PTH

Calcitriol (1,25-(0H) 2DI) » Ca2*

» P0.J (02)

OR

Synthesued from cholesterol: UV light on skm makes

cholecalciferol|03|.liver then converts if to calcidiol

|2S-|0H)D3|and kidneys convert it to calcitriol

Inhibited by:

High serum P0<

J"

low PTH

Calcitriol (negative feedback)

FGF23

Stimulated by:

Pentagastrin (GI hormone) and high serum Ca2

-;inhibited by

*

P0«3-

lowsemm CatSeeJle^

hrology.HP16

See Nephrology. NP15

Calcitonin Thyroid C cells a Ca 2-(in pharmacologic doses) r

HgCat- Cofactor for PTH secretion

CatMajor intracellular divalent cation

POJ Intracellular amon foundIn all lissues +

Activate Windows

Go to Settings to activat

E-13 Endocrinology Toronto Notes 2023

UV light Diet J ECF Mg

’

lacute) lECFCa1

'

I I

*

Total Ca2

- does not reflect ionized Ca 2

-in

the following circumstances:

• Abnormal albumin levels

• Critical illness

• Chronic hepatic failure/renal failure

When albumin is low,ionized calcium

assessment should be performed

Cholecalcilerol PARATHYROID GLAND -4 Q

i

LIVER tPTH

I f

25 (OH) vitamin D > KIDNEY If ionized calcium is not available,total

calcium can be corrected for albumin using

this approximation:

Corrected Ca2

*

(mmol/ ) - measured Ca 2*

+ 0.02 (40 - albumin)

• for every decrease in albumin by10.

increase in Ca2

'

by 0.2

1-a-hydroxylase

1

T 24.25 (OH)

vitamin D (inert)

11,25 (OH):

calcitriol

iP02 reabsorption

resulting in

r POa excretion in the urine

tCa!

,

and Mg!

-

reabsorption

f 1

Gl KIDNEY Treatment of Hypercalcemia in Clinical

Practice

In clinical practice,treatment is required

if the patient has a) symptomatic

hypercalcemia or b) extremely high

levels of corrected CaJ>

.laboratory

cutoffs may not always be used

BONE

1

I

1 I

r Ca

*

’

-tP0 /

absorption

l Ca

’

excretion Reabsorption 4 T Osteoclast 4

activity

t Ca- + P0 i

2

release

=

J NET EFFECT

V tECFCa2

-

i TECF Calcitriol

IECFP02

i

The symptoms and signs of

hypercalcemia include:

“Bones, stones,groans,and

psychiatric overtones”

n

©

Figure 19. Parathyroid hormone (PTH) regulation

Hypercalcemia

Definition

• total corrected serum (.

'

a i *>2.6 nimol/L OR ionized (.

'

a 2*>l.35 nimol/L

High Ca1

-

Initial investigations

* : PTH

; r

i PTH Normal or t PTH

1 1

4 1 i

i Ported to T PTHrP) Normal or T ROx*

- Drugs: Familial Hypocalcluric Primary Hyperparathyroidism: Tertiary Hyperparathyroidism:

Lithium Hypercalcemia (FHH):

I I

CaJ‘receptor gene defect

Solitary adenoma (81%)

Hyperplasia (15%)

Carcinoma (4%)

MEN 1 and 2a

Increased PTH after

prolonged secondary

hyperparathyroidism

due to renal failure

Humoral mediation: Vitamin D related

Lung cancer.RCC.

pheochromocytoma

1 i I

r Calcidiol

(25-OH vitamin D)

t Calcitriol

l1,25-(0H)ivitamin D)

Low vitamin D metabolites

l i 1

Granulomatous disease:

eg. tuberculosis,sarcoid,

lymphoma

(esp. Hodgkin) which causes

extra-renal production of

calcitriol by macrophages in

the lung and lymph nodes

Excessive calcitriol intake

Immobilization

Malignancy

High bone turnover:

e.g.hypervitaminosis A,

thyrotoxicosis. Paget’s disease

Milk alkali syndrome:

(hypercalcemia,metabolic alkalosis,

and renal insufficiency)

Drugs:theophylline,thiazide

diuretics, estrogen/tamoxifen

Hypervitaminosis D:

Excessive intake ol

vitamin D or its

metabolites

r-i

L J

Figure 20.Differential diagnosis of hypercalcemia

+

Activate Windows

Go to Settings to activate Windi

E l l Endocrinology Toronto Xotes 2023

Approach to Hypercalcemia

1.isthe patient hypercalcemic?

2.is the PTH high/normal or low?

3.if PTH is low, is phosphate high /normal or low?

4.if phosphate is high/normal, is the level of vitamin D metabolites high or low?

