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Open access

Nobuhiro Miyamura, Shuhei Nishida, Mina Itasaka, Hirofumi Matsuda, Takeshi Ohtou, Yasuhiro Yamaguchi, Daisuke Inaba, Sadahiro Tamiya, and Tetsuo Nakano

Summary

Hepatitis C-associated osteosclerosis (HCAO), a very rare disorder in which an extremely rapid bone turnover occurs and results in osteosclerosis, was acknowledged in 1990s as a new clinical entity with the unique bone disorder and definite link to chronic type C hepatitis, although the pathogenesis still remains unknown. Affected patients suffer from excruciating deep bone pains. We report the 19th case of HCAO with diagnosis confirmed by bone biopsy, and treated initially with a bisphosphonate, next with corticosteroids and finally with direct acting antivirals (DAA: sofosbuvir and ribavirin) for HCV infection. Risedronate, 17.5 mg/day for 38 days, did not improve the patient’s symptoms or extremely elevated levels of bone markers, which indicated hyper-bone-formation and coexisting hyper-bone-resorption in the patient. Next, intravenous methylprednisolone pulse therapy followed by high-dose oral administration of prednisolone evidently improved them. DAA therapy initiated after steroid therapy successfully achieved sustained virological response, but no additional therapeutic effect on them was observed. Our results strongly suggested that the underlying immunological alteration is the crucial key to clarify the pathogenesis of HCAO. Bone mineral density of lumbar vertebrae of the patient was increased by 14% in four-month period of observation. Clarification of the mechanisms that develop osteosclerosis in HCAO might lead to a new therapeutic perspective for osteoporosis.

Learning points:

  • HCAO is an extremely rare bone disorder, which occurs exclusively in patients affected with HCV, of which only 18 cases have been reported since 1992 and pathogenesis still remains unclear.

  • Pathophysiology of HCAO is highly accelerated rates of both bone formation and bone resorption, with higher rate of formation than that of resorption, which occur in general skeletal leading to the diffuse osteosclerosis with severe bone pains.

  • Steroid therapy including intravenous pulse administration in our patient evidently ameliorated his bone pains and reduced elevated values of bone markers. This was the first successful treatment for HCAO among cases reported so far and seemed to propose a key to solve the question for its pathogenesis.

  • The speed of increase in the bone mineral content of the patient was very high, suggesting that clarification of the mechanism(s) might lead to the development of a novel therapy for osteoporosis.

Open access

Katsumi Taki, Takahiko Kogai, Junko Sakumoto, Takashi Namatame, and Akira Hishinuma

Summary

A de novo heterozygous inactivating mutation of calcium-sensing receptor (CASR) gene typically causes neonatal hyperparathyroidism (NHPT) with moderate hypercalcemia and hyperparathyroid bone disease. We present a case of asymptomatic hypocalciuric hypercalcemia with a de novo heterozygous mutation in CASR, S591C, which is primarily reported to be responsible for NHPT. A 54-year-old female was referred for investigation of asymptomatic hypercalcemia that was initially found in the 1980s but without a history of bone disease during the perinatal period. She had moderate hypercalcemia (12.4 mg/dl) and relative hypocalciuria (fractional extraction of calcium 1.07%) but normal intact parathyroid hormone and serum 1,25-dihydroxyvitamin D3. Pedigree analysis revealed that she carried a de novo heterozygous mutation of S591C, which she transmitted to an affected child with moderate hypercalcemia but not to other children, who had normal serum calcium levels. A de novo heterozygous CASR mutation that is responsible for NHPT may also present in individuals with asymptomatic hypocalciuric hypercalcemia. Caution is required when predicting course and outcome in a pedigree with CASR mutation, as well as incidental hypercalcemia, because of its variable phenotypes.

Learning points

  • The phenotype and severity of CASR mutations are thought to be dependent on genotypes.

  • We report an asymptomatic case of the de novo heterozygous S591C mutation in CASR, which has previously been reported as a responsible mutation of NHPT with bone diseases.

  • Variable phenotypes of CASR raise a cautionary note about predicting outcome by genotyping in a pedigree with CASR mutation.