Osteoporosis by drdoc on-line  
   

Osteoporosis, definition:

Osteoporosis is defined as a musculoskeletal disease characterized by low bone mass, micro-architectural deterioration, increased fragility and a resulting susceptibility to fracture.

The main consequence is a reduction in the amount of bone.
Because there are no symptoms or warning signs of osteoporosis, there is a gradual and progressive loss of bone.  If fracture occurs, then the problem becomes symptomatic and painful, with consequences. Therefore, because osteoporosis, prior to fracture is asymptomatic, vigilance is required as the problem is preventable and treatable.

Classification of osteoporosis.

Generalized osteoporosis

Regional osteoporosis

·        Primary -- unassociated with other disease
Juvenile.
Postmenopausal.
Aging -- senile

·         Associated with Endocrine Disease.
Thyrotoxicosis/Cushings/hypogonadism
Pregnancy.
Anorexia/exercise amenorrhoea.

·         Functional
Immobilization/Weightlessness
emphysema/rheumatoid arthritis

·         Environmental
calcium deficiency.
Vitamin D. deficiency.
Alcoholism.
Drugs. 

·         Transient osteoporosis.

·         Immobilization osteoporosis/disuse osteoporosis.

·         Algodystrophy.

 

 

Certain risk factors can be identified.

This will enable implementation of screening procedures for those most at risk.

Genetic risk.
Family history.
Caucasian / asian
A
bsence of generalized osteoarthritis

Dietary
Low calcium intake.
Excess or deficient protein in the diet.

Anthropometric
Small stature.
Thin pale and fair complexion.

Lifestyle.
Sedentary or immobilized.
Excessive smoking or alcohol or caffeine

Hormonal
Woman
Early menopause.
Later menarche.
Nulliparity.
Exercise induced amenorrhoea.
Low levels vitamin D.

Concurrent illness or drugs.
Gastrectomy.
Hyperparathyroidism.
Cushing’s disease.
Corticosteroid therapy.
Rheumatoid arthritis.
Cerebrovascular accident.
Parkinsonism.

 Because of the consequences, osteoporosis is incredibly costly to society.  It will affect 18% of all woman and 6% of males at age 50.33% of woman aged 60 to 70 years of age and 66% of those 80 years or older have osteoporosis.  Fracture results in financial cost as well as morbidity.  After hip fracture 40% will lose walking independence, 20% return to form of function and in fact 20% of patients die within 12 months.  A higher percentage of males die as a consequence of the hip fracture and up to 37% of males die.

What determines fracture?

1.  Age.  We know that we are living longer.  In 1960, life expectancy was between 70 to 75 years in females and 60 to 70 years in males.  However, we would now expect to live between 80 to 85 years.  In females, and 75 to 80 years in males.  Therefore age related bone fracture will become more prevalent in the future. Males tend to notice an increase in hip fractures in the 70s, followed by vertebral fracture, becoming more common in the 80s.  Females however have an early increase in wrist fracture – Colles fracture from the 60s onwards.  From the 70s there is an exponential increase in hip fractures, reaching a peak in the late 80s.  A rapid and steady rise in vertebral fractures occurs from the 70s.

2.  Extra skeletal factors – tendency to fall because of balance or weakness problems.  This is affected by central nervous system problems or problems relating to posture and balance.  The greater the tendency to fall, because of general medical reasons, the greater the risk of fracture.

3.  Bone status.  This includes the strength of the bone, the quantity of the bone – the bone mass as well as the quality of bone – the architecture at a microscopic level of the bone.  The site or geometry of bone affected by osteoporosis or the fall also clearly important.  Risk fragility fractures will occur in the wrist – collies fracture, the thoracic vertebra, the hip, and the ribs.  A fracture of a metatarsal bone in the foot, does not constitute a high risk fracture and does not predict future events. We can measure, the quantity of bone using bone mineral density techniques...

Bone mineral density is measured as a deviation from either peak bone mass – the “T-score” or the age average bone mass – the “Z- score”.  The T-score remains the most useful as we are able to predict risk of fracture, depending on how low the bone mass is compared too strong bone.  The lower the bone mineral density, the greater the risk of fracture.  A bone mineral density between zero and -2.0 represents Osteopenia – thin bone but not osteoporotic bone mass between -2, and -2.5 represents osteoporosis. 

 4.  Previous fracture.

 Previous fracture represents a definite increased risk factor.  We know that a previous vertebral fracture will increase risk of further fracture within the next 12 months.  Lindsay et al, illustrated this clearly.  Within 12 months of a previous vertebral fracture, 3.62% will fracture a hip or pelvis, 3.53% will fracture a humerus or leg, 17.35% will fracture the spine, 1.58% will fracture at the wrist and effectively overall, 26.08% will fracture within 12 months.

A wrist fracture will double the risk of a vertebral fracture, which will give you five times the risk of a hip fracture, which will double the risk of death.  In the case of a hip fracture, the maximal risk of death is in the first three to six months following the event.  20 to 30% of deaths are causally related to the fracture itself. Immediate risks of death include the medical complications of a fracture such as hemorrhage, trauma, bleeding, infection risk, general medical risk in the elderly, such as heart attack or stroke.  Intermediate and longer-term consequences include thrombosis and venous embolism.