The most common cause of

hypercalcemia in hospital is

malignancy-associated hypercalcemia

• Usually occurs In the later stages of

disease

• Most commonly seen in lung,renal,

breast,ovarian,and squamous

tumours,as well as lymphoma and

multiple myeloma

Mechanisms:

• Secretion of PTHrP which mimics PTH

action by preventing renal calcium

excretion and activating osteoclastinduced bone resorption

• Cytokines in multiple myeloma

• Calcitriol production by lymphoma

• Osteolytic bone metastases direct

effect

• Excess PTH in parathyroid cancer

Clinical Features

• symptoms depend on the absolute Ca -Value and the rate of its rise (may be asymptomatic)

Table 28. Symptoms of Hypercalcemia

Cardiovascular Gl Renal Rheumatological MSK Psychiatric Neurologic

Constipation

Anorexia

Nausea

>3 mmol/L (12 mgfdL) Hypotonia

Increased alertness Hyporeflexia

Anxiety

Depression

Cognitive

dysfunction

Organic brain

syndromes

>4 mmol/L|16 mg/dl)

Psychosis (moans)

KIN Polyuria

(Nephrogenic Dl) Pseudogoul

Polydipsia

Nephrolithiasis

(stones)

Renal failure

(irreversible)

Dehydration

Goul Weakness

Bone pain

Chondrocalcinosis (bones)

Arrhythmia

Short 01

Deposition ol Vomiting

Ca tonvalves. (groans)

coronary arteries. PUD

myocardial

fibres

Myopathy

Paresis

Pancreatitis

*'Hypercalcemic crisis (usually >4 mmol/L or 16mg/dl): primary symptoms include oliguria/anuria and mental status changes including

somnolenceand eventually coma *

this is a medical emergency and should be treated immediately!

Before prescribing calcitonin, remember

to ask about fish allergies Treatment

• <3.0 mmol/L:mild, often asymptomatic and does not usually require urgent correction

• 3.0-3.5 mmol/L: may he well tolerated chronically and may not require immediate treatment but may

be symptomatic and prompt treatment is usually indicated

• >3.5 mmol/L: severe hypercalcemia requiring urgent correction due to risk of dysrhythmia and coma

• aggressive treatment of acute symptomatic hypercalcemia

• next treat the underlying cause

• mild asymptomatic hypercalcemia: monitor and avoid thiazide, volume depletion, high Ca -'

diet,

lithium, and bed rest

Differential Diagnosis of Hypercalcemia

• Primary hyperparathyroidism

• Malignancy: hematologic, humoral,

skeletal metastases (>90% from 1

or 2)

• Renal disease:tertiary

hyperparathyroidism

• Drugs: calcium carbonate,milk

alkali syndrome,thiazide, lithium,

theophylline, vitamin A/D intoxication

• Familial hypocakiutic hypcrcakemia

• Granulomatous disease: sarcoidosis,

tuberculosis,Hodgkin's lymphoma

• Thyroid disease:thyrotoxicosis

• Adrenal disease: adrenal

insufficiency, phcochtomocyloma

• Immobilization

Table 29. Treatment of Acute Hypercalcemia/Hypercalcemic Crisis

Increase Urinary Ca

*

1ictetion FLUIDS. FLUIDS. FLUIDS!

Isotonic saline (4-6 L) over 24 hr loop diuretic (e.g. furosernide) but only ilhypervolemic (urine output

>200ml/h)

Calcitonin:

4 lU/kg IM.' SC q12 h

8 lU/kg IM/SC q6 h

Only works lor 48 h.can develop tachyphylaxis

Rapid onset within 4- 6 h

Before prescribing calcitonin,reinember loask about lishallergies

Blsphosphonates (healincnl olchoice)

Suggest zolcdionic acid 4 mg IV ovci 15 min or pairudronatc 60 90 nig IV over 2 h

Inhibits osteoclastic bone resorption, pieventing calcium release horn bone

Effects on calcium levels aie typically seen at 24- 48 li alter administration

Calcitonin often given inconjunction with bisphosphonale. given rapid onset of effect

Indicated in malignancy - related hypercalcemia |IV pamldronatc or aoledronlc acid used)

IIbisphosphonales are contraindicated (i.e. severe renal impairment), donosumab canbe administered

concurrently with calcitonin

Coilicostcioids can be used in hypercalcemia mediated by 1,25 vitamin D. Corticosteroids are polenl

inhibitors ol la hydroxylase and therefore,decrease calcitriol production by activated mononuclear cells

(e.g. in lymphoma,granuloma)

Effects will be seen in 2- 5 d

Treatment of last resort

Indication: severe malignancy-associated hypercalcemia and renal insufficiency or heart failure

Diminish Bone Resorption

Acute Management of Hypercalcemia/

Hypercalcemic Crisis

. Volume expansion (e.g. NS IV 300-

500 cc/h):initial therapy

• Calcitonin (SC): transient, partial

response

• Bisphosphonale (IV): treatment of

choice, adjust dose if CrCi <30 ml/

Oecrease Gl Ca ^'Absorption

min

• Corticosteroid:most useful in vitamin

D toxicity, granulomatous disease,

some malignancies

• Saline diuresis "

loop diuretic

(for volume overload): temporary

measure

Dialysis

Hypocalcemia

Definition

• total corrected serum Ca:

,

<2.2 mmol/L

• mild, asymptomatic:serum Ca -

+<1.9 mmol/L, ionized C a >0 . 8 mmol/L

• severe:serum Ca -'

<1.9 mmol/L and/or symptomatic

r n

L J

+

Activate Windows

Go to Settings to activate Windows.

