Strontium Chloride Sr-89 (Metastron)

Number: 0361

Table Of Contents

Policy
Applicable CPT / HCPCS / ICD-10 Codes
Background
References

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Policy

Scope of Policy

This Clinical Policy Bulletin addresses strontium chloride Sr-89 (Metastron) for commercial medical plans. For Medicare criteria, see Medicare Part B Criteria.

Note: Requires Precertification:

Precertification of strontium chloride Sr-89 (Metastron) is required of all Aetna participating providers and members in applicable plan designs. For precertification of strontium chloride Sr-89 (Metastron), call (866) 752-7021 or fax (888) 267-3277. For Statement of Medical Necessity (SMN) precertification forms, see Specialty Pharmacy Precertification.

Strontium Chloride Sr-89 (Metastron)

1. Criteria for Initial Approval

   Aetna considers strontium chloride Sr-89 (Metastron) medically necessary for the relief of bone pain when all of the following criteria are met:

   1. The member has a malignant/cancer diagnosis; and
   2. The member has bone metastases.

   Aetna considers all other indications as experimental and investigational (for additional information, see Experimental and Investigational and Background sections).

2. Continuation of Therapy

   Aetna considers continuation of strontium chloride Sr-89 (Metastron) therapy medically necessary in members requesting reauthorization for an indication listed in Section I when there is no evidence of unacceptable toxicity while on the current regimen.

Dosage and Administration

Strontium Chloride Sr-89 (Metastron)

Strontium Chloride Sr-89 is supplied in a 5 mL vial containing 148 MBq, 4mCi as a single dose for intravenous administration.

The recommended dosing is as follows:

Relief of bone pain in painful skeletal metastases:

Strontium chloride Sr-89 is administered as 148 MBq, 4 mCi by slow intravenous injection (1-2 minutes). Alternatively, a dose of 1.5 - 2.2 MBq/kg, 40-60 µCi/kg body weight may be used. (MBq = megabecquerel (one mCi equals 37 MBq); mCi = milliCurie). Repeated administrations of strontium chloride Sr-89 should be based on an individual’s response to therapy, current symptoms, and hematologic status, and are generally not recommended at intervals of less than 90 days. The individual dose should be measured by a suitable radioactivity calibration system immediately prior to administration. 

Note: Metastron is no longer available commercially.

Source: QBioMed, 2020

Experimental and Investigational

Aetna considers radiopharmaceuticals such as strontium chloride Sr-89 experimental and investigational for all other indications including the following (not an all-inclusive list):

• Use in members with cancer not involving the bone
• For controlling intractable hypoglycemia in persons with malignant insulinoma
• For incorporating into calcium phosphate to improve bone repair
• For pre-conditioning of mesenchymal stromal cell-derived extracellular vesicles in bone regeneration
• For supplementing on implant osseointegration in the presence of osteoporotic bone
• For treating beta-thalassemia-associated osteoporosis.

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Table:

CPT Codes / HCPCS Codes / ICD-10 Codes

Code	Code Description
Other CPT codes related to the CPB:
77261 - 77525	Radiation oncology
79101	Radiopharmaceutical therapy, by intravenous administration
96401 - 96450	Chemotherapy administration
HCPCS codes covered if selection criteria are met:
A9600	Strontium Sr-89 chloride, therapeutic, per millicurie
ICD-10 codes covered if selection criteria are met:
C40.00 – C41.9	Malignant neoplasm of bone and articular cartilage [osteosarcoma]
C79.51 - C79.52	Secondary malignant neoplasm of bone and bone marrow
ICD-10 codes not covered for indications listed in the CPB (not all-inclusive):
C00.0 – C39.9, C61, C79.49 C79.60 - C96.9	Malignant neoplasms [other than metastatic to bone] [other than osteosarcoma]
C78.7	Secondary malignant neoplasm of liver and intrahepatic bile duct
D00.00 - D09.9	Carcinoma in situ
D13.7	Benign neoplasm of endocrine pancreas
D56.1	Beta thalassemia [beta-thalassemia-associated osteoporosis]
E15 - E16.2	Hypoglycemia
M05.00 - M08.99	Rheumatoid arthritis [with knee synovitis]
M12.261 - M12.269	Villonodular synovitis (pigmented), knee [related to the rheumatoid arthritis]
M81.0 – M81.8	Osteoporosis without current pathological fracture [beta-thalassemia-associated osteoporosis]

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Background

U.S. Food and Drug Administration (FDA)-Approved Indications

Strontium-89 (Metastron)

• Indicated for the relief of bone pain in patients with painful skeletal metastases.

