Vitamin D VD2 - uniba.sk · 2015-11-07 · Payer J., Rovenský J., Killinger Z. Lexikón...

21
7.11.2015 1 Disorders of the parathyroid glands 5 th Department of Internal Medicine Comenius University Faculty of Medicine University Hospital Bratislava Winter semester 2015/16 Vitamin D 25(OH)D 1,25(OH) 2 D 7-dehydroxycholesterol VD2 VD3 25-hydroxylase 1α-hydroxylase Ca absorption Ca PTH Effects on Bone PTH Bone resorption Stimulates Ca into ECF Ca http://courses.washington.edu/conj/bess/bone/bone2.html PTH Effects on Kidney the loss of Ca++ ions in the urine by stimulating Ca++ reabsorption inhibits phosphate reabsorption stimulate production of 1,25(OH)2D Ca ↓ PO4 1 2 Endocrine Regulation of [Ca ++ ] ECF http://courses.washington.edu/conj/bess/calcium/calcium.html 1. PTH stimulates the release of Ca++ from bone, in part by stimulating bone resorption. 2. PTH decreases urinary loss of Ca++ by stimulating Ca++ reabsorption. 3. PTH indirectly stimulates Ca++ absorption in the small intestine by stimulating synthesis of 1,25(OH)2D in the kidney. Parathyroid hormone Parathyroid hormone (PTH) plays a key role in the regulation of calcium and phosphate homeostasis and vitamin D metabolism. The four parathyroid glands lie behind the lobes of the thyroid. The parathyroid chief cells respond directly to changes in calcium concentrations When serum ionised calcium levels fall, PTH secretion rises.

Transcript of Vitamin D VD2 - uniba.sk · 2015-11-07 · Payer J., Rovenský J., Killinger Z. Lexikón...

7.11.2015

1

Disorders of the parathyroid glands

5th Department of Internal MedicineComenius University Faculty of Medicine

University Hospital Bratislava

Winter semester 2015/16

Vitamin D

25(OH)D

1,25(OH)2 D

7-dehydroxycholesterol

VD2

VD3

25-hydroxylase

1α-hydroxylase Ca absorption

↑Ca

PTH Effects on Bone

PTH

Bone resorption

Stimulates

↑Ca into ECF

↑ Cahttp://courses.washington.edu/conj/bess/bone/bone2.html

PTH Effects on Kidney

• ↓the loss of Ca++ ions in the urine by stimulating Ca++ reabsorption

• inhibits phosphate reabsorption

• stimulate production of 1,25(OH)2D

↑Ca

↓ PO4

1

2

Endocrine Regulation of [Ca++]ECF

http://courses.washington.edu/conj/bess/calcium/calcium.html

1. PTH stimulates the release of Ca++ frombone, in part by stimulating boneresorption.

2. PTH decreases urinary loss of Ca++ bystimulating Ca++ reabsorption.

3. PTH indirectlystimulates Ca++ absorption in the smallintestine by stimulating synthesis of1,25(OH)2D in the kidney.

Parathyroid hormone

• Parathyroid hormone (PTH) plays a key role inthe regulation of calcium and phosphatehomeostasis and vitamin D metabolism.

• The four parathyroid glands lie behind thelobes of the thyroid. The parathyroid chiefcells respond directly to changes in calciumconcentrations When serum ionised calciumlevels fall, PTH secretion rises.

7.11.2015

2

Hypercalcemia: causesWith normal or elevated (i.e. inappropriate) PTH levels

• Primary or tertiary hyperparathyroidism • Lithium-induced hyperparathyroidism • Familial hypocalciuric hypercalcaemia , MEN

With low (i.e. suppressed) PTH levels

• Malignancy (e.g. lung, breast, renal, ovarian, colonic and thyroid carcinoma, lymphoma, multiple myeloma)

• Elevated 1,25(OH)2 vitamin D (vitamin D intoxication, sarcoidosis, HIV, other granulomatous disease)

• Thyrotoxicosis , pheochromocytoma• Paget's disease with immobilisation• Milk-alkali syndrome • Thiazide , Lithium, theophylline• Glucocorticoid deficiency

Signs/Symptoms

• The classic symptoms are described as'bones,stones , psychic moans and abdominal groans'.

• Polyuria and polydipsia, renal colic, lethargy,anorexia, nausea, dyspepsia and pepticulceration, constipation, depression, drowsinessand impaired cognition.

• Patients with malignant hypercalcaemia can havea rapid onset of symptoms.

• A family history of hypercalcaemia raises thepossibility of FHH or MEN .

Table

Disease Ca PTH

Hyperparathyroidism High High

Hypoparathyroidism low Low

Hypercalcemia of malignancy

High Low

Secondary hyperparathyroidism in renal disease

Low High

Hypercalcemia of malignancy

• one of the most common causes of non-PTH-mediated hypercalcemia.

• DX : confirmed by demonstrating an ↑serumconcentration of PTH-related protein (PTHrp) .

• Levels of PTH and 1,25-dihydroxyvitamin D(calcitriol) are usually appropriatelysuppressed in these patients.

Management

• Mild /mod hypercalcemia : asymptomatic ormildly symptomatic hypercalcemia

• do not require immediate Rx. Howevermaintain adequate hydration and avoidfactors that aggravate .

