "

0

5

! - - k

1

I !

3 0 6 0

N o r m a l ( n = 20 )

- - " O s t e o p e n i a ( n =

m , p < 0.001

I I

I I I I

9 0 1 2 0 1 5 0 1 8 0 TIME (months)

7)

Fig. 4. Actuarial survival curve showing time to the development of multiple myeloma and overall survival in patients with solitary myeloma of bone

Fig. 5. Effect of osteopenia at presentation on overall survival in patients with solitary myeloma of bone

% S U R V I V I N G

1 0 0

7 5

5 0

2 5

_ _ N o r m a l ( n = 19 )

' [ . . . . . . . . . �9 . . . . . . . . . . . O n e R isk F a c t o r ( n = 13 )

. . . . . . . . . . . . . . . . . . . . . . i p < 0.0001

I I I I | I

0 3 0 6 0 9 0 1 2 0 1 5 0 1 8 0 TIME (months)

6 Fig. 6. Effect of risk factors (osteopenia and/or immunoparesis) on overall survival in patients with solitary myeloma of bone

Significance of risk factors

Multivariate analysis of the prognostic significance of all risk factors (Table 2) revealed osteopenia (P< 0.000003) and immunoparesis (P< 0.00002) as the only independent prognosticators of overall survival,

Some 13/32 patients had one significant risk factor (osteopenia or immunoparesis) at presentation. Posses- sion of one risk factor was associated with early develop- ment of multiple myeloma (P<0.03) and decreased overall survival (P<0.0007; Fig. 6). A finding of osteo- penia at presentation was the most significant overall prognosticator with a 5-year survival rate of 25% in osteopenic patients compared with 95% in non-osteo- penic patients�9

Discussion

Osteopenia

A subjective diagnosis of osteopenia was made in 6 of the 32 patients. Radiogrammetric assessment was per- formed in 27 patients since original humeral radiographs were unavailable (2 patients) or technically unacceptable due to tumor involvement (1 patient) or radiographic positioning (2 patients). This group of 27 patients in- cluded 19/20 patients who subsequently developed mul- tiple myeloma and all 13 patients who died of disease.

Radiogrammetric assessment demonstrated signifi- cant osteopenia in 7 cases (4 male and 3 female), includ- ing the 6 in whom osteopenia was originally diagnosed on subjective criteria (Fig. 3).

Univariate statistical analysis revealed that osteopen- ia was associated with the early development of multiple myeloma (P < 0.0002) and reduced overall survival (P< 0.01; Fig. 5).

Many workers have developed radiogrammetric meth- ods to estimate bone mineral content, based on the use of cortical measurements or derived indices at standard sites [5, 6, 17, 20]. Radiogrammetry is an insensitive method for assessing the loss of bone mineral when com- pared with modern techniques but is unique in enabling an assessment of bone mass solely on the basis of exist- ing plain radiographs.

The proximal humeral shaft was used in the current study since no previously described site was included in the limited skeletal survey used in our patients. The measurement of CCT was chosen since it has been shown to have significant advantages over other mea- surements and derived indices [4, 6, 11, 19]. Initial as- sessment demonstrated that a point for measurement lying midway between the upper border of the deltoid tuberosity and the lower border of the surgical neck of the bone can be easily and reliably identified. Assess- ment at multiple sites demonstrated only minimal varia-

A. Jackson and J.H. Scarffe: Upper humeral cortical thickness in osteopenia 367

tion in cortical thickness in the upper humeral shaft so that reasonable precision could be expected, even if the point of measurement varied slightly f rom that de- scribed. Variation in cortical thickness in the normal population, together with measurement error and ob- server error, means that the mineral bone mass loss which can be detected by such methods lies between 8% and 20% in longitudinal studied [5], whilst a bone mass must be as low as 50% of the mean value for a normal populat ion to fall below the 95% confidence limits [11]. Although the upper humeral shaft appears to compare favorably with radiogrammetr ic sites used previously, it can be seen to exhibit similar limitations, particularly poor sensitivity and an inability to assess any changes in trabecular bone [5, 11].

Bone destruction is a common feature in patients with plasma cell tumors, particularly in association with mul- tiple myeloma. Well-demarcated, purely lytic lesions are typical and are seen at the site of tumor in patients with solitary myeloma of bone and throughout the skele- ton in approximately 75 % of patients with multiple mye- loma. Less typically, 10%-15% of patients with multiple myeloma will present with generalised osteopenia with- out evidence of localised lyric lesions [18].

