Interferon Gamma-1b Does Not Increase Markers of Bone Resorption in Autosomal Dominant Osteopetrosis

Erik A. Imel, Ziyue Liu, Dena Acton, Melissa Coffman, Netsanet Gebregziabher, Yan Tong, Michael J. Econs

Research output: Contribution to journalArticle

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Abstract

In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was <25% above baseline at week 8, targeting doses of 100 µg/m 2 three times a week. The primary outcomes were change from baseline in CTX and N-telopeptide/creatinine ratio (NTX/Cr) at week 14. Secondary outcomes included changes in urine calcium/creatinine ratio, bone formation markers and tolerability. Nine adults and three children were recruited. Severe manifestations of ADO2 included histories of fractures (100%), osteomyelitis (16.7%), vision loss (50%), and anemia (58.3%). Baseline CTX and NTX/Cr were generally low-normal. Procollagen type I N-terminal propeptide was elevated or in the upper-normal range in 11 of 12 (91.6%) subjects. Elevations of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were common. One subject withdrew due to rash. Five subjects achieved doses of 50 µg/m 2 3 days a week, while six reached the full dose of 100 µg/m 2 3 days a week. Only 3 of 11 (27.3%) completing subjects achieved the primary outcome of increasing CTX ≥25% above baseline at week 14. The mean ± SD change from baseline in CTX at week 14 was +2.2% ± 43.2%, p = 0.86). Likewise, there was no significant change in NTX/Cr (mean change –2.1%, p = 0.81). Interferon gamma-1b was poorly tolerated. Most subjects had adverse events, and the Mental Health and Mental Component Scales of the SF-36v2 health survey declined slightly (p < 0.05). Over 14 weeks, interferon gamma-1b failed to significantly increase bone turnover markers in ADO2 and was poorly tolerated. Consequently, interferon gamma-1b is unlikely to be effective for decreasing bone mass in ADO2.

Original languageEnglish (US)
JournalJournal of Bone and Mineral Research
DOIs
StatePublished - Jan 1 2019

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Osteopetrosis
Bone Resorption
Osteomyelitis
Creatinine
Bone and Bones
Osteonecrosis
Cranial Nerves
Bone Remodeling
Osteoclasts
Aspartate Aminotransferases
Collagen Type I
Exanthema
Health Surveys
L-Lactate Dehydrogenase
Osteogenesis
interferon gamma-1b
Anemia
Fasting
Mental Health
Reference Values

Keywords

  • CLINICAL TRIALS
  • OSTEOCLASTS
  • OSTEOPETROSIS
  • OTHER THERAPEUTICS

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Orthopedics and Sports Medicine

Cite this

Interferon Gamma-1b Does Not Increase Markers of Bone Resorption in Autosomal Dominant Osteopetrosis. / Imel, Erik A.; Liu, Ziyue; Acton, Dena; Coffman, Melissa; Gebregziabher, Netsanet; Tong, Yan; Econs, Michael J.

In: Journal of Bone and Mineral Research, 01.01.2019.

Research output: Contribution to journalArticle

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abstract = "In autosomal dominant osteopetrosis type 2 (ADO2) CLCN7 mutations cause impaired osteoclast function. Severe consequences include skeletal fragility despite high bone mass, osteomyelitis, osteonecrosis, bone marrow failure, and severe cranial nerve impingement. There is no effective medical treatment for ADO2. We recruited subjects with ADO2 into a 14-week, open-label, pilot clinical trial of interferon gamma-1b. Doses were titrated based on tolerability and if fasting serum C-telopeptide (CTX) was <25{\%} above baseline at week 8, targeting doses of 100 µg/m 2 three times a week. The primary outcomes were change from baseline in CTX and N-telopeptide/creatinine ratio (NTX/Cr) at week 14. Secondary outcomes included changes in urine calcium/creatinine ratio, bone formation markers and tolerability. Nine adults and three children were recruited. Severe manifestations of ADO2 included histories of fractures (100{\%}), osteomyelitis (16.7{\%}), vision loss (50{\%}), and anemia (58.3{\%}). Baseline CTX and NTX/Cr were generally low-normal. Procollagen type I N-terminal propeptide was elevated or in the upper-normal range in 11 of 12 (91.6{\%}) subjects. Elevations of aspartate aminotransferase (AST) and lactate dehydrogenase (LDH) were common. One subject withdrew due to rash. Five subjects achieved doses of 50 µg/m 2 3 days a week, while six reached the full dose of 100 µg/m 2 3 days a week. Only 3 of 11 (27.3{\%}) completing subjects achieved the primary outcome of increasing CTX ≥25{\%} above baseline at week 14. The mean ± SD change from baseline in CTX at week 14 was +2.2{\%} ± 43.2{\%}, p = 0.86). Likewise, there was no significant change in NTX/Cr (mean change –2.1{\%}, p = 0.81). Interferon gamma-1b was poorly tolerated. Most subjects had adverse events, and the Mental Health and Mental Component Scales of the SF-36v2 health survey declined slightly (p < 0.05). Over 14 weeks, interferon gamma-1b failed to significantly increase bone turnover markers in ADO2 and was poorly tolerated. Consequently, interferon gamma-1b is unlikely to be effective for decreasing bone mass in ADO2.",
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