The New Osteoporosis Drugs, the Good, Bad and Ugly

The New Osteoporosis Drugs, the Good, Bad and Ugly

by Jeffrey Dach MD

Maria is 76 years old, has never taken hormone replacement, and visited her doctor complaining of shooting pain in the right leg. The doctor ordered a few tests, including an X-Ray which showed advanced degenerative disk disease, severe osteoarthritis and scoliosis of the spine, and NO compression fractures.  Maria’s DEXA bone mineral density scan showed a T score at the femur of -2.6, reported as osteoporosis , since this was more negative than the -2.5 cutoff value.

No Compression Fractures

Maria’s symptoms were not due to osteoporosis, since she had no compression fractures of the spine.  Instead, her symptoms were related to disk degeneration with nerve root impingement, and thankfully resolved a few weeks later with conservative treatment.

The New Osteoporosis Drugs

However, the doctor offered Maria a new osteoporosis drug, Romosozumab (Evenity). Maria declined the drug and instead called me for my opinion. I explained to Maria, that since she did not have a vertebral compression fracture, she was not a good candidate for Romosozumab (Evenity) which is reserved for the very severe cases of osteoporosis, patients who already have compression fractures.

Fosamax on Steroids

Denosumab (Prolia, FDA approved 2010) and Romosozumab (Evenity, FDA approved 2019), are similar to the older bisphosphonate drugs (Fosamax, Alondronate) in two ways.  Number one, they are both antiresorptive, osteoclast inhibitors, same as the bisphosphonates such as Fosamax (Alondrenate). Number two, the adverse side effects are similar to the older bisphosphonates, namely, the dreaded Avascular Necrosis of the Jaw and Atypical Femur Fractures. (96-102)

Header image: Atypical femur fracture after 5 years of denosomab courtesy of Kumar, Shejil, et al. “Atypical femoral fracture in a bisphosphonate-naïve patient on denosumab for osteoporosis.” Archives of Osteoporosis 17.1 (2022): 131.

The Good and Bad News

Denosumab (Prolia) is given as 60 mg injection twice a year. When discontinued, Prolia is replaced by a bisphosphonate drug. Denosumab is a humanized mouse monoclonal antibody which inhibits the receptor activator of nuclear factor κ-Β ligand (RANKL) in osteocyts, rendering them non-functional. On the other hand, Bisphosphonates are synthetic analogs of pyrophosphate that bind to the hydroxyapatite in bone, inhibiting osteoclast-mediated bone resorption.  Bisphosphonates stay in bone for years, with a very long duration of action. The Monoclonal Antibodies Agents wash out of the bone fairly quickly, accounting for the rebound phenomenon when discontinued.

Romosozumab (Evenity) is given as 12 monthly injections (cost $21,900), then discontinued and replaced by a bisphosphonate drug. The drug stops working after a year and must be stopped.

The good news is studies show these new humanized monoclonal antibody osteoporosis drugs increased bone density and reduced fragility fractures. The bad news is there is an even greater incidence of Avascular  Necrosis of the Jaw and Atypical Femur Fractures. Why would a drug intended to prevent fractures cause spontaneous mid-femur fracture with no trauma ? The reason is obvious. This is a “Bad Drug”.  I am dubbing Prolia with the name, “Fosamax on Steroids” because the incidence of Avascular Necrosis of the JAW is increased 7.7 more than Fosamax.

Denosumab (Prolia) AVN of the JAW –

The risk of AVN (avascular necrosis) of the jaw with denosumab is an order of magnitude greater than the bisphosphonates (2.3% vs 0.3%). In 2023, Dr. Anthony Colella writes:

The risk of ONJ [Osteonecrosis of Jaw] in patients on denosumab for osteoporosis is a magnitude greater than for patients on the oral bisphosphonates 2.3% vs. zero to 0.3%, which is 7.7 times more likely. (7)

In 2014, the dentist, Dr. Michael O’Halloran reported two cases of Denosumab related osteonecrosis of the jaw, writing:

It would appear that DONJ [Denosumab related osteonecrosis of the jaws] is more likely than BRONJ [bisphosphonate related osteonecrosis of the jaws] to occur earlier and spontaneously or with very minor trauma. It is important that dentists avoid even minor dental manipulation for these patients. Procedures such as dental extractions should not occur until denosumab has been withdrawn for at least six months.(89-94)

Avascular Necrosis of the Jaw can be a fatal outcome for an elderly patient with osteoporosis. In 2016, Dr. Sarina Pichardo reported on 11 patients treated for denosumab-related osteonecrosis of the jaws. Nine patients were cured with jaw surgery. However, two patients could not be cured and died.  Dr. Sarina Pichardo writes:

Eleven patients met the criteria to be included in this study. Nine patients experienced healing within 4 weeks after surgery. Two patients were not cured and died as a result of their underlying disease.(102)

Fosamax on Steroids

I have dubbed these two monoclonal antibody anti-resorptive drugs, “Fosamax on Steroids” because they are both osteoclast inhibitors, same as Fosamax.  However, they are stronger drugs in terms of more rapid and greater increases in bone mineral density as revealed by bone density (DEXA) scan. And secondly, these new drugs cause similar adverse side effects in increased numbers.  Dentists are reporting avascular necrosis of the jaw with denosumab in greater numbers than with Fosamax. Since these cases of jaw necrosis come to the attention of dentists at the dental office, orthopedic surgeons and medical doctors may not be aware of the this, and assume the drug is safe.  It is not safe.

What about worrisome Atypical Femur Fractures with Denosumab? Case reports are being reported in the medical literature.  Are these Atypical Femur Fractures appearing in the same increasing numbers as AVN? We do not have the data on this yet to confidently state this is the case. However, considering the current knowledge of bone pathology and osteoclast inhibition, I would not be surprised if this same increase in Atypical Femur Fractures becomes more apparent over time with the new drugs.

Without Clear Guidelines / Denosumab Rebound

In 2022, Dr. Alastair Goss says that without clear guidelines to favor denosumab, the drug has replaced bisphosphonates as first line treatment for osteoporosis in Australia. Once Denosumab is started, the drug can not be stopped because vertebral fractures accelerate when stopped, a “rebound” phenomenon. For this reason, upon discontinuing denosumab, the drug must be replaced by a bisphosphonate drug, taken for life. Dr. Alastair Goss writes:

Despite having no clear guidelines to favour denosumab, it has substantially replaced the oral bisphosphonates as the first-line treatment for osteoporosis in Australia. Denosumab is effective when given as a six-monthly 60 mg subcutaneous injection and has few adverse reactions. The main concern medically is that, if denosumab is discontinued or the injection is substantially delayed, there is a risk of vertebral fracture. This means effectively that, once started, the patient must remain on denosumab or another antiresorptive drug for the rest of their life. (6)

This is another troubling feature of these two drugs, the “rebound phenomenon” when stopped. To prevent accelerated osteoporosis upon discontinuing Prolia or Evenity, a bisphosphonate drug must be taken for life.

Romosozumab – Only For Severe Cases

Romosozumab (Evenity) is a humanised monoclonal antibody against sclerostin, FDA approved in April 9, 2019. This is a relatively new drug, and recommended only for very severe cases which have already suffered osteoporotic fractures, and is usually given over one year as 12  monthly injections for $22,000.

Romosozumab can only be given for one year, because it stops working, and is no longer effective after one year. Upon discontinuing, Romosozumab must be followed by a potent AR (anti-resorptive drug) such as a bisphosphonate or Denosumab.  A few cases of AVN Jaw and Atypical Femur fractures have already been reported. The drug is so new, that it may take another 5-10 years of long term safety data for full evaluation of benefits and adverse effects.

Increased Mortality from Romosozumab

Because the first clinical trials showed increased mortality (0.5%) in the Romosozumab group compared to Alendronate (Fosamax), and 2.5% experienced cardiovascular events, the FDA rejected the drug in 2017. However, they later approved the drug in 2019 only for very severe cases of osteoporosis at high risk for fracture. In 2023 Dr. Piet Geusens writes:

Romosozumab is new and unique osteoanabolic drug that simultaneously increases bone formation and decreases bone resorption. Compared to antiresorptive agents, this unique combination results in a more rapid and greater increase in BMD [bone mineral density], and in repair and restoration of trabecular and cortical bone microarchitecture. Additionally, the reduction of fracture risk during treatment with romosozumab is more rapidly and more effectively than the AR [anti-resorptive] alendronate, with persisting effects for at least two years after transition to AR agents. This finding has introduced the concept that in patients at very high risk of fractures may benefit from initial treatment with an osteoanabolic agent [Evenity], followed by a potent AR agent [Fosamax], as recommended in recent national and international guidelines.(28)

Note, the above quote describes Evenity as an osteoanabolic agent which means it builds bone. However, the use of this drug is limited to the most severe cases of osteoporosis in the elderly because of increased all-cause and cardiovascular mortality in clinical trials and post marketing surveillance.  This means the drug is killing people. To qualify for this drug, the patient must have multiple compression fractures. (103)

Romosozumab Stronger Drug for BMD Compared to Denusamab

In 2021, Dr Kobayakawa studied the efficacy of 12-month denosumab or romosozumab treatment in postmenopausal osteoporosis patients, finding greater increase in Bone Mineral Density (BMD) in the romosozumab group compared to denosumab, writing:

In terms of BMD of the lumbar spine, total hip, and femoral neck, the 12-month gains in the romosozumab group were all significantly higher than those in the denosumab group, indicating a potential therapeutic advantage that warrants further validation. (4)

Anabolic Therapy – PTH Analog Drugs

Anabolic PTH analog drugs such as Forteo are available and have good efficacy. These are preferred by orthopedic surgeons to improve bone and fracture healing.  For this reason, PTH analogs are my preference over the osteoclast inhibitor, antiresorptive drugs for severe cases of osteoporosis with ongoing fragility fractures. However, discontinuing a PTH analog drug requires a replacement drug, Denosumab or a bisphosphonate. In 2022, Dr. Yevgeniya Kushchayeva writes:

Teriparatide (TPTD) [Forteo] and abaloparatide [TYMLOS] are anabolic medications that are recombinant fragments of human PTH…New bone formation with TPTD is characterized by an increased cancellous bone volume and connectivity, improved trabecular morphology, and a shift toward a more plate-like structure, with an increased cortical bone thickness…In general, anabolic therapy is preferred over antiresorptive medications for optimizing outcomes of orthopedic surgery… In general, treatment with Dmab [Denosumab] or BPs [bisphosphonates] is recommended after the discontinuation of any anabolic medication. Emphasis Mine (1)

When orthopedic surgeons operate, they want to have confidence the operative site will be able to heal properly. It is very revealing that orthopedic surgeons prefer to use PTH analog anabolic therapies for optimizing outcomes of orthopedic surgery. They avoid other antiresorptive drugs, Bisphosphonates, Prolia and Evenity. These drugs create pathologic bone which heals poorly. This tells you everything you need to know.