• Severe hypercalcemia : Patients require moreaggressive treatment.

Severe Hypercalcemia

• Volume expansion – up to 6 l / 24 hours

• Furosemide 40-80 mg every 2-4 hours

• Calcitonin

• Glucocorticoids (HCT 200-300 mg /24 hours)

• Bisphosopnates- zoledronic acid (4 mg i.v.) or pamidronate(30-90 mg i.v. / 8-24 hours)

• Calcimimetics - cinacalcet

• Hemodialysis

• Treatment of underlying condition (parathyreoidectomy inPHPT)

7.11.2015

3

Hyperparathyroidism

Type Serum Ca PTH

Primary Raised Not suppressed

Single adenoma (90%) Multiple adenomas (4%) Nodular hyperplasia (5%) Carcinoma (1%)

Secondary Low raised

Chronic renal failure MalabsorptionOsteomalacia and rickets

Tertiary Raised Not suppressed

Multiple endocrine neoplasia

Features MEN1 MEN2A MEN2B

Alias: Wermer S Sipple S

Pancreatic tumors ++

Pituitary adenoma ++

Parathyroid hyperplasia

+++ +

Angiofibroma/Lipoma +

Medullary thyroid ca +++ ++

Pheochromocytoma + +

Mucosal neuroma +++

Marfanoid habitus

Primary hyperparathyroidism (PHPT)

• overproduction of parathyroid hormone results in elevated levels of plasma calcium

• Sporadic – 90%

• Familial – 10% (associated with MEN I, MEN 2A)

Ethiology:

• Single adenoma 80-85%

• Hyperplasia 10-15%

• Carcinoma - rare

PHPTclinical features

• Asymptomatic 80%

• Symptomatic • bone changes

• Renal impairment – stones, nefrokalcinosis

• Gastrointestinal symptoms – anorexia, nausea, vomitus, ulcerative disease

• Psychic changes

• Neuromuscular changes – fatigue, muscle pain and weakness

• Articular changes

• Eye changes – calcifications in cornea

Other imaging

• In the early stages there is demineralisation, withsubperiosteal erosions and terminal resorption in thephalanges.

• A 'pepper-pot' appearance :lateral X-rays of the skull.

• Reduced bone mineral density, resulting in eitherosteopenia or osteoporosis. And is assessed by DEXA

• In nephrocalcinosis, scattered opacities within therenal outline.

• There may be soft tissue calcification in arterial walls,soft tissues of the hands and the cornea.

Images

Source: http://uwmsk.org/residentprojects/hpth.html

7.11.2015

4

PHPTwork up

• Laboratory : • elevated S-Ca, i-Ca, U-Ca/ 24hours

• Elevated iPTH

• 25-OH-D3 to exclude secondary HPT in hyperPTH states

• Imaging studies:• Ultrasound of the neck – sensitivity for adenoma 69-

96%

• scinitigraphy

PHPTTreatment

• Surgery• Adenoma – extirpation

• Hyperplasia – resection of 3 and ½ of parathyreoid glands / totalparathyreoidectomy with autotransplantation

– Indications for surgery

• Symptomatic

• Asymptomatic + age (<50y), S-Ca > 0,25 mmol over upper levelof normal, GF<60 ml/min , decrease in BMD ( T-score/Z-score < -2,5 SDs)

• Non-surgical– Calcimimetics (cinacalcet- MIMPARA)- decrease calcium and PTH

levels, but no increase in BMD

Hypocalcemia

• Hypocalcaemia is much less common thanhypercalcaemia.

• The most common cause of hypocalcaemia isa low serum albumin with normal ionisedcalcium concentration.

Differential diagnosis of hypocalcaemia

Source: Davidson

Hypocalcemia:Clinical manifestation

• Hypocalcemic tetany : This is characterised by musclespasms due to increased excitability of peripheralnerves.

• Triad of carpopedal spasm, stridor and convulsions.

• Trousseau's sign; inflation of a bp cuff on the upperarm to >the SBP is f/b carpal spasm within 3 min.

• Chvostek's sign: tapping over the branches of the facialnerve produces twitching of the facial muscles.

• „Hungry bones“ syndrome – postoperativehypocalcemia is severe and prolonged, despite normalor even elevated levels of PTH

http://www.fpnotebook.com/legacy/Ortho/Wrist/CrpdlSpsm.htm

7.11.2015

5

Management

• Milder symptoms of neuromuscular irritability(paresthesias) and corrected S. Ca >1.875mmol/l : initial Rx with oral Casupplementation.

• 1500-2000 mg of elemental Ca given ascalcium carbonate or calcium citrate/d, individed doses.

• If symptoms do not improve with oralsupplementation, iv Ca infusion is required.

Management of severe hypocalcaemia

• 10-20mL 10% ca gluconate i.v. over 10-20 min

• Continuous i.v. infusion may be required forseveral hrs (equivalent of 10 mL 10% calciumgluconate/hr)

• Cardiac monitoring is recommended .

• If Mg deficiency :50 mmol Mgcl i.v. over 24 hrs

Hypoparathyroidism

• The MC cause is damage to the parathyroidglands (or their bld supply) during thyroid Sx.

