Bisphosphonates in multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder - an alternative therapeutic approach

Abstract

Multicentric osteolysis, nodulosis and arthropathy (MONA) spectrum disorder is a rare inherited progressive skeletal disorder caused by mutations in the matrix metalloproteinase 2 (MMP2) gene. Treatment options are limited. Herein we present successful bisphosphonate therapy in three affected patients. Patients were treated with bisphosphonates (either pamidronate or zoledronate) for different time periods. The following outcome variables were assessed: skeletal pain, range of motion, bone densitometry, internal medical problems as well as neurocognitive function. Skeletal pain was dramatically reduced in all patients soon after initiation of therapy and bone mineral density increased. Range of motion did not significantly improve. One patient is still able to walk with aids at the age of 14 years. Neurocognitive development was normal in all patients. Bisphosphonate therapy was effective especially in controlling skeletal pain in MONA spectrum disorder. Early initiation of treatment seems to be particularly important in order to achieve the best possible outcome.

Figure 1. Patient 1 at the age of 4 years, when first symptoms of MONA spectrum disorder developed.

She shows mild coarsening of the face (a). At the age of 12 years severe flexion contractures were present in both her feet (b) and hand joints (c).

Figure 2

Hematoxylin and eosin stain of the muscle-tendon biopsy of patient 1 at the age of 4.5 years shows a mildly increased fiber size variability (a). Immuno-histochemistry using antibodies against leucocyte common antigen (LCA) revealed an accumulation of mononuclear inflammatory cells especially perivascularly at the muscle-tendon junction (b). NADH-TR stain indicates a regular enzyme activity, but the weakly stained type II fibers are smaller than the more intensely stained type I fibers (c); original magnifications x20.

Figure 3. Dorsopalmar radiographs of the left hand demonstrate severe general osteopenia, progressive destruction of carpal bones and joints, multiple osteolyses, widening of phalanges and metacarpals with thinning of cortical bone and irregular epiphyses.

Pronounced sklerotic metaphyseal lines most evident at the radial and ulnar bone are due to bisphosphonate therapy.

Figure 4. Dorsoplantar radiographs of the feet show general osteopenia, progressive joint destruction and osteolyses most pronounced at the tarsal bones.

Patients 2 and 3 have more severe findings compared to patient 1.

Figure 5

Bisphosphonate therapy increased overall bone mineral content (a), as well as bone mineral content in the axial (b) and appendicular skeleton (c). Bone mineral content was below the 3rd percentile at all measured time points but increase was steady and similar to age, sex and ethnicity matched healthy controls *. Data are given exemplarily for patient 1 including therapeutic interventions (a). Graphs demonstrate bone mineral content.