_07c

Chinese Herbs and Bone Disease

Junichi Hoshino, Yoshifumi Ubara, Tetsuo Tagami, Naoki Sawa, Masafumi Yokota, Hideyuki Katori, Fumi Takemoto, Yoshihisa Mikami*, Shigeo Hara** and Shigeko Hara

We treated a patient with an unusual bone disease at least partly associated with Chinese herbs. Seven years after 65-year-old man had begun to consume Chinese herbs, multifocal osteoarthralgias were noted, and the patient was hospitalized for renal dysfunction (serum creatinine, 2.8 mg/dl; urea nitrogen, 19 mg/dl). Fanconi syndrome also was apparent. A renal biopsy specimen showed tubulo-interstitial fibrosis. Chinese herbs were discontinued and prednisolone was started, but bone and joint pain as well as renal function gradually worsened. Four years later, creatinine was 9.0 mg/dl and alkaline phosphatase was 571 IU/l. As bone scintigraphy revealed localized asymmetric lesions, Paget's disease of bone was suspected at first. However, neither osteosclerosis nor hypertrophy was seen in radiographs. Based on a bone specimen histology we diagnosed as mixed-type renal osteodystrophy including osteomalacia and osteitis fibrosa. Mosaic pattern of cement lines was not present. This case was not compatible with either Paget's disease or typical renal osteodystrophy as seen in dialysis patients. Etidronate disodium was effective in alleviating bone symptoms. The patient's bone disorder may be a new disease at least partly related to Chinese herbs independently of nephropathy.

(Internal Medicine 42: 345–350, 2003)

Key words:

osteitis fibrosa, osteomalacia, renal osteodystrophy, Paget's disease, osteopathy