• Rarely, hypoparathyroidism can occur as aresult of infiltration of the glands, e.g. inhaemochromatosis and Wilson's disease.

Pseudohypoparathyroidism

• The disorder is characterized by a lack ofresponsiveness to PTH, resulting in ↓ Ca, ↑Po4,and appropriately ↑ PTH.

• Individuals with Albright’s hereditaryosteodystrophy have short stature, shortened 4th

& 5th metacarpals, rounded facies, and oftenmild mental retardation.

• The kidney responds as if PTH were absent. ThePTH receptor itself is normal, but there aredefective post-receptor mechanisms due tomutations.

Albright's hereditary osteodystrophy

Source:www.netterimages.com

Management of hypoparathyroidism(peristent/longterm hypocalcaemia)

• Persistent hypoparathyroidism andpseudohypoparathyroidism are Rx with oralcalcium salts and vitamin D analogues, either1α-hydroxycholecalciferol (alfacalcidol) or1,25-dihydroxycholecalciferol (calcitriol).

• Recombinant PTH is available as SC injectiontherapy for osteoporosis.

7.11.2015

6

Osteoporosis

Definition of OsteoporosisNIH Consensus Conference

• Osteoporosis is a skeletal disorder characterized by compromised bone strength predisposing to an increased risk of fracture.

• Osteoporosis is due to:

– Low peak bone mass

– Bone loss

– Both low peak bone mass and bone loss

• Bone strength reflects the integration of two main features:

– bone density

– bone quality

NIH Consensus Development Panel. JAMA. 2001;285:785.

Fragility Fracture

• A fragility fracture is one that results from mechanical forces that would not ordinarily cause fracture in a healthy young adult.

• This is quantified as forces equivalent to a fall from a standing height or less.

• 1 in 2 women and 1 in 5 men aged 50 will suffer a fragility fracture in their remaining lifetime

Normal Osteoporosis

SKELETAL FORM AND

FUNCTION

OSTEOPOROSIS

The Skeleton is Composed of Cortical and

Trabecular Bone• The skeleton is a dynamic organ comprised of over 200 discrete bones with

mechanical, protective, and metabolic functions

• Composed of two types of bone:

– Cortical bone: Outer dense shell (~ 80% of total skeletal mass)

– Trabecular bone: Network of connecting plates inside the cortical shell (~ 20% of total skeletal mass)

Femur

Trabecular bone Cortical

bone

Periosteum

Haversian system

Vertebrae

Dempster DW. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 6th ed. 2006:7-11.

Distribution of

Cortical and Trabecular BoneThoracic and 75% trabecularLumbar Spine 25% cortical

Femoral Neck25% trabecular75% cortical

Hip Intertrochanteric Region 50% trabecular

50% cortical

1/3 Radius >95% Cortical

Ultradistal Radius25% trabecular

75% cortical

7.11.2015

7

A Healthy Skeleton Requires a Balance of Bone

Resorption and Bone Formation

Baron R. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 5th ed. 2003:1-8. Bringhurst FR, et al. Harrison’s Principles of Internal Medicine. 16th ed. 2005:2238-2249.

Lindsay R, et al. Treatment of the Postmenopausal Woman: Basic and Clinical Aspects. 2nd ed. 1999:305-314.

Resting Reversal

Activation

When bone turnover is increased, bone loss

dominates

Formation: 3 months

Resorption: 10 days

Mineralization

Lanham-New SA. Proc Nutr Soc. 2008;67: 163-176; Burger H, et al. Am J Epidemiol 1998;147: 871-879; Recker R, et al. J Bone Miner Res 2000;15:1965-1973; Sambrook P, et al. Baillieres Clin Rheumatol 1993;7: 445-457; Weaver CM, et al. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 7th ed. 2008:206-208.

Bone Mass Rapidly Decreases with the Onset of

Menopause

Onset of Menopause*

Attainment of peak bone mass

Bo

ne

Mas

s

Age (years)10 20 40 50 60 70 80300

Formation >

Resorption

Peak bone mass

Resorption >

Formation

Bone loss

* Menopause occurs for approximately one year period during this timeframe

Looker, A.C., et al. Osteoporos Int 1998 8:468-89, with permission from Springer-Verlag.

Patterns of Bone Loss is in both sexes

OSTEOPOROSIS

OSTEOPOROSIS

Wasnich RD: Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4th edition, 1999 p.257

50 60 70 80

Vertebrae

Hip

Wrist

40

30

20

10

Age (Years)

An

nu

al in

cid

ence

per

10

00

w

om

en

Main osteoporotic fractures Forms of osteoporosis

• Primary osteoporosis

– postmenopausal (type 1)

– senile (type 2)

• Secondary osteoporosis

• Idiopatic osteoporosis

– in premenopausal women and men

• Idiopatic juvenile osteoporosis

Payer J., Rovenský J., Killinger Z. Lexikón osteoporózy. SAP 2007

7.11.2015

8

Women: 10-20% ; Men: 45-60%

Genetic (congenital)