Pre-Operative use of Anabolic PTH Drugs

In 2019, Dr. Patrick K Cronin discussed the preoperative use of PTH analog (Forteo) prior to spinal fusion surgery in a case report of a 73 year old female with degenerative scoliosis, osteoporosis and spinal stenosis. Dr Cronin says that prior studies using Forteo (20 mcg/d injected daily) over 12 months was found to  increase lumbar spine bone mineral density by 11 per cent.  However, there are no human studies showing increased post-operative spinal fusion rates. PTH analog animal studies are more encouraging, showing a four-fold increase in post-op fusion rates in animals with osteoporosis. Dr. Patrick K Cronin writes:

A 12 month course of once daily 20 μg teriparatide has been shown to increase lumbar spine bone mineral density (BMD) by 11%. In a prospective cohort of 1,996 Japanese patients undergoing treatment at the aforementioned dose for 24 months, a 56.4% reduction in the odds ratio for fracture was seen at 6-12 months, 51.6% reduction at 12-18 months, and 58.8% reduction at 18-24 months without any notable adverse effects. It has not been shown in humans whether teriparatide increases lumbar spine fusion rates following surgery. Administration in rodent models does appear to improve post-operative fusion rates with some studies showing over a four-fold increase in fusion rates; these results appear to be retained in rodents with pre-operative osteoporosis…Because of her medical comorbidities and osteoporosis, this patient has a complication rate nearing 70% in some studies if she were to undergo an instrumented decompression and fusion. The panel concludes that a decompression and limited fusion without instrumentation may be the best overall option for this patient.(24)

Post Menopausal Hormone Replacement

Post menopausal osteoporosis is a hormone deficiency disease, not a bisphosphonate deficiency syndrome. Post-Menopausal Hormone replacement is the accepted first line for prevention and treatment of skeletal bone loss associated with menopause. Our office protocol includes the bioidentical human hormones, estradiol, progesterone, DHEA and testosterone (ie bioidentical hormones). In my opinion, these are preferred over anti-resorptive osteoporosis drugs in the typical post-menopausal female.  Many post menopausal women are worried about a DEXA bone density report showing a low T score of less than -2.5, but have have not yet had fragility fractures, and are seeking prevention.These women should be offered a bioidentical hormone replacement program. In my opinion, the use of anti-resorptive drugs is not justified in this group. (13-21)

For elderly women who have declined post menopausal hormone replacement, usually over the age of 75-80 years,  presenting with far advanced osteoporosis, vertebral compression fractures, spinal degeneration, spinal stenosis etc., the use of osteoporosis drugs could be justified, and a PTH analog would be the first choice of most orthopedic surgeons over the osteoclast inhibitor antiresorptive drugs. This is especially true if future need for spinal surgery is contemplated.  (13-21)(24)

In 2021, Dr Anna Gosset reviewed menopausal hormone therapy for the management of osteoporosis, writing:

Postmenopausal osteoporosis is for a large part the consequence of both quantitative and qualitative bone alterations induced by estrogen deficiency which occurs within the first years of the menopause transition. Bone is a strong estrogen-dependent tissue and estrogens play a major role in the acquisition and maintenance of bone mineral content throughout life. (13)

For more information on Bioidentical Hormone Replacement, see my free e-book online at Bioidentical Homones 101.

The Natural Bone Building Program

This is our natural bone building and osteoporois prevention program.  I am listing two bone building combination supplements below. Choose one. Many similar products are comercially available:

1) Bone Guard by Perque. Ingredient List: Vitamins, C, D, K, Calcium, Magnesium, Strontium, Zinc, Manganese, Selenium, Chromium, Iodine, Copper, Boron, Vanadium, Silica

OR

2) New Chapter Calcium Supplement – Bone Strength Ingredient List: Vitamin D, Vitamin K, Calcium, Magnesium , Strontium, Silica, Vanadium

3) DHEA 5 mg PO daily

4) Vitamin D3 5,000 iu per day PO

Strontium Approved in Europe for Osteoporosis

Notice the two above products contain strontium, a mineral approved in Europe for treatment of osteoporosis. Many clinical studies of Strontium have shown high level of safety with excellent anabolic bone effects with improvement in bone healing and prevention of vertebral and hip fractures.  Strontium has none of the adverse effects of avascular necrosis of the jaw or atypical femur fracture associated with Fosamax and denosumab. In my opinion, strontium has superior efficacy and safety compared to the bisphosphonates. (51-62)

Optimize Vitamin D Levels

Calcium and vitamin D3 are accepted treatment for prevention of osteoporosis and fracture risk. Post-menopausal women are given vitamin D3 5,000 iu per day and levels monitored serially. (72-78)

DHEA/ Testosterone

DHEA and Testosterone are anabolic hormones, both excellent for preventing osteoporosis, building strong bones and speeding fracture healing. Post-menopausal women are routinely given DHEA 5 mg daily.

Testosterone deficiency is a well known cause of osteoporosis in males, commonly treated with testosterone injections or topical creams. However, testosterone is rarely used by mainstream medicine for females.This is an error of mainstream medicine. Our hormone replacement program includes low dose topical testosterone for all post-menopausal women. This usually achieves a serum level of 70-80 ng/dL (normal range 20-30 ng/dL).  As a result of our bioidentical hormone program, over the years, we have found bone density on DEXA scan either stays the same or increases with time.(47-50) (82-85)

Recombinant Growth Hormone/HGH

In terms of a natural treatment to prevent osteoporosis and associated fracture risk, build strong healthy bone, speed fracture healing, there is nothing like human growth hormone (HGH). However, for political reasons, this is not widely used in conventional medicine for this purpose. (63-71)

Pitfalls and Limitations of DEXA Bone Mineral Density Measurements – Patient Selection – No Consensus on Initiating Drug Therapy

Although some practitioners base osteoporosis drug treatment solely on T score less than -2.5 on a DEXA Bone Mineral Density Scan, a number of authors have advised against this for a number of reasons as discussed by Dr. Hans Dimai below.  In 2022, Dr. Hans Dimai says there is no consensus on whom and when exactly to treat with osteoporosis drugs, and suggests the criteria for initiating treatment includes a prior fragility fracture.

Pitfalls and Limitaions of DEXA Bone Density Scan

Bone Mineral Density measurements at the spine are invalidated by spinal deformity such as degenerative scoliosis, spinal stenosis, multi-level degenerative disc disease etc. In 2013, Dr. M.K. Garg writes:

In patients with scoliosis, measurement of BMD [bone mineral density] becomes invalid because patient can not be positioned straight. (33)

In 2007, Dr Gopinath Gnanasegaran writes:

… the spine may not be evaluable when there are extensive degenerative changes…the spine values are not of diagnostic value in view of the extensive degenerative changes. (34)

In 1997, Dr. Rand proposed using the bone density of the femur rather than the spine in patients with spinal degenerative changes, writing:

Our results indicate that assessment of BMD for the diagnosis and follow-up of osteoporosis with PA-DXA is substantially influenced by degenerative factors. According to the age-related probability of degenerative factors, we propose alternative options for diagnosis, such as DXA of the proximal femur…strongly recommend an individual analysis, with emphasis on femoral neck or lateral spine measurements, or the coincidental evaluation of radiographs in questionable cases for a correct interpretation of BMD in older subject groups.(34)

No International Consensus – Prior Fragility Fracture

Which patients should be selected for treatment with the new osteoporosis drugs? A prior fragility fracture such as a vertebral compression fracture is an accepted criteria. In 2022, Dr. Hans Dimai says there is no consensus on whom and when exactly to treat with osteoporosis drugs, and suggests the criteria for initiating treatment includes a prior fragility fracture, writing:

Currently, there is no international consensus in whom and when exactly pharmacological osteoporosis treatment should be initiated. In short, many national guidelines recommend that women (and men) with a prior fragility fracture be considered for pharmacological intervention because such fractures are associated with a high risk of subsequent fractures.(12)
Emphasis mine

Interventions Based Solely on T-Score Are Less Than Optimal

Dr. Hans Dimai also writes:

interventions solely based on BMD T-scores have been shown to be less optimal because at a given T-score the fracture risk of different populations and ethnicities may vary considerably. Furthermore, the relevance of the T-score in terms of its fracture risk relevance is largely dependent on age.(12)

Using Bone Density DEXA and Pharmacotherapy to Prevent Osteoporotic Fracture is an Intellectual Fallacy We Will Live to Regret

in 2015 BJM, Dr. Teppo Järvinen raised alarm saying fracture prevention using pharmacotherapy based on bone mineral density (BMD) is a non-feasible intellectual fallacy. Dr. Teppo Järvinen writes:

Alendronate, the first bone targeted drug shown to prevent hip fractures, was introduced in 1995. By the early 2000s, it became clear that a fracture prevention strategy based on bone mineral density is not feasible. Most of the fracture burden arises from uncommon events among people who do not have osteoporosis rather than from common events in the relative few with the condition. The dominant approach to hip fracture prevention is neither viable as a public health strategy nor cost effective. Pharmacotherapy can achieve at best a marginal reduction in hip fractures at the cost of unnecessary psychological harms, serious medical adverse events, and forgone opportunities to have greater impacts on the health of older people. As such, it is an intellectual fallacy we will live to regret.(36)

Atypical Femur Fractures

We have two post-menopausal women in our community I have known personally for many years. Both have husbands who are physicians.  Both sustained atypical femur fractures after many years of bisphosphonate use.  On X-Ray, these fractures resemble stress fractures caused by underlying metabolic bone disease occurring with minimal or no impact or trauma, merely by walking across the room. Surgical repair of these Atypical Femur Fractures is challenging because of prolonged healing time and increased rate of nonunion. The underlying bone quality is pathological, a form of stress fracture seen in the genetic bone disease called osteopetrosis. In 2018, Dr. Michael Githens writes:

Atypical femur fractures associated with long-term bisphosphonate use can be challenging injuries to manage. Not only do they have a prolonged healing time and increased rate of nonunion as compared to typical femur fractures, intraoperative complications are not infrequent and can be catastrophic.(38)

Bisphosphonate Induced Osteopetrosis

First described in 2003, by Dr. Michael Whyte, long term bisphosphonate drug use creates a form of bone disease similar if not identical to the genetic bone disease called Osteopetrosis. This is a genetic disease in which the osteoclasts are dysfunctional, also called the Toulouse Lautrec Syndrome. Note all the anti-resorptive osteoporosis drugs inhibit osteoclast activity, same as the genetic disease.

Toulouse Lautrec Syndrome

The famous French Impressionist artist, Toulouse Lautrec had a genetic bone disease called osteopetrosis, and sustained spontaneous fractures of both mid femurs at the age of 12 and 14. The mid-femur fractures never healed properly. The non-healing mid femur fractures caused Toulouse Lautrec to have short stature, attaining a final height of only four and a half feet.  Note Mr. Lautrec wore a  beard to hide his jaw deformity (photo upper left). Avascular necrosis of the jaw is common in osteopetrosis patients.(39-46) (79-81)

Above Left image Henri de Toulouse-Lautrec, 1894 courtesy of wikimedia commons

Conclusion: The new Osteoporosis Drugs Denosumab (Prolia) and Romosozumab (Evenity) are “Bisphosphonates on Steroids”.  The fact that we are seeing atypical fractures and AVN of the jaw indicates the drugs create pathological bone, a metabolic bone disease identical to osteopetrosis, the genetic bone disease of Toulouse Latrec, the famous French impressionist artist. I must agree with the opinion of Dr. Teppo Järvinen’s who says the use of Pharmacotherapy based on Bone Density Testing to prevent osteoporotic fragility fractures is an intellectual fallacy which should have been halted years ago. (36)(39-46)

Rather than use pharmacotherapy for osteoporosis, first line therapy for the recently post menopausal female should always be bioidentical hormone replacement.  Additionally, an excellent bone building program consists of Calcium, Magnesium, Vitamin D3, Vitamin K2, Strontium, DHEA, etc. as listed above.

The use of anti-resorptive osteoclast inhibitor drugs is debatable. If there is any group in which osteoclast inhibitor drugs might be justified, it is the elderly female over the age of 80 with severe osteoporosis and ongoing fragility fractures.  However, perhaps strontium and other natural measures would be a better alternative.

