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(Chest. 2000;118:434-439.)
© 2000 American College of Chest Physicians

Bone Histomorphometry in Adult Patients With Cystic Fibrosis*

Charles S. Haworth; A. Kevin Webb; James J. Egan; Peter L. Selby; Philip S. Hasleton; Paul W. Bishop and Tony J. Freemont

* From the Manchester Adult Cystic Fibrosis Unit (Drs. Haworth and Egan, Mr. Webb), and the Department of Pathology (Dr. Bishop and Mr. Hasleton), South Manchester University Hospitals NHS Trust, Wythenshawe Hospital, Manchester; the Department of Medicine (Dr. Selby), University of Manchester, Manchester Royal Infirmary, Manchester; and Osteoarticular Pathology (Mr. Freemont), Musculoskeletal Research Group, University of Manchester, Manchester, UK.

Correspondence to: A. Kevin Webb, FRCP, Manchester Adult Cystic Fibrosis Unit, South Manchester University Hospitals NHS Trust, Wythenshawe Hospital, Southmoor Road, Manchester, M23 9LT, UK


   Abstract
TOP
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Study objective: Low bone mineral density is a common complication of cystic fibrosis (CF), and recent studies have implicated vitamin D insufficiency as a significant etiologic factor. The aim of this study was to establish whether there was bone biopsy evidence of vitamin D deficiency osteomalacia in patients with CF and to document the general histomorphometric characteristics of CF bone.

Patients and methods: A retrospective descriptive and histomorphometric study of postmortem L2/L3 vertebral bone biopsy specimens was undertaken on tissue from 11 posttransplant CF patients and 4 nontransplanted CF patients. Control data were derived from postmortem bone specimens from 15 young adults.

Results: Bone from all CF patients was characterized by severe osteopenia in both trabecular and cortical bone. At the cellular level, there was decreased osteoblastic and increased osteoclastic activity. The reduction in osteoblastic activity was due to both a decrease in osteoblast number and a decrease in the biosynthetic potential of osteoblasts. The osteoclastic changes were due to an increase in the number of osteoclasts. The increase in osteoclasis and the uncoupling of osteoblastic and osteoclastic activity resulted in an increase in resorptive surfaces. Although there were few significant differences between the transplanted and nontransplanted CF groups, both cortical and trabecular bone mass tended to be lower after transplantation. None of the CF undecalcified biopsy specimens showed osteoid parameters characteristic of vitamin D deficiency osteomalacia.

Conclusions: CF patients have an unusual and complex pattern of cellular changes within bone that are not typical of vitamin D deficiency osteomalacia.

Key Words: bone histology • bone histomorphometry • cystic fibrosis • osteomalacia • osteoporosis • vitamin D


   Introduction
TOP
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
The median survival for cystic fibrosis (CF) patients in the United States is now 32.2 years.1 With this increased survival, further complications of the disease have emerged, an example of which is low bone mineral density (BMD). Both children and adults are affected,2 3 4 5 6 7 8 and longitudinal studies suggest that the deficit in BMD results from a reduced rate of bone accretion in childhood and an accelerated rate of bone loss in adult life.9 10 In fact, both before and after lung transplantation, CF patients have lower BMD than any other patient group with chronic lung disease.11

Low BMD is clinically important in CF, as it has resulted in an increased rate of fracture compared to the general population.3 Vertebral and rib fractures are particularly detrimental, as sputum clearance can be compromised, resulting in pulmonary exacerbation. Fragility fractures may also effect quality of life, and some centers now consider symptomatic osteopenia to be a relative contraindication to lung transplantation.

Although low BMD in CF patients is likely to be multifactorial in origin,12 one study implicated vitamin D deficiency as a major etiologic factor.4 These findings are supported by the results of our own study in which 38% of adult CF patients (53 of 139) were found to be vitamin D-deficient despite being prescribed daily vitamin D supplements (900 IU), and parathyroid hormone levels were significantly related to BMD across several skeletal sites.2 In order to develop appropriate therapeutic strategies, it is therefore important to establish whether there is bone biopsy evidence of vitamin D deficiency osteomalacia in patients with CF, and to document the general histomorphometric characteristics of CF bone.