•Cystic fibrosis

•Ehlers-Danlos syndrome

•Glycogen storage disease

•Gaucher disease

•Hemochromatosis

•Homocystinuria

•Hypophosphatasia

•Idiopathic hypercalciuria

•Marfan syndrome

•Menkes steely hair syndrome

•Osteogenesis imperfecta

•Porphyria

•Riley-Day syndrome

•Hypogonadal states

Hypogonadal states

•Androgen insensitivity

•Anorexia nervosa/bulimia

•Female athlete triad

•Hyperprolactinemia

•Panhypopituitarism

•Premature menopause

•Turner syndrome

•Klinefelter syndrome

Endocrine

•Acromegaly

•Adrenal insufficiency

•Cushing syndrome

•Estrogen deficiency

•Diabetes mellitus

•Hyperparathyroidism

•Hyperthyroidism

•Pregnancy

Deficiency states

•Calcium deficiency

•Magnesium deficiency

•Protein deficiency

•Vitamin D deficiency

•Bariatric surgery

•Celiac disease

•Gastrectomy

•Malabsorption

•Malnutrition

•Parenteral nutrition

•Primary biliary cirrhosis

Inflammatory diseases

•Inflammatory bowel disease

•Ankylosing spondylitis

•Rheumatoid arthritis

Hematologic and neoplastic

•Hemochromatosis

•Hemophilia

•Leukemia

•Lymphoma

•Multiple myeloma

•Sickle cell anemia

•Systemic mastocytosis

•Thalassemia

•Metastatic disease

Drug-induced

•Anticonvulsants

•Antipsychotic drugs

•Antiretroviral drugs

•Cyclosporines and tacrolimus

•Cytotoxic drugs

•Furosemide

•Glucocorticoids

•GnRH analogs

•Heparin

•Lithium

•Selective serotonin reuptake inhibitors

•Thyroxine (excessive)

Miscellaneous

•Alcoholism

•Amyloidosis

•Congestive heart failure

•Depression

•Chronic renal disease

•HIV disease/AIDS

•Immobility

•Multiple sclerosis

•Organ transplantation

•Sarcoidosis

•Weightlessness

Causes of secondary

osteoporosisMain causes of secondary osteoporosis

• Endocrine disorders

• Cushing sy,

• Thyrotoxicosis,

• Hyperprolactinemia,

• Hypogonadism,

• GH-deficiency,

• Diabetes mellitus

• Gastrointestinal disorders

• Drug-induced osteoporosis

DIAGNOSIS

OF OSTEOPOROSIS

OSTEOPOROSIS

Physical examination

Osteoporosis

• Osteoporosis

• Height loss

• Body weight

• Kyphosis

• Humped back

• Tooth loss

• Skinfold thickness

• Grip strength

Vertebral fracture

• Vertebral fracture

• Arm span-height difference

• Wall-occiput distance

• Rib-pelvis distance

Amanda D. Green. JAMA 2001 vol.292(23)

Physical examination Bone Densitometry

• Non-invasive test for measurement of BMD

• Major technologies

– Dual-energy X-ray Absorptiometry (DXA)

– Quantitative Ultrasound (QUS)

– Quantitative Computerized Tomography (QCT)

• Many manufacturers

• Numerous devices

• Different skeletal sites

7.11.2015

9

DXA

• “Gold-standard” for BMD measurement

• Measures “central” or “axial” skeletal sites: spine and hip

• May measure other sites: total body and forearm

• Extensive epidemiologic data

• Correlation with bone strength in-vitro

• Validated in many clinical trials

• Widely available

51

Diagnosis of Osteoporosis Using

Central DXA: WHO Definition

• DXA Dual Energy X-ray Absorptiometry

1. To diagnose osteoporosis

2. To predict fracture risk

3. To monitor therapy

World Health Organization. Technical Report Series 921. Prevention and Management of Osteoporosis: Report of a WHO Scientific Group. 2003.National Osteoporosis Foundation. Clinician’s Guide to Prevention and Treatment of Osteoporosis. 2008

Normal bone density

Osteopenia

T-s

core

- 1.0

- 2.5

Osteoporosis

Using T-scores vs. Z-scores

T-scores

• WHO diagnositic classification in postmenopausal women and men age 50 and older

• WHO classification with T-score cannot be applied to healthy premenopausal women, men under age 50, and children

Z-scores

• For use in reporting BMD in healthy premenopausal women, men under age 50, and children

• Z-score -2.0 or less is defined as “below the expected range for age”

• Z-score above -2.0 is “within the expected range for age”

Which Skeletal Sites Should Be Measured?

Every Patient

• Spine– L1-L4

• Hip– Total Hip

– Femoral Neck

Some Patients

• Forearm (33% radius, 1/3 radius)

– If hip or spine cannot be measured

– Hyperparathyroidism

– Very obese

Osteoporotic fracture and BMDFractures/1,000 person-years Number of fractures

1.0 0.5 0.0 -0.5 -1.0 -1.5 -2.0 -2.5 -3.0 -3.5

Fracture rate

Women with fractures

0

10

20

30

40

50

0

100

200

300

400

• Fracture rates increase with decreasing BMD

• However, the absolute number of women with fractures is highest for women with mid-range T-scores

Siris ES, et al. Arch Intern Med 2004;164:1108-1112.