Strontium-89 is a beta-emitting radionuclide that preferably localizes in areas of active bone formation (areas of high osteoblast activity such as metastatic lesions).  It functions as a calcium analog that releases high-energy beta particles as the compound decays to yttruim-89.  This local radiation results in at least partial pain relief without extensive hematologic toxicity or myelosuppression.  The mechanism by which strontium-89 relieves bone pain is not known.  Some believe that local irradiation stops the tumor from producing pain-producing enzymes, while others believe it may act through suppression of tumor growth.

Strontium-89 was approved by the FDA for the treatment of bone pain in cancer patients with painful skeletal metastases.  It is not indicated for use in patients with cancer not involving the bone.  Strontium-89 was marketed under the brand name Metastron through a joint venture of Amersham Healthcare and Zeneca Pharmaceuticals, and then subsequently GE Healthcare. However, in 2019, Metastron was acquired by QBioMed, Inc. and now Metstron is primarily referred to as strontium-89 (SR89).

Strontium-89 is indicated for patients with definite signs of discomfort from skeletal metastases and with inadequate relief with other forms of therapy (e.g., chemotherapy, hormone therapy, and analgesics).  Other causes of bone pain (e.g., osteoarthritis, nerve root compression) should be ruled out.  Strontium-89 is contraindicated in patients with elevated calcium levels.  According to established guidelines, white blood counts should be greater than 2,400 to 3,000 and platelets greater than 40 to 100 10(9)/L prior to therapy.  Product information indicates that caution should be used in patients with platelet counts below 60 x 10(9)/L and white blood cell counts below 2,400.

Strontium-89 is an effective alternative for the treatment of bone pain in patients with painful skeletal metastases.  The drug is only a palliative measure and not a cure for bone pain or cancer.  Moreover, it is ineffective in relieving pain originating from soft tissue tumors, unless bone metastases are involved.

Evidence of pain relief is generally seen within 7 to 21 days and sustained for 3 to 6 months.  The literature indicates that a repeat dose can be administered at 3-month intervals if necessary.

Amato et al (2008) noted that bone-targeted therapy that combines strontium-89 (Sr-89) with alternating weekly chemohormonal therapy may improve clinical outcomes in patients with metastatic hormone-refractory prostate cancer.  This phase II study examined the addition of Sr-89 to an alternating weekly regimen of doxorubicin and ketoconazole with paclitaxel and estramustine in patients with progressive prostate cancer and bone involvement.  A total of 29 patients with progressive adenocarcinoma of the prostate and osteoblastic bone metastases who failed conventional hormonal therapy were registered for the study.  Of those, 27 were treated with Sr-89 on day 1 of week 1.  On weeks 1, 3, and 5, patients received doxorubicin (20 mg/m on day 1) and oral ketoconazole (400 mg 3 times a day for 7 days).  On weeks 2, 4, and 6, patients received paclitaxel (100 mg/m(2)) and oral estramustine (280 mg 3 times a day for 7 days).  No treatment was given during weeks 7 and 8.  Cycles were repeated every 8 weeks.  A greater than or equal to 50 % reduction in prostate-specific antigen level was maintained for at least 8 weeks in 77.7 % of the patients (n = 21) at 16 weeks and in 66.6 % (n = 18) at 32 weeks.  The median progression-free survival was 11.27 months (range of 1.83 to 29.53), and the median overall survival was 22.67 months (range of 1.83 to 57.73+).  Two patients died during study because of disease progression.  Overall, the chemotherapy combined with Sr-89 was well-tolerated.  The authors concluded that these findings demonstrated that the combination of alternating weekly chemohormonal therapies with Sr-89 resulted in a prolonged progression-free and overall survival with acceptable toxicity.  They stated that further investigation of combination therapies with Sr-89 is warranted.