Site of bone and Bone composition.

 The two major types of bone include compact / cortical bone and trabecular/Cancellous bone.

Trabecular bone is the mesh like bone, which is found in the spine, in the vertebral bodies, in the plate of the skull and at the end of long bone.  Cortical bone is the tubular bone found in the long bones.

Cortical bone consists of 75% of all the bone mass and is responsible for mechanical protection and structural function.  Trabecular bone because of the large surface area is involved in bone metabolism.  Calcium homoeostasis takes place on this bone surface.  Bone is in a continual turnover.  Bone is a living cellular system.  The mineral component of bone consists of hydroxy appetite, with calcium and phosphate moieties.  The mineral component comprises 70% of the bone.  22% of bone is protein, mainly made of type 1 collagen (95%), as well as proteoglycans (5%) and water (8%).  In the long bone, the bone is laid down in long tubular arrays, known as haversion systems, with concentric layering of bone and mineral around vascular and capillary bundles.  These concentric bundles are called lamellae.

bone 

The bone cells include the osteoclast, the osteoblast and the osteocyte.  The osteoclasts consist of multi nucleated cells with a ruffled border.  They are highly energized.  They consist of numerous nuclei, Golgi and mitochondrial bodies and secrete proteinase and bone lysis, chemicals, to dissolve the bone surface and dig pits into the bone.  The osteoclast is formed from hematopoietic progenitors – bone marrow origins cells.  These cells form pre-osteoclasts, which then mature into the more mature in active osteoclasts before finally becoming active and functional.  The carbonic acid pathway is used to pump hydrogen ions into the cleft between the cell and the bone surface, as well as enzymes such as Cysteine proteinase, mixed matrix metalloproteinases and Cathepsin K .The consequence is a reduction in ph and lytic enzymes that dissolve and liquidize the bone surface—thereby digging a pit into the bone surface.

osteoclast

The osteoclasts come under multiple cytokine influences. The surface of the osteoclasts have a receptor called RANK – receptor activator of nuclear factor – kappa beta.  This binds RANK Ligand which is a soluble receptor of the TNF superfamily.  RANK Ligand binds to the RANK receptor on the surface of the pre-fusion osteoclast, stimulating the cell to become multinucleated and activated.  RANK Ligand, is produced by the osteoblast.  The osteoblast is influenced by multiple other cytokines and hormones to produce RANK Ligand. 

bonecyclegraphic courtesy amgen corp

These cytokines include primarily, IL-6, IL-1 and tumour necrosis factor alpha --TNF alpha.  However the prostaglandins, vitamin D., glucocorticoids, parathormone and parathormone recombinant protein, as well as IL11, all increase RANK Ligand production.  A consequence of these hormones and cytokines is to stimulate the osteoclast, which as a consequence results in bone resorption.  Because IL-1,TNF alpha and IL-6 are involved in inflammatory arthritis, it becomes easy to see how inflammation causes erosions and osteoporosis. Estrogen deficiency is associated with an increase in IL1, IL-6, and TNF alpha.  The consequence is therefore, RANK Ligand production, activation of RANK, and activation of the osteoclast and explains the mechanism for bone loss in estrogen deficiency.

The body employs several homoeostatic mechanisms to oppose the effect of RANK Ligand on bone loss.  The osteoblast produces an antagonistic TNF family molecule called Osteoprotegerin.  Osteoprotegerin binds to circulating RANK Ligand, mopping it up in the extracellular fluid and preventing binding of the RANK Ligand to RANK.  Osteoprotegerin production is increased by growth factors, cytokines and hormones. Therefore, RANK Ligand stimulates RANK to stimulate the osteoclast, whilst Osteoprotegerin binds RANK Ligand and prevents RANK activation and prevents osteoclast activation.  The effect is that Osteoprotegerin by reducing osteoclast activity will reduce bone resorption and prevent osteoporosis.

If RANK Ligand overwhelms Osteoprotegerin, resorption becomes dominant, and osteoporosis will occur. Osteoprotegerin was first described in 1997.it is a soluble receptor and a member of the TNF family of receptors.  By blocking RANK Ligand, it reduces osteoclast activity, proliferation, and therefore increases bone density.

osteoprotegeringraphic courtesy amgen corp

RANK Ligand plays a key role in osteoporosis and other conditions of bone loss and destruction.  It is involved in postmenopausal osteoporosis, erosion of bone in rheumatoid arthritis and similar inflammatory arthropathies, cancer related bone destruction, and corticosteroid induced bone loss. Inflammatory arthritis will cause erosions and osteoporosis through this RANK Ligand mechanism.  IL1 IL-6 IL11, and TNF alpha stimulate osteoblasts to produce RANK Ligand, which stimulates the RANK on the osteoclasts to activate the osteoclast, which will then dig the hole in the bone – the erosion. Patients with erosive rheumatoid arthritis have higher levels of IL-1 compared to patients without erosions or non-rheumatoid patients. The same pattern is not seen with tumour necrosis factor in synovial fluid – TNF, where similar levels of TNF found in patients with erosions, without erosions and non-rheumatoid arthritis patients.