Articles with Related Interest:

Estrogen Hormone Replacement Prevents Osteo-arthritis and Osteoporosis

Fosamax, Actonel, Osteoporosis and Toulouse Lautrec

Fosamax Study Denies Link with Femur Fractures

Fosamax, Actonel, Osteoporosis and Toulouse Lautrec

FDA Says Osteoporosis Drugs Cause Femur Fractures

Jeffrey Dach MD
7450 Griffin Road Suite 180/190
Davie, Fl 33314
954-792 4663

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References

Drug Prolia (denosumab) Injection
Company: Amgen, Inc.
Approval Date: 6/1/2010

1) Kushchayeva, Yevgeniya, et al. “Advancement in the Treatment of Osteoporosis and the Effects on Bone Healing.” Journal of Clinical Medicine 11.24 (2022): 7477.

Dmab, which is not retained in the skeleton, should be followed by another medication, usually a BP, after discontinuation. Dmab is administered every 6 months; non-compliance with the dosing schedule can lead to a rebound increase in bone remodeling and bone loss, and an increased risk of multiple VFs ]vetebral faractures] [159]. The discontinuation of Dmab leads to an enhanced osteoclastogenesis and osteoblastogenesis, resulting in a loss in cortical thickness and trabecular bone volume along with a rapid acceleration of bone turnover and increased amount of unmineralized bone. Bone loss during the first year after Dmab discontinuation is approximately 5–11% at all skeletal sites [160]. BP-naïve patients may experience more bone loss after the discontinuation of Dmab in comparison with BP-treated patients [161]. BP-treated patients who have transitioned to Dmab have a greater BMD increase than those who continue BP therapy [162].

Teriparatide (TPTD) and abaloparatide are anabolic medications that are recombinant fragments of human PTH (1–34). TPTD is recombinant PTH (1–34); abaloparatide is a synthetic analog of PTH-related protein PTHrP (1–34). Abaloparatide has a 41% homology to PTH (1-34) and 76% homology to PTHrP (1–34).
Although a sustained PTH elevation in patients with hyperparathyroidism leads to an increased bone resorption and bone loss [167], the intermittent administration of TPTD stimulates bone remodeling and increases bone formation in excess of bone resorption [168]. Although TPTD also upregulates osteoclasts, the anabolic effect dominates [169]. New bone formation with TPTD is characterized by an increased cancellous bone volume and connectivity, improved trabecular morphology, and a shift toward a more plate-like structure, with an increased cortical bone thickness [170].

In general, anabolic therapy is preferred over antiresorptive medications for optimizing outcomes of orthopedic surgery.

Based on an analysis of four prospective observational studies, TPTD reduces rates of clinical VFs, non-VFs, clinical fractures, and hip fractures by 62%, 43%, 50%, and 56%, respectively, with >6 mo of therapy compared with 0 to 6 mo [182]. Abaloparatide has been shown to reduce rates of VFs, non-VFs, and major osteoporotic fractures by 86%, 43%, and 70%, respectively, compared with placebo [183].
TPTD was initially limited to 24-month lifetime use due to an increase in the risk of osteosarcoma in rats. However, this restriction has been recently removed based on reviews of long-term post-marketing data, showing no evidence of an increase in osteosarcoma risk in humans [184,185].

In general, treatment with Dmab or BPs is recommended after the discontinuation of any anabolic medication.

Romosozumab (Rmab) is a humanized monoclonal antibody against sclerostin with the dual effect of stimulating bone modeling and inhibiting resorption, in contrast to other anabolic agents that stimulate remodeling via an increased formation and resorption of bone. Sclerostin, the Rmab target, is a glycoprotein produced by osteocytes that inhibits bone formation due to the downregulation of the Wnt pathway. Rmab binds to sclerostin and inhibits it activity [188], resulting in an increase in osteoblastic differentiation, proliferation, and survival. In the presence of Rmab, the Wnt signaling pathway is activated, leading to bone formation and BMD gain.

In postmenopausal women, the dual effect of Rmab leads to a significant increase in BMD and a reduction in the fracture risk compared with alendronate and placebo [193,194]. Rmab 12 mo therapy led to a 73% lower relative risk of new VFs, 36% lower risk of clinical fractures, and no significant effect on non-VFs [194,195].

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2) Bone, Henry G., et al. “10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomised FREEDOM trial and open-label extension.” The lancet Diabetes & endocrinology 5.7 (2017): 513-523.

Background: Long-term safety and efficacy of osteoporosis treatment are important because of the chronic nature of the disease. We aimed to assess the long-term safety and efficacy of denosumab, which is widely used for the treatment of postmenopausal women with osteoporosis.

Methods: In the multicentre, randomised, double-blind, placebo-controlled, phase 3 FREEDOM trial, postmenopausal women aged 60-90 years with osteoporosis were enrolled in 214 centres in North America, Europe, Latin America, and Australasia and were randomly assigned (1:1) to receive 60 mg subcutaneous denosumab or placebo every 6 months for 3 years. All participants who completed the FREEDOM trial without discontinuing treatment or missing more than one dose of investigational product were eligible to enrol in the open-label, 7-year extension, in which all participants received denosumab. The data represent up to 10 years of denosumab exposure for women who received 3 years of denosumab in FREEDOM and continued in the extension (long-term group), and up to 7 years for women who received 3 years of placebo and transitioned to denosumab in the extension (crossover group). The primary outcome was safety monitoring, comprising assessments of adverse event incidence and serious adverse event incidence, changes in safety laboratory analytes (ie, serum chemistry and haematology), and participant incidence of denosumab antibody formation. Secondary outcomes included new vertebral, hip, and non-vertebral fractures as well as bone mineral density (BMD) at the lumbar spine, total hip, femoral neck, and one-third radius. Analyses were done according to the randomised FREEDOM treatment assignments. All participants who received at least one dose of investigational product in FREEDOM or the extension were included in the combined safety analyses. All participants who enrolled in the extension with observed data were included in the efficacy analyses. The FREEDOM trial (NCT00089791) and its extension (NCT00523341) are both registered with ClinicalTrials.gov.

Findings: Between Aug 3, 2004, and June 1, 2005, 7808 women were enrolled in the FREEDOM study. 5928 (76%) women were eligible for enrolment in the extension, and of these, 4550 (77%) were enrolled (2343 long-term, 2207 crossover) between Aug 7, 2007, and June 20, 2008. 2626 women (1343 long-term; 1283 crossover) completed the extension. The yearly exposure-adjusted participant incidence of adverse events for all individuals receiving denosumab decreased from 165·3 to 95·9 per 100 participant-years over the course of 10 years. Serious adverse event rates were generally stable over time, varying between 11·5 and 14·4 per 100 participant-years. One atypical femoral fracture occurred in each group during the extension. Seven cases of osteonecrosis of the jaw were reported in the long-term group and six cases in the crossover group. The yearly incidence of new vertebral fractures (ranging from 0·90% to 1·86%) and non-vertebral fractures (ranging from 0·84% to 2·55%) remained low during the extension, similar to rates observed in the denosumab group during the first three years of the FREEDOM study, and lower than rates projected for a virtual long-term placebo cohort. In the long-term group, BMD increased from FREEDOM baseline by 21·7% at the lumbar spine, 9·2% at total hip, 9·0% at femoral neck, and 2·7% at the one-third radius. In the crossover group, BMD increased from extension baseline by 16·5% at the lumbar spine, 7·4% at total hip, 7·1% at femoral neck, and 2·3% at one-third radius.

Interpretation: Denosumab treatment for up to 10 years was associated with low rates of adverse events, low fracture incidence compared with that observed during the original trial, and continued increases in BMD without plateau.

3) Osteoporosis drugs: Which one is right for you? September 12, 2021 Harvard Health

Denosumab (Prolia) is a monoclonal antibody given as a twice-yearly injection. It prevents bone-dissolving osteoclast cells from forming. Denosumab may be an option if a woman cannot tolerate bisphosphonates. Once started, women usually stay on this therapy indefinitely because if stopped than bone resorption will accelerate.

Romosozumab (Evenity) is another monoclonal available for women with very severe osteoporosis, usually considered after a woman has had a fragility fracture. It acts by blocking sclerostin, a protein that inhibits bone formation. The medication is injected once a month using two separate prefilled syringes for a full dose.

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4) Kobayakawa, T., Miyazaki, A., Saito, M. et al. Denosumab versus romosozumab for postmenopausal osteoporosis treatment. Sci Rep 11, 11801 (2021).

Osteonecrosis of JAW

5) Tagliamento, Marco, et al. “Denosumab related osteonecrosis of the jaw: Unusual pattern with periosteal reaction.” European Journal of Cancer 166 (2022): 33-37.

6) Goss, Alastair N. “Osteonecrosis of the jaw and denosumab.” Australian Prescriber 45.6 (2022): 208.
Despite having no clear guidelines to favour denosumab, it has substantially replaced the oral bisphosphonates as the first-line treatment for osteoporosis in Australia.1 Denosumab is effective when given as a six-monthly 60 mg subcutaneous injection and has few adverse reactions. The main concern medically is that, if denosumab is discontinued or the injection is substantially delayed, there is a risk of vertebral fracture. This means effectively that, once started, the patient must remain on denosumab or another antiresorptive drug for the rest of their life.

Medication-related osteonecrosis of the jaw is a well-documented severe complication of dental extractions in patients on the oral bisphosphonates. It has been assumed that the risk with denosumab is similar to that with bisphosphonates.2 This is incorrect. In the 2022 update of its position paper, the American Association of Oral and Maxillofacial Surgeons has stated that the risk is a magnitude higher for denosumab than the oral bisphosphonates.3 The risk is 0.3%.

7) Colella, Anthony, et al. “What is the Risk of Developing Osteonecrosis Following Dental Extractions for Patients on Denosumab for Osteoporosis?.” Journal of Oral and Maxillofacial Surgery, 81.2, (Feb 2023) 232-237

Conclusions The risk of ONJ in patients on denosumab for osteoporosis is a magnitude greater than for patients on the oral bisphosphonates 2.3% v 0 – 0.3%, which is 7.7 times more likely. Number of extractions and early resumption of the next dose of denosumab increases the risk of ONJ.

Atypical Femur Fractures

8) Goh, Jeremy Keng Meng, et al. “Bilateral atypical femur fractures after denosumab in a bisphosphonate naïve patient: a case report.” Calcified Tissue International 111.1 (2022): 96-101.
A case report of bilateral atypical femur fractures (AFF) in a bisphosphonate naive patient. A 62-year-old female bisphosphonate naive patient was started on denosumab for osteoporosis. Approximately 3 years later she complained of right hip pain and was found to have a bilateral incomplete AFFs. She was asymptomatic on the left lower limb. Patient was managed conservatively and placed on protected weight bearing on both legs. Symptoms subsequently resolved over a period of 3 months, although radiographic findings remained at approximately 1 year. AFFs may be associated with patients on denosumab therapy even without a prior history of bisphosphonate use. Patients should be counselled appropriately and monitored for such complications.

9) Kumar, Shejil, et al. “Atypical femoral fracture in a bisphosphonate-naïve patient on denosumab for osteoporosis.” Archives of Osteoporosis 17.1 (2022): 131.
Summary A post-menopausal Caucasian woman sustained an atypical femoral fracture (AFF) after 5-years continuous denosumab for osteoporosis without prior bisphosphonate exposure. This is only the fifth case reported of AFF in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should consider AFF in patients taking denosumab even without prior bisphosphonate exposure.

