Hataikarn Nimitphong, MDDivision of Endocrinology,

Department of Medicine, Ramathibodi HospitalMahidol University, Thailand

Outline of

• To define osteoporosis : primary vs. secondary

• Who need to be screened for secondary causes for osteoporosis and how?

• Cases study

WHO Classification of Bone Health Based on BMD(postmenopausal women and men older than 50 year)

Diagnosis BMDSevere (established) osteoporosis

Bone density is < -2.5 SD in the presence of one or more fragility fractures

WHO 2004

T-score

BMD interpretation

• Areal BMD= grams of mineral/square centimeter scanned (g/cm2).• Z-score: expected BMD for the patient’s age and sex • T-score: BMD compared to “young normal” adults of the same sex • The difference between the patient’s score and the norm is expressed in standard deviations (SD) above or below the mean.

T Z

To Define Osteoporosis

2/3 of men

1/2 of premenopausal women

1/5 of postmenopausal women

Is secondary osteoporosis common???

Some factors that may accelerate bone loss

Some factors that may accelerate bone loss

Who need to be screened for secondary causes for osteoporosis?

Young patientsPremenopausal womenMen younger than 65 yr of age

In all patients with unexpected or severe osteoporosis

In those with accelerated bone lossThose experiencing bone loss under treatment

with conventional osteoporosis therapy

Primer on the metabolic bone diseases and disorder of mineral metabolism2008

Exclusion of Causes of Secondary Osteoporosis

Blood or SerumComplete blood count (CBC) Chemistry levels (Calcium, renal function, phosphorus and magnesium) Liver function tests Serum 25(OH)D level Total testosterone and gonadotropin levels in younger men[Parathyroid hormone (PTH)] [Thyroid-stimulating hormone (TSH) level]

Urine 24-hour urinary calcium

NOF 2013

Exclusion of Causes of Secondary Osteoporosis

Consider in selected patients

Blood or SerumSerum protein electrophoresis (SPEP), serum immunofixation, serum free light chains Tissue transglutaminase antibodiesIron and ferritin levels Homocysteine in select cases Tryptase

Urine Protein electrophoresis (UPEP) Urinary free cortisol level Urinary histamine

NOF 2013

• A 70 year-old female was send to your clinic because of high PTH levels.

2000: ankle fracturefirst BMD revealed osteoporosisstart raloxifenenormal laboratory results (Ca2+ = 9.5

mg/dL)

2005: compression fracture at spines were found switched raloxifene to alendronate

2009: BMD: T-score at lumbar spine = -2.3, T-score at FN = -1.4

Calcium and TSH were all normal

2012: a complaint about progressive low back pain BMD: T-score at lumbar spine = -2.3T-score at FN = -2.4, total neck -0.9

Laboratory results: CBC, Cr, TSH, alb, chem were normal except

scenario Calcium (mg/dl)8.5-10.5

PTH(pg/mL)

25(OH)D(ng/mL)

Diagnosis

I 12, 11.5 98,115 42

II 9,9.5 67,83 25III 9,9.5 67,83 12

2012: a complaint about progressive low back pain. BMD: T-score at lumbar spine = -2.3T-score at FN = -2.4, total neck -0.9

Laboratory results: CBC, Cr, TSH, alb, chem were normal except

scenario Calcium (mg/dl)8.5-10.5

PTH(pg/mL)

25(OH)D(ng/mL)

Diagnosis

I 12, 11.5 98,115 42 Primary hyperparathyroidism (PHPT)

II 9,9.5 67,83 21.5III 9,9.5 67,83 12

2012: a complaint about progressive low back pain. BMD: T-score at lumbar spine = -2.3T-score at FN = -2.4, total neck -0.9

Laboratory results: CBC, Cr, TSH, alb, chem were normal except

scenario Calcium (mg/dl)8.5-10.5

PTH(pg/mL)

25(OH)D(ng/mL)

Diagnosis

I 12, 11.5 98,115 42 Primary hyperparathyroidism (PHPT)

II 9,9.5 67,83 21.5 Normocalcemic HPTIII 9,9.5 67,83 12

2012: a complaint about progressive low back pain. BMD: T-score at lumbar spine = -2.3T-score at FN = -2.4, total neck -0.9

Laboratory results: CBC, Cr, TSH, alb, chem were normal except

scenario Calcium (mg/dl)8.5-10.5

PTH(pg/mL)

25(OH)D(ng/mL)

Diagnosis

I 12, 11.5 98,115 42 Primary hyperparathyroidism (PHPT)

II 9,9.5 67,83 21.5 Normocalcemic HPTIII 9,9.5 67,83 12 Secondary HPT

Vitamin D deficiency as a cause of 2nd hyperparathyroidism(HPT).