E45 Endocrinology Toronto Notes 2023

Table 30. Clinical Features of Hypocalcemia Signs and Symptoms ol Acute

Hypocalcemia

• Paresthesias:perioral,hands,and feet

• Chvostek’s sign:percussion ot the

facial nerve just anterior to the

external auditory meatus elicits

ipsilateral spasm of the orbicularis

oculi or orbicularis oris muscles

• Trousseau's sign:inflation of a blood

pressure cuff above systolic pressure

for 3 min elicits carpal spasm and

paresthesia

Acute Hypocalcemia Chronic Hypocalcemia

CNS:lethargy,seizures, psychosis,basal ganglia calcification.

Parkinson’s,dystonia,hcmiballismus.papilledema,pseudotumour

cerebri

CVS:prolonged 01interval » Torsades de pointes (ventricular

tachycardia)

Gl:steatorrhea

ENDO:impaired insulin release

SKIH:dry,scaling,alopecia,brittle and transversely fissured nails,

candidiasis,abnormal dentition

OCULAR:cataracts

MSK:generalized muscle weakness and wasting

Paresthesia

laryngospasm jwilh stridor)

Hyperreflexia

letany

Chvostek's sign (tap CN VII)

Trousseau's sign (carpal spasm)

ECG changes

Oelirium

Psychiatric Sx:emotional instability,anxiety,and depression

Seizure

Note:tetany is a hallmark of hypocalcemia - can be mild or severe

Mild:perioral numbness,paresthesia of hands and feet,muscle spasm

Severe:carpopaedal spasm,laryngospasm, focal/generalized seizures

Hypomagnesemia can impair PTH

secretion and action

Approach to Hypocalcemia

1 . is the patient hypocalcemic?

2. is the PTH high or low?

3. if PTH is high, is phosphate low or normal?

4. is the Mg- * level low?

Watch Out for:

t Volume depletion via diuresis

# Arrhythmias

Approach to Treatment

1. rapidity of treatment depends on severity of symptoms and serum calcium level

a) mild, asymptomatic

calcium supplementation (i.e. elemental calcium 1 g then 500 mg PO '

1 ID)

b)severe and/or symptomatic

severe hypocalcemia is a medical emergency

IV calcium gluconate 1-2 g over 10-20 min followed by slow infusion

if positive Chvostek’s and Trousseau orseizures, first give IV calcium bolus, i.e. 1 amp IV push,

then run Ca2+ IV drip at 1-2 mg/kg/h

2. vitamin D replacement

• needed for Cil absorption of calcium; must use 1,25 vitamin D if PTH level low (hypoparathyroidism)

3. must treat concurrent hypomagnesemia or calcium will not normalize

4. if underlying cause is hypoparathyroidism, the goal is to raise Ca2

'to low normal range (2.0-2.1

mmol/L ) to prevent symptoms but allow maximum stimulation of PTH secretion

Differential Diagnosis of Tetany

• Hypocalcemia

• Metabolic alkalosis (with

hyperventilation)

• Hypokalemia

• Hypomagnesemia

Transient hypoparathyroidism (resulting

in hypocalcemia) is common after total

thyroidectomy (permanent in<3% of

surgeries)

Low Ca'

1

Initial investigations: PTH (PO*

1 ,Cr, Mg;

)

1

I i

t PTH Normal or 1 PTH

1 |

I i i i

Parathyroid Gland

Destruction

Normal P0P iPQ 3

Low Mg!

‘

Liver

Dysfunction 4 I

1

I 1

Vitamin D related 1

Pseudohypoparathyroidism:

PTH resistance secondary to

G-protein deficiency

Acute Pancreatitis:Release of

pancreatic caldecrin decreases

bone resorption

Drugs:Calcitonin,loop diuretics

I T

Drugs: Alcoholism

Antineoplastic

agents

Iatrogenic

Hypoparathyroidism: Hypoparathyroidism:

Post-thyroidectomy Idiopathic/autoimmune

hypoparathyroidism

Post-surgical Infiltrative disease ol

correction of primary parathyroid gland

hyperparathyroidism

Hemuchromatosis Primary

"'

Iablation

HIV

i

t Calcidiol

(25-OH vitamin D)

ICalcitriol

(1,25-

(OH).vitamin 0)

