GP Questions

On Wednesday 26 November 2014, Garvan hosted a live webcast about Osteoporosis broadcast to GPs across Australia. It featured Prof John Eisman in discussion with Dr Amanda McBride.

The event was sponsored by Australian Doctor, Medical Observer and 6Minutes. Prior to the webcast, the three publications promoted the event heavily, and invited GPs to submit questions in advance for Prof Eisman to answer on the night. While there was time to answer in a general sense, there was no time to address specifics.

Professor Eisman responded in writing to each GP. The questions asked, and the responses given by Professor Eisman are listed below.

What do you do after 3x aclasta infusions?
What do you do after 5 years of bisphosophonate therapy?

Most evidence supports continuing treatment long term, i.e. after Aclasta infusions or 5 years of bisphosphonate therapy, unless bone density is above the osteoporotic level, i.e. T score above -2.5.  If treatment is stopped in individuals with T-scores below that level, there is evidence of increased fracture rates.  

When do you do a fasting metabolic bone study?

A fasting metabolic bone study is usually looking at the bone turnover markers.  These should always be done in the fasting state but are not very onerous as individuals can drink water. 

Does the location of a fracture influence your choice of therapy?

The location of fracture does influence the choice of therapy in the sense that if the fractures are in central bones (i.e., spine, pelvis, hips, upper and lower limbs centrally) then they are very likely to be low trauma fractures and thus associated with increased risk of future fractures and good reason for initiating or continuing therapy. 

By contrast, peripheral fractures of fingers or toes and ankles (in women) aren’t necessarily associated with increased risk of future fractures.  Hence, they do not indicate need for treatment in the absence of other indications.

Does a silent  reduction of 20% vertebral height have the same clinical fracture significance as a low trauma wrist or hip fracture? I know they are counted as equal  in FRAX.

A reduction in vertebral height of 20% or more is considered to be a vertebral fracture.  The difficulty with a vertebral fracture is that it is not clear when it may have occurred, as more often than not people do not have symptoms associated with them. As a finding, a vertebral fracture has the same clinical significance in terms of increased fracture risk as wrist, hip or other low trauma fracture.

What monitoring is required for someone with osteoporosis on bisphosphonates eg repeat bone scans and for how long?

Monitoring after initiation of bisphosphonates or other antiresorptive therapy is a matter under considerable discussion. Bone density changes relatively slowly and, in most cases, virtually all people respond to these agents.   However, in my opinion, bone density tests, at one year initially and subsequently at 2-3 year intervals thereafter, are useful as part of maintaining patient understanding of the importance of the consideration and, as an indication of adherence to treatment.  Oral bisphosphonates can easily be taken incorrectly, for example after some food, and in that case bone density decrease can continue and bone density testing can help identify this potential problem.

Bone density and measurements of bone turnover markers, which change relatively soon after initiation of treatment, may well be useful as part of the on-going adherence to therapy program.

When do you consider stopping bisphosphonates or other osteoporosis treatments in a patient with osteoporosis?

I consider it is rational to continue bisphosphonates or other antiresorptive agents as long as the bone density is in the osteoporotic range.  In the unusual circumstance that the bone density increases to such an extent that it is no longer in the osteoporotic but only in the osteopenic range, one could argue for an individual to have a break from treatment for a short period of time.

I have read that bisphsphonates should be ceased after 5 year's treatment. Is this true?

The concept of a bisphosphonate “drug holiday” was based on a study carried out in women who were on average osteopenic.  In a recent re-analysis, those women who stopped the bisphosphonates and had bone density T-score actually in the osteoporotic range had an increased risk of fracture compared to those that continued therapy. Thus there is little or no scientific rational for a drug holiday in women whose BMD remains in the osteoporotic range.

Is it advisable to use the newer injectable bisphosphonates (Prolia is one I am using these days) after a patient has been taking the oral versions for 5 years +? Is there a limit to their use?

The injectable antiresorptive denosumab (Prolia) acts in quite a different way to prevent the generation and survival of osteoclasts, i.e. quite different from the bisphosphonates that are toxic to preformed and active osteoclasts.  Despite their different mode of action, there is no evidence that one agent is better than another and there is no reason to shift from one to another apart from other factors such as patient preference or convenience and importantly likely therapy adherence.