Introduction Denosumab has demonstrated overwhelmingly favourable skeletal benefit/risk profile in managing post-menopausal osteoporosis with up to 10-year exposure in the extension of the pivotal FREEDOM randomised placebo-controlled trial. Four previous cases of atypical femoral fracture have been reported in bisphosphonate-naïve patients receiving deno-sumab for osteoporosis.
Methods We present an 85-year-old Caucasian post-menopausal woman without prior fragility fracture who sustained unilateral atypical femoral fracture after 5-years continuous subcutaneous denosumab for osteoporosis. She had no prior bisphosphonate or glucocorticoid exposure and had known chronic kidney disease.
Results X-ray scan demonstrated complete, non-comminuted left proximal femoral shaft fracture meeting radiographic criteria for an atypical femoral fracture. Computed tomography (CT) scan lower limbs revealed unusual side-by-side appearance of proximal and distal fragments of left proximal femur. DXA BMD was artefactually elevated at lumbar spine (1.504 g/cm 2 , T-score + 2.5) and low-normal at right femoral neck (0.856 g/cm2 , T-score -1.0). Serum biochemistry showed renal impairment at baseline (eGFR 30 mL/min/1.73m 2 ). Low-normal serum C telopeptide of type 1 collagen (CTX) (230 ng/L) indicated therapeutic suppression of bone resorption.
Conclusion The patient underwent intramedullary nailing of the femur and denosumab was ceased. This is only the fifth case reported of atypical femoral fracture in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should maintain a high index of suspicion for atypical femoral fracture in a patient taking denosumab even without prior bisphosphonate exposure

Denosumab

10) Kendler, David L., et al. “Denosumab in the treatment of osteoporosis: 10 years later: a narrative review.” Advances in therapy 39.1 (2022): 58-74.

11) Sølling, Anne Sophie, et al. “Denosumab Discontinuation.” Current Osteoporosis Reports (2022): 1-9.

12) Dimai, Hans P., and Astrid Fahrleitner-Pammer. “Osteoporosis and Fragility Fractures: Currently available pharmacological options and future directions.” Best Practice & Research Clinical Rheumatology (2022): 101780.

interventions solely based on BMD T-scores have been shown to be less optimal because at a given T-score the fracture risk of different populations and ethnicities may vary considerably. Furthermore, the relevance of the T-score in terms of its fracture risk relevance is largely dependent on age [2].

Currently, there is no international consensus in whom and when exactly pharmacological osteoporosis treatment should be initiated. In short, many national guidelines recommend that women (and men) with a prior fragility fracture be considered for pharmacological intervention because such fractures are associated with a high risk of subsequent fractures [5]. The latter has been shown to be even excessively high within the first and second year after the index fracture and any other subsequent fracture [6]. Consequently, the category of a “very high” or “immanent” fracture risk has been introduced recently and integrated into the FRAX® fracture risk assessment tool [9]. Furthermore, it has led to the recommendation that drugs with proven faster and more pronounced onset of antifracture efficacy should be considered in these patients [9]. In men and women without a prevalent fracture, the intervention threshold can be set at the FRAX®-based age-specific fracture probability equivalent to a person (of the same age) with a prior fragility fracture [10].

Interventions solely based on BMD T-scores have been shown to be less optimal because at a given T-score the fracture risk of different populations and ethnicities may vary considerably. Furthermore, the relevance of the T-score in terms of its fracture risk relevance is largely dependent on age [2].

Osteonecrosis of the jaw (ONJ), medication-related ONJ (MRONJ)

Initially, the occurrence of ONJ was believed to be associated exclusively to BP use, which led to the term “BP-related ONJ (BRONJ)” [51]. Later, when it was found to be associated to Dmab as well, the term “medication-related ONJ” (MRONJ) was introduced. A multidisciplinary expert group developed a case definition with the consequence that all subsequent studies could report on the same condition [52]. ONJ was defined as the presence of exposed bone in the maxillofacial region that would not heal within 8 weeks after identification by a healthcare provider. The risk of BRONJ associated with oral BPs was estimated between 1 in 10,000 and < 1 in 100,000 patient-treatment years. According to a more recent consensus finding, BRONJ incidence in osteoporosis patients may range from 0.01% to 0.06%, with a somewhat higher incidence in the Asian population [53]. A critical review which was recently conducted by an expert working group of the European Calcified Tissue Society found that, as expected, the risk for MRONJ is much higher in patients with advanced malignancies compared to those with benign bone diseases [54]. It was concluded that the benefits of antiresorptive treatment far outweigh the potential risk of an MRONJ.
Atypical femoral fractures (AFF)

The occurrence of unusual subtrochanteric and shaft fractures of the femur, also referred to as atypical femoral fractures (AFF), in association with BP treatment has first been published in some case reports in the mid 2000s [55,56]. Later, similar events have been reported in patients treated with Dmab [57]. Consensus criteria for AFF have been published by an expert group with an update a few years later [58,59]. Typically, unilateral or bilateral cortical thickening (hypertrophy) is present in the region where the fracture occurs, but cortical thickening may also be more generalized. Another radiographic feature is a transverse fracture line at the point of origination in the lateral cortex, and a more oblique fracture line to the medial cortex with the latter exhibiting a typical spike in the case of complete fracture. Risk-benefit analyses have shown that benefits of treatment in terms of preventing osteoporotic fractures by far outweigh the risks of AFF [60]. For example, it has been shown that for 1 AFF associated with 3 years of BP treatment, roughly 1200 fractures would be prevented. Nevertheless, irrespective of this impressively positive benefit-risk ratio, BP use decreased dramatically not only in the United States in the following years [61].

Denosumab

Denosumab (Dmab) is a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL) that plays a crucial role in formation, survival, and lifespan of osteoclasts and osteoclast precursors [99]. By binding to RANKL, Dmab blocks the interaction between RANKL and its receptor RANK and therefore reversibly inhibits bone resorption [100].

Dmab significantly reduced the risk of new radiographic vertebral fractures (RRR −68%), hip fractures (RRR −40%), and nonvertebral fractures (RRR −20%). Interestingly, no safety issues were reported in the study.

A phenomenon commonly described as a “rebound phenomenon” has been observed after cessation or discontinuation of Dmab treatment [107]. Histomorphometric analyses of patients who discontinued Dmab without subsequent medication demonstrated increased osteoclast number, osteoclast surface, and eroded bone surface, together with increased osteoblast numbers and osteoblast-covered bone surface [108]. The dramatic increase in bone turnover has been shown to revert many of the favorable skeletal effects that were gained during Dmab treatment. Accordingly, most patients experience a rapid and marked bone loss that leads to increased fragility and the occurrence of low trauma fractures specifically of the spine including multiple vertebral fractures

To avoid above-mentioned consequences, subsequent osteoprotective treatment with other antiresorptive drugs is necessary, whereby the time of consolidating treatment initiation has been shown to be crucial. Based on currently available evidence, initiation of either a potent oral (ALN) or intravenous (ZOL) BP is recommended. The question, whether treatment with a bone anabolic drug such as teriparatide could be beneficial to counteract the detrimental effects of the rebound phenomenon, cannot be answered at this time [110]. Bone turnover markers should be measured 3 months after initiation of oral BP to monitor adherence and effectiveness and 6 months after ZOL infusion as a second infusion might be necessary [[111],

One AFF occurred in each group during the extension phase. Seven cases of ONJ were reported in the long-term group and six cases in the crossover group. Hypocalcemia was reported at low rates (0.05–1.7%), but in a real-life study in community-dwelling osteoporotic men and women, a 7.4% rate of denosumab-induced hypocalcemia was found [114]. Furthermore, in a 3 year observational study, hypocalcemia developed in almost 4% of the patients treated with Dmab [115]. Consequently, it has been recommended to start Dmab treatment only in calcium replete patients [114,116].

Practice points

•There is increasing evidence that bisphosphonate drug holidays may be associated with an increased fracture risk, particularly if one or more additional strong fracture risk factors are present.
•Anti fracture efficacy of menopausal hormone treatment (MHT) has been demonstrated by numerous studies of different study designs. However, it should be kept in mind that so far no data are available from prospective randomized controlled trials with antifracture efficacy as the primary endpoint.
After discontinuation of denosumab treatment, most patients experience a rapid and marked bone loss, which leads to increased fragility and the occurrence of low trauma fractures, specifically of the spine, including multiple vertebral fractures. To avoid such undesirable consequences, subsequent osteoprotective treatment with antiresorptive drugs, e.g., ALN or ZOL, is necessary. The optimal time point at which to begin this treatment is crucial.
•One of the very few potential and promising future osteoporosis treatment options is mesenchymal stem cell infusion, but first results from an ongoing clinical trial investigating safety and efficacy in patients with osteoporosis will not be available before 2026.

 

HRT

13) Gosset, Anna, Jean-Michel Pouillès, and Florence Trémollieres. “Menopausal hormone therapy for the management of osteoporosis.” Best Practice & Research Clinical Endocrinology & Metabolism 35.6 (2021): 101551.

Postmenopausal osteoporosis is for a large part the consequence of both quantitative and qualitative bone alterations induced by estrogen deficiency which occurs within the first years of the menopause transition. Bone is a strong estrogen-dependent tissue and estrogens play a major role in the acquisition and maintenance of bone mineral content throughout life.

14) Yong, Eu-Leong, and Susan Logan. “Menopausal osteoporosis: screening, prevention and treatment.” Singapore Medical Journal 62.4 (2021): 159.

Oestrogen is one of the very few drugs with both anabolic and anti-resorptive effects on bone cells.(2) Randomised, controlled trials and observational studies show that standard-dose MHT reduces hip fractures by 28% (relative risk [RR] 0.72 [0.53–0.98]), vertebrae fractures by 35% (RR 0.65 [0.46–0.92]) and other non-vertebral fractures by 27% (RR 0.73 [0.58–0.94]).(44) MHT utilises lower levels of hormones compared to oral contraceptive formulations that require supraphysiological doses to suppress ovulation, increasing its level of safety. The benefit-risk ratio is most favourable for women with oestrogen deficiency due to POI and early menopause. These women, especially those who experience surgical menopause, frequently suffer from distressing vasomotor symptoms, which MHT largely resolves. MHT also protects against genitourinary syndrome of menopause (GSM), which affects the lower genitourinary tract and is characterised by vulval itch, vaginal dryness, dyspareunia, urinary frequency, urgency, nocturia, urge incontinence and urinary tract infection. Therapy should continue until at least the age of menopause (49 years in Singapore). Observational studies suggest that benefits outweigh risks for effects on bone, heart, cognition, genitourinary symptoms, sexual function, mood and quality of life.(39)

A large trial involving women with a BMD T-score of less than −2.5 but not less than −4.0 at the lumbar spine or total hip showed that treatment with denosumab (60 mg administered twice yearly by subcutaneous injection) resulted in a significantly lower risk of vertebral fractures (by 68%), hip fractures (by 40%), and nonvertebral fractures (by 20%) compared to a placebo.(55) As with bisphosphonates, rare cases of atypical femur fractures and osteonecrosis of the jaw have been observed. Recent concerns about rapid rebound bone loss following cessation of denosumab therapy, exceeding those on placebo,(54) necessitate re-examination of its costs and benefits.(56)

15) Gamsjaeger, Sonja, Erik F. Eriksen, and Eleftherios P. Paschalis. “Effect of hormone replacement therapy on bone formation quality and mineralization regulation mechanisms in early postmenopausal women.” Bone reports 14 (2021): 101055.

16) Lin, Shih-Yin, et al. “Efficacy and safety of postmenopausal osteoporosis treatments: a systematic review and network meta-analysis of randomized controlled trials.” Journal of Clinical Medicine 10.14 (2021): 3043.

17) Vigneswaran, Kugajeevan, and Haitham Hamoda. “Hormone replacement therapy–Current recommendations.” Best Practice & Research Clinical Obstetrics & Gynaecology 81 (2022): 8-21.

