PTH for the Treatment of Osteoporosis

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PTH for the Treatment of Osteoporosis
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PTH for the Treatment of Osteoporosis

• Case
• Background
• Evidence
• Commentary

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Case

• 69 yo WF with PMH of CAD sp CABG, HTN, CVA, mild
  vascular dementia, GERD osteoporosis by DEXA
• Hip fracture x 2
• Unable to tolerate bisphosphonates
• My Question
• Would a course of PTH effectively treat her
  osteoporosis help prevent more fractures?

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Osteoporosis

• Definition
• A disease characterized by low bone mass and
  microarchitectural deterioration of bone tissue,
  leading to enhanced bone fragility and an
  increase in fracture risk.
• Consensus Development Conference, 1993
• Diagnosis, prophylaxis, and treatment of
  osteoporosis

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Osteoporotic Fractures

• 1.3 million fractures per year
• Women gtgtgt Men
• Incidence increases markedly after menopause in
  women and in both sexes over age 80
• Caucasian gtgt African American, Hispanic
• gt20 million/year in social costs
• (healthcare dollars and lost productivity)

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Fracture Risk in Osteoporosis
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Increased Osteoporotic Fracture Risk with Age
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Risk Factors for Osteoporosis

• Nonmodifiable
• Gender
• Age
• Race
• Dementia
• Frailty
• First-degree relative with fracture
• Personal history of fracture

• Modifiable
• Tobacco use
• Alcohol abuse
• Low body weight
• Low calcium intake
• Estrogen deficiency
• Impaired eyesight
• Recurrent falls
• Physical inactivity

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Etiology of Osteoporosis

• Primary
• Postmenopausal
• Age-related
• Secondary
• Immobilization
• CTD
• Homocystinuria, Marfans, Ehlers-Danlos
• Drug-induced
• Glucocorticoids, alcohol, thyroxine,
  anticonvulsants, long-term heparin
• Hematologic disorders
• Multiple myeloma, systemic mastocytosis
• Endocrine
• Hypogonadism, hypercortisolism, hyperthyroidism,
  hyperparathyroidism, diabetes
• Gastrointestinal
• biliary cirrhosis, obstructive jaundice,
  subtotal gastrectomy, malabsorption

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Treatment of Osteoporosis

• Nonpharmacologic
• Diet
• Adequate calories
• Calcium
• Vitamin D
• Weight-bearing exercise
• 30 minutes 3 times per week
• Smoking cessation

• Pharmacologic
• Bisphosphonates
• Selective Estrogen Receptor Modulators (SERMs)
• Estrogen
• Calcitonin
• Calcitriol
• PTH

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PTH Why would it treat osteoporosis?

• A paradox
• Hyperparathyroidism is a risk factor for
  osteoporosis
• Renal osteodystrophy is caused by
  hyperparathyroidism

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Why it works

• The actions of PTH are a balance between bone
  resorption and bone formation
• Chronic high levels of PTH cause greater bone
  resorption
• Intermittently high levels of PTH cause greater
  bone formation

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PTH Homeostasis
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Forteo/rhPTH(1-34)

• Subcutaneous injection
• Prefilled injector pen with 20mcg dose
• Daily dosing

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Evidence

• Crandall, C. Parathyroid hormone for the
  treatment of osteoporosis. Arch Intern Med.
  2001 Nov 11 162(20)2297-2309.
• Neer et al. Effect of parathyroid hormone (1-34)
  on fractures and bone mineral density in
  postmenopausal women with osteoporosis. N Engl J
  Med. 2001 344 1434-1441.

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Crandall, 2001

• Methods
• MEDLINE (1966-2002) search
• Cochrane Database search
• Data extraction
• Outcomes incidence of fracture and bone mineral
  density
• Baseline characteristics
• Details of the interventions
• Sample size

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Results
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Results

• 20 RCTs (2361 patients)
• Range of treatment 6 weeks to 3 years
• Sample size 9 to 1637 participants
• Numerous PTH regimens
• Markedly different dosages

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Fracture Data
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Fracture Data

• Difficult to gather
• Often only tallied as adverse effect
• Radiographically detectable fractures occur at
  low rates
• Often too low to allow statistical measurements

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Fracture Data

• Lindsay et al, 1997
• Incidence of new vertebral fractures lower
• No statistical significance (P0.09)
• Hodsman et al, 1997
• Fewer fractures in PTH alone group
• No statistical significance (P0.08)
• Lane et al, 1998
• Fewer fractures in PTH alone group
• No statistical significance

• Fujita et al, 1999
• Only 8 new vertebral fractures between the three
  PTH groups
• No statistical significance
• Kurland et al, 2000
• No statistical significance
• Reeve et al, 2001
• Lower incidence of new vertebral fractures in HRT
  PTH group
• No statistical significance (P0.28)