   Materials and Methods
TOP
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Population
Pathology records were examined to identify all CF patients who had undergone postmortem examinations at our institution. Using this methodology, L2/L3 vertebral bone specimens from 15 CF patients were identified: 11 from posttransplant CF patients and 4 from nontransplanted CF patients.

Control Population
Prospectively, L2/L3 vertebral bone specimens were taken from 15 young adult (nontransplanted, non-CF) control subjects undergoing postmortem examination at the Manchester Royal Infirmary. This was necessary, as histomorphometric parameters vary according to skeletal site, and most bone histomorphometric control data are derived from iliac crest biopsy specimens.13

Study Design
This was a retrospective study. Eight of the posttransplant CF biopsy specimens and one of the nontransplant CF biopsy specimens had been decalcified in formic acid and embedded in paraffin wax before being archived. These specimens were stained with hematoxylin and eosin.

Biopsy specimens from three patients in each of the CF groups had been processed into a glycolmethacrylate resin and sectioned undecalcified before being archived. These were stained with von Kossa’s stain for phosphate and toluidine blue.

Finally, because some biopsy specimens were only available decalcified and others undecalcified, and it is recognized that decalcification and processing might cause changes in relative histomorphometric parameters, the bone specimens from each of the 15 control subjects were divided, one portion being decalcified and processed into paraffin wax and the other processed through resin and examined undecalcified. Control data were therefore available for both the decalcified paraffin-embedded and the undecalcified resin-embedded biopsy specimens.

Histomorphometry was performed blinded on all bone biopsy specimens using a semiautomated image analysis system (Quantimet 600; Leica Cambridge Ltd; Cambridge, UK). The parameters assessed were based on the internationally accepted standard for the presentation of histomorphometric data and are described in Table 1 .14 15 16 The full spectrum of histomorphometric data could not be obtained from these specimens for several reasons. The absence of double tetracycline labeling (which allows the rate of mineralization to be assessed) precludes assessment of dynamic parameters. In addition, not all biopsy specimens were sectioned undecalcified, meaning that certain osteoid parameters could not be measured in these cases. This is because it is not possible to distinguish nonmineralized osteoid and mineralized bone after decalcification. Thus, our results incorporate some measurements that can only be made in resin-embedded tissue and others that can be measured in both. Finally, there are theoretical problems in comparing absolute values derived from decalcified and undecalcified tissue, due to the differential shrinkage caused by the two processing methods.


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  		Table 1.. Bone Histomorphometry Parameters

 
We have therefore adopted two separate approaches to circumvent this problem. Firstly, we expressed our data as the number of SDs (z scores) from the mean assessed against equivalently processed control tissue. Secondly, we used statistical adjustment to allow for differences in the processing technique and to generate gender- and method-corrected mean values for the parameters of interest.

Statistical Analysis
Statistical analysis was undertaken using SPSS v9.0 software (SPSS; Chicago, IL). Anthropometric data are presented as mean (SD). The bone histomorphometry values are expressed as z scores corrected against the mean parameter values for the 15 control patients. In addition, the histomorphometric parameters were entered into the univariate General Linear Model function within SPSS. The diagnosis, gender, and method of preparation were entered as fixed factors. Adding age as a covariate did not improve the model, and so the age correction was not maintained in the final analysis. From this, the marginal means for the parameters of interest were taken to represent an estimate of that parameter corrected for gender and method of preparation. Bonferroni’s post hoc test was used to assess the significance of the differences between each patient group.


   Results
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Patient Characteristics
In the CF posttransplant group, there were 11 patients (8 males) with a mean age at death of 23.9 (6.0) years. Eight patients underwent double lung transplantation, two patients underwent heart-lung transplantation, and one patient had initially undergone liver transplantation and 2 years later underwent double lung transplantation. The mean time from transplantation to death was 29.2 (28.0) months. One patient in the transplant group took alfacalcidol and calcium supplements, and two patients took cyclical etidronate. All patients had been prescribed regular pancreatic enzyme supplements and 900 IU vitamin D per day. The standard immunosuppressive regimen in the transplant recipients was cyclosporin, 4 to 8 mg/kg/d, maintenance levels from 150 to 250 µg/L; prednisolone, 1 mg/kg/d in the immediate postoperative period and reduced thereafter; and azathioprine, 2 mg/kg/d. Episodes of acute rejection were treated with methylprednisolone, 500 mg/d for 3 days, in addition to an appropriate augmentation of their standard immunosuppressive therapy.