Further Independent Risk Factors for Fracture

• Risk factors:– Age

– Low BMD

– Previous fractures

– Low BMI

– Prior history of fracture

– Family history of hip fracture

– Current smoking

– High intake of alcohol

– Rheumatoid arthritis

– Glucocorticoid therapy

Kanis JA, et al. Osteoporos Int. 2001;12:989-995. Kanis JA, et al. Osteoporos Int. 2001;12:417-427. Kanis JA, et al. Osteoporos Int. 2005;16:581-589.

All risk factors add

to the 10 – year probability

of fracture that

can be estimated

using FRAX ®

7.11.2015

10

http://www.shef.ac.uk/FRAX/index.htm.

The FRAX® tool has been developed by WHO to evaluate fracture risk of patients.

The FRAX® models have been developed from studying population-based cohorts from Europe, North America, Asia and Australia. In their most sophisticated form, the FRAX® tool is computer-driven and is available on website.

Enhances ability to predict fracture risk for an individual given the bone mineral density

of femoral neck (if available) plus clinical risk factors

Provides individualized ABSOLUTE RISK over a 10-year period (similar to Gail model

for risk of breast cancer or Framingham model for risk of cardiovascular disease)

Hip fracture

Major osteoporotic fracture

Guidelines regarding WHEN to intervene are emerging

FRAX™Fracture Risk Assessment

11ca023

US FRAX

Genant & Wu

Normal (Grade 0)

Wedge fracture Biconcave fracture Crush fracture

Mild fracture(Grade 1, ~20-25%)

Moderate fracture(Grade 2, ~25-40%)

Severe fracture(Grade 3, ~40%)

X-ray examination Semiquantitative visual grading of vertebral fractures

Biochemical Markers of Bone Turnover

Formation

osteoblasts

Resorption

osteoclasts

Formation Markers

• Osteocalcin (OC)

• Bone-specific alkaline

phosphatase (BAP)

• Amino terminal propeptide of

type I collagen (PINP)

• Carboxyl terminal propeptide of

type I collagen (PICP)

Resorption Markers

• Pyridinoline (Pyr)

• Deoxypyridinoline (dPyr)

• Amino terminal telopeptide of

type I collagen (NTX)

• Carboxyl terminal telopeptide of

type I collagen (CTX)

Monitoring of treatment

• Measurement of bone mass by DXA

– 12 months after begining of treatment and than at 24-month

intervals as needed

• Biochemical markers of bone turnover

– At 3 and 6 months after therapy initiation

• Clinical examination

– After initiating of therapy in 1 month to reelevauteand to assess

tolerance and therafter at 3 months, 6 month and 1 year

• 25-hydroxyvitamin D

– Should be measured after 3-4 months of adequate

supplementation and should not be repeated if an optimal level

(at least 75 nmol/l) is achieved.

Favus MJ. Bisphosponates for Osteoporosis. N Engl J Med 2010; 363:2027-35Papaioannou A et al. 2010 clinical practice guidelines for diagnosis and management

of osteoporosis in Canada. CMAJ 2010. 182(17): 1864-1873

THE BURDEN OF

OSTEOPOROSIS

OSTEOPOROSIS

7.11.2015

11

Osteoporosis is a Prevalent

DiseaseAffects 200 million women worldwide1

• 1/3 of women aged 60 to 70

• 2/3 of women aged 80 or older

Approximately 20-25% of women over the age of 50 have one or more vertebral fractures2

• United States: 25%3

• Australia: 20%4

• Western Europe: 19%5

• Scandinavia: 26%5

• Denmark: 21%6

• Slovakia: 15-20%

1. International Osteoporosis Foundation 4. Jones G et al., Osteoporos Int 1996, 6:2332. Melton LJ 3rd et al., Spine 1997, 22:2S 5. O'Neill et al., J Bone Miner Res 1996, 11:10103. Ettinger B et al., J Bone Miner Res 1992,7:449 6. Jensen GF et al., Clin Orthop 1982,166:75

Prior Fractures Predict Future Fractures

• Women with a prior fracture have an 86% increased risk of any subsequent fracture1

• 1 in 5 postmenopausal women with prior vertebral fracture will have another vertebral fracture within 1 year2

• 45% of women with hip fracture report prior fragility fracture3-5

• Women with prior fracture have approximately 2-fold higher risk of suffering a hip fracture6

1. Kanis JA, et al. Bone 2004; 285: 375-382; 2. Lindsay R, et al. JAMA 2001; 285: 320-323; 3. Lyles KW, et al. ASBMR 2006; 4. Edwards BJ, et al. Clin Orthop Rel Res 2007; 461: 226-230; 5. McLellan AR, et al. (2004) Effectiveness of Strategies for the Secondary Prevention of Osteoporotic Fractures in Scotland (CEPS 99/03). NHS Quality

Improvement Scotland; 6. Klotzbuecher CM et al. J Bone Min Res 2000;15:721-739.

Hip fractures are associated with a significant increase in mortality.

Consequences of hip fracture

Cooper. Am J Med 1997; 103(2A):12-19.

40%

Unable to walk independently

30%

Permanentdisability

20%

Death within one year

80%

Unable to carry out at least one independent activity of daily living

One year after hip fracture

Consequences of osteoporosis

• Acute & chronic pain

• Breathing difficulties

• Problems with digestion

• Depression

• Possible long-term nursing care

• Surgical complications

• Increased mortality

TREATMENT

OF OSTEOPOROSIS

OSTEOPOROSIS

Principles of the Care for a Patient with

Osteoporosis

• General principles– elimination of known risk factors of osteoporosis

– reduction of risk of fall (various barriers, bad sight, drugs ...)

