Division of Endocrinology, Department of Medicine, Ramathibodi Hospital Mahidol University, Thailand

Hataikarn Nimitphong, MD

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)
T-score

Diagnosis Severe (established) osteoporosis

BMD Bone density is < -2.5 SD in the presence of one or more fragility fractures
WHO 2004

BMD interpretation

Areal BMD= grams of mineral/square centimeter scanned (g/cm2). Z-score: expected BMD for the patients age and sex T-score: BMD compared to young normal adults of the same sex The difference between the patients score and the norm is expressed in standard deviations (SD) above or below the mean.

To Define Osteoporosis
Primary
Due to aging Due to decreasing estrogen such as occurs with menopause

Secondary
A drug, disease or deficiency is the underlying cause Example: men who have osteoporosis and hypogonad

Is secondary osteoporosis common???

2/3 of men

1/2 of premenopausal women 1/5 of postmenopausal women

Some factors that may accelerate bone loss

Endocrine disorders Hyperthyroidism Hypopituitarism Hypogonadism Cushing disease Primary hyperparathyroidism Gastrointestinal disorders Celiac disease Short bowel syndrome Hematologic disorders

Multiple myeloma
Systemic mastocytosis Renal disorders Chronic renal failure

Idiopathic hypercalciuria
Neuromuscular disorders Muscular dystrophy Paraplegia, quadriplegia Proximal myopathy

Some factors that may accelerate bone loss

Medications Nutritional deficiency Calcium Vitamin D Protein

Corticosteroid
Proton pump inhibitors Antiepilepsy drugs

Medroxyprogesterone acetate
SSRI Thiazolidinediones Thyroxine in supraphysiologic dose Excess vitamin A Aromatase inhibitors Androgen deprivation therapy

Who need to be screened for secondary causes for osteoporosis?

Young patients Premenopausal women Men younger than 65 yr of age In all patients with unexpected or severe osteoporosis In those with accelerated bone loss Those experiencing bone loss under treatment with conventional osteoporosis therapy
Primer on the metabolic bone diseases and disorder of mineral metabolism 2008

Exclusion of Causes of Secondary Osteoporosis

Blood or Serum Complete 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 Serum Serum protein electrophoresis (SPEP), serum immunofixation, serum free light chains Tissue transglutaminase antibodies Iron 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 fracture first BMD revealed osteoporosis start raloxifene normal 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 = -2.3 T-score at FN = -2.4, total neck -0.9 Laboratory results: CBC, Cr, TSH, alb, chem were normal except Calcium PTH 25(OH)D Diagnosis (mg/dl) (pg/mL) (ng/mL) 8.5-10.5 12, 11.5 98,115 42
9,9.5 9,9.5 67,83 67,83 25 12

scenario

I II III

2012:

a complaint about progressive low back pain. BMD: T-score at lumbar spine = -2.3 T-score at FN = -2.4, total neck -0.9 Laboratory results: CBC, Cr, TSH, alb, chem were normal except Calcium PTH 25(OH)D Diagnosis (mg/dl) (pg/mL) (ng/mL) 8.5-10.5 12, 11.5 98,115 42 Primary hyperparathyroidism (PHPT) 9,9.5 67,83 21.5 9,9.5 67,83 12

scenario

II

III

2012:

a complaint about progressive low back pain. BMD: T-score at lumbar spine = -2.3 T-score at FN = -2.4, total neck -0.9 Laboratory results: CBC, Cr, TSH, alb, chem were normal except Calcium PTH 25(OH)D Diagnosis (mg/dl) (pg/mL) (ng/mL) 8.5-10.5 12, 11.5 98,115 42 Primary hyperparathyroidism (PHPT) 9,9.5 67,83 21.5 Normocalcemic HPT 9,9.5 67,83 12

scenario

II

III

2012:

a complaint about progressive low back pain. BMD: T-score at lumbar spine = -2.3 T-score at FN = -2.4, total neck -0.9 Laboratory results: CBC, Cr, TSH, alb, chem were normal except Calcium PTH 25(OH)D Diagnosis (mg/dl) (pg/mL) (ng/mL) 8.5-10.5 12, 11.5 98,115 42 Primary hyperparathyroidism (PHPT) 9,9.5 67,83 21.5 Normocalcemic HPT 9,9.5 67,83 12 Secondary HPT

scenario

II

III

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

25(OH)D
1-hydroxylase

25(OH)D: low

1,25(OH)2D

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

Low

Ca2+

Ca2+: normal or low normal

PTH

Hyperphosphaturia Hypophosphatemia

Presentations of patients with PHPT

normocalcemic PHPT

Classic PHPT
Symptomatic Asympatomatic

NCPHP: normocalcemic PHPT NHPHP: normohormonal PHPT

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

Management guideline for patients with asymptomatic primary hyperparathyroidism

Measurement Indication for parathyroidectomy 1.0 mg/dl Follow up

Serum Ca2+ (upper limit of normal)