In the nontransplanted CF group, there were four patients (all male) with a mean age at death of 29.3 (6.1) years. All patients had received oral corticosteroid therapy in the year prior to death, and one patient had been taking cyclical etidronate for approximately 2 years. Three of the four patients had been prescribed regular pancreatic enzyme supplements and vitamin D, 900 IU/d.

In the control group there were 15 age-matched (within 1 year) and gender-matched control subjects who died of suicide (3 subjects), trauma (5 subjects), and cerebral hemorrhage (7 subjects).

Bone Histomorphometry
The histomorphometry results are summarized in Tables 2 , 3 . The control data derived from the lumbar spine were all within ± 2 SD of previously published normal age- and sex-matched iliac crest data sets.13 Bone from all patients with CF was characterized by severe cortical and trabecular osteopenia. The trabecular bone loss was manifest by discontinuity and thinning of the trabeculae.


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  		Table 2.. Bone Histomorphometry z Scores*

 
The histomorphometric parameters of the decalcified and undecalcified biopsies showed a high level of agreement. Furthermore, there was agreement between the two different ways of expressing the results (Tables 2 , 3) . At the cellular level, the histomorphometric data were indicative of decreased osteoblastic and increased osteoclastic activity. The reduction in osteoblastic activity was due to both a decrease in osteoblast number and a decrease in the biosynthetic potential of osteoblasts, as evidenced by osteoid production. The osteoclastic changes were due to an increase in the number of osteoclasts and an increase in resorptive activity. The increase in osteoclasis and the uncoupling of osteoblastic and osteoclastic activity resulted in an increase in resorptive surfaces.


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  		Table 3.. Bone Histomorphometric Parameters Corrected for Gender and Method of Preparation*

 
Although there were few significant differences between the transplanted and nontransplanted CF groups, both cortical and trabecular bone mass tended to be lower after transplantation. There was little difference in the markers of osteoblast or osteoclast activity between these two groups, except for reduced cortical bone volume. This may therefore represent bone loss that occurred at the time of transplantation and then the later recovery of bone cell activity to pretransplant levels.


   Discussion
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
CF patients, both before and after lung transplantation, have an unusual and complex metabolic bone disease that is not typical of vitamin D deficiency osteomalacia. The predominant abnormality was marked trabecular and cortical osteopenia.

In the nontransplanted CF group, there was uncoupling of osteoblastic and osteoclastic activity. Osteoblasts were decreased in number, and the osteoid seams they synthesized were somewhat decreased in thickness, suggesting that osteoblast function was also compromised. By comparison, osteoclasts were increased in number, although parameters of function were within normal limits. These results are consistent with the findings of Baroncelli et al,18 who, using biochemical markers of bone turnover, demonstrated an imbalance of bone resorption over bone formation in young adults with CF. Although there were few statistically significant differences between the nontransplant and posttransplant CF groups, nearly all measured parameters were worse after transplantation. The lack of statistical significance between the CF groups might reflect a type 2 statistical error, since only four nontransplant CF bone specimens were examined.