25(OH)D

1,25(OH)2D

1α-hydroxylase

Low Ca2+

PTH

HyperphosphaturiaHypophosphatemia

25(OH)D: low

1,25(OH)2D: normal or high

Ca2+:normal or low normal

Presentations of patients with PHPT

• NCPHP: normocalcemic PHPT• NHPHP: normohormonal PHPT

Jin J, et al. surgery 2012;152(6);1184-1192

Classic PHPTSymptomaticAsympatomatic

normocalcemic PHPT

Measurement Indication for parathyroidectomy

Follow up

Serum Ca2+

(upper limit of normal)

1.0 mg/dl Annually

24-h urine for calcium

Not indicated Not recommended

Creatinine clearance (calculated)

Reduced to 60 ml/min Not recommended

BMD T-score 2.5 at any siteand/or previous fracture fragility

Annually

Age (yr) <50 Bilezikian et al. JCEM 2009; 94(2):335-339

Management guideline for patients with asymptomatic primary hyperparathyroidism

• Diagnosis : exclude secondary causes of an elevated PTH level

1. Vitamin D deficiency2. Reduced creatinine clearance (GFR < 60 mL/min)3. Medications: Hydrochlorothiazide and lithium4. Hypercalciuria5. Gastrointestinal disorders associated with calcium

malabsorption

J Clin Densitom. 2013 Jan-Mar;16(1):33-9

PHPT and vitamin D deficiency/insufficiency are two frequent conditions.

Vitamin D deficiency seems to occur more frequently in patients with PHPT.

“Vitamin D deficiency is more prevalent in PHPT”Explanations: 1.Increase metabolic clearance (24-hydroxylase)2.An inhibition of the production of vitamin D3 in skin

3.Decreased bioavailability of vitamin D in PHPT because of increased BW4.Increased renal conversion of 25(OH)D to 1,25(OH)2D?

The Effect of PHPT on Vitamin D

• The disease is more severe in those with concomitant vitamin D deficiency.

- more symptom, higher PTH levels, calcium and ALP- worse bone morphology, increased risk of fractures- ± larger tumors

• ±Worse post-PTX outcomes such as persistent elevation of PTH, delay bone recovery (hungry bone syndrome)

Silverberg SJ. J Bone Miner Res 2007;22;S2;V100-V104Souberbielle JC, et al. J of Steroid Biochem Mol Biol 2010;121:199-203

The Effect of Vitamin D on PHPT

Back to our patientScenario 2

Ca (mg/dL)

Alb(g/L)

In. P (mg/dL)

PTH(pg/mL)

25(OH)D(ng/mL)

D2 Rx(IU/wk)

7/11 9 38.6 3.31/12 83.3 21.5 20,0002/12 9 3.4 67.4

DiagnosisDiagnosis

1.Postmenopausal osteoporosis +2.Secondary osteoporosis due to

2.1 Normocalcemic HPT2.2 Secondary HPT2.3 Both 2.1 + 2.2

Back to our patientScenario 2

Ca (mg/dL)

Alb(g/L)

In. P (mg/dL)

PTH(pg/mL)

25(OH)D(ng/mL)

Vitamin D2 Rx(IU/wk)

7/11 9 38.6 3.31/12 83.3 21.5 20,0002/12 9 3.4 67.4 60,000

MIBI scan

DiagnosisDiagnosis

1.Postmenopausal osteoporosis +2.Secondary osteoporosis due to

2.1 Normocalcemic HPT2.2 Secondary HPT2.3 Both 2.1 + 2.2

Tc-99m MIBI

Ca (mg/dL)

Alb(g/L)

In. P (mg/dL)

PTH(pg/mL)

25(OH)D(ng/mL)

D2 Rx(IU/wk)

7/11 9 38.6 3.31/12 83.3 21.5 20,0002/12 9 3.4 67.4 60,000

MIBI scan4/12 8.7 4.5 70.2 30.3 40,0005/12 9.4 41.3 4.3 54.3 34.6 40,0006/12 9.1 39.3 4.4 54-55 34.7 20,000

Laboratory results

Final diagnosis

1. Postmenopausal osteoporosis

++2. Secondary osteoporosis

due to“Secondary HPT from vitamin

D deficiency”

Mikhail N. Southern Medical Journal;104:29-33

• Diagnosis Issues:Normalization of vitamin D status [25(OH)D > 30 ng/mL]

is essential for making the correct diagnosis:1. Secondary hyperparathyroidism

2. Concomitant PHPT and vitamin D deficiency

3. Normocalcemic PHP

4. Unmask hypercalcemic primary hyperparathyroidism which is masked by the vitamin D deficiency

The Effect of Vitamin D on PHPT

Summary part I

PTH is high [in osteoporotic patients]

