dr. Judit Tőke DISEASES OF THE PARATHYROID GLAND METABOLIC BONE DISEASES OSTEOPOROSIS SEMMELWEIS UNIVERSITY 2nd Department of Medicine

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1 DISEASES OF THE PARATHYROID GLAND METABOLIC BONE DISEASES OSTEOPOROSIS dr. Judit Tőke SEMMELWEIS UNIVERSITY 2nd Department of Medicine

2 Diseases of the parathyroid gland Outline Primary hyperparathyroidism Primary hypoparathyroidism Metabolic bone diseases Disorders in Vitamin D action (rickets and osteomalatia) Secondary hyperparathyroidism in chronic kidney disease Osteogenesis imperfecta Paget s Disease of Bone Osteoporosis

3 The last anatomical discovery... Sandström IV: On a new gland in man and several mammals glandulae parathyroideae. Upsala Läk Förenings Förh ;15: Swedish Ivar Sandström, That remarkable discovery was made in 1877 at the Anatomical Department in Uppsala. At that time Sandström was a young medical student, who had worked as an assistant at the department since Virchow declined its publication in his journal, because of the length of the paper (30 pages)... Johansson H: The Uppsala anatomist Ivar Sandström and the parathyroid gland. Ups J Med Sci May; 120(2): 72 77

4 Primary hyperparathyroidism (PHPT) Prevalence of PHPT: - North-America: 1/ North-Europe: 3-4/ in the population oldre than 75 years: 20/ women:men=2-3:1 Pathology of parathyroid glands causing PHPT: - single adenoma (80-85%) - double adenoma (1-2%) - hyperplasia (10-15%) - carcinoma (<1%) - cyst (1-3%)

5 Symptoms of PHPT Skeleton: Joints: Muscles: Renal: Gastrointestinal: Psychiatric: - bone pain - fractures - decrease of BMD: osteopenia/osteoporosis - osteitis fibrosa cystica - arthralgy - weakness of proximal muscles - muscle atrophy - renal stones - nephrocalcinosis - nephrogene diabetes insipidus - renal insufficiency - peptic ulcer - acute pancreatitis - depression Rare: Hypercalcemic crisis!! Causes: - parathyroid npl. hemorrhage/necrosis - infection - exsiccosis

6 Changes in clinical picture of PHPT Author Cope Heath Mallette Silverberg (%) (%) (%) (%) Renal stones Skeletal symptoms Hypercalciuria NA Asymptomatic John P. Bilezikian and Shonni J. Silverberg Reviews in Endocrine & Metabolic Disorders 2000;

7 Diagnosis of PHPT - Laboratorical investigations elevated or normal PTH concentration > 63 pg/ml AND hypercalcaemia: total serum calcium corrected to albumin > 2.63 mmol/l ionized serum calcium > 1.25 mmol/l N.B:in the absence of conditions mimicking PHPT (thiazide diuretics or lithium) Diagnosis of PHPT Radiological investigations CT, MRI: sensitivity:50-70% Ultrasound: sensitivity: 40-80% 99mTc-sestamibi substraction isotope: sensitivity for single adenoma: 90% for the diagnosis of ectopic parathyroid tissue

8 99m Tc-sestaMIBI scan (MIBI = methoxyisobutylisonitrile)

9 Indications for surgery for the treatment of PHPT Khan AA et al: Primary hyperparathyroidism: review and recommendations on evaluation, diagnosis, and management. A Canadian and international consensus. Osteoporos Int (1):1-19

10 Surgery for the treatment of symptomatic PHPT Parathyroidectomy (PTx) is the only curative approach to this disease. Cure rates following PTx ~ 95 % Post-PTX: reductions in the risk of all fractures decrease of renal stone risk IOPTH: intraoperative PTH - measurement with a rapid assay is of value in confirming adequate resection of abnormal parathyroid tissue and increases surgical success rates Persistent PHPT = development of hypercalcemia within 6 months of PTx If there is a contraindication for surgery: Vitamin D supplementation goal: serum 25OHD > 50nmol/l antiresorptive therapy (bisphosphonates) in patients with osteoporosis cinacalcet

11 Management of asymptomatic PHPT Monitoring appears to be a safe option for possibly up to 8 to 10 years for patients with asymptomatic PHPT Bilezikian et al. Guidelines for the Management of Asymptomatic Primary Hyperparathyroidism: Summary Statement from the Fourth International Workshop. J Clin Endocrinol Metab, 2014, Aug 27

12 Familial syndromes with PHPT More than one parathyroid gland are affected in 15% of all cases and half of them is a part of a familial syndrome (5-8% of all cases) Multiplex endocrine neoplasia type 1 -prevalence: 30-40/million MEN1-2% of all cases Multiplex endocrine neoplasia type 2A -prevalence: 40/million Hyperparathyreosis-jaw tumor syndrome Familial isolated primary hyperparathyroidism Familial hypocalciuric hypercalcemia MEN2A HPT-JT FIHP FHH

13 Primary hypoparathyroidism Iatrogen: neck irradiation, neck surgery (thyroid!!!) Infiltrativ / destructive diseases: haemochromatosis, sarcoidosis, Wilson-disease, amyloidosis Genetic disease: DiGeorge-syndrome APS-1 syndrome: - Hypoparathyroidism diabetes mellitus type 1 - Addison-disease autoimmune thyroid disease - Mucocutan candidiasis chronic active hepatitis alopecia vitiligo