tnf

We now use this knowledge to oppose deterioration of erosions in inflammatory arthritis, by the use of biologic drugs – anti-cytokine therapies, anti-IL-1, and anti IL-6 inhibitors are well documented to reduce the effect of osteoclasts on bone and reduce bone erosion in rheumatoid patients. Inhibition of radiographic progression has been identified with multiple biologic drugs, including Adalimumab (Humira), etanercept(Enbrel), infliximab (Remicade/REVELLEX),as well as anti-IL-6 agents such as Tocilizumab (Roactemra).

biologics 

The osteoblast cell: this is a cell made from mesenchymal cells which mature to pre-osteoblast cells and then the mature osteoblast itself.  Bone morphogenetic protein and WNT, stimulate the early differentiation to the Preosteoblast.  The Preosteoblast is influenced by insulin like growth factor ILGF-1, to mature to the osteoblast.  Parathyroid hormone and growth hormone will both stimulate ILGF-1.  Hence growth hormone and parathyroid hormone will both result in growth of the bone skeleton. The role of the osteoblast is to fill the but that has been done by the osteoclast.  The early un- mineralized protein containing bone matrix, is called osteoid.  The osteoblast therefore grows the bony skeleton and osteoid becomes mineralized and calcified to complete the cycle.  Osteoblasts that are left within the layers in the reconstituted bone, then form into the Osteocytes.  These Osteocytes communicate with each other via canaliculi, with long interdigitating cellular extensions, that enable communication between cells.  The network of Osteocytes form a pressure and structural monitoring system within the bone. This system therefore can identify microscopic cracks in the bone architecture and can call in the osteoclasts and osteoblasts to repair any microscopic damage. In fact bone undergoes a usual remodeling cycle that continues through life, continually restoring and replacing the bone surface.  Resting osteoblasts, activate the osteoclast via RANK Ligand.  The osteoclasts dig a pit over approximately 12 days.  Reversal then occurs, the osteoclasts die or become apoptotic and are replaced by osteoblasts, which layer osteoid into the pit, filling the pit.  The osteoid then becomes mineralized.  This formation phase lasts approximately 13 days.

osteocyte

The bone cycle varies during different times of life.  In the growing years up to age 30, there is a high turnover of formation and resorption.  During this phase, formation is greater than resorption and the bone grows.  In the second phase of life during stability between the ages of 30 and 50, bone turnover remains prominent but formation equals resorption, and the bone is stabilized.  In the early menopause however, this system becomes unstable because of a rise of resorption compared to formation with a high turnover state.  The consequence is bone loss during the early menopausal years.  This will set the pace for the future.  In the fourth days, in the elderly years, Bone turnover is low and resorption still exceeds formation, although at a much lower pace compared to menopause.

oseocytes

Because we know that bone loss accelerates at menopause, we can assess peak bone mass before onset of menopause and assess risk for that individual.  A bone mineral density lower than -2.5 standard deviation from the peak bone mass, is defined as osteoporosis.  However any bone mass above or below -2.5 standard deviation, in the presence of fracture or previous fracture, defines the patient as having severe osteoporosis.  The reduction of standard deviation by one unit will double lifetime risk of fracture.  One standard deviation below the mean will give a 30% life time fracture risk.  Two standard deviations below the mean doubles the risk to 60%.  This is different to the current fracture risk.  (Which is much lower).  Current fracture risk for one standard deviation below the mean is 4% risk of hip fracture.  Two standard deviation below the mean equals 12% risk fracture for hip.  Three standard deviations below the mean will give a 18% hip fracture risk.

dexa

We can optimize bone by preventing bone loss, and to achieve as maximal peak bone mass as possible.

Hormones and hormone replacement therapy.

Endogenous estrogen, suppresses IL-1 and TNF and IL-6.  It causes therefore suppression of RANK Ligand and stimulates production of Osteoprotegerin.  As a result there is promotion of osteoclasts apoptosis.  There is an increase in .early osteoclast death and reduction in function.  The osteoblasts on the other hand, has increased lifespan and therefore bone density is enhanced.  RANK Ligand expression is measurable.  Experimentally, untreated postmenopausal women express higher level of RANK Ligand, compared to premenopausal woman or post menopausal woman on hormone replacement therapy.

By measuring bone mineral density, it is clear that hormone replacement therapy prevents bone loss.  Delay in provision of hormone replacement therapy results in further bone loss. Initiation of hormone replacement therapy in patient after oophorectomy, prevents bone loss. After oophorectomy, bone loss can be monitored and shown to reduce in a manner typical of a postmenopausal population.  Introduction of hormone replacement therapy prevents bone loss.  Delay in giving hormone replacement therapy results in a lower basal – baseline bone mineral content.

 The effect of hormone replacement therapy has been shown by Gallagher, to improve spinal bone mineral density by approximately 4 to 6% over three years and in the femoral neck by 3 to 4%.after starting conjugated estrogen -- .625 mg per day, with medroxyprogesterone acetate, 2.5 mg per day as hormone replacement therapy.  However, the bone mineral density starts to drop back towards the initial level over the next 18 months.