18) Brommage, Robert. “New targets and emergent therapies for osteoporosis.” Bone Regulators and Osteoporosis Therapy (2020): 451-473.

19) Podfigurna, Agnieszka, et al. “Impact of hormonal replacement therapy on bone mineral density in premature ovarian insufficiency patients.” Journal of Clinical Medicine 9.12 (2020): 3961.

20) Gambacciani, M., A. Cagnacci, and S. Lello. “Hormone replacement therapy and prevention of chronic conditions.” Climacteric 22.3 (2019): 303-306\

21) Langer, R. D., et al. “Hormone replacement therapy–where are we now?.” Climacteric 24.1 (2021): 3-10.

22) Gupta, Anmol, et al. “DEXA sensitivity analysis in patients with adult spinal deformity.” The Spine Journal 20.2 (2020): 174-180.

23) Routh, R. Hank, et al. “The relationship between bone mineral density and biomechanics in patients with osteoporosis and scoliosis.” Osteoporosis international 16 (2005): 1857-1863.

Nearly one-third of all women and one-sixth of all men over age 65 have osteoporosis, and this condition is often accompanied by lumbar scoliosis. Previous work has shown that, in a group of postmenopausal women with scoliosis and osteoporosis, both the bone mineral content (BMC) and bone mineral density (BMD) were greater on the concave side than the convex side.

24) Cronin, Patrick K., and Jay M. Zampini. “Degenerative Scoliosis with Osteoporosis and Spinal Stenosis: Surgical Planning and Survey of the Supporting Literature.” The Orthopaedic Journal at Harvard Medical School 20 (2019): 36-41.

We report the case of a 73-year-old female with degenerative scoliosis with positive sagittal balance, osteoporosis, and functional impairment secondary to lumbar spinal stenosis. Principal considerations in selecting surgical management include comorbidities, fitness for surgery, bone mineral density, sagittal plane alignment, and concordance of history, physical examination, and imaging findings.

The diagnosis of osteoporosis has been made via DEXA scan in our patient, and quantitative CT evaluation of the lumbar spine could be used to make a more accurate determination of bone mineral density.29-31 Given that our patient has already sustained a vertebral compression fracture, she meets diagnostic criteria for severe osteoporosis.32,33

A 12 month course of once daily 20 μg teriparatide has been shown to increase lumbar spine bone mineral density (BMD) by 11%.34 In a prospective cohort of 1,996 Japanese patients undergoing treatment at the aforementioned dose for 24 months, a 56.4% reduction in the odds ratio for fracture was seen at 6-12 months, 51.6% reduction at 12-18 months, and 58.8% reduction at 18-24 months without any notable adverse effects.35 It has not been shown in humans whether teriparatide increases lumbar spine fusion rates following surgery. Administration in rodent models does appear to improve post-operative fusion rates with some studies showing over a four-fold increase in fusion rates;36,37 these results appear to be retained in rodents with pre-operative osteoporosis.38

Because of her medical comorbidities and osteoporosis, this patient has a complication rate nearing 70% in some studies if she were to undergo an instrumented decompression and fusion.39 The risk of hardware failure in long fusion constructs has been posited to be due to increased load and motion at the last instrumented vertebrae.40 Some surgeons have advocated cement augmentation of the upper one or two instrumented vertebrae.41 A double-trajectory method for pedicle screw insertion has been employed by some to increase fixation in osteoporotic bone.42 Extending the caudal fixation to the sacrum has been shown to improve sagittal correction but at the expense of being a longer, more invasive procedure with a higher major complication risk.43 Non-instrumented fusion has the benefit of reducing operative time and the risks associated with instrumentation, including proximal junctional kyphosis. These benefits are at the cost of possible blunting of the postoperative improvement secondary to residual spinal deformity; consistent with results after decompression without fusion for DS with stenosis.44

The panel concludes that a decompression and limited fusion without instrumentation may be the best overall option for this patient.

25) York, Philip J., and Han Jo Kim. “Degenerative scoliosis.” Current reviews in musculoskeletal medicine 10 (2017): 547-558.

Patients typically present in the sixth decade of life and often with symptoms of spinal stenosis, reported in up to 90% of symptomatic patients [22]. Patients with neurogenic claudication typically do not report relief with a forward posture as in typical neurogenic claudication, but rather if they sit with their trunk supported by their arms [1]. Often symptoms are due to multilevel foraminal stenosis rather than central stenosis (Fig. 2). Back pain is reported by 60–80% of patients with symptomatic ADS and most commonly on the convex side of the curve. This is due to degenerative changes within the spine as well muscle fatigue as a result of spinal imbalance [3] (Fig. 3). This pain is often worsened by exertion and not relieved simply by sitting, often requiring the patient to lie down to obtain relief [23]. Symptomatic radiculopathy has been reported to occur in 47–78% of patients [24]. Foraminal stenosis is common on the concave side and is associated with facet joint hypertrophy and lateral subluxation. Pedicular kinking of the concave nerve between the disc and the pedicle can cause radiculopathy

In patients that present with symptoms of spinal stenosis, it is important to evaluate for tandem stenosis in the cervical spine as an association has been shown in patients with congenital lumbar stenosis on anatomic studies [25]. Additionally, studies have shown that asymptomatic thoracic stenosis is present in approximately 30% of patients undergoing lumbar decompressive surgery with the potential for significant impairment if missed [26].

Obtaining the necessary imaging is crucial. Thirty-six-inch posteroanterior (PA) and lateral scoliosis radiographs from the base of the skull proximally to the femoral heads distally are a minimal requirement for evaluating patients with a spinal deformity and should, ideally, be obtained with the patient standing, free of supports to evaluate all compensatory mechanisms [27]. Radiographic measurements such as loss of lumbar lordosis, thoracolumbar kyphosis, olisthesis, and L3 and L4 end plate obliquity angles have been shown to be correlated with increased pain levels [28].

26) Yagi, Mitsuru, Akilah B. King, and Oheneba Boachie-Adjei. “Characterization of osteopenia/osteoporosisin adult scoliosis: does bone density affect surgical outcome?.” Spine 36.20 (2011): 1652-1657.

27) Sadat-Ali, Mir, et al. “Does scoliosis causes low bone mass? A comparative study between siblings.” European Spine Journal 17.7 (2008): 944.

Our study indicates that the scoliosis causes osteopenia and osteoporosis among girls while their siblings with normal spine remain with normal bone mass.

28) Geusens, Piet, et al. “Romosozumab for the treatment of postmenopausal women at high risk of fracture.” Expert Opinion on Biological Therapy 23.1 (2023): 11-19.

romosozumab can nowadays only be given for one year

Romosozumab is a new osteoanabolic drug, with a unique mechanism of action by simultaneously increasing bone formation and decreasing bone resorption. Compared to AR treatment with alendronate, an active and reliable comparator, this results in a quicker and greater increase of BMD and of repair and restoration of trabecular and cortical microarchitecture, and a quicker and more substantial decrease of the risk of vertebral, clinical, and non-VFs, with persistent benefits after transition to ARs, including a decrease in the risk of hip fractures.

The studies with romosozumab have introduced the concept that in very high-risk patients the optimal sequence of treatment is starting with an osteoanabolic agent followed by a potent AR drug, because such sequence is building up new bone followed by preservation of the newly formed bone when followed by AR, instead of mainly preserving the existing disturbed microarchitecture, as in treatment with ARs alone.

romosozumab initiated a new and unique paradigm of sequential treatment by introducing the concept of using osteoanabolic drugs as the initial treatment in patients at very high risk of fractures.

Given the quick and favorable effects of romosozumab with a superiority versus alendronate, it can be expected that physicians will prescribe romosozumab in very high-risk patients.

Since the use of romosozumab should be followed by ARs, we still need long-term data in extension studies (now up to 3 years) of the original RCTs with romosozumab, and studies comparing romosozumab to other ARs than denosumab and alendronate and evaluating the effect of other ARs after romosozumab.

29) Khalid, Syed I., et al. “The role of bone mineral density in adult spinal deformity patients undergoing corrective surgery: a matched analysis.” Acta neurochirurgica 164.9 (2022): 2327-2335.

A total of 258 (37.1%) patients with osteoporosis were pretreated with anti-osteoporotic medications and there was no statistically significant decrease in odds of proximal or distal junctional kyphosis or revision surgery in these patients.

30) Smith, Evan J., et al. “Interventions for osteoporosis in patients with degenerative scoliosis.” Seminars in Spine Surgery. Vol. 29. No. 2. WB Saunders, 2017.

Additionally, medications like bisphosphonates, denosumab, and recombinant PTH (teriparatide) directly alter the biochemical process regulating resorportion and bone formation. While initial studies have generally shown positive effects of these therapies on bone quantity, their effectiveness in spine surgery and in improving fusion rates is inconsistent. As a result, there is no consensus on preoperative and postoperative protocols.

31) Zhang, Andrew, et al. “Medical optimization of osteoporosis for adult spinal deformity surgery: a state-of-the-art evidence-based review of current pharmacotherapy.” Spine Deformity (2022): 1-18.

Conclusion Bisphosphonates are first-line agents due to their low cost and robust evidence behind their utility. However, in the absence of contraindications, optimizing bone quality with anabolic medications should be strongly considered in preparation for spinal deformity surgeries due to their beneficial and favorable effects on fusion and hardware compared to the anti-resorptive medications.

32) Syed, Zeba, and Aliya Khan. “Bone densitometry: applications and limitations.” Journal of Obstetrics and Gynaecology Canada 24.6 (2002): 476-484.
Bone mineral density (BMD) should be considered in conjunction with independent clinical risk factors for fracture, including: low body weight, history of postmenopausal fracture, family history of fracture, and poor neuromuscular function.

32) Choksi, Palak, Karl J. Jepsen, and Gregory A. Clines. “The challenges of diagnosing osteoporosis and the limitations of currently available tools.Clinical diabetes and endocrinology 4.1 (2018): 1-13.

Goal-directed treatment for osteoporosis has been advocated as a superior strategy rather than treatment decisions made solely on DXA T-scores [73]. Rather than arbitrary recommendations to treat osteoporosis for 5 or 10 years with oral bisphosphonates or 3 to 6 years with IV bisphosphonates, depending on T-scores or whether a patient is deemed either low or high risk for fracture, treatment length should ideally be based on achieving a particular fracture risk threshold [74].

postmenopausal women with smaller femoral neck size may in fact be at lower risk for fracture as they age compared to women with larger femoral neck size due to adapted changes with aging [32]. How these inter-individual differences in the age-changes of structure and mass affect bone strength and fracture has yet to be fully determined.

With advancing imaging methods, we can envision a treatment strategy whereby osteoporosis medications are selected based on individual skeletal characteristics. For example, patients with larger bones, and thinner and porous cortices may benefit from bisphosphonates and denosumab, to reduce endocortical resorption that would ultimately increase cortical thickness. Conversely in patients with smaller bones whose cortex is not especially porous, teriparatide or abaloparatide may provide maximal bone strength. Clearly, this is an area of further research.

33) Garg, M. K., and Sandeep Kharb. “Dual energy X-ray absorptiometry: Pitfalls in measurement and interpretation of bone mineral density.” Indian journal of endocrinology and metabolism 17.2 (2013): 203.

In patients with scoliosis, measurement of BMD becomes invalid because pateint can not be positioned straight.

34) Gnanasegaran, Gopinath, et al. “Facts and artefacts in bone densitometry.” Current Medical Imaging 3.1 (2007): 67-75. free pdf

… the spine may not be evaluable when there are extensive degenerative changes…the spine values are not of diagnostic value in view of the extensive degenerative changes.

