The development of metabolic bone disease that followed after gastrectomy has been reported many years ago, but the incidence of bone metabolism changes after gastrectomy has tended to have quite different results according to authors^1–8). Furthermore, the mechanisms of these metabolic changes were not apparent. Either a vitamin D or a calcium deficiency or, perhaps, even both together, contributes to reduced bone mass⁹⁾.

In the past, although numerous measurements have been used for quantitative methods of bone mass and biochemical markers of bone metabolism in patients with gastrectomy, great divergences were reported in the incidences and results of postgastrectomy bone disease^2–8,13,14).

Therefore, we tried to determine what appropriate screening tests during long-term follow-up periods might be valuable for gastrectomized (subtotal gastrectomy) men, comparing with age and a sex-matched control group, and also to define the usefulness of new biochemical markers for bone metabolism by comparing with the old traditional markers.

Metabolic bone diseases have long been associated with gastric surgery. The incidence of metabolic bone disease after gastrectomy has been estimated about 1-42% even though there was great discrepancy between authors^1–8). A reduced bone mass has been reported as occurring 5 or more years after gastrectomy⁷⁾. In our study, the average interval since operation was 113± 23.7 months. Osteomalacia is most commonly reported, but osteoporosis or combination of osteomalacia and osteoporosis, and less well-characterized forms of osteopenia, have been described^1,7,8).

In fact, the pathogenesis of osteoporosis has not been explained as satisfactorily as that of osteomalacia⁷⁾. Osteoporosis is a generalized bone disorder, characterized by a decrease in the quantity of bone but no change in quality. It occurs most frequently in postmenopausal women and the aged. Osteomalacia is a failure of the organic matrix to mineralize normally. Therefore, osteoporosis was thought to be present if there were radiological abnormalities only, particularly if it was confined to the axial skeleton. If a biochemical disturbance existed, osteomalacia was diagnosed. In certain cases, these diagnoses were supported by bone biopsy.

Although the etiology of postgastrectomy bone disease remains unclear, either a vitamin D or a calcium deficiency or, perhaps, even both together, contribute to a reduced bone mass⁹⁾. Proposed causes of a vitamin D or a calcium deficiency have included malabsorption of vitamin D or calcium⁷⁾, a decreased intake of vitamin D or calcium¹¹⁾, inadequate contact between nutrients and their absorptive sites (either because of altered anatomy or rapid transit)²³⁾ and reduced exposure to sunlight²³⁾. In our study, all participants had a normal nutritional status, lived at home, had work and led normal life styles, including average physical activity and sexual activity. On the basis of the above facts, it is difficult to assume that either reduced exposure to sunlight or a decreased intake of vitamin D or calcium contributed to a vitamin D or a calcium deficiency. Also no patient has complained of steatorrhea or indigestion or other gastrointestinal symptoms to suggest malabsorption syndrome clinically. Therefore, the loss of gastric acid secretion necessary for solubilization of dietary calcium or the by-pass of the critical absorption surface of the duodenum could be responsible¹²⁾.

An apparent relationship between bone mass and body weight indicates that a poor nutritional state contributes to the condition^24,25). In our study, weight and BMI in the patient group are significantly lower than those of the control (Table 1). According to Korean statistics²⁶⁾, BMI in the normal weight group ranges from 20 to 25 and lean group is definded when BMI is less than 20. We compared 4 patients whose BMI are less than 20 with patients whose BMI are above 20. We could not find any difference in blood chemistries and biochemical parameters of bone metabolism. Furthermore, bone densitometry using QCT did not reveal any difference between the two groups. Therefore, lean body weight in 4 out of 10 patients did not influence low bone density in the patient group.

Biochemical parameters of bone metabolism were divided into bone formation (osteoblastic activity) and bone resorption (osteoclastic activity) markers. The serum alkaline phosphatase has been a sensitive marker for bone formation in the past. Serum calcium and phosphorus values seldom lead to detection of postoperative bone disease or indicate specific types of osseous lesion²⁷⁾. However, serum alkaline phosphatase levels, reasonably good as screening tests for osteomalacic bone disease, reported as being elevated in 10 to 30% of affected persons and are a more reliable index to postgastrectomy bone disease²⁷⁾. In our study, whereas serum calcium was slightly lower in the patient group, phosphorus, alkaline phosphatase, intact PTH and 25-hydroxy vitamin D were slightly higher than the control. However, there was no statistical significance between the two groups in terms of mean serum calcium, phosphorus, alkaline phosphatase, intact PTH and 25-hydroxy vitamin D.