Calcium High Slightly high , normal or slightly low

25(OH)D Normal low low normal

Initialdiagnosis

- PHPT -suspectedNCPHP

Next step - MIBI Re-measured lab in 2-3 mo→MIBI (if PTH is high and Ca2+

is normal

PTH is high in osteoporotic patients

Calcium High Slightly high , normal or slightly low

25(OH)D Normal low low normal

Initialdiagnosis

- PHPT - PHPT and 2ºHPT

-suspected2ºHPT

-suspectedNCPHP

Next step - MIBI Re-measured lab in 2-3 mo→MIBI (if PTH is high and Ca2+

is normal

Vitamin D treatmentRe-measure lab in 2-3 mo:

25(OH )D normal

PTH is high in osteoporotic patients

Calcium High Slightly high , normal or slightly low

25(OH)D Normal low low normal

Initialdiagnosis

- PHPT - PHPT and 2ºHPT

-suspected2ºHPT

-suspectedNCPHP

Next step - MIBI Re-measured lab in 2-3 mo→MIBI (if PTH is high and Ca2+ is normal

-normocalcemic PHP -PHPT Confirm 2ºHPT

Vitamin D treatmentRe-measure lab in 2-3 mo:

25(OH )D normal

Ca2+ normalPTH: high Ca2+ /PTH: normal

Ca2+ /PTH high

Definitediagnosis

The patient, a 52-year-old man, was referred for a work up for osteoporosis.

History from the primary care doctor• He was seen for back pain incurred while playing football (2 months ago). • On the initial evaluation:tenderness and a decreased range of motion of

the thoracic spine.

»Plain spine films had revealed a T-4 compression fracture with anterior wedging as well as general deossification of the thoracic vertebrae

»BMD : T-score in L-S spine: -2.7Total hip: -1.6Femoral neck: -1.9

The patient, a 49-year-old man, was referred for a work up for osteoporosis.

At endocrine clinicPast history and systemic review• A lifelong, large dietary intake of milk products.• No use of alcohol or tobacco. • He had not had previous surgical procedures and did not have GI

disorders.

Physical examination• Normal trunk and extremity proportions. • A back examination revealed only mild, midthoracic tenderness to

percussion.• Otherwise: unremarkable

• Scenario I

• Scenario II

Test Results Normal rangeCalcium (mg/dl) 9 8.5-10.5Phosphorus (mg/dl) 4.2 2.7-4.5Alkaline phosphatase (U/l) 130 <270Testosterone (ng/dl) 378 350-900LH (mIU/ml) 2.3 1.7–8.625(OH)D(ng/ml) 16 10–40TSH (µIU/ml) 2.09 0.3–4.7Parathyroid hormone (pg/ml) 46.8 10-65Calcium excretion/24 hours (mg/day) 503 42-353

Creatinine excretion/24 hours (mg/Kg/day) 21.1 11-26

The results of tests of the patient

• Secondary Osteoporosis“Most likely due to : idiopathic hypercalciuia”+ vitamin D deficiency

Final diagnosis

Need to exclude other causes of hypercalciuria:primary hyperparathyroidismhyperthyroidismPagets diseasemyeloma, malignancyimmobilityaccelerated osteoporosissarcoidosisrenal tubular acidosis

Idiopathic Hypercalciuria

• The persistence of hypercalciuria in spite of normal or restricted calcium intake = fasting hypercalciuria

• Lab: normal levels of PTH, phosphorous and 1,25(OH)2D.

IL-1, TNF, GM-CSFexpression of RANKL

Ryan LE, et al. Curr Osteoporos Rep (2012) 10:286–295

Clinical Characteristic of Patients with Idiopathic Hypercalciuria

• A high incidence of renal stone formation.(40 %–50 % of lithiasic patients)

• 10 %–19 % of both healthy men with low bone mass as well as postmenopausal osteoporotic women

• Lower spine BMD > total hip BMD • A higher risk for vertebral and hip fracture

(more data in men > women)

Ryan LE, et al. Curr Osteoporos Rep (2012) 10:286–295

How to collect a 24-hour urine calcium? Duration: collect urine from the second urine of the 1st day to the first urine

upon wakening on the 2nd morning.

Between collection time points and prior to submission, urine must be refrigerated. Turning the urine into the lab immediately upon completion is recommended.

The urine should be tested both for 24-hour calcium and 24-hour creatinine excretion. (+sodium)

Avoid urine collection within 1 month of an acute kidney stone episode or lithotripsy.

If feasible, 2 separate collections

How to interpret a 24-hour urine calcium?

• Results: include 24-hour urine calcium values in mg/24 h, volume of urine submitted, and creatinine excretion in mg/24 h.