– modification of eating habits and physical activity

• Supporting therapy– physical therapy, physiotherapy,

analgetics, myorelaxants

• Specific therapy

Rovenský J., Payer J. (Edt.), The Dictionary of Rheumatology. Springer Verlag 2009

7.11.2015

12

Summary of Evidence for Fracture Risk

Reduction

Drug

Fracture risk reduction

Vertebral Nonvertebral Hip

Calcitonine Yes No effect demonstrated No effect demonstrated

Raloxifene Yes No effect demonstrated No effect demonstrated

Ibandronate Yes No effect demonstrated No effect demonstrated

Alendronate Yes Yes Yes

Risedronate Yes Yes Yes

Zolendronic acid Yes Yes Yes

Denosumab Yes Yes Yes

Strontium ranelate Yes Yes Yes

Teriparitide Yes Yes No effect demonstrated

AACE Postmenopausal Osteoporosis Guidelines, Endocr Pract. 2010; 16(Suppl 3), p. 22Body JJ et al. Osteoporos Int (2010) 21:1657-1680

Osteoporosis Therapies

and Patient Adherence

Side effects

Safety

concerns

Health

problems

Lack of

results

Siris E.S. et al. Am. J. Med. 2009; 122: S3-S13

Patients initiating therapy

Patients continuing therapy

Adherence

Lack of

motivation

Cost

Inconvenient

dosing

Withdrawn

by others

Less than 50% of patients persist with their osteoporosis therapy for more than 1 year

VITAMIN D

OSTEOPOROSIS

Vitamin D and Calcium Insufficiency-Related loss

of Bone Quality

Age-related vitamin D and calcium insufficiency

Negative calcium balance

Insufficient supply of calcium

Impaired mineralization

Secondary hyperparathyroidism

Increased bone turnover

Loss of bone quality in women and men

Effects of vitamin D

• Cardiovascular events

• Arterial hypertension

• Metabolic syndrome

– Diabetes mellitus

– Obesity

– Dyslipidemy

• Autoimunity

– Intestinal bowel disease

– Inflamatory diseases

– Sclerosis multiplex

– Psoriasis

Osteoporosis Falls

Dawson-Hughes B. et al. Osteoporos Int 2010; 21:1151-1154

7.11.2015

13

VDR localisation

System Tissue – cells

Gastrointestinal tract esophagus, stomach, intestinal cells, hepatocytes

Cardiovascular system myocytes, vascular smooth muscle, endotel

Kidneys proximal and distal tubules

Endocrine system thyroid, parathyroid, pancreas

Reproductive system testes, ovarium, placenta, uterus, endometrium

Immunity thymus, bone marrow, B-, T-lymphocytes

Respiratory system alveoles

Skeleton osteoblasts, osteocytes, chondrocytes

Muscles muscle fiber, fibroblasts, collagen

Skin epidermis, hair follicles

CNS neurons, glioblast, astrocytes

Clasification of vitamin D

saturationKALCIDIOL (25-OH vitD3)

• Deficiency 9 ng/ml (22.5 nmol/l)

• Light definciency 20 ng/ml (50 nmol/l)

• Insuficiency 30 ng/ml (75 nmol/l)

• Optimum 30 – 80 ng/ml

• Toxicity 150 ng/ml (375 nmol/l)

Serum 25(OH)D3, ng/mL

Serum 25(OH)D3, nmol/L

0 25 50 75 100 nmol/l

0 10 20 30 40 ng/ml

DEFICIENCY INSUFICIENCY OPTIMUM

HYPOVITAMINOSIS

Recommended daily intake in women older than

50 years

Calcium Vitamin D3

NOF 1200 mg/day 800 – 1000 IU/day

IOF 1 300 mg/day 800 – 1000 IU/day

WHO/FAO 1 300 mg/day 600 – 800 IU/day

NOF = National Osteoporosis Foundation 2010

NOF Scientific Statement: Update Recommendations for Calcium and Vitamin D3 Intake. 7. April 2010

IOF = International Osteoporosis Foundation 2010

Dawson-Hughes B., et al. Osteoporos Int. 2010; 21(7): 1151-4

WHO/FAO = World Health Organization/Food and Agricultural Organization of United Nations 2010

Vitamin and mineral requirements in human nutrition. 6. June 2010

Endocrinology of gonads

Male hypogonadism

Female hypogonadism

Hyperandrogenism in females

Male sex hormones

Hormone Testicular secretion Adrenal secretion Peripheral

secretion

Testosterone 95 <1 <5

Dihydrotestosterone <20 <1 80

Estradiol <20 <1 80

Estron <2 <1 98

DHEAS <10 90 -

Androgen Androgenic potential

Dihydrotestosterone 300

Testosterone 100

Androstendion 10

DHEA, DHEAS 5

Testosterone

• Produced in Leydig cells (95%) and adrenals (5%)

• In blood:

– 60% bound to sex hormone binding globuline (SHBG)