Tu and Lin (2008) stated that the propensity of prostate cancer to metastasize to bone and the prognostic significance of bone metastasis suggest that effective treatment of bone metastasis may provide clinical benefits.  Both osteoblasts and osteoclasts have been shown to play a central role in the interactions between the metastatic prostate cancer cells and bone.  Although most prostate cancer bone metastasis is osteoblastic, it remains unclear which cell type is initially involved in the process.  Other components in the bone, such as the endothelium and stroma, may also play an important role in this process.  The osteoblastic feature of prostate cancer bone metastasis has led to therapies focused on targeting osteoblast activity.  Clinical trials targeting osteoblasts use radiopharmaceuticals (e.g., Sr-89), the endothelin A receptor inhibitor atrasentan, or the vitamin D analog calcitriol.

Naganuma et al (2012) reported the case of a 57-year old woman with liver and bone metastases from malignant insulinoma, who was afflicted with severe hypoglycemia.  Treatment of the liver metastases using octreotide, diazoxide and trans-arterial embolization failed to raise her blood glucose level and she required constant glucose infusion (about 1,000 kcal/day) and oral feeding (about 2,200 kcal/day) to avoid a hypoglycemic attack.  Subsequently, 110 MBq (2.0 MBq/kg) of strontium-89 were administered by intravenous injection.  Three weeks after the strontium-89 injection, the dose of constant glucose infusion could be reduced while maintaining a euglycemic status.  Six weeks after the injection, the constant glucose infusion was discontinued.  Although strontium-89 therapy is indicated for patients with multiple painful bone metastases, it was also useful as a means of inhibiting tumor activity and controlling hypoglycemia in this case.  The authors concluded that this is the first report to provide evidence that strontium-89 can be useful in controlling intractable hypoglycemia in patients with malignant insulinoma with bone metastases.  The findings of this single-case study need to be validated by well-designed studies.

The National Institute for Health and Care Excellence’s clinical guideline on “Prostate cancer: diagnosis and treatment” (2014) stated that “Strontium-89 should be considered for men with hormone-relapsed prostate cancer and painful bone metastases, especially those men who are unlikely to receive myelosuppressive chemotherapy”.

Note: Individuals with disseminated intravascular coagulation must be excluded from therapy with strontium-89.  The American College of Radiology (ACR) and the American Society for Radiation Oncology (ASTRO)'s practice guideline for the performance of therapy with unsealed radiopharmaceutical sources (2010) listed disseminated intravascular coagulation (DIC) as a contraindication of strontium-89.  Thus, patients with DIC must be excluded from therapy with strontium-89.

Ye and colleagues (2018) comparatively evaluated the efficacy of Sr-89 chloride (89 SrCl2) in treating bone metastasis-associated pain in patients with lung, breast, or prostate cancer.  The 126 patients with lung cancer included 88, 16, 15, 4, and 3 patients with adenocarcinoma, squamous cell carcinoma, non-small cell carcinoma, mixed carcinoma, and small cell carcinoma, respectively, and the control group consisted of patients with breast (71 patients) or prostate cancer (49 patients) who underwent 89 SrCl2 treatment during the same period.  The treatment dose of 89 SrCl2 was 2.22 MBq/kg.  The efficacy rate of treatment in the lung cancer group was 75.4 %, compared to 95.0 % in the control group.  Approximately 67 % of patients with lung cancer and bone metastases and 47 % of control patients exhibited mild-to-moderate reductions of leukocyte and platelet counts 4 weeks after 89 SrCl2 treatment.  The authors concluded that 89 SrCl2 could safely and effectively relieve bone pain caused by bone metastasis from lung cancer.  However, its efficacy was lower in patients with lung cancer with bone metastasis than in those with breast or prostate cancer with bone metastasis, and its effects on the peripheral hemogram were also significantly stronger in the lung cancer group.