 Publication of the woman’s health initiative study, however has changed that perception of hormone replacement therapy, since this study showed increased risk of breast cancer, stroke, venous thromboembolism, and possibly coronary artery disease.  He was a hazard of cardiovascular event, equivalent to eight additional events, in 10,000 patient years of exposure.  This study, we changed our usage of HRT in osteoporosis.  Estrogen – progesterone combination therapy is no longer first line approach for osteoporosis treatment or prevention in postmenopausal women.  Indications for hormone replacement therapy include persistent menopausal symptoms, inability to tolerate other options or failure to respond to other options.

The woman’s health initiative study despite all the controversies, showed a 35% reduction in hazard of developing vertebral fracture over seven years (95% confidence intervals .46--.92)

 Calcium and vitamin D

Worldwide there is increasing concern regarding deficiency of vitamin D in our population deprived of sunlight.  This is either because of overzealous protection from sunlight, because of fear of skin cancer or lack of sunlight in the northern populations.  Even in Cape Town, Hough et al demonstrated low levels of vitamin D compared to Johannesburg, between March and October, winter months. Vitamin D. deficiency is widespread and plays a critical role in fracture.  Calcium begins to be taken from bone, when vitamin D levels reduced below 30 ng per milliliter.  At further reductions, below 10 ng per milliliter, there is a steep rise in parathormone, PTH, and thus development of osteomalacia.  Insufficiency occurs between 10 to 30 ng per milliliter and deficiency is below 10 ng per milliliter.  The low circulating levels of calcium as a consequence of vitamin D. deficiency begin to trigger the calcium sensing receptor to stimulate parathormone release below 30 ng per milliliter. In a study of 3270 ambulatory elderly woman receiving 1200 mg of calcium and 800 units of vitamin D. versus placebo over 36 months, hip bone mineral density increased by 2.7% versus a reduction in the control population of 4.6%, and there was a reduction in hip fracture of 43%. Bischoff et al. demonstrated that vitamin D. also effectively reduces falls, in a metaanalysis of published data.

Drugs in osteoporosis

Medical therapy in the treatment of osteoporosis can be divided into anti- resorptive agents versus stimulating agents – anabolic therapy.

Antiresorptive agents

Anabolic agents

Drugs in development

Calcium.

Fluoride

Denosumab

Vitamin D. and metabolites.

Anabolic steroids

 

Sex hormones/SERMS

Low-dose PTH

 

calcitonin

Strontium salts

 

Bisphosphonate therapies

 

 

 Use of these agents is often affected by affordability and finding as the new agents are often more expensive.

 SERMS – selective estrogen receptor modulators.

 SERMS are neither an estrogen nor hormones. They bind to estrogen receptors, and had estrogen like effects in some tissues, but also blocking effects in certain other tissues. Therefore they can have both estrogenic and anti-estrogenic effect in the case of new SERMS, and it can be a positive bony effect, but no hormonal effect.

Raloxifene is shown to reduce the risk of new clinical vertebral fractures at one year in woman with and without prevalent vertebral fracture at baseline.  There is a 68% reduction in the risk of vertebral fracture, compared to 66% reduction in woman with a previous history of vertebral fracture given Raloxifene. In addition Raloxifene, he has been shown to reduce the incidence of breast cancer in patients followed up with annual mammogram, there was a 62% reduction over four years compared to placebo.(the more trial).

 Bisphosphonates.

Bisphosphonate inhibit bone resorption by an effect on the osteoclasts.  As a class, all Bisphosphonates bind phosphonate groups in the hydroxyapatitie of bone.  Nitrogen-containing Bisphosphonates inhibit  Farnesyl pyrophosphate synthetase, which results in prenylation of G-proteins.  G-proteins are involved in the secretion of acidic vesicles, from the ruffled border of osteoclasts.  On Bisphosphonate therapy, the osteoclast border becomes unruffled, and the life span of the osteoclast is reduced, with increased apoptosis.  The Bisphosphonates drugs are badly absorbed as oral drugs.  Intestinal absorption is only about 5%, but from the circulation, they are taken up rapidly by a bone.  They bind to food content, and require specific instruction in their use.  Generic products may have problems with absorption.  Absorption is further aggravated in the presence of malabsorption or intestinal disease. Once absorbed and bound to bone, they are remarkably consistent.  Skeletal half life can last as long as 10 years with the alendronate.

Types of orally available Bisphosphonates.

Oral agents

Oral dose

Risedronate-Actonel

5 mg per day or 35 mg per week

Alendronate-Fosamax

10 mg per day or 70 mg per week

Fosavance

70 mg per week – includes 5600 units of vitamin D

Ibandronate – Boniva

150 mg per month (in the USA)

 Fosamax – alendronate remains the gold standard against which osteoporosis drugs are measured.  The fracture intervention trial assessed the effects of Fosamax in women aged 55 to 80 with a low bone mineral density – femoral neck T-score -1.6 or less over 36 months.  Results showed a 59% reduction in vertebral fracture at 12 months and a 3% reduction of hip fracture at 18 months and 59% reduction in hip fracture at 36 months. Studies to look at the tolerability and long-term benefit over 10 years in 994 patients, showed a plateau of effects at six to 10 years at a sustained improvement.  Total spine improvement at 10 years was 13.7%,  Total hip improvement was 6.7% and the trochanter of the hip10.3%.