I would like to know the level of the evidence backing the use of Boron, Magnesium, Zinc,Copper, Vit K, Manganase in the treatment of osteoporosis

There is virtually no evidence to supports the use of Boron, Magnesium, Zinc, Copper, Vitamin K or Manganese in the treatment of osteoporosis.  There needs to be an adequate magnesium level in order for calcium to be adsorbed. However this is unlikely to be an issue except in malaborption. 

In regards to Prolia, in your experience what is the incidence of infections and osteonecrosis of the jaw?

In relation to denosumab (Prolia), in the high doses used in malignancy, much higher than those used in osteoporosis, there has been an incidence of osteonecrosis of the jaw.  This appears seems to that seen in high dose bisphosphonates used in malignancy.  However as with bisphosphonates for osteoporosis, it is likely to be a rare or very complication, perhaps 1 in 10,000 person.years of treatment and unlikely to be of the severity reported initially in high dose therapy in malignancy.

In relation to denosumab (Prolia), I am unaware of any evidence of significant clinical infections.  

Would you recommend Prolia to a patient who has an Autoimmune Disorder,is on corticosteroids and unable to use Biphophanates?

The challenging situation of an individual with autoimmune disease who is on corticosteroids and has apparently been intolerant of bisphosphonates, denosumab (Prolia) would be a reasonable option. However, I would discuss this with the immunologist or rheumatologist treating the autoimmune disorder.

Are there are any types of minimal trauma fractures that you would NOT consider indicative of bone fragility?  

I am particularly interested in whether you would include ankle fractures, 5th MT fractures, tibial plateau fractures, clavicle fractures, phalanx fractures

Minimal traumas of fingers and toes are not considered as indicative of bone fragility. 

Ankle fractures in women have been consistently shown not to be associated with other fractures.  By contrast, ankle fractures in men are associated with an increased risk of other fractures.  

It is not clear whether metatarsal fractures or other phalange fractures have such relationships. 

Tibial plateau fractures and clavicle fractures are worth investigating in relation to potential osteoporosis. 

Given the major problems and the dreadful morbidity associated with bone disease in fully established myeloma, do you believe that every person in this country who has scan proven decreased bone density due to MGUS (approximately 3% over 60 and 5% of the population over 70) should be on a biphosphonate medication (Zolendronic Acid) and should it be on the Pharmaceutical Benefit list for such an indication?

If not, then shouldn’t a major double blind cross-over trial be undertaken in this country to prove efficacy or otherwise?

It is possible that individuals with MGUS may be losing bone at a relatively rapid rate.

I am not aware of a current trial demonstrating efficacy as regards fracture risk reduction.  It would be useful to have randomised controlled trial evidence of this sort of benefit.

What are the pros and cons of CT BMD? Can we use this for those with spinal OA in preference to DEXA?

CT bone density can be used particularly in individuals who have particularly problematic measurements in the spine due to degenerative change. However, bone density in other sites, such as proximal femora, is likely to be informative in this situation. CT bone density has the issues of much higher radiation exposure and lower precision than DXA, so is not recommended. 

Is there a treatment that is particularly appropriate when we find spinal osteoporosis but hips ok? Or vice versa?

In a postmenopausal woman with spinal osteoporosis but hip bone density is OK, one could make the case for Raloxifene which has good anti-fracture efficacy but relatively less efficacy in the hips.  If there is osteoporosis in the hips but the spine looks reasonable this is likely to be due to degenerative changes in the spine.  On that basis it is reasonable to continue with therapy aimed at treating osteoporosis with any of the potent anti-resorptives, sex hormones, bisphosphonates or denosumab.  

How long should we use bisphosphonates? Is this different advice in younger and older people?

Bisphosphonate treatment should logicaly be continued as long as the individual is osteoporotic, i.e. BMD T-score <-2.5.  It is much more difficult in young people to make some of these decisions and secondary causes of osteoporosis should always be sought in younger people.

Aside from the manufacturer PI what Vitamin D levels are recommended by medical experts prior to administration of Prolia (denosumab) and what evidence is there for this?

The concept of adequate vitamin D levels is based on the fact that, with marked inhibition of bone resorption with potent subcutaneous or intravenous anti-resorptive agents, hypocalcaemia may ensue.  For that reason adequate vitamin D levels of the order of >50-60 nmol/L are recommended prior to administration of potent anti-resorptive agents, including denosumab (Prolia), zoledronic acid (Aclasta) and even oral bisphosphonates.  