Incorporating Into Calcium Phosphate to Improve Bone Repair

Yan et al (2022) noted that the use of calcium phosphate (CaP)-based bone substitutes plays an important role in periodontal regeneration, implant dentistry and alveolar bone reconstruction.  The incorporation of strontium (Sr) into CaP-based bone substitutes appeared to improve their biological properties; however, the reported in-vivo bone repair performance is inconsistent among studies.  In a systematic review and meta-analysis, these investigators examined the in-vivo performance of Sr-doped materials.  They searched PubMed, Embase (via OVIDSP), and reference lists to identify relevant animal studies.  The search, study selection, and data extraction were carried out independently by 2 investigators.  Meta-analyses and sub-group analyses were performed using Revman version 5.4.1.  The heterogeneity between studies were assessed by I2; and publication bias was examined via a funnel plot.  A total of 35 studies were reviewed, of which 16 articles that reported on new bone formation (NBF) were included in the meta-analysis, covering 31 comparisons and 445 defects.  The overall effect for NBF was 2.25 (95 % CI: 1.61 to 2.90, p < 0.00001, I2 = 80 %); 8 comparisons from 6 studies reported the outcomes of bone volume/tissue volume (BV/TV), with an overall effect of 1.42 (95 % CI: 0.65 to 2.18, p = 0.0003, I2 = 75 %); and 14 comparisons reported on the material remaining (RM), with the overall effect being -2.26 (95 % CI: - 4.02 to - 0.50, p = 0.0009, I2 = 86 %).  The authors concluded that this trial showed that Sr-doped calcium phosphate bone substitutes improved in-vivo performance of bone repair; however, more studies are also recommended to further verify this conclusion.  These researchers stated that determining the optimum concentrations of Sr and the best Sr-doped CaP materials is an important future research direction.  Furthermore, the angiogenic potential of materials could be another research direction worth focusing on, in addition to osteogenesis.

The authors stated that this study had several drawbacks.  First, in this study, high heterogeneity was found in the meta-analysis of NBF and residual materials.  Subgroup analyses based on material type, implantation period, experimental animal species, etc., also had high heterogeneity.  In view of the significant heterogeneity among the studies included in this meta-analyses, caution should be exercised when generalizing the conclusions.  It was suggested that homogenized study settings should be adopted in subsequent studies to provide more convincing evidence for clinical applications.  Second, the quality of the included studies was not high enough.  The details of sample size estimation and randomization methodology were not found in most studies.  Third, although Sr has a beneficial effect on bone formation, its potential negative effects should also be considered, especially in high doses.  A dose-dependent effect of Sr on osteoblasts could be detected in some in-vitro studies.  Animal studies have shown that the Sr dosage was very important, as high doses could cause osteomalacia.  In this trial, the included studies used different concentrations of Sr, and some did not report relevant data; thus, it is necessary to further examine the optimal concentration of Sr.

Pre-Conditioning of Mesenchymal Stromal Cell-Derived Extracellular Vesicles in Bone Regeneration

Hertel et al (2022) stated that mesenchymal stromal cells (MSCs) have long been employed in research for bone regeneration.  In the segmental area of MSC-based therapies, MSC-derived extracellular vesicles (EVs) have also demonstrated marked therapeutic effects in several diseases, including bone healing.  These researchers examined if the pre-conditioning of MSCs would improve the therapeutic effects of their derived extracellular vesicles for bone regeneration.  They carried out electronic research until February 2021 to identify studies in the following databases: PubMed, Scopus, and Web of Science.  The studies were screened based on the inclusion criteria.  Relevant information was extracted, including in-vitro as well as in-vivo experiments; and animal studies were assessed for risk of bias by the SYRCLE tool.  A total of 463 studies were retrieved, and 18 studies met the inclusion criteria (10 studies for their in-vitro analysis, and 8 studies for their in-vitro as well as in-vivo analysis).  The pre-conditioning methods reported included: osteogenic medium; dimethyloxalylglycine; dexamethasone; strontium-substituted calcium silicate; hypoxia; 3D mechanical micro-environment; and the over-expression of miR-375, bone morphogenetic protein-2, and mutant hypoxia-inducible factor-1α.  The pre-conditioning methods of MSCs in the reported studies generated exosomes able to significantly promote bone regeneration.  However, heterogeneity regarding cell source, pre-conditioning method, EV isolation and concentration, and defect model was observed among the studies.  The authors concluded that the different pre-conditioning methods reported in this review improved the therapeutic effects of MSC-derived EVs for bone regeneration; however, they still need to be addressed in larger animal models for further clinical application.