1Calcitriol

<1.25-(0H)yitamin D)

I I I

:Intake and/or Malabsorption: Chronic Renal Failure

e g. celiac disease,IBD,

gastric bypass. CF

Nephrotic Syndrome:

Lose vitamin D binding protein

Drugs:Phenobarbital,phenytoin,

carbamazepine.rifampin,isoniazid

Figure 21. Etiology and clinical approach to hypocalcemia

Hereditary Vitamin D

Resistant Rickets Type II:

Receptor defect

Secondary

Hyperparathyroidism:

Appropriate PT gland response

to low serum CarVitamin D Dependent

Rickets Type I:

Renal 1-a-hydroxyfase

deficiency

r“i

L J

+

Activate Windows

Go to Settings to activate Windows.

E16 Endocrinology Toronto Notes 2023

Metabolic Bone Disease

Corticosteroid Theropy is a Common

Cause of Secondary Osteoporosis

Individuals receiving >7.5 mg of

prednisone daily for over 3 mo should be

assessed for bone-sparing therapy

Mechanism: increased resorption

decreased formation + increased urinary

calcium loss + decreased intestinal

calcium absorption +decreased sex

steroid production

• see 2022 Clinical Practice Guidelines for the Diagnosis and Management of Osteoporosis for details

Osteoporosis

Definition

• a condition characterized by decreased bone mass and microarchitectural deterioration with a

consequent increase in bone fragility and susceptibility'to fracture

• BMD is measured at hip and lumbar spine, BMD '

l

'

-score <-2.5 is indicative of osteoporosis

• osteopenia (low bone mass):BMD with l

'

-score between -1.0 and -2.5

ETIOLOGY AND PATHOPHYSIOLOGY Calcium plus Vitamin D Supplementation and Sisk

of Fractures

0 steoporosis lot 2015:27:367 -376

Purpose: fo review trials of vitan n D and iikum

therapy lor reduung fracture risk in osteoporosis.

Study Systematic review searching Mil 2015.

mlutine, identified 8 ICIs totaling 30970

participants. SCIs reviewed included healthy

adults and ambulatory older adults with medical

conditions (excluding cancer).Vitem in D and cakun

combination therapy was compared to placebo.

Results: Analysis of SCI data revealed that

calcium plus vitamin 0 supplementation produced

a statistically significant reduction in risk of total

fractures(0.85; Cl:0.73-0.98|and in hipfractures

(0.70; CL0.56-0.87).Subgroup analysis was

significant for community dwellingoriisfitutioiialized

patients.

Conclusions:Systematic analysissuggeststhat

vitamin D and calcium therapy significantly decreases

fracture nsk.This study did notspecifically look

at individuals with osteoporosis,however,d sidl

supportsthat vitamin 0 and calcium should continue

to be used as prevenbve treatment for indmduaSat

increased riskof fractures.

Table 31. Secondary Osteoporosis

Gastrointestinal diseases

Gastrectomy

Malabsorption (c.G. Celiac disease,ibd. bariatric surgery)

Chronic liver disease

fating disorder

Poor nutrition

Bone marrow disorders

Multiple myeloma

lymphoma

leukemia

Endocrinopathies

Cushing's syndrome

Hyperparathyroidism

Hyperthyroidism

Premature menopause

Pheumatologic disorders

Rheumatoid arthritis

Sit

Ankylosing spondylitis

Drugs and chemotherapy

Corticosteroid therapy

Anti-epileptic drugs

Chronic heparin therapy

Androgen deprivation therapy

Aromatase inhibitors

Renal disease

Immobilization

C0PD (due to disease,tobacco,and glucocorticoid use)

Dm

Hypogonadism

Malignancy

Secondary to chemotherapy

Myelomaseverc:carpopaedal spasm, laiyngospasm. focal/

generalizedseizures

Clinical Features

• commonly asymptomatic

• height loss due to col lapsed vertebrae

• fractures: most commonly in hip, vertebrae, humerus, and wrist (see Figure 22, E48)

fragility fractures: fracture with fall from standing height or less (does not include fractures of

lingers and toes)

• Dowager’s hump: collapse fracture of vertebral bodies in mid-dorsal region

• x-ray: vertebral compression fractures (described as wedge fractures, require a minimum of 20%

height loss), “codfishing” sign (weakening of subchondral plates and expansion of intervertebral

discs)

• pain, especially backache, associated with fractures

Vitamin D and Calcium for tbc Prtvtntioa »1

Fracture:ASystcmatic Reviewand Meta-analysis

J AM It Netw Open 2019:2x1917789

Purpose: To investigate if fracture r s < sassociated

with supplementation with vitamin D alone or vitamin

Din combination with calcium.

Study Selection:Observational studies with >200

fracture cases and RCTs with >500 participantsthat

reported >10 incident fractures.

