osteoporosis 2016 | parathyroid hormone good, bad, but not ugly!: richard eastell #osteo2016

Parathyroid Hormone: Good, bad, but not ugly!

Richard Eastell University of Sheffield, based on invited talk by

John P. Bilezikian, MD College of Physicians and Surgeons , Columbia University

New York, NY USA

National Osteoporosis Society

Osteoporosis Conference

Birmingham, England

7-9 November 2016

The bad and the good

Bad:oToo Much Parathyroid HormoneoGood:oWhen used as an osteoanabolic

RE - Conflicts of Interest

• Lilly– Speaker fees– Consultant– Research grants

• Radius– consultant

PRIMARY HYPERPARATHYROIDISM

A common endocrine disorder characterized by incompletely regulated, chronic, excessive secretion of parathyroid hormone from one or more parathyroid glands.

Primary Hyperparathyroidism is associated with hypercalcemia and elevated levels of parathyroid hormone.

Three generational phenotypes of Primary Hyperparathyroidism

Before 1970: A disease of bone, stones, and groans

PHPT IN THE EARLY YEARS, 1929-1970PHPT IN THE EARLY YEARS, 1929-1970

Captain Martell (1918-1926)Captain Martell (1918-1926) and The lady (1970)and The lady (1970)

Pepper Pot Skull Erosion of distal clavicle

Sub-periosteal erosions brown tumours

Before 1970: A disease of bone, stones, abdominal groans and psychic moans

After 1970:A disease with primarily biochemical and densitometric signatures

The biochemical signatures of primary hyperparathyroidism in the modern era

Index Patients nl range• Calcium (mmol/L) 2.68±0.03 2.10-2.55• Phosphorus (mmol/L) 0.94±0.03 0.81-1.40• Alk Phos (IU/l) 114±4 <100• PTH (pg/ml) 121±7 10-65• 25-OH Vit D (ng/ml) 21±1 30-100• 1,25-OH2 Vit D (pg/ml) 59±2 15-60• Urinary Ca (mmol/d) 6.6+ 0.3 2.5-7.5

Silverberg, Bilezikian et al. 1989

Lumbar Spine Femoral Neck Radius

The densitometric signature of primary hyperparathyroidism in the modern era

** Differs from radius,p<.05

Silverberg, Bilezikian Silverberg, Bilezikian et al.et al.

JBMR, 1989JBMR, 1989

Before 1970: A disease of bone, stones, abdominal groans and psychic moans

After 1970:A disease with primarily biochemical and densitometric signatures

After 2000: A disease that may present with a more subtle biochemical signature, namely only with PTH levels elevated, at first.

Schini M..Eastell R. NOS 2016NHYPER, normocalcaemic hyperparathyroidism

• Vitamin D deficiency– 25-hydroxyvitamin D < 75 nmol/L

• Renal insufficiency– eGFR < 60 mL/min

• Medications– Thiazide diuretics– Lithium

• Hypercalciuria• Gastrointestinal malabsorption• Other metabolic bone diseases that could be associated

with elevated PTH (e.g., Paget’s disease)

Normocalcemic primary hyperparathyroidism: what must be ruled out?

The phenotypes of Primary Hyperparathyroidism:

what form in what countries?

Symptomatic PHPT: where multichannel screening is not routinely performed and where vitamin D deficiency is common

Asymptomatic PHPT: In countries where multichannel screening is routinely performed

Normocalcemic PHPT : in countries where PTH is measured proactively in the evaluation of a suspected metabolic bone disease

Management of Asymptomatic PHPT

• Who needs surgery?• Who doesn’t need surgery?