These researchers stated that despite the evidence of the therapeutic potential of EVs derived from pre-conditioned MSCs, the heterogeneity of the cell sources, EV concentrations, and the scaffolds used limited the evidence supporting a particular pre-conditioning method as the best option for bone regeneration so far.  Furthermore, the reporting of outcomes could be better addressed in further studies, advocating for the quantitative analysis of standardized methods for in-vivo bone regeneration assessment.  Moreover, they noted that limitations were found mostly regarding the unclear risk of bias in most of the SYRCLE tool’s domains.  The lack of reporting information pertaining to allocation concealment, housing randomization/conditions, blinding of performance, and blinding outcome assessment meant that the studies were at risk of bias.  In addition, the lack of reports of the methodology (i.e., the specific method of assessment and how it was performed) diminished the strength of the studies’ evidence.  For further studies focusing on the therapeutic potential of EVs derived from conditioned MSCs, this review suggested critically analyzing the best pre-conditioning method according to the specific objective of the study, including the most suitable cell source, an approach that increases the yield of EVs, diminishes the concentration for clinical application, and is financially viable.  Furthermore, following the guidelines for studies of extracellular vesicles and the ARRIVE guidelines for reporting in-vivo studies can improve the reproducibility of a study and translate the science from bench to bedside.

Note: Both samarium-153 and Quadramet are no longer available commercially.

Supplementation on Implant Osseointegration in the Presence of Osteoporotic Bone

Shen et al (2021) noted that the excessive accumulation of reactive oxygen species (ROS) under osteoporosis precipitates a micro-environment with high levels of oxidative stress (OS).  This could markedly interfere with the bioactivity of conventional titanium implants, impeding their early osseointegration with bone.  These researchers prepared a series of strontium (Sr)-doped titanium implants via micro-arc oxidation (MAO) to verify their effectiveness and differences in osteo-induction capabilities under normal and osteoporotic (high OS levels) conditions.  Apart from the chemical composition, all groups exhibited similar physicochemical properties (morphology, roughness, crystal structure, and wettability).  Among the groups, the low Sr group (Sr25%) was more conducive to osteogenesis under normal conditions.  In contrast, by increasing the catalase (CAT)/superoxide dismutase (SOD) activity and decreasing ROS levels, the high Sr-doped samples (Sr75% and Sr100%) were superior to Sr25% in inducing osteogenic differentiation of MC3T3-E1 cells and the M2 phenotype polarization of RAW264.7 cells; therefore, enhancing early osseointegration.  In addition, the results of both in-vitro cell co-culture as well as in-vivo studies also showed that the high Sr-doped samples (especially Sr100%) had positive effects on osteo-immunomodulation under the OS micro-environment.  The authors concluded that the collated findings indicated that the high proportion Sr-doped MAO coatings were more favorable for osteoporosis patients in implant restorations.  These investigators believed that the fabrication of a high proportion Sr-doped Ti coatings utilizing MAO, notably the Sr100% group, holds a promising theoretical and practical significance for the future development of ion-doped implants equipped with anti-oxidative properties to promote the early osseointegration of implants in patients with osteoporosis.

The authors stated that this study had 2 main drawbacks.  First, there has been inadequate research into the mechanisms of anti-oxidative stress and osteo-immunomodulation in high Sr groups.  Second, it was unclear if patients with osteoporosis should choose various proportions of Sr-doped implants depending on the severity of the illness.  These researchers planned to carry out comprehensive research in the future to examine the functions and potential mechanisms between different OS levels and Sr-doped implants, which will be critical for patients with varying degrees of osteoporosis in order to select the most appropriate Sr-doped implants.