• Adequate collection: In women: creatinine excretion of 15–20 mg/kg In men: creatinine excretion 20–25 mg/kg

How to interpret a 24-hour urine calcium?

Normal 24-hour urine calcium excretion: In women: <250 mg/dayIn men: <300 mg/dayor < 4 mg of urinary calcium/kg of BW/day

Managing hypercalciuria in a patient with low bone mass

Test Results Normal rangeCalcium (mg/dl) 9 8.5-10.5Phosphorus (mg/dl) 4.2 2.7-4.5Alkaline phosphatase (U/l) 130 <270Testosterone (ng/dl) 119 350-900LH (mIU/ml) 0.6 1.7–8.625(OH)D(ng/ml) 16 10–40TSH (lIU/ml) 2.09 0.3–4.7Parathyroid hormone (pg/ml) 46.8 10-65Calcium excretion/24 hours (mg/day) 135 42-353Creatinine excretion/24 hours (mg/Kg/day) 21.1 11-26

The results of tests of the patient

Additional information

Go back to endocrine clinic!!!!Past history and systemic review• He admitted to ceasing all sexual activity in his marriage some 10 years

earlier and had fathered three children some 15 years earlier.

Physical examination• Normal quality and distribution of facial and body hair, and no palpable

gynecomastia. • Visual fields were grossly full. • The testes measured 3.0cm in length, and on palpation the prostate

was of normal size. • The skin was without unusual pigmentation or creases.

• Prolactin : 475 ng/mL• Pituitary tumor size 3.2 cm

• Secondary Osteoporosis“due to : macroprolactinoma induced

hypogonadotropic hypogonadism + vitamin D defiency

Final diagnosis

The effects of hyperprolactinemia on bone

• The bone loss is associated with an increase in bone resorption and is secondary to prolactin-induced hypogonadism.

• Trabecular bone in the spine and hip is more affected than cortical bone in the distal radius.

Shibli-Rahhal A, et al Pituitary 2009;12:96–104

• Five studies: decreased BMD in spine > hip > forearm

• Natalio et al. showed an 8% decrease in spinal bone density and a positive correlation between serum estradiol and bone mass

• In men, reversal of hyperprolactinemia (with dopamine agonists, transsphenoidal surgery or radiation therapy) leads to improvement in bone density only when hypogonadism is reversed.

• Testosterone replacement has been shown to improve bone density in hypogonadal men in general, but the effect of testosterone replacement on bone density in men with prolactin-induced hypogonadism has not been systematically evaluated.

The effects of hyperprolactinemia on bone (in men)

Shibli-Rahhal A, et al Pituitary 2009;12:96–104

Free estrodiol (E2), but not free testosterone (T), was independently associated with fracture risk.

• n = 2639; mean age of 75 yr, the prospective population-based MrOS Sweden cohort, average follow-up of 3.3 yr

• The incidence for having at least one validated fracture after baseline was 20.9/1000 person-years

Yearly incidence of fractures in relation to total E2

Mellstrom D, et al. J Bone Miner Res 2008;23:1552-1560

Management of hypogonadal men at high riskof fracture.

• Low libido• Unexplained chronic fatigue• Loss of body hair• Hot flush

• Hypothalamic, pituitary• Specific testicular disorder

The endocrine society’s clinical guidelines 2012

Management of hypogonadal men at high riskof fracture.

“high risk for fracture”

Men who have had a hip or vertebral fracture without major traumaBMD of the spine, femoral neck, and/or total hip is <-2.5FRAX: in USA: 10yr probability of

any fracture > 20%hip fracture > 3%

Receiving long-term glucocorticoidtherapy in pharmacological doses (e.g. prednisone or equivalent >7.5 mg/d

The endocrine society’s clinical guidelines 2012

Management of hypogonadal men at high riskof fracture.

The endocrine society’s clinical guidelines 2012

Receiving T → add anti-fracture agents

Combine T + anti-fracture agents Only T if contraindicate for anti-

fracture agents

Only T → re-evaluate symptom after 3-6 mo

• Secondary causes for osteoporosis in men are different from those in women

• The osteoporotic men have several factors that contribute to the disease.

• The most importance risk factors include alcohol abuse, glucocorticoid excess and hypogonadism

Summary part II

Conclusions• Secondary causes of osteoporosis are ranging from easily

identifiable specific diseases (systemic inflammatory diseases, malignancy, endocrinopathies and use of medicine) to more occult conditions (vitamin D deficiency, idiopathic hypercalciuria, asymptomatic hyperparathyroidism).

• Secondary causes for osteoporosis are potentially reversible

• A high degree of suspicion and confirmed by appropriate investigation are an important tool.