4th International Workshop on:THE MANAGEMENT OF ASYMPTOMATIC PRIMARY

HYPERPARATHYROIDISMFlorence (Italy), September 19th – 21st, 2013

Organized byUNIVERSITÀ DEGLI STUDI DI FIRENZE, FLORENCE, ITALY

MASSACHUSETTS GENERAL HOSPITAL, HARVARD MEDICAL SCHOOL,BOSTON, MASSACHUSETTS, USA

COLLEGE OF PHYSICIANS AND SURGEONS, COLUMBIA UNIVERSITY,NEW YORK, NY, USA

andFONDAZIONE INTERNAZIONALE MENARINI

Palazzo Ximènes Panciatichi(Borgo Pinti, 68)

Maria Luisa Brandi John T. Potts, Jr. John P. BilezikianUniversità degli Studi di Firenze MGH College of Phys & Surg

Florence (Italy) Harvard Medical School Columbia University

Fondazione Internazionale MenariniVia W. Tobagi, 8

I-20068 Peschiera Borromeo (Milan, Italy)Phone: +39 02 55308110Fax: +39 02 55305739

E-mail: milan@fondazione-menarini.itHttp:\\www.fondazione-menarini.it

Bilezikian et al. Guidelines Statement of the 4th International ConferenceOn the management of Asymptomatic PHPT. J Clin Endocrinol Metab, 2014 Eastell R et al. Diagnostic Considerations PHPT. J Clin EndocrinolMetab 2014 Silverberg et al. Clinical Presentations of PHPT. J Clin Endocrinol Metab 2014 Udelsman et al. Surgery in PHPT. J Clin Endocrinol Metab, 2014Marcocci et al. Medical Management of PHPT J Clin Endocrinol Metab, 2014

Skeletal Assessment

Renal Assessment

Traditional Aspects of Primary Hyperparathyroidism

Based upon BMD and bone biopsy data, expectations for fracture incidence in PHPT:

Vertebral sites

Non-vertebral sites

But…., Fracture Risk in Primary Hyperparathyroidism

is increased at all sites

Khosla et al,J Bone Min Res14:1700-1707, 1999

Vertebral Vertebral Distal ForearmDistal Forearm

Rib Rib All All

Increased Fracture Risk at all sites:Confirmatory evidence

High Resolution peripheral Computed Tomography (Hansen et al. JBMR, 2012; Stein, Silva et al. JBMR, 2013)

Trabecular Bone Score (Silva et al. J Clin Endocrinol Metab, 2013)

Moving the field forward with a “new” hypothesis

Primary hyperparathyroidism, even when presenting as an asymptomatic disorder, is characterized by compromised cortical and trabecular compartments and increased fracture risk

Skeletal Assessmen

t Renal

Assessment

Traditional Aspects of Primary Hyperparathyroidism

Emergence of the Modern Clinical Profile of

Primary HyperparathyroidismCope et al.’30-’65

Mallette et al. ‘65-’74

Silverberg et al. ‘84-’00

Cusano et al.’10-’12

Nephrolithiasis 57% 37% 17% 14.3%

Hypercalciuria Not reported

40% 39% 29%

Overt Skeletal Disease

23% 14% 1.4% <1%

Asymptomatic 0.6% 22% 80% >80%

New data and reinterpretation of old data• Skeletal involvement more evident in PHPT when

the eGFR < 60 cc/min (Walker et al, 2012)• A 24-hour urine for analysis of biochemical stone

risk factors (Ca, P, SO4, uric acid etc) is predictive of stones in PHPT (Peacock, 2013)

• Kidney stones can be detected by non-invasive imaging (e.g. X-ray, ultrasound, CT)

• Kidney stones are still the most common complication of PHPT

Neuro-cognitiv

eCardio-

vascular

Other Aspects of Primary Hyperparathyroidism

Gastro-intestinal

Vitamin D

Neurocognitive and CVsystems:Data are not secure enough for

decisions on the surgical management of PHPT

(Bilezikian et al. JCEM, 2014)

Neuro-cognitiv

eCardio-

vascular

Other Aspects of Primary Hyperparathyroidism

Gastro-intestinal

Vitamin D

PTH Levels as function of Vitamin D status (Stein et al. JCEM, 2011)