Risedronate is more modest compared to the alendronate Bonnick et al demonstrated 1.3% improvement in total hip bone mineral density improvement compared to 3% for alendronate at 24 months. The lumbar spine bone mineral density increased by 3.4% versus 5.2% with the alendronate.

However Bisphosphonates require regular oral therapy, and because of problems of absorption require specific protocols.  The drug must be taken with a full glass of water, first thing in the morning, fasting, and the patient must not recline or lie flat, after taking the medication for at least 30 minutes.  The latter is to prevent reflux and esophageal ulceration. Under no circumstances must the drug be used with food, as the drug will bind and absorption will not take place. Because of these requirements Bisphosphonate persistence is poor over 12 months of use.  Ettinger et al demonstrated that only 31% of patients took weekly Bisphosphonate after 12 months and only 15% of daily regimen patients still complied after 12 months.

The commonest side-effect of orally administered Bisphosphonate is esophageal ulceration and dyspepsia. Some patients also complained of arthralgia and myalgia. Much has been made about bone Osteonecrosis in oral Bisphosphonates, but this is exceedingly rare, with fewer than 200 cases described, despite multimillions of users.  The risk of fracture far exceeds the risk of Osteonecrosis of bone from these drugs.

Because of difficulty with tolerance and compliance, especially related to the gastrointestinal side-effects, an alternative therefore has been the recent introduction of the intravenous agents.

Drug.

Dose.

Administration.

Pamidronate -- Aredia

30 to 60 mg, three to six monthly

Three to six monthly infusion

Zoledronic acid-- Aclasta

5 mg per year

Yearly infusion

Ibandronate

150 mg per month

Monthly infusion

Pamidronate – Aredia: Has been licensed for Pagets disease and treatment of hypercalcaemia and malignancy, but has been used for osteoporosis and has good efficacy in my own experience for bone pain, and treatment for osteoporosis in those patients who cannot tolerate oral Bisphosphonates. In my practice an infusion is given over three hours of between 30 to 60 mg, mixed in saline solution. The drug is extremely well tolerated with arthralgia and myalgias for 48 hours and a feeling of mild flu, in perhaps 10% of patients.

Zoledronic acid -- Aclasta

Aclasta – Zoledronic acid, has been licensed for the treatment of osteoporosis around the world.  The drug is given as 5 mg in an infusion over 10 to 15 minutes, with minimal practical side effects.  Patients can develop flulike symptoms, over 24 to 48 hours, but these are treatable with a simple analgesic or anti-inflammatory as required.

 Zoledronic acid is a potent nitrogen containing Bisphosphonate.  It has high binding affinity for bone, and potent Farnesyl pyrophosphate synthetase inhibition. 61% of the infused drug, is redistributed to bone, and 39% and is excreted by the kidney within 24 hours.  There are no circulating metabolites.  The half life is short.  Caution is required in patients with renal failure.  We advise assessment of renal function in patients who are administered the drug as a routine.  The pivotal trial, was published by Black et al.  this was the health outcomes and reduced fracture incidence with Zoledronate once yearly pivotal study – “Horizon” study. 

This was a multinational multicentre controlled trial over three years looking at 7736 woman aged between 65 and 89 with a femoral neck T-score less than 2.5 or less than 1.5, but with an existing vertebral fracture.  Calcium between one to 1 ˝ a gram per day, was administered plus vitamin D. between 400 and 1200 units per day.  No strontium salts or parathormone or steroids were allowed and oral Bisphosphonates were not allowed within a two-year period.  Some patients were allowed Raloxifene or hormone replacement therapy and the, these patients were included in a second Strata in the study. The results were impressive.  There was an increase in lumbar spine bone mineral density of 6.71% compared to placebo over three years.  There was an increase in total hip bone mineral density of 6.02% over the three years.  There was an increase in femoral neck bone mineral density of 5.06% over three years. The cumulative risk of vertebral fracture was reduced by 77%.  Patients in strata 1 – without exposure to hormone replacement therapy, calcitonin or Raloxifene, improved by 60% in the first year, 70% in the second year and 70% in the third year regarding rates of vertebral fracture.

There was a 41% reduction in the hip fracture, compared to the placebo, and 25% cumulative risk of other non-vertebral fracture. 

Notably, in another trial, published by Lyles in 2007 in the New England Journal of Medicine, the mortality, was reduced by 28% over 36 months. In this trial re fracture after use of Zoledronic acid was markedly reduced.  There was a 35% re fracture rate amongst all fractures, 27% reduction in on vertebral fracture and 46% in the clinical vertebral fracture.

Bone markers were measured in these trials, and this showed a reduction in C-Telopeptide, a marker of bone resorption within six months with a steady level with drug-repeat exposure.  C-Telopeptide levels did not reduce to zero

Trials have been done in Glucocorticoid related osteoporosis.  The gold standard for treatment of Glucocorticoid related osteoporosis has been Risedronate, which is licensed for treatment of steroid related osteoporosis.  Reid et al showed superiority of Zoledronate over Risedronate in a study published in 2009.  This included both a treatment and prevention population. This effect was demonstrated in spine as well as the femoral neck.