33) Sarioglu, Orkun, et al. “Evaluation of vertebral bone mineral density in scoliosis by using quantitative computed tomography.” Polish Journal of Radiology 84 (2019): 131-135.

Although DEXA is quick, flexible, and has low radiation dose, it cannot separate cortical and trabecular bone. Moreover, DEXA may affect from aortic atherosclerosis, degeneration, and osteoarthrosis. Most of the studies in the literature were done using the DEXA method, which may lead to errors in scoliosis patients because of spinal deformities. The three-dimensional disorder of the vertebrae may provoke false results when DEXA is used for evaluating BMD in scoliosis. Especially in severe scoliosis, invalid results may occur due to positioning problems with DEXA [10]. It is also reported that both curvature and rotation of the spine may affect the DEXA results [11].

34) Rand, T. H., et al. “Impact of spinal degenerative changes on the evaluation of bone mineral density with dual energy X-ray absorptiometry (DXA).” Calcified tissue international 60 (1997): 430-433.

Our results indicate that assessment of BMD for the diagnosis and follow-up of osteoporosis with PA-DXA is substantially influenced by degenerative factors. According to the age-related probability of degenerative factors, we propose alternative options for diagnosis, such as DXA of the proximal femur.

strongly recommend an individual analysis, with emphasis on femoral neck or lateral spine measurements, or the coincidental evaluation of radiographs in questionable cases for a correct interpretation of BMD in older subject groups.

35) Bone Health and Osteoporosis foundation Romosozumab-aqqg (Evenity®)

Romosozumab-aqqg is approved for treatment of osteoporosis in postmenopausal women at high risk for fracture defined as: history of osteoporotic fracture, multiple risk factors for fracture, and patients who have failed or are intolerant to other available osteoporosis therapy.

Romosozumab-aqqg is a humanized monoclonal antibody (IgG2) produced in a mammalian cell line by recombinant DNA technology that binds to and inhibits sclerostin.

Romosozumab-aqqg is should be administered by a healthcare provider. Two separate subcutaneous injections, injected one after the other, are needed to administer the total dose of 210 mg. Injections should be administered once every month for 12 doses in the abdomen, thigh or upper arm.

The anabolic effect of Romosozumab-aqqg wanes after 12 monthly doses of therapy; therefore, you should limit use to 12 monthly doses. If osteoporosis therapy remains warranted, you should consider continued therapy with an anti-resorptive agent.

36) Järvinen, Teppo LN, et al. “Overdiagnosis of bone fragility in the quest to prevent hip fracture.” BMJ 2015

Alendronate, the first bone targeted drug shown to prevent hip
fractures, was introduced in 1995. By the early 2000s, it became clear that a fracture prevention strategy based on bone mineral density is not feasible. Most of the fracture burden arises from uncommon events among people who do not have osteoporosis rather than from common events in the relative few with the condition.7

The dominant approach to hip fracture prevention is neither viable as a public health strategy nor cost effective. Pharmacotherapy can achieve at best a marginal reduction in hip fractures at the cost of unnecessary psychological harms, serious medical adverse events, and forgone opportunities to have greater impacts on the health of older people. As such, it is an intellectual fallacy we will live to regret.

Atypical fractures –

Several real-world epidemiological studies were unable to confirm the efficacy claimed from the randomized controlled trials;

37) Hinshaw, W. Banks, and Jennifer P. Schneider. “Bisphosphonate-associated atypical fractures that are not “Atypical Femoral Fractures”.” Brit J Med & Med Res 19.7 (2017): 1-17.

Several real-world epidemiological studies were unable to confirm the efficacy claimed from the randomized controlled trials;
additionally, the cited Canadian and Finnish meta-analyses call the trial data into question. These reports suggest that therapeutic benefit to-
risk ratio assumed by most authorities may not be as favorable to the BPs as claimed….Such studies might challenge the assumed risk benefit ratio of the BP drugs based on the pivotal clinical trials. It is to be expected that an accelerating number of reports of non-femur BP related
fractures will continue to appear, lending support to this hypothesis.

38) Githens, Michael, Matthew R. Garner, and Reza Firoozabadi. “Surgical management of atypical femur fractures associated with bisphosphonate therapy.” JAAOS-Journal of the American Academy of Orthopaedic Surgeons 26.24 (2018): 864-871.

Atypical femur fractures associated with long-term bisphosphonate use can be challenging injuries to manage. Not only do they have a prolonged healing time and increased rate of nonunion as compared to typical femur fractures, intraoperative complications are not infrequent and can be catastrophic.

Bisphosphonate-induced osteopetrosis

39) Whyte, Michael P., et al. “Bisphosphonate-induced osteopetrosis.” New England Journal of Medicine 349.5 (2003): 457-463.

40) Marx, Robert E., et al. “Bisphosphonate-induced exposed bone (osteonecrosis/osteopetrosis) of the jaws: risk factors, recognition, prevention, and treatment.” Journal of oral and maxillofacial surgery 63.11 (2005): 1567-1575.

41) Vance, Michael A. “Osteonecrosis of the jaw and bisphosphonates: A comparison with white phosphorus, radium, and osteopetrosis.” Clinical Toxicology 45.7 (2007): 753-762.

42) Leite, André Ferreira, et al. “Bisphosphonate-associated osteonecrosis of the jaws. Report of a case and literature review.” Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 102.1 (2006): 14-21.

43) Kelleher, F. C., et al. “Is bisphosphonate-induced osteonecrosis of the jaw (BONJ) an ischemic manifestation of pseudo-osteopetrosis?: Biochemical, densitometric, and imaging evidence.” Journal of Clinical Oncology 24.18_suppl (2006): 18621-18621.

44) Hellstein, John W., and Cindy L. Marek. “Bisphosphonate osteochemonecrosis (bis-phossy jaw): is this phossy jaw of the 21st century?.” Journal of oral and maxillofacial surgery 63.5 (2005): 682-689.

45) Boyce, Rogely W., et al. “Infant cynomolgus monkeys exposed to denosumab in utero exhibit an osteoclast-poor osteopetrotic-like skeletal phenotype at birth and in the early postnatal period.” Bone 64 (2014): 314-325.

46) Wenkert, Deborah, et al. “Long-Term Sequelae of Bisphosphonate-Induced Osteopetrosis: Metaphyseal Osteopenia, Osteosclerosis Fragility, and Novel Bone Modeling Defects After Drug Administration Ceases.”

DHEA/Testosterone

47) Kirby, David J., et al. “DHEA in bone: the role in osteoporosis and fracture healing.” Archives of osteoporosis 15.1 (2020): 84.

48) Yokomoto-Umakoshi, Maki, et al. “Protective role of DHEAS in age-related changes in bone mass and fracture risk.” The Journal of Clinical Endocrinology & Metabolism 106.11 (2021): e4580-e4592.

49) Sakr, Hussein F., et al. “Impact of dehydroepiandrosterone (DHEA) on bone mineral density and bone mineral content in a rat model of male hypogonadism.” Veterinary Sciences 7.4 (2020): 185.

50) Weber, Alexander E., et al. “Anabolic Androgenic Steroids in Orthopaedic Surgery: Current Concepts and Clinical Applications.” JAAOS Global Research & Reviews 6.1 (2022).

Strontium

51) Chadha, Manoj, et al. “Osteoporosis: Epidemiology, Pathogenesis, Evaluation and Treatment.” Open Journal of Orthopedics 12.4 (2022): 153-182.

Strontium ranelate is the first antiosteoporotic agent that exhibits a dual mechanism of increasing bone formation and decreasing bone resorption, thus resulting in the creation of new bone. Strontium ranelate is known to be effective in various patient profiles, from early postmenopausal women and osteopenic subjects to elderly women over the age of 80 years in reducing the risk of vertebral as well as non-vertebral fractures [83]. Previous studies in postmenopausal women showed that strontium ranelate reduced the risk of vertebral fractures and lumbar spine osteopenia [84] [85]. It also significantly reduces the risk of vertebral fractures in frail, intermediate, and robust older patients [86].

52) Alsoqour, Hussein Nasher Fahad, et al. “Effect of Anti-Osteoporotic Drugs in Prevention of Bone Fracture: A Scoping Review.” Annals of Clinical and Analytical Medicine 10.1 (2022).

osteoporotic medications are split into two major categories: the antiresorptive medications, consisting of bisphosphonates, denosumab, calcitonin, oestrogen, and selective oestrogen receptor modulators (SERMs), and the anabolic agents, which include parathyroid hormone (PTH) analogy and strontium ranelate (SR)

53) Mesquita, Patrícia Nunes, et al. “Postmenopausal osteoporosis.” Endocrinology and Diabetes: A Problem Oriented Approach. Cham: Springer International Publishing, 2022. 257-271.

The SOTI (Spinal Osteoporosis Therapeutic Intervention) study [ 64 ] evaluated women with previous vertebral fractures, and the use of strontium was associated with a 49 % reduced risk of vertebral fractures in the fi rst year, and a 41 % reduction in risk after 3 years, while the TROPOS (Treatment of Peripheral Osteoporosis ) study [ 65 ] demonstrated a 16 % reduction in the relative risk of all non-vertebral fractures over 3 years. During the studies, increases in markers for bone formation and reductions in markers for resorption were observed, data consistent with the idea that this medicine works by stimulating bone formation and inhibiting bone resorption…an extension study lasting 10 years showed that long-term treatment with strontium is associated with sustained increases in BMD, and that it has a good safety profile.

In patients taking strontium, the assessment of BMD is not a good indicator of fracture risk reduction, because the medication is incorporated into the bone, thereby weakening DXA ray penetration, since it has an atomic number greater than that of calcium, and can cause overestimation of the BMD

54) O’Donnell, Siobhan, et al. “Strontium ranelate for preventing and treating postmenopausal osteoporosis.” Cochrane database of systematic reviews 4 (2006).

A 37% reduction in vertebral fractures (RR 0.63, 95% CI 0.56, 0.71), and a 14% reduction in non‐vertebral fractures with the upper boundary of the confidence interval approaching one (RR 0.86, 95% CI 0.75, 0.98), were demonstrated over three years with 2 g of strontium ranelate daily in a treatment population. An increase in BMD was shown at all sites after two to three years of treatment in both populations.

55) Cianferotti, Luisella, Federica D’Asta, and Maria Luisa Brandi. “A review on strontium ranelate long-term antifracture efficacy in the treatment of postmenopausal osteoporosis.” Therapeutic advances in musculoskeletal disease 5.3 (2013): 127-139.

Recent economic impact analyses have proved that long-term treatment with strontium ranelate is highly cost effective, especially in women older than 70 years of age. Histomorphometric analyses in animals and humans participating in the phase III trials have proved that the quality of mineralization is preserved in the long term and bone microarchitecture is
ameliorated, with increased bone strength. Thus, strontium ranelate has been confirmed to be an effective compound for the long-term, chronic treatment of postmenopausal osteoporosis.

56) Meunier, P. J., et al. “Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis.” Osteoporosis International 20 (2009): 1663-1673.

large placebo-controlled trial in postmenopausal women with osteoporosis, strontium ranelate reduced vertebral fracture risk by 33% over 4 years, confirming the role of strontium ranelate as an effective long-term treatment in osteoporosis.

Conclusions: Long-term treatment with strontium ranelate 2 g/day in postmenopausal osteoporotic women leads to continued increases in BMD at all sites. The data also provide some evidence for a sustained antifracture efficacy

57) Reginster, Jean-Yves, et al. “Maintenance of antifracture efficacy over 10 years with strontium ranelate in postmenopausal osteoporosis.” Osteoporosis International 23 (2012): 1115-1122.