Annually

24-h urine for Not indicated calcium Reduced to 60 ml/min Creatinine clearance (calculated) BMD T-score 2.5 at any site and/or previous fracture fragility <50

Not recommended Not recommended

Annually

Age (yr)

Bilezikian et al. JCEM 2009; 94(2):335-339

 Diagnosis : exclude secondary causes of an elevated PTH level

1. 2. 3. 4. 5. Vitamin D deficiency Reduced creatinine clearance (GFR < 60 mL/min) Medications: Hydrochlorothiazide and lithium Hypercalciuria 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.

The Effect of PHPT on Vitamin D

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 BW 4. Increased renal conversion of 25(OH)D to 1,25(OH)2D?

The Effect of Vitamin D on PHPT

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-V104 Souberbielle JC, et al. J of Steroid Biochem Mol Biol 2010;121:199-203

Back to our patient Scenario 2

Ca (mg/dL) 7/11 1/12 2/12 9 3.4 9 Alb In. P (g/L) (mg/dL) 38.6 3.3 83.3 67.4 21.5 20,000 PTH (pg/mL) 25(OH)D D2 Rx (ng/mL) (IU/wk)

Diagnosis
1. Postmenopausal osteoporosis + 2. Secondary osteoporosis due to
2.1 Normocalcemic HPT 2.2 Secondary HPT 2.3 Both 2.1 + 2.2

Back to our patient Scenario 2

Ca Alb In. P PTH 25(OH)D Vitamin D2 Rx (mg/dL) (g/L) (mg/dL) (pg/mL) (ng/mL) (IU/wk) 7/11 1/12 2/12 9 3.4 9 38.6 3.3 83.3 67.4 21.5 20,000 60,000 MIBI scan

Diagnosis
1. Postmenopausal osteoporosis + 2. Secondary osteoporosis due to
2.1 Normocalcemic HPT 2.2 Secondary HPT 2.3 Both 2.1 + 2.2

Tc-99m MIBI

Laboratory results
Ca Alb In. P (mg/dL) (g/L) (mg/dL)
7/11 9 9 8.7 9.4 41.3 38.6 3.4 4.5 4.3

PTH (pg/mL)
3.3

25(OH)D D2 Rx (ng/mL) (IU/wk)

1/12 2/12
4/12 5/12

83.3 67.4
70.2 54.3

21.5

30.3 34.6

6/12

9.1

39.3

4.4

54-55

34.7

20,000 60,000 MIBI scan 40,000 40,000 20,000

Final diagnosis
1. Postmenopausal osteoporosis

+
2. Secondary osteoporosis due to
Secondary HPT from vitamin D deficiency

Summary part I

The Effect of Vitamin D on PHPT

Diagnosis Issues: Normalization of vitamin D status [25(OH)D > 30 ng/mL] is essential for making the correct diagnosis:
1. 2. 3. 4. Secondary hyperparathyroidism Concomitant PHPT and vitamin D deficiency Normocalcemic PHP Unmask hypercalcemic primary hyperparathyroidism which is masked by the vitamin D deficiency
Mikhail N. Southern Medical Journal;104:29-33

PTH is high [in osteoporotic patients]

Calcium 25(OH)D
High Normal low Slightly high , normal or slightly low low normal

Initial diagnosis Next step

- PHPT

-suspected NCPHP
Re-measured lab in 2-3 mo MIBI (if PTH is high and Ca2+ is normal

- MIBI

PTH is high in osteoporotic patients

Calcium 25(OH)D
High Normal low Slightly high , normal or slightly low low normal

Initial diagnosis Next step

- PHPT

- PHPT and 2HPT

-suspected 2HPT

-suspected NCPHP
Re-measured lab in 2-3 mo MIBI (if PTH is high and Ca2+ is normal