Results:Vitamin D suppleraentaton alone wasnot

associated with a reduced risk of any fracture«

hip fracture (RR,1.14:95% Cl.0.98-1.32).Howerer.

combined supplementation with vitamin 0 (400-800

IU daily) and calcium (1000-1200 mg daily) was

associated with a G% reduction in fracture risk (RR.

0.94;95% Cl.0.89-0.991and a IS% reduction of hip

fratlure nsk|RR.0.84;95% Cl, 0.72-0.971.

Conclusion VitannDalonewasnotassociatedwdh

reduced fracture risk but dally supplementation with

a tom bma bon of vitamin 0 and cakium was.

Approach to Osteoporosis

1. assess risk factors for osteoporosis on Hx and physical

2. decide if patient requires BMD testing with dual-energy x-ray absorptiometry (DEXA): men and

women 265 yr (or younger if presence of risk factors,seeTabic 33, E47 )

3. initial investigations

• all patients with osteoporosis: calcium corrected for albumin, CBC, creatinine, ALP, TSH

• also consider serum and urine protein electrophoresis if vertebral fractures, celiac workup, and

24 h urinary Ca•

'

excretion to rule out additional secondary causes

• 25-OH-vitamin D level should only be measured after 3-4 mo of adequate supplementation and

should not be repeated if an optimal level 275 nmol/L is achieved

lateral thoracic and lumbar x-ray if clinical evidence of vertebral fracture (or in individuals at

moderate risk of fracture to help decide if they require medical therapy)

4. assess 10 yr fracture risk by combining BMD result and risk factors

1) WHO Fracture Risk Assessment Tool (ERAX)

2) Canadian Association of Radiologists and Osteoporosis Canada Risk Assessment Tool

(CAROC)

approach to management guided by 10 yr risk stratification into low, medium,and high-risk

5.for all patients being assessed for osteoporosis, encourage appropriate lifestyle changes (see Table 34,

E47)

Clinical Signs of Fractures or

Osteoporosis

• Height loss >3 cm (Sn 92%)

. Weight <51kg (Sp 97%)

. Kyphosis (Sp 92%)

• Tooth count <20 (Sp 92%)

• Grip strength

• Armspan-height difference >5cm

(Sp 76%)

• Wall-occiput distance >4 cm (Sp 92%)

. Rib-pelvis distance <2 finger breadth

(Sn 88%)

r -i

t

_ j

+

Activate Windows

Go to Settings to activate Windows.

EI7 Endocrinology Toronto Notes 2023

1

Table 32. Indications for BMD Testing

Older Adults (age >50 yr) Younger Adults (age <50 yr)

Online Clinical Tools

FRAX

www.shef.ac.uk/FRAX/tool.aspx

CAROC

www.osteoporosis.ca/multimedia/pdf/

CAROC.pdf

All women and men age >65 yr

Menopausal women,and men 50- 64 yr with clinical risk factors for fracture:

Fragility fracture after age40

Prolonged glucocorticoid use

Other high-risk medicationuse (aromatase inhibitors,androgen deprivation therapy)

Parental hip fracture

Vertebral fracture or osteopenia identified on x-ray

Current smoking

High alcoholintake

Low body weight (- 60 kg) or major weight loss (>10% ol weight at age 2Syr)

Rheumatoid arthritis

Other disorders strongly associated with osteoporosis:primary hyperparathyroidism,I10M.

osteogenesis imperfecta,uncontrolledhyperthyroidism,hypogonadism or premature

menopause MSyr). Cushing's disease,chronic malnutrition or malabsovplion.chronic liver

disease.COPD. and chronic inflammatory conditions (c.g.inflammatory bowel disease)

Fragility fracture:

Prolonged use of glucocorticoids

Use of other high-risk medications (aromatase

inhibitors,androgen deprivation therapy,

anticonvulsants)

Hypogonadism or premature menopause

Malabsorption syndrome

Primary hyperparathyroidism

Other disorders strongly associated with rapid

bone loss and/or fracture

Prevention - Hip

Alendronate

Risedronate

Oenosuntab

Teriparatde

Romosozumatr 0.44 RR (0.24-0.79)

Prevention - Honvertebral

Alendronate

Risedronate

Oenosumab

Teriparatde

Romosozunrab 0.67 RR (0.53-0.86)

Prevention - Vertebral

Alendronate

Risedronate

Oenosumab

ferlparatde

Romosozumah 0.33 RR (0.22 0.49)

0.61RR (0.42- 0.901

0.73 RR (0.58 0.92)

0.56RRI0.35-0.90)

0.64 RR (0.25-1.681

Table 33. Osteoporosis Risk Stratification 0.84 RR (0.74-0.941

0.78 RR (0.68-0.89)

0.80 RR (0.67-0.96)

0.62 RR (0.47-0.80)

Unlikely to benefit from pharmacotherapy:encourage lifestyle changes

Reassess risk in 5 yr

Discuss patient preference for management and consider additionalrisk factors

Factors that warrant consideration for pharmacotherapy:

