Working group Siggelkow

Hypoparathyroidism (HypoPT) is a disease characterized by hypocalcemia and hyperphosphatemia resulting from the absence or inappropriately low levels of parathyroid hormone (PTH). The most common cause is dysfunction of the remaining parathyroid tissue after thyroid or parathyroid surgery. In contrast to other endocrine disorders, the standard therapy cannot replace the deficient hormone, supplementing active vitamin D and calcium instead. Patients have an increased risk for renal and basal ganglia calcifications, cataracts, as well as premature chronic kidney dysfunction, neuropsychiatric disease und infections. Morbidity and also mortality are increased.

These patients suffer from a reduced quality of life. During the last years we developed a specific patient questionnaire, the Hypoparathyroidism Questionnaire 28 (HPQ 28), to better evaluate and measure the symptom burden of HypoPT patients. The questionnaire consists of 28 specific questions, assigned to 5 scales: neurovegetative symptoms, pain and cramps, depression and anxiety, gastro-intestinal symptoms and loss of vitality. Three single items: numbness and tingling, memory problems and heart palpitations were not related to a scale. While analyzing of the questionnaire, the scale „pain and cramps“ could be identified as significantly higher in comparison to two well-chosen control groups (Kooperation C. Herrmann-Lingen).

We now intensively investigate the questionnaire HPQ 28 in HypoPT patients with a focus on the newly diagnosed pain as one of the main symptoms. The questionnaire is also used in a number of cooperations in other European countries for further evaluation.

The questionnaire HPQ28 will be tested in 2.500 normal controls. In addition, a digital tool for easier application and automated analysis is in development.

Mastocytosis is a heterogeneous disease characterized by an anormal proliferation of mast cells (MC) in the skin (cutaneous mastocytosis (CM)), in bone marrow or other organs (indolent systemic mastocytosis (ISM)). It is hypothesized that the increased production of inflammatory mediators by mast cells as well as the mast cell infiltration itself is responsible for bone deterioration and osteoporosis. Mastocytosis often is associated with a severe form of osteoporosis with multiple bone fractures. Patients suffer from diffuse bone pain predominantly in the spine. Indolent systemic mastocytosis can only be diagnosed by a biopsy of the affected organ e.g. the bone marrow. Compact mast cell infiltrates with more than 15 cells in bone marrow is the major criterion. Minor criteria are: 25% of mast cells with atypical spindle-shaped morphology in blood, cKIT‐Mutation D816V in bone marrow or a long-lasting elevated tryptase > 20 ng/ml. If the bone marrow is affected by mast cells, the risk to develop osteoporosis is increased up to 30%. The risk of fractures is increased to 15% up to 50%. In a prospective study, we aim to identify factors contributing to the increased fracture risk in patients with indolent systemic mastocytosis compared to aged matched controls by using different approaches. Furthermore, we will perform genetic analysis in COP Zellen (Circulating osteoprogenitor cells), to evaluate the fraction of genetic disposition of osteoporosis in mastocytosis (supported by Elsbeth-Bonhoff-Foundation).

As defined, osteoporosis is characterized by reduced bone mass, associated with a dysfunction of the bone micro architecture and an increase in fractures. To exclude forms of secondary osteoporosis in case of atraumatic fractures additional diagnostics can be performed in addition to baseline diagnostics according to the guidelines. This includes bone biopsies and furthermore genetic analyses. The genetic analysis initially includes 9 target genes from the NGS-Gen-Bone-Panel: ALPL, BMP1, COL1A1, COL1A2, CRTAP, IFITM5, LRP5, WNT1 and PLS3. For single patients a separate analysis of the COL1A1- und COL1A2-gene by MPLA (Multiplex Ligation-dependent Probe Amplification) can be performed. This genetic analysis can be helpfull to find the cause of severe osteoporosis especially in young patients. At the moment we reevaluate our diagnostic procedures by analyzing retrospective patient data.

Methotrexat (MTX) is used as standard treatment of e.g. rheumatoid arthritis. In some patients under treatment with MTX, fractures of the tibia occur, similar to stress fractures and not as a typical consequence of osteoporosis. These fractures are reflected by the name MTX osteopathy. The cause of these fractures is unclear, the only possibility to help the patients, is the termination of the MTX therapy. It is known that MTX has negative effects at bone. These negative effects are elevated levels of homocysteine, negative influence on the RANKL/OPG ratio and an elevated cytokine secretion. Homocysteine destabilizes the bone matrix; an increased RANKL/OPG ratio activates bone resorbing cells, which is also induced by increased cytokine levels. Additional effect can be caused by the co-medication in rheumatoid arthritis, the glucocorticoids. Under therapy with MTX, also caffeine and theophylline have negative effects on bone. Our research focus is on cell culture experiments, to evaluate the influence of mediators like homocysteine, glucocortocoids, caffeine in the precence of MTX on osteoblast differentiation and cytokine production. To understand the local mechanism at the bone cell in the presence of MTX, the mystery of MTX-osteopathy might be solved. The clinical part of the project is the comparison of patients with MTX with and without this bone fractures.