Side effects were noted in the horizon study published by Black included fever in 15% myalgia 8% and flulike symptoms.  There was no cases of jaw related Osteonecrosis, (but two cases of Osteonecrosis elsewhere, one in the treatment and one in the placebo group-- both of which resolved without treatment).

Atrial fibrillation, was observed in the horizon study, with a 1.2% incidence in the patient group versus 0.4% of placebo group. This was not replicated in other trials.  The USA food and drug administration has assessed this issue and found no suggestion of this as a significant problem with the drug in general.

Bone Osteonecrosis however has been a concern with the intravenous Bisphosphonate drugs. This is especially so with the higher doses and frequent uses in oncology use.  The drugs are used for myeloma and also breast cancer, where studies show a reduction in mortality and metastatic disease in breast cancer in patients using Aclasta. Osteoclast function is impaired by the drug, and the osteoid sites are not replaced, with the bone becoming tense and choking the capillary network, potentially causing ischaemia of bone.  The mandible – at the jaw has a high trabecular surface area, and appears to have significant effect from Bisphosphonates.  Incidents of Osteonecrosis of the jaw and mandible have been reported with the intravenous Bisphosphonates, especially with frequent dosing, and are strongly associated with gum or jaw sepsis and chronic sepsis or dental caries. My practice is to avoid them, if patients have chronic sepsis or are scheduled for periodontal surgery, extractions or implants in the near future. These procedures are not a contraindication to use, but require caution.  The American dental Association recommends a strict regimen of post operative antimicrobial and antibiotics before extractions.  Washing with chlorhexidine and oral antibiotics are recommended post procedure. They recommend a maximal of two teeth extracted per visit, with two months between extractions.

After five years of using Aclasta, I have never seen a single case of Osteonecrosis of the jaw.  Similarly, after using an Aredia – Pamidronate over the last 10 years, I have never seen a single case of Osteonecrosis of the jaw.

Experience of the Bisphosphonates in general has now reached 30 years since the first studies of Clodronate, but the latter was shown to have bony mineralization problems, and therefore never went into widespread clinical use.  Alendronate became the gold standard, and patients have been using this drug for over 10 years.  In the recent past, cases of mid femoral shaft fracture have been described with low level trauma in patients who have been taking Bisphosphonates for over 10 years.  These fractures are exceedingly rare, but are unusual.  They are usually preceded by a bone pain.  They can be bilateral.  They occur with mild or minimal trauma.  They tend to be transverse fracture.  Hypertrophy of the cortex of the bone is noted in these cases.  They are thought to result from diminished osteoclasts activity and impaired micro-damage repair after prolonged use.  Fewer than 200 cases have been described.  However, they are a concern.  Some experts are recommending a drug holiday after five years of using Bisphosphonate.  There is no data to support this conclusion.  Ongoing observation of patients on long duration Bisphosphonate continues.  Cases must be assessed on a individual basis for osteoporosis risk.  The bone mineral density should be monitored on Bisphosphonate patients yearly for response.  If after five years, the levels are adequate, withdrawal of drug may be advised and monitoring without drug continued.  However, if the bone mineral density remains low and in fracture threshold, then the risk of fracture from osteoporosis exceeds by far, the rare incidence of shaft fracture, and the drug should be continued.  If the patient complains of painful legs, especially in the mid thigh region, x-rays should be done and if cortical thickening is noted the Bisphosphonate should be withdrawn.

 However, Bisphosphonates have radically improved.  The managements of osteoporosis with clear reduction in incidence of fracture of both the vertebral fracture and hip fracture plus reduction in re-fracture rates, and improvement in mortality.  The use of intravenous Bisphosphonates has radically improved the problem of compliance issues, and offer a low side effect and clinically proven benefit in the treatment and prevention of primary and corticosteroid induced osteoporosis.

Anabolic therapies.

 Strontium Ranelate -- Protos

Strontium Ranelate, is a old drug that has been revisited in the management of osteoporosis. Strontium salts have been documented for years to increase bone mineral density. Strontium is now licensed as Protos in the European Union and South Africa for the management of osteoporosis. For uncertain reasons, the drug has never been submitted for authorization in the United States of America. Therefore it is unavailable in the USA. Strontium Ranelate works with bone formation as well as a reduction in bone resorption.  Whilst these actions are not fully categorized, the is some suggestion that there is an increase in Osteoprotegerin and a reduction in RANK with increased activity of osteoblast and reduced activity of osteoclast.  Bone mineral density with the drug increases both from bone density itself as well as the molecular weight effect of strontium.  A correction factor has to be applied in the interpretation of bone mineral density data, to remove this strontium effect on the measurement of the bone mineral density itself.  Two major studies have been done with strontium.  The first was the spinal osteoporosis therapeutic intervention study.-SOTI study.  This was published in the New England journal of medicine.  720 patients were included of Strontium Ranelate versus placebo.  These were post menopausal.  They included patients with a reduction in bone mineral density at the femoral neck less than -2.5 or previous spinal fracture.  Results showed a significant reduction in new vertebral fracture of 49%, at one year, and at three years a reduction of 41%.