The trabeculae and cortex of the nontransplant and posttransplant CF bone specimens were perforated and thin (Fig 1 ). This contrasts to the changes seen in postmenopausal (type 1) osteoporosis, where there is perforation of the trabeculae, which are of relatively normal thickness.19 It also differs from senile (type 2) osteoporosis, where the trabeculae are thin and not extensively perforated.19



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  		Figure 1.. Bone from posttransplant CF patients (A, C, and D) and nontransplanted CF patients (B, E, and F). B = bone; M = marrow. A, B: undecalcified sections of cortical bone and periosteum (P) (von Kossa’s stain for phosphate, original x 100; toluidine blue, original x 250, respectively). The amount of bone in the cortex (black), usually about 95% of the sectional area, here is down to about 40%. The periphery of the Haversian canal (H) is very irregular as a result of osteoclastic bone resorption. Cortical osteopenia is so severe that hemopoietic marrow is in contact with periosteal fibrous tissue (arrow). Elsewhere in the cortex, very active osteoclasis (Oc) is seen at the periphery of an Haversian system. C, D: decalcified sections show trabecular osteopenia with loss of connectivity of trabeculae (C, x 100) and active osteoclasis (D, x 400); nowhere are osteoblasts (lines of touching surface cells) seen on bone surfaces. E, F: undecalcified sections show earlier stages in the development of trabecular osteopenia. Osteoclasts are prominent on bone surfaces, but there is no osteoid (smooth pale bands on bone surfaces) or osteoblastic activity (x 200 and x 250, respectively).

 
Although bone density is generally reduced in CF adults and there is evidence relating this to vitamin D insufficiency,2 4 we are only aware of one report of bone biopsy confirmed osteomalacia and that is from 1985.20 None of the CF patients’ undecalcified biopsy specimens in the present study demonstrated the osteoid parameters (excess osteoid surfaces and thick osteoid seams) characteristic of vitamin D deficiency osteomalacia. This observation, in conjunction with the fact that clinically apparent osteomalacia is exceptionally rare in adults with CF, suggests that CF-related bone disease has a more complex etiology than just vitamin D deficiency alone. Additional factors such as CF disease severity (possibly mediated through cytokine-driven bone resorption), general malnutrition, reduced levels of weight-bearing activity, and biliary disease are also thought to effect BMD in this patient population.2

There are several methodologic limitations to this study. Tetracycline-labeled bone biopsy specimens are required to accurately assess whether there is a mineralization defect affecting CF bone. In addition, the CF biopsy specimens were from a heterogeneous group of individuals who had died of a chronic illness complicated by stress, immobilization, steroid therapy, and infection. Cyclosporin therapy may also have contributed to the histomorphometric appearances observed in the transplant patients.21 In contrast, the control population died acutely without interference from other comorbid factors. In such circumstances, it is difficult to state which histomorphometric changes were specifically CF related and which resulted from complicating factors. However, it is the CF patients with the worst disease severity that have the lowest bone density and the greatest risk of sustaining a clinically relevant fracture. We have therefore studied a patient population in whom, prior to death, fracture prevention was most indicated. Although antemortem biopsies would have been preferable, there are practical difficulties in performing invasive procedures in patients with severe lung disease, particularly if they are immunosuppressed after transplantation. Thus, despite the aforementioned limitations, this study provides novel data and adds significantly to our current knowledge of CF-related bone disease.

In summary, the bone histomorphometry demonstrates profound disturbances in bone cell function in CF patients, both before and after transplantation. Despite the limited framework of potential bone cell and matrix changes possible within bone, the pattern of cell defect appears to be different to that seen in other causes of osteoporosis. This may reflect that CF patients have abnormalities involving several organ systems including the gut, liver, pancreas, and lungs. The histomorphometric changes are not characteristic of simple vitamin D deficiency osteomalacia, though vitamin D insufficiency may still contribute to the pathogenesis of low bone density in CF. It is also possible that due to the limited number of biopsy specimens analyzed in this study, a small proportion of CF patients may have osteomalacia. Treatment strategies must therefore be individualized. Overall, the histomorphometric findings of increased osteoclasis (in the absence of osteomalacia) indicates that the use of bisphosphonates may be appropriate in adult CF patients with low BMD. Finally, labeled bone biopsy specimens are required in a larger number of CF patients to more precisely define this complex metabolic bone disease.22


   Footnotes
 
Abbreviations: BMD = bone mineral density; CF = cystic fibrosis

Received for publication July 19, 1999. Accepted for publication April 13, 2000.