Additional vertebral fraclure(s) identifred on vertebral fracture assessment (VFA) or lateral spine

x-ray

Previous wrist fracture in individuals»65 yr or with1-score <

-2.5

lumbar spine T-score much lower than femoralneckI

- score

Rapid bone loss

Men receiving androgen-deprivation therapy lot prostate cancer

Women receiving aromalase- inhibitor therapy for breast cancer

Long term or repeated systemic glucocorticoid use (oral or parenteral) that docs not meet the

conventional criteria for recent prolonged systemic glucocorticoid use

Recurrent falls (defined as falling 2 or more times in the past 12 mo)

Other disorders strongly associated with osteoporosis

Low-Risk

10 yr fracture risk <10%

Medium-Risk

10 yr fracture risk10-20%

0.57 RR 10.45-0.71)

0.61RR (0.48-0.78)

0.32RR (0.22- 0.45)

0.27 RR 10.19- 0.381

Repeat BMD and reassess risk every1-3 yr initially

Start pharmacotherapy (need to consider patient preference)

Factors Necessary for Mineralization

• Quantitatively and qualitatively

normal osteoid formation

• Normal concentration of calcium and

phosphate in EOF

• Adequate bioactivity of ALP

• Normal pH at site of calcification

• Absence of inhibitors of calcification

High-Risk

10 yr fracture risk >20%;OR

Prior fragility fracture of hip or spine;OR

More than one fragility fracture

Treatment of Osteoporosis

Table 34. Treatment of Osteoporosis in Women and Men

Treatment for Both Men and Women

Diel: elemental calcium 1000-1200 mgfd:vitamin D1000 lU/d

Exercise: 3x30 rain weight bearing exercises,balance exercise,and aerobic exercise/wk

Cessation ol smoking,reduce caffeine intake

Stop/avoid osteoporosis-inducing medications

lifestyle

Effect of High-Dose Vitamin 0 Supplementation

on Volumetric BoneDensity and Bone Strength:A

IfandomizedClinical Trial

JAMA 2019:322:736-45

Purpose:To investigate the effects of vitamin D

supplementation on volumetricBMD and strength.

Methods:311healthy adults (ages 55-701without

osteoporosis,with baseline concentrations of

25-hydroxyvitamr Dof 30-125 nmol/L, were

randomized to receive daily doses ol400 II)

.

4000 IU.or 10004IUvitamin 03 for 3 years.For

parbupantswilh cak

'

un- dietary intake * 1200 mg

'

d,

supplementation was provided. Primary Outcome:

Total volumetric BUD at radius andMia.

Results:Compared wdh the 400 IUgroup,radial

volumetric 8M0 was significantly lower lor the 4000

IUgroup (-3.9 mg HAfcni3:95% confidence interval

(Cl),-6.5 to -1.3) and10040 IUgroup (-7.5 mg HA/

cm3;95% Cl.-10.1to -5.0) with mean

“

« change of

-1.2% (400 IU).-2.4% (4000 IU).and -3.5% (10000

IU|.Compared witbtlie400 IU group,tibia! volumetric

8M 0 differences were -18 ngHA/cm3 (95% Cl,-3.2

In 0.1) (4000 IU)and 4.1mg HA /cm3 (95% Cl.4.0to

-2.2)(10000 IU).with mean % change values of -0.4%

(400 IU).-1.0% (4000If),and -1.7% (10000 IU).

Conclusion. In hear y adults,supplementation win

daily 4000 IU or 10000 Mvitamin 0 lor 3 years was

associated with lower rad a BMD compared with 400

III.10000 IU was assocrated with lower libial BMD.

There were no apparent benefits olh- gh-dose vitamin

0 supplementation for bone health.

Drug Therapy

Bisphosphonate:Inhibitors of

osteoclasts

1st linein prevention of hip,nonvertebral,and vertebral fractures (Grade A):alendronate (PO).risedronate

(PO). zoledronic acid (IV)

Dennsumab:1stline in prevention of hip.nonvertebral.vertebral fractures (Grade A)

'Denosumab should not be abruptly stopped/administration delayed.Increasedrisk of multiple vertebra!

fractures due to increased bone turnover on discontinuation. Used as an alternative initial treatment in

postmenopausal women with osteoporosis who ate at high risk lor osteoporilic fractures.