The mechanism of bone destruction in plasma cell tumors has been widely studied in patients and animal models. Both lytic lesions and generalised osteopenia are believed to be effects of a humoral factor, secreted by abnormal plasma cells, capable of activating osteo- clasts with resulting bone resorption [12, 16, 18]. Pro- duction of this humoral mediator is related to the mass of abnormal plasma cells, and it acts primarily at sites of mar row infiltration. Widespread lytic lesions or gener- alised osteopenia therefore reflect both tumor extension and tumor mass [3, 18].

The occurrence and prognostic significance of gener- alised osteopenia have not been documented previously in patients with solitary myeloma of bone. In view of the postulated mechanism of bone loss, it seems prob- able that these patients have widespread dissemination of abnormal p lasma cells at diagnosis, despite normal bone mar row studies. Tumor dissemination would ex- plain the poor response to local radiotherapy, and the use of systemic therapeutic regimes appears justified in patients showing generalised osteopenia at presentation.

The finding of immunoparesis is also a well-recog- nised humoral effect of multiple myeloma [4, 15]. Al- though previously described in solitary myeloma [2, 10], its prognostic significance has not been appreciated.

On the basis of the current study, we conclude that the finding of osteopenia or immunoparesis at diagnosis should be taken to indicate disseminated disease and that these patients should receive parenteral chemother- apy appropr ia te to multiple myeloma. The use of these

modified criteria in the present study would have re- sulted in the early use of systemic chemotherapy in 95% of patients who died within 5 years.

The use of more accurate techniques to assess osteo- penia and to assess medullary bone loss may improve recognition of patients at risk of dissemination, and fur- ther work is currently being undertaken to evaluate this.

References

1. Alexanian R (1980) Localised and indolent myeloma. Blood 56:521

2. Bataille R, Sany J (1981) Solitary myeloma; clinical and prog- nostic features of a review of 114 cases. Cancer 48 : 845

3. Bertolini DR, Nedwin G, Bringman T (1986) Stimulation of bone resorption and stimulation of bone formation in vitro by human tumour necrosis factor. Nature 319: 516

4. Bloom RA (1980) A comparative estimation of the combined cortical thickness of various bone sites. Skeletal Radiol 5:167

5. Bloom RA, Laws JW (1970) Humeral cortical thickness as an indicator of osteoporosis in women. Br J Radiol 43 : 522

6. Bloom RA, Pogrund H, Libson E (1983) Radiogrammetry of the metacarpal" a critical reappraisal. Skeletal Radiol 10: 5

7. Christopherson WM, Miller AJ (1950) A re-evaluation of soli- tary plasma-cell myeloma of bone. Cancer 3 : 240

8. Chronic Leukaemia and Myeloma Task Force. National Cancer Institute (1973) Proposal guidelines for protocol studies II. Plasma cell myeloma. Cancer Chemother Rep 4(3): 145

9. Conklin R, Alexanian R (1975) Clinical classification of plasma cell myeloma. Arch Intern Med 135:139

10. Corwin J, Lindberg RD (1979) Solitary plasmacytoma of bone vs. extramedullary plasmacytoma and their relationship to mul- tiple myeloma. Cancer 43:1007

11. Dequeker J (1976) Quantitative radiology: radiogrammetry of cortical bone. Br J Radiol 49:912

12. Dewhurst FE, Stashenko PP, Mole JE (1985) Purification of partial sequences of human osteoclast activting factor: identity with interleukin 1 beta. J Immunol 135:2562

13. Durie BGM (1986) Staging and kinetics of multiple myeloma. Semin Oncol 13(3):300

14. Durie BJM, Salmon SE (1975) A clinical staging system for multiple myeloma. Cancer 36: 842

15. Jacobson DR, Zolla-Pazner S (1986) Immunosuppression and infection in multiple myeloma. Semin Oncol 13(3):282

16. Josse RG, Murray TM, Mundy GR (I98t) Observations on the mechanisms of bone resorption induced by multiple myelo- ma marrow culture fluids and partially purified osteoclast acti- vating factor. J Clin Invest 67:1472

17. Meema HE (1963) Cortical bone atrophy and osteoporosis as a manifestation of ageing. Am J Roentgen 89:1287

18. Mindy GR, Bertolini DR (1986) Bone destruction and hyper- calcaemia in plasma cell myeloma. Semin Oncol 13(3):291

19. Morgan DB (1973) The metacarpal bone: a comparison of the various indices for the assessment of the amount of bone and for the detection of bone loss. Clin Radiol 24: 77

20. Virtama P, Telkka A (1962) Cortical thickness as an estimate of mineral content of the human humerus and femur. Br J Radiol 35: 632

21. Wiltshaw E (1976) The natural history of extramedullary plas- macytoma and its relationship to solitary myeloma of bone and myelomatosis. Medicine 55: 217