Mean ±SD 20 ng/mL = 50 nmol/L

Nutritional elements:Vitamin D sufficiency (25-OH D levels > 50 nmol/L are

recommended)*Calcium intake should follow

national guidelines(Bilezikian et al. JCEM, 2014) Some experts recommend > 75 nmol/L

Pharmacological Approaches to PHPTAgent Serum

calciumBone Mineral Density

Estrogen1

Raloxifene2

Bisphosphonate3 (Alendronate)

Cinacalcet4

Cinacalcet andBisphosphonate5

1Marcus et al, 1991; Marcus et al, 1991; 2Rubin et al, 2005, Rubin et al, 2005, 3Khan et al.2004, Khan et al.2004, 4Peacock et al, 2005, 2009, Peacock et al, 2005, 2009, 5Faggiano et al, 2011Faggiano et al, 2011

2014 Guidelines for Surgery in Asymptomatic Primary Hyperparathyroidism (Bilezikian et al. JCEM, 2014)

Recommended Index

3rd Int’l Workshop (Bilezikian et al. JCEM 2009)

4th Int’l Workshop (Bilezikian et al., 2014)

Serum calcium(above normal) >0.25 mmol/L > 0.25 mmol/L

Skeletal DXA: T-Score <-2.5 at any site; any fragility fracture

DXA: T-Score < -2.5 at any site; Vert Fx by X-ray or VFA

RenaleGFR< 60 mL/min24 hr urine: Not recommended

eGFR< 60 mL/minStone by X-ray, CT, or ultrasoundUrinary calcium: >10 mmol/d plus other urinary biochemical indices of increased stone risk

Age <50 < 50

2014 Guidelines for Monitoring in Asymptomatic Primary Hyperparathyroidism

(Bilezikian et al. JCEM, 2014)

Index 3rd Int’l Workshop (Bilezikian et al. JCEM, 2009)

4th Int’l Workshop (Bilezikian et al, JCEM, 2014)

Serum Calcium Annually Annually

Skeletal DXA: Every 1 or 2 years

DXA: Every 1 or 2 years; CT or VFA if clinically indicated

Renal Clcr-Annually Clcr-Annually; stone risk profile if clinically indicatedAbdominal imaging (X-ray, CT, or ultrasound) if clinically indicated

The bad and the good

Bad:oToo Much Parathyroid HormoneoGood:oWhen used as an osteoanabolic

The “Holy Grail” of osteoporosis therapyWhat the antiresorptives

don’t do…

AnabolicDaily(low dose)

CatabolicContinuous (high dose)

EFFECTMODE

The clue to discovering that PTH, under specifiedcircumstances, can serve as an osteoananabolic

treatment for osteoporosis

Dobnig H, et al. Endocrinology 1997;138:4607-12.

BADGOOD

Cellular Mechanisms

PTH treatment initially stimulates bone formation PTH treatment initially stimulates bone formation directly with or without the involvement of the bone directly with or without the involvement of the bone remodeling unitremodeling unit

PTH as an Anabolic Agent for Bone:A Kinetic Model

Months

Bone formation markers

Bone resorptionmarkers

“Anabolic Window”

Effect of Teriparatide on Incidence of Vertebraland Non-Vertebral Fractures in

Postmenopausal Women with Osteoporosis

Neer RM, et al. N Engl J Med. 2001;344:1434-41

20Non-vertebral fractures

Patients (%) with fracture

P< 0.01

20 g PTH0

20New vertebral fracture

Patients (%) with fracture

P< 0.01

20 g PTH PlaceboPlacebo

3-D µCT Images of iliac crest biopsies before and after Teriparatide

Placebo Teriparatide

Emergence of a new osteoanabolicAbaloparatide, an analogue of PTHrP

Hattersley G, Bilezikian JP, Kumar P et al. The Endocrine Society 94th Annual Mtg Houston, 2012