Parathyroid Hormone Analogue lerrparatide:18- 24 mo duration,followed by long-term arilr- iesorplivc therapy with bisphosphonate or

RANKl inhibitor

RANKL Inhibitors

Sclcrostin Inhibitors Romosozumab: 12 moduration

Treatment Specific to Post-Menopausal Women

SERM (selective estrogen-receptor Ratoxilene:1st line in prevention of vertebral fractures (Grade A)

modulator):agonistic effect on

bone but antagonistic effect on

uterus andbreast

HRT:combined estrogen

progesterone

(sed>ynaecology,GY37)

Advantages:prevents osteoporotic fractures (Grade A to B evidence),improves lipid profile,decreased

breast cancer risk

Disadvantages:increased risk ol OVT/PE.strokemortality,hot flashes,legcramps

Indicated for vasomotor symptoms of menopause

For most women,risks >benefits

Combined estrogen/progestin prevents hip.vertebral, total fractures

Increased risks of breast cancer,cardiovascular events,and DVT/PE r *i

L J

+

Activate Windows

Go to Settings To activate Windows. AL GRAWANY

E-18 Endocrinology Toronto Notes 2023

Wall-Occiput Test for Thoracic Fracturo Rib-Polvis Distanco Tost for Lumbar Fracture

S

'

*

t

rWall

-Occiput

Distance >0 cm '

Rib-Pelvis

Distance <2

Fingerbreadths

Negative Test Positive Test Negative Test Positive Test

Figure 22. Physical examination test for vertebral fractures

Osteomalacia and Rickets

Definition

• osteopenia with disordered calcification leading to a higher proportion of osteoid (unmineralized)

tissue prior to epiphyseal closure:rickets (in childhood), osteomalacia (in adulthood)

Etiology and Pathophysiology

Vitamin D Deficiency

• deficient uptake or absorption

nutritional deficiency

malabsorption: post-gastrectomy,small bowel disease (e.g. celiac sprue), pancreatic insufficiency

• defective 25-hydroxylation

liver disease

anticonvulsant therapy (phenytoin, carbamazepine, phenobarbital)

• loss of vitamin D binding protein

• nephrotic syndrome

• decreased l-a-25 hydroxylation

hypoparathyroidism

• renal failure

Mineralization Defect

• abnormal matrix

• osteogenesis imperfecta

• enzyme deficiency

hypophosphatasia (inadequate ALP bioactivity')

• presence of calcification inhibitors

• aluminum, high dose fluoride, anticonvulsants

Calcium Deficiency

• deficient uptake or absorption

• nutritional deficiency

• malabsorption

• hypercalciuria (in combination with renal phosphate wasting)

Hypophosphatemia

• gastrointestinal: poor nutritional intake, chronic diarrhea, excessive phosphate binders

• renal phosphate wasting

tumour-induced osteomalacia

• Eanconi syndrome

X-linked/autosomal dominant/recessive hypophosphatemic rickets

+

Activate Windows

Go to Settings to activate Windows;

E49 Endocrinology Toronto Notes 2023

Matrix Abnormalities

• type IV osteogenesis imperfecta

• fibrogenesis imperfecta ossium

• axial osteomalacia

Table 35. Clinical Features of Rickets and Osteomalacia

Rickets Osteomalacia

Skeletal pain and deformities, bow-legged

Fracture susceptibility

Weakness and hypotonia

Disturbed growth

Ricketic rosary (prominent costochondral junctions)

Harrison's groove (indentation of lower ribs)

Hypocalcemia

Not assevere

Diiluse skeletal pain

Bone tenderness

Fractures

Gait disturbances(waddling)

Proximal muscle weakness

Hypotonia

Investigations

Table 36. Laboratory Findings in Osteomalacia and Rickets KOIGO 2017Clinical Practice Guideline lor the

{valuation and Management olChronic Kidney

Disease

• Kidney Inter Suppl 2017:7(1):1-6O

• Recommendations far Metabobc Bone Disease

(USD) in Chronic Kdney Oisease (CKO)

Screening

• h CKO patients with evidence ol(KD- MBD and

'

or risk (actorsfor osteoporosis, perforin 6M0

testing to assessfracture risk if resultswi impact

treatment decisions

• In patientswitn CKO-BMD.rt is reasoneple to

perform a bone biopsy if knowledge of the type

of renal osteodystrophy will impact treatment

decisions

Management

• Treatment of CKD MBO should be based on serial

assessments of PO ^

Ci\ and PIH levels,

ccrsdered together

• Suggest owerirg elevated P043- tei-els towards

the normal range

• Hvoidbyperglycemiainidnltpatienlsandmanlaiii

serum Cahn age appropr ate normal range in

cMdien

Disorder Serum Phosphate Serum Calcium Serum ALP Other Features

Vitamin D Deficiency

Hypophosphatemia

Proximal Renal Tubular Decreased

Acidosis

Conditions Associated with Normal

Abnormal Matrix Formation

Decreased to normal

Normal

Decreased

Decreased

Increased

Increased

Decreased ealertriol

Normal Normal Associated with hyperchloremic

metabolic acidosis

Normal Normal

• radiologic findings

• pseudofractures (AKA Looser zones),fissures, narrow radiolucent lines-thought to be healed

stress fractures or the result of erosion by arterial pulsation

loss of distinctness of vertebral body trabeculae;concavity of the vertebral bodies

changes due to secondary hyperparathyroidism:subperiosteal resorption of the phalanges, bone

cysts,resorption of the distal ends of long bones

others:bowing of tibia, coxa profundus hip deformity

• bone biopsy: usually not necessary but considered the gold standard for diagnosis