Introduction
	Chinese herbs, long regarded as a relatively safe traditional remedy, rarely have caused adverse reactions despite their wide use. However, since the initial report in 1993 by Vanherweghem and colleagues (1), nephropathy induced by Chinese herbs has drawn increasing attention. Extra renal lesions associated with Chinese herbs involving the lung, liver, heart, and lower urinary tract also have been reported. However, we know of no reported occurrences of bone disease caused by Chinese herbs. We encountered an unusual case with radiologically localized, asymmetric bone lesions, and a histologically mixed pattern including both osteitis fibrosa and osteomalacia, which became evident 7 years after the patient began to consume Chinese herbs. Paget's disease of bone and renal osteodystrophy might be considered as the differential diagnosis.
Case Report
	A 65-year-old Japanese man was admitted to our hospital because of generalized fatigue and multiple bone and joint pains including low back pain. Since 1989 the patient had taken Chinese herbs (Table 1) imported from Taiwan, intending to promote his general health. On July 4, 1989, serum urea nitrogen (s-UN), serum creatinine (s-Cr), and serum uric acid (s-UA) concentrations were 16, 1.1, and 5.4 mg/dl, respectively. Multiple asymmetric osteoarthralgia in the right lumbar lesion, both knees, and feet first appeared in January 1996. In November, renal dysfunction was noted. The patient was admitted to our hospital on December 19, 1996 for further evaluation. Laboratory findings at that time were: s-UN, 20 mg/dl; s-Cr, 2.5 mg/dl; and s-UA, 2.5 mg/dl. Sodium was 140 mmol/l, potassium 4.1 mEq/l, chloride 113 mmol/l, calcium 4.1 mEq/l, and phosphate 1.6 mg/dl. Alkaline phosphatase (Al-P) was 804 IU/l (normal range; 120 to 350); the elevated Al-P isoenzyme was the bone-derived type. Fasting blood glucose was 104 mg/dl, and HbA1c 5.4%. By arterial blood gas analysis, pH was 7.32; HCO₃⁻ 17 mmol/l; and anion gap 10. On endocrinologic examination, intact parathyroid hormone (i-PTH) was 104 pg/ml (normal range; 20.0 to 53.0), 1,25(OH)₂ Vitamin D₃ concentration was below 7.9 ng/l (normal range; 20 to 60) and bone gla protein(BGP) was 11.2 ng/ml (normal range; 3.1 to 12.7). On urinalysis, pH was 6.5. Dipstick reagent readings were glucose, 3+; protein, 1+; and occult blood, 3+. Amino acid analysis of urine revealed accelerated excretion of 19 kinds of amino acids, and Fanconi syndrome was diagnosed. With his mouth dryness and fibrous salivary gland was also diagnosed by lip biopsy. The Chinese herbs formula was analyzed by high performance liquid chromatography (HPLC) and aristolochic acid (AA) was detected. A renal biopsy was performed on January 13, 1997; the specimen showed extensive tubulo-interstitial fibrosis with scant cell infiltration (Fig. 1), compatible with Chinese herb nephropathy. Although bone scintigraphy with ^99mTc-labeled methylene diphosphonate revealed asymmetric areas of intense uptake (a characteristic of Paget's disease) in the right iliac bone, both knees (right dominant), and joints of the feet, only localized changes were shown by radiography and computed tomography; no areas of bone enlargement or thickening were seen. Right iliac bone biopsy showed evidence of increased bone resorption such as increased number and size of osteoclasts, and evidence of increased percentage of fibrous tissue (Fig. 2). Osteitis fibrosa was diagnosed at that time. Neither any bone tumors nor metastasis was shown. We could not analyze further because it was a decalcified section. Chinese herbs were discontinued, and prednisolone (20 mg p.o. on alternate days), and calcitriol (0.25 μg p.o. daily) were initiated. In 1998, Fanconi syndrome showed improvement, and the elevated serum Al-P concentration decreased (Fig. 3). Bone and joint pains also decreased. [Laboratory findings at that time were: s-UN, 35 mg/dl; s-Cr, 4.6 mg/dl; and s-UA, 7.3 mg/dl. Sodium was 140 mmol/l, potassium 4.0 mEq/l, chloride 109 mmol/l, calcium 4.0 mEq/l, phosphate 2.4 mg/dl, and Al-P 334 IU/l. By arterial blood gas analysis, pH was 7.39; HCO₃⁻ 20 mmol/l; and anion gap 11. On urinalysis, neither aminoaciduria nor glycosuria nor proteinuria was detected]. In December 1999, the pain increased, as did Al-P. The patient was admitted to our hospital for further evaluation of bone metabolism on February 24, 2000. On admission, s-UN was 42 mg/dl; s-Cr, 9.0 mg/dl; s-UA, 6.8 mg/dl; calcium, 4.3 mEq/ l; phosphate, 4.6 mg/dl; intact PTH, 248.1 pg/ml; Al-P, 571 IU/l; BGP, 54.7 ng/ml; and cross-linked C-terminal telopeptide of type I collagen (ICTP), 26.3 ng/ml (normal range; 0.6 to 4.9). Results of repeat bone scintigraphy (Fig. 4A), radiography, and computed tomography (Fig. 4B) appeared as previously. On February 24, 2000, right iliac bone biopsy was performed again, 14 days after administration of tetracycline for double labeling studies. Undecalcified thin sections 5μm in thickness were prepared from the bone specimen and were stained by the Villanueva methods. Histomorphometric analysis is shown in Table 2. Light microscopic examination showed evidence of increased bone resorption such as increased number and size of osteoclasts and an increased percentage of lacunar bone surface. This osteolysis was accompanied by evidence of bone formation, and fibrous tissue was increased adjacent to the trabecular bone. Excessive unmineralized lamellar osteoid also was present (Fig. 5A). Osteoclasts with more than 50 nuclei were observed (Fig. 5B). Deposition of aluminum was not found within the mineralization in the surface of the bone. Polarizing microscopic examination showed normal lamellar bone, but also woven bone (a sign of high bone turnover). No mosaic pattern of cement lines (a characteristic of Paget's disease) was seen (Fig. 5C). Fluorescence microscopy showed a singly labeled surface as well as a doubly labeled surface (Fig. 5D), indicating osteomalacia (unmineralized, low-turnover bone) and osteitis fibrosa (high-turnover bone) admixed in a single specimen. Histomorphometric analysis according to Coburn's classification yielded a diagnosis of mixed-type renal osteodystrophy, with excessive total osteoid volume (>15%) and excessive fibrous tissue volume (>0.5%) (2, 3). The patient was given etidronate disodium (200 mg daily for 14 days every 12 weeks). Osteoarthralgia gradually resolved, and Al-P decreased to 220 mg/dl and BGP to 24.0 ng/ml. However, s-Cr had increased further to 12.6 mg/dl, by July 2002.