22 30 34100% hPTHrP

38% hPTHrP

Teriparatide

hPTHrP1-34

Abaloparatide100% hPTHrP 38% hPTHrP

based on amino acid replacements between residues 22-34

Taking advantage of basic mechanisms to develop a PTH/PTHrP

analogue that has greater osteoanabolic activity

Hypothesis:

Abaloparatide will bind more selectively bind to the transient RG configuration of the PTH/PTRrP receptor

The binding of ABL, PTH (1–34), PTHrP (1–36) and LA-PTH to two distinct PTHR1 conformations RG (A) and R0 (B)The binding of ABL, PTH (1–34), PTHrP (1–36) and LA-PTH to two distinct PTHR1 conformations RG (A) and R0 (B) was assessed by competition methods in membranes prepared from GP-2.3 cells stably expressing the PTHR1.was assessed by competition methods in membranes prepared from GP-2.3 cells stably expressing the PTHR1.

RG reactions used 125I-M-PTH (1–15) as tracer radioligand, which binds selectively to the G protein–coupled receptor RG reactions used 125I-M-PTH (1–15) as tracer radioligand, which binds selectively to the G protein–coupled receptor conformation (RG). R0 reactions used 25I-PTH (1–34) as tracer radioligand and contained an excess concentration conformation (RG). R0 reactions used 25I-PTH (1–34) as tracer radioligand and contained an excess concentration

(1 × 10−5 M) of GTPγS, which enriches for the G protein–uncoupled receptor conformation (R0). Data are means (± SEM) (1 × 10−5 M) of GTPγS, which enriches for the G protein–uncoupled receptor conformation (R0). Data are means (± SEM) of six experiments, each performed in duplicate. Curve fitting parameters are reported in Table 1.of six experiments, each performed in duplicate. Curve fitting parameters are reported in Table 1.

Hattersley, G et al. Endocrinology 2016, 157, 141-149.

Abaloparatide binding to the PTH receptor differs from PTH binding

Update on Abaloparatide

• International Phase 3 trial ended, September, 2014• Results made available, December, 2014• Presented by Miller et al, Endocrine Society, March,

2015, 2016• Clinical Trial Results JAMA (2016) 1

1 Miller PD, et al. JAMA. 2016 Aug 16;316(7):722-33.

Phase 3 Trial Design of Abaloparatide Clinical Trial

Placebo

Abaloparatide 80 mcg Daily SC

Teriparatide 20 mcg Daily SC

Months 6 12 18

N = 2463

Miller et al, Endo Soc 3-15Miller et al, Endo Soc 3-15

P1NPP1NPCTXCTX

Months Months

*p < 0.0001 vs placebo#p < 0.01 vs teriparatide

Teriparatide

-46% -12%-56%

Changes in Bone Turnover Markers:Abaloparatide vs. Teriparatide vs. Placebo

(Miller et al. Endo Soc 3-15)

“Anabolic window”

PTH/PTHrP analogues that stimulate bone formation to a greater extent than bone

resorption: a time dependent model

Months

Bone Formation Markers

Bone ResorptionMarkers

Teriparatide

Lumbar Spine BMD

Months

#p < 0.01 vs TP

Changes in BMD at the Spine and Reduction in New Vertebral Fractures: All 3 Groups

(Miller et al. Endo Soc 3-15)

Abalopara

teripara

Changes in BMD at Non-Vertebral Sites and NVF Risk Reduction: All 3 Groups (Miller et al. Endo Soc 3-15)Total Hip BMD

Months

#^#p < 0.0001 vs TP

p̂ = 0.0003 vs TP

Femoral Neck BMD

Months

@#p < 0.0001 vs TP@p = 0.0016 vs TP

Life with PTH

• Too much (Primary Hyperparathyroidism)- not good

• When used in just the right way: an important osteoanabolic therapy for osteoporosis

THANK YOU!

osteoporosis 2016 | parathyroid hormone good, bad, but not ugly!: richard eastell #osteo2016

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