The treatment of peripheral osteoporosis studies – Tropos study included 2500 patients of Strontium Ranelate versus placebo with a T-score of -2.5 in the femoral neck, or worse.  Patients were older then 74 years of age.

In this study the effect of Protos on peripheral or non-vertebral fracture was studied.  All non-vertebral fractures were reduced in three years by 16% and hip fracture was reduced by 36%, but was not significant statistically.  However, if a subgroup of high risk patients with hip T-score -3, or worse was assessed then the results showed a statistically significant improvement of the hip fracture reduction by 41%.  Bone mineral density improvement with Strontium Ranelate at 36 months in the lumbar spine was 14.4%.  (But adjusted to 8.1% using the conversion factors).  In the hip.  There was an improvement of 8.3% compared to placebo with elevated bone mineral density of 6% at the three years, with a mean increase of plus 2% per year.

Bone biopsy studies have been done showing increased trabecular decreased trabecular spacing and improvements in bone mineral architecture.  A new technique to assess bone mineral microstructure using three-dimensional Micro CT scan has been developed and used in the Protos development programme to show improvement, in bone architecture. The Rizzoli study the at a comparison between the alendronate, and Protos using this technique.

In this study.  Patients with T-score less than 2.5 were put on Strontium Ranelate 2 g a day, versus alendronate 70 mg per week, and scanned every three months for two years. Micro architecture was then compared. There was a significant increase in trabecular number, cortical thickness and trabecular bone volume compared to alendronate.  There was a reduction in trabecular separation.  Birth suggests an improvement in bone quality.

Protos – Strontium Ranelate is given as a daily medication, made up from a sachet of 2 g of Strontium Ranelate powder, mixed in a glass of water and taken at least two hours after or before food.  This does give compliance problems.  The main issue is, that absorption will not take place if Strontium is given with food containing calcium, in particular. Side effects include nausea, in 7%, diarrhea 7%, headache, 3% and dermatitis in 2%. 

Forteo – Teriparatide, recombinant parathormone/parathyroid.

Teriparatide is a medication, developed from recombinant, technology, forming the active component of parathyroid hormone.  The parathyroid is a gland in the thyroid gland comprising of four components in each lobe of the thyroid.  Metabolically, parathyroid hormone is produced as a response to low calcium level, and acts to restore the blood calcium level and keep it constant, in a normal range at all times. Accordingly the effect of parathyroid is to take calcium from bone and to cause calcium retention at the kidney and reduce urinary calcium.  Abnormal sustained high level of parathyroid hormone from an overactive gland will result in Osteopenia, with hyperparathyroidism.

However, pulsatile use of parathyroid hormone has been shown to build bone. Teriparatide is given as a daily injection of 20 µg.  The injection is given subcutaneous, and there is a device delivery system provided by the manufacturer.  Jiang et al, reported improved skeletal architecture with Teriparatide 20 µg per day, with bone biopsies showing increased trabecular volume, increased trabecular connections, increased cortical thickness, and generally a much more solid bone.

They looked at 1637 postmenopausal woman with osteoporosis in the Teriparatide fracture prevention trial with the median duration of treatment of 19 months.  Patients were randomized to 20 µg per plus calcium and vitamin D., compared to tell some and vitamin D. alone.  Results showed a increased bone mineral density in the lumbar spine of 7.4% and in the hip of 5.2%.  Teriparatide is licensed for the treatment of osteoporosis.  However there are concerns about sarcoma in animal models and therefore Teriparatide is restricted to two years of use.  It is expensive and is used for the most severe osteoporosis with fractures, not responsive to the Bisphosphonate group. It may offer potential for a Bisphosphonate suspension after prolonged use as a temporary drug holiday. It should not be used in pregnancy.

Monitoring for high calcium levels should be taken as a routine monitoring follow up.  Common side effects include nausea, joint pain, cramps and injection site reactions. Postural hypotension can also be a problem.

Denosumab—prolia

Denosumab is the therapy of the future.  We all understand the mechanism now of osteoporosis by the RANK and RANK Ligand systems which influence the osteoblast and osteoclast  bone  activity cycle.  Denosumab is the first fully human monoclonal antibody that specifically and with high affinity, binds to RANK Ligand.  This effectively does the same job as Osteoprotegerin, but the antibody is more potent and has a longer half life than Osteoprotegerin. By preventing rank Ligand from binding to rank, osteoclast differentiation activation and survival are reduced and therefore osteoporosis is prevented and treated.

Becker PJ, did a single dose placebo-controlled study of Denosumab, and this was published in Journal of bone mineral research. Cummings, SR,  Martin, J. S., and McClung MR et al published a study in the New England Journal of Medicine in 2006, and showed enhanced bone mineral density at six months at 14 mg to 210 mg of Denosumab. 7868 woman with a bone mineral density of less than 2.5 at the spine or hip were randomized to either 60 mg of Denosumab every six months for 36 months , or placebo. Results showed a 68% reduction in incidence of new vertebral fracture and a reduced hip fracture risk of 40%.  Non-vertebral fracture was reduced by 20%.  No side-effects of infection was noted and no adverse reactions were noted.  At this time licensing for Denosumab has not occurred in the United States but recommendation for licensing has been granted by the European agencies, for consideration for marketing the drug.  Concerns in the United States at this time are largely related to infection risks, and more studies are being conducted to confirm safety before licensing by the Food and Drug Administration.