Lu et al (2022) stated that Sr has been validated for potent bone-seeking and anti-osteoporotic properties and elicits a potentially beneficial impact on implant osseointegration in patients with osteoporosis; however, the effectiveness of Sr supplementation on improving new bone formation and implant osseointegration in the presence of osteoporotic bone is still unclear.  In a systematic review, these researchers examined the effectiveness of Sr supplementation, encompassing oral intake and local delivery of Sr, on implant osseointegration in patients with osteoporosis.  Searches on electronic databases (Medline or PubMed, Web of Science, EBSCO, Embase, and Clinicaltrials.gov) and manual searches were carried out to identify relevant pre-clinical animal studies up to June 2020.  The primary outcomes were the percentage of bone-implant contact and bone area; the secondary outcomes were quantitative parameters of biomechanical tests and micro-computed tomography (μCT).  A total of 14 pre-clinical trials (1 rabbit, 1 sheep, and 12 rat), with a total of 404 ovariectomized animals and 798 implants, were eligible for analysis.  The results revealed a significant 17.1 % increase in bone-implant contact and 13.5 % increase in bone area, favoring Sr supplementation despite considerable heterogeneity.  Subgroup analyses of both bone-implant contact as well as bone area exhibited similar outcomes with low-to-moderate heterogeneity.  Results of biomechanical and μCT tests demonstrated that Sr-enriched implantation tended to optimize the mechanical strength and micro-architecture of newly formed bone despite moderate-to-generally high heterogeneity.  The authors concluded that based on the available pre-clinical evidence, Sr supplementation, including local and systemic delivery, demonstrated promising results for enhancing implant osseointegration in the presence of osteoporosis during 4 to 12 weeks of healing.  Moreover, these researchers stated that future well-designed standardized studies are needed to validate the safety and effectiveness of Sr supplementation and to establish a standard methodology for incorporating Sr into implant surfaces in a clinical setting.

Sheng et al (2023) Sr and Sr ranelate (SR) are commonly used therapeutic drugs for patients suffering from osteoporosis.  Research has showed that Sr can significantly improve the biological activity as well as physicochemical properties of materials in-vitro and in-vivo; thus, a large number of Sr-containing biomaterials have been developed for repairing bone defects and promoting osseointegration.  In this review, these investigators provided a comprehensive overview of Sr-containing biomaterials along with the current state of their clinical use.  For this purpose, the different types of biomaterials including calcium phosphate, bioactive glass, and polymers were discussed and provided future outlook on the fabrication of the next-generation multi-functional and smart biomaterials.  Moreover, these researchers stated that studies on Sr-containing biomaterials are only limited to cell and animal experiments, clinical applications and large-scale production are still far away.  These biomaterials should be verified as having the ability to play expected roles in the human body.  Additionally, the stability, durability, economic benefits, and repeatability of materials are key factors for their commercialization.  Lastly, treatment and surgical indications as well as potential complications following implantation of these materials should be further examined.

Treatment for Osteoporosis in Individuals with Beta-Thalassemia

Bhardwaj et al (2023) noted that osteoporosis is characterized by low bone mass and micro-architectural deterioration of bone tissue leading to increased bone fragility.  In individuals with beta-thalassemia, osteoporosis represents an important cause of morbidity and is due to a number of factors.  First, ineffective erythropoiesis causes bone marrow expansion, resulting in reduced trabecular bone tissue with cortical thinning.  Second, excessive iron loading causes endocrine dysfunction, resulting in increased bone turnover.  Third, disease complications can result in physical inactivity, with a subsequent reduction in optimal bone mineralization.  Treatments for osteoporosis in individuals with beta-thalassemia include bisphosphonates (e.g., clodronate, pamidronate, alendronate; with or without hormone replacement therapy (HRT)), calcitonin, calcium, zinc supplementation, hydroxyurea, and HRT alone (for preventing hypogonadism).  Denosumab inhibits bone resorption and increases bone mineral density (BMD).  Lastly, strontium ranelate simultaneously promotes bone formation and inhibits bone resorption; therefore, contributing to a net gain in BMD, increased bone strength, and reduced fracture risk.  This is an update of a previously published Cochrane Review.  These investigators examined the evidence on the safety and effectiveness of treatment for osteoporosis in individuals with beta-thalassemia.  They searched the Cochrane Cystic Fibrosis and Genetic Disorders Group's Haemoglobinopathies Trials Register, which includes references identified from comprehensive electronic database searches and hand-searches of relevant journals and abstract books of conference proceedings.  These investigators also searched online trial registries; and date of most recent search was August 4, 2022.  RCTs in individuals with beta-thalassemia with a BMD Z score below -2 standard deviations (SDs) for children aged under 15 years, adult males (aged 15 to 50 years) and pre-menopausal females aged over 15 years; or a BMD T score below -2.5 SDs for post-menopausal females and males aged over 50 years were selected for analysis.  Two review authors examined the eligibility and risk of bias of the included RCTs, and extracted and analyzed data.  They assessed the certainty of the evidence using the GRADE approach.