Over 10 years, lumbar BMD increased continuously and significantly (P < 0.01 versus previous year) with 34.5 ± 20.2% relative change from baseline to 10 years. The incidence of vertebral and nonvertebral fracture with strontium ranelate in the 10-year population in years 6 to 10 was comparable to the incidence between years 0 and 5, but was significantly lower than the incidence observed in the FRAX®-matched placebo group over 5 years (P < 0.05); relative risk reductions for vertebral and nonvertebral fractures were 35% and 38%, respectively. Strontium ranelate was safe and well tolerated over 10 years.

58) Koukou, Ourania I., et al. “The effect of strontium ranelate on fracture healing: an animal study.” BioMed Research International 2020 (2020).

Conclusion. StR [strontium] appears to enhance fracture healing but further studies are warranted in order to better elucidate the mechanisms and benefits of StR treatment.

59) Mecca, Leomar Emanuel de Almeida, et al. “Absence of medication-related jaw osteonecrosis after treatment with strontium ranelate in ovariectomized rats.” Brazilian Oral Research 36 (2022).

The lower first molars were extracted after 60 days of drug therapy. Drug administration was continued for another 30 days after tooth extraction. in ovariectomized rats.  The mandibles were subjected to clinical, histological, radiographic, and microtomographic evaluations. Only the BP [bisphosphonate Group] group showed clinical changes, characterized by the presence of 70% (n = 7) and 20% (n = 2) of ulcers and extraoral fistulas. Radiographic evaluation demonstrated bone sequestration only in the BP group (n = 7, 70%). Microtomographic analysis revealed increased bone porosity after ovariectomy, particularly in the the control group (p < 0.05). The BP group showed a higher bone surface density, bone volume, and trabecular number than SR and control groups, but with less trabecular separation (p < 0.05). All the animals in the BP group demonstrated histological osteonecrosis. There was no evidence of osteonecrosis in the control and SR groups, which was characterized by the absence of empty osteocyte gaps and associated with the gradual healing of the extraction area. Also, an increased number of blood vessels and a reduced number of osteoclasts were observed in the SR group (p < 0.05). Therefore, SR treatment increased angiogenesis and osteoclastogenesis in the healing socket and was not associated with MRONJ development after tooth extraction in ovariectomized rats.

60) Gonçalves, Fernanda Castanheira, et al. “Strontium ranelate improves post-extraction socket healing in rats submitted to the administration of bisphosphonates.” Odontology 110.3 (2022): 467-475.

62) Yousef, Einas Mohamed, et al. “Therapeutic Effects of Strontium Ranelate and Risedronate on a Glucocorticoid-Induced Osteoporosis Rat Model: A Comparative Histological and Morphometric study.” Egyptian Journal of Histology (2022).

Conclusion: Our data suggest that SR [STRONTIUM] outperforms RIS [Risedronate] in alleviating glucocorticoid-induced osteoporotic changes in cortical bone tissues

HGH

63) Krantz, Emily, Penelope Trimpou, and Kerstin Landin-Wilhelmsen. “Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: a 10-year follow-up study.” The Journal of Clinical Endocrinology & Metabolism 100.9 (2015): 3251-3259.

64) Landin-Wilhelmsen, Kerstin, et al. “Growth hormone increases bone mineral content in postmenopausal osteoporosis: a randomized placebo-controlled trial.” Journal of bone and mineral research: the official journal of the American Society for Bone and Mineral Research 18.3 (2003): 393-405.

Eighty osteoporotic, postmenopausal women, 50-70 years of age, with ongoing estrogen therapy (HRT), were randomized to recombinant human growth hormone (GH), 1.0 U or 2.5 U/day, subcutaneous, versus placebo. This study was double-blinded and lasted for 18 months. The placebo group then stopped the injections, but both GH groups continued for a total of 3 years with GH and followed for 5 years. Calcium (750 mg) and vitamin D (400 U) were given to all patients. Bone mineral density and bone mineral content were measured with DXA. At 18 months, when the double-blind phase was terminated, total body bone mineral content was highest in the GH 2.5 U group (p = 0.04 vs. placebo). At 3 years, when GH was discontinued, total body and femoral neck bone mineral content had increased in both GH-treated groups (NS between groups). At 4-year follow-up, total body and lumbar spine bone mineral content increased 5% and 14%, respectively, for GH 2.5 U (p = 0.01 and p = 0.0006 vs. placebo). Femoral neck bone mineral density increased 5% and bone mineral content 13% for GH 2.5 U (p = 0.01 vs. GH 1.0 U). At 5-year follow-up, no differences in bone mineral density or bone mineral content were seen between groups. Bone markers showed increased turnover. Three fractures occurred in the GH 1.0 U group. No subjects dropped out. Side effects were rare. In conclusion, bone mineral content increased to 14% with GH treatment on top of HRT and calcium/vitamin D in postmenopausal women with osteoporosis. There seems to be a delayed, extended, and dose-dependent effect of GH on bone. Thus, GH could be used as an anabolic agent in osteoporosis.

65) Krantz, Emily, Penelope Trimpou, and Kerstin Landin-Wilhelmsen. “Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: a 10-year follow-up study.” The Journal of Clinical Endocrinology & Metabolism 100.9 (2015): 3251-3259.

66) Theyse, L. F. H., et al. “Growth hormone stimulates bone healing in a critical-sized bone defect model.” Clinical Orthopaedics and Related Research® 446 (2006): 259-267.

67) Krantz, Emily, Penelope Trimpou, and Kerstin Landin-Wilhelmsen. “Effect of growth hormone treatment on fractures and quality of life in postmenopausal osteoporosis: a 10-year follow-up study.” The Journal of Clinical Endocrinology & Metabolism 100.9 (2015): 3251-3259.

68) Sugimoto, Toshitsugu, et al. “Effect of recombinant human growth hormone in elderly osteoporotic women.” Clinical endocrinology 51.6 (1999): 715-724.

69) Hedner, Ewa, Anders Linde, and Anders Nilsson. “Systemically and locally administered growth hormone stimulates bone healing in combination with osteopromotive membranes: an experimental study in rats.” Journal of Bone and Mineral Research 11.12 (1996): 1952-1960.

70) Raschke, M. J., et al. “Recombinant growth hormone accelerates bone regenerate consolidation in distraction osteogenesis.” Bone 24.2 (1999): 81-88.

71) Andreassen, T. T., and H. Oxlund. “Local anabolic effects of growth hormone on intact bone and healing fractures in rats.” Calcified tissue international 73 (2003): 258-264.

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Calcium and vitamin D3

72) Lips, Paul, et al. “Reducing fracture risk with calcium and vitamin D.” Clinical endocrinology 73.3 (2010): 277-285.

73) Sunyecz, John A. “The use of calcium and vitamin D in the management of osteoporosis.” Therapeutics and clinical risk management 4.4 (2008): 827-836.

74) Rizzoli, René, et al. “The role of calcium and vitamin D in the management of osteoporosis.” Bone 42.2 (2008): 246-249.

75) Lanham-New, Susan A. “Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment: symposium on ‘diet and bone health’.” Proceedings of the Nutrition Society 67.2 (2008): 163-176.

76) Morgan, Sarah L. “Calcium and vitamin D in osteoporosis.” Rheumatic Disease Clinics of North America 27.1 (2001): 101-130.

Vitamin K

77) Braam, L. A. J. L. M., et al. “Vitamin K1 supplementation retards bone loss in postmenopausal women between 50 and 60 years of age.” Calcified tissue international 73 (2003): 21-26.

78) Knapen, M. H. J., L. J. Schurgers, and C. Vermeer. “Vitamin K 2 supplementation improves hip bone geometry and bone strength indices in postmenopausal women.” Osteoporosis international 18 (2007): 963-972.

79) Markeas, Nikolaos G., and Dimitrios Begkas. “The extraordinary case of Henri de Toulouse-Lautrec. Dwarfism in combination with bone fragility.” Acta Orthopaedica Et Traumatologica Hellenica 73.2 (2022): 118-124.

80) Clark, A. R. “Two cases of pycnodysostosis (the malady of Toulouse-Lautrec).” Postgraduate Medical Journal 45.528 (1969): 684.

81) Turan, Serap. “Current research on pycnodysostosis.” Intractable & rare diseases research 3.3 (2014): 91-93.

Testosterone for Women

82) Donovitz, Gary S. “A Personal Prospective on Testosterone Therapy in Women—What We Know in 2022.” Journal of Personalized Medicine 12.8 (2022): 1194.

83) Mohamad, Nur-Vaizura, Ima-Nirwana Soelaiman, and Kok-Yong Chin. “A concise review of testosterone and bone health.” Clinical interventions in aging (2016): 1317-1324.

84) Jassal, Simerjot K., Elizabeth Barrett‐Connor, and Sharon L. Edelstein. “Low bioavailable testosterone levels predict future height loss in postmenopausal women.” Journal of Bone and Mineral Research 10.4 (1995): 650-654.

85) Maclaran, Kate, and Nick Panay. “The safety of postmenopausal testosterone therapy.” Women’s Health 8.3 (2012): 263-275.

AVN

86) Everts‐Graber, Judith, et al. “Risk of osteonecrosis of the jaw under denosumab compared to bisphosphonates in patients with osteoporosis.” Journal of bone and mineral research 37.2 (2022): 340-348.

87) Bagan, J., et al. “Medication‐related osteonecrosis of the jaw associated with bisphosphonates and denosumab in osteoporosis.” Oral diseases 22.4 (2016): 324-329.

88) Jung, Seoyeon, et al. “A 5-year retrospective cohort study of denosumab induced medication related osteonecrosis of the jaw in osteoporosis patients.” Scientific reports 12.1 (2022): 8641.

89) Khan, A., et al. “Osteonecrosis of the jaw (ONJ): diagnosis and management in 2015.” Osteoporosis international 27 (2016): 853-859.

90) Dinca, O., et al. “Extensive osteonecrosis of the mandible after therapy with denosumab following bisphosphoantes therapy.” Acta Endo 10 (2014): 457-462.

91) Kyrgidis, A., and K. A. Toulis. “Denosumab-related osteonecrosis of the jaws.” Osteoporosis international 22 (2011): 369-370.

92) Wick, Alexander, et al. “Risk factors associated with onset of medication-related osteonecrosis of the jaw in patients treated with denosumab.” Clinical oral investigations (2022): 1-14.

93) Voss, P. J., et al. “Osteonecrosis of the jaw in patients transitioning from bisphosphonates to denosumab treatment for osteoporosis.” Odontology 106 (2018): 469-480.

94) O’Halloran, Michael, N. M. Boyd, and Andrew Smith. “Denosumab and osteonecrosis of the jaws–the pharmacology, pathogenesis and a report of two cases.” Australian dental journal 59.4 (2014): 516-519.

It would appear that DONJ is more likely than BRONJ [bisphosphonate related osteonecrosis of the jaws] to occur earlier and spontaneously or with very minor trauma. It is important that dentists avoid even minor dental manipulation for these patients.Procedures such as dental extractions should notoccur until denosumab has been withdrawn for at least six months.

95) Hernandez, Adrian V., et al. “Comparative efficacy of bone anabolic therapies in women with postmenopausal osteoporosis: A systematic review and network meta-analysis of randomized controlled trials.” Maturitas 129 (2019): 12-22.

Objective: To systematically evaluate the effects of bone anabolic therapies (BATs) – specifically, drug therapy with teriparatide, abaloparatide or romosozumab – on fractures, bone mineral density (BMD), and bone metabolites in postmenopausal osteoporosis.