Bone mineral high-density CT scan and bone biopsy, shows anabolic response to the trabecular structure with thickening of the trabeculae and reduction of space between trabeculae and increased trabecular number.

Surgery.

Kyphoplasty / Vertebroplasty have become more used, especially by orthopedic and neurosurgery – surgical specialists for acute fracture.  The aim of the procedure is to either inject a cement into the vertebral body or to inflate a balloon into the collapsed vertebral body structure.

Studies do show reduction in pain with these procedures and persistence of improvement.  Vertebral height is also improved.  However, the procedure does nothing to treat the underlying disease.  Pain recurrence occurs usually due to collapse of new fractures affecting adjacent vertebra.

The procedure is best for single level therapy within two months of a fracture.  Appropriate management of the osteoporosis and exclusion of other underlying disease must still be initiated and continued.  It is a palliative procedure.  Unfortunately, patients who have this procedure are often neglected regarding other underlying cause and failed to be treated for ongoing osteoporosis itself.

Overall summary and management guideline of osteoporosis

At a practical level, when a patient presents, they either come for prevention advice or for treatment after an event has occurred.  Ideally screening and prevention, early on, is the goal.  Therefore, bone mineral density screening for high risk patients, or for patients in whom osteoporosis is likely to develop, should be performed. This includes patient to have family history, insulin deficiency, including anorexia, malnutrition, early menopause.  Patients who have other diseases such as hyperparathyroidism or rheumatoid arthritis or Parkinson’s disease or immobilizing conditions.  Patients who have existing vertebral abnormality or x-ray changes should also be screened.  X-ray changes are usually late compared to the changes of bone mineral density screening. All patients have had a potential fragility fracture should be screened.  Patient demand itself should be encouraged, and such patients should be screened.  Bone mineral density monitoring should also be performed on an ongoing basis, to assess response to therapy. The timing of repeat bone mineral density is depends on the severity of the problem.

A good clinical history and clinical examination, should be conducted. It is important to exclude other causes of fracture for example, regional osteoporosis or even malignancy, and in particular, myeloma should be excluded.  Other causes of bone matrix abnormalities such as osteomalacia should be excluded.  Basic blood tests such as a blood count, ESR, C-reactive protein and protein electrophoresis, are recommended. A blood calcium, alkaline phosphatase and parathyroid level, and thyroid level should be done.  Tumour markers should be done where appropriate and scanning, including CT or MRI should be done where appropriate.

Decision regarding treatment.

To assist in the risk stratification and of a patient, a computer model known as the FRAX– fracture risk assessment tool, has been developed by Dr John Kanis at the University of Sheffield. This includes details on age, sex, weight and height as well as previous fracture previous hip fracture, smoking history and excessive alcohol consumption. Input regarding history of Glucocorticoid exposure and rheumatoid arthritis, as well as history of other underlying cause of osteoporosis are included.  Finally, the bone density at the femoral neck is required.  The computer generates a model of risk, including probability of major osteoporotic or hip fracture over a 10-year period. The practitioner can then use this guidance to calculate probability of fracture and assist with treatment.

Initiation of treatment.

 In the case of prevention, a bone mineral density score of less than -2.5 is defined as osteoporosis and requires treatment.  In the case of established fracture – spinal or hip, any bone mineral density score will warrant treatment.  It is foolhardy to have patients with a bone mineral density greater than -2.5 , who have had a previous fracture, but not treat them, because of a bone mineral density, which does not reflect osteoporosis.  Previous fracture immediately places a patient in an osteoporotic category. Interestingly, some funders failed to appreciate this, and motivation for funders to pay for osteoporosis therapy with bone mineral density that fails to reflect osteoporosis, but have existing fractures should be done by the practitioner.  False negative bone mineral density reports may occur in the presence of osteoarthritis, where osteophytes give a spurious high-level of the bone density itself.  Radiologists, should be able to assess these patients by focusing on unaffected vertebral bodies, if possible.

In the case of osteopenic patients without previous fracture , with T-score -1.0  to -2.5,clinical risk factors for fracture including a possibility of falling as well as using the FRAX model may assist in determining who to treat.  We do not recommend that all osteopenic patients receive therapy, but rather stratify the risk and treat only if appropriate.

We live in an era where drugs are available.  Fracture is preventable.  Osteoporosis may be detected in any and risk patients can be screened more easily.  Bone mineral density machines are widely available.  Choice of drug is dependent on severity of the process, availability, funding availability and cost, compliance, and a myriad of possibilities that require specialist input.  A specialist with experience and a special interest in osteoporosis, should  assess these cases.  There are several specialties, who have interest in osteoporosis. These include the endocrinologists, gynaecologists and rheumatologist.

 

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The Microarchitecture


Bone structure with fracture of the microstructural bone bridges



Vertebral fracture

 

Dr David Gotlieb
Original Article : copyright
Cape Town
South Africa
Jan 2010


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