Treatment

• definitive treatment depends on the underlying cause

• vitamin D supplementation

• PO-i 3-supplements if low serum POt 3~,Ca—supplementsfor isolated calcium deficiency

• bicarbonate if chronic metabolic acidosis

Renal Osteodystrophy

Definition

• changes to mineral metabolism and bone structure secondary to CKD

• represents a mixture of four types of bone disease:

• osteomalacia:low bone turnover combined with increased unmineralized bone (osteoid)

adynamic bone disease:low bone turnover due to excessive suppression of parathyroid gland

osteitis fibrosa cystica:increased bone turnover due to secondary hyperparathyroidism

• mixed uremic osteodystrophy: both high and low bone turnover, characterized by marrow

fibrosis and increased osteoids

• metastatic calcification secondary to hyperphosphatemia may occur

Pathophysiology

• metabolic bone disease secondary to chronic renal failure

• combination of hyperphosphatemia (inhibits l,25(OH)2 vitamin D synthesis) and loss of renal mass

(reduced 1-a-hydroxylase)

Clinical Features

• soft tissue calcifications, necrotic skin lesions if vessels involved

• osteodystrophy, generalized bone pain, and fractures

• pruritus

• neuromuscular irritability and tetany may occur (with low serum calcium)

• radiologic features of osteitis fibrosa cystica,osteomalacia, osteosclerosis, osteoporosis

ri

u J

Investigations

• serum (.

'

a -'corrected for albumin, POt > -, P I H, AI.P, ± imaging (x-ray, BMD), ± bone biopsy (gold

standard;only done if results inform treatment) +

Activate Windows

Go to Settingsto activate Window:

E50 Endocrinology Toronto Xotcs 2023

Treatment

• prevention

• maintenance of normalserum Ca -’

and P04 -*-by restricting P04 Hntake to 1 g once daily

• Ca Supplements; PO4 -' binding agents (calcium carbonate, aluminum hydroxide)

• activated vitamin D (calcitriol) with close monitoring to avoid hypercalcemia and metastatic

calcification

• bisphosphonates and denosumab are not often used for treatment (can worsen the adynamic

components of renal osteodystrophy); bone biopsy may indicate if there are signs of increased bone

turnover amenable to bisphosphonates

Paget’s Disease of Bone

Definition

• a metabolic disease characterized by excessive bone destruction and repair

Epidemiology

• 3% of the population, 10% of population >80 y/0

• consider Paget'

s disease of bone in older adults with elevated ALP but normal GGT

Etiology and Pathophysiology

• postulated to be related to a slowly progressing viral infection of osteoclasts, possibly paramyxovirus

• strong familial incidence

• initiated by increased osteoclastic activity leading to increased bone resorption;osteoblastic activity

increases in response to produce new bone that isstructurally abnormal and fragile

Differential Diagnosis

• osteogenic sarcoma

• multiple myeloma

• fibrous dysplasia

• osteitis fibrosa cystica

• metastases

Clinical Features

• usually asymptomatic (routine x-ray finding or elevated serum ALP with normal LPTs)

• 3characteristic findings:osteolytic lesions, cortical thickening, pseudofractures (small fissures which

develop in the convex surface of long bone)

• most commonly affects:skull, thoracolumbar spine, pelvis, and long bones of lower extremities

• severe bone pain (e.g. pelvis,femur,tibia)

• skeletal deformities:bowed tibias,kyphosis,frequent fractures

• increased risk of osteosarcoma and giant cell tumours

Investigations

• laboratory

high serum ALP, normal or high Ca -+, normal PO43"

normal tests LFTs (prothrombin time/international normalized ratio (PT/1NR), activated partial

thromboplastin time (aPTT), albumin, bilirubin)

elevated procollagen type 1 N-terminal propeptide (PINP) (bone formation marker)

• imaging

plain x-ray ofskull and facial bones, abdomen, and tibiae are recommended as initial screening in

patientssuspected to have Paget'

s

confirmation on x-ray required for diagnosis

denser bone with cortical thickening

characteristic findings: osteolytic lesions, cortical thickening, and pseudofractures

burned-out Paget’

s disease: when the disease has been present for a long time

• bone scan to evaluate the extent of disease and identify asymptomatic sites

radionuclide bone scintigraphy, in addition to targeted x-ray, are recommended as a means of

fully and accurately defining the extent of metabolically active Paget’s disease

• MKI or CT are not recommended for diagnosis, but can be used to assess disease complications,

particularly if malignancy issuspected

r1

L J

+