- MIBI Vitamin D treatment Re-measure lab in 2-3 mo: 25(OH )D normal

PTH is high in osteoporotic patients

Calcium 25(OH)D
High Normal low Slightly high , normal or slightly low low normal

Initial diagnosis Next step

- PHPT

- PHPT and 2HPT

-suspected 2HPT

-suspected NCPHP
Re-measured lab in 2-3 mo MIBI (if PTH is high and Ca2+ is normal Ca2+ /PTH: normal

- MIBI Vitamin D treatment Re-measure lab in 2-3 mo: 25(OH )D normal

Ca2+ normal PTH: high

Ca2+ /PTH high

Definite diagnosis

-normocalcemic PHP

-PHPT

Confirm 2HPT

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: -2.7 Total hip: -1.6 Femoral neck: -1.9

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

The results of tests of the patient

Test Calcium (mg/dl) Phosphorus (mg/dl) Alkaline phosphatase (U/l) Testosterone (ng/dl) LH (mIU/ml) 25(OH)D(ng/ml) TSH (IU/ml) Results Normal range 9 8.5-10.5 4.2 130 378 2.3 16 2.09 2.7-4.5 <270 350-900 1.78.6 1040 0.34.7

Parathyroid hormone (pg/ml) Calcium excretion/24 hours (mg/day)

Creatinine excretion/24 hours (mg/Kg/day)

46.8 503
21.1

10-65 42-353
11-26

Final diagnosis
Secondary Osteoporosis Most likely due to : idiopathic hypercalciuia + vitamin D deficiency
Need to exclude other causes of hypercalciuria: primary hyperparathyroidism hyperthyroidism Pagets disease myeloma, malignancy immobility accelerated osteoporosis sarcoidosis renal tubular acidosis

Idiopathic Hypercalciuria

IL-1, TNF, GM-CSF expression of RANKL

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.
Ryan LE, et al. Curr Osteoporos Rep (2012) 10:286295

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) 10:286295

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 1520 mg/kg In men: creatinine excretion 2025 mg/kg

How to interpret a 24-hour urine calcium?

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

Managing hypercalciuria in a patient with low bone mass

The results of tests of the patient

Test Calcium (mg/dl) Phosphorus (mg/dl) Results 9 4.2 Normal range 8.5-10.5 2.7-4.5

Alkaline phosphatase (U/l) Testosterone (ng/dl) LH (mIU/ml) 25(OH)D(ng/ml) TSH (lIU/ml) Parathyroid hormone (pg/ml) Calcium excretion/24 hours (mg/day) Creatinine excretion/24 hours (mg/Kg/day)

130 119 0.6 16 2.09 46.8 135 21.1

<270 350-900 1.78.6 1040 0.34.7 10-65 42-353 11-26

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

Final diagnosis
Secondary Osteoporosis due to : macroprolactinoma induced hypogonadotropic hypogonadism + vitamin D defiency

The effects of hyperprolactinemia on bone

The bone loss is associated with an increase in bone resorption and is secondary to prolactininduced 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;12:96104

The effects of hyperprolactinemia on bone (in men)

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 prolactininduced hypogonadism has not been systematically evaluated.
Shibli-Rahhal A, et al Pituitary 2009;12:96104

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

Yearly incidence of fractures in relation to total E2

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

Management of hypogonadal men at high risk of fracture.

Hypogonadal men T < 200 ng/dL *2
Signs and symptoms of androgen deficiency Low libido Unexplained chronic fatigue Loss of body hair Hot flush

Organic hypogonad

Hypothalamic, pituitary Specific testicular disorder

The endocrine societys clinical guidelines 2012

Management of hypogonadal men at high risk of fracture.

Risk
high risk for fracture
Men who have had a hip or vertebral fracture without major trauma BMD of the spine, femoral neck, and/or total hip is <-2.5 FRAX: in USA: 10yr probability of any fracture > 20% hip fracture > 3% Receiving long-term glucocorticoid therapy in pharmacological doses (e.g. prednisone or equivalent >7.5 mg/d
The endocrine societys clinical guidelines 2012

stratification

High risk

Borderline high risk

Management of hypogonadal men at high risk of fracture.

Risk

stratification
Receiving T add anti-fracture agents Combine T + anti-fracture agents Only T if contraindicate for antifracture agents
Only T re-evaluate symptom after 3-6 mo
The endocrine societys clinical guidelines 2012

High risk

Borderline high risk

Summary part II 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

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.