14 Definition of hypocalcemia: Serum calcium < 2.23 mmol/l, Ionic calcium < 1.05 mmol/l Symptoms of hypocalcemia: It depends on: - the rate of the development - the severity of the hypocalcemia - and the elapsed time from the begining * neuromuscular : enhanced excitation in neurons paresthesia, tetania, laryngospasmus, bronchospasmus * neurol-psych : intracran. calcification (basal ggl, cortex), change in personality, parkinsonism, psychosis * skin : dry skin, atopic ekzema, caries * GI : dysphagia, abdominal pain, colica in bile ducts * pulmonary : dyspnoe, wheezing * cardiovascular : longer QT-interval, congestive heart failure, cardiomyopathy

15 Disorders in Vitamin D action Rickets: defects in mineralisation of bone and cartilage during childhood Osteomalatia: defects in mineralisation of bone in adulthood Serum levels 24h urinary calcium excretion Etiology Calcium Phosphorous ipth Bone specific ALP Hypocalcemic e.g. vitamin D deficiency Low to low normal Low Elevated Elevated Low Hypophosphatemic e.g. X-linked hypophosphatemia Normal Low Normal to low normal Elevated Low to elevated No abnormality in mineral homeostasis e.g. hypophosphatasia Normal Normal Normal Low Normal From: Disorders in Vitamin D Action Endotext [Internet]. De Groot LJ, Chrousos G, Dungan K, et al., editors. South Dartmouth (MA): MDText.com, Inc.;

16 Rickets Clinical features: weakness, bone pain, bone deformity, fracture 0-1 years: craniotabes, widening of the wrists, rachitic rosary, deformed rib cage > 2 years: bow legs (genu varum) or knock-knee (genu valgum), widening of the end of long bones

17 Osteomalatia Clinical features: bone pain or low back pain, muscle weakness, hypotonia acute fracture of the long bones, pubic ramii, ribs, or spine Looser-zones (pseudofractures) biconcave vertebrae From: Disorders in Vitamin D Action Endotext [Internet]. De Groot LJ, Chrousos G, Dungan K, et al., editors. South Dartmouth (MA): MDText.com, Inc.;

18 Michael P.Whyte, Rajesh V.Thakker: Rickets and osteomalacia. Medicine 33 (12) p70-74, 2005

19 Secondary hyperparathyroidism in chronic kidney disease Clinical features: usually silent disease severe osteitis fibrosa clinical signs of hyperca, hyperp Treatment: Vitamin D: active vitamin D calcitriol! Calcimimetics Phosphate binders Oral phosphate restriction Kobama H: FGF23-parathyroid interaction: implications in chronic kidney disease. Kidney Int. 77(4):292-8, 2010

20 Osteogenesis imperfecta Clinically and genetically heterogeneous group of heritable disorders of connective tissue (collagen related disorder) 85%: AD mutations in the genes that encode type I collagen, COL1A1 and COL1A2 Clinical features: bone fragility, bone deformity, growth deficiency macrocephaly, blue sclerae, dentinogenesis imperfecta, hearing loss, neurological defects (macrocephaly and basilar invagination) cardiopulmonary complications Treatment: physical rehabilitation, supplemented with orthopedic intervention as needed oral bisphosphonates gene therapy?

21 Paget s Disease of Bone Clinical features: skeletal deformity which evolves over many years: skull and lower extremities. pathological fractures in the femurs. pain of skeletal, joint, neurologic or muscle origin. The radiologic features: 1. localized area of osteolysis which advances very slowly 2. the lesion becomes osteosclerotic 3. entire bone is affected the entire lesion is sclerotic with areas of osteolysis Treatment: iv. zoledronate surgery: lower extremity joint replacement correction of deformities of the lower extremity.

22 Osteoporosis Osteoporosis is a systemic, progressive disease. Decreased bone mass, altered microarchitecture --- fragile bones which are at an increased risk for fractures.

23 Diagnosis 1. Fracture risk assessment

24 Diagnosis 2. Finding secondary causes

25 Osteoporosis prevention 1. Physical activity 2. Optimal diet with mg calcium daily 3. Optimal vitamind with supplementation ( IU cholecalciferol daily), if needed 4. Discontinuation of smoking

26 I: Antiresorptive mediactaions Treatment Bisphosphonates: Alendronate oral; prevents vertebral, non-vertebral-, hip fractures in postmenopausal women Risedronate oral; prevents vertebral, non-vertebral-, hip fractures in postmenopausal women Ibandronate oral or iv. ; prevents vertebral fractures Zoledronate iv; prevents vertebral, non-vertebral-, hip fractures in postmenopausal women Caution: in high doses, increases the risk of osteonecrosis of jaw Raloxifene oral; prevents vertebral fractures in postmenopausal women Caution: may increases the risk of thromboembolic disease and stroke Denosumab sc; prevents vertebral, non-vertebral-, hip fractures in postmenopausal women Calcitonin intranasal spray; : Reduces incidence of vertebral fractures in post-menopausal women Consider as an alternative when other more effective drugs cannot be used Effective in decreasing acute pain associated with vertebral osteoporotic fractures Hormone replacement therapy mainly in those women who have symptoms of menopause Caution: increase the risk of breast carcnoma, thromboembolic disease, ischaemic heart disease (gestagen containing drugs!!) II. Bone-forming medication Teriparatide sc; prevents vertebral and non-vertebral fractures in postmenopausal women with severe OP