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Fracture Data Cosman et al, 2001

• 52 women, ages 58-63 with osteoporosis, currently
  taking HRT
• PTH HRT vs HRT alone for 3 years, followed by 1
  year of HRT alone
• Lower incidence of radiographically detectable
  vertebral fractures in the PTH HRT group
• P0.001
• 8.3 vs 37.5 of women had vertebral fractures
• Plt0.02

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Neer et al, 2001

• Randomized, placebo controlled, triple-blinded
  trial
• Median follow-up 21 months
• 99 centers in 17 countries

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Neer et al, 2001
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Baseline characteristics
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Baseline Studies

• Labs
• Calcium, creatinine, CrCl, height, CBC, UA, PTH
  Ab
• Imaging studies
• DEXA (lumbar spine, proximal femur, radius)
• Total body bone mineral
• Thoracolumbar radiography
• All labs imaging repeated at varying intervals

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Neer et al, 2001

• Outcomes
• New vertebral fractures
• New nonvertebral fragility fractures
• Bone mineral density
• Rate of compliance 79-83
• Adequate baseline and follow-up radiographs in 81

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Neer et al, 2001

• Results
• Fewer vertebral, nonvertebral fragility
  fractures in the PTH groups when compared to the
  placebo group
• Trial stopped early by Eli Lily
• Increased incidence of osteosarcoma in rat
  studies

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New Vertebral Fractures
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New Vertebral Fractures
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Moderate to Severe New Vertebral Fractures
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New Nonvertebral Fragility Fractures
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New Nonvertebral Fragility Fractures
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New or Worsening Pain

• P0.007
• Data and method of collection not reported

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Bone Mineral Density

• Increase in BMD at hip and spine in PTH groups vs
  placebo
• Plt0.001
• Dose dependent
• Decrease BMD at radius in PTH groups vs placebo
• Significant decrease between placebo and 40 mcg
  PTH group
• Plt0.001

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Adverse EventsCrandall, 2001
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Adverse EventsCrandall, 2001

• Malignancy
• Increased osteosarcoma incidence in rodents
• Not duplicated in monkey models
• No osteosarcoma reported in any of the 20 RCTs
• Chronic hyperparathyroidism not associated with
  osteosarcoma in humans

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Adverse EffectsNeer et al, 2001

• No significant difference in deaths,
  hospitalizations, gout, nephrolithiasis
• Nausea/headache
• Increased incidence in 40 mcg PTH group vs
  placebo 20 mcg PTH groups
• Dizziness/leg cramps
• Increased incidence in 20 mcg PTH groups vs
  placebo 40 mcg PTH groups

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Adverse EffectsNeer et al, 2001

• Hypercalcemia
• Occurred early in the trial
• Dose dependent
• 2 of placebo, 11 of 20 mcg PTH groups, 28 of
  40 mcg PTH group
• All participants returned to or approached
  pretreatment levels by approx 5 weeks after
  cessation of PTH treatment

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Adverse EffectsNeer et al, 2001

• Malignancy
• No incidence of osteosarcoma
• 40 cases of new malignancy
• Higher incidence in the placebo group
• 4 of placebo group vs 2 in each of the PTH
  groups

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Advantages

• The only FDA-approved treatment for osteoporosis
  that forms new bone
• Increases bone mass
• Decreases fracture rates
• Only minor adverse effects reported
• No stringent administration regimen like
  bisphosphonates

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Disadvantages

• Cost
• gt6000/year
• Financial aid
• Daily Injections
• Long term safety data unavailable

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Questions that need to be investigated

• Would repeated courses of PTH reduce fracture
  rates further?
• Would shorter courses produce larger fracture
  rate reduction?
• Would shorter courses of PTH produce greater
  reductions in fracture rates than long term
  antiresorptive treatments?

• Does PTH reduce fracture rates in men?
• Does PTH reduce fracture rates in younger
  patients?
• Should PTH be given alone or in conjunction with
  antiresorptives?
• If a patient fails bisphosphonate therapy, should
  they then be given a trial of PTH?

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Forteo/rhPTH (1-34)

• Precautions
• Pagets dz.
• Prior XRT
• Unexplained Alk Phos elevation
• Nephrolithiasis
• Open epiphyses
• Contraindications
• Hx of skeletal mets
• Hyperparathyroidism
• Pretreatment calcium elevation

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When How Should I Use PTH?

• In osteoporotic patients with at least one
  vertebral fracture who are at high risk for
  another fracture
• A single 18-24 month course of daily 20 mcg PTH
  SC injections
• Debate exists whether it should be a first line
  agent

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Many thanks to

• Drs. Manus, McCallister, Powers
• Dr. Larry Cantley
• Dr. Roger Smith
• B.L. Lewis
• And of course,
• David John Burns

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