Discussion
	Vanherweghem et al first reported Chinese herb nephropathy occurring in Belgium in 1993 (1). One year later, Vanhaelen et al reported that in Belgium, the number of known cases of Chinese herb nephropathy had risen to 70 (4). Subsequently, renal damage from Chinese herbs has been recognized in many countries. Renal biopsy specimens in these cases showed extensive tubulo-interstitial fibrosis without glomerular lesions. In 1993, Izumotani (5) first reported a similar case in Japan, followed by many other Japanese reports of Chinese herb nephropathy. Characteristically many Japanese cases have been complicated by Fanconi syndrome. Extra-renal disease caused by Chinese herbs has included pneumonitis associated with Ougon and Ouren-gedoku-to (6); hepatitis with Jin Bu Huan (7); meningoencephalocele with Tripterygium wilfordii (8); cardiotoxicity with Aconitum rootstocks (9); valvular heart disease with Stephania tetrandra and others (10); aplastic anemia (11); pulmonary embolism; thromboembolism (12); and urothelial cancer (13). Although Chinese herbs have been linked to disease in many organs, no report has suggested a relationship between Chinese herbs and bone disease. Renal disease is well known to cause bone disease, and a relationship has been reported between Fanconi syndrome and osteomalacia (14). Renal osteodystrophy, which occurs in chronic renal failure, is encountered frequently. Lesions are classified into osteitis fibrosa, representing high-turnover bone disease; and osteomalacia and aplastic bone disease, representing low-turnover bone disease. Osteitis fibrosa results from excess in secretion of parathyroid hormone (PTH); characteristics include increased surface resorption caused by hyperactivity of both osteoblasts and osteoclasts, as well as endosteal fibrosis. Osteomalacia, in which aluminum toxicity is the most common cause, is a condition showing excessive unmineralized lamellar osteoid. In mixed-type renal osteodystrophy the characteristics of both osteitis fibrosa and osteomalacia coexist symmetrically in the same patient. Asymmetric mixed-type renal osteodystrophy has not been reported. Paget's disease of bone, well known as a localized bone disease showing osteitis fibrosa, is descriptively termed osteitis deformans (15) and affects approximately 3% of Caucasians over the age of 40 years old in Western countries (16). In Japan, Paget's disease is rare. Although the cause of this disease is unknown, some reports have suggested that various paramyxoviruses including the measles virus might have roles in initiation (17). However, Paget's disease has not been reported as an adverse reaction to drugs. None have suggested a relationship to Chinese herbs. Histologically, the characteristic feature is increased resorption of bone accompanied by an increase in bone formation, followed by replacement of marrow by fibrous tissue. In the sclerotic phase, an increase in the number of irregular cement lines is observed as a "mosaic" pattern. Radiologically, the bone enlarges to show an irregularly widened cortex in a coarse, striated pattern, with lesions occurring in a focal distribution. The present case showed distinctive characteristics compared with osteitis fibrosa in renal osteodystrophy and with Paget's disease. Bone scintigraphy revealed asymmetrical bone disease. Neither radiography nor computed tomography showed osteosclerosis with hypertrophy. Histologically, this case showed mixed findings including both osteomalacia and osteitis fibrosa. A mosaic pattern of cement lines, characteristic of Paget's disease, was not seen. This case, then, was incompatible with Paget's disease, while its asymmetry differed from classic mixed-type renal osteodystrophy as seen in uremia. Other asymmetric bone disease, for example prostatic carcinoma and bone fracture due to prednisolone were excluded radiographically and histologically. At least in part, this case is likely to be a new bone disease distinct from presently established categories. Aristolochic acid (AA), a constituent of Chinese herbs, has been considered one possible cause (18–21). This suspicion was strengthened by the discovery of AA-DNA adducts in the kidney tissue of affected patients (22, 23). The recent demonstration that, in rabbits, AA alone causes similar renal lesions removes any doubt on the causal role of AA (24). Here, in the clinical course, the serum Al-P concentration became elevated twice, irrespective of prednisolone or calcitriol. The first elevation may relate to osteomalacia caused by Fanconi syndrome, because it was decreased after the treatment of Fanconi syndrome. But the cause of the second elevation can't be explained only by chronic renal failure because of the asymmetric radiological findings. On the other hand, Chinese herb-induced nephropathy can result in gradual clinical deterioration even after discontinuation of herbs. For these reasons, the Chinese herbs may conceivably have caused osteopathy either directly, indirectly through renal disease, or both. Accumulation of more cases and further clinical investigation of Chinese herb users should be pursued. Steroids and other immunosuppressant therapy have been reported to have a slight beneficial effect in this nephropathy (25). In the present case, steroid administration was not consistently effective against either bone disease or nephropathy. In contrast, etidronate disodium showed a clear effect against bone disease; Al-P decreased and bone pain abated. This modality may be an important therapeutic option in this kind of bone disease. Acknowldgements: Histomorphometric analysis of bone tissue was performed by Dr. Hideaki Takahashi and Mrs. Akemi Itou at the Niigata Bone Science Institute, Niigata, Japan.