What is the cut off level of vitamin D where it is too risky to give Prolia and how soon after starting Vitamin D supplements should the vitamin D level be rechecked again?

Vitamin D supplementation requirement and follow-up depends largely on the level.  If the levels are very low, for example <30 nmol/L, it makes good sense to ensure that the 25-hydroxyvitamin D levels are around 50-60nmol/L prior to using potent anti-resorptive agents.  Usually individuals should continue on some replacement and in that case if stable 25-hydroxyvitamin D levels are seen, it is not necessary to continually recheck vitamin D levels and calcium levels.  

Should Vitamin D, Calcium levels and renal function be checked prior to each 6 monthly denosumab injection? Should patients remain on long term Vitamin D supplements while on Prolia?

Renal function should be checked particularly before intravenous bisphosphonates and these should be re-considered if there is any suggestion of deterioration.  If individuals have low 25-hydroxyvitamin D levels the reason for this should be investigated, i.e. malabsorption excluded, and they should be vitamin D supplemented and this may need to be long-term.

Is Prolia a good and safe option for treatment of osteoporosis?

Denosumab (Prolia) is a very good and safe option for treatment of osteoporosis, along with intravenous and oral bisphosphonates.  Similarly, raloxifene is a useful treatment particularly in females with predominantly spinal osteoporosis. 

Strontium ranelate has also been shown to be effective, particularly in older individuals.  The recent warnings about cardiovascular disease are based on fairly slim evidence.

Should vitamin D levels be tested and on what patients? Have seen a number of Indian ethnic women in their 30s with extremely low vitamin D readings.

25-hydroxyvitamin D levels should be checked prior to intravenous or subcutaneous potent anti-resorptive agents. It is particularly important to check in individuals with dark skin or who wear very occlusive clothing where low vitamin D levels are not uncommon.  They should also be considered in individuals where there may be the possibility of malabsorption.  

Should a postmenopausal woman be advised to have regular calcium with D tab?

Calcium requirements in a postmenopausal woman relate to nutritional intake.  It is suggested that older individuals, both women and men, maintain an adequate calcium intake of about 1000 mg/day.  In individuals having two serves of dairy or similar daily, it is not necessary to recommend a calcium supplement. 

Similarly, if an individual’s 25-hydroxyvitamin D level is normal, they do not need to have a vitamin D supplement.  One the other hand, individuals with low 25-hydroxyvitamin D need to have causes identified and vitamin D supplementation.

Can you please comment on the role of anti-depressant use in the aetiology of osteoporosis?

There is some evidence that antidepressants are associated with some worsening on bone density.   Clearly this is worth considering in individuals with pre-existing low bone mass.  However, there is no reason this concern should interfere with their use.

ON the other hand, in individuals with pre-existing osteoporosis with antidepressant use the use of anti-resorptive therapy should be considered even more strongly, 

Is there any clinical benefit to choose the injectable longer lasting bisphosphonates over the oral ones?

There have been no head-to-head comparisons, as far as fracture outcomes, between oral and intravenous bisphosphonates or subcutaneous denosumab.  There is some evidence of better improvements in bone density with the injectable agents.  It is possible that this relates to compliance or adherence to drug therapy and the way in which the oral drugs must be taken.

Hospitals are getting better at sending discharge summaries to GPs. We often receive news that a fracture, heart attack, pneumonia or biliary colic has been treated. Are you aware of any systems for alerting GPs that more investigation and treatment is needed for a fracture patient, who may be osteoporotic?

Hospitals are getting better at sending discharge summaries to GPs about clinical events.  However, this seems to be less efficient when it comes to osteoporotic/fragility fractures. More importantly, hospitals do not provide full information on investigations and recommendations for treatment.  At the Garvan Institute we have developed not only the Fracture Risk Calculator which relates individuals risk to easily identifiable risk factors (i.e. age, sex, bone density, prior fracture events and prior falls) but we are in the process of integrating this into a tool that advises about MBS approved investigations, such as bone density, and individuals that meet current PBS requirements for various treatments.  Anyone who is interesting in looking at this in a beta test version can contact us about it.