These researchers included 6 RCTs (298 participants).  Active interventions included bisphosphonates (3 trials, 169 subjects), zinc supplementation (1 trial, 42 subjects), denosumab (1 trial, 63 subjects), and strontium ranelate (1 trial, 24 subjects).  The certainty of the evidence ranged from moderate to very low and was down-graded mainly due to concerns surrounding imprecision (low subject numbers), but also risk of bias issues related to randomization, allocation concealment, and blinding.  Bisphosphonates versus placebo or no treatment: Two RCTs compared bisphosphonates to placebo or no treatment.  After 2 years, 1 study (25 subjects) found that alendronate and clodronate may increase BMD Z score compared to placebo at the femoral neck (mean difference (MD) 0.40, 95 % CI: 0.22 to 0.58) and the lumbar spine (MD 0.14, 95 % CI: 0.05 to 0.23).  One study (118 subjects) reported that neridronate compared to no treatment may increase BMD at the lumbar spine and total hip at 6 and 12 months; for the femoral neck, the study found increased BMD in the neridronate group at 12 months only.  All results were of very low-certainty.  There were no major adverse effects of treatment.  Subjects in the neridronate group reported less back pain; these investigators considered this representative of improved quality of life (QOL), although the certainty of the evidence was very low.  One subject in the neridronate study (116 subjects) sustained multiple fractures as a result of a traffic accident.  No trials reported BMD at the wrist or mobility.  Different doses of bisphosphonate compared: One 12-month trial (26 subjects) examined different doses of pamidronate (60 mg versus 30 mg) and found a difference in BMD Z score favoring the 60-mg dose at the lumbar spine (MD 0.43, 95 % CI: 0.10 to 0.76) and fore-arm (MD 0.87, 95 % CI: 0.23 to 1.51), but no difference at the femoral neck (very low-certainty evidence).  This trial did not report fracture incidence, mobility, QOL, or adverse effects of treatment.  Zinc versus placebo: One study (42 subjects) showed zinc supplementation probably increased BMD Z score compared to placebo at the lumbar spine after 12 months (MD 0.15, 95 % CI: 0.10 to 0.20; 37 subjects) and 18 months (MD 0.34, 95 % CI: 0.28 to 0.40; 32 subjects); the same was true for BMD at the hip after 12 months (MD 0.15, 95 % CI: 0.11 to 0.19; 37 subjects) and 18 months (MD 0.26, 95 % CI: 0.21 to 0.31; 32 subjects).  The evidence for these results was of moderate certainty.  The trial did not report BMD at the wrist, fracture incidence, mobility, QOL, or adverse effects of treatment.   Denosumab versus placebo:  Based on 1 trial (63 subjects), these researchers were unsure regarding the effect of denosumab on BMD Z score at the lumbar spine, femoral neck, and wrist joint after 12 months compared to placebo (low-certainty evidence).  This trial did not report fracture incidence, mobility, QOL, or adverse effects of treatment, but the investigators reported a reduction in bone pain measured on a visual analog scale (VAS) in the denosumab group after 12 months of treatment compared to placebo (MD -2.40 cm, 95 % CI: -3.80 to -1.00).  Strontium ranelate: One trial (24 subjects) only narratively reported an increase in BMD Z score at the lumbar spine in the intervention group and no corresponding change in the control group (very low-certainty evidence).  This trial also found a reduction in back pain measured on a VAS after 24 months in the strontium ranelate group compared to the placebo group (MD -0.70 cm (95% CI -1.30 to -0.10); the authors considered this measure representative of improved QOL.  The authors concluded that bisphosphonates may increase BMD at the femoral neck, lumbar spine, and fore-arm compared to placebo after 2 years' therapy.  Zinc supplementation probably increases BMD at the lumbar spine and hip after 12 months.  Denosumab may make little or no difference to BMD, and these researchers were uncertain regarding the effect of strontium on BMD.  They recommended further long-term RCTs on different bisphosphonates and zinc supplementation therapies in individuals with beta-thalassemia-associated osteoporosis.

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References