– 38% bound to albumin

– 2% free (active)

• It is converted to dihydrotestosterone in tissues

• Production is regulated by pituitary (luteinazinghormone)

7.11.2015

14

Effects of testosterone

• Sexual differentiation

• Spermatogenesis

• Libido

• Effect on CNS, cognitive function

• Effect on blood coagulation

• Effect on cardiovascular system

Male hypogonadism

• Clinical syndrome associated with inadequate production of testosterone (androgen deficiency) and lowered amount of spermatozoa production

Classification of hypogonadism

1) Primary• Klinefelter syndrome• Iné chrom. defekty (XY/XXY,

XX/XXY, XXXY, XXXXY...)• Anorchism• Kryptorchism• Leydig cells aplasia• Noonan syndrome• „Adult seminiferous tubule

failure“• „Adult Leydig cell failure“• Defect testosterone synthesis• other (trauma, RAT, drugs…)

2) Secundary• Panhypopituitarism• Defect of LH + FSH production

– Kallmann sy– Prader-Williho sy– Laurence-Moon sy– Bardet-Biedl sy– Gordon-Holmes sy

• Inactive LH production• Hyperprolaktinemia• Hypothalamic disorders

(stress, alcohol, malnutrition)• Cushing sy

3) Defect of androgen receptors

Diagnosis of hypogonadism

• Clinical symptoms typical for hypogonadism

+

• Inadequately low total testosterone levels

• (never treat just lab test!)

Clinical symptoms of hypogonadism

Typical Associated

Disturbance of sexual differentiation,

aspermia

Low energy, motivation

Reduced libido Depression

Reduced erection Impaired concentration and memory

Gynaecomastia Sleep disturbance

Reduced sexual hair (pubic, face) Mild anemia

Small testes Higher fat mass

Low BMD Lower physical activity

Reduced muscle strength

„Hot flushes“

7.11.2015

15

Klinefelter syndromeExamination of patient with

hypogonadism

• Physical examintion

• Lab tests

• Spermiogram

• Testicular biopsy

• Genetics

Physical examination

• Reduced men hair

• “hypogonadal facies”

• Gynecomastia

• Eunuchoid habitus (when onset before puberty)

• Genital examination (volume on Prader orchidometer min 15 ml)

Lab tests

• Total testosterone

• Free testosterone when indicated

• FSH

• LH

• PRL

• TSH

Other tests

• LHRH test (when hypothalamic disorder is suspected)

• Genetics (susp. Klinefelter syndrome)

• Pituitary MRI (in secondary hypogonadism)

• DXA

Treatment

• 2 problems:

• Clinical symptoms of hypogonadism

– Testosterone substitution

• Fertility

– Spermatogenesis induction

7.11.2015

16

Testosterone treatment-contraindications

• Prostate cancer, breast cancer

• Hematocrit> 50%

• Sleep apnoe syndrome

• Heart failure

• Prostate nodules, or PSA 4 ng/ml or PSA 3 ng/ml with high risk of prostate cancer after urologist agreement

Testosterone medication

• T enanthenate alebo cypionate 75- 100 mg i.m. weekly or150- 200 mg every 2 weeks

• T patches á 5 mg 1-2 daily

• T gel 1% 5-10 g

• 30 mg bucal T every 12 hours

• Subcutaneous T every 3- 6 months•

• Oral T undekanoate, i.m. T undekanoate

Take home message- male hypogonadism

• Primary (genetic or urologic disorders)• Secondary (hypothalamic, pituitary disorders)

• Diagnosis: total T, free T, FSH, LH, PRL, TSH, spermiogram, urologic, genetic tests, pituitary MRI

• Treatment: – causal treatment (e.g. surgery)– Testosterone subst. or fertility induction

Case report 1

• 55 years old patient was sent to endocrinology room with weakness, low libido and low total testosterone in lab. Urologic examination was negative. What will you do:

• A) testosterone substitution• B) check FSH, LH, PRL a TSH• C) Send the patient to genetic tests• D) nothing- testosterone declines usually with

age

Case report 1

• In patient we found very low level of FSH and LH. PRL and TSH is in normal range. What is the next step:

• A) it is primary hypogonadism I will send the patient to genetic tests

• B) it is primary hypogonadism I will send the patient to testes biopsy

• C) it is secondary hypogonadism I will order pituitary MRI

• D) it is secondary hypogonadism I will send the patient to genetic tests

Case report 1

• On MRI we found pituitary tumor 3x2 cm without optic nerve compression. Next step is?