   References
TOP
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

  1. Patient registry 1998 annual data report. Bethesda, MD: Cystic Fibrosis Foundation, 1999
  2. Haworth, CS, Selby, PL, Webb, AK, et al (1999) Low bone mineral density in adults with cystic fibrosis. Thorax 54,961-967[Abstract/Free Full Text]
  3. Aris, RM, Renner, JB, Winders, AD, et al (1998) Increased rate of fractures and severe kyphosis: sequelae of living into adulthood with cystic fibrosis. Ann Intern Med 128,186-193[Abstract/Free Full Text]
  4. Donovan, DS, Papadopoulos, A, Staron, RB, et al (1998) Bone mass and vitamin D deficiency in adults with advanced cystic fibrosis lung disease. Am J Respir Crit Care Med 158,1892-1899
  5. Bhudhikanok, GS, Lim, J, Marcus, R, et al (1996) Correlates of osteopenia in patients with cystic fibrosis. Pediatrics 97,103-111[Abstract/Free Full Text]
  6. Gray, AB, Ames, RW, Matthews, RB, et al (1993) Bone mineral density and body composition in adult patients with cystic fibrosis. Thorax 48,589-593[Abstract]
  7. Gibbens, DT, Gilsanz, V, Boechat, MI, et al (1988) Osteoporosis in cystic fibrosis. J Pediatr 113,295-300[CrossRef][ISI][Medline]
  8. Shaw, N, Bedford, C, Heaf, D, et al (1995) Osteopenia in adults with cystic fibrosis [letter]. Am J Med 99,690-691[ISI][Medline]
  9. Bhudhikanok, GS, Wang, M-C, Marcus, R, et al (1998) Bone acquisition and loss in children and adults with cystic fibrosis: a longitudinal study. J Pediatr 133,18-27[CrossRef][ISI][Medline]
  10. Haworth, CS, Selby, PL, Mawer, EB, et al (1999) Reduced bone accretion and accelerated bone loss in cystic fibrosis adults. Pediatr Pulmonol S19,295[CrossRef]
  11. Aris, RM, Neuringer, IP, Weiner, MA, et al (1996) Severe osteoporosis before and after lung transplantation. Chest 109,1176-1183[Abstract/Free Full Text]
  12. Haworth, CS, Selby, PL, Webb, AK, et al (1998) Osteoporosis in adults with cystic fibrosis. J R Soc Med 91(Suppl 34),14-18
  13. Rehman, MTA, Hoyland, JA, Denton, J, et al (1994) Age related histomorphometric changes in bone in normal British men and women. J Clin Pathol 47,529-534[Abstract/Free Full Text]
  14. Parfitt, AM (1988) Bone histomorphometry: proposed system for standardization of nomenclature, symbols, and units. Calcif Tissue Int 42,284-286[ISI][Medline]
  15. Parfitt, AM (1988) Bone histomorphometry: standardization of nomenclature, symbols and units; summary of proposed system. Bone Miner 4,1-5[CrossRef][ISI][Medline]
  16. Parfitt, AM, Drezner, MK, Glorieux, FH, et al (1987) Bone histomorphometry: standardization of nomenclature, symbols, and units; report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 2,595-610[ISI][Medline]
  17. Hutchison, AJ, Whitehouse, RW, Boulton, HF, et al (1993) Correlation of bone histology with parathyroid hormone, vitamin D3, and radiology in end-stage renal disease. Kidney Int 44,1071-1077[ISI][Medline]
  18. Baroncelli, GI, De Luca, F, Magazzu, G, et al (1997) Bone demineralization in cystic fibrosis: evidence of imbalance between bone formation and degradation. Pediatr Res 41,397-403[ISI][Medline]
  19. Rehman, M, Hoyland, J, Denton, J, et al (1995) Histomorphometric classification of postmenopausal osteoporosis: implications for the management of osteoporosis. J Clin Pathol 48,229-235[Abstract/Free Full Text]
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  22. Haworth, CS, Selby, PL, Webb, AK, et al (1998) Severe bone pain after intravenous pamidronate in adult patients with cystic fibrosis. Lancet 352,1753-1754[CrossRef][ISI][Medline]



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