It is difficult to state whether vitamin D deficiency in our study contributed to osteopenia because 25-hydroxy vitamin D is higher in the patient group. Slightly high PTH in the patient group could be a compensation for low calcium. Therefore, we can speculate that reduced bone mass in the patient group could be attributed to a combination of osteoporosis, induced by slightly increased PTH overactivity in compensation for relative calcium deficiency, and osteomalacia on the basis of slightly elevated alkaline phosphatase.

In recent times, new markers for bone metabolism introduced. The serum levels of osteocalcin bone-specific protein have become a most sensitive and specific test for osteoblastic activity⁵⁾. Type I collagen accounts for about 90% of the organic matrix of mineralized bone. The synthetic rate of type I procollagen can be assessed by measuring the serum concentration of its carboxy terminal propeptide, PICP. The serum PICP levels reflect the synthesis of type I collagen and osteoblastic activities^5,15). In our study, serum osteocalcin levels were slightly increased in the patients, but there was no statistical difference (Figure 3). Serum PICP levels, in general, tended to be increased in gastrectomized patients^5,15). Our patients also had slightly increased PICP levels than the controls but there were not statistically significant (Figure 4). Recently developed serum ICTP, which is a carboxy terminal telopeptide of type I collagen, cross-linked via pyridinoline cross-links and liberated during the degradation of type I collagen and serum ICTP level, which reflects the activity of bone resorption may be of use in the diagnosis and follow-up of the metabolic status of the bone, especially in states associated with increased lysis of the bone (such as multiple myeloma, osteolytic metastasis, rheumatoid arthritis, immobilization and osteoporosis)¹⁷⁾.

The 24-hour urinary hydroxyproline excretion in the fasting state was widely used as a marker of bone resorption till now^5,7). The hydroxypyridinium derivatives pyridinoline (PYD) and deoxypyridinoline (DPD) are trifunctional crosslinks found exclusively in mature fibrillar collagens of skeletal tissues. Urinary DPD is considered to be derived from only skeletal collagens. In contrast to hydroxyproline as a conventional bone resorption marker, the pyridinium crosslinks are released during the breakdowm of mature collagen and, therefore, are excreted without interference from newly synthesized or intermediate products. Furthermore, urinary concentration appears not to be influenced by the effects of diet or physical exercise. Therefore, pyridinium crosslinks have also been used as a marker of bone resorption^18–20). In our study, urinary DPD excretion and serum ICTP were measured. Although the ICTP level was slightly higher in the patient group, there was no statistical significance (Figure 4). However, urinary DPD excretions of gastrectomized patients were significantly more increased than those of controls (p<0.025)(Figure 1).

Roentgenologic differentiation of osteomalacia from osteoporosis in a patient without pseudofractures may be impossible. It is an accepted concept that at least 30–50% of the bone must be demineralized before detection is possible²⁸⁾. No patient in our study showed osteopenia by plain lumbar X-ray AP and lateral view. Therefore, detection of osteopenia needs bone densitometry. The fact that the degree of osteopenia tends to increase with the length of time after surgery points to the need for long-term surveillance¹⁴⁾.

Noninvasive methods measuring bone mass are radiologic photodensitometry, single or dual photon absorptiometry, QCT and dual energy X-ray absorptiometry (DEXA). Invasive method is a bone biopsy in the iliac crest^21,22). There are two kinds of QCT, i.e. single energy QCT and dual energy QCT. Dual energy QCT may measure most accurately bone mineralization, because vertebral trabecular bone measurements are summed with adjacent calcium deposits in the cortical bone, osteophytes, compression fracture and other factors. The X-ray source used in DEXA has several advantages over the isotope source used in DPA, which has led to discontinuation of DPA in favor of DEXA in recent years. DEXA has better image resolution and a faster scanning speed²⁹⁾. DEXA and dual energy QCT were not available in our institution during this study. In our study, we used single energy (80kVp) QCT with the addition of a mineral calibration phantom (K₂HPO₄). Using this technique, the bone mineral density of gastrectomy patients was significantly lower than that of controls (p<0.01.(Figure 1).

In conclusion, markers for bone metabolism and bone are necessary in order to bone diseases after gastrectomy, because routine biochemical chemistry and routine lumbar spine X-ray failed to detect these diseases. Therefore, we suggest that urinary DPD and bone densitometry like QCT are appropriate parameters for screening tests for the detection of bone metabolism abnormalities in the gastrectomized patient during a long-term follow-up period especially after 5 years.

Urinary DPD is, specially, a simple and rapid test which can replace the cumbersome 24-hour urinary hydroxyproline. Also, prophylactic administration of supplemental calcium and/or vitamin D, if indicated with monitoring of serum calcium, 25-hydroxy vitamin D and 24-hour urinary calcium might be reasonable after gastric surgery.