• A) evaluation of other pituitary hormones

• B) send the patient for surgery

• C) I will prescribe testosterone patches

• D) I will send the patient for genetic tests

7.11.2015

17

Case report 1

• In other pituitary tests we found panhypopituitarism

• After hormonal pre-treatment he absolved transsphenoidal surgery

• Histology: nonfunctionig adenoma

• 2 months after surgery the patient had normal hormonal levels without any medication

Female hypogonadism

Female sex hormones

• Estradiol

– Most potent

– Production: ovaries

• Estron

– Postmenopausal

– Production: ovaries + peripheral tissues

• Progesterone

– Produced in corpus luteum

Menstrual cycle

Effects of estrogens

• Sexual differentiation

• Menstrual cycle

• Body changes during pregnancy

• Saving calcium for bones (osteoporosis prevention)

• HDL rise, TAG decline

• Activation of coagulation

Female hypogonadism

• Primary

– Prepubertal (genetic syndromes)

– Postpubertal (premature ovarian failure)

• Secondary

– Pituitary or hypothalamic dysfunction

7.11.2015

18

Premature ovarian failure (POF)

• Amenorhea and estrogen deficiency associated with high levels of gonadotropins in women younger than 40 years

Causes of POF

• Chromosomal abnormalities (60%)

• Autoimunity (20%)

• Others (20%)

Other causes of POF

• Iatrogenic– CHT, RAT, drugs

• Metabolic disorders – (galactosemia)

• Infections – mumps, CMV, HIV, shigella

• Idiopathic – Enviromental factors

Genetic causes of hypogonadism

• Turner syndrome /45X/+ mosaic

• Trisomy X /47XXX/

• Gene mutations

– Swyer syndrome /XY gonad. dysgenesis/

– Savage syndrome

– Genetic mutations of LH, FSH and their receptors

Turner syndrome

• Monosomy of X

• Incidence 1:3000

• Short stature, gonad. dysgenesis, anomaliesuropoet. system, heart, aortal defects

Turner syndrome

7.11.2015

19

Clinical signs of ovarian failure

• Amenorhea

• Symptoms of estrogen deficiency (hot flushes, osteoporosis etc)

Diagnosis of POF

• High FSH, LH

– FSH is higher then 40 mIU/l

• Low estradiol

• Karyotype

• Pelvic ultrasound

• DXA

• Screening of autoimmune diseases (celiakia, DM 1, Hashimoto dis., Addison dis.)

Treatment of female hypogonadism

• HST (estrogens)

• Fertility

– Usually problematic issue

– Ovarian stimulation in IVF usually not succesfull

– Donors of oocytes

– Glucocorticoids in autoimune ovarian failure

Take home message: female hypogonadism

• Classification– Primary (POF)– Secundary (pituitary, hypothalamus)

• Diagnosis– estradiol, FSH, LH -3-5 day of cycle, TSH, PRL / dif dg amenorhea

also androgens/, gynecol. exam, genetics

• Treatment– Treat the cause if its possible– HST– Induction of fertility when desired

Female hyperandrogenic diseases

Classification

• Polycystic ovarian syndrome (PCOS)- 95%

• Tumors producing androgens (ovarian, adrenal)

• Congenital adrenal hyperplasia

7.11.2015

20

PCOS

• Prevalence 5-10%

• Overproduction of androgens in ovaries and adrenals associated with insulin resistance

• Exact patomechanism is not known

Clinical signs of PCOS

• Anovulation, oligomenorhea- amenorhea

• Hirsutism

• Acne

• Alopecia

Scale of hirsutism according toFerriman- Gallway score

Diagnostic criteria of PCOS

• Clinical and/or lab signs of hypernadrogenism

• Oligomenorhea- amenorhea

• Polycystic ovaries on ultrasound

• For diagnosis you need 2 of 3 criteria

Lab tests in PCOS

• Elevated testosterone (total and free)

• Elevated adrenal androgens (DHEAS, androstendion)

• Elevated LH (not specific)

• Elevated insulin level

Differential diagnosis

• Androgens producing tumors

– Older women, quick onset of clinical signs

• Congenital adrenal hyperplasia

– Typically elevated 17 OH progesterone

7.11.2015

21

Treatment of PCOS

• Causal treatment ? (pathogenesis not known)

• We solve 2 problems:

• Treatment of hirsutism– HAK, cyproteron acetate

• Ovulation induction– Clomiphen citrate

Take home message: female hyperandrogenism

• Causes: PCOS /95%/, CAH, adrenal and ovarian tumors

• Clinical signs: oligo/amenorhea, hirsutism

• Diagnosis– Lab.: testosterone- total and free, FSH, LH, DHEAS,

androstendion, 17-OH progesterone, kortisol

– Imaging: CT, MRI, ovarian ultrasound

• Treatmet: depends on the cause

Case report 2

• 22 year old women was sent to endocr. room with oligomenorhea

• Menarche in 13, till 20 regular cycle

• Objective examination: overweight, hirsutism in linea alba, breast and face

• Gynecol. ultrasound: normal

Case report 2

• Which lab test do we need to evaluate oligomenorhea:

• A) FSH, LH, estradiol, testosterone, DHEAS, androstendion, 17-OH progesterone, kortisol, TSH, PRL

• B) only androgens: testosterone, DHEAS, androstendion, 17-OH progesterone

• C) FSH, LH, estradiol, testosterone, DHEAS, androstendion, 17-OH progesterone

Case report 2

• We found elevated levels of testosterone, DHEAS and androstendion, all other tests were normal. What are we going to do:

• A) MRI of adrenals to exclude adrenal tumors

• B) MRI of pituitary to exclude pituitary tumors

• C) genetics for Turner syndrome

Case report 2

• We know the lab test and now we also know that the MRI of adrenals was negative. What is the diagnosis in this patient:

• A) Congenital adrenal hyperplasia

• B) Cushing syndrome

• C) PCOS

• D) Ovarian tumor