Methods: Six computerized engines were searched through to November 2018. We selected randomized controlled trials (RCTs) evaluating the effect of BATs on postmenopausal osteoporosis and with at least 6 months of follow-up. Controls were placebo, no treatment, or bisphosphonates. Primary outcomes were vertebral and non-vertebral fractures. Secondary outcomes were: BMD determined by dual energy X-ray absorptiometry at total hip, lumbar spine, and femoral neck;  risk-of-bias tool.

Results: Sixteen RCTs (n = 18,940) were evaluated. Mean ages ranged between 61 and 74 years, and follow-up times between 6 and 30 months. Four RCTs (n = 971) excluded patients with previous fractures. In contrast to placebo/no treatment, all BATs significantly reduced the risk of vertebral fractures, but no intervention significantly reduced the risk of non-vertebral fractures; abaloparatide ranked better than other interventions for both fracture types (p-scores: 0.95, and 0.89, respectively). All BATs significantly increased BMD at all locations in comparison with placebo/no treatment; romosozumab consistently ranked better than other interventions at all BMD locations (p-scores >0.86). Teriparatide ranked better than other interventions for increasing PINP. No differences in SAE were observed among treatments.

Conclusions: Abaloparatide, romosozumab, and teriparatide are the best treatments, respectively, to reduce vertebral/non-vertebral fractures, increase BMD, and increase bone formation.

96) Everts‐Graber, Judith, et al. “Incidence of Atypical Femoral Fractures in Patients on Osteoporosis Therapy—A Registry‐Based Cohort Study.” JBMR plus 6.10 (2022): e10681.

The pathogenesis of AFFs remains poorly understood, but the
long-term suppression of bone resorption with prolonged use of
BPs, leading to micro-crack propagation and a stress reaction of
the lateral femur cortex, has been well explored.(4)

97) Pearce O, Edwards T, Al-Hourani K, Kelly M, Riddick A. Evaluation and management of atypical femoral fractures: an update of current
knowledge. Eur J Orthop Surg Traumatol. 2021;31(5):825-840.

98) Anastasilakis, Athanasios D., et al. “Osteonecrosis of the jaw and antiresorptive agents in benign and malignant diseases: a critical review organized by the ECTS.” The Journal of Clinical Endocrinology & Metabolism 107.5 (2022): 1441-1460.

99) Aoki, Kazumitsu, et al. “Persistent bone resorption lacunae on necrotic bone distinguish bisphosphonate-related osteonecrosis of jaw from denosumab-related osteonecrosis.” Journal of Bone and Mineral Metabolism 39 (2021): 737-747.

100) Matsushita, Yuki, et al. “Denosumab-associated osteonecrosis of the jaw affects osteoclast formation and differentiation: Pathological features of two cases.” Molecular and clinical oncology 4.2 (2016): 191-194.

101) Egloff‐Juras, Claire, et al. “Denosumab‐related osteonecrosis of the jaw: A retrospective study.” Journal of Oral Pathology & Medicine 47.1 (2018): 66-70.

In this study, we obtained a DRONJ rate of 1% from beginning to
6 months of treatment and of 8% until 30 months of treatment.
From 12 months of treatment, the rate reached 3% and then
exceeded the average rates frequently reported in the literature (between
1% and 2%).

102) Pichardo, Sarina EC, and JP Richard van Merkesteyn. “Evaluation of a surgical treatment of denosumab-related osteonecrosis of the jaws.” Oral surgery, oral medicine, oral pathology and oral radiology 122.3 (2016): 272-278.

Results: Eleven patients met the criteria to be included in this study. Nine patients experienced healing within 4 weeks after surgery. Two patients were not cured and died as a result of their underlying disease.

103) Kawaguchi, Hiroshi. “Serious adverse events with romosozumab use in Japanese patients: Need for clear formulation of contraindications worldwide.” Journal of Bone and Mineral Research 35.5 (2020): 994-995.

104) Goh, Jeremy Keng Meng, et al. “Bilateral atypical femur fractures after denosumab in a bisphosphonate naïve patient: a case report.” Calcified Tissue International 111.1 (2022): 96-101.

105) Piponov, H. I., J. M. Goldstein, and G. M. Eisenberg. “Multiple ipsilateral femoral stress fractures in a patient taking denosumab for osteoporosis—a case report.” Osteoporosis International 31 (2020): 2263-2267.

106) Thompson, Robin N., Ciara L. Armstrong, and Gary Heyburn. “Bilateral atypical femoral fractures in a patient prescribed denosumab—a case report.” Bone 61 (2014): 44-47.

107) Schilcher, Jörg, and Per Aspenberg. “Atypical fracture of the femur in a patient using denosumab–a case report.” Acta orthopaedica 85.1 (2014): 6-7.

108) Selga, J., et al. “Simultaneous bilateral atypical femoral fracture in a patient receiving denosumab: case report and literature review.” Osteoporosis International 27.2 (2016): 827-832.

109) Drampalos, Efstathios, et al. “Atypical femoral fractures bilaterally in a patient receiving denosumab.” Acta Orthopaedica 85.1 (2014): 3-5.

110) Austin, Daniel C., et al. “Atypical femoral fractures mimicking metastatic lesions in 2 patients taking denosumab.” Acta orthopaedica 88.3 (2017): 351-353.

111) Aspenberg, Per. “Denosumab and atypical femoral fractures.” Acta orthopaedica 85.1 (2014): 1-1.

112) Paparodis, Rodis, et al. “A case of an unusual subtrochanteric fracture in a patient receiving denosumab.” Endocrine Practice 19.3 (2013): e64-e68.

113) Lamy, Olivier, et al. “Severe rebound-associated vertebral fractures after denosumab discontinuation: 9 clinical cases report.” The Journal of Clinical Endocrinology & Metabolism 102.2 (2017): 354-358.

114) Tripto-Shkolnik, Liana, et al. “Long-term follow-up of denosumab discontinuers with multiple vertebral fractures in the real-world: a case series.” Hormone and Metabolic Research 53.03 (2021): 185-190.

115) Prolia Side Effects: You Just Can’t Make This One Up
By Chris Centeno, MD Published on Sep 30, 2017

PEMF

Zhang, Weifei, et al. “The Possible Role of Electrical Stimulation in Osteoporosis: A Narrative Review.” Medicina 59.1 (2023): 121.

Huang, Jinming, et al. “Combined Effects of Low‐Frequency Pulsed Electromagnetic Field and Melatonin on Ovariectomy‐Induced Bone Loss in Mice.” Bioelectromagnetics 42.8 (2021): 616-628.

Liu, Yingxin, et al. “Therapeutic effect of pulsed electromagnetic field on bone wound healing in rats.” Electromagnetic Biology and Medicine 40.1 (2021): 26-32.

Xiao, Hao, Jing Liu, and Jun Zhou. “Research progress of pulsed electromagnetic field in the treatment of postmenopausal osteoporosis.” Chinese Journal of Tissue Engineering Research 26.8 (2022): 1266.

Liu, Wei, et al. “Pulsed electromagnetic field affects the development of postmenopausal osteoporotic women with vertebral fractures.” BioMed Research International 2021 (2021).

Zhu, Siyi, et al. “Pulsed electromagnetic fields may be effective for the management of primary osteoporosis: a systematic review and meta-analysis.” IEEE Transactions on Neural Systems and Rehabilitation Engineering (2022).

Zhu, Siyi, et al. “Effects of pulsed electromagnetic fields on postmenopausal osteoporosis.” Bioelectromagnetics 38.6 (2017): 406-424.

Wang, T., et al. “Pulsed electromagnetic fields: promising treatment for osteoporosis.” Osteoporosis International 30 (2019): 267-276.

Melatonin

Da, Wacili, et al. “Protective role of melatonin against postmenopausal bone loss via enhancement of citrate secretion from osteoblasts.” Frontiers in Pharmacology 11 (2020): 667.

Guan, Huanshuai, et al. “Melatonin increases bone mass in normal, perimenopausal, and postmenopausal osteoporotic rats via the promotion of osteogenesis.” Journal of Translational Medicine 20.1 (2022): 132.

Bone mass continuously decreased after ovariectomy, while melatonin increased bone mass and ameliorated bone metabolism in normal, perimenopausal, and postmenopausal osteoporotic rats due to the induction of osteogenic differentiation in BMSCs.

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Denosumab versus Bisphosphonates for Reducing Fractures in Postmenopausal Women with Osteoporosis: A Meta-Analysis

Denosumab versus Bisphosphonates for Reducing Fractures in Postmenopausal Women with Osteoporosis: A Meta-Analysis
By Staff Last updated Jan 18, 2023 Aging Adjustments News that Matters

Based on the results of this review, there is limited evidence to support denosumab as a first-line alternative to bisphosphonates. Despite denosumab increasing BMD at both the hip and spine in all trials, denosumab did not reduce fracture compared with bisphosphonates.

Prolia (Denosumab): My Review


by Vivian Goldschmidt, MA
Prolia (Denosumab): My Review

Denosumab by Susan Ott MD

Sclerostin (SOST) Evenity by Susan Ott MD

Berberine for bone density

Qi, Guobin, et al. “Berbamine inhibits RANKL-and M-CSF-mediated osteoclastogenesis and alleviates ovariectomy-induced bone loss.” Frontiers in Pharmacology 13 (2022).
Osteoporosis is a common public health problem characterized by decreased bone mass, increased bone brittleness and damage to the bone microstructure. Excessive bone resorption by osteoclasts is the main target of the currently used drugs or treatment for osteoporosis. Effective antiresorptive drugs without side effects following long-term administration have become a major focus of anti-osteoporotic drugs. In the present study, we investigated the effect of berbamine, a small molecule natural product from Berberis amurensis Rupr, a traditional Chinese medicine, on RANKL-induced osteoclast differentiation in vitro and ovariectomy-induced bone loss in vivo. The results demonstrated that berbamine at a safe and effective dose inhibited osteoclastogenesis and bone resorption function in vitro by suppressing the nuclear factor-κB signaling pathway. In addition, berbamine protected against osteoporosis by inhibiting osteoclastogenesis and bone resorption function without affecting osteogenesis in the ovariectomy mouse model. These findings revealed that berbamine has a protective role against osteoporosis and may represent a novel promising treatment strategy for osteoporosis.

 

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By Vivian Goldschmidt, MA
Evenity (Romosozumab): Everything You Need To Know About This New Osteoporosis Drug

1 Sharma, Abhishek, M.D., et al. “Risk of Serious Atrial Fibrillation and Stroke With Use of Bisphosphonates: Evidence From a Meta-analysis.” CHEST. October 2013. 144(4): 1311-1322. Web. https://journal.publications.chestnet.org/article.aspx?articleid=1691936

2 Edwards, Beatrice J., et al. “Bisphosphonates and esophageal cancer: A RADAR report.” Journal of Clinical Oncology. 2012 ASCO Annual Meeting. Web. https://meetinglibrary.asco.org/content/92963-114

3 Shane E. et al. Atypical subtrochanteric and diaphyseal femoral fractures: report of a task force of the American Society for Bone and Mineral Research. J. Bone Miner Res. 2010 Nov;25(11):2267-94.

4 Perrone, Matthew. “FDA panel sees risk in long-used osteoporosis drug.” Associated Press. Google News. March d40593c619

Amgen sets $21,900 annual price for new Evenity bone drug

By Deena Beasley(Reuters) – Amgen Inc on Monday set the U.S. list price for its new Evenity osteoporosis drug at $1,825 a month, or $21,900 for a full 12-month course of injections.

Last updated on by Jeffrey Dach MD

4 thoughts on “The New Osteoporosis Drugs, the Good, Bad and Ugly

  1. Thank you so very much for your most comprehensive and informed overview of osteoporosis, current treatments and their potential benefits and side effects. The highly researched and ethical information you provide is invaluable and very much appreciated.

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