References
1)	Vanherweghem JL, Depierreux M, Tielemans C, et al. Rapidly progressive interstitial renal fibrosis in young women: association with slimming regimen including Chinese herbs. Lancet 341: 387–391, 1993 (see comments).
2)	Coburn JW. Renal osteodystrophy. Kidney Int. 677–693, 1980.
3)	Sherrard DJ, Hercz G, Pei Y, et al. The spectrum of bone disease in end-stage renal failure-An evolving disorder. Kidney Int 43: 436–442, 1993.
4)	Vanhaelen M, Vanhaelen-Fastre R, But P, Vanherweghem JL. Identification of aristolochic acid in Chinese herbs. Lancet 343: 174, 1994 (letter).
5)	Izumotani T, Ishimura E, Tsumura K, Goto K, Nishizawa Y, Morii H. An adult case of Fanconi syndrome due to a mixture of Chinese crude drugs. Nephron 65: 137–140, 1993.
6)	Nishimori F, Yamazaki K, Jin Y, et al. Pneumonitis induced by the drug Ougon. Nihon-Kokyuki-Gakkai-Zasshi 37: 396–400, 1999.
7)	Picciotto A, Campo N, Brizzolara R, et al. Chronic hepatitis induced by Jin Bu Huan. J Hepatol 28: 165–167, 1998.
8)	Takei A, Nagashima G, Suzuki R, et al. Meningoencephalocele associated with Tripterygium wilfordii treatment. Pediatr Neurosurg Jul 27: 45–48, 1997.
9)	Tai YT, But PP, Young K, Lau CP. Cardiotoxicity after accidental herb-induced aconite poisoning. Lancet 340: 1254–1256, 1992 (see comments).
10)	Vanherweghem JL. Association of valvular heart disease with chinese-herb nephropathy. Lancet 350: 1858, 1997.
11)	Nelson L, Shih R, Hoffman R. Aplastic anemia induced by an adulterted herbal medication. J Toxicol Clin Toxicol 33: 467–470, 1995.
12)	Gorey JD, Wahlqvist /ML, Boyce NW. Adverse reaction to a Chinese herbal remedy. Med J Aust 157: 484–486, 1992.
13)	Cosyns JP, Jadoul M, Squifflet JP, Van Cangh PJ, van Ypersele de Strihou C. Urothelial malignancy in nephropathy due to Chinese herbs. Lancet 344: 188, 1994 (letter).
14)	Clarke BL, Wynne AG, Wilson DM. Osteomalacia associated with adult Fanconi's syndrome: clinical and diagnostic features. Clin Endocrinol (Oxf) Oct 43: 479–490, 1995.
15)	Paget J. On a form of chronic inflammation of bones (osteitis deformans). Med Chir Trans 60: 37–63, 1877.
16)	Barker DJP. Paget's disease of bone: the Lancashire focus. Br Med J 280: 1105–1107, 1980.
17)	Kurihara N, Reddy SV, Menaa C, Anderson D, Roodman GD. Osteoclasts expressing the measles virus nucleocapsid gene display a pagetic phenotype. J Clin Invest 105: 607–614, 2000.
18)	But PPH. Need for correct identification of herbs in herbal poisoning. Lancet 341: 637, 1993 (letter; see comments).
19)	Depierreux M, Van Damme B, Nanden HK, Vanherweghem JL. Pathologic aspects of a newly described nephropathy related to the prolonged use of chinese herbs. Am J Kidney Dis 24: 172–180, 1994.
20)	Jadoul M, de Plaen JF, Cosyns JP, van Ypersele de Strihou C. Adverse effects from traditional Chinese medicine. Lancet 341: 892–893, 1993 (letter; comment).
21)	Cosyns JP, Jadoul M, Squifflet JP, Plaen JF, Ferluga D, van Ypersele de Strihou C. Chinese herbs nephropathy: A clue to Balkan endemic nephropathy? Kidney Int 45: 1680–1688, 1994.
22)	Schmeiser HH, Bieler CA, Wiessler M, van Ypersele de Strihou C, Cosyns JP. Detection of DNA adducts formed by aristolochic acid in renal tissue from patients with Chinese herbs nephropathy. Cancer Res 56: 2025–2028, 1996.
23)	Bieler CA, Stiborova M, Wiessler M, Cosyns JP, van Ypersele de Strihou C, Schmeiser HH. 32P-post labelling analysis of DNA adducts formed by aristolochic acid in tissues from patients with Chinese herbs nephropathy. Carcinogenesis 18: 1063–1067, 1997.
24)	Cosyns JP, Dehoux JP, Guiot Y, et al. Chronic aristolochic acid toxicity in rabbits: A model of Chinese herbs nephropathy? Kidney Int 59: 2164–2173, 2001.
25)	Vanherweghem JL, Abramowicz D, Tielemans C, Depierreux M. Effects of steroids on the progression of renal failure in chronic interstitial renal fibrosis: a pilot study in Chinese herbs nephropathy. Am J Kidney Dis 27: 209–215, 1996.

From Kidney Center, Department of Orthopedics and *Department of Pathology, Toranomon Hospital, Tokyo Received for publication August 15, 2002; Accepted for publication January 16, 2003 Reprint requests should be addressed to Dr. Junichi Hoshino, Kidney Center, Toranomon Hospital, 2-2-2 Toranomon, Minato-ku, Tokyo 105-8470


	Copyright(C) 1997-2003, The Japanese Society of Internal Medicine. Allright reserved. E-mail : naika@naika.or.